3-aminopyrrolidine derivatives as chemokine receptor modulators

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I: , their optical isomers or optical isomer mix, and pharmaceutically acceptable salts, where: R1 is independently selected out of group including: aryl, heteroaryl, arylcarboxyamido, heteroarylcarboxyamido, aryloxy, arylalcoxy or arylamino, and where indicated groups of aryl, aryalkyl or heteroaryl can be substituted by 0-3 substitutes R1a, where R1a is independently selected out of group including: halogen, alkyl, alkenyl, alcoxy, alcoxyalkyl, hydroxyalkyl, mono-, di- or trihalogenoalkyl, mono-, di- or trihalogenoalcoxy, mono- or disubstituted aminoalkyl, aminocarbonyl, mono- or disubstituted aminocarbonyl, cyclic aminocarbonyl, alkylsulfonyl, etherified carboxylic acid residue, arylcarbonylamino, carbamate, R1b-aryl or R1b-heteroaryl where R1b is H, halogen, OH, amino, mono- or disubstituted amino, mono-, di- or trihalogenoalkyl, alkcoxy, mono-, di- or trihalogenoalcoxy, hydroxyalkyl; R2 is independently selected out of group including: H, OH, cyano, halogen or aryl; optionally R1 and R2 can be linked to form spirocyclyl; R3, R4, R5 and R6 are H; optionally R1 and R3 can be cyclised to form carbocycle; optionally R3 and R4 or R5 and R6 are cyclised to form bicyclic bridge system including ethylene bridge; optionally R3 and R6 are cyclised to form bicyclic bridge system including methylene or ethylene group; R7 and R8 are independently selected out of group including hydrogen, OH, C1-C8alkyl, arylalcoxy, heteroarylalcoxy; optionally R7 and R9 can be cyclised to form spirocarbocycle or spiroheterocycle; and m=0-5; where "aryl" term denotes aromatic carbocyclic groups such as phenyl, biphenyl, indenyl, naphthyl, and aromatic groups condensed with heterocycles; where "heterocycle" term denotes aromatic and non-aromatic rings including 3 to 10 atoms in the ring, 1-4 of which are heteroatom selected out of oxygen, sulfur or nitrogen; where "alkyl" term, when used separately or as suffix, denotes branched or non-branched alkyl group including 1 to 8 carbon atoms in chain; where "alkenyl" term denotes non-saturated branched or non-branched alkyl group including 2 to 12 carbon atoms in chain.

EFFECT: compounds applicable as chemokine receptor activity modulators.

15 cl, 1 tbl, 372 ex

 

The present invention relates to modulators of receptors chemokines, such as antagonists, and their use as medicinal agents. The present invention also relates to new compounds and medical methods of treatment of inflammation and other diseases, especially those associated with the accumulation of lymphocytes or monocytes, which is observed in rheumatoid arthritis, lupus, the disease is graft versus host and/or transplant rejection. More specifically, the present invention relates derivative 3-aminopyrrolidine and to their use as modulators of receptors chemokines.

More specifically, the present invention relates to new anti-inflammatory and immune modulating the bioactive compounds and the pharmaceutical compositions that act via antagonism of the CCR2 receptor (also known as MCP-1 receptor) and thus lead to inhibition monolitnogo chemoattractant protein-1 (Monocyte Chemoattractant Protein-1 (MCP-1)). New compounds are derivatives of 3-aminopyrrolidine. The invention further relates to new compounds, designed for use in the compositions, to processes for their preparation, to intermediate compounds that are useful for their production and to their use as therapeutic agents.

Fashion is atory/antagonists of receptors chemokines of the present invention may be effective as therapeutic agents and/or prophylactic agents for diseases such as atherosclerosis, asthma, pulmonary fibrosis, myocarditis, ulcerative colitis, psoriasis, nephritis (nephropathy), multiple sclerosis, lupus, systemic lupus erythematosus, hepatitis, pancreatitis, sarcoidosis, organ transplantation, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease and sepsis, in which infiltration in tissue blood leukocytes, such as monocytes and lymphocytes, plays a major role in the initiation, development, or maintenance of the disease.

The present invention also proposed immunomodulatory bioactive compounds and their pharmaceutical compositions that act via antagonism of the CCR5 receptor.

Background of the invention

Migration and transport of leukocytes from blood vessels in diseased tissue is apparently crucial in initiating normal inflammatory responses in the fight against disease. This process, known as the process of attracting leukocytes, also refers to the emergence and development of life-threatening inflammation, as well as debilitating autoimmune diseases. Occur in these diseases, the pathology is a result of the attacks of the immune system of the body to normal tissue. Accordingly, preventing and blocking Pref is ecene of cells to target tissues in inflammatory and autoimmune diseases could serve as a highly effective approach to therapeutic intervention.

Different classes of cells leukocytes that are involved in cellular immune reactions include monocytes, lymphocytes, neutrophils, eosinophils and basophils. In most cases, the lymphocytes are a class of cells that initiate, coordinate and support the chronic inflammatory response, and thus are usually the most important class of cells to be blocked from penetrating into areas of inflammation. Cells attract monocytes to the sites of tissue, which together with lymphocytes responsible for the majority of existing tissue damage observed in inflammatory diseases. It is known that infiltration of lymphocytes and/or monocytes leads to a wide range of chronic, autoimmune diseases, and rejection of transplanted organs. Such diseases include, but are not limited to, rheumatoid arthritis, chronic contact dermatitis, inflammatory bowel disease, lupus, systemic lupus erythematosus, multiple sclerosis, atherosclerosis, psoriasis, sarcoidosis, idiopathic pulmonary fibrosis, dermatomyositis, skin disease and related diseases (for example, common bladderwort, leaf bladderwort, erythematous disease), glomerulonephritis, vasculitis, hepatitis, diabetes, rejection of allografts ireally “graft versus host”.

The process by which leukocytes leave the blood stream and accumulate in areas of inflammation and disease occurs, has at least three stages, which are described as (1) movement, (2) activation/strong adhesion, and (3) transendothelial migration [Springer, T.A., Nature 346:425-433 (1990); Lawrence and Springer, Cell 65:859-873 (1991); Butcher, E.C., Cell 67:1033-1036 (1991)]. The second stage is also mediated at the molecular level chemoattractant receptors. Chemoattractant receptors on the surface of cells then bind chemoattractant cytokines that are secreted by cells at sites of injury or infection. Receptor binding activates leukocytes, increases the adhesiveness of the adhesive molecules that posredstwom transendothelial migration and promotirovat direct the migration of cells toward the source of chemoattractant cytokines.

Cytokines, chemotactic (leucocytes the chemoattractant/activating factors), also known as chemokines, also known as intercine and SIS cytokines, are a group of inflammatory/immunomodulatory polypeptide factors with molecular weight 6-15 kDa, which are released on a broad range of cells, such as macrophages, monocytes, eosinophils, neutrophils, fibroblasts, vascular endothelial cells, the cells are smooth we have the C and the fat cells in areas of inflammation (review in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). In addition, chemokines have been described Oppenheim, J.J. et al., Annu. Rev. Immunol., 9:617-648 (1991); Schall and Bacon, Curr. Opin. Immunol., 6:865-873 (1994); Baggiolini, M., et al., and Adv. Immunol., 55:97-179 (1994). Chemokines have the ability to stimulate directed cell migration, a process known as chemotaxis. Each chemokine contains four cysteine residue (C) and two internal disulfide bonds. Chemokines can be grouped into two subfamilies on the basis of whether two aminoterminal cysteine residues immediately adjacent (CC family) or separated by one amino acid (CXC family). These differences correlate with the organization of these two subfamilies in a separate gene clusters. Within each gene cluster chemokines usually demonstrate the similarity of the sequences from 25 to 60%. CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and protein, stimulating the growth of melanoma (MGSA)are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MEP-1α, MIP-1β, monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4 and MCP-5) and eotaxin (-1 and -2), are chemotactic for along with other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There are also the chemokines lymphotactin-1, lymphotactin-2 (both C hamaki the s), fractalkine (CXXXC chemokine), which do not fall into the major subfamily of chemokines.

MCP-1 (also known as MCAF (abbreviation for macrophage - chemotactic and activating factor) or JE) is a CC-chemokine produced by monocytes/macrophages, smooth muscle cells, fibroblasts and endothelial cells of blood vessels, and causes migration and cell adhesion of monocytes (see, for example, Valente, A.J., et al., Biochemistry, 1988, 27, 4162; Matsushima, K., et al., J. Exp. Med., 1989, 169, 1485; Yoshimura, T., et al., J. Immunol., 1989, 142, 1956; Rollins, B.J., et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 3738; Rollins, B.J., et al., Blood, 1991, 78, 1112; Jiang, Y., et al., J. Immunol., 1992, 148, 2423; Vaddi, K., et al., J.Immunol., 1994, 153, 4721), T lymphocyte memory (see, for example, Carr, M.W., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3652), T lymphocytes (see, for example, Loetscher, P., et al., FASEB J., 1994, 8, 1055) and natural killer cells (see, for example, Loetscher, P., et al., J. Immunol., 1996, 156, 322; Allavena, P., et al., Eur. J. Immunol., 1994, 24, 3233), as well as the mediating histamine release basophils (see, for example, Alam, R., et al., J. Clin. Invest., 1992, 89, 723; Bischoff, S. C, et al., J. Exp. Med., 1992, 175,1271; Kuna, P., et al., J. Exp. Med., 1992, 175, 489). In addition, it was reported high expression of MCP-1 in such cases, where the accumulation of monocytes/macrophages and/or T cells, as it is considered to be an important factor for the emergence or development of diseases, such as atherosclerosis (see, for example, Hayes, I.M., et al., Arterioscler. Thromb. Vase. Biol., 1998, 18, 397; Takeya, M., et al., Hum. Pathol., 1993, 24, 534; Ylä-Herttuala, S., et al., Proc. Natl. Acad. Sci. USA, 1991, 88, 5252; Nelken, N.A., J. Cin. Invest., 1991, 88, 1121), rheumatoid arthritis (see, for example, Koch,. A.E., et al., J. Clin. Invest 1992, 90, 772; Akahoshi, T., et al., Arthritis Rheum., 1993, 36, 762; Robinson, E., et al., Clin. Exp. Immunol., 101, 398), jade (see, for example, Noris, M., et al., Lab. Invest, 1995, 73, 804; Wada, T., at al., Kidney Int., 1996; 49, 761; Gesualdo, L., et al., Kidney Int., 1997, 51, 155), nephropathy (see, for example, Saitoh, A., et al., J. Clin. Lab. Anal., 1998, 12, 1; Yokoyama, H., et al., J. Leukoc. Biol., 1998, 63, 493), pulmonary fibrosis, sarcoidosis of the lungs (see, for example, Sugiyama, Y., et al., Internal Medicine, 1997, 36, 856), asthma (see, for example, Karina, M., et al., J. Invest. Allergol. Clin. Immunol., 1997, 7, 254; Stephene, T.H., Am. J. Respir. Crit. Care Med., 1997, 156, 1377; Sousa, A.R., et al., Am. J. Respir. Cell Mol. Biol., 1994, 10, 142), multiple sclerosis (see, for example, McManus, C, et al., J. Neuroimmunol., 1998, 86, 20), psoriasis (see, for example, Gillitzer, R., et al., J. Invest Dermatol., 1993, 101, 127), inflammatory bowel disease (see, for example, Grimm MC, et al., J. Leukoc. Biol., 1996, 59, 804; Reinecker, H.C, et al., Gastroenterology, 1995, 106, 40), myocarditis (see, for example, Seino, Y., et al., Cytokine, 1995, 7, 301), endometriosis (see, for example, Jolicoeur C, et al., Am. J. Pathol., 1998, 152, 125), intraperitoneal adhesions (see, for example, Zeyneloglu, H.B., et al., Human Reproduction, 1998, 13, 1194), congestive heart failure (see, for example, Aurust, P., et al., Circulation, 1998, 97, 1136), chronic liver disease (see, for example, Marra, F., et al., Am. J. Pathol., 1998, 152, 423), viral meningitis (see, for example, Lahrtz, F., et al., Eur. J. Immunol., 1997, 27, 2484), Kawasaki disease (see, for example, Wong, M.; et al., J. Rheumatol., 1997, 24, 1179) and sepsis (see, for example, Salkowski, C.A.; et al., Infect. Immun., 1998, 66, 3569). In addition, it was reported that antibodies to p is otiv MCP-1 demonstrate the inhibiting effect or therapeutic effect in animal models of such diseases as rheumatoid arthritis (see, for example, Schimmer, R, et al., J. Immunol., 1998, 160, 1466; Schrier, D.J., J. Leukoc. Biol., 1998, 63, 359; Ogata, H., et al., J. Pathol., 1997, 182, 106), multiple sclerosis (see, for example, Karpus, W.J., et al., J. Leukoc. Biol., 1997, 62, 681), jade (see, for example, Lloyd, C.M., et al., J. Exp. Med., 1997, 185, 1371; Wada, T., et al., FASEB J. 1996, 10, 1418), asthma (see, for example, Gonzalo, J.-A., et al., J. Exp. Med., 1998, 188, 157; The Lukacs, N. W., J. Immunol., 1997,158,4398), atherosclerosis (see, e.g., Guzman, L.A., et al., Circulation, 1993, 88 (suppl.), 1-371), delayed-type hypersensitivity (see, for example, Rand, M.L., et al., Am. J. Pathol., 1996, 148, 855), pulmonary hypertension (see, for example, Kimura, H., et al., Lab. Invest., 1998, 78, 571) and intraperitoneal adhesions (see, for example, Zeyneloglu, H.B., et al., Am. J. Obstet. GynecoL, 1998, 179, 438). It was also reported that peptide antagonists of MCP-1, MCP-1(9-76), inhibit arthritis in mice (see Gong, J.-H., J. Exp., 4ed., 1997, 186, 131), as well as research on MCP-1-deficient mice showed that MCP-1 are necessary to attract monocytes in vivo (see Lu, B., et al., J. Exp. Med., 1998, 187, 601; Gu, L., et al., Moll. Cell, 1998, 2, 275).

Published data from the literature indicate that chemokines, such as MCP-1 and MIP-1α, attract monocytes and lymphocytes to the inflamed areas and posredstwom their activation, and therefore believe that they are ultimately involved in the initiation, development and maintenance of the disease, which actively participate monocytes and lymphocytes, such as atherosclerosis, restenosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis nephropathy) multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, and sepsis (see, for example, Rovin, B.H., et al., Am. J. Kidney. Dis., 1998, 31, 1065; Lloyd, C, et al., Curr. Opin. Nephrol. Hypertens., 1998, 7, 281; Conti, P., et al., Allergy and Asthma Proc, 1998, 19, 121; Ransohoff, R., et al., Trends Neurosci., 1998, 21, 154; MacDermott, R.P., et al., Inflammatory Bowel Diseases, 1998, 4, 54).

Chemokines bind with specific receptors on the surface of cells belonging to the family associated with G protein-seven-transmembranic proteins (review in Horuk, Trends Pharm. 25 Sci., 15, 159-165 (1994)), which are called "receptors chemokines". When binding to cognate ligands receptors chemokines convert intracellular signal through the associated trimeric G proteins, which leads, among other reactions, a rapid increase of intracellular calcium concentration, changes of cell shape, increased expression of cellular adhesion molecules, degranulation and to the promotion of cell migration.

Genes encoding receptors specific chemokines, have been cloned, and it is now known that these receptors are linked to G protein semitransparency receptors present in different populations of leukocytes. To date we have identified at least five CXC receptors chemokines (CXCR1-CXCR5) and eight CC receptors chemokines (CCR1-CCR8). For example, IL-8 is a ligand for CXCR1 and CXCR2, MIP-1α is a ligand for CCR1 and CCR5, and MCP-1 is a ligand for CCR2A and CCR2B (for references see, for example, Holmes, W.E., et al., Science 1991, 253, 1278-1280; Murphy P.M., et al., Science, 253, 1280-1283; Neote, K. et al, Cell, 1993, 72, 415-425; Charo, I.P., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2752-2756; Yamagami, S., et al., Biochem. Biophys. Res. Commun., 1994, 202, 1156-1162; Combadier, C., et al., The Journal of Biological Chemistry, 1995, 270, 16491-16494, Power, C.A., et al., J. Biol. Chem., 1995, 270, 19495-19500; Samson, M., et al., Biochemistry, 1996, 35, 3362-3367; Murphy, P.M., Annual Review of Immunology, 1994, 12, 592-633). It was reported that the lung inflammation and granuloma formation is suppressed in CCR1-deficient mice (see Gao, J.-L., et al., J. Exp. Med., 1997, 185, 1959; Gerard C, et al., J. Clin. Invest., 1997, 100, 2022) and the attraction of macrophages and the formation of atherosclerotic plaques is reduced in CCR2-deficient mice (see Boring, L., et al., Nature, 1998, 394, 894; Kuziel, W.A., et al., Proc. Natl. Acad. Sci., USA, 1997, 94, 12053; Kurihara, T., et al., J. Exp. Med., 1997, 186, 1757; Boring, L., et al., J. Clin. Invest., 1997, 100, 2552).

Accordingly, drugs which inhibit the binding of chemokines such as MCP-1 and/or MIP-1α, with these receptors, such as receptor antagonists of chemokines, could be useful as pharmaceutical agents which inhibit the action of chemokines such as MCP-1 and/or MIP-1α, on target cells, but in the prior art there is no guidance on derivatives of 3-aminoe is alidina, which possess pharmacological properties. Detection of compounds that modulate the function of CCR2 and/or CCR5, is a superb approach to create medicines for the development of pharmacological agents for the treatment of inflammatory conditions and diseases associated with activation of CCR2 and/or CCR5, such as rheumatoid arthritis, lupus and other inflammatory diseases. The present invention overcomes the long-term need in the field of modulators and antagonists of receptors chemokines.

The purpose of the present invention

Given all the above, an important aim of this invention is to provide antagonists of receptors chemokines and receptor modulators chemokines for the treatment of rheumatoid arthritis.

Another primary aim of the present invention is to provide antagonists of receptors chemokines and their use as pharmaceuticals.

An additional objective of the present invention is to provide modulators of receptors chemokines and their use as pharmaceuticals.

Another objective of the present invention is to provide derivatives of 3-aminopyrrolidine.

Another objective of the present invention relates to new compounds and medical methods of treatment of inflammation.

Another objective of the present invention which is the creation of new anti-inflammatory and immunomodulatory bioactive compounds and containing pharmaceutical compositions which act as antagonists of CCR2 receptors.

An additional objective of the present invention is to provide derivatives of 3-aminopyrrolidine and their use as modulators of receptors chemokines.

Another additional objective of the present invention is to provide derivatives of 3-aminopyrrolidine and their use for the treatment and prevention of atherosclerosis and restenosis.

Another objective of the present invention is to provide derivatives of 3-aminopyrrolidine and their use as modulators of CCR5 receptors.

Another major aim of the present invention is the creation of bioactive compounds 3-aminopyrrolidine containing pharmaceutical compositions that act as antagonists of the CCR5 receptor.

Other objectives and specific embodiment of the present invention will be discussed below. However, it is important to note that many additional variations of the present invention, are not described in the present application, however, can be included in the nature and scope of the present invention and/or in the claims.

Brief description of the invention

The present invention relates, in its broadest embodiment, the compounds of the formula I:

its enantiomers, diastereoisomers, enantiomerically enriched mixture is m, its racemic mixtures, prodrugs, crystalline forms, non-crystalline forms, its amorphous form, solvate, metabolites and pharmaceutically acceptable salts, where:

X is chosen from the group consisting of aryl, mono - or preparation of polysubstituted aryl, heterocycle, heteroaryl, mono - or preparation of polysubstituted heteroaryl, carbocycle, mono - or preparation of polysubstituted carbocycle (CR9R10)nwhere n=0-5;

Y represents a bond, or it is chosen from the group consisting of oxygen, sulfur, nitrogen, amide linkages, thioamides communication sulfonamida, ketone, -CHOH-, -CHO-alkyl-, oxime or urea;

Z is chosen from the group consisting of carbocycle, aryl, heterocycle or heteroaryl containing 0-3 substituent R11where R11independently selected from the group consisting of halogen, alkyl, alkenyl, quinil, alkoxy, alkoxyalkyl, alkylthiomethyl, thioalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, nitro, amino, mono - or disubstituted amino, mono - or disubstituted aminoalkyl, carboxyl, esterified carboxyl, carboxamido, mono - or disubstituted, carboxamide, carbamate, mono - or disubstituted carbamate, sulfonamida, mono - or disubstituted sulfonamida, alkylcarboxylic, cyclic alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylcarboxylic, the CEC is of practical alkylcarboxylic, arylcarbamoyl, heteroarylboronic, thiocarboxamide, cyano and R11a-aryl, or R11a-heteroaryl, where R11arepresents H, halogen, OH, amino, mono - or disubstituted amino, mono-, di - or trihalogen, alkoxy, mono-, di - or trigalogenmetany, carboxamide, sulfonamide, carbamate, urea or cyano;

R1independently selected from the group consisting of carbocycle, heterocycle, aryl, heteroaryl, arylalkyl, heteroallyl, arylalkyl, heteroallyl, arylalkyl, heteroallyl, arylenecarborane, heteroarylboronic, arylcarboxamide, heteroarylboronic, amiloride, heteroaromatic, aryloxy, heteroaromatic, Allakaket, heteroaromatics, arylamino or heteroarenes, and where these groups carbocycle, heterocycle, aryl, arylalkyl, heteroaryl or heteroaromatic can be substituted by 0-3 substituents R1awhere R1aindependently selected from the group consisting of halogen, alkyl, alkenyl, quinil, alkoxy, alkoxyalkyl, alkylthiomethyl, hydroxyalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, nitro, amino, mono - or disubstituted amino, mono - or disubstituted aminoalkyl, aminocarbonyl, mono - or disubstituted aminocarbonyl, cyclic aminocarbonyl, aminosulfonyl, mono - or disubstituted aminosol who were radioactive, alkylcarboxylic, cyclic alkylcarboxylic, arylcarbamoyl, heteroarylboronic, alkylsulfonyl, cyclic alkylsulfonyl, arylsulfonyl, heteroarylboronic, carboxylic acids, esterified carboxylic acid, alkylcarboxylic, cyclic alkylcarboxylic, arylcarboxamide, heteroarylboronic, cyano, arylalkyl, heteroallyl, aryloxyalkyl, heteroepitaxial, alltoall, heteroalicyclic, carbamate, mono - or disubstituted carbamate, R1b-aryl, or R1b-heteroaryl, where R1brepresents H, halogen, OH, amino, mono - or disubstituted amino, mono-, di - or trihalogen, alkoxy, mono-, di - or trigalogenmetany, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono - or disubstituted aminoalkyl, carboxamide, sulfonamide, carbamate, urea or cyano;

R2independently selected from the group consisting of H, amino, mono - or disubstituted amino, OH, carboxyl, esterified carboxyl, carboxamide, N-monosubstituted carboxamide and N,N-disubstituted carboxamide, cyano, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, alkoxy, thioalkyl, mono-, di - or trialogical, halogen, aryl or heteroaryl;

optional R1and R2can be connected to each other with the formation of spirocyclic;

R3, R4, R5 and R6independently selected from the group consisting of H, amino, OH, alkyl, halogenoalkane, dihalogenoalkane, trialogical, alkenyl, quinil, aryl, heteroaryl, arylalkyl, heteroallyl, alkoxy and thioalkyl,

optional R1and R3can be cyklinowanie education carbocycle or heterocycle containing 0-3 substituent Rawhere Raselected from the group consisting of halogen, alkyl, alkoxy, thioalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, nitro, amino, carboxyl, esterified carboxyl, carboxamido, thiocarboxamide, cyano, mono-, or disubstituted preparation of polysubstituted aryl and heterocycle, optionally containing 0-3 Rbwhere Rbselected from the group consisting of halogen, alkyl, alkoxy, thioalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, nitro, amino, carboxyl, esterified carboxyl, carboxamido, thiocarboxamide and cyano;

optional R3and R4or R5and R6cyklinowanie with the formation of bridged bicyclic system containing ethylene bridge;

optional R3and R6cyklinowanie with the formation of bridged bicyclic systems containing a methylene group or ethylene group, or a heteroatom selected from the group consisting of N, O and S;

R7and R8independently selected from the group consisting of hydrogen, C1-C8of alkyl, and optional chain C1-C8the alkyl may be interrupted by oxygen or sulfur; alkoxy, mono-, di - or trialogical, mono-, di - or trigalogenmetany, alkoxyalkyl, aryloxy, heteroaromatic, Allakaket, heteroaromatics, aryloxyalkyl, heteroepitaxial, allakariallak or heteroarylboronic;

optional R7and R8can be cyklinowanie education pyrocarbonate or spiroheterocyclic;

R9and R10independently selected from the group consisting of H, OH, amino, alkoxy, mono - or disubstituted amino, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, heteroaromatic, carbocycle or heterocycle;

optional R9and R10can be cyklinowanie education carbocycle or heterocycle; and r=0-3.

The present invention also provides compounds of formula II:

where the values of X, Y, Z, R1, R2, R3, R4, R5, R6, R7and R8details are disclosed below in the description of preferred options; for the sake of brevity, it should be stated that each of the groups of substituents identified as the most preferred subgroup of the respective groups of the substituents, as ODA is defined for compounds of formula I.

Considering the invention relates also to compounds of formula III:

where the values of R1, R2, R3, R4, R5, R6, R7and R8details are disclosed below in the description of preferred options; for the sake of brevity, it should be stated that each of the groups of substituents identified as the most preferred subgroup of the respective groups of the substituents as defined for compounds of formula I.

Considering the invention relates also to pharmaceutical compositions that contain anti-inflammatory and/or immunomodulatory compounds of formulas I, II and III, as described above, which act as antagonists of the receptor CCR2 (also known as the receptor for MCP-1) and therefore inhibit monotany chemoattractant protein-1 (MCP-1).

Considering the invention relates also to pharmaceutical compositions that contain anti-inflammatory and/or immunomodulatory compounds of the formula I, II, and III, as described above, which act as antagonists of the CCR5 receptor, (also known as the receptor for MCP-1) and therefore inhibit monotany chemoattractant protein-1 (MCP-1).

The present invention relates also to compounds of formulas I, II and III, which are modulators of the function of the receptor CCR2 chemokines and which are useful for the prevention and or treatment of inflammatory diseases, such as rheumatoid arthritis, allergic diseases, psoriasis, atopic dermatitis, lupus and asthma.

The present invention discloses compounds of formulas I, II and III, which are modulators of the function of receptors chemokines CCR5 and which are useful for the prevention or treatment of inflammatory conditions and diseases, such as rheumatoid arthritis, allergic diseases, psoriasis, atopic dermatitis, lupus and asthma.

Further, the present invention relates to a method of modulating the activity of receptors chemokines in mammals, which includes the introduction of an effective amount of the compounds of formula I or II or III.

In this proposed invention is also pharmaceutical compositions containing the compounds selected from the group of compounds of formulas I, II and III, and the use of these compounds and compositions containing them for prevention or treatment of diseases involving receptors CCR2 chemokines.

In this proposed invention is also pharmaceutical compositions containing the compounds selected from the group of compounds of formulas I, II and III, and the use of these compounds and compositions containing them for prevention or treatment of diseases involving receptors chemokines CCR5.

In addition, in the present invention, a method for treatment of inflammation, rheumatoid the th arthritis, erythematosus, systemic lupus erythematosus, atherosclerosis, restenosis, immune system disorders, and transplant rejection in need in mammals, comprising introducing a therapeutically effective amount of a pharmaceutical composition containing a compound according to formulas I, II and III, in a mixture with a pharmaceutically acceptable excipient, diluent or carrier.

Description of the preferred options

The present invention relates to compounds of the following chemical structures I and II:

their enantiomers, diastereoisomers, enantiomerically enriched mixtures, its racemic mixtures, prodrugs, crystalline forms, non-crystalline forms, amorphous forms, solvate, metabolites and pharmaceutically acceptable salts, where:

X is chosen from the group consisting of aryl, mono - or preparation of polysubstituted aryl, heterocycle, heteroaryl, mono - or preparation of polysubstituted heteroaryl, carbocycle, mono - or preparation of polysubstituted carbocycle (CR9R10)nwhere n=0-5;

Y represents a bond, or it is chosen from the group consisting of oxygen, sulfur, nitrogen, amide linkages, thioamides communication sulfonamida, ketone, -CHOH-, -CHO-alkyl-, oxime or urea;

Z is chosen from the group consisting of carbocycle, aryl, hetero the KLA or heteroaryl, containing 0-3 substituent R11where R11independently selected from the group consisting of halogen, alkyl, alkenyl, quinil, alkoxy, alkoxyalkyl, alkylthiomethyl, thioalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, nitro, amino, mono - or disubstituted amino, mono - or disubstituted aminoalkyl, carboxyl, esterified carboxyl, carboxamido, mono - or disubstituted, carboxamide, carbamate, mono - or disubstituted carbamate, sulfonamida, mono - or disubstituted sulfonamida, alkylcarboxylic, cyclic alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylcarboxylic, cyclic alkylcarboxylic, arylcarbamoyl, heteroarylboronic, thiocarboxamide, cyano and R11a-aryl, or R11a-heteroaryl, where R11arepresents H, halogen, OH, amino, mono - or disubstituted amino, mono-, di - or trihalogen, alkoxy, mono-, di - or trigalogenmetany, carboxamide, sulfonamide, carbamate, urea or cyano;

R1independently selected from the group consisting of carbocycle, heterocycle, aryl, heteroaryl, arylalkyl, heteroallyl, arylalkyl, heteroallyl, arylalkyl, heteroallyl, arylenecarborane, heteroarylboronic, arylcarboxamide, heteroarylboronic, amiloride, heteroaromatic, aryloxy, heteroa is iloxi, Allakaket, heteroaromatics, arylamino or heteroarenes, and where these groups carbocycle, heterocycle, aryl, arylalkyl, heteroaryl or heteroaromatic can be substituted by 0-3 substituents R1awhere R1aindependently selected from the group consisting of halogen, alkyl, alkenyl, quinil, alkoxy, alkoxyalkyl, alkylthiomethyl, hydroxyalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, nitro, amino, mono - or disubstituted amino, mono - or disubstituted aminoalkyl, aminocarbonyl, mono - or disubstituted aminocarbonyl, cyclic aminocarbonyl, aminosulfonyl, mono - or disubstituted aminosulfonyl, alkylcarboxylic, cyclic alkylcarboxylic, arylcarbamoyl, heteroarylboronic, alkylsulfonyl, cyclic alkylsulfonyl, arylsulfonyl, heteroarylboronic, carboxylic acids, esterified carboxylic acid, alkylcarboxylic, cyclic alkylcarboxylic, arylcarboxamide, heteroarylboronic, cyano, arylalkyl, heteroallyl, aryloxyalkyl, heteroepitaxial, alltoall, heteroalicyclic, carbamate, mono - or disubstituted carbamate, R1b-aryl, or R1b-heteroaryl, where R1brepresents H, halogen, OH, amino, mono - or disubstituted amino, mono-, di - or trihalogen, alkoxy, mono -, di - or trigalogenmetany, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono - or disubstituted aminoalkyl, carboxamide, sulfonamide, carbamate, urea or cyano;

R2independently selected from the group consisting of H, amino, mono - or disubstituted amino, OH, carboxyl, esterified carboxyl, carboxamide, N-monosubstituted carboxamide and N,N-disubstituted carboxamide, cyano, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, alkoxy, thioalkyl, mono-, di - or trialogical, halogen, aryl or heteroaryl;

optional R1and R2can be connected to each other with the formation of spirocyclic;

R3, R4, R5and R6independently selected from the group consisting of H, amino, OH, alkyl, halogenoalkane, dihalogenoalkane, trialogical, alkenyl, quinil, aryl, heteroaryl, arylalkyl, heteroallyl, alkoxy and thioalkyl,

optional R1and R3can be cyklinowanie education carbocycle or heterocycle containing 0-3 substituent Rawhere Raselected from the group consisting of halogen, alkyl, alkoxy, thioalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, nitro, amino, carboxyl, esterified carboxyl, carboxamido, thiocarboxamide, cyano, mono-, or disubstituted preparation of polysubstituted aryl and heterocycle, neobyazatel the containing 0-3 R bwhere Rbselected from the group consisting of halogen, alkyl, alkoxy, thioalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, nitro, amino, carboxyl, esterified carboxyl, carboxamido, thiocarboxamide and cyano;

optional R3and R4or R5and R6cyklinowanie with the formation of bridged bicyclic system containing ethylene bridge;

optional R3and R6cyklinowanie with the formation of bridged bicyclic systems containing a methylene group or ethylene group, or a heteroatom selected from the group consisting of N, O and S;

R7and R8independently selected from the group consisting of hydrogen, C1-C8of alkyl, and optional chain C1-C8the alkyl may be interrupted by oxygen or sulfur; alkoxy, mono-, di - or trialogical, mono-, di - or trigalogenmetany, alkoxyalkyl, aryloxy, heteroaromatic, Allakaket, heteroaromatics, aryloxyalkyl, heteroepitaxial, allakariallak or heteroarylboronic;

optional R7and R8can be cyklinowanie c education pyrocarbonate or spiroheterocyclic;

R9and R10independently selected from the group consisting of H, OH, amino, alkoxy, mono - or disubstituted amino, alkyl, alkenyl, quinil, ar is La, arylalkyl, heteroaryl, heteroaromatic, carbocycle or heterocycle;

optional R9and R10can be cyklinowanie education carbocycle or heterocycle; and

r=0-3.

The present invention relates also to the compound of formula III:

its enantiomers, diastereoisomers, enantiomerically enriched mixtures, racemic mixtures, prodrugs, crystalline forms, non-crystalline forms, its amorphous form, solvate, its metabolites, and pharmaceutically acceptable salts, where:

R1independently selected from the group consisting of carbocycle, heterocycle, aryl, heteroaryl, arylalkyl, heteroallyl, arylalkyl, heteroallyl, arylalkyl, heteroallyl, arylenecarborane, heteroarylboronic, arylcarboxamide, heteroarylboronic, amiloride, heteroaromatic, aryloxy, heteroaromatic, Allakaket, heteroaromatics, arylamino or heteroarenes, and where these groups carbocycle, heterocycle, aryl, arylalkyl, heteroaryl or heteroaromatic can be substituted by 0-3 substituents R1awhere R1aindependently selected from the group consisting of halogen, alkyl, alkenyl, quinil, alkoxy, alkoxyalkyl, alkylthiomethyl, hydroxyalkyl, mono-, di - or trialogical, mono-, di - or TRIG is loginwelcome, nitro, amino, mono - or disubstituted amino, mono - or disubstituted aminoalkyl, aminocarbonyl, mono - or disubstituted aminocarbonyl, cyclic aminocarbonyl, aminosulfonyl, mono - or disubstituted aminosulfonyl, alkylcarboxylic, cyclic alkylcarboxylic, arylcarbamoyl, heteroarylboronic, alkylsulfonyl, cyclic alkylsulfonyl, arylsulfonyl, heteroarylboronic, carboxylic acids, esterified carboxylic acid, alkylcarboxylic, cyclic alkylcarboxylic, arylcarboxamide, heteroarylboronic, cyano, arylalkyl, heteroallyl, aryloxyalkyl, heteroepitaxial, alltoall, heteroalicyclic, carbamate, mono - or disubstituted carbamate, R1b-aryl, or R1b-heteroaryl, where R1brepresents H, halogen, OH, amino, mono - or disubstituted amino, mono-, di - or trihalogen, alkoxy, mono-, di - or trigalogenmetany, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono - or disubstituted aminoalkyl, carboxamide, sulfonamide, carbamate, urea or cyano;

R2independently selected from the group consisting of H, amino, mono - or disubstituted amino, OH, carboxyl, esterified carboxyl, carboxamide, N-monosubstituted carboxamide and N,N-disubstituted carboxamide, cyano, alkyl, alkenyl, quinil, cycloalkyl, C is kloeckera, alkoxy, thioalkyl, mono-, di - or trialogical, halogen, aryl or heteroaryl;

optional R1and R2can be connected to each other with the formation of spirocyclic;

R3, R4, R5and R6independently selected from the group consisting of H, amino, OH, alkyl, halogenoalkane, dihalogenoalkane, trialogical, alkenyl, quinil, aryl, heteroaryl, arylalkyl, heteroallyl, alkoxy and thioalkyl,

optional R1and R3can be cyklinowanie education carbocycle or heterocycle containing 0-3 substituent Rawhere Raselected from the group consisting of halogen, alkyl, alkoxy, thioalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, nitro, amino, carboxyl, esterified carboxyl, carboxamido, thiocarboxamide, cyano, mono-, or disubstituted preparation of polysubstituted aryl and heterocycle, optionally containing 0-3 Rbwhere Rbselected from the group consisting of halogen, alkyl, alkoxy, thioalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, nitro, amino, carboxyl, esterified carboxyl, carboxamido, thiocarboxamide and cyano;

optional R3and R4or R5and R6cyklinowanie with the formation of bridged bicyclic system containing ethylene is the bridge;

optional R3and R6cyklinowanie with the formation of bridged bicyclic system containing methylene group, or ethylene group, or a heteroatom selected from the group consisting of N, O and S;

R7and R8independently selected from the group consisting of hydrogen, C1-C8of alkyl, and optional chain C1-C8the alkyl may be interrupted by oxygen or sulfur; alkoxy, mono-, di - or trialogical, mono-, di - or trigalogenmetany, alkoxyalkyl, aryloxy, heteroaromatic, Allakaket, heteroaromatics, aryloxyalkyl, heteroepitaxial, allakariallak or heteroarylboronic;

optional R7and R8can be cyklinowanie education pyrocarbonate or spiroheterocyclic;

and m=0-5.

As defined above in respect of compounds of formulas I and II, X is chosen from the group consisting of aryl, mono - or preparation of polysubstituted aryl, heterocycle, heteroaryl, mono - or preparation of polysubstituted heteroaryl, carbocycle, mono - or preparation of polysubstituted carbocycle (CR9R10)nwhere n=0-5. The term aryl group include aromatic carbocyclic group, such as phenyl, biphenylyl, indenyl, naphthyl and condensed with the aromatic heterocyclic groups such as 2-benzothiazyl, 3-benzothiazol, 2-benzofuranyl, 3-benzofuranyl, 2-in which oil, 3-indolyl, 2-chinoline, 3-chinoline, 2-benzothiazole, 2-benzooxazole, 2-benzimidazole, 1-ethenolysis, 4-chinoline, 1-isoindolyl, 3-isoindolyl and acridines. The term heterocyclic group includes aromatic and non-aromatic rings, for example, containing from 3 to 20, preferably from 4 to 10 atoms in the ring, at least one of which is a heteroatom such as oxygen, sulfur, phosphorus or nitrogen. Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, chinoline, ethenolysis, honokalani, benzothiazolyl, benzoxazolyl, benzothiazyl or benzofuran. Other examples include non-aromatic heterocyclic rings, which are non-aromatic carbocyclic rings, which contain one or more heteroatoms, such as nitrogen, oxygen or sulfur in the ring. The ring can be five-, six-, seven - or eight-membered. Examples include 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydrofuranyl, 2-morpholino, 3 morpholino, 4-morpholino, 2-thiomorpholine, 3 thiomorpholine, 4-thiomorpholine, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinil, 2-piperazinil, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl and 4-thiazolidine. In t the m case, when X and Z have the same values, then the identical definition applicable to their definitions. In addition, if heteroaryl or heterocyclic groups are nitrogen-containing heterocycles, nitrogen can be modified and can exist in the form N→O-(N oxides), and such oxides included in the scope of the present invention. In the case of serosoderjaschei heterocycles sulfur oxides are also included in the scope of the present invention.

The substituents at the aryl groups, arylalkyl groups, heteroaryl groups, heteroarylboronic groups and heterocyclic groups of the present invention are selected from the group consisting of halogen, alkyl, alkoxy, monohalogenated, dihalogenoalkane, trigalogenmetany, thioalkyl and monohalogenated, dihalogenoalkane, trialogical, nitro, amino, carboxy, esterified carboxy, carboxamide, thiocarboxamide and cyano. In particular, the substituents can also be selected from the group consisting of trifloromethyl, C1-4of alkyl, halogen, triptoreline,

formatosi, deformedarse, C1-5alkoxy, C1-5alkanoyl,

C1-5alkanoyloxy, C1-5alkylamino, di(C1-5alkyl)amino,

C1-5alkanolamine, nitro, carboxy, carbamoyl,

C1-5alkoxycarbonyl, thiol, C1-5sulfonamide,

carbamoyl1-5of alkyl, N-(C1-5/sub> alkyl)carbamoyl1-5of alkyl,

N-(C1-5alkyl)2carbamoyl1-5of alkyl, hydroxys1-5the alkyl or

C1-5alkoxyl1-4the alkyl.

The terms halo or halogen, by themselves or as part of another substituent, means, unless otherwise specified, fluorine atoms, chlorine, bromine and iodine. Similarly, terms such as halogenoalkane include monohalogenated and POLYHALOGENATED. For example, the term halogeno(C1-C4)alkyl include trifluoromethyl, 2,2,2-triptorelin, 4-chlorobutyl, 3-bromopropyl and the like.

The term alkyl when used alone or as a suffix consists of an unbranched chain and branched structures, such as primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Such groups can contain up to 15, preferably up to 8, and more preferably up to 4 carbon atoms. Similarly, the terms of alkenyl and quinil refer to unsaturated, unbranched or branched structures containing, for example, from 2 to 12, preferably from 2 to 6 carbon atoms. Cyclic fragments, such as cycloalkyl, cycloalkenyl and cycloalkenyl similar in nature, but contain at least 3 carbon atoms. Examples of saturated hydrocarbon radicals include such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and butil, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentile, n-hexyl, n-heptyl, n-Attila and the like. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethinyl, 1 - and 3-PROPYNYL, 3-butynyl and higher homologs and isomers. In this application, the term cycloalkyl includes Adamantine groups and other bridge connection. The terms alkoxy, alkylamino, alkylthio (or dialkoxy) used in their ordinary sense, and they include such alkyl groups that are attached to the rest of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively. Therefore, terms such as alkoxy and thioalkyl include alkyl fragments as defined above, attached to the corresponding functional group.

Other suitable substituents, which can be used in many carbon rings of the present invention, such as cycloaliphatic, aromatic, non-aromatic heterocyclic ring or benzyl group include, for example, -OH, halogen (-Br, -Cl, -I and-F), -O(aliphatic, substituted aliphatic, benzyl, substituted benzyl, phenyl, substituted phenyl, an aromatic or substituted aromatic group), -CN, -NO2, -COOH, -NH2, -H(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, phenyl, substituted phenyl, an aromatic or substituted aromatic group), -N(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, phenyl, substituted phenyl, an aromatic or substituted aromatic group)2, -COO - (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, phenyl, substituted phenyl, an aromatic or substituted aromatic group), -CONH2, -CONH(aliphatic, substituted aliphatic group, benzyl, substituted benzyl, phenyl, substituted phenyl, an aromatic or substituted aromatic group), -SH, -S(aliphatic, substituted aliphatic group, benzyl, substituted benzyl, phenyl, substituted phenyl, an aromatic or substituted aromatic group),- NH-C=NH-NH2. Substituted non-aromatic heterocyclic ring, benzyl group or aromatic group may also contain aliphatic or substituted aliphatic group as a substituent. Substituted alkyl or aliphatic group may also contain non-aromatic heterocyclic ring, benzyl, substituted benzyl, aromatic or substituted aromatic group as a substituent. Samisen the e non-aromatic heterocyclic ring may contain =O, =S, =NH or =N(aliphatic, aromatic or substituted aromatic group) as a substituent. Substituted aliphatic, substituted aromatic group, substituted non-aromatic heterocyclic ring or a substituted benzyl group can contain more than one Deputy.

Carbocyclic Deputy, as defined for R1includes cycloalkyl containing 3-10 carbon atoms, and bicyclic or bridged polycyclic systems, such as norbornanyl, and substituted bicyclo[2.2.2]octyl. Carbocyclic Deputy, as defined for R1may be optionally substituted heterocyclic or heteroaryl ring, such as pyridyl, pyrrolidinyl and all those that have been defined for X above.

Specific examples of R1substituents include phenyl,

pyridine-2-yl, 4-were, 3-were, 2nd were,

4-bromophenyl, 3-bromophenyl, 4-chlorophenyl, 3-chlorophenyl,

4-triptoreline, 3-triptoreline, 2-triptoreline,

2-methoxyphenyl, 3-pyridyl, 4-pyridyl, 2-methoxy-5-pyridyl,

2 ethoxy-5-pyridyl, 3,4-methylenedioxyphenyl, 4-forfinal,

3-trifluoromethyl-1H-pyrazole-1-yl, 3-forfinal, 4-methoxyphenyl,

3-methoxyphenyl, pyridin-4-yl, pyridine-3-yl,

5-methylpyridin-2-yl, 6-methylpyridin-2-yl, quinoline-4-yl,

3-methyl-1H-pyrazole-1-yl, 3,5-dimethyl-1H-pyrazole-1-yl,

4-trif ermatinger, 3-triptoreline,

3,4-methylenedioxyphenyl, 4-cyanophenyl,

4-(methylaminomethyl)phenyl, 1-oxidability-4-yl,

pyridine-2-yl, pyridin-3-yl, pyridine-4-yl, 4-methylpyridin-2-yl,

5-methyl-pyridine-2-yl, 6-methylpyridin-2-yl,

6-methoxypyridine-2-yl, 6-methoxypyridine-3-yl,

6-methylpyridin-3-yl, 6-ethylpyridine-3-yl,

6-isopropylpyridine-3-yl, 6-cyclopropylamino-3-yl,

1-oxidability-3-yl, 1-oxidability-2-yl, 3-cyanophenyl,

3-(methylaminomethyl)phenyl, 4-(morpholine-4-ylcarbonyl)phenyl,

5-(morpholine-4-ylcarbonyl)pyridine-2-yl,

6-(morpholine-4-ylcarbonyl)pyridine-3-yl,

4-(4-methylpiperazin-1-ylcarbonyl)phenyl,

6-(azatin-1-yl)pyridine-3-yl, 5-cyano-2-yl,

6-cyano-3-yl, 5-(methoxymethyl)pyridine-2-yl,

5-(1-hydroxy-1-methylethyl)pyridine-2-yl, 5-dimethylaminomethyl,

4-ethylaminoethanol, 4-isopropylaminocarbonyl,

4-tert-butylaminoethyl, 4-dimethylaminocarbonylmethyl,

4-(azetidin-1-yl)carbonitril,

4-(pyrrolidin-1-yl)carbonitril,

4-(morpholine-4-yl)carbonitril,

4-(dimethylaminoethyl)-2-were,

2-methyl-4-(methylaminomethyl)phenyl,

3-methyl-4-(methylaminomethyl)phenyl,

4-(dimethylaminoethyl)-3-were,

3-methyl-4-(pyrrolidin-1-ylcarbonyl)phenyl,

4-(dimethylaminoethyl)-3-forfinal,

4-[(2,2,2-triptorelin)aminocarbonyl]phenyl,

3-fluoro-4-metiram nonaboriginal,

4-ethylaminomethyl-3-forfinal, 3-methylaminoethanol,

3-dimethylaminocarbonylmethyl,

5-dimethylaminoethyl-2-methoxyphenyl,

2-methoxy-5-methylaminoethanol,

3-(methylaminoquinoline)phenyl,

6-(morpholine-4-yl)pyridine-3-yl, 6-dimethylaminopyridine-3-yl,

6-isopropylaminomethyl-3-yl, 6-(pyrrolidin-1-yl)pyridine-3-yl,

6-cyclopropylamino-3-yl, 6-ethoxypyridine-3-yl,

6-(2-floratone)pyridine-3-yl, 6-(2,2-diflorasone)pyridine-3-yl,

6-(2,2,2-triptoreline)pyridine-3-yl, 4-iodophenyl,

5-(pyrrolidin-1-ylcarbonyl)-2-pyridyl,

5-(morpholine-4-ylcarbonyl)-2-pyridyl,

5-dimethylaminoethyl-2-pyridyl,

4-methylaminomethyluridine,

6-(1-hydroxy-1-methylethyl)pyridine-3-yl,

4-(1-hydroxy-1-methylethyl)phenyl, 4-(methoxymethyl)phenyl,

3-fluoro-4-(methoxymethyl)phenyl, 4-(dimethylamino)phenyl,

4-(dimethylamino)-3-forfinal, 1H-indazol-5-yl,

1-methyl-1H-indazol-5-yl, 2-methyl-1H-indazol-5-yl,

1,3-thiazol-2-yl, 5-ethyl-1,3-thiazol-2-yl,

5-(methylaminomethyl)-1,3-thiazol-2-yl, 1,3-thiazol-5-yl,

2-(methoxycarbonylamino)-1,3-thiazol-5-yl,

2-isopropyl-1,3-thiazol-5-yl, 5-(pyridine-3-yl)-1,3-thiazol-2-yl,

5-(morpholine-4-ylcarbonyl)-1,3-thiazol-2-yl,

5-aminocarbonyl-1,3-thiazol-2-yl,

5-dimethylaminoethyl-1,3-thiazol-2-yl,

5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl,

5-allyl-1,3-thiazol-2-yl, 5-propyl-1,3-thiazol-2-yl,

5-ethyl shall aminocarbonyl-1,3-thiazol-2-yl, 5-phenyl-1,3-thiazol-2-yl,

5-methyl-1,3-thiazol-2-yl, 5-hydroxymethyl-1,3-thiazol-2-yl,

5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl,

5-methoxymethyl-1,3-thiazol-2-yl, 5-(2-pyridyl)-1,3-thiazol-2-yl,

2-(pyrrolidin-1-yl)-1,3-thiazol-4-yl,

2-(morpholine-4-yl)-1,3-thiazol-4-yl, 2-methyl-1,3-thiazol-5-yl,

2-(1-hydroxy-1-methylethyl)-1,3-thiazol-5-yl,

2-(pyrrolidin-1-yl)-1,3-thiazol-5-yl, 2-ethoxy-1,3-thiazol-5-yl,

2-ethyl-1,3-thiazol-5-yl,

2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-5-yl,

2-(morpholine-4-yl)-1,3-thiazol-5-yl,

2-methoxymethyl-1,3-thiazol-5-yl, 2-isobutyl-1,3-thiazol-5-yl,

2-ethylaminomethyl-1,3-thiazol-5-yl,

2-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-5-yl,

2-(morpholine-4-ylcarbonyl)-1,3-thiazol-5-yl,

2-(3-pyridyl)-1,3-thiazol-5-yl, 2-(2-pyridyl)-1,3-thiazol-5-yl,

4-methyl-1,3-thiazol-2-yl, 1,3-benzothiazol-2-yl, pyrimidine-5-yl,

pyrimidine-2-yl, pyridazin-4-yl, pyridazin-3-yl, pyrazin-2-yl,

2-methoxypyridine-5-yl, 2-ethoxypyridine-5-yl,

2-(2-floratone)pyrimidine-5-yl, 2-methylpyrimidin-5-yl,

2-ethylpyrimidine-5-yl, 2-isopropylpyrimidine-5-yl,

2-cyclopropylamino-5-yl, pyrimidine-4-yl,

4-(pyrimidine-5-yl)phenyl, 4-(1,3-oxazol-2-yl)phenyl,

4-(1H-imidazol-1-yl)phenyl, 4-(morpholine-4-yl)phenyl,

5-(pyrazin-2-yl)pyridine-2-yl,

4-(1-methyl-1H-imidazol-5-yl)phenyl,

4-(4,6-dimethylpyrimidin-5-yl)phenyl, 6-bromopyridin-3-yl,

5-bromopyridin-2-yl, 4'-(methylsulphonyl) - biphenyl-4-yl,

3'-(methylsulfone the l)biphenyl-4-yl,

3'-(methoxycarbonyl)biphenyl-4-yl,

4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl,

4'-(dimethylamino)biphenyl-4-yl, 4-(pyridin-3-yl)phenyl,

4-(1H-pyrazole-4-yl)phenyl, 3,3'-bipyridine-6-yl,

3,4'-bipyridine-6-yl, 5-(3-acetylphenyl)pyridine-2-yl,

5-[3-(dimethylamino)phenyl]pyridine-2-yl,

5-[3-(trifluoromethyl)phenyl]pyridine-2-yl,

5-[4-(methylsulphonyl)phenyl]pyridine-2-yl,

5-(4-methoxyphenyl)pyridine-2-yl, 5-(3-methoxyphenyl)pyridine-2-yl,

5-[3-(aminocarbonyl)phenyl]pyridine-2-yl,

5-(4-forfinal)pyridine-2-yl, 5-(3,4-differenl)pyridine-2-yl,

5-(3,5-dimethylisoxazol-4-yl)pyridine-2-yl,

5-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl,

5-(1H-pyrazole-4-yl)pyridine-2-yl,

5-(1-benzofuran-2-yl)pyridine-2-yl,

5-(1,3-benzodioxol-5-yl)pyridin-2-yl,

5-(2-formylphenyl)pyridine-2-yl, 4-(2'-formylphenyl)-4-yl,

5-(1,3-oxazol-2-yl)pyridine-2-yl,

6-(1,3-oxazol-2-yl)pyridine-3-yl, 4-(1,3-thiazol-2-yl)phenyl,

5-(1,3-thiazol-2-yl)pyridine-2-yl,

6-(1,3-thiazol-2-yl)pyridine-3-yl,

6-(1H-imidazol-1-yl)pyridine-3-yl],

5-(1H-imidazol-1-yl)pyridin-2-yl, 6-vinylpyridin-3-yl,

5-(pyrimidine-5-yl)pyridin-2-yl,

5-(pyrimidine-2-yl)pyridine-2-yl,

5-(3-aminocarbonylmethyl)pyridine-2-yl,

4-(1-methyl-1H-imidazol-4-yl)phenyl, 4-(1H-imidazol-4-yl)phenyl,

5-[2-(hydroxymethyl)phenyl]pyridin-2-yl,

2'-(hydroxymethyl)biphenyl-4-yl,

5-{2-[(dimethylamino)methyl]phenyl}pyridine-2-yl,

2'-[(dimethylamino)methyl]biphenyl-4-yl, 5-timetemperature-2-yl,

5-deformalisation-2-yl, 5-methylpyridin-2-yl,

2-methylpyrimidin-5-yl, 2-formerpresident-5-yl,

2-diformylpiridine-5-yl, 2-cryptomaterial-5-yl,

2-cyclopropylamino-5-yl, isothiazol-5-yl,

3-metalization-5-yl, 3-formalisation-5-yl,

4-(dimethylaminoethyl)phenyl, 4-(methylaminomethyl)phenyl,

4-(morpholine-4-ylcarbonyl)phenyl,

4-(piperidine-1-ylcarbonyl)phenyl,

3-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl,

5-(pyrrolidin-1-ylcarbonyl)pyridine-2-yl,

5-(dimethylaminoethyl)pyridine-2-yl,

5-(morpholine-4-ylcarbonyl)pyridine-2-yl, quinoline-4-yl,

6-methoxypyridine-3-yl, 6-(morpholine-4-yl)pyridine-3-yl,

4-(dimethylaminomethyl)phenyl, 5-(dimethylaminomethyl)pyridine-2-yl,

5-(dimethylaminoethyl)pyridine-2-yl,

4-[hydroxy(pyridin-3-yl)methyl]phenyl,

6-[(hydroxy(pyridin-3-yl)methyl]pyridine-3-yl,

6-(dimethylaminoethyl)pyridine-3-yl,

4-(4-hydroxypiperidine-1-ylcarbonyl)phenyl,

4-(4-methoxypiperidine-1-ylcarbonyl)phenyl,

5-(4-methoxypiperidine-1-ylcarbonyl)pyridine-2-yl,

6-(4-methoxypiperidine-1-ylcarbonyl)pyridine-3-yl, phenoxy,

benzyloxy, 2-thienyl, 5-(methoxymethyl)-1,3-thiazol-2-yl,

5-(morpholine-4-ylcarbonyl)-1,3-thiazol-2-yl,

2-isopropyl-1,3-thiazol-5-yl, 2-(methoxymethyl)-1,3-thiazol-5-yl,

5-(methoxymethyl)-1,3-thiazol-2-yl, 4-(pyrimidine-2-yl)phenyl,

4-(pyrimidine-4-yl)phenyl and 5-(methoxymethyl)is iridin-2-yl.

The radicals R3and R4or R5and R6cyklinowanie with the formation of bridged bicyclic system containing ethylene bridge, which includes a system bicyclo[2.2.2]octyl and all its isomeric forms, substituted and all its isomeric forms, which may not necessarily be substituted heterocycle, heteroaryl, hydroxyl, amino, halogen, and those substituents that provide stable molecules, such as C1-C5alkoxy, halogen, halogenated and all those substituents defined above.

The radicals R3and R6cyklinowanie with the formation of bridged bicyclic systems containing a methylene group or a heteroatom selected from the group consisting of N, O and S, which includes norbornanyl and all those stable bridge systems, which also contain heteroatoms, as defined above. They can also be optionally substituted heterocycle, heteroaryl, hydroxyl, amino, halogen, and those substituents that provide stable molecules, such as1-C5alkoxy, halogen, halogenated and all those substituents defined above.

If R7and R8independently selected from alkoxygroup, such as OR, where R can be selected from the group consisting of H, but-2-in-1-yl, benzyl, pyridin-2-ylmethyl, PI is one-3-ylmethyl, propoxy, ethoxy.

If not specified, it is assumed that the compounds represented by the above formula include pharmaceutically acceptable salts, their prodrugs, enantiomers, diastereoisomers, their racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms and their solvate.

The term pharmaceutically acceptable salts include salts of the active compounds, which are obtained from relatively nontoxic acids or bases, depending on the particular substituents disclosed in the present description connections. If the compounds of the present invention contain relatively acidic functional group, can be obtained basically additive salts by contacting the neutral form of such compounds with a sufficient amount of the desired base, or in pure form, or in a suitable inert solvent. Examples of pharmaceutically acceptable basic additive salts include salts of sodium, potassium, calcium, ammonium, organic amine or magnesium, or a similar salt. If the compounds of the present invention contain relatively basic functional group, an acid additive salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, or in pure form, or in a suitable inert the second solvent. Examples of pharmaceutically acceptable acid additive salts include those that are derived from inorganic acids such as hydrochloric, Hydrobromic, nitric, carbonic, phosphoric, partially neutralized phosphoric acid, sulfuric, partially neutralized sulfuric, idiscovered or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids, such as acetic, propionic, somalina, maleic, malonic, benzoic, succinic, cork, fumaric, almond, phthalic, benzolsulfonat, p-toluensulfonate, citric, tartaric, methanesulfonate and the like. They also include salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acid, and the like. Some specific compounds of the present invention can contain both basic and acidic functional groups, which allow you to turn them on or in primary additive salt, or an acid additive salt.

The neutral forms of the compounds of the present invention can be recovered by contacting the salt with a base or acid and separating the source connection in the usual way. The original form of the compound differs from the various salt forms of some the mi physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the original form of connection for the purposes of the present invention.

As mentioned above, some of the compounds of the present invention contain chiral or asymmetric carbon atoms (optical centers) or double bonds; it is assumed that all of the racemates, diastereoisomers, geometric isomers and individual optical isomers are included in the scope of the present invention.

Some of the compounds of formula I, II or III can exist in resolutiony forms as well as solvated forms, including hydrated forms. In General, the solvated forms are equivalent nonsolvated forms and they must be included in the scope of the present invention. Some compounds of the present invention may exist in multiple crystalline or amorphous forms. In General, all physical forms are equivalent for the uses discussed in the present invention, and is included in the scope of the present invention.

In addition to salt forms of the present invention proposed connections that can be in the form of prodrugs. Prodrugs disclosed in the description of compounds are those compounds that readily undergo chemical changes under physiological conditions, which then leads to the formation of compounds of the present invention. Additionally, prodrugs can be converted into compounds of the present invention, using chemical or biological methods in an ex vivo environment. For example, prodrugs can be slowly converted to compounds of the present invention being placed in a transdermal patch with an appropriate enzyme or chemical reagent.

Compounds of the present invention can be obtained in a number of ways, well known to experts in the field of organic synthesis. Various intermediate compounds 3-aminopyrrolidine can be obtained from commercial sources or synthesized using methods presented in figures 1-6. Tert-butyl TRANS-3-amino-4-hydroxypyrrolidine-1-carboxylate 1-4 can be synthesized on the basis of tert-butyl 2,5-dihydro-1H-pyrrol-1-carboxylate 1-1 (Scheme 1). In the epoxidation 1-1, using an oxidant such as m-chloroperoxybenzoic acid (mCPBA), with subsequent ring opening by benzylamino or sodium azide, receive tert-butyl TRANS-3-benzylamino-4-hydroxypyrrolidine-1-carboxylate or tert-butyl TRANS-3-azido-4-hydroxypyrrolidine-1-carboxylate 1-3. In the hydrogenation using a catalyst such as palladium on coal or palladium hydroxide, get the connection 1-4.

Scheme 1

Benzyl-TRANS-3-amino-4-hydroxypyrene the Jn-1-carboxylate 2-3 possible to synthesize, using the sequence of reactions presented in scheme 2. In the epoxidation benzyl-3-pyrrolin-1-carboxylate 2-1, using an oxidant such as mCPBA, followed by ring opening with ammonium hydroxide, get a connection 2-3.

Scheme 2

The introduction of alkyl 4-hydroxy near pyrrolidine can be performed using the sequence of reactions presented in scheme 3. By reaction of intermediate compounds 1-3 with N-(benzyloxycarbonyloxy)succinimide (CbzOSu), get the connection 3-1. After alkylation of the hydroxyl group of alkylhalogenide using sodium hydride, benzyl and Cbz group is removed by hydrogenation using a palladium catalyst such as palladium hydroxide, and get derivatives of 3-alkoxyamine formula 3-3.

Scheme 3

Alternatively, alkylation of 4-hydroxy near pyrrolidine can be performed using the method presented in scheme 4. In the result of the introduction of the Boc protective groups in the intermediate compound 2-3, followed by alkylation with alkylhalogenide using sodium hydride as the base, get the intermediate connection 4-2. Processing the connection 4-2 acid, such as HCl in dioxane or TFA obtain compounds of formula 4-3.

Scheme 4

Derivatives of spiropyran, such as the compound of formula 5-6, it is possible to synthesize, using the sequence of reactions shown in the scheme 5. Introducing Cbz protective groups in the intermediate compound 1-4, followed by oxidation using an oxidizing agent, such as a complex of sulfur trioxide and pyridine, receive ketone 5-2. As a result of merger of allylanisole to the ketone 5-2 receive tertiary alcohol 5-3. Olefin in connection 5-3 turn into alcohol, and processing 9-BBN/H2About2. After processing the obtained alcohol methanesulfonamido, the reaction mixture is refluxed, carrying out ring closure and receiving the product 5-5. Result from the removal of Cbz using hydrogenation, get the connection 5-6.

Scheme 5

5-alkyl substituted derivatives of 3-aminopyrrolidine, such as the compound of formula 6-5, can be obtained by using the sequence of reactions presented in scheme 6. Connection 6-1, which is synthesized in accordance with methods disclosed in the literature (T. Rosen, et al. J. Med. Chem. 1988, 31, 1598-1611), is subjected to reaction combinations Mitsunobu with benzoic acid, receiving ester 6-2. As a result of hydrolysis of ester using the K2CO3/MeOH, get alcohol 6-3. In the reaction of ethanol with methanesulfonamido with subsequent processing by the scientists nelfinavir sodium azide at elevated temperature, get etidocaine 6-4. The transformation of azide in connection 6-4 in the amino group with the use of hydrogenation and the use of a catalyst, such as Pd-C, gives the compounds of formula 6-5.

Scheme 6

Various derivatives of cyclohexanone can be synthesized using the sequence of reactions represented in the diagrams 7-19. The compounds of formula 7-2 can be obtained by joining arylalkylamine or aryl halides/BuLi to 1,4-cyclohexandione 7-1. Alternatively, compounds 7-2 can be synthesized by attaching arylalkylamine, aryl halides/BuLi or heteroaryl/Cityterminalen to monoelemental 1,4-cyclohexandione 7-3, followed by treatment of the acid obtained Catala 7-4.

Scheme 7

Derivatives of 4-arylcyclohexylamine formula 8-3 and 8-5 can be synthesized using the sequence of reactions presented in scheme 8. The intermediate connection 7-4 processed dehydrating agent such as thionyl chloride/pyridine, followed by reduction of the obtained olefin by hydrogenation using a catalyst such as Pd-C or PtO2. Processing the intermediate 7-4 DAST makes the hydroxy-group of the group of fluorine. In the removal of ketala connections 8-2 and 8-4 by processing Ki is lotay get the ketones of formula 8-3 and 8-5.

Scheme 8

Alternatively, the compounds of formula 8-3 can be obtained by using the sequence of reactions presented in scheme 9. Monogamia cyclohexane-1,4-diol 9-1 tert-butyldimethylsilyl (TBDMS), followed by metilirovaniem results nelfinavir 9-3. Replacement nelfinavir by heteroaryl, such as pyrazole, imidazole, triazole or tetrazole, leads to the production of intermediate compounds 9-4. Result from the removal of the TBDMS group using TBAF, followed by oxidation in Turn receive the compounds of formula 8-3.

Scheme 9

Ar represents a substituted pyrazole, imidazole, triazole or tetrazole.

Alternatively, the compounds of formula 8-3 can be synthesized according to scheme 10. In the recovery of the ketone 7-3 using a reducing agent such as sodium borohydride is formed alcohol 10-1, which in turn mesilate 10-2, by processing methanesulfonanilide. Substitution nelfinavir 10-2 a heterocycle, such as pyrazole, imidazole, triazole or tetrazole, leads to the production of intermediate compounds 10-3, which is transformed into the compounds of formula 8-3 by treatment with acid, such as HCl.

Scheme 10

Ar represents a substituted pyrazole, imidazole, triazole or tetrazole.

4-Hydroxy-4-(Pirim the DIN-2-yl)cyclohexanone 11-4 possible to synthesize, using the sequence of reactions presented in scheme 11. 2-Chloropyrimidine 11-1 processed LDA/(Bu)3SnH, getting derived channelmarketing 11-2. As a result of processing the connection 11-2 n-butyllithium and subsequent quenching by monoelemental 1,4-cyclohexandione 7-3 receive intermediate ketal 11-3. Removal of protective groups Catala acid, such as HCl, yields a ketone 11-4.

Scheme 11

Derivatives of spirocyclohexane formula 12-3 can be synthesized using the sequence of reactions presented in scheme 12. As a result of processing R-substituted 2-bromobenzylamine alcohol 12-1 n-butyllithium and adding the resulting solution to monoelemental 1,4-cyclohexandione 7-3 receive adduct 12-2. The process of joining 12-2 TFA/CH2Cl2leads to the closure ring and the simultaneous removal of ketala, resulting in spirochete 12-3.

Scheme 12

Spirometry formulas 13-6 and 13-8) can be obtained using the sequence of reactions presented in scheme 13. After protection of the ketone in connection 13-1 using ethylene glycol/TMSCl complex fluids 13-2 reduced to diol 13-3 using a reducing agent such as sociallyengaged. The obtained diol turn in dimesylate 13-4, which ACC is Laut interaction with derivatives of indene, using LHMDS and receiving the intermediate connection of spyroidea 13-5. In the hydrogenation of compounds 13-5 get derived spiropentane 13-7. In the result of the removal of the protective groups Catala in connection 13-5 and 13-7 using acids such as HCl, get the appropriate ketones 13-6 and 13-8.

Scheme 13

Figure 14 shows the synthesis of compounds of formula 14-4. As a result of processing R-substituted 4-cyanoferrate n-butyllithium with subsequent quenching by monoelemental 1,4-cyclohexandione 7-3 receive the intermediate connection 14-1. After hydrolysis of ceanography base interact obtained carboxylic acid with an amine using a binding agent, such as BOP, and getting amide 14-3. As a result of processing Catala 14-3 acid get ketones of the formula 14-4.

Scheme 14

The compounds of formula 15-4 can be obtained by using the sequence of reactions represented in scheme 15. As a result of dehydration of the intermediate hydroxycodone 14-1 by treatment with a mixture of thionyl chloride/pyridine get olefinic intermediate compound 15-1. As a result of hydrolysis of cyano in connection 15-1 using the base and re-attaching the obtained carboxylic acid to amine, get amide intermediate compound 15-3. Then p is to obtain the compounds of formula 15-4 by hydrogenation of compound 15-3 using a catalyst, such as Pd-C, followed by treatment with acid.

Scheme 15

Introduction of the substituent in the aryl or heteroaryl in position 4-cyclohexanone can be made based on the intermediate Catala 16-1, where X represents bromine or iodine. As a result of processing Catala 16-1 butyllithium with subsequent quenching electrophilic compound such as alkylhalogenide, aldehyde, ketone, isocyanate, chloroformate or carbonate, a combination of Suzuki connections 16-1 with Bronevoy acid or by reaction of the compound 16-1 with ZnX (X is a halide) receive R-substituted arylphosphonate 16-2. Alternatively, the compounds of formula 16-2 can be obtained by transforming 16-1 in complex baranovy ether, followed by reaction mix Suzuki received broowaha of ester and RX (X is Br, I). After processing Catala 16-2 acid get ketone 16-4.

Scheme 16

If you Ar in the compound 16-4 represents a thiazole residue, the introduction of the R substituent can be performed using the sequence of reactions presented on figures 17-19. 5-R-substituted derivatives of 1,3-thiazol-2-yl of the formula 17-5 can be obtained by using the sequence of reactions represented in scheme 17. As a result of processing 1,3-thiazole n-butyllithium with subsequent quenching by monoelemental 1,4-cyclohexandione 7-3 education is : intermediate connection 17-2. Litrovaya in position 5 of the thiazole followed by quenching electrophilic compound such as alkylhalogenide, isocyanates, carbon dioxide, aldehyde or ketone, leads to the production of intermediate compounds 17-4. Turning Catala in ketone 17-5 carried out by treatment with acid.

Scheme 17

Synthesis of 2-R-substituted derivatives of 1,3-thiazol-5-yl of the formula 18-3 includes litrovaya 18-1 with subsequent quenching by monoelemental 1,4-cyclohexandione and converting the received Catala in the ketone.

Scheme 18

Alternatively, the compounds of formula 18-3 can be obtained by using the sequence of reactions represented in scheme 19. Litrovaya 2-trimethylsilyl-protected thiazole 19-1 with subsequent quenching compound 7-3 gives an intermediate compound 19-2. After removal trimethylsilyl groups with TBAF, litrovaya connection 19-3 with subsequent quenching electrophilic compound such as alkylhalogenide, aldehyde, ketone, isocyanate, chloroformate or carbonate, yields a 5-R-substituted derivative of thiazole 19-4. After processing 19-4 acid get ketone 18-3.

Scheme 19

The final compounds of formula I can be obtained by combining the intermediate compound 3-aminopyrrolidine with intermediate connections is cyclohexanone, as shown in figure 20. The combination of derivatives of 3-aminopyrrolidine 20-1 with a carboxylic acid of the formula 20-2 using a coupling agent such as BOP, chloroformate or EDC, leads to the formation of amide 20-3. After removal of the protective group (P) of nitrogen pyrrolidine acid or hydrogenation reductive amination of the resulting pyrrolidine 20-4 ketone of formula 20-5 using a reducing agent such as triacetoxyborohydride sodium, or catalytic hydrogenation gives the target compounds of formula 20-6. Alternatively, the compounds of formula 20-6 can be obtained by reductive amination of compound 20-3 (P is Cbz, Bn) a ketone of formula 20-5 by hydrogenation using a catalyst such as Pd-C or Pd(OH)2.

Scheme 20

Alternatively, different final compounds of formula I can be synthesized using the sequence of reactions represented in scheme 21. In the reductive amination of 3-tert-butoxycarbonylmethylene 21-2 ketone 21-1 (M. Povarny et al. Tetrahedron Lett. 1984, 25, 1311-1312) using a reducing agent such as triacetoxyborohydride sodium, receive intermediate compound 21-3. The process of joining 21-3 acid in aqueous solution turns ketal in ketone, and about which simultaneously removes the Boc group. The obtained amine is subjected to interaction with di-tert-BUTYLCARBAMATE, receiving Boc-protected intermediate compound aminoketone 21-4. Attaching Arild or ArX/BuLi to the ketone 21-4 formed alcohol 21-5. Removal of Boc using acids, such as 4h. HCl in dioxane, followed by the accession of the obtained amine 21-6 to the carboxylic acid of the formula 20-2 using a coupling agent such as BOP, gives the target compounds of formula 21-7.

Scheme 21

Alternatively, different final compounds of formula I can be obtained by using the sequence of reactions represented in scheme 22. Attaching Arild or ArX/BuLi to the ketone 21-1 (M. Povarny et al. Tetrahedron Lett. 1984, 25, 1311-1312) get alcohol 22-1. Ketal in 22-1 converted into ketone, treating acid, such as HCl in aqueous solution. The resulting ketone 22-2 is subjected to reductive aminating intermediate connection pyrrolidine 20-4 using a reducing agent such as triacetoxyborohydride sodium, receiving the target compounds of formula 22-3.

Scheme 22

Alternatively, various compounds of formula I can be synthesized using the sequence of reactions represented in scheme 23. Oxidation by Turn 5-norbornene-2-ol (23-1) (G.T. Wang et al. J. Org. Chem. 2001, 66, 2052-2056) with the following accession Arild or ArX/BuLi to the obtained ketone 23-2 leads to the formation of the tertiary alcohol 23-3 (C.J. Collins, B.M. Benjamin, J. Am. Chem. Soc. 1967, 89, 1652-1661). Olefin in connection 23-3 turn into alcohol 23-4 , treating a mixture of borane/hydrogen peroxide (C. J. Collins, B.M. Benjamin, J. Org. Chem. 1972, 37, 4358-4366). As a result of oxidation by the Turn of the alcohol produced ketone 23-5, which is subjected to reductive aminating derived pyrrolidine 20-4 using a reducing agent such as triacetoxyborohydride sodium, and get the target compounds of formula 23-6.

Scheme 23

Alternatively, various compounds of formula I can be synthesized using the sequence of reactions represented in scheme 24. The interaction of TRANS-4-aminocyclohexanol 24-1 with di-tert-BUTYLCARBAMATE leads to the production of TRANS-4-tert-butoxycarbonylmethylene 24-2, which is subjected to oxidation reaction in Turn, receiving ketone 24-3. In the reductive amination of the ketone 24-3 derived pyrrolidine 20-4 using a reducing agent such as triacetoxyborohydride sodium, receive intermediate connection 24-4. After removal of the Boc in connection 24-4 acid, such as 4h. HCl in dioxane obtained Amin 24-5 acelerou arylcarbamoyl the acid chloride or arylcarbamoyl acid with coupling agent such as BOP, and get the target compounds of formula 24-6

Scheme 24

Alternatively, the compounds of formula I can be obtained by using the sequence of reactions represented in scheme 25. In the recovery of the intermediate ketone 7-2 using a reducing agent such as sociallyengaged or sodium borohydride receive CIS-diol 25-1. Selective metilirovanie can be done by processing the compound 25-1 one equivalent of methanesulfonanilide, receiving TRANS-mesilate 25-2. Replacement nelfinavir derived 3-aminopyrrolidine, such as 21-2, leads to the production of TRANS-1,4-disubstituted cyclohexane derivative 25-3. After removal of Boc groups with acid followed by reaction of the combination of the obtained amine with a carboxylic acid of the formula 20-2 receive the target compounds of formula 25-5.

Scheme 25

Alternatively, the compounds of formula I can be synthesized using the sequence of reactions represented in the diagrams 26-27. Intermediate compound 26-2 can be obtained in three ways (Scheme 26). Method 1 involves the reaction mix Mitsunobu alcohol 25-1 with succinimido 26-1, which is obtained by processing D-asparagine is a mixture of thionyl chloride/methanol (etherification) followed by cyclization with base, such as NaOH. Method 2 involves replacing intermediate the first connection nelfinavir 25-2 succinimido 26-1 in the presence of a base, such as CsF. In method-3 mesilate 25-2 replace sodium azide and the resulting intermediate etidocaine 26-3 reduced to amine (26-4) by hydrogenation. The ring opening of the anhydride of D-aspartic acid 26-5 using 26-4 with the subsequent closure ring with carbonyldiimidazole leads to the production of intermediate compound 26-2.

Scheme 26

The transformation of the intermediate compound 26-2 in the final products 27-3 can be performed using the sequence of reactions presented in figure 27. After removal of the Cbz group 26-2 in the hydrogenation of succinimide 27-1 restore to pyrrolidine, processing borane, followed by the destruction complex by hydrogenation. In the reaction of a combination of amine 27-2 and carboxylic acids of the formula 20-2 using a coupling agent such as BOP, chloroformate or EDC, get the final compounds of formula 27-3.

Scheme 27

Alternatively, the final compounds of formula I can be obtained by using the sequence of reactions represented in scheme 28. If Ar is the residue of cyclohexyl in 28-1 contains a group of iodine, iodine can be turned into the ether Bronevoy acid. Carrying out the reaction mix of the received broadcast Bronevoy acid and ArX (X is Br, I) in the presence of PdCl2(dppf)receive R-substituted with the organisations formula 28-2. Alternatively, the compounds of formula 28-2 can be obtained by carrying out the reaction mix Suzuki Bronevoy acid compound 28-1.

Scheme 28

Alternatively, intermediate compounds of formula 25-4 can be obtained by using the sequence of reactions represented in scheme 29. Restoring N-Cbz-protected dimethyl ether of D-aspartic acid 29-1 using a reducing agent such as LAH, followed by treatment of the diol obtained by methanesulfonamido, get dimesylate 29-2. Processing the intermediate amine compound 26-4 dimesylate 29-2 in the presence of NaI and "proton sponge", are derived pyrrolidine 29-3. Result from the removal of Cbz group in connection 29-3 by hydrogenation using a catalyst such as Pd-C, obtain the intermediate compound of formula 25-4.

Scheme 29

Alternatively, the compounds of formula I can be obtained by using the sequence of reactions represented in scheme 30. In the reductive amination derived pyrrolidine formula 30-1 derived ketone of formula 30-2 using a reducing agent such as triacetoxyborohydride sodium, receive intermediate connection 30-3. Removing the protective group P (P is Boc or Cbz) and the subsequent implementation of the PE the functions of the combination of the obtained amine and carboxylic acid of the formula 20-2 leads to the production of the compounds of formula 30-5.

Compounds of the present invention may be modulators of MCP-1 receptor, such as antagonists and may have the ability to inhibit the binding of MCP-1 to its receptors. Surprising that the compounds block the migration of T cells in vitro and have a strong impact on the attraction of inflammatory cells in many models of inflammatory diseases. Therefore, the compounds of formula I are useful as agents for the treatment of inflammatory diseases, especially those associated with the accumulation of lymphocytes and/or monocytes, such as arthritis, rheumatoid arthritis, multiple sclerosis, neuropathic pain, atherosclerosis and transplant rejection. In addition, these compounds can be used to treat disorders of the type of allergic hypersensitivity, such as asthma and allergic rhinitis, which is characterized by activation of basophils and recruitment of eosinophils, as well as for treatment of restenosis and acute or chronic immune disorders.

Modulation of activity of receptors chemokines, as used in the context of the present invention, includes antagonism, agonism, partial antagonism and/or partial agonism activity associated with specific receptors chemokines, preferably with CCR2 receptor. The term composition in the sense used in this description, includes p is oduct, contains specific ingredients in specific amounts, as well as any product that is obtained, directly or indirectly, as the result of a combination of specific ingredients in specific amounts. The term pharmaceutically acceptable mean carrier, diluent or excipient, which should be compatible with other ingredients of the composition and should not have a harmful impact on their host recipient.

The compounds of formula I of the present invention and compositions containing them can be used to modulate the activity of receptors chemokines, especially CCR2. Accordingly, the compounds of the present invention are such compounds which inhibit at least one function or characteristic CCR2 protein mammals, such as CCR2 protein man. The ability of compounds to inhibit this function can be demonstrated by analysis of the binding (for example, binding of a ligand or promoter binding), analysis of signaling (e.g., activation of G protein mammals, induction of rapid and transient increase in the concentration does not contain cytosole calcium) and/or function of cell reactions (e.g., stimulation of chemotaxis, associate or selection of a mediator of inflammatory leukocytes).

Further, the present invention is illustrated which is associated with the following examples, which in no way should be considered as limiting.

EXAMPLES

Used the following reagents and solvents can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). The results of the mass spectrometric studies are presented as the ratio of mass to charge, and then providing relative content of each of the ions (in parentheses). The tables contain the same value for M+H (or, if specified, M-H) ion containing most common atomic isotopes. The isotopic composition corresponds to the expected formula in all cases.

Example 1

Stage A

Tert-butyl-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate.

To a solution of 3-chloroperoxybenzoic acid (13,0 g, 75,3 mmol) in CH2Cl2(50 ml), cooled in a bath with ice, added dropwise a solution of tert-butyl-2,5-digidroergotoksina (5 g, 29.5 mmol) in CH2Cl2(50 ml). The mixture is stirred in a bath with ice for 30 minutes and at room temperature over night. The hard part is filtered off. The filtrate is washed twice with a solution of Na2S2About3, NaHCO3and saturated salt solution, dried over MgSO4and concentrate. The result chromatography on silica gel, elwira 20% EtOAc in hexano, gain of 4.75 g of the desired compound in the form of oil. MS Vice the Leno: (M+H) +186, found: 186.

Stage B

Tert-butyl(3S,4S)-3-(benzylamino)-4-hydroxypyrrolidine-1-carboxylate.

A solution of epoxide (4.6 g, 24,9 mmol) from step A and benzylamine (5,2 g, to 48.6 mmol) in ethanol was stirred at 85°C during the night. The solvent is removed by concentration under reduced pressure, obtaining a solid substance. The solid is washed with a mixed solvent consisting of 50% mixture of EtOAc/hexane, obtaining 6.2 g of the desired compound. MS calculated: (M+H)+293, found: 293.

Stage C

Tert-butyl(3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate.

A solution of intermediate compound (5.4 g, 18.5 mmol) from step B, Pd(OH)2/C (0.3 g) in MeOH (200 ml) is stirred in hydrogen atmosphere at a pressure of 55 psi overnight. The catalyst is filtered off, the filtrate concentrated, gaining 3.7 g of the desired product as a solid. MS calculated: (M+H)+203, found: 203.

Stage D

Tert-butyl(3S,4S)-3-hydroxy-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-carboxylate.

To a solution of 3-(trifluoromethyl)benzoyl chloride (21 g, by 98.7 mmol) in toluene (400 ml), cooled in a bath with ice, add a solution of the hydrochloride of the methyl complex ester of glycine (11,5 g, 94 mmol) and triethylamine (100 ml) in the e (210 ml) and THF (65 ml). After stirring at room temperature for 8 hours the two phases are separated. The aqueous layer was extracted with EtOAc. The combined organic phases are washed with NaHCO3and saturated salt solution, dried over MgSO4and concentrate. The residue is placed in MeOH (150 ml) and THF (300 ml). Add 2n. NaOH solution (300 ml). The mixture is stirred at room temperature overnight, acidified with concentrated HCl (pH 2) and twice extracted with EtOAc. The organic phase is washed with saturated salt solution, dried over MgSO4and concentrate. As a result of crystallization from a mixture of EtOAc/hexane obtain 18 g of the desired product (3-triphtalocyaninine)acetic acid in the form of solids. MS calculated: (M+H)+248, found: 248.

To the solution obtained above carboxylic acid (3.2 g, 13 mmol) and amerosport (2,02 g, 10 mmol), obtained in stage C in DMF (15 ml), cooled in a bath with ice, add NEt3(of 4.2 ml, 30 mmol) and then BOP (5.8 g, 13 mmol). The mixture is stirred at room temperature overnight. To the mixture add salt solution (100 ml). The solution is twice extracted with EtOAc. The organic phase is washed with NaHCO3and saturated salt solution, dried over MgSO4and concentrate. The result chromatography on silica gel, elwira first with a mixture of 70% EtOAc/hexane and then 20% MeOH/EtOAc, obtain 3.7 g of the desired product as firmly what about the substance. MS calculated: (M+H)+432, found: 332 (M+H-Boc)+.

Stage E

N-(2-{[(3S,4S)-4-hydroxypyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

The product (3.7 g, 8.6 mmol) from step D was dissolved in CH2Cl2(10 ml) and TFA (10 ml). After stirring at room temperature for 40 minutes, the volatile compounds are removed in the concentration under reduced pressure, to obtain the desired product in the form of oil. MS calculated: (M+H)+332, found: 446 (M+H+TFA)+.

Stage F

N-(2-{[(3S,4,S)-1-cyclohexyl-4-hydroxypyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

To a solution of intermediate compound (444 mg, 1 mmol) from step E and cyclohexanone (196 mg, 2 mmol) in THF (5 ml) add NEt3(of 0.42 ml, 3 mmol) and then Na(OAc)3BH (424 mg, 2 mmol). The mixture is stirred at room temperature overnight and poured into a solution of NaCl. The resulting solution was twice extracted with EtOAc. The combined EtOAc layers are washed with NaHCO3and saturated salt solution, dried over MgSO4and concentrate. The result chromatography on silica gel obtain 324 mg of the desired product. MS calculated: (M+H)+414, found: 414.

Example 2

N-(2-{[(3S,4S)-4-(but-2-in-1 yloxy)-1-cyclohexylpiperidine-3-yl]amino}-2-oxoethyl)-3-(triptime the Il)benzamide.

To a solution of compound of example 1 (41 mg, 0.1 mmol) in THF (3 ml), cooled in a bath with ice, add NaH (16 mg, 0.4 mmol) and then 2-butylbromide of 9.6 μl, 0.11 mmol). After stirring in a bath with ice for 3 hours add saturated NH4Cl and then EtOAc. The EtOAc layer emit, washed with saturated salt solution, dried over MgSO4and concentrate. In the purification using HPLC with reversed-phase receive specified in the title compound in the form of powder. MS calculated: (M+H)+466, found: 466.

Example 3

N-(2-{[(3S,4S)-4-(benzyloxy)-1-cyclohexylpiperidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the connection produced by alkylation of the compound of example 1 benzylbromide with subsequent use of the method disclosed in example 2. MS calculated: (M+H)+504, found: 504.

Example 4

N-(2-{[(3S,4S)-1-cyclohexyl-4-(pyridine-2-ylethoxy)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the connection receives the same way as the example 3. MS calculated: (M+H)+505, found: 505.

Example 5

N-(2-{[(3S,4S)-1-cyclohexyl-4-(pyridine-3-ylethoxy)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the connection receives the same way as the example 3. MS calculated: (M+H)+505, found: 505.

Example 6

Stage And

4-hydroxy-4-phenylcyclohexanone.

To a solution of 1,4-cyclohexandione (6,72 g, 60 mmol) in THF (100 ml), cooled in a bath with ice, add a 1M solution of phenylmagnesium in THF (20 ml, 20 mmol). The mixture is stirred at room temperature for 3 hours and quenched with a solution of NH4Cl. The resulting solution was thrice extracted with EtOAc. The combined organic phases are washed with saturated salt solution, dried over MgSO4and concentrate. The result chromatography on silica gel, elwira a mixture of 1:1 EtOAc/hexane get 0,83 g (22%) specified in the connection header. MS calculated: (M+H)+190, found: 173 (M+H-H2O)+.

Stage B

N-(2-{[(3S,4S)-4-hydroxy-1-(4-hydroxy-4-phenylcyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

To a solution of the ketone from step A (198 mg, 1.1 mmol) and intermediate compounds pyrrolidine with stage E of example 1 (331 mg, 1 mmol) in THF added Na(OAc)3BH (424 mg, 2 mmol). The mixture is stirred at room temperature overnight and poured into a solution of NaCl. The resulting solution was twice extracted with EtOAc. The combined EtOAc layers are washed with NaHCO3and a saturated solution of the m salt, dried over MgSO4and concentrate. The result chromatography on silica gel 150 mg fast coming isomer of {TRANS-isomer, MS calculated: (M+H)+506, found: 506) and 130 mg slowly coming isomer (CIS-isomer, MS calculated: (M+H)+506, found: 506).

Example 7

Stage A

8-pyridin-2-yl-1,4-dioxaspiro[4,5]Decan-8-ol.

To a solution of 2-bromopyridine (14 g and 88.6 mmol) in anhydrous ether (300 ml), cooled to -78°C, slowly add a solution of 2,5M, utility (36 ml). After the addition stirring is continued at -78°C for 1 hour. Slowly add a solution of monoelemental 1,4-cyclohexandione (15 g, 96 mmol) in anhydrous ether (300 ml). After complete addition, the mixture is left to warm to 0°C and stirring is continued for 1 hour. The reaction is quenched by adding an aqueous solution (100 ml) ameriglide (4.5 g). The organic phase is isolated and the aqueous phase is extracted with methylene chloride 4 times. The combined organic phases are dried over MgSO4and concentrate. As a result of crystallization from EtOAc obtain 7 g of the desired product. The mother liquor is purified on silica gel, elwira a mixture of 10% MeOH/EtOAc, receiving 3 g of the desired product. MS calculated: (M+H)+236, found: 236,0.

Stage B

4-hydroxy-4-pyridine-2-illlogical.

Obtained you the e product is dissolved in THF (30 ml) and 3n. HCl solution in water (30 ml). The mixture is stirred at 50°C for 3 hours. After cooling to room temperature NaHCO3add to the solution with stirring until it stops bubbling. The organic phase is isolated and the aqueous layer was thrice extracted with THF. The combined organic phases are dried over MgSO4and concentrate. The residue is triturated with EtOAc, getting 5.5 g specified in the connection header. MS calculated: (M+H)+192, found: 192.

Stage C

N-(2-{[(3S,4S)-4-hydroxy-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

In the reductive amination of the ketone from step B derived pyrrolidine with stage E of example 1 using the same method of example 6, receive specified in the header connection. MS calculated: (M+H)+507; found: 507.

The following compounds produced by the methods disclosed in examples 6 and 7.

Example No.RMS (M+H)+
84-were520
93-were 520
102-were520
114-bromophenyl584
123-bromophenyl584
134-chlorophenyl539
143-chlorophenyl539
154-triptoreline574
163-triptoreline574
172-triptoreline574
184-methoxyphenyl536
193-methoxyphenyl536
202-methoxyphenyl536
21pyridine-3-yl507
22 pyridine-4-yl507
236-methoxypyridine-3-yl537
246-ethoxypyridine-3-yl551
253,4-methylenedioxyphenyl550

Example 26

N-(2-{[(3S,4S)-1-(4-cyano-4-phenylcyclohexyl)-4-hydroxypyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained reductive amination of 4-cyano-4-phenylcyclohexanone intermediate compound from step E of example 1 using the same method of example 6. MS calculated: (M+H)+515, found: 515.

Example 27

Stage A

8-(4-forfinal)-1,4-dioxaspiro[4,5]Dec-7-ene.

To a solution of monoelemental 1,4-cyclohexandione (8.1 g, 50 mmol) in THF (20 ml) at 10°C add a 1M solution of 4-performancebased in THF (65 ml, 65 mmol). The resulting mixture was stirred at room temperature for 2 hours before quenched with saturated solution of NH4Cl. The solution thrice extracted with EtOAc. The combined organic phases are washed with saturated salt solution, dried over MgSO4 and concentrate. The residue is placed in toluene (80 ml). Add monohydrate p-toluensulfonate acid (80 mg). The mixture is stirred while boiling under reflux with removal of water using a trap Dean-stark for 2 hours. The resulting solution was washed with saturated NaHCO3and saturated salt solution, dried over MgSO4and concentrate. In the purification on silica gel, elwira 5%, 10% and then 15% EtOAc in hexano get mentioned in the title compound (8.8 g, 75%) as a solid. MS calculated: (M+H)+235, found: 235.

Stage B

8-(4-forfinal)-1,4-dioxaspiro[4,5]decane.

The intermediate compound from step A (8.8 g, of 37.6 mmol) is dissolved in toluene and add PtO2(0.5 g). The resulting mixture was stirred in an atmosphere of hydrogen at atmospheric pressure overnight. The catalyst is filtered off and the filtrate removed under reduced pressure. Using flash chromatography on silica gel, elwira 5% and then 10% EtOAc in hexano get mentioned in the title compound (8.6 g, 98%) as oil. MS calculated: (M+H)+237, found: 237.

Stage C

4-(4-forfinal)cyclohexanone.

A solution of the intermediate from step B (8.6 g, of 36.5 mmol) in toluene (40 ml), THF (20 ml) and 10% H2SO4in water (25 ml) stirred at boiling the situation under reflux overnight. After cooling to room temperature the organic layer emit, washed with saturated salt solution, dried over MgSO4and concentrate. Using flash chromatography on silica gel, elwira 5% and then 10% EtOAc in hexano get mentioned in the title compound (6.0 g, 86%) as oil. MS calculated: (M+H)+193, found: 193.

Stage D

N-[2-({(3S,4S)-1-[4-(4-forfinal)cyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained reductive amination of the ketone from step C of intermediate compound from step E of example 1 using the same method of example 6. MS calculated: (M+H)+508, found: 508.

Example 28

Stage A

2-(l,4-dioxaspiro[4,5]Dec-7-EN-8-yl)pyridine.

Ketal (2 g, 8.5 mmol)obtained in stage A of example 7, is dissolved in pyridine (40 ml) and the solution is cooled in a bath with ice. Add SOCl2(3.1 ml, to 42.5 mmol). The solution is allowed to warm to room temperature and stirring is continued over night. The reaction is quenched by adding ice and then water. The resulting solution was thrice extracted with EtOAc. The combined EtOAc layers dried over MgSO4and concentrate. Using flash chromatography on silica gel, elwira mixture from 0 to 55% EtOAc/g is Xana, obtain 1.54 g specified in the connection header. MS calculated: (M+H)+218, found: 218.

Stage B

2-(l,4-dioxaspiro[4,5]Dec-8-yl)pyridine.

Olefin (1.54 g, 7.1 mmol)obtained above, dissolved in MeOH (40 ml) and added Pd/C (160 mg). System hydronaut at 53 psi for 3 hours. The catalyst is filtered off and the filtrate is concentrated and receiving specified in the header connection. MS calculated: (M+H)+220, found: 220.

Stage C

4-pyridin-3-illlogical.

The above ketal is converted into a ketone, treating aqueous HCl, the way opened for stage B of example 7. MS calculated: (M+H)+176, found: 176.

Stage D

N-(2-{[(3S,4S)-4-hydroxy-1-(4-pyridine-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained reductive amination obtained above ketone derivative of pyrrolidine obtained in stage E of example 1 using the same method of example 6. MS calculated: (M+H)+490, found: 490.

Example 29

Stage A

4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol.

To a solution of 1,4-cyclohexanediol (5 g, 43 mmol), imidazole (2,92 g, 43 mmol) and NEt3(7 ml) is CH 2Cl2(100 ml), cooled in a bath with ice, add tert-butyldimethylsilyloxy (6,47 g, 43 mmol). The mixture is stirred at room temperature overnight. Add water and the organic phase is isolated. The aqueous layer was extracted with EtOAc. The combined organic phases are dried over MgSO4and concentrate. Using a chromatographic column filled with silica gel, elwira a mixture of 3:1 EtOAc/hexane receive specified in the header connection (4,2 g, 42%) as oil. MS calculated: (M+H)+231, found: 231.

Stage B

4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanesulfonic.

To a solution of silyl intermediate compound obtained in stage A, in

CH2Cl2(40 ml), cooled in a bath with ice, add NEt3(6 ml), then methanesulfonanilide (1.8 ml). After stirring at room temperature for 2 hours the solution was diluted with water. The organic phase is isolated and the aqueous layer was extracted with EtOAc. The combined organic phases are dried over MgSO4and concentrate. In the purification on silica gel, elwira a mixture of 2:1 EtOAc/hexane get mentioned in the title compound (4.6 g, 82%) as oil. MS calculated: (M+H)+309, found: 309.

Stage C

1-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-3-(triptime the l)-1H-pyrazole.

To a solution of 3-trifluoromethyl-1H-pyrazole (1.0 g, 7,35 mmol) in DMF (10 ml), cooled in a bath with ice, add NaH (0.3 g, 60% in mineral oil). The mixture is stirred for 10 minutes before add mesilate (1.13 g, 3,68 mmol) from step B in DMF (5 ml). Stirring is continued at room temperature for 1 hour and then at 100°C during the night. After the solution is cooled to room temperature, it was poured into ice-cold water and thrice extracted with EtOAc. The combined extracts washed with saturated salt solution, dried over MgSO4and concentrate. Using purification on silica gel, elwira a mixture of 5:1 EtOAc/hexane get mentioned in the title compound (0.56 g, 44%) as oil. MS calculated: (M+H)+349, found: 349.

Stage D

4-[3-(trifluoromethyl)-1H-pyrazole-1-yl]cyclohexanol.

The intermediate compound (0.56 g, 1.6 mmol) from step C was dissolved in CH2Cl2(10 ml) and added dropwise 1M solution of TBAF in CH2Cl2(5 ml). After stirring at room temperature for 2 hours the solution was diluted with CH2Cl2. The resulting solution was washed with saturated salt solution, dried over MgSO4and concentrate. Using purification on silica gel, elwira a mixture of 2:1 EtOAc/hexane get mentioned in the title compound (0.27 g, 71%) as oil. MS calculated: (M+H) +235, found: 235.

Stage E

4-[3-(trifluoromethyl)-1H-pyrazole-1-yl]cyclohexanone.

To a solution of oxalicacid (0.25 ml, is 2.88 mmol) in THF (10 ml), cooled to -78°C, add DMSO (0.3 ml, to 4.23 mmol). The mixture is stirred for 20 minutes and add a solution of alcohol from step D (0.27 g, 1.15 mmol) in THF (2 ml) and then NEt3(1 ml, 7.1 mmol). After stirring at room temperature for 2 hours the solution was diluted with EtOAc. The resulting solution was washed with saturated salt solution, dried over MgSO4and concentrate. Using purification on silica gel, elwira a mixture of 2:1 EtOAc/hexane receive specified in the header connection (0,22 g, 82%) as oil. MS calculated: (M+H)+233, found: 233.

Stage F

N-{2-[((3S,4S)-4-hydroxy-1-{4-[3-(trifluoromethyl)-1H-pyrazole-1-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained reductive amination of the ketone from step E derivative pyrrolidine with stage E of example 1 using the same method of example 6. MS calculated: (M+H)+548 found: 548.

The following connections will be received, using similar methods disclosed in examples 27-29.

Example No.RMS (M+H)+
303-forfinal508
314-chlorophenyl523
323-chlorophenyl523
334-bromophenyl568
343-bromophenyl568
354-were504
363-were504
372-were504
384-methoxyphenyl520
393-methoxyphenyl520
40pyridine-4-yl490
41pyridine-3-yl425-methylpyridin-2-yl504
436-methylpyridin-2-yl504
44the quinoline-4-yl540
453-methyl-1H-pyrazole-1-yl494
463,5-dimethyl-1H-pyrazole-1-yl508
474-triptoreline558
483-triptoreline558
493,4-methylenedioxyphenyl534

Example 50

Stage A

8-[2-(hydroxymethyl)phenyl]-1,4-dioxaspiro[4,5]Decan-8-ol.

To a solution of 2-bromobenzylamine alcohol (3.0 g, 16 mmol) in THF (40 ml), cooled to -78°C, add 2.5m solution of n-BuLi in hexano (14.1 ml). The mixture was stirred at -4°C for 1 hour and again cooled to -78°C. Add a solution of monoelemental 1,4-cyclohexandione (2.5 g, 16 mmol) in THF (10 ml) for 15 the minutes. Stirring is continued at -78°C for 30 minutes and at -4°C for 1 hour. The reaction is quenched by adding a solution of NH4Cl in water. The resulting solution was thrice extracted with EtOAc. The combined extracts washed with saturated salt solution, dried over MgSO4and concentrate. Using purification on silica gel, elwira a mixture of 5% MeOH/CH2Cl2receive specified in the header connection. MS calculated: (M+H)+265, found: 287 (M+Na)+.

Stage B

3H,4'H-Spiro[2-benzofuran-1,1'-cyclohexane]-4'-he.

Ketal dissolved in a mixture of 80% TFA/CH2Cl2. After stirring at room temperature for 3.5 hours the solution is concentrated. The residue is placed in EtOAc. The resulting solution was washed with 1N. NaOH and saturated salt solution, dried over MgSO4and concentrate.

Stage C

N-(2-{[(3S,4S)-4-hydroxy-1-(3H-Spiro[2-benzofuran-1,1'-cyclohexane]-4'-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained reductive amination of the ketone from step B of intermediate compound from step E of example 1 using the same method of example 6. MS (M+H)+518, found: 518.

Example 51

Stage A

Dimethyl-2,2'-(1,3-dioxolane-2,2-diyl)diacetate.

To a solution of 4.2 g (24 mmol) of dimethyl-3-oxopentanoate and 2.7 ml (48 mmol) of ethylene glycol in 50 ml of methylene chloride add 12 ml (96 mmol) of TMSCl at room temperature. The reaction mixture was stirred at 50°C for 3 days. The reaction is quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with ether. The combined organic layers washed with saturated salt solution, dried over Na2SO4that is evaporated under reduced pressure. The result chromatography on silica gel get the right product, dimethyl-2,2'-(1,3-dioxolane-2,2-diyl)diacetate (2.6 g, 12 mmol, yield: 50%): MS (m/e): 219 (M+1)+.

Stage B

2,2'-(1,3-dioxolane-2,2-diyl)diethanol.

To a solution of 2.6 g (12 mmol) of dimethyl-2,2'-(1,3-dioxolane-2,2-diyl)diacetate in 100 ml of dry THF added 1.4 g (36 mmol) of LAH at 0°C. the Reaction mixture was then refluxed for 1 hour, quenched with 15% aqueous NaOH solution (3 ml) and water (3 ml). The mixture is stirred overnight and filtered through celite. The residue is twice washed with THF (100 ml×2). The combined organic phases are evaporated. The result chromatography on silica gel get 1.3 g (8.0 mmol, yield: 66%) of 2,2-(1,3-dioxolane-2,2-diyl)diethanol: MS (m/e): 163 (M+1)+.

Stage C

1,3-dioxolane-2,2-ChildItem-2,1-valdemarakalpaka.

To a solution of 2,2-(1-dioxolane-2,2-diyl)diethanol (1.3 g, 8.0 mmol) in methylene chloride (100 ml), add triethylamine (3.4 ml, 24 mmol) at room temperature. The solution is cooled to a temperature of -40°C and then added dropwise to methylchloride (1.65 ml, 20 mmol). The reaction mixture was stirred at -40°C for 30 minutes, then gradually heated to 0°C. the Reaction is quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with methylene chloride. The combined organic extracts washed with saturated salt solution, dried over Na2SO4then evaporated, obtaining the crude product, 1,3-dioxolane-2,2-ChildItem-2,1-valdemarakalpaka: MS (m/e): 319 (M+1)+.

Stage D

Despero[1,3-dioxolane-2,1'-cyclohexane-4',1"-inden].

To a solution of indene (0.5 g, 4.3 mmol) in THF (10 ml), cooled in a bath with ice, add a 1M solution of LHMDS in THF (8.6 ml, 8.6 mmol). After stirring for 30 minutes, add a solution of the above crude of dimesylate in THF (5 ml). The mixture is stirred at room temperature overnight and quenched by adding cold water. The resulting solution was twice extracted with EtOAc. The combined extracts dried over MgSO4and concentrate. Using purification on silica gel, elwira mixture 1:5 EtOAc/hexane receive 250 mg (26%) specified in the connection header. MS calculated: (M+H)+243, found: 243.

Stage E

4H-Spiro[cyclohexane-1,1'-inden]-4-one.

To a solution of ketala with stage D (0.24 g, 1 mmol) in THF (3 ml) add a solution of 1H. HCl (3 ml). After stirring at room temperature overnight the solution was diluted with EtOAc and a solution of saturated NaHCO3. The organic phase is isolated and the aqueous layer was twice extracted with EtOAc. The combined organic phases are dried over MgSO4and concentrate. In the purification on silica gel, elwira mixture 1:5 EtOAc/hexane, obtain 170 mg (86%) specified in the connection header. MS calculated: (M+H)+199, found: 199.

Stage F

N-(2-{[(3S,4S)-4-hydroxy-1-Spiro[cyclohexane-1,1'-inden]-4-iparralde-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

In the reductive amination of intermediate compounds of pyrrolidine with stage E of example 1, the ketone from step E, using the same method of example 6, receive specified in the header connection. MS calculated: (M+H)+514, found: 514.

Example 52

N-(2-{[(3S,4S)-1-(2',3'-dihydrospiro[cyclohexane-1,1'-inden]-4-yl)-4-hydroxypyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

In the hydrogenation of the compound of example 52, using Pd/C as catalyst, receive specified in the header connection. MS calculated: (M+H)+516; found: 16.

Example 53

Stage A

Tert-butyl(3S,4S)-3-{[(benzyloxy)carbonyl]amino}-4-hydroxypyrrolidine-1-carboxylate.

To a solution of 1.4 g of the amine obtained in stage C of example 1 (6,9 mmol) in THF (40 ml), add 2.1 g CbzSu (8.4 mmol) and then Et3N (1.1 ml, 7.6 mmol). The reaction mixture was stirred at room temperature overnight. The solvent is removed in vacuum. The residue is placed in a mixture of EtOAc/water. The two phases are separated and the aqueous phase is twice extracted with EtOAc. The combined organic extracts dried over Na2SO4and concentrated in vacuo. The result chromatography on silica gel, elwira a mixture of 2:1 hexane/EtOAc, obtain 1.6 g (68%) specified in the connection header. MS found: USD 237.2 (M-Boc+1)+, 336,9 (M+1)+, 359,2 (M+Na)+.

Stage B

Tert-butyl(3S)-3-{[(benzyloxy)carbonyl]amino}-4-oxopyrrolidin-1-carboxylate.

To a solution of 0.7 ml of oxalicacid in THF (10 ml), cooled to -78°C, add 1.5 ml of anhydrous DMSO. After stirring for 5 minutes, add a solution of 1.6 g of intermediate compounds of the alcohol from step A in 20 ml of anhydrous THF and then added to 2.3 ml of triethylamine. The cooling bath removed. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was quenched using a mixture of 50/50 ml of EtOAc/water is. The aqueous phase is twice extracted with EtOAc. The combined organic phases are dried over Na2SO4and concentrated in vacuo. The result chromatography on silica gel using a mixture of 2:1 hexane/EtOAc, obtain 1.44 g specified in the connection header. MS (M+H)+335.

Stage C

Tert-butyl(4S)-3-allyl-4-{[(benzyloxy)carbonyl]amino}-3-hydroxypyrrolidine-1-carboxylate.

To a solution of 1.44 g of the ketone from step B in 20 ml of anhydrous THF, cooled to 0°C, add a solution of 6.2 ml of 1M allylanisole. The solution immediately becomes dark. After stirring at room temperature overnight, the reaction mixture was quenched using a mixture of 50/50 ml of EtOAc/water. The aqueous phase is twice extracted with EtOAc. The combined organic phases are dried over Na2SO4and concentrated in vacuo. The result chromatography on silica gel using a mixture of 3:1-2:1 hexane/EtOAc as eluent, get 0,85 g specified in the connection header. MS (M+H)+377.

Stage D

Tert-butyl(4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-3-(3-hydroxypropyl)pyrrolidin-1-carboxylate.

To a solution of 0.85 g of allyl alcohol from step C in 20 ml of anhydrous THF added a solution of 15 ml 0,5h. 9-BBN. The reaction mixture is stirred for 2 days. Add water (0.5 ml), then 1 ml of 30% H O2and 1 ml of a mixture of NaOAc/water. After stirring for 1 hour the organic phase is isolated. The aqueous solution is neutralized with HCl and twice extracted with EtOAc. The combined organic phases are dried over Na2SO4. The solvent is removed in vacuum. The result chromatography on silica gel using pure EtOAc as eluent, get 0,80 g specified in the connection header. MS (M+H)+395.

Stage E

Tert-butyl-(9S)-9-{[(benzyloxy)carbonyl]amino}-1-oxa-7-azaspiro[4,4]nonan-7-carboxylate.

To a solution of 0.80 g of the diol from step D in 15 ml dichloromethane at 0°C, add 0.2 ml of methanesulfonanilide and 0.8 ml of triethylamine. After stirring for 1 hour the mixture is refluxed at 60°C over night. The solvent is removed in vacuum. The residue is placed in a mixture of EtOAc/water and the two phases are separated. The aqueous phase is twice extracted with EtOAc. The combined organic phases are dried over Na2SO4. The solvent is removed in vacuum. The result chromatography on silica gel using a mixture of 15% EtOAc/hexane to 100% EtOAc as eluent, to obtain 0.32 g specified in the connection header. MS (M+H)+377.

Stage F

Tert-butyl-(9S)-9-amino-1-oxa-7-azaspiro[4,4]nonan-7-carboxylate.

The sample obtained above (0.3 g), dissolved in 10 ml of methanol. D. billaut 0.2 g Pd/C. The resulting mixture was stirred at a pressure of 1 ATM H2(balloon) overnight and filtered. The solvent is removed in vacuum, obtaining 0,22 g of the crude product. The result chromatography on silica gel, elwira a mixture of 2:1 EtOAc/MeOH, gain of 0.13 g (64%) specified in the connection header. MS found: 143,1 (M-Boc+1).

Stage G

Tert-butyl-(9S)-9-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1-oxa-7-azaspiro[4,4]nonan-7-carboxylate.

To a solution of amine from step F (of 0.13 g, 0.54 mmol) and (3 triphtalocyaninine)acetic acid (of 0.133 g, 0.54 mmol) in DMF (7 ml) in a bath with ice add the reagent BOP (0,238 g, 0.54 mmol) and then triethylamine (0.5 ml, 3.5 mmol). The reaction mixture was stirred at room temperature overnight. The solvent is removed at 60°C under high vacuum. The residue is placed in an aqueous solution of a mixture of EtOAc/NaHCO3. The two phases are separated and the aqueous phase is twice extracted with EtOAc. The combined organic phases are dried over Na2SO4and concentrated in vacuo. The result chromatography on silica gel, elwira EtOAc, obtain 0.18 g (70%) indicated in the title compounds as a mixture of two diastereoisomers. MS (M+H)+472.

Stage H

N-{2-[(9S)-1-oxa-7-azaspiro[4,4]non-9-ylamino]-2-oxoethyl}-3-(trifluoromethyl)benzamid.

The intermediate connection with the article is Hai G (0.18 g) is mixed with 5 ml of a mixture of 4h. HCl/dioxane. The solution is stirred for 2 hours and concentrated in vacuo. MS (M+H)+372.

Stage I

N-(2-{[(9S)-7-(4-hydroxy-4-phenylcyclohexyl)-1-oxa-7-azaspiro[4,4]non-9-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

To a solution of amine from step H (90 mg, 0,243 mmol) and 4-hydroxy-4-phenylcyclohexanone (43 mg, 0,226 mmol) in THF (5 ml) add triacetoxyborohydride sodium (129 mg, 0.61 mmol) and then Et3N (to 0.29 ml, 2 mmol). The mixture is stirred at room temperature overnight. The solvent is removed in vacuum. The residue is placed in an aqueous solution of a mixture of EtOAc/NaHCO3. The two phases are separated and the aqueous layer was twice extracted with EtOAc. The combined organic phases are dried (Na2SO4) and concentrate. In the purification by using preparative HPLC receive two isomers. MS: 546,4 (M+1)+.

Example 54

Stage A

Tert-butyl(3S,4S)-3-{benzyl[(benzyloxy)carbonyl]amino}-4-hydroxypyrrolidine-1-carboxylate.

To a solution of the intermediate from step B of example 1 (3.2 g, 11 mmol) and N-(benzyloxycarbonyloxy)succinimide (to 4.23 g, 11 mmol) in DMF (20 ml) add NEt3(4.6 ml, 33 mmol). The mixture is stirred at room temperature overnight and diluted with water. The resulting solution was thrice extracted with EtOAc. The combined extracts TRIG the s washed with saturated salt solution, dried over MgSO4and concentrate. The result chromatography on silica gel, elwira a mixture of 30% EtOAc/hexane get mentioned in the title compound (2.5 g, 53%) as oil.

MS calculated: (M+H)+427, found: 449 (M+Na)+.

Stage B

Tert-butyl(3S,4S)-3-{benzyl[(benzyloxy)carbonyl]amino}-4-ethoxypyrrolidine-1-carboxylate.

To the solution obtained above intermediate compound (1 g, 2.3 mmol) in THF (6 ml), cooled in a bath with ice, add NaH (184 mg, 4.6 mmol). After stirring the mixture for 30 minutes add iodoethane (of 0.96 ml, 12 mmol). The mixture is stirred at room temperature overnight and quenched with aqueous solution of NH4Cl. The resulting solution was thrice extracted with EtOAc. The combined extracts washed with saturated salt solution, dried over MgSO4and concentrate. The result chromatography on silica gel, elwira 10% EtOAc in hexano get mentioned in the title compound (0.9 g, 90%) as oil. MS (M+H)+455, found: 478 (M+Na)+.

Stage C

Tert-butyl(3S,4S)-3-amino-4-ethoxypyrrolidine-1-carboxylate.

The result of the above intermediate compound (2.0 g, 4.5 mmol) dissolved in MeOH. Add Pd(OH)2coal (0.2 g). The mixture is stirred at a pressure of 55 psi overnight. The catalyst of hoteltravel the t and the filtrate concentrated. MS calculated: (M+H)+231, found: 231.

Stage D

Tert-butyl(3S,4S)-3-ethoxy-4-[({[3-trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-carboxylate.

To a solution of amine (1.0 g, 4,43 mmol) and (3 triphtalocyaninine)acetic acid (1,09 g, 4,43 mmol) in DMF (20 ml), cooled in a bath with ice, add BOP (1,96 g, 4,43 mmol) and then NEt3(5 ml). The mixture is stirred at room temperature overnight and concentrated under reduced pressure. The residue is placed in EtOAc. The resulting solution was washed with NaHCO3and saturated salt solution, dried over MgSO4and concentrate. The result chromatography on silica gel, elwira a mixture of 2:1 EtOAc/hexane get mentioned in the title compound (1.8 g, 88%) as a solid. MS (M+H)+460, found: 460.

Stage E

N-(2-{[(3S,4S)-4-ethoxypyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

The result of the above intermediate compound is dissolved in 4n. HCl in dioxane (20 ml). After stirring at room temperature for 2 hours the solvent otparivat, getting solid. MS calculated: (M+H)+360, found: 360.

Stage F

N-(2-{[(3S,4S)-4-ethoxy-1-(4-hydroxy-4-phenylcyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid./p>

In the reductive amination of amine obtained above the ketone from step A of example 6 using the same method of example 6, receive specified in the header connection. MS calculated: (M+H)+534, found: 534.

Example 55

Stage A

4-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)benzonitrile.

A solution of 4-bromobenzonitrile (10 g, by 0.055 mol) in 260 ml of dry THF and 70 ml of dry hexane in an argon atmosphere cooled to -100°C in a bath with a mixture of liquid nitrogen-Et2O added dropwise n-utility (34,3 ml, by 0.055 mol, 1.6 m solution in hexane) in such a way that the internal temperature does not exceed -95°C. the Orange solution is stirred an additional 10 minutes at a temperature from -100°C to -95°C and then treated dropwise within 10 minutes with a solution of monoelemental 1,4-cyclohexandione (8,75 g, by 0.055 mol) in 55 ml of dry THF, again carefully maintaining the temperature below -95°C. the Reaction mixture is stirred for 10 minutes at a temperature from -100°C to -95°C leave to warm to 20°C and poured into ice water (400 ml). The organic layer is separated and the aqueous layer was twice extracted with Et2O (200 ml). The combined organic extracts dried over MgSO4and evaporated, receiving 14.1 g of a solid crystalline substance of white color. Thorough trituration with Et2O the floor is up to 9.9 g (70% yield) of white crystals: 1H NMR (CDC13):1,6-2,2 (8H, m, cyclohexane), of 3.97 (4H, s, ketal), 7,63 (4H, s, Ar); MS: 260 (M+1)+.

Stage B

4-(1-hydroxy-4-oxocyclohexyl)benzonitrile.

4-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)benzonitrile (520 mg, 2.0 mmol) dissolved in a mixed solvent consisting of 10 ml of THF and 10 ml of aqueous 1N. HCl at room temperature. The reaction mixture was then stirred at 60°C for 1 hour. The solution is cooled to room temperature, bringing the pH to 7-8 with saturated aqueous solution of NaHCO3. The organic layer is isolated and the aqueous layer was twice extracted with EtOAc (20 ml×2). The combined organic extracts dried over MgSO4and evaporated, obtaining an oily residue. The result chromatography on silica gel (flash chromatography)using a mixture of 40% ethyl acetate-hexane to obtain 410 mg (95%) of the desired product:1NMR (CDCl3) δ: 7,7 (2H, d, J=11,0 Hz), 7,42 (2H, d, J=10,7 Hz), 4,10 (H, s), 2,79-to 2.74 (2H, m), 2,63-2,49 (2H, m), 1,95-1,89 (2H, m), 1,67-to 1.59 (2H, m); MS: 216 (M+1)+.

Stage C

N-[2-({(3S,4S)-1-[4-(4-cyanophenyl)-4-hydroxycyclohexyl]-4-ethoxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

In the reductive amination of ketone obtained above intermediate compound from step E of example 54, using triacetoxyborohydride sodium as the e reducing agent, after chromatography receive specified in the header connection. MS: 559 (M+1)+.

Example 56

Stage A

4-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)benzoic acid.

A mixture of 4-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)benzonitrile (7.5 g, 0,029 mol) in 190 ml of 2-methoxyethanol and 190 ml of 2,5h. NaOH is heated on a steam bath for 15 hours. The solution is cooled in a bath with ice, the pH adjusted to 7-8 using concentrated HCl, and evaporated to dryness. Add water (375 ml) and the pH adjusted to 2 using HCl. Solid yellow-brown color is filtered off and washed with water, gaining 7.6 g (94% yield) of 4-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)benzoic acid:1H NMR (CDC13) δ: 1,6-2,3 (8H, m, cyclohexane), of 4.00 (4H, s, ketal), 7,60 (2H, s, Ar), 8,00 (2H, Ar); MS: 279 (M+1)+.

Stage B

4-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)-N-methylbenzamide.

4-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)benzoic acid (560 mg, 2 mmol), methylamine (1.2 ml, 2.0m solution in THF), BOP reagent (1.07 g, 2.4 mmol) and 0.8 ml (6 mmol) of triethylamine are dissolved in 15 ml of DMF at room temperature. The reaction mixture was stirred at room temperature overnight. The result chromatography on silica gel (flash chromatography)using 50% ethyl acetate-hexane to obtain 410 mg (70%) of the desired product is KTA: 1NMR (CDCl3) δ: 7,76 (2H, d, J=11.2 Hz), 7,56 (2H, d, J=10,9 Hz), 5,01 (H, s), 3,90 (4H, s), 3,37 (3H, s), 2,80-of 2.75 (2H, m), 2,60 at 2.45 (2H, m), 1,95-1,90 (2H, m), 1,63-of 1.52 (2H, m); MS: 292 (M+1)+.

Stage C

4-(1-hydroxy-4-oxocyclohexyl)-N-methylbenzamide.

4-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)-N-methylbenzamide (410 mg, 1.4 mmol) was dissolved in a mixed solvent consisting of 7 ml of THF and 7 ml of aqueous 1N. HCl at room temperature. The reaction mixture was then stirred at 60°C for 1 hour. The solution is cooled to room temperature, the pH was adjusted to 7-8 using an aqueous solution of saturated NaHCO3. The organic layer is isolated and the aqueous layer was twice extracted with EA (20 ml×2). The combined organic extracts dried over MgSO4and evaporated, obtaining an oily residue. The result chromatography on silica gel (flash chromatography)using a mixture of 40% ethyl acetate-hexane to obtain 410 mg (90%) of the desired product:1NMR (CDCl3) δ: for 7.78 (2H, d, J=l1,2 Hz), 7,51 (2H, d, J=10,9 Hz), 4,10 (H, C)3,37 (3H, s), 2,79-to 2.74 (2H, m), 2,63-2,49 (2H, m), 1,95-1,89 (2H, m), 1,67-to 1.59 (2H, m); MS: 248 (M+1)+.

Stage D

N-(2-{[(3S,4S)-4-ethoxy-1-(4-hydroxy-4-{4-[(methylamino)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained vosstanovitelnaya obtained above ketone intermediate compound from step E of example 54, using triacetoxyborohydride sodium as a reducing agent and then chromatography. MS (M+H)+591.

Example 57

Stage A

8-(1-oxidability-4-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

To a solution of 2.35 g (10 mmol) of 8-pyridin-4-yl-1,4-dioxaspiro[4,5]Decan-8-ol (obtained by the method of example 7) in 20 ml of methylene chloride added 2.6 g (15 mmol) of mCPBA. The reaction mixture was stirred at room temperature for 1.5 hours. The result chromatography on silica gel get mentioned in the title compound (2,45 g, 98%).

Stage B

4-hydroxy-4-(1-oxidability-4-yl)cyclohexanone.

Specified in the title compound synthesized from 8-(1-oxidability-4-yl)-1,4-dioxaspiro[4,5]Decan-8-ol, using the usual method of removal of the protective groups.

Stage C

N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(1-oxidability-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using conventional methods of rehabilitation amination. MS (M+H)+551.

The following connections will be received, using similar methods disclosed in examples 54-57.

Example No.R1R2MS (M+H)+
58OH4-were548
59OH4-methoxyphenyl564
60OH3-methoxyphenyl564
61OH4-forfinal552
62OH3-forfinal552
63OH4-chlorophenyl568
64OH3,4-methylenedioxyphenyl578
65OHpyridine-2-yl535
66OHpyridine-3-yl 535
67OHpyridine-4-yl535
68OH4-methylpyridin-2-yl549
69OH5-methylpyridin-2-yl549
70OH6-methylpyridin-2-yl549
71OH6-methoxypyridine-3-yl565
72OH1-oxidability-3-yl551
73OH1-oxidability-2-yl551
74OHthe quinoline-4-yl585
75OH3-cyanophenyl559
76OH 3-(methylaminomethyl)phenyl591
77Hpyridine-3-yl519
78Hpyridine-4-yl519
79Hpyridine-2-yl519
80H1-oxidability-2-yl535
81H1-oxidability-3-yl535
82H1-oxidability-4-yl535
83H6-methoxypyridine-3-yl549
84H4-(morpholine-4-ylcarbonyl)phenyl631
85H5-(morpholine-4-ylcarbonyl)pyridine-2-yl632
86H6-(morpholine-4-ylcarbonyl)pyridine-3-yl632
87H4-(4-methylpiperazin-1-ylcarbonyl)phenyl644
88H3-methyl-1H-pyrazole-1-yl522
89H3-trifluoromethyl-1H-pyrazole-1-yl576

Example 90

N-(2-{[(3S,4S)-4-ethoxy-1-(3H-Spiro[2-benzofuran-1,1'-cyclohexane]-4'-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the sequence of reactions disclosed in example 54. MS calculated: (M+H)+546, found: 546.

Example 91

N-(2-{[(3S,4S)-4-ethoxy-1-Spiro[cyclohexane-1,1'-inden]-4-iparralde-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the sequence of reactions disclosed in example 52. MS calculated: (M+H)+542 found: 542.

Example 92

N-(2-{[(3S,4S)-1-(2',3'-Digue is Prospero[cyclohexane-1,1'-inden]-4-yl)-4-ethoxypyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the sequence of reactions disclosed in example 54. MS calculated: (M+H)+544, found: 544.

Example 93

Stage A

Benzyl-6-oxa-3-azabicyclo[3,1,0]hexane-3-carboxylate.

To a solution of 30 g (133 mmol) benzyl-3-pyrrolin-1-carboxylate in 700 ml of methylene chloride add to 57.2 g (200 mmol) of mCPBA. The reaction mixture was stirred at room temperature overnight and quenched using 250 ml of 20% aqueous NaHSO3. The organic phase is isolated and the aqueous layer was extracted with methylene chloride twice (100 ml×2). The combined extracts washed twice with a saturated aqueous solution of NaHCO3(250 ml×2), saturated salt solution, dried over Na2SO4that is evaporated under reduced pressure. The result chromatography on silica gel using a mixture of 40% EtOAc-hexane, get mentioned in the title compound (24 g, 83%). MS (M+H)+220.

Stage B

Benzyl-(3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate.

To a solution of 20.7 g (94,4 mmol) benzyl-6-oxa-3-azabicyclo[3,1,0]hexane-3-carboxylate in 80 ml of methanol, add 80 ml of ammonium hydroxide. The reaction mixture was stirred at 60°C over night. After concentrating the reaction mixture under reduced pressure to obtain an oily residue (223 g, 94,4 mmol), which was used directly in further N-Boc-protective reaction. MS(M+H)+237.

Stage C

Benzyl-(3S,4S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate.

To a solution of 22.3 g (94,4 mmol) obtained above amerosport in 200 ml of THF added to 26.8 g (123 mmol) of di-tert-BUTYLCARBAMATE and 17.1 ml (123 mmol) of triethylamine at 0°C. the Reaction mixture was stirred at room temperature overnight. The reaction is quenched using 100 ml of ethyl acetate and 100 ml of water. The organic phase is isolated and the aqueous layer was extracted twice with ethyl acetate (100 ml×2). The combined extracts washed twice with a saturated aqueous solution of NaHCO3(250 ml×2), saturated salt solution, dried over

Na2SO4that is evaporated under reduced pressure. The result chromatography on silica gel using a mixture of 70% EtOAc-hexane, get mentioned in the title compound (27,3 g, 86%). MS (M+H)+337.

Stage D

Benzyl-(3S,4S)-3-(allyloxy)-4-[(tert-butoxycarbonyl)amino]pyrrolidin-1-carboxylate.

To a solution of 26 g (77 mmol) benzyl-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate in 120 ml of THF added 5 g (211 mmol) of sodium hydride at 0°C. the Reaction mixture was stirred at 0°C for 1 hour, then add 10 ml (115 mmol) of allylbromide the and. The reaction mixture is heated to room temperature and continuously stirred at room temperature overnight. To quench the reaction, water is added (50 ml). The organic phase is isolated and the aqueous layer was extracted twice with ethyl acetate (100 ml×2). The combined extracts washed with saturated salt solution, dried over Na2SO4that is evaporated under reduced pressure. The result chromatography on silica gel using a mixture of 25% EtOAc-hexane, get mentioned in the title compound (21,3 g, 73%). MS (M+H)+377.

Stage E

Benzyl-(3S,4S)-3-(allyloxy)-4-aminopyrrolidine-1-carboxylate.

To a solution of 21.3 g (56,6 mmol) benzyl-3-(allyloxy)-4-[(tert-butoxycarbonyl)amino]pyrrolidin-1-carboxylate in 125 ml THF added 250 ml of a 4n solution. HCl in dioxane. The reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, obtaining an oily residue. The residue is again dissolved in 200 ml of a saturated aqueous solution of NaHCO3. the pH of the mixture was adjusted to 7-8, and then extracted twice with ethyl acetate (100 ml×2). The combined extracts washed with saturated salt solution, dried over Na2SO4that is evaporated under reduced pressure, obtaining an oily residue. The result chromatography on silica gel, elwira a mixture of 5% MeOH-EtOAc, get the criminal code is related to the title compound (10.5 g, 68%). MS (M+H)+277.

Stage F

Benzyl-(3S,4S)-3-(allyloxy)-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-carboxylate.

To a solution of 10 g (36 mmol) benzyl-3-(allyloxy)-4-aminopyrrolidine-1-carboxylate in 150 ml of DMF added 12 g (105 mmol) of N-methylmorpholine, 19 g (44 mmol) of BOP reagent and 10 g (39 mmol) derived glycine acid at room temperature. The reaction mixture was stirred at room temperature overnight. The result chromatography on silica gel, elwira a mixture of 50% EtOAc-hexane, get mentioned in the title compound (14.5 g, 79.8 per cent). MS (M+H)+506.

Stage G

The hydrochloride of N-(2-oxo-2-{[(3S,4S)-(4-proximinality)-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide.

To a solution of 3.7 g of benzyl-3-(allyloxy)-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-carboxylate in 35 ml of methanol is added to 3.6 ml of 6N. aqueous HCl and 171 mg of Pd/C (10% coal). The reaction mixture was stirred at room temperature in hydrogen atmosphere (40 psi) overnight. The mixture is filtered through celite and concentrated under reduced pressure, obtaining specified in the header of the connection (1,73g, 58%). MS (M+H)+374.

Stage H

N-[2-({(3S,4S)-1-[4-hydroxy-4-(1-oxidability-4-yl)cyclohexyl]-4-propoxyphen ridin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

The specified connection hydrochloride synthesized from N-(2-oxo-2-{[4-proximinality-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide and 4-hydroxy-4-(1-oxidability-4-yl)cyclohexanone using a specific method of rehabilitation amination. MS (m/e): 565 (M+1)+.

The following connections receive using the same method of example 93.

Example No.R1R2MS (M+H)+
94OHphenyl548
95OH4-methoxyphenyl578
96OH3,4-methylenedioxyphenyl592
97OHpyridine-2-yl549
98OHpyridine-3-yl549
99OHPiri is in-4-yl 549
100OHthe quinoline-4-yl599
101OH6-methoxypyridine-3-yl579
102OH4-methylpyridin-2-yl563
103OH5-methylpyridin-2-yl563
104OH6-methylpyridin-2 Il563
105OH6-methoxypyridine-2-yl579
106OH1-oxidability-3-yl565
107Hpyridine-3-yl533
108Hpyridine-4-yl533
109H 3,5-dimethyl-1H-pyrazole-1-yl550
110H3-methyl-1H-pyrazole-1-yl536
111H1-oxidability-3-yl549

Example 112

N-(2-oxo-2-{[(3S,4S)-4-propoxy-1-(3H-Spiro[2-benzofuran-1,1'-cyclohexane]-4'-yl)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the sequence of reactions disclosed in example 93. MS calculated: (M+H)+560, found: 560.

Example 113

N-(2-oxo-2-{[(3S,4S)-4-propoxy-1-Spiro[cyclohexane-1,1'-inden]-4-iparralde-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the sequence of reactions disclosed in example 93. MS calculated: (M+H)+556 found: 556.

Example 114

Stage A

(3 triphtalocyaninine)acetic acid.

To the rapidly stirred solution of glycine (15,014 g, 0.20 mol) in MeCN (400 ml) and 2M NaOH (250 ml) at 0°C is added slowly a solution of 3-(trifluoromethyl)benzoyl chloride (41,714 g, 0.20 mol) in 75 ml of MeCN in 30 minutes. Muddy yellow R is the target stirred at 0°C for 30 minutes. The reaction mixture is acidified using 3M HCl, up to rn, then remove MeCN using a rotary evaporator. The resulting mixture was then extracted with EtOAc (400 ml×3). The combined organic layers dried, filtered and concentrated, gaining solid light yellow (48,53 g), which was triturated with toluene (500 ml). After filtration, the solid is washed with cold toluene to until the filtrate becomes colorless. After drying in vacuum over the weekend to receive the product in the form of a white powder: 44,60 g (90%) MS (M+H+)=248,1.1NMR (DMSO-d6) δ: 12,70 (users, 1H), 9,17 (m, 1H), to 8.20 (DD, 2H), 7,94 (DD, 1H), 7,78 (m, 1H), 3,97 (d, 2H).

Stage B

N-(2-{[(3R)-1-benzylpyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

To a solution of (3-triphtalocyaninine)acetic acid (4,2 g, 17 mmol) and NMM (2.8 ml, 25.5 mmol) in dry THF (30 ml) at a temperature of (-10)-(-15)°C in an atmosphere of N2slowly add isobutylparaben (2.4 ml, 17,85 mmol) via syringe. The reaction mixture gradually becomes pink. After 15 minutes, a solution of (3R)-1-benzylpyrrolidine-3-amine (3.0 g, 17 mmol) in THF (15 ml) was added dropwise to the above mixed anhydride for 20 minutes, maintaining the temperature of the reaction mixture <-10°C. the Reaction mixture becomes dark red. After 1 hour actionnow the mixture is left to warm to room temperature and quenched with water (25 ml), extracted with EtOAc×3, dried, filtered and concentrated, gaining a solid orange color. Add MeCN and concentrated to remove EtOAc. Then add

MeCN (15-20 ml)to obtain a suspension which is cooled in a bath with ice, and stirred for 30 minutes. After filtration of the solid product is washed with cold MeCN (10-15 ml) up until the filtrate becomes colorless. After drying under high vacuum over night, get a solid pale yellow: 5.0 g (73%). MS (M+N+)=406,2;1NMR (CDCl3) δ: 8,16 (s, 1H), 8,00 (DD, 1H), 7,78 (DD, 1H), EUR 7.57 (m, 1H), 7,25 (m, 6H), 7,06 (m, 1H), 6,39 (m, 1H), 4,48 (m, 1H), Android 4.04 (d, 2H), 3,62 (d, 2H), 2,86 (m, 1H), 2.63 in (m, 1H), 2.57 m (m, 1H), a 2.36 (m, 2H).

Stage C

N-((R)-pyrrolidin-3-ylcarbonyl)-3-trifluoromethyl-benzamide.

In a Parr shaker containing compound from step B (14.0 g, 34.5 mmol)dissolved in MeOH (50 ml), added palladium hydroxide (2.8 g, 20 wt.%). The suspension is shaken at room temperature in hydrogen atmosphere (55 psi) overnight. The mixture is filtered through celite and concentrated, obtaining mentioned in the title compound as a white solid; yield of 10.5 g, 97%;1NMR (CDCl3) δ: 9,06 (t, 1H), to 8.20 (m, 3H), 7,94 (d, 1H), of 7.75 (t, 1H), 4,23 (m, 1H), 3,89 (d, 2H), 3.00 and-up 3.22 (m, 4H), 2,82 (m, 1H), 2.05 is (m, 1H), 1,73 (m, 1H); MS m/z=316,3 (M+H)+.

Stage D

p> 8-(6-methoxypyridine-3-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

In a dry 3-necked flask of 5-bromo-2-methoxypyridine (12,6 g, and 67.2 mmol) dissolved in dry THF (130 ml) and cooled to -78°C in an atmosphere of N2. Added dropwise 2.5m n-BuLi in hexano (28,2 ml of 70.4 mmol) and the mixture was stirred at -78°C for 50 minutes. To pyridine mixture slowly add a solution of monoelemental 1,4-cyclohexandione (10.0 g, 64,0 mmol) in dry THF (25 ml). The resulting mixture was stirred at -78°C for 80 minutes. The reaction is quenched using saturated solution of NH4Cl, and extracted with CH2Cl2(3×). The combined extracts dried (MgSO4), filtered and concentrated, obtaining a yellow oil. The result chromatography on silica gel (flash chromatography), elwira a mixture of 10% MeOH/CH2Cl2get listed in the title compound in the form of solid yellow; yield 16.5 g, 62,2 mmol, 97%;1NMR (CDCl3) δ: compared to 8.26 (s, 1H), 7,72 (d, 1H), 6,69 (d, 1H), 3.96 points (t, 4H), 3,91 (s, 3H), of 2.21 (s, 1H), 2,08 (m, 4H), equal to 1.82 (m, 2H), 1-66 (m, 2H); MS m/z=266,1 (M+H)+.

Stage E

4-hydroxy-4-(6-methoxypyridine-3-yl)cyclohexanone.

To a solution of ketala with stage D (11.5g, to 43.3 mmol) in THF (100 ml) was added 3n. HCl (75 ml) and the solution stirred overnight at room temperature. the pH of the solution was adjusted to ~11, by adding 3h. the NaOH solution. After removal of the greater part of th is on a rotary evaporator, the aqueous portion is extracted with CH2Cl2(3×). The combined extracts dried (MgSO4), filtered and concentrated, obtaining specified in the title compound in the form of solid yellow; the output of 8.2 g of 37.1 mmol, 86%;1NMR (CDCl3) δ: compared to 8.26 (s, 1H), of 7.75 (d, 1H), 6.73 x (d, 1H), 3,91 (s, 3H), 2.91 in (m, 2H), 2,78 (s, 1H), 2,32 (m, 2H), of 2.21 (m, 4H); MS m/z=222,1.

Stage F

N-({(3R)-1-[4-hydroxy-4-(6-methoxypyridine-3-yl)cyclohexyl]pyrrolidin-3-ylcarbonyl}methyl)-3-cryptomelane.

In a dry flask containing a solution of N-((R)-pyrrolidin-3-ylcarbonyl)-3-cryptomelane (5.0 g, 15.9 mmol) in dry CH2Cl2(1.0 l), add the ketone from step E (4,56 g of 20.6 mmol) and then triacetoxyborohydride sodium (6,72 g, and 31.7 mmol). The resulting mixture is stirred over night at room temperature. The reaction mixture is neutralized using NaOH (250 ml) and extracted with CH2Cl2(3×). The combined extracts dried (MgSO4), filtered and concentrated, getting sticky solid. Using flash chromatography on silica gel and elwira a mixture of 1% NH4OH/15% MeOH/EtOAc, to get the desired isomer as a white solid; yield (less polar isomer) 3,68 g, 7.1 mmol, 45%;1NMR (CDCl3) δ: 8,28 (s, 1H), of 8.09 (s, 1H), of 7.97 (d, 1H), of 7.75 (DD, 2H), 7,55 (m, 2H), 6.90 to (d, 1H), 6,72 (d, 1H), of 4.44 (m, 1H), 4,12 (s, 2H), 3,92 (s, 3H), 2,87 (m, 1H), 2,65 (m, 2H), and 2.27 (m, 4H), 2,1 (users, 1H), 1.93 and (m, 2H), 1,64 (m, 5H); MS m/z=521,2 (M+H).

Example 115

Stage A

CIS-1-pyridin-2-illlogical-1,4-diol.

To a solution of LAH (50 ml, 1.0m THF) in a 1 l 4-necked flask add THF (150 ml) and then added dropwise a solution of 4-hydroxy-4-pyridine-2-illlogical (10.0 g, 52,3 mmol) in THF (100 ml) for 1.5 hours. The temperature throughout the reaction is about 30°C. On completion of the reaction is judged according to HPLC analysis, and according to HPLC ratio of TRANS-diol to CIS-dialo is 1:9. The reaction is quenched by slowly adding water (8 ml) and 15% NaOH (2 ml)and the mixture filtered through celite. The filtrate is concentrated and receiving oil (10.1 g), which is subjected to chromatography on silica gel (350 g), elwira a mixture of 1% TEA/5% IPA/hexane (400 ml) and then with a mixture of 1% TEA/15% IPA/10% tBME/hexane (6 l). The appropriate fractions are combined and concentrated in vacuo, receiving CIS-1-pyridin-2-illlogical-1,4-diol (6.3 g, 63%) as a white solid. JHMS: FOR 194.3 (M+H, 100%).1NMR (CDCl3) δ: 8,54 (DD, 1H), 7,72 (DD, 1H), 7,68 (DD, 1H),7,39 (d, 1H), 5,09 (users, 1H), 3,82 is 3.76 (m, 1H), 2,56-2,49 (m, 1H), 2,01-to 1.98 (m, 2H), 1,96-of 1.84 (m, 2H), 1,80 is 1.75 (m, 2H), 1,64 is 1.58 (m, 2H).

Stage B

CIS-4-hydroxy-4-pyridine-2-enciclopedia.translate.

To a solution of alcohol from step A (6.3 g, a 32.6 mmol) and TEA (to 13.6 ml, 97.8 mmol) in THF (100 ml) at 0°C add methylchloride (3,78 ml, for 48.9 mmol). After the lane is masiania for 1.5 hours, the reaction is finished, what is judged according to GHMC. The reaction is quenched by adding 20% KHCO3(40 ml), and extracted with EtOAc (300 ml). The organic layer is washed with 10% KHCO3then with saturated salt solution, dried over sodium sulfate and concentrated in vacuo. The residue is crystallized in toluene (100 ml) at 70°C and the solid is dried by air, getting a crystalline solid (5,25 g, 59.4 per cent). JHMS: 272,3 (M+N+, 100%);1NMR (CDCl3) δ: 8,54 (d, 1H), 7,76 (DD, 1H), 7,35 (DD, 1H), 7,26 (DD, 1H), 5,20 (users, 1H), 4,86-of 4.77 (m, 1H), 3,06 (s, 3H), 2,30 is 2.10 (m, 4H), 1,96-of 1.88 (m, 2H), 1,80-of 1.78 (m, 2H).

Stage C

Tert-butyl[(3R)-1-(TRANS-4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]carbamate.

4-Hydroxy-4-pyridine-2-enciclopedia.translate (0,245 g, 0.9 mmol) and tert-butyl(3R)-pyrrolidin-3-ylcarbamate (1.6 g, 8,59 mmol) is weighed and placed in a vial for microwave ovens. Clean the reaction mixture is placed in a microwave for 15 minutes at a temperature of 71°C. the Mixture is subjected to chromatography on silica gel, elwira 1% NH4OH in a mixture of ethyl acetate/methanol (100/0 to 10/90)to give tert-butyl[(3R)-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]carbamate. JHMS: 362,2 (M+H, 100%).1NMR (CDCl3) δ: charged 8.52 (m, 1H), of 7.70 (m, 1H), 7,43 (d, 1H), 7,19 (m, 1H), 4,86 (users, 2H), 4,20 (users, 1H), 2,82 (m, 1H), 2,68 (s, 1H), has 2.56 (m, 1H), 2.40 a (m, 1H), 2,31 (s, 1H), 2,27-2,17 (m, 3H), 2,04-to 1.98 (m, 2H), 1,78-of 1.74 (m, 3H), of 1.61 (m, 2H), of 1.46 (s, 9H).

Stage D

TRANS-4-[(3R)-3-aminopyrrolidine-1-yl]-1-pyridin-2-illlogical.

Tert-butyl[(3R)-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]carbamate (50 mg, 0.14 mmol) is added 4.0m HCl in 1,4-dioxane (3 ml) at room temperature. After stirring for 5 minutes the product precipitates. To the mixture is added methanol (0.6 ml) and the solution becomes almost transparent, and have some amount of resinous substances. According to HPLC and IHMS the reaction is finished within 2.5 hours. The resulting mixture was concentrated, obtaining the HCl salt of 4-[(3R)-3-aminopyrrolidine-1-yl]-1-pyridin-2-illlogical (72 mg, 99%). LC/MS: 262,1 (M+H, 100%).

Stage E

N-(2-{[(3R)-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

To a solution of 4-[(3R)-3-aminopyrrolidine-1-yl]-1-pyridin-2-illlogical (69 mg, 0.26 mmol) in anhydrous THF (5 ml) is added TEA (0.10 ml) and another solution of (3-triphtalocyaninine)acetic acid (60 mg, 0.24 mmol), hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (50 mg, 0.26 mmol) in THF (5.0 ml) at room temperature and then added DMF (0,07 ml) and an additional amount of TEA (0.05 ml)to turn everything into a solution. The reaction mixture was stirred at room temperature overnight, quenched with water (25 ml) and extracted with ethyl acetate (4×35 ml). Merged the content of inorganic fillers layers dried over sodium sulfate, filtered and the solvent is removed under reduced pressure. The residue is subjected to chromatography on silica gel, elwira 1% NH4OH in a mixture of ethyl acetate/methanol (100/0 to 10/90), then purified using HPLC, elwira of 0.05% TFA in a mixture of CH3CN/water, receiving TFA salt of bis(triptorelin) N-(2-{[(3R)-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (68 mg, 57%). LRMS: 491 (M+H, 100%).1NMR (CD3OD) δ: to 8.20 (s, 1H), 8,12 (d, 1H), a 7.85 (d, 1H), to 7.67 (t, 1H), of 6.96 (s, 2H), 4,37 (m, 1H), 4,01 (s, 2H), 2,88 (m, 1H), 2,77 (m, 1H), 2,61 (m, 1H), 2,52 (m, 2H), 2,44 (square, 1H), of 2.21 (m, 2H), 1,96 (m, 2H,), of 1.65 (m, 3H), of 1.40 (m, 2H).

Example 116

Stage A

2 azetidin-1-yl-5-bromopyridin.

The mixture of the HCl salt of azetidine (590 mg, 6.3 mmol), 5-bromo-2-herperidin (1,11 g, 6.3 mmol), Cs2CO3(4.1 g, 12.6 mmol) and dry DMSO (7 ml) is stirred and heated at 95°C for 20 hours. The reaction mixture is cooled and filtered. The solid is treated with H2O, extracted with CH2Cl2×3. The combined organic layers dried, filtered, getting to 1.15 g (86%) of the desired product in the form of a solid of light yellow color. MS (M+H+)=213,0/215,0.1NMR (CDCl3) δ: 8,18 (d, 1H), 7,50 (DD, 1H), 6,18 (d, 1H), a 4.03 (t, 4H), 2.40 a (square, 2H).

Stage B

8-(6-azetidin-1-espiridion-3-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

2 azetidin-1-yl-5-bromopyridin (mg, 0.30 mmol) dissolved in dry THF (1.5 ml) and cooled to -78°C, then adding n-BuLi (0,196 ml, 1.6 m in hexano). After 30 minutes, added dropwise a solution of monoelemental 1,4-cyclohexandione (44,6 mg, 0,286 mmol) in dry THF (0.2 ml) at -78°C with constant stirring. After 1 hour the reaction is quenched using NH4Cl (aq.), and slowly warmed to room temperature. The aqueous layer was extracted with CH2Cl2×3, dried, filtered and concentrated, obtaining the crude product, which was purified using flash chromatography on a column (100% EtOAc)to give 35 mg (43%) of a solid white product. MS (M+H+) 291,1.

Stage C

4-(6-azetidin-1-espiridion-3-yl)-4-hydroxycyclohexanone.

8-(6-azetidin-1-espiridion-3-yl)-1,4-dioxaspiro[4,5]Decan-8-ol (35 mg) was dissolved in THF (1.2 ml) and then added 3M HCl (0.8 ml) at room temperature. The resulting solution was stirred at room temperature for 2 hours, then alkalinized using 6N. NaOH in a bath with ice to pH 10. The aqueous layer was extracted with CH2Cl2×3. The combined organic layers dried, filtered and evaporated on a rotary evaporator, receiving 28 mg (97%) of a white solid without further purification. MS (M+H+)=247,0.

Stage D

N-[2-({(3R)-1-[4-(6-azetidin-1-espiridion-3-yl)-4-hydroxycyclohexyl is]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

To a solution of 4-(6-azetidin-1-espiridion-3-yl)-4-hydroxycyclohexanone (115 mg, 0,467 mmol) and N-((R)-pyrrolidin-3-ylcarbonyl)-3-cryptomelane (140,4 mg, 0,445 mmol) in dry CH2Cl2(19 ml) was added Na(OAc)3BH (198 mg, 0,934 mmol) in one portion in an atmosphere of N2at room temperature. The reaction mixture was stirred in nitrogen atmosphere overnight (16 h) and treated with Na2CO3(aq.), extracted with CH2Cl2×3, dried, filtered and concentrated, obtaining the crude product, which was purified column chromatography (20:80:0.5 in MeOH/EtOAc/NH4OH)to give 60 mg (25%) of the desired isomeric product (top spot on TLC) as a white solid. MS (M+H+)=546,1.1NMR (CD3OD) δ: 8,24 (m, 2H), 8,17 (m, 2H), 7,88 (m, 2H), 7,74 (m, 2H), 6,56 (d, 1H), 4,36 (m, 2H), 4,27 (m, 3H), 4,06 (m, 3H), 3,86 (m, 1H), 3,48 (m, 2H), 3,20 (m, 1H), 2,69 (m, 1H), 2,60 (m, 2H), 2,35-2,30 m, 4H), 2,20-of 1.97 (m, 4H), at 1.73 (m, 2H).

Example 117

Stage A

6-bromonicotinate.

6-chloronicotinamide (13.8 g, 100 mmol) is heated at 145°C in tribromide phosphorus (150 ml) for 32 hours. After cooling, the mixture was concentrated in vacuo. To the residue add trichromacy phosphorus (150 ml) and the mixture is heated at 145°C for 32 hours. After cooling, the mixture was concentrated in vacuo and add a mixture of ice-water (500 ml). Add sodium bicarbonate, Thu is to neutralize the mixture, and the product extracted with ethyl acetate (3×250 ml). The combined organic extracts washed with saturated salt solution and dried over magnesium sulfate. The solvent is removed in vacuum and the residue is subjected to chromatography (hexane-ethyl acetate)to give 14.9 g (81%) of 6-bromonicotinate in the form of a white solid:1NMR (400 MHz, CDCl3) δ: 7,66 (d, J=11.0 cm Hz, 1H), 7,80 (DD, J=3,1, and 11.0 Hz, 1H), 8,67 (d, J=3.1 Hz, 1H); MS m/z USD 183.0, to 185.0 (M+H+).

Stage B

6-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)nicotinamide.

A solution of 6-bromonicotinate (2 g, to 0.011 mol) in 50 ml dry THF and 15 ml of dry hexane in an argon atmosphere cooled to -100°C in a bath with a mixture of liquid nitrogen-Et2O. Rapidly added dropwise n-utility (7.5 ml, to 0.011 mol, 1.6 m solution in hexane) in such a way that the internal temperature does not exceed -95°C. the Orange solution is stirred additionally for 10 minutes at a temperature from -100°C to -95°C and then treated dropwise within 10 minutes with a solution of monoelemental 1,4-cyclohexandione (1.8 g, to 0.011 mol) in 55 ml of dry THF, again carefully maintaining the temperature below -95°C. the Reaction mixture is stirred for 10 minutes at a temperature from -100°C to -95°C, allowed to warm to 20°C and poured into ice water (400 ml). The organic layer is isolated and the aqueous layer was twice extracted with Et2(200 is l). The combined organic extracts dried over MgSO4and evaporated, obtaining 2.8 g of a white solid crystalline substances. Thorough trituration with Et2O gain of 1.9 g (67% yield) of white crystals: MS: 261 (M+1)+.

Stage C

6-(1-hydroxy-4-oxocyclohexyl)nicotinamide.

Specified in the title compound synthesized from 6-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)nicotinanilide using the usual method of removal of the protective groups for 4-(1-hydroxy-4-oxocyclohexyl)benzonitrile.

Stage D

N-[2-({(3R)-1-[4-(5-cyano-2-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is synthesized using the methodology of restorative amination, analogously to example 114. MS (M+H)+516.

Example 118

Stage A

8-(6-herperidin-3-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

A solution of 5-bromo-2-herperidin (2 g, to 0.011 mol) in 50 ml dry ether under nitrogen atmosphere cooled to -78°C. added dropwise n-utility (7.5 ml, to 0.011 mol, 1.6 m solution in hexane) and TMEDA (2.5 g, of 0.022 mol). The orange solution is stirred for an additional 1 hour at -78°C and then treated dropwise within 10 minutes with a solution of monoethyl is Natalia 1,4-cyclohexandione (1.8 g, to 0.011 mol) in 20 ml of dry THF. The reaction mixture is stirred for 1 hour, allowed to warm to 20°C and poured into ice water (400 ml). The organic layer is isolated and the aqueous layer was twice extracted with EtOAc (20 ml×2). The combined organic extracts dried over MgSO4and evaporated, receiving 2 g of white solid. The result chromatography on silica gel get 1.7 g (67% yield) of white crystals: MS: 254 (M+1)+.

Stage B

5-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)pyridine-2-carbonitrile.

To a solution of 1.7 g (6.6 mmol) of 8-(6-herperidin-3-yl)-1,4-dioxaspiro[4,5]Decan-8-ol in 20 ml of DMF added KCN (430 g, 6.6 mmol) and 18-crown-6 ether (1.8 g, 6.6 mmol). The reaction mixture was refluxed for 2 days. The result chromatography on silica gel get 5-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)pyridine-2-carbonitrile (620 mg, 36%): MS (m/e): 261 (M+1)+

Stage C

5-(1-hydroxy-4-oxocyclohexyl)pyridine-2-carbonitrile.

Specified in the title compound synthesized from 5-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)pyridine-2-carbonitrile using the usual method of removal of the protective groups for 4-(1-hydroxy-4-oxocyclohexyl)benzonitrile.

Stage D

N-[2-({(3R)-1-[4-(6-cyano-3-yl)-4-hidroxizina exil]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is synthesized using the method of reductive amination, as in example 114. MS 516 (M+H)+.

Example 119

Stage A

2-bromo-5-bromomethylphenyl.

2-bromo-5-methylpyridin (5,00 g of 29.1 mmol) and N-bromosuccinimide (5,22 g of 29.3 mmol) dissolved in carbon tetrachloride (40 ml) under nitrogen atmosphere. Add benzoyl peroxide (0.35 g, 1.4 mmol) and the mixture heated to boiling under reflux for four hours. The mixture is cooled to room temperature, filtered and washed with a mixture of NaHCO3/H2O. the Mixture adsorb on silica gel and then subjected to chromatography through a gradient elution from hexane to 10% ethyl acetate/hexane. Pure fractions are combined and concentrated, getting the right monobromobimane product in the form of solid pale yellow color of 3.60 g (49%). LC/MS (positive ion) m/z=249,8, 251,8, 253,8, (M+H)+.

Stage B

2-bromo-5-(methoxymethyl)pyridine.

2-bromo-5-bromomethylphenyl, 4 (3.58 g, and 14.3 mmol) dissolved in methanol (20 ml) under nitrogen atmosphere. Add sodium methoxide (0,89 g, 15.7 mmol, 95%) and the mixture is stirred at room temperature. After 3 hours, the methanol is distilled off on a rotary evaporator, the residue is dissolved in dichloromethane and washed with water. The body is ical extracts adsorb on silica gel and subjected to chromatography performing a gradient elution from hexane to a mixture of 20% ethyl acetate/hexane. Pure fractions are combined and concentrated, obtaining mentioned in the title compound as a colourless oil, 2,62 g (90%). LC/MS (positive ion) m/z=202,0, 204,0 (M+H)+.

Stage C

4-hydroxy-4-[5-(methoxymethyl)pyridine-2-yl]cyclohexanone.

2-bromo-5-(methoxymethyl)pyridine (2,61 g, 12.9 mmol) dissolved in dry THF (40 ml) under nitrogen atmosphere and cooled to -78°C. added dropwise n-utility (6,20 ml of 15.5 mmol, 2.5m in hexane) in 10 minutes, resulting in a solution of black color. After 15 minutes, added dropwise a solution of l,4-dioxaspiro[4,5]decane-8-it (of 2.21 g, 14.1 mmol) in THF within 2 minutes and the mixture is gradually heated to room temperature within 3 hours. According to TLC (50% ethyl acetate/hexane) and LC/MS transformation ended. Add water HCl (14 ml, 6,0 M)and the mixture is stirred for 3 hours at room temperature and then neutralized using NaHCO3/H2O. the Mixture was extracted three times with ethyl acetate, the combined extracts adsorb on silica gel and subjected to chromatography through a gradient elution from hexane to a mixture of 40% ethyl acetate/hexane. Pure fractions are combined and concentrated, obtaining mentioned in the title compound as a pale yellow solid in the society, to 1.00 g (33%). LC/MS (positive ion) m/z=236,1 (M+H)+.

Stage D

N-{2-[((3R)-1-{TRANS-4-hydroxy-4-[5-(methoxymethyl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamid.

The hydrochloride of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (100 mg, 0,284 mmol) and 4-hydroxy-4-[5-(methoxymethyl)pyridine-2-yl]cyclohexanone (67,0 mg, 0,284 mmol) dissolved in 2-propanol (15 ml). Add triethylamine (80 μl, or 0.57 mmol) and triacetoxyborohydride sodium (120 mg, or 0.57 mmol) and the mixture is stirred at room temperature overnight. The reaction mixture adsorb on silica gel and subjected to chromatography, elwira dichloromethane to a mixture of 10% methanol/dichloromethane/0.5% ammonium hydroxide. Factions unite, receiving net higher Rf isomer in the form of a white solid (90 mg, 59%) and clean the lower Rf isomer in the form of a white solid (39 mg, 26%). The higher Rf product: LC/MS (positive ion) m/z=535,2 (M+H); lower Rf product: LC/MS (positive ion) m/z=535,2 (M+H)+.

Example 120

Stage A

2-(6-bromopyridin-3-yl)propan-2-ol.

2.5-dibromopyridin 3,05 g (12.5 mmol) dissolved in 20 ml of THF and 120 ml of anhydrous ether and cooled to -78°C. Slowly dropwise via syringe add 5.0 ml n-utility (2,5M, 12.5 mmol) within 30 min After mixing etc is -78°C for 30 minutes add acetone (2 ml, 20 mmol). The reaction mixture was warmed to room temperature for two hours and then quenched using 10 ml of water. The mixture is extracted twice using EtOAc. The combined extracts are dried and concentrated. After crystallization using 20% EtOAc in hexane, gain of 1.30 g of white crystals (48% yield), MS: 215,0, 217,0 (M++1).

Stage B

8-[5-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,4-dioxaspiro[4,5]Decan-8-ol.

2-(6-bromopyridin-3-yl)propan-2-ol (1.08 g, 5 mmol) dissolved in 10 ml of THF and 50 ml of anhydrous ether. After the solution cooled to -78°C and slowly added dropwise via syringe 4,20 ml n-utility (2,5M, 11 mmol) for 10 minutes. After stirring at -78°C for 30 minutes add monoelemental 1,4-cyclohexandione (0,80 g, 5 mmol). The reaction mixture was warmed to room temperature for two hours and then quenched by adding 5 ml of water. The mixture is extracted twice using EtOAc. The combined extracts are dried and concentrated. After treatment with the help of a flash chromatography column using 40-70% EtOAc in hexane, get to 0.48 g of white crystals (42% yield), MS: 294,1 (M++1).

Stage C

4-hydroxy-4-[5-(1-hydroxy-1-methylethyl)methyl]pyridine-2-yl}-cyclohexanone.

8-[5-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,4-dioxaspiro[4,5]Decan-8-ol (0.18 g, 2,9 the mol) is dissolved in 10 ml of THF and add 10 ml of 2n. HCl solution. After stirring for two hours the reaction mixture is neutralized to pH~8-9 using saturated aqueous solution of NaHCO3and twice extracted using EtOAc. The combined extracts are dried and concentrated, gaining 0.15 g of a white solid (98% yield), MS: 250,2 (M++1).

Stage D

N-{2-[((3R)-1-{4-hydroxy-4-[5-(1-hydroxy-1-methylethyl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from the ketone from step C in accordance with the method of example 114. MC: 549 (M+H)+.

Example 121

Stage A

6-bromopyridin-3-carbaldehyde.

2.5-dibromopyridin 9,48 g (40 mmol) dissolved in 60 ml of THF and 150 ml of anhydrous ether. After the solution cooled to -78°C and slowly added dropwise via syringe 16 ml of n-utility (2,5M, 40 mmol) over 30 minutes. After stirring at -78°C for 30 minutes, add N,N-dimethylformamide (3.5 g, 48 mmol). The reaction mixture was warmed to room temperature for two hours and then quenched by adding 10 ml of water. The mixture is extracted twice using EtOAc. The combined extracts are dried and concentrated. After flash chromatographic processing on a column using 30-40% EtOAc in hexane, get 2,80 g of white solids which (28% yield), MS: of 186.0, 188,0 (M++1).

Stage B

1-(6-bromopyridin-3-yl)-N,N-dimethylethanamine.

To a solution of tetraisopropoxide titanium (6.4 g, 22 mmol) and 2.0m dimethylamine in methanol (22 ml, 44 mmol) is added 6-bromopyridin-3-carbaldehyde (2.10 g, 11 mmol) in 20 ml of methanol. After stirring at room temperature for 5 hours add sodium borohydride (0,43 g, 11 mmol) and the mixture is stirred over night. The reaction is quenched by adding 10 ml of water and extracted twice using EtOAc. The combined extracts are dried and concentrated. After treatment with the help of a flash chromatography column using 20-40% methanol in EtOAc and 0.5% NH4OH, get to 1.15 g of oil (47% yield), MS: 214,0, 216,0 (M++1).

Stage C

8-{5-[(dimethylamino)methyl]pyridine-2-yl}-1,4-dioxaspiro[4,5]Decan-8-ol.

1-(6-bromopyridin-3-yl)-N,N-dimethylethanamine (1,15 g, 5.4 mmol) dissolved in 30 ml of THF and 80 ml of anhydrous ether. After the solution cooled to -78°C and slowly added dropwise via syringe 2,60 ml n-utility (2,5M, 6,40 mmol) for 10 minutes. After stirring at -78°C for 30 minutes add monoelemental 1,4-cyclohexandione (1.01 g, 6.4 mmol). The reaction mixture was left to warm to room temperature for two hours and then quenched by adding 10 ml of water. The mixture is extracted twice using the UYa EtOAc. The combined extracts are dried and concentrated. After treatment with the help of a flash chromatography column using 20-40% methanol in EtOAc and 0.5% NH4OH, get 0,85 g oil (54% yield), MS: 293,20 (M++1).

Stage D

4-{5-[(dimethylamino)methyl]pyridine-2-yl}-4-hydroxycyclohexanone.

8-{5-[(dimethylamino)methyl]pyridine-2-yl}-1,4-dioxaspiro[4,5]Decan-8-ol (0,85 g, 2.9 mmol) dissolved in 10 ml of THF and add 10 ml of 2n. HCl solution. After stirring for two hours the reaction mixture is neutralized to about pH 8-9 by adding a saturated aqueous solution of NaHCO3and twice extracted using EtOAc. The combined extracts are dried and concentrated, receiving and 0.37 g of a white solid (51% yield), MS: 249,2 (M++1).

Stage E

N-(2-{[(3R)-1-(4-{5-[(dimethylamino)methyl]pyridine-2-yl}-4-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from the ketone from step D in accordance with the method of example 114. MS 548 (M+H)+.

Compounds of the following examples is obtained by methods analogous to those disclosed in the examples 114-121.

Example No.RMS (M+H)+
122pyridine-3-yl491
123pyridine-4-yl491
1246-methylpyridin-2-yl505
1255-methylpyridin-2-yl505
1264-methylpyridin-2-yl505
1271-oxidability-3-yl507
1281-oxidability-4-yl507
1291-oxidability-2-yl507
1306-methoxypyridine-2-yl521
131the quinoline-4-yl541
1324-cyanophenyl515
1333-cyanophenyl515
134 4-(methylaminomethyl)phenyl547
1354-(ethylaminomethyl)phenyl561
1364-(isopropylaminocarbonyl)phenyl575
1374-(tert-butylaminoethyl)phenyl589
1384-(dimethylaminoethyl)phenyl561
1394-[(azetidin-1-yl)carbonyl]phenyl573
1404-[(pyrrolidin-1-yl)carbonyl]phenyl587
1414-[(morpholine-4-yl)carbonyl]phenyl603
1424-(dimethylaminoethyl)-2-were575
1432-methyl-4-(methylaminomethyl)phenyl561
1443-methyl-4-(methylaminomethyl)phenyl561
145 4-(dimethylaminoethyl)-3-were575
1463-methyl-4-(pyrrolidin-1-ylcarbonyl)phenyl601
1474-(dimethylaminoethyl)-3-forfinal579
1484-[(2,2,2-triptorelin)aminocarbonyl]phenyl615
1493-fluoro-4-(methylaminomethyl)phenyl565
1504-(ethylaminomethyl)-3-forfinal579
1513-(methylaminomethyl)phenyl547
1523-(dimethylaminoethyl)phenyl561
1535-(dimethylaminoethyl)-2-methoxyphenyl591
1542-methoxy-5-(methylaminomethyl)phenyl577
1553-(methylaminoquinoline)phenyl 562
1566-(morpholine-4-yl)pyridine-3-yl576
1576-dimethylaminopyridine-3-yl534
1586-isopropylaminomethyl-3-yl549
1596-(pyrrolidin-1-yl)pyridine-3-yl560
1606-cyclopropylamino-3-yl546
1616-ethoxypyridine-3-yl535
1626-(2-floratone)pyridine-3-yl553
1636-(2,2-diflorasone)pyridine-3-yl571
1646-(2,2,2-triptoreline)pyridine-3-yl589
165phenyl490
1664-were504
167508
1683-forfinal508
1694-bromophenyl568
1704-iodophenyl616
1715-(pyrrolidin-1-ylcarbonyl)-2-pyridyl588
1725-(morpholine-4-ylcarbonyl)-2-pyridyl604
1735-dimethylaminoethyl-2-pyridyl562
1744-methylaminomethyluridine562
1756-(1-hydroxy-1-methylethyl)pyridine-3-yl549
1764-(1-hydroxy-1-methylethyl)phenyl548
1774-(methoxymethyl)phenyl534
1783-fluoro-4-(methoxymethyl)phenyl552
1794-(dimethylaminomethyl)phenyl547
1804-(dimethylaminomethyl)-3-forfinal565
1811H-indazol-5-yl530
1821-methyl-1H-indazol-5-yl544
1832-methyl-1H-indazol-5-yl544

Example 184

Stage A

4-(l,4-dioxaspiro[4,5]Dec-7-EN-8-yl)benzonitrile.

To a solution of 4-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)benzonitrile (7,8 g) in methylene chloride (100 ml), add triethylamine (21 ml) at room temperature. The solution is cooled to -40°C and then added dropwise to methylchloride (4,7 ml). The reaction mixture was stirred at -40°C for 30 minutes, then gradually warmed to room temperature and continuously stirred during the night. The reaction is quenched using saturated aqueous solution of NaHCO3. The aqueous layer was extracted with methylene chloride. The combined organic extracts washed with saturated salt solution, dried over Na2SO4, then evaporated. The remainder of the colon cleanse is the offered by chromatography (hexane/EtOAc=5/1), receiving the product of 5.2 g of white solids (yield: 71%):1NMR (CDCl3) δ: 7,62-of 7.55 (2H, m), 7,50 was 7.45 (2H, m), 6,17-6,13 (1H, m), was 4.02 (4H, s), 2,68-2,62 (2H, m), 2,53-2,47 (2H, m), 1,96-of 1.92 (2H, m); MS: 242 (M+1)+.

Stage B

4-(l,4-dioxaspiro[4,5]Dec-7-EN-8-yl)benzoic acid.

A mixture of 4-(l,4-dioxaspiro[4,5]Dec-7-EN-8-yl)benzonitrile (5,2 g 0,021 mol) in 190 ml of 2-methoxyethanol and 190 ml of 2,5h. NaOH is heated on a steam bath for 15 hours. The solution is cooled in a bath with ice, the pH adjusted to 7-8 using concentrated HCl, and evaporated to dryness. Add water (375 ml) and the pH adjusted to 2 using HCl. Yellow-brown solid is filtered off and washed with water, getting to 5.3 g (94% yield) of 4-(l,4-dioxaspiro[4,5]Dec-7-EN-8-yl)benzoic acid:1NMR (CDCl3) δ: 8,06 shed 8.01 (2H, m), 7,53-7,46 (2H, m), 6,18-6,14 (1H, m), a 4.03 (4H, s), 2,73-to 2.67 (2H, m), 2,52-2,49 (2H, m), 2.00 in of 1.93 (2H, m); MS: 260 (M+1)+.

Stage C

4-(l,4-dioxaspiro[4,5]Dec-8-yl)benzoic acid.

To a solution of 5.3 g of 4-(l,4-dioxaspiro[4,5]Dec-7-EN-8-yl)benzoic acid in 30 ml of methanol is added 2.3 g of Pd/C (10%by weight). The suspension is stirred in an atmosphere of H2(balloon) for 1 hour, filtered through a layer of celite and concentrated to dryness, obtaining the desired product (5.2 g, yield: 97%) as white solids:1NMR (CDCl3) δ: 8,06 shed 8.01 (2H, m), 7,58-7,53 (2H, m), was 4.02 (4H, s), 2,73-to 2.67 (2H, m), 2,70-2,61 (1H, m), 1.93 and-of 1.64 (8H, m); MS: 262 (M+1)+.

Stage D

4-(l,4-dioxaspiro[4,5]Dec-8-yl)-N,N-dimethylbenzamide.

564 mg (2 mmol) of 4-(l,4-dioxaspiro[4,5]Dec-8-yl)benzoic acid, N,N-dimethylamine (1.2 ml, 2.0m solution in THF), BOP reagent (1.07 g, 2.4 mmol) and 0.8 ml (6 mmol) of triethylamine are dissolved in 15 ml of DMF at room temperature. The reaction mixture was stirred at room temperature overnight. The result chromatography on silica gel (flash chromatography)using a mixture of 50% ethyl acetate-hexane to obtain 466 mg (80%) of the desired product, 4-(l,4-dioxaspiro[4,5]Dec-8-yl)-N,N-dimethylbenzamide:1NMR (CDCl3) δ: 7,39 (2H, d, J=11,6 Hz), 7,29 (2H, d, J=0.6 Hz), 3,93 (4H, s), 3,17-2,99 (7H, m), 2,55-2,49 (4H, m), 2.13 and is 2.10 (2H, m), 2.00 in 1,90 (2H, m); MS: 289 (M+1)+.

Stage E

N,N-dimethyl-4-(4-oxocyclohexyl)benzamide.

466 mg (1.6 mmol) 4-(l,4-dioxaspiro[4,5]Dec-8-yl)-N,N-dimethylbenzamide dissolved in a mixed solvent consisting of 8 ml of THF and 8 ml of 1N. aqueous HCl, at room temperature. The reaction mixture was then stirred at 60°C for 1 hour. The solution is cooled to room temperature, the pH adjusted to 7-8 with saturated aqueous solution of NaHCO3. The organic layer is isolated and the aqueous layer was twice extracted with EtOAc (20 ml×2). The combined organic extracts dried over MgSO4is evaporated, getting oily residue. The result chromatography on silica gel (flash chromatography)using a mixture of 40% ethyl acetate-hexane to obtain 360 mg (90%) of the desired product, N,N-dimethyl-4-(4-oxocyclohexyl)benzamide.1NMR (CDCl3) δ: 7,39 (2H, d, J=11,6 Hz), 7,29 (2H, d, J=a 10.6 Hz), 3,15-2,99 (7H, m), 2,56-2,49 (4H, m), 2,15-2,10 (2H, m), 2,01-of 1.94 (2H, m); MS: 245 (M+1)+.

Stage F

N,N-dimethyl-4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)benzamide.

100 mg (0.4 mmol) of N,N-dimethyl-4-(4-oxocyclohexyl)benzamide and 126 mg (0.4 mmol) of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide are dissolved in 10 ml of methylene chloride. To the solution was added 170 mg (0.8 mmol) of triacetoxyborohydride sodium. The reaction mixture was stirred at room temperature for 2 hours. The result chromatography on silica gel get the final target product 45 mg (top spot on TLC and the first peak on HPLC), yield: 22%. MS: 545 (M+1)+.

Compounds of the following examples get the same way.

Example No.RMS (M+H)+
1854-(methylaminomethyl)phenyl531
1864-(morpholine-4-ylcarbonyl)phenyl587
1874-(piperidine-1-ylcarbonyl)phenyl585
1883-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl589
1895-(pyrrolidin-1-ylcarbonyl)pyridine-2-yl572
1905-(dimethylaminoethyl)pyridine-2-yl546
1915-(morpholine-4-ylcarbonyl)pyridine-2-yl588
192pyridine-2-yl475
193pyridine-3-yl475
194pyridine-4-yl475
1951-oxidability-2-yl491
1961-oxidability-3-yl491
197 1-oxidability-4-yl491
198the quinoline-4-yl525
1996-methoxypyridine-3-yl505
2006-(morpholine-4-yl)pyridine-3-yl560
2014-(dimethylaminomethyl)phenyl531
2025-(dimethylaminomethyl)pyridine-2-yl532
2035-(dimethylaminoethyl)pyridine-2-yl546
2044-[hydroxy(pyridin-3-yl)methyl]phenyl581
2056-[(hydroxy(pyridin-3-yl)methyl]pyridine-3-yl582
2066-(dimethylaminoethyl)pyridine-3-yl546
2074-(4-hydroxypiperidine-1-ylcarbonyl)phenyl601
208 4-(4-methoxypiperidine-1-ylcarbonyl)phenyl615
2095-(4-methoxypiperidine-1-ylcarbonyl)pyridine-2-yl616
2106-(4-methoxypiperidine-1-ylcarbonyl)pyridine-3-yl616

Example 211

Stage A

l,4-dioxaspiro[4,5]Decan-8-ol.

To monoelemental 1,4-cyclohexandione (5.0 g, 32 mmol) in 20 ml of a mixture of MeOH/water (1:1) is added NaBH4(1,21 g, 32 mmol). The mixture is stirred at room temperature overnight. MeOH is removed on a rotary evaporator. The aqueous layer was extracted with EtOAc (3×). The combined organic layers are dried

(MgSO4and focus, getting the oil that is stored under high vacuum overnight, getting 5,12 g l,4-dioxaspiro[4,5]Decan-8-ol in the form of oil. MC(EI) calculated: (M+H)+=159,1; found: 159,2.

Stage B

8 phenoxy-1,4-dioxaspiro[4,5]decane.

To a solution of l,4-dioxaspiro[4,5]Decan-8-ol (1,05 g, 6,63 mmol), phenol (0.75 g, of 7.95 mmol), triphenylphosphine (1,91 g, 7,29 mmol) in CH2Cl2(20 ml) add isopropylaminocarbonyl (1,57 ml of 7.95 mmol). After stirring overnight at room temperature in a nitrogen atmosphere, the reaction mixture con is intronaut. The residue is subjected to flash chromatography using a mixture of 10:90 hexane-EtOAc, getting 1,09 g 8 phenoxy-1,4-dioxaspiro[4,5]decane. MS (EI) calculated: (M+H)+=235,1; found: 235,0.

Stage C

4-phenoxytoluene.

A solution of 8-phenoxy-1,4-dioxaspiro[4,5]decane (1,05 g, 4,48 mmol) in 20 ml THF/3h. HCl (1:1) is stirred over night at room temperature. The aqueous portion extracted with EtOAc (3×). The combined organic layers are dried (MgSO4and concentrate, receiving 4-penicillamine in the form of oil. MS(EI) calculated: M+H=191,1; found: 191,0.

Stage D

N-(2-oxo-2-{[(3R)-1-(4-phenoxytoluene)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamid.

To a mixture of 4-penicillamine (0,091 g, 0.475 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide in 2% AcOH/CH2Cl2(10 ml) was added NaB(OAc)3H (0,134 g, 0,634 mmol). After stirring overnight at room temperature in a nitrogen atmosphere, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous portion extracted with EtOAc (3×). The combined organic layers are dried (MgSO4), concentrated and subjected to flash chromatography (EtOAc to EtOAc:MeOH:Et3N=9:1:0,1), receiving 0.12 g specified in the connection header. MS(EI) calculated: (M+H)+=490,2; found: 490,0.

Example 212

Stage A

8-(benzyloxy)-1,4-dioxaspiro[4,5]decane.

To a mixture of l,4-dioxaspiro[4,5]Decan-8-ol (1.18 g, 7,46 mmol) and NaH (0,358 g, 8,96 mmol) in DMF (5 ml) at 0°C add benzylbromide (1,06 ml of 8.95 mmol). After stirring overnight under nitrogen atmosphere add water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic layers are dried (MgSO4), concentrated and subjected to flash chromatography using a mixture of 10% EtOAc/hexane, getting 1,524 g specified in the connection header. MS(EI) calculated: (M+1)+=249,1; found: 249,2.1NMR (300 MHz, CDCl3) δ: (ppm) to 7.35 (5H, m)to 4.52 (2H, s), of 3.95 (4H, m), 3,5 (1H, m), 1,95 of 1.50 (8H, m).

Stage B

4-(benzyloxy)cyclohexanone.

Specified in the header of the connection get on A stage in accordance with the method disclosed for the stage With an example 211. MS(EI) calculated: (M+H)+=205,1; found: 205,0.

Stage C

N-[2-({(3R)-1-[4-(benzyloxy)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the header of the connection get on stage B in accordance with the method disclosed for stage D of example 211. MS(EI) calculated: (M+H)+=504,2; found: 504,4.

Example 213

Stage A

4,4-diphenylsiloxane.

In the apparatus PA is the RA for the hydrogenation put 4,4-diphenyl-2-cyclohexen-1-he (0,91 g, 3,66)dissolved in methanol (20 ml), then add 10% Pd/C (0.2 g). This mixture hydronaut at 50 psi overnight. After the catalyst is filtered off and washed with methanol, filtrate was concentrated in vacuo, obtaining of 0.90 g of 4,4-diphenylsiloxane. MS(EI) calculated: M+H=251,1; found: 251,1.

Stage B

N-(2-{[(3R)-1-(4,4-diphenylsiloxane)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the connection get on A stage in accordance with the method disclosed for stage D of example 211. MS(EI) calculated: (M+H)+=550,3; found: 550,5.

Example 214

Stage A

Tert-butyl[(3R)-1-(TRANS-2-hydroxycyclohexyl)pyrrolidin-3-yl]carbamate.

In a vial was placed cyclohexenone (2,34 ml, 23,2), tert-butyl(3R)-pyrrolidin-3-ylcarbamate (2,16 mmol) and MeOH (2 ml). A vial with a mixture sealed, heated at 60°C and stirred overnight. The reaction mixture was concentrated, receiving 3,29 g of tert-butyl[(3R)-1-(2-hydroxycyclohexyl)pyrrolidin-3-yl]carbamate.

MS(EI) calculated: (M+H)+=RUB 285.2; found: 285,1.

Stage B

Tert-butyl{(3R)-1-[TRANS-2-(benzyloxy)cyclohexyl]pyrrolidin-3-yl}carbamate.

To a mixture of tert-butyl[(3R)-1-(TRANS-2-hydroxycyclohexyl)pyrrolidin-3-yl]carbamate (0,70 g of 2.46 mmol) and 60% NaH (to 0.108 who, a 2.71 mmol) in DMF (5 ml) at 0°C add benzylbromide (0,79 ml, a 2.71 mmol). After stirring overnight under nitrogen atmosphere add water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic layers are dried (MgSO4), concentrated and subjected to flash chromatography (EtOAc to 10% MeOH/EtOAc)to give 0,60 g specified in the connection header. MS(EI) calculated: (M+H)+=375,3; found: 375,4.

Stage C

(3R)-1-[TRANS-2-(benzyloxy)cyclohexyl]pyrrolidin-3-amine.

A mixture of tert-butyl{(3R)-1-[2-(TRANS-benzyloxy)cyclohexyl]pyrrolidin-3-yl}carbamate (0,60 g 1,602 mmol) in 4n. HCl/dioxane (10 ml) was stirred at room temperature for 1 hour. The solution is concentrated and receiving 0.55 g specified in the title compound as HCl salt 2. MS(EI) calculated: (M+1)+=275,2; found: 275,3.

Stage D

N-[2-({(3R)-1-[TRANS-2-(benzyloxy)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

To mix the salt solution 2 HCl (3R)-1-[TRANS-2-(benzyloxy)cyclohexyl]pyrrolidin-3-amine (0.14 g, 0.45 mmol) and (3 triphtalocyaninine)acetic acid (0,111 g, 0.45 mmol) in CH2Cl2(5 ml) was added Et3N (0,188 ml, 1.35 mmol) and then EDC (0,0863 g, 0.45 mmol) and HOBt (0,069 g, 0.45 mmol). The mixture is stirred at room temperature overnight. Then the reaction mixture is izbavlyayut EtOAc and washed with saturated Na 2CO3and a saturated solution of salt. The organic layers are dried (MgSO4), concentrated and subjected to flash chromatography (EtOAc to 10% MeOH/EtOAc)to give 0,186 g specified in the connection header. MS(EI) calculated: M+1=504,2; found: 504,4.

Example 215

Stage A

Tert-butyl[(3R)-1-(CIS-2-asadollahi)pyrrolidin-3-yl]carbamate.

To a mixture of tert-butyl[(3R)-1-(2-hydroxycyclohexyl)pyrrolidin-3-yl]carbamate (3,29 g, 11,60 mmol) and Et3N (3,23 ml, 23,17) in CH2Cl2(20 ml) was added MsCl (1.08 ml, 12,86 mmol) at 0°C. After stirring overnight under nitrogen atmosphere add water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic layers are dried (MgSO4) and concentrate. The residue is mixed with NaN3in 20 ml of DMF and stirred at 80°C overnight under nitrogen atmosphere. Then the reaction mixture was diluted with EtOAc and washed with water (3×). The organic layers are dried (MgSO4and concentrate, receiving 2,87 g specified in the connection header. MS(EI) calculated: (M+H)+=310,2; found: 310,1.

Stage B

(3R)-1-(CIS-2-asadollahi)pyrrolidin-3-amine.

A mixture of tert-butyl[(3R)-1-(CIS-2-asadollahi)pyrrolidin-3-yl]carbamate (0,57 g 1,842 mmol) in 4n. HCl/dioxane (10 ml) was stirred at room temperature for 1 hour. The solution is concentrated and receiving 0,48g specified in the title compound as HCl salt. MS(EI) calculated: (M+H)+=210,2; found: 210,2.

Stage C

N-(2-{[(3R)-1-(CIS-2-asadollahi)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

To a stirred solution of (3R)-1-(CIS-2-asadollahi)pyrrolidin-3-amine (0,453 g 1,842 mmol) and (3 triphtalocyaninine)acetic acid (0,478 g, 1,934 mmol) in CH2Cl2(15 ml) was added Et3N (or 0.57 ml, 4,06 mmol)and then EDC (0,389 g, 2.03 mmol) and HOBt (0,287 g, 2,13 mmol). The mixture is stirred at room temperature for 3 hours. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3and a saturated solution of salt. The organic layer is dried (MgSO4), concentrated and subjected to flash chromatography (EtOAc to 10% MeOH/EtOAc)to give 0,745 g specified in the connection header. MS(EI) calculated: (M+H)+=RUR 439,3; found: 439,4.

Stage D

N-(2-{[(3R)-1-(CIS-2-aminocyclohexane)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

In a Parr apparatus for hydrogenation placed N-(2-{[(3R)-1-(CIS-2-asadollahi)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (0,745 g, 1.70 mmol)dissolved in methanol (20 ml), then add 10% Pd/C (0.15 g). The mixture hydronaut at 50 psi for 3 hours. After the catalyst is filtered off and washed with methanol, the filtrate contentresult vacuum, getting to 0.70 g of N-(2-{[(3R)-1-(CIS-2-aminocyclohexane)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide. MS(EI) calculated: (M+H)+=413,2; found: 413,3.

Stage E

N-[2-({(3R)-1-[CIS-2-(benzoylamine)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

To a stirred solution of N-(2-{[(3R)-1-(CIS-2-aminocyclohexane)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (0,48 g, 0.6 mmol) and benzoic acid (0,088 g to 0.72 mmol) in CH2Cl2(5 ml) was added Et3N (0.25 ml, 1.8 mmol)and then EDC (was 0.138 g, to 0.72 mmol) and HOBt (0,097 g to 0.72 mmol). The mixture is stirred at room temperature overnight. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3and a saturated solution of salt. The organic layer is dried

(MgSO4), concentrated and subjected to flash chromatography (EtOAc to 10% MeOH/EtOAc)to give 0,13 g specified in the connection header. MS(EI) calculated: (M+H)+=from 517.2; found: 517,3.

Example 216

N-{2-oxo-2-[((3R)-1-{CIS-2-[(phenylacetyl)amino]cyclohexyl}pyrrolidin-3-yl)amino]ethyl}-3-(trifluoromethyl)benzamid.

Specified in the header connection receive in accordance with the method of example 215. MS(EI) calculated: (M+H)+=531,3; found: 531,3.

Example 217

N-[2-({(3R)-1-[CIS-2-(gasoline is amino)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

To a mixture of benzaldehyde (0,061 ml, 0.6 mmol) and N-(2-{[(3R)-1-(CIS-2-aminocyclohexane)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (0,278 g to 0.60 mmol) in CH2Cl2(10 ml) add

NaB(OAc)3H (0,128 g, 0.60 mmol). After stirring overnight at room temperature in a nitrogen atmosphere, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers are dried over MgSO4), concentrated and subjected to flash chromatography (EtOAc to EtOAc:MeOH:et 3 n=9:1:0.5)to give 0.21 g specified in the connection header. MS(EI) calculated: (M+H)+=503,3; found: 503,4.

Example 218

Stage A

8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

A solution of n-utility (8,1 ml of 1.6 m solution in hexane, 12,92 mmol) are added to the thiazole (1.0 g, 11,75 mmol) in THF (10 ml) at -78°C under stirring in nitrogen atmosphere. After stirring at -78°C for 1 hour is added by syringe a solution of monoelemental 1,4-cyclohexandione (1.84 g, 11,75 mmol) in THF (10 ml) to a solution of lithium compounds and stirred for 3 hours at -78°C. Add water (5 ml), the reaction mixture is heated to room temperature and extracted using EtOAc (3×). The combined organic layers are dried (MgSO4), filtered, concentrated in vacuo and subjected to what cromatografia, getting 2,531 g of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol with a yield of 89%. MS(EI) calculated: (M+H)+=242,1; found: 242,2.

Stage B

4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanone.

A solution of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol (1.0 g, 4.14 mmol) in 20 ml THF/3h. HCl (1:1) is stirred for 1 hour at 50°C. After cooling to room temperature, the mixture is treated with Na2CO3to pH 8 and extracted with EtOAc (3×). The combined organic layers washed with saturated NaCl solution, dried (MgSO4and concentrate the receiving of 0.82 g of 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanone with 99% yield. MS(EI) calculated: (M+H)+=198,1; found: 198,2.

Stage C

N-[2-({(3R)-1-[4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

To a mixture of 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanone (0.075 g, 0.38 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide (0.10 g, MX 0.317 mmol) in 2% AcOH/CH2Cl2(10 ml) was added NaB(OAc)3H (0,134 g, 0,634 mmol). After stirring overnight at room temperature in a nitrogen atmosphere, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous portion extracted with EtOAc (3×). The combined organic layers are dried (MgSO4), concentrated and subjected the Ute flash chromatography [EtOAc to MeOH/EtOAc (1:9) and then to 5% MeOH/EtOAc/Et 3N (1:9:0.5)], getting 0,141 g specified in the connection header with 90% yield. MS(EI) calculated: (M+H)+=497,2; found: 497,3.

Example 219

Stage A

8-(5-ethyl-1,3-thiazol-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

A solution of n-utility (5,70 ml of 1.6 m solution in hexane, 9,12 mmol) is added to 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4,5]decane-8-Olu (1,00 g, 4.14 mmol) in THF (10 ml) at -78°C under stirring in nitrogen atmosphere. After stirring at -78°C for 1 hour ethyliodide (0,736 ml, 9,12 mmol) are added to a solution of lithium compounds via syringe at -78°C. the Reaction mixture was left to slowly warm to room temperature and stirred over night. Add water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic layers washed with saturated NaCl, dried (MgSO4), concentrated and subjected to flash chromatography using 20% EtOAc/hexane, getting 0,79 g specified in the connection header with 71% yield. MS(ED calculated: (M+H)+=270,1; found: 270,1.

Stage B

4-(5-ethyl-1,3-thiazol-2-yl)-4-hydroxycyclohexanone.

Specified in the title compound is obtained from katala with A stage, using a method analogous opened in stage B of example 218. MS(EI) calculated: (M+H)+=226,1; found: 226,2.

Stage C

N-[2-({(3R)-1-[4-(5-this is l-1,3-thiazol-2-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from the ketone from step B, using the same method of example 218. MS(EI) calculated: (M+H)+=525,2; found: 525,2.

Example 220

Stage A

2-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)-1,3-thiazole-4-carboxylic acid.

A solution of n-utility (17,1 ml of 1.6 m solution in hexane 27,35 mmol) is added to 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4,5]decane-8-Olu (3.00 g, 12,43 mmol) in THF (50 ml) at -78°C under stirring in nitrogen atmosphere. After stirring at -78°C for 1 hour dry ice (10 g, 227 mmol) are added to a solution of a lithium compound and stirred for 2 hours at -78°C. water is Added and the solution warmed to room temperature. The mixture was then treated with 1N. HCl to pH 3-4 and extracted with EtOAc (3×). The combined organic layers washed with saturated NaCl solution, dried (MgSO4), concentrated and subjected to chromatography (EtOAc to 1% AcOH/EAOAc), receiving of 3.23 g of 2-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)-1,3-thiazole-4-carboxylic acid. MS(EI) calculated: (M+H)+=286,1; found: 286,0.

Stage B

2-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)-N-methyl-1,3-thiazole-4-carboxamide.

To a stirred solution of 2-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)-1,3-thiazole-4-carboxylic acid (0,30 g, 1.05 mmol) and methylamine (2M in THF, 2 ml, 4 mmol) in CH2 2(10 ml) was added Et3N (0.5 ml, 3.6 mmol)and then EDC (0,242 g, 1,262 mmol) and HOBt (0,193 g of 1.26 mmol). The mixture is stirred at room temperature overnight. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3and a saturated solution of salt. The organic layer is dried (MgSO4), concentrated and subjected to flash chromatography (50% EtOAc EtOAc)to give 0.16 g specified in the connection header with a 50% output. MS(EI) calculated: (M+H)+=299,1; found: 299,0.

Stage C

2-(1-hydroxy-4-oxocyclohexyl)-N-methyl-1,3-thiazole-4-carboxamide.

Specified in the title compound is obtained by turning Catala from stage B to the ketone using a method analogous opened on stage In example 218. MS(EI) calculated: (M+H)+=255,1; found: 255,0.

Stage D

2-(1-hydroxy-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino]acetyl)amino}pyrrolidin-1-yl}cyclohexyl)-N-methyl-1,3-thiazole-5-carboxamide.

Specified in the title compound is obtained from the ketone from step C using the same method of example 218. MS(EI) calculated: (M+H)+=554,2; found: 554,1.

Example 221

Stage A

8-(1,3-thiazol-5-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

2-TMS-thiazole (2.5 g, 15,89 mmol) are added to a solution of n-utility (11.9 ml 1.6 m solution in hexane, 1907 mmol) in THF (20 ml) at -78°C under stirring in nitrogen atmosphere. After stirring at -78°C for 0.5 hours, the solution of monoelemental 1,4-cyclohexandione (2,48 g, 15,89 mmol) in THF (20 ml) was added to a solution of lithium compounds via syringe and stirred for 1 hour at -78°C. Add water (5 ml) and EtOAc, the reaction mixture is heated to room temperature and extracted using EtOAc (3×). The combined organic layers are dried (MgSO4), filtered and crystallized from EtOAc, obtaining 3.4 g of 8-(1,3-thiazol-5-yl)-1,4-dioxaspiro[4,5]Decan-8-ol with 90% yield. MS(EI) calculated: (M+H)+=242,1; found: 242,1.

Stage B

3-(trifluoromethyl)-N-[2-({(3R)-1-[4-hydroxy-4-(1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]benzamide.

Specified in the title compound is obtained from 8-(1,3-thiazol-5-yl)-1,4-dioxaspiro[4,5]Decan-8-ol, using the same method of example 218. MS(EI): Calculated: (M+H)+497,1, found: 497,1

Example 222

Stage A

Methyl[5-(8-hydroxy-1,4-dioxaspiro[4,5]Dec-8-yl)-1,3-thiazol-2-yl]carbamate.

A solution of n-utility (10.0 ml 1.6 m solution in hexane, 15,93 mmol) is added to methyl-1,3-thiazol-2-ylcarbamate (1,05 g, only 6.64 mmol) in THF (10 ml) at -78°C under stirring in nitrogen atmosphere. After stirring at -78°C for 1 hour the solution monoelemental 1,4-cyclohexandione (1.84 g, 11,75 mmol) in THF (10 ml) are added to a solution if avago connection via a syringe at -78°C. The reaction mixture was left to slowly warm to room temperature and stirred over night, add water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic layers washed with saturated NaCl, dried (MgSO4), concentrated and subjected to flash chromatography (50% EtOAc/hexane to 75% EtOAc/hexane)to give 0,744 g specified in the connection header with 51% yield. MS(EI) calculated: (M+H)+=315,1; found: 315,0.

Stage B

Methyl[5-(1-hydroxy-4-oxocyclohexyl)-1,3-thiazol-2-yl]carbamate.

Specified in the title compound is obtained from Catala from step A, using the method analogous opened on stage In example 218. MS(EI) calculated: (M+H)+=270,1; found: 270,0.

Stage C

Methyl[5-(1-hydroxy-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)-1,3-thiazol-2-yl]carbamate.

Specified in the title compound is obtained from the ketone from step B, using the same method of example 218. MS(EI) calculated: (M+H)+=569,2; found: 569,1.

Example 223

Stage A

2-isopropyl-1,3-thiazole.

In a Parr apparatus for hydrogenation placed 2-Isopropenyl-1,3-thiazole (1.8 g, 14,38)dissolved in methanol (25 ml), then added Pd(OH)2(0.6 g). This mixture hydronaut at 50 psi in t is an increase of 48 hours. After the catalyst is filtered off and washed with methanol, filtrate was concentrated in vacuo, obtaining of 1.65 g of 2-isopropyl-1,3-thiazole with 92% yield. MS(EI) calculated: (M+H)+=128,1; found: USD 128.0.

Stage B

8-(2-isopropyl-1,3-thiazol-5-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

Specified in the title compound is obtained from the intermediate from step A, using a method analogous opened on stage And example 221. MS(EI) calculated: (M+H)+=284,1; found: 284,2.

Stage C

4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanone.

A solution of 8-(2-isopropyl-1,3-thiazol-5-yl)-1,4-dioxaspiro[4,5]Decan-8-ol (0,714 g, 2,52 mmol) in 15 ml THF/1N. HCl (1:1) is stirred over night at room temperature. The mixture is treated with Na2CO3bringing the pH to 8, and extracted with EtOAc (3×). The combined organic layers washed with saturated NaCl solution, dried (MgSO4and concentrate, receiving 0.65 g of 4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanone with 98% yield. MS(EI) calculated: (M+H)+=240,1; found: 240,0.

Stage D

N-[2-({(3R)-1-[4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

In a Parr apparatus for hydrogenation placed 4-hydroxy-4-(2-isopropyl-1,3-enous is l-5-yl)cyclohexanone (0,363 g, of 1.52 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide (0,435 g, 1.38 mmol)dissolved in CH2Cl2(20 ml), then add 10% Pd(OH)2(0.8 g). The mixture hydronaut at 50 psi for 24 hours. After the catalyst is filtered off and washed with methanol, filtrate was concentrated in vacuo and subjected to chromatography, getting 0,345 g specified in the title compound in 62% yield. MS(EI) calculated: (M+1)+=539,2; found: 539,1.

Example 224

Stage A

8-(5-pyridin-3-yl-1,3-thiazol-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

A solution of n-utility (7,8 ml of 1.6 m solution in hexane, 12,45 mmol) is added to 8-(1,3-thiazol-5-yl)-1,4-dioxaspiro[4,5]decane-8-Olu (1.0 g, 4,15 mmol) in THF (20 ml) at -78°C under stirring in nitrogen atmosphere. After stirring at -78°C for 0.5 hours add 12.5 ml of 0.5 m solution of ZnCl2(6,23 mmol) in THF. The resulting mixture was stirred at room temperature for 0.5 hours and through a syringe add a mixture of 3-bromopyridine (and 0.40 ml, 4,15 mmol) and PdCl2(PPh3)2(0.11 g, 0.16 mmol) in 5 ml of THF. After boiling under reflux overnight the reaction is quenched using 10 ml of a saturated solution of NH4Cl. The aqueous layer was extracted using EtOAc (3×). The combined organic layers are dried (MgSO4), filtered, and conc the Ute in vacuo and subjected to chromatography getting to 0.68 g specified in the connection header with 52% yield. MS(EI) calculated: (M+H)+=319,1; found: 319,1.

Stage B

N-[2-({(3R)-1-[4-hydroxy-4-(5-pyridin-3-yl-1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from katala with A stage, using the same method of example 218. MS(EI): calculated: (M+H)+574,2;

found: 574,1.

The following examples get, using similar methods disclosed in the examples 218-224.

241
Example No.RMS(M+H)+
2255-(morpholine-4-ylcarbonyl)-1,3-thiazol-2-yl610
2265-aminocarbonyl-1,3-thiazol-2-yl540
2275-dimethylaminoethyl-1,3-thiazol-2-yl568
2285-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl594
2295-allyl-1,3-thiazol-2-yl 536
2305-propyl-1,3-thiazol-2-yl538
2315-ethylaminomethyl-1,3-thiazol-2-yl568
2325-phenyl-1,3-thiazol-2-yl573
2335-methyl-1,3-thiazol-2-yl511
2345-hydroxymethyl-1,3-thiazol-2-yl527
2355-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl555
2365-methoxymethyl-1,3-thiazol-2-yl541
2375-(pyridine-2-yl)-1,3-thiazol-2-yl574
2382-(pyrrolidin-1-yl)-1,3-thiazol-4-yl566
2392-(morpholine-4-yl)-1,3-thiazol-4-yl(M-H2O+H)+=564
2402-methyl-1,3-thiazol-5-yl511
2-(1-hydroxy-1-methylethyl)-1,3-thiazol-5-yl555
2422-(pyrrolidin-1-yl)-1,3-thiazol-5-yl566
2432 ethoxy-1,3-thiazol-5-yl541
2442-ethyl-1,3-thiazol-5-yl525
2452-(pyrrolidin-1-ylmethyl)-1,3-thiazol-5-yl580
2462-(morpholine-4-yl)-1,3-thiazol-5-yl582
2472-methoxymethyl-1,3-thiazol-5-yl541
2482-isobutyl-1,3-thiazol-5-yl553
2492-ethylaminomethyl-1,3-thiazol-5-yl568
2502-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-5-yl594
2512-(morpholine-4-ylcarbonyl)-1,3-thiazol-5-yl610
2-(pyridin-3-yl)-1,3-thiazol-5-yl574
2532-(pyridin-2-yl)-1,3-thiazol-5-yl574
2544-methyl-1,3-thiazol-2-yl511
2551,3-benzothiazol-2-yl547

Example 256

Stage A

2-(l,4-dioxaspiro[4,5]Dec-7-EN-8-yl)-1,3-thiazole.

To a mixture of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol (0.8 g, of 3.32 mmol) in pyridine (10 ml) at 0°C, add thionyl chloride (2.5 ml, to 34.3 mmol) under nitrogen atmosphere. After stirring for 2 hours at 0°C under nitrogen atmosphere add water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic layers washed with saturated NaCl, dried (MgSO4), concentrated and subjected to flash chromatography using a mixture of 10% EtOAc/hexane, getting 0.27 g specified in the connection header with 36% yield. MS(EI) calculated: (M+1)+=224,1; found: 224,2.

Stage B

2-(l,4-dioxaspiro[4,5]Dec-8-yl)-1,3-thiazole.

In a Parr apparatus for hydrogenation placed 2-(l,4-dioxaspiro[4,5]Dec-7-EN-8-yl)-1,3-thiazole (0,22 g, 0,99 mmol)dissolved in methanol (15 ml), then add 10% Pd/C (,08). This mixture hydronaut at 50 psi overnight. After the catalyst is filtered off and washed with methanol, filtrate was concentrated in vacuo, getting 0.21 g of 2-(l,4-dioxaspiro[4,5]Dec-8-yl)-1,3-thiazol with 95% yield. MS(EI) calculated: (M+1)+=226,1; found: 225,9.

Stage C

4-(1,3-thiazol-2-yl)cyclohexanone.

A solution of 2-(l,4-dioxaspiro[4,5]Dec-8-yl)-1,3-thiazole (0.21 g, of 0.93 mmol) in 10 ml THF/3h. HCl (1:1) is stirred for 2 hours at 50°C. After cooling to room temperature, the mixture is treated with Na2CO3bringing the pH to 8, and extracted with EtOAc (3×). The combined organic layers washed with saturated NaCl solution, dried (MgSO4and concentrate, receiving 0.16 g of 4-(1,3-thiazol-2-yl)cyclohexanone with access 95%. MS(EI) calculated: (M+H)+=182,1; found: 181,9.

Stage D

N-[2-oxo-2-({(3R)-1-[4-(1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)ethyl]-3-(trifluoromethyl)benzamid.

To a mixture of 4-(1,3-thiazol-2-yl)cyclohexanone (0,069 g, 0.38 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide (0.10 g, 0.32 mmol) in 2% AcOH/CH2Cl2(10 ml) was added NaB(OAc)3H (0,134 g, 0,634 mmol). After stirring overnight at room temperature in a nitrogen atmosphere, the reaction mixture was diluted with EtOAc and washed with saturated Na2 CO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers are dried (MgSO4), concentrated and subjected to flash chromatography [EtOAc to MeOH/EtOAc (1:9), then to 5% MeOH/EtOAc/Et3N (1:9:0,5)], getting 0,129 g specified in the connection header with the release of 85%. MS(EI) calculated: (M+H)+=of 480.2; found: 480,3.

Example 257

Stage And

2-(8-chloro-1,4-dioxaspiro[4,5]Dec-8-yl)-5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazole.

To a mixture of 8-[5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4,5]Decan-8-ol (0.2 g, of 3.32 mmol) in pyridine (3 ml) at 0°C is added thionyl chloride (0.5 ml, 6,86 mmol) under nitrogen atmosphere. The mixture is heated to room temperature and stirred over night. After the solution concentrate, add water and EtOAc. The aqueous layer was extracted with EtOAc (2×). The combined organic layers washed with saturated NaCl, dried (MgSO4), concentrated and subjected to flash chromatography (50% EtOAc/hexane to EtOAc)to give 0.10 g specified in the connection header with the release of 53%. MS(EI) calculated: (M+1)+=356,1; found: 357,0.

Stage B

2-(l,4-dioxaspiro[4,5]Dec-8-yl)-5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazole.

In a Parr apparatus for hydrogenation placed 2-(8-chloro-1,4-dioxaspiro[4,5]Dec-8-yl)-5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazole (0,095 g 0,266 mmol)dissolved in methanol (10 ml), then add the amount of 10% Pd/C (0.02 g). The mixture hydronaut at 50 psi overnight. After the catalyst is filtered off and washed with methanol, filtrate was concentrated in vacuo, getting 0.083 g of 2-(l,4-dioxaspiro[4,5]Dec-8-yl)-5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol with the release of 97%. MS(EI) calculated: (M+H)+=322,1; found: 322,0.

Stage C

4-[5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl]cyclohexanone.

Specified in the title compound is obtained from katala with stage B, using the method analogous opened on stage With an example 256. MS(EI) calculated: (M+H)+=279,1; found: 279,0.

Stage D

N-{2-oxo-2-[((3R)-1-{4-[5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]ethyl}-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from the ketone from step C using the same method of example 256. MS(EI) calculated: (M+H)+=578,2; found: 578,1.

Below in the examples, the compounds have a similar way.

Example 258

N-[2-oxo-2-({(3R)-1-[4-(2-thienyl)cyclohexyl]pyrrolidin-3-yl}amino)ethyl]-3-(trifluoromethyl)benzamid.

MS(EI): calculated: (M+H)+479,2 found: 479,3.

Example 259

3-(trifluoromethyl)-N-{2-[((3R)-1-{4-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)amine is]-2-oxoethyl}benzamide.

MS(EI): calculated: (M+H)+525,2, found: 525,2.

Example 260

3-(trifluoromethyl)-N-{2-[((3R)-1-{4-[5-(morpholine-4-ylcarbonyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}benzamide.

MS(EI): calculated: (M+H)+594,2 found: 594,2.

Example 261

Stage A

Tert-butyl{(3R)-1-[4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}carbamate.

In a Parr apparatus for hydrogenation placed 4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanone (0.50 g, is 2.09 mmol) and tert-butyl(3R)-pyrrolidin-3-ylcarbamate (0,373 g, 2.0 mmol)dissolved in CH2Cl2(20 ml), then add 10% Pd/C (0.12 g). The mixture hydronaut at 35 psi for 24 hours. After the catalyst is filtered off and washed with methanol, filtrate was concentrated in vacuo and subjected to chromatography using MeOH/EtOAc/Et3N (1:9:0,1), receiving of 0.62 g specified in the connection header with the release of 76%. MS(EI) calculated: (M+1)+=409,2; found: 410,2.

Stage B

4-[(3R)-3-aminopyrrolidine-1-yl]-1-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanol.

A mixture of tert-butyl{(3R)-1-[4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}carbamate (0.50 g, 1,22 mmol) in 4n. HCl/dioxane (10 ml) was stirred at room temperature for 1 hour. Will restaurantcenter, getting 0,397 g specified in the title compound as HCl salt 2. MS(EI) calculated: (M+1)+=309,2; found: 310,2.

Stage C

N-{(3R)-1-[4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}-4-oxo-4-[3-(trifluoromethyl)phenyl]butanamide.

To a stirred solution of 3 HCl salt of 4-[(3R)-3-aminopyrrolidine-1-yl]-1-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanol (0,233 g, 0,557 mmol) and 4-oxo-4-[3-(trifluoromethyl)phenyl]butane acid (0.15 g, 0.61 mmol) in DMF (5 ml) was added Et3N (0,34 ml of 2.44 mmol) and then BOP (0,296 g, 0.67 mmol). The mixture is stirred over night at room temperature. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3and a saturated solution of salt. The organic layer is dried (MgSO4), concentrated and subjected to flash chromatography (EtOAc to 10% MeOH/EtOAc)to give 0.075 g specified in the connection header. MS(EI) calculated: (M+H)+=538,2; found: 538,1.

Below in the examples, the compounds have a similar way.

Example 262

4-[3-(trifluoromethyl)phenyl]-N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)-4-oxobutanamide.

MS(EI): calculated: (M+H)+540,2 found: 540,2.

Example 263

4-[3-(trifluoromethyl)phenyl]-N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)-4-oxobutanamide.

MS(EI): calculated: (M+H)+540,2 found: 540,2.

Example 264

N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)-4-[3-(trifluoromethyl)phenyl]butanamide.

To a solution of N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)-4-oxo-4-[3-(trifluoromethyl)phenyl]butanamide (19.2 mg, being 0.036 mol) in methanol (1.0 ml) add tetrahydroborate sodium (2.7 mg, 0,071 mol) and the mixture is stirred for 1 hour. The mixture was purified using preparative HPLC, elwira H2O/CH3CN/0,05% TFA, getting the desired compound in the form of a mixture of two diastereoisomers (10 mg, 99.7 per cent pure). JHMS: 542,2 (M+H+100%);1NMR (CD3OD) δ: of 7.70 (s, 1H), 7,63-7,53 (m, 4H), 4.80 to of 4.77 (m, 1H)and 4.65 (s, 2H), 4,4 (m, 1H), 3.96 points-3,93 (m, 1H), 3,84-and 3.72 (m, 1H), 3,57-to 3.49 (m, 1H), 3,38 (s, 3H), 3,24-of 3.12 (m, 0,5H), 3,10-of 3.06 (m, 0,5H), 2,53 is 2.51 (m, 0,5H), 2,36-2,31 (m, 4,5H), 2,19 (s, 2H), 2,09 of 1.99 (m, 6H), 1,92 is 1.86 (m, 2H).

Example 265

Stage A

(3-tryptophanyl)sulfonyl]aminouksusnoy acid.

To a solution of glycine (0.75 g, mmol) in water (30 ml) and THF (30 ml) at 0°C portions over 5 minutes add 3-(trifluoromethyl)benzosulphochloride (2,44 g, 10 mmol). After complete addition, the reaction mixture is stirred for an additional 0.5 hour at room temperature and then cooled in a bath with ice. After acidification of reaction the th mixture of concentrated HCl to pH 1, the crude product is extracted with ethyl acetate. The organic extracts are combined, washed with saturated salt solution (50 ml), dried over sodium sulfate, concentrated in vacuo, forming a dense precipitate white solids. The product is recrystallized from aqueous ethanol, getting the right connection ([(3-tryptophanyl)sulfonyl]aminouksusnoy acid, 58%) as a white solid crystalline substances with the following characteristics: JHMS: 282,2 (M-H)+

Stage B

N-((3R)-1-{4-[5-(methoxymethyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)-2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)ndimethylacetamide.

To a solution

({[3-(trifluoromethyl)phenyl]sulfonyl}amino)acetic acid (64 mg, 0.22 mmol) dihydrochloride and 4-[(3R)-3-aminopyrrolidine-1-yl]-1-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexanol (72 mg, 0,19 mmol) in DMF (5 ml) at 0°C add TEA (38 mg, 0.38 mmol) and BOP, hexaflurophosphate (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium (99 mg, 0.22 mmol). The reaction mixture is stirred for 2 hours, quenched with water (5 ml) and extracted with ethyl acetate (2×25 ml). The organic extracts are combined, washed with saturated salt solution (10 ml), dried over sodium sulfate, concentrated in vacuo. The residue is subjected to chromatography on silica gel, elwira 1% ammonium hydroxide in a mixture of ethyl acetate/methanol (100/0 to 90/10). Appropriate coat the AI unite, getting two isomers of the desired compound in a ratio of 1:1 with the following characteristics: MS: 577,4 (M+H+100%).

Example 266

Stage A

3-(trifluoromethyl)benzaldehyde.

Into a flask containing 3-tripersonality (1,74 g, 10 mmol) and hydroxylamine hydrochloride (0,76 g, 11 mmol) in methanol (25 ml), add TEA (0.65 g, 11 mmol). The reaction mixture is heated at the boil under reflux for 3 hours, neutralized to pH 6.0 and extracted with ethyl acetate (3×20 ml). The organic extracts are combined, washed with saturated salt solution (20 ml), dried over sodium sulfate, concentrated in vacuo, obtaining 3-(trifluoromethyl)benzaldehyde (1.9 g) as a colourless oil. JHMS: 190,2 (M+H+, 100%).

Stage B

N-hydroxy-3-(trifluoromethyl)benzonorbornadiene

In a dry flask containing 3-(trifluoromethyl)benzaldehyde (1.89 g, 10 mol) in methylene chloride (100 ml)is added slowly N-chlorosuccinimide (1.40 g, 10.5 mmol) at 0°C. the Reaction mixture is heated at 45°C for 2 hours, poured onto ice, diluted with H2O (20 ml) and extracted with EtOAc (100 ml). The organic phase is washed with H2O (2×25 ml) and saturated salt solution (25 ml), dried over sodium sulfate, concentrated in vacuo, obtaining N-hydroxy-3-(trifluoromethyl)benzoperoxide olklore (2 g, 90%). JHMS: 224,4 (M+H)+.

Stage C

Methyl-3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylate.

Into a flask containing N-hydroxy-3-(trifluoromethyl)benzonorbornadiene (2.0 g, 8.9 mmol) and methyl acrylate (0.7 g, 8 mmol) in methylene chloride (100 ml) at 0°C in an inert atmosphere add TEA (0,90 g, 8,8 mmol). The reaction mixture is slowly warmed to room temperature, stirred for 20 hours, quenched with water (30 ml) and extracted with methylene chloride (2×50 ml). The organic extracts are combined, washed with saturated salt solution (50 ml), dried over sodium sulfate, concentrated in vacuo and subjected to chromatography on silica gel, elwira a mixture of methylene chloride/methanol (100/1 to 95/5).

The appropriate fractions are combined and concentrated in vacuo, obtaining methyl-3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylate (2.3 g, 100%): JHMS: 274,2 (M+N+, 100%);1NMR (CDCl3) δ: 8,03 (s, 1H), 7,92 (d, 1H), 7,71 (d, 1H), to 7.59 (DD, 1H), 5,28 (DD, 1H), 3,86 (s, 3H), 3,71 (DD, 2H).

Stage D

3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylic acid.

To a solution of methyl-3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylate (2.3 g, 8.4 mmol) in THF (10 ml) is added 2M sodium hydroxide solution in water (10 ml) at 0°C. the Reaction mixture is slowly heated to anatoy temperature, stirred for 2 hours, neutralized using 2n. HCl to pH 7 and extracted with ethyl acetate (2×50 ml). The organic extracts are combined, washed with saturated salt solution (50 ml), dried over sodium sulfate, concentrated in vacuo. The residue is subjected to chromatography on silica gel, elwira a mixture of methylene chloride/methanol (95/5 to 80/20). The appropriate fractions are combined and concentrated in vacuo, obtaining 3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylic acid (2,18 g,100%) as a white solid crystalline substances JHMS: 258,2 (M-N-, 100%).

Stage E

N-((3R)-1-{4-hydroxy-4-[2-(methoxymethyl)-1,3-thiazol-5-yl]cyclohexyl}pyrrolidin-3-yl)-3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxamide.

To a solution of dihydrochloride of 4-[(3R)-3-aminopyrrolidine-1-yl]-1-[2-(methoxymethyl)-1,3-thiazol-4-yl]cyclohexanol (90,0 mg, 0,234 mmol) in DMF (5 ml) is added 3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylic acid (60,7 mg, 0,234 mmol), hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (49,4 mg, 0,258 mmol) and TEA (28,4 mg, 0,281 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with water (5 ml) and extracted with ethyl acetate (2×25 ml). The organic extracts are combined, washed with saturated salt solution (10 ml), dried over sodium sulfate, concentrated in in the cosmology vacuum. The residue is subjected to chromatography on silica gel, elwira a mixture of 1% ammonium hydroxide in ethyl acetate/methanol (100/0 to 90/10). The appropriate fractions are combined to obtain CIS - and TRANS-isomers in a ratio of 1:1. Each isomer purified further by HPLC, elwira a mixture of N2O/CH3CN/TFA (10/90/0,05 to 100/0/0,05)to give the TFA salt of N-((3R)-1-{4-hydroxy-4-[2-(methoxymethyl)-1,3-thiazol-5-yl]cyclohexyl}pyrrolidin-3-yl)-3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxamide (40 mg, 31%) as solids. JHMS: 553 (M+H+100%). According to analytical HPLC and each fraction shows two peaks (1:1) and has a degree of purity greater than 95%.

Example 267

(4Z) and (4E)-4-(hydroxyimino)-N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)-4-[3-(trifluoromethyl)phenyl]butanamide.

To a solution of N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)-4-oxo-4-[3-(trifluoromethyl)phenyl]butanamide (19.2 mg, being 0.036 mmol) in methanol (1.0 ml) is added hydroxylamine hydrochloride (9,9 mg, 0.14 mmol) and TEA (14 mg, 0.14 mmol). After boiling under reflux for 4 hours the mixture is concentrated and the residue purified using preparative HPLC, elwira a mixture of H3O/CH3CN/0,05% TFA, getting the desired compound as TFA salt (15 mg, 97% purity). JHMS: 555,2 (M+H)+;1NMR (CD3OD) δ: 7,98 (s, 1H), 7,92 (m, 1H), to 7.67-of 7.55 (m, 3H), with 4.64 (s, 2H), or 4.31 (m, 1H), 3,86-3,66 (m, 2H), 3,50 is-3.45 (m, 1H), 3,44 (s, 3H), 3,20 (m, 0,5H), 3,11 (m, 2H), 2,98 (m, 0,5H), of 2.51 (m, 3H), 2,33 (m, 2H), 2,16 (, 2H), of 1.97 (m, 4H), of 1.84 (m, 2H).

Example 268

(4Z) and (4E)-4-(amoxiillin)-N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)-4-[3-(trifluoromethyl)phenyl]butanamide.

Specified in the header of the get connection using the same method of example 267. MS(M+H)+583,2.

Example 269

N-[2-({(3R)-1-[4-fluoro-4-(1,3-thiazol]-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

DAST (0.2 ml, 1.5 mmol) are added to N-[2-({(3R)-1-[4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (0.06 g, 0.12 mmol) in CH2Cl2(5 ml) at -78°C under stirring in nitrogen atmosphere. The solution is left to rise slowly to 0°C and stirred for 1 hour. Add water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic layers washed with saturated NaCl, dried (MgSO4), concentrated and purified using flash chromatography and HPLC with reversed phase, receiving 0,020 g specified in the connection header with the release of 31%. MS(EI) calculated: (M+H)+=499,2; found: 499,1.

Presented below in the examples, the compounds have a similar way.

Example 270

N-(2-{[(3R)-1-(4-fluoro-4-pyridin-3-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

MS(M+H)+493,2.

Example 271

N-[2-({(3R)-1-[4-fluoro-4-(6-methoxypyridine-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

MS(M+H)+523,2

Example 272

N-[2-({(3R)-[(1-{4-fluoro-4-[6-(1,3-oxazol-2-yl)pyridine-3-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamid.

MS(M+H)+560.

Example 273

N-(2-{[(3R)-1-(4-fluoro-4-{4-[(methylamino)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

MS calculated: (M+H)+549, found: 549.

Example 274

Stage A

8-pyrimidine-5-yl-1,4-dioxaspiro[4,5]Decan-8-ol.

A solution of n-utility (4,32 ml of 1.6 m solution in hexane, 6,92 mmol) are added to 5-bromopyrimidine (1.0 g, of 6.29 mmol) in THF (10 ml) at -78°C under stirring in nitrogen atmosphere. After stirring at -78°C for 1 hour to a solution of lithium compounds via syringe add solution monoelemental 1,4-cyclohexandione (0,982 g of 6.29 mmol) in THF (10 ml) and stirred for 4 hours at -78°C. Add water (5 ml), the reaction mixture is heated to room temperature and extragere is t, using EtOAc (3×). The combined organic layers are dried (MgSO4), filtered, concentrated in vacuo and subjected to chromatography, getting 0.18 g 8-pyrimidine-5-yl-1,4-dioxaspiro[4,5]Decan-8-ol with a yield of 12%. MS(EI) calculated: (M+H)+=237,1; found: USD 237.2.

Stage B

4-hydroxy-4-pyrimidine-5-illlogical.

A solution of 8-pyrimidine-5-yl-1,4-dioxaspiro[4,5]Decan-8-ol (0.14 g, 0.59 mmol) in 10 ml of a mixture of THF/1N HCl (1:1) is stirred for 24 hours at room temperature. The mixture is treated with Na2CO3to pH 8 and extracted with EtOAc (3×). The combined organic layers washed with saturated NaCl solution, dried (MgSO4and concentrate, receiving 0.11 g of 4-hydroxy-4-pyrimidine-5-illlogical with the release of 79%. MS(EI) calculated: (M+H)+=USD 192.1; found: USD 192.1.

Stage C

N-(2-{[(3R)-1-(4-hydroxy-4-pyrimidine-5-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from the ketone from step B, using the same method of example 218. MS(EI) calculated: (M+H)+=492,2; found: 492,2.

Example 275

Stage A

8-pyrimidine-2-yl-1,4-dioxaspiro[4,5]Decan-8-ol.

To a solution of 2-channelmarketing (200 mmol, 80 g), obtained in accordance with literature data (Tetrahedron, 1994, 50, 275-28), in THF (1 l) is added n-utility (240 mmol, 150 ml) at -78°C. the Reaction mixture is stirred for 30 minutes at -78°C and added l,4-dioxaspiro[4,5]decane-8-he (200 mmol, 30 g). The reaction mixture is left under stirring overnight, while it is heated to room temperature. Then the reaction is quenched using NH4Cl, and extracted using EtOAc (3×400 ml). The organic layers are combined, dried over MgSO4and concentrated in vacuo. The crude product used in the next stage.

Stage B

4-hydroxy-4-pyrimidine-2-illlogical.

To the product from step A (190 mmol, 44 g) in THF (200 ml) add a solution of HCl (300 mmol, 100 ml). The reaction mixture is stirred for 2 days, then the reaction mixture was washed with diethyl ether. The aqueous layer was then quenched using NaOH (50%), bringing the pH to 11. The aqueous layer was extracted using EtOAc (6×300 ml). The organic layers are combined, dried over MgSO4and concentrated in vacuo. The residue is purified using flash chromatography, obtaining the desired ketone (18 g, 49%). MS [M+H]+193,1

Stage C

N-{[(R)-1-(4-hydroxy-4-pyrimidine-2-illlogical)pyrrolidin-3-ylcarbonyl]methyl}-3-cryptomelane.

To the product from step C (62 mmol, 12 g) in CH2Cl2(500 ml) is added N-((3R)-pyrrolidin-3-ylcarbonyl)-3-crypto methylbenzamide (60 mmol, 20 g) and then triacetoxyborohydride sodium (100 mmol, 30 g). The reaction mixture is stirred for 2 hours and then quenched using NaOH (2 M), bringing the pH to 11. The reaction mixture is extracted using CH2Cl2(3×300 ml). The organic layers are combined, dried over MgSO4and then concentrated in vacuo. The residue is purified using flash chromatography to separate two diastereoisomers, and then treated using HPLC, getting the right diastereoisomer Amin. MS [M+H]+492,1.

Example 276

Stage A

8-pyridazin-3-yl-1,4-dioxaspiro[4,5]Decan-8-ol.

To a solution of pyridazine (17,7 mmol, of 1.28 ml) in THF (60 ml) was added 2,2,6,6-tetramethylpiperidine lithium (71 mmol, 10 g) at -78°C. Then the reaction mixture is stirred for 6 minutes and add 1,4-dioxaspiro[4,5]decane-8-he (71 mmol, 11 g). The reaction mixture is stirred for 5 hours at -78°C and then the reaction is quenched using a solution of ethanol, hydrochloric acid and THF (30 ml, 1:1:1). The reaction mixture was left to warm to room temperature and the reaction mixture was extracted using EtOAc. The organic layers are combined and dried over MgSO4. The residue is then purified using flash chromatography, obtaining the desired alcohol (44%, 1.84 g). MS [M+H]+237,1.

Stage B

4-hydroxy-4-peridas the n-3-illlogical.

To the product from step A (7,79 mmol, 1.84 g) in THF (15 ml) is added HCl (45 mmol, 15 ml). The reaction mixture is stirred overnight and then quenched using Na2CO3. Then the reaction mixture was extracted using EtOAc (3×100 ml). The organic layers are combined, dried and concentrated in vacuo, obtaining the desired ketone (780 mg, 52%). MS [M+H]+193,1.

Stage C

N-[2-({(3R)-1-[4-hydroxy-4-pyridazin-3-illlogical]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

To the product from step B (1,19 mmol, 215 mg) in CH2Cl2(10 ml) is added N-((3R)-pyrrolidin-3-ylcarbonyl)-3-cryptomelane (1,19 mmol, 375 mg). Then add triacetoxyborohydride sodium (2,38 mmol, 504 mg) and the reaction mixture is stirred for 4 hours and then quenched using NaOH (1M). The aqueous layer was extracted using CH2Cl2then the organic layer was washed with saturated salt solution and then dried over MgSO4. The organic layers concentrated in vacuo, obtaining the desired diastereoisomer Amin after flash chromatography and HPLC (17%, 10 mg) [M+H]+492,1.

Example 277

N-(2-{[(3R)-1-(4-hydroxy-4-pyrazin-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same SP is the way of example 276. MC [M+H]+492,1.

Example 278

Stage And

5-bromo-2-ethoxypyridine.

To EtOH (15 ml) was slowly added sodium hydride (14 mmol, 330 mg) at 0°C. the Reaction mixture is stirred for 30 minutes and add 5-bromo-2-chloropyrimidine (3.2 mmol, 620 mg). The reaction mixture was left to warm to room temperature overnight, then quenched using water, and extracted with EtOAc. The organic layers are combined and concentrated in vacuo, obtaining the desired bromide (470 mg, 72%). MS [M+2]+203,4.

Stage

8-(2-ethoxypyridine-5-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

To the product from step A (2.3 mmol,471 mg) in THF (20 ml), cooled to -78°C and added dropwise n-utility (2.8 mmol, 1.7 ml). The reaction mixture is stirred for 10 minutes at -78°C and added 1,4-dioxaspiro[4,5]decane-8-he (3.5 mmol, 540 mg). The reaction mixture was left to warm to room temperature for 12 hours, then the reaction is quenched using NH4Cl and then extracted with EtOAc (3×30 ml). The organic layers dried over MgSO4and then was concentrated in vacuo, obtaining the desired crude ketal (22%, 184 mg), which is used in the next stage.

Stage C

4-(2-ethoxypyridine-5-yl)-4-hydroxycyclohexanone.

To the product from step B (0.3 mm is l, 184 mg) is added a solution of HCl in water (30 mmol, 10 ml). The reaction mixture was stirred over night. Then the reaction is quenched using NaOH (1N.) to achieve a pH of 11. Then the reaction mixture was extracted using EtOAc (2×30 ml). The organic layers are dried and concentrated in vacuo. The residue is purified using HPLC, obtaining the desired ketone (70%, 100 mg). MS [M+H]+237,1.

Stage D

N-(2-{[(3R)-1-(4-hydroxy-4-pyrazin-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

The ketone from step C (0.4 mmol, 100 mg) in CH2Cl2(10 ml) is added N-((3R)-pyrrolidin-3-ylcarbonyl)-3-cryptomelane (0.4 mmol, 100 mg) and then triacetoxyborohydride sodium (0.8 mmol, 200 mg). The reaction mixture is stirred overnight and then quenched using NaOH (1N.). The reaction mixture was extracted using EtOAc (3×10 ml). The organic layers are combined, dried over MgSO4and then concentrated in vacuo. The residue is purified using HPLC, getting the right diastereoisomer amine (18%, 40 mg). MS [M+H]+536,1.

Example 279

N-{2-[((3R)-1-{4-[2-(2-floratone)pyrimidine-5-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 278. MS [M+H]+554,2.

Primer

N-[2-({(3R)-1-[4-hydroxy-4-(2-methoxypyridine-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 278. MS(M+H)+522.

Example 281

N-(2-{[(3R)-1-(4-hydroxy-4-pyrimidine-4-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 276. MS [M+H]+492,2.

Example 282

Stage A

8-(4-iodophenyl)-1,4-dioxaspiro[4,5]Decan-8-ol.

To a solution of 1,4-diiodobenzene (16.5 g, 50 mmol) in THF (350 ml) at -78°C add n-BuLi (2.5 m, 24 ml) for 1 hour. After stirring for an additional 30 minutes, add a solution of 1,4-dioxaspiro[4,5]decane-8-she (7.8 g, 50 mmol) in THF (30 ml) and the resulting mixture is stirred for 3 hours. To this mixture TMSC1 (5.4 g, 50 mmol), the mixture was left to warm to room temperature and stirred at room temperature for 18 hours. The reaction mixture was neutralized to pH 6.0 and extracted with ethyl acetate (3×50 ml). The organic extracts are combined, washed with saturated salt solution (2×50 ml), dried over sodium sulfate, concentrated in vacuo. Estato is subjected to chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (95/5 to 100/0). The appropriate fractions are combined to a receiving 8-(4-iodophenyl)-1,4-dioxaspiro[4,5]Decan-8-ol (12 g, 66.6 per cent), for which JHMS: 361,2 (M+H+100%) and {[8-(4-iodophenyl)-1,4-dioxaspiro[4,5]Dec-8-yl]oxy}(trimethyl)silane (6 g, 27%), for which JHMS: 433,1 (M+H+100%).

Stage B

4-hydroxy-4-(4-iodophenyl)cyclohexanone.

To a solution of 8-(4-iodophenyl)-1,4-dioxaspiro[4,5]Decan-8-ol (2 g) in acetone (10 ml) is added 5% HCl (20 ml) and the mixture is stirred at room temperature for 14 hours. The mixture is neutralized using NaOH to pH 7, concentrated on a rotary evaporator and then extracted with ethyl acetate (2×50 ml). The organic extracts are combined, washed with saturated salt solution (2×50 ml), dried over sodium sulfate, concentrated in vacuo, obtaining 4-hydroxy-4-(4-iodophenyl)cyclohexanone (1.7 g, 98%). JHMS: 317,3 (M+N+, 100%).

Stage C

N-[2-({(3R)-1-[4-hydroxy-4-(4-iodophenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

To a solution of 4-hydroxy-4-(4-iodophenyl)cyclohexanone (624 mg, 2 mmol) in CH2Cl2(10 ml) is added N-((3R)-pyrrolidin-3-ylcarbonyl)-3-cryptomelane (730 mg, 2 mmol) and then NaBH(OAc)3(666 mg, 3 mmol). After stirring for 1 hour the reaction is quenched using 10% NaHCO 3and extracted with EtOAc. The organic extracts are combined, washed with saturated salt solution, dried over sodium sulfate, concentrated in vacuo. The residue is subjected to chromatography on silica gel, elwira 1% NH4OH in a mixture of ethyl acetate/methanol (100/0 to 10/90)to give the major isomer (544 mg, 44.2 per cent) and the minor isomer (446 mg, 36.3% of output). For the main isomer JHMS: 615,2 (M+H+, 100%);1NMR (CDCl3) δ: 8,09, (s, 1H); 7,98, (d, 1H); to 7.77 (d, 1H); to 7.67 (d, 2H); EUR 7.57 (t, 1H); 7,28, (d, 2H); 7,22, (t, 1H, NH); 6,44, (d, 1H, NH); 4,49, (m, 1H); 4,12, (m, 2H); 2,87, (m, 1H); 2,64, (m, 2H); 2,38, (m, 1H); 2,25, (m, 4H); 1.93 and, (m, 2H); 1,54-1,70, (m, 6H).

Stage D

N-[2-({(3R)-1-[4-hydroxy-4-(4-pyrimidine-5-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

To a solution of N-[2-({(3R)-1-[4-hydroxy-4-(4-iodophenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (61 mg, 0.1 mmol) and pyrimidine-5-Voronovo acid (26 mg, 0.2 mmol) in THF (5 ml) is added 2M NaHCO3(5 ml) and the mixture Tegaserod using N2three times. Add Pd(0)(PPh3)4(5.7 mg, 5%) and the resulting mixture is heated to boiling under reflux in nitrogen atmosphere for 4 hours. The mixture is diluted with ethyl acetate (50 ml) and the organic layer was washed with saturated salt solution (2×10 ml), dried over sodium sulfate and concentrated in vacuo. The residue is subjected to chromatogra the AI on silica gel, elwira 1% NH4OH in a mixture of ethyl acetate/methanol (100/0 to 90/10); in the subsequent HPLC purification, elwira of 0.05% TFA in a mixture of AcCN/water, get a TFA salt of N-[2-({(3R)-1-[4-hydroxy-4-(4-pyrimidine-5-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (28.5 mg, 41%). JHMS: 568,4 (M+H+, 100%). For neutral molecules:1NMR (CD3OD) δ: 9,15 (s, 1H), remaining 9.08 (s, 1H), they were 8.22 (s, 1H), 8,14 (d, 1H), 7,86 (d, 1H), 7,76-to 7.67 (m, 5H), 4,45-and 4.40 (m, 1H), of 4.05 (s, 2H), 2,86 (t, 2H), 2,60 of $ 2.53 (m, 2H), 2,42-of 2.38 (m, 2H), 2,32 of 2.68 (m, 2H), 2.05 is-a 2.01 (m, 2H), 1,75-1,72 (m, 2H), 1,67-to 1.63 (m, 3H);19F NMR: (CDC16) δ -64,58.

Example 283

Stage A

4-hydroxy-4-[4-(1,3-oxazol-2-yl)phenyl]cyclohexanone.

To a solution of oxazole (240 mg, 3.5 mmol) in THF (5 ml) at -78°C add n-BuLi (1.6 m, and 2.6 ml). After the mixture is stirred for 1 hour, add a solution of zinc chloride in THF (0.5m, and 8.2 ml) and the resulting mixture left to warm to 0°C for 1 hour. To the mixture of 8-(4-iodophenyl)-1,4-dioxaspiro[4,5]Decan-8-ol (1.35 g, 3.5 mmol) and the resulting mixture three times Tegaserod using N2. To a suspension of PdCl2(PPh3)2(122 mg, 5%) in THF (2 ml) is added n-BuLi (1.6 m, of 0.26 ml) and the resulting mixture was added into the above mixture. The resulting mixture is heated to boiling under reflux in nitrogen atmosphere for 4 hours. The resulting mixture was diluted with ethyl acetate (50 ml). The organization is a mini layer is filtered through celite and the filtrate washed with saturated salt solution (2×10 ml), dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in THF (2.5 ml) and treated with 5% HCl (22.5 ml) at room temperature for 24 hours. The mixture is neutralized 1H. NaOH to pH 7, concentrated on a rotary evaporator and then extracted with EtOAc (2×50 ml). The organic extracts are combined, washed with saturated salt solution (2×50 ml), dried over sodium sulfate, concentrated in vacuo. The resulting residue is subjected to chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (100/0 to 100/0)to give the desired compound (0.56 g, 62% after two steps). JHMS: 258,2 (M+H+, 100%).1NMR (CDCl3) δ: of 8.06 (d, 2H), 7,73 (s, 1H), 7,63 (d, 2H), 2,99-only 2.91 (m, 2H), 2,42-of 2.30 (m, 4H), 2,22-2,05 (m, 2H).

Stage B

N-[2-({(3R)-1-[4-hydroxy-4-(4-oxazol-2-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from the ketone from step A, using the same method of example 282. MS(M+H)+557,3.

Example 284

Stage A

4-hydroxy-4-[4-(1H-imidazol-1-yl)phenyl]cyclohexanone.

To a solution of imidazole (102 mg, 15 mmol) and 8-(4-iodophenyl)-1,4-dioxaspiro[4,5]Decan-8-ol (316 mg, 1 mmol) in DMF (1 ml) was added CuI (19 mg, 0.1 mmol) and Cs2CO3(488 mg, 1.5 mmol) and the mixture was stirred at 190°C under the action of microwave radiation in t the value of 10 minutes. The mixture is diluted with ethyl acetate (50 ml) and water (10 ml). The organic layer is filtered through celite and the filtrate washed with saturated salt solution (2×10 ml), dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in THF (1 ml) and treated with 5% HCl (9 ml) at room temperature for 14 hours. The mixture is neutralized with NaOH to pH 7, concentrated on a rotary evaporator and then extracted with EtOAc (2×50 ml). The organic extracts are combined, washed with saturated salt solution (2×50 ml), dried over sodium sulfate, concentrated in vacuo. The resulting residue is subjected to chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (100/0 to 0/100)to give the desired compound (180 mg, 70% over two stages). JHMS: 257,2 (M+H+, 100%);1NMR (CDCl3) δ: of 7.82 (s, 1H), to 7.64 (d, 2H), 7,40 (s, 1H), 7,28 (s, 1H), 7,21 (s, 1H), 2,99-only 2.91 (m, 2H), 2,43-of 2.28 (m, 4H), 2,23-to 2.18 (m, 2H).

Stage B

N-[2-({(3R)-1-[4-hydroxy-4-(4-1H-imidazol-1-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from the ketone from step A, using the same method of example 282. MS(M+H)+556,3.

Example 285

Stage And

4-hydroxy-4-(4-(morpholine-4-ylphenyl)cyclohexanone.

In dried thermostat flask is charged with Pd2(dba)3(4.6 mg, 0.005 mm is l), (o-biphenyl)P(tert-Bu)2(6.0 mg, 0.02 mmol, 2 mol %) and NaO-Bu (135 mg, 1.4 mmol). The flask was pumped, again filled with nitrogen and then closed with a rubber stopper. Add toluene (0.5 ml), allided (360 mg, 1.0 mmol), morpholine (102 mg, 1.2 mmol) and additional toluene (0.5 ml). The mixture is stirred at room temperature until, until completely used up the original allided what is judged according to TLC analysis. The mixture is diluted with ether (20 ml), filtered through celite and concentrated in vacuo. The crude residue is dissolved in THF (1 ml) and treated with 5% HCl (9 ml) at room temperature for 14 hours. The mixture is neutralized 1H. NaOH to pH 7, concentrated on a rotary evaporator and then extracted with EtOAc (2×50 ml). The organic extracts are combined, washed with saturated salt solution (2×50 ml), dried over sodium sulfate, concentrated in vacuo. The resulting residue is subjected to chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (100/0 to 0/100)to give the desired compound (100 mg, 36% after two steps). JHMS: 276,2 (M+H+, 100%).1NMR (CDCl3) δ: 7,42 (d, 2H), to 6.88 (d, 2H), 3,99-of 3.94 (m, 4H), 3,86-a-3.84 (m, 4H), 3,16-3,13 (m, 4H).

Stage B

N-[2-({(3R)-1-[4-hydroxy-4-(4-(morpholine-4-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from the of etona with stage A, using a similar way of example 282. MS (M+H)+575,3.

Example 286

Stage A

8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

To a solution of 2,5-dibromopyridine (4,10 g, 17 mmol) in anhydrous toluene (250 ml) at -78°C is added dropwise n-BuLi (1.6 m, 12 ml). After stirring at -78°C for 2.5 hours, the reaction mixture was added a solution of 1,4-dioxaspiro[4,5]decane-8-it (2,73 g, 17 mmol) in methylene chloride (25 ml), the mixture was additionally stirred for 1 hour and left to slowly warm to room temperature. The reaction mixture was poured in aqueous NaHCO3(200 ml) and then extracted with EtOAc (2×50 ml). The organic extracts are combined, washed with saturated salt solution (2×50 ml), dried over MgSO4concentrate in vacuo. The obtained solid is triturated with ether and the filtrate collected. The ether is removed and the solid is subjected to chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (2 to 1)to give 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol (4,27 g) as a pale yellow solid. JHMS: 316,10/314,10 (M+H+, 100%).1NMR δ: 8,6 (s, 1H), 7,82 (d, 1H), 7,38 (d, 1H), 4,6 (s, 1H), 4,0 (m, 4H), 2,2 (m, 4H), to 1.7 (m, 4H).

Stage B

8-(5-pyrazin-2-espiridion-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

To a solution of 8-(5-bromopyridin-2-yl)-1,-dioxaspiro[4,5]Decan-8-ol (0.50 g, to 1.59 mmol) in THF (7.5 ml) is added dropwise isopropylaniline (2M in THF, 1.8 ml) at room temperature. After stirring for 1 hour the solution Tegaserod using N2three times. Another degassed solution of THF (2.5 ml) at room temperature add acetylacetonate Nickel (20 mg, 0,080 mmol) and 1,2-bis(diphenylphosphino)ethane (32 mg, 0,080 mmol), intensively blowing with nitrogen. After stirring for 10 minutes add 2-chloropyrazine (0,155 ml of 1.59 mmol) and the resulting mixture is stirred for 30 minutes. The mixture was then transferred to a freshly prepared solution of the Grignard reagent obtained previously. The mixture is stirred at room temperature for 18 hours and quenched with a saturated solution of NH4Cl. The aqueous solution is extracted with ethyl acetate and the combined organic phases are washed with saturated salt solution (2×50 ml), dried over MgSO4concentrate in vacuo. The residue is subjected to chromatography on SiO2, elute with a mixture of hexane/ethyl acetate (1:1) and the appropriate fractions are collected, receiving 8-(5-pyrazin-2-espiridion-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol (95 mg, 19%) as oil. JHMS: 314,2 (M+H+, 100%).

Stage C

4-hydroxy-4-(5-pyrimidine-5-espiridion-2-yl)cyclohexanone.

To a solution of 8-(5-pyrazin-2-espiridion-2-yl)-1,4-dioxaspiro[4,5]Decan-8-ol (95 mg, 0.30 mol) in THF (2.0 ml) to ablaut 10% HCl (2 ml). The reaction mixture is heated at 40°C for 60 minutes and cooled to room temperature. The mixture is neutralized using solid NaHCO3, extracted with ethyl acetate. The organic extracts are combined, washed with saturated salt solution, dried with MgSO4concentrate in vacuo. The residue is subjected to chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (1:1)to give the desired product as a white solid (32 mg, 40%). JHMS: 270,2 (M+H+100%);1NMR δ: which 9.22 (s, 1H), 9,10 (s, 1H), 8,72 (d, 1H), at 8.60 (d, 1H), 8,40 (d, 1H), 7,56 (d, 1H), are 5.36 (s, 1H), 3.04 from (m, 2H), 2,44 (DD, 2H), a 2.36 (m, 2H), 2,10 (m, 2H).

Stage D

N-[2-({(3R)-1-[4-hydroxy-4-(5-(pyrazin-2-yl)pyridine-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from the ketone from step C using the same method of example 282. MS (M+H)+569,3.

Example 287

Stage A

N-{2-[((3R)-1-{4-hydroxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamid.

In the flask is charged with bis(pinacolato)LIBOR (538 mg, 2.1 mmol), KOAc (589 mg, 6 mmol) and PdCl2(dppf) [dichloro(diphenylphosphinomethyl)palladium] (49 mg, 0.06 mmol) under nitrogen atmosphere. A solution of N-[2-({(3R)-1-[4-hydroxy-4-(4-iodophenyl)cyclohexyl]pyrrolidin-3-yl}amino-2-oxoethyl]-3-(trifluoromethyl)benzamide (1.23 g, 2 mmol) in DMSO (12 ml) in an additional funnel Tegaserod, barbotine through him N2; then added into the flask and the mixture is heated to 70°C. After 1 hour the reaction is quenched with water, extracted with CH2Cl2concentrate, getting the desired compound (190 mg, 15%). JHMS: 616,2

(M+H+, 100%).

Stage B

N-{2-[((3R)-1-{4-hydroxy-4-[4-(1-methyl-1H-imidazol-5-yl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamid.

In degassed solution of a mixture of N-{2-[((3R)-1-{TRANS-4-hydroxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide (60 mg, 0.1 mmol), 5-bromo-1-methylimidazole (63 mg, 0,39 mmol) and aqueous Na2CO3(0.5 ml) in DMF (0.5 ml) is added PdCl2(dppf) (4 mg, of 0.005 mmol)). After stirring at 80°C for 18 hours the reaction is terminated by 66%, according to GHMC. The crude product was then purified using preparative IHMS, the appropriate fractions are combined and dried in the freeze dryer, receiving di-TFA salt of N-{2-[((3R)-1-{4-hydroxy-4-[4-(1-methyl-1H-imidazol-5-yl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide (8 mg, 14%) as a white powder. JHMS: 570,2 (M+H+, 100%);19F NMR (CD3OD) δ: -64,6 (aryl-CF3); -77,50 (TFA);1NMR (CD3OD) δ: 9,02, (s, 1H); 8,18, (s, 1H); 8,12, (d, 1H); 7,81, (d, 2H); 7,78, (d, 1H); 7,63, (t, 1H; at 7.55 (s, 1H); to 7.32 (d, 2H); 4,40, (m, 1H); 4,11, (s, 2H); 3,90 (m, 1H) a 3.83 (s, 3H); 3,48, (m, 2H); 3,20, (m, 1H); 2,70, (m, 1H); 2,37, (m, 3H); 2,24, (m, 2H); 2,01, (m, 2H); 1,82, (m, 3H).

The following connections will be received, using similar methods disclosed in the examples 282-287.

609,4 307
Example No.RMS (M+H)+
2884-(4,6-dimethylpyrimidin-5-yl)phenyl596,4
2896-bromopyridin-3-yl569,3
2905-bromopyridin-2-yl569,3
2914'-(methylsulphonyl) - biphenyl-4-yl644,4
2923'-(methylsulphonyl) - biphenyl-4-yl644,4
2933'-(methoxycarbonyl)biphenyl-4-yl624,3
2944-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl624,3
2954'-(dimethylamino)biphenyl-4-yl
2964-(pyridin-3-yl)phenyl567,3
2974-(1H-pyrazole-4-yl)phenyl556,3
2983,3'-bipyridine-6-yl568,2
2993,4'-bipyridine-6-yl568,2
3005-(3-acetylphenyl)pyridine-2-yl609,3
3015-[3-(dimethylamino)phenyl]pyridine-2-yl610,4
3025-[3-(trifluoromethyl)phenyl]pyridine-2-yl634,3
3035-[4-(methylsulphonyl)phenyl]pyridine-2-yl645,2
3045-(4-methoxyphenyl)pyridine-2-yl597,3
3055-(3-methoxyphenyl)pyridine-2-yl597,3
3065-[3-(aminocarbonyl)phenyl]pyridine-2-yl610,3
5-(4-forfinal)pyridine-2-yl585,4
3085-(3,4-differenl)pyridine-2-yl603,3
3095-(3,5-dimethylisoxazol-4-yl)pyridine-2-yl585,4
3105-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl571,4
3115-(1H-pyrazole-4-yl)pyridine-2-yl557,3
3125-(1-benzofuran-2-yl)pyridine-2-yl607,2
3135-(1,3-benzodioxol-5-yl)pyridin-2-yl611,3
3145-(2-formylphenyl)pyridine-2-yl595,3
3154-(2'-formylphenyl)-4-yl594,3
3165-(1,3-oxazol-2-yl)pyridine-2-yl558,4
3176-(1,3-oxazol-2-yl)pyridine-3-yl558,4
3184-(1,3-thiazol-2-yl)phenyl573,2
3195-(1,3-thiazol-2-yl)pyridine-2-yl574,2
3206-(1,3-thiazol-2-yl)pyridine-3-yl574,2
3216-(1H-imidazol-1-yl)pyridine-3-yl557,4
3225-(1H-imidazol-1-yl)pyridin-2-yl557,4
3236-vinylpyridin-3-yl567,3
3245-(pyrimidine-5-yl)pyridin-2-yl569,3
3255-(pyrimidine-2-yl)pyridine-2-yl569,3
3265-(3-aminocarbonylmethyl)pyridine-2-yl620,3
3274-(1-methyl-1H-imidazol-4-yl)phenyl570,3
3284-(1H-imidazol-4-yl)phenyl]556,4
329 5-[2-(hydroxymethyl)phenyl]pyridin-2-yl597,4
3302'-(hydroxymethyl)biphenyl-4-yl596,2
3315-{2-[(dimethylamino)methyl]phenyl}pyridine-2-yl624,3
3322'-[(dimethylamino)methyl]biphenyl-4-yl623,3

Example 333

Stage A

Tert-butyl(4-oxocyclohexyl)carbamate.

To a solution of HCl salt of TRANS-4-aminocyclohexanol (5 g, 33 mmol) and 1-methylmorpholine (9 ml, 82 mmol) in acetonitrile (35 ml) and water (30 ml) in a bath with ice add di-tert-BUTYLCARBAMATE (7.2 g, 33 mmol). The mixture is stirred at room temperature over night and add EtOAc. The organic phase is isolated. The aqueous layer was twice extracted with EtOAc. The combined organic phases are washed with saturated salt solution, dried over MgSO4and concentrate. To a solution of oxalicacid (2,33 ml, or 26.7 mmol) in methylene chloride (50 ml), cooled to -60°C, add a solution of DMSO (4 ml, 56 mmol) in methylene chloride (5 ml) and then the solution obtained above TRANS-4-tert-butoxycarbonylmethylene (5 g, 23 mmol) in methylene chloride (20 ml). After stirring at -60°C for 20 the minutes add triethylamine (16.1 ml, 116 mmol). The mixture is left to warm to room temperature and stirring is continued for 30 minutes. Add the water. The organic phase is isolated and the aqueous layer was extracted twice with methylene chloride. The combined organic phases are washed with saturated salt solution, dried over MgSO4and concentrate. Using flash chromatography, performing a gradient elution from 3% to 5% to 10% MeOH/CH2Cl2receive 4.5 g (90%) specified in the connection header. MS (M+H)+214, found: 236 (M+Na)+.

Stage B

Tert-butyl(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)carbamate.

To a solution of the ketone from step A (0.4 g, 1.9 mmol) and intermediate compounds pyrrolidine obtained in stage C of example 114 (0.4 g, 1.3 mmol)in THF (15 ml) add triacetoxyborohydride sodium (0.4 g, 1.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched by adding aqueous NaHCO3. The resulting solution was thrice extracted with EtOAc. The combined organic phases are washed with NaHCO3and saturated salt solution, dried over MgSO4and concentrate. Using flash chromatography and performing gradient elution 0-20% MeOH/CH2Cl2receive 300 mg specified in the connection header. MS calculated: (M+H)+513, Nai is prohibited: 513.

Stage C

N-(2-{[1-((3R)-4-aminocyclohexane)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

The intermediate compound from step B (256 mg, 0.5 mmol) is dissolved in a solution of 4n. HCl in dioxane (10 ml). After stirring at room temperature for 1 hour the solution is concentrated and receiving solid. MS calculated: (M+H)+413, found: 413,1.

Stage D

N-[2-({(3R)-1-[4-(benzoylamine)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

To a solution of amine from step C (80 mg, 0.18 mmol) in methylene chloride (2 ml) was added benzoyl chloride (25 μl, 0.21 mmol) and then triethylamine (62 μl, 0.45 mmol). After stirring at room temperature for 2 hours the solution is concentrated. Using flash chromatography and elution 0-20% MeOH/CH2Cl2receive specified in the header connection. MS calculated: (M+H)+517, found: 517,1.

Below in the examples, compounds of gain, using a similar method of example 333.

Example No.RMS (M+H)+
334pyridine-2-yl518
335pyridine-3-yl518
336pyridine-4-yl518
3376-methylpyridin-2-yl532
3385-methylpyridin-2-yl532
3394-methylpyridin-2-yl532
3406-methoxypyridine-2-yl548
341the quinoline-4-yl568

Example 342

Stage A

3H-Spiro[bicyclo[3.2.1]octane-8,2'-[l,3]dioxolane]-3-one.

Specified in the header connection receive in accordance with the method disclosed in the literature (M. Povarny et al. Tetrahedron Lett. 1984, 25, 1311-1312 and are there links). MS calculated: (M+H)+183, found: USD 183.0.

Stage B

3-pyridin-2-inspire[bicyclo[3.2.1]octane-8,2'-[l,3]dioxolane]-3-ol.

To a solution of 2-bromopyridine (0.04 ml, 0,422 mmol) in ether (2 ml), cooled to -78°C, add 2,5M solution of utility in hexano (0.17 ml, 0,425 mmol). After AC is shivani at -78°C for 1 hour add a solution of ketone, obtained in stage A (70 mg, 0.384 mmol)in ether (2 ml). Stirring is continued at -78°C for 2 hours and the reaction mixture is left to warm to 0°C before being quenched with a solution of ameriglide. The resulting solution was extracted three times with ether. The combined ether layers dried over MgSO4and concentrate. The result chromatography on silica gel, elwira a mixture of 50% EtOAc/hexane, obtain 58 mg (60%) specified in the connection header. MS calculated: (M+H)+262, found: 262,1.

Stage C

3-hydroxy-3-pyridine-2-albicilla[3.2.1]octane-8-he.

Ketal (58 mg, 0.22 mmol)obtained in stage B is dissolved in MeOH (2 ml) and 10% HCl (1 ml). After stirring at room temperature overnight the solution is refluxed for 10 minutes and neutralized by adding NaOH solution after cooling to room temperature. The resulting solution was condensed on a rotary evaporator under reduced pressure, obtaining the crude product, which is used in the next stage without additional purification. MS calculated: (M+H)+ 218, found: 218,0.

Stage D

N-(2-{[(3R)-1-(3-hydroxy-3-pyridine-2-albicilla[3.2.1]Oct-8-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

In the reductive amination of the ketone obtained above, p is ossadnik of pyrrolidine, obtained in stage B of example 1, using the method analogous opened in stage D of example 1, get mentioned in the title compound in the form of a mixture (2:3) of the two isomers. MS calculated: (M+H)+517, found: 517,1.

Example 343

N-[2-({(3R)-1-[3-hydroxy-3-(5-methylpyridin-2-yl)bicyclo[3.2.1]Oct-8-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 342. MS calculated: (M+H)+531, found: 531,2.

Example 344

N-(2-{[(3R)-1-(3-hydroxy-3-pyridin-3-albicilla[3.2.1]Oct-8-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 342. MS calculated: (M+H)+517, found: 517,1.

Example 345

N-[2-({(3R)-1-[3-hydroxy-3-(6-methoxypyridine-3-yl)bicyclo[3.2.1]Oct-8-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 342. MS calculated: (M+H)+547, found: 547,2.

Example 346

Stage And

Tert-butyl[(3R)-1-Spiro[bicyclo[3.2.1]octane-8,2'-[l,3]dioxolane]-3-iparralde-3-yl]carbamate.

To a solution of ketone (0.1 g, 0.55 mmol), n is obtained in stage a of example 342, and (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (0.1 g, 0.55 mmol) in methylene chloride (4 ml) add triacetoxyborohydride sodium (0,13 g to 0.60 mmol). The reaction mixture was stirred at room temperature overnight and quenched using an aqueous solution of sodium bicarbonate. The resulting solution was thrice extracted with EtOAc. The combined EtOAc layers dried over MgSO4and concentrate. Using flash chromatography on silica gel, elwira a mixture of 30% EtOAc/hexane, EtOAc and then with 10% MeOH/CH2Cl2get two isomers specified in the connection header. MS calculated: (M+H)+353, found: 353,1.

Stage B

Tert-butyl[(3R)-1-(8-oxabicyclo[3.2.1]Oct-3-yl)pyrrolidin-3-yl]carbamate.

The above isomer 1 (30 mg, of 0.085 mmol) was dissolved in MeOH (1 ml) and 2n. HCl solution (0.5 ml). The solution was stirred at room temperature overnight and refluxed at 110°C for 2 hours. After the solution is cooled to room temperature, the solution was neutralized with NaOH solution. Add a solution of di-tert-BUTYLCARBAMATE (50 mg) in THF (2 ml) and then triethylamine (0.05 ml). After stirring at room temperature overnight the solution was diluted with EtOAc. The organic phase is isolated and the aqueous layer was twice extracted with EtOAc. The combined organic phases are dried over MgSO4and concentrate. And the after flash chromatography on silica gel, performing a gradient elution CH2Cl2, 5%, 10% and 20% MeOH/CH2Cl2receive 10 mg specified in the connection header. MS calculated: (M+H)+309, found: 309,0.

Stage C

Tert-butyl[(3R)-1-(8-hydroxy-8-Panevezio[3.2.1]Oct-3-yl)pyrrolidin-3-yl]carbamate.

To a solution of the ketone obtained in stage B (65 mg, 0.21 mmol)in THF (2 ml) and cooled in a bath with ice, add a 1M solution of phenylmagnesium in THF (0.25 ml). After stirring at -78°C for 3 hours the reaction is quenched using an aqueous solution of ameriglide. The resulting solution was thrice extracted with EtOAc. The combined EtOAc layers dried over MgSO4and concentrate. Using flash chromatography on silica gel, elwira 5%, 10% and 50% MeOH/CH2Cl2get 27 mg specified in the title compounds as a mixture of two isomers (7:3). MS calculated: (M+H)+387, found: 387,1.

Stage D

N-(2-{[(3R)-1-(8-hydroxy-8-Panevezio[3.2.1]Oct-3-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

The alcohol obtained in stage C (27 mg, 0.07 mmol), dissolved in 2 ml of 4n. HCl in dioxane. After stirring at room temperature for 1 hour the solution is concentrated. The residue is placed in DMF (1 ml). Add carboxylic acid, obtained in stage A of example 1 (25 mg, 0.1 mmol), and then BOP(45 mg, 0.1 mmol) and triethylamine (0.05 ml, 0.36 mmol). The mixture is stirred at room temperature for 5 hours and diluted with EtOAc. The resulting solution was washed with sodium bicarbonate and a saturated salt solution, dried over MgSO4and concentrate. Purifying by HPLC with reversed phase, obtain 22 mg specified in the title compounds as a mixture of two isomers (7:3). MS calculated: (M+H)+516, found: 516,1. Using a method analogous opened higher, isomer 2 from step A in turn specified in the title compound in the form of an individual isomer. MS calculated: (M+H)+516, found: 516,1.

Example 347

Stage A

Bicyclo[2.2.1]hept-2-EN-5-he.

Specified in the header connection receive in accordance with those disclosed in the literature (G.T. Wang et al. J. Org. Chem. 2001, 66, 2052-2056).

Stage B

2-Panevezio[2.2.1]hept-5-EN-2-ol.

Specified in the header connection receive in accordance with those disclosed in the literature (C.J. Collins, B. M. Benjamin, J. Am. Chem. Soc. 1967, 89, 1652-1661).

Stage

2-Panevezio[2.2.1]heptane-2,5-diol.

Specified in the header connection receive in accordance with those disclosed in the literature (C.J. Collins, B. M. Benjamin, J. Org. Chem. 1972, 37,4358-4366).

Stage D

5-hydroxy-5-phenyl who icicle[2.2.1]heptane-2-it.

Specified in the title compound is obtained by oxidation by the Turn of the alcohol obtained above. MS calculated: (M+H)+203, found: 203 and 225 (M+Na)+.

Stage E

N-(2-{[(3R)-1-(5-hydroxy-5-Panevezio[2.2.1]hept-2-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

To a solution of the ketone obtained in stage D of example 45 (0.28 g, 1.38 mmol), and intermediate compounds pyrrolidine obtained in stage B of example 1 (0,43 g, 1.38 mmol)in THF (15 ml) is added acetic acid (0.1 ml). After the mixture was stirred at 50°C for 30 minutes, the solution is concentrated. The remainder is added in THF (5 ml). Add triacetoxyborohydride sodium (300 mg, of 1.42 mmol). After stirring at room temperature overnight the reaction is quenched using an aqueous solution of NaHCO3. The solution thrice extracted with EtOAc. The combined organic phases are washed with saturated salt solution, dried over MgSO4and concentrate. In the purification HPLC with reversed-phase receive specified in the title compound as TFA salt. MS calculated: (M+H)+502, found: 502.

Example 348

N-(2-{[(3R)-1-(5-hydroxy-5-pyridin-2-albicilla[2.2.1]hept-2-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using analogs is their way of example 347. MS calculated: (M+H)+503, found: 503.

Example 349

N-(2-{[(3R)-1-(5-hydroxy-5-pyridin-3-albicilla[2.2.1]hept-2-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 347. MS calculated: (M+H)+503, found: 503.

Example 350

N-[2-({(3R)-1-[5-hydroxy-5-(6-methoxypyridine-3-yl)bicyclo[2.2.1]hept-2-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 347. MS calculated: (M+H)+533 found: 533.

Example 351

N-(2-{[(3R)-1-(5-hydroxy-5-pyridin-4-albicilla[2.2.1]hept-2-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 347. MS calculated: (M+H)+503, found: 503.

Example 352

Stage A

Tert-butyl(2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate.

Specified in the header connection receive in accordance with the method disclosed in the literature (T. Rosen, et al. J. Med. Chem. 1988, 31, 1598-1611).

Stage B

Tert-butyl(2S,4S)-4-(benzoyloxy)-2-methylpyrrolidine-1-carboxylate./b>

To a solution of alcohol from step A (0,81 g, 4.0 mmol), benzoic acid (0.74 g, 6.0 mmol) and triphenylphosphine (2,11 g, 8.0 mmol) in toluene (20 ml) was added DIAD (1,67 ml, 8.0 mmol). After stirring at room temperature for 4 hours the solution is concentrated. The residue is purified flash chromatography, elwira a mixture of 0%, 5% and 20% EtOAc/hexane, and obtain 1.0 g specified in the connection header. MS calculated: (M+H)+308, found: 308,1.

Stage C

Tert-butyl(2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate.

To a solution of ester from step B (1.0 g, of 3.48 mmol) in MeOH (30 ml) add K2CO3(1.2 g, 8,7 mmol). After stirring at room temperature for 4 hours the solution is concentrated. The residue is placed into the ether. The resulting solution was washed with saturated salt solution, dried over MgSO4and concentrate. Using flash chromatography, performing a gradient elution from 0% to 20% to 40% EtOAc/hexane receive 0.56 g specified in the connection header. MS calculated: (M+H)+202, found: 202,1.

Stage D

Tert-butyl(2S,4R)-4-azido-2-methylpyrrolidine-1-carboxylate.

To a solution of alcohol from step C (0.55 g, 2,73 mmol) in methylene chloride (30 ml), cooled in a bath with ice, add triethylamine (0.51 ml, of 3.69 mmol), then methanesulfonanilide (0,29 ml of 3.69 mmol who). After stirring in a bath with ice for 30 minutes, the reaction mixture continued to stir at room temperature for 40 minutes. The solution is washed with water, dried over MgSO4and concentrate. The above residue was dissolved in DMF (15 ml) and add NaN3(1.06 g, 16.3 mmol). The mixture is stirred at 50°C overnight and diluted with tert-butylmethylamine ether. The resulting solution was washed with saturated salt solution, 5% citric acid and saturated solutions NaHCO3, dried over MgSO4and concentrate, receiving 0,58 g specified in the connection header. MS calculated: (M+H)+227, found: 227,2.

Stage E

Tert-butyl(2S,4R)-4-amino-2-methylpyrrolidine-1-carboxylate.

To the solution obtained above etidocaine (0,58 g, 2.56 mmol) in MeOH (30 ml) is added 5% Pd/C (100 mg). The mixture is stirred in hydrogen atmosphere (balloon) for 3 hours. The catalyst is filtered off and the filtrate is concentrated and receiving 0.5 g specified in the connection header. MS calculated: (M+H)+201, found: 201,1.

Stage F

Tert-butyl(2S,4R)-2-methyl-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-carboxylate.

To a solution of amine from step D (0.5 g, 2.5 mmol), carboxylic acid, obtained in stage a of example 114, and triethylamine (0.7 ml, 5.0 mmol) in Meath is Langlade (25 ml), chilled in a bath with ice, add EDC (0,53 g, a 2.75 mmol). After stirring at room temperature overnight the solution concentrate. The residue is purified on silica gel performing a gradient elution 0-4% MeOH/CH2Cl2receive 0.6 g specified in the connection header. MS calculated: (M+H)+430, found: 430,1.

Stage G

N-(2-{[(3R,5S)-5-methylpyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

The intermediate compound from step F (0.6 g, 1.4 mmol) dissolved in MeOH (3 ml) and a solution of 4n. HCl in dioxane (3 ml). After stirring at room temperature for 4 hours the solution is concentrated and receiving 0.56 g specified in the connection header. MS calculated: (M+H)+330, found: 330,2.

Stage H

N-(2-{[(3R,5S)-1-(4-hydroxy-4-phenylcyclohexyl)-5-methylpyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained reductive amination of amine from step G of 4-hydroxy-4-phenylketone using the same method of example 114. MS calculated: (M+H)+504, found: 504,1.

Below in the examples, compounds of gain, using a similar method of example 352.

Example RMS (M+H)+
3534-were518
354pyridine-2-yl505
3555-methylpyridin-2-yl519
356pyridine-3-yl505
3576-methoxypyridine-3-yl535
358pyridine-4-yl505

Example 359

2-(1,3-benzothiazol-2-ylamino)-N-[(3R)-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]ndimethylacetamide.

A mixture of 2-amino-N-[(3R)-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]ndimethylacetamide (0,080 g, 0.25 mmol), Et3N (0.35 ml, 2.5 mmol) and 2-chlorobenzothiazole (0,424 g, 2.5 mmol) in isopropanol is stirred overnight at 90°C. the Reaction mixture was concentrated and subjected to chromatography, receiving 55 mg specified in the connection header with the release of 49%. MS(EI) calculated: (M+H)+=452,2; found: 452,2.

Example 360

N-[(3R)-1-(4-hydroxy-pyridin-2-illlogical)pyrrolidin-3-yl]-2-{[5-(trifluoromethyl)pyrimidine-2-yl]amino}ndimethylacetamide.

Specified in the header of the get connection using the same method of example 359. MS(EI) calculated: (M+H)+=465,2; found: 465,1.

Example 361

N-[1-({[(3R)-1-(4-phenylcyclohexyl)pyrrolidin-3-yl]amino}carbonyl)cyclopropyl]-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 114. MS(EI): Calculated: (M+H)+500,2 found: 500,4.1NMR (CDCl3) δ: 8,61 (1H, d), 8,21 (1H, s), 8,15 (1H, d), 7,78 (1H, s), of 7.75 (1H, d), 7,58 (1H, DD), 7,22 (5H, m), to 4.81 (1H, m), and 3.8 (1H, m), 3,62 (1H, DD), 3,17 (1H, m), of 2.92 (2H, m), 2,8 (1H, m), 2,48 (1H, m), to 2.18 (2H, m), 2,1 (2H, m)of 1.75 (3H, m)of 1.55 (4H, m)of 1.18 (2H, m).

Example 362

Stage A

Ethyl-2-(permitil)acrylate.

To a solution of ethyl-2-(hydroxymethyl)acrylate (5 g, 38 mmol) in 50 ml of methylene chloride added DAST (6,0 ml of 46.1 mmol) at -78°C. the Reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature and continuously stirred during the night. Add 20 ml of a saturated aqueous solution of NaHCO3and 20 ml of ethyl acetate, to suppress the reaction. The organic layer is isolated and the aqueous layer was twice extracted with EtOAc (20 ml×2). The combined organic extracts dried over MgSO4and evaporated, obtaining an oily residue (2.8 g, yield: 56%). MS (m/z): 131 (M+1)+.

Stage B

Ethyl-1-benzyl-3-(permitil)pyrrolidin-3-carboxylate.

To a solution of N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (2.5 g, 21 mmol) and ethyl-2-(permitil)acrylate (5.0 g, 21 mmol) in methylene chloride (30 ml) is added TFA (0.15 ml, 2.1 mmol) at 0°C. the Reaction mixture was stirred at 0°C during the night. Add 20 ml of a saturated aqueous solution of NaHCO3and 20 ml of ethyl acetate, to suppress the reaction. The organic layer is isolated and the aqueous layer was twice extracted with EtOAc (20 ml×2). The combined organic extracts dried over MgSO4and evaporated, obtaining an oily residue. The result chromatography on silica gel with a mixture of 10% EtOAc-hexane obtain 1.27 g (4.8 mmol, yield: 23%) ethyl-1-benzyl-3-(permitil)pyrrolidin-3-carboxylate:1NMR (400 MHz, CDCl3) δ: 7,39-7,20 (5H, m), 4,62-of 4.44 (2H, m), 4,18-is 4.21 (2H, m), 3,62 (2H, s), 2,81-of 2.72 (2H, m), 2,60-of 2.50 (2H, m), 2,22 (2H, s), 1,25 (3H, t, J=6,7 Hz); MS (m/e): 266 (M+1)+.

Stage C

Ethyl-3-(permitil)pyrrolidin-3-carboxylate.

To a solution of 1.27 g (4.8 mmol) of ethyl-1-benzyl-3-(permitil)pyrrolidin-3-carboxylate in 20 ml of methanol is added 500 mg of Pd/C (10% coal) and 1.5 g (24 mmol) HCOONH4. The reaction mixture is refluxed for 1 hour, filtered through a layer of celite and evaporated, receiving the remainder. The residue is then dissolved in ethyl acetate, the resulting solution was washed with saturated in the s ' solution of NaHCO 3saturated salt solution, dried over Na2SO4that is evaporated, getting the final crude product (426 mg, 2.4 mmol, yield: 50%): MS (m/e): 176 (M+H)+.

Stage D

1-tert-butyl-3-ethyl-3-(permitil)pyrrolidin-1,3, in primary forms.

To a solution of ethyl-3-(permitil)pyrrolidin-3-carboxylate (2.4 mmol) in 20 ml of methylene chloride add 786 mg (Boc)2O (3.6 mmol) and 0.67 ml (4.8 mmol) of triethylamine at room temperature. The reaction mixture was stirred over night. By direct chromatography on silica gel get 562 mg (2.0 mmol, yield: 85%) of the desired product, 1-tert-butyl-3-ethyl-3-(permitil)pyrrolidin-1,3-in primary forms:1NMR (400 MHz, CDCl3) δ: 4,65 was 4.42 (2H, m), 4,28-4,19 (2H, m), 3,80-and 3.72 (1H, m), 3,56 is 3.40 (3H, m), 2,40-of 2.20 (1H, m), 2,08-of 1.93 (1H, m)of 1.45 (9H, s), 1,1,32-1,25 (3H, m); MS (m/e): 276 (M+1)+.

Stage E

1-(tert-butoxycarbonyl)-3-(permitil)pyrrolidin-3-carboxylic acid.

To a solution of 562 mg of 1-tert-butyl-3-ethyl-3-(permitil)pyrrolidin-1,3-in primary forms (2.0 mmol) in 10 ml THF and 5 ml of water is added 420 mg of LiOH·H2About (10 mmol) at room temperature. The reaction mixture is stirred for 5 hours. The reaction mixture is quenched using an aqueous solution of HCl, and bring the pH to 3-4, extracted with ethyl acetate twice (20 ml×2). The combined extracts washed with saturated is the first salt solution, dried over Na2SO4that is evaporated, obtaining the final product (530 mg, 2.0 mmol), 1-(tert-butoxycarbonyl)-3-(permitil)pyrrolidin-3-carboxylic acid:1NMR (400 MHz, CDCl3) δ: 4,70-4,22 (2H, m), 3,81 of 3.75 (1H, m), 3,60-to 3.41 (3H, m), 2,41-of 2.30 (1H, m), 2,10-1,99 (1H, m)of 1.47 (9H, s); MS (m/e): 248 (M+1)+.

Stage F

Tert-butyl 3-{[(benzyloxy)carbonyl]amino}-3-(permitil)pyrrolidin-1-carboxylate.

To a solution of 530 mg (2.0 mmol) of 1-(tert-butoxycarbonyl)-3-(permitil)pyrrolidin-3-carboxylic acid in toluene (30 ml) is added to 0.69 ml (3.2 mmol) of DPPA and 0.36 ml (2.6 mmol) of triethylamine. The reaction mixture was stirred at 110°C for 4 hours. Then add 0.33 ml (3.2 mmol) of benzyl alcohol and the reaction mixture was stirred overnight at 110°C. the Mixture is cooled and evaporated, receiving the remainder. The residue is dissolved in methylene chloride, washed with 5% aqueous citric acid solution, saturated aqueous K2CO3saturated salt solution, dried over Na2SO4that is evaporated. The result chromatography on silica gel get 540 mg (1.53 mmol, yield: 73%) of the desired product, tert-butyl 3-{[(benzyloxy)carbonyl]amino}-3-(permitil)pyrrolidin-1-carboxylate:1NMR (400 MHz, CDCl3) δ: 7,40-to 7.35 (5H, m), 5,10 (2H, s), 4,94 (1H, s), 4,70-4,50 (2H, m), 3,60 is 3.40 (4H, m), 2.40 a is 2.00 (2H, m)of 1.45 (9H, s); MS (m/e): 353 (M+1)+.

Stage G

Tert-butyl 3-amino-3-(permitil)pyrrolidin-1-carboxylate.

To a solution of 540 mg (1.53 mmol) of tert-butyl 3-{[(benzyloxy)carbonyl]amino}-3-(permitil)pyrrolidin-1-carboxylate in 10 ml of methanol added 330 mg (10% coal) Pd/C. the Suspension is stirred at room temperature in an atmosphere of H2(balloon) for 2 hours. The reaction mixture was filtered through a layer of celite, evaporated, getting 337 mg (of 1.52 mmol, yield: 99%) of the crude product, tert-butyl 3-amino-3-(permitil)pyrrolidin-1-carboxylate: MS (m/e): 219 (M+1)+.

Stage H

Tert-butyl 3-(permitil)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-carboxylate.

337 mg (of 1.52 mmol) of tert-butyl 3-amino-3-(permitil)pyrrolidin-1-carboxylate, 457 mg (of 1.85 mmol) of {[3-(trifluoromethyl)benzoyl]amino}acetic acid, BOP reagent (817 mg, of 1.85 mmol) and 0.64 ml (4.6 mmol) of triethylamine are dissolved in 15 ml of DMF at room temperature. The reaction mixture was stirred at room temperature overnight. By direct chromatography on silica gel (flash chromatography)using a mixture of 50% ethyl acetate-hexane, receive 578 mg (1,29 mmol, 84%) of tert-butyl 3-(permitil)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-carboxylate:1NMR (400 MHz, CDCl3) δ: 8,15-to 8.12 (1H, m), 8,05-7,98 (1H, m), 7,81-to 7.77 (1H, m), 7,63-7,58 (1H, m), 6,64-6,62 (1H, m), 4,20 of 4.1 (2H, m), 3,61 is 3.57 (2H, m), 3,55-of 3.42 (1H, m), 2,98-to 2.94 (2H, m), 2,90-of 2.86 (2H, m), 1,62 is 1.60 (2H, m)of 1.45 (9H, s); MS (m/e): 448 (M+1)+.

Stage I

N-(2-{[3-(permitil)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

To a solution of 578 mg (1,29 mmol) of tert-butyl 3-(permitil)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-carboxylate in 5 ml of THF is added 2 ml of 4n. HCl solution in dioxane. The reaction mixture was stirred at room temperature for 1 hour and evaporated, getting solid yellow, HCl salt of N-(2-{[3-(permitil)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide: MS (m/e): 347 (M+1)+.

Stage J

N-(2-{[3-(permitil)-1-(4-hydroxy-4-phenylcyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

100 mg (of 0.53 mmol) 4-hydroxy-4-phenylcyclohexanone and 184 mg (of 0.53 mmol) of N-(2-{[3-(permitil)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide are dissolved in 10 ml of methylene chloride. To the solution add 221 mg (1.06 mmol) of triacetoxyborohydride sodium. The reaction mixture was stirred at room temperature for 2 hours. By direct chromatography on silica gel get the right kind of product: 41 mg (top spot on TLC and the first peak on the HPLC chromatogram, output: 16,7%, MS: 522 (M+1)+and the other isomer: 51 mg (second peak on XP is metagame HPLC, yield: 20%, MS: 522 (M+1)+.

Example 363

Stage A

(3a'R,6A's)-tetrahydro-1'H-Spiro[l,3-dioxolane-2,2'-pentalen]-5'(3'H)-he.

CIS-tetrahydroindole-2,5(1H,3H)-dione (5 g, 36 mmol) and ethylene glycol (2.3 g, 36 mmol) dissolved in toluene. To the resulting solution was added PTSA (684 mg, 3.6 mmol). The reaction mixture is refluxed for 12 hours while removing the formed water. By direct chromatography on silica gel get 2.0 g (11 mmol, yield: 31%) of the desired product, (3a'R,6A's)-tetrahydro-1'H-Spiro[1,3-dioxolane-2,2'-pentalen]-5'(3H)-it: MS (m/e): 183 (M+1)+.

Stage B

(3a'R,6A's)-5'-(6-methoxypyridine-3-yl)hexahydro-1'H-Spiro[1,3-dioxolane-2,2'-pentalen]-5'-ol.

A solution of 5-bromo-2-methoxypyridine (1 g, 5.3 mmol) in 50 ml dry THF under nitrogen atmosphere cooled to -78°C. added dropwise n-utility (3.5 ml, 5.6 mmol, 1.6 m solution in hexane). The orange solution is stirred for an additional 1 hour at -78°C and then treated dropwise within 10 minutes with a solution of monoelemental 1,4-cyclohexandione (960 mg, 5.3 mmol) in 20 ml of dry THF. The reaction mixture is stirred for 1 hour, allowed to warm to 20°C and poured into ice water (400 ml). The organic layer is isolated and the aqueous layer was twice extracted with EtOAc (20 ml×2). United'or is adicheskie extracts dried over MgSO 4and evaporated. The result chromatography on silica gel get 1,08 g (3.7 mmol, yield: 70%) of white crystals, (3a'R,6A's)-5'-(6-methoxypyridine-3-yl)hexahydro-1'H-Spiro[1,3-dioxolane-2,2'-pentalen]-5'-ol: MS: 292 (M+1)+.

Stage C

(3aR,6aS)-5-hydroxy-5-(6-methoxypyridine-3-yl)hexahydrophthalic-2(1H)-he.

Specified in the title compound synthesized from (3a'R,6A's)-5'-(6-methoxypyridine-3-yl)hexahydro-1 N-Spiro[1,3-dioxolane-2,2'-pentalen]-5'-ol using a regular method of removal of the protective groups.

Stage D

N-[2-({(3R)-1-[(3aR,6aS)-5-hydroxy-5-(6-methoxypyridine-3 - yl)octahydrophenanthrene-2-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is synthesized using the same method of example 114. MS (M+H)+547.

Example 364

N-[2-({(3R)-1-[(3aR,6aS)-5-hydroxy-5-ventilatierooster-2-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 363. MS (M+H)+516.

Example 365

N-[2-({(3R)-1-[(3aR,6aS)-5-hydroxy-5-pyridin-3-eloctricamente-2-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the header connection receive, and which uses a similar way of example 363. MS (M+H)+517.

Example 366

Stage A

5-pyridin-3-inspire[bicyclo[2.2.2]octane-2,2'-[1,3]dioxolane]-5-ol.

A solution of 3-bromopyridine (1.13 g, 7,13 mmol) dissolved in dry ether under nitrogen atmosphere, cooled to -78°C and then added dropwise n-utility (4,50 ml, 7,13 mmol, 1.6 m in hexane). After 30 minutes, added dropwise a solution of 5H-Spiro[bicyclo[2.2.2]octane-2,2'-[1,3]dioxolane]-5-it (0.65 g, of 3.56 mmol, J. Org. Chem. 1991, 56, 1052-1058) in ether and the mixture is stirred for two hours at -78°C. the Mixture was then heated to 0°C and diluted with ethyl acetate. The organic extract was washed with NaHCO3/H2O and saturated salt solution and then dried over MgSO4filter and concentrate. The residue is subjected to chromatography on silica gel using ethyl acetate as eluent, receiving two isomeric product as a white solid: product with higher Rf, 0,294 g (32%); the product of lower Rf, 0,220 g (24%). A product with higher Rf:1NMR (CDCl3) δ: 8,87 (s, 1H), 8,49 (d, 1H), to $ 7.91 (dt, 1H), 7,27 (m, 1H), 3,92 (m, 4H), 2,69 (dt, 1H), measuring 2.20 (m, 1H), 1.85 to to 2.15 (m, 3H), 1.60-to to 1.83 (m, 4H), 1,50 (m, 1H). A product with a lower Rf:1NMR (CDCl3) δ: 8,80 (s, 1H), and 8.50 (d, 1H), 7,86 (dt, 1H), 7,29 (m, 1H), 3,90-4,10 (m, 4H), 2,44 (dt, 1H), 2,33 (DD, 1H), 2,15-of 2.27 (m, 2H), 2,00 (m, 1H), 1,75-of 1.88 (m, 2H), 1.70 to (m, 1H)and 1.51 (m, 2H), 1,34 (m, 1H).

Stage B

5-hydroxy-5-pyridine-albicilla[2.2.2]octane-2-it.

The alcohol from step A (isomer with higher Rf, 0,290 g, 1.11 mmol) dissolved in THF (10 ml) under nitrogen atmosphere. Add hydrochloric acid (2.0 ml, 4.0m aqueous solution, 8.0 mmol) and the mixture is stirred for 4 hours at room temperature. The mixture was then diluted with NaHCO3/H2O and extracted twice with ethyl acetate. The extracts are washed with saturated salt solution, dried over MgSO4, filtered and concentrated, obtaining a light yellow solid, 0,204 g (85%). The crude product 2 are used directly in the next stage without additional purification.1NMR (CDCl3) δ: a total of 8.74 (s, 1H), charged 8.52 (d, 1H), 7,72 (dt, 1H), 7,30 (DD, 1H), 2,66 (dt, 1H), 2,53 (m, 2H), 2,41 (t, 1H), 2,18 (t, 1H), 2.13 in (d, 1H), 2,09 (m, 1H), 1,99 (m, 1H), 1,89 (m, 1H), 1,62 (m, 2H).

Stage C

N-(2-{[(3R)-1-(5-hydroxy-5-pyridin-3-albicilla[2.2.2]Oct-2-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

The hydrochloride of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (100 mg, 0,284 mmol) and 5-hydroxy-5-pyridin-3-albicilla[2.2.2]octane-2-he (62,0 mg, 0,284 mmol) dissolved in dry THF (10 ml). Add triethylamine (80 μl, or 0.57 mmol) and triacetoxyborohydride sodium (120 mg, or 0.57 mmol) and the mixture is stirred at room temperature overnight. According to TLC cause conversion to the desired products in the ratio of isomers of about 1:1. Adsorb reactio the ing the mixture on silica gel and subjected to chromatography elwira dichloromethane to a mixture of 10% methanol/dichloromethane/0.5% ammonium hydroxide. Factions unite, getting pure isomer with higher Rf and pure isomer with lower Rf. A product with higher Rf: LC/MS (positive ion) m/z=517,1 (M+H)+; a product with a lower Rf: LC/MS (positive ion) m/z=from 517.2 (M+H)+.

Example 367

Stage A

3-metalization.

Specified in the header connection receive in accordance with the method disclosed in the literature (Lucchesini, F.; Pied, N.; Pocci, M., HeterocyCles, 1989, 29, 97). At 0°C, 3-butyn-2-he (2.5 ml, to 0.032 mol) and hydroxylamine-O-sulfonic acid (3,67 g, 0,0324 mol) is mixed in water (15 ml, 0.83 mol). After stirring for 30 minutes, portions slowly add solid sodium bicarbonate (3.0 g, being 0.036 mol) (30 minutes). To the thus obtained reaction mixture was added dropwise a solution of acid dihydrate sodium sulphide (3.3 grams, being 0.036 mol) in water (25 ml, 1.4 mol). Then remove the bath with ice. Stirring is continued for 4 hours at room temperature. The mixture is extracted with ether. The extract is dried and concentrated. The result chromatography on silica gel, elwira a mixture of ether/hexane (1/3), gain of 1.37 g (48,2%) specified in the connection header.

Stage B

8-(3-metalization-5-yl)-1,4-dioxaspiro[4,5]Decan-8-ol.

PR Is -78°C, 1,5M n-utility in hexane (6,7 ml) is added slowly to a solution of 3-methylisothiazolone (1.0 g, 0,010 mol) in tetrahydrofuran (15 ml) for 20 minutes. After stirring for a further 30 minutes, within 10 minutes add l,4-dioxaspiro[4,5]decane-8-he (1.56 g, 0,00999 mol) in tetrahydrofuran (5 ml). The reaction mixture is stirred for 2 hours at -78°C and allowed to warm overnight to room temperature. After the mixture was quenched with a saturated salt solution, the mixture is extracted with EtOAc. The organic layer is dried and concentrated. The result chromatography on silica gel, elwira a mixture of hexane/EtOAc(1:5~1:1), obtain 1.8 g (70.6 per cent) specified in the connection header. MS (M+H)+256.

Stage C

4-hydroxy-4-(3-metalization-5-yl)cyclohexanone.

8-(3-metalization-5-yl)-1,4-dioxaspiro[4,5]Decan-8-ol (0,76 g, 0,0030 mol) is dissolved in tetrahydrofuran (10 ml) and add 3.0m solution of hydrogen chloride in water (5.0 ml). The mixture is stirred over night. Add solid potassium carbonate to neutralize the acid and EtOAc are added to extract the product. The extract is dried and concentrated, obtaining the crude product is used directly in the next stage.

Stage D

N-[2-({(3R)-1-[4-hydroxy-4-(3-metalization-5-yl)cyclohexyl]pyrrolidin-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the title compound is obtained from the ketone from step D, using the same method of example 114. MS (M+H)+511.

Example 368

N-{2-[((3R)-1-{4-[3-(permitil)isothiazol-5-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 367. MS(M+H)+529.

Example 369

N-(2-{[(3R)-1-(4-hydroxy-4-isothiazol-5-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 367. (M+H)+497.

Example 370

N-[2-({(3R)-1-[4-hydroxy-4-(4-(pyrimidine-2-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 282. MS 568 (M+H)+.

Example 371

N-[2-({(3R)-1-[4-(2-cyclopropylamino-5-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 276. MS 532 (M+H)+.

Example 372

N-(2-{[(3R)-1-(4-hydrox the-4-pyridazin-4-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

Specified in the header of the get connection using the same method of example 276. MS 492 (M+H)+.

PHARMACEUTICAL use of the COMPOUNDS of the PRESENT INVENTION

The ability of new compounds of the present invention to anlagenservice CCR2 function can be defined using the appropriate screening (for example, high-yield analysis (high through-put assay)). For example, the agent can be tested in the extracellular analysis of acidification, in the analysis of the influx of calcium, the analysis of the ligand binding or the analysis of chemotaxis (see, for example, Hesselgesser et al., J. Biol. Chem. 273(25):15687-15692 (1998); WO 00/05265 and WO 98/02151).

In practical analysis using CCR2 protein, which can be selected or recombinante received and which has at least one property, activity or function characteristic of CCR2 protein mammals. This specific property can be a property of binding (e.g., ligand or inhibitor), a signaling activity (e.g., activation of G protein mammals, induction of rapid and transient increase in the concentration does not contain cytosole calcium [Ca++]i, function of cellular responses (e.g., stimulation of chemotaxis, or the release of a mediator of inflammatory leukocytes), and the like.

In one embodiment, the composition comprising CCR2 protein or its variant, uderjivayut in terms suitable for linking. Carry out the contacting CCR2 receptor with a test compound and determine and measure the binding.

In alternative embodiments, the assay is a cell analysis, which use cells that stably or short-transfected with a vector or expression cassette containing the sequence of the nucleic acid, which encodes the CCR2 receptor. Cells are incubated under conditions suitable for expression of the receptor, and maintain contact with the agent under conditions suitable for the purpose of linking. Binding may be determined using standard techniques. For example, the degree of binding can be defined relative to the corresponding control. In addition, instead of whole cells can be used cellular fractions, such as a membrane fraction containing the receptor.

The fact of binding or formation of the complex can be determined directly or indirectly. For example, the agent can be marked, by introducing a suitable label (e.g., a fluorescent label, isotope label, enzyme label, and the like), and the binding can be defined, detektywa this label. Specific and/or competitive binding can be assessed using competitive or substitute research, using as competing the Ghent agent without a label or ligand.

Antagonistic activity against CCR2 test agents (e.g., 3,4 disubstituted compounds pyrrolidine formulas I, II or III of the present invention) can be described as the concentration of inhibitor required for 50% inhibition (value IR50) specific binding in the assays of receptor binding using125I-labeled MCP-1 as a ligand, and the mononuclear cells of peripheral blood (Peripheral Blood Mononuclear Cells (PBMC))obtained from whole blood of a healthy person using gradient centrifugation. Specific binding is preferably defined as the total binding (for example, the total number of pulses per minute on filters) minus non-specific binding. Nonspecific binding is defined as the number of pulses per minute, which is still registered in the presence of excess competing agents without a label (e.g., MCP-1).

The above-described human PBMC can be used in the matching analysis of binding. For example, from 200,000 to 500,000 cells can be incubated with 0.1 to 0.2 nm125I-labeled MCP-1 in the presence or in the absence of a competing agent without a label (l0 nm MCP-1) or in the presence of different concentrations be checked connections.125I-labeled MCP-1 can be obtained using appropriate technique, or purchasing commercial suppliers (Prkin Elmer, Boston MA). Binding assays can be performed in 50-250 ál binding buffer consisting of 1M HEPES pH of 7.2, and 0.1% BSA (albumin calf serum)for 30 minutes at room temperature. Binding assays can be completed by collecting membrane using a rapid filtration through glass fiber filters (Perkin Elmer), which can be pre-moistened with 0.3% polyethylenimine or phosphate buffered saline (PBS). The filters are washed with about 600 μl of binding buffer containing 0.5 m NaCl or PBS, then dried and the amount of bound radioactivity determined by counting the pulses using a counter gamma particles (Perkin Elmer).

The ability of compounds to anlagenservice CCR2 function can also be determined by analysis of the chemotaxis of leukocytes, using the appropriate cells. Suitable cells include, for example, cell lines, recombinant cells or selected cells that Express CCR2 and undergo ligand-induced CCR2 (e.g., MCP-1) chemotaxis. In applied analyses using single cells of peripheral blood in a modified chamber Boyden Chamber (Neuro Probe). 500,000 cells not containing serum DMEM medium (In-Vitrogen) incubated in the presence or in the absence of inhibitors and heated to 37°C. the Chamber chemotaxis (Neuro Probe) is also pre-heated. 400 μl of the heated l0 n the MCP-1 is placed into the camera all wells, in addition to the negative control, which contains added DMEM. 8 micron membrane filter (Neuro Probe) is placed on top and the camera cover is closed. The cells are then added to the holes in the lid of the chamber, which are connected with the holes of the chamber below the membrane filter. The whole cell is incubated at 37°C, 5% CO2within 30 minutes. The cells are then sucked off the camera cover open and the filter is carefully removed. The upper part of the filter three times washed with PBS and the lower part is left untouched. Filter are air-dried and stained by the dye Wright Geimsa (Sigma). The filters are counted under a microscope. Wells negative control serve as background and their values are subtracted from all values. Antagonistic efficiency can be determined by comparing the number of cells that migrate in the lower part of the chamber in the wells that contain the antagonist, and the number of cells that migrate in the lower part of the chamber in the control MCP-1 wells.

When using the Protocol analysis of the binding compounds of the present invention demonstrate IR50in the interval from about 0.01 to about 500 (nm). In the analysis of chemotaxis compounds of the present invention demonstrate value IR50in the interval from about 1 to about 3000 (nm).

Compounds of the present invention is administered to mammals, such as man, but they also can is about to use for other mammals, such as animals in need of veterinary treatment, such as domestic animals (e.g. dogs, cats and the like), farm animals (e.g. cows, sheep, pigs, horses and the like) and laboratory animals (e.g., rats, mice, Guinea pigs and the like). Mammals, which are treated by the methods of the present invention are mammals of both sexes, for which you want to modulating the activity of receptors chemokines. The term modulation includes antagonism, agonism, partial antagonism and/or partial agonism.

In the present description, the term therapeutically effective amount means the number of pending connections, which causes the biological or medical response of a tissue, system, animal or human, which offers researchers, veterinarians, physicians or other clinicians.

Compounds of the present invention is administered in therapeutically effective amounts for the treatment of diseases, such as rheumatoid arthritis. A therapeutically effective amount of compound is an amount which leads to inhibition of one or more of the processes, oposredstvovanii binding of chemokines to receptors, such as CCR2 for a subject with a disease associated with aberrant recruitment and/or what ctivities leukocytes. Typical examples of such processes include leukocyte migration, integrin activation, transient increase in the concentration of intracellular free calcium [Ca2+]i and the release of granules of proinflammatory mediators. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve the desired therapeutic and/or prophylactic effect, such as the number, which leads to the prevention or mitigation of symptoms associated with a disease associated with aberrant attraction of leukocytes and/or their activation.

Additional diseases or conditions of humans or other species which can be treated with inhibitors or modulators of the function of receptors chemokines include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, diseases of hypersensitivity lung, hypersensitive pneumonitis, eosinophilic cellulitis (e.g., wells syndrome), eosinophilic pneumonias (e.g., syndrome Leffler, chronic eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman syndrome), delayed-type hypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathic Le is full fibrosis, or ILD, associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren syndrome, polymyositis or dermatomyositis); systemic anaphylactic reaction or hypersensitivity reactions, allergic to medicines (e.g., to penicillin, cephalosporins), syndrome eosinophilia-myalgia associated with the absorption of contaminated tryptophan, allergic to insect bites; autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, severe myasthenia gravis, juvenile diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or disease graft versus host disease; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including psoriasis, mediate T-cells) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitive vasculitis); eosinophilic myositis, eosinophilic fasciitis; cancers with infiltration of leukocytes into the skin or organs. Other disease or condition is s, when it is necessary to inhibit unwanted inflammatory reactions can be treated include, but are not limited to, reperfusion damage, atherosclerosis, restenosis, some hematological malignant condition, the toxicity induced by cytokines (e.g., septic shock, endotoxic shock), polyanionic, dermatomyositis.

Compounds represented by formulas I, II or III of the present invention, it is possible to enter in such oral dosage forms as tablets, capsules (each of which includes a song with a slow release or release at a specified time), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. They can also be administered by intravenous (bolus or by intravenous infusion), intraperitoneally, subcutaneously, or intramuscularly, using dosage forms well known to experts in the field of pharmaceutics. You can enter them separately, but they are usually administered together with a pharmaceutically acceptable carrier selected in accordance with the route of administration and standard pharmaceutical practice.

The dosage of the compounds of the present invention is, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, its type and the pic is b its introduction; metabolic stability, rate of excretion, depending on the combination of drugs and duration of action of such compounds, age, sex, General health status, medical condition, and weight of the recipient; nature and extent of symptoms; type accompanying treatment; frequency of treatment; the specific method of administration; the renal and hepatic function of the patient and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, suspend or stop the development of a particular disease that should be treated.

Usually when administered orally daily dose of each active ingredient, when used for the indicated effects, will be in the range from about 0.0001 to 1000 mg/kg body weight, preferably from about 0.001 to 100 mg/kg of body weight per day and most preferably from about 0.1 to 20 mg/kg/day. When administered intravenously, the most preferred doses will be in the range of from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. When orally administered compositions preferably are in the form of tablets containing 1.0 to 1000 mg of active ingredient, more specifically 1,0, 5,0, 10,0, 15,0. 20,0, 25,0, 50,0, 75,0, 100,0, 150,0, 200,0, 250,0, 300,0, 400,0, 500,0, 600,0, 750,0, 800,0, 900,0 and 1000,0 mg of the active ingredient for the symptomatic determining the dose to be patient. Connection, you can enter the scheme from 1 to 4 times a day, preferably once or twice a day.

Compounds of the present invention can also be entered in the form intended for intranasal, by local application of intranasal media, or transdermal method, using transdermal skin patches. With the introduction in the form of a transdermal delivery system, the input dose will, of course, continuous rather than periodic in terms of dosage.

Compounds of the present invention is usually administered in a mixture with suitable pharmaceutical diluents, excipients or carriers (collectively they are called here pharmaceutical carriers), appropriately selected depending on the intended form of administration, i.e. in the form of tablets for oral administration, capsules, elixirs, syrups and the like, and consistent with the usual pharmaceutical practice.

For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. For oral call is to be placed in the form of liquid components of the medicinal product for normal injection can be combined with any non-toxic pharmaceutically acceptable carrier for oral administration, such as ethanol, glycerol, water and the like.

In addition, if desired or necessary, suitable binders, lubricants, dezintegriruetsja agents and coloring agents can also be included in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn syrup, natural and synthetic resins, such as resin acacia, tragakant or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants that are used in such forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrant include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan resin and the like.

Compounds of the present invention can also enter the patient in the form of liposomal delivery systems, such as small single-layer vesicles, large single-layer and multi-layered vesicles vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

Compounds of the present invention can be also associated with soluble polymers as targeted carriers of drugs. Such polymers can include polyvinylpyrrolidone, a copolymer of Piran, on hydroxypropylmethacrylamide, polyhydroxyethylmethacrylate or polyethylenepolyamine, substituted palmitoleate remains. In addition, the compounds of the present invention can be associated with a class of biodegradable polymers that can be used to achieve controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acids, polietilen caprolacton, polyhydroxyalkane acid, complex poliorcetes, Polyacetals, polyhydraminos and sewn or amphipatic block copolymers of hydrogels.

Dosage forms of the compounds of the present invention, suitable for administration may contain from about 0.1 mg to about 100 mg of the active ingredient in dosage unit. In these pharmaceutical compositions the active ingredient is typically present in an amount of about 0.5 to 95 wt.% calculated on the total weight of the composition.

Gelatin capsules can also be used as dosage forms, and they may contain the active ingredient and powders carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to obtain CT. As tablets and capsules can be obtained as products of the process plants the military release, designed for continuous release of drugs within hours. Molded tablets may be coated with sugar or film-coated to mask any unpleasant taste and protect the tablet from atmospheric influences, or can be interoperation for selective disintegration in the gastrointestinal tract.

If you use liquid dosage forms for oral administration, they may contain coloring and flavoring agents to make the medicine the patient more pleasant.

Usually water, suitable oil, saline, aqueous dextrose (glucose) and solutions related sugars and glycols, such as propylene glycol or glycols are suitable carriers for the preparation of solutions for parenteral administration. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.

Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, singly or combined, are suitable stabilizing agents. Also use citric acid and its salts and sodium EDTA. In addition, solutions for parenteral administration may contain preservatives, such as Benz is conifold, methyl - or propylparaben and chlorbutanol. Suitable pharmaceutical carriers are disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference book in the field of pharmacology.

The pharmaceutical compositions of the present invention may also be in the form of emulsions of the type oil-in-water. The oil phase can serve as a vegetable oil, such as olive oil, or peanut oil, or mineral oil, for example liquid paraffin or mixtures of these oils. Suitable emulsifying agents may be natural gums, for example gum Arabic or resin tragakant, natural phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and anhydrides hexitol, such as servicemanual, and condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Compounds of the present invention can also be entered in the form of suppositories for rectal administration of drugs. These compositions can be obtained by mixing the drug with a suitable not irritating excipient, which is in solid state at ordinary temperature, but liquid at rectal temperature and therefore will melt in rectuma you Vologda drug. Such materials are cocoa butter and polyethylene glycols.

For local applications use creams, ointments, jellies, solutions or suspensions, etc. containing compounds of the present invention. In the sense used in this description, the term local use also includes the use of a gargle for mouth and throat.

Pharmaceutical compositions and methods of the present invention can additionally include other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions.

Examples of useful pharmaceutical dosage forms for administration of the compounds of the present invention can be illustrated as follows.

Capsules

A large number of unit capsules can be obtained by filling in a standard, two-part gelatin capsules 50 mg of powder of the active ingredient, 100 mg of lactose, 25 mg of cellulose and 3 mg of magnesium stearate in each.

Soft gelatin capsules

The mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and put in gelatin using a pump with positive displacement, to obtain soft gelatin capsules containing 75 mg of active ingredient. Capsules should be washed and dried.

T is blacki

Tablets can be obtained by conventional means, so that the dosage unit contains 75 mg of the active ingredient, 0.15 mg of colloidal silicon dioxide, 4 mg of magnesium stearate 250 mg microcrystalline cellulose, 9 mg of starch and 75 mg of lactose. On the surface of the tablets can apply suitable coatings well known in the art, in order to increase palatability or slow down the absorption.

Preparations for injection

Compositions for parenteral administration, suitable for injection, you can cook, stirring to 1.0 wt.% the active ingredient in 8 % (by volume) of propylene glycol and water. The solution should be made isotonic by using sodium chloride, and subjected to sterilization.

Suspension

The aqueous suspension can be prepared for oral administration so that each 5 ml contain 75 mg of finely powdered active ingredient, 150 mg of sodium carboxymethyl cellulose, 3.75 mg sodium benzoate, 0.75 mg of sorbitol solution, U.S.P., and 0.015 ml of vanillin.

Example 373

In this example, disclosed a method of evaluating the effectiveness of CCR2 antagonists for the treatment of rheumatoid arthritis.

The model of rheumatoid arthritis animals provides his induction in rodents by injection of collagen type II in the selected adjuvant. Three series of groups of rodents, consisting of 15 Genet the Cesky susceptible mice or rats in the group, administered by injection subcutaneously or intradermally collagen type II emulsified in complete adjuvant Freund on days 0 and 21. One series rodents impose additional phosphate buffered saline (PBS) and Tween 0.5% of the intraperitoneally at the initial sensitization, and then in various dosing schemes. The second series consists of a group of rodents, which is administered various doses of CCR2 antagonist(antagonist) or intraperitoneally, or intravenously, or subcutaneously, or intramuscularly, or orally, or by any other method of administration during the initial sensitization, and then in various dosing schemes. The third series of rodents, which serves as a positive control, consists of a group, which is treated or murine IL-10 intraperitoneally, or antibodies against TNF intraperitoneally at the initial sensitization, and then in various dosing schemes.

The animals watch from 3 weeks to 8, paying attention to the development of swollen joints or claws, and classify changes in accordance with the standard scale of severity. The severity of the disease is confirmed by histological analysis of the joints.

All publications, patents and patent applications, including all the cited methods and cited references, are included in this description by reference in its entirety for all purposes

Although many of the disclosed forms of the present invention are currently the preferred option, it may be many other variations and additional details of preferred options and other options, and they should not be construed as limitations. It should be understood that in this description, the terms are simply rather descriptive, and not restrictive and that can be done many different replacement equivalents, without departing from the essence and scope of the claimed invention.

1. The compound of the formula I

its optical isomer or mixture of optical isomers and pharmaceutically acceptable salts, where
R1independently selected from the group consisting of: aryl, heteroaryl, arylcarboxamide, heteroarylboronic, aryloxy, Allakaket or arylamino, and where these groups of aryl, arylalkyl or heteroaryl can be substituted by 0-3 substituents R1awhere R1aindependently selected from the group consisting of: halogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, hydroxyalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, mono - or disubstituted aminoalkyl, aminocarbonyl, mono - or disubstituted aminoalkyl, aminocarbonyl, mono - or disubstituted aminocarbonyl, cyclic aminocarbonyl, alkylsulfonyl, residue esterified carboxylic acid, arylcarboxylic, carbamate, 1b-aryl, or R1b-heteroaryl, where R1brepresents H, halogen, HE, amino, mono - or disubstituted amino, mono-, di - or trihalogen, alkoxy, mono-, di - or trigalogenmetany, hydroxyalkyl;
R2independently selected from the group consisting of: H, HE, cyano, halogen or aryl;
optional R1and R2can be connected to each other with the formation of spirocyclic;
R3, R4, R5and R6represent H;
optional R1and R3can be cyklinowanie education carbocycle;
optional R3and R4or R5and R6cyklinowanie with the formation of bridged bicyclic system containing ethylene bridge;
optional R3and R6cyklinowanie with the formation of bridged bicyclic systems containing a methylene group or ethylene group;
R7and R8independently selected from the group consisting of hydrogen, HE, WITH1-C8of alkyl, Allakaket, heteroaromatics;
optional R7and R8can be cyklinowanie education pyrocarbonate or spiroheterocyclic; and
m=0-5;
where the term "aryl" includes aromatic carbocyclic group, such as phenyl, biphenyl, indenyl, naphthyl, and condensed with an aromatic heterocycle group;
where the term "heterocycle" includes the aromatic and non-aromatic rings, containing from 3 to 10 atoms in the ring, 1-4 of which are heteroatoms selected from oxygen, sulfur or nitrogen;
where the term "alkyl", when used alone or as a suffix, means a branched or unbranched alkyl group containing from 1 to 8 carbon atoms in the chain;
where the term "alkenyl" means an unsaturated branched or unbranched alkyl group containing from 2 to 12 carbon atoms in the chain.

2. The compound of formula II

its optical isomer or mixture of optical isomers and pharmaceutically acceptable salts, where R1independently selected from the group consisting of: aryl, heteroaryl, arylcarboxamide, heteroarylboronic, aryloxy, Allakaket or arylamino, and where these groups of aryl, arylalkyl or heteroaryl can be substituted by 0-3 substituents R1awhere R1aindependently selected from the group consisting of: halogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, hydroxyalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, mono - or disubstituted aminoalkyl, aminocarbonyl, mono - or disubstituted aminocarbonyl, cyclic aminocarbonyl, alkylsulfonyl, residue esterified carboxylic acid, arylcarboxylic, carbamate, R1b-aryl, or R1b-heteroaryl, where R1bR2independently selected from the group consisting of: H, HE, cyano, halogen or aryl;
optional R1and R2can be connected to each other with the formation of spirocyclic;
R3, R4, R5and R6represent H;
optional R1and R3can be cyklinowanie education carbocycle;
optional R3and R4or R5and R6cyklinowanie with the formation of bridged bicyclic system containing ethylene bridge;
optional R3and R6cyklinowanie with the formation of bridged bicyclic systems containing a methylene group or ethylene group;
R7and R8independently selected from the group consisting of hydrogen, HE, WITH1-C8of alkyl, Allakaket, heteroaromatics;
optional R7and R8can be cyklinowanie education pyrocarbonate or spiroheterocyclic;
where the term "aryl" includes aromatic carbocyclic group, such as phenyl, biphenyl, indenyl, naphthyl, and condensed with an aromatic heterocycle group;
where the term "heterocycle" includes aromatic and non-aromatic ring containing from 3 to 10 atoms in number is CE, 1-4 of which are heteroatoms selected from oxygen, sulfur or nitrogen;
where the term "alkyl", when used alone or as a suffix, means a branched or unbranched alkyl group containing from 1 to 8 carbon atoms in the chain;
where the term "alkenyl" means an unsaturated branched or unbranched alkyl group containing from 2 to 12 carbon atoms in the chain.

3. The compound according to claim 2, where R2is HE, R3, R4, R5, R6, R7and R8represent hydrogen, R1selected from the group consisting of phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-bromophenyl, 3-bromophenyl, 4-chlorphenyl, 3-chlorphenyl, 4-trifloromethyl, 3-triptoreline, 2-triptoreline, 2-methoxyphenyl, 2-methoxy-5-pyridyl, 2-ethoxy-5-pyridyl, 3,4-methylenedioxyphenyl, 4-ftoheia, 3-trifluoromethyl-1H-pyrazole-1-yl, 3-ftoheia, 4-methoxyphenyl, 3-methoxyphenyl, the quinoline-4-yl, 3-methyl-1H-pyrazole-1-yl, 3,5-dimethyl-1H-pyrazole-1-yl, 4-trifloromethyl, 3-triptoreline, 4-(methylaminomethyl)phenyl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, 4-methylpyridin-2-yl, 5-methylpyridin-2-yl, 6-methylpyridin-2-yl, 6-methoxypyridine-2-yl, 6-methoxypyridine-3 ILA, 6-methylpyridin-3-yl, 6-ethylpyridine-3-yl, 6-isopropylpyridine-3-yl, 6-ticlopidin-3-yl, 1-oxidability-3-yl, 1-oxidability-2-yl) - Rev., the quinoline-4-yl, 3-(methylaminomethyl)phenyl, 1-oxidability-4-yl, 4-(morpholine-4-ylcarbonyl)phenyl, 5-(morpholine-4-ylcarbonyl)pyridine-2-yl, 6-(morpholine-4-ylcarbonyl)pyridine-3-yl, 4-(4-methylpiperazin-1-ylcarbonyl)phenyl, 6-(azetidin-1-yl)pyridine-3-yl, 5-(methoxymethyl)pyridine-2-yl, 5-(1-hydroxy-1-methylethyl)pyridine-2-yl, 4-(ethylaminomethyl)phenyl, 4-(isopropylaminocarbonyl)phenyl, 4-(tert-butylaminoethyl)phenyl, 4-(dimethylaminoethyl)phenyl, 4-[(azetidin-1-yl)carbonyl]phenyl, 4-[(pyrrolidin-1-yl)carbonyl]phenyl, 4-[(morpholine-4-yl)carbonyl]phenyl, 4-(dimethylaminoethyl)-2-methylphenyl, 2-methyl-4-(methylaminomethyl)phenyl, 3-methyl-4-(methylaminomethyl)phenyl, 4-(dimethylaminoethyl)-3-methylphenyl, 3-methyl-4-(pyrrolidin-1-ylcarbonyl)phenyl, 4-(dimethylaminoethyl)-3-ftoheia, 4-[(2,2,2-triptorelin)aminocarbonyl]phenyl,
3-fluoro-4-metilaminopropionitrila,
4-ethylaminomethyl-3-ftoheia, 3-metilaminopropionitrila,
3-dimethylaminocarbonylmethyl,
5-dimethylaminoethyl-2-methoxyphenyl,
2-methoxy-5-metilaminopropionitrila,
3-(methylaminoquinoline)phenyl,
6-(morpholine-4-yl)pyridine-3-yl, 6-dimethylaminopyridine-3-Il,
6-isopropylaminomethyl-3-yl, 6-(pyrrolidin-1-yl)pyridine-3-Il,
6-cyclopropylamino-3-yl, 6-ethoxypyridine-3-Il,
6-(2-floratone)pyridine-3-Il,
6-(2,2-diflorasone)pyridine-3-Il,
6-(2,2,2-crypto is ethoxy)pyridine-3-yl, 4-iodophenyl,
5-(pyrrolidin-1-ylcarbonyl)-2-pyridyl,
5-(morpholine-4-ylcarbonyl)-2-pyridyl,
5-dimethylaminoethyl-2-pyridyl,
4-metilaminopropionitrila,
6-(1-hydroxy-1-methylethyl)pyridine-3-Il,
4-(1-hydroxy-1-methylethyl)phenyl, 4-(methoxymethyl)phenyl,
3-fluoro-4-(methoxymethyl)phenyl, 4-(dimethylamino)phenyl,
4-(dimethylamino)-3-ftoheia, 1H-indazol-5-yl, 1-methyl-1H-indazol-5-yl, 2-methyl-1H-indazol-5-yl, 1,3-thiazol-2-yl, 5-ethyl-1,3-thiazol-2-Il,
5-(methylaminomethyl)-1,3-thiazol-2-yl, 1,3-thiazol-5-yl, 2-(methoxycarbonylamino)-1,3-thiazol-5-yl, 2-isopropyl-1,3-thiazol-5-yl, 5-(pyridine-3-yl)-1,3-thiazol-2-yl, 5-(morpholine-4-ylcarbonyl)-1,3-thiazol-2-yl, 5-aminocarbonyl-1,3-thiazol-2-yl, 5-dimethylaminoethyl-1,3-thiazole-2-yl, 5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl, 5-allyl-1,3-thiazol-2-yl, 5-propyl-1,3-thiazol-2-yl, 5-ethylaminomethyl-1,3-thiazol-2-yl, 5-phenyl-1,3-thiazol-2-yl, 5-methyl-1,3-thiazol-2-yl, 5-hydroxymethyl-1,3-thiazol-2-yl, 5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl, 5-methoxymethyl-1,3-thiazol-2-yl, 5-(2-pyridyl)-1,3-thiazol-2-yl, 2-(pyrrolidin-1-yl)-1,3-thiazol-4-yl, 2-(morpholine-4-yl)-1,3-thiazol-4-yl, 2-methyl-1,3-thiazol-5-yl, 2-(1-hydroxy-1-methylethyl)-1,3-thiazole-5-yl, 2-(pyrrolidin-1-yl)-1,3-thiazol-5-yl, 2-ethoxy-1,3-thiazol-5-yl, 2-ethyl-1,3-thiazol-5-yl, 2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-5-yl, 2-(morpholine-4-yl)-1,3-thiazol-5-yl, 2-methoxymethyl-1,3-thiazol-5-yl, 2-isobutyl-1,3-thiazole-5 ILA 2-ethylaminomethyl-1,3-thiazol-5-yl, 2-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-5-yl, 2-(morpholine-4-ylcarbonyl)-1,3-thiazol-5-yl, 2-(3-pyridyl)-1,3-thiazol-5-yl, 2-(2-pyridyl)-1,3-thiazol-5-yl, 4-methyl-1,3-thiazol-2-yl, 1,3-benzothiazol-2-Il,
pyrimidine-5-yl, pyrimidine-4-yl, pyrimidine-2-yl, pyridazin-3-yl, pyrazin-2-yl, 2-methoxypyridine-5-yl, 2-ethoxypyridine-5-yl, 2-(2-floratone)pyrimidine-5-yl, 2-methylpyrimidin-5-yl, 2-ethylpyrimidine-5-yl, 2-isopropylpyrimidine-5-yl, 2-cyclopropylamino-5-yl, pyrimidine-4-yl, 4-(pyrimidine-5-yl)phenyl, 4-(1,3-oxazol-2-yl)phenyl, 4-(1H-imidazol-1-yl)phenyl, 4-(morpholine-4-yl)phenyl, 5-(pyrazin-2-yl)pyridine-2-yl, 4-(1-methyl-1H-imidazol-5-yl)phenyl,
4-(4,6-dimethylpyrimidin-5-yl)phenyl, 6-bromopyridin-3-Il,
5-bromopyridin-2-yl, 4'-(methylsulphonyl) - biphenyl-4-Il,
3'-(methylsulphonyl) - biphenyl-4-Il,
3'-(methoxycarbonyl)biphenyl-4-Il,
4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl,
4'-(dimethylamino)biphenyl-4-yl, 4-(pyridin-3-yl)phenyl,
4-(1H-pyrazole-4-yl)phenyl, 3,3'-bipyridine-6-Il,
3,4'-bipyridine-6-yl, 5-(3-acetylphenyl)pyridine-2-Il,
5-[3-(dimethylamino)phenyl]pyridine-2-Il,
5-[3-(trifluoromethyl)phenyl]pyridine-2-Il,
5-[4-(methylsulphonyl)phenyl]pyridine-2-Il,
5-(4-methoxyphenyl)pyridine-2-Il,
5-(3-methoxyphenyl)pyridine-2-Il,
5-[3-(aminocarbonyl)phenyl]pyridine-2-Il,
5-(4-forfinal)pyridine-2-yl, 5-(3,4-differenl)pyridine-2-Il,
5-(3,5-dimethylisoxazol-4-yl)pyridine-2-Il,
5-(1-m the Teal-1H-pyrazole-4-yl)pyridine-2-Il,
5-(1H-pyrazole-4-yl)pyridine-2-Il,
5-(1-benzofuran-2-yl)pyridine-2-Il,
5-(1,3-benzodioxol-5-yl)pyridine-2-Il,
5-(2-formylphenyl)pyridine-2-yl, 4-(2'-formylphenyl)-4-Il,
5-(1,3-oxazol-2-yl)pyridine-2-Il,
6-(1,3-oxazol-2-yl)pyridine-3-yl, 4-(1,3-thiazol-2-yl)phenyl,
5-(1,3-thiazol-2-yl)pyridine-2-Il,
6-(1,3-thiazol-2-yl)pyridine-3-Il,
6-(1H-imidazol-1-yl)pyridine-3-Il,
5-(1H-imidazol-1-yl)pyridin-2-yl, 6-vinylpyridin-3-Il,
5-(pyrimidine-5-yl)pyridine-2-Il,
5-(pyrimidine-2-yl)pyridine-2-Il,
5-(3-aminocarbonylmethyl)pyridine-2-Il,
4-(1-methyl-1H-imidazol-4-yl)phenyl, 4-(1H-imidazol-4-yl)phenyl,
5-[2-(hydroxymethyl)phenyl]pyridine-2-Il,
2'-(hydroxymethyl)biphenyl-4-Il,
5-{2-[(dimethylamino)methyl]phenyl}pyridine-2-Il,
2'-[(dimethylamino)methyl]biphenyl-4-Il,
5-formatieren-2-yl, 5-deformalisation-2-Il,
5-methylpyrazine-2-yl, 2-methylpyrimidin-5-Il,
2-formerpresident-5-yl, 2-diformylpiridine-5-Il,
2-cryptomaterial-5-yl, isothiazol-5-yl, 3-metalization-5-Il,
3-formalisation-5-yl, 4-(dimethylaminoethyl)phenyl, 4-(methylaminomethyl)phenyl, 4-(morpholine-4-ylcarbonyl)phenyl, 4-(piperidine-1-ylcarbonyl)phenyl,
3-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl,
5-(pyrrolidin-1-ylcarbonyl)pyridine-2-Il,
5-(dimethylaminoethyl)pyridine-2-Il,
5-(morpholine-4-ylcarbonyl)pyridine-2-yl, quinoline-4-Il,
6-methoxypyridine-3-yl, 6-(morph the Lin-4-yl)pyridine-3-Il,
4-(dimethylaminomethyl)phenyl,
5-(dimethylaminomethyl)pyridine-2-Il,
5-(dimethylaminoethyl)pyridine-2-Il,
4-[hydroxy(pyridin-3-yl)methyl]phenyl,
6-[(hydroxy(pyridin-3-yl)methyl]pyridine-3-Il,
6-(dimethylaminoethyl)pyridine-3-Il,
4-(4-hydroxypiperidine-1-ylcarbonyl)phenyl,
4-(4-methoxypiperidine-1-ylcarbonyl)phenyl,
5-(4-methoxypiperidine-1-ylcarbonyl)pyridine-2-Il,
6-(4-methoxypiperidine-1-ylcarbonyl)pyridine-3-Il,
phenoxy, benzyloxy, 2-tanila, 2-isopropyl-1,3-thiazole-5-Il,
4-(pyrimidine-2-yl)phenyl, 4-(pyrimidine-4-yl)phenyl and
5-(methoxymethyl)pyridine-2-yl.

4. The compound according to claim 2, where R2represents H, R3, R4, R5, R6, R7and R8represent hydrogen, R1selected from the group consisting of phenyl, pyridin-2-yl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-bromophenyl, 3-bromophenyl, 4-chlorphenyl, 3-chlorphenyl, 4-trifloromethyl, 3-triptoreline, 2-triptoreline, 2-methoxyphenyl, 3,4-methylenedioxyphenyl, 4-ftoheia, 3-trifluoromethyl-1H-pyrazole-1-yl, 3-ftoheia, 3-chlorphenyl, 4-methoxyphenyl, 3-methoxyphenyl, pyridine-4-yl, pyridine-3-yl, 6-methylpyridin-2-yl, 6-methyl pyridine-3-yl, 6-ethylpyridine-3-yl, 6-isopropylpyridine-3-yl, quinoline-4-yl, 3-methyl-1H-pyrazole-1-yl, 3,5-dimethyl-1H-pyrazole-1-yl, 4-(methylaminomethyl)phenyl, 1-oxidability-4-yl, pyridine-2-yl, 4-methylpiperid the h-2-yl, 5-methylpyridin-2-yl, 6-methoxypyridine-2-yl, 6-methoxypyridine-3-yl, 6-methylpyridin-3-yl, 6-ethylpyridine-3-yl, 6-isopropylpyridine-3-yl, 1-oxidability-3-yl, 1-oxidability-2-Il,
3-(methylaminomethyl)phenyl, 1-oxidability-4-Il,
4-(morpholine-4-ylcarbonyl)phenyl,
5-(morpholine-4-ylcarbonyl)pyridine-2-Il,
6-(morpholine-4-ylcarbonyl)pyridine-3-Il,
4-(4-methylpiperazin-1-ylcarbonyl)phenyl,
6-(azetidin-1-yl)pyridine-3-yl, 6-cyano-3-yl, 5-(methoxymethyl)pyridine-2-Il,
5-(1-hydroxy-1-methylethyl)pyridine-2-yl, 5-dimethylaminomethyl,
4-ethylaminoethanol, 4-isopropylaminocarbonyl,
4-tert-butylaminoethyl, 4-dimethylaminocarbonylmethyl,
4-(azetidin-1-yl)carbonifera,
4-(pyrrolidin-1-yl)carbonifera,
4-(morpholine-4-yl)carbonifera,
4-(dimethylaminoethyl)-2-methylphenyl,
2-methyl-4-(methylaminomethyl)phenyl,
3-methyl-4-(methylaminomethyl)phenyl,
4-(dimethylaminoethyl)-3-methylphenyl,
3-methyl-4-(pyrrolidin-1-ylcarbonyl)phenyl,
4-(dimethylaminoethyl)-3-ftoheia,
4-[(2,2,2-triptorelin)aminocarbonyl]phenyl,
3-fluoro-4-metilaminopropionitrila,
4-ethylaminomethyl-3-ftoheia, 3-metilaminopropionitrila,
3-dimethylaminocarbonylmethyl, 5-dimethylaminoethyl-2-methoxyphenyl,
2-methoxy-5-metilaminopropionitrila,
3-(methylaminoquinoline)phenyl,
6-(morpholine-yl)pyridine-3-yl, 6-dimethylaminopyridine-3-Il,
6-isopropylaminomethyl-3-yl, 6-(pyrrolidin-1-yl)pyridine-3-Il,
6-ethoxypyridine-3-yl, 6-(2-floratone)pyridine-3-Il,
6-(2,2-diflorasone)pyridine-3-Il,
6-(2,2,2-triptoreline)pyridine-3-yl, 4-iodophenyl,
5-(pyrrolidin-1-ylcarbonyl)-2-pyridyl,
5-(morpholine-4-ylcarbonyl)-2-pyridyl,
5-dimethylaminoethyl-2-pyridyl,
4-metilaminopropionitrila,
6-(1-hydroxy-1-methylethyl)pyridine-3-Il,
4-(1-hydroxy-1-methylethyl)phenyl, 4-(methoxymethyl)phenyl,
3-fluoro-4-(methoxymethyl)phenyl, 4-(dimethylamino)phenyl,
4-(dimethylamino)-3-ftoheia, 1H-indazol-5-Il,
1-methyl-1H-indazol-5-yl, 2-methyl-1H-indazol-5-Il,
1,3-thiazol-2-yl, 5-ethyl-1,3-thiazol-2-Il,
5-(methylaminomethyl)-1,3-thiazol-2-yl, 1,3-thiazol-5-Il,
2-(methoxycarbonylamino)-1,3-thiazole-5-Il,
2-isopropyl-1,3-thiazole-5-Il,
5-(pyridine-3-yl)-1,3-thiazol-2-Il,
5-(morpholine-4-ylcarbonyl)-1,3-thiazol-2-Il,
5-aminocarbonyl-1,3-thiazol-2-Il,
5-dimethylaminoethyl-1,3-thiazol-2-Il,
5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-Il,
5-allyl-1,3-thiazol-2-yl, 5-propyl-1,3-thiazol-2-yl, 5-ethylaminomethyl-1,3-thiazol-2-yl, 5-phenyl-1,3-thiazol-2-yl, 5-methyl-1,3-thiazol-2-yl, 5-hydroxymethyl-1,3-thiazol-2-yl, 5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl, 5-methoxymethyl-1,3-thiazol-2 ILA, 5-(2-pyridyl)-1,3-thiazol-2-yl, 2-(pyrrolidin-1-yl)-1,3-thiazol-4-yl, 2-(morpholine-4-yl)-1,3-thiazol-4-yl, 2-methyl-1,3-thiazol-5-yl) - Rev., 2-(1-hydroxy-1-methylethyl)-1,3-thiazol-5-yl, 2-(pyrrolidin-1-yl)-1,3-thiazol-5-yl, 2-ethoxy-1,3-thiazol-5-yl, 2-ethyl-1,3-thiazol-5-yl, 2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-5-yl, 2-(morpholine-4-yl)-1,3-thiazol-5-yl, 2-methoxymethyl-1,3-the thiazole-5-yl, 2-isobutyl-1,3-thiazol-5-yl, 2-ethylaminomethyl-1,3-thiazol-5-yl, 2-(pyrrolidin-1-ylcarbonyl)-1,3-thiazole-5-Il,
2-(morpholine-4-ylcarbonyl)-1,3-thiazol-5-yl, 2-(3-pyridyl)-1,3-thiazol-5-yl, 2-(2-pyridyl)-1,3-thiazol-5-yl, 4-methyl-1,3-thiazol-2-yl, 1,3-benzothiazol-2-yl, pyrimidine-5-yl, pyrimidine-2-yl, pyridazin-4-yl, pyridazin-3-yl, pyrazin-2-yl, 2-methylpyrimidin-5-yl, 2-ethylpyridine-5-yl, 2-isopropylpyrimidine-5-yl, 2-cyclopropylamino-5-yl, 2-methoxypyridine-5-yl, 2-ethoxypyridine-5-yl, 2-(2-floratone)pyrimidine-5-yl, pyrimidine-4-yl, 4-(pyrimidine-5-yl)phenyl, 4-(1,3-oxazol-2-yl)phenyl, 4-(1H-imidazol-1-yl)phenyl, 4-(morpholine-4-yl)phenyl, 5-(pyrazin-2-yl)pyridine-2-Il,
4-(1-methyl-1H-imidazol-5-yl)phenyl,
4-(4,6-dimethylpyrimidin-5-yl)phenyl, 6-bromopyridin-3-Il,
5-bromopyridin-2-yl, 4'-(methylsulphonyl) - biphenyl-4-Il,
3'-(methylsulphonyl) - biphenyl-4-Il,
3'-(methoxycarbonyl)biphenyl-4-Il,
4-(2,3-Dihydro-1,4-benzodioxin-6-yl)phenyl,
4'-(dimethylamino)biphenyl-4-yl, 4-(pyridin-3-yl)phenyl,
4-(1H-pyrazole-4-yl)phenyl, 3,3'-bipyridine-6-Il,
3,4'-bipyridine-6-yl, 5-(3-acetylphenyl)pyridine-2-Il,
5-[3-(dimethylamino)phenyl]pyridine-2-Il,
5-[3-(trifluoromethyl)the dryer is l]pyridine-2-Il,
5-[4-(methylsulphonyl)phenyl]pyridine-2-Il,
5-(4-methoxyphenyl)pyridine-2-Il,
5-(3-methoxyphenyl)pyridine-2-Il,
5-[3-(aminocarbonyl)phenyl]pyridine-2-Il,
5-(4-forfinal)pyridine-2-yl, 5-(3,4-differenl)pyridine-2-Il,
5-(3,5-dimethylisoxazol-4-yl)pyridine-2-Il,
5-(1-methyl-1H-pyrazole-4-yl)pyridine-2-Il,
5-(1H-pyrazole-4-yl)pyridine-2-Il,
5-(1-benzofuran-2-yl)pyridine-2-Il,
5-(1,3-benzodioxol-5-yl)pyridine-2-Il,
5-(2-formylphenyl)pyridine-2-yl, 4-(2'-formylphenyl)-4-Il,
5-(1,3-oxazol-2-yl)pyridine-2-Il,
6-(1,3-oxazol-2-yl)pyridine-3-yl, 4-(1,3-thiazol-2-yl)phenyl,
5-(1,3-thiazol-2-yl)pyridine-2-Il,
6-(1,3-thiazol-2-yl)pyridine-3-Il,
6-(1H-imidazol-1-yl)pyridine-3-Il,
5-(1H-imidazol-1-yl)pyridin-2-yl, 6-vinylpyridin-3-Il,
5-(pyrimidine-5-yl)pyridine-2-Il,
5-(pyrimidine-2-yl)pyridine-2-Il,
5-(3-aminocarbonylmethyl)pyridine-2-Il,
4-(1-methyl-1H-imidazol-4-yl)phenyl, 4-(1H-imidazol-4-yl)phenyl,
5-[2-(hydroxymethyl)phenyl]pyridine-2-Il,
2'-(hydroxymethyl)biphenyl-4-Il,
5-{2-[(dimethylamino)methyl]phenyl}pyridine-2-Il,
2'-[(dimethylamino)methyl]biphenyl-4-Il,
5-formatieren-2-yl, 5-deformalisation-2-Il,
5-methylpyrazine-2-yl, 2-methylpyrimidin-5-Il,
2-formerpresident-5-yl, 2-diformylpiridine-5-Il,
2-cryptomaterial-5-yl, 2-cyclopropylamino-5-yl, isothiazol-5-yl, 3-metalization-5-Il,
3-formalisation-5-yl, 4-(dimethylamino bonyl)phenyl, 4-(methylaminomethyl)phenyl, 4-(morpholine-4-ylcarbonyl)phenyl, 4-(piperidine-1-ylcarbonyl)phenyl, 3-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl,
5-(pyrrolidin-1-ylcarbonyl)pyridine-2-Il,
5-(dimethylaminoethyl)pyridine-2-Il,
5-(morpholine-4-ylcarbonyl)pyridine-2-yl, quinoline-4-Il,
6-methoxypyridine-3-yl, 6-(morpholine-4-yl)pyridine-3-Il,
4-(dimethylaminomethyl)phenyl,
5-(dimethylaminomethyl)pyridine-2-Il,
5-(dimethylaminoethyl)pyridine-2-Il,
4-[hydroxy(pyridin-3-yl)methyl]phenyl,
6-[(hydroxy(pyridin-3-yl)methyl]pyridine-3-Il,
6-(dimethylaminoethyl)pyridine-3-Il,
4-(4-hydroxypiperidine-1-ylcarbonyl)phenyl,
4-(4-methoxypiperidine-1-ylcarbonyl)phenyl,
5-(4-methoxypiperidine-1-ylcarbonyl)pyridine-2-Il,
6-(4-methoxypiperidine-1-ylcarbonyl)pyridine-3-Il,
phenoxy, benzyloxy, 2-tanila, 2-isopropyl-1,3-thiazole-5-Il,
4-(pyrimidine-2-yl)phenyl, 4-(pyrimidine-4-yl)phenyl and
5-(methoxymethyl)pyridine-2-yl.

5. The compound according to claim 2, where R2represents H, R3, R4, R5, R6represent hydrogen, R7is hydroxy and R8is hydrogen; R1selected from the group consisting of phenyl, pyridin-2-yl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-bromophenyl, 3-bromophenyl, 4-chlorphenyl, 3-chlorphenyl, 4-trifloromethyl, 3-triptoreline, 2-triptoreline, 2-methoxyphenyl, 3,4-methylene is oxyphenyl, 4-ftoheia, 3-trifluoromethyl-1H-pyrazole-1-yl, 3-ftoheia, 4-methoxyphenyl, 3-methoxyphenyl, pyridine-4-yl, pyridine-3-yl, quinoline-4-yl, 3-methyl-1H-pyrazole-1-yl, 3,5-dimethyl-1H-pyrazole-1-yl, 4-(methylaminomethyl)phenyl, 1-oxidability-4-yl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 4-ftoheia,
3-ftoheia, pyridine-2-yl, pyridin-3-yl, pyridine-4-Il,
4-methylpyridin-2-yl, 5-methylpyridin-2-Il,
6-methylpyridin-2-yl, 6-methoxypyridine-2-Il,
6-methoxypyridine-3-yl, 6-methylpyridin-3-Il,
6-ethylpyridine-3-yl, 6-isopropylpyridine-3-Il,
1-oxidability-3-yl, 1-oxidability-2-Il,
3-(methylaminomethyl)phenyl, 1-oxidability-4-Il,
4-(morpholine-4-ylcarbonyl)phenyl,
5-(morpholine-4-ylcarbonyl)pyridine-2-Il,
6-(morpholine-4-ylcarbonyl)pyridine-3-Il,
4-(4-methylpiperazin-1-ylcarbonyl)phenyl,
6-(azetidin-1-yl)pyridine-3-yl, 5-methoxymethyl)pyridine-2-Il,
5-(1-hydroxy-1-methylethyl)pyridine-2-yl, 5-dimethylaminomethyl,
4-ethylaminoethanol, 4-isopropylaminocarbonyl,
4-tert-butylaminoethyl, 4-dimethylaminocarbonylmethyl,
4-(azetidin-1-yl)carbonifera,
4-(pyrrolidin-1-yl)carbonifera,
4-(morpholine-4-yl)carbonifera,
4-(dimethylaminoethyl)-2-methylphenyl,
2-methyl-4-(methylaminomethyl)phenyl,
3-methyl-4-(methylaminomethyl)phenyl,
4-(dimethylaminoethyl)-3-methylphenyl,
3-methyl-4-(p is Raiden-1-ylcarbonyl)phenyl,
4-(dimethylaminoethyl)-3-ftoheia,
4-[(2,2,2-triptorelin)aminocarbonyl]phenyl,
3-fluoro-4-metilaminopropionitrila,
4-ethylaminomethyl-3-ftoheia, 3-metilaminopropionitrila, 3-dimethylaminocarbonylmethyl, 5-dimethylaminoethyl-2-methoxyphenyl,
2-methoxy-5-metilaminopropionitrila,
3-(methylaminoquinoline)phenyl,
6-(morpholine-4-yl)pyridine-3-yl, 6-dimethylaminopyridine-3-Il,
6-isopropylaminomethyl-3-yl, 6-(pyrrolidin-1-yl)pyridine-3-Il,
6-ethoxypyridine-3-Il,
6-(2-floratone)pyridine-3-Il,
6-(2,2-diflorasone)pyridine-3-Il,
6-(2,2,2-triptoreline)pyridine-3-yl, 4-iodophenyl,
5-(pyrrolidin-1-ylcarbonyl)-2-pyridyl,
5-(morpholine-4-ylcarbonyl)-2-pyridyl,
5-dimethylaminoethyl-2-pyridyl,
4-metilaminopropionitrila,
6-(1-hydroxy-1-methylethyl)pyridine-3-Il,
4-(1-hydroxy-1-methylethyl)phenyl, 4-(methoxymethyl)phenyl,
3-fluoro-4-(methoxymethyl)phenyl, 4-(dimethylamino)phenyl,
4-(dimethylamino)-3-ftoheia, 1H-indazol-5-Il,
1-methyl-1H-indazol-5-yl, 2-methyl-1H-indazol-5-Il,
1,3-thiazol-2-yl, 5-ethyl-1,3-thiazol-2-Il,
5-(methylaminomethyl)-1,3-thiazol-2-yl, 1,3-thiazol-5-Il,
2-(methoxycarbonylamino)-1,3-thiazole-5-Il,
2-isopropyl-1,3-thiazole-5-Il,
5-(pyridine-3-yl)-1,3-thiazol-2-Il,
5-(morpholine-4-ylcarbonyl)-1,3-thiazol-2-Il,
5-aminocarbonyl-1,3-thiazol-2-Il,
5-dimethylaminoethyl-1,3-thiazol-2-Il,
5-(pyrrol the DIN-1-ylcarbonyl)-1,3-thiazol-2-Il,
5-allyl-1,3-thiazol-2-yl, 5-propyl-1,3-thiazol-2-Il,
5-ethylaminomethyl-1,3-thiazol-2-yl, 5-phenyl-1,3-thiazol-2-Il,
5-methyl-1,3-thiazol-2-yl, 5-hydroxymethyl-1,3-thiazol-2-Il,
5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-Il,
5-methoxymethyl-1,3-thiazol-2-Il,
5-(2-pyridyl)-1,3-thiazol-2-Il,
2-(pyrrolidin-1-yl)-1,3-thiazole-4-Il,
2-(morpholine-4-yl)-1,3-thiazole-4-Il,
2-methyl-1,3-thiazole-5-Il,
2-(1-hydroxy-1-methylethyl)-1,3-thiazole-5-Il,
2-(pyrrolidin-1-yl)-1,3-thiazole-5-Il,
2 ethoxy-1,3-thiazol-5-yl, 2-ethyl-1,3-thiazole-5-Il,
2-(pyrrolidin-1-ylmethyl)-1,3-thiazole-5-Il,
2-(morpholine-4-yl)-1,3-thiazole-5-Il,
2-methoxymethyl-1,3-thiazole-5-Il,
2-isobutyl-1,3-thiazole-5-Il,
2-ethylaminomethyl-1,3-thiazole-5-Il,
2-(pyrrolidin-1-ylcarbonyl)-1,3-thiazole-5-Il,
2-(morpholine-4-ylcarbonyl)-1,3-thiazole-5-Il,
2-(3-pyridyl)-1,3-thiazol-5-yl, 2-(2-pyridyl)-1,3-thiazole-5-Il,
4-methyl-1,3-thiazol-2-yl, 1,3-benzothiazol-2-Il,
pyrimidine-5-yl, pyrimidine-2-yl, pyridazin-4-Il,
pyridazin-3-yl, pyrazin-2-yl, 2-methoxypyridine-5-Il,
2-ethoxypyridine-5-yl, 2-(2-floratone)pyrimidine-5-Il,
2-methylpyrimidin-5-yl, 2-ethylpyridine-5-Il,
2-isopropylpyrimidine-5-yl, 2-cyclopropylamino-5-Il,
pyrimidine-4-yl, 4-(pyrimidine-5-yl)phenyl,
4-(1,3-oxazol-2-yl)phenyl, 4-(1H-imidazol-1-yl)phenyl,
4-(morpholine-4-yl)phenyl, 5-(pyrazin-2-yl)pyridine-2-Il,
4-(1-methyl-1H-imidazol-5-yl)phenyl,
4-(4,6-dimethylpyrimidin-5-yl)Fe the sludge, 6-bromopyridin-3-Il,
5-bromopyridin-2-yl, 4'-(methylsulphonyl) - biphenyl-4-yl, 3'-(methylsulphonyl) - biphenyl-4-Il,
3'-(methoxycarbonyl)biphenyl-4-Il,
4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl,
4'-(dimethylamino)biphenyl-4-yl, 4-(pyridin-3-yl)phenyl,
4-(1H-pyrazole-4-yl)phenyl, 3,3'-bipyridine-6-Il,
3,4'-bipyridine-6-yl, 5-(3-acetylphenyl)pyridine-2-Il,
5-[3-(dimethylamino)phenyl]pyridine-2-Il,
5-[3-(trifluoromethyl)phenyl]pyridine-2-Il,
5-[4-(methylsulphonyl)phenyl]pyridine-2-Il,
5-(4-methoxyphenyl)pyridine-2-Il,
5-(3-methoxyphenyl)pyridine-2-Il,
5-[3-(aminocarbonyl)phenyl]pyridine-2-Il,
5-(4-forfinal)pyridine-2-yl, 5-(3,4-differenl)pyridine-2-Il,
5-(3,5-dimethylisoxazol-4-yl)pyridine-2-Il,
5-(1-methyl-1H-pyrazole-4-yl)pyridine-2-Il,
5-(1H-pyrazole-4-yl)pyridine-2-Il,
5-(1-benzofuran-2-yl)pyridine-2-Il,
5-(1,3-benzodioxol-5-yl)pyridine-2-Il,
5-(2-formylphenyl)pyridine-2-yl, 4-(2'-formylphenyl)-4-Il,
5-(1,3-oxazol-2-yl)pyridine-2-Il,
6-(1,3-oxazol-2-yl)pyridine-3-yl, 4-(1,3-thiazol-2-yl)phenyl,
5-(1,3-thiazol-2-yl)pyridine-2-Il,
6-(1,3-thiazol-2-yl)pyridine-3-Il,
6-(1H-imidazol-1-yl)pyridine-3-Il,
5-(1H-imidazol-1-yl)pyridin-2-yl, 6-vinylpyridin-3-Il,
5-(pyrimidine-5-yl)pyridine-2-Il,
5-(pyrimidine-2-yl)pyridine-2-Il,
5-(3-aminocarbonylmethyl)pyridine-2-Il,
4-(1-methyl-1H-imidazol-4-yl)phenyl, 4-(1H-imidazol-4-yl)phenyl,
5-[2-(hydroxymethyl)phenyl]pyridine-2-Il,
2'-(hydroxymethyl)biphenyl-4-Il,
5-{2-[(dimethylamino)methyl]phenyl}pyridine-2-Il,
2'-[(dimethylamino)methyl]biphenyl-4-Il,
5-formatieren-2-yl, 5-deformalisation-2-Il,
5-methylpyrazine-2-yl, 2-methylpyrimidin-5-Il,
2-formerpresident-5-yl, 2-diformylpiridine-5-Il,
2-cryptomaterial-5-yl, 2-cyclopropylamino-5-yl, isothiazol-5-yl, 3-metalization-5-Il,
3-formalisation-5-yl, 4-(dimethylaminoethyl)phenyl,
4-(methylaminomethyl)phenyl, 4-(morpholine-4-ylcarbonyl)phenyl,
4-(piperidine-1-ylcarbonyl)phenyl,
3-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl,
5-(pyrrolidin-1-ylcarbonyl)pyridine-2-Il,
5-(dimethylaminoethyl)pyridine-2-Il,
5-(morpholine-4-ylcarbonyl)pyridine-2-yl, quinoline-4-Il,
6-methoxypyridine-3-yl, 6-(morpholine-4-yl)pyridine-3-Il,
4-(dimethylaminomethyl)phenyl,
5-(dimethylaminomethyl)pyridine-2-Il,
5-(dimethylaminoethyl)pyridine-2-Il,
4-[hydroxy(pyridin-3-yl)methyl]phenyl,
6-[(hydroxy(pyridin-3-yl)methyl]pyridine-3-Il,
6-(dimethylaminoethyl)pyridine-3-Il,
4-(4-hydroxypiperidine-1-ylcarbonyl)phenyl,
4-(4-methoxypiperidine-1-ylcarbonyl)phenyl,
5-(4-methoxypiperidine-1-ylcarbonyl)pyridine-2-Il,
6-(4-methoxypiperidine-1-ylcarbonyl)pyridine-3-yl, phenoxy, benzyloxy, 2-tanila, 2-isopropyl-1,3-thiazole-5-Il,
4-(pyrimidine-2-yl)phenyl, 4-(pyrimidine-4-yl)phenyl and
5-(methoxymethyl)pyridine-2-yl, and

6. Connected the e formula III

its optical isomer or mixture of optical isomers and pharmaceutically acceptable salts, where
R1independently selected from the group consisting of: aryl, heteroaryl, arylcarboxamide, heteroarylboronic, aryloxy, Allakaket or arylamino, and where these groups of aryl, arylalkyl or heteroaryl can be substituted by 0-3 substituents R1awhere R1aindependently selected from the group consisting of: halogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, hydroxyalkyl, mono-, di - or trialogical, mono-, di - or trigalogenmetany, mono - or disubstituted aminoalkyl, aminocarbonyl, mono - or disubstituted aminocarbonyl, cyclic aminocarbonyl, alkylsulfonyl, residue esterified carboxylic acid, arylcarboxylic, carbamate, R1b-aryl, or R1b-heteroaryl, where R1brepresents H, halogen, HE, amino, mono - or disubstituted amino, mono-, di - or trihalogen, alkoxy, mono-, di - or trigalogenmetany, hydroxyalkyl;
R2independently selected from the group consisting of: H, HE, cyano, halogen or aryl;
optional R1and R2can be connected to each other with the formation of spirocyclic;
R3, R4, R5and R6represent H;
optional R1and R3can be cycles is designed with the formation of carbocycle;
optional R3and R4or R5and R6cyklinowanie with the formation of bridged bicyclic system containing ethylene bridge;
optional R3and R6cyklinowanie with the formation of bridged bicyclic systems containing a methylene group or ethylene group;
R7and R8independently selected from the group consisting of hydrogen, HE, WITH1-C8of alkyl, Allakaket, heteroaromatics;
optional R7and R8can be cyklinowanie education pyrocarbonate or spiroheterocyclic; and
m=1 or 2;
where the term "aryl" includes aromatic carbocyclic group, such as phenyl, biphenyl, indenyl, naphthyl, and condensed with an aromatic heterocycle group;
where the term "heterocycle" includes aromatic and non-aromatic ring containing from 3 to 10 atoms in the ring, 1-4 of which are heteroatoms, such as oxygen, sulfur or nitrogen;
where the term "alkyl", when used alone or as a suffix, means a branched or unbranched alkyl group containing from 1 to 8 carbon atoms in the chain;
where the term "alkenyl" means an unsaturated branched or unbranched alkyl group containing from 2 to 12 carbon atoms in the chain.
group containing from 2 to 12 carbon atoms in the chain.

7. Connect the s, selected from the group consisting of:
N-(2-{[(3S,4S)-1-cyclohexyl-4-hydroxypyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-(but-2-in-1 yloxy)-1-cyclohexylpiperidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-(benzyloxy)-1-cyclohexylpiperidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-1-cyclohexyl-4-(pyridine-2-ylethoxy)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-1-cyclohexyl-4-(pyridine-3-ylethoxy)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-hydroxy-1-(4-hydroxy-4-phenylcyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-hydroxy-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-hydroxy-4-(4-were)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-hydroxy-4-(3-were)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[hydroxy-4-(2-were)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(4-bromophenyl)-4-hydroxycyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(3-bromophenyl)-4-hydroxycyclohexyl]-4-hydroxypyrrolidine-3-the l}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(4-chlorophenyl)-4-hydroxycyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(3-chlorophenyl)-4-hydroxycyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-hydroxy-4-(4-triptoreline)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-hydroxy-4-(3-triptoreline)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy]-[4-hydroxy-4-(2-triptoreline)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-hydroxy-4-(4-methoxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-hydroxy-4-(3-methoxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-hydroxy-4-(2-methoxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-hydroxy-4-(3,4-methylenedioxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-hydroxy-1-(4-hydroxy-4-pyridin-3-illlogical)pyrrolidin-3-yl}amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-hydroxy-1-(4-hydroxy-4-pyridin-4-illlogical)pyrrolidin-3-yl]amino}-2-oxoe who yl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-hydroxy-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-hydroxy-4-(6-methoxypyridine-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(6-ethoxypyridine-3-yl)-4-hydroxycyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-1-(4-cyano-4-phenylcyclohexyl)-4-hydroxypyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(4-forfinal)cyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-([(3S,4S)-4-hydroxy-1-(4-pyridine-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-{2-[((3S,4S)-4-hydroxy-1-{4-[3-(trifluoromethyl)-1H-pyrazole-1-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(3-forfinal)cyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(4-chlorophenyl)cyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(3-chlorophenyl)cyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(4-bromophenyl)cyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(3-bromophenyl)cyclohexyl]-4-hydroxypyrrolidine-3-and the}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(4-were)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(3-were)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(2-were)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(4-methoxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-l-[4-(3-methoxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(pyridin-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(pyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(5-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(6-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(quinoline-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(4-triptoreline)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(3-triptoreline)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(three is tormentil)benzamide,
N-[2-({(3S,4S)-4-hydroxy-1-[4-(3,4-methylenedioxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3S,4S)-4-hydroxy-1-{4-[3-(methyl)-1H-pyrazole-1-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(3,5-dimethyl-1H-pyrazole-1-yl)cyclohexyl]-4-hydroxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-hydroxy-1-(3H-Spiro[2-benzofuran-1,1'-cyclohexane]-4'-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-hydroxy-1-Spiro[cyclohexane-1,1'-inden]-4-iparralde-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-1-(2',3'-dihydrospiro[cyclohexane-1,1'-inden]-4-yl)-4-hydroxypyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(9S)-7-(4-hydroxy-4-phenylcyclohexyl)-1-oxa-7-azaspiro[4,4]non-9-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-ethoxy-1-(4-hydroxy-4-phenylcyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(4-cyanophenyl)-4-hydroxycyclohexyl]-4-ethoxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(4-cyanophenyl)-4-hydroxycyclohexyl]-4-ethoxypyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(1-oxidability-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)--ethoxy-1-[4-hydroxy-4-(4-were)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(4-methoxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(3-methoxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-(4-forfinal)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-(3-forfinal)-4-hydroxycyclohexyl] pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-(4-chlorophenyl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(3,4-methylenedioxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(pyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(pyridin-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(pyridin-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(4-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(5-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(6-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(6-methoxypyridine-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(1-oxidability-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(1-oxidability-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(quinoline-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-(3-cyanophenyl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(3-methylaminoethanol)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-ethoxy-1-(4-pyridin-4-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-ethoxy-1-(4-pyridine-3-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-ethoxy-1-(4-pyridine-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-(1-oxidability-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-(1-oxidability-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-(1-acidophil the Jn-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-(6-methoxypyridine-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3S,4S)-4-ethoxy-1-{4-[4-(morpholine-4-ylcarbonyl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3S,4S)-4-ethoxy-1-{4-[5-(morpholine-4-ylcarbonyl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3S,4S)-4-ethoxy-1-{4-[6-(morpholine-4-ylcarbonyl)pyridine-3-yl]cyclohexyl}-pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3S,4S)-4-ethoxy-1-{4-[4-(4-methylpiperazin-1-ylcarbonyl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-(3-methyl-1H-pyrazole-1-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-4-ethoxy-1-[4-(3-trifluoromethyl-1H-pyrazole-1-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-ethoxy-1-(3H-Spiro[2-benzofuran-1,1'-cyclohexane]-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-4-ethoxy-1-Spiro[cyclohexane-1,1'-inden]-4-iparralde-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3S,4S)-1-(2',3'-dihydrospiro[cyclohexane-1,1'-inden]-4-yl)-4-ethoxypyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(1-oxidability-4-yl)cyclohexyl]-4-proximinality-3-yl}amino-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(pyridin-4-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(pyridin-3-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(pyridin-2-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(quinoline-4-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(6-methoxypyridine-3-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(4-methylpyridin-2-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(5-methylpyridin-2-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(6-methylpyridin-2-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(6-methoxypyridine-2-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(1-oxidability-3-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-phenylcyclohexyl]-4-proximinality-3-yl}amino)-2-octoate the]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(4-methoxyphenyl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-hydroxy-4-(3,4-methylenedioxyphenyl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-oxo-2-{[(3S,4S)-4-propoxy-1-(4-pyridine-3-illlogical)pyrrolidin-3-yl]amino}-ethyl)-3-(trifluoromethyl)benzamide,
N-(2-oxo-2-{[(3S,4S)-4-propoxy-1-(4-pyridin-4-illlogical)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(3-methyl-1H-pyrazole-1-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3S,4S)-1-[4-(3,5-dimethyl-1H-pyrazole-1-yl)cyclohexyl]-4-proximinality-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-oxo-2-{[(3S,4S)-4-propoxy-1-(3H-Spiro[2-benzofuran-1,1'-cyclohexane]-4'-yl)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide,
N-(2-oxo-2-{[(3S,4S)-4-propoxy-1-Spiro[cyclohexane-1,1'-inden]-4-iparralde-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide,
N-({(3R)-1-[4-hydroxy-4-(6-methoxypyridine-3-yl)cyclohexyl]pyrrolidin-3-ylcarbonyl}methyl)-3-cryptomelane,
N-(2-{[(3R)-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(6-azetidin-1-espiridion-3-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(5-cyano-2-yl)-4-guide is oxocyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(6-cyano-3-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R))-1-{TRANS-4-hydroxy-4-[5-(methoxymethyl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(1-hydroxy-1-methylethyl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{5-[(dimethylamino)methyl]pyridine-2-yl}-4-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-pyridin-3-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-pyridin-4-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(6-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)4-[4-hydroxy-4-(4-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(1-oxidability-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(1-oxidability-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(1-acidophil the Jn-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R-1-[4-hydroxy-4-(6-methoxypyridine-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(quinoline-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(4-cyanophenyl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(3-cyanophenyl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-{4-[(methylamino)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(ethylamino)carbonyl]phenyl}-4-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-{4-[(isopropylamino)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-((tert-butylamino)carbonyl]phenyl}-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(dimethylamino)carbonyl]phenyl}-4-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(azetidin-1-yl)carbonyl]phenyl}-4-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{(3R)-1-(4-hydroxy-4-{4-[(pyrrolidin-1-yl)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide
N-(2-{[(3R)-1-(4-hydroxy-4-{4-[(morpholine-4-yl)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-{[(2,2,2-triptorelin)amino]carbonyl}phenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(3-{[(methylamine)carbonyl]amino}phenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(6-morpholine-4-espiridion-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[6(dimethylamino)pyridin-3-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[6-(isopropylamino)pyridine-3-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[6-(pyrrolidin-1-yl)pyridine-3-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[6-(cyclopropylamino)pyridine-3-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(6-ethoxypyridine-3-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[6-(2-floratone)pyridine-3-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[6-(2,2-diflorasone)pyridine-3-yl]-4-hydroxycyclohexyl}pyrrolic the n-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[6-(2,2,2-triptoreline)pyridine-3-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-Rensselaer)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-were)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(4-forfinal)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(3-forfinal)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(4-bromophenyl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-iodophenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(pyrrolidin-1-ylcarbonyl)pyridine-2-yl}cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(morpholine-4-ylcarbonyl l)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
6-(1-hydroxy-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)-N,N-diethylnicotinamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-{[(methylamine)carbonyl]amino}phenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[6-(1-hydroxy-1-methylethyl)PI is one-3-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[4-(1-hydroxy-1-methylethyl)phenyl]cycle hexil}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[4-(methoxymethyl)phenyl]cyclohexyl} pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[3-fluoro-4-(methoxymethyl)phenyl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(dimethylamino)methyl]phenyl}-4-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-(4-[(dimethylamino)methyl]-3-forfinal}-4-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(1H-indazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(1-methyl-1H-indazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(2-methyl-1H-indazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N,N-dimethyl-4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(methylamino)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(morpholine-4-yl)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(piperidine-1-ylcarbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[3-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-oxo-2-[((3R)-1-{4-[5-(pyrrolidin-1-ylcarbonyl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]ethyl}-3-(trifluoromethyl)benzamide,
N,N-dimethyl-6-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)nicotinamide,
N-{2-[((3R)-1-{4-[5-(morpholine-4-ylcarbonyl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-(2-oxo-2-{[(3R)-1-(4-pyridine-2-illlogical)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide,
N-(2-oxo-2-{[(3R)-1-(4-pyridine-3-illlogical)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide,
N-(2-oxo-2-{[(3R)-1-(4-pyridin-4-illlogical)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)4-[4-(1-oxidability-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(1-oxidability-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(1-oxidability-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(quinoline-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(6-methoxypyridine-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(6-morpholine-4-espiridion-3-yl)cyclohe the forces]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(dimethylamino)methyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{5-[(dimethylamino)methyl]pyridine-2-yl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{5-[(dimethylamino)carbonyl]pyridin-2-yl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[hydroxy(pyridin-3-yl)methyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{6-[hydroxy(pyridin-3-yl)methyl]pyridine-3-yl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N,N-dimethyl-5-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)pyridine-2-carboxamide,
N-(2-{[(3R)-1-(4-{4-[(4-hydroxypiperidine-1-yl)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(3-hydroxypiperidine-1-yl)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(4-methoxypiperidine-1-yl)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{4-[(3-methoxypiperidine-1-yl)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{5-[(4-methoxypiperidine-1-yl)carbonyl]pyridin-2-yl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoid the l)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{6-[(4-methoxypiperidine-1-yl)carbonyl]pyridin-3-yl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-oxo-2-{[(3R)-1-(4-phenoxytoluene)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(benzyloxy)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4,4-diphenylsiloxane)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[TRANS-2-(benzyloxy)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[CIS-2-(benzoylamine)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-oxo-2-[((3R)-1-{CIS-2-[(phenylacetyl)amino]cyclohexyl}pyrrolidin-3-yl)amino]ethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[CIS-2-(benzylamino)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(5-ethyl-1,3-thiazol-2-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
2-(1-hydroxy-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)-N-methyl-1,3-thiazole-5-carboxamide,
3-(trifluoromethyl)-N-[2-({(3R)-1-[4-hydroxy-4-(1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]benzamide,
methyl[5-(1-hydroxy-4-{(3R)-3-[({[3-(triform the Teal)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)-1,3-thiazol-2-yl]carbamate,
N-[2-({(3R)-1-[4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-pyridin-3-yl-1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(morpholine-4-ylcarbonyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
2-(1-hydroxy-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)-1,3-thiazole-5-carboxamide,
2-(1-hydroxy-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)-N,N-dimethyl-1,3-thiazole-5-carboxamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(5-allyl-1,3-thiazol-2-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-propyl-1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-ethyl-2-(1-hydroxy-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)-1,3-thiazole-5-carboxamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-phenyl-1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-methyl-1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(Tr is permitil)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-hydroxymethyl-1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-methoxymethyl-1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-pyridin-2-yl-1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(2-pyrrolidin-1-yl-1,3-thiazol-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(2-morpholine-4-yl-1,3-thiazol-4-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(2-methyl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[2-(1-hydroxy-1-methylethyl)-1,3-thiazol-5-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(2-pyrrolidin-1-yl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(2-ethoxy-1,3-thiazol-5-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(2-ethyl-1,3-thiazol-5-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoe the yl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-5-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[2-(morpholine-4-yl)-l,3-thiazol-5-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[2-(methoxymethyl)-1,3-thiazol-5-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(2-isobutyl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-ethyl-5-(1-hydroxy-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-rclocal)-1,3-thiazole-2-carboxamide,
N-{2-[((3R)-1-{4-hydroxy-4-[2-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-5-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[2-(morpholine-4-ylcarbonyl)-1,3-thiazol-5-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(2-pyridin-3-yl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(2-pyridin-2-yl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-methyl-1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({3R)-1-[4-(1,3-benzothiazol-2-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-oxo-2-({(3R)-1-[4-(1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)ethyl]-3-(trifluoromethyl)benzamide,
N-{2-oxo-2-[((3R)-1-{4-[5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]ethyl}-3-(trifluoromethyl)benzamide,
N-[2-oxo-2-({(3R)-1-[4-(2-thienyl)cyclohexyl]pyrrolidin-3-yl}amino)ethyl]-3-(trifluoromethyl)benzamide,
3-(trifluoromethyl)-N-{2-[((3R)-1-{4-[5-(methoxymethyl)-1,3-thiazol-2-yl] cyclohexyl} pyrrolidin-3-yl)amino]-2-oxoethyl}benzamide,
3-(trifluoromethyl)-N-{2-[((3R)-1-{4-[5-(morpholine-4-ylcarbonyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}benzamide,
N-{(3R)-1-[4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}-4-oxo-4-[3-(trifluoromethyl)phenyl]butanamide,
4-[3-(trifluoromethyl)phenyl]-N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)-4-oxobutanamide,
4-[3-(trifluoromethyl)phenyl]-N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)-4-oxobutanamide,
N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)-4-[3-(trifluoromethyl)phenyl]butanamide,
N-((3R)-1-{4-[5-(methoxymethyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexyl} pyrrolidin-3-yl)-2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)acetamide", she
N-((3R)-1-{4-hydroxy-4-[2-(methoxymethyl)-1,3-thiazol-5-yl]cyclohexyl}pyrrolidin-3-yl)-3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxamide,
(4Z) and (4E)-4-(hydroxy) - Rev. Mino)-N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)-4-[3-(trifluoromethyl)phenyl]butanamide,
(4Z) and (4E)-4-(amoxiillin)-N-((3R)-1-{4-hydroxy-4-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexyl}pyrrolidin-3-yl)-4-[3-(trifluoromethyl)phenyl]butanamide,
N-[2-({(3R)-1-[4-fluoro-4-(1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-fluoro-4-pyridin-3-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-fluoro-4-(6-methoxypyridine-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-[(1-{4-fluoro-4-[6-(1,3-oxazol-2-yl)pyridine-3-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-fluoro-4-{4-[(methylamino)carbonyl]phenyl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-pyrimidine-5-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-{[(3R)-1-(4-hydroxy-4-pyrimidine-2-illlogical)pyrrolidin-3-ylcarbonyl]methyl}-3-cryptomelane,
N-[2-({(3R)-1-[4-hydroxy-4-pyridazin-3-illlogical]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-pyrazin-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-pyrazin-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[2-(2-floratone)pyrimidine-5-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-octoate the}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(2-methoxypyridine-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-pyrimidine-4-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-pyrimidine-5-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-oxazol-2-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-1H-imidazol-1-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-(morpholine-4-yl phenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-(pyrazin-2-yl)pyridine-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[4-(1-methyl-1H-imidazol-5-yl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[4-(4,6-dimethylpyrimidin-5-yl)phenyl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(6-bromopyridin-3-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(5-bromopyridin-2-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[4'-(metals hanil)biphenyl-4-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-(4-hydroxy-4-[3'-(methylsulphonyl) - biphenyl-4-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[4'-(dimethylamino)biphenyl-4-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-pyridine-3-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[4-(1H-pyrazole-4-yl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(3,3'-bipyridine-6-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(3,4'-bipyridine-6-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[5-(3-acetylphenyl)pyridine-2-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[5-(3-dimethylaminophenyl)pyridine-2-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-{5-[4-(trifluoromethyl)phenyl]pyridine-2-yl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-{5-[4-(methylsulphonyl)phenyl]pyridine-2-yl}cyclohexyl)pyrrolidin-3-yl]amino}-2-OK is oethyl)-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(4-methoxyphenyl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(3-methoxyphenyl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{5-[3-(aminocarbonyl)phenyl]pyridine-2-yl}-4-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[5-(4-forfinal)pyridine-2-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[5-(3,4-differenl)pyridine-2-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[5-(3,5-dimethylisoxazol-4-yl)pyridine-2-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(1H-pyrazole-4-yl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[5-(1-benzofuran-2-yl)pyridine-2-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[5-(1,3-benzodioxol-5-yl)pyridin-2-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[5-(2-formylphenyl)pyridine-2-yl]-4-hydroxilase the forces}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(1,3-oxazol-2-yl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3JR)-1-{4-hydroxy-4-[6-(1,3-oxazol-2-yl)pyridine-3-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[4-(1,3-thiazol-2-yl)phenyl]cycle hexil}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(1,3-thiazol-2-yl)pyridine-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[6-(1,3-thiazol-2-yl)pyridine-3-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[5-(1H-imidazol-1-yl)pyridin-2-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[6-(1H-imidazol-1-yl)pyridine-3-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(6-vinylpyridin-3-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-pyrimidine-5-espiridion-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(5-pyrimidine-2-espiridion-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{5-[3-(aminocarbonyl)phenyl]pyridine-2-yl}-4-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(t is iformity)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[4-(1-methyl-1H-imidazol-4-yl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[4-(1H-imidazol-4-yl)phenyl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-{5-[2-(hydroxymethyl)phenyl]pyridin-2-yl}cyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-hydroxy-4-[2'-(hydroxymethyl)biphenyl-4-yl]cyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(5-{2-[(dimethylamino)methyl]phenyl}pyridine-2-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-{2'-[(dimethylamino)methyl]biphenyl-4-yl}-4-hydroxycyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(benzoylamine)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(4-{(3R)-3-[(2-{[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)pyridine-2-carboxamide,
N-(4{(3R)-3-[(2-{[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)pyridine-3-carboxamide,
N-(4-{(3R)-3-[(2-{[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)pyridine-4-carboxamide,
6-methyl-N-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)pyridine-2-carboxamide,
5-methyl-N-(4-{(3R)-3-[({3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)pyridine-2-carboxamide,
4-methyl-N-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)pyridine-2-carboxamide,
6-methoxy-N-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)pyridine-2-carboxamide,
N-(4-{(3R)-3-[(2-{[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}cyclohexyl)quinoline-4-carboxamide,
N-(2-{[(3R)-1-(3-hydroxy-3-pyridine-2-albicilla[3.2.1]Oct-8-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[3-hydroxy-3-(5-methylpyridin-2-yl)bicyclo[3.2.1]Oct-8-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(3-hydroxy-3-pyridin-3-albicilla[3.2.1]Oct-8-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[3-hydroxy-3-(6-methoxypyridine-3-yl)bicyclo[3.2.1]Oct-8-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(8-hydroxy-8-Panevezio[3.2.1]Oct-3-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(5-hydroxy-5-Panevezio[2.2.1]hept-2-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(5-hydroxy-5-pyridin-2-albicilla[2.2.1]hept-2-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide
N-(2-{[(3R)-1-(5-hydroxy-5-pyridin-3-albicilla[2.2.1]hept-2-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[5-hydroxy-5-(6-methoxypyridine-3-yl)bicyclo[2.2.1]hept-2-yl]pyrrolidin the-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(5-hydroxy-5-pyridin-4-albicilla[2.2.1]hept-2-yl)pyrrolidin-3-ylamino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R,5S)-1-(4-hydroxy-4-phenylcyclohexyl)-5-methylpyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R,5S)-1-[4-hydroxy-4-(4-methyl phenyl)cyclohexyl]-5-methylpyrrolidine-3-yl}amino)-2-oxoethyl]-3 -(trifluoromethyl)benzamide,
N-(2-{[(3R,5S)-1-(4-hydroxy-4-pyridine-2-illlogical)-5-methylpyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R,5S)-1-(4-hydroxy-4-pyridin-3-illlogical)-5-methylpyrrolidine-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-(2-{[(3R,5S)-1-(4-hydroxy-4-pyridin-4-illlogical)-5-methylpyrrolidine-3-yl]amino}-2-oxoethyl)-3-trifluoromethyl)benzamide
N-[2-({(3R,5S)-1-[4-hydroxy-4-(5-methylpyridin-2-yl)cyclohexyl]-5-methylpyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R,5S)-1-[4-hydroxy-4-(6-methylpyridin-3-yl)cyclohexyl]-5-methylpyrrolidine-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
2-(1,3-benzothiazol-2-ylamino)-N-[(3R)-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]acetamide", she
N-[(3R)-1-(4-hydroxy-4-pyridine-2-illlogical)pyrrolidin-3-yl]-2-{[5-(trifluoromethyl)pyrimidine-2-yl]amino}ndimethylacetamide,
N-[1-({[(3R)-1-(4-phenylcyclohexyl)pyrrolidin-3-yl]amino}carbonyl)cyclopropyl]-3-(trifluoromethyl)benzamide,
N-(2-{[3-(permitil)-1-(4-hydroxy-4-phenylcyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(reformer)benzamide,
N-[2-({(3R)-1-[(3aR,6aS)-5-hydroxy-5-(6-methoxypyridine-3-yl)octahydrophenanthrene-2-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[(3aR,6aS)-5-hydroxy-5-ventilatierooster-2-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3JR)-1-[(3aR,6aS)-5-hydroxy-5-pyridin-3-eloctricamente-2-yl] pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(5-hydroxy-5-pyridin-3-albicilla[2.2.2]Oct-2-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(3-metalization-5-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-{2-[((3R)-1-{4-[3-(permitil)isothiazol-5-yl]-4-hydroxycyclohexyl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide,
N-(2-{[(3R)-1-(4-hydroxy-4-isothiazol-5-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-hydroxy-4-(4-(pyrimidine-2-ylphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide,
N-[2-({(3R)-1-[4-(2-cyclopropylamino-5-yl)-4-hydroxycyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide and
N-(2-{[(3R)-1-(4-hydroxy-4-pyridazin-4-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide.

8. Pharmaceutical composition for treatment of inflammation, rheumatoid arthritis, atherosclerosis, neuropathic pain, lupus, systemic cu is red lupus, restenosis, immune disorders, and rejection of transplants in need of this mammal containing a therapeutically effective amount of a compound according to claims 1 to 6 or 7 in a mixture with a pharmaceutically acceptable excipient, diluent or carrier.

9. The method of modulating the activity of receptors chemokines in a mammal, comprising introducing an effective amount of a compound according to claims 1 to 6 or 7.

10. The method of treatment CCR2-indirectly condition or disease in a subject, and this method includes the introduction of the needy in this subject an effective amount of a compound according to claims 1 to 6 or 7.

11. The compound according to claim 1, represents N-[2-({(3S,4S)-4-ethoxy-1-[4-hydroxy-4-(3,4-methylenedioxyphenyl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamid.

12. The compound according to claim 1, represents N-({(3R)-1-[4-hydroxy-4-(6-methoxypyridine-3-yl)cyclohexyl]pyrrolidin-3-ylcarbonyl}methyl)-3-cryptomelane.

13. The compound according to claim 1, represents N-{[(R)-1-(4-hydroxy-4-pyrimidine-2-illlogical)pyrrolidin-3-ylcarbonyl]methyl}-3-cryptomelane.

14. The compound according to claim 1, which represents the N-(2-{[(3R)-1-(4-hydroxy-4-pyrazin-2-illlogical)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.

15. The compound according to claim 1, which represents the N-(2-{[(3R)-1-(4-hydroxy-4-pyrimidine-4-allclose the forces)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamid.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazol derivatives of general formula (I) and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and to based medicinal agent. In general formula (I) , R1 represents 1,4-dioxepanyl or tetrahydropyran-4-yl; R2 represents -N(R)-(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with one-two substitutes chosen from group, consisting of C1-C6alkyl or -NR2, or represents -(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 heteroatoms chosen of N, S or O, optionally substituted with group -(CH2)n-OH, C1-C6alkyl, C1-C6alkoxy, or represents -(CH2)n-5-or 6-merous aromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with the following group: C1-C6alkyl, C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), -CH2N(R)(CH2)2OCH3, -N(R)(CH2)2OCH3, - CH2-morpholinyl or -CH2-pyrrolidinyl or represents (CH2)n-C3-C6cycloalkyl optionally substituted with group hydroxy, or represents -N(R)-C3-C6cycloalkyl optionally substituted with group hydroxy or C1-C6alkyl, or represents phenyl optionally substituted with group C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), C1-C6alkyl, -CH2-pyrrolidine-1-yl, CH2N(R)(CH2)2OCH3 or -CH2-N(R)C(O)-(C1-C6alkyl), or represents 1,4-dioxa-8-azaspiro[4,5]decane, or 2-oxa-5-azabicyclo[2,2,1]heptane, or 1-oxa-8-azaspiro[4,5]decane, or -N(R)-7-oxabicyclo[2,2,1]hept-2-yl, or 2-azabicyclo[2,2,2]octane; R represents hydrogen or C1-C6alkyl; n stands for 0 or 1.

EFFECT: compounds can be applied for treatment and prevention of diseases mediated by adenosine A2A and A1 receptors, eg Alzheimer's disease, some depressions, toxicomania, Parkinson's disease.

8 cl, 3 dwg, 61 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: compounds of formula (I) as inhibitors of phosphotyrosine phosphotase 1B and their pharmaceutically acceptable salts, their application, based pharmaceutical composition and method of production. In general formula (I) , R1 indicates phenyl, naphthyl, thionaphthyl, pyridyl. Phenyl, naphthyl, thionaphthyl and pyridyl can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, CF3, OCF3, N(R9)(R10), piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)-alkyl, S(O)0-2-(C1-C6)-alkyl, SO2-N(R9)(R10), CO-(C1-C6)-alkyl, -COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkyleny-COO(C1-C6)-alkyl, (C3-C10)-cycloalkyl, phenyl. These piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, and phenyl rings can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, COOH, CN, NO2, O-(C1-C6)-alkyl, -NH-O-(C1-C6)-alkyl, -(CO)-NH-O-(C1-C6)-alkylene-N(R9)(R10), -(CO)-(C1-C6)-alkyl, -(C1-C6)-alkyl, CF3, OCF3, N(R9)(R10); R2 indicates H, (C1-C6)-alkyl, COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkylene-COO(C1-C6)-alkyl; R3 indicates H, (C1-C6)-alkyl, (C1-C6)-alkylenphenyl, -C(O)-phenyl, (C1-C6)-alkylenheterocycle, where heterocycle represents 5-6-merous heterocyclic ring containing 1-2 heteroatoms, chosen of nitrogen and oxygen, CO-(C1-C6)alkyl; R4, R5 indicate H; R6 indicates H, R9 indicates H, (C1-C4)-alkyl; R10 indicates H, (C1-C4)-alkyl.

EFFECT: applications for treating diseases mediated with phosphotyrosine phosphotase 1B activity, such as diabetes type II, lipidosis and carbohydrate metabolic imbalance, insulin resistivity, reduced sugar content in blood.

9 cl, 2 tbl, 1 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (1) and their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands with high affinity to A2A adenosine receptor, and based medicine. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In general formula (I) , R is C5-C6-cycloalkyl non-substituted or substituted by hydroxy group, or is ethyl or isobutyl, or is tetrahydropyrane-4-yl or -(CH2)n-tetrahydrofurane-2 or 3-yl or is 5-hydroxybicyclo[2,2,1]hept-2-yl; X is CH or N; n is 0 or 1.

EFFECT: enhanced efficiency of composition and treatment method.

12 cl, 2 dwg, 14 ex

The invention relates to new imidazole derivative of formula I and II

< / BR>
or

< / BR>
where 1, m, r, s, and t = 0 or 1; n = 1 or 2; provided that when 1 and m = 0, n = 2 Y - SO2or CH2; Z - CR12, NR32SO; NR13, NR36CO., OCONR15, SO2NR14; R1selected from the group consisting of hydrogen, alkyl, or aralkyl, the symbola single or double bond, R7, R8selected from the group consisting of hydrogen, aryl, - CN, halogen, and U-R44group, where U = O and R44and R11selected from the group consisting of hydrogen, alkyl, aralkyl, aryl; R32selected from the group consisting of hydrogen, lower alkyl, unsubstituted or substituted phenyl, and tanila; R9, R10, R12, R13, R14, R15, R36, R57and R58represent hydrogen or lower alkyl; one of R, S and T is CH2or CH(CH2)pQ, where Q denotes NR57R58; where p = 0,1 or 2; provided that when Y is - SO2, R11cannot be hydrogen; its enantiomers, diastereoisomers, pharmaceutically priemel the

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of pyridine [2,3-d] pyrimidine of general formula (I) and their pharmaceutically acceptable salts, which possess properties of KDR and FGFR inhibitors. Compounds can be applied to produce medications for treatment of cancer, for instance, of mammary gland, large intestine, lungs and prostate gland. In general formula (I) , Ar and Ar' independently on each other are selected from group that includes phenyl; phenyl substituted with 1-3 substituents selected from group C1-C4alkyl, hydroxy, halogen, halogen-substituted C1-C4alkyl, C1-C4alkoxy; 6-member nitrogen-containing heteroaryl and 6-member nitrogen-containing heteroaryl substituted with C1-C4alkoxygroup, on condition that Ar standing for heteroaryl does not represent 2-pyridyl, and standing for substituted heteroaryl does not represent substituted 2-pyridyl, R1 is selected from group including phenyl, C1-C10alkyl, C1-C10alkyl independently containing substituents selected from group that includes phenyl, C3-C6cycloalkyl. Invention also relates to intermediate compounds for compounds of general formula (I) and to pharmaceutical compositions.

EFFECT: obtaining derivatives and their pharmaceutically acceptable salts which possess properties of selective KDR and FGFR inhibitors.

21 cl, 2 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

The invention relates to new derivatives of 4-hydroxypiperidine General formula (I), where X denotes-O-, -NH-, -CH2-, -CH= , -CO2-, -SOP(lower alkyl) -, or-CONH-, R1- R4independently from each other, is hydrogen, hydroxy, nitro-group, a lower alkylsulfonyl, 1 - or 2-imidazolyl, 1-(1,2,4-triazolyl), R5and R6independently from each other, is hydrogen, lower alkyl, hydroxy - or oxoprop, R7- R10independently from each other, is hydrogen, lower alkyl, halogen, trifluoromethyl or lower alkoxygroup, n = 0 or 1, or their pharmaceutically acceptable acid additive salts

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to new biologically active compounds, in particular to new pyridone derivative exhibiting analgesic activity

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts or solvates wherein m represents 0, 1, 2 or 3; each R1 represents halogen atom or (C1-C6)-alkylcarbonyl; Z1 represents a bond or group -(CH2)q wherein q represents 1 or 2; Z2 represents a bond or group -CH2 under condition that both Z1 and Z2 don't represent a bond simultaneously; Q represents oxygen or sulfur atom or group -CH2 or -NH; R2 represents group of the formula: ; n = 0; each R4, R5, R6 and R7 represents hydrogen atom; R8 represents hydrogen atom or (C1-C6)-alkyl group; R15 represents -C(O)NR17R18 or -NHC(O)R20; t represents 0, 1, 2 or 3; each R16 represents halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, phenyl or (C1-C6)-alkyl; each R17 and R18 represents hydrogen atom or (C1-C6)-alkyl; R20 represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heterocyclic system that can be substituted with (C1-C6)-alkyl. Compounds of the formula (I), their salts and solvates possess a modulating activity with respect to chemokine MIP-1α receptors and can be used in medicine.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

19 cl, 64 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to method for production of N,N,1-trimethyl-2-(3,4-fullero[60])pyrrolidine amine of formula 1 .

Claimed method includes reaction of fullerene[60] (C60) with N,N,N,N-tetramethylmethane diamine of general formula (CH3)2-N-CH2-N-(CH3)2 in C60:(CH3)2-N-CH2-N-(CH3)2 molar ratio of 0.01:(0.01-0.011) in presence of Cp2TiCl2 as catalyst in amount of 15-25 mol.% based on fullerene in argon atmosphere in toluene medium as solvent at 140-160°C for 2-4 hours. Yield of target product is 79-89 %.

EFFECT: compound useful as complexing agents, sorbents, biologically active materials and in production of materials with desired electronic, magnetic and optical characteristics.

1 tbl, 1 ex

The invention relates to derivatives of cyclic amines and their use as pharmaceuticals, particularly to a compound represented by the General formula (I), its pharmaceutically acceptable acid additive salts or its pharmaceutically acceptable C1-C6alcaldicios salt, R1-phenyl, C3-8-cycloalkyl, aromatic heterocycle with 1-3 heteroatoms selected from O, S, N, or combinations thereof, and these groups may be condensed with benzene ring or an aromatic heterocyclic group with heteroatoms, selected from O, S or N, or combinations thereof, and may also have different substituents

The invention relates to amino acid derivatives of the formula I

< / BR>
or its non-toxic salt or its hydrate, the pharmaceutical composition having inhibitory effect on calcium channel iv-type; the inhibitor calcium channel N-type; a pharmaceutical composition for prevention and/or treatment of cerebral infarction and pharmaceutical compositions for the treatment of pain
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