UA90138C2 - Alpha ketoamide compounds as cysteine protease inhibitors - Google Patents

Abstract

The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

Description

The present invention relates to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, I, E and 5, and therefore can be used in the treatment of diseases mediated by these proteases. The invention also relates to pharmaceutical compositions containing the proposed compounds and processes for manufacturing these compounds.

Cysteine proteases are a class of peptidases that are characterized by the presence of a cysteine residue in the catalytic sites of these enzymes. Cysteine proteases are involved in the normal decomposition and processing of proteins. However, abnormal activity of cysteine proteases, for example, as a result of increased expression or activation, may have pathological consequences. In this regard, certain cysteine proteases are associated with numerous disease states, including arthritis, muscular dystrophy, inflammation, tumorigenesis, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy, and the like. For example, increased levels of cathepsin B and redistribution of this enzyme are found in tumors, which indicates its certain role in the malignant process and metastasis. In addition, abnormal cathepsin B activity is associated with such disease states as rheumatoid arthritis, osteoarthritis, rheumatoid arthritis, acute pancreatitis, inflammatory airway diseases, and bone and joint disorders.

The marked expression of cathepsin K in osteoclasts and osteoclast-related multinucleated cells, as well as its high collagenolytic activity, suggest that this enzyme is involved in osteoclast-mediated bone resorption and, therefore, in the bone abnormalities that occur in osteoporosis.

In addition, the expression of cathepsin K in the lungs and its elastinolytic activity suggest that this enzyme also plays a role in pulmonary disorders.

Cathepsin I is also involved in normal lysosomal proteolysis in some disease states, including, for example, melanoma metastasis. Cathepsin 5 is involved in Alzheimer's disease and some autoimmune disorders, including, for example, juvenile diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis5, systemic lupus erythematosus, rheumatoid arthritis, neuropathic pain, and Hashimoto's thyroiditis. In addition, cathepsin 5 is involved in: allergic disorders, including, for example, asthma; and allogeneic immune responses, including, for example, rejection of organ or tissue transplants.

Thus, taking into account the numerous diseases in which an increase in cysteine protease activity contributes to the pathology and/or symptomatology of the disease, it is possible to predict the effectiveness of the use of therapeutically effective molecular agents that inhibit the activity of enzymes of this class. This, in particular, concerns molecules that inhibit cathepsins B, K, I, E and/or 5.

The essence of the invention

In one of its aspects, the present invention is directed to the compound according to formula (1):

Hey there is n in A huya () in I eye where:

IN! is hydrogen or alkyl;

B: is cycloalkyl, cycloalkylalkyl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted with one or two substituents independently selected from alkyl, alkoxy, or halide;

BZ is hydrogen, alkyl or alkoxyalkyl;

B" is alkyl; or

B3 and B" together with the carbon atom to which they are attached form a cycloalkylene, if necessary it can be substituted by one to four fluorine atoms, or a heterocycloalkylene, if necessary it can be substituted by alkyl, alkoxyalkyl, hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl or haloalkyl;

BZ is alkyl, haloalkyl, if necessary can be substituted by cycloalkyl, aryl, heteroaryl or heterocycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, -(alkylene)-X-B? (where X is -

O-, -5-, -5BO-, -502-, - ССОМН-, -МНСО- or -МН5О»-, and B? is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl) or -(alkylene)-X!-(haloalkylene)-B!? (where X! is -O-, -5-, -50-, -502-, -"COMNH-, -MNCO- or -MNOO"-, and B'O is cycloalkyl, aryl, heteroaryl or heterocycloalkyl), where aromatic or alicyclic ring in B? may optionally be substituted with one, two, or three He, independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, halo, carboxy, or alkoxycarbonyl; or, if desired, may be substituted with one or two HBs independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkyloxy, halide, carboxy, or alkoxycarbonyl, and one HA selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, acylalkyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, heterocycloalkyloxycarbonyl, cycloalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or 5028!! (where B! is alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl); and also where the aromatic or alicyclic ring in WO can optionally be substituted with one, two or three NU independently selected from alkyl, alkylsulfonyl, haloalkyl, alkoxy, hydroxy, haloalkoxy or halo;

Ve is an alkyl halide;

B" is hydrogen, alkyl or haloalkyl; and

BZ is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl attached through a carbon atom, where is the aromatic or alicyclic ring in B? may optionally be substituted with one, two or three Be independently selected from alkyl, halide, haloalkyl, hydroxy, alkoxy, haloalkyloxy, alkylcarbonyl, alkoxycarbonyl, carboxy, cyano, alkylsulfonyl, alkylsulfonylamino, aminocarbonyl or aminosulfonyl; or pharmaceutically acceptable salts thereof.

In its second aspect, the present invention is directed to a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with one or more acceptable excipients.

In its third aspect, the present invention is directed to the process of treating an animal from a disease mediated by cysteine proteases and, in particular, cathepsin 5, where the specified process includes administering to the animal a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with one or more acceptable excipients.

The fourth aspect of this invention is directed to the processes of manufacturing compounds according to formula (1).

In its fifth aspect, the present invention is directed to a process of treating a patient to whom a therapy is applied that causes an immune reaction in the patient, which is predominantly a harmful immune reaction, wherein said process includes administering to the patient a compound of formula (I) or a pharmaceutically acceptable thereof salt In the best version, the immune reaction is mediated by class II molecules of the major histocompatibility complex (HCC). A compound according to the invention can be administered before, simultaneously with, or after the above therapy. In the best option, treatment with biological agents is involved in the indicated therapy. In a preferred embodiment, said therapy involves small molecule treatment.

In the best embodiment of the invention, the biological agent is a protein, preferably an antibody, and even better - a monoclonal antibody. In an even better version, the biological agent is VNetisadebF (Remicad), VegasuF (Refracto), Netegop-AF (Referon-A), Rasiog MI! (factor MI), Ratiog MI! (Factor MI), VehazegopFb (Betaseron),

ErodepF (Epogen), Eprgekyu (Enbrel), Ipiepegop bBeia (Beta-interferon), VoiohF (Botox), ERabgalguteF (Fabrazym), EIzrag» (Elspar), SegeguteF (Cerezym), Muoriostb (Myobloc), AIdigalguteb (Aldurazim),

Mepitaf (Verluma), Ipiepegop airpa (Alpha interferon), NitigafFf (Gumira), Agape5rF (Aranesp), 7emaipe (Zevalin) or OKTZ.

In the best embodiment of the invention, heparin, low molecular weight heparin, procainamide or hydralazine are used in the treatment.

In its sixth aspect, the present invention is directed to the process of treating an animal from an immune reaction caused by the administration of a biological agent to this animal, where the specified process includes the administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an animal in need of such treatment.

In its seventh aspect, the present invention is directed to the process of conducting clinical trials of a biological agent, which includes the administration of a compound of formula (I) or its pharmaceutically acceptable salt with a biological agent to an individual who is a participant in these clinical trials.

In its eighth aspect, the present invention is directed to the process of prophylactic treatment of a patient who receives treatment with a certain biological agent, a compound of formula (I) or a pharmaceutically acceptable salt thereof to suppress the immune response caused by this biological agent in the patient.

In its ninth aspect, the present invention is directed to the process of determining the loss of effectiveness of a biological agent in an animal as a result of an immune reaction caused by this biological agent, where the specified process includes the administration of this biological agent to the animal in the presence and absence of the compound of formula (I) or its pharmaceutically acceptable salt.

In its tenth aspect, the present invention is directed to the process of increasing the effectiveness of a biological agent in an animal, where the specified process includes the introduction of this biological agent to the animal together with the compound of formula (I) or its pharmaceutically acceptable salt.

In its eleventh aspect, the present invention is directed to the use of a compound of formula (I) or its pharmaceutically acceptable salt in the manufacture of a medication. In a preferred embodiment of the invention, the aforementioned medicament is intended for the treatment of a disease mediated by cathepsin 5.

A twelfth aspect of the present invention is directed to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for combination therapy together with a biological agent, where the compound according to the invention suppresses the immune response caused by the biological agent used. In a preferred embodiment, the compound (or compounds) of the present invention is administered prior to administration of the biological agent. In a preferred embodiment, the compound (or compounds) of the present invention is administered together with the administration of the biological agent. In a preferred embodiment, the compound (or compounds) of the present invention is administered after administration of the biological agent.

Detailed description of the invention

Terminology

Unless otherwise indicated, the following terms used in this description and the Formulas of the Invention have the following meanings corresponding to the purposes of this application.

The term "alicyclic" means a part of a compound characterized by the arrangement of carbon atoms in closed non-aromatic ring structures, for example, cycloalkyl and heterocycloalkyl rings as defined herein.

The term "alkyl", used alone, unless otherwise indicated, means a straight or branched, saturated aliphatic radical containing from one to eight carbon atoms; alkyl can be, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, etc.

The term "alkylene", unless otherwise specified, means a linear or branched, saturated aliphatic, divalent radical having from one to six carbon atoms, such as methylene (-

SnHe-), ethylene (-CH»SNeg-), trimethylene (-"СНаСНесСнН»-), tetramethylene (-"СНгСНаСНоСснН»-), 2-methyltetramethylene (-снНСн(СНаз)СнНоснН»-), pentamethylene (-СНаСНа. СНоСНесСнН g-) etc.

The term "alkylsulfonyl" means a radical of the form -502H, where B is alkyl as defined herein, e.g., methylsulfonyl, ethylsulfonyl, and the like.

The term "alkylsulfonylamino" means a radical of the form -MNOO»B, where A is alkyl as defined herein, e.g., methylsulfonylamino, ethylsulfonylamino, etc.

"Alkoxy" means -OA radical, where A is an alkyl group as defined above, for example, methoxy, ethoxy, etc.

The term "Alkoxyalkyl" means a linear monovalent hydrocarbon radical containing from one to six carbon atoms, or a branched monovalent hydrocarbon radical containing from three to six carbon atoms, substituted by at least one, preferably one or two, alkoxy groups as defined above, for example, 2-methoxyethyl, 1-, 2- or 3-methoxypropyl, 2-ethoxyethyl, etc.

The term "alkoxycarbonyl" means a radical of the form -С(ОЙОВ), where B is an alkyl group as defined above, for example, methoxycarbonyl, ethoxycarbonyl, etc.

The term "aminoalkyl" means a linear monovalent hydrocarbon radical containing from one to six carbon atoms or a branched monovalent hydrocarbon radical containing from three to six carbon atoms substituted with at least one, and preferably with one or two -MAP, where B is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkylalkyl, and B" is hydrogen, alkyl, hydroxyalkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonyl, or aminosulfonyl according to as defined herein, e.g., aminomethyl, methylaminoethyl, dimethylaminoethyl, 1,3-diaminopropyl, acetylaminopropyl, etc.

The term "acyl" means a radical of the form -CON, wherein BA is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl as defined herein, e.g., formyl, acetyl, trifluoroacetyl, benzoyl, piperazine-1- ylcarbonyl, etc. When B is alkyl, it is referred to herein as alkyl carbonyl.

The term "acylalkyl" means a linear monovalent hydrocarbon radical containing from one to six carbon atoms or a branched monovalent hydrocarbon radical containing from three to six carbon atoms substituted by at least one, and preferably one acyl group or two acyl groups according to by the definitions given here, for example, methylcarbonylmethyl, benzoylethyl, piperidin-1-ylcarbonylmethyl or ethyl, etc.

The term "aminocarbonyl" means -"SOMARE: a radical where BA and B" are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkylalkyl, or B and B" together with the nitrogen atom to which they are attached form heterocycloamino group as defined herein.

The term "aminosulfonyl" means a -5OamMAv" radical, wherein A and B" are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkylalkyl, or B and B" together with the nitrogen atom to which they are attached form a group heterocycloamino as defined herein.

The term "animal" means a human, a non-human mammal (eg, a dog, a cat, a rabbit, a cow, a horse, a sheep, a goat, a pig, a deer, etc.), and a non-mammalian animal (eg, a bird etc.).

The term "aromatic" is used as a sign of a part of a compound in which the atoms that make it up form an unsaturated ring system, where all the atoms in this ring system are 5p-hybridized, and the total number of pi-electrons is 4p--2.

The term "aryl" means a monocyclic or fused bicyclic ring assembly that contains from 6 to 10 carbon atoms in a ring, where each ring is aromatic, for example, phenyl or naphthyl.

The term "aryloxy" means a radical of the form -O-H, where B is aryl as defined above, for example, phenoxy, naphthyloxy, etc.

The term "aryloxycarbonyl" means a radical of the form -C(O)OB, where A is aryl as defined above, for example, phenyloxycarbonyl, naphthyloxycarbonyl, and the like.

The term "aralkyl" means a radical of the form -(alkylene)-A, where I is aryl as defined above, for example, benzyl, phenethyl, etc.

The term "aralkyloxy" means a radical of the form -O-BA, where A is aralkyl as defined above, for example, benzyloxy, phenethyloxy, etc.

The term "aralkyloxycarbonyl" means a radical of the form -C(O)OB, where BA is aralkyl as defined above, for example, benzyloxycarbonyl, phenethyloxycarbonyl, etc.

The term "biological agent" means a therapeutic agent derived from living organisms to treat or alleviate a particular disease. Biological means can be, for example, proteins (recombinant or obtained from plasma), monoclonal or polyclonal, humanized or mouse antibodies, toxins, hormones, etc. Many biologics are available today to treat a variety of diseases, such as cancer, rheumatoid arthritis, hemophilia, and more.

The term "carboxy" means a radical of the form -C(O)OH.

The term "cycloalkyl" means a monovalent saturated monocyclic ring containing from three to eight carbon atoms in the ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "cycloalkylalkyl" means a radical of the form -(alkylene)-H, where AB is cycloalkyl as defined above, for example, cyclopropylmethyl, cyclobutylethyl, cyclobutylmethyl, etc.

The term "cycloalkyloxycarbonyl" means a radical of the form -C(O)OB, where A is cycloalkyl as defined above, for example, cyclopropyloxycarbonyl, cyclopentyloxycarbonyl, etc.

The term "cycloalkylene" means a divalent saturated monocyclic ring containing from three to eight carbon atoms in the ring. For example, variants in which "B3 and B" together with the carbon atom to which both B" and B? are attached form a cycloalkylene" can be as follows: c; oh 7 And! "E A" t

Etc.

The term "disease" means any unhealthy condition of an animal or part of its body and, in particular, an unhealthy condition which may be caused by, or be inherent to, i.e. a "side effect" of, medical or veterinary intervention applied to that animal.

The terms "derived from" or "derived from" mean the origin of a given agent from its original source.

The term "harmful immune response" means an immune response that interferes with the effective treatment of the patient or causes disease in the patient. Such a reaction can occur, for example, in response to the introduction of a therapeutic or diagnostic mouse antibody into the patient's body, as a result of which the patient's body will produce human antibodies against the mouse, which will interfere with further treatment measures.

Such production of human antibodies against pure mouse monoclonal antibodies can exceed 7090 (Kpalgaeii, M.V. ei ai 9. Ittipoipeg. 1994, 15, pp. 42-52; OiItap V. 0. ei a). Sapseg Vioipeg. 1994, 9, pp. 17-28;

AVeiiperegoa, 9. Nubgidota. 1995, 14, pp. 205-208). Another example of known agents that are adversely affected by immune reactions are blood coagulation factors and, in particular, the MIII factor. When the latter is administered to patients with hemophilia A, the MI factor restores the ability of blood to clot. But although the MI factor is a human protein, it still causes an immune reaction in hemophiliacs, because the endogenous MI factor! is not in their blood and acts on their immune system as a foreign antigen. Approximately 29-339% of new patients produce antibodies that bind and neutralize the therapeutic MI factor administered to them! (Hizpeg.). M. Zetip Tygot Netozvi. 2002, 28(3), pp. 273-276). To maintain blood coagulation parameters within normal limits, these neutralizing antibodies cause the need to inject larger amounts of the MI factor! thus, they make the treatment regimen expensive due to the need to achieve immune tolerance (Vgieyi Eyi ayi. Adm. Ehr. Med. Vio. 2001, 489, pp. 89-97). Another immunogenic example is adenoviral factors. Retroviral therapy is currently at the experimental level of its development and has limited application.

One of the reasons for this is that the use of a therapeutic virus causes an immune response that can block any subsequent introduction of the same or similar virus (Miripd Mapd ei ai. 9. oi

Migoiod. 1995, 69, 2004-2015). This is unequivocal evidence that retroviral therapy should be based on transient protein expression or direct integration of the viral sequence into the host's genome. Directed to this research managed to identify numerous epitopes of viral neutralization recognized by host antibodies (Nappe, Sanegu-Zedaga ei ai. ui. oi Migoodu 1998. 72, pp. 2388-2397), and this indicates that only viral modifications will not be enough to overcome this obstacle. Accordingly, the present invention provides a process that makes adenoviral therapy useful when repeated. Another example of an immunogenic agent that causes the appearance of neutralizing antibodies is the well-known cosmetic product Voiokh. Botulinum toxin protein is obtained by purification from the fermentation of Siovipait roshiipit. In addition to cosmetics, it is used as a therapeutic agent for the treatment of muscle disorders such as cervical dystonia. After its repeated use, patients produce neutralizing antibodies to this toxin, as a result of which its effectiveness decreases (Viikieip E. ei a! App Meshhoi 2002, 52, pp. 68-73; Voipiik, 9. O. ei a! Meshhoi! Siip. MeigorNpuzioi 2001, 2001(3), pp. 2-4). The meaning of the term "harmful immune reaction" also includes diseases caused by therapeutic agents. One of the typical examples of this is the immune response to therapeutic intervention using recombinant human erythropoietin (ERPO). Erythropoietin is used to stimulate the growth of red blood cells and restore the number of red blood cells in patients who have undergone chemotherapy or dialysis. In a small percentage of patients, antibodies to ERO were produced, as a result of which these patients became tolerant both to the therapeutic ERO introduced into them and to their own endogenous ERO (Sazademayi, M. Yeyi, MEUM. 2002, 346, pp. 469-475). They had a disorder, pure erythrocyte aplasia, in which the production of erythrocytes was significantly reduced (Segzpop 5. K. eyi. a! MEOM. 2002, 346, pp. 1584-1586). This complication of ERO therapy, if left untreated, is fatal. Another specific example is the murine antibody, OKTZ (also known as "Orthoclone" (Opposiope)), which is a monoclonal antibody directed against the CO-3 domain of activated T cells. In clinical trials, 20-4,095 patients administered OKTZ developed antibodies against this therapeutic agent. These antibodies not only neutralized this agent, but also stimulated a strong immune response in the host. This immune reaction is so severe that patients with high titers of human anti-mouse antibodies have to limit the use of this medication (Instructions for use on the package

Orthoclone). And finally, one more example related to human immunotherapy. A drug called Gumira (Nitigabt)) is a monoclonal antibody against TME (tumor necrosis factor) and is used in the treatment of patients with rheumatoid arthritis. With its isolated use, neutralizing antibodies are produced in approximately 1,295 patients. In addition, a small percentage of patients receiving this drug also develop a condition similar to systemic lupus erythematosus, which is an Id(-mediated immune reaction caused by this therapeutic agent (Instructions for use on the package of the therapeutic agent Nitiga).

An example of a "harmful immune reaction" is also the host's reaction to low molecular weight drugs. It is well known to those skilled in the art that some chemical structures conjugate with host proteins to stimulate immune recognition (Di. S. Yei Am. 2002. Sstepi Ogpid Meiaroiiet 3, pp. 367-37795; Kitbreg 1. Yei AI. 2002, Tochisiodis

Raiyoiyudu 30, pp. 54-58). A significant part of these host reactions is mediated by immunoglobulin da.

Specific IDS-mediated "harmful immune reactions" are, for example: hemolytic anemia, Stevens-Johnson syndrome (5iemep-Woppz5op) and drug-induced lupus.

The term "halide" means fluorine, chlorine, bromine or iodine.

The term "haloalkyl" means alkyl as defined above, substituted with one or more, for example, one to thirteen, preferably one to seven, "halo" atoms. As defined herein, haloalkyl may be monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, etc., such as chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2, 2-trifluoro-1,1-dichloroethyl, etc.

The term "haloalkylene" means an alkylene radical as defined above in which one to four, preferably one or two, hydrogen atoms in the alkylene chain have been replaced by a fluorine atom (or atoms).

The term "haloalkyloxy" means a radical of the form -OH, where A is a haloalkyl group as defined above, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, etc.

The term "heteroaryl" as a group or part of a group means an aromatic monocyclic or bicyclic moiety of 5-10 ring atoms in which one or more, preferably one, two or three ring atoms are selected from nitrogen, oxygen or sulfur and the remainder of the ring is carbon atoms. Typical heteroaryl rings are, for example, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolyl. etc.

The term "heteroaryloxy" means a radical of the form -O-Y, where A is heteroaryl as defined above, for example, furanyloxy, pyridinyloxy, indolyloxy, etc.

The term "heteroaryloxycarbonyl" means a radical of the form -C(O)O-H, where BA is heteroaryl as defined above, for example, pyridinyloxycarbonyl, pyrimidinyloxycarbonyl, etc.

The term "heteroaralkyl" means a radical of the form -(alkylene)-B, where A is heteroaryl as defined above, for example, pyridinylmethyl, 1- or 2-furanylethyl, imidazolylmethyl, and the like.

The term "heteroaralkyloxy" means a radical of the form -O-H, where A is heteroaralkyl as defined above, for example, pyridinylmethyloxy, furanylethyloxy, etc.

The term "heteroaralkyloxycarbonyl" means a radical of the form -С(О0)О-СХЯ, where A is heteroaralkyl as defined above, for example, pyridinylmethyloxycarbonyl, pyrimidinylmethyloxycarbonyl, and the like.

The term "heterocycloalkyl" means a saturated or partially unsaturated, mono- or bicyclic radical having 4, 5 or 6 carbon atoms in the ring, where one or more, and preferably one, two or three ring carbon atoms are substituted by a heteroatom selected from - M:, -M-, -O-, -5-, -50- or -5(0)2-, and where one or two carbon atoms in the ring can be replaced by a keto group (-CO-) if necessary.

A heterocycloalkyl ring may optionally be fused to a cycloalkyl, aryl, or heteroaryl ring as defined herein. Typical examples of these groups are imidazolidinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxo-tetrahydrothiopyranyl, 1,1-dioxotetrathio-pyranyl, indolinyl, piperazinyl, piperidyl , pyrrolidinyl, pyrrolinyl, quinuclidinyl, 3,4-dihydroisoquinolinyl, dihydroindolyl, etc.

If the heterocycloalkyl group contains at least one nitrogen atom in the ring, it is referred to herein as a "heterocycloamino group" and is a subset of the heterocycloalkyl group as defined above.

The term "heterocyclylalkylene" means a divalent heterocyclyl group as defined herein. For example, in the case in which BZ and B" together with the carbon atom to which both BZ and B" are attached form a heterocyclylalkylene, the heterocyclyl groups are, in particular, the following:

C 9) in which A is a substituent defined in the section on the essence of the invention. "Heterocycloalkylalkyl" means a radical of the form -(alkylene)-H, where A is heterocycloalkyl as defined above, for example, pyrrolidinylmethyl, tetrahydrofuranylethyl, pyridinylmethylpiperidinylmethyl, and the like.

The term "heterocycloalkyloxycarbonyl" means a radical of the form -C(O)OB, where A is heterocycloalkyl as defined above, for example, pyridinyloxycarbonyl, pyrimidinyloxycarbonyl, etc.

The term "hydroxy" means a radical of the form -OH. Unless otherwise stated, compounds of the present invention that contain hydroxy radicals include, among others, their protected derivatives. Suitable protecting groups for hydroxy groups are, for example, benzyl, etc.

The term "hydroxyalkyl" means a linear monovalent hydrocarbon radical containing from one to six carbon atoms or a branched monovalent hydrocarbon radical containing from three to six carbon atoms substituted by one or two hydroxy groups, provided that, in the case of two hydroxy groups, they not both on the same carbon atom. Typical hydroxyalkyl groups are, for example, s-hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1 -(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, and the best among them are 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl) )-2-hydroxyethyl.

The term "isomers" means compounds described by formula (I) and having identical molecular formulas, but differing from each other in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ from each other in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" and sometimes also "optical isomers". A carbon atom bound to four nonidentical substituents is called a "chiral center." A compound with one chiral center, which has two enantiomeric forms of opposite chirality, is called a "racemic mixture". A compound that has two or more chiral centers has 27 enantiomeric pairs, where n is the number of chiral centers. Compounds with two or more chiral centers can exist either in the form of an individual diastereomer, or in the form of a mixture of diastereomers, which is called a "diastereomeric mixture". In the presence of only one chiral center, a stereoisomer can be characterized by the absolute configuration of this chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to this chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers, and they are described by the rules of Kahn-Ingold-

Preloga (Sapp, Ipdoii apa Rge!od) B- and 5-ordering. Conventions regarding stereochemical nomenclature, methods for determining stereochemistry and separation of stereoisomers are well known to those skilled in the art, for example ("Admapseid Organic Spetivgu", 4" edyiop, Magsy, Uegu, dopp Umieu 8. ope, Mem Moik, 1992). It is quite clear. , that the names and illustrations used in this application to describe the compounds of formula (I) are intended to cover all possible stereoisomers.

The terms "optional", "optional" and "if necessary may be" mean that the event or circumstance described after them may or may not occur, and that the description assumes equally the existence of options, in in which this event or circumstance takes place, and options in which it does not take place.

For example, the phrase "wherein the aromatic ring of Ba may optionally be substituted with one or two substituents independently selected from alkyl" means that the aromatic ring may or may not be substituted with alkyl in order to be within the scope of this invention .

The scope of this invention also covers M-oxide derivative compounds according to formula (I). An M-oxide derivative is a compound according to the formula (I) in which the nitrogen atom is in an oxidized state (ie, M-»0), for example, pyridine-M-oxide, and which has the desired pharmacological activity.

The term "pathology" of a disease means the nature, causes and development of the disease, as well as the structural and functional changes resulting from the disease processes.

The term "pharmaceutically acceptable" is used to denote that which is suitable for use in the preparation of a pharmaceutical formulation and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and all that is acceptable for use in veterinary medicine, as well as in pharmaceuticals for humans.

The term "pharmaceutically acceptable salts" means salts of compounds of formula (I) which are pharmaceutically acceptable as defined above and possess the desired pharmacological activity. Such salts include, inter alia, addition salts of acids formed with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids, for example, acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid , malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, 1,2 -ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesul background acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo(2.2.2|oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4"-methylene- bis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurylsulphuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and etc.

Pharmaceutically acceptable salts can also be base addition salts, which can be formed when the available acid protons are able to react with inorganic or organic bases.

Acceptable inorganic bases are, for example, sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include, for example, ethanolamine, diethanolamine, triethanolamine, tromethamine, M-methylglucamine, and the like.

The present invention also provides prodrugs of the compound of formula (I). A prodrug is a compound capable of being converted directly by a metabolic pathway (for example, by hydrolysis) into a compound of formula (1).

For example, an ester of a compound of formula (I), which contains a hydroxy group, can be converted directly into the parent molecule by hydrolysis. Alternatively, the ester of the compound of formula (I), which contains a carboxy group, can be converted directly into the parent molecule by hydrolysis.

Suitable esters of compounds of formula (I) containing a hydroxy group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bis-

Vb-hydroxynaphthoates, gentisates, isethionates, di-p-toluene tartrates, methylsulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates. Suitable esters of compounds according to the formula (I), which contain a carboxy group, are, for example, the compounds described in the work (I eipmereg, BO. Opidmegar.

Vez., 1987, 78, page 379). A particularly useful class of esters of compounds according to the formula (I), which contain a hydroxy group, can be created from acidic moieties selected from those described in the work (Vypaddaaga ei ai, U. Med. Snet., 1989, 32, pp. 2503-2507), and includes substituted (aminomethyl)benzoates, such as dialkylaminomethylbenzoates, in which two alkyl groups may be joined together and/or terminated by an oxygen atom or an optionally substituted nitrogen atom, such as an alkylated nitrogen atom, and in particular, ( morpholinomethyl)benzoates, for example 3- or 4-(morpholinomethyl)benzoates, and (4-alkylpiperazin-1-yl)benzoates, for example 3- or 4-(4-alkylpiperazin-1-yl)benzoates.

The term "protected derivatives" means derivatives of compounds of formula (I) in which the chemically active site or sites are blocked by protective groups. Protected derivatives of compounds of formula (I) may be used in the preparation of compounds of formula (I) or may themselves serve as active cathepsin 5 inhibitors.

A comprehensive list of suitable protective groups can be found in the work (T.M. Sgeepe, Rgoiesiime SpgoiMrz ip Ogdapis zZupipevivs, Zga edibyop, dopp UMieu 5 opv, Ips. 1999).

The term "therapeutically effective amount" means an amount which, when administered to an animal for the treatment of a disease, is sufficient to effect that treatment.

The term "treatment" means any administration of a compound according to the present invention and includes in its meaning: (1) preventing the occurrence of a disease in an animal that may be susceptible to the disease, but does not yet have or exhibits signs of the pathology or symptomatology of the disease; (2) inhibition of the disease in an animal that has the disease or shows signs of the pathology or symptomatology of the given disease (ie, stopping the further development of the pathology or symptomatology); or (3) improvement in the condition of a sick animal that has a given disease or shows signs of pathology or symptomatology of a given disease (ie, reversal of the development of pathology and/or symptomatology).

The term "treatment" from the point of view of combination therapy, i.e. use together with a biological agent,

means any administration of a compound according to the present invention and includes within its meaning: (1) preventing the occurrence of an immune response in an animal that may be susceptible to a given immune response, but does not yet have it or exhibits signs of the pathology or symptomatology of a given immune response; (2) inhibition of an immune response in an animal that has a given immune response or exhibits signs of pathology or symptomatology of a given immune response (ie, stopping further development of the pathology or symptomatology); or (3) improvement of the immune response in an animal that has a given immune response or exhibits signs of pathology or symptomatology of a given immune response (i.e., a reduction in the degree or severity or duration of obvious manifestations of a given immune response or reversal of the development of pathology and/or symptomatology, for example, reducing the binding and presentation of antigenic peptides by HCG class II molecules, reducing the activation of T cells and B cells, reducing humoral and cell-mediated reactions and, as far as this may be acceptable for a specific immune reaction, alleviating inflammation, congestion, pain , necrosis, reduction in the loss of effectiveness of a biological agent, etc.).

The expression "where the aromatic or alicyclic ring in B: may optionally be substituted with one, two, or three He, independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkyl, or halide; or may optionally be substituted with one or two B, independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halide, carboxy or alkoxycarbonyl, and one He selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,..." in definition B? in the compound of formula (I) means that all aromatic and alicyclic rings in the volume of VU are directly or indirectly attached (for example, B is cycloalkylalkyl, -alkylene-X-VU, where X is as defined in the section Essence of the invention, and B: is aryl, aralkyl, etc.), if necessary, can be substituted for B2 or for Be and VU, or only for VU.

The best options for implementing the invention

I. Certain compounds according to the formula (I) within the widest limits of the volume defined in the section on the essence of the invention are preferred. For example: (A) The best group of compounds is one in which:

IN! there is hydrogen or methyl, and better - hydrogen;

IN? is cyclopropyl, 1-phenylethylI-CH(SeH5)CH3zi or 1H-pyrazol-5-yl, and better - cyclopropyl. (1) In the above-defined preferred group (A) and the more preferred group included in it, the more preferred group of compounds is one where B3 is hydrogen and B" is alkyl, preferably methyl, ethyl, propyl or butyl, and even better, if B" is ethyl or propyl. (2) In the above-defined preferred group (A) and the more preferred group included in it, the more preferred group of compounds is one where B3 is alkyl, preferably methyl or ethyl, and B" is alkyl, preferably methyl, ethyl , propyl or butyl, and even better if B" is methyl. In a preferred embodiment, BZ and B" are methyl. (3) In the above-defined preferred group (A) and more preferred groups included in it, a more preferred group of compounds is one where BZ and B" together with the carbon atom to which they are attached to form cycloalkylene, preferably cyclopropylene, cyclopentylene or cyclohexylene, and even better cyclopropylene. (4) In the above-defined preferred group (A) and the more preferred group included in it, the more preferred group of compounds is one where B3 and B" together with the carbon atom to which they are attached form piperidin-4-yl, substituted on the nitrogen atom by ethyl, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl or 1,1-dioxotetrahydrothiopyran-4-yl. () In the above-defined best groups (A) and A (1-4), as well as better groups included in them, a better group of compounds is one where B is haloalkyl, in the best version difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2 ,2,2-pentafluoroethyl, 1,1,2,2,3,3,3-heptafluoropropyl, and B" and BZ are hydrogen. (i) In the above-defined better groups (A) and A(1-4), as well as more better groups included in them, a more better group of compounds is one where B? is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, B/ is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl or 1, 1,2,2,2-pentafluoroethyl, and VZ is hydrogen. (ii) In the above-defined better groups (A) and A(1-4), as well as more better groups included in them, a more better group of compounds is one where B? is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, A is alkyl, preferably methyl, ethyl or propyl, and A is hydrogen. (mM) In the above-defined better groups (A) and A(1-4), as well as more better groups included in them, a more better group of compounds is one where B? is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, B' is haloalkyl, preferably trifluoromethyl or 2,2,2-trifluoroethyl, and B : is aryl, which can be optionally substituted with one, two or three Be. In a preferred embodiment, VZ is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl. In an even better version B? and

B" is trifluoromethyl, and B: is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4,- or 3,5-difluorophenyl. (m) In the above-defined better groups (A) and A(1-4), as well as more better groups included in them, a more better group of compounds is one where B is haloalkyl, in the best version difluoromethyl, trifluoromethyl, 2,2 ,2-trifluoroethyl or 1,1,2,2,3-pentafluoroethyl, B" is alkyl, preferably methyl or ethyl, and B3 is aryl, which, if necessary, can be substituted by one, two or three B". In a preferred embodiment, VZ is phenyl, 4-fluorophenyl, 2,3-, 2,A-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl. In an even better version B? is trifluoromethyl, B" is methyl, and B" is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4,- or 3,5-difluorophenyl. (M) In the above-defined better groups (A) and A(1-4), as well as more better groups included in them, a more better group of compounds is one where B is haloalkyl, preferably trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, B" is hydrogen, and BZ is aryl, which, if necessary, can be substituted with one, two or three He. In the best case, B? is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4,- or 3,5-difluorophenyl. In an even better version, Be is trifluoromethyl, and BZ is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, better - 2,4-difluorophenyl. (mi) In the above-defined better groups (A) and A(1-4), as well as more better groups included in them, a more better group of compounds is one where B? is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, B" is haloalkyl, preferably trifluoromethyl or 2,2,2-trifluoroethyl, and BZ is heteroaryl , which, if necessary, can be replaced by one, two or three B". In a preferred embodiment, AZ is indol-5-yl, benzoxazol-b-yl, thiophene-Z-yl, thiophene-2-yl, furan-2-yl, pyridin-4-yl, pyridin-Z-yl, pyridin-2 -yl, imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl . -yl, thiazol-5-yl, which can be substituted with one or two methyls if necessary.

(my) In the above-defined better groups (A) and A(1-4), as well as more better groups included in them, a more better group of compounds is one where B? is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, B" is alkyl, preferably methyl or ethyl, and B: is heteroaryl, which if necessary can be replaced by one, two or three Ve.

In a preferred embodiment, the VZ is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2 -yl, imidazol-b5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl , (1,2,3|hiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrole-2-yl, pyrrole-Z-yl, thiazol- 4-yl, thiazol-b5-yl, which can be substituted with one or two methyls if necessary.

(my) In the above-defined better groups (A) and A(1-4), as well as more better groups included in them, a more better group of compounds is one where B? is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, B" is hydrogen, and BZ is heteroaryl, which, if necessary, can be substituted with one, two or three B". In the best version of the VZ is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol- g-yl, (1,2,3)hiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrole-2-yl, pyrrole-3-yl , thiazol-4-yl, thiazol-5-yl, which, if necessary, can be substituted with one or two methyls.

(a) In the above-defined best groups (A), A(1-4), A(i-mii) and A(1-4)(i-miii), as well as more excellent groups included in them, a better group of compounds is one where B? is cycloalkylalkyl, which, if necessary, can be substituted by one, two or three Be, independently selected from among alkyl or halide, or VU, selected from among aralkyl or heteroaralkyl, preferably - 1-methylcyclopentylmethyl, 1-methylcyclohexylmethyl, 1-methylcyclobutylmethyl, 1-methyl -3,3-difluorocyclobutyl methyl, 1-methyl-4,4-difluorocyclohexylmethyl, 1-benzylcyclopropylmethyl, 1-thiazol-2-ylmethylcyclopropylmethyl or 1-methyl-3,3-difluorocyclopentylmethyl.

(p) In the above-defined better groups (A), A(1-4), A(i-mii) and A(i-4)(i-mii), as well as more better groups included in them, more a more preferable group of compounds is one where HO is alkyl, better - 2,2-dimethylpropyl, 3,3-dimethylpentyl, 2,2,3,3-tetramethylbutyl.

(c) In the above-defined best groups (A), A(1-4), A(i-mii) and A(i-4)(i-miii), as well as the better groups included in them, more a better group of compounds is one where B? is haloalkyl, preferably 2,2-dichloroethyl, 3,3,3-trifluoropropyl, 2,2-trifluoromethylethyl or 2,2,2-trifluoroethyl.

(C) In the above-defined best groups (A), A(1-4), A(i-mii) and A(1-4)(i-mii), as well as more excellent groups included in them, a more preferable group of compounds is one where B? is haloalkyl substituted by aryl, heteroaryl or heterocycloalkyl, preferably 2,2-difluoro-3-phenylpropyl, 2,2-difluoro-3-tetrahydropyran-4-ylpropyl, 2,2-difluoro-3-morpholin-4-ylpropyl, 2,2-difluoro-3-pyridin-2-ylpropyl, 2,2-difluoro-3-pyridin-3-ylpropyl or 2,2-dichloro-3-phenylpropyl.

(j) In the above-defined best groups (A), A(1-4), A(i-mii) and A(1-4)(i-miii), as well as more excellent groups included in them, a more preferable group of compounds is the one where VZ? is aralkyl, which may optionally be substituted with one, two, or three Be, independently selected from alkyl, haloalkyl, hydroxy, hydroxy, haloalkyl, cyano, or halide, or which may optionally be substituted with one or two Be, independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halide, carboxy or alkoxycarbonyl, and one HB" selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, aryloxycarbonyl , aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, heterocycloalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl or -5028!! (where B! is alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl); and where the aromatic or alicyclic ring in B : if necessary, can be replaced by one, two or three VOs, independently selected among alkyl, haloalkyl, alkyloxy, hydroxy, haloalkyloxy or halide.

In the best case, B? are benzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 2-chlorobenzyl, 4-ethoxybenzyl, biphen-4-ylmethyl, naphth-1-ylmethyl, naphth-2-ylmethyl, 4-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl , 2-phenethyl, 4-hydroxybenzyl, 2-(4-hydroxyphenyl)ethyl, 2,6-difluorobenzyl, biphenyl-3-ylmethyl, 3-phenylpropyl or 2,2-dimethyl-3-phenylpropyl.

In the best case, B? is 2-chlorobenzyl, 3-chlorobenzyl or 4-fluorobenzyl.

(Y) In the above-defined best groups (A), A(1-4), A(i-mii) and A(1-4)(i-mii), as well as more excellent groups included in them, a better group of compounds is one where B? is heteroaralkyl, which may optionally be substituted with one, two, or three Be, independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halo; or which may optionally be substituted with one or two BE independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halide, carboxy or alkoxycarbonyl, and one HA" selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl , aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl or -5028! (where B! is alkyl, aryl, heteroaryl or heterocycloaryl ); and where the aromatic or alicyclic ring in B" can optionally be substituted with one, two, or three R, independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkyl, or halo.

In the best case, B? is 2-bromothiophen-5-ylmethyl, pyridin-4-ylmethyl or 2,2-dimethyl-3-pyridin-3-ylpropyl.

(9) In the above-defined best groups (A), A(1-4), A(i-mii) and A(1-4)(i-mii), as well as more excellent groups included in them, a more preferable group of compounds is one where B? is -(alkylenealkylene)-5(0)2-VU, where B? there is alkyl, better -

IN? is methylsulfonylmethyl, ethylsulfonylmethyl, propyl-1-sulfonylmethyl, 2-methylpropylsulfonylmethyl, 2-methylsulfonylethyl or 2-ethylsulfonylethyl. (n) In the above-defined best groups (A), A(1-4), A(i-mii) and A(1-4)(i-miii), as well as the better groups included in them, also a better group of compounds is one where B? is -(alkylene)-5(0)2-BU, where BZ is aryl or aralkyl, which may optionally be substituted with one, two or three Be independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkyl, cyano or halide, or which may optionally be substituted with one or two BP independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halide, carboxy, or alkoxycarbonyl, and one B" selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl , heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl or -5028!! (where B! is alkyl, aryl, heteroaryl or heterocycloalkyl); and where the aromatic or alicyclic ring in A: may optionally be substituted with one, two or three BUs independently selected from a alkyl, haloalkyl, alkoxy, hydroxy, haloalkyl or halide. In the best variant, the VZ is 2-difluoromethoxyphenylmethanesulfonylmethyl, 2-phenylsulfonylethyl, 4-fluorophenylmethanesulfonylmethyl, 4-aminocarbonylphenylmethanesulfonylmethyl, 4-piperazin-1-ylphenylmethanesulfonylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3-fluorophenylmethanesulfonylpiethyl, 2,4,6-trifluorophenylmethanesulfonylmethyl, 2,4,6-trifluorophenylmethanesulfonylmethyl, 2,4,6-trifluorophenylmethanesulfonylmethyl, or 4-trifluoromethylphenylmethanesulfonylmethyl, phenylmethanesulfonylmethyl, 2-(2-, 3- or 4- trifluoromethylphenyl)sulfonylethyl or 2-(2-, 3- or 4-fluorophenyl)sulfonylethyl. () In the above-defined best groups (A), A(1-4), A(i-miii) and A(1-4)(i-miii), as well as the better groups included in them, even more the best group of compounds is the one where B? is -(alkylene)-5(0)2-VU, where B? is heteroaryl or heteroaralkyl, optionally substituted with one, two, or three He, independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halide; or optionally substituted with one or two B independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halide, carboxy, or alkoxycarbonyl, and one PH selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl y, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl or -5028! (where B! is alkyl, aryl, heteroaryl or heterocycloalkyl); and also where the aromatic or alicyclic ring in B" may optionally be substituted with one, two or three R, independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkyl or halide. In a preferred embodiment, B" is pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, 3-difluoromethoxypyridin-2-ylmethanesulfonylmethyl, 2-difluoromethoxypyridin-3-ylmethanesulfonylmethyl, -4-difluoromethoxypyridin-3-ylmethanesulfonylmethyl, 3-difluoromethoxypyridin-4-ylmethanesulfonylmethyl, pyrimidine-2-ylmethanesulfonylmethyl . furan-2-ylmethanesulfonyl methyl, 2-pyridin-2-ylethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl, 2-pyridin-4-ylethanesulfonylmethyl, 2-pyridin-3-ylsulfonylethyl, 2-pyridin-4-ylsulfonyl letyl, 3-pyridin-3-ylsulfonylpropyl, 1,3,5-triazin-2-ylmethanesulfonylmethyl, 1,3,4-thiadiazol-2-ylmethanesulfonylmethyl, oxazol-5-ylmethanesulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl or thiazol-2-yl ylmethanesulfonylmethyl.

In the above-defined better groups (A), A(1-4), A(i-my) and A(1-4X(i-my), as well as more better groups included in them, an even better group of compounds is one wherein B is -(alkylene)-5(O)287U, wherein B is heterocycloalkyl or heterocycloalkylalkyl, optionally substituted with one, two or three He, independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano or halide, or optionally substituted with one or two B independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halide, carboxy or alkoxycarbonyl, and one HA selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl , aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl or -5028" (where B" is alkyl, cycloalkyl, aryl heteroaryl or heterocycloalkyl); and wherein the aromatic or alicyclic ring in BO may optionally be substituted with one, two, or three NU independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkyloxy, or halide. In the best version of the VO is piperidin-1-ylsulfonylmethyl or piperidin-4-ylmethanesulfonylmethyl where the nitrogen atom in the piperidine ring is replaced by methyl, ethyl, acetyl, methylsulfonyl or aminosulfonyl, tetrahydropyran-4-ylsulfonylmethyl, tetrahydropyran-4-ylsulfonylmethyl, 1,1 -dioxotetrahydrothiopyran-4-ylmethanesulfonylmethyl or morpholin-4-ylmethanesulfonylmethyl. (K) In the above-defined better groups (A), A(1-4), A(i-miii) and A(1-4)(i-miii), as well as more better groups included in them, also a more preferable group of compounds is one where B? is -(alkylene)-5(0)2-VU, where B? is cycloalkylalkyl, and in the best version B? is cyclopropylmethylsulfonylmethyl. (I) In the above-defined best groups (A), A(1-4), A(i-my) and A(1-4)(i-my), as well as the better groups included in them, B ? is ethylsulfonylmethyl, 2-methylsulfonylethyl, 2-methylpropylsulfonylmethyl, benzenesulfonylmethyl, 2-phenylsulfonylethyl, naphth-2-ylmethanesulfonylmethyl, biphenyl-2-ylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, phenylmethanesulfonylmethyl, 2-phenylmethanesulfonylmethyl, 4-tert-butylphenylmethanesulfonylmethyl, 2 , 3-fluorophenylmethanesulfonylmethyl, 4-fluorophenylmethanesulfonylmethyl, 2-chlorophenylmethanesulfonylmethyl, 3-chlorophenylmethanesulfonylmethyl, 4-chlorophenylmethanesulfonylmethyl, 2-methoxyphenylmethanesulfonylmethyl,

4-метоксифенілметансульфонілметил, 2-трифторметоксифенілметансульфонілметил, 3- трифторметоксифенілметансульфонілметил, 4-трифторметоксифенілметансульфонілметил, 2- трифторметилфенілметансульфонілметил, З-трифторметилфенілметансульфонілметил, 4- трифторметилфенілметансульфонілметил, 2-ціанофенілметансульфонілметил, 3- ціанофенілметансульфонілметил, 2-бромфенілметансульфонілметил, 2-метилфенілметансульфонілметил, 3- метилфенілметансульфонілметил, 4- methylphenylmethanesulfonylmethyl, 2-(4- trifluoromethoxybenzenesulfonyl)ethyl, 2-(3-trifluoromethoxybenzenesulfonyl)ethyl, 2-(2- trifluoromethoxybenzenesulfonyl)ethyl, 2-difluoromethoxyphenylmethanesulfonyl methyl, 3- difluoromethoxyphenylmethanesulfonylmethyl, 4-difluoromethoxyphenylmethanesulfonylmethyl, 2-(4- difluoromethoxyethylbenzenesulfonyl) . ulfonylmethyl, 2,6-difluorophenylmethanesulfonylmethyl, 2,3- difluorophenylmethanesulfonylmethyl, 3,4-difluorophenylmethanesulfonylmethyl, 2,A- difluorophenylmethanesulfonylmethyl, 2,5-dichlorophenylmethanesulfonylmethyl, 3,4- dichlorophenylmethanesulfonylmethyl, 2,6-dichlorophenylmethanesulfonylmethyl, 2-fluoro-3- methylphenylmethanesulfonylmethyl, 4-fluoro-2-trifluoromethoxyphenylmethanesulfonylmethyl, 2-fluoro-6-trifluoromethyl-phenylmethanesulfonylmethyl, 2-fluoro-3-trifluoromethylphenylmethanesulfonylpiethyl, 2-fluoro-4-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-5-trifluoromethylphenylmethanesulfonylmethyl, 4-fluoro-3- trifluoromethylphenylmethanesulfonylmethyl, 2-chloro-5-trifluoromethylphenylmethanesulfonylmethyl, 2,4,6- trifluorophenylmethanesulfonylmethyl, 2,4,5-trifluorophenylmethanesulfonylmethyl, 2,3,4- trifluorophenylmethanesulfonylmethyl, 2,3,5-trifluorophenylmethanesulfonylmethyl, 2,5,6- trifluorophenylmethanesulfonylmethyl, 3,4,5-trimethoxyphenylmethanesulfonylmethyl, pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-yl-methanesulfonylmethyl, 2-(pyridin-2 - ylsulfonyl)ethyl, 2-(pyridin-4-ylsulfonyl)ethyl, oxypyridin-2-ylmethanesulfonylmethyl, cyclohexylmethanesulfonylmethyl, cyclohexylmethanesulfonylmethyl, cyclopropylmethanesulfonylmethyl, thiophene-2-sulfonylmethyl, 5-chlorothien-2-ylmethanesulfonylmethyl or 3,5-dimethylisoxazole-4- ylmethanesulfonylmethyl. (t) In the above-defined better groups (A), A(1-4), A(i-mii) and A(1-4)(i-mii), as well as more better groups included in them, VO are 1-ethoxycarbonylpiperidin-4-ylmethyl, 1-methylpiperidin-4-ylmethyl, 2-tetrahydropyran-4-ylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, 2-morpholin-4-ylethyl , thiomorpholin-4-ylmethyl, 1-oxo-thiomorpholin-4-ylmethyl, 1,1-dioxothiomorpholin-4-ylmethyl, tetrahydrothiopyran-4-ylmethyl, 1-oxotetrahydrothiopyran-4-yl methyl, 1,1-dioxotetrahydrothiopyran-4-yl yl methyl, 1-methylpiperazin-4-ylmethyl, benzyloxymethyl, ethoxymethyl, isopropyloxymethyl, 2-piperidin-1-yl-ethyl, 2-pyrrolidin-1-ylethyl, tert-butyloxymethyl, imidazol-4-ylmethyl, indol-3-ylmethyl , indol-2-ylmethyl, 1-benzyl-imidazol-4-ylmethyl, 4-ethyl-4-methylpiperidin-1-ylmethyl, indol-1-ylmethyl, 1-methyl-piperidin-2-ylmethyl, 2,2,- difluoro-3-thien-2-ylmethyl or pyridin-4-ylmethyl. (n) In the above-defined best groups (A), A(1-4), A(i-mii) and A(1-4)(i-miii), as well as more excellent groups included in them, B ? is 3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl; 2-SEzmethylphenylmethanesulfonylmethyl, 3-

SEzpyridin-2-ylmethanesulfonylmethyl, 2-E-furan-5-ylmethanesulfonylmethyl, 2-methylthiazol-4-ylmethanesulfonylmethyl, tetrahydropyran-4-ylmethanesulfonylmethyl, 1,1-dioxo-1/6-hexahydrothiopyran-4-ylmethanesulfonylmethyl, 1-ethylpiperidine- 4-ylmethanesulfonylmethyl, 2-oxo-tetrahydropyrimidin-4-ylmethanesulfonylmethyl, 1-ethyl-2-oxopiperidin-4-ylmethanesulfonylmethyl, 1-acetylpiperidin-4-ylmethanesulfonylmethyl, 1-ethoxycarbonylpiperidin-4-ylmethanesulfonylmethyl, 1-methylsulfonylpiperidin-4-ylmethanesulfonylmethyl ylmethanesulfonylmethyl, 1-cyclopropylpiperidin-4-ylmethanesulfonylmethyl, 1-acetylazetidin-3-ylmethanesulfonylmethyl, 1-ethoxycarbonylazetidin-3-ylmethanesulfonylmethyl, 1-methylsulfonylazetidin-3-ylmethanesulfonylmethyl, 1-ethylazetidin-3-ylmethanesulfonylmethyl, 1-cyclopropylazetidin-3-ylmethanesulfonylmethyl ylmethanesulfonylmethyl furan-2-ylmethanesulfonylmethyl, difluoro-(4-fluorophenyl)methanesulfonylmethyl, difluoro-(pyrazin-2-yl)umethanesulfonylmethyl, difluoro-(2-difluoromethoxyphenyl)methanesulfonylmethyl, 1-acetylpiperidin-4-ylsulfonylmethyl, 1-ethoxycarbon lpiperidin-4-ylsulfonyl methyl, 1-cyclopropylpiperidin-4-ylsulfonylmethyl, 2-(pyridin-2-yl)ethanesulfonylmethyl, 2-(pyridin-3-yl)ethanesulfonylmethyl, 2-(pyridin-4-yl)ethanesulfonylmethyl, 3-(pyridin-2-yl)propanesulfonylmethyl, 2,6-difluorophenylmethanesulfonyl, I,3.5)griazin-2-ylmethanesulfonyl methyl, I,Z.AThiadiazol-2-ylmethanesulfonylmethyl, oxazol-5-ylmethanesulfonylmethyl, thiazol-5- ylmethanesulfonylmethyl, 4-fluorophenylmethanesulfonylmethyl, 4-aminocarbonylphenylmethanesulfonylmethyl, 4-piperazin-4-ylphenylmethanesulfonylmethyl, 5-fluoroindol-3-ylmethanesulfonylmethyl, 4,6-difluoroindol-3-ylmethanesulfonylmethyl, 1-methylindol-3-ylmethanesulfonylmethyl, 4-fluoroindole-3-ylmethanesulfonylmethyl ylmethanesulfonylmethyl, 2-(5-fluoroindol-3-yl)/ethanesulfonylmethyl, /- 2-(4,6-difluoroindol-3-ilueethanesulfonylmethyl, / 2-(1-methylindol-3-yl)ethanesulfonylmethyl, 2-(4- fluorindole-3-yl)ethanesulfonylmethyl, 2-quinolin-3-ylethanesulfonylmethyl, -2-quinolin-2-ylethanesulfonylmethyl, isoquinolin-3-ylmethanesulfonylmethyl 2-(isoquinolin-3-yl)ethanesulfonylmethyl . (2,4-difluoropyridin-3-ylmethanesulfonylmethyl, fluoro-(3,4-difluoropyridin-4-yl)umethanesulfonylmethyl, 2,A-diSEzpyridin-3-ylmethanesulfonylmethyl, 3,4-diSEzpyridin-4-ylmethanesulfonylmethyl, 2-(2,4-diSEzpyridin-3-yl)ethanesulfonylmethyl, 2-(3,4-diSEzpyridin-4-yl)ethanesulfonylmethyl, fluoro-(2,4-diSEzpyridin-3-yl)umeethanesulfonylmethyl, fluoro-(3, 4-DiSRzpyridin-4-ylmethanesulfonylmethyl, 4-E-pyridin-3-ylmethanesulfonylmethyl, 3-E-pyridin-5-ylmethanesulfonylmethyl, 2-E-pyridin-5-ylmethanesulfonylmethyl, 2-BE-pyridin-3-ylmethanesulfonylmethyl, 5- E-pyridin-2-ylmethanesulfonylmethyl, 4-E-pyridin-2-ylmethanesulfonylmethyl, 4-E-1-oxopyridin-3-ylmethanesulfonylmethyl, 3-E-1-oxopyridin-5-ylmethanesulfonylmethyl, 2-B- 1-oxopyridin-5-ylmethanesulfonylmethyl, 2-E-1-oxopyridin-3-ylmethanesulfonylmethyl, 5-E-1-oxopyridin-

2-ylmethanesulfonylmethyl, 4-E-1-oxopyridin-2-ylmethanesulfonylmethyl, 4-SEz-pyridin-2-ylmethanesulfonylmethyl, 3-SEz-pyridin-5-ylmethanesulfonylmethyl, 3-E-pyridin-2-ylmethanesulfonylmethyl, 2-

CE3-pyridin-3-ylmethanesulfonylmethyl, 4-CE3-1-oxopyridin-2-ylmethanesulfonylmethyl, 3-CE3-1-oxopyridin-5-ylmethanesulfonylmethyl, 3-E-1-oxopyridin-2-ylmethanesulfonylmethyl, 2-Сгз-1- Oxopyridin-3-ylmethanesulfonylmethyl, 5-C3-1-oxopyridin-2-ylmethanesulfonylmethyl, 2-CH3-pyridin-6-ylmethanesulfonylmethyl, 3-CH3-pyridin-2-ylmethanesulfonylmethyl, 4-CH3-pyridin-4-ylmethanesulfonylmethyl, 3-CH3-pyridin-4-ylmethanesulfonylmethyl CH3-pyridin-4-ylmethanesulfonylmethyl, /- 2-(2-CH3-pyridin-6-ylethanesulfonylmethyl, /- 2-(3-CH3-pyridin-2-yl)ethanesulfonylmethyl, 2-(4-CH3-pyridin-3 -yl)ethanesulfonylmethyl, 2-(3-SE3-pyridin-4-yl)ethanesulfonylmethyl, 2-С2Н5-pyridin-b6-ylmethanesulfonylmethyl, 2-С2Нв-pyridin-2-ylmethanesulfonylmethyl, 4-С2Не-pyridin-3-ylmethanesulfonylmethyl, / 3-С2Не-pyridin-4-ylmethanesulfonylmethyl, /-2-(2-С2Н5-pyridin-6-yl)ethanesulfonylmethyl, 2-(3-С2Н5-pyridin-2-yl)ethanesulfonylmethyl, 2-(4-С2Н5- pyridin-3-yl)ethanesulfonylmethyl, 2-(3-C2H5-pyridin-4-yl)ethanesulfonylmethyl, 2-(2-CH3-pyridin-3-yl)ethanesulfonylmethyl, 2-SE3-pyridin-3- lmethanesulfonylmethyl, 2-(3-SEz-pyridin-4-yl)ethanesulfonylmethyl,

C3-SE3-pyridin-4-ylmethanesulfonylmethyl, cinolin-3-ylmethanesulfonylmethyl, 2-(cinolin-3-yl)ethanesulfonylmethyl, phthalazin-1-ylmethanesulfonylmethyl, 2-(phthalazin-1-yl/oethanesulfonylmethyl, -2- ( quinoxalin-2-ylethanesulfonylmethyl, quinazolin-2-ylmethanesulfonylmethyl, 2-(quinazolin-2-yl)ethanesulfonylmethyl, P,8Inaphthyridin-2-ylmethanesulfonylmethyl, 2-(1,8Inaphthyridin-2-yl)ethanesulfonylmethyl, (1,8|Inaphthyridine -3-ylmethanesulfonylmethyl, 2-(1,8|Inaphtyridin-3-yl)ethanesulfonyl methyl, 3-CI-pyridin-2-yl methanesulfonylmethyl, 4-CI-pyridin-33-ylmethanesulfonylmethyl, 3-CI-pyridin-4- ylmethanesulfonylmethyl, 3-E-pyridin-2-ylmethanesulfonylmethyl, 4-E-pyridin-3-ylmethanesulfonylmethyl, 3-BE-pyridin-4-ylmethanesulfonylmethyl, isoquinolin-4-ylmethanesulfonylmethyl, 6b-phenylpyridin-2-ylmethanesulfonylmethyl, З- phenylpyridin-2-ylmethanesulfonylmethyl, 4-phenylpyridin-3-ylmethanesulfonylmethyl, 3-phenylpyridin-4-ylmethanesulfonylmethyl, 2-(6-phenylpyridin-2-yl)ethanesulfonylmethyl, 2-(3-phenylpyridin-2-yl)ethanesulfonylmethyl, 2- (4-phenyl pyridin-3-yl)ethanesulfonylmethyl, 2-(3-phenylpyridin-4-yl)ethanesulfonylmethyl, 6-(pyridin-2-yl)pyridin-2-ylmethanesulfonylmethyl, 3Z-(pyridin-2-yl)/pyridin-2- ylmethanesulfonylmethyl, 4-(pyridin-2-yl)pyridin-3-ylmethanesulfonylmethyl, 3-(pyridin-2-yl)/pyridin-4-ylmethanesulfonylmethyl, 2-16-(pyridin-2-yl)pyridin-2-yl| ethanesulfonylmethyl, 2-13-(pyridin-2-yl)pyridin-2-yl|estanesulfonylmethyl, /- 2-14-(pyridin-2-yl)pyridin-3-yl|estanesulfonylmethyl, 2-13-(pyridin-2 -yl)pyridin-4-ylfuietansulfonylmethyl, 6-(pyridin-3-yl)pyridin-2-ylmethanesulfonylmethyl, 3-(pyridin-3-yl)/pyridin-2-ylmethanesulfonylmethyl, 4-(pyridin-3-yl) )pyridin-3-ylmethanesulfonylmethyl, 3-(pyridin-3-yl)/pyridin-4-ylmethanesulfonylmethyl, 2-16-(pyridin-3-yl)pyridin-2-yl]ethanesulfonylmethyl, 2-IZ-(pyridin-3 -yl)pyridin-2-yl]ethanesulfonylmethyl, 2-(14-(pyridin-3-yl)pyridin-3-yl]ethanesulfonylmethyl, 2-3-(pyridin-3-yl)pyridin-4-yl]ethanesulfonylmethyl, 6-(pyridin-4-yl)pyridin-2-ylmethanesulfonylmethyl, 33-(pyridin-4-yl)/pyridin-2-yl methanesulfonylmethyl, 4-(pyridin-4-yl)pyridin-3-ylmethanesulfonylmethyl, 3-(pyridin-4-yl)/pyridin-4-ylmethanesulfonylmethyl, 2-I(6-(pyridin-4-yl)pyridin-2- yl-ethanesulfonylmethyl, 2-13-(pyridin-4-yl)pyridin-2-yl-ethanesulfonylmethyl, 2-(14-(pyridin-4-yl)pyridin-3-yl ethanesulfonylmethyl, 2-13-(pyridin-4 -yl)pyridin-4-ylphyethanesulfonylmethyl, 2,2-dimethylcyclopropylmethanesulfonylmethyl, biphen-2-ylmethanesulfonylmethyl, 2-thiophen-2-ylphenylmethanesulfonylmethyl, 2-thiazol-2-ylphenylmethanesulfonylmethyl, 2-thiazol-5-ylphenylmethanesulfonylmethyl, 2-11.2,3Hyadiazole -5-ylphenylmethanesulfonylmethyl, 2-isoxazol-5-ylphenylmethanesulfonylmethyl, 2-(1-methylpyrazol-5-yl)/uphenylmethanesulfonylmethyl, 2-11.2,3)|)griazol-5-ylphenylmethanesulfonylmethyl, 2-11.2,3 |oxadiazol-5-ylphenylmethanesulfonylmethyl, 2-M1.2,3)triazol-5-yl||renylmethanesulfonylmethyl, -2-((1.2,3)triazol-1-yl|renylmethanesulfonylmethyl, oxazoli5,4-b|pyridin-2 - ylmethanesulfonylmethyl, oxazoles -2-ylmethanesulfonylmethyl, benzimidazol-5-ylmethanesulfonylmethyl, benzimidazol-4-ylmethanesulfonylmethyl, 3 -SEz-ZH-imidazo|4,5-b|pyridin-2-ylmethanesulfonylmethyl, 3-Sz-ZH-imidazo|4,5-s|Ipyridin-2-ylmethanesulfonylmethyl, 1-Sez3-1H-imidazoi(4,5 - c|Ipyridin-2-ylmethanesulfonylmethyl, /- 1-SEz-1H-imidazo(4,5-b|pyridin-2-ylmethanesulfonylmethyl, thiazoles(5,4-

BIpyridin-2-ylmethanesulfonylmethyl, thiazolyl4,5-c|Ipyridin-2-ylmethanesulfonylmethyl, thiazolyl4,5-b|pyridin-2-ylmethanesulfonylmethyl, /5-SEzthiazole(I5,4-b|Ipyridin-2-ylmethanesulfonylmethyl, / 4- CE3-thiazolyl4,5-c|Ipyridin-ylmethanesulfonylmethyl, 7-CE3-thiazolI4,5-b|pyridin-2-ylmethanesulfonylmethyl, 3-CE3-1H-pyrrolyl2,3-b|pyridin-2-ylmethanesulfonylmethyl, 3-CE3- 1H-pyrrolyl3,2-c|Ipyridin-2-ylmethanesulfonylmethyl, 3-C3-1H-pyrrolyl3,2-

BIpyridin-2-ylmethanesulfonylmethyl, imidazo(1,2-c|Ipyrimidine-2-methanesulfonylmethyl, 8-SEz-imidazo|1,2- c|Ipyrimidine-2-methanesulfonylmethyl, imidazo(1,2-a|pyrimidine-2- methanesulfonylmethyl, 8-SEz-imidazo|1,2-

BIpyridazin-2-ylmethanesulfonylmethyl, imidazo|(1,2-a|Ipyrazine-2-methanesulfonylmethyl, 8-SEz-imidazo|(1,2- aIpyrazine-2-methanesulfonylmethyl, pyrazoli1,5-c|Ipyrimidin-2-ylmethanesulfonylmethyl, 3-SEz-pyrazoli1,5-s|Ipyrimidin-2-ylmethanesulfonylmethyl, 4-SEz-pyrazoli1,5-s|Ipyrimidin-2-ylmethanesulfonylmethyl, imidazo(|1,2- 4111,2,4)griazine-2-methanesulfonylmethyl , 3-SEz-imidazo|(1,2-41(11,2,4)|triazine-2-methanesulfonylmethyl,

I,Z|benzoxazol-2-ylmethanesulfonylmethyl, 5-E-(1,3|benzoxazol-2-ylmethanesulfonylmethyl/(1,3|benzoxazol-4-ylmethanesulfonylmethyl, 2-СЕ5-И1,3|benzoxazol-4-ylmethanesulfonyl- methyl, I1,3|benzoxazol-7-ylmethanesulfonylmethyl, 2-СЕ5-И1,3|benzoxazol-7-ylmethanesulfonylmethyl, I,2Ibenzoxazol-3-ylmethanesulfonylmethyl, I1,2|Ibenzoxazol-4-ylmethanesulfonylmethyl, 5-СЕ3- I1,2|benzoxazol-4-ylmethanesulfonylmethyl, 3-СЭ5-(1,2|benzoxazol-4-ylmethanesulfonylmethyl, 6-СЭ5-И1 2|benzoxazol-7-ylmethanesulfonylmethyl, 6-СЧ-И,2|benzoxazol- 7-ylmethanesulfonylmethyl, 3-Ce3-P1,2|benzoxazol-7-ylmethanesulfonylmethyl, 5-E-(11,2|benzoxazol-3-ylmethanesulfonylmethyl, (2,3|benzoxazol-7-ylmethanesulfonylmethyl, 6-Ceez-(2 ,3|benzoxazol-7-ylmethanesulfonylmethyl, 1-Сге3-(2,3|benzoxazol-7-ylmethanesulfonyl methyl, /5-СЕз5-(2,3|benzoxazol-4-ylmethanesulfonylmethyl, /-5-СМ-( 2,3|benzoxazol-4-ylmethanesulfonylmethyl, 1-Sez3-(2,3|benzoxazol-4-ylmethanesulfonylmethyl, benzothiazol-2-ylmethanesulfonylmethyl, 5-E-benzothiazol-2-ylme tansulfonylmethyl, benzothiazol-4-ylmethanesulfonylmethyl, 2-

CeE3-benzothiazol-4-ylmethanesulfonylmethyl, benzothiazol-7-ylmethanesulfonylmethyl, 2-CE3-benzothiazol-7-ylmethanesulfonylmethyl, I1,2Ibenzothiazol-3-ylmethanesulfonylmethyl, I1,2Ibenzothiazol-4-ylmethanesulfonylmethyl, 5-SiE5-11,2Ibenzothiazol-4- ylmethanesulfonylmethyl, 3-СЕ3-П1,2|benzothiazol-4-ylmethanesulfonylmethyl, 6-СЕ35-И1,2|benzothiazol-7-ylmethanesulfonylmethyl, 6-СМ-И1 2|benzothiazol-7-ylmethanesulfonylmethyl, 3-СЕ53-И1 ,2Ibenzothiazol-7-ylmethanesulfonylmethyl, 5-E-I1,2|benzothiazol-3-ylmethanesulfonylmethyl, (|2,3|benzothiazol-7-ylmethanesulfonyl methyl, 6-SEz-(2,3|benzothiazol-7-ylmethanesulfonylmethyl . (2,3|Benzothiazol-4-ylmethanesulfonylmethyl, 4-C3-2-CH3-thiazol-5-ylmethanesulfonylmethyl, 4-C3-thiazol-5-ylmethanesulfonylmethyl, 4-C3-2-phenyl-thiazol-5-ylmethanesulfonylmethyl, 5 -SEz-2-CHz-thiazol-4-ylmethanesulfonylmethyl, 5-SEz-thiazol-4-ylmethanesulfonylmethyl l, 5-CH3-2-phenyl-thiazol-4-ylmethanesulfonylmethyl, 5-CH3-thiazol-2-ylmethanesulfonylmethyl, 5-CH3-thiazol-2-ylmethanesulfonylmethyl 5-phenyl-thiazol-2-ylmethanesulfonylmethyl, 4-CH3-thiazole -2-ylmethanesulfonylmethyl, 4-C3-thiazol-2-ylmethanesulfonylmethyl, 4-phenyl-thiazol-2-ylmethanesulfonylmethyl, 5-CH3-2-(pyridin-2-yl)-(1,2,3)|)griazol- 4-ylmethanesulfonylmethyl, 5-SEz-2-(pyridin-2-yl)-11,2,3)|)griazol-4-ylmethanesulfonylmethyl, 5-SEz3-2-(4- methylsulfonylphenyl)-(1,2,3 |)triazol-4-ylmethanesulfonylmethyl, 4,5-dimethyl-1,2,4|griazol-3-ylmethanesulfonylmethyl, 5-SEz-4-CHz-(1,2,4|griazol-3Z-ylmethanesulfonylmethyl, 4 -CH3-5-phenyl-Y1,2,4|griazole-

3-ylmethanesulfonylmethyl, 5-SEz-4-cyclopropyl-(1,2,4|griazol-3-ylmethanesulfonylmethyl, 2,5-dimethyl-

I1,2,Al-triazole-3-ylmethanesulfonylmethyl, /5-SE3-2-CH3-(/1,2,4|)triazole-3-ylmethane-sulfonylmethyl, /--2-CH3-5-phenyl-(1, 2,4|griazol-3-ylmethanesulfonylmethyl, 2-cyclopropyl-5-phenyl-(1,2,4)griazol-3-ylmethanesulfonylmethyl, 5-СЕ3-1-СН3-(1,2,А|griazol-3- ylmethane-sulfonylmethyl, 1-CH3-5-phenyl-|І1,2,4|griazol-

3-ylmethanesulfonylmethyl, 5-CH3-1-phenyl-(1,2,4)triazol-3-ylmethanesulfonylmethyl, 3-CH3-(1,2,4|oxadiazol-5-ylmethanesulfonylmethyl) 3-СЕ5-(1,2, oxadiazol-5-ylmethanesulfonylmethyl, 3-phenyl-/1,2,oxadiazol-5-ylmethanesulfonylmethyl, 5-CH3-11,2,oxadiazol-3-ylmethanesulfonylmethyl, 5-Cie53-(1,2,4|oxadiazol- 3-ylmethanesulfonylmethyl, 5-phenyl-(1,2,4oxadiazol-3-ylmethanesulfonylmethyl, 2-CH3-(11,3 4|oxadiazol-5-ylmethanesulfonylmethyl, 2-СиЕ3-11,3 4|oxadiazol-5-ylmethane- sulfonylmethyl, 2-phenyl-/1,3,4|oxadiazol-5-ylmethanesulfonylmethyl, 3-CH3-11,2,A)hiadiazol-5-ylmethanesulfonylmethyl, 3-Cie5-(11,2,A|hiadiazol-5- ylmethanesulfonylmethyl, 3-phenyl-/(1,2,4Hiadiazol-5-ylmethanesulfonylmethyl, 5-CH3-(11,2,4|hiadiazol-3-ylmethanesulfonylmethyl, 5-СЕ5-(1,2,А)thiadiazole- 3-ylmethanesulfonylmethyl, 5-phenyl-(1,2,4|hiadiazol-3-ylmethanesulfonylmethyl, 2-CH3-I11,3,Ahiadiazol-5-ylmethanesulfonylmethyl, 2-CEE3-11,3,Ahiadiazol-5-ylmethanesulfonylmethyl, 2 -phenyl-/1,3,4|hiadiazol-5-ylmethanesulfonylmethyl, 2,2-difluoropyrrolidinyl ethanesulfonylmethyl, 3,3-difluoropyrrolidinyl-methanesulfonylmethyl, 3-SEz-M-CHz-pyrrol-2-ylmethanesulfonylmethyl, 3-CM-M-CHz-pyrrole-2-ylmethanesulfonylmethyl, 4-Sz-M-CHz-pyrrole-2- ylmethanesulfonylmethyl, 4-(1-CH3-1-hydroxyethyl)-M-CH3-pyrrol-2-ylmethanesulfonylmethyl, 1,3-dimethylpyrrol-2-ylmethanesulfonylmethyl, 4-CH3-M-CH3-pyrrol-3-ylmethanesulfonylmethyl, 4- CM-M-CH3-pyrrole-3-ylmethanesulfonylmethyl, 4-CM-M-(3,3,3-trifluoropropyl)-pyrrole-3-ylmethanesulfonylmethyl, 2-SE3-M-CH3-pyrrole-3-ylmethanesulfonylmethyl, 2- Cgz-M-phenyl-pyrrole-3-ylmethanesulfonylmethyl, 4-Cgz-pyrrole-2-ylmethanesulfonylmethyl, 4-(1-CH3-1-hydroxyethyl)-pyrrole-2-ylmethanesulfonylmethyl, 3-CH3-pyrrole-2-ylmethanesulfonylmethyl, 4-SEz-pyrrole-3-ylmethanesulfonylmethyl, 2-SEz-pyrrole-3-ylmethanesulfonylmethyl, 3-

C3-pyrrole-2-ylmethanesulfonylmethyl, 2-C3-pyrrol-4-ylmethanesulfonylmethyl, /2-C3-M-CH3-pyrrole-4-ylmethanesulfonylmethyl, 3-C3-fur-2-ylmethanesulfonylmethyl, 3-CM-fur -2-ylmethanesulfonylmethyl, 3-SEz-fur-4-ylmethanesulfonylmethyl, 3-CM-fur-ylmethanesulfonylmethyl, 3-SEz-thiazol-2-ylmethanesulfonylmethyl, 3-CM-thiazol-2-ylmethanesulfonylmethyl, 3-SEz-thiazol-4-ylmethanesulfonylmethyl -ylmethanesulfonylmethyl, 3-CM-thiazol-4-ylmethanesulfonylmethyl, 2-SEz-thiazol-3-ylmethanesulfonylmethyl, M-CHz-3-SEz3-1H-pyrazol-5-ylmethanesulfonylmethyl, M-CHz-3-(1-CHz- 1-hydroxyethyl)-1H-pyrazol-5-ylmethanesulfonylmethyl, M-CH3-3-phenyl-1H-pyrazol-5-ylmethanesulfonylmethyl, /- M-CH3-3-CE3-1H-pyrazol-4-ylmethanesulfonylmethyl, /- M -CH3-3-C1M-1H-pyrazol-3-ylmethanesulfonylmethyl, M-phenyl-4-CM-1H-pyrazole-3-ylmethanesulfonylmethyl, M-phenyl-5-C3-1n-pyrazol-4-ylmethanesulfonylmethyl, (M -CH3-4-CH3-1H-imidazol-2-ylmethane)sulfonylmethyl, (M-CH3-4-(1-CH3-1-hydroxyethyl)-1H-imidazol-2-ylmethane|-sulfonylmethyl, (M-CH3- 4-phenyl-1H-imidazol-2-ylmethane)-sulfonylmethyl,

M-CH3-3-CE3-1H-pyrazol-4-ylmethanesulfonylmethyl, (M-CH3-2-CE3-1H-imidazol-5-ylmethane)-sulfonylmethyl, (M-

CH3-2-phenyl-1H-imidazol-5-ylmethane)-sulfonylmethyl, / (M-CH3-5-CE3-1H-imidazol-4-ylmethane)-sulfonylmethyl, (M-phenyl-5-CE3-1H-imidazole -4-ylmethane)-sulfonylmethyl, 4-SIM-(1,2|oxazol-5-ylmethanesulfonylmethyl. 4-CM-3-phenyl-(1,2|oxazol-5-ylmethanesulfonylmethyl, /--4-SM-I1 ,2|oxazol-3-ylmethanesulfonylmethyl, 4-CM-5-phenyl-

P,2|oxazol-3-ylmethanesulfonylmethyl, 4-CM-isothiazol-5-ylmethanesulfonylmethyl, 4-CM-3-phenyl-isothiazol-5-ylmethanesulfonylmethyl, 4-CM-isothiazol-3-ylmethanesulfonylmethyl, 4-CM-5- phenyl-isothiazol-3Z-ylmethanesulfonylmethyl, 4-СЕ3-ИП1 2|oxazol-5-ylmethanesulfonylmethyl, 4-Sez-3-СН3-1/1,2|oxazol-5-ylmethanesulfonylmethyl, 4-Sz-3-phenyl -I(1,2|oxazol-5-ylmethanesulfonylmethyl, 4-СЕ8-И1 2|oxazol-3-ylmethanesulfonylmethyl, /4-СЕ3-5-СН3-(/1,2|oxazol-3-ylmethanesulfonylmethyl and /4- СЕ3-5-phenyl-(1 2|oxazol-3-ylmethanesulfonylmethyl. 3-СЕ53-И1,2|oxazol-4-ylmethane-sulfonylmethyl, 5-СЕ3-П1,2|oxazol-4-ylmethanesulfonylmethyl, 4-СЕ5- I1,2|oxazol-5-ylmethanesulfonylmethyl, 4-Sez-3-CH3 -І1,2|oxazol-3-ylmethanesulfonylmethyl, 4-СЕ3з-5-СН3-(/1,2|oxazol-3-ylmethanesulfonylmethyl, 4-СЕ3-5-phenyl-/1,2|oxazol-3-ylmethanesulfonylpiethyl, 3-Се53-І1,2|oxazol-4-ylmethanesulfonylmethyl, 5-Сез5-(11,2|oxazol-4-ylmethanesulfonylmethyl) tyl, 4-CH3-P,2|oxazol-5-ylmethanesulfonylmethyl, 4-CH3-3-phenyl-/1,2|oxazol-5-ylmethanesulfonylmethyl, 4-CH3-(P1,2|oxazol-3-ylmethanesulfonylmethyl, 4-CH3-5-phenyl-/1,2|oxazol-3-ylmethanesulfonylmethyl, 3-CH3-P,2|oxazol-4-ylmethanesulfonylmethyl, 5-CH3-P,2|oxazol-4-ylmethanesulfonylmethyl, 4-CH3 -isothiazol-5-ylmethanesulfonylmethyl, 4-CHz-3-phenyl-isothiazol-5-ylmethanesulfonylmethyl, 4-CHz-isothiazol-3-ylmethanesulfonylmethyl, 4-CHz-5-phenyl-isothiazol-3-ylmethanesulfonylmethyl, 3-CHz -isothiazol-4-ylmethanesulfonylmethyl, 5-CH3-isothiazol-4-ylmethanesulfonylmethyl, 4-СЕ3-2-СН3-/,3|oxazol-b5-ylmethanesulfonylmethyl, 4-СЕ3-1/1,3|oxazol-5-ylmethanesulfonylmethyl , 4-SEz-2-

phenyl-(1,3|oxazol-5-ylmethanesulfonylmethyl, / 5-СЕз-2-СНз-(/1,3|oxazol-4-yl-methanesulfonylmethyl, /-5-СЕз-

I,Z|oxazol-4-ylmethanesulfonylmethyl, 5-SEz-2-phenyl-/1,3|oxazol-4-ylmethanesulfonylmethyl, 5-CHz-

I,Z|oxazol-2-ylmethanesulfonylmethyl, 5-SEz-I,Z|oxazol-2-ylmethanesulfonylmethyl, 5-phenyl-/1,Z|oxazol-2-ylmethanesulfonylmethyl, 4-CHz-(/1,3|oxazole -2-ylmethanesulfonylmethyl, 4-SEz-M1,3|oxazol-2-ylmethanesulfonylmethyl, 4-phenyl-(1,3|oxazol-2-ylmethanesulfonylmethyl, M-methyl-indol-2-ylmethanesulfonylmethyl, 3-SEz-indol- 2-ylmethanesulfonylmethyl, 3-SEz-M-methyl-indol-2-ylmethanesulfonylmethyl, 5-fluoro-M-methyl-indol-Z3-ylmethanesulfonylmethyl, M-methyl-indol-3-ylmethanesulfonylmethyl, 2-SEz-indole-Z3- ylmethanesulfonylmethyl, 2-SEz-M-methyl-indol-3-ylmethanesulfonylmethyl, 5-fluoro-M-methyl-indol-3-ylmethanesulfonylmethyl, 5-SEz-M-methyl-indol-4-ylmethanesulfonylmethyl, 5-СМ-М- methyl-indol-4-ylmethanesulfonylmethyl, 2-SEz-M-methyl-indol-4-ylmethanesulfonylmethyl, 3-SEz-M-methyl-indol-4-ylmethanesulfonylmethyl, 6-SEz-M-methyl-indol-7-ylmethanesulfonylmethyl, 6-CM-M-methyl-indol-7-ylmethanesulfonylmethyl, 2-SEz-M-methyl-indol-7-ylmethanesulfonylmethyl, 3-Sg-M-methyl-indol-7-ylmethanesulfonylmethyl, benzofuran-2-ylmethanesulfonylmethyl yl, 3-SEz-benzofuran-2-ylmethanesulfonylmethyl, 3-SM-benzofuran-2-ylmethanesulfonylmethyl, 5-E-benzofuran-2-ylmethanesulfonylmethyl, benzofuran-3-ylmethanesulfonylmethyl, 2-SEz-benzofuran-3-ylmethanesulfonylmethyl, 2- CH3-benzofuran-3-ylmethanesulfonylmethyl 5-E-benzofuran-3-ylmethanesulfonylmethyl, 5-SEz-benzofuran-4-ylmethanesulfonylmethyl, 5-СМ-benzofuran-4-ylmethanesulfonylmethyl, 2-SEz-benzofuran-4-ylmethanesulfonylmethyl, 3-SEz -benzofuran-4-ylmethanesulfonylmethyl, 6-SEz-benzofuran-7-ylmethanesulfonylmethyl, 6-SM-benzofuran-7-ylmethanesulfonylmethyl, 2-SEz-benzofuran-7-ylmethanesulfonylmethyl, 3-SEz-benzofuran-7-ylmethanesulfonylmethyl, benzothien-2 -ylmethanesulfonylmethyl, (3-SE3-benzothien-2-ylmethane)-sulfonylmethyl, (3-CM-benzothien-2-ylmethane)-sulfonylmethyl, (5-E-benzothien-2-ylmethane)-sulfonylmethyl, benzothien-3-ylmethanesulfonylmethyl , (2-CH3-benzothien-3-ylmethane)-sulfonylmethyl, (2-CH3-benzothien-3-ylmethane)-sulfonylmethyl, (5-fluoro-benzothien-3-ylmethane)-sulfonylmethyl, (5-CH3-benzothien-3-ylmethane)- 4-ylmethane)-sulfonylmeth yl, (5-SEz-benzothien-4-ylmethane)-sulfonylmethyl, (2-SEz-benzothien-4-ylmethane)-sulfonylmethyl, (3-SEz-benzothien-4-ylmethane)-sulfonylmethyl, (6-SEz-benzothien -7-ylmethane)-sulfonylmethyl, (6-CM-benzothien-7-ylmethane)-sulfonylmethyl, (2-SEz-benzothien-7-ylmethane)-sulfonylmethyl, (3-SEz-benzothien-7-ylmethane)-sulfonylmethyl,

M-methyl-benzimidazol-2-ylmethanesulfonylmethyl, (5-fluoro-M-methyl-benzimidazol-2-ylmethane)-sulfonylmethyl, (M-methyl-indazol-3-ylmethane)-sulfonylmethyl, (5-fluoro-M-methyl -indazol-3-ylmethane)-sulfonylmethyl, (2-SEz-M-methyl-benzimidazol-7-ylmethane)-sulfonylmethyl, /(M-methyl-indazol-4-ylmethane)-sulfonylmethyl, / (5-SEz-M - methyl-indazol-4-ylmethane)-sulfonylmethyl, (3-SEz-M-methyl-indazol-4-ylmethane)-sulfonylmethyl, (6-SEz-M-methyl-indazol-7-ylmethane)-sulfonylmethyl, (6 -CM-M-methyl-indazol-7-ylmethane)-sulfonylmethyl or (3-SEz-M-methyl-indazol-7-ylmethane)-sulfonylmethyl.

In the groups defined above, the stereochemistry on the carbon to which B" is attached is (B), and to which B" and HE are attached is (5).

In the groups defined above, the stereochemistry of the carbon to which B is attached? and Ve, is (B), and to which VU is attached, is (5). (B) Another preferred group of compounds according to formula (I) is one where:

BZ is alkyl, preferably methyl or ethyl, and B" is alkyl, preferably methyl, ethyl, propyl or butyl, and even better if

B" is methyl. In the best version, BZ and B? are methyl. (C) Another best group of compounds according to formula (I) is one where BZ and B" together with the carbon atom to which they are attached form a cycloalkylene, better -cyclopropylene, cyclopentylene or cyclohexylene, and even better - cyclopropylene. (0) Another better group of compounds according to the formula (I) is one where B3 and B" together with the carbon atom to which they are attached form piperidin-4-yl substituted on the nitrogen atom by ethyl, 2,2,2 -trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl or 1,1-dioxotetrahydrothiopyran-4-yl (E) Another preferred group of compounds of formula (I) is that wherein Ve is haloalkyl, preferably variant is difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, and B" and BZ are aqueous. (P) Another preferred group of compounds according to formula (I) is one where B is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, B" is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, and BZ is hydrogen.(c) Another preferred group of compounds of formula (I) is one wherein B? is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, B" is alkyl, preferably methyl, ethyl or propyl, and BZ is hydrogen . (NU) Another better group of compounds according to formula (I) is the one where B? is haloalkyl, preferably 1,1,2,2,2-pentafluoroethyl or 1,1,2,2,3,3,3-heptafluoropropyl, and B" and B3 are hydrogen.

Among the preferred groups (8)-(H), the more preferred groups of compounds are those where B', B2, B", Be, B" and B? are as defined above for group (A).

Among the best groups (0)-(H), the best groups of compounds are those where B, B, VU, B? and B? are as defined above for group (A).

It should be noted that, unless otherwise specified, the above preferred embodiments of the present invention also include all combinations of special and preferred groups.

Below in Table. And the stereochemical characteristics and values of the components in different versions of the typical compound according to the formula (I) are given, in which B! is hydrogen, and B? is trifluoromethyl. vro i AI Le

Hour and two

Spo | Schereochemistry on e ke et r z V -e ipuka u i

ME oon A nn shi p M MNN 41655) 00 cycloproptl|.D V lepropit sh cykpopropynmethanesulfonipmethyl 1 HO) FfEpheni.

RU 5 cdiclopropyl. nn p-propyl pyridine-Zipmethanesulfonylmethyl. |. - M a-Ephenil

With | TEKU NO propyl What 3 cyclopropipmethanesulfonipmethyl 417 BA 0 cyclopropion Y cyclopropylene | cyclopropylmethanesulfonylmethyl | "Fefenius

SB cyclopropyl) CH Koch shk cyclopropylmethanesulfonipmethyl | BUT | AEphenyl

With HOW to drink I am the type. 01121 cyclopropovmethanesulfonipmethyl | СН 7 ША cyclopropion cyclopralylene | lyridin-z-ipmethanesulchonemethy n 4-Ephenyl sulfonipmethyl and 81885) 0 cyclokyl! NOI network 000000 | cyclopropylmethanesulfovmethyl | BUT 1 I Ephenil then FOR I obenvmy 1 THESE lights 01000000 cyclopropipmethanesulfoniamethy BUT 1 I Ephenium

SHO BM 000obenvydo | CH SN 1700001 | pyridineZsukoethanesulfoniomethyl | NOI I phenyl Z

And 2 b. | pyridine-Zipmethanesulfonylmethet GO ONO 1 I-Epheniy 1:13 Kola benzyl sv! Sn | Cyclopropylmethanesulfonylmethyl |B 4-Efenip also B, gasoline (СНУ СН. D.. Myclopropylmethanesulfonylmethyl HO 1 4 Ephenyl

OBOV) 1obenzyl CH 00 p cyclopropylmethanesulfonlmethyl NO I Efengyo 16 | FA) 3ocyclopropyl. NOI leto 00000000) lyridinose -ylmethanesulfonylmethyl 0 0) "Ephenyl o g (5 cyclopropy! I ety pyridin-2-ylmethanesulfonylmethyl OH ZA ! | sho SHO dehyen. 8 et scycloprotea | SNI Osn s OK pyridino ylmetant 000321 orphenia,

Y SHY ilfonylmethyl sypshtnY 19 5 cyclopropyl 1 2-pyridin-2-ylethanesulfonylmethia | MH - Ephenyl

IE) VEK ON V Efeniya,

І 2 СВК) "cycloprogyl o Mdiclopropyl ospiridine-o-ylethanesulfonylmethyl HO ERphenium 22. OB K) cycloprogyl cycloprotyl SE pyridine-Z ipmethane-HO (e-Ephenyl y sulfonipmethyl 3 SE) cyclopropip! CH" Сn; pyridine-Z /ipmethanesuphefonylmethyg

Ts F

24 he B) cykpopropium! ST SN. pyidin-Z-ipmethanesulfonizmethyl A 1

And digphenia.

Sk) cyclopropyl, cyclopropion, pyridine-Z-1lmethanesupephonipmethyl, and 4 МШШ, НШ, digphenite, and 25 СА) cyclopropyl, cyclopropite. pyridine-Z lipmethanesulfonylmethyl HO

What What I dikfenigi 7 Seya cyclopropion cyclopropyl t-oxopyridine-3-ipmetan- t! hair dryer

VI and KI MI no 000 vulfonylmethyl Y diphenyl 28 CA) cyclopropyl cyclopropyl 1-oxopyridine-Z-ipmethane- lfonylmethyl diEphenip plini icloloronya, sulfonipmethyl ee) (AB |cyclopropyl! NOI yezhya 00/77 2-42 Z-diokooindel te 7 sho ethanesulfomylmethyl It is for cloprodium | SNU Sy. hapanopheniummethanesulfonipmetiya | and on

YOU) | cyclopropl CH 1ООН 001101 ОН phenylmethaneulfocylmethyl Mo aofeniio

And ethyleupfonilmethyg and And then cycloprovy OH vtyl phenipsulfovipmethyl no Aechrenii --- PE "Cyclopropyl. | СН» СВ С З-СНи5Ochrenylmethanesulfoniummethyl 1003 I Kfeni

Kk (5 "pyyklloprogyl. nn ethyl 2-cyclopropipmethanesulfonylethyl | NO A-E-Phenyl av BA) | cyfuprota SNI | SN 77111701 OSNO phenylmethanesulfonymethyt | VO I Ephenia 7361 5AB 01 cyclopropy NO yclobutyimethy! cyclopropylmethanesulfonymethyt. 10600 asefenia

About Niklopron | by tsinlopropishchen | Z-cyanophenylmethanesulfonimety» 00800 SEFenia 1 and SITA cyclopropium Her CA CH 2-cyanophenip methanesulfonizmethyl No AtFphenia n ethyl | 4-4 fluorobenzotriol)-piperavinyl-o-Nouteene

And ipselphonismety Ya

SM ach4fluorobenzoyl)-piperazine-y- H a Ephenylylsulfonylethyl ethyl 2-chlorobenzyl N av 1 SIM) | cyclopropyl Hv ethyl htrifluoromethipsulfonylmethyl HO b fent

Со47 000 BV) Iciyuprony NO 0etmya 00000000 |Zsmetipsulfonylbenzylsulfonipmetip! BUT Efenilo is Zevareot from the dog

SVO | Sen) (cyclopropv HO / etmy | saprifluorophenipsulfenylmetit 10800 and Efenil 50. aura) zuiklopropyl! H ethyl I a-methyloupephonipphenylsulfonylmethyl CH 4-Ephenium

Ov B BY5) | cyclopropyl! BUT ethyl 01 adiclohexylethyl CHO fefenium 53 By cdicloproput! vyl benzyloxymethyl n 4-Ephenium 54. iclopropium naftd-ipsulfonylmethy INOZ Azhphenium 5 1 8 5ÿTYA) oxykpopropyl| N s ethide I Tretbutypmethyl NO SHE Ffeniyai

B Not clopropyl| Not typical! pyrid-Z hyleulsvonylkety n a-Ephenium

N. rear

SWYTI) icyclopropyl| BUT | vtyl sh phenylylsulfonymethyt m No Ifenipy in 0 SBevANB) ocycloproly| НО100еМмп 01 Naft-i-ipsulfonimitil 31 EfEN. 76101 5 By) tsikpopropium! HO 1000 el SP oZbdimethylientiai 00000080 Efenii

BE SY" 5) cyclopropip! N etypd cyclopropylethylsulfeonipmethyl nn tetrahydro- 4 pet mice p shkliranoyl 63 1 SL cloprovy| etl Z.a-trifluoromethylphenylsulfonylmethyl | MH a-Ephenyl 64 BILIN) | cyclopropyl ethyl her pyrid-i-ipsulfonylmethy OH I Ephenyl o 85 1 SI) fcyclopropyl | H tyl | 2,2:diphther-Z-vaniprogyl ! H A-Ephenyl

88 And icloprolil! НН тыл З-methoxyphenipsulfonylmethyl 0 HO phen

About 0 Сl) icyclopropie! BUT floor 0 03300100 40 methoxyphenipsulfonylmethyl 00 OFEpheny 70 1 OBLEONV). tet o util shi --N. Acefeniya 71 GBSVOSVI ukilopropya n ethyl isoquinoline-4alsulsonivmethy MO zhefennyi 72 Kona ikpopropyl! H ethyl BN phenipsulfonylmethyl HO (a-ephbeny 278 1 С5СВЛЮБ) and cyclopropya. NOI em 01000101... Zobumi 00000010 diHphenium 75 1 (SB) |cyclopropyl|./ НН ethyl benzyl HO (4-Ephenyl. - piraneanya, ov o 1 SB) Icyclopropyl| In VUL What 0 2-methanesulfonylethyl No 4Ephenium 78 SB BYNV ocyklovrolni NOGO 0etmlo 00003000 IKLOpropylmethy 2.002581 Ephenium in tya cykpopropyn. nn ethyl cycloprolipmetiya n Itetranhydro-

Sh Shh sp

SvBeBieV) ICyclopropya) M VIK 00 opo o DY fluoromethyllentyl 01 I Cphenyl, 82 С5 BY B) INiclopropyl! And ethyld phenylulfoylamino methyl is. Ia Ephenium va 00 sSByVIii cyclopropyl ethyl and isopropipsulfonipamichomethyl HO ARFhenium vezi y, methylsulfonipaminomethylo HO 14-Ephenium cyclopropion! НН 2-(4-trifluoromethyp» ION a-Ephenium nin IOANA YN phenylsulfonigetyl

Вб 1 condominium, ocyclopropyl! HO 0000. |24xtrifluoromethylphenylsulfani)ethyl| BUT I am Efenil. Iclopropyl --koke sepon n oMETYLsulfinylethylo020yu 302023... 0 Efeniv av 1 SBvnno) | cykpepropyl SN el. Sspiridobidsulfonylethyl 030000 Befenl according to EB 5) cyclopropyl ethyl Y and Z-Phenippropyshy methylsulfonipphenipsulfoncetyl

PNYA soi'kyi PL PIY NNYA Bil pini NI bin i ipmethyli 88 1 SIM, icycloproply YAN Ho ethyl pysi g-chlorobenzii i reni 93 Ceto ou cyclopropiy nn ethyl i difluoro-»-fPhenyletiy No ytetrihydro-

Yshi virvn-Ya-l 94 1 555) | cyclopropyl NN ethyl A-methyloulfonylpiperidin-ya-ip methyl HO k-Pphenyl 6 "58, 5). icyclopropyl| ethyl p 1-methylcyclorekylmethyl no ephenium 98 SV) | cyclopropyl In ethyl 1-methylcyclopentylmyethyl Но tetrahydrogenation on pre ions

Below in Table. II presents the stereochemical characteristics and values of the components in various variants of a typical compound according to the formula (I), in which B", B" and B: are hydrogen. t NAH de

M -k nN oto raw I re m shsh

Mo sho: i o 1 NOI etd niridin-3-ylmethanesulfonimethine o 151,2,5,2-pentafluoroethia 2 min) NO ovtiv cyclopropynemethanesulfovip-methy | 01,1.2.,2,2-pentafluoroethium

With C) dcyclopropyl) No uUethyl -5ZeyK6. tridin-z-pmethanesulfonip-methyl | 0 trifluoromethyl..// -y B) I schikpopropyl BNO) thiorolyl cyclopropylmethanesulfonylmethych | 1.5.2, e-pentafluoroethyl,

From the ravine to cyclopropyl! NOI p-prolyl pyridin-3-ylpmethanesulfonylmethylm 1,1,252,2-pentafluoroethyl 781 (8BYUB) oicyclopronin| NOI etmpo | 3001 cyclopropipmethanesulfonyl-methium | 1,1.2.2-tetrafluoroethylene - КИ О8). about Icloprova NOI etilo | 03000000 pyridinosiamethanesulfonyl methyl 01.12 2 tetrafluoroethyl 8 (tiv) cyclopropyl| НН ethyl cyclopropylmethanesulfonymethyl 2 2,3,33- on PO Pn syny M pet rent deren nia Den pf. 7 KI) cycloprovia| etype Pyridine-Z lmethanesulfonyl-methyl Tl 3- sh sh NE shshch sho heptafluoroaropium 8 ANYA cpopropidi A SEbzliridim "Z ipmethane-sulfonipmethyli 1,1,2,2.2-pentafluoroethyl 800 (vin H sh nshni "2cyclopropylmethanesulfronyl-ethyl | 31.2,2- 2-pentafluoroethyl cyt Ethia -sh- 2-(pyridin-Z-ylmethanesulfonipnethyl. | Z olentafluoroethy 1 ery nicloprolyl NN 2-icyclopropylethanesulsonit-ethyl trifluoromethyl 13 movement in ikpopropyl. nn til ! ikpopropylmethanesulsonipmethyl SEN» 5208. 4 (VIM pyridine-Z -ylmethanesulfonylmethyl and) Icyclopropyl NN 1 ethyl ! "lyperidine-y-ylsulfoniummethyp trifluoromethy nowris lvoto Mokhtin -sh- cyclopropylmethanesulfenylmethy overfluoropentyl 00371 ETK icyclopropyl!y// MH ethyl 4 cyclopropylmethanesulfonylmethyh 11,1.2,2,3,3-gasafluoropropium 18 cry 2-methylsulfonylenzilsulfonizmethyl trifluoromethyl in K.V) and cyclopropion|SNU|

STY 5) I dikpopropyl nev I cykpopropipmethanesulfonipmethyl I perfluoropropyl -methyl bark Ov) cyclopropyl n atyp pyid-2-ylmethanesulfonipmethyl - TA SHI i i octafluorobutyl 2 svi SHI I pyrid-2-pimethanesuphefoanilmethy 1.1. 2,2,3 3-hexafluorobutyl cyclopropion NN | ethyl | pyride-z-ylmethanesupphonipmetium | 1.1,2,2.3.Z-hexafluorobutyl

The table below shows the stereochemical characteristics and values of the components of some compounds according to the present invention.

From all sides

And two

M on the 1st SB, cycloprogil | and cyclopropylene! 4-CE 5 pyridine-Z-ylmethane-sulfonylmethyl s-Ephenyl ny pkyvonia BAGUET AND SHEEN pyridine-Z-ipmethane-sulfonylmethyl

Tebe "pyklopranya NT BN; PT YASE utiridinoz iimethane-sulfonylpetium 000 12 -diphenium in amy smeloprony SN. Tebe pyridine-zapmethanesulfonylmethium 0100 BUT see phenyl p S TI "cyclopropyl | And | cyclopropylene 4-STa-pyridine-3-ipmethane-sulfonylmethyl | HO biedifenium in CA 1 cyclopropion 0000 nicloprogylene pyridine-Z-iliethanesulfoniamethyl HO 25A-diphenyl

General synthesis scheme

Compounds of the present invention may be prepared by the processes illustrated in the synthesis schemes below.

The starting materials and reagents required for the production of these compounds can be obtained from industrial suppliers, for example, AiYdgpsp Spetis! Co., (Milwaukee, WI), Waspet (Torrance, CA), Bidta (St. Louis, MO), or prepared by processes well known to those skilled in the art and described, for example, in such publications (Riezeg apa Riezeg5 Neagentv og

Ogdapis Zupipezivs, Moishtev 1-17 (Chopp U/ieu apa bopv, 1991); Nodaz Spetivigu oi Saprop Sotroshpaz, Moiitev 1-5 apa B,uirrieeteepiai! (EIbhemieg bsiepse Rybiiepege, 1989); or Ogdapis Neasiyop5, Moishtev 1-40 (opp Umieu apa

Zopv, 1991), Magsp'z Admapsea Ogdapis Spetivigu, (donp Umieu apa bopv, 4" Edikop) apa I agoskye Sotrgepepvime

Ogdapis Tgapegopptaiope (MSN Rybiizpegv Ips., 1989). The schemes provided herein are merely illustrative of some of the processes by which the compounds of the present invention may be synthesized, and are not intended to exclude various modifications which may be made by those skilled in the art with reference to this disclosure.

Primary materials and reaction intermediates can, if necessary, be separated and purified by conventional technical means, including, for example, filtration, distillation, crystallization, chromatography, etc. Common physical constants, spectral data, etc. can be used to characterize these materials.

Unless otherwise noted, the reactions described here are carried out under atmospheric pressure at temperatures ranging from approximately -787C to 150"C, in the best versions - from approximately 0"C to 125"C, and in the best - at approximately room temperature (or ambient) temperature, for example, 207C.

In the reactions described below, it may be necessary to protect chemically active functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, if these groups are essential in the final product, to prevent their participation in these reactions. For this purpose, conventional protective groups, well known to specialists in this field and described, for example, in the work (T. MU. Steepe apa R. skh. M. MU/tsiv ip "Rgoyesiime) can be used

Stotsrz ip Ogdapis Spetivigu" dopp U/Lieu apa bopv, 1999).

Compounds according to the formula (I), where B', B, VU, VU, B", Ve and VZ are as defined in the section on the essence of the invention, and

B" is hydrogen, can be produced according to Scheme 1 of the synthesis presented below.

Scheme 1 ve v vot bebi ' 2 Z 4 peru y Hu v y Duet ev - te v v Fo

The reaction of a ketone that has formula 1, where B? and B? are as defined in the Summary of the Invention section, with an α-amine ester according to formula 2, where A is a protecting group of a carboxyl residue, which is preferably an alkyl group, and more preferably methyl, and B? is as defined in the section The essence of the invention, under the conditions of the reductive amination reaction gives the compound according to formula 3. The reaction is carried out in the presence of a suitable dehydrating agent, for example Tissium, magnesium sulfate, isopropyltrifluoroacetate, in the presence of a base, for example diisopropylethylamine, pyridine, etc. . in a suitable organic solvent, which can be, for example, methylene chloride, and as a result, an imine is obtained. The imine intermediate is reduced using a suitable reducing agent, for example, sodium borohydride, sodium cyanoborohydride, etc. in a suitable organic solvent, which can be, for example, methanol, ethanol, etc.

Compounds of formula 1, such as 2,2,2-trifluoromethylacetophenone and 2,2,2,4-tetrafluoroacetophenone, are commercially available. Other reagents can be prepared by methods well known to those skilled in the art. a-Amino esters according to formula 2 can be obtained using the methods described, for example, in the publications of PCT patent applications (PCT Arriisayope Rybiisayop MeMeUUO 03075836, MO 00/55144, MO 01/19816, MO

О2/20485, MO 03/029200), previous US application (0.5. Rgomysiopa! Arriisaiop Me60/422,337), US patents (M. 5. Raiepi MeMob,353,01781, 6,492,66281, 6,353,017 VI, 6,525,03681, 6b ,229,01181, 6,610,700), the disclosures of which are incorporated herein by reference in their entirety.

By hydrolysis of the ester group in compound C, a compound according to formula 4 is obtained. The conditions of hydrolysis depend on the nature of the protective group. For example, when E is alkyl, hydrolysis is carried out under conditions of an alkaline aqueous solution and the corresponding acid according to formula 4 is obtained. This reaction is carried out, as a rule, with the help of cesium carbonate, lithium hydroxide, etc. in an aqueous solution of alcohol, for example, methanol, ethanol, etc.

After that, the reaction of compound 4 with α-hydroxyketoamide according to formula 5 is carried out, obtaining the compound according to formula 6. This reaction is carried out, as a rule, in the presence of a suitable binding agent, for example, benzotriazol-1-yloxytrispyrrolidinephosphonium-hexafluorophosphate (RUVORF), O-benzotriazolyl -М,М,М'М'- tetramethyluronium-hexafluorophosphate (NVTI), 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium-hexafluorophosphate (NATI), 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride (ES) or 1,3-dicyclohexyl-carbodiimide (OSS), if necessary in the presence of 1-hydroxy-benzotriazole (NOVT), and a base, for example, M,M-diisopropylethylamine, triethylamine, M- methylmorpholine, etc. This reaction is carried out, as a rule, at temperatures from 20 to 30 "C, better - at a temperature of about 25 "C, during the time from 2 to 24 hours, which is required for its completion. Suitable solvents for this reaction are inert organic materials, for example, halogenated organic solvents (methylene chloride, chloroform, etc.), acetonitrile,

M,M-dimethylformamide, ether solvents, for example, tetrahydrofuran, dioxane, etc.

Alternatively, the aforementioned coupling step can be carried out first by converting compound 4 to its active acid derivative, for example, a succinimide ester, and then reacting it with an a-hydroxyketoamide of formula 5. This reaction usually requires 2 to From hours The conditions for this reaction depend on the nature of the above-mentioned active acid derivative. For example, if it is a chloride acid derivative of compound 4, then the reaction is carried out in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, pyridine, etc.). Suitable solvents for this reaction are polar organic solvents, for example acetonitrile, M,M-dimethylformamide, dichloromethane or any suitable mixture of these materials. Compounds of formula 5 can be prepared by well-known methods and in particular, for example, by the processes described in the publication of the patent application (PCT arrisaiop ribiisaiop MeUUO 02/18369), the description of which is incorporated herein in its entirety by reference.

Oxidation of the hydroxyl group in compound 6 with a suitable oxidizing agent, for example OHOMEF, gives the compound of formula (I).

Alternatively, compounds of formula (I) wherein B", B, BZ, B", B", Be and BZ are as defined in the Summary of the Invention section and B' is hydrogen can be prepared by the process illustrated in Synthesis Scheme 2 below.

Schema2 he is 5 ok sn "she CHA. - v'eullote 7 8 9 710

Vbodo g - Abr - - ru 11 4

The reaction of the compound according to formula 8, where B? is as defined in the Summary section, and PO is a suitable protecting group for oxygen, with a hemiacetal of formula 7, where Be is as defined in the Summary section, gives an imine compound of formula 9. Reaction of 9 with an organolithium compound of by the VZ formula, where

VAZ is not hydrogen, giving compound 10. After removal of the protecting group for oxygen and subsequent oxidation of the formed alcohol 11, a compound of formula 4 is obtained, which is further converted to a compound of formula (I) as shown in Scheme 1 above. Suitable protecting groups for oxygen and the reaction conditions for their attachment and removal are described, for example, in the publication (Steepe, T.MU.; apa MUtsiv, R. sh. M.; Rgoiesiipd Stoyrz ip Ogdapis

Zupipeviv; duopp UMieu 8 bopv, Ips. 1999).

In an alternative version of the compound according to formula (I), where B", B, VU, B", B", B? and BZ are as defined in the Summary of the Invention section, and B" is hydrogen, can be prepared by the process illustrated in Synthesis Scheme C below.

Scheme From t to t to t to t st brackets. chu tyu tu sake 7 2 12 Z -- 8

The reaction of an amino acid compound according to formula 2, where B is alkyl, and B? is as defined in the section The essence of the invention, with hemiacetal according to formula 7 has the product 2-(1-hydroxy-2,2,2-trifluoroethylamino)acetate, which is described by formula 12. The reaction is carried out in the presence of a catalytic amount of acid, which can be , for example, p-toluenesulfonic acid, and an aromatic hydrocarbon solvent, for example, toluene, benzene, etc.

As a result of the interaction of product 12 with a compound of the formula BN, where BZ is aryl or heteroaryl, under the conditions of the Friedel-Crafts (Egede!-Stayve) reaction or with trialkylaluminum in toluene, a compound of the formula is obtained

C, which is further converted into a compound of formula (I) as described above.

In an alternative version of the compound according to formula (I), where B", B, VU, B", B", B? and BZ are as defined in the Summary of the Invention section, and B" is hydrogen, can be prepared by the process illustrated in Synthesis Scheme 4 below.

Scheme 4 ve ii sun: in . as oriyupvi ee he in rt tru yutu with 14 15 16 ve -e- і 5 o -- -ї (3 ogreoivogiyu () 17 Gu GI asbuayey asii dep. oriiopa!: optional og rgesigvog (o (I): or precursor of compound (I) asiimagea asia depm.: activated acid derivative

As a result of the reaction of the compound according to formula 13, where is HB? and BZ are as defined in the Summary of the Invention section, with a compound of formula 14, where B" is hydrogen or a protecting group for the carboxyl moiety, and B? is B5 or a precursor (eg, -alkylene-b-trityl, -alkylene- b-alkylene heteroaryl, etc.) for group B, obtain a compound according to formula 15. The reaction is carried out in a suitable organic solvent, which can be, for example, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, etc. or a mixture thereof, and if necessary with the presence of an organic or inorganic base. In a preferred embodiment, the organic base can be triethylamine, pyridine, M-methylmorpholine, collidine, diisopropylethylamine, etc. Even better, when the inorganic base is cesium carbonate, sodium carbonate , sodium bicarbonate, etc. The reaction is carried out if necessary in the presence of a drying agent, which can be used, for example, molecular sieves. In the best version, the reaction is carried out at room temperature.

Compounds of formula 13 can be prepared by well-known methods. For example, the compound according to formula 13, where BZ is phenyl or 4-fluorophenyl, and B? is trifluoromethyl, can be easily prepared from commercially available 2,2,2-trifluoroacetophenone or 2,2,2,4-tetrafluoroacetophenone, respectively, by reducing the keto group to the alcohol group with a suitable reducing agent, for example, sodium borohydride, lithium aluminum hydride, etc. The solvent used depends on the type of reducing agent selected. For example, in the case of using sodium borohydride, the reaction is carried out in an organic alcohol solvent, for example, methanol, ethanol, etc. When using lithium aluminum hydride, the reaction is carried out in an ether solvent, for example, tetrahydrofuran, etc. As a result of the reaction of 2,2,2-trifluoro-1-phenylethanol or 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol with triflinic anhydride or trifluoromethanesulfonyl chloride, the target compound is obtained. Compounds according to formula 13, where B" and B" are hydrogen, and Be is 1,1,2,2,2-pentafluoroethyl, can be obtained from industrially produced 2,2,3,3,3-pentafluoropropan-1-ol, respectively to that described above. Optically enriched compounds of formula 15 can be obtained by reduction of the corresponding halogenated acetophenone with a suitable reducing agent, for example catecholborane or the ВН3-ЮМ5 complex in the presence of a suitable catalyst, for example (5) or (A)-methyl-СВ5-oxazaborolidine catalyst or (5) or (H)-α,α-diphenyl-2-pyrrolidinemethanol in the presence of BVM, thereby obtaining a chiral alcohol and subsequent processing of this alcohol to compound 13 as described above. Compounds of formula 14 are commercially available, or they can be obtained using well-known methods.

After removing the protective group of the carboxyl part from the compound according to the formula 15, where EB: is a protective group, the compound according to the formula 16 is obtained. The conditions for the step of removing the protective group of the carboxyl part depend on the nature of the used protective group. For example, in the case when PE" is alkyl, the protective group is removed under the conditions of an alkaline hydrolysis reaction in an aqueous alkali solution, which can be, for example, an aqueous solution of lithium hydroxide, sodium hydroxide, etc., in an alcoholic solvent, for example, methanol , ethanol, etc. In addition, if the group B: in compound 14 is a precursor group to B", then it can be transformed into B? before or after the ester hydrolysis step.

After that, the compound 15 (where B" is hydrogen) or 16 is converted into an activated acid derivative 17 (where X is a leaving group) and after the reaction of the latter with aminoacetonitrile according to the formula 5, the compound according to the formula (I) is obtained, when B: is B ", or a precursor to compound (I) when B: is a precursor group to VU. It is also possible to first obtain an activated acid derivative and then react it with compound 5 in a sequential process, or it is possible to create an activated acid derivative from in the presence of compound 5.

For example, if the activated acid is a halide, then it is obtained first by reacting compound 16 with a halogenating agent, for example, thioinyl chloride, oxalyl chloride, etc., and then by reacting with compound 5. Alternatively, the activated acid derivative is created using reactions between compounds 16 and 5 in the presence of a suitable binding agent, for example benzotriazol-1-yloxytrispyrrolidinephosphonium hexafluorophosphate (RUVORF)), O-benzotriazol-1-yl-M,M,M',M'-tetramethyluronium hexafluorophosphate /(NVTI) . etc., if necessary in the presence of 1-hydroxybenzotriazole (NOVT) and a base, for example M,M-diisopropylethylamine, triethylamine, M-methylmorpholine, etc. Suitable solvents for this reaction are suitable inert organic materials, such as halogenated organic solvents (methylene chloride, chloroform, etc.), acetonitrile, M,M-dimethylformamide, ether solvents, such as tetrahydrofuran, dioxane, etc. In the case when B: is a precursor group to B", then it is converted into a group B", obtaining a compound of formula (I), for example, by converting -alkylene-5-alkylene-heteroaryl to -alkylene-5O5- alkyleneheteroaryl in the conditions of the oxidation reaction.

The compound of formula (I) can be converted into other compounds of formula (I). Some examples of this transformation are described below.

Compounds according to the formula (I), which contain a hydroxyl group, can be obtained by dealkylation/benzylation of an alkoxy/benzyloxy substituent, those containing an acid group - by hydrolysis of an ester group, and those containing a cyano group - by replacing the bromine atom in the corresponding compounds according to formula (I). A compound of formula (I) containing a cyano group can be converted into a corresponding compound containing a carboxyl group by hydrolysis of this cyano group. The carboxyl group, in turn, can be transformed into an ester group.

The compound of formula (I) can be prepared in the form of a pharmaceutically acceptable acid addition salt by reacting this compound in the form of a free base with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable addition base salt of a compound of formula (I) can be prepared by reacting this compound in free acid form with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the manufacture of pharmaceutically acceptable salts of compounds of formula (I) are specified in this description in the definition section. Alternatively, salt forms of compounds of formula (I) can be obtained from salts of primary materials or intermediates.

Free acid or free base forms of the compounds of formula (I) can be obtained from the corresponding addition salts of bases or addition salts of acids. For example, a compound of formula (I) in the form of an acid addition salt can be converted into a corresponding free base by treating it with a suitable base (for example, a solution of ammonium hydroxide, sodium hydroxide, etc.). A compound of formula (I) in the form of a base addition salt can be converted into the corresponding free acid by treating it with a suitable acid (for example, hydrochloric acid, etc.).

M-oxides of compounds according to formula (I) can be obtained using methods well known to specialists in this field. For example, M-oxides can be prepared by treating the unoxidized form of a compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, metachloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g., halogenated hydrocarbon and, in particular, dichloromethane) at a temperature of approximately 0"C. Alternatively, the M-oxides of the compounds of formula (I) can be obtained from the M-oxide of the corresponding primary material.

Compounds of formula (I) in unoxidized form can be obtained from M-oxides of compounds of formula (1) by treating them with a reducing agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc. .) in a suitable inert organic solvent (for example, acetonitrile, ethanol, aqueous solution of dioxane, etc.) at a temperature from 0 to 8070.

Prodrugs of compounds according to formula (I) can be obtained using methods well known to specialists in this field, more detailed information about which can be found in the work (Zatsipieg ei a/I. (1994), Viogdapis apa

Measipa! Spetivigu I etsegvs, Moi!.4, p. 1985). For example, suitable prodrugs can be prepared by reacting a non-derivatized compound of formula (I) with a suitable carbamylating agent (which can be used, for example, 1,1-acyloxyalkylcarbon chloride, paranitrophenyl carbonate, etc.).

Protected derivatives of compounds of formula (I) can be prepared using conventional methods well known to those skilled in the art. Detailed descriptions of suitable methods of creating protective groups and their removal can be found in the work (T.M. Sgeepe, Rgoiesiipd Stoyrz ip Ogdapis bBupipeviv, 3'Ya eyiop, Chopp Umieu 8 bopv, Ips. 1999).

The compounds of the present invention can be very advantageously manufactured or created during the process of the present invention in the form of solvates (eg, hydrates). The hydrates of the compounds according to the present invention can be profitably obtained by recrystallization from an aqueous-organic solvent mixture in which organic solvents, for example, dioxin, tetrahydrofuran or methanol, are used.

Compounds of formula (I) can be obtained in the form of their individual stereoisomers by reacting a racemic mixture of this compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and restoring the optically pure enantiomer. In addition to the fact that the resolution of enantiomers can be carried out with the help of covalent diastereomeric derivatives of compounds of formula (I), dissociable complexes (for example, crystalline diastereoisomeric salts) are preferred. Diastereomers have different physical properties (eg, melting points, boiling points, solubilities, chemical activities, etc.) and can be easily separated by these differences.

Diastereomers can be separated by chromatography or, preferably, by separation and resolution techniques based on the difference in their solubility. After separation, the optically pure enantiomer is reconstituted with the resolving agent by any suitable means, provided that it does not lead to racemization. A more detailed description of means and methods of separation of stereoisomers of compounds from their racemic mixtures can be found in the work (Uuvap Chasdiez Apage SoPei, Zatie! N. UMiep, Epapioteg"zv,

Vasetaiyez apa Nezoiishiopv, dopp UMieu 5 Bopv, Ips. (1981)).

Preparation of biological agents

In the practical application of this invention, certain processes are used to create or purify biological agents. Methods of manufacturing such biological agents are well known to those skilled in the art and are discussed in general terms below.

Monoclonal antibodies can be obtained using well-known standard methods, and in particular, for example, using the Kohler-Milstein method (Kopieg apa Miywieip, Maite 1975, 256: 495) or its modification, for example, described in the work (ViskK eyii a). 1982, Ip Migo 18: 377). According to this method, usually a mouse or rat is immunized with a derivative of MepB RB conjugated with a protein carrier, re-immunized, the spleen (and, if necessary, several large lymph nodes) are removed, which is separated into individual cells.

If necessary, spleen cells can be screened (after removal of non-specifically attached cells) by plating the cell suspension on an antigen-coated plate or well. At the same time, B-cells expressing membrane-bound immunoglobulin specific to this antigen bind to the tablet and are not washed away from it by the rest of the suspension. After that, treated B-cells or all cells of the dissociated spleen are forced to fuse with myeloma cells to form a hybrid.

Typical murine myeloma lines suitable for such hybridization can be obtained from the American Type Culture Collection (ATOS: Ategisap Toure Sisshgte SoiPPEsiyop).

Chimeric antibodies, consisting of human and non-human amino acid sequences, to reduce their immunogenicity in humans, can be formed from mouse monoclonal antibody molecules (M/ipieg eyi a. Maishge 1991 349: 293; I oridio eyi a!. Rgos. Mai Asai. 5si. OA 1989 86: 4220; Zpamu vii a). in.

And so on. 1987 138: 4534; Vgomp ei ai. Sapseg Nev5. 1987 47: 3577; Wiesptapp ei a). Mate 1988 332: 323;

Mepoeuep ei a). Zsiepse 1988 239: 1534; udChopez her ai. Mayte 1986 321: 522; ER Rybiysayop Mo. 519, 596, published on December 23, 1992; England Patent Publication 28 2,276,169, published September 21, 1994).

Fragments of antibody molecules, for example molecules K(abr)2, EM and 5Em, capable of demonstrating the properties of immunological binding of the molecule of the parent monoclonal antibody, can be produced using known methods (Ipragyei AI. Rgos. Mai. Asad. 5si. OBA 1972 69 :2659; Nosptap ei ai. Viosnet. 1976 15:2706; Enpisp ei ai. Viospet. 1980 19:4091; Nizyup ei ai. Rgos. Mai. Asad. si. OBA 1988 85(16): 5879; 0.5. Rai.

MoMe5,091,513 and 5,132,405 and 0.5. Paradise Mo4,946,778).

Alternatively, a phage display system can be used to expand populations of monoclonal antibody molecules (Zaiki, et al. Mashge 1986 324: 163; 5spaii et al.). Zsiepse 1986 233:1076; 0.5. Paradise MoMo4,683,195 and 4,683,202; Hapod ei ai. 9. My Vioi. 1995 254: 392; Vagbav, I ei a). Meijoazv:

Satr. My Epgutoi!. 1995 8: 94; Vagbav, II! her a. Rgos. May). Asad si. BOTH 1991 88: 7978).

The coding sequences for the heavy chain and light chain portions of EPar molecules selected from a phage display library can be isolated or synthesized and cloned into any suitable vector or replicon for expression. Any suitable expression system may be used, including, for example, bacterial, yeast, insect, and amphibian and mammalian expression systems. Expression systems in bacteria include those described in publications (Spapo ei a. Maishge 1978 275: 615, Soedaeyi ei aiI. Mashte 1979 281: 544, Sboedaeyi ei aiY. Mysieis Asii5 NKez. 1980 8: 4057, Eigoreap

Arriisaiop Mo. ER 36,776, 0.5. Paradise Mo. 4,551,433, aeVoeg and aII. Rgos. May Asad bsi OBA 1983 80: 21-25, i

Zierepiivy eyi ai. Sow! 1980 20: 269).

Expression systems in yeast include, among others, those described in publications (Nippep et al.). Rgos. Mai). Asad

All together. BOTH 1978 75: 1929, Mo ei ai. U. Vasietio!. 1983 153: 163, Kygi» ei aI. My. Sei). Vio!. 1986 6: 142, Kyp2e vy a...

Wavis Misgobio!. 1985 25: 141, Sivezop ei a). U. Ep. Misgobio!. 1986 132: 3459, Noddepkatrei a. My. Sept. Sepoys 1986 202: 302, Raz ei ai. 9. Wasiegpio!. 1984 158: 1165, Oe I oshmepsoityi ei ai. U. VasiegioI. 1983 154: 737, Map dep

Vego her a. Vio/Hesppoiodu 1990 8: 135, Kyp2e ei a. 9. Vazis Misgorio!. 1985 25: 141, Stgedod eyi aI. My. Sow! Vio!. 1985 5: 3376, 0.5. Paradise MoMe 4,837,148 and 4,929,555, Veasey and I. Mashge 1981 300: 706, YuOamidom ei aI. Sy. Sepoys 1985 10: 380, Sayagaip eyi aI. Sigt. (zepei. 1985 10: 49, VaIapse ei ai. Viospet. Viorpuz. Nez. Sottip. 1983 112: 284-289, Tirit ei a. Sepe 1983 26: 205-221, Heiyup ei ai. Rgos. Mai). Asad axis OBA 1984 81: 1470-1474, KeiYu yei a! EMVO 3). 1985 4: 475479; Epgoreap Arriisaiop MeER 244234 and Ipieegpanopa! Rybiysanop MeU/O 91/00357).

Expression of heterologous genes in insects can be carried out as described in publications (0.5. Rai.

Me4,745,051, Epigoreap Ariisaiop MeMeER 127,839 and ER 155,476, Miak ei ai. 9. Sep. Migoi. 1988 69: 765-776, MiIPeg ei ai. App. German Misgobio!. 1988 42: 177, Sapopei! oh oh Sepe 1988 73: 409, Maeda Yei A. Mashte 1985 315: 592-594,

It's erasd-Meteudep it's ai. My. Sow! Vioi 1988 8: 3129, those a). Rgos. May Asai. axis BOTH 1985 82: 8404,

Miuaiita ei aI. Sepe 1987 58: 273 and Mapip et al. OMA 1988 7: 99). Numerous baculovirus strains and variants, as well as the corresponding permissive insect host cells from the hosts, are described in publications (GyskKom/ ei ai.

Vio/Hesppoiodu 1988 6: 47-55, MiPeg ei ai. SEMETIS EMSIMEENIMO, Zeyom, 9. K. ейі айЙ. edv., MoiI.8, Riepyt

Rybiiepipo, 1986, 277-279 and Mayeda and I. Mashte 1985 315: 592-594).

Expression in mammals can be carried out as described in the publications of (Oi)Keta et al. EMVO 9. 1985 4: 761, Soptap ei aiYi. Rgos. May Asad Axes OBA 1982 79: 6777, Vovpagy yei ai. SeiI 1985 41: 521 and ).5. Paradise

Mo. 4,399,216). Other features of expression in mammals can be implemented as described in the publications (Nat eyi aI. Meii. Et. 1979 58: 44, Vagpez eyi a). Father Viospet. 1980 102: 255, 0.5. Paradise Moz. 4,767,704, 4,657,866, 4,927,762, 4,560,655 and Reissued Sh.5. Paradise Mo. VE 30,985, and in Ipiegpaiopai International Publications!

Rybiysayop Language MO 90/103430, UUO 87/00195).

Methods of producing recombinant adenoviral vectors are described in (0.5. Rai. Mo. 6,485,958).

Botulinum toxin type A can be obtained by creating and growing cultures of Sioziaisht roishipit in a fermenter, followed by harvesting and purifying the fermented mixture according to known procedures.

Any of the protein production methods described above can be used to produce a biological agent that would benefit from this invention.

Pharmacology and usefulness

The compounds of the present invention are selective inhibitors of cysteine proteases, for example, cathepsin 5, K, B and/or E and, in particular, cathepsin 5, and therefore can be used to treat diseases in which cysteine protease activity contributes to the pathology and/or or symptomatology of the disease. For example, the compounds of the present invention can be used in the treatment of autoimmune disorders including, for example, juvenile diabetes, psoriasis, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis5, systemic lupus erythematosus, rheumatoid arthritis and Hashimoto's thyroiditis, allergic disorders including, for example, asthma, allogeneic immune reactions, including, for example, rejection of organ or tissue transplants, and endometriosis.

Cathepsin 5 is also involved in disorders that cause excessive elastosis, such as chronic obstructive pulmonary disease (eg, emphysema), bronchiolitis, excessive airway elastosis in asthma and bronchitis, pneumonitis, and cardiovascular diseases, such as plaque ruptures and atheroma. Cathepsin 5 is involved in the formation of fibrils, so cathepsin 5 inhibitors can be used in the treatment of systemic amyloidosis.

The inhibitory activity of compounds of formula (I) against cysteine proteases can be measured using methods well known to those skilled in the art. Immunoassay methods suitable for measuring protease activity and its inhibition by test compounds are well known. Usually, in these methods, protease-induced hydrolysis of the peptide substrate is measured. Methods for measuring protease inhibition activity are described in detail in Biological Examples 1-5, below.

Methods of administration and pharmaceutical compositions

In general, compounds of formula (I) are administered in therapeutically effective amounts by any of the conventional methods well known to those skilled in the art, either alone or in combination with one or more other therapeutic agents. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and general health of the subject, the therapeutic potency of the compound used, and a number of other factors. For example, a therapeutically effective amount of a compound of formula (I) can range from about 10 micrograms per kilogram of body weight (μg/kg) per day to 100 milligrams per kilogram of body weight (mg/kg) per day and usually lies within about from 100mcg/kg/day to 1O0mg/kg/day. Thus, a therapeutically effective amount for a human patient weighing 80 kg may be from about 1mg/day to 8g/day, and is typically from about 1mg/day to 800mg/day. In general, one skilled in the art, guided by his own experience and the information provided herein, will be able to readily determine an appropriate therapeutically effective amount of a compound of formula (I) for the treatment of a particular disease.

The compounds of formula (I) can be administered in the form of pharmaceutical formulations by one of the following routes: oral, systemic (eg, transdermal, intranasal or suppository) or parenteral (eg, intramuscular, intravenous or subcutaneous). Pharmaceutical formulations may be in the form of tablets, pills, capsules, semi-solid preparations, powders, sustained release preparations, solutions, suspensions, elixirs, aerosols or other suitable forms and generally contain a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient .

Acceptable are excipients that are non-toxic, facilitate drug administration and do not adversely affect the therapeutic effect of the active ingredient. Such excipients can be in solid, liquid, semi-solid or aerosol form, which is generally available to a person skilled in the art.

Solid pharmaceutical excipients can be, for example, starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, condensed milk, etc. p. Liquid and semi-solid excipients can be, for example, water, ethanol, glycerin, propylene glycol and various oils, including oils of petroleum, animal and synthetic origin and vegetable oils (for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. .). The best liquid carriers, especially in solutions for injections, are water, saline, aqueous dextrose, and glycols.

The amount of the compound according to the formula (I) in the pharmaceutical composition can vary widely depending on the type of drug, the amount of the unit dose, the type of excipients and other factors well known to specialists in the field of pharmaceuticals. In general, the composition with the compound according to the formula (I) for the treatment of a certain disease contains from 0.0195 (wt.) to 9095 (wt.), better - from 59b (wt.) to 5095 (wt.) of the active ingredient, and the rest of it constitutes an excipient or excipients. In the best version, the proposed pharmaceutical composition is administered in a single-dose dosage form for continuous treatment or in a single-dose dosage form ai Prisht, when the goal of treatment is to relieve symptoms. Typical pharmaceutical preparations containing a compound of formula (I) are described below.

Examples

Below are some examples of the implementation of this invention in practice, which do not carry any limitations, but only illustrate the process of manufacturing compounds of formula (I) (Examples) and intermediate products (References) according to this invention.

Link A

Synthesis of 2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ester of trifluoromethanesulfonic acid

Ra ru

IS

Stage 1

Mavna (0.98g, 26.5mmol) was added to a stirred solution of 2,2,2,4"-t-etrafluoroacetophenone (10g, 52.1mmol) in methanol (50ml) at a temperature of 0"C. After stirring at a temperature of 2573 for 2 hours. the reaction mixture was quenched by adding In. solution of NSI (100 ml), and then extracted with ethyl ether. The ether extract was washed with saline, dried over Md5O" and concentrated to obtain 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (11.32 g), which was used in the next step without further purification.

Stage 2 man (640mg, 1bmmol, 6095 in mineral oil) was washed twice with hexane (20ml) and then suspended in dried diethyl ether (20ml). At a temperature of 0"C, a solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (1.94 g, 10 mmol) in diethyl ether (10 ml) was added. After stirring for 2 hours at room temperature, a solution was added of trifluoromethanesulfonyl chloride (1.68g, 10mmol) in diethyl ether (10ml). After 2 hours, the reaction mixture was quenched by the addition of Manceau's solution, and the product was extracted with diethyl ether. The extracts were washed with brine and dried, and the solvent was removed to give 2,2,2-trifluoro -1-(4-fluorophenyl)ethyl ester of trifluoromethanesulfonic acid (3.3 g).

Link V

Synthesis of 2,2,2-trifluoro-1(H)-(4-fluorophenyl)ethanol

Sez

E in

To a solution of 2,2,2,4-tetrafluoroacetophenone (2.5g, 13.01mmol) and 1M 5-methyl-СВ5-oxazaborolidine catalyst (1.3ml, 1.3mmol) in a mixture of toluene (25ml) and dichloromethane (25ml) freshly distilled catecholborane (1.6 bml, 15.62 mmol) was added at a temperature of -787C. The reaction mixture formed in this way was kept at a temperature of -78"C for 16 hours, and at the end of this time period, a 4N solution of HCl (5 ml in dioxane) was added to it, and the reaction mixture was allowed to warm to room temperature. The heated reaction mixture was diluted with ethyl acetate and washed saturated saline solution.

The organic layer was dried over magnesium sulfate, filtered and concentrated to give a solid. This solid was suspended in a hexane mixture and filtered. The hexane filtrate containing the target product was concentrated and the residue subjected to flash chromatography (10 hexanes:1 ethyl acetate) to afford the title compound as a colorless oil (2.2 g, 8795 yield). According to the results of chiral liquid chromatography with high resolution (HPLC) (Spigaise! OO column, mobile phase 95 hexanes: 5 isopropanol. Retention time of the main product 6.757x8V.

The retention time of the secondary isomer was 8.274 min.) the ratio of enantiomers was 95:5.

Link Yu

Synthesis of 2(H)-(2,2,2-trifluoro-1 (5)-(4-fluorophenyl)ethylamino|-3-tritylsulfanylpropionic acid of beeswax without "Z suk

E 9)

Diisopropylethylamine (9.32 ml, 53.48 mmol) was added to a suspension of 5-trityl-i-cysteine (4.86 g, 13.37 mmol) in dichloromethane (97 ml, 20 ml/g of allyl alcohol) at room temperature, and then a solution of 2.2 ,2-trifluoro-1(85)-phenylethyl ester of trifluoromethanesulfonic acid (5.32g, 16.04mmol) (major enantiomer (5), 9095 ee (enantiomeric excess)) in dichloromethane (15ml) using a syringe all at once. After 19 hours, the reaction mixture was concentrated on a rotary evaporator, resulting in an oil. Diethyl ether was added to this oil, and the resulting solution was washed with 1N. NOSI solution and saline solution. The organic layer was dried over Ma 5 O", filtered and concentrated. After flash chromatographic processing of the residue with an eluent from a mixture of 2 parts of hexanes/1 part of ethyl acetate/0.2595 acetic acid, 2(H)-(2,2,2-trifluoro-1(85)-(4-fluorophenyl) was obtained )ethylamino|-3-tritylsulfanylpropionic acid (bg) (main diastereomer (H,5), 9095 de (diastereomeric excess)) in the form of oil with foam.

Link E

Synthesis of 2-(1-aminocyclopropyl)-M-cyclopropyl-2-hydroxyacetamide what: Poison

Stage 1

Chlorohydrate of 1-aminocyclopropanecarbonitrile (6.1 g, 51.4 mmol) was boiled under reflux in bn. hydrochloric acid solution (500 ml) for 7 hours and then concentrated, obtaining the target chlorhydrate of 1-aminocyclopropanecarboxylic acid in the form of a not completely white solid, which was used in the next stage without additional purification.

Stage 2

A solution of 1-aminocyclopropanecarboxylic acid hydrochloride (3.6 g, 26.2 mmol) in MeOH (100 mL) containing potassium carbonate (4.0 g, 28.94 mmol) was stirred at room temperature for 48 hours. After filtration, MeOH was removed from the solution under reduced pressure, resulting in 1-aminocyclopropanecarboxylic acid (2.64 g), which was used in the next stage without additional purification.

Stage Z

1-Aminocyclopropanecarboxylic acid (2.64g, 26.1mmol) and tetramethylammonium hydroxide (2.38g, 26.1mmol) obtained in the previous stage were added to acetonitrile (150ml). After stirring at room temperature for about one hour, the resulting reaction mixture became homogeneous. After that, VosgO (8.54 g, 39.2 mmol) was added to it and all this was stirred for 2 days. On the third day, another portion of VosgO (2.85 g, 13.1 mmol) was added to the mixture, and the reaction mixture was stirred for another day.

The acetonitrile was removed under reduced pressure and the residue was partitioned between HgO and EBO. The aqueous layer was washed with ESO, then acidified with solid citric acid to pH -3. The aqueous solution was extracted with ethyl acetate.

The combined EtOAc extracts were washed with saline, dried (Ma25O4), and EtOAc was removed under reduced pressure to obtain 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid as a white solid (2.32 g), which was used in the next step without further purification.

Stage 4

M,O-dimethylhydroxylamine hydrochloride (1.24g, 12.7mmol), triethylamine (2, 57g, 3.54ml, 25.4mmol) and NATI (4.82g, 12.7mmol). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure and partitioned between EC2O and water. The aqueous layer was extracted with EC2 O. The combined organic layer was washed with brine, dried (Ma»5O»4) and concentrated under reduced pressure to give (|1-(methoxymethylcarbamoyl)cyclopropylcarbamic acid tert-butyl ester, which was used in the next step without additional cleaning.

Stage 5

Up to 0.05M solution of tert-butyl ester | Lithium aluminum hydride (1.0 M in ESO, 5 ml, 5.0 mmol) was added dropwise to 1-(methoxy-methyl-carbamoyl)cyclopropylcarbamic acid in EBO (8 Oml, 4.00 mmol) at room temperature. The resulting reaction mixture was stirred for 20 minutes, and then quenched with the addition of bml of a solution of KNOO»x in water. The layers of the mixture were separated and the aqueous layer was extracted with EbC2O. The combined organic layer was washed with solution of HCI, saturated solution of MansSoOz and saline solution, dried (Ma»5O»4) and concentrated, obtaining tert-butyl ester of (1-formylcyclopropyl)carbamic acid in the form of a colorless oil (393 mg), which was used directly in the next stage without additional purification .

Stage 6

To a solution of tert-butyl ester (1-formylcyclopropyl)/ucarbamic acid (393 mg, 2.12 mmol) in

Acetic acid (191mg, 0.182ml, 3.18mmol) and cyclopropylisocyanide (142mg, 2.12mMmmMole) were added to SNesi" (4ml).

The resulting reaction mixture was stirred overnight at room temperature, and then concentrated under reduced pressure to obtain crude (1-tert-butoxycarbonylaminocyclopropyl)/ucyclopropylcarbamoylmethyl acetic acid, which was used in the next step without further purification.

Stage 7

1095 Maon (ml) was added to the solution of (1-tert-butoxycarbonylaminocyclopropyl)-cyclopropylcarbamoylmethyl acetic acid ester obtained at the previous stage in MeOH (5 ml). The resulting reaction mixture was stirred at room temperature for 2 hours, and then acidified to 2.5N. solution

NSI to pH7. The solution was extracted with EtOAc, washed with brine, dried (Ma50O") and concentrated under reduced pressure, obtaining tert-butyl ester of P-(cyclopropylcarbamoylhydroxymethyl)cyclopropylcarbamic acid in the form of a yellow oil, which was used in the next stage without additional purification.

Stage 8

A solution of the tert-butyl ester of P-(cyclopropylcarbamoylhydroxymethyl)cyclopropyl|carbamic acid obtained at the previous stage in СНоСи» (5 ml) and TEA (5 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated and washed with toluene to give 2-(1-aminocyclopropyl)-M-cyclopropyl-2-hydroxyacetamide.

Applying the process described above in Stages 3-8 but using 1-aminocyclohexanecarboxylic acid instead of /-1-aminocyclopropanecarboxylic acid, 2-(1-aminocyclohexyl)-M-cyclopropyl-2-hydroxyacetamide was obtained.

Link E

Synthesis of 3-amino-M-cyclopropyl-2-hydroxy-3-methylbutyramide

Stage 1

To a solution of tert-butyl ester (2-hydroxy-1,1-dimethylethyl)carbamic acid (284 mg, 1.5 mmol) in

Dess-Martin periodane (Oeez5-Mapip) (76mg, 1.8mmol) was added to SNesi" (5ml) at a temperature of 0O"C. After 1.5h, a solution of 0.26M Mag52Oz3 in saturated MansCO3 (bml) was added and the mixture created in this way was stirred for 15 min. After that, the layers of the mixture were separated, and the aqueous layer was extracted with

SNesi". The combined organic layers were dried (Mag505) and concentrated to give (1,1-dimethyl-2-oxoethyl)carbamic acid tert-butyl ester as a white solid, which was used in the next step without further purification.

Stage 2

Acetic acid (180 mg, 0.172 ml, 3.0 mmol) and cyclopropyl isocyanide (101 mg, 1.5 mmol) were added to the solution of tert-butyl ester (1,1-dimethyl-2-oxoethyl)carbamic acid in СНоСи» obtained at the previous stage. The resulting reaction mixture was stirred overnight at room temperature and then concentrated to obtain crude 2-tert-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl acetic acid ester, which was used in the next step without further purification.

Stage Z

1095 Mn (1.5 ml) was added to the solution of 2-tert-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl acetic acid ester obtained at the previous stage in MeOH (10 ml). The resulting reaction mixture was stirred at room temperature for 3 hours, and then acidified with In. hydrochloric acid solution to pH. Next, the reaction mixture was extracted with EtOAc. The organic layer was dried (Ma?50O4) and concentrated, obtaining tert-butyl ester (2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethylethyl)carbamic acid, which was used in the next stage without additional purification.

Stage 4

The solution of tert-butyl ester (2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethylethyl)carbamic acid obtained at the previous stage in СНоСи» (10 ml) and TEA (5 ml) was stirred at room temperature for 4 hours. The resulting reaction mixture was concentrated and washed with toluene, obtaining 3-amino-N-cyclopropyl-2-hydroxy-33-methylbutyramide.

Link S

Synthesis of 3-amino-M-benzyl-2-hydroxy-3-methylbutyramide

Ko 6)

3-Amino-M-benzyl-2-hydroxy-3-methylbutyramide was obtained in accordance with the process described above, applied to the production of 3-amino-M-cyclopropyl-2-hydroxy-3-methylbutyramide, where benzyl isocyanide was used instead of cyclopropyl isocyanide.

Example 1

Synthesis of cyclopropylamide 2-oxo-3(5)-(3-(pyridin-3-ylmethanesulfonyl)-2(H)-(2,2,2-trifluoro-1(5)-(4-

fluorophenyl)ethylamino|propionylaminohexanoic acid winter

Ez I o N a; in and

Oh and

Stage 1

A dichloromethane solution of catecholborane was added dropwise to a solution of 5-methyl-СВ5-oxazaborolidine (13ml, 1mmol) and 2,2,2,4-tetrafluoroacetophenone (18.2ml, 130.13mmol) in dichloromethane at a temperature of -78°С over 30 minutes. (19.4ml, 182mmol) (15ml). The resulting reaction mixture was stirred at -78°C overnight. After that, the reaction mixture was quenched with an additive of 4N. solution of NCI (13 ml) in dioxane at a temperature of -78"С, warmed to room temperature and the solvent was removed from it under reduced pressure. Manzose 1095 solution (200 ml) was added to the concentrate, and the aqueous layer was extracted with hexane. The organic layer was washed with water and dried over Mod5O". The solvent was removed under reduced pressure to give 2,2,2-trifluoro-1(8)-(4-fluorophenyl)ethanol (20g) as a colorless oil (9095 enantiomeric residue).

Stage 2

Mann (11.87g, 296.7mmol) was added to ESO (700ml) at a temperature of 0"C in an M atmosphere, and then a solution of 2,2,2-trifluoro-1(P)-(4-fluorophenyl)ethanol was added (44.3g, 228.2mmol) in EBO. The resulting reaction mixture was stirred for 10 minutes at a temperature of 0"C, and then for 1 hour. at room temperature.

Next, a solution of trifluoromethanesulfonyl chloride (50 g, 296.7 mmol) in ESO was added at a temperature of 0"C in an atmosphere of Mo, and the reaction mixture was stirred for 10 minutes at a temperature of 0"C, and then for at room temperature. Next, the solvent was removed from the mixture under reduced pressure and HgO (100 mL) was slowly added. The aqueous layer was extracted with hexane, and the combined organic layer was dried over Md 5 O»x. The solvent was removed under reduced pressure to give /2,2,2-trifluoro-1(H)-(4-fluorophenyl)ethyl trifluoromethanesulfonic acid (70g) as a colorless oil.

Stage C 2(8)-Amino-3-tritylsulfanylpropionic acid (78g, 214.6mmol) was dissolved in СНоСи», PIREA (112ml, 643.8mmol) was added to the solution, and the reaction mixture thus created was stirred for 10 min. at room temperature. After that, 2,2,2-trifluoro-1(B)-(4-fluorophenyl)ethyl ester of trifluoromethanesulfonic acid (70 g, 214.6 mmol) obtained in the previous stage was added to the mixture in SNCl, and the reaction mixture was stirred overnight at room temperature. temperature Next, the solvent was removed from the mixture under reduced pressure, and the residue was dissolved in EC6O and washed with other NSI solution, saline solution and dried over

M95oh. The solvent was removed to give 2(K)-(2,2,2-trifluoro-1(5)-(4-fluorophenyl)ethylamino-1|-3-tritylsulfanylpropionic acid (90g) as a yellow solid

Stage 4

The 2(K)-I2,2,2-trifluoro-1(5)-(4-fluorophenyl)ethylamino|-3-tritylsulfanylpropionic acid obtained at the previous stage (5.4 g, 100 mmol) was dissolved in СНеСи» and dissolved in the atmosphere TEA (3.1ml, 40mmol) was added to M2 at a temperature of 0"C. After that, EVV5IN (3.2ml, 20mmol) was added to the mixture in an atmosphere of Mo at a temperature of 0"C, and the reaction mixture created in this way was warmed to room temperature.

After stirring for 2 hours, the solvent was removed under reduced pressure, and the residue was dissolved in it. Mason solution (120 ml). The aqueous layer was extracted with hexane. To this aqueous solution was added dioxane (120ml), 3-picolyl chloride hydrochloride (1.97g, 12mmol) and tris(2-carboxyethylphosphine) hydrochloride (280mg, 1mmol).

The reaction mixture was stirred at room temperature overnight. Dioxane was removed under reduced pressure. The aqueous solution was adjusted to pH 33 and extracted with ethyl acetate. The combined organic extracts were dried over NaCl, filtered and concentrated under reduced pressure to give 3-(pyridin-3-ylmethanesulfanyl)-2(H)-(2,2,2-trifluoro-1(5)-(4 -fluorophenyl)ethylamino|propionic acid, which was used in the next stage without additional purification.

Stage 5

An aqueous solution of OHOMEF was added to a solution of 3-(pyridin-3-ylmethanesulfanyl)-2(H)-(2,2,2-trifluoro-1(5)-(4-fluorophenyl)-ethylamino|propionic acid in methanol (10 ml) (4.68g, 15mmol in 10ml HgO). The resulting reaction mixture was stirred at room temperature. After 2 hours, the solvent was removed under reduced pressure.

The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over Md5Ox, and filtered, the filtrate was concentrated under reduced pressure to give 3-(pyridine-

Z-ylmethanesulfonyl)-2-(B)(2,2,2-trifluoropropionic acid, which was used in the next stage without additional purification.

Stage 6

A mixture of 3-(pyridin-3-ylmethanesulfonyl)-2-(B)(2,2,2-trifluoro-1(5)-(4-fluorophenyl)ethylamino|propionic acid (420 mg, tmol), cyclopropylamide obtained at the previous stage of 3(5)-amino-2-hydroxyhexanoic acid (186 bmg, Tmmol), prepared as described in the publication of the application (PCT MeUuO-02/18369 for compound Xia), HBTOSH (455mg, 1.2mmol) and MMM (0, 44ml, 4mmol) in acetonitrile was stirred at room temperature overnight. After that, saturated MNaCl (100ml) and ethyl acetate (10ml) were added to the mixture, and after 20 min the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over MabBO »x, filtered and the filtrate was concentrated under reduced pressure, obtaining cyclopropylamide 2-hydroxy-3(5)-(3-(pyridin-3-ylmethanesulfonyl)-2(H)-I(2,2,2-trifluoro-1( 5)-(4-fluorophenyl)ethylamino|propionylamino)-hexanoic acid, which was used at the next stage without additional purification.

Stage 7

To the solution of cyclopropylamide obtained at the previous stage, 2-hydroxy-3(5)-(3-(pyridin-3-ylmethanesulfonyl)-2(H)-(2,2,2-trifluoro-1(5)-(4-fluorophenyl) )ethylamino|propionyl-aminohexanoic acid (590 mg, immole) in methylene chloride was slowly added OMR. The resulting reaction mixture was stirred at room temperature for 30 min., after which 0.26 M Mag252Oz3 in saturated Mansoz was added to it. Then the reaction mixture was stirred for 20 min. Aqueous layer was extracted with methylene chloride.

The combined organic extracts were dried over NaCl, filtered and concentrated to give cyclopropylamide 2-oxo-3(5)-3-(pyridin-3-ylmethanesulfonyl)-2(H)-(2,2,2-trifluorophenyl) )ethylamino |-propionylaminohexanoic acid, which was purified on a flash column (295 MeOonH-SNesi»). As a result, a pure product was obtained in the form of a yellow solid.

IN-NMR (OM50O-yv): b 0.80(t, 12Н), 2.02(t, 1Н), 3.3-3.7(р, ЗН), 4.00(t, 1Н), 4.46(t, 1H), 4.79(t, 2H), 7.25(t, 2H), 7.5O(t, 2H), 7.65(B, 1), 7.72(9 , 1H), 8.01 (a, 1H), 8.71 (t, ЗН). GS-M5 (liquid chromatography - mass spectrometry): 587 (Ma-1), 585, (M-1), 609 (M23).

Following the process described above, but using cyclopropyl methyl bromide instead of 3-picolyl chloride, cyclopropylamide 2-oxo-3(5)-3-(cyclopropylmethanesulfonyl)-2(H)-(2,2,2-trifluoro-1(5)- (4-fluorophenyl)ethylamino|-propionylamino)hexanoic acid (compound 1). "H-NMR. (0M50th): b 0.32-0.41 (t, 2H), 0.53-0.67 (t, 6H), 0.81 (i, 9-7.2 Hz, ZN), 1.06-1.38 (t, 4H), 1.52-1.61 (t, 1H), 2.69-2.76 (t, 1H), 2.98 (aa, y- 2.8Hz, 0-14.8Ha 1), 3.19 (aa, d-8Hutz, y-14Gu, 1), 3.28-3.50 (t, ZN), 3.82-3.88 ( t, 1H), 4.37 (dshipi, u7.6Hz, 1), 4.70-4.76 (t, 1H), 7.22 (i, 9-8.4Hz, 2H), 7.43 ( ai, 9U-5.6Hz, 9U-8.4Gu, 2H), 8.51 (y, 9-7.2Hz, 1H), 8.73 (a, 9-5.2Hz, 1). GO-M5 : 550(М--1), 548, (М-1).

Example 2

Synthesis of cyclopropylamide 2-oxo-3(5)-3-(2(8)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridyl-3-ylmethanesulfonyl)propionylamino|pentanoic acid and; E - we

WITH

Sho

Stage 1

To a solution of 2,2,3,3,3-pentafluoropropan-I-ol (1.5 g, 10.0 mmol) and OIREA (b, ml, 35.0 mmol) in methylene chloride (75 ml) at a temperature of -78"C was added triflin anhydride (1.78 ml, 10.5 mmol). After 2.5 h, the entire amount of 5-tritylcysteine was added at once, and the resulting reaction mixture was stirred at a temperature of 0"C for 8 h. After that, the reaction mixture was stirred at room temperature for 18 hours and then concentrated on a rotary evaporator. Ethyl acetate was added to the concentrate, and the reaction mixture was washed with HCl solution. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (3 parts hexanes/1 part ethyl acetate 196 acetic acid), obtaining 2(n)-(2,2,3,3,3-pentafluoropropylamino)-3-tritylsulfanylpropionic acid (3.29 g) .

Stage 2

To a solution of /2(H)-(2,2,3,3,3-pentafluoropropylamino)-3-tritylsulfanylpropionic acid (1.05g, 2.12mmol) in methylene chloride (15ml) was added TEA (0.653ml, 8.48mmol ), followed by triethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was stirred for 1.5 hours. at room temperature and then concentrated on a rotary evaporator. 2n were added to the remainder. Mahon's solution (20 ml), and the reaction mixture was extracted with hexanes. Tris(2-carboxytriethyl)/phosphine hydrochloride (bomg) was added to the MaonH layer followed by 3-picolyl chloride hydrochloride (348mg, 2.12mmol). After 1.5 hours. the reaction mixture was acidified with concentrated HCl to pH-4 and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain 2(H)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethanesulfanyl)propionic acid (530 mgHg).

Stage Z

To a solution of 2(H)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethanesulfanyl)propionic acid (151 mg, 0.44 mmol), cyclopropylamide hydrochloride 3(5)-amino-2- hydroxypentanoic acid (92 mg, 0.44 mmol),

M-methylmorpholine (0.194 ml, 1.76 mmol) was added to EOS (102 mg, 0.6 mmol) and NOVi hydrate (71 mg, 0.53 mmol) in methylene chloride. The reaction mixture was stirred for 2 hours, and then diluted with ethyl acetate and washed with sodium bicarbonate solution. After concentrating the organic layer, 2-hydroxy-3(5)-I2(B)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethanesulfanyl)propionylamino|pentanoic acid cyclopropylamide was obtained (17OmgHg) .

Stage 4

To a solution of 2-hydroxyhydroxy-3(5)-I2(B8)-(2,2,3,3,3-pentafluoropropylamino)-3-pyridin-3-ylmethanesulfanyl)propionylamino|pentanoic acid cyclopropylamide (170 mg, 0.34 mmol) an aqueous solution was added to the MMR

OKOMEF (209 mg, 0.34 mmol). After 2 hours more OHOMEF (105mg, 0.17mmol) was added with additional water plus some methanol. After 1 hour 40 min. the reaction mixture was diluted with ethyl acetate and washed with water. After concentrating the organic layer, 2-hydroxy-3(5)-I2(B)-(2,2,3,3,3-pentafluoropropyl-amino)-3-pyridin-3-ylmethylsulfonyl)propionylamino|pentanoic acid cyclopropylamide was obtained (1 76 mg).

Stage 5

To a heterogeneous mixture of cyclopropylamide 2-hydroxy-3(5)-I2(8)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethanesulfonyl)propionylamino|pentanoic acid (17bmg, 0, 3Zmmol) in methylene chloride was added Dess-Martin periodinan (Oez5-Mapip) (18Zmg, 0.4Zmmol). After a few minutes, the reaction mixture became more heterogeneous. Through the Agreement acetonitrile (Zml) was added to the mixture, followed by MMR (bml). As a result, a homogenous reaction took place. At this time, Dess-Martin periodinan (100 mg) was added. After another 70 Ohv. stirring, the reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution.

The organic layer was separated and concentrated. The residue was flash chromatographed (9595 methylene chloride/595 methanol) to give a solid which was suspended in a 1:1 mixture

IRA/ethanol and allowed to evaporate to dryness. After evaporation, the target cyclopropylamide 2-oxo-3(5)-3-I2(8)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridyl-3-ylmethanesulfonyl)propionylamino|pentanoic acid ( 87 mg).

Example C

Synthesis of M-(1-cyclopropylaminooxalylcyclopropyl)-3-diclopropylmethanesulfonyl-2(H)-(2,2,2-trifluoro-1(5)-(4-fluorophenyl)ethylamino|propionamide

MD ND and others

water

Stage 1

To a solution of 3-cyclopropylmethanesulfanyl-2(H)-(2,2,2-trifluoro-1(5)-(4-fluorophenyl)ethylamino|propionic acid (148 mg, 0.42 mmol) prepared by the process described above in Example 1, where cyclopropyl methyl bromide was used instead of picolyl chloride, and /2-(1-amino-cyclopropyl)-M-cyclopropyl-2-hydroxyacetamide (108 mg, 0.6 mmol) in M-methylpyrrolidine (bml) at a temperature of 0"C was added M, M-diethylpropylamine (272mg, 0.37mL, 2.11mmol) and NATO. The reaction mixture was stirred for 4 hours at room temperature. The mixture was then diluted with ethyl acetate (EtOAc) and washed with washed H2O. The organic layer was dried (Mag25054) and concentrated to give M-|1-(cyclopropylcarbamoylhydroxymethyl)cyclopropyl|-

3-cyclopropylmethylsulfanyl-2-|(2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino|propionamide) which was converted to the title compound as described above in Example 2, steps 4 and 5. M5 ( 534.2 Ma1, 532.1 M-1).

Following the process described above in Example 3, but using 3-amino-M-benzyl-2-hydroxy-3-methylbutyramide instead of 2-(1-amino-cyclopropyl)-M-cyclopropyl-2-hydroxyacetamide, M-benzyl- 5-(3-cyclopropylmethanesulfonyl-2(H)-(2,2,2-trifluoro-1(5)-(4-fluorophenyl)ethylamino|propionylamino)-3-methyl-2-oxobutyramide. Mass spectrometry: M5 ( 586.3 Man1, 584.3 M-1).

Following the process described above in Example 3, but instead of 2-(1-amino-cyclopropyl)-M-cyclopropyl-2-hydroxyacetamide using 3-amino-M-benzyl-2-hydroxy-3-methylbutyramide, and instead of 2(K )-(2,2,2- trifluoro-1(5)-(4-fluorophenyl)ethylamino|-3-tritylsulfanylpropionic acid using 2(K)-|(2,2,2- trifluoro-1(8)-( 4-fluorophenyl)ethylamino|-3-tritylsulfanylpropionic acid, obtained /M-benzyl-3-(3-cyclopropylmethanesulfonyl-2(H)-(2,2,2-trifluoro-1(8)-(4-fluorophenyl)ethylamino |propionyl-amino)-3-methyl-2-oxo-butyramide and M-benzyl-3-(3-cyclopropylmethanesulfonyl-2-(2,2,2-trifluoro-1-(4-fluoro-phenyl)-ethylamino| propionylamino)-3-methyl-2-oxo-butyramide Mass spectrometry: M5 (586.1 Man1, 584.1 M-1).

Following the process described above in Example 3, but using 3-amino-M-cyclopropyl-2-hydroxy-3-methylbutyramide instead of 2-(1-amino-cyclopropyl)-M-cyclopropyl-2-hydroxyacetamide, /-M- cyclopropyl-3-(3-cyclopropylmethanesulfonyl-2(H)-I(2,2,2-trifluoro-1(5)-(4-fluorophenyl)ethylamino|propionylamino)-3-methyl-2-oxo-butyramide. Mass. - spectrometry: M5 (536.0 Ma1, 534.2 M-1).

Example 4

Synthesis of cyclopropylamide 3(5)-I(3-cyclopropylmethanesulfonyl-2(H)-(2,2,3,3)-3-pentafluoropropylamino)-propionylamino|-2-oxo-pentanoic acid

And for?

Stage 1

To a solution of 2,2,3,3,3-pentafluoropentan-1-ol (1.5g, 10.0mmol) and OIREA (6b.1ml, 35.0mmol) in dichloromethane (75ml) at a temperature of -78"C dropwise triflinic anhydride (1.78 mL, 10.5 mmol) was added. After 2 h 20 min, 5-tritylcysteine was added to the reaction mixture, and the mixture was stirred for another h 15 min at "C" and then for 19 h. at room temperature. Next, the reaction mixture was concentrated on a rotary evaporator, and the residue was subjected to flash chromatography (3:11 hexanes/ethyl acetate from 195 acetic acid), resulting in 2(8)-(2,2,3,3,3-pentafluoropropylamino)-3 -tritylsulfanylpropionic acid (3.29 g).

Stage 2

TEA (0.653 ml, 8.48 mmol) was added to a solution of /2(H8)-(2,2,3,3,3-pentafluoropropylamino)-3-trityl-sulfanylpropionic acid (1.05 g, 2.12 mmol) in dichloromethane, followed by triethylsilane (0.677 ml, 4.24 mmol). The reaction mixture was stirred for an hour. 20 min. at room temperature and then concentrated on a rotary evaporator. 2n were added to the remainder. Mahon's solution and hexanes. The resulting mixture was shaken, as a result of which the layer of MaOH was separated. Cyclopropyl methyl bromide (0.206 mL, 2.12 mmol) was added to the MaOnH layer. The reaction mixture was stirred for 17 hours. at room temperature, then acidified yin. solution of NCI and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to obtain 2(8)-(2,2,3,3,3-pentafluoropropylamino)-3-(cyclopropyl-methanesulfanyl)propionic acid (428 mgHg).

Stage Z

To a mixture of 2(H)-(2,2,3,3,3-pentafluoropropylamino)-3--(cyclopropyl-methanesulfanyl)propionic acid (150 mg, 0.49 mmol), cyclopropylamide hydrochloride 3(5)-amino-2- of hydroxypentanoic acid (102mg, 0.49mmol), EOS (114mg, 0.74mmol) and NOVI (79mg, 0.59mmol) in dichloromethane was added M-methylmorpholine (0.215ml, 1.96mmol). The resulting reaction mixture was stirred for 2 hours at room temperature, and then diluted with ethyl acetate and washed with sodium bicarbonate solution. The organic layer was dried and concentrated, obtaining cyclopropylamide //2-hydroxy-3(5)-I2(B8)-(2,2,3,3,3-pentafluoropropylamino)-3-(cyclopropylmethanesulfanyl)propionylamino|pentanoic acid (169 mg) .

Stage 4

To a solution of 2-hydroxy-3(5)-I2(8)-(2,2,3,3,3-pentafluoropropylamino)-3-(cyclopropylmethanesulfanyl)propionylamino|pentanoic acid cyclopropylamide (169 mg, 0.37 mmol) in MMP ( 5ml) added an aqueous solution (Hml) of OHOME (342mg, 0.5bmmol). After stirring for 2 hours at room temperature, more aqueous solution of OHOME (228mg) was added together with methanol (5ml). After stirring for another 2 hours. the reaction mixture was diluted with ethyl acetate and washed with saturated saline.

The organic layer was separated, dried and concentrated to give a white solid, to which dichloromethane (10ml) and Dess-Martin periodane (Oez5-Mapip) were added. Acetonitrile (Zml) was added to this heterogeneous mixture, followed by MMP (bml), which ensured the homogeneity of the reaction. In 5 hours the reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution. The organic layer was dried and concentrated to give the crude product as a white solid. Ethanol was added to this substance, and the mixture was refluxed. This still heterogeneous mixture was allowed to cool to room temperature and filtered to afford the title compound as a white solid (115mg). Melting point: 196.1-196.776.

Using the above-described process, the following compounds were obtained: M-cyclopropyl-35-(3-benzenesulfonyl-28-2,2,2-trifluoro-15-(4-fluoro-phenyl)-ethylamino|-propionylamino)-2-oxopentanamide, Liquid chromatography - mass spectrometry: I С-М5 558(МН); and

M-cyclopropyl-35-|3-cyclopropylmethanesulfonyl-2B-(2,2,3,3,4,4,4-heptafluorobutylamino)-propionylamino|-2-oxo-pentanamide, I С-М5 542 (МН).

Example 5

Synthesis of M-cyclopropyl-35-(4-methanesulfonyl-25-(2,2,2-trifluoro-15-(4-fluorophenyl)-ethylamino!|-butyrylamino)-2-oxo-pentanamide

(5) Methyl-2-amino-4-methylsulfanylbutyrate hydrochloride (750 mg, 3.7 mmol) and 2,2,2-trifluoro-1-(4-fluoro-phenyl)ethanone (721 mg, 3.76 mmol) were dissolved in methanol (15 ml) and potassium carbonate (1.04 g, 7.52 mmol) was added to the solution. The resulting mixture was stirred at a temperature of 55"C for 23 hours, and then concentrated to dryness on a rotary evaporator. The residue was combined with toluene (20 ml), and the mixture was concentrated to dryness on a rotary evaporator. The residue was combined with acetonitrile (1Oml ), and the mixture was stirred at a temperature of approximately -30"C. To the mixture was added zinc borohydride, prepared by adding a 1M solution of zinc chloride in ether (5.64ml) to a mixture of sodium borohydride (427mg, 11.28mmol), stirring in ether (1Oml) and then stirring this mixture for 19h, and the reaction mixture stirred for about 7 hours at reduced temperature and then for another 16 hours at room temperature. After that, the reaction mixture was quenched by HCl solution, diluted with ethyl acetate and washed with saline solution (2x5O0ml). The organic layer was dried and concentrated, obtaining /25-|2,2,2-trifluoro-15-(4-fluorophenyl)ethylamino|-4-methylsulfonylbutyric acid (1.15g) in the form of a solid substance. 2(5)-(2,2,2-Trifluoro-15-(4-fluorophenyl)ethylamino|-4-methylsulfonylbutyric acid (150mg, 0.4b6bmmol), cyclopropyl-35-amino-2-hydroxypentanamide hydrochloride (106bmg, 0 .51mmol), EOS (132mg, 0.69mmol) and NOVI (75mg, 0.55mmol) were combined in OSM (10ml) and the mixture was stirred at room temperature by adding

M-methylmorpholine (0.253 ml, 2.3 mmol). After that, the mixture was stirred for 2 hours 15 minutes and then diluted with ethyl acetate. Next, the mixture was washed with sodium bicarbonate solution (2x35 ml), and the organic layer was dried and concentrated, obtaining M-cyclopropyl-2-hydroxy-35-4-methanesulfonyl-25-(2,2,2-trifluoro-15-(4-fluorophenyl) ethylamino|butyrylamino)pentanamide (188 mg) as a white solid.

M-Cyclopropyl-2-hydroxy-35-(4-methanesulfonyl-25-12,2,2-trifluoro-15-(4-fluoro-phenyl)-

ethylamino|butyrylamino)pentanamide (188 mg, 0.39 mmol) was dissolved in 1-methyl-2-pyrrolidinone (5 mL) and the solution was stirred at room temperature by adding an aqueous oxone solution (5 mL, 434 mg, 0.71 mmol).

The resulting mixture was stirred for 1 hour 45 minutes, and then diluted with ethyl acetate. Next, the mixture was washed with a saline solution (3x25 ml). The organic layer was dried and concentrated. The residue was dissolved in 1-methyl-2-pyrrolidinone (ml), and Oev5-Mayip (232 mg, 0.55 mmol) was added to the solution. The reaction continued for another 1 hour, after which the solution was diluted with ethyl acetate. The reaction mixture was washed with sodium bicarbonate solution (300 ml) and the organic layer was dried and concentrated. The residue, combined with ether, added a solid. The mixture was purified and filtered, obtaining M-cyclopropyl-35-(4-methanesulfonyl-25-12,2,2-trifluoro-5-(4-fluorophenyl)ethylamino|butyrylamino)-2-oxo-pentanamide (114 mg) as a solid white substance (melting point: 152.5-153.57C). And S-M5 519(MN).

Biological examples

Example 1

Cathepsin B test

Solutions of the tested compounds were prepared in different concentrations in 10 μl of dimethylsulfoxide (OM50), and then diluted in analytical buffer (40 μl, which contained: M,M-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (885), 50 mM (rnb) ; polyoxyethylene sorbitan monolaurate 0.0595; and dithiotriitol (OT), 2.5 mM). Human cathepsin B (0.025 pmol in 25 μl of analytical buffer) was added to the solutions. Analytical solutions were mixed for 5-10 seconds on a shaker plate, covered with a lid and incubated for 30 minutes at room temperature. 2-EV-AMS (20 nmol in 25 μl of analytical buffer) was added to analytical solutions and hydrolysis was observed by spectrophotometric monitoring at a wave (X) of 46 Ohm for 5 minutes. Apparent inhibition constants (KI) were calculated from enzymatic development curves using standard mathematical models.

The compounds of the present invention were tested by the method described above, where they demonstrated inhibitory activity against cathepsin B.

Example 2

Cathepsin K test

Solutions of the tested compounds were prepared at various concentrations in 10 μl of dimethyl sulfoxide (OM50), and then diluted in analytical buffer (40 μl, which contained: ME5, 50 mM (pH5.5); EOTA, 2.5 mM; and OTT, 2.5 mM).

Human cathepsin K (0.0906 bpmol in 25 μl of analytical buffer) was added to the solutions. Analytical solutions were mixed for 5-10 seconds on a shaker plate, covered with a lid and incubated for 30 minutes at room temperature. 2-EV-AMS (20 nmol in 25 μl of analytical buffer) was added to analytical solutions and hydrolysis was observed by spectrophotometric monitoring at a wave (X) of 46 Ohm for 5 minutes. Apparent inhibition constants (Ki) were calculated from enzymatic development curves using standard mathematical models.

The compounds of the present invention were tested by the method described above, where they demonstrated inhibitory activity against cathepsin K.

Example C

Cathepsin G test.

Solutions of the tested compounds were prepared at various concentrations in 10 μl of dimethyl sulfoxide (OM50), and then diluted in analytical buffer (40 μl, which contained: ME5, 50 mM (pH5.5); EOTA, 2.5 mM; and OTT, 2.5 mM).

Human cathepsin GI (0.05 pmol in 25 μl of analytical buffer) was added to the solutions. Analytical solutions were mixed for 5-10 seconds on a shaker plate, covered with a lid and incubated for 30 minutes at room temperature. 2-EV-AMS (20 nmol in 25 μl of analytical buffer) was added to analytical solutions and hydrolysis was observed by spectrophotometric monitoring at a wave (X) of 46 Ohm for 5 minutes. Apparent inhibition constants (Ki) were calculated from enzymatic development curves using standard mathematical models.

The compounds of the present invention were tested according to the method described above, where they demonstrated inhibitory activity against cathepsin Y.

Example 4

Cathepsin 5 test

Solutions of the tested compounds were prepared in different concentrations in 10 μl of dimethylsulfoxide (OM50), and then diluted in analytical buffer (40 μl, which contained: ME5, 50 mM (rhb,5); EOTA, 2.5 mM; and Masi, 100 mM); B-mercaptoethanol, 2.5 mM, and B5A, 0.0095. Human cathepsin 5 (0.05 pmol in 25 μl of analytical buffer) was added to the diluted solutions. Analytical solutions were mixed for 5-10 seconds on a shaker plate, covered with a lid and incubated for 30 minutes at room temperature. 2-MaI-MaI-Aga-AMS (4 nmol in 25 μl of analytical buffer containing 1095 OM5O) was added to the analytical solutions and the hydrolysis was monitored by spectrophotometric monitoring at a wavelength of 46 Ohm for 5 min.

Apparent inhibition constants (Ki) were calculated from enzymatic development curves using standard mathematical models.

The compounds of the present invention were tested according to the method described above, where they demonstrated inhibitory activity of " or -" 100 nM against cathepsin 5.

Example 5

Test for cathepsin E

Solutions of the tested compounds were prepared at different concentrations in 10 μl of dimethylsulfoxide (OM50), and then diluted in analytical buffer (40 μl, which contained: ME5, 50 mM (rhb,5); EOTA, 2.5 mM; and Masi, 100 mM); OTT, 2.5 mM; and VB5A, 0.0195. Human cathepsin E (0.1 pmol in 25 μl of analytical buffer) was added to the diluted solutions. Analytical solutions were mixed for 5-10 seconds on a shaker plate, covered with a lid and incubated for 30 minutes at room temperature. 2-Rpe-Ag9-AMSO (2 nmol in 25 μl of analytical buffer containing 1095 OM50) was added to the analytical solutions, and hydrolysis was monitored by spectrophotometric monitoring at a wavelength of 46 Ohm for 5 min.

Apparent inhibition constants (K) were calculated from enzymatic development curves using standard mathematical models.

The compounds of the present invention were tested according to the method described above, where they demonstrated inhibitory activity against cathepsin EC.

Example 1

Typical pharmaceutical preparations containing the compound of formula (I)

Drug for oral administration

Compound according to formula (I) 10-100 mg

Citric acid monohydrate 105 mg

Sodium hydroxide 18mMg

Taste corrector

How much water is needed up to 100 ml

Drug for intravenous administration

Compound according to formula (I) 0.1-10 mg

Dextrose monohydrate as needed for isotonicity

Citric acid monohydrate 1.05 mg

Sodium hydroxide 018 mg

Water for injections as needed up to 1.0 ml

The drug is in the form of tablets

Compound according to formula (I) 196

Macrocrystalline cellulose 7390

Stearic acid 2590

Colloidal silicon dioxide 196

The above description of the present invention in some details and examples is for illustrative and explanatory purposes only. It is quite clear that this description in the implementation of the invention in practice does not exclude various changes and additions that can be made within the scope outlined by the Formula of the invention attached here. Therefore, this description does not impose any restrictions on various other variants of the invention that are not specified by it. Thus, the scope of this invention is determined not by this description, but by the Formula of the invention, as well as the full scope of equivalents to which the clauses of this Formula give the right.

Claims (43)

1. Compound according to formula (1): ve Z o Toj d7 M i ovo ; where VE is hydrogen or alkyl; IN? is cycloalkyl, cycloalkylalkyl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted with one or two substituents independently selected from alkyl, alkoxy, or halide; E- is alkyl or alkoxyalkyl; E" is hydrogen or alkyl; or EO and BE" together with the carbon atom to which they are attached form a cycloalkylene, optionally substituted with one to four halides or heterocycloalkylenes, optionally substituted with alkyl, alkoxyalkyl, hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl or haloalkyl; IN? is aalkyl, haloalkyl, optionally substituted with cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, -(alkylene)-X-B (where X is -O-, -5-, -50-, -502-, -СОМН-, -МНСОО- or -МН5О»-, and EC? is alkyl, haloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl) or -(alkylene)-X!- (haloalkylene )-BO (where X! is -O-, -5-, -50-, -5025-, -СОМН-, -МНСО- or -МН5О»- and BO is cycloalkyl, aryl, heteroaryl or heterocycloalkyl), where the aromatic or alicyclic ring in E7 may optionally be substituted with one, two, or three K" independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkyloxy, cyano, or halide; or may optionally be substituted with one or by two K" independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkyl, halide, carboxy or alkoxycarbonyl, 1 by one K" selected from cyano, hydroxyalkyl, alkoxyalkyl, amino алкілу, арилу, гетероарилу, аралкілу, гетероаралкілу, циклоалкілу, циклоалкілалкілу, гетероциклоалкілу, гетероциклоалкілалкілу, ацилу, ацилалкілу, алкоксикарбонілу, арилоксикарбонілу, аралкілоксикарбонілу, гетероарилоксикарбонілу, гетероаралкілоксикарбонілу, гетероциклоалкілоксикарбонілу, циклоалкілоксикарбонілу, арилокси, гетероарилокси, аралкілокси, гетероаралкілокси, амінокарбонілу, аміносульфонілу або -500К (where B is alkyl, aryl, heteroaryl or heterocycloalkyl); and wherein the aromatic or alicyclic ring in K" may optionally be substituted with one, two, or three CO independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkyl, or halide; BE is haloalkyl; E" is hydrogen or haloalkyl; and B) is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, attached through a carbon atom, where the aromatic or alicyclic ring in KE" may, if desired, be substituted with one, two, or three K" independently selected from alkyl, halide, haloalkyl, hydroxy, alkoxy, haloalkyloxy, alkoxycarbonyl, carboxy, cyano, alkylsulfonyl, or aminosulfonyl; or pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, where B is hydrogen, and B" is cyclopropyl, 1-phenylethyl or 1H-pyrazol-5-yl. 3. Compound according to claim 1, where K! is hydrogen, and B" is cyclopropyl. 4. The compound according to claim 2 or 3, where B" is hydrogen, and K- is alkyl. 5. The compound according to claim 2 or 3 where В" is hydrogen and K" is methyl, ethyl, propyl or butyl. 6. The compound according to claim 2 or 3, where B" is hydrogen and B" is ethyl. 7. The compound according to claim 2 or 3, where B" and B are alkyl. 8. The compound according to claim 2 or 3, where B" and B" independently of each other are methyl or ethyl. 9. The compound according to claim 2 or 3, where B" and B" are methyl. 10. The compound according to claim 2 or 3, where K" and BV" together with the carbon atom to which they are attached form a cycloalkylene. 11. The compound according to claim 2 or 3, where КЕ" and Б" together with the carbon atom to which they are attached form cyclopropylene. 12. A compound according to any one of claims 2-11, where KE is haloalkyl, and B. and B" are hydrogen. 13. The compound according to any of claims 2-11, where BO is 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, and B and B are hydrogen. 14. A compound according to any of claims 2-11, where CO is haloalkyl, B/ is haloalkyl, and KZ is hydrogen. 15. The compound according to any one of claims 2-11, where KE is haloalkyl, KE. is alkyl, and B" is hydrogen. 16. The compound according to any of claims 2-11, where 2? is haloalkyl, B is hydrogen, and BZ is aryl, optionally substituted with one, two, or three KU. 17. A compound according to any of claims 2-11, where BO is trifluoromethyl or difluoromethyl, VC is hydrogen, and VE" is 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6 -, 3,4- or 3,5-difluorophenyl. 18. The compound according to any of claims 2-11, where B? is haloalkyl, B is hydrogen, and BEU and B? each is heteroaryl optionally substituted with one, two or three KU. 19. The compound according to any of claims 2-18, where KB? is cycloalkylalkyl, optionally substituted with one, two or three K", independently selected from alkyl or halide, or K", selected from aralkyl or heteroaralkyl. 20. The compound according to any of claims 2-18, where B? is 1-methylcyclopentylmethyl, 1-methylcyclohexyl, 1-methylcyclobutyl, 1-methyl-3,3-difluorocyclobutylmethyl, 1-methyl-4,4-difluorocyclohexylmethyl, 1-benzylcyclopropylmethyl, 1-thiazol-2-ylmethylcyclopropylmethyl or 1-methyl-3 ,3-difluorocyclopentylmethyl. 21. The compound according to any of claims 2-18, where B" is alkyl. 22. The compound according to any of claims 2-18, where BC? is haloalkyl substituted with aryl, heteroaryl or heterocycloalkyl. 23. The compound according to any of claims 2-18, where B" is 2,2-difluoro-3-phenylpropyl, 2,2-difluoro-3-tetrahydropyran-4-ylpropyl, 2,2-difluoro-3-morpholine -1-ylpropyl, /2,2-difluoro-3-pyridin-2-ylpropyl, 2,2-difluoro-3-pyridin-3-ylpropyl or 2,2-dichloro-3-phenylpropyl. 2A. The compound according to any one of claims 2-18, where ВЕ" is -(alkylene)-5(0)2-Е7, where Е" is alkyl. 25. A compound according to any one of claims 2-18, where B is methylsulfonylmethyl, ethylsulfonylmethyl, propyl-1-sulfonylmethyl, 2-methylpropylsulfonylmethyl, 2-methylsulfonylethyl or 2-ethylsulfonylethyl. 26. The compound according to any of claims 2-18, where B? is -(alkylene)-50)2-B7, where E" is aryl or aralkyl, optionally substituted with one, two or three K", independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano or halo; or optionally substituted with one or two B's independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkyloxy, halo, carboxy, or alkoxycarbonyl, and one K'' selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl or -502K"! (where BK"! is alkyl, aryl, heteroaryl, or heterocycloalkyl); and where the aromatic or alicyclic ring in K" can optionally be substituted with one, two, or three KU independently selected from alkyl, haloalkyl, alkoxy, hydroxy , haloidalcox or haloid. 27. The compound according to any of claims 2-18, where CC is 2-difluoromethoxyphenylmethanesulfonylmethyl, 2-phenylsulfonylethyl, 4-fluorophenylmethanesulfonylmethyl, (K(4-aminocarbonylphenylmethanesulfonylmethyl, 4-piperazin-1-ylphenylmethanesulfonylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3 -fluorophenylmethanesulfonylmethyl, 2,4,6- trifluorophenylmethanesulfonylmethyl, 2-, 3- or 4-trifluoromethylphenylmethanesulfonylmethyl, phenylmethanesulfonylmethyl, 2-(2-, 3- or 4-trifluoromethylphenyl)sulfonylethyl, phenylmethanesulfonylmethyl or 2-(2-, 3- or 4-trifluoromethyl) -fluorophenyl)sulfonylethyl. 28. The compound according to any one of claims 2-18, where B" is -(alkylene)-5(0)2-B7, where B" is heteroaryl or heteroaralkyl, optionally substituted with one, two or three K". independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano or halide; or optionally substituted with one or two B", independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halide, carboxy or alkoxycarbonyl , and one KU selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, aryloxy, heteroamyloxyalkyl, heteroaryloxyaryl , aminosulfonyl or -500K (where B is alkyl, aryl, heteroaryl or heterocycloalkyl); and where the aromatic or alicyclic ring in K", if desired, can be substituted with one, two or three CO independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkyloxy or halo. 29. The compound according to any of claims 2-18, where B" is pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, 3-difluoromethoxypyridin-2-ylmethanesulfonylmethyl, 2-difluoromethoxypyridin-3-ylmethane - sulfonylmethyl, 4-difluoromethoxypyridin-3-ylmethanesulfonylmethyl, 3-difluoromethoxypyridin-4-ylmethanesulfonylmethyl, pyrimidine-2-ylmethanesulfonylmethyl, pyrimidine-5-ylmethanesulfonylmethyl, 4-trifluoromethylpyridin-3-ylmethanesulfonylmethyl, 3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl, 2 -fluorofuran-5-ylmethanesulfonylmethyl, (/(2-methylthiazol-4-ylmethanesulfonylmethyl, furan-2-ylmethanesulfonylmethyl, 2-pyridin-2-ylethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl, 2-pyridin-4-ylethanesulfonylmethyl, 2- pyridin-3-ylsulfonylethyl, 2-pyridin-4-ylsulfonylethyl, /(3-pyridin-3-ylsulfonylpropyl, /1,3,5-triazin-2-ylmethanesulfonylmethyl, 1,3,4-thiadiazol-2-ylmethanesulfonylmethyl, oxazole -5-ylmethanesulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl or thiazol-2-ylmethanesulfonylmethyl. 30. A compound according to any one of claims 2-18, where B is -(alkylene)-50)2-B7, where B" is cycloalkylalkyl. 31. The compound according to any of claims 2-18, where B" is cyclopropylmethanesulfonylmethyl. 32. The compound according to claim 1, where B" is alkyl and B" is alkyl. 33. The compound according to claim 1, where EO and ВЕ together with the carbon atom to which they are attached form a cycloalkylene. 34. The compound according to claim 1, where EO and ВЕ together with the carbon atom to which they are attached form piperidin-4-yl substituted on the nitrogen atom by ethyl, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl , tetrahydrothiopyran-4-yl or 1,1-dioxotetrahydrothiopyran-4-1yl. 35. The compound according to claim 1, where B is haloalkyl, and B and KU are hydrogen. 36. The compound according to claim 1, where EB is haloalkyl, B is haloalkyl, and B is hydrogen. 37. The compound according to claim 1, where Eg is haloalkyl, B" is alkyl, and B" is hydrogen. 38. Compound according to claim 1, where VE! is hydrogen, EE is cyclopropyl, E- is hydrogen, B is ethyl, B? is 2-methylsulfonylethyl, EC is trifluoromethyl, B is hydrogen, and BZ is 4-fluorophenyl, namely M-cyclopropyl-3-|(4-methanesulfonyl-2-|2,2,2-trifluoro-1-(4 - fluorophenyl)ethylamino (butyrylamino)-2-oxopentanamide. 39. The compound according to claim 38, which is M-cyclopropyl-35-14-methanesulfonyl-25-|2,2,2-trifluoro-15-(4-fluorophenyl)ethylamino|butyrylamino)-2-oxopentanamide. 40. Compound according to item I, where VE! is hydrogen, EE is cyclopropyl, E- is hydrogen, E- is ethyl, B is 2-phenylsulfonylmethyl, B is trifluoromethyl, E" is hydrogen, and VE is 4-fluorophenyl, namely M-cyclopropyl-3-(3-benzenesulfonyl-2-(2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino | propionylamino)-2-oxopentanamide. 41. The compound according to claim 40, which is M-cyclopropyl-35-| 3Z-benzenesulfonyl-2K-I2,2,2-trifluoro-15-(4-fluorophenyl)ethylamino|propionylamino)pentanamide. 42. Compound according to claim 1, where VE! is hydrogen, EE is cyclopropyl, E- is hydrogen, E- is ethyl, VE? is cyclopropylmethylsulfonylmethyl, B is perfluoropropyl, E" is hydrogen, and BEU is hydrogen, namely M-cyclopropyl-3-|3-cyclopropylmethanesulfonyl-2-(2,2,3,3,4.44- heptafluorobutylamino)propionylamino |-2- oxopentanamide. 43. The compound according to claim 42, which is M-cyclopropyl-35-|33-cyclopropylmethanesulfonyl-2K-(2,2,3,3,4,4,4-heptafluorobutylamino)propionylamino|-2-oxopentanamide.