Quinazolinones as prolyl hydroxylase inhibitors

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

 

Cross-reference to related inventions

This application will require priority on provisional application for U.S. patent number 61/151429, filed February 10, 2009.

The scope of the invention

The present invention relates to certain derivatives of hintlian containing their pharmaceutical compositions and methods for their use for the treatment of pathological conditions, disorders and conditions mediated by the activity of prolylhydroxylase.

Background of invention

Cells respond to hypoxia by activating transcription of genes involved in cell survival, delivery and use of oxygen, angiogenesis, cellular metabolism, regulation of blood pressure, hematopoesis and preservation of tissue. Induced by hypoxia factors (HIF) 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). Describe the three types of factors HIF-a: HIF-1β, HIF-2a and HIF-3a (Scheuermann et al., 2007, Methods Enzymol., 435:3-24). Algae HIFa subunit with HIF-1b forms a functional heterodimeric protein that, 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 the enzymes of 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 makes HIF target for polyubiquitination complex ubiquitin-E3 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 concentrations. Thus, HIF rapidly decomposed under normal conditions of supply of oxygen, but accumulates in the cells under hypoxic conditions or in the inhibition of PHD.

Describes the four isotype 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 isotypes expressed everywhere, but are regulated in different ways and play different physiological roles in cellular responses to hypoxia. There is evidence that different isotypes have different selectivity with respect to three different subtypes HIFa (Epstein et al., see above). Terms of subcellular localization, PHD1 is mainly in the nucleus, PHD2 in the cytoplasm, and PHD3 distributed both in the nucleus and in citpl is the PCA (Metzen E, et al., 2003, J Cell Sci., 116(7):1319-26). PHD2 is the predominant HIFα by prolylhydroxylase in hypoxic conditions (Ivan et al., 2002. Proc Natl Acad Sci. USA, 99(21):13459-64; Berra et al., 2003, EMBO J. 22:4082-90). All three isotype 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 function, and apoptosis/cell proliferation. The first gene, described as a target for HIF, 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 react to 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 protecting tissue cytokine (Arcasoy, 2008, Br J Haematol., 141:14-31). Today, therefore, are expected to participate EPO in the processes of wound healing and angiogenesis, and tissue reaction to ischemic stroke. Most involved in anaerobic glycolysis enzymes encoded HIF target genes, resulting in glycolysis gain is provided 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 breakdown of glucose to pyruvate, such as glucokinase and phosphoglucomutase 1 (Firth et al., 1994, Proc Natl Acad Sci. USA91:6496-6500), 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 the 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 processes of angiogenesis. For example, the growth factor vascular endothelial (VEGF) (Liu et al., 1995, Circ Res., 77(3):638-43) is a known regulator of angiogenesis processes and vasculogenesis. Products HIF target gene are also involved in the regulation of vascular tone and include hemoxygenase-1 (Lee et al., 1997, J Biol Chem., 272(9):5375-81). A number of products regulated HIF genes, such as platelet-derived growth factor (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), also jointly participate in the reaction at the wound healing.

Directed bre is the activity of the enzyme prolylhydroxylase (PHD) using small molecules can be used to treat disorders of perception and distribution of oxygen. Examples of the latter 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; 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 direction of the disturbance activity PHD may find use for the treatment of such metabolic disorders as 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 HIF is a major transcription factor that 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 n what are the advantages in comparison with treatment with erythropoietin. In particular, the functioning of other gene products HIF is necessary for hematopoiesis, and regulation of these factors increases the efficiency of hemopoiesis. Examples of products that are critical for hematopoiesis HIF target gene, 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 inhibiting PHD small molecules have 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 other therapies anemia, including the introduction of iron and (or) exogenous erythropoietin. Research natural PHD2 gene mutations in human populations provide another basis for use of PHD inhibitors in the treatment of anemia. In two recent studies it was 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., 40:16065). In addition, low molecular weight inhibitor PHD was tested in healthy volunteers and patients with chronic kidney disease (Application for U.S. patent US2006/0276477, December 07, 2006). In patients with chronic kidney diseases contents of erythropoietin in the plasma was increased depending on the dose and increase the amount of hemoglobin 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 conditions of ischemia (Semenza, 2007, Biochem J., 405:1-9). Many of the genes encoding involved in anaerobic glycolysis enzymes that are regulated by HIF, and inhibition of PHD increases glycolysis (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 the Krebs cycle. 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 in the composition of cytochromes optimizes the efficiency of ATP production in hypoxia and reduces production is aka harmful by-products of oxidative phosphorylation, as the hydrogen peroxide and the peroxide anion. 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 peroxide anion, when the cell uses mainly glycolysis for energy production. Another adaptive response induced by increased expression of HIF is activated factors in the survival of cells. These factors include the following: insulin-like growth factor (IGF) 2, IGF-binding proteins 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 superoxide, and optimization of oxidative phosphorylation, protecting cells from ischemic damage. Therefore, it is expected that PHD inhibitors can be used for preservation of organs and tissues for transplantation (Bernhardt et al., 2007, Methods Enzymol., 435:221-45). Although beneficial effects may be obtained by the introduction of PHD inhibitors before collection of organs for transplantation, the introduction of the inhibitor directly into the organ/tissue after harvesting, during storage (for example, cardioplegic solution) or after transplantation, t is the train can have a therapeutic effect.

It is expected that PHD inhibitors will be effective to protect fabrics from local ischemia and / or hypoxia, including ischemia/hypoxia related, 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 increased expression of HIF is a possible method of conservation of ischemic tissue. Recently it has been shown that ischemic preconditioning is HIF-dependent phenomenon (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., 18:1218-26). Despite the fact that the concept of preconditioning is most known for its protective effects on the heart, it also applies to other tissues, including, without limitation, the following: liver, skeletal muscle, lungs, kidneys, 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 of protection is its action on the tissues of PHD inhibition and increased HIF obtained in several animal models, including: nokautiroval germline PHD1 that ensured the protection of skeletal muscle from ischemic stroke (Aragones et al., 2008, Nat Genet., 40(2):170-80), off PHD2 by applying miRNAs that ensured the protection of the heart from ischemic stroke (Natarajan et al., 2006, Circ Res., 98(1):133-40), inhibition of PHD by introducing carbon monoxide, which ensured the protection of 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 increases the tolerance to ischemia (Bernaudin et al., 2002, J Cereb Blood Flow Metab., 22(4):393-403). In addition, low molecular weight inhibitors PHD protect 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 of mice with diabetes, where the results are usually worse (Natarajan et al., 2008, J Cardiovasc Pharmacol., 51(2):178-187). Effects of tissue protection can also be observed obliterative obliterans (Buerger's disease), symmetrical gangrene (Raynaud's disease) and acrocyanosis.

Reducing dependence on aerobic metabolism, Krebs cycle in the mitochondria and the role of 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 the expression of HIF under conditions of normal oxygen supply. Thus inhibition of PHD causes pseudogobio, caused initiated by hypoxic HIF response, but when this tissue oxygenation remains normal. You can also expect that due to the inhibition of PHD restructuring of metabolism will allow you to implement a method of treatment of diabetes, obesity and related disorders, including co-morbidities.

In General, the aggregate caused by PHD inhibition of gene expression changes 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 with those effects, which may be useful in the treatment of diabetes and obesity. So, it is well known that training at high altitude reduces the amount of fat in the body (Armellini et al., 1997, Horm Metab Res., 29(9):458-61). It is shown that hypoxia mimic hypoxia substances such as desferrioxamine, prevents differentiation into adipocytes (Lin et al., 2006, J Biol Chem., 281(41):30678-83; Carriere 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). G is poxia, the cobalt chloride and desferrioxamine increase the expression of HIF and inhibit transcription by nuclear hormone receptors PPAR gamma 2 (Yun et al., 2002, Dev Cell., 2:331-41). Because PPAR gamma 2 is an important signal for differentiation into adipocyte, it should be expected that inhibition of PHD will be to inhibit differentiation to adipocytes. It was shown that these effects are mediated by regulated HIF gene DEC1/Stra13 (Yun et al., see above).

It is shown that small molecule inhibitors PHD exert therapeutic effects in animal models of diabetes and obesity (proc. 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 rats Zucker fa/fa included the reduction of the following: concentration of glucose in the blood, body fat mass, as in abdominal and visceral fat, the concentration of hemoglobin A1c, triglycerides in plasma, body weight, and changes in concentrations of known biomarkers of disease, such as increased levels adrenomedullin and leptin. Leptin is a famous product of the target gene HIF (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, it should be regulated by inhibition of PHD HIF-dependent manner (international patent application WO2004/052285, see above). Such products there are: apolipoprotein A-IV, acyl-CoA-thioesterase, carnitine-transferase and binding insulin-like growth factor protein (IGFBP)-1.

It is expected that PHD inhibitors may be therapeutically effective as stimulants vasculogenesis, angiogenesis 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 the expression of 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 endothelium) is a well-known product HIF target gene, which is a key factor in angiogenesis (Liu et al., see above). Despite the fact that the introduction of various forms of activators of the receptor VEGF is a potent stimulus of angiogenesis resulting from this potential method of treatment of blood vessels are leaky. It is believed that this limits the possibility of using VEGF for the treatment of disorders of oxygen delivery. The increased expression of a single angiogenic factor may be insufficient for functional vascularization (Semenza, 2007, see above). Potentially the e benefits of PHD inhibition in comparison with other similar methods angiogenic therapy consists in stimulating the controlled expression of multiple angiogenic growth factors HIF-dependent manner, including, without limitation, the following: placental 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 process of angiogenesis leads to the formation of dense blood vessels, unlike blood vessels, resulting in the introduction 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(19):2520-32). It was shown that the growth factor stromal cells 1 (SDF-1) is extremely important for the activation of 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 of 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 in adult mice involving precursors of endothelial cells to sites of injury is reduced, and this may be offset by interventions that increase HIF activity at the wound site (Chang et al., 2007, Circulation, 116(24):2818-29). Inhibition of PHD is AET benefits not only by increasing the expression of a number of angiogenic factors, but also through the coordination of their expression during the whole process of angiogenesis and recruitment of precursors of endothelial cells to ischemic tissue.

Evidence of the applicability of PHD inhibitors in Pro-angiogenic therapy are presented in the following studies. It was shown that mediated by adenovirus increased expression of HIF induces angiogenesis in noiselessly tissue of adult animals (Kelly et al., 2003, Circ Res., 93(11):1074-81), suggesting that therapy with increased expression of HIF, such as inhibition of PHD, will cause the development of blood vessels. It has been shown that placental growth factor (PLGF), which is also a target gene of HIF plays an important role in angiogenesis 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 therapy with increased expression of HIF by increasing the expression of 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 by the product of the target gene HIF SDF-1 (Abbott et al., 2004, Circulation, 110(21):3300-05). These results support the General concept that PHD inhibitors will be effective to stimulate angiogenesis in ischemic tissues tissues, including ischemia of the muscles. It is expected that due PHD inhibitors therapeutic development of blood vessels is 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, intermittent claudication, stomach ulcers and duodenal ulcers, ulcerative colitis and inflammatory bowel disease.

PHD and HIF plays a Central role in the restoration and regeneration of tissues, including the healing of wounds and ulcers. Recent studies have shown increased expression of all three types of PHD at the places wounds in adult mice and, as a result, a reduction in the accumulation of HIF (Chang et al., see above). Thus, the increased expression 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, the increased expression of HIF was suppressed compared with mice of the same litter without diabetes (Mace et al., 2007, Wound Repair Regen., 15(5):636-45). Local application of the simulator hypoxia of cobalt chloride or increased expression of murine HIF missing the oxygendependent degradation domain (ODD), which thus provides a constantly active form of HIF leads to increased activity of HIF in the wound, increasing the structure of the 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 small molecule inhibitors PHD also give a positive result in mice with colitis (Robinson et al., 2008, Gastroenterology, 134(1):145-55).

It is assumed that lead to the accumulation of HIF inhibition of PHD includes at least four mechanisms of action, each of which contributes to faster and more complete healing of wounds: 1) fabric protector susceptible to hypoxia and / or ischemia, 2) stimulation of angiogenesis 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 growth factors that specifically stimulate healing and regeneration.

Recombinant human platelet-derived growth factor (PDGF) sold under the name becaplermin (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 expression of endogenous PDGF and will provide similar or more pronounced favorable effect compared with the effect of taking only becaplermin. Animal studies have shown that topical application of PDGF increases the amount of DNA, protein and hydroxyproline in the wound, forming a thicker layer of granulation and epidermal tissue, increased cellular secondary colonization of faults. PDGF causes 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, due to the additional effect of protection fabric and Pro-angiogenic effect, mediated by the HIF.

It is expected that the beneficial effects of inhibition of PHD will apply not only to accelerate wound healing of the skin and 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 the inside of the body, and hypoxia regulates their differentiation and the fate of the cells (Simon et al., 2008, Nat Rev Mol Cell Biol., 9:285-96). Thus, the PHD inhibitors can be used to maintain stem cells and precursor cells in a pluripotent state and stimulate differentiation into cells of a desired type. Stem cells can be used for the cultivation and growth of populations of stem cells and can hold cells in a pluripotent state, while in cells injected with hormones and other factors for the correction of differentiation and cell fate.

Continued use of PHD inhibitors in therapy of stem cells and precursor cells 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 to generate a corresponding reaction of the organism, resulting in the implantation of stem cells and the cells of the predecessor will become 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. These formed blood vessels will also be a transfer of hormones and other liberated these cells factors in the rest of the body./p>

The PHD inhibitors may also find application in the treatment of infections (Peyssonnaux et al., 2005, J Invest Dermatol., 115(7):1806-15; Peyssonnaux et al., 2008 J Invest Dermatol., August 2008; 128(8):1964-8). It was shown that the increased expression of HIF enhances the innate immune response to infection in phagocytes and keratinocytes. Phagocytes with an increased level of HIF demonstrate higher bactericidal activity, increased production of nitric oxide and increased expression of antimicrobial 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., 2003 J Cell Sci., 116(Pt 9):1819-26., Wang et al., 2007 J 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 recovery process of the bone.

The literature describes some small molecules c antagonistic activity against prolylhydroxylase. Such molecules include, among others, some of the producers who by imidazo[1,2-a]pyridine (Warshakoon et al., 2006, Bioorg Med Chem Lett., 16(21):5598-601), substituted derivatives of pyridine (Warshakoon et al., 2006, Bioorg Med Chem Lett., 16(21):5616-20), some pyrazolidine (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 derivatives of glycine (international patent application WO2007/150011, December 27, 2007), substituted aryl - or heteroelement connection (Application for U.S. patent US 2007/0299086, December 27, 2007) and substituted 4-hydroxypyrimidine-5-carboxamide (international patent application WO2009/117269, 24 September 2009).

However, there remains a need for effective modulators of prolylhydroxylase with the desired pharmaceutical properties. It was found that in the context of the present invention, some derivatives of hintlian have modulating prolylhydroxylase activity.

Brief description of the invention

The present invention relates to compounds that can be used as inhibitors of PHD. The compounds forming the subject of the present invention have the General formula (I),

where:

n=0 to 3,

R1is a Deputy,is independently selected from the group consisting of halogen, -C1-4of alkyl, -C1-4the quinil, -C1-4alkenyl, optionally substituted with halogen, -CF3, -OCF3, -SCF3, S(O)CF3, -C(O)-Rc, -C(O)N-Rc, -OH, -NO2, -CN, -OC1-4of alkyl, -SC1-4of alkyl, -S(O)-C1-4of alkyl, -SO2-C1-4of alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2N-Rc, -O-Rc, -NRaRb, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxole, 1H-indole, benzyl, biphenyl, optionally substituted by one or more Rd, benzyloxy, optionally substituted by one or more Rd, phenyl or monocyclic heteroaryl, optionally substituted by one or more Rd, -C3-8cycloalkyl, optionally substituted by one or more Rd, -C3-8geterotsiklicheskie, optionally substituted by one or more Rcand two adjacent groups R1can be connected in the form of an optionally substituted 3-8-membered cycle, optionally substituted by one or more O, S or N;

Raand Rbindependently selected from the group consisting of H, C1-4of alkyl, -C(O)C1-4of alkyl, -C(O)-Rc, -C(O)NH-Rc, -SO2-Rc, -SO2-C1-4of alkyl, phenyl, optionally substituted by Rd, benzyl, optionally substituted by Rdor monocyclic aromatic heterocycle, optionally umestnogo R d; or Raand Rbalong with carrying their nitrogen atom form an optionally substituted monocyclic heteroseksualci containing one or more O, S or N;

Rcis a Deputy, is independently selected from the group consisting of-C3-8cycloalkyl, -C3-8geterotsiklicheskie, biphenyl, phenyl, optionally substituted by one or more Rd, benzyl, optionally substituted by one or more Rd, naphthyl, indanyl, 5,6,7,8-tetrahydronaphthyl and pyridyl, optionally substituted by one or more Rd;

Rdis a Deputy, is independently selected from the group consisting of-H, halogen, -OH, -C1-4of alkyl, -SO2-C1-4of alkyl, -CN, or-CF3, -OCF3, -OC1-4of alkyl, -C(O)NH2, -O-phenyl and -- O-benzyl;

and their pharmaceutically acceptable salts.

The present invention also includes isomeric forms of the compounds of formula (I) and their pharmaceutically acceptable salts, and reference in this application to one of such isomeric forms indicates a reference to at least one of such isomeric forms. Specialist in this field will determine 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.

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

The following General aspect, the present invention relates to pharmaceutical compositions, each of which includes: (a) an effective amount of the compounds of formula (I) or its 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 treating a patient with existing or diagnosed disease, disorder, or medical condition mediated by the activity of the enzyme prolylhydroxylase, which consists in the introduction in need of such treatment to the patient an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite.

In some preferred embodiments, the implementation process which is the subject of the present invention, the said disease, disorder or medical condition selected from: the nemai, vascular diseases, metabolic disorders and wound healing.

Additional implementation options, features and advantages of the invention will become clear from the following detailed description of the invention and its practical application.

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, the contents of all cited in this application publications, including patents, are included in the present description by reference.

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

Used in this application, the term "alkyl" refers to alkyl group with a linear or branched chain containing from 1 to 12 carbon atoms. Examples of alkyl groups include methyl (Me, which also may be structurally marked with the symbol "/"), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl and groups that in light of the common knowledge and described in this application views can be considered equivalent to one of the above examples.

Used in this application, the term "alkenyl" refers to Elke the strong group with a linear or branched chain, containing from 2 to 12 carbon atoms. (The double bond alkenylphenol group formed between two sp2-hybridized carbon atoms.) Typical examples alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, Gex-2-enyl and other similar groups.

Used in this application, the term "quinil" refers to alkenylphenol group with a linear or branched chain containing from 2 to 12 carbon atoms. (Triple bond alkenylphenol group formed between the two sp-hybridized carbon atoms.) Typical examples etkinlik groups include prop-2-inyl, but-2-inyl, but-3-inyl, 2-methylprop-2-inyl, Gex-2-inyl and other similar groups.

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. Typical examples cycloalkyl groups include the following groups in the form of appropriately related fragments:

Used in this application, the term "heteroseksualci" refers to monocyclic ring structure that is saturated or partially saturated monocycle or a condensed polycyclic system; heterocyclic the l in the cycle contains 3 to 8 atoms, presents carbon atoms and not more than two heteroatoms, such as nitrogen, oxygen and sulfur. The ring structure may also optionally contain up to two oxoprop attached to the sulfur atoms of the ring. Typical examples geterotsiklicheskikh groups include the following groups in the form of appropriately related fragments:

Used in this application, the term "heteroaryl" means a monocyclic, condensed bicyclic or condensed polycyclic aromatic heterocycle (ring structure, the ring atoms of which are 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. Typical examples of heteroaryl groups include the following groups in the form of appropriately related fragments:

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.

Used in this application, the term "halogen" means chlorine, fluorine, bromine or iodine. And is used in this application, the term "halo" means chloro, fluorine, bromine and iodine.

Used in this application, the term "substituted" means that the specified functional group or a fragment has one or more substituents. Used in this application, the term "unsubstituted" means that the specified group does not have substituents. Used in this application, the term "optionally substituted" means that the specified group or do 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 in any position allowed by valence. In cases where for a particular fragment or group explicitly stated that she is optionally substituted or substituted some specific Deputy, it is understood that such a fragment or group is unsubstituted.

Each of these in this application of the formulas is as connections with the structures shown 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 mentioned General formula, and with whom thou there, considered in this formula. Therefore, any information provided in this application, 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 thereof. In addition, some patterns may exist in the form of geometrical isomers (e.g. CIS - and TRANS-isomers, tautomers or atropisomers. In addition, any information provided in this application, the formula includes a hydrate, solvate and polymorphs of such compounds, and mixtures thereof.

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 or 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) and 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. In other embodiments, the implementation of 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 resembles the EIT is to be placed. 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 stated, all cited in percent concentrations are related to mass ratios.

The mention of chemical structural units in this 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 from any other page is tournoi unit, which give R-COO-when 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) of such structural units 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 agents 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, is that choice in any way is not a limitation and was done 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, solvation, 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 against Apolonia characters. 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, zwitterionic connection, inner 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 is described in this application formula is also as unlabeled, 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 present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,15N18O,17O,31P,32P,35S18F,36Cl125I, respectively. Such labeled isotopes connection can be used for studies of metabolism (preferably14C)studies of the kinetics of reactions (for example, with2H or3H), methods of detecting or receiving images [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)], including quantitative analyses of the distribution of the 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), can give Oprah Lennie therapeutic benefits due to the greater metabolic stability of the compounds, for example, increased half-life in vivo or reduce the required dosage. Isotopically labeled compounds of the present invention and their prodrugs can, in General, be obtained by the procedures described below, schemes or examples and methods of obtaining, by replacing containing no tracer reagent on readily available reagent labeled with atoms.

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 S2examplerepresents the S3; S1examplerepresents the S2and S2examplerepresents the S4; and is equivalent to each of these sets of deputies. Therefore, to kratkoeizlozhenie without limiting the generality of the present application uses the abbreviated terminology: "S 1examplerepresents 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 principle denote substituents extends, when applicable, on such groups as R1, R2, A, X4X5X6X7, Ra, Rb, Rc, Rd, Re, Rfand Rgand any other General symbolic notation of the substituents used in the present application.

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 denote substituents 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; Sexamplepre is is a S 2; 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 principle denote substituents extends, when applicable, on such groups as R1, R2, A, X4X5X6X7, Ra, Rb, Rc, Rd, Re, Rfand Rgand any other General symbolic notation of the substituents used in the present application.

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 indie is idealno 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 replaceable 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 that PR is the presence of a chemical sense, and unless otherwise stated, 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 present invention includes the use of compounds of formula (I),

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

The present invention describes a compound of formula (I), where n is from 0 to 3, and R1independently represent halogen, hydroxyl, alkyl, alkenyl, quinil, alkoxy, thioalkyl, alkyl sulfoxide, alkyl sulfon, optionally substituted 3-8 membered aliphatic, aromatic or heterocyclic fragments, amino, alkylamino, alkylsulfonyl, arylsulfonyl, nitro, cyano, -SCF3

In the following preferred embodiments, the implementation of n is from 1 to 2, R1independently represents halogen, alkyl (C1-4with a linear or branched chain, triptoreline group with a linear or branched chain C1-4, triptorelin group with a linear or branched chain C1-4or monocyclic saturated or partially saturated C3-8carbocycle.

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

In some other preferred embodiments, n=2, and R1independently represents halogen, C1-4alkyl, -CF3, -OCF3replaced phenoxy and optionally substituted 3-8 membered aromatic carbocycle.

In the following preferred embodiments, the implementation of n is 1, and R1represents an optionally substituted, phenoxy-group containing from one to three halogen; -C1-4alkyl or C1-4alkoxy group; phenylsulfonyl, optionally substituted from one to three halogen; -C1-4lkyl or-C 1-4alkoxy group; cyclohexyl; chlorine; fluorine; iodine; -OCF3and-CF3.

In some other preferred embodiments, the implementation of one to three R1independently selected from the group consisting of chlorine, fluorine, bromine, iodine, -NO2, -OH, -CF3, -CH3, -CH2CH3, -CH2CH2CH3, -OCF3, -OCH3, -OCH2CH3, -SCH3, -SCF3, -S(O)CF3, -SO2CH3, -NH2, -N(CH3)2, -NH(CH2CH3), cyano, isopropoxy, isopropyl, sec-butyl, tert-butyl, ethinyl, 1-chloride, 4-methylpiperazine, morpholine-4-yl, pyrrolidinyl, pyrrolidin-1-carbonyl, piperidinyl, phenyl, benzyl, diphenyl, talila, phenoxy, cyclopropyl, cyclohexyl, phenylsulfanyl, 3,4-dimethoxyphenylacetone, 4-tert-butylphenylmethyl, 7 piperidinyl, 2,6-dimethylphenoxy, 3,4,5-trimethoxyphenol, naphthalene-1-yloxy, naphthalene-2-yloxy, 5,6,7,8-tetrahydronaphthalen-1 iloxi, indan-5-yloxy, 3 chlorophenoxy, 4-chlorophenoxy, 2,3-dichlorophenoxy, 3 methoxyphenoxy, 4-fervency, 2-fervency, 3 fervency, 3,5-di-tert-butylphenoxy, 3 methylphenoxy, 2,6 - dichlorophenoxy, 2,5-dichlorophenoxy, 4-methoxyphenoxy, pyridine-3-yloxy, tetrahydropyran-4-yl, 3,4-dihydro-1H-isoquinoline-2-yl, 7-bromo-3, 4-dihydro-1H-isoquinoline-2-yl, 3-methoxyphenylpiperazine and benzosulfimide.

In the following preferred valentinorossini n=1.

In the following preferred embodiments, the implementation of n=2.

In the following preferred embodiments, the implementation of n=3.

In the following the preferred options for implementation-RaRbindependently selected from the group consisting of-H, -CH3, -CH2CH3, benzoyl, 2,6-dimethylbenzoyl, acetyl-C(O)NH-phenyl, benzosulfimide, methanesulfonyl, benzyl, 2-methylbenzyl, 2-Chlorobenzyl, 2,6-dimethylbenzyl, 2,6-diferenzia, 2-cyanobenzyl, 3-cyanobenzyl, 3-carbamoylmethyl, 2,6-dichlorobenzyl, 3-Chlorobenzyl and 4-methylbenzyl.

In the following preferred embodiments, the implementation of Raand Rbalong with carrying their nitrogen atom may form an optionally substituted N-methylpiperazin-1-yl, 3,4-dihydro-1H-isoquinoline-2-yl, piperidine, morpholine-4-yl and pyrrolidinyl.

In the following preferred embodiments, the implementation of Rcindependently selected from the group consisting of phenyl, cyclohexyl, 4-tert-butylphenyl, 3,4-acid, 2,6-dimetilfenil, 3,4,5-trimethoxyphenyl, naphthalene-1-yl, 3-chlorphenyl, 4-chlorphenyl, 3-methoxyphenyl, 4-ftoheia, 2-ftoheia, 3-ftoheia, 3,5-di-tert-butylphenyl, 4-oxo-6-m-tolila, 4-oxo-6-o-tolila, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 4-methoxyphenyl, 2,6-dimetilfenil, naphthalene-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 4-chlorphenyl, p-tolila, indan-5-yl, 2,3-dihl is Hanila and pyridine-3-yl.

In the following preferred embodiments, the implementation of Rdindependently selected from the group consisting of-H, chlorine, fluorine, bromine, iodine, -C1-4of alkyl, -CF3, -OCF3, -OC1-4of alkyl, phenyl, -O-phenyl or O-benzyl.

In some preferred embodiments of the invention the compounds of formula (I) selected from the group consisting of the following compounds:

ExampleChemical name
11-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
21-(7-trifluoromethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;

31-(6,7-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
41-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
51-(6,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
61-(5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-piraso the-4-carboxylic acid;
71-(8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
81-(6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
91-(8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
101-(7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
111-(8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
121-(6-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
131-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
141-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
151-(4-oxo-6-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
161-(4-oxo-8-trifluoromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid is;
171-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
181-(5,6,7-trimetoksi-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
191-(6-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;

201-(4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
211-(6-cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
221-(7-chloro-4-oxo-8-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
231-(1-oxo-2,7-dihydro-1H-pyrrolo[3,2-f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid;
241-[6-(4-tert-butylphenylmethyl)-7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
251-(7-chloro-4-oxo-6-phenylsulfonyl-1,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid is the same;
261-[7-chloro-6-(3,4-dimethoxyphenylacetone)-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
271-[6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
281-[4-oxo-6-(3,4,5-trimethoxyphenyl) -3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
291-[6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
301-[6-(3-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
311-[6-(3-methoxyphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
321-[6-(4-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
331-[6-(2-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
341-[6-(3-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
351-[6-(3,5-di-tert-butylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
361-(4-oxo-6-m-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
371-(4-oxo-6-o-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-

pyrazole-4-carboxylic acid;
381-[6-(2,6-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
391-[6-(2,4-dichlorphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
401-[6-(2,5-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
411-[6-(4-methoxyphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
421-[6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
431-[6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydrobenzo the Jn-2-yl]-1H-pyrazole-4-carboxylic acid;
441-[4-oxo-6-(5,6,7,8-tetrahydronaphthalen-1 yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
461-[6-(4-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
471-(4-oxo-6-p-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
481-[7-chloro-6-(4-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
491-[7-chloro-6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
501-[6-(2,6-dichlorophenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
511-[6-(2,6-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
521-[7-fluoro-6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
531-[7-chloro-6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic Ki the lot;
541-[7-chloro-6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
551-[7-chloro-4-oxo-6-(5,6,7,8-tetrahydronaphthalen-1 yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-

carboxylic acid;
561-[7-fluoro-6-(3-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
571-[7-fluoro-6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
581-[7-fluoro-6-(indan-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
591-(7-methyl-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
601-[6-(2,3-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
611-[6-(2,6-dimethylphenoxy)-7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
621-(7-methoxy-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
631-[6-(2,6-dimethylphenoxy)-5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
641-(5,7-debtor-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
651-[4-oxo-6-(pyridine-1-yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
661-(4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
67salt of 1-[4-oxo-7-(tetrahydropyran-4-yl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid and Tris(hydroxymethyl)aminomethane;
681-(7-chloro-4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
691-(4-oxo-6-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
701-(6-diphenyl-3-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
71 1-[7-chloro-6-(3,4-dimethoxybenzonitrile)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
721-[6-(4-tert-butylbenzenesulfonyl)-7-chloro-4-oxo-3,4-

dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
731-(7,7-dimethyl-4-oxo-3,7-dihydro-4H-8-oxa-1,3-vasantrao-2-yl)-1H-pyrazole-4-carboxylic acid;
741-(4-oxo-6-phenoxymethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
751-[6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
761-(6-ethinyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
771-[6-(1-vinyl chloride)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
781-(4-oxo-7-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
791-[7-(4-chlorophenylsulfonyl)-4-oxo-3,4-dihydr hinzelin-2-yl]-1H-pyrazole-4-carboxylic acid;
801-[7-(2-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
811-(7-benzazolyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
821-[7-(4-chlorobenzenesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
831-[7-(2-chlorobenzenesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
841-[7-chloro-6-(3,4-dihydro-1H-isoquinoline-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
851-[6-(7-bromo-3,4-dihydro-1H-isoquinoline-2-yl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
86(rac)-1-{7-chloro-6-[3-(3-methoxyphenyl)-piperidine-1-yl]-4-oxo-3,4-dihydroquinazolin-2-yl}-1H-pyrazole-4-carboxylic acid;
871-[6-(2,5-dichlorophenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;

88 1-[6-(3,4-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
891-[6-(3,5-dimethylphenoxy)-7-methyl-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
901-[6-(2,5-dichlorophenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
911-[6-(diphenyl-3-yloxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
921-[6-(3,4-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
931-[7-methyl-4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
941-[6-(3,5-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
951-[7-fluoro-4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
961-[6-(2-fluoro-3-triptoreline)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
971-[6-(3-fluoro-5-triptoreline)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
981-[6-(3,5-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
991-[6-(diphenyl-3-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1001-[4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1011-[6-(2,6-dichlorophenoxy)-5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1021-(6-cyclohexyloxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1031-[6-(4-methylpiperazin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1041-(6-isopropoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;

1051-(6-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid is;
1061-(4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1071-(6-morpholine-4-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1081-[6-(1H-indol-6-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1091-(6-cyclopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1101-(6-cyclohexyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1111-(4-oxo-8-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1121-(4-oxo-8-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1131-(4-oxo-8-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1141-(8-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1151-(8-tert-butyl-4-oxo-3,4-Digi rohinton-2-yl)-1H-pyrazole-4-carboxylic acid;
1161-(5,8-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1171-(4-oxo-8-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1181-(8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1191-(6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1201-(6-sec-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1211-(6-ethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;

1221-(6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1231-(4-oxo-6-pyrrolidin-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1241-(4-oxo-6-piperidine-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
125 1-(6-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1261-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1271-(6-bromo-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1281-(6-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1291-(4-oxo-6-propyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1301-(6-bromo-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1311-(5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1321-(5,7-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1331-(7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1341-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
135 1-(7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1361-(7-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1371-(4-oxo-3,4,8,9-tetrahydro-7H-6,10-dioxo-1,3-disallowable[b]naphthalene-2-yl)-1H-pyrazole-4-carboxylic acid;
1381-(8-oxo-2,3,7,8-tetrahydro-1,4-dioxa-5,7-diazapentane-6-yl)-1H-pyrazole-4-carboxylic acid;

1-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid; 154
1391-(4-oxo-3,4,7,8-tetrahydro-[1,4]like[2,3-g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1401-(4-oxo-4,6,7,8-tetrahydro-3H-cyclopent[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1411-(6-oxo-2,3,6,7-tetrahydro-1H-7,9-disallowment[a]naphthalene-8-yl)-1H-pyrazole-4-carboxylic acid;
1421-(4-oxo-3,4,7,8,9,10-hexahydrobenzo[h]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1431-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
144
1451-(5,7-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1461-(7-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1471-(7-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1481-(4-oxo-7-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1491-(7-isopropoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1501-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1511-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1521-(7-ethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1531-(6-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-hydroxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1551-(6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;

1561-(4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1571-(6-methanesulfonyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1581-(7-chloro-6-methanesulfonyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1591-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1601-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1611-[4-oxo-6-(pyrrolidin-1-sulfonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1621-[4-oxo-6-(pyrrolidin-1-carbonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazol-carboxylic acid;
1631-[6-(2,6-dimethylphenylcarbamate)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1641-(6-nitro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid
1651-(6-benzoylamine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1661-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1671-(6-acetylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1681-[4-oxo-6-(3-phenylurea)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1691-(6-benzosulfimide-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1701-(6-methanesulfonamido-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1711-(6-benzylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
172 1-(6-ethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;

1-[6-(2,6-dichlorobenzamide)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1731-[6-(2-methylbenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1741-[6-(2-chlorobenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1751-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1761-[6-(2,6-diferentiating)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1771-[6-(2-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1781-[6-(3-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1791-[6-(3-carbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1801-(6-amino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
181
1821-[6-(3-chlorobenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1831-[6-(4-methylbenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1841-(4-oxo-7-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1851-[7-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1861-[7-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1871-[7-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1881-(4-oxo-7-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1891-(4-oxo-7-m-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;

1901-(4-oxo-6-m-tolyl-3,4-di is hydrogenation-2-yl)-1H-pyrazole-4-carboxylic acid;
1911-(4-oxo-6-p-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1921-[6-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1931-[6-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1941-[6-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1951-[6-(2-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1961-[6-(3-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1971-[6-(4-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1981-[6-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1991-[6-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
2001-[6-(4-methoxyphenyl)-4-the CSR-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
2011-[4-oxo-6-(2-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
2021-[4-oxo-6-(2-trifloromethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
2031-[6-(2-ethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
2041-[6-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
2051-[4-oxo-6-(3-trifloromethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
2061-[6-(3-methanesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;

2071-(6-benzo[1,3]dioxol-5-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
2081-(7-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
2091-(6-benzosulfimide-7-chloro-4-oxo-3,4-dihydrogen the Olin-2-yl)-1H-pyrazole-4-carboxylic acid;
2101-(6-benzazolyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; and
2111-(4-oxo-6-piperidine-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

and their pharmaceutically acceptable salts.

The present invention also includes pharmaceutically acceptable salts of compounds of formula (I), preferably those described above, and of those of these compounds, examples of which are shown in this application, and methods of treatment using such salts.

Used in this application, 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, in General, 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, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts include pharmacologically effective salts that may come into contact with the patient's tissue without causing unacceptable toxicity, irritation is whether 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, pyrosulfite, 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 basic nitrogen atom, the desired pharmaceutically acceptable salt may be obtained by any appropriate known method, including the following methods: processing free the aqueous base inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and so forth, or an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleimide acid, setinova acid, 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 tartaric 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 presented in this application as examples, and any other acid or a mixture of such is the x, 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 obtained by any appropriate method, including the following: treatment of the free acid inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, alkali earth metal hydroxide, any compatible mixture of bases, such as described in this application 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. Typical examples of these salts include organic salts derived from amino acids such as N-methyl-D-glucamine, lysine, choline, glycine, and arginine, ammonium salts, carbonates, bicarbonates, salts of primary, secondary and tertiary amines, and cyclic amines, such as tromethamine, benzylamine, pyrrolidine, piperidine, morpholine and piperazine, and inorganic salts - derivatives of sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Examples of prodrugs include compounds having aminokislotnyj residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently linked by an amide or ester bond with the free amino, hydroxy or carboxy group in 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, when using the free carboxyl groups of the formula (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. Secondary amines include fragments with a 5 - or 6-membered heteroseksualnymi or heteroaryl ring. Examples of amides include derivatives of ammonia, primary C1-3alkylamines followed and di(C1-2alkyl)amines. Examples of esters of the present invention include C1-7alkyl, C5-7cycloalkyl, phenyl and phenyl(C1-6alkyl) esters. Preferred esters include methyl esters. Prodrugs can also be obtained by fuctionalization of free hydroxyl groups to obtain samisen the x derivative, including hemisuccinate, phosphate esters, diethylaminoacetate and phosphorylethanolamine, following the procedures described in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130. To obtain prodrugs can also be used urethane derivatives of hydroxyl and amino groups. To obtain prodrugs can also be used carbonate derivatives, sulphonate esters and sulfate esters of hydroxy groups. 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, optionally substituted by 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 obtained in accordance with the description given in Robinson et al., J Med Chem. 1996, 39 (1), 10-18. Free amino groups can also be used 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 groups, amino groups and carboxyl groups.

The present invention also relates to pharmaceutically active metabolites of compounds of formula (I), which can also be is used in the methods of the present invention. Used in this application, the term "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, the work of 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 can find use as modulators PHD in methods of the present invention. The term "modulators" include both inhibitors and activators, where "inhibitors" refers to compounds that decrease, prevent, inactivate, desencibiliziruta or regulate the expression or activity of PHD in the fall, and "activators" refers to compounds that increase, activate, facilitate, sensibiliser or regulate the expression or activity of PHD on the increase.

Used in this application, the terms "treat" or "treatment" refer to the introduction of the active AG of the NTA or compounds 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 mediated by modulation of the activity of PHD. Used in this application, the term "patient" refers to a mammalian patient in need of such treatment, for example to man.

Accordingly, the present invention relates to methods described in the present application of the compounds for the treatment of those patients diagnosed mediated by prolylhydroxylase disease, disorder or condition, such as anemia, cardiovascular disorders, metabolic disorders and wound healing. Symptoms of pathological conditions means included in the scope of the concept of "medical condition, disorder or disease."

Used in this application, the term "hypoxia" or "hypoxic disorder" 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), lack of the enough blood flow to the tissue and / or organ, the cause is 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 malfunctioning cells are unable to use oxygen properly (i.e. gistologicheskoe state). Accordingly, the person skilled in the art determines that the present invention may find application in the treatment of various hypoxic conditions, including anemia, heart failure, ischemic heart disease, thromboembolism, stroke, angina and the like.

In a preferred embodiment, the molecules constituting the present invention can find use for the treatment or prevention of anemia, including the treatment of anemic conditions associated with such diseases as chronic kidney disease, polycystic 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, nocturnal paroxysmal hemoglobinuria is, 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 nanamica patients undergoing surgical treatment, anemia associated with or caused by trauma, sideroblastic anemia, anemia, resulting from any treatment, including the use of inhibitors revertase for the treatment of HIV or corticosteroid hormones, cyclic chemotherapy cisplatin-containing or cisplatin-nesteriak drugs, Vinca alkaloids, inhibitors of mitosis inhibitors topoisomerase II, anthracyclines, alkylating agents, in particular, anemia, resulting from inflammation, aging, and (or) chronic diseases. Inhibition of PHD may also find use for the treatment of symptoms of anemia, including chronic fatigue, pallor and dizziness.

In another preferred embodiment, the molecules constituting the present invention can find use for the treatment or prevention of diseases, metabolic disorders, including, without limitation, diabetes, and obesity. In another preferred embodiment, implemented what I molecules, forming the subject of the present invention can find use for the treatment or prevention of vascular disorders. The latter include, without limitation, 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 the methods of treatment that are the subject of the present invention, the effective amount of the pharmaceutical agent in accordance with the present invention is administered to a patient with an existing or diagnosed disease, disorder or condition. Used in this application, the term "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 clinical 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 is its treatment of the patient, health status 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 a day). For a person weighing 70 kg typical dosage range 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 long-term intermittent treatment.

In addition, the agents of the present invention can be used in combination with an additional active component is customers to ensure the above conditions. Such additional compounds can be administered separately from the agent of the formula (I) or to be combined with this agent as an additional active component in the pharmaceutical composition of the present invention. In the variant example of implementation of additional active ingredients are compounds known to be effective for treating conditions, disorders or diseases mediated by the enzyme PHD, or compounds that are active against another target associated with the particular condition, disorder or disease, such as alternative modulator PHD. This combination can be used to improve efficiency (for example, by including in the combination of the compounds that increase the effectiveness or efficiency of the connection in accordance with the present invention), reducing one or more side effects or decrease the required dose of the compounds constituting the subject matter of the present invention.

Compounds of the present invention can be used alone or in combination with one or more other active ingredients for the preparation of pharmaceutical compositions of the present invention. The pharmaceutical composition of the present invention comprises: (a) an effective amount of the compounds of formula (I) or its pharmaceutically p is yimlamai salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite; and (b) pharmaceutically acceptable excipient.

Used in this application, the term "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically acceptable for administration to a patient, such as an inert substance added to a pharmaceutical composition or otherwise used as transport, the carrier or diluent to increase the effectiveness of the compounds of the present invention and is compatible with this connection. Examples of fillers include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Forms of delivery pharmaceutical compositions containing one or more dosage units of a compound of the present invention, can be prepared using appropriate pharmaceutical excipients and methods of preparation, now or in the future known or available to the person skilled in the art. In the methods of the present invention compositions may be administered topically, ocular, oral, parenteral, rectal, and by inhalation. The composition may be in the form of tablets, capsules, sachets, pills, powders, granules, tablets, powders for recovery, liquid preparations or suppositories. Preferably the composition will be prepared for intravenous infusion, 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 achieved using a special catheter balloon for angioplasty or balloon for insertion of the stent.

For oral administration the compounds of the present invention can be prepared 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 present invention, mixed with pharmaceutically acceptable excipients such as inert diluents, substances to improve raspadaemosti tablets, binding agents, lubricants, sweeteners, cusomizable, dyes 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 use include hard and soft gelatin capsules. For the preparation of hard gelatin capsules of the compounds of the present invention can be mixed with solid, semi-solid or liquid diluent. Soft gelatin capsules can be prepared by mixing the compounds of the present invention with water or oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono - and digitzer the species of fatty acids with short-chain, polyethylene glycol 400 or propylene glycol.

Liquid for oral administration can be prepared 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, for example, oils (such as 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, flavorings or colorings.

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 present invention can be represented as sterile is adnych solutions or suspensions, buffered until the corresponding values of pH and isotonicity, or parenterally acceptable oil. Appropriate liquid carriers include ringer's solution and isotonic sodium chloride solution. Such forms can be prepared in the form of a standard single dose, such as ampoules or disposable devices for injection, in the form of a dosage for a few doses, such as bottles, of which there can be selected an appropriate dose, or in solid form or in the form of a concentrate, which can be used to prepare compositions for injection. Typical dosages for intravenous infusion can be in the range of from about 1 to 1000 μg/kg/min connection in a mixture with a pharmaceutical carrier over a period of time from several minutes to several days.

For local application connections can be mixed with a pharmaceutical carrier in a concentration of from about 0.1% to about 10% of drugs in the media. Examples include lotions, creams, ointments, etc. and can be made by known methods. In another way of introducing the compounds of the present invention can be used in the form of a patch for transdermal delivery of active compounds.

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

In this application uses the following abbreviations:

The termReduction
DiisopropylethylamineDIEA
TetrahydrofuranTHF
DichloromethaneDCM
The sulfoxideDMSO
DimethylacetamideDMA
2-(Trimethylsilyl)ethoxymethyleneSEM-Cl

2-MethoxyethoxymethylMEMCl
meta-Chloroperoxybenzoic acidmCPBA
N,N-DimethylformamideDMF
EthanolEtOH
AcetonitrileACN
The ethyl acetateEtOAc
N-(3-Dimethylaminopropyl)-N-ethylcarbodiimideEDCI
N,N'-DiisopropylcarbodiimideDIC
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimideEDAC
Hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylureaHATU
1,8-Diazabicyclo[5.4.0]undec-7-ENDBU
DichloroethaneDCE

Below are examples of compounds that can be used in the methods of the present invention, by reference to the illustrative scheme of synthesis for General receiving and subsequent specific examples. The specialists will determine that for various disclosed in this application connections source reagents can be selected accordingly so that the desired substituents present at the holding of the whole scheme of the reaction in the presence or in the 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 appropriately is as required by the Deputy. Unless otherwise stated, all chemical variables correspond to the definitions above in the description of formula (I). The reaction may be carried out in the temperature range from the melting temperature to the boiling point of the solvent and preferably from 0°C to the boiling point of the solvent. The reaction can also be carried out in a hermetically sealed reactor at a temperature normal boiling point of the solvent.

Scheme A

According to scheme a, compounds of formula (I) are obtained from derivatives of Anthranilic acid (III), where G2represents-OH, -NH2or-OC1-4alkyl, and R1is a Deputy, is independently selected from the group consisting of H, halogen, C1-4of alkyl, CF3drifters1-4alkoxy, -OC1-4the alkyl and-NO2. Various derivatives of Anthranilic acid of General formula (III)are commercially available or obtained in accordance with known methods, compounds, when heated, is introduced into reaction with urea to obtain hinzelin-2,4-diones of the formula (IV). The chlorination of compounds of formula (IV) using known methods or methods described in Bioorganic & Medicinal Chemistry, 2003, 11, 2439-2444, using phosphorus oxychloride (POCl3) in a solvent such as acetonitrile (can also be used auxiliary main EXT is Cai, such as tertiary amines, for example, alkyl substituted anilines or diisopropylethylamine (DIEA)) when heated get dechlorination formula (V). The hydrolysis of compounds of formula (V) using known methods or the methods described in Journal of Medicinal Chemistry, 2007, 50, 2297-2300, using an appropriate base such as aqueous NaOH solution, an aqueous LiOH solution or an aqueous solution of KOH and the like, in a solvent such as THF, gives chlorination formula (VI). To protect chlorination formula (VI) use appropriate protective reagents, such as 2-methoxyethoxymethyl chloride (MEM-Cl)in the presence of a base, such as DIEA, in a solvent such as THF, receiving (VIIaor (VIIb) or their mixture. The substitution of chlorine in the 2-position in compounds of formula (VIIaor VIIbwith the help of various commercially available pyrazole-4-carboxylates of the formula (IX) is carried out in a polar aprotic solvent such as DMF, N,N-dimethylacetamide (DMA) or THF or mixtures thereof, in the presence of an appropriate base, such as Cs2CO3, K2CO3, Na2CO3, NaH or mixtures thereof, at elevated temperature, typically in the range from 80°C to 120°C. the Subsequent removal of the protective group with an acid, such as HCl, in an appropriate solvent, such as ethanol, gives the compounds of formula (VIII). Locnagetro compounds of the formula (VIII) with a suitable base, 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, gives the compounds of formula (I).

Alternatively, the compounds of formula (VI) directly injected into the reaction with a variety of commercially available pyrazole-4-carboxylates of the formula (IX)in a solvent such as xylene, at elevated temperatures, typically in the range from 100°C to 130°C, to obtain the compounds of formula (VIII), excluding, therefore, the use of protective groups. Subsequent alkaline hydrolysis of the compounds of the formula (VIII) an appropriate base, 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, gives the compounds of formula (I).

Scheme B

The compounds of formula (I) also receive the scheme B from an appropriately substituted commercially available or synthesized anilines of the formula (X), (XV), (XVII), (XXVII) or (XXX), which is obtained using known methods or the methods described in scheme C, or methods described in Journal of Organic Chemistry, 2008, 73 (6), 2473-75. According to scheme B, functionalityand anilines of the formula (X), (XV), (XVII), (XXVII) or (XXX) condense with isothioscyanates, such as ethoxycarbonylmethylene, in a solvent such as dichloromethane (DCM), at temperatures from room temperature up to tempera is URS boiling solvent, obtaining the compounds of formula (XXIV). The subsequent combination of compounds of the formula (XXIV) with a commercially available substituted pyrazole-4-carboxylates of the formula (IX)in the presence of agents of combination reaction, such as EDCI, DIC, etc. in the presence or in the absence of a nitrogen base, such as triethylamine, gives the compounds of formula (XI). Cyclization of compounds of formula (XI) in the presence of an appropriate Lewis acid, such as trimethylchlorosilane, chloride titanium (IV) and the like, additives such as 2,6-di-tert-butylpyridinium that can be used or not used, in a solvent such as DCE or DMF, toluene and the like, at temperatures from room temperature up to the boiling point of the solvent gives compounds of formula (VIII). Alkaline hydrolysis of compounds of formula (VIII) an appropriate base, 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, gives the compounds of formula (I). The above scheme can be used a variety of known and commercially available anilines. These schemes also serve as a basis for the synthesis of various intermediate products that are not always commercially available and which can be used to produce compounds that are the subject of the present invention.

Scheme C

Intermediate thioether the formula (XV) are obtained according To the scheme, where HAL represents Cl, I, or F. Commercially available appropriately substituted halogen-nitrobenzol formula (XIII) enter into reaction with substituted alkylsilane or thiophenolate formula (XXVIIIa) in the presence of a base such as DBU in a solvent such as DMF and the like, at temperatures from room temperature up to the boiling point of the solvent, obtaining the intermediate nitro derivative of formula (XIV). The restoration of the nitro group using well-known specialists of ways, for example, zinc dust in the presence of a saturated aqueous solution of NH4Cl, in a solvent such as acetone and the like, gives the intermediate anilines of the formula (XV).

The scheme also receive intermediate ethers of the formula (XVII), where HAL represents F or Cl. Commercially available appropriately substituted halogen-nitrobenzol formula (XIII) enter into reaction with phenols (XXVIIIb) in the presence of a base such as potassium carbonate, in a solvent such as DMSO, DMF, DMA, etc. at a temperature from room temperature up to the boiling point of the solvent, obtaining the intermediate nitro compounds of formula (XVI). The restoration of the nitro group using well-known specialists of ways, for example, zinc dust in the presence of a saturated aqueous solution of NH4Cl in a solvent such as acetone and the like, gives the intermediate anilines of the formula (XVII).

With the EME To receive the intermediate amino compounds of the formula (XXVII). Commercially available appropriately substituted halogen-nitrobenzol formula (XIII), where HAL=Cl, is introduced into reaction with commercially available or synthesized substituted heterocyclisation formula (XXVIIIc) in the presence of a base such as potassium carbonate, in a solvent such as DMSO, DMF, DMA, etc. at a temperature from room temperature up to the boiling point of the solvent, obtaining the intermediate nitro compounds of formula (XXVI). The restoration of the nitro group using well-known specialists of ways, for example, zinc dust in the presence of a saturated aqueous solution of NH4Cl in a solvent such as acetone and the like, gives the intermediate anilines of the formula (XXVII).

The scheme also synthesize intermediate darily formula (XXX). The compounds of formula (XIII), where HAL is a suitable halogen, in the conditions of the Suzuki reaction is introduced into a reaction with a monocyclic aromatic or heteroaromatic boronic acids or esters of formula (XXVIIId), in the presence of an ORGANOMETALLIC catalyst based on transition metal, such as PdCl2(dppf) and the appropriate base, such as CsF, in a solvent such as THF, receiving the intermediate darily formula (XXIX). The restoration of the nitro group using well-known specialists of ways, for example, zinc dust in the presence of nasusunog the aqueous solution of NH 4Cl in a solvent such as acetone and the like, gives the intermediate anilines of the formula (XXX).

Scheme D

Intermediate compounds of formula (XIX) can be obtained according to scheme D. the Interaction of substituted derivatives of 2-amino-4-halogen-benzoic acid of the formula (IIIa), where G1represents-NH2and HAL=Cl or F, with aromatic, heteroaromatic, benzyl - and alkylsilane or alcohols of the formula (XVIII) in the presence of a base, such as K2CO3, NaH and the like, in a solvent such as DMF, allows to obtain an intermediate thioesters or esters of the formula (XIX). When the intermediate compounds of formula (XIX) are thioethers, oxidation of the sulfur atom using oxone, mCPBA or other organic peroxides allows to obtain intermediate sulfones and sulfoxidov formula (XX). Also it may be useful to conduct the oxidation at other stages of the synthesis. The racemic sulfoxidov can be separated at this or at a later stage using known in the art methods, such as chiral chromatography or crystallization, etc. Under the scheme D can also be obtained intermediate compound of formula (XXII). Substituted derivatives of 2-amino-4-halogen-benzoic acid of the formula (III), where G1represents-NH2and HAL represents Cl, Br, or , enter into reaction with otherrFgformula (XXI), where otherrFgis an aromatic, heteroaromatic, benzyl, alkyl - or cycloalkylation, in the presence of a base, such as K2CO3and the like, in a solvent such as DMF or THF, receiving the intermediate amino compounds of the formula (XXII).

Scheme E

The compounds of formula (I)in which Ar1represents optionally substituted phenyl or monocyclic heteroaromatic ring, get on the scheme I.e. the compounds of formula (VIII)in which Y represents the corresponding halogen or triflate, in the conditions of the Suzuki reaction is introduced into a reaction with a monocyclic aromatic or heteroaromatic boronic acids or esters, in the presence of an ORGANOMETALLIC catalyst based on transition metal, such as PdCl2(dppf), and the appropriate base, such as CsF, receiving the intermediate darily formula (XXIII). In addition to the terms Suzuki, can be used other known in the field of combination reaction, such as reaction involving tsinkorganicheskih, ORGANOTIN, magyarkanizsa reagents and other. Alkaline hydrolysis of carboxylic groups pyrazol cycle in the compounds of formula (XXIII) with a suitable base, such as water plants is the PR NaOH, aqueous LiOH solution or an aqueous solution of KOH or a mixture thereof in a solvent such as THF, at temperatures from room temperature to the boiling point of the solvent gives compounds of formula (I).

In addition, hintline formula (VIII) before the reaction mix can be protected with a suitable protective group, for example, using 2-(trimethylsilyl)ethoxymethylene (SEMCl) or 2-methoxyethoxymethyl chloride (MEM-Cl) in the presence of a base, such as DIEA, and the like, in a solvent such as THF and the like, to obtain the compounds of formula (XXXX). Protective group protects the oxygen atom or the nitrogen of hintlian or a mixture of O - and N-protected compounds, as indicated above the dotted lines. Removing the protective group after the reaction combinations (as described above) is carried out using acids such as HCl, in an appropriate solvent, such as ethanol, to obtain the compounds of formula (XXIII). Alkaline hydrolysis of carboxylic groups pyrazol cycle in the compounds of formula (XXIII) with a suitable base, 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 to the boiling point of the solvent gives compounds of formula (I).

Scheme F

The compounds of formula (I) can be polucheniya scheme F. The compounds of formula (XXXI) are oxidized using known reagents such as meta-chlormadinone acid or a complex of urea/hydrogen peroxide and the like, in an appropriate solvent, such as DCE and the like, with the formation of the compounds of formula (XXXII). Get sulfoxidov and sulfones of the formula (XXXII), where m=1 or 2, depending on the stoichiometry of the used oxidizing agent and (or) the reactivity of the substrate. If sulfoxide derived from the enantiomers can be separated using known in the art methods, such as chiral chromatography or classical division. Alkaline hydrolysis of carboxylic groups pyrazol cycleusing the appropriate base, 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 to the boiling point of the solvent gives compounds of formula (I).

Scheme G

The compounds of formula (XXXIV) are obtained according to scheme G. Hintline formula (VIII) protect suitable protective group using 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) or 2-methoxyethoxymethyl chloride (MEM-Cl) in the presence of a base, such as DIEA, and the like, in a solvent such as THF and the like, receiving the connection is of formula (XXXIII). Protective group protects the oxygen atom or the nitrogen of hintlian or a mixture of O - and N-protected compounds, as indicated above the dotted lines. The restoration of the nitro group of compounds of formula (XXXIII) using well-known specialist of ways, for example, zinc dust in the presence of a saturated aqueous solution of NH4Cl, in a solvent such as acetone and the like, gives the intermediate anilines of the formula (XXXIV).

Scheme H

The compounds of formula (XXXVI) are obtained according to scheme G. by Reductive amination khinazolinov formula (XXXIV), using well-known specialist of ways, for example, reaction of compounds of formula (XXXIV) with an appropriate aldehyde of formula (XXXVa) in the presence of a reducing agent such as NaBH(OAc)3, NaBH4or NaCNBH3in a solvent such as 1,2-dichloroethane (DCE) and the like, with possible additives, such as acetic acid or the Lewis acid, receive hintline formula (XXXVI). Subsequent removal of the protective group with an acid, such as HCl, in an appropriate solvent, such as ethanol, followed by alkaline hydrolysis using an appropriate base 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, dataelement formula (I).

Compounds of formula (XXXVII), (XXXVIII) and (XXXIX) are obtained according to scheme G. Hintline General formula (XXXIV) is injected into the reaction mix with commercially available or synthesized by sulphonylchloride formula (XXXVb), anhydrides of acids of the formula ( XXXVc), or isocyanates of the formula (XXXVd), in the presence of a base, such as DIEA, pyridine and the like, in a solvent such as THF and the like, at temperatures from 0°C to 60°C, to form compounds of formula (XXXVII), (XXXVIII) and (XXXIX). Subsequent removal of the protective group with an acid, such as HCl, in an appropriate solvent, such as ethanol, followed by alkaline hydrolysis using an appropriate base such as aqueous NaOH solution, an aqueous LiOH solution or an aqueous solution of KOH or mixtures thereof in a solvent such as THF gives the sulfonamides of the formula (I)amides of the formula (I) and urea of formula (I).

EXAMPLES

Chemistry

Unless otherwise stated, to obtain described in the examples below, compounds and corresponding analytical data 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 xtracta were "concentrated", usually they were concentrated on a rotary evaporator under reduced pressure.

Thin-layer chromatography (TLC) was performed on plates coated with silicagel coating Merck 60 F2542.5 cm x 7.5 cm 250 μm or 5.0 cm x 10.0 cm 250 μm. Preparative thin-layer chromatography was performed on plates coated with silicagel coating EM Science 60 F25420 cm x 20 cm 0.5 mm with concentrating zone 20 cm x 4 see

Unless otherwise stated, normal-phase flash column chromatography (KFH) was performed on silica gel (SiO2), using as eluent a mixture of hexane/ethyl acetate.

Reversed-phase high-performance liquid chromatography (HPLC) was performed on a HPLC chromatograph Hewlett Packard series 1100 column Eclipse XDB-C8(3.5 µm, 4,6 x 150 mm). Detection conducted at λ=230, 254 and 280 nm. Used the gradient ranged from 1 to 99% acetonitrile/water (+0.05% of triperoxonane acid) within 8,0 min at a velocity of the flow 0.75 ml/min Alternative, preparative HPLC was performed using an automated HPLC system Shimadzu with the input device and the liquid collection Gilson 215 and LCMSsolution software. UV peak detection was performed at λ=254 nm. Used a column of reversed phase Inertsil ODS-3 (3 ám, 30 X 100 mm); gradient mobile phase from 5 to 99% acetonitrile/water (+0.05% of triperoxonane acid) for 7 min at speed on the Oka 80 ml/min The column was heated to 45°C in a water bath. Alternatively, preparative HPLC was performed using an automated HPLC system Dionex APS software Chromeleon and UV-detection of the peak at λ=220 and 254 nm, equipped with a column with reversed phase Sunfire prep C18 OBD (5 μm, 30 X 150 mm); used a gradient mobile phase ranged from 15 to 100% acetonitrile/water (+0.05% of triperoxonane acid) for 10-20 min at a flow rate of 20 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 were obtained on Bruker spectrometers, model DRX. Below is the format1H NMR: chemical shift in ppm in the weak field from the signal tetramethylsilane used as the standard (observed multipletness, constant spin-spin interaction J in Hz, integral).

Chemical names were generated using the software ChemDraw version 6.0.2 (CambridgeSoft, , Cambridge, Massachusetts, USA) or ACD/Name version 9 (Advanced Chemistry Development, Toronto, Prov. Ontario, Canada).

Example 1: 1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. Obtain 7-chloro-1H-hinzelin-2,4-dione. The mixture amino-4-chlorbenzoyl acid (2.00 g, 11.6 mmol) and urea (2,80 g and 46.6 mmol) stood at 200°C for 1 h Then the mixture was cooled to room temperature and the resulting mass is well rubbed with water. The product was separated by filtration (2.30 g, 100%). Data MS and NMR were consistent with previously described data: Organic Process Research & Development, 2003, 7, 700-706.1H NMR (600 MHz, DMSO-d6): 12,00 (ush s, 2H); 8,59 are 8.53 (m, 1H); 7,93-7,80 (m, 2H).

Stage B. Obtaining 2,4,7-trichloroaniline. A mixture of 7-chloro-1H-hinzelin-2,4-dione (2.0 g, 10 mmol) suspended in acetonitrile (ACN) (50 ml) and then added POCl3 (5.0 ml, 55 mmol). After this was added DIEA (5.0 ml, 28 mmol). The resulting mixture was boiled under reflux for 36 h, then cooled to room temperature and concentrated. The residue was carefully treated with a mixture of ice and sodium bicarbonate. The obtained solid substance was collected by filtration and dried. Chromatographic purification (EtOAc/hexane from 0:100 to 10:90) provided the desired compound (2.1 g, 89%). Data MS and NMR were consistent with previously described data: Bioorganic & Medicinal Chemistry, 2003, 11, 2439-2444.1H NMR (400 MHz, DMSO-d6): 8,32 (d, J=8.7 Hz, 1H); to 8.20 (d, J=1.9 Hz, 1H); to 7.93 (DD, J=9,0, 2.1 Hz, 1H).

Stage C. Obtaining 2,7-dichloro-4-oxothiazolidine. To a cooled to 0°C mixture of 2,4,7-trichloroaniline (2.0 g, 8.5 mmol) and tetrahydrofuran (30 ml) was added 1.0 M aqueous sodium hydroxide solution (19 ml, 19 mmol). The reaction mixture is allowed to be heated up to matnog temperature and vigorously stirred for 2 hours The mixture was concentrated to remove THF, the remaining aqueous phase was cooled to 0°C and acidified by addition of 1.0 M aqueous HCl (25 ml). The resulting mixture was stirred at 0°C for 20 min, the separated precipitate is filtered and dried, obtaining the desired compound (1.7 g, 92%). Data MS and NMR were consistent with previously described data: Journal of Medicinal Chemistry, 2007, 50, 2297-2300.

Stage D. Obtaining 2,7-dichloro-4-(2-methoxyethoxyethoxy)-hintline. To a solution of 2,7-dichloro-4-oxothiazolidine (1.7 g, 7.8 mmol) and DIEA (2.1 ml, 12 mmol) in THF (20 ml) was dropwise added 2-methoxyethoxymethyl (1.0 ml, 8,8 mmol). The reaction was performed at room temperature for 16 h, then added EtOAc (250 ml). The resulting solution was washed with water (2 X 100 ml) and saturated saline (100 ml). Then the organic phase is dried and concentrated, and the obtained residue was washed with EtOH, having the desired compound (2.0 g, 83%). This substance was used directly without further purification.

Stage E. obtaining the ethyl ester of 1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of 2,7-dichloro-4-(2-methoxyethoxyethoxy)-hintline (0.68 g, 2.2 mmol), aripirazole-4-carboxylate (0.34 g, 2.4 mmol), Cs2CO3(1.2 g, 3.6 mmol) and anhydrous DMF (10 ml) stood at 120°C for 20 min and then was cooled to 0°C. Then the mixture was carefully diluted with 1 M aqueous HCl (30 ml). the received mixture allowed to warm to room temperature and filtration was collected precipitate, having obtained the desired compound (0.35 g, 50%). MS (HEE): calculated for C14H11ClN4O3: 318,7; received m/z: 317,0 [M-H]-.1H NMR (400 MHz, DMSO-d6): 13,04 (ush s, 1H); 8,99 (s, 1H); 8,32 (s, 1H); 8,11 (d, J=8.5 Hz, 1H); of 7.75 (s, 1H); rate of 7.54 (DD, J=8,5, and 2.1 Hz, 1H); 4,30 (kV, J=7,1 Hz, 2H); of 1.33 (t, J=7,1 Hz, 3H).

Stage F. Obtain 1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester of 1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (240 mg, of 0.74 mmol), 1 M aqueous LiOH solution (4.0 ml) and THF (6 ml) was stirred at high speed for 6 hours the mixture is Then concentrated to remove THF, the aqueous residue was cooled to 0°C and acidified to pH 2 1 M aqueous HCl. The precipitation was collected by filtration and obtained the desired compound (205 mg, 71%). MS (HEE): calculated for C12H7ClN4O3, 290,7; received m/z: 289,0 [M-H]-.1H NMR (400 MHz, DMSO-d6): 12,99 (ush s, 2H); 8,93 (d, J=0.7 Hz, 1H); of 8.27 (s, 1H); 8,11 (d, J=8.5 Hz, 1H); 7,74 (d, J=1.9 Hz, 1H); rate of 7.54 (DD, J=8,5, and 2.1 Hz, 1H).

Compounds in Examples 2 to 16 were obtained using methods similar to those described in Example 1.

Example 2: 1-(7-trifluoromethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 1, using on-stage And 2-amino-4-triftorperasin key is lots. MS (HEE): calculated for C13H7F3N4O3: 324,2; received m/z: 323,0 [M-H]-.1H NMR (400 MHz, DMSO-d6): 14,17-12,12 (ush m, 2H); 8,98 (d, J=0.6 Hz, 1H); 8,32 (d, J=8,3 Hz, 1H); 8,29 (s, 1H); 8,02 (s, 1H); 7,80 (d, J=8,3 Hz, 1H).

Example 3: 1-(6,7-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 1, using on-stage And 2-amino-4,5-dichlorobenzoyl acid. MS (HEE): calculated for C12H6Cl2N4O3: 325,1; received m/z: 323,0 [M-H]-.1H NMR (500 MHz, DMSO-d6): of 13.58-12,82 (ush m, 2H); of 8.92 (s, 1H); of 8.28 (s, 1H); 8,21 (s, 1H); of 7.96 (s, 1H).

Example 4: 1-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-5-fermenting acid. MS (HEE): calculated for C12H7FN4O3: 274,2; received m/z: 273,0 [M-H]-.1H NMR (500 MHz, DMSO-d6): 13,53-12,42 (ush m, 2H); 8,93 (s, 1H); compared to 8.26 (s, 1H); 7,87-the 7.65 (m, 3H).

Example 5: 1-(6,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid, trifurcata salt.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-the Mino-4,5-diferential acid. The desired compound was purified using preparative reversed-phase HPLC. MS (IER): calculated for C12H6F2N4O3: 292,2; received m/z: 209,9 [M-H]-.1H NMR (500 MHz, DMSO-d6): 13,79-12,30 (ush m, 2H); 8,95-8,87 (ush m, 1H); compared to 8.26 (s, 1H); 8,04 (s, 1H); 7,76 (s, 1H).

Example 6: 1-(5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-6-chlorbenzoyl acid. MS (IER): calculated for C12H7ClN4O3: 290,7; received m/z: 289,0 [M-H]-.1H NMR (500 MHz, DMSO-d6): 13,39-12,49 (m, 2H); to 8.94 (s, 1H); of 8.27 (s, 1H); of 7.75 (t, J=8.0 Hz, 1H); 7,63 (d, J=7.9 Hz, 1H); 7,51 (d, J=7.8 Hz, 1H).

Example 7: 1-(8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-3-methoxybenzoic acid. MS (IER): calculated for C13H10N4O4: of 286.2; received m/z: 287,2 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,97 (ush s, 1H); 12,85 (ush s, 1H); 8,88 (s, 1H); 8,24 (s, 1H); of 7.70 (d, J=7,6 Hz, 1H); 7,46 (t, J=6,9 Hz, 1H); 7,42 (d, J=6,5 Hz, 1H); of 3.95 (s, 3H).

Example 8: 1-(6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

ISCO is the first connection is received by way similar to that described in Example 1, using on-stage And 2-amino-5-methylbenzoic acid. MS (IER/CHI): calculated for C13H10N4O3: 270,2; received m/z: 271,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,14-12,84 (ush s, 1H); 12,82-12,56 (ush s, 1H); 8,93 (s, 1H); 8,24 (s, 1H); 7,94 (s, 1H); to 7.68 (d, J=7.9 Hz, 1H); of 7.60 (d, J=7.8 Hz, 1H); to 2.46 (s, 3H).

Example 9: 1-(8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-3-methylbenzoic acid. MS (IER): calculated for C13H10N4O3: 270,3; received m/z: 269,2 [M-H]-.1H NMR (500 MHz, DMSO-d6): to 13.29-12,58 (ush m, 2H); 9,03 (s, 1H); of 8.25 (s, 1H); of 7.97 (d, J=7.9 Hz, 1H); of 7.70 (d, J=7.2 Hz, 1H); 7,40 (t, J=7,6 Hz, 1H); of 2.58 (s, 3H).

Example 10: 1-(7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-4-methylbenzoic acid. MS (IER/CHI): calculated for C13H10N4O3: 270,3; received m/z: 271,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,97 (ush s, 1H); 12,70 (ush s, 1H); 8,93 (s, 1H); of 8.25 (s, 1H); 8,02 (d, J=8.0 Hz, 1H); 7.50 for (s, 1H); to 7.35 (d, J=7.9 Hz, 1H); 2,47 (s, 3H).

Example 11: 1-(8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-Kurbanova the acid.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-3-bromobenzoyl acid. MS (HEE): calculated for C12H7BrN4O3: 335,1; received m/z: 333,0 [M-H]-.1H NMR (400 MHz, DMSO-d6): 13,31-12,94 (ush s, 2H); 8,91 (s, 1H); of 8.28 (s, 1H); by 8.22-8,07 (m, 2H); 7,41 (t, J=7.8 Hz, 1H).

Example 12: 1-(6-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-5-iodobenzoyl acid. MS (HEE): calculated for C12H7IN4O3: 382,1; received m/z: 380,9 [M-H]-.1H NMR (400 MHz, DMSO-d6): 13,00 (ush s, 2H); to 8.94 (s, 1H); scored 8.38 (s, 1H); of 8.27 (s, 1H); to 8.12 (d, J=8.6 Hz, 1H); 7,49 (d, J=8.5 Hz, 1H).

Example 13: 1-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-5-bromobenzoyl acid. MS (IER/CHI): calculated for C12H7BrN4O3: 335,1; received m/z: 336,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,87 (ush s, 2H); to 8.94 (s, 1H); of 8.27 (s, 1H); 8,04 (d, J=8.5 Hz, 1H); to $ 7.91 (s, 1H); to 7.68 (DD, J=8,5, 1.9 Hz, 1H).

Example 14: 1-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid is the same.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-3-chlorbenzoyl acid. MS (HEE): calculated for C12H7ClN4O3: 290,7; received m/z: 292,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,13 (ush s, 2H); of 8.92 (s, 1H); 8,29 (s, 1H); of 8.09 (d, J=6,7 Hz, 1H); 8,00 (d, J=7.8 Hz, 1H); 7,49 (t, J=7.9 Hz, 1H).

Example 15: 1-(4-oxo-6-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-5-cryptomaterial acid. MS (HEE): calculated for C13H7F3N4O4: 340,2; received m/z: 341,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,00 (ush s, 2H); 8,96 (s, 1H); of 8.28 (s, 1H); of 7.97 (s, 1H); 7,89-7,79 (ush m, 2H).

Example 16: 1-(4-oxo-8-trifluoromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 1, using on-stage And 2-amino-3-triftorperasin acid. MS (HEE): calculated for C13H7F3N4O3: 324,2; received m/z: 325,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,28 (ush s, 1H); 13,15 (ush s, 1H); 8,81 (s, 1H); to 8.40 (d, J=6,9 Hz, 1H); 8,32 (s, 1H); by 8.22 (d, J=7.5 Hz, 1H); to 7.64 (t, J=7.8 Hz, 1H).

Example 17 1-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-[(3,4-dimethoxyphenylthio)-ethoxycarbonylmethyl]-1H-pyrazole-4-carboxylic acid. A solution of 3,4-dimethoxyaniline (0.15 g, 1.0 mmol), ethylisothiocyanate (of 0.14 ml, 1.2 mmol) in DCM (10 ml) was stirred at room temperature for 1 h and Then added triethylamine (of 0.42 ml, 3.0 mmol), aripirazole-4-carboxylate (0.17 g, 1.2 mmol) and EDCI (0,19 g, 1.2 mmol) and stirred solution at room temperature for 5 hours the mixture was concentrated, diluted with water and was extracted with DCM. The organic phase is dried and concentrated, obtaining the crude desired compound (390 mg, 100%). This substance was used without further purification. MS (IER): calculated for C18H22N4O6: RUR 390.4; received m/z: 391,4 [M+H]+.

Stage B. obtaining the ethyl ester of 1-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[(3,4-dimethoxyphenylthio)-ethoxycarbonylmethyl]-1H-pyrazole-4-carboxylic acid (0.39 g, 1.0 mmol) in DMF (3 ml) was added chlorotrimethylsilane (1,26 ml, 10.0 mmol) and kept the mixture at 80°C for 16 h in a sealed reactor. Then the reaction mixture is cooled and added water (2 ml). The crude reaction mixture was concentrated in vacuum and brought the pH of the resulting aqueous mixture to a pH of 7 using 2 M vodno the solution of NH 4OH. The residue was well washed and collected by vacuum filtration. Obtained the desired compound (0.28 g, 81%) was purified using preparative reversed-phase HPLC. MS (IER): calculated for C16H16N4O5: to 344.4; received m/z: of 345.7 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,06-12,23 (ush m, 1H); 8,97 (s, 1H); of 8.28 (s, 1H); 7,47 (s, 1H); 7,21 (s, 1H); 4,29 (kV, J=7,1 Hz, 2H); 3,93 (s, 3H); to 3.89 (s, 3H); 1.32 to (t, J=7,1 Hz, 3H).

Stage C. Obtain 1-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester of 1-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (0.28 g, 0.81 mmol), 1 M aqueous solution of KOH (3.0 ml) and THF (3.0 ml) was stirred for 4 h Then the mixture was concentrated to remove THF, and the remaining aqueous phase was acidified to pH 2 by addition of 1.0 M aqueous HCl. The precipitation was collected by filtration, obtaining the desired compound (0,23 g, 89%). MS (IER): calculated for C14H12N4O5: 316,3; received m/z: is 317.1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,32-12,29 (ush m, 2H); of 8.90 (s, 1H); by 8.22 (s, 1H); 7,47 (s, 1H); 7,19 (s, 1H); 3,93 (s, 3H); to 3.89 (s, 3H).

Example 18: 1-(5,6,7-trimetoksi-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 17, using on stage And 3,4,5-trimethoxyaniline. The (IER): calculated for C 15H15N4O6: 346,3; received m/z: 347,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,16-12,82 (ush m, 1H); 12,64-12,20 (ush m, 1H); of 8.90 (s, 1H); 8,24 (s, 1H);? 7.04 baby mortality (s, 1H); of 3.94 (s, 3H); a 3.83 (s, 3H); 3,79 (s, 3H).

Example 19: 1-(6-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 17, using on-stage And 4-tertbutylamine. MS (IER): calculated for C16H16N4O3: 312,3; received m/z: 313,2 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,90 (ush m, 2H); to 8.94 (s, 1H); of 8.25 (s, 1H); 8,07 (d, J=2.1 Hz, 1H); 7,94 (DD, J=8,6, 2.2 Hz, 1H); 7,66 (d, J=8,4 Hz, 1H); of 1.36 (s, 9H).

Example 20: 1-(4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 17, using on-stage And 4-phenoxyimino. MS (IER): calculated for C18H12N4O4: 348,3; received m/z: 349,2 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,16-12,96 (ush m, 2H); to 8.94 (s, 1H); 8,24 (s, 1H); 7,74 (s, 1H); of 7.60 (DD, J=8,9 Hz to 2.9, 1H); of 7.48 (t, J=8.0 Hz, 3H); to 7.25 (t, J=7,4 Hz, 1H); to 7.15 (d, J=7.8 Hz, 2H).

Example 21: 1-(6-cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 17, using the article on the Hai And 4-cyclohexylaniline. MS (IER): calculated for C18H18N4O3: 338,3; received m/z: 339,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,95 (s, 1H); 12,78 - 12,59 (ush m, 1H); 8,93 (s, 1H); 8,24 (s, 1H); to 7.95 (s, 1H); 7,74 (d, J=7,3 Hz, 1H); a 7.62 (d, J=8.0 Hz, 1H); 2,68 (s, 1H); 1,82 (d, J=a 12.7 Hz, 4H); 1,72 (d, J=a 12.7 Hz, 1H); of 1.44 (DD, J=24.5cm, and 12.6 Hz, 4H); of 1.29 (s, 1H).

Example 22: 1-(7-chloro-4-oxo-6-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 17, using on-stage And 3-chloro,4-triphtalocyaninine. MS (IER): calculated for C13H6ClF3N4O4: 374,6; received m/z: 375,3 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,49-13,16 (ush m, 1H); 13,08 (s, 1H); of 8.95 (s, 1H); 8.30 to (s, 1H); 8,10 (s, 1H); with 8.05 (s, 1H).

Example 23: 1-(1-oxo-2,7-dihydro-1H-pyrrol[3,2-f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 17, using on-stage And 5-aminoindole. MS (IER): calculated for C14H9N5O3: 295,3; received m/z: 296,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): to 11.79 (s, 1H); 8,97 (s, 1H); 8,24 (s, 1H); to 7.93 (d, J=8.6 Hz, 1H); a 7.62 (t, J=2.7 Hz, 1H); was 7.45 (d, J=8.6 Hz, 1H); 7,30 (s, 1H).

Example 24: 1-[6-(4-tert-butylphenylmethyl)-7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A. Receipt is 1-(4-tert-butylphenylmethyl)-2-chloro-4-nitrobenzene. To a solution of 4-tert-butylthiophenol (0.95 g, 5.7 mmol) and 3,4-dichloronitrobenzene (1.0 g, 5.2 mmol) in DMF (15 ml) was dropwise added pure 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.2 ml, 7.8 mmol). The solution was stirred for 1 h at room temperature and then for 1 h at 60°C. the mixture is allowed to cool and poured on ice. The obtained yellow precipitate was collected and dried. The resulting crude product was used without further purification.

Stage B. Obtain 4-(4-tert-butylphenylmethyl)-3-Chloroaniline. 1-(4-tert-butylphenylmethyl)-2-chloro-4-nitrobenzene was dissolved in acetone (15 ml), then added a saturated aqueous solution of NH4Cl (5 ml) and cooled the mixture to 0°C. Then with rapid stirring for 10 minutes in small portions was added zinc dust (3.7 g, 56 mmol). The resulting mixture allowed to warm to room temperature and was stirred for 3 hours Then the mixture was diluted with EtOAc (250 ml), dried and filtered through Celite®. After removal of solvent received a yellow residue which was used without further purification. MS (IER): calculated for C16H18ClNS: 291,1; received m/z: 292,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 7,33-7,21 (m, 3H); to 6.95 (d, J=8.5 Hz, 2H); 6,77 (d, J=2.4 Hz, 1H); 6,55 (DD, J=8,4, 2.4 Hz, 1H); 5,80 (s, 2H); 1,22 (s, 9H).

Stage C. Obtaining 1-[6-(4-tert-butylphenylmethyl)-7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carbon is howling acid. The desired compound was obtained in a manner analogous to the one described in Example 17 using 4-(4-tert-butylphenylmethyl)-3-Chloroaniline. MS (IER): calculated for C22H19ClN4O3S: 454,9; received m/z: 455,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,01 (ush s, 2H); 8,91 (s, 1H); compared to 8.26 (s, 1H); 7,87 (s, 1H); EUR 7.57 (d, J=8.5 Hz, 2H); rate of 7.54 (s, 1H); 7,50 (d, J=8,4 Hz, 2H); 1,22 (s, 9H).

Example 25: 1-(7-chloro-4-oxo-6-phenylsulfonyl-1,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 24, using on stage And thiophenol. MS (IER): calculated for C18H11ClN4O3S: 398,0; received m/z: 399,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,04 (ush s, 2H); 8,91 (s, 1H); compared to 8.26 (s, 1H); 7,87 (s, 1H); 7,63-7,47 (m, 6H).

Example 26: 1-[7-chloro-6-(3,4-dimethoxyphenylacetone)-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 24, using on stage And 3,4-dimethoxyphenol. MS (IER): calculated for C20H15ClN4O5S: 458,9; received m/z: 459,1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13,02 (ush s, 2H); of 8.90 (s, 1H); 7,83 (s, 1H); 7,40 (s, 1H); 7,26 for 7.12 (m, 3H); 3,86 (s, 3H); of 3.77 (s, 3H).

Example 27: 1-[6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A. Obtain 4-(2,6-dimethylphenoxy)-3-methylnitrobenzene. A solution of 2,6-dimethylphenol (0.87 g, 7.1 mmol), potassium carbonate (0,98 g, 7.1 mmol) and 2-fluoro-5-nitrotoluene (1.0 g, 6.4 mmol) in DMF (20 ml) was stirred at 100°C for 2 h Then the reaction mixture was diluted with 100 ml of water and was extracted with 250 ml of EtOAc. The organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated, obtaining the crude desired compound (1.5 g, 92%). The resulting material was used without further purification. MS (IER): calculated for C15H15NO3: 257,3; received m/z: 258,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,16 (DD, J=2,8, 0.7 Hz, 1H); 7,92 (DD, J=9,1, 2.7 Hz, 1H); 7.18 in-7,07 (m, 3H); 6,33 (d, J=9.0 Hz, 1H); 2.50 each (s, 3H); of 2.09 (s, 6H).

Stage B. Obtain 4-(2,6-dimethylphenoxy)-3-methylaniline. In a mixture of 4-(2,6-dimethylphenoxy)-3-methylnitrobenzene (1.5 g, 5.9 mmol), acetone (20 ml) and saturated aqueous solution of ammonium chloride (20 ml) at 0°C under stirring was added zinc dust (3,86 g, to 59.1 mmol). The resulting mixture was let warm up to room temperature and was stirred for 1 h Then the reaction mixture was diluted with 200 ml EtOAc and filtered through diatomaceous earth. The organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated, obtaining the crude desired compound (0,79 g, 59%). The resulting material was used without further sight of the TCI. MS (IER): calculated for C15H17NO: 227,3; received m/z: 227,1 [M+H]+.1H NMR (500 MHz, CDCl3): 7,07 (d, J=7.2 Hz, 2H); 7,01 (DD, J=8,3, 6.5 Hz, 1H); 6,60 (t, J=3,4 Hz, 1H); of 6.31 (DD, J=8,5, 2,9 Hz, 1H); the 6.06 (d, J=8.5 Hz, 1H); to 3.36 (s, 2H); of 2.34 (s, 3H); 2,11 (s, 6H).

Stage C. obtaining the ethyl ester of 1-{[4-(2,6-dimethylphenoxy)-3-methylpentylamino]-ethoxycarbonylmethyl}-1H-pyrazole-4-carboxylic acid. A solution of 4-(2,6-dimethylphenoxy)-3-methylaniline (0,80 g, 3.5 mmol), ethylisothiocyanate (and 0.40 ml, 3.5 mmol) in DCM (30 ml) was stirred at room temperature for 1 h and Then added aripirazole-4-carboxylate (0.54 g, 3.9 mmol) and DIC (0.54 ml, 3.5 mmol) and stirred solution at room temperature for 16 hours the mixture was concentrated and purified KFH (EtOAc/hexane from 0:100 to 50:50), having the desired compound (0,97 g, 60%). MS (IER): calculated for C25H28N4O5: 464,5; received m/z: 465,1 [M+H]+.

Stage D. obtaining the ethyl ester of 1-[6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-{[4-(2,6-dimethylphenoxy)-3-methylpentylamino]-ethoxycarbonylmethyl}-1H-pyrazole-4-carboxylic acid (0.97 g, 2.1 mmol) in DCE (10 ml) was added titanium chloride (IV) (0.25 ml, 2.3 mmol) and kept the mixture at 90°C for 16 hours Then the reaction mixture was cooled to room temperature and poured into 50 ml of EtOH. The mixture re esale for 30 min and concentrated until dry. The obtained dry material was purified KFH (CH3CN/DCM, gradient 0:100 to 20:80) and got the desired compound (0.28 g, 32%). MS (IER): calculated for C23H22N4O4: 418,4; received m/z: 419,2 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,77 (s, 1H); 8,96 (s, 1H); of 8.28 (s, 1H); of 7.69 (s, 1H); to 7.25 (d, J=7,4 Hz, 2H); 7.18 in (DD, J=8,3, 6,7 Hz, 1H); is 6.78 (s, 1H); 4,30 (kV, J=7,1 Hz, 2H); to 2.55 (s, 3H); of 2.08 (s, 6H); 1.32 to (t, J=7,1 Hz, 3H).

Stage E. Obtaining 1-[6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester 1-[6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0.25 g, of 0.60 mmol), 1 M aqueous solution of KOH (5.0 ml) and THF (5.0 ml) was stirred for 4 h Then the mixture was concentrated to remove THF, and the remaining aqueous phase was acidified to pH 2 by adding 1 M aqueous HCl. The precipitation was collected by filtration, obtaining the desired compound (0,22 g, 93%). MS (IER): calculated for C21H18N4O4: 390,1; received m/z: to € 391.1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,99 (s, 1H); 12,72 (s, 1H); of 8.90 (d, J=13,2 Hz, 1H); by 8.22 (s, 1H); 7,68 (s, 1H); to 7.25 (d, J=7,4 Hz, 2H); 7.18 in (DD, J=8,3, 6,7 Hz, 1H); is 6.78 (s, 1H); to 2.55 (s, 3H); 2,07 (d, J=8,2 Hz, 6H).

Example 28: 1-[4-oxo-6-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-{[4-(3,4,5-trimethoxyphenyl)-phenyl is Mino]-ethoxycarbonylmethyl}-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 27, the stage And, using A stage 3,4,5-trimethoxyphenol and 4-peritrabecular. MS (IER): calculated for C25H28N4O8: 512,5; received m/z: 513,2 [M+H]+.

Stage B. Obtain 1-[4-oxo-6-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 27, the stage D-E, using in stage D of chlorotrimethylsilane instead of titanium chloride (IV). MS (IER): calculated for C21H18N4O7: 438,1; received m/z: 439,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,99 (s, 1H); 12,89 (s, 1H); to 8.94 (s, 1H); 8,24 (s, 1H); 7,73 (d, J=8,3 Hz, 1H); EUR 7.57 (DD, J=8,8, 2,9 Hz, 1H); of 7.48 (s, 1H); 6,50 (s, 2H); 3,74 (s, 6H); 3,68 (s, 3H).

Example 29: 1-[6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-{ethoxycarbonylmethyl-[4-(naphthalene-1-yloxy)-phenylamino]-methyl}-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 27, stages A-C, using A stage 1-naphthol and 4-peritrabecular. MS (IER): calculated for C26H24N4O5: 472,2; received m/z: 473,2 [M+H]+.

Stage B. obtaining the ethyl ester of 1-[6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroxy azolin-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-{ethoxycarbonylmethyl-[4-(naphthalene-1-yloxy)-phenylamino]-methyl}-1H-pyrazole-4-carboxylic acid (0.74 g, 1.6 mmol) in DCE (10 ml) was added titanium chloride (IV) (0,86 ml, 7.8 mmol) and kept the mixture at 90°C for 16 hours Then the reaction mixture was cooled to room temperature and poured into 50 ml of EtOH. The resulting mixture was stirred for 30 min and then collected solid precipitate by vacuum filtration (0,46 g, 69%). MS (IER): calculated for C24H18N4O4: 426,1; received m/z: 427,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,87 (s, 1H); 8,99 (s, 1H); 8,29 (s, 1H); with 8.05 (d, J=7.5 Hz, 1H); 8,02 (d, J=8,3 Hz, 1H); 7,86 (d, J=8,3 Hz, 1H); 7,79 (d, J=7,6 Hz, 1H); of 7.70 (DD, J=8,9, 2,9 Hz, 1H); to 7.64-of 7.60 (m, 1H); 7,60-7,53 (m, 2H); 7,39 (d, J=2,8 Hz, 1H); 7.23 percent (d, J=7,4 Hz, 1H); 4,30 (kV, J=7,1 Hz, 2H); to 1.32 (t, J=7,1 Hz, 3H).

Stage C. Obtaining 1-[6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester 1-[6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0,42 g 0,99 mmol), 1 M aqueous solution of KOH (5.0 ml) and THF (5.0 ml) was stirred for 4 h Then the mixture was concentrated to remove THF, and the remaining aqueous phase was acidified to pH 2 by adding 1 M aqueous HCl. The precipitation was collected by filtration, obtaining the desired compound (0.34 g, 86%). MS (IER): calculated for C22H14N4O4: 398,1; received m/z: 399,1 [M+H]+/sup> .1H NMR (500 MHz, DMSO-d6): 12,99 (s, 1H); 12,86 (s, 1H); to 8.94 (s, 1H); 8,24 (s, 1H); of 8.06 (d, J=8,1 Hz, 1H); 8,02 (d, J=8,3 Hz, 1H); 7,87 (d, J=8,2 Hz, 1H); for 7.78 (d, J=8,2 Hz, 1H); 7,71 (DD, J=8,9, 2,9 Hz, 1H); a 7.62 (t, J=7.5 Hz,, 1H); 7,60-rate of 7.54 (m, 2H); 7,38 (s, 1H); from 7.24 (d, J=7,4 Hz, 1H).

Example 30: 1-[6-(3-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 3-chlorophenol and 4-peritrabecular. MS (IER): calculated for C18H11ClN4O4: 382,1; received m/z: 383,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,00 (s, 1H); 12,95 (s, 1H); of 8.95 (s, 1H); of 8.25 (s, 1H); to 7.77 (d, J=8.6 Hz, 1H); 7,63 (DD, J=8,8, 2,9 Hz, 1H); at 7.55 (s, 1H); of 7.48 (t, J=8,2 Hz, 1H); 7,30 (d, J=8.0 Hz, 1H); from 7.24 (s, 1H); 7,11 (d, J=8,2 Hz, 1H).

Example 31: 1-[6-(3-methoxyphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 28, using on-stage And 3-methoxyphenol and 4-peritrabecular. MS (IER): calculated for C19H14N4O5: 378,1; received m/z: 379,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,99 (s, 1H); 12,89 (s, 1H); to 8.94 (s, 1H); of 8.25 (s, 1H); 7,74 (d, J=8.7 Hz, 1H); of 7.60 (DD, J=8,9, 2,9 Hz, 1H); 7,49 (s, 1H); 7,37 (t, J=8,2 Hz, 1H); 6,83 (DD, J=8,3, 1.9 Hz, 1H); 6.73 x (s, 1H); 6,69 (d, J=7.8 Hz, 1H); of 3.77 (s, 3H).

Example 32: 1-[6-(4-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-feast of the evil-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 4-terfenol and 4-peritrabecular. MS (IER): calculated for C18H11FN4O4: 366,1; received m/z: 367,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,89 (s, 2H); to 8.94 (s, 1H); of 8.25 (s, 1H); 7,76 (d, J=7.7 Hz, 1H); to 7.59 (DD, J=8,9, 2,9 Hz, 1H); the 7.43 (d, J=2,9 Hz, 1H); 7,35-7,28 (m, 2H); 7,25-7,19 (m, 2H).

Example 33: 1-[6-(2-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 2-terfenol and 4-peritrabecular. MS (IER): calculated for C18H11FN4O4: 366,1; received m/z: 367,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,99 (s, 1H); 12,91 (s, 1H); to 8.94 (s, 1H); of 8.25 (s, 1H); 7,76 (d, J=8,3 Hz, 1H); 7,63 (DD, J=8,9, 3.0 Hz, 1H); 7,53-7,44 (m, 1H); 7,42-7,28 (m, 4H).

Example 34: 1-[6-(3-fluoro-phenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 3-terfenol and 4-peritrabecular. MS (IER): calculated for C18H11FN4O4: 366,1; received m/z: 367,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,00 (s, 1H); 12,97-12,79 (m, 1H); of 8.95 (s, 1H); compared to 8.26 (s, 1H); 7,76 (s, 1H); 7,63 (DD, J=8,8, ,9 Hz, 1H); 7,56 (s, 1H); 7,49 (DD, J=15,1, 8,2 Hz, 1H); 7,07 (DD, J=17,0, and 9.2 Hz, 2H); 6,97 (d, J=8.0 Hz, 1H).

Example 35: 1-[6-(3,5-di-tert-butylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 3,5-di-tert-butylphenol and 4-peritrabecular. MS (IER): calculated for C26H28N4O4: 460,2; received m/z: 461,2 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,99 (s, 1H); 12,93-12,74 (m, 1H); to 8.94 (s, 1H); of 8.25 (s, 1H); 7,73 (s, 1H); at 7.55 (DD, J=8,8, 2.8 Hz, 1H); of 7.48 (s, 1H); 7,28 (s, 1H); of 6.96 (d, J=1.2 Hz, 2H); of 1.28 (s, 18H).

Example 36: 1-(4-oxo-6-m-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 3-METHYLPHENOL and 4-peritrabecular. MS (IER): calculated for C19H14N4O4: 362,1; received m/z: 363,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,96 (s, 1H); 12,84 (s, 1H); to 8.94 (s, 1H); 8,24 (s, 1H); 7,74 (d, J=7.5 Hz, 1H); 7,58 (DD, J=8,9, 2,9 Hz, 1H); 7,46 (d, J=2.6 Hz, 1H); to 7.35 (t, J=7.8 Hz, 1H); 7,06 (d, J=7.5 Hz, 1H); 6,97 (s, 1H); 6,93 (d, J=8.0 Hz, 1H); of 2.33 (s, 3H).

Example 37: 1-(4-oxo-6-o-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using EQ what whether on stage And 2-METHYLPHENOL and 4-peritrabecular. MS (IER): calculated for C19H14N4O4: 362,1; received m/z: 363,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,99 (s, 1H); 12,86 (s, 1H); 8,93 (s, 1H); 8,23 (s, 1H); 7,74 (d, J=9.0 Hz, 1H); EUR 7.57 (DD, J=8,9, 3.0 Hz, 1H); 7,40 (d, J=7,4 Hz, 1H); 7,31 (t, J=7,1 Hz, 1H); 7,27 (s, 1H); 7,22 (t, J=7,0 Hz, 1H); 7,08 (d, J=7.9 Hz, 1H); 2,17 (s, 3H).

Example 38: 1-[6-(2,6-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 2,6-dichlorophenol and 4-peritrabecular. MS (IER): calculated for C18H10Cl2N4O4: 416,0; received m/z: 417,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,94 (s, 2H); 8,93 (s, 1H); 8,23 (s, 1H); of 7.75 (s, 1H); 7,72 (d, J=8.1 Hz, 2H); of 7.60 (DD, J=8,9, 3.1 Hz, 1H); 7,45 (t, J=8,2 Hz, 1H); 7,17 (s, 1H).

Example 39: 1-[6-(2,4-dichlorphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 2,4-dichlorophenol and 4-peritrabecular. MS (IER): calculated for C18H10Cl2N4O4: 416,0; received m/z: 417,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,96 (s, 1H); 12,94-of 12.73 (m, 1H); to 8.94 (s, 1H); 8,24 (s, 1H); a 7.85 (d, J=2.5 Hz, 1H); 7,76 (d, J=8,2 Hz, 1H); to 7.61 (DD, J=8,9, 3.0 Hz, 1H); 7,53 (DD, J=8,8, 2.5 Hz, 1H); 7,39 (s, 1H); 7,33 (d, J=8,8 Hz, 1H).

Example 40: 1-[6-(2,5-dichlo is phenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 2,5-dichlorophenol and 4-peritrabecular. MS (IER): calculated for C18H10Cl2N4O4: 416,0; received m/z: 417,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,95 (s, 2H); to 8.94 (s, 1H); of 8.25 (s, 1H); for 7.78 (d, J=8.6 Hz, 1H); 7,71 (d, J=8,8 Hz, 1H); 7,63 (DD, J=8,9, 3.0 Hz, 1H); 7,42 (d, J=4,1 Hz, 2H); 7,39 (d, J=2.4 Hz, 1H).

Example 41: 1-[6-(4-methoxyphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 4-methoxyphenol and 4-peritrabecular and with the addition of stage D of 1.5 equiv. 2,6-di-tert-butylpyridinium. MS (IER): calculated for C19H14N4O5: 378,1; received m/z: 379,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,93 (s, 1H); 12,88-12,67 (m, 1H); 8,93 (s, 1H); 8,23 (s, 1H); 7,72 (d, J=8,1 Hz, 1H); at 7.55 (DD, J=8,9, 2,9 Hz, 1H); of 7.36 (d, J=2,8 Hz, 1H); 7,17-was 7.08 (m, 2H); 7,08-of 6.99 (m, 2H); 3,79 (s, 3H).

Example 42: 1-[6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 2,6-dimethylphenol and 4-peritrabecular. MS (IER): calculated for C20H16N4O4: 37,1; the obtained m/z: 377,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,82 (s, 2H); of 8.92 (s, 1H); 8,23 (s, 1H); 7,74 (d, J=8,8 Hz, 1H); rate of 7.54 (DD, J=8,9, 3.0 Hz, 1H); from 7.24 (d, J=7,4 Hz, 2H); 7.18 in (DD, J=8,3, and 6.6 Hz, 1H); was 7.08 (s, 1H); of 2.09 (s, 6H).

Example 43: 1-[6-(naphthalene-2-ilxi)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 2-naphthol and 4-peritrabecular. MS (IER): calculated for C22H14N4O4: 398,1; received m/z: 399,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,00 (s, 1H); 12,91 (s, 1H); of 8.95 (s, 1H); of 8.25 (s, 1H); with 8.05 (d, J=8,9 Hz, 1H); of 7.97 (d, J=7.9 Hz, 1H); 7,89 (d, J=8.0 Hz, 1H); for 7.78 (d, J=8,1 Hz, 1H); to 7.68 (DD, J=8,8, 2,9 Hz, 1H); to 7.59 (s, 1H); EUR 7.57-7,47 (m, 3H); 7,39 (DD, J=8,9, and 2.4 Hz, 1H).

Example 44: 1-[4-oxo-6-(5,6,7,8-tetrahydronaphthalen-1 yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 5,6,7,8-tetrahydronaphthalen-1-ol and 4-peritrabecular. MS (IER): calculated for C22H18N4O4: 402,1; received m/z: 403,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,00 (s, 1H); 12,83 (s, 1H); 8,93 (s, 1H); 8,24 (s, 1H); 7,73 (d, J=8.6 Hz, 1H); at 7.55 (DD, J=8,8, 2.8 Hz, 1H); 7.29 trend (s, 1H); 7,20 (t, J=7.8 Hz, 1H); 7.03 is (d, J=7,6 Hz, 1H); 6.87 in (d, J=7.9 Hz, 1H); 2,84 was 2.76 (m, 2H); 2,59-2,52 (m, 2H); 1,76-of 1.66 (m, 4H).

Example 46: 1-[6-(4-chlorphenoxy is)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, stage C-E, using on stage With 4-(4-chlorphenoxy)-phenylamine. MS (IER): calculated for C18H11ClN4O4: 382,1; received m/z: 383,2 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,00 (s, 1H); 12,93 (s, 1H); of 8.95 (s, 1H); of 8.25 (s, 1H); 7,76 (d, J=7,4 Hz, 1H); a 7.62 (DD, J=8,8, 2,9 Hz, 1H); 7,51 (d, J=8,9 Hz, 3H); to 7.18 (d, J=8.7 Hz, 2H).

Example 47: 1-(4-oxo-6-p-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, stage C-E, using on stage With 4-p-tolylacetylene. MS (IER): calculated for C19H14N4O4: 362,1; received m/z: 363,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,99 (s, 1H); 12,87 (s, 1H); 8,93 (s, 1H); 8,24 (s, 1H); 7,73 (d, J=8,9 Hz, 1H); 7,58 (DD, J=8,8, 2,9 Hz, 1H); 7,40 (s, 1H); 7,28 (d, J=8,2 Hz, 2H); 7,06 (d, J=8,3 Hz, 2H); of 2.34 (s, 3H).

Example 48: 1-[7-chloro-6-(4-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, stage C-E, using on stage With 3-chloro-4-(4-chlorphenoxy)-phenylamine. MS (IER): calculated for C18H10Cl2N4O4: 416,0; received m/z: 417,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,4 (, 2H); 8,93 (s, 1H); of 8.27 (s, 1H); 7,98 (s, 1H); 7,56 (s, 1H); 7,52 (d, J=8,9 Hz, 2H); 7,17 (d, J=8,8 Hz, 2H).

Example 49: 1-[7-chloro-6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 2,6-dimethylphenol and 2-chloro-1-fluoro-4-nitrobenzene. MS (IER): calculated for C20H15ClN4O4: 410,1; received m/z: 411,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,01 (s, 2H); 8,91 (s, 1H); of 8.25 (s, 1H); to 7.99 (s, 1H); 7,28 (d, J=7,3 Hz, 2H); 7,22 (DD, J=8,4, 6.5 Hz, 1H); 6,92 (s, 1H); of 2.09 (s, 6H).

Example 50: 1-[6-(2,6-dichlorophenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 2,6-dichlorophenol and 3,4-deformirovannoe. MS (IER): calculated for C18H9Cl2FN4O4: 434,0; received m/z: 435,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,98 (s, 2H); 8,91 (s, 1H); of 8.25 (s, 1H); 7,80 (d, J=11,4 Hz, 1H); of 7.75 (d, J=8,2 Hz, 2H); 7,49 (t, J=8,2 Hz, 1H); 7,07 (d, J=8,9 Hz, 1H).

Example 51: 1-[6-(2,6-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 2,6-dimetyl is Nola and 3,4-deformirovannoe. MS (IER): calculated for C20H15FN4O4: 394,1; received m/z: 395,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,92 (s, 2H); of 8.90 (s, 1H); 8,23 (s, 1H); 7,74 (d, J=11,6 Hz, 1H); 7,27 (d, J=6,7 Hz, 2H); 7,21 (DD, J=8,7, 6.0 Hz, 1H); 6,97 (d, J=9.1 Hz, 1H); 2,11 (s, 6H).

Example 52: 1-[7-fluoro-6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 2-naphthol and 3,4-deformirovannoe. MS (IER): calculated for C22H13FN4O4: 416,1; received m/z: 417,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,04 (s, 2H); to 8.94 (s, 1H); of 8.27 (s, 1H); with 8.05 (d, J=8,9 Hz, 1H); of 7.97 (d, J=8.0 Hz, 1H); 7,87 (d, J=8,1 Hz, 1H); for 7.78 (d, J=11.3 Hz, 1H); to 7.68 (d, J=8,8 Hz, 1H); at 7.55 (s, 1H); 7,54-7,52 (m, 1H); 7,50 (DD, J=10,8, a 4.1 Hz, 1H); 7,44 (DD, J=8,9 and 2.5 Hz, 1H).

Example 53: 1-[7-chloro-6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 1-naphthol and 2-chloro-1-fluoro-4-nitrobenzene. MS (IER): calculated for C22H13ClN4O4: 432,1; received m/z: 433,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,03 (s, 2H); 8,93 (s, 1H); compared to 8.26 (s, 1H); 8,07 (d, J=8,2 Hz, 1H); 8,01 (d, J=7.7 Hz, 2H); 7,88 (d, J=8,2 Hz, 1H); 7,60 (DDD, J=24.5cm, 15,4, 7.5 Hz, 3H); 7,37 (s, 1H); 7,19 (d, J=7.5 Hz, 1H).

Example 54: 1-[7-chlorine is-6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 2-naphthol and 2-chloro-1-fluoro-4-nitrobenzene. MS (IER): calculated for C22H13ClN4O4: 432,1; received m/z: 433,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): of 13.05 (s, 2H); to 8.94 (s, 1H); of 8.27 (s, 1H); of 8.06 (d, J=8,9 Hz, 1H); 8,01 (s, 1H); 7,98 (d, J=8.0 Hz, 1H); 7,88 (d, J=7.9 Hz, 1H); 7,58 (s, 1H); EUR 7.57-of 7.48 (m, 3H); 7,42 (DD, J=8,9, and 2.4 Hz, 1H).

Example 55: 1-[7-chloro-4-oxo-6-(5,6,7,8-tetrahydronaphthalen-1 yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 5,6,7,8-tetrahydronaphthalen-1-ol and 2-chloro-1-fluoro-4-nitrobenzene. MS (IER): calculated for C22H17ClN4O4: 436,1; received m/z: 437,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,04 (s, 2H); of 8.92 (s, 1H); of 8.25 (s, 1H); of 7.96 (s, 1H); 7,27 (s, 1H); 7,21 (t, J=7.8 Hz, 1H); 7,05 (d, J=7,6 Hz, 1H); 6,86 (d, J=7.9 Hz, 1H); 2,84-2,78 (m, 2H); 2,59-2,52 (m, 2H); 1.77 in-1,67 (m, 4H).

Example 56: 1-[7-fluoro-6-(3-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 3-terfenol and 3,4-deformirovannoe. MS (IER): calculated for C18H10F2N4O4 : 384,1; received m/z: 385,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,08 (s, 2H); to 8.94 (s, 1H); of 8.28 (s, 1H); 7,76 (d, J=11,4 Hz, 1H); 7,72 (d, J=8,8 Hz, 1H); 7,53-7,44 (m, 1H); 7,14-7,05 (m, 2H); 7,00-to 6.95 (m, 1H).

Example 57: 1-[7-fluoro-6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 1-naphthol and 3,4-deformirovannoe. MS (IER): calculated for C22H13FN4O4: 416,1; received m/z: 417,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): of 13.05 (s, 2H); 8,93 (s, 1H); compared to 8.26 (s, 1H); 8,08 (t, J=9.4 Hz, 2H); 7,86 (d, J=8,3 Hz, 1H); 7,80 (d, J=11,4 Hz, 1H); 7,63 (TD, J=13,7, 5,9 Hz, 2H); at 7.55 (t, J=7.9 Hz, 1H); of 7.48 (d, J=8,9 Hz, 1H); 7,19 (d, J=7.5 Hz, 1H).

Example 58: 1-[7-fluoro-6-(indan-5-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 5-indanol and 3,4-deformirovannoe. MS (IER): calculated for C21H15FN4O4: 406,1; received m/z: 407,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,04 (s, 2H); of 8.92 (s, 1H); compared to 8.26 (s, 1H); 7,71 (d, J=11.5 Hz, 1H); of 7.48 (d, J=8,9 Hz, 1H); 7,30 (d, J=8,1 Hz, 1H);? 7.04 baby mortality (d, J=2.0 Hz, 1H); 6,93 (DD, J=8,1, 2.3 Hz, 1H); is 2.88 (t, J=7.4 Hz, 4H); to 2.06 (Quint, J=7.5 Hz, 2H).

Example 59: 1-(7-methyl-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And phenol and 2-fluoro-5-nitrotoluene. MS (IER): calculated for C19H14N4O4: 362,1; received m/z: 363,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,01 (s, 1H); 12,79 (s, 1H); 8,91 (s, 1H); 8,24 (s, 1H); to 7.67 (s, 1H); 7,46 (DD, J=8,6, 7.5 Hz, 2H); to 7.32 (s, 1H); 7.23 percent (t, J=7,4 Hz, 1H); 7,10 (d, J=7.7 Hz, 2H); to 2.41 (s, 3H).

Example 60: 1-[6-(2,3-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 2,3-dichlorophenol and 4-peritrabecular. MS (IER): calculated for C18H10Cl2N4O4: 416,0; received m/z: 417,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,00 (s, 1H); 12,97-12,67 (m, 1H); of 8.95 (s, 1H); of 8.25 (s, 1H); to 7.77 (s, 1H); to 7.64 (DD, J=8,9, 2,9 Hz, 1H); to 7.59 (d, J=8,1 Hz, 1H); 7,47 (t, J=8,2 Hz, 1H); 7,40 (s, 1H); 7,28 (d, J=8.0 Hz, 1H).

Example 61: 1-[6-(2,6-dimethylphenoxy)-7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 2,6-dimethylphenol and 4-fluoro-3-methoxyethanol. MS (IER): calculated for C21H18N4O5: 406,1; received m/z: 407,1 [M+H]+.1H NMR (400MHz, DMSO-d6): 12,99 (s, 1H); 12,70 (s, 1H); 8,91 (s, 1H); by 8.22 (s, 1H); 7,34 (s, 1H); from 7.24 (d, J=7,4 Hz, 2H); 7,17 (DD, J=8,5, 6.3 Hz, 1H); 6,79 (s, 1H); 4,07 (s, 3H); 2,07 (s, 6H).

Example 62: 1-(7-methoxy-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And phenol and 4-fluoro-3-methoxyethanol. MS (IER): calculated for C19H14N4O5: 378,1; received m/z: 379,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,01 (s, 1H); 12,79 (s, 1H); 8,93 (s, 1H); of 8.25 (s, 1H); 7,45 (s, 1H); 7,41 (DD, J=8,6, 7.5 Hz, 2H); to 7.35 (s, 1H); 7,17 (t, J=7,4 Hz, 1H); 7.03 is (d, J=7.7 Hz, 2H); of 3.95 (s, 3H).

Example 63: 1-[6-(2,6-dimethylphenoxy)-5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on stage And 2,6-dimethylphenol and 3,4,5-cryptomaterial. MS (IER): calculated for C20H14F2N4O4: 412,1; received m/z: 413,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,07 (s, 2H); 8,91 (d, J=0.4 Hz, 1H); of 8.27 (s, 1H); 7,52 (d, J=11,6 Hz, 1H); for 7.12 (d, J=7.5 Hz, 2H); 7,06 (DD, J=8,5, 6.2 Hz, 1H); of 2.16 (s, 6H).

Example 64: 1-(5,7-debtor-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to describe the approach in Example 29, using on stage And phenol and 3,4,5-cryptomaterial. MS (IER): calculated for C18H10F2N4O4: 384,1; received m/z: 385,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,10 (s, 2H); to 8.94 (s, 1H); 8.30 to (s, 1H); to 7.61 (d, J=10,7 Hz, 1H); 7,39 (DD, J=8,6, 7.5 Hz, 2H); 7,14 (t, J=7,4 Hz, 1H);? 7.04 baby mortality (d, J=8.0 Hz, 2H).

Example 65: 1-[4-oxo-6-(pyridine-3-yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, using on-stage And 3-hydroxypyridine and 4-peritrabecular. MS (IER): calculated for C17H11N5O4: 349,1; received m/z: 350,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,00 (s, 1H); 12,96-12,70 (m, 1H); of 8.95 (s, 1H); 8,51 (s, 1H); 8,48 (d, J=3.8 Hz, 1H); compared to 8.26 (s, 1H); for 7.78 (s, 1H); 7,66 (DD, J=8,8, 2.2 Hz, 1H); a 7.62 (d, J=8,4 Hz, 1H); 7,56-of 7.48 (m, 2H).

Example 66: 1-(4-oxo-7-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 29, stage C-E, using on stage With 3-phenoxyimino. MS (IER): calculated for C18H12N4O4: 348,1; received m/z: 349,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,97 (s, 1H); 12,77 (s, 1H); 8,93 (s, 1H); 8,24 (s, 1H); to 8.14 (d, J=7.9 Hz, 1H); 7,52 (t, J=7.9 Hz, 2H); 7,31 (t, J=7,4 Hz, 1H); 7,22 (d, J=7.7 Hz, 2H); 7,17 (d, J=8.5 Hz, 1H); of 6.96 (s, 1H).

Example 67: 1-[4-oxo-7-(Tetra drapery-4-yl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, Tris(hydroxymethyl)aminobutanova salt.

Stage A. Obtain tert-butyl ester [4-(4-hydroxyethylamino-4-yl)-phenyl]-carbamino acid. THF (50 ml) dried in the oven odnogolosy flask of 500 ml was cooled in a bath temperature of -78°C in an atmosphere of N2. Then for 10 min using a syringe dropwise added a solution of n-utility in hexano (15,4 ml, 2.5 M, and 38.6 mmol). The obtained clear solution was stirred at -78°C for 30 minutes and Then for 10 min with stirring dropwise added N-tert-butoxycarbonyl-4-bromaniline (of 5.00 g, 18.4 mmol), dissolved in 10 ml of THF, after which the stirring was continued for another 30 min at -78°C. and Then for 10 min dropwise added a solution of tetrahydro-4H-Piran-4-it (2,02 g, a 20.2 mmol) in 5 ml of THF. After 150 min the reaction mixture allowed to warm to room temperature, a saturated solution of NH4Cl brought the volume up to 200 ml) and was extracted with ether (3 x 100 ml). The combined organic phases are washed with water (50 ml) and saturated saline (50 ml) and dried over MgSO4. Filtration followed by concentration obtained crude product, which was recrystallize from 70 ml of DCM to obtain the pure product in the form of a solid white color (to 2.29 g, 42%). MS (IER): calculated for C16H23NO4: 293,3; received m/z: 276,1 [M-H2O+H] +.1H NMR (500 MHz, CDCl3): 7,46-7,38 (m, 2H); of 7.36 (d, J=8.6 Hz, 2H); 6.48 in (s, 1H); 3,90 (m, 4H); 2,30-to 1.98 (m, 2H); 1,68 (d, J=12.1 Hz, 2H); of 1.52 (s, 9H).

Stage B. Obtaining trifenatate 4-(tetrahydropyran-4-yl)-phenylamine. tert-Butyl ester 4-(4-hydroxy-tetrahydropyran-4-yl)-phenyl]-carbamino acid (1.85 g, of 6.31 mmol) suspended in a mixture of 40 ml of DCM and 20 ml of triethylsilane and within 2 minutes was dispersively using ultrasound. Then added triperoxonane acid (40 ml) and the obtained clear solution. The solution stood at room temperature for 16 h and concentrated in vacuum, obtaining the desired product in the form of amorphous solids (2,40 g, 75%). MS (IER): calculated for C11H14NO: 177,2; received m/z: 178,1 [M+H]+.1H NMR (400 MHz, DMSO): 10,17 (s, 3H); to 7.35 (d, J=8,4 Hz, 2H); from 7.24 (d, J=8,4 Hz, 2H); 4,13-3,81 (m, 2H); 3.43 points (TD, J=11,2, 3,4 Hz, 2H); 2,97-of 2.64 (m, 1H); 1,91-of 1.35 (m, 3H).

Stage C. Obtaining 1-[4-oxo-7-(tetrahydropyran-4-yl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained from trifenatate 4-(tetrahydropyran-4-yl)-phenylamine using the methods described in Example 27, stages C, D and E, using EDCI instead of DIC at the stage of C. MS (IER): calculated for C17H16N4O4: 340,3; received m/z: 341,1 [M+H]+, 379,1 [M+K]+1H NMR (400 MHz, DMSO):12,92 (s, 2H); to 8.94 (s, 1H); of 8.25 (s, 1H); of 7.96 (s, 1H); to 7.77 (s, 1H); to 7.67 (s, 1H); 3,98 (m, 2H); 3,47 (m, 2H); 3,29 (m, 4H); 2,96 (m, 1H).

tadia D. Obtaining Tris(hydroxymethyl)aminometanului salt of 1-[4-oxo-7-(tetrahydropyran-4-yl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. 1-[4-Oxo-7-(tetrahydropyran-4-yl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0,158 g, 0,464 mmol) in form of the free acid suspended in a mixture of 10 ml of MeOH and 10 ml of THF and then added a solution of Tris(hydroxymethyl)aminomethane (0,0562 g, 0,464 mmol) in 1 ml of water. The resulting solution was stirred for 2 h, then concentrated in vacuum and dried in a drying pistol (0.1 mm, RT. senior, 60°C)with 214 mg of white powder (99%). MS (IER): calculated for C17H16N4O4: 340,3; received m/z: 341,1 [M+H]+.

Example 68: 1-(7-chloro-4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. Obtain 2-chloro-4-nitrobiphenyl. A mixture of potassium carbonate (1.48 g, is 10.7 mmol), phenylboric acid (645 mg, from 5.29 mmol), 3-chloro-4-initlabel (1,00 g of 3.53 mmol) and THF (31 ml) for 10 min was degirolami nitrogen in a hermetically sealed reactor. Then to the reaction mixture was added dichloromethane adduct [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (351 mg, 0,429 mmol) and hermetically closed reactor. The resulting mixture was stirred at 100°C for 42 h and Then the mixture was cooled to 23°C, diluted with DCM (40 ml) and was filtered. The obtained filtrate with whom he koncentrirebuli. The obtained residue was purified KFH (EtOAc/hexane from 3 to 50%) and obtained the desired compound (796 mg, 97%).1H NMR (600 MHz, DMSO-d6): 8,42-to 8.41 (m, 1H); compared to 8.26 (DD, J=8,5, 2,2, Hz, 1H); 7,72 (d, J=8.5 Hz, 1H); 7,55-of 7.48 (m, 5H).

Stage B. Obtain 1-(7-chloro-4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 27, steps In, using 2-chloro-4-nitrobiphenyl. MS (IER): calculated for C18H11ClN4O3: 366,1; received m/z: 367,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,04 (ush s, 2H); 8,97 (s, 1H); 8,29 (s, 1H); 8,03 (s, 1H); to $ 7.91 (s, 1H); 7,52 (d, J=4.4 Hz, 4H); 7,49 was 7.45 (m, 1H).

Example 69: 1-(4-oxo-6-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(6-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 17, stages a and b, using on-stage And 4-iodine-phenylamine. MS (IER): calculated for C14H11IN4O3: 410,0; received m/z: 411,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 9,01 (d, J=0.6 Hz, 1H); 8,39 (d, J=2.0 Hz, 1H); 8.34 per (s, 1H); to 8.14 (DD, J=8,5, and 2.1 Hz, 1H); 7,52 (s, 1H); 4,30 (q, J=7,1 Hz, 2H); to 1.32 (t, J=7,1 Hz, 3H).

Stage B. obtaining the ethyl ester of 1-[6-iodine-4-oxo-3-(2-trimethylsilyl-ethoxymethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid is. In a mixture of ethyl ester of 1-(6-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (500 mg, 1,22 mmol) and THF (6 ml) at 23°C was added diisopropylethylamine (0,425 ml of 2.44 mmol) and then 2-(trimethylsilyl)-ethoxymethylene (0,205 ml of 1.34 mmol). After stirring for 18 h the reaction mixture was concentrated under reduced pressure. The obtained residue was purified KFH (EtOAc/hexane from 5 to 45%) and obtained the desired compound (603 mg, 92%). MS (IER): calculated for C20H25IN4O4Si: 540,1; received m/z: 483,0 [M-CH2OCH2CH2+H]+.1H NMR (600 MHz, DMSO-d6): 8,91 (d, J=0.6 Hz, 1H); and 8.50 (d, J=2.0 Hz, 1H); 8,30 (d, J=0.6 Hz, 1H); 8,24 (DD, J=8,5, and 2.1 Hz, 1H); at 7.55 (d, J=8.5 Hz, 1H); 5,61 (s, 2H); 4,29 (kV, J=7,1 Hz, 2H); 3,41-3,37 (m, 2H); of 1.30 (t, J=7,1 Hz, 3H); to 0.72-0.69 (m, 2H); -0,12 - -0,13 (m, 9H).

Stage C. obtaining the ethyl ester of 1-[4-oxo-6-o-tolyl-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. A mixture of potassium carbonate (85,4 mg, 0,618 mmol), 2-methylphenylimino acid (63,3 mg, 0,466 mmol), ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (110 mg, 0,204 mmol) and THF (1.5 ml) was degirolami nitrogen for 5 minutes in a hermetically sealed reactor. Then to the reaction mixture was added dichloromethane adduct of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (20.2 mg, 0,0246 mmol) and hermetically closed re ctor. The resulting mixture was stirred at a temperature of 80°C for 18 h Then the reaction mixture was cooled to 23°C, diluted with DCM (10 ml) and was filtered. The obtained filtrate was concentrated. The obtained residue was purified KFH (EtOAc/hexane from 3 to 40%), having the desired compound (92.0 mg, 90%). MS (IER): calculated for C27H32N4O4Si: 504,22; received m/z: 446,6 [M-CH2OCH2CH2+H]+.1H NMR (600 MHz, CDCl3): 8,68 (d, J=0.6 Hz, 1H); 8,31 - 8,30 (m, 1H); 8,18 (d, J=0.6 Hz, 1H); 7,79 (DD, J=8,3, 2.1 Hz, 1H); 7,76-7,74 (m, 1H); 7,33-7,28 (m, 4H); 5,91 (s, 2H); 4,39 is 4.35 (m, 2H); 4,37 (kV, J=7.2 Hz, 2H); 2,31 (s, 3H); of 1.39 (t, J=7,1 Hz, 3H); 0,83-of 0.79 (m, 2H); -0,08 (s, 9H).

Stage D. obtaining the ethyl ester of 1-(4-oxo-6-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To ethyl ether, 1-[4-oxo-6-o-tolyl-3-(2-trimethylsilyl-ethoxymethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (88,0 mg, 0,174 mmol) was added a solution of HCl in dioxane (4 M, 0,872 ml of 3.48 mmol). The reaction mixture was stirred at 23°C. After 18 h, the reaction mixture was concentrated under reduced pressure. Then added Et2O (5 ml), the precipitate was collected by filtration and well washed Et2O, having the desired compound (52,0 mg, 80%). MS (IER): calculated for C21H18N4O3: 374,1; received m/z: 375,2 [M+H]+.1H NMR (600 MHz, CDCl3): 9,05 (s, 1H); 8,35 (s, 1H); 8,02 (s, 1H); 7,86 (d, J=6,6 Hz, 1H); for 7.78 (s, 1H); 7,37-7,28 (m, 4H); or 4.31 (q, J=7,1 Hz, 2H); 228 (, 3H); of 1.33 (t, J=7,1 Hz, 3H).

Stage E. Obtain 1-(4-oxo-6-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester of 1-(4-oxo-6-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (40,0 mg, 1.07 mmol), 1 M aqueous solution of KOH (0.5 ml) and THF (1 ml) was stirred for 16 hours Then the reaction mixture was concentrated under reduced pressure to remove THF, and the remaining aqueous phase was acidified to pH 2 by addition of 1 M aqueous HCl. The resulting precipitate was collected by filtration, obtaining the desired compound (30.0 mg, 81%). MS (IER): calculated for C19H14N4O3: 346,1; received m/z: 347,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,04 (s, 1H); 12,93 (s, 1H); 8,99 (s, 1H); of 8.28 (s, 1H); 8,02 (s, 1H); 7,86 (d, J=7.5 Hz, 1H); 7,76 (d, J=7.8 Hz, 1H); 7,37-7,29 (m, 4H); of 2.28 (s, 3H).

Example 70: 1-(6-diphenyl-3-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using the ethyl ester of 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (product of Example 69, step B) and diphenyl-3-boric acid. MS (IER): calculated for C24H16N4O3: 408,1; received m/z: 409,1 [M+H]+.1HNMR (600 MHz, DMSO-d6): 13,01 (s, 1H); 12,92 (s, 1H); 9,00 (s, 1H); 8,44 (s, 1H); 8,2-of 8.25 (m, 2H); 8,01 (s, 1H); 7,83-to 7.77 (m, 4H); 7,72 (d, J=7.8 Hz, 1H); a 7.62 (t, J=7.7 Hz, 1H); 7,53-of 7.48 (m, 2H); 7,43-7,40 (m, 1H).

Example 71: 1-[7-chloro-6-(3,4-dimethoxybenzonitrile)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-[7-chloro-6-(3,4-dimethoxybenzonitrile)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. Suspension of urea·H2O2(941 mg, 11.0 mmol) in DCM (8.6 ml) was cooled in an ice bath and dropwise added triperoxonane anhydride (2.4 ml, of 17.0 mmol). The resulting mixture was stirred for 1 hour. Part of the resulting solution cryptanalyses acid (0,86 ml, 0.86 mmol) dropwise added to a solution of ethyl ester 1-[7-chloro-6-(3,4-dimethoxyphenylacetone)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate compound from Example 26, 140 mg, 0.28 mmol) in DMA (1 ml). After 16 h was added to a second aliquot of the solution cryptanalyses acid (1 ml, 1 mmol) and passed the mixture for another 12 hours the mixture was cooled in an ice bath and then added water (15 ml). The resulting precipitate was collected by filtration and used in the subsequent stage without further purification.

Stage B. Obtaining 1-[7-chloro-6-(3,4-dimethoxybenzonitrile)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. Ethyl ester of 1-[7-chloro-6-(3,4-dimethoxybenzonitrile)4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid was mixed with THF (5 ml) and then added a 1 M aqueous solution of KOH (2.7 ml, 2.7 mmol) and the mixture was stirred for 16 hours, the Reaction mixture was cooled in an ice bath and then added a 1 M aqueous solution of HCl (5 ml) and water (5 ml). The resulting precipitate was collected by filtration and purified HPLC, obtaining the desired compound (16 mg, 12%). MS (HEE): calculated for C20H15ClN4O7S: 490,0; received m/z: 489,0 [M-H]-.1H NMR (500 MHz, DMSO-d6): 13,10 (s, 2H); of 8.95 (s, 1H); 8,86 (s, 1H); 8,32 (s, 1H); 7,87 (s, 1H); to 7.59 (DD, J=8,6, 1.8 Hz, 1H); 7,41 (d, J=2.0 Hz, 1H); 7,19 (d, J=8.6 Hz, 1H); 3,85 (s, 3H); 3,81 (s, 3H).

Example 72: 1-[6-(4-tert-butylbenzenesulfonyl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 71, using the ethyl ester of 1-[6-(4-tert-butyl-phenylsulfanyl)-7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate compound from Example 24). MS (HEE): calculated for C22H19ClN4O5S: 486,1; received m/z: 485,0 [M-H]-.1H NMR (500 MHz, DMSO - d6): 12,97 (s, 1H); 12,77 (s, 1H); 8,93 (s, 1H); 8,24 (s, 1H); to 8.14 (d, J=7.9 Hz, 1H); 7,52 (t, J=7.9 Hz, 2H); 7,31 (t, J=7,4 Hz, 1H); 7,22 (d, J=7.7 Hz, 2H); 7,17 (d, J=8.5 Hz, 1H); of 6.96 (s, 1H). to 13.09 (s, 1H); of 8.95 (s, 1H); 8,88 (s, 1H); 8,31 (s, 1H); of 7.90 (d, J=8,6, 2H); 7,87 (s, 1H); to 7.67 (d, J=8,7, 2H); of 1.29 (s, 9H).

Example 73: 1-(7,7-dimethyl-4-oxo-3,7-dihydro-4H-8-oxa-1,3-vasantrao-2-yl)-1H-pyrazole-4-carboxylic acid.

/p>

The desired compound was obtained in a manner analogous to the one described in Example 27, stage C-E, using 2,2-dimethyl-6-amino-2H-1-benzopyran on stage and With the addition of 4.0 EQ. 2,6-di-tert-butylpyridinium on stage D. MS (IER): calculated for C17H14N4O4: 338,1; received m/z: 339,1 [M+H]+.1H NMR (500 MHz, DMSO - d6): 12,94 (s, 2H); 8,88 (s, 1H); 8,23 (s, 1H); 7,44 (s, 1H); 7,31 (s, 1H); only 6.64 (d, J=9.9 Hz, 1H); 6,10 (d, J=9.9 Hz, 1H); USD 1.43 (s, 6H).

Example 74: 1-(4-oxo-6-phenoxymethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 27, stage C-E, using 4-phenoxyethylamine at the stage C and with the addition of 4.0 EQ. 2,6-di-tert-butylpyridinium on stage D. MS (IER): calculated for C19H14N4O4: 362,1; received m/z: 363,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,97 (s, 2H); 8,96 (s, 1H); of 8.27 (s, 1H); to 8.20 (s, 1H); to $ 7.91 (DD, J=8,4, 1.9 Hz, 1H); 7,73 (d, J=8,2 Hz, 1H); 7,35-7,27 (m, 2H); 7,05 (DD, J=8,7, 0.9 Hz, 2H); of 6.96 (t, J=7,3 Hz, 1H); at 5.27 (s, 2H).

Example 75: 1-[6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 27, stage C-E, using 4-(2,6-dimethyl)phenoxyethylamine at the stage C and with the addition of 4.0 EQ. 2,6-di-tert-butylpyridinium on stud and D. MS (IER): calculated for C21H18N4O4: 390,1; received m/z: to € 391.1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,99 (s, 2H); 8,96 (d, J=and 12.2 Hz, 1H); compared to 8.26 (d, J=15,8 Hz, 2H); of 7.97 (DD, J=8,4, 1.9 Hz, 1H); 7,76 (d, J=7.8 Hz, 1H); 7,11? 7.04 baby mortality (m, 2H); 7,01-6,93 (m, 1H); of 4.95 (s, 2H); of 2.28 (s, 6H).

Example 76: 1-(6-ethinyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(6-ethinyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 27, stage C-D, using 4-itineraria at the stage C and with the addition of 4.0 EQ. 2,6-di-tert-butylpyridinium at stage D. the Crude product contained a mixture of the desired compounds and ethyl ester 1-[6-(1-vinyl chloride)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid in a ratio of 2.4:1. To obtain the ethyl ester of 1-(6-ethinyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid portion of this mixture was purified using HPLC. MS (IER): calculated for C16H12N4O3: 308,1; received m/z: 309,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,98 (ush s, 1H); of 8.95 (s, 1H); of 8.27 (s, 1H); 8,07 (s, 1H); of 7.82 (DD, J=8,4, 1.9 Hz, 1H); 7,72-rate of 7.54 (m, 1H); or 4.31 (s, 1H); to 4.23 (q, J=7,1 Hz, 2H); of 1.26 (t, J=7,1 Hz, 3H).

Stage B. Obtain 1-(6-ethinyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained is a procedure, similar to that described in Example 27, step E. MS (IER): calculated for C14H8N4O3: 280,1; received m/z: 281,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): of 13.05 (s, 2H); 8,96 (s, 1H); 8,28 (ush s, 1H); 8,13 (ush s, 1H); 7,89 (DD, J=8,4, 2.0 Hz, 1H); 7,79-7,58 (m, 1H); 4,39 (s, 1H).

Example 77: 1-[6-(1-vinyl chloride)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 76. MS (IER): calculated for C14H9ClN4O3: 317,0; received m/z: 318,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): of 13.05 (s, 3H); 8,97 (s, 1H); to 8.41-8,24 (m, 2H); 8,19 (d, J=6,5 Hz, 1H); 7,80-to 7.64 (m, 1H); 6,29 (m, 1H); 5,77 (d, J=2.6 Hz, 1H).

Example 78: 1-(4-oxo-7-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. Obtaining 3-nitrophenyl-persulfide. A mixture of thiophenol (1.0 g, 9.1 mmol), 3-initlabel (1.9 g, 7.6 mmol), CuI (0.14 g, from 0.76 mmol), K2CO3(1,67 g, 12.1 mmol) and DMF (10 ml) stood at 100°C for 16 h in a tightly closed reactor, dried way fire-cured. The resulting mixture allowed to cool and poured on ice. The resulting mixture was extracted with EtOAc (2X), the organic extracts combined and washed successively with equal volumes of 1 M aqueous HCl, water and 1 M aqueous NaOH solution. The resulting solution was dried, scancenter the Wali, and the obtained residue was purified KFH (hexane/EtOAc from 100:0 to 95:5), having the desired compound which is contained as an impurity OK. 10% of thiophenol (1,43 g) and was used at subsequent stages without additional purification.

Stage C. Obtaining 3-phenylsulfanyl-phenylamine. 3-Nitrophenyl-persulfide obtained in stage A mixture of a purity of about 90% (1,43 g, 6.2 mmol)was dissolved in acetone (20 ml) and cooled in an ice bath. Then added a saturated solution of NH4Cl (5 ml), followed by vigorously stirring for 5 min in small portions was added zinc dust (3.7 g, 56 mmol). Ice bath, allowed to melt, and the resulting mixture was stirred for 16 hours Then to the mixture was added EtOAc (200 ml) and then anhydrous sodium sulfate (20 g). Stirring was continued for another 1 h, after which the mixture was filtered through a layer of silica gel, using as eluent an additional amount of EtOAc. The obtained transparent solution was concentrated, and the obtained residue was purified KFH (hexane/EtOAc 99:1 to 70:30), having the desired compound (1,43 g, 69%). MS (IER): calculated for C12H11NS: 201,3; received m/z: 202,1 [M+H]+.

Stage C. obtaining the ethyl ester of 1-(4-oxo-7-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in accordance with the methods described in Example 27, stage C-D, used with the eating stage 3-difenilamina. MS (IER): calculated for C20H16N4O3S: 392,4; received m/z: 393,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,94 (s, 1H); 8,97 (s, 1H); 8.30 to (s, 1H); 8,03 (d, J=8,4 Hz, 1H); 7,66-7,58 (m, 2H); 7,58-7,51 (m, 3H); 7,29 (DD, J=8,4, 1.8 Hz, 1H); 7,22 (s, 1H); 4,28 (kV, J=7,1 Hz, 2H); to 1.31 (t, J=7,1 Hz, 3H).

Stage D. Obtain 1-(4-oxo-7-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in accordance with the methods described in Example 27, step E, using 1-(4-oxo-7-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. MS (IER): calculated for C18H12N4O3S: 363,0; received m/z: 365,1 [M+H]+.1H NMR (500 MHz, DMSO - d6): to 13.09-12,70 (m, 2H); of 8.90 (s, 1H); 8,24 (s, 1H); 8,03 (d, J=8,4 Hz, 1H); to 7.64-to 7.59 (m, 2H); EUR 7.57-7,52 (m, 3H); 7,28 (DD, J=8,4, 1.8 Hz, 1H); 7,21 (ush s, 1H).

Example 79: 1-[7-(4-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 78, using on-stage And 4-chlorothiophenol. MS (IER): calculated for C18H11ClN4O3S: 398,0; received m/z: 399,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): to 13.09-12,78 (m, 2H); 8,93 (s, 1H); of 8.25 (s, 1H); 8,04 (d, J=8,2 Hz, 1H); to 7.64-EUR 7.57 (m, 4H); 7,34-of 7.23 (m, 2H).

Example 80: 1-[7-(2-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 78, using on-stage And 2-chlorothiophenol. MS (IER): calculated for C18H11ClN4O3S: 398,0; received m/z: 399,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): of 13.18-12,66 (m, 2H); of 8.92 (s, 1H); of 8.25 (s, 1H); 8,07 (d, J=8,3 Hz, 1H); 7,72 (DD, J=8,0, 1.3 Hz, 1H); the 7.65 (DD, J=7,7, and 1.6 Hz, 1H); at 7.55 (TD, J=7,7, 1.7 Hz, 1H); of 7.48 (TD, J=7,6, and 1.4 Hz, 1H); 7,30 (DD, J=8.4 and, 1.8 Hz, 1H); from 7.24 (s, 1H).

Example 81: 1-(7-benzazolyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(7-benzazolyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. In the solution of the ethyl ester of 1-(4-oxo-7-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 78, the product obtained in stage C, 130 mg, 0.33 mmol) in DCM (10 ml) was added mCPBA in the form of a solid (305 mg, 0.133 mmol). The reaction was performed at room temperature for 16 hours. Then the reaction mixture was diluted with DCM, washed with saturated aqueous sodium thiosulfate solution, saturated aqueous NaHCO3, dried and concentrated. The resulting crude product was used without further purification (52 mg, 37%). MS (IER): calculated for C20H16N4O5S: 424,1; received m/z: 425,1 [M+H]+.

Stage B. Obtain 1-(7-benzazolyl-4-oxo-3-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester of 1-(7-benzazolyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (50 mg, 0.12 mmol), THF (2 ml) and 1 M aqueous LiOH (0.6 ml, 0.6 mmol) was stirred for 16 hours Then THF was removed under reduced pressure and added 1 M aqueous solution of HCl (3 ml, 3 mmol). The resulting crude product was collected by filtration and purified HPLC, obtaining the desired compound (7.0 mg, 14 %). MS (IER): calculated for C18H12N4O5S: 396,1; received m/z: 397,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,43-12,81 (m, 2H); 8,99 (s, 1H); 8.34 per is 8.25 (m, 2H); 8,18 (s, 1H); with 8.05 (d, J=7,6 Hz, 2H); of 7.96 (DD, J=8,3, 1.5 Hz, 1H); 7,78-7,71 (m, 1H); 7,71-7,63 (m, 2H).

Example 82: 1-[7-(4-chlorobenzenesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 81, using on stage And ethyl ester 1-[7-(4-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate compound from Example 79). MS (IER): calculated for C18H11ClN4O5S: 430,0; received m/z: 431,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,06 (ush s, 2H); 8,99 (s, 1H); 8,35 is 8.25 (m, 2H); 8,19 (s, 1H); 8,08 (d, J=8,4 Hz, 2H); of 7.97 (DD, J=8,3 Hz, 1,7, 1H); 7,78-7,71 (m, 2H).

Example 83: 1-[7-(2-chlorobenzenesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 81, using the ethyl ester of 1-[7-(2-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate compound from Example 80). MS (IER): calculated for C18H11ClN4O5S: 430,0; received m/z: 431,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,40-12,82 (m, 2H); of 9.02 (s, 1H); 8,39 (d, J=7.8 Hz, 1H); at 8.36-of 8.25 (m, 2H); to 8.12 (s, 1H); of 7.90 (d, J=8,3 Hz, 1H); 7,84-7,66 (m, 3H).

Example 84: 1-[7-chloro-6-(3,4-dihydro-1H-isoquinoline-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A. Obtaining 2-(2-chloro-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline. A mixture of 3,4-dichloronitrobenzene (1.0 g, 5.2 mmol), 1,2,3,4-tetrahydroisoquinoline (0.97 g, 7,3 mmol), K2CO3(3.6 g, 26 mmol) and DMSO (20 ml) under stirring stood at 80°C for 16 hours the mixture is allowed to cool to room temperature and poured on ice. The precipitation was collected by filtration and obtained the desired compound (1.5 g, 98%). MS (IER): calculated for C15H13ClN2O2: 288,7; received m/z: 289,1 [M+H]+.

Stage B. Obtaining 2-(2-chloro-4-AMINOPHENYL)-1,2,3,4-tetrahydroisoquinoline. A mixture of 2-(2-chloro-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (1.4 g, 4.8 mmol), saturated aqueous solution of ammonium chloride (5 ml) and acetone (20 ml) cooled in an ice bath. C is the for 10 min with stirring in small portions was added zinc dust (3.2 g, 48 mmol). Ice bath, allowed to melt, and the resulting mixture was stirred for 16 hours Then to the mixture was added EtOAc (200 ml) and then anhydrous sodium sulfate (20 g). The mixture was mixed for 15 min and was filtered through a layer of silica gel, using as eluent an additional amount of EtOAc. The obtained transparent solution was concentrated, obtaining the desired compound (1.2 g, 96%).1H NMR (500 MHz, CDCl3): 7,20-7,11 (m, 3H); 7,11? 7.04 baby mortality (m, 1H); to 6.95 (d, J=8.5 Hz, 1H); is 6.78 (d, J=2.7 Hz, 1H); 6,56 (DD, J=8,5, 2.7 Hz, 1H); to 4.17 (s, 2H); 3,55 (s, 2H); with 3.27 (t, J=5.8 Hz, 2H); 3,00 (t, J=5.8 Hz, 2H).

Stage C. obtaining the ethyl ester of 1-{[4-chloro-3-(3,4-dihydro-1H-isoquinoline-2-yl)-benzoylamine]-ethoxycarbonylmethyl}-1H-pyrazole-4-carboxylic acid. A solution of 2-(2-chloro-4-AMINOPHENYL)-1,2,3,4-tetrahydroisoquinoline (1.2 g, 4.6 mmol) and ethylisothiocyanate (0,61 g, 4.6 mmol) in DCM (20 ml) stood at room temperature for 16 hours Then the reaction mixture is concentrated until dry and re-dissolved in DCM (20 ml). To the mixture was added aripirazole-4-carboxylate (0,98 g, 10 mmol), triethanolamine (tea) (1.4 g, 14 mmol), EDCI (1.3 g, 7.0 mmol) and kept for 4 hours for reaction. Then the mixture was diluted with EtOAc (200 ml), washed with equal volumes of water (2X) and saturated salt solution, dried and concentrated. The obtained residue was purified KFH (EtOAc/hexane from 1:99 to 30:70) to give justicesystem guanidine intermediate compound (1.2 g, 52%).

Stage D. obtaining the ethyl ester of 1-[7-chloro-6-(3,4-dihydro-1H-isoquinoline-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. A solution of ethyl ester 1-{[4-chloro-3-(3,4-dihydro-1H-isoquinoline-2-yl)-benzoylamine]-ethoxycarbonylmethyl}-1H-pyrazole-4-carboxylic acid (1.2 g, 2.4 mmol) in a mixture of DCE (5 ml) and chlorotrimethylsilane (2.8 ml, 22 mmol) stood at 110°C in a tightly closed reactor for 16 hours and Then the reactor contents were passed in an ice bath for 1 h and the precipitate was collected by filtration, washed with cold DCE and dried in vacuum, obtaining the desired compound (0.40 g, 19%). MS (IER): calculated for C23H20ClN5O3: 449,9; received m/z: of 450.1 [M+H]+.

Stage E. Obtaining 1-[7-chloro-6-(3,4-dihydro-1H-isoquinoline-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester of 1-[7-chloro-6-(3,4-dihydro-1H-isoquinoline-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0.35 g, 0.78 mmol), THF (12 ml) and 1 M aqueous LiOH solution (7.8 ml, 7.8 mmol) was stirred at room temperature for 16 hours Then THF was removed and the aqueous phase was cooled in an ice bath. the pH of the resulting mixture is brought to about pH 5 with 1 M aqueous HCl, the precipitate was collected, thoroughly washed with water and dried, obtaining the desired compound (0.33 g, 99%). MS (IER): calculated for C21H16ClN O3: 421,1; received m/z: 422,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,22-12,69 (ush m, 2H); of 8.92 (s, 1H); of 8.25 (s, 1H); 7,88-7,73 (m, 2H); 7.24 to 7,16 (m, 4H); or 4.31 (s, 2H); 3,39 (t, J=5.6 Hz, 2H); 3,00 (t, J=5.5 Hz, 2H).

Example 85: 1-[6-(7-bromo-3,4-dihydro-1H-isoquinoline-2-yl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 84 using on stage And 7-bromo-1,2,3,4-tetrahydroisoquinoline and 2,3-dichloronitrobenzene. MS (IER): calculated for C21H15BrClN5O3: 499,0; received m/z: 500,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,93 (s, 2H); of 8.92 (s, 1H); of 8.25 (s, 1H); 7,80 (s, 2H); 7,47 (s, 1H); 7,38 (d, J=8,1 Hz, 1H); 7,17 (d, J=8,2 Hz, 1H); or 4.31 (s, 2H); 3.45 points-to 3.35 (m, 3H); 3,01-2,90 (m, 2H).

Example 86: (rat)-1-{7-chloro-6-[3-(3-methoxyphenyl)-piperidine-1-yl]-4-oxo-3,4-dihydroquinazolin-2-yl}-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 84 using on-stage And 3-(3-methoxyphenyl)piperidine and 2,3-dichloronitrobenzene. MS (IER): calculated for C24H22ClN5O4: 479,1; received m/z: of 480.2 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,32 was 12.61 (ush m, 2H); of 8.90 (s, 1H); 8,24 (s, 1H); 7,76 (s, 1H); 7,72 (s, 1H); 7.23 percent (t, J=7.9 Hz, 1H); of 6.96-to 6.88 (m, 2H); 6,84-6,76 (m, 1H); of 3.75 (s, 3H); 3.43 points-to 3.36 (m, 2H); 2,96 (t, J=11.3 Hz, 1H); 2,89-of 2.72 (m, 2H); 2,02-of 1.74 (m, 3H); 1,73 is 1.58 (m, 1H).

Por the measures 87: 1-[6-(2,5-dichlorophenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on stage And 2,5-dichlorophenol and 3,4-deformirovannoe. MS (IER): calculated for C18H9Cl2FN4O4: 434,0; received m/z: 434,9 [M+H]+.1H NMR (400 MHz, DMSO-d6): to 13.09 (s, 2H); of 8.92 (s, 1H); of 8.27 (s, 1H); of 7.75 (d, J=11,4 Hz, 1H); 7,72 (d, J=8.6 Hz, 1H); rate of 7.54 (d, J=8,8 Hz, 1H); 7,44 (d, J=2.4 Hz, 1H); 7,40 (DD, J=8,6, and 2.4 Hz, 1H).

Example 88: 1-[6-(3,4-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on stage And 3,4-dimethylphenol and 3,4-deformirovannoe. MS (IER): calculated for C20H15FN4O4:394,1; received m/z: 395,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,04 (s, 1H); 13,04-12,92 (m, 1H); 8,91 (s, 1H); compared to 8.26 (s, 1H); of 7.70 (d, J=11.5 Hz, 1H); 7,47 (d, J=8,9 Hz, 1H); 7,22 (d, J=8,2 Hz, 1H); 6,99 (d, J=2.7 Hz, 1H); 6.89 in (DD, J=8,2, 2.7 Hz, 1H); 2,24 (s, 6H).

Example 89: 1-[6-(3,5-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on stage And 3,5-dimethylphenol and 4-fluoro-3-methylnitrobenzene. MS (IER): calculated for C21H18N4O4: 3901; the obtained m/z: to € 391.1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,99 (s, 2H); 8,91 (s, 1H); 8,24 (s, 1H); 7,66 (s, 1H); 7,30 (s, 1H); 6,86 (s, 1H); 6,70 (s, 2H); 2,39 (s, 3H); and 2.27 (s, 6H).

Example 90: 1-[6-(2,5-dichlorophenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on stage And 2,5-dichlorophenol and 4-fluoro-3-methylnitrobenzene. MS (IER): calculated for C19H12Cl2N4O4: 430,0; received m/z: 431,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,02 (s, 1H); 12,87 (s, 1H); of 8.92 (s, 1H); of 8.25 (s, 1H); 7,72 (d, J=8.6 Hz, 2H); 7,40 (DD, J=8,6, and 2.4 Hz, 1H); to 7.35 (d, J=2.2 Hz, 1H); 7.23 percent (s, 1H); 2,43 (s, 3H).

Example 91: 1-[6-(diphenyl-3-yloxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on-stage And 3-phenylphenol and 4-fluoro-3-methylnitrobenzene. MS (IER): calculated for C25H18N4O4: 438,1; received m/z: 439,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,91 (s, 2H); 8,91 (s, 1H); by 8.22 (s, 1H); 7,72-the 7.65 (m, 3H); rate of 7.54 (DD, J=3,8, and 2.3 Hz, 2H); 7,46 (t, J=7.5 Hz, 2H); 7,41-7,37 (m, 3H); 7,10-7,03 (m, 1H); 2,43 (s, 3H).

Example 92: 1-[6-(3,4-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

IP is omogo compound was obtained in accordance with methods, described in Example 27, using on stage And 3,4-dimethylphenol and 4-fluoro-3-methylnitrobenzene. MS (IER): calculated for C21H18N4O4: 390,1; received m/z: to € 391.1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,01 (s, 1H); 12,77 (s, 1H); of 8.90 (s, 1H); 8,24 (s, 1H); the 7.65 (s, 1H); 7.23 percent (s, 1H); 7,21 (d, J=8,3 Hz, 1H); 6,93 (d, J=2.4 Hz, 1H); 6,83 (DD, J=8,1, 2.5 Hz, 1H); to 2.41 (s, 3H); of 2.23 (s, 6H).

Example 93: 1-[7-methyl-4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on-stage And 3-triptoreline and 4-fluoro-3-methylnitrobenzene. MS (IER): calculated for C20H13F3N4O4: 430,0; received m/z: 431,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,03 (s, 1H); 12,97-to 12.44 (m, 1H); of 8.92 (s, 1H); compared to 8.26 (s, 1H); 7,71 (d, J=5,1 Hz, 1H); to 7.68 (t, J=8.0 Hz, 1H); EUR 7.57 (d, J=7.8 Hz, 1H); the 7.43 (s, 2H); of 7.36 (d, J=8,2 Hz, 1H); of 2.38 (s, 3H).

Example 94: 1-[6-(3,5-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on stage And 3,5-dimethylphenol and 3,4-deformirovannoe. MS (IER): calculated for C20H15FN4O4: 394,1; received m/z: 395,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,02 (s, 1H); 13,02-12,88 (m, H); of 8.92 (s, 1H); compared to 8.26 (s, 1H); 7,71 (d, J=11,4 Hz, 1H); 7,56 (d, J=8,9 Hz, 1H); to 6.88 (s, 1H); 6,76 (s, 2H); of 2.28 (s, 6H).

Example 95: 1-[7-fluoro-4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on-stage And 3-triptoreline and 3,4-deformirovannoe. MS (IER): calculated for C19H10F4N4O4: of 434.1; ion-predecessor was not found.1H NMR (400 MHz, DMSO-d6): 13,07 (s, 2H); 8,93 (s, 1H); of 8.28 (s, 1H); of 7.75 (DD, J=10,1, 5.0 Hz, 2H); of 7.69 (t, J=8.0 Hz, 1H); of 7.60 (d, J=7.8 Hz, 1H); 7,52 (s, 1H); 7,44 (DD, J=8,2, 2.1 Hz, 1H).

Example 96: 1-[6-(2-fluoro-3-triptoreline)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on-stage And 2-fluoro-3-triptoreline and 4-peritrabecular. MS (IER): calculated for C19H10F4N4O4: of 434.1; ion-predecessor was not found.1H NMR (400 MHz, DMSO-d6): 13,02 (s, 2H); of 8.95 (s, 1H); compared to 8.26 (s, 1H); for 7.78 (s, 1H); 7,73-of 7.60 (m, 3H); rate of 7.54 (s, 1H); 7,49 (t, J=8,2 Hz, 1H).

Example 97: 1-[6-(3-fluoro-5-triptoreline)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with methods for the AMI, described in Example 27, using on-stage And 3-fluoro-5-triptoreline and 4-peritrabecular. MS (IER): calculated for C19H10F4N4O4: 434,0; received m/z: 435,0 [M+H]+.1H-NMR (400 MHz, DMSO-d6): 13,03 (s, 2H); 8,96 (s, 1H); of 8.27 (s, 1H); 7,79 (s, 1H); 7,71-7,66 (m, 2H); rate of 7.54 (d, J=8,4 Hz, 1H); 7,39 (d, J=9.9 Hz, 1H); 7,33 (s, 1H).

Example 98: 1-[6-(3,5-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on stage And 3,5-dimethylphenol and 4-peritrabecular. MS (IER): calculated for C20H16N4O4: 376,1; received m/z: 377,1 [M+H]+.1H-NMR (400 MHz, DMSO-d6): 13,01 (s, 1H); 12,91 (s, 1H); to 8.94 (s, 1H); of 8.25 (s, 1H); 7,73 (d, J=8,2 Hz, 1H); EUR 7.57 (DD, J=8,9, 2,9 Hz, 1H); the 7.43 (s, 1H); 6.89 in (s, 1H); 6.75 in (s, 2H); of 2.28 (s, 6H).

Example 99: 1-[6-(biphenyl-3-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on-stage And 3-phenylphenol and 4-peritrabecular. MS (IER): calculated for C24H16N4O4: 424,1; received m/z: 425,1 [M+H]+.1H-NMR (400 MHz, DMSO-d6): 12,96 (s, 2H); to 8.94 (s, 1H); of 8.25 (s, 1H); to 7.77 (d, J=8,9 Hz, 1H); of 7.69 (d, J=7.7 Hz, 2H); to 7.64 (DD, J=8,9, 2.7 Hz, 1H); 7,56 (d, J=4,7 Hz, 2H); 7,53 (d, J=2.8 G is, 1H); 7,50-7,42 (m, 3H); 7,39 (t, J=7,3 Hz, 1H); 7.18 in-7,10 (m, 1H).

Example 100: 1-[4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on-stage And 3-triptoreline and 4-peritrabecular. MS (IER): calculated for C19H11F3N4O4: 416,0; received m/z: 417,0 [M+H]+.1H-NMR (400 MHz, DMSO-d6): 13,02 (s, 2H); of 8.95 (s, 1H); of 8.27 (s, 1H); 7,79 (d, J=8,9 Hz, 1H); of 7.69 (t, J=8.0 Hz, 1H); the 7.65 (DD, J=8,9, 2,9 Hz, 1H); of 7.60 (d, J=7.8 Hz, 1H); EUR 7.57 (d, J=2,9 Hz, 1H); 7,49 (s, 1H); 7,44 (d, J=8,1 Hz, 1H).

Example 101: 1-[6-(2,6-dichlorophenoxy)-5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, using on stage And 2,6-dichlorphenol and 3,4,5-cryptomaterial. MS (IER): calculated for C18H8Cl2F2N4O4: 452,0; ion-predecessor was not found.1H-NMR (500 MHz, DMSO-d6): 13,06 (s, 2H); 8,91 (s, 1H); of 8.27 (s, 1H); 7,63 (d, J=8,2 Hz, 2H); EUR 7.57 (d, J=11,6 Hz, 1H); to 7.35 (t, J=8,2 Hz, 1H).

Example 102: 1-(6-cyclohexyloxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 27, and the use on stage And cyclohexanol and 4-peritrabecular. MS (IER): calculated for C18H18N4O4: 354,1; received m/z: 355,1 [M+H]+.1H-NMR (400 MHz, DMSO-d6): 12,92 (s, 1H); 12,85-12,50 (m, 1H); 8,91 (s, 1H); by 8.22 (s, 1H); 7,63 (d, J=8.0 Hz, 1H); 7,52 (d, J=2.7 Hz, 1H); was 7.45 (DD, J=8,9 and 2.8 Hz, 1H); 4,50 (s, 1H); 1,95 (s, 2H); 1,73 (s, 2H); 1,55-of 1.42 (m, 4H); 1,31-1,22 (m, 2H).

Example 103: 1-[6-(4-methylpiperazin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 17, using on-stage And 4-(4-methylpiperazin-1-yl)-aniline. MS (IER): calculated for C17H18N6O3: 354,1; received m/z: 355,2 [M+H]+.1H-NMR (400 MHz, DMSO-d6): 12,88-11,90 (m, 2H); 8,79 (s, 1H); to $ 7.91 (s, 1H); to 7.64-7,20 (m, 3H); 3.15 in (d, J=4.8 Hz, 4H); 2,24 (s, 3H).

Example 104: 1-(6-isopropoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 17, using on-stage And 4-isopropoxyaniline. MS (IER): calculated for C15H14N4O4: 314,1; received m/z: 315,1 [M+H]+.1H-NMR (500 MHz, DMSO-d6): 12,96 (s, 1H); of 12.76 (s, 1H); of 8.92 (s, 1H); 8,23 (s, 1H); 7,63 (d, J=8.7 Hz, 1H); 7,51 (s, 1H); the 7.43 (d, J=8,9 Hz, 1H); 4,90-br4.61 (m, 1H); to 1.32 (d, J=6.0 Hz, 6H).

Example 105: 1-(6-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 17, using on-stage And 4-benzylaniline. MS (IER): calculated for C19H14N4O3: 346,1; received m/z: 347,1 [M+H]+.1H-NMR (500 MHz, DMSO-d6): 12,99 (s, 1H); 12,77 (s, 1H); 8,93 (s, 1H); 8,24 (s, 1H); of 7.96 (s, 1H); 7,73 (d, J=8.0 Hz, 1H); a 7.62 (d, J=8,1 Hz, 1H); 7,34-7,28 (m, 4H); 7,21 (t, J=6,9 Hz, 1H); 4,11 (s, 2H).

Example 106: 1-(4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 17, using on-stage And 4-aminobiphenyl. MS (IER): calculated for C18H12N4O3: 332,1; received m/z: 333,1 [M+H]+.1H-NMR (500 MHz, DMSO-d6): 13,03 (s, 1H); 12,92 (s, 1H); 8,98 (s, 1H); 8.34 per (s, 1H); of 8.28 (s, 1H); 8.17 and (d, J=8,3 Hz, 1H); 7,79 (d, J=7,4 Hz, 3H); 7,53 (t, J=7.7 Hz, 2H); the 7.43 (t, J=7,4 Hz, 1H).

Example 107: 1-(6-morpholine-4-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 17, using on-stage And 4-(1-morpholino)-aniline. MS (IER): calculated for C16H15N5O4: 341,1; received m/z: 342,1 [M+H]+.1H-NMR (500 MHz, DMSO-d6): 12,95 (s, 1H); 12,63 (s, 1H); of 8.90 (s, 1H); by 8.22 (s, 1H); 7,60 (s, 2H); the 7.43 (d, J=24,2 Hz, 1H); 3,84-and 3.72 (m, 4H); 3.27 to is 3.21 (m, 4H).

Example 108: 1-[6-(1H-indol-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in accordance with the methods described in Example 69, stage C-E, using on stage With ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (product of Example 69, obtained in stage B) and indole-6-boronic acid. MS (IER): calculated for C20H13N5O3: 371,1; received m/z: 372,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,01 (s, 1H); 12,86 (s, 1H); 11,23 (s, 1H); 8,99 (s, 1H); of 8.37 (s, 1H); of 8.27 (s, 1H); to 8.20 (s, 1H); to 7.77 (s, 2H); to 7.67 (d, J=8,2 Hz, 1H); the 7.43 (s, 2H); 6.48 in (s, 1H).

Example 109: 1-(6-cyclopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-[(4-brompheniramine)-ethoxycarbonylmethyl]-1H-pyrazole-4-carboxylic acid. To a solution of 4-brompheniramine (1,91 g, 11.1 mmol) in DCM (37 ml) was added ethylisothiocyanate (of 1.44 ml, 12.2 mmol). After 1 h to the reaction mixture were added triethylamine (4,65 ml, 33.4 mmol) and then aripirazole-4-carboxylate (1,87 g, 13.3 mmol) and EDCI (3,20 g, and 16.7 mmol). After 18 h the reaction mixture was diluted with DCM (150 ml), washed with saturated saline (50 ml), dried over MgSO4and concentrated. The obtained residue was purified KFH (EtOAc/hexane 5-40%) and obtained the desired compound (1.84 g, yield 40%). MS (IER/CHI): calculated for C16H17rN 4O4: 408,1; received m/z: 409,1 [M+H]+.

Stage B. obtaining the ethyl ester of 1-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[(4-brompheniramine)-ethoxycarbonylmethyl]-1H-pyrazole-4-carboxylic acid (1.84 g, 4,50 mmol) and DCE (45 ml) was carefully added chloride titanium (IV) (2,47 ml of 22.5 mmol) and passed the resulting solution at 100°C for 15 hours, the Reaction mixture was cooled to room temperature and poured into ice-cold water (50 ml), then added DCM (100 ml). The obtained two-phase mixture was stirred for 2 h and then divided layers. The aqueous phase is further extracted with DCM (2 x 50 ml). The combined organic phases are washed with saturated saline (50 ml), dried over MgSO4and concentrated. The obtained residue was rubbed from EtOH and got the desired compound (1,05 g, yield 64%). MS (IER/CHI): calculated for C14H11BrN4O3: 362,0; received m/z: 363,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,15 (s, 1H); 9,01 (d, J=0.5 Hz, 1H); with 8.33 (s, 1H); to 8.20 (d, J=2.3 Hz, 1H); to 7.99 (DD, J=8,7, 2.4 Hz, 1H); 7,66 (d, J=8,8 Hz, 1H); 4,30 (kV, J=7,1 Hz, 2H); to 1.32 (t, J=7,1 Hz, 3H).

Stage C. obtaining the ethyl ester of 1-[6-bromo-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester of 1-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (0,980 g, 2,70 mmol) in the THF (13.5 ml) was added DIEA (1.23 ml, was 7.08 mmol) and then (2-hermeticity)-trimethylsilane (0,500 ml of 3.27 mmol). The reaction mixture was stirred at room temperature for 18 h and concentrated. The obtained residue was purified KFH (EtOAc/hexane 0-20%) and obtained the desired compound (1.27 g, yield 95%). MS (IER/CHI): calculated for C20H25BrN4O4Si: 492,1; received m/z: 435,1 [M-58+H]+.

Stage D. obtaining the ethyl ester of 1-[6-cyclopropyl-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester 1-[6-bromo-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0,500 g, 1.01 mmol), cyclopropylboronic acid (0,199 g, 2.32 mmol), dichloromethane adduct dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium (II) (0,100 g, 0,123 mmol), K2CO3(0,420 g, 3.04 from mmol) and THF (10 ml) was purged with nitrogen for 15 minutes and then stood at 80°C for 15 hours the mixture is Then cooled to room temperature and was filtered through a layer of CELITE®. The filter cake was washed with dichloromethane and concentrated. The obtained residue cleanse KFH (EtOAc/hexane 0-20%) and obtained the desired compound (0,120 g, yield 26%). MS (IER/CHI): calculated for C23H30N4O4Si: 454,2; received m/z: to 455.2 [M+H]+.

Stage E. obtaining the ethyl ester of 1-(6-cyclopropyl-4-oxo-3,4-dihydroquinazolin the-2-yl)-1H-pyrazole-4-carboxylic acid. To ethyl ether, 1-[6-cyclopropyl-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0.12 g, 0,264 mmol) was added HCl (4 M in dioxane, to 1.32 ml, 5,28 mmol). The reaction mixture was stirred 1 h at room temperature and concentrated. The obtained residue was washed with diethyl ether (10 ml), precipitated precipitate was collected and dried, obtaining the desired compound (0,072 g, yield 84%). MS (IER/CHI): calculated for C17H16N4O3: 324,1; received m/z: 325,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,81 (s, 1H); 8,99 (d, J=0.5 Hz, 1H); 8.30 to (s, 1H); 7,81 (s, 1H); 7,65 is 7.50 (m, 2H); 4,30 (kV, J=7,1 Hz, 2H); 2,17-2,03 (m, 1H); to 1.32 (t, J=7,1 Hz, 3H); 1,09 is 0.99 (m, 2H); 0,81-to 0.72 (m, 2H).

Stage F: 1-(6-cyclopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester of 1-(6-cyclopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (0,045 g, 0,139 mmol), 1 M aqueous solution of KOH (0,694 ml) and THF (0,694 ml) was stirred for 18 hours the mixture is Then concentrated to remove THF, and the remaining aqueous phase was acidified by adding 6 M aqueous HCl at 0°C. the precipitation was collected by filtration, obtaining the desired compound (0.035 g, 85%). MS (IER/CHI): calculated for C15H12N4O3: 296,1; received m/z: 297,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,92 (s, 2H); 8,93 (d, J=0.5 Hz, 1H); 8,24 (s, 1H); 7,81 (s, 1H); 7,65 is 7.50 (m, 2H); 2,22-2,04 (m, 1H); 1,14-0,94 (m, 2H); of 0.85 and 0.68 (m, 2H).

Example 110: 1-(6-cyclohexyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(6-bromo-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a and b), using at the stage of A 4-bromo-3-ftorhinolona. MS (IER/CHI): calculated for C14H10BrFN4O3: 380,0; received m/z: 381,0 [M+H]+.1H NMR (400 MHz, CDCl3): 10,29 (s, 1H); 8,99 (d, J=0.6 Hz, 1H); 8,51 (d, J=7,4 Hz, 1H); 8,15 (d, J=0.5 Hz, 1H); 7,40 (d, J=9.0 Hz, 1H); to 4.38 (q, J=7,1 Hz, 2H); of 1.40 (t, J=7,1 Hz, 3H).

Stage B. obtaining the ethyl ester of 1-(6-cyclohexyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a THF (5 ml) was added 1 M solution of ZnCl2in the air (5,00 ml, 5.00 mmol) and then 2 M solution of cyclohexylaniline in ether (2,50 ml, 5.00 mmol). The reaction mixture was stirred over night at room temperature. Then the stirring was stopped and stood mixture, so just drop the sediment at the bottom of the flask. In another flask, to a mixture of palladium acetate (11.8 mg, 0,053 mmol), Ru-Phos (48,9 mg, 0,105 mmol) and ethyl ester of 1-(6-bromo-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (0,200 g, 0,525 mmol) was added THF (4 ml) and purged the contents of the flask with nitrogen for 5 min is so Then added cyclohexylethane (the 5.25 ml, 2,62 mmol), obtained as described above, and the mixture was stirred for 18 hours the Crude reaction mixture was poured in EtOH (10 ml) and was acidified by slowly adding 6 M aqueous HCl (1 ml). The precipitation was collected by filtration, washed with EtOH and again filtered, obtaining the desired compound (0,110 g, 54%). MS (IER/CHI): calculated for C20H21FN4O3: 384,2; received m/z: 385,2 [M+H]+.

Stage C. Obtain 1-(6-cyclohexyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 109 (stage F), using the ethyl ester of 1-(6-cyclohexyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. MS (IER/CHI): calculated for C18H17FN4O3: 356,1; received m/z: 357,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,01 (s, 2H); of 8.92 (d, J=0.6 Hz, 1H); compared to 8.26 (s, 1H); 8,03 (d, J=8,1 Hz, 1H); was 7.45 (d, J=11.2 Hz, 1H); 2,89 (t, J=11.7 Hz, 1H); of 1.84 (d, J=8,4 Hz, 4H); 1,73 (d, J=a 12.7 Hz, 1H); 1,59 is 1.16 (m, 5H).

Example 111: 1-(4-oxo-8-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on stage And diphenyl-2-ylamine. MS (IER/CHI): calculated for C18H12N4O3: 332,1; getting/z: 333,1 [M+H] +.1H NMR (500 MHz, DMSO-d6): 13,00 (s, 2H); 8,58 (s, 1H); 8,24 (s, 1H); 8,18 (d, J=7.9 Hz, 1H); 7,89 (d, J=7,4 Hz, 1H); of 7.70 (d, J=8.1 Hz, 2H); 7,60 (t, J=7.7 Hz, 1H); 7,52 (t, J=7,6 Hz, 2H); 7,46-the 7.43 (m, 1H).

Example 112: 1-(4-oxo-8-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 2-phenoxybenzamine. MS (IER/CHI): calculated for C18H12N4O4: 348,1; received m/z: 349,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,97 (s, 2H); to 8.41 (s, 1H); 8,21 (s, 1H); 8,02-7,88 (m, 1H); 7,51 (DD, J=7,4, 6,0 Hz, 2H); 7,39 was 7.36 (m, 2H); 7,11 (t, J=7,4 Hz, 1H); 7,02 (d, J=7.8 Hz, 2H).

Example 113: 1-(4-oxo-8-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 2-vinylsulfonylacetamido. MS (IER/CHI): calculated for C18H12N4O3S: 364,1; received m/z: 365,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,06 (s, 2H); 8,76 (d, J=0.6 Hz, 1H); of 8.27 (d, J=0.6 Hz, 1H); 7,92 (DD, J=7.9 Hz, 1,3, 1H); 7,60-7,42 (m, 5H); of 7.36 (t, J=7.8 Hz, 1H); 7,17 (d, J=7.7 Hz, 1H).

Example 114: 1-(8-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to describe the approach in Example 109 (stage A, In and F), using on-stage And 2-isopropylaniline. MS (IER/CHI): calculated for C15H14N4O3: 298,1; received m/z: 299,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,92 (s, 2H); 9,00 (s, 1H); compared to 8.26 (s, 1H); 8,00 (DD, J=7,9, 1.3 Hz, 1H); 7,76 (d, J=7,4 Hz, 1H); of 7.48 (t, J=7.7 Hz, 1H); 4,03-3,93 (m, 1H); of 1.30 (d, J=6.9 Hz, 6H).

Example 115: 1-(8-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 2-tert-butylbenzylamine. MS (IER/CHI): calculated for C16H16N4O3: 312,1; received m/z: 313,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,01 (s, 2H); 8,82 (s, 1H); of 8.28 (s, 1H); of 8.06 (DD, J=7,9, and 1.4 Hz, 1H); 7,79 (DD, J=7,7, and 1.4 Hz, 1H); 7,45 (t, J=7.8 Hz, 1H); was 1.58 (s, 9H).

Example 116: 1-(5,8-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on stage And 2,5-dipertanyakan. MS (IER/CHI): calculated for C12H6F2N4O3: 292,0; received m/z: 293,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,07 (s, 2H); 8,91 (s, 1H); of 8.28 (s, 1H); of 7.75 (TD, J=9,5, 4,2 Hz, 1H); 7,28 (TD, J=10,4, 3.6 Hz, 1H).

Example 117: 1-(4-oxo-8-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

p>

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 2-triphtalocyaninine. MS (IER/CHI): calculated for C13H7F3N4O4: 340,1; received m/z: 341,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,12 (s, 2H); 8,84 (d, J=0.6 Hz, 1H); 8,30 (d, J=0.6 Hz, 1H); 8,16 (DD, J=8.0 a, and 1.4 Hz, 1H); 7,95-to 7.84 (m, 1H); 7,58 (t, J=8.0 Hz, 1H).

Example 118: 1-(8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 2-ftorhinolona. MS (IER/CHI): calculated for C12H7FN4O3: 274,0; received m/z: 275,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): of 13.05 (s, 2H); of 8.92 (s, 1H); of 8.28 (s, 1H); of 7.96 (d, J=7,6 Hz, 1H); 7,75-7,73 (m, 1H); 7,51 (TD, J=8.0 a, a 4.7 Hz, 1H).

Example 119: 1-(6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 4-isopropylbenzylamine. MS (IER/CHI): calculated for C15H14N4O3: 298,1; received m/z: 299,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,90 (s, 2H); to 8.94 (s, 1H); of 8.25 (s, 1H); of 7.97 (d, J=1.7 Hz, 1H); to 7.77 (DD, J=8,4, 2.0 Hz, 1H); the 7.65 (d, J=7.8 Hz, 1H); of 3.1 to 3.0 (m, 1H); of 1.27 (d, J=6.9 Hz, 6H).

Example 120: 1-(6-sec-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 4-second-butylbenzylamine. MS (IER/CHI): calculated for C16H16N4O3: 312,1; received m/z: 313,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,91 (s, 2H); to 8.94 (s, 1H); of 8.25 (s, 1H); to 7.93 (s, 1H); 7,72 (DD, J=8,4, 1.8 Hz, 1H); the 7.65 (d, J=8,3 Hz, 1H); 2,82-2,77 (m, 1H); 1,76 of 1.50 (m, 2H); 1.26 in (d, J=6.9 Hz, 3H); of 0.79 (t, J=7,3 Hz, 3H).

Example 121: 1-(6-ethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 4-ethoxyphenylurea. MS (IER/CHI): calculated for C14H12N4O4: 300,1; received m/z: 301,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,96 (s, 1H); 12,79 (s, 1H); of 8.92 (s, 1H); 8,23 (s, 1H); to 7.64 (d, J=7.8 Hz, 1H); 7,51 (d, J=2.3 Hz, 1H); was 7.45 (DD, J=8,8, 2.8 Hz, 1H); 4,16 (kV, J=6,9 Hz, 2H); to 1.38 (t, J=6.9 Hz, 3H).

Example 122: 1-(6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 4-methoxybenzylamine. MS (IER/CHI): calculated the La C 13H10N4O4: 286,1; received m/z: 287,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,95 (s, 2H); of 8.92 (s, 1H); 8,24 (s, 1H); the 7.65 (d, J=7.7 Hz, 1H); 7,53 (d, J=2.6 Hz, 1H); 7,46 (DD, J=8,9, 2,9 Hz, 1H); to 3.89 (s, 3H).

Example 123: 1-(4-oxo-6-pyrrolidin-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 4-pyrrolidin-1-ilfenomeno. MS (IER/CHI): calculated for C16H15N5O3: 325,1; received m/z: to 326.1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,91 (s, 1H); to 12.44 (s, 1H); 8,87 (d, J=0.6 Hz, 1H); to 8.20 (s, 1H); at 7.55 (d, J=8,9 Hz, 1H); to 7.15 (DD, J=9,0, 2,9 Hz, 1H);? 7.04 baby mortality (d, J=2,8 Hz, 1H); to 3.34 (t, J=6,4 Hz, 4H); 2,00 (t, J=6.5 Hz, 4H).

Example 124: 1-(4-oxo-6-piperidine-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 4-piperidine-1-ilfenomeno. MS (IER/CHI): calculated for C17H17N5O3: 339,1; received m/z: 340,2 [M+H]+.1H NMR (500 MHz, DMSO-d6): of 8.92 (s, 1H); 8,24 (s, 1H); 7,79 (ush s, 2H); to 7.67 (s, 1H); or 4.31 (ush s, 4H); 1,76 (s, 4 H); of 1.62 (s, 2H).

Example 125: 1-(6-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired connection get and by the way, similar to that described in Example 109 (stages a, b and F), using on stage And N,N-xylene-1,4-diamine. MS (IER/CHI): calculated for C14H13N5O3: 299,1; received m/z: 300,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,94 (s, 1H); 12,55 (s, 1H); 8,88 (d, J=0.5 Hz, 1H); to 8.20 (s, 1H); 7,56 (d, J=9.0 Hz, 1H); of 7.36 (DD, J=9,1, 3.0 Hz, 1H); 7,21 (d, J=2,8 Hz, 1H); 3,03 (s, 6H).

Example 126: 1-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on stage And phenylamine. MS (IER/CHI): calculated for C12H8N4O3: 256,1; received m/z: 257,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,00 (s, 2H); 8,96 (s, 1H); of 8.27 (s, 1H); to 8.14 (d, J=7,6 Hz, 1H); 7,89-7,83 (m, 1H); 7,71 (d, J=7.7 Hz, 1H); 7,52 (DD, J=11,5, 4.5 Hz, 1H).

Example 127: 1-(6-bromo-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 4-bromo-3-ftorhinolona. MS (IER/CHI): calculated for C12H6BrFN4O3: 352,0; received m/z: 353,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,08 (s, 2H); 8,93 (s, 1H); 8,35 (d, J=7,6 Hz, 1H); 8,29 (s, 1H); of 7.69 (d, J=9.6 Hz, 1H).

Example 128: 1-(6-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid is.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 4-ethylvanillin. MS (IER/CHI): calculated for C14H12N4O3: 284,1; received m/z: 285,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,89 (ush s, 2H); to 8.94 (s, 1H); of 8.25 (s, 1H); of 7.96 (s, 1H); 7,72 (d, J=7,0 Hz, 1H); to 7.64 (s, 1H); 2,77 (kV, J=7.5 Hz, 2H); 1,25 (t, J=7,6 Hz, 3H).

Example 129: 1-(4-oxo-6-propyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 4-propylaniline. MS (IER/CHI): calculated for C15H14N4O3: 298,1; received m/z: 299,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,97 (s, 2H); to 8.94 (s, 1H); compared to 8.26 (s, 1H); to 7.93 (s, 1H); of 7.70 (DD, J=8,3, 1.9 Hz, 1H); 7,63 (d, J=7.9 Hz, 1H); a 2.71 (t, J=7.5 Hz, 2H); 1.70 to to 1.61 (m, 2H); of 0.91 (t, J=7,3 Hz, 3H).

Example 130: 1-(6-bromo-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 109 (stages a, b and F), using on-stage And 4-bromo-2-ftorhinolona. MS (IER/CHI): calculated for C12H6BrFN4O3: 352,0; received m/z: 353,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,30 (s, 1H); 13,08 (s, 1H); 8,91 (s, 1H); 8,29 (s, 1H); 8,08 (DD, J=,7, the 2.2 Hz, 1H); 8,04 (DD, J=2,1, 1.0 Hz, 1H).

Example 131: 1-(5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-[(3,5-diftorhinolonom)-ethoxycarbonylmethyl]-1H-pyrazole-4-carboxylic acid. To a solution of 3,5-diferencia (0,680 g, at 5.27 mmol) in DCM (26 ml) was added ethylisothiocyanate (0.68 ml, 5.8 mmol). After 3 h the reaction mixture was added triethylamine (2.20 ml, 15.8 mmol), then aripirazole-4-carboxylate (0,812 g, 5,79 mmol) and EDCI (1,21 g, 6,32 mmol). After 1.5 h the reaction mixture was diluted with DCM (25 ml), washed with water (3 x 30 ml) and saturated salt brine (50 ml), dried over MgSO4and concentrated. The obtained residue was purified KFH (EtOAc/hexane 3-45%) and obtained the desired compound (0,323 g, yield 17%). MS (IER/CHI): calculated for C16H16F2N4O4: 366,1; received m/z: 367,1 [M+H]+.

Stage B. obtaining the ethyl ester of 1-(5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[(3,5-diftorhinolonom)-ethoxycarbonylmethyl]-1H-pyrazole-4-carboxylic acid (0,321 g, 0,876 mmol) in DCE (2.7 ml) was carefully added chloride titanium (IV) (0,39 ml, 3.5 mmol) and passed the resulting solution at 110°C for 1.5 hours Then the reaction mixture was cooled to room temperature and added water (50 ml), methanol (1 ml) and DCM (40 ml). Received the second two-phase mixture was stirred for 30 min, and then divided phase. The aqueous phase was extracted with further DCM (2x30 ml). The combined organic phases are washed with saturated brine (40 ml), dried over MgSO4and concentrated. The obtained residue was rubbed from EtOH and got the desired compound (0.172 g, yield 60%). MS (IER/CHI): calculated for C14H10F2N4O3: 320,1; received m/z: 321,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): to 13.09 (s, 1H); 8,99 (d, J=0.5 Hz, 1H); 8,35 (s, 1H); 7,42-to 7.32 (m, 2H); 4,30 (kV, J=7,1 Hz, 2H); to 1.32 (t, J=7,1 Hz, 3H).

Stage C. Obtain 1-(5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester of 1-(5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (0.152 g, 0.475 mmol) in THF (1.7 ml) was added 1 M aqueous solution of potassium hydroxide (1.7 ml, 1.7 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated. The resulting residue re-dissolved in water (5 ml) and brought to pH 1 with 1 M aqueous HCl. The precipitation was collected by filtration and obtained the desired compound (0,137 g, yield 98%). MS (IER/CHI): calculated for C12H6F2N4O3: 292,0; received m/z: 293,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,07 (s, 2H); 8,93 (d, J=0.4 Hz, 1H); of 8.28 (s, 1H); 7,44 - 7,27 (m, 2H).

Example 132: 1-(5,7-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 131, using on stage And 3,5-dichloraniline. MS (IER/CHI): calculated for C12H6Cl2N4O3: 324,0; received m/z: 325,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,08 (s, 2H); 8,93 (s, 1H); of 8.28 (s, 1H); of 7.70 (s, 1H); the 7.65 (d, J=2.0 Hz, 1H).

Example 133: 1-(7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 131, using on-stage And 3-foranyone. MS (IER/CHI): calculated for C12H7FN4O3: 274,1; received m/z: 275,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,04 (s, 2H); to 8.94 (s, 1H); of 8.28 (s, 1H); 8,19 (DD, J=8,7, 6.4 Hz, 1H); 7,49 (d, J=9.1 Hz, 1H); 7,38 (TD, J=8,7, 2.5 Hz, 1H).

Example 134: 1-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 131, using on-stage And 3-bromoaniline. MS (IER/CHI): calculated for C12H7BrN4O3: 334,0; received m/z: 335,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): of 13.05 (s, 2H); to 8.94 (d, J=0.5 Hz, 1H); of 8.28 (s, 1H); 8,03 (d, J=8.5 Hz, 1H); of 7.90 (s, 1H); to 7.68 (DD, J=8,5, 1.9 Hz, 1H).

Example 135: 1-(7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The claim is e connection received by way similar to that described in Example 131, using on-stage And 3-methoxyaniline. MS (IER/CHI): calculated for C13H10N4O4: 286,1; received m/z: 287,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,01 (s, 1H); 12,68 (s, 1H); to 8.94 (s, 1H); of 8.25 (s, 1H); 8,04 (d, J=8,8 Hz, 1H); 7,14 (s, 1H); 7,10 (DD, J=8,8, 2.2 Hz, 1H); 3,91 (s, 3H).

Example 136: 1-(7-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 131, using on-stage And 3-benzylaniline. MS (IER/CHI): calculated for C19H14N4O3: 346,1; received m/z: 347,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,00 (s, 1H); was 12.75 (s, 1H); 8,93 (s, 1H); of 8.25 (s, 1H); with 8.05 (d, J=8.0 Hz, 1H); 7,52 (s, 1H); 7,41 (d, J=8,4 Hz, 1H); of 7.36-7,26 (m, 4H); 7,26-to 7.18 (m, 1H); of 4.12 (s, 2H).

Example 137: 1-(4-oxo-3,4,8,9-tetrahydro-7H-6,10-dioxo-1,3-disallowable[b]naphthalene-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 131, using on stage And 3,4-dihydro-2H-benzo[b][1,4]doxepin-7-ylamine. The desired compound was isolated as sodium salt by grinding residue from step C with ethanol and concentration of the reaction mixture. MS (IER/CHI): calculated for C15H12N4O5: 328,1; received m/z: 329,1 [M+H]+.1H NMR (400 MHz, DMSO-d6 ): to 8.41 (d, J=0.8 Hz, 1H); rate of 7.54 (d, J=0.8 Hz, 1H); 7,44 (s, 1H); 6,93 (s, 1H); 4,19 is 4.13 (m, 2H); 4,10 (t, J=5.4 Hz, 2H); 2,17-2,03 (m, 2H).

Example 138: 1-(8-oxo-2,3,7,8-tetrahydro-1,4-dioxa-5,7-diazapentane-6-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-[(2,3-dihydrobenzo[1,4]dioxin-5-elimina)-ethoxycarbonylmethyl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, step A, using 2,3-dihydrobenzo[1,4]dioxin-5-ylamine. MS (IER/CHI): calculated for C18H20N4O6: 388,1; received m/z: 389,2 [M+H]+.

Stage B. obtaining the ethyl ester of 1-(8-oxo-2,3,7,8-tetrahydro-1,4-dioxa-5,7-diazapentane-6-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[(2,3-dihydrobenzo[1,4]dioxin-5-elimina)-ethoxycarbonylmethyl]-1H-pyrazole-4-carboxylic acid (1.39 g, 3.58 mmol) in DCE (11 ml) was carefully added chloride titanium (IV) (1.2 ml, 11 mmol) and passed the resulting solution at 110°C for 2 h Then the reaction mixture was cooled to room temperature and added ethanol (60 ml). The resulting suspension was mixed at room temperature for 30 min; then the precipitation is collected, obtaining the desired compound (0,970 g, yield 78%). MS (IER/CHI): calculated for C16H14N4O5: 342,1; received m/z: 343,1 [M+H]+.1H NMR (400 MHz, DMSO-d6 ): 12,78 (s, 1H); of 8.90 (d, J=0.5 Hz, 1H); 8,31 (s, 1H); a 7.62 (d, J=8.7 Hz, 1H); 7,06 (d, J=8,8 Hz, 1H); 4,48 is 4.35 (m, 4H); 4,30 (kV, J=7,1 Hz, 2H); of 1.33 (t, J=7,1 Hz, 3H).

Stage C. Obtain 1-(8-oxo-2,3,7,8-tetrahydro-1,4-dioxa-5,7-diazapentane-6-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester of 1-(8-oxo-2,3,7,8-tetrahydro-1,4-dioxa-5,7-diazapentane-6-yl)-1H-pyrazole-4-carboxylic acid (0,298 g, 0,869 mmol) in THF (2.6 ml) was added 1 M aqueous solution of potassium hydroxide (2.6 ml, 2.6 mmol). The reaction mixture was stirred at room temperature for 2 days and then concentrated. The resulting residue re-dissolved in water (10 ml) and brought to pH 1 with 1 M aqueous HCl. The precipitation was collected by filtration and obtained the desired compound (0,235 g, yield 85%). MS (IER/CHI): calculated for C14H10N4O5: 314,1; received m/z: 315,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,01 (s, 1H); of 12.73 (s, 1H); 8,86 (d, J=0.7 Hz, 1H); 8,24 (d, J=0.6 Hz, 1H); to 7.61 (d, J=8,8 Hz, 1H); 7,05 (d, J=8.7 Hz, 1H); however, 4.40 (s, 4H).

Example 139: 1-(4-oxo-3,4,7,8-tetrahydro-[1,4]like[2,3-g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(4-oxo-3,4,7,8-tetrahydro-[1,4]like[2,3-g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, phase-In, using on stage And 2,3-dihydrobenzo[1,4]dioxin-6-and the amine. At the stage B as solvent instead of DCE used toluene and purified the resulting product KFH (DCM/MeOH 0-10%). MS (IER/CHI): calculated for C16H14N4O5: 342,1; received m/z: 343,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,69 (s, 1H); 8,95 (d, J=0.6 Hz, 1H); of 8.27 (s, 1H); of 7.48 (s, 1H); 7,13 (s, 1H); 4,42-to 4.33 (m, 4H); 4,29 (kV, J=7,1 Hz, 2H); to 1.32 (t, J=7,1 Hz, 3H).

Stage B. Obtain 1-(4-oxo-3,4,7,8-tetrahydro-[1,4]like[2,3-g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester of 1-(4-oxo-3,4,7,8-tetrahydro-[1,4]like[2,3-g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid (78,0 mg, 0,228 mmol) in THF (0,85 ml) was added monohydrate of lithium hydroxide (28,7 mg, 0,684 mmol) and water (0,29 ml). The reaction mixture was stirred at room temperature for 18 h, then concentrated and the resulting residue re-dissolved in water (5 ml). The resulting solution was brought to pH 1 with 1 M aqueous HCl. The precipitation was collected and dried, obtaining the desired compound (54,3 mg, 75%yield). MS (IER/CHI): calculated for C14H10N4O5: 314,1; received m/z: 315,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,97 (s, 1H); was 12.61 (s, 1H); 8,89 (d, J=0.6 Hz, 1H); 8,23 (s, 1H); of 7.48 (s, 1H); 7,14 (s, 1H); 4,46-the 4.29 (m, 4H).

Example 140: 1-(4-oxo-4,6,7,8-tetrahydro-3H-cyclopent[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(4-oxo-4,6,7,8-t is trihydro-3H-cyclopent[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, phase-In, using on stage And indan-5-ylamine. At the stage B received a mixture of the desired compounds and ethyl ester 1-(1-oxo-2,7,8,9-tetrahydro-1H-cyclopent[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid in a ratio of 10:1.

Data for the ethyl ester of 1-(4-oxo-4,6,7,8-tetrahydro-3H-cyclopent[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid: MS (IER/CHI): calculated for C17H16N4O3: 324,1; received m/z: 325,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,72 (s, 1H); 8,98 (d, J=0.6 Hz, 1H); 8.30 to (s, 1H); to 7.95 (s, 1H); 7,52 (s, 1H); 4,30 (kV, J=7,1 Hz, 2H); 3,01 (t, J=7,3 Hz, 2H); 2,98 (t, J=7,3 Hz, 2H); of 2.09 (Quint, J=7.5 Hz, 2H); to 1.32 (t, J=7,1 Hz, 3H).

Stage B. Obtain 1-(4-oxo-4,6,7,8-tetrahydro-3H-cyclopent[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(4-oxo-4,6,7,8-tetrahydro-3H-cyclopent[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid and ethyl ester 1-(1-oxo-2,7,8,9-tetrahydro-1H-cyclopent[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid in the ratio 10:1 (1.18 g, 0,228 mmol) in THF (13,6 ml) was added monohydrate of lithium hydroxide (0,611 g, 14.6 mmol) and water (9.1 ml) and stirred the reaction mixture at room temperature for 18 hours Then the reaction mixture was concentrated and the resulting residue re-dissolved in water (20 ml). The resulting solution was brought to pH 1 with 1 M vodno the HCl solution. The precipitation was collected and dried, obtaining a mixture of the desired compound 1-(1-oxo-2,7,8,9-tetrahydro-1H-cyclopent[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid in the ratio 10:1 (of 1.05 g, yield 98%). Some of the collected sediment (0,511 g) was twice washed with 10 ml of DMSO, receiving a pure sample of the desired compound (0,310 g, yield 61%). MS (IER/CHI): calculated for C15H12N4O3: 296,1; received m/z: 297,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,00 (s, 1H); 12,68 (s, 1H); 8,93 (s, 1H); 8,24 (s, 1H); of 7.96 (s, 1H); 7,52 (s, 1H); 3,05-of 2.93 (m, 4H); of 2.09 (Quint, J=7.4 Hz, 2H).

Stage C. Obtain 1-(4-oxo-4,6,7,8-tetrahydro-3H-cyclopent[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid, potassium salt. To a solution of 1-(4-oxo-4,6,7,8-tetrahydro-3H-cyclopent[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid (0,250 g, services, 0.844 mmol) in methanol (4,2 ml) was added potassium carbonate (58,3 mg, 0,422 mmol) and boil the mixture under reflux for 3 hours and Then the temperature was lowered to 60°C and kept stirring for another 18 hours and Then the reaction mixture was cooled to room temperature, the precipitation was filtered and dried, obtaining potassium salt of the desired compound (0,204 g, 71%yield). MS (IER/CHI): calculated for C15H12N4O3: 296,1; received m/z: 297,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,63 (s, 1H); 8,81 (s, 1H); 7,92 (s, 1H); 7,80 (s, 1H); 7.29 trend (s, 1H); 2,96-2,89 (m, 4H); 2,04 (Quint, J=7.4 Hz, 2H).

Example 141: 1-(6-oxo-,3,6,7-tetrahydro-1H-7,9-disallowment[a]naphthalene-8-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 138 using indan-4-ylamine on A stage and quenching the reaction mixture with a solution of ethanol/water in a ratio of 50:1 instead of pure ethanol at stage C. MS (IER/CHI): calculated for C15H12N4O3: 296,1; received m/z: 297,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,02 (s, 1H); 12,66 (s, 1H); 8,96 (d, J=0.7 Hz, 1H); of 8.25 (d, J=0.6 Hz, 1H); to 7.93 (d, J=7.9 Hz, 1H); 7,38 (d, J=8.0 Hz, 1H); and 3.16 (t, J=7.5 Hz, 2H); 3.04 from (t, J=7.5 Hz, 2H); and 2.14 (Quint, J=7,6 Hz, 2H).

Example 142: 1-(4-oxo-3,4,7,8,9,10-hexahydrobenzo[h]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 131, using 5,6,7,8-tetrahydronaphthalen-1-ylamine on A stage and the selection of the desired compound in the form of potassium salt by rubbing obtained in stage C of the residue with ethanol and concentration of the reaction mixture. MS (IER/CHI): calculated for C16H14N4O3: 310,1; received m/z: 311,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): of 8.50 (d, J=0.8 Hz, 1H); 7,66 (d, J=8,1 Hz, 1H); at 7.55 (d, J=0.8 Hz, 1H); is 6.78 (d, J=8,1 Hz, 1H); of 2.97 (t, J=5.8 Hz, 2H); to 2.75 (t, J=5.8 Hz, 2H); 1,89 by 1.68 (m, 4H).

Example 143: 1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. Obtaining ethyl EF is RA 1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, phase-In, using on stage And 5,6,7,8-tetrahydronaphthalen-2-ylamine. At the stage B received a mixture of the desired compounds and ethyl ester 1-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid in 2:1 ratio.

Data for the ethyl ester of 1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid: MS (IER/CHI): calculated for C18H18N4O3: 338,1; received m/z: 339,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,66 (s, 1H); 8,98 (s, 1H); 8.30 to (s, 1H); to 7.84 (s, 1H); 7,40 (s, 1H); 4,30 (kV, J=7,1 Hz, 2H); 2,97-2,77 (m, 4H); 1,87 by 1.68 (m, 4H); of 1.33 (t, J=7,1 Hz, 3H).

Stage B. obtaining the ethyl ester of 1-[3-(2-methoxyethoxymethyl)-4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl]-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid and ethyl ester 1-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid in the ratio 2:1 (0,500 g 1,478 mmol) in THF (7.4 ml) was added DIEA (from 0.76 ml, 4.4 mmol) and then 1-chloromethoxy-2-methoxyethane (0,186 ml of 1.63 mmol). The reaction mixture was stirred at room temperature for 18 h, then was diluted with EtOAc (40 ml) and washed with water (30 ml). The resulting aqueous phase was extracted with EtOAc (2 x 30 ml), the combined organic phases are washed on Ishenim salt solution (40 ml), dried over MgSO4and concentrated. The obtained residue was purified KFH (EtOAc/hexane 5-60%) and obtained the desired compound (0,257 g, yield 41%) and ethyl ester of 1-[2-(2-methoxyethoxymethyl)-1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl]-1H-pyrazole-4-carboxylic acid (69,0 mg, yield 11%).

Data for the ethyl ester of 1-[3-(2-methoxyethoxymethyl)-4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl]-1H-pyrazole-4-carboxylic acid:1H NMR (500 MHz, CDCl3): at 8.60 (s, 1H); to 8.14 (s, 1H); 8,02 (s, 1H); 7,39 (s, 1H); 5,90 (s, 2H); 4,35 (kV, J=7,1 Hz, 2H); 3,63 is 3.57 (m, 2H); 3,37-of 3.31 (m, 2H); 3,20 (s, 3H); of 2.93 (s, 4H); to 1.86 (t, J=3.2 Hz, 4H); to 1.38 (t, J=7,1 Hz, 3H).

Stage C. obtaining the ethyl ester of 1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[3-(2-methoxyethoxymethyl)-4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl]-1H-pyrazole-4-carboxylic acid (0,254 g, 0,596 mmol) in ethanol (2.0 ml) was added HCl (4 M in dioxane, and 2.1 ml, 8.3 mmol). The reaction mixture was stirred at room temperature for 4 h, then added diethyl ether (2 ml) and collected sediment. The residue was thrice washed with ethanol, once with a mixture of ethanol/THF (1:1) and once with DMSO. The filter cake was washed with ethanol and dried, obtaining the desired compound (89,4 mg, yield 44%). MS (IER/CHI): calculated for C18H18N4O3: 338,1; received m/z: 339,1 [M+H]+.1H NMR (600 MHz, DSO-d 6): 12,66 (s, 1H); 8,98 (s, 1H); 8.30 to (s, 1H); to 7.84 (s, 1H); 7,40 (s, 1H); 4,30 (kV, J=7,1 Hz, 2H); 2.95 and-and 2.83 (m, 4H); 1,82-of 1.74 (m, 4H); to 1.32 (t, J=7,1 Hz, 3H).

Stage D. Obtain 1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester of 1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid (87,5 mg, 0,259 mmol) in THF (0,55 ml) was added monohydrate of lithium hydroxide (to 25.5 mg, 0,608 mmol) and water (0.45 ml). The reaction mixture was stirred at room temperature for 18 h and then concentrated. The resulting residue re-dissolved in water (5 ml) and the resulting solution was brought to pH 1 with 1 M aqueous HCl. The precipitation was collected and dried, obtaining the desired compound (76,6 mg, yield 95%). MS (IER/CHI): calculated for C16H14N4O3: 310,1; received m/z: 311,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,00 (s, 1H); was 12.61 (s, 1H); 8,91 (s, 1H); 8,24 (s, 1H); 7,83 (s, 1H); 7,40 (s, 1H); 2,89 (ush d, J=4,7 Hz, 4H); 1,84-1,72 (m, 4H).

Example 144: 1-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, phase-In, using on stage And 5,6,7,8-tetrahydronaphthalen-2-ylamine. At stage B, the floor is, or a mixture of ethyl ester of 1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid and the desired compounds in a ratio of 2:1.

Data for ethyl ester 1-(1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid: MS (IER/CHI): calculated for C18H18N4O3: 338,1; received m/z: 339,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,49 (s, 1H); 8,99 (s, 1H); 8.30 to (s, 1H); to 7.84 (d, J=8,2 Hz, 1H); 7,45-7,38 (m, 1H); 4,30 (kV, J=7,1 Hz, 2H); 3.46 in-3,25 (m, 2H); 2,97-2,77 (m, 2H); 1,87 by 1.68 (m, 4H); of 1.33 (t, J=7,1 Hz, 3H).

Stage B. obtaining the ethyl ester of 1-[2-(2-methoxyethoxymethyl)-1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl]-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid and ethyl ester 1-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid in the ratio 2:1 (0,500 g 1,478 mmol) in THF (7.4 ml) was added DIEA (from 0.76 ml, 4.4 mmol) and then 1-chloromethoxy-2-methoxyethane (0,186 ml of 1.63 mmol). The reaction mixture was stirred at room temperature for 18 h, then was diluted with EtOAc (40 ml) and washed with water (30 ml). The resulting aqueous phase was extracted with EtOAc (2 x 30 ml), the combined organic phases are washed with saturated brine (40 ml), dried over MgSO4and concentrated. The obtained residue was purified KFH (EtOAc/hexane 5-60%) and received the ethyl ester of 1-[3-(2-methoxyethoxymethyl)-4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl]-1H-pyrazole-4-carboxylic acid (0,257 g, yield 41%) and the desired compound (690 mg, yield 11%).

Data for the ethyl ester of 1-[2-(2-methoxyethoxymethyl)-1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl]-1H-pyrazole-4-carboxylic acid:1H NMR (500 MHz, CDCl3): to 8.62 (s, 1H); to 8.14 (s, 1H); 7,47 (d, J=8,4 Hz, 1H); 7,42 (d, J=8,3 Hz, 1H); of 5.84 (s, 2H); of 4.35 (q, J=7.2 Hz, 2H); 3,64-to 3.58 (m, 2H); 3,47 (t, J=6,1 Hz, 2H); 3,41-to 3.34 (m, 2H); 3,23 (s, 3H); 2,89 (t, J=6,1 Hz, 2H); 1.91 a-of 1.78 (m, 4H); to 1.38 (t, J=7,1 Hz, 3H).

Stage C. obtaining the ethyl ester of 1-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[2-(2-methoxyethoxymethyl)-1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl]-1H-pyrazole-4-carboxylic acid (70.0 mg, 0,164 mmol) in ethanol (0,57 ml) was added 4 M HCl solution in dioxane (0,57 ml, 2.3 mmol). The reaction mixture was stirred at room temperature for 4 h, then was added ether (2 ml) and collected sludge having the desired compound (27.0 mg, yield 49%). MS (IER/CHI): calculated for C18H18N4O3: 338,1; received m/z: 339,1 [M+H]+.

Stage D. Obtain 1-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid. To ethyl ether 1-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid (25.0 mg, 73,9 mmol) in THF (of 0.28 ml) was added monohydrate of lithium hydroxide (9.3 mg, 0.22 mmol) and water (0,19 ml). The reaction mixture was stirred at room temperature for 18 h and then concentrated. P is obtained residue re-dissolved in water (3 ml) and the resulting solution was brought to pH 1 with 1 M aqueous HCl. The precipitation was collected and dried, obtaining the desired compound (19.6 mg, yield 85%). MS (IER/CHI): calculated for C16H14N4O3: 310,1; received m/z: 311,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,98 (s, 1H); 12,42 (s, 1H); of 8.92 (s, 1H); 8,23 (s, 1H); 7,51 (d, J=8.5 Hz, 1H); 7,41 (d, J=8,3 Hz, 1H); 3,37 (t, J=5.8 Hz, 2H); and 2.83 (t, J=5.3 Hz, 2H); 1,84-to 1.67 (m, 4H).

Example 145: 1-(5,7-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 138 using on stage And 3,5-dimethylaniline. On stage instead of adding to the reaction mixture of ethanol, the reaction mixture was carefully added in ethanol dropwise with a pipette. MS (IER/CHI): calculated for C14H12N4O3: 284,1; received m/z: 285,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,99 (s, 1H); KZT 12.39 (s, 1H); 8,89 (d, J=0.5 Hz, 1H); 8,24 (s, 1H); 7,30 (s, 1H); to 7.09 (s, 1H); 2,73 (s, 3H); 2,39 (s, 3H).

Example 146: 1-(7-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 138 using on-stage And 3-isopropylaniline. On stage instead of adding to the reaction mixture of ethanol, the reaction mixture was carefully added in ethanol dropwise with a pipette. MS (IER/CHI): calculated for C15H14 N4O3: 298,1; received m/z: 299,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,01 (s, 1H); 12,74 (s, 1H); to 8.94 (s, 1H); compared to 8.26 (s, 1H); of 8.06 (d, J=8,1 Hz, 1H); rate of 7.54 (s, 1H); 7,44 (d, J=8,2 Hz, 1H); 3,13-3,00 (m, 1H); of 1.28 (d, J=6.9 Hz, 6H).

Example 147: 1-(7-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 138 using on-stage And 3-tert-butylaniline. On stage instead of adding to the reaction mixture of ethanol, the reaction mixture was carefully added in ethanol dropwise with a pipette. MS (IER/CHI): calculated for C16H16N4O3: 312,1; received m/z: 313,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,00 (s, 1H); was 12.75 (s, 1H); 8,97 (s, 1H); compared to 8.26 (s, 1H); 8,07 (d, J=8,3 Hz, 1H); 7,69-7,56 (m, 2H); of 1.36 (s, 9H).

Example 148: 1-(4-oxo-7-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 138 using on-stage And 3-triphtalocyaninine. On stage instead of adding to the reaction mixture of ethanol, the reaction mixture was carefully added in ethanol dropwise with a pipette. MS (IER/CHI): calculated for C13H7F3N4O4: 340,0; received m/z: 341,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,06 (s, 2H); 8,97 (s, 1H); 8,29 (s, 1H); 8,25 (who, J=8,8 Hz, 1H); 7,63 (s, 1H); 7,49 (d, J=8,8 Hz, 1H).

Example 149: 1-(7-isopropoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 17, using 3-isopropylaniline on stage and with the exception of purification by reverse-phase HPLC on stage C. MS (IER/CHI): calculated for C15H14N4O4: 314,1; received m/z: 315,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,99 (s, 1H); was 12.61 (s, 1H); to 8.94 (s, 1H); of 8.25 (s, 1H); 8,02 (d, J=8.6 Hz, 1H); 7,11 (s, 1H); 7,05 (DD, J=8,8, 2.1 Hz, 1H); of 4.83 (ush s, 1H); of 1.34 (d, J=6.0 Hz, 6H).

Example 150: 1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, phase-In, using on-stage And 3-(N,N-dimethyl)aniline. At the stage B received a mixture of the desired compounds and ethyl ester of 1-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid in the ratio 3:2.

Data for the ethyl ester of 1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid: MS (IER/CHI): calculated for C16H17N5O3: 327,1; received m/z: 328,1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12,22 (s, 1H); 8,98 (s, 1H); of 8.28 (s, 1H); of 7.90 (d, J=8,9 Hz, 1H); 6,93 (DD, J=8,9, and 2.1 Hz, 1H); 6.73 x (s, 1H); 4,29 (kV, J=7,1 Hz, 2H); of 3.07 (s, 6H); 1.32 to (t, J=7,1 Hz, 3H).

Stage B. Obtain 1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid and ethyl ester of 1-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid in the ratio 3:2 (0,415 g of 1.27 mmol) in THF (3.8 ml) was added 1 M aqueous solution of KOH (3.8 ml, 3.8 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated. The residue re-dissolved in water (10 ml) and acidified using 1 M aqueous HCl (3 ml). The precipitation was collected by filtration and obtained a mixture of the desired compound 1-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The collected precipitate was washed from DMSO and washed with ethanol, having a pure 1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (0,113 mg, yield 29%). The filtrate was retained for further purification. MS (IER/CHI): calculated for C14H13N5O3: 299,1; received m/z: 300,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,97 (s, 1H); 12,21 (s, 1H); of 8.92 (s, 1H); by 8.22 (s, 1H); of 7.90 (d, J=8,9 Hz, 1H); 6,93 (DD, J=9,0, 2.3 Hz, 1H); 6,72 (s, 1H); of 3.07 (s, 6H).

Example 151: 1-(5-dimethylamino-4-oxo-3,4-d is hydrogenation-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, phase-In, using on-stage And 3-(N,N-dimethyl)aniline. At the stage B received a mixture of ethyl ester of 1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid and the desired compounds in a ratio of 3:2.

Data for the ethyl ester of 1-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid: MS (IER/CHI): calculated for C16H17N5O3: 327,1; received m/z: 328,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,22 (s, 1H); 8,98 (s, 1H); to 8.20 (s, 1H); 8,01-7,39 (ush m, 3H); 4,29 (kV, J=7,1 Hz, 2H); and 3.31 (s, 6H); 1.32 to (t, J=7,1 Hz, 3H).

Stage B. Obtain 1-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid and ethyl ester of 1-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid in the ratio 3:2 (0,415 g of 1.27 mmol) in THF (3.8 ml) was added 1 M aqueous solution of KOH (3.8 ml, 3.8 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated. The resulting residue re-dissolved in water (10 ml) and was acidified aq is m HCl solution (1 M, 3 ml). The precipitation was collected by filtration and obtained a mixture of the desired compound 1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The collected precipitate was washed from DMSO and washed with ethanol, having a pure 1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. Collected after grinding the filtrate was purified by reverse-phase HPLC to obtain the desired compound (49,7 mg, yield 13%). MS (IER/CHI): calculated for C14H13N5O3: 299,1; received m/z: 300,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,99 (s, 2H); 8,96 (d, J=0.6 Hz, 1H); of 8.25 (s, 1H); to 7.84 (t, J=8,1 Hz, 1H); to 7.67-of 7.48 (m, 2H); of 3.12 (s, 6H).

Example 152: 1-(7-ethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 138 using on-stage And 3-ethoxyaniline. On stage instead of adding to the reaction mixture of ethanol, the reaction mixture was carefully added in ethanol dropwise with a pipette. MS (IER/CHI): calculated for C14H12N4O4: 300,1; received m/z: 301,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,01 (s, 1H); 12,66 (s, 1H); 8,93 (s, 1H); of 8.25 (s, 1H); 8,02 (d, J=8.7 Hz, 1H); 7,21-7,02 (m, 2H); 4,19 (kV, J=6,8 Hz, 2H); of 1.39 (t, J=7.0 Hz, 3H).

Example 153: 1-(6-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 138 using on-stage And 4-Chloroaniline. On stage instead of adding to the reaction mixture of ethanol, the reaction mixture was carefully added in ethanol dropwise with a pipette. MS (IER/CHI): calculated for C12H7ClN4O3: 290,0; received m/z: 291,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): of 13.05 (s, 2H); of 8.95 (s, 1H); of 8.28 (s, 1H); of 8.06 (d, J=2.3 Hz, 1H); 7,88 (DD, J=8,7, 2.5 Hz, 1H); 7,72 (d, J=7.8 Hz, 1H).

Example 154: 1-(7-hydroxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 131, using on-stage And 3-isopropylaniline. At the stage B of the formed product (ethyl ester of 1-(7-hydroxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid) was collected by filtration phase water/DCM. MS (IER/CHI): calculated for C12H8N4O4: 272,1; received m/z: 273,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,94 (s, 2H); 10,66 (s, 1H); to 8.94 (s, 1H); 8,24 (s, 1H); of 7.97 (d, J=8,8 Hz, 1H); 7,09-6,85 (m, 2H).

Example 155: 1-(6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired connection is s got a way similar to that described in Example 131, phase-In, using on-stage And 4-methylsulfonylamino. MS (IER/CHI): calculated for C15H14N4O3S: 330,1; received m/z: 331,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,95 (s, 1H); 9,00 (s, 1H); 8,31 (s, 1H); 7,86 (d, J=1.9 Hz, 1H); 7,74 (DD, J=8,6, 2.2 Hz, 1H); to 7.64 (d, J=7,4 Hz, 1H); 4,30 (kV, J=7,1 Hz, 2H); at 2.59 (s, 3H); 1.32 to (t, J=7,1 Hz, 3H).

Stage B. Obtain 1-(6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, step C, using the ethyl ester of 1-(6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. MS (IER/CHI): calculated for C13H10N4O3S: 302,1; received m/z: 303,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,13-12,78 (m, 2H); to 8.94 (s, 1H); of 8.25 (s, 1H); 7,86 (s, 1H); 7,74 (DD, J=8,6, and 2.3 Hz, 1H); 7,63 (d, J=8,3 Hz, 1H); at 2.59 (s, 3H).

Example 156: 1-(4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 131, using on-stage And 4-triftormetilfullerenov. MS (IER/CHI): calculated for C13H7F3N4O3S: 356,0; received m/z: 357,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,20 (s, 1H); 13,08 (s, 1H); 8,98 (s, 1H); at 8.36 (s, 1H); 8,31 (s, 1H); 8,10 (DD, J=8,5, 2.2 Hz, 1H); 782 (ush with, 1H).

Example 157: 1-(6-methanesulfonyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(6-methanesulfonyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester of 1-(6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (intermediate compound from Example 155, the product of stage A) (64,0 mg, 0,194 mmol) in DCM (1.0 ml) was added 3-chloroperoxybenzoic acid (91,2 mg, 0,407 mmol). The reaction mixture was stirred for 18 h and then concentrated. The residue is rubbed from ethanol and obtained the desired compound (63,0 mg, yield 90%). The filtrate was repaid by a 0.5 M aqueous solution of sodium thiosulfate. MS (IER/CHI): calculated for C15H14N4O5S: 362,1; received m/z: 363,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,39 (s, 1H); 9,07 (d, J=0.5 Hz, 1H); to 8.57 (d, J=2.1 Hz, 1H); scored 8.38 (s, 1H); 8.30 to (DD, J=8,6, and 2.3 Hz, 1H); to $ 7.91 (d, J=8,3 Hz, 1H); or 4.31 (q, J=7,1 Hz, 2H); to 3.33 (s, 3H); of 1.33 (t, J=7,1 Hz, 3H).

Stage B. Obtain 1-(6-methanesulfonyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, step C, using the ethyl ester of 1-(6-methanesulfonyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. MS (IER/CHI): calculated for C13H10N4O5S: 33,0; the obtained m/z: 335,0 [M+H]+; 333,1, [M-H]-.1H NMR (400 MHz, DMSO-d6): 13,35 (s, 1H); to 13.09 (s, 1H); 9,01 (s, 1H); to 8.57 (d, J=2.1 Hz, 1H); 8,32 (s, 1H); 8,29 (DD, J=8,6, 2.2 Hz, 1H); of 7.90 (d, J=7.5 Hz, 1H); to 3.33 (s, 3H).

Example 158: 1-(7-chloro-6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 131, using on-stage And 3-chloro-4-methylsulfonylamino. MS (IER/CHI): calculated for C13H9ClN4O3S: 336,0; received m/z: 337,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,04 (s, 2H); of 8.92 (d, J=0.6 Hz, 1H); compared to 8.26 (s, 1H); a 7.85 (s, 1H); of 7.82 (s, 1H); 2,62 (s, 3H).

Example 159: 1-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, phase-In, using on-stage And 3-chloro-4-triftormetilfullerenov. MS (IER/CHI): calculated for C15H10ClF3N4O3S: 418,0; received m/z: 419,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,38 (s, 1H); of 9.02 (d, J=0.7 Hz, 1H); 8,46 (s, 1H); scored 8.38 (s, 1H); with 8.05 (s, 1H); or 4.31 (q, J=7,1 Hz, 2H); to 1.32 (t, J=7,1 Hz, 3H).

Stage B. Obtain 1-(7-chloro-4-oxo-6-trifloromethyl lpanel-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 131, step C, using the ethyl ester of 1-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. MS (IER/CHI): calculated for C13H6ClF3N4O3S: 390,0; received m/z: 389,0 [M-H]-.1H NMR (400 MHz, DMSO-d6): 13,35 (s, 1H); 13,11 (s, 1H); 8,96 (d, J=0.6 Hz, 1H); 8,46 (s, 1H); 8,32 (s, 1H); 8,03 (s, 1H).

Example 160: 1-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained by a method similar to that described in Example 157 using on stage And 1-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (intermediate compound of Example 159, the product of stage A) instead of the ethyl ester of 1-(6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. MS (IER/CHI): calculated for C13H6ClF3N4O4S: 406,0; received m/z: 407,0 [M+H]+;405,0[M-H]-.1H NMR (400 MHz, DMSO-d6): 13,46 (ush s, 1H); 13,12 (s, 1H); 8,97 (d, J=0.6 Hz, 1H); 8,54 (s, 1H); with 8.33 (s, 1H); 8,03 (s, 1H).

Example 161: 1-[4-oxo-6-(pyrrolidin-1-sulfonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained by the method, similar to cnym described in Example 17, using 4-(pyrrolidin-1-sulfonyl)aniline instead of 3,4-dimethoxyaniline on A stage and with the exception of purification by reverse-phase HPLC on stage B. MS (IER/CHI): calculated for C16H15N5O5S: 389,1; received m/z: 390,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,31 (s, 1H); to 13.09 (s, 1H); 9,00 (s, 1H); to 8.40 (d, J=1.9 Hz, 1H); 8,32 (s, 1H); 8,19 (DD, J=8,6, 2.2 Hz, 1H); 7,89 (s, 1H); 3.25 to 3,10 (m, 4H); 1,74-to 1.59 (m, 4H).

Example 162: 1-[4-oxo-6-(pyrrolidin-1-carbonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-{ethoxycarbonylmethyl-[4-(pyrrolidin-1-carbonyl)-phenylamino]-methyl}-1H-pyrazole-4-carboxylic acid. To a suspension of (4-AMINOPHENYL)-pyrrolidin-1-yl-methanone (0,873 g, 4,59 mmol) in DCM (15 ml) was added ethylisothiocyanate (of 0.60 ml, 5.1 mmol) and stirred the reaction mixture at room temperature for 1 h then added DIC (1,01 ml of 5.05 mmol) and then aripirazole-4-carboxylate (0,707 g of 5.05 mmol). Stirring was continued for another 18 h, after which the reaction mixture was concentrated. To the residue was added diethyl ether (25 ml), the resulting suspension was cooled to 0°C and filtered. The obtained filtrate was concentrated and the residue purified KFH (EtOAc/hexane 2-100%), having the desired compound (1,502 g, yield 77%). MS (IER/CHI): calculated for C21H25N5O5: 427,2; received m/z: 428,2 [MH] +.

Stage B. obtaining the ethyl ester of 1-[4-oxo-6-(pyrrolidin-1-carbonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-{ethoxycarbonylmethyl-[4-(pyrrolidin-1-carbonyl)-phenylamino]-methyl}-1H-pyrazole-4-carboxylic acid (0,977 g to 2.29 mmol) in DCE (5.5 ml) was carefully added chloride titanium (IV) (0,377 ml of 3.43 mmol). The reaction mixture stood at 100°C for 2.5 h, then cooled to room temperature and diluted with ethanol (10 ml). The resulting solution was concentrated and divided the remainder between DCM (30 ml) and water (30 ml). Both phase was filtered to remove solid by-product and then divided. The aqueous phase is washed DCM (30 ml), the combined organic phases are washed with saturated saline solution (30 ml), dried over MgSO4and concentrated. The obtained residue was washed with diethyl ether and then with ethanol, having the desired compound (18 mg, yield of 2.0%). MS (IER/CHI): calculated for C19H19N5O4: 381,1; received m/z: 382,1 [M+H]+.

Stage C. Obtaining 1-[4-oxo-6-(pyrrolidin-1-carbonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of 1-[4-oxo-6-(pyrrolidin-1-carbonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (18,0 mg, to 43.1 mmol) in THF (0.2 ml) was added 1 M aqueous solution of KOH (of 0.13 ml, 0.13 mmol). The reaction mixture was stirred at room temp is the temperature for 2 days and then concentrated. The resulting residue re-dissolved in water (2 ml) and acidified using 1 M aqueous HCl (0.5 ml). The precipitation was collected by filtration and obtained the desired compound (11 mg, yield 70%). MS (IER/CHI): calculated for C17H15N5O4: 353,1; received m/z: 354,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,24-was 12.75 (m, 2H); 8,98 (s, 1H); of 8.28 (s, 1H); 8,23 (s, 1H); of 7.97 (d, J=8,3 Hz, 1H); 7,73 (s, 1H); 3,51 (t, J=6,8 Hz, 2H); of 3.45 (t, J=6.5 Hz, 2H); 1,95-of 1.78 (m, 4H).

Example 163: 1-[6-(2,6-dimethylphenylcarbamate)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A. Obtain 4-amino-N-(2,6-dimetilfenil)-benzamide. To a solution of DMF (1.7 ml, 22 mmol) in DCM (22 ml) at 0°C dropwise added oxalicacid (1.9 ml, 22 mmol). The obtained foamy white suspension was mixed for 30 min, allowed to warm to room temperature and then cooled to 0°C. then added 4-aminobenzoic acid (1.50 g, 10.9 mmol) and stirred the reaction mixture at room temperature for 1 h Then the flask was again cooled to 0°C and added DCM (11 ml) and pyridine (2.6 ml, 33 mmol). Stirring was continued for another 50 minutes, after which was added 2,6-dimethylphenylamine (of 1.33 g, 10.9 mmol). The reaction mixture was stirred at room temperature for 1.5 h and concentrated until dry. The obtained residue was dissolved in ethanol (30 ml) and d is bavili 1,2-Ethylenediamine (3,3 ml, 49 mmol). The reaction mixture is boiled under reflux for 2 h, then allowed to cool to room temperature, was stirred for 2 days and concentrated. To the obtained residue were added water (50 ml), precipitated precipitate was collected, well washed with water and dried, obtaining the desired compound (1,904 g, yield 70%). MS (IER/CHI): calculated for C15H16N2O: 240,1; received m/z: 241,1 [M+H]+.1H NMR (400 MHz, CD3OD): 7,76 (d, J=8,8 Hz, 2H); 7,10 (s, 3H); 6,72 (d, J=8,8 Hz, 2H); 2,24 (s, 6H).

Stage B. Obtaining 1-[6-(2,6-dimethylphenylcarbamate)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 162, using on-stage And 4-amino-N-(2,6-dimetilfenil)benzamide (obtained in accordance with the method described in J. Org. Chem. 2008, 73, 8954-8959). MS (IER/CHI): calculated for C21H17N5O4: 403,1; received m/z: 404,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,07 (s, 2H); 10,08 (s, 1H); 9,01 (s, 1H); 8,81 (s, 1H); 8,39 (d, J=7.7 Hz, 1H); 8.30 to (s, 1H); 7,81 (d, J=7,6 Hz, 1H); 7,14 (s, 3H); of 2.21 (s, 6H).

Example 164: 1-(6-nitro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. Obtaining 6-nitro-1H-hinzelin-2,4-dione. Urea (of 9.89 g, 0,165 mol) and 5-nitroanthranilic acid (6,00 g of 32.9 mmol) was vigorously stirred for 1 h at 200°C. Polucen the mu melt is allowed to cool to 150°C and slowly added water (150 ml). The resulting suspension was dispersively ultrasound for 1 h and vigorously stirred for another 2 hours Then it was cooled to 0°C, the precipitation was collected and washed with water, having the desired connection (to 6.43 g, yield 94%). The resulting substance was dried in a vacuum oven and used without additional purification. For this connection has not been obtained mass spectrometric data.

Stage B. Obtain 2,4-dichloro-6-nitroquinazoline. To a suspension of 6-nitro-1H-hinzelin-2,4-dione (5,01 g, and 24.2 mmol) in toluene (100 ml) was added phosphorus oxychloride (6,64 ml, to 72.6 mmol) and heated the reaction mixture to 55°C. and Then for 25 minutes using a dropping funnel dropwise added tri-n-Propylamine (12.1 ml, and 63.9 mmol). The reaction mixture stood at 110°C for 6 h, was stirred at room temperature for 4 days, then the pipette was moved into water (75 ml) and vigorously stirred for 1 h Two phase formed was filtered and separated. The organic phase is washed with saturated saline solution (30 ml), dried over MgSO4and concentrated, obtaining the desired compound (3,79 g, yield 67%, purity 95%) after 24 h under high vacuum. For this connection has not been obtained mass spectrometric data.1H NMR (600 MHz, CDCl3): 9,18 (d, J=2.4 Hz, 1H); is 8.75 (DD, J=9,2, 2.5 Hz, 1H); 8,18 (d, J=9,2 Hz, 1H).

Stage C. Obtain 2-chloro-6-nitro-3H-hinzelin-4-it. 2,-dichloro-6-nitroquinazoline (3,61 g, of 14.8 mmol) was added 2 M aqueous NaOH (22,2 ml, 44.4 mmol). The resulting mixture was dispersively ultrasound, mixed at room temperature for 3 h and was filtered, washing with water (60 ml). To collect the filtrate was added acetic acid (3,81 ml 66,6 mmol) and the obtained precipitate, which was collected and dried in a vacuum oven, having the desired compound (2,99 g, yield 90%). For this connection has not been obtained mass spectrometric data.1H NMR (400 MHz, CDCl3): 9,07 (s, 1H); 8,56 (d, J=8,9 Hz, 1H); for 7.78 (d, J=8,8 Hz, 1H).

Stage D. obtaining the ethyl ester of 1-(6-nitro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a suspension of 2-chloro-6-nitro-3H-hinzelin-4-it (2,95 g of 13.1 mmol) in xylene (52 ml) was added aripirazole-4-carboxylate (1,83 g of 13.1 mmol). The reaction mixture stood at 130°C for 1 h, then allowed to cool and was stirred at room temperature for 18 hours the precipitation was collected and washed with ether (20 ml), obtaining the desired compound (4,22 g, 98%). MS (IER/CHI): calculated for C14H11N5O5: 329,1; received m/z: 330,1 [M+H]+.

Stage E. Obtain 1-(6-nitro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 1, step C. the target compound was obtained by rubbing of DMSO. MS (IER/CHI): calculated for C12H7 5O5: 301,0; received m/z: 302,2 [M+H]+, 300,1 [M-H]-.1H NMR (400 MHz, DMSO-d6): 13,47 (s, 1H); 13,11 (s, 1H); of 9.02 (s, 1H); 8,80 (d, J=2.7 Hz, 1H); 8,58 (DD, J=9,0, 2.7 Hz, 1H); with 8.33 (s, 1H); 7,88 (d, J=8.7 Hz, 1H).

Example 165: 1-(6-benzoylamine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-[6-nitro-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. To a suspension of ethyl ether 1-(6-nitro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (intermediate compound from Example 164, the product of stage (D) (4,21 g, 12.8 mmol) in THF (64 ml) was added DIEA (to 4.41 ml, 25.6 mmol) and then (2-hermeticity)-trimethylsilane (2,49 ml, 14.1 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated. The obtained residue was separated between water (75 ml) and EtOAc (75 ml), the organic phase is washed with water (2 x 75 ml) and saturated saline (50 ml), dried over MgSO4and concentrated, obtaining the desired compound (of 5.92 g, yield 86%, purity 85%). The obtained substance was used in the next stage without additional purification. MS (IER/CHI): calculated for C20H25N5O6Si: 459,2; received m/z: 402,1 [M+H-58]+.

Stage B. obtaining the ethyl ester of 1-[6-amino-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydr hinzelin-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[6-nitro-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (of 5.92 g, purity 85%, 10.9 mmol) in acetone (46 ml) was added ammonium chloride (4,10 g, to 76.6 mmol) and water (9.1 ml). Then, with vigorous stirring, in small portions was added zinc dust (5,01 g, to 76.6 mmol). Stirring is continued for another 45 min, after which the reaction mixture was filtered through diatomaceous earth. The filter cake is thoroughly washed EtOAc (100 ml). The collected filtrate was concentrated and the residue was dissolved in EtOAc (75 ml), the drain layer with remaining salt. The organic phase is washed with saturated salt solution (45 ml), dried over MgSO4and concentrated. The obtained residue was purified KFH (EtOAc/hexane 2-70%) and obtained the desired compound (4,19 g, yield 89%). MS (IER/CHI): calculated for C20H27N5O4Si: 430,2; received m/z: 429,2 [M+H]+.1H NMR (400 MHz, CDCl3): 8,56 (d, J=0.6 Hz, 1H); 8,15 (d, J=0.6 Hz, 1H); 7,53 (d, J=8.6 Hz, 1H); 7,49 (d, J=2.6 Hz, 1H); 7,13 (DD, J=8,6, 2.8 Hz, 1H); 5,78 (s, 2H); 4,35 (kV, J=7,1 Hz, 2H); 4.09 to (s, 2H); 3,57-of 3.43 (m, 2H); 1,37 (t, J=7,1 Hz, 3H); 0,86-0,74 (m, 2H); -0,08 (s, 9H).

Stage C. obtaining the ethyl ester of 1-[6-benzoylamine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[6-amino-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-shall irsol-4-carboxylic acid (0,200 g, 0,466 mmol) and TEA (rate £ 0.162 ml of 1.16 mmol) in DCM (2.3 ml) is dropwise added benzoyl chloride (81,1 μl, 0,698 mmol). The reaction mixture was stirred at room temperature for 1.5 h, then was diluted with DCM (25 ml) and extinguished with water (15 ml). The organic phase was washed with water (20 ml) and saturated saline (20 ml), dried over MgSO4and concentrated. The obtained residue was purified KFH (EtOAc/hexane 10-70%) and obtained the desired compound (0,240 g, yield 97%). MS (IER/CHI): calculated for C27H31N5O5Si: 533,2; received m/z: 476,2 [M+H-58]+.

Stage D. obtaining the ethyl ester of 1-(6-benzoylamine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[6-benzoylamine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0,239 g, 0,488 mmol) in dioxane (2.0 ml) was added hydrochloric acid (4 M solution in dioxane, 2.0 ml, 8.0 mmol). The reaction mixture was stirred at room temperature for 18 h, then was added ether (10 ml) and collected sludge having the desired connection (of) 0.157 g, yield 86%). MS (IER/CHI): calculated for C21H17N5O4: 403,1; received m/z: 404,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,87 (s, 1H); to 10.62 (s, 1H); 9,01 (s, 1H); 8,69 (s, 1H); 8,32 (s, 1H); 8,23 (DD, J=8,9, and 2.4 Hz, 1H); 8,06-of 7.96 (m, 2H); 7,84-7,49 (m, 4H); or 4.31 (q, J=7,1 Hz, 2H); of 1.33 (t, J=7,1 Hz, 3H).

Stage E. Obtain 1-(6-benzo is amino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester of 1-(6-benzoylamine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (0,142 g, 0,343 mmol) in THF (1.0 ml) was added 1 M aqueous solution of KOH (of 1.06 ml, 1.06 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated. The resulting residue re-dissolved in water (5 ml) and brought to pH 1 with 1 M aqueous HCl (3 ml). The precipitation was collected by filtration and obtained the desired compound (0,110 g, yield 82%). MS (IER/CHI): calculated for C19H13N5O4: 375,1; received m/z: 376,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,99 (s, 1H); 12,79 (s, 1H); or 10.60 (s, 1H); of 8.95 (s, 1H); 8,68 (s, 1H); compared to 8.26 (s, 1H); 8,23 (DD, J=8,8, 2.4 Hz, 1H); 8,04-to 7.99 (m, 2H); 7,71 (d, J=7.8 Hz, 1H); 7,65-of 7.60 (m, 1H); to 7.59-rate of 7.54 (m, 2H).

Example 166: 1-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A. Obtaining 2,6-dimethylbenzylamine. To a solution of 2,6-dimethylbenzoic acid (0,100 g, 0,666 mmol) in thionyl chloride (0,50 ml and 6.9 mmol) was added DMF (2 drops). The reaction mixture was mixed for 2 h and concentrated, obtaining the desired compound, which was used in the next stage without additional purification.

Stage B. Obtaining 1-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained by a method similar to that described in Example 165, stage C-E, using on stage With 2,6-dimethylbenzylamine instead of benzoyl chloride. MS (IER/CHI): calculated for C21H17N5O4: 403,1; received m/z: 404,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,00 (s, 1H); 12,83 (s, 1H); 10,78 (s, 1H); of 8.95 (s, 1H); 8,72 (s, 1H); of 8.25 (s, 1H); 8,03 (DD, J=8,8, 2.4 Hz, 1H); of 7.69 (d, J=8,8 Hz, 1H); 7.29 trend-of 7.23 (m, 1H); 7,14 (d, J=7.5 Hz, 2H); 2,30 (s, 6H).

Example 167: 1-(6-acetylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained by a method similar to that described in Example 165, using on stage With acetylchloride instead of benzoyl chloride. MS (IER/CHI): calculated for C14H11N5O4: 313,1; received m/z: 314,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,97 (s, 1H); of 12.73 (s, 1H); 10,30 (s, 1H); of 8.92 (d, J=0.6 Hz, 1H); 8,48 (s, 1H); of 8.25 (s, 1H); 7,94 (DD, J=8,8, 2.5 Hz, 1H); the 7.65 (d, J=8.6 Hz, 1H); 2,10 (s, 3H).

Example 168: 1-[4-oxo-6-(3-phenylurea)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-[4-oxo-6-(3-phenylurea)-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[6-amino-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0,240 g, 0,559 mmol) in THF (11.2 ml) dropwise added benzylsuccinic (79,2 μl, advanced 0.729 mmol). P is a promotional mixture was stirred at room temperature for 24 h, and then at 50°C for 18 hours then added another aliquot benzylisothiocyanate (60,9 μl, 0,561 mmol) and continued heating for another 6 hours Then the reaction mixture was concentrated and divided the remainder between EtOAc (30 ml) and water (30 ml). The resulting aqueous phase was extracted with EtOAc (30 ml), the combined organic phases are washed with saturated saline solution (30 ml), dried over MgSO4and concentrated. The obtained residue was purified KFH (EtOAc/hexane) and obtained the desired compound (0,287 g, yield 94%). MS (IER/CHI): calculated for C27H32N6O5Si: 548,2; received m/z: 491,2 [M+H-58]+.

Stage B. Obtain 1-[4-oxo-6-(3-phenylurea)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained by a method similar to that described in Example 165, the stage D-E. MS (IER/CHI): calculated for C19H14N6O4: 390,1; received m/z: to € 391.1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,22-12,51 (m, 2H); 9,12 (s, 1H); 8,93 (d, J=0.7 Hz, 1H); 8,80 (s, 1H); of 8.37 (d, J=2.5 Hz, 1H); of 8.25 (s, 1H); 7,81 (DD, J=8,9, and 2.6 Hz, 1H); the 7.65 (d, J=8,8 Hz, 1H); 7,49 (DD, J=8,6, 1,1 Hz, 2H); 7,31 (DD, J=10,7, 5,2 Hz, 2H);? 7.04 baby mortality-of 6.96 (m, 1H).

Example 169: 1-(6-benzosulfimide-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-[6-benzosulfimide-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pee the azole-4-carboxylic acid. To a solution of ethyl ester 1-[6-amino-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0,200 g, 0,466 mmol) in pyridine (2.3 ml) is dropwise added benzosulphochloride (0,131 ml of 1.02 mmol). The reaction mixture was mixed for 2 h, and then extinguished with water (15 ml) and was extracted with EtOAc (30 ml). The organic phase was washed with water (15 ml) and saturated brine (15 ml), dried over MgSO4and concentrated. The obtained residue was purified KFH (EtOAc/hexane 5-50%) and obtained the desired compound (0,253 mg, yield 95%). MS (IER/CHI): calculated for C26H31N5O6SSi: 569,2; received m/z: 512,1 [M+H-58]+.

Stage B. Obtain 1-(6-benzosulfimide-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained by a method similar to that described in Example 165, the stage D-E. MS (IER/CHI): calculated for C18H13N5O5S: 411,1; received m/z: 412,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,97 (s, 1H); 12,80 (s, 1H); 10,71 (s, 1H); 8,88 (s, 1H); by 8.22 (s, 1H); 7,81 (s, 1H); 7,79 (d, J=7,3 Hz, 2H); to 7.64-7,53 (m, 5H).

Example 170: 1-(6-methanesulfonamido-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained by a method similar to that described in Example 169, using on stage methanesulfonamide instead of benzolsulfonat the chloride. MS (IER/CHI): calculated for C13H11N5O5S: 349,1; received m/z: 350,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,00 (s, 1H); 12,88 (s, 1H); 10,18 (s, 1H); 8,93 (s, 1H); of 8.25 (s, 1H); to 7.95 (s, 1H); 7,75 to 7.62 (m, 2H); to 3.06 (s, 3H).

Example 171: 1-(6-benzylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-[6-benzylamino-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. In a vial was placed ethyl ester 1-[6-amino-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0,250 g, 0,582 mmol), benzaldehyde (59,2 μl, 0,582 mmol) and molecular sieves 4 Å (0.25 g). Then added DCE (1.9 ml) and stirred the reaction mixture at room temperature for 18 hours then added triacetoxyborohydride sodium (0,308 g of 1.46 mmol) and stirred the reaction mixture for another 24 h the reaction mixture is repaid saturated aqueous sodium bicarbonate (10 ml) and then was extracted with DCM (3 x 15 ml). The combined organic phases are washed with saturated saline (20 ml), dried over MgSO4and concentrated. The obtained residue was purified KFH (EtOAc/hexane 2-40%) and obtained the desired compound (0,273 g, yield 90%). MS (IER/CHI): calculated for C27H33N5O4Si: 519,2; received the m/z: 520,2 [M+H] +.

Stage B. Obtain 1-(6-benzylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained by a method similar to that described in Example 165, the stage D-E. At stage D before rubbing of the product from diethyl ether was evaporated dioxane. MS (IER/CHI): calculated for C19H15N5O3: 361,1; received m/z: 362,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,93 (s, 1H); to 12.44 (s, 1H); cent to 8.85 (d, J=0.6 Hz, 1H); 8,19 (s, 1H); 7,46 (d, J=8.7 Hz, 1H); 7,39 (d, J=7.7 Hz, 2H); 7,34 (t, J=7.7 Hz, 2H); 7,28-7,19 (m, 2H); to 7.09 (d, J=2.7 Hz, 1H); 6,92 (s, 1H); to 4.38 (s, 2H).

Example 172: 1-(6-ethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-[6-ethylamino-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[6-amino-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (0,250 g, 0,582 mol) in ethanol (1.9 grams) with molecular sieves 4 Å (0.35 g) was added acetaldehyde (1 ml). The reaction mixture was stirred at room temperature for 18 h and then was filtered. Then under high vacuum removed the ethanol and acetaldehyde. The resulting residue re-dissolved in DCE (1.5 ml) and added triacetoxyborohydride sodium (0,308 g of 1.46 mmol). The reaction mixture was stirred PR is room temperature for 6 days, then was diluted with EtOAc (30 ml) and washed with saturated aqueous sodium bicarbonate solution (20 ml). The aqueous phase was extracted with EtOAc (30 ml), the combined organic phases are washed with saturated saline (20 ml), dried over MgSO4) and concentrated. The obtained residue was purified KFH (EtOAc/hexane 5-65%) and obtained the desired compound (87,0 mg, yield 33%). MS (IER/CHI): calculated for C22H31N5O4Si: 457,2; received m/z: 458,2 [M+H]+.

Stage B. Obtain 1-(6-ethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained by a method similar to that described in Example 165, the stage D-E. At stage D before rubbing the product from the ether was evaporated dioxane. MS (IER/CHI): calculated for C14H13N5O3: 299,1; received m/z: 300,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,04-12,24 (m, 2H); cent to 8.85 (d, J=0.7 Hz, 1H); 8,19 (s, 1H); 7,46 (d, J=8,8 Hz, 1H); 7,16 (DD, J=8,8, 2.7 Hz, 1H); 7,06 (d, J=2.7 Hz, 1H); 6,23 (s, 1H); 3,12 (ush kV, J=7,0 Hz, 2H); to 1.21 (t, J=7,1 Hz, 3H).

Example 173: 1-[6-(2-methylbenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 2-methylbenzaldehyde instead of benzaldehyde. MS (IER/CHI): calculated for C20H17N5O3: 375,1; received m/z: 376,1 [M+H]+.1 H NMR (600 MHz, DMSO-d6): 12,92 (s, 1H); 12,46 (s, 1H); 8,86 (d, J=0.5 Hz, 1H); 8,19 (s, 1H); 7,46 (d, J=8,8 Hz, 1H); 7,28 (d, J=7,1 Hz, 1H); 7,26 for 7.12 (m, 4H); to 7.09 (s, 1H); 6,74 (s, 1H); or 4.31 (d, J=5,2 Hz, 2H); of 2.36 (s, 3H).

Example 174: 1-[6-(2-chlorobenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 2-chlorobenzaldehyde instead of benzaldehyde. MS (IER/CHI): calculated for C19H14ClN5O3: 395,1; received m/z: 396,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,93 (s, 1H); 12,48 (s, 1H); 8,86 (d, J=0.6 Hz, 1H); 8,19 (s, 1H); 7,53-7,46 (m, 2H); 7,40 (DD, J=5,9, 3.5 Hz, 1H); 7,33-7,28 (m, 2H); 7.23 percent (d, J=9.0 Hz, 1H); 7.03 is (d, J=2.2 Hz, 1H); to 6.95 (s, 1H); of 4.44 (d, J=4,6 Hz, 2H).

Example 175: 1-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 2,6-dimethylbenzaldehyde instead of benzaldehyde. MS (IER/CHI): calculated for C21H19N5O3: 389,2; received m/z: 390,2 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,92 (s, 1H); 12,49 (s, 1H); 8,88 (d, J=0.7 Hz, 1H); to 8.20 (s, 1H); 7,47 (d, J=8,8 Hz, 1H); 7,30 (DD, J=8,7, 2.7 Hz, 1H); 7.23 percent (d, J=2.5 Hz, 1H); 7,17-7,05 (m, 3H); 6,23 (t, J=3,9 Hz, 1H); is 4.21 (d, J=the 4.1 Hz, 2H); to 2.35 (s, 6H).

Example 176: 1-[6-(2,6-diferentiating)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-Piras the l-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 2,6-diferentialglea instead of benzaldehyde. MS (IER/CHI): calculated for C19H13F2N5O3: 397,1; received m/z: 398,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,94 (s, 1H); 12,49 (s, 1H); 8,86 (d, J=0.6 Hz, 1H); 8,21 (s, 1H); of 7.48 (d, J=8.6 Hz, 1H); 7,46-7,39 (m, 1H); to 7.25 (dt, J=8,7, 2.7 Hz, 2H); 7.18 in-7,11 (m, 2H); 6,69 (s, 1H); 4,37 (s, 2H).

Example 177: 1-[6-(2-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 2-cyanobenzaldehyde instead of benzaldehyde and purification of the desired compounds by reversed-phase HPLC. MS (IER/CHI): calculated for C20H14N6O3: 386,1; received m/z: 387,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,23 (s, 1H); to 13.09 (s, 1H); 10,18 (s, 1H); of 9.30 (s, 1H); of 9.02 (s, 1H); 8,44 (s, 1H); 8,32 (d, J=7.8 Hz, 2H); 8,10 (d, J=9,2 Hz, 1H); 7,94 (s, 1H); 7,89 (DD, J=11,3, a 4.7 Hz, 1H); to 7.84 (d, J=7.7 Hz, 1H); of 7.75 (t, J=7.7 Hz, 1H); are 5.36 (s, 2H).

Example 178: 1-[6-(3-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 3-cyanobenzaldehyde instead of be the of zaldehyde. On phase C received a mixture of the desired compound, 1-[6-(3-carbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid and 1-[6-amino-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, which was separated using reverse-phase HPLC.

Data for 1-[6-(3-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid: MS (IER/CHI): calculated for C20H14N6O3: 386,1; received m/z: 387,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,93 (s, 1H); 12,48 (s, 1H); cent to 8.85 (d, J=0.5 Hz, 1H); 8,19 (s, 1H); 7,83 (s, 1H); 7,73 (DD, J=7,8, 1.2 Hz, 2H); EUR 7.57 (t, J=7.8 Hz, 1H); 7,47 (d, J=8,8 Hz, 1H); 7.23 percent (d, J=6,5 Hz, 1H); was 7.08 (d, J=2.1 Hz, 1H); 6,99 (t, J=5,9 Hz, 1H); to 4.46 (d, J=5,9 Hz, 2H).

Example 179: 1-[6-(3-carbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 3-cyanobenzaldehyde instead of benzaldehyde. On phase C received a mixture of 1-[6-(3-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, the desired compound 1-[6-amino-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, which was separated using reverse-phase HPLC.

Data for 1-[6-(3-carbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid: MS (IER/X is): calculated for C 20H16N6O4: 404,1; received m/z: 405,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,92 (s, 1H); 12,45 (s, 1H); cent to 8.85 (d, J=0.6 Hz, 1H); 8,18 (s, 1H); of 7.96 (s, 1H); 7,92 (s, 1H); of 7.75 (d, J=7.8 Hz, 1H); 7,53 (d, J=7,6 Hz, 1H); 7,46 (d, J=8,8 Hz, 1H); 7,42 (t, J=7.7 Hz, 1H); of 7.36 (, 1H); 7,28-7,19 (m, 1H); was 7.08 (d, J=2.4 Hz, 1H); of 6.96 (t, J=5.8 Hz, 1H); was 4.42 (d, J=5.7 Hz, 2H).

Example 180: 1-[6-amino-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 3-cyanobenzaldehyde instead of benzaldehyde. On phase C received a mixture of 1-[6-(3-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, 1-[6-(3-carbarnoyl-benzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid and the desired connection. The mixture was separated using reverse-phase HPLC; the desired compound was isolated as a salt triperoxonane acid.

Data for 1-[6-amino-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, salt triperoxonane acid: MS (IER/CHI): calculated for C12H9N5O3: 271,1; received m/z: 272,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,93 (s, 1H); 12,40 (s, 1H); cent to 8.85 (d, J=0.6 Hz, 1H); to 8.20 (s, 1H); the 7.43 (d, J=8.7 Hz, 1H); from 7.24 (d, J=2.5 Hz, 1H); for 7.12 (DD, J=8,7, and 2.6 Hz, 1H); of 5.84 (s, 3H).

Example 181: 1-[6-(2,6-dichlorobenzamide)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-Carbo the OIC acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 2,6-dichlorobenzaldehyde instead of benzaldehyde. MS (IER/CHI): calculated for C20H13Cl2N5O3: 429,0; received m/z: 430.2.1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,93 (s, 1H); 12,50 (s, 1H); 8,87 (d, J=0.6 Hz, 1H); to 8.20 (s, 1H); at 7.55 (d, J=8.1 Hz, 2H); of 7.48 (d, J=8.6 Hz, 1H); 7,41 (DD, J=8,5, and 7.8 Hz, 1H); 7,28 (d, J=8.6 Hz, 1H); 7,26 (s, 1H); 6,50 (s, 1H); 4,49 (d, J=4.5 Hz, 2H).

Example 182: 1-[6-(3-chlorobenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 3-chlorobenzaldehyde instead of benzaldehyde. MS (IER/CHI): calculated for C19H14ClN5O3: 395,1; received m/z: 396,2 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,86 (d, J=0.6 Hz, 1H); to 8.20 (d, J=0.5 Hz, 1H); of 7.48 (d, J=8,8 Hz, 1H); 7,44 (s, 1H); 7,42-7,29 (m, 3H); from 7.24 (DD, J=8,8, 2.8 Hz, 1H); to 7.09 (d, J=2.7 Hz, 1H); to 4.41 (s, 2H).

Example 183: 1-[6-(4-methylbenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 171 using at the stage of A 4-methylbenzaldehyde instead of benzaldehyde. MS (IER/CHI): calculated for C20H17N5O3: 375,1; is luceno m/z: 376.3 on [M+H] +.1H NMR (400 MHz, DMSO-d6) 12,90 (s, 1H); 12,46 (s, 1H); cent to 8.85 (s, 1H); 8,19 (s, 1H); was 7.45 (d, J=8.7 Hz, 1H); 7,27 (d, J=8.0 Hz, 2H); 7,21 (DD, J=8,9, 2.7 Hz, 1H); to 7.15 (d, J=7.9 Hz, 2H); 7,07 (d, J=2.6 Hz, 1H); 6.87 in (t, J=4,8 Hz, 1H); 4,32 (d, J=5.5 Hz, 2H); and 2.27 (s, 3H).

Example 184: 1-(4-oxo-7-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A. obtaining the ethyl ester of 1-(7-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a manner analogous to the one described in Example 27, stage C-D, using phase C 3-iodoaniline. MS (IER): calculated for C14H11IN4O3: 410,0; received m/z: 411,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,04 (s, 1H); 9,00 (d, J=0.6 Hz, 1H); 8.34 per (s, 1H); 8,11 (s, 1H); a 7.85 (s, 2H); 4,30 (kV, J=7,1 Hz, 2H); to 1.32 (t, J=7,1 Hz, 3H).

Stage B. obtaining the ethyl ester of 1-[7-iodine-3-(2-methoxyethoxymethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(7-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (1.65 g, 4.02 mmol) and THF (20 ml) was added DIPEA (2.10 ml, 12.1 mmol) and then 1-chloromethoxy-2-methoxyethane (1,01 ml cent to 8.85 mmol) at 23°C. After stirring for 18 h the reaction mixture was concentrated under reduced pressure. The obtained residue was used in the subsequent reactions without further purification (1.89 g, 94%). MS (IER): calculated for C18H19IN4O 5: 498,0; received m/z: 499,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): cent to 8.85 (d, J=0.6 Hz, 1H); 8,30 (d, J=0.6 Hz, 1H); 8.17 and (d, J=1.4 Hz, 1H); 8,00 (DD, J=8,3, and 1.6 Hz, 1H); to 7.95 (d, J=8,3 Hz, 1H); the 5.65 (s, 2H); 4,30 (kV, J=7,1 Hz, 2H); 3,50-of 3.48 (m, 2H); 3,26 is 3.23 (m, 2H); 3,05 (s, 3H); to 1.31 (t, J=7,1 Hz, 3H).

Stage C. obtaining the ethyl ester of 1-[3-(2-methoxyethoxymethyl)-4-oxo-7-phenyl-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid. A mixture of potassium carbonate (210 mg, of 1.52 mmol), phenylboric acid (156 mg, 1.28 mmol), ethyl ester 1-[7-iodine-3-(2-methoxyethoxymethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (250 mg, 0,502 mmol) and THF (4.4 ml) for 10 min was degirolami nitrogen in a hermetically sealed reactor. Then to the reaction mixture was added dichloromethane adduct of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (48,9 mg, 0,0610 mmol) and hermetically closed reactor. The resulting mixture was stirred at a temperature of 80°C for 18 h Then the reaction mixture was cooled to 23°C, diluted with DCM (15 ml) and was filtered. The obtained filtrate was concentrated. The obtained residue was purified KFH (EtOAc/hexane 5-45%) and obtained the desired compound (192 mg, 85%). MS (IER): calculated for C24H24N4O5: USD 448,2; received m/z: 449,2 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,88 (d, J=0.6 Hz, 1H); 8,30 (d, J=0.6 Hz, 1H); 8,04 (d, J=1.5 Hz, 1H); 8,00 (DD, J=8,3, 1.8 Hz, 1H); 7,88-to 7.84 (m, 2H); for 7.78 (DD, J=8,0, 1.5 Hz, 1H); 7,58-7,52 (m, 2H); 7,51-7,46 (m, 1H); 5,67 (s, 2H); 4,30 (kV, J=7,1 Hz, 2H); 3,5-3,50 (m, 2H); 3,29-of 3.25 (m, 2H); is 3.08 (s, 3H); 1.32 to (t, J=7,1 Hz, 3H).

Stage D. obtaining the ethyl ester of 1-(4-oxo-7-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To ethyl ether, 1-[3-(2-methoxyethoxymethyl)-4-oxo-7-phenyl-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (90,0 mg, 0,201 mmol) was added 4 M HCl solution in dioxane (3,00 ml of 12.0 mmol). The resulting reaction mixture was stirred at 23°C. After 18 h, the reaction mixture was concentrated under reduced pressure. Then added Et2O (5 ml), precipitated precipitate was collected by filtration and well washed Et2O, having the desired compound (38,0 mg, 53%). MS (IER): calculated for C20H16N4O3: 360,1; received m/z: 361,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,93 (s, 1H); 9,04 (s, 1H); 8.34 per (s, 1H); to 8.20 (d, J=8,2 Hz, 1H); 7,98 (s, 1H); to 7.84 (DD, J=10,5, 4,2 Hz, 3H); at 7.55 (t, J=7,6 Hz, 2H); 7,49-7,46 (m, 1H); or 4.31 (q, J=7,1 Hz, 2H); of 1.33 (t, J=7,1 Hz, 3H).

Stage E. Obtain 1-(4-oxo-7-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(4-oxo-7-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (48,0 mg, 0.133 mmol), water (0.8 ml) and THF (0.8 ml) was added potassium hydroxide (or 37.4 mg, 0,666 mmol). The resulting mixture was stirred for 16 h at 23°C. Then the reaction mixture was concentrated under reduced pressure to remove THF, and the remaining aqueous phase was acidified to pH 2 1 M aqueous HCl. The precipitation was collected filtration is the Finance and obtained the desired compound (42,0 mg, 85%). MS (IER): calculated for C18H12N4O3: 332,1; received m/z: 333,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): to 8.45 (d, J=0.8 Hz, 1H); to 7.99 (d, J=8,2 Hz, 1H); 7,78-7,72 (m, 2H); a 7.62 (d, J=1.5 Hz, 1H); at 7.55 (d, J=0.8 Hz, 1H); 7,49 (t, J=7,6 Hz, 2H); 7,41 and 7.36 (m, 2H).

Example 185: 1-[7-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 184, stage C-E, using on stage With ethyl ester 1-[7-iodine-3-(2-methoxyethoxymethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate compound of Example 184, the product of stage B) and 2-chloraniline acid. MS (IER): calculated for C18H11ClN4O3: 366,1; received m/z: 367,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,02 (ush s, 1H); 12,92 (ush s, 1H); 8,97 (s, 1H); of 8.28 (s, 1H); by 8.22 (d, J=6,6 Hz, 1H); 7,71 (s, 1H); to 7.67 to 7.62 (m, 1H); 7,58 (d, J=7,3 Hz, 1H); 7,55-7,47 (m, 3H).

Example 186: 1-[7-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 184, stage C-E, using on stage With ethyl ester 1-[7-iodine-3-(2-methoxyethoxymethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate compound of Example 184, the product of stage B) and 3-chloraniline cyclotis (IER): calculated for C 18H11ClN4O3: 366,1; received m/z: 367,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,04 (ush s, 1H); 12,94 (ush s, 1H); 8,97 (s, 1H); of 8.28 (s, 1H); 8,21 (d, J=8.0 Hz, 1H); 8,00 (s, 1H); to $ 7.91 (s, 1H); 7,87 (d, J=8,4 Hz, 1H); of 7.82 (d, J=6,7 Hz, 1H); 7,60-7,52 (m, 2H).

Example 187: 1-[7-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 184, stage C-E, using stage C ethyl ester 1-[7-iodine-3-(2-methoxyethoxymethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate compound of Example 184, the product of stage B) and 4-chloraniline acid. MS (IER): calculated for C18H11ClN4O3: 366,1; received m/z: 367,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,99 (ush s, 2H); 8,97 (d, J=0.6 Hz, 1H); of 8.28 (s, 1H); to 8.20 (d, J=8,3 Hz, 1H); of 7.97 (s, 1H); 7,87 (d, J=8.5 Hz, 2H); 7,83 (DD, J=8,3, 1.7 Hz, 1H); 7,63-7,58 (m, 2H).

Example 188: 1-(4-oxo-7-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 184, stage C-E, using stage C ethyl ester 1-[7-iodine-3-(2-methoxyethoxymethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate compound of Example 184, the product of stage B) and 2-methylphenylimino acid. MS (IER): expect the but for C 19H14N4O3: 346,1; received m/z: 347,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,82 (ush s, 1H); of 8.92 (s, 1H); 8,10 (s, 1H); 8,08 (d, J=8,1 Hz, 1H); 7,47 (s, 1H); of 7.36-7,27 (m, 5H); of 2.28 (s, 3H).

Example 189: 1-(4-oxo-7-m-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 184, stage C-E, using stage C ethyl ester 1-[7-iodine-3-(2-methoxyethoxymethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate compound of Example 184, the product of stage B) and 3-methylphenylamine acid. MS (IER): calculated for C19H14N4O3: 346,1; received m/z: 347,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,04 (s, 1H); 12,87 (s, 1H); 8,98 (s, 1H); of 8.28 (s, 1H); to 8.20 (d, J=8,2 Hz, 1H); 7,94 (s, 1H); 7,83 (d, J=8,1 Hz, 1H); to 7.67 (s, 1H); a 7.62 (d, J=7,0 Hz, 1H); the 7.43 (t, J=7,6 Hz, 1H); 7,29 (d, J=7.5 Hz,, 1H); to 2.42 (s, 3H).

Example 190: 1-(4-oxo-6-m-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 3-methylphenylamine acid. MS (IER): calculated for C19H14N4O3 : 346,1; received m/z: 347,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,02 (s, 1H); 12,91 (s, 1H); 8,98 (s, 1H); 8.34 per (s, 1H); of 8.27 (s, 1H); 8.17 and (d, J=7.9 Hz, 1H); for 7.78 (d, J=6.3 Hz, 1H); a 7.62 (s, 1H); 7,58 (d, J=7,3 Hz, 1H); 7,41 (t, J=7,6 Hz, 1H); from 7.24 (d, J=7,0 Hz, 1H); to 2.42 (s, 3H).

Example 191: 1-(4-oxo-6-p-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 4-methylphenylimino acid. MS (IER): calculated for C19H14N4O3: 346,1; received m/z: 347,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,03 (s, 1H); 12,92 (s, 1H); 8,98 (s, 1H); with 8.33 (s, 1H); of 8.27 (s, 1H); is 8.16 (d, J=7.9 Hz, 1H); to 7.77 (s, 1H); of 7.69 (d, J=8.0 Hz, 2H); 7,33 (d, J=7.9 Hz, 2H); is 2.37 (s, 3H).

Example 192: 1-[6-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 2-chloraniline acid. MS (IER): calculated for C18H11ClN4O3: 366,1; receiving what about the m/z: 367,0 [M+H] +.1H NMR (600 MHz, DMSO-d6): 12,99 (s, 2H); 8,98 (d, J=0.6 Hz, 1H); of 8.27 (s, 1H); 8,13 (d, J=2.1 Hz, 1H); to $ 7.91 (DD, J=8,4, and 2.1 Hz, 1H); for 7.78 (d, J=8,4 Hz, 1H); to 7.64-to 7.61 (m, 1H); 7,55-7,52 (m, 1H); 7,47 (square d, J=7,4, 1.8 Hz, 2H).

Example 193: 1-[6-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 3-chloraniline acid. MS (IER): calculated for C18H11ClN4O3: 366,1; received m/z: 367,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,00 (ush s, 2H); 8,98 (s, 1H); at 8.36 (d, J=2.2 Hz, 1H); of 8.28 (s, 1H); to 8.20 (DD, J=8,5, 2.3 Hz, 1H); a 7.85 (t, J=1.9 Hz, 1H); 7,81 to 7.75 (m, 2H); at 7.55 (t, J=7.9 Hz, 1H); 7,49 (DDD, J=8.0 a, 2,0, 1.0 Hz, 1H).

Example 194: 1-[6-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 4-chloraniline acid. MS (IER): calculated for C18H11ClN4O3: 366,1; received m/z: 367,0 [MH] +.1H NMR (600 MHz, DMSO-d6): 13,02 (s, 1H); 12,95 (s, 1H); 8,99 (s, 1H); 8,28 (s, 2H); with 8.05 (d, J=8.5 Hz, 1H); 7,81 (s, 1H); to 7.67 (t, J=7.9 Hz, 1H); 7,49 (TDD, J=7,1, 5,1, 1.7 Hz, 1H); 7,40-7,34 (m, 2H).

Example 195: 1-[6-(2-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 2-ftorpolimernoj acid. MS (IER): calculated for C18H11FN4O3: 350,1; received m/z: 351,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,02 (ush s, 1H); 12,95 (ush s, 1H); 8,99 (s, 1H); 8,28 (s, 2H); with 8.05 (d, J=8.5 Hz, 1H); 7,81 (s, 1H); to 7.67 (t, J=7,9, 1H); 7,49 (TDD, J=7,1, 5,1, 1,7, 1H); 7,40-7,34 (m, 2H).

Example 196: 1-[6-(3-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 3-ftorpolimernoj acid. MS (IER): calculated for C18H11FN4O3: 350,1; received m/z: 351,1 [M+H]+.1H NMR (600 MHz, DMSO-d6 ): 13,01 (ush s, 2H); 8,98 (s, 1H); scored 8.38 (d, J=2.0 Hz, 1H); 8,29 (s, 1H); by 8.22-to 8.20 (m, 1H); 7,80 (d, J=8.0 Hz, 1H); 7.68 per-to 7.64 (m, 2H); 7,58-rate of 7.54 (m, 1H); 7,28-7,24 (m, 1H).

Example 197: 1-[6-(4-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 4-ftorpolimernoj acid. MS (IER): calculated for C18H11FN4O3: 350,1; received m/z: 351,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,01 (ush s, 1H); 12,92 (ush s, 1H); 8,98 (s, 1H); 8,32 (s, 1H); of 8.28 (s, 1H); 8,16 (DD, J=8,5, 2.2 Hz, 1H); 7,88-of 7.82 (m, 2H); 7,79 (s, 1H); 7,37-to 7.32 (m, 2H).

Example 198: 1-[6-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 2-methoxyflavone acid. MS (IER): calculated for C19H14N4O4: 362,1; received m/z: 363,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,00 (ush s, 1H); 12,84 (ush s, 1H); 8,98 (s, 1H); of 8.28 (s, 1H; 8,21 (d, J=1.7 Hz, 1H); of 7.97 (DD, J=8,4, and 2.1 Hz, 1H); 7,74 (d, J=7,0 Hz, 1H); 7,43-7,39 (m, 2H); 7,19 - 7,16 (m, 1H); to 7.09 (TD, J=7,5, 1.0 Hz, 1H); 3,81 (s, 3H).

Example 199: 1-[6-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 3-methoxyflavones acid. MS (IER): calculated for C19H14N4O4: 362,1; received m/z: 363,1 [M+H]+.1HNMR (600 MHz, DMSO-d6): 13,01 (ush s, 1H); 12,91 (ush s, 1H); 8,98 (s, 1H); 8.34 per (s, 1H); of 8.28 (s, 1H); 8,18 (d, J=6,7 Hz, 1H); for 7.78 (s, 1H); 7,44 (t, J=7.9 Hz, 1H); to 7.35 (d, J=7.8 Hz, 1H); 7.29 trend (s, 1H); 7,00 (DD, J=8,2, 1.8 Hz, 1H); 3,86 (s, 3H).

Example 200: 1-[6-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 4-ethoxyphenylurea acid. MS (IER): calculated for C19H14N4O4: 362,1; received m/z: 363,1 [M+H]+.1H NMR (600 MHz, DMSO-d-sub> 6): 12,99 (ush s, 1H); 12,88 (ush s, 1H); 8,97 (s, 1H); of 8.28 (d, J=a 13.9 Hz, 2H); 8,13 (d, J=8,4 Hz, 1H); 7,78-7,72 (m, 3H); 7,09-7,06 (m, 2H); is 3.82 (s, 3H).

Example 201: 1-[4-oxo-6-(2-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 2-cryptomaterial acid. MS (IER): calculated for C19H11F3N4O3: 400,1; received m/z: 401,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,01 (ush s, 2H); 8,99 (s, 1H); 8,42 (d, J=1.6 Hz, 1H); 8,31 is 8.25 (m, 2H); 8,13 (d, J=7,6 Hz, 1H); 8,10 (s, 1H); 7,83 (s, 1H); to 7.77 (dt, J=15,3, and 7.8 Hz, 2H).

Example 202: 1-[4-oxo-6-(2-trifloromethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 2-triphtalocyaninine acid. MS (IER): calculated for C19H11F3N4O4: 416,1; received m/z: 417,1 [M+H]+.1HNMR (600 MHz, DMS-d 6): 13,02 (s, 1H); 12,95 (s, 1H); 8,99 (s, 1H); of 8.28 (s, 1H); to 8.20 (s, 1H); of 7.96 (d, J=7.5 Hz, 1H); 7,81 (s, 1H); 7,69-7,66 (m, 1H); to 7.61-7,53 (m, 3H).

Example 203: 1-[6-(2-ethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 2-ethylvanillin acid. MS (IER): calculated for C20H16N4O3: 360,1; received m/z: 361,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,01 (ush s, 1H); 12,91 (ush s, 1H); 8,99 (s, 1H); of 8.28 (s, 1H); to 7.99 (s, 1H); 7,81 (DD, J=8,2, 1.8 Hz, 1H); to 7.77 (s, 1H); 7,40 and 7.36 (m, 2H); 7,32-7,29 (m, 1H); to 7.25 (d, J=7.2 Hz, 1H); 2,59 (kV, J=7.5 Hz, 2H,); of 1.05 (t, J=7.5 Hz, 3H).

Example 204: 1-[6-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 1,4-benzodioxan-5-boric acid. MS (IER): calculated for C20H14N4O5: 390,1; received m/z: to € 391.1 [M+H]+.1H NMR (600 M is C, DMSO-d6): 13,00 (s, 1H); 12,87 (s, 1H); 8,97 (s, 1H); of 8.25 (s, 2H); 8,10 (d, J=7.8 Hz, 1H); 7,73 (s, 1H); 7,28-7,24 (m, 2H); 6,99 (d, J=8,4 Hz, 1H); 4,30 (s, 4H).

Example 205: 1-[4-oxo-6-(3-trifloromethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 3-triphtalocyaninine acid. MS (IER): calculated for C19H11F3N4O4: 416,1; received m/z: 417,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,06-12.92 (m, 2H); 8,99 (s, 1H); 8,39 (s, 1H); of 8.28 (s, 1H); by 8.22 (DD, J=8,4, 1.8 Hz, 1H); 7,86 (d, J=8.0 Hz, 1H); 7,79 (s, 2H); 7,66 (t, J=8.0 Hz, 1H); 7,46-7,40 (m, 1H).

Example 206: 1-[6-(3-methanesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 3-(methylsulphonyl)phenylboric acid. MS (IER): calculated for C19H14N4O5S: 410,1; received m/z: 411,1 [M+H]+.1H NMR(600 MHz, DMSO-d6): 13,01 (ush s, 2H); 8,99 (s, 1H); of 8.47 (d, J=2.1 Hz, 1H); 8,31-of 8.27 (m, 3H); 8,18 (d, J=8.5 Hz, 1H); 7,97 (DDD, J=7,8, and 1.7, 1.0 Hz, 1H); a 7.85 (d, J=7.7 Hz, 1H); 7,80 (t, J=7.8 Hz, 1H); to 3.34 (s, 3H).

Example 207: 1-(6-benzo[1,3]dioxol-5-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 69, stage C-E, using stage C ethyl ester 1-[6-iodine-4-oxo-3-(2-trimethylsilylethynyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid (Example 69, the product of stage B) and 3,4-methylenedioxyaniline acid. MS (IER): calculated for C19H12N4O5: 376,1; received m/z: 377,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 12,96 (ush s, 2H); 8,97 (s, 1H); 8,29 is 8.25 (m, 2H); 8,11 (DD, J=8,5, 2.2 Hz, 1H); of 7.75 (d, J=8.5 Hz, 1H); 7,38 (d, J=1.7 Hz, 1H); 7,27 (DD, J=8,1, 1.8 Hz, 1H); 7,05 (d, J=8,1 Hz, 1H); 6,10 (s, 2H).

Example 208: 1-(7-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in a manner analogous to the one described in Example 184, step E, using the ethyl ester of 1-(7-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 184, the product of stage A). MS (IER): calculated for C12H7IN4O3: 382,0; received m/z: 382,9 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,06 (s, 1H); 12,99 (s, 1H); to 8.94 (s, 1H); of 8.27 (s, 1H); of 8.09 (s, 1H); a 7.85 (s, 2 is).

These proposed compounds can be synthesized using the above General schema.

Example 209: 1-(6-benzosulfimide-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

MS (IER/CHI): calculated for C18H11ClN4O4S: 414,8.

Example 210: 1-(6-benzazolyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

MS (IER/CHI): calculated for C18H11ClN4O5S: 430,8.

Example 211: 1-(4-oxo-7-piperidine-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

The above compound may be obtained according to scheme B using 3-piperidine-1-yl-phenylamine. MS (IER/CHI): calculated for C17H17N5O3: 339,1.

Biological protocols:

Expression and purification PHD2181-417

The design for the expression of PHD2 person containing amino acids 181-417 sequence GenBank Accession ID NM_022051, cloned in the vector pBAD (Invitrogen), introducing as N-terminal his-tag tag and Smt3 tag, both of which are removed by the protease Ulp1. Protein was gained expression in BL21 cells grown on rich medium Terrific Broth containing 100 μg/ml ampicillin. Cell cultures were inoculable at 37°C and grown to gaining the optical density OD 600=0,8. Then the cell culture was induced with 0.1% arabinose solution and were grown overnight at 20°C, continuously shaking with a frequency of 225 Rev/min 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, of 0.05% (wt/V) NP-40, 50 mm imidazole) and then added to it secrete lysozyme and Benzonase endonuclease. Cells were literally on the ultrasonic bath, the lysate was cleared by centrifugation (15,000 rpm, 90 min, 4°C). Accumulated protein was purified using Nickel-affinity chromatography on a column (HisTrap Crude FF (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 Crude FF (GE Healthcare) to remove protein from neotdalennyh label. Passed through the second column were dialyzed solution is then in a solution containing 50 mm MES pH of 6.0, 1 mm TCEP, 5 mm NaCl, for ion-exchange chromatography on a cation-exchange column (HiTrap SP Cation Exchange (GE Healthcare). Protein PHD2181-417was suirable with a gradient of NaCl 0-0,2 M. the Collected fractions were pooled for further purification by gel permeation chromatography on a column of Superdex 75 Size Exclusion Column (GE Healthcare). Isolated protein of concentri is ovali up to 4 mg/ml were dialyzed in solution, containing 10 mm PIPES pH 7.0, 100 mm NaCl, 0.5 mm TCEP. According to the results of the gel-electrophoretic analysis of the purity of the obtained protein was >95%.

Analysis of enzyme activity

Analysis of enzyme activity PHD was carried out in 0.5 ml reaction mixture containing the following components: purified polypeptide PHD2181-417(3 µg), a synthetic peptide HIF-1a containing residues [KNPFSTGDTDLDLEMLAPYIPMDDDFQLRSFDQLS] (10 ám company California Peptide Research Inc., NAPA, PCs California, USA) and [5-14C]-2-oxoglutaric acid (50 MCI/mmol, the company Moravek Chemicals, brie, PCs California, USA) in a reaction buffer solution (40 mm Tris-HCl, pH 7.5, 0.4 mg/ml catalase, 0.5 mm DTT, 1 mm ascorbic acid) for 10 minutes. The reaction was stopped by adding 50 μl of 70 mm solution of H3PO4and 50 ál of 500 mm solution of NaH2PO4pH of 3.2. The presence of [14C]-succinic acid was determined by separation of [5-14C]-2-oxoglutaric acid during the incubation of the reaction mixture with a solution of 100 μl of 0.16 M solution of DNP in 30%perchloric acid. Then to the reaction mixture were added 50 μl of a solution containing 20 mm unlabeled 2-oxoglutaric acid and 20 mm unlabeled succinic acid, used as a carrier of radioactive labels, and the resulting mixture was left for 30 min at room temperature. Then the reaction mixture was incubated with 50 μl of 1 M solution of 2-oxoglutaric acid deposition and Bytca DNP. After the reaction mixture was centrifuged at 2800 x g at 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, PCs California, USA). The degree of inhibition of activity of PHD2181-417was defined as a decrease in the production of [14C]-succinic acid. The values 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, PCs California, USA).

Cell analysis

Cell line Hep-3B (ATCC, Manassas, PCs 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% fetal bovine serum, 1% nonessential amino acids, 50 IU/ml penicillin and 50 µg/ml streptomycin (all reagents for cell culture medium company Invitrogen, carlsbad, PCs California, USA). At 24 h after seeding in the wells was added to the analyzed compounds and incubated tablet for another 24 hours, All connections were tested under saturated conditions at the final concentration of the compound at 100 μm. Fifty μl of the supernatant is then transferred in diagnostic set the reagents for assessing hypoxia person (Meso-Scale Discovery, Waitsburg, items of Maryland, 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 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. The obtained data was analyzed by determining the percentage of secretion of EPO in the presence of 100 μm of compounds in relation to the secretion of EPO in the presence of a control compound, 7-[(4-chlorophenyl)-(5-methylisoxazol-3-ylamino)-methyl]-quinoline-8-ol.

The test results of the compounds described in the analyses are presented in Table 1 as the average values of the results obtained (NT=not tested). Compounds were tested in the form of the free base (*), hydrochloride (^) or salt triperoxonane acid (“). If the activity is shown as greater than (>) a certain value, this value represents the highest tested concentration.

Table 1
ExampleChemical namepIC50 enzymeCell % stimulation of EPO
11-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,337
21-(7-trifluoromethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,821

td align="center"> 7,2
31-(6,7-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,637
41-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,415
51-(6,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,721
61-(5-chloro-4-oxo-3,4-dihydrobenzo the Jn-2-yl)-1H-pyrazole-4-carboxylic acid; 6,819
71-(8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,825
81-(6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,414
91-(8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,149
101-(7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,332
111-(8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,840
121-(6-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,650
131-(6-Bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;35
141-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-6,68

pyrazole-4-carboxylic acid;
151-(4-oxo-6-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,819
161-(4-oxo-8-trifluoromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,616
171-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,733
181-(5,6,7-trimetoksi-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,542
191-(6-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 7,445
201-(4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,6104
211-(6-cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,684
221-(7-chloro-4-oxo-6-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,561
231-(1-oxo-2,7-dihydro-1H-pyrrolo[3,2-f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid;6,833
241-[6-(4-tert-butyl-phenylsulfanyl)-7-chloro-4-oxo-1,4-dihydroquinazolin-2-7,650

yl]-1H-pyrazole-4-carboxylic acid;
251-(7-chloro-4-oxo-6-phenylsulfonyl-1,4-dihydroquinazolin-2-yl)-1H-shall irsol-4-carboxylic acid; 7,468
261-[7-chloro-6-(3,4-dimethoxyphenylacetone)-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.7,555
271-[6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,710
281-[4-oxo-6-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,79
291-[6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,6124
301-[6-(3-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,615
311-[6-(3-methoxyphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,7129
2 1-[6-(4-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,668

331-[6-(2-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,556
341-[6-(3-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,673
351-[6-(3,5-di-tert-butylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,58
361-(4-oxo-6-m-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,422
371-(4-oxo-6-o-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,678
381-[6-(2,6-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-feast of the ol-4-carboxylic acid; 7,791
391-[6-(2,4-dichlorphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,677
401-[6-(2,5-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,677
411-[6-(4-methoxyphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,7112
421-[6-(2,6-dimethylphenoxy)-4-7,6117

oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
431-[6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,676
441-[4-oxo-6-(5,6,7,8-tetrahydronaphthyl the Jn-1 yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 7,652
461-[6-(4-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,5126
471-(4-oxo-6-p-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,595
481-[7-chloro-6-(4-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,551
491-[7-chloro-6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,555
501-[6-(2,6-dichlorophenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,567
511-[6-(2,6-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,6100

521-[7-fluoro-6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,476
531-[7-chloro-6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,545
541-[7-chloro-6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,490
551-[7-chloro-4-oxo-6-(5,6,7,8-tetrahydronaphthalen-1 yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,525
561-[7-fluoro-6-(3-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,768
571-[7-fluoro-6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,7135
581-[7-fluoro-6-(Indus is-1 yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 7,562
591-(7-methyl-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,680
601-[6-(2,3-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-7,570

yl]-1H-pyrazole-4-carboxylic acid;
611-[6-(2,6-dimethylphenoxy)-7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,786
621-(7-methoxy-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,47
631-[6-(2,6-dimethylphenoxy)-5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,714
641-(5,7-debtor-4-OK the-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 7,622
651-[4-oxo-6-(pyridine-1-yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,642
661-(4-oxo-7-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,241
67salt of 1-[4-oxo-7-(tetrahydropyran-4-yl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid and Tris(hydroxymethyl)aminomethane;7,818
681-(7-chloro-4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,759

691-(4-oxo-6-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;8,157
701-(6-diphenyl-3-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,5 41
711-[7-chloro-6-(3,4-dimethoxybenzonitrile)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,816
721-[6-(4-tert-butyl-benzazolyl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,322
731-(7,7-dimethyl-4-oxo-3,7-dihydro-4H-8-oxa-1,3-vasantrao-2-yl)-1H-pyrazole-4-carboxylic acid;7,788
741-(4-oxo-6-phenoxymethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,535
751-[6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,720
761-(6-ethinyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,516
771-[6-(1-vinyl chloride)-4-oxo-34-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 7,627

781-(4-oxo-7-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,45
791-[7-(4-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,46
801-[7-(2-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,55
811-(7-benzazolyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,126
821-[7-(4-chlorobenzenesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,215
831-[7-(2-chlorobenzenesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7 11
841-[7-chloro-6-(3,4-dihydro-1H-isoquinoline-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,7101
851-[6-(7-bromo-3,4-dihydro-1H-isoquinoline-2-yl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,649
86(rat)-1-{7-chloro-6-[3-(3-methoxyphenyl)-piperidine-1-7,671

yl]-4-oxo-3,4-dihydroquinazolin-2-yl}-1H-pyrazole-4-carboxylic acid;
871-[6-(2,5-dichlorophenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,784
881-[6-(3,4-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,895
891-[6-(3,5-DIMET is phenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 7,6137
901-[6-(2,5-dichlorophenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,6113
911-[6-(diphenyl-3-yloxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,675
921-[6-(3,4-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,7137
931-[7-methyl-4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,7153
941-[6-(3,5-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,790

951-[7-fluoro-4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 7,761
961-[6-(2-fluoro-3-triptoreline)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,651
971-[6-(3-fluoro-5-triptoreline)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,737
981-[6-(3,5-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,785
991-[6-(diphenyl-3-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,681
1001-[4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,655
1011-[6-(2,6-dichlorophenoxy)-5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,624
102 1-(6-cyclohexyloxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,759
1031-[6-(4-methylpiperazin-1-yl)-7,230

4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1041-(6-isopropoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,575
1051-(6-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,5129
1061-(4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,5129
1071-(6-morpholine-4-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,445
08 1-[6-(1H-indol-6-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,685
1091-(6-cyclopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,6100
1101-(6-cyclohexyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,847
1111-(4-oxo-8-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,924
1121-(4-oxo-8-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,818
1131-(4-oxo-8-phenylsulfonyl-6,717

3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1141-(8-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,616
1151-(8-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,827
1161-(5,8-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,717
1171-(4-oxo-8-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,112
1181-(8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,116
1191-(6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,8115
1201-(6-sec-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,7
1211-(6-ethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;830
1221-(6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,616
1231-(4-oxo-6-pyrrolidin-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,417

1241-(4-oxo-6-piperidine-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,471
1251-(6-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,319
1261-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,29
1271-(6-bromo-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-Kurbanova acid; 7,59
1281-(6-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,453
1291-(4-oxo-6-propyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,594
1301-(6-bromo-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,112
1311-(5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,221
1321-(5,7-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,916
1331-(7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,410
1341-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carbon whom I acid; 7,318
1351-(7-methoxy-4-oxo-3,4-7,117

dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1361-(7-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,523
1371-(4-oxo-3,4,8,9-tetrahydro-7H-6,10-dioxo-1,3-disallowable[b]naphthalene-2-yl)-1H-pyrazole-4-carboxylic acid;7,315
1381-(8-oxo-2,3,7,8-tetrahydro-1,4-dioxa-5,7-diazapentane-6-yl)-1H-pyrazole-4-carboxylic acid;6,640
1391-(4-oxo-3,4,7,8-tetrahydro-[1,4]like[2,3-g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;7,4515
1401-(4-oxo-4,6,7,8-tetrahydro-encyclopedia[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid; 7,4562
1411-(6-oxo-2,3,6,7-tetrahydro-1H-7,9-disallowment[a]naphthalene-8-yl)-1H-pyrazole-4-carboxylic acid;6,325
1421-(4-oxo-3,4,7,8,9,10-hexahydrobenzo[h]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;6,623
1431-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;7,575

1441-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid;7,442
1451-(5,7-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,416
1461-(7-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,916
1-(7-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,411
1481-(4-oxo-7-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,910
1491-(7-isopropoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,49
1501-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,824
1511-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,211
1521-(7-ethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;6,838
1531-(6-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,4 22
1541-(7-hydroxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-7,312

pyrazole-4-carboxylic acid;
1551-(6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,540
1561-(4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,519
1571-(6-methanesulfonyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,517
1581-(7-chloro-6-methanesulfonyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,415
1591-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic to the slot; 7,616
1601-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,413
1611-[4-oxo-6-(pyrrolidin-1-sulfonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,417
1621-[4-oxo-6-(pyrrolidin-1-carbonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,515
1631-[6-(2,6-dimethylphenylcarbamate)-4-7,414

oxo-3,4-dihydro-hinzelin-2-yl]-1H-pyrazole-4-carboxylic acid;
1641-(6-nitro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,617
1651-(6-benzo is ylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 7,619
1661-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,511
1671-(6-acetylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,526
1681-[4-oxo-6-(3-phenylurea)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,54
1691-(6-benzosulfimide-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,634
1701-(6-methanesulfonamido-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,515
1711-(6-benzylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,634
172 1-(6-ethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,620

1731-[6-(2-methylbenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,7101
1741-[6-(2-chlorobenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7.724
1751-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,597
1761-[6-(2,6-diferentiating)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,426
1771-[6-(2-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,313
1781-[6-(3-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-spirutal-4-carboxylic acid; 7,712
1791-[6-(3-carbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,612
1801-(6-amino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,28
1811-[6-(2,6-dichlorobenzamide)-4-oxo-3,4-dihydroquinazolin-7,6118

2-yl]-1H-pyrazole-4-carboxylic acid;
1821-[6-(3-chlorobenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,626
1831-[6-(4-methylbenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,889
1841-(4-oxo-7-phenyl-3,4-dihydroxy azolin-2-yl)-1H-pyrazole-4-carboxylic acid; 7,112
1851-[7-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;715
1861-[7-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,326
1871-[7-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,224
1881-(4-oxo-7-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,111
1891-(4-oxo-7-m-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,325
1901-(4-oxo-6-m-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,691
1911-(4-oxo-6-p-tolyl-3,4-31

dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1921-[6-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,587
1931-[6-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,5141
1941-[6-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,762
1951-[6-(2-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,6100
1961-[6-(3-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,492
1971-[6-(4-forfinal)-4-oxo-3,4-dihyd Akhenaton-2-yl]-1H-pyrazole-4-carboxylic acid; 7,7108
1981-[6-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,7178
1991-[6-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,6119
2001-[6-(4-methoxyphenyl)-4-oxo-7,8118

3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
2011-[4-oxo-6-(2-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,678
2021-[4-oxo-6-(2-trifloromethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,829
2031-[6-(2-ethylphenyl)-4-oxo-3,4-d is hydrogenation-2-yl]-1H-pyrazole-4-carboxylic acid; 7,577
2041-[6-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,8111
2051-[4-oxo-6-(3-trifloromethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,658
2061-[6-(3-methanesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;7,613
2071-(6-benzo[1,3]dioxol-5-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;7,684
2081-(7-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.6,920

Histology

For histological analysis used different animal models. In one of the examples was evaluated by the effect on the dog 1-[6-(2,6-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carb is new acid when administered orally via a stomach tube in phase with increasing single dose (Single Dose Escalation, SDE) and then up to 5 days in the phase of using a constant dose. The histological results of this analysis are shown in Table 2 below.

Table 2
Body10 mg/kg/day - 1001 (male)10 mg/kg/day - 1501 (female)
EasyBZPBZP
HeartBZPBZP
KidneyMinor bilateral acute multifocal inflammation; interstitial tissue of pelvis
Minor pelvic mineral deposits (right kidney)
BZP
LiverMinor acute inflammation of the Central share with necrosis of individual hepatocytesMinor acute inflammation of the Central share
Minor acute portal inflammation
Minor acute portal inflammation

Spleen Moderate EMG with a moderate increase in the number of megakaryocytesModerate EMG with a moderate increase in the number of megakaryocytes
Minor brown pigmentation inside macrophagesMinor brown pigmentation inside macrophages
StomachBZPBZP
Testis/ EpididymisBZP
Bone marrowBZPBZP
45 mg/kg/day in 2001 (male)45 mg/kg/day - 2501 (female)
EasyBZPBZP
HeartBZP
KidneyMinor bilateral acute multifocal inflammation; interstitial tissue of pelvisMinor bilateral acute multifocal inflammation; interstitial tissue t is for
Multiple cysts with minor interstitial inflammation and basophilic tubulesMinor tubular vacuolization
Minor papillary mineralization of the kidney
LiverModerate acute inflammation and necrosis of the Central shareModerate acute inflammation and necrosis of the Central share
Moderate acute portal inflammation and necrosisModerate acute portal inflammation and necrosis

Moderate changes, apoptotic and microtecnica cells in the sinusoidsModerate hyperplasia of the bile ducts
Multifocal thrombosis of the portal zone
Moderate multifocal expansion of lymphatic vessels of the portal zoneModerate changes, apoptotic and microtecnica cells in the sinusoids
A slight extension of lymphatic the ski vessels of the portal zone
Minor deposition of brown pigment in Kupffer cells
SpleenModerate EMGModerate EMG
A moderate increase in the number of megakaryocytesA moderate increase in the number of megakaryocytes
Minor brown pigmentation inside macrophagesMinor brown pigmentation inside macrophages
StomachBZPBZP
Testis/ EpididymisBZP
Bone marrowBZPBZP
BZP=without significant damage, EMG=extramedullary haematopoiesis

Although the disclosed invention has been illustrated 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=0 to 3,
R1is a Deputy, is independently selected from the group consisting of halogen, -C1-4of alkyl, -C2-4the quinil, -C2-4alkenyl, optionally substituted with halogen, -CF3, -OCF3SCF3, S(O)CF3, -C(O)-Rc, -C(O)N-Rc, -OH, -NO2, -OS1-4of alkyl; -SC1-4of alkyl, -S(O)-C1-4of alkyl, -SO2-C1-4of alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -O-Rc, -NRaRb, 2,3-dihydrobenzo[1,4]dioxin; benzo[1,3]dioxole; 1H-indole, benzyl, biphenyl, optionally substituted by one or more Rd, benzyloxy, optionally substituted by one or more Rd, phenyl, optionally substituted by one or more Rd, -C3-8cycloalkyl, tetrahydropyranyl, and two adjacent groups R1can be joined to form a 5-7 membered cycle, optionally containing one or 2 heteroatom O or N, optionally substituted C1-4alkyl groups;
Raand Rbindependently selected from the group consisting of H, C1-4of alkyl, -C(O)C1-4of alkyl, -C(O)-Rc, -C(O)NH-Rc, -SO2-Rc, -SO2-C1-4of alkyl, phenyl, optionally substituted by Rd, benzyl, optionally substituted by Rdor Raand Rbalong with carrying their nitrogen atom form an optionally substituted C1-4Ala is scrap 5-6-membered monocyclic heteroseksualci, containing one or 2 heteroatom O, S or N;
Rcis a Deputy, is independently selected from the group consisting of-C3-8cycloalkyl, pyrrolidine, biphenyl, phenyl, optionally substituted by one or more Rd, naphthyl, indanyl, 5,6,7,8-tetrahydronaphthyl and pyridyl;
Rdis a Deputy, is independently selected from the group consisting of-H, halogen, -C1-4of alkyl, -SO2-C1-4of alkyl, -CN, or-CF3, -OCF3, -OC1-4of alkyl, -C(O)NH2;
and its pharmaceutically acceptable salts.

2. The compound according to claim 1, in which R1independently selected from the group consisting of halogen, -C1-4of alkyl, -OCF3, -CF3, -OH, NO2, -OC1-4of alkyl, -SC1-4of alkyl, -S(O)-C1-4of alkyl, -SO2-C1-4of alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -O-Rc, -NRaRb, phenyl, optionally substituted by one or more Rdand-C3-8cycloalkyl.

3. The compound according to claim 1, in which two adjacent groups R1United in a 5-7 membered cycle, optionally containing one or two O or N.

4. The compound according to claim 1, in which two adjacent groups R1United in a 5-7 membered cycle containing one or two O or N, optionally substituted C1-4alkyl groups.

5. The compound according to claim 1, in which n=1.

6. The compound according to claim 1, in which n=2.

<> 7. The compound according to claim 1, in which n=3.

8. The compound according to claim 1, in which the Deputy-Raand Rbindependently selected from the group consisting of-H, -CH3, -CH2CH3, benzoyl, 2,6-dimethylbenzoyl, acetyl, -C(O)NH-phenyl, benzosulfimide, methanesulfonyl, benzyl, 2-methylbenzyl, 2-Chlorobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 3-carbamoylethyl, 3-Chlorobenzyl and 4-methylbenzyl.

9. The compound according to claim 1, in which Raand Rbalong with carrying their nitrogen atom form a N-methylpiperazin-1-yl, piperidine, morpholine-4-yl and pyrrolidinyl.

10. The compound according to claim 1, in which Rcindependently selected from the group consisting of phenyl, cyclohexyl, 4-tert-butylphenyl, 3,4-acid, 2,6-dimetilfenil, 3,4,5-trimethoxyphenyl, naphthalene-1-yl, 3-chlorphenyl, 4-chlorphenyl, 3-methoxyphenyl, 4-ftoheia, 2-ftoheia, 3-ftoheia, 3,5-di-tert-butylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 4-methoxyphenyl, 2,6-dimetilfenil, naphthalene-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 4-chlorphenyl, p-tolila, indan-5-yl, 2,3-dichlorophenyl and pyridine-3-yl.

11. The compound according to claim 1, in which Rdindependently selected from the group consisting of-H, chlorine, fluorine, bromine, iodine, -C1-4of alkyl, -CF3, -OCF3or-OC1-4the alkyl.

12. The compound according to claim 1, in which R1independently selected from the group consisting of chlorine, fluorine, bromine, iodine is, -NO2, -OH, -CF3, -CH3, -CH2CH3, -CH2CH2CH3, -OCF3, -OCH3, -OCH2CH3, -SCH3, -SCF3, -S(O)CF3, -SO2CH3, -NH2, -N(CH3)2, -NH(CH2CH3), isopropoxy, isopropyl, sec-butyl, tert-butyl, ethinyl, 1-chloride, pyrrolidin-1-carbonyl, phenyl, benzyl, biphenyl, talila, phenoxy, cyclopropyl, cyclohexyl, phenylsulfanyl, 3,4-dimethoxyphenylacetone, 4-tert-butyl-phenylsulfanyl, 2,6-dimethylphenoxy, 3,4,5-trimethoxyphenol, naphthalene-1-yloxy, naphthalene-2-yloxy, 5,6,7,8-tetrahydronaphthalen-1 iloxi, indan-5-yloxy, 3 chlorophenoxy, 4-chlorophenoxy, 2,3-dichlorophenoxy, 3 methoxyphenoxy, 4-fervency, 2-fervency, 3 fervency, 3,5-di-tert-butylphenoxy, 3 methylphenoxy, 2,6-dichlorophenoxy, 2,5-dichlorophenoxy, 4-methoxyphenoxy, pyridine-3-yloxy, tetrahydropyran-4-yl and benzosulfimide.

13. A compound selected from the group consisting of:
1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-trifluoromethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6,7-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-4-oxo-3,4-dihydro is Natolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-8-trifluoromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,6,7-trimetoksi-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-chloro-4-oxo-8-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(1-oxo-2,7-dihydro-1H-pyrrolo[3,2-f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid;
-[6-(4-tert-butylphenylmethyl)-7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(7-chloro-4-oxo-6-phenylsulfonyl-1,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(3,4-dimethoxyphenylacetone)-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid.
1-[6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-methoxyphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,5-di-tert-butylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-m-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-o-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,4-dichlorphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,5-dichloro is enocsi)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-methoxyphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(5,6,7,8-tetrahydronaphthalen-1 yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-p-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(4-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dichlorophenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-fluoro-6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-4-oxo-6-(5,6,7,8-tetrahydronaphthalen-1 yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-fluoro-6-(3-pertenece)-4-oxo-3,4-dihydroxy azolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-fluoro-6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-fluoro-6-(indan-5-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(7-methyl-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,3-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(7-methoxy-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5,7-debtor-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(pyridine-3-yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
salt of 1-[4-oxo-7-(tetrahydropyran-4-yl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid and Tris(hydroxymethyl)aminomethane;
1-(7-chloro-4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-diphenyl-3-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(3,4-dimethoxybenzonitrile)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-piraso the-4-carboxylic acid;
1-[6-(4-tert-butylbenzenesulfonyl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(7,7-dimethyl-4-oxo-3,7-dihydro-4H-8-oxa-1,3-vasantrao-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-phenoxymethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-ethinyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(1-vinyl chloride)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-(4-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-(2-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(7-benzazolyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-(4-chlorobenzenesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-(2-chlorobenzenesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(3,4-dihydro-1H-isoquinoline-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(7-bromo-3,4-dihydro-1H-isoquinoline-2-yl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
(rat)-1-{7-chloro-6-[3-(3-methoxyphenyl)-piperidine-1-yl]-4-OK what about-3,4-dihydroquinazolin-2-yl}-1H-pyrazole-4-carboxylic acid;
1-[6-(2,5-dichlorophenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,4-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,5-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,5-dichlorophenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(diphenyl-3-yloxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,4-dimethyl-phenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-methyl-4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,5-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-fluoro-4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-fluoro-3-triptoreline)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-fluoro-5-triptoreline)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,5-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(diphenyl-3-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dichlo is phenoxy)-5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-cyclohexyloxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(4-methylpiperazin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-isopropoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-morpholine-4-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(1H-indol-6-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-cyclopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-cyclohexyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-8-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-8-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-8-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,8-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-8-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-fluoro-4-oxo-3,4-dihydroquinazolin--yl)-1H-pyrazole-4-carboxylic acid;
1-(6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-sec-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-ethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-pyrrolidin-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-piperidine-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-bromo-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-propyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-bromo-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,7-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-benzyl-4-oxo-3,4-is hydrogenation-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-3,4,8,9-tetrahydro-7H-6,10-dioxo-1,3-disallowable[b]naphthalene-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-oxo-2,3,7,8-tetrahydro-1,4-dioxa-5,7-diazapentane-6-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-3,4,7,8-tetrahydro-[1,4]like[2,3-g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-4,6,7,8-tetrahydro-3H-cyclopent[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-oxo-2,3,6,7-tetrahydro-1H-7,9-disallowment[a]naphthalene-8-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-3,4,7,8,9,10-hexahydrobenzo[h]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,7-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-isopropoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-ethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-feast of the ol-4-carboxylic acid;
1-(6-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-hydroxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methanesulfonyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-chloro-6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(pyrrolidin-1-sulfonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(pyrrolidin-1-carbonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenylcarbamate)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-nitro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid
1-(6-benzoylamine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-acetylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(3-phenylurea is up)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-benzosulfimide-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methanesulfonamido-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-benzylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-ethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2-methylbenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-chlorobenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-diferentiating)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-carbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-amino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dichlorobenzamide)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-chlorobenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-methylbenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-phenyl-3,4-is hydrogenation-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-m-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-m-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-p-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(2-triptoreline)-3,4-dihydro is Natolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(2-trifloromethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-ethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(3-trifloromethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-methanesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-benzo[1,3]dioxol-5-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-benzosulfimide-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-benzazolyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; and
1-(4-oxo-7-piperidine-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; and their pharmaceutically acceptable salts.

14. Pharmaceutical composition having inhibitory activity against PHD, containing a pharmaceutically acceptable excipient and an effective amount of the compounds of formula (I):

where:
n=0 to 3,
R1is a Deputy, is independently selected from the group consisting of halogen, -C1-4of alkyl, -C2-4the quinil, -C2-4alkenyl, n is necessarily substituted with halogen, -CF3, -OCF3, -SCF3, S(O)CF3, -C(O)-Rc, -C(O)N-Rc, -OH, -NO2, -OC1-4of alkyl, -SC1-4of alkyl, -S(O)-C1-4of alkyl, -SO2-C1-4of alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -O-Rc, -NRaRb, 2,3-dihydrobenzo[1,4]dioxin; benzo[1,3]dioxole; 1H-indole, benzyl, biphenyl, optionally substituted by one or more Rd, benzyloxy, optionally substituted by one or more Rd, phenyl, optionally substituted by one or more Rd- 3-8cycloalkyl, tetrahydropyranyl, and two adjacent groups R1can be joined to form a 5-7 membered cycle, optionally containing one or 2 heteroatom O or N, optionally substituted C1-4alkyl groups;
Raand Rbindependently selected from the group consisting of H, C1-4of alkyl, -C(Oh)1-4of alkyl, -C(O)-Rc, -C(O)NH-Rc, -SO2-Rc, -SO2-C1-4of alkyl, phenyl, optionally substituted by Rd, benzyl, optionally substituted by Rdor Raand Rbalong with carrying their nitrogen atom form an optionally substituted C1-4the alkyl 5-6-membered monocyclic heteroseksualci containing one or 2 heteroatom O, S or N;
Rcis a Deputy, is independently selected from the group consisting of-C3-8cycloalkyl, Pirro is Idina, biphenyl, phenyl, optionally substituted by one or more Rd, naphthyl, indanyl, 5,6,7,8-tetrahydronaphthyl and pyridyl;
Rdis a Deputy, is independently selected from the group consisting of-H, halogen, -C1-4of alkyl, -SO2-C1-4of alkyl, -CN, or-CF3, -OCF3, -OC1-4of alkyl, -C(O)NH2;
or its pharmaceutically acceptable salt.

15. Pharmaceutical composition having inhibitory activity against PHD, containing one or more compounds selected from the group consisting of:
1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-trifluoromethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6,7-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-bromo-4-oxo-3,4-dehydrogenase the Lin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-8-trifluoromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,6,7-trimetoksi-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-chloro-4-oxo-6-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(1-oxo-2,7-dihydro-1H-pyrrolo[3,2-f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(4-tert-butylphenylmethyl)-7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(7-chloro-4-oxo-6-phenylsulfonyl-1,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(3,4-dimethoxyphenylacetone)-4-oxo-1,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-CT is about acid;
1-[4-oxo-6-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-methoxyphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,5-di-tert-butylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-m-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-o-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,4-dichlorphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,5-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-methoxyphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroxy the Zolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(5,6,7,8-tetrahydronaphthalen-1 yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-p-tolyloxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(4-chlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dichlorophenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-fluoro-6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(naphthalene-2-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-4-oxo-6-(5,6,7,8-tetrahydronaphthalen-1 yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-fluoro-6-(3-pertenece)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-fluoro-6-(naphthalene-1-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-fluoro-6-(indan-5-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(7-methyl-4-oxo-6-phenoxy-3,4-Digi rohinton-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,3-dichlorophenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(7-methoxy-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5,7-debtor-4-oxo-6-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(pyridine-3-yloxy)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
salt of 1-[4-oxo-7-(tetrahydropyran-4-yl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid and Tris(hydroxymethyl)aminomethane;
1-(7-chloro-4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-diphenyl-3-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(3,4-dimethoxybenzonitrile)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-tert-butylbenzenesulfonyl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(7,7-dimethyl-4-oxo-3,7-dihydro-4H-8-oxa-1,3-vasantrao-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-phenoxymethyl-3,4-dihydroquinazolin-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-ethinyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(1-vinyl chloride)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-(4-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-(2-chlorophenylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(7-benzazolyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-(4-chlorobenzenesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-(2-chlorobenzenesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-chloro-6-(3,4-dihydro-1H-isoquinoline-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(7-bromo-3,4-dihydro-1H-isoquinoline-2-yl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
(rat)-1-{7-chloro-6-[3-(3-methoxyphenyl)-piperidine-1-yl]-4-oxo-3,4-dihydroquinazolin-2-yl}-1H-pyrazole-4-carboxylic acid;
1-[6-(2,5-dichlorophenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,4-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,5-dimethylphenoxy)-7-methyl-4-about the co-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,5-dichlorophenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(diphenyl-3-yloxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,4-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-methyl-4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,5-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-fluoro-4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-fluoro-3-triptoreline)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-fluoro-5-triptoreline)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3,5-dimethylphenoxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(diphenyl-3-yloxy)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(3-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dichlorophenoxy)-5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-cyclohexyloxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(4-methylpiperazin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-isopropoxy-4-OK what about-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-morpholine-4-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(1H-indol-6-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-cyclopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-cyclohexyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-8-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-8-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-8-phenylsulfanyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,8-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-8-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-sec-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-ethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carbon is th acid;
1-(6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-pyrrolidin-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-piperidine-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-bromo-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-propyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-bromo-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,7-debtor-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,7-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-3,4,8,9-tetrahydro-7H-6,10-dioxo-1,3-disallowable[b]naphthalene-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(8-oxo-2,3,7,8-tetrahydro-1,4-dioxa-5,7-diazapentane-6-yl)-1H-pyrazole-4-carb is new acid;
1-(4-oxo-3,4,7,8-tetrahydro-[1,4]like[2,3-g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-4,6,7,8-tetrahydro-3H-cyclopent[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-oxo-2,3,6,7-tetrahydro-1H-7,9-disallowment[a]naphthalene-8-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-3,4,7,8,9,10-hexahydrobenzo[h]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-3,4,6,7,8,9-hexahydrobenzo[g]hinzelin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(1-oxo-1,2,7,8,9,10-hexahydrobenzo[f]hinzelin-3-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,7-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-triptoreline-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-isopropoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-dimethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-ethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-hydroxy-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-metilsulfate the Il-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methanesulfonyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-chloro-6-methylsulfanyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-chloro-4-oxo-6-trifloromethyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(pyrrolidin-1-sulfonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(pyrrolidin-1-carbonyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylphenylcarbamate)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-nitro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid
1-(6-benzoylamine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-acetylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(3-phenylurea)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-benzosulfimide-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methanesulfonamido-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid is you;
1-(6-benzylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-ethylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2-methylbenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-chlorobenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dimethylbenzylamine)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-diferentiating)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-cyanobenzylidene)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-carbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-amino-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2,6-dichlorobenzamide)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-chlorobenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-methylbenzylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-phenyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[7-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin the-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[7-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-o-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-m-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-m-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-6-p-tolyl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-forfinal)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(2-triptoreline)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(2-trifloromethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2-ethylphenyl)-4-oxo-34-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[4-oxo-6-(3-trifloromethyl)-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(3-methanesulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-benzo[1,3]dioxol-5-yl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-iodine-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-benzosulfimide-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-benzazolyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-oxo-7-piperidine-1-yl-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid, and their pharmaceutically acceptable salts.

16. A method of treating a pathological condition selected from the group consisting of anemia, hypoxia, ischemia, peripheral vascular disease, myocardial infarction, stroke, diabetes, obesity, inflammatory bowel disease, ulcerative colitis, Crohn's disease, wounds, infections, burns and broken bones; and the method includes a step of introducing to a patient in need of treatment a therapeutically effective amount of the compounds of formula (I)with inhibitory activity towards PHD:

where
n=from 0 to 3,
R1is a Deputy, is independently selected from the group consisting of halogen, -C1-4of alkyl, -C2-4the quinil, -C2-4alkenyl, optionally substituted with halogen, -CF3, -OCF3SCF3, S(O)CF3, -C(O)-Rc, -C(O)N-Rc, -OH, -NO2, -OC1-4of alkyl, -SC1-4of alkyl, -S(O)-C1-4of alkyl, -SO2-C1-4of alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -O-Rc, -NRaRb, 2,3-dihydrobenzo[1,4]dioxin; benzo[1,3]dioxole; 1H-indole, benzyl, biphenyl, optionally substituted by one or more Rd, benzyloxy, optionally substituted by one or more Rd, phenyl, optionally substituted by one or more Rd, -C3-8cycloalkyl, tetrahydropyranyl, and two adjacent groups R1can be joined to form a 5-7 membered cycle, optionally containing one or 2 heteroatom O or N, optionally substituted C1-4alkyl groups;
Raand Rbindependently selected from the group consisting of H, C1-4of alkyl, -C(O)C1-4of alkyl, -C(O)-Rc, -C(O)NH-Rc, -SO2-Rc, -SO2-C1-4of alkyl, phenyl, optionally substituted by Rd, benzyl, optionally substituted by Rdor Raand Rbalong with carrying their nitrogen atom form an optionally substituted C1-4the alkyl 5-6-membered of monoc Klionsky heteroseksualci, containing one or 2 heteroatom O, S or N;
Rcis a Deputy, is independently selected from the group consisting of-C3-8cycloalkyl, pyrrolidine, biphenyl, phenyl, optionally substituted by one or more Rd, naphthyl, indanyl, 5,6,7,8-tetrahydronaphthyl and pyridyl;
Rdis a Deputy, is independently selected from the group consisting of-H, halogen, -C1-4of alkyl, -SO2-C1-4of alkyl, -CN, or-CF3, -OCF3, -OC1-4of alkyl, -C(O)NH2;
and its pharmaceutically acceptable salts.

17. A method of treating hypoxic disorders, including the introduction phase to a patient in need of treatment a therapeutically effective amount of the compounds of formula (I)with inhibitory activity towards PHD:

where:
n=0 to 3,
R1is a Deputy, is independently selected from the group consisting of halogen, -C1-4of alkyl, -C2-4the quinil, -C2-4alkenyl, optionally substituted with halogen, -CF3, -OCF3SCF3, S(O)CF3, -C(O)-Rc, -C(O)N-Rc, -OH, -NO2, -OC1-4of alkyl, -SC1-4of alkyl, -S(O)-C1-4of alkyl, -SO2-C1-4of alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -O-Rc, -NRaRb, 2,3-dihydrobenzo[1,4]dioxin; benzo[1,3]dioxole; 1H-indole; Ben the sludge; biphenyl, optionally substituted by one or more Rd, benzyloxy, optionally substituted by one or more Rd, phenyl, optionally substituted by one or more Rd, -C3-8cycloalkyl, tetrahydropyranyl, and two adjacent groups R1can be joined to form a 5-7 membered cycle, optionally containing one or 2 heteroatom O or N, optionally substituted C1-4alkyl groups;
Raand Rbindependently selected from the group consisting of H, C1-4of alkyl, -C(O)C1-4of alkyl, -C(O)-Rc, -C(O)NH-Rc, -SO2-Rc, -SO2-C1-4of alkyl, phenyl, optionally substituted by Rd, benzyl, optionally substituted by Rdor Raand Rbalong with carrying their nitrogen atom form an optionally substituted C1-4the alkyl 5-6-membered monocyclic heteroseksualci containing one or 2 heteroatom O, S or N;
Rcis a Deputy, is independently selected from the group consisting of-C3-8cycloalkyl, pyrrolidine, biphenyl, phenyl, optionally substituted by one or more Rd, naphthyl, indanyl, 5,6,7,8-tetrahydronaphthyl and pyridyl;
Rdis a Deputy, is independently selected from the group consisting of-H, halogen, -C1-4of alkyl, -SO2-C1-4of alkyl, CN, or-CF3, -OCF3OC 1-4of alkyl, -C(O)NH2;
or its pharmaceutically acceptable salt.

18. The method according to 17, in which the specified hypoxic disorder selected from the group consisting of anemia, ischemia, stroke, myocardial infarction and ischemic heart disease.

19. A method of treating diabetes, comprising introducing a therapeutically effective amount of a compound according to claim 1 in need of treatment for the patient.

20. The method of treatment of wounds, comprising introducing a therapeutically effective amount of a compound according to claim 1 in need of treatment for the patient.

21. Method for the treatment of metabolic disorders, including the introduction of a therapeutically effective amount of a compound according to claim 1 in need of treatment for the patient.

22. The method according to item 21, in which the specified metabolic disorders is an obesity or diabetes.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula

,

where R1 is an alkoxy group; R2 is H or F; each of R3, R4, R5 and R6 is independently H or D; V is CH and W is CH or N, or V is N and W is CH; Y is CH or N; Z is O, S or CH2 and A is CH2, CH2CH2 or CD2CD2; or a salt of said compound. The invention also describes a antibacterial pharmaceutical composition which contains the compound of formula (I) as a basic component, and use of the compound of formula (I).

EFFECT: obtaining novel compounds possessing useful biological properties.

25 cl, 2 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyridoxine derivatives general formula I, where: when R2+R3=-C(CH3)2- or -CH(CH3)-; , when R1=H; R2=H; , when R1=H; R3=H; , .

EFFECT: pyridoxine derivatives, having high anti-inflammatory activity and low toxicity.

2 cl, 2 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyridoxine derivatives of general formula

,

where R1-is a hydrogen atom or methyl, R2 is a hydrogen atom, methyl, linear, branched or cyclic alkyl or R1 and R2 together form a cyclic alkyl capable of powder second-harmonic generation (SHG).

EFFECT: invention can be used in laser technology and communication equipment.

1 cl, 1 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound, namely 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluor-1,5-naphthyridin-2(1H)-one monohydrate which possess strong antibacterial activity. This compound is highly safe and applicable in the production of pharmaceutical preparations as a parent drug. What is furthermore described is a method for preparing 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluor-1,5-naphthyridin-2(1H)-one monohydrate of formula 19 and methods for preparing intermediate compounds.

EFFECT: preparing the compounds possessing strong antibacterial activity.

8 cl, 1 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

EFFECT: obtaining compounds, which demonstrate inhibiting activity with respect to ERK.

5 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof: (I) where R1, R2 and R3, which are identical or different, denote H, lower alkyl; R4, R5, R6, R7 and R8, which are identical or different, denote H, lower alkyl, halogen, nitro, -X-OR0, -X-NR10R11, -X-NR0C(O)R10, -X-O-halogen lower alkyl, -X-O-X-phenyl; or R6 and R7 are combined to form -O-lower alkylene-O-; R, which is identical or different, denotes H, lower alkyl; R10, R11, which are identical or different, denote H, lower alkyl; X, which is identical or different, denotes a bond, lower alkylene.

EFFECT: compounds exhibit type 5 17βHSD inhibiting activity, which enables their use in producing a pharmaceutical composition and in a method of inhibiting type 5 17βHSD.

15 cl, 11 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

EFFECT: compounds are strong mGluR5 modulators.

21 cl, 2 tbl, 274 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclohexylamine derivatives of formula (I), having inhibiting properties towards at least one monoamine transporter, such as serotonin transporter, dopamine transporter or norepinephrine transporter, or a combination of two or more transporters. The compounds can be used to treat and/or prevent central nervous system disorders such as pain, depression, anxiety, schizophrenia, sleep disorder etc. In formula (I) , n equals 0 or 1; s equals 1, 2 or 3, m equals a whole number from 0 to 12; Ar is

or where Y and Z are (i) both halogen; or (ii) one of Y and Z is CF3 or OCF3 and the other is hydrogen; Y1, Z1, Y2 and Z2 each independently denotes H or a halogen; each X independently denotes H, halogen, CF3, OR5, (C1-C4)alkyl, optionally substituted with halogen or OH, or NR6R7; each R1 and R2 independently denotes H or (C1-C6)alkyl; and each R3 and R4 independently denotes H or (C1-C9)alkyl optionally substituted with OH; where each R5 independently denotes H, (C1-C4)alkyl or phenyl; and each R6 and R7 independently denotes H or (C1-C4)alkyl; where at least two of R1, R2, R3, R4 and X together with atoms to which they are bonded are optionally bonded to form a 5-6-member ring, where the 5-6-member ring is selected from: a) R3 and R4 together with a nitrogen atom to which they are bonded optionally form a pyrrolidine, piperidine, piperazine or morpholine ring, which is optionally substituted with (C1-C4)alkyl; b) when R3 is H or lower alkyl, X and R4 together with atoms to which they are bonded optionally form a 1,3-oxazine ring; c) two X substitutes together with a carbon atom to which they are bonded optionally form a 1,3-dioxolane ring; and d) when R1 and R3 denote hydrogen, R2 and R4 together with atoms to which they are bonded optionally form a 5- or 6-member saturated heterocyclic ring containing one nitrogen atom.

EFFECT: high efficiency of using the compounds.

29 cl, 36 dwg, 11 tbl, 6 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

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 the chemical-pharmaceutical industry and represents a compound having a structure according to formula I:

,

compositions containing the compounds of the above formula applicable to stimulate neurogenesis and/or inhibition of neuron degeneration.

EFFECT: invention may be used in treating diseases and conditions characterised by neuron loss and lower neurogenesis, including Alzheimer's disease, stroke, traumatic brain injury, traumatic nerve injury and depression.

8 cl, 2 tbl, 2 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a novel crystalline salt of sitagliptin - sitagliptin malate and containing it pharmaceutical composition; the described salt is dipeptidylpeptidase-IV inhibitor and can be applied in medicine in treatment of type 2 diabetes mellitus.

EFFECT: invention can be applied in medicine in treatment of type 2 diabetes mellitus.

2 cl, 17 ex, 29 tbl, 18 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to isoindoline compounds, such as compounds of Formula or to their pharmaceutically acceptable salts or stereoisomers, wherein X represents CH2; Y represents O, cyanamido (N-C≡N) or amido (NH); m represents an integer of 0 or 1; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-10 alkyl, C0-6alkyl-(5-10-merous heteroaryl containing one, two or three heteroatoms independently specified in O, S or N), C0-6alkyl-(6-merous heterocyclyl which represents morpholinyl or piperazinyl), C0-6alkyl-OH, -NHCO-C1-6alkyl, -OR21 or - (CH2-Z)-(6-merous heteroaryl which represents pyridinyl), wherein each heteroaryl and heterocyclyl is optionally substituted by one or more C1-6 alkyls; R3 represents hydrogen, halogen, -NO2, C0-6alkyl-OH, C0-4 alkyl-NH2 or -OR21; R21 represents phenyl, pyridinyl, piperidinyl or -CO(CH2)R22; R22 represents -NH2 or piperazinyl; and Z represents O; provided R1 represents hydrogen, then R2 is other than hydrogen or C1-10alkyl; provided R3 represents halogen, then R2 represents C0-6alkyl-(5-6-merous heterocyclyl). The invention also refers to pharmaceutical compositions for controlling angiogenesis or inhibiting the TNFα production on the basis of the above compounds.

EFFECT: there are prepared new compounds and compositions based thereon to be used in medicine for treating or preventing a disease or a disorder, such as cancer, pain skin diseases, lung disorders, parasitic diseases, immunodeficiency disorders, CNS disorders, CNS injuries, atherosclerosis or associated disorders, sleep disorders or associated disorders.

26 cl, 68 ex

Up!