2-aminobenzoxazole carboxamides as 5-ht3 modulators

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

 

Cross-reference to related applications

This application claims the priority of provisional patent application U.S. No. 60/821646, filed August 7, 2006, the full contents of which are incorporated here by reference.

The technical field to which the invention relates

This invention relates to a group of 2-aminobenzenesulfonamide that are applicable in the treatment of chemotherapy-induced nausea and vomiting (CINV) in the treatment of irritable bowel syndrome with predominant diarrhea (IBS-D).

The level of technology

Nausea and vomiting caused by chemotherapy, belong to the most unpleasant side effects in patients undergoing treatment for cancer. Depending on the chemotherapeutic agents or adopted schemes receive up to 90% of patients may suffer some form of chemotherapy-induced nausea and vomiting (CINV). The CINV symptoms can be very debilitating and often lead to failure patients from further courses of chemotherapy with clearly adverse effects against the progression of cancer. In addition, CINV is a burden on the health care system, spending time medical staff, which could otherwise help other patients or to pay attention to other health problems.

CINV divided into the two main categories: acute CINV and delayed CINV. Acute CINV occurs within the first 24 hours of treatment; delayed CINV occurs from 24 hours up to 120 hours after treatment. Delayed CINV remains a frequently occurring in the treatment of side effects in patients subjected to chemotherapy, although healthcare has a tendency to underestimate the number of patients who experience a delayed CINV. In addition, delayed CINV significantly reduces patients ' ability to care for themselves after they were discharged from hospital.

Compounds that inhibit serotonin receptors, are currently the most effective antiemetic means; they govern only the most significant success in eliminating nausea and vomiting in patients with cancer and have additional application in radiation-induced nausea and vomiting (RINV) and postoperative nausea and vomiting (PONV). Apparently, blocking receptor 5-NT3 in the signal of serotonin caused by chemotherapy induced damage enterochromaffin cells of the intestine, which is the main part of the inventory of serotonin the body, either through a peripheral or Central mechanism prevents acute vomiting. Except palonosetron (aloxi®), an inhibitor of 5-NT3 permitted for the treatment of acute CINV and are is the most effective for such treatment. Palonosetron, which should be administered intravenously, is currently the only inhibitor of 5-NT3 allowed for the prevention of acute and delayed CINV. Postulated that the effectiveness of palonosetron against delayed vomiting due to its long half-life in serum. Therefore, experts in the field recognize that inhibitors of 5-NT3, which have long elimination half-life of the serum, can be effective therapeutic agents for acute and delayed CINV, whereas inhibitors of 5-NT3, which have a short elimination half-life may be applicable for the treatment of acute CINV. In addition, we discovered that the combination of palonosetron, an inhibitor of 5-NT3 and aprepitant (emend®)antagonist neirokinina, is very effective in preventing both acute and delayed CINV after different treatment regimens with vomiting from moderate to very strong in clinical trials. Especially combination therapy using either NK1 antagonists or antagonists of 5-NT3 with corticosteroids, such as dexamethasone, increases the effectiveness of these drugs against acute or delayed vomiting. Essentially, marking emend® indicates that the dose of this drug is injected with a corticosteroid and an is an agonist of 5-NT3.

Irritable bowel syndrome (IBS) usually exists in the form of three types: with predominant diarrhea (IBS-D), with the predominant higher (IBS-C) and IBS with alternating symptoms, called IBS-A, or mixed symptoms (IBS-M). Irritable bowel syndrome with predominant diarrhea is weakening the body, although rarely fatal disease. Typical suffering from IBS-D patient manifests primary symptoms, including multiple and daily explosive bouts of diarrhea and severe daily spasms of the abdominal cavity. The most common secondary side effects include panic attacks, depression, withdrawal from social and family activities and the failure or malnutrition.

Currently, compounds that inhibit the receptors 5-NT3, are the only effective means for the treatment of IBS-D. the Only drug currently approved for treatment of IBS-D is alosetron, which was put into use Glaxo withdrawn from use by the Department of quality control of food, drugs and cosmetics (FDA)because it apparently causes ischemic colitis, then restored to use by the FDA, as the need in the treatment of IBS-D was also high. In 2002, the Department for control over the quality of the food product is, drug and cosmetics USA has authorized the use of tablets hydrochloride alosetron (lotronex®) under limited conditions for women that the medical benefits outweigh the risks. Limitations on permit applications represent serious gastrointestinal adverse cases, which are described in the application of alosetron. The second group of structurally related inhibitor 5-NT3 is cilansetron, who has gone through clinical trials, but recently a letter was received from the FDA, which does not allow its use. For the treatment of IBS-D can be applied to new, structurally unrelated inhibitors of IBS-D.

It is clear that there is a need for improved therapy for CINV and IBS-D.

The invention

Now discovered that the compounds of formulas I, II and III are potent and selective inhibitors of the receptor 5-NT3:

In these compounds R1, R2and R3independently selected from hydrogen, halogen, cyano, alkyl - or arylsulfonate, alkyl - or arylsulfonyl, amino, alkylamino, dialkylamino, acylamino, morpholinyl, lower-alkyl, hydroxy, lower alkyl, lower foralkyl, lower O-foralkyl, methylendioxy, Ethylenedioxy, alkoxy-lower alkyl and lower hydroxyalkyl.

R4represents a saturated azote is th a heterocycle or substituted stands saturated nitrogenous heterocycle, in which the nitrogen atom is tertiary, and said heterocycle contains at least one 5 - or 6-membered ring;

R10selected from the group consisting of

(i) hydrogen;

(ii) (C1-C10)alkyl;

(iii) substituted (C1-C10)alkyl;

(iv) heterocyclyl;

(v) substituted heterocyclyl;

(vi) aryl and

(vii) substituted aryl;

R11selected from the group consisting of hydrogen and (C1-C10)alkyl; or

R10, R11and the nitrogen atom to which they are attached, together form a nitrogenous heterocycle or substituted nitrogenous heterocycle.

In another aspect the invention relates to pharmaceutical compositions comprising pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds of formula I, II or III. The composition can contain additional antiemetic agent, especially the antagonist neirokinina. The composition can also contain a corticosteroid.

In another aspect the invention relates to a method of treating disorders arising from inappropriate activity of the serotonin receptor type 3 or dependent modulation of the serotonin receptor type 3. The method includes the introduction of a therapeutically effective amount of the compounds of formula I, II or III. Examples of disorders that occur due to the improper activity and serotonin receptor type 3 or dependent modulation of the serotonin receptor type 3 include vomiting, especially CINV, IBS-D, postoperative nausea and vomiting and radiation-induced nausea and vomiting. Other such violations include physiological disorders, obesity, disorders relating to the abuse of various substances, dementia associated with a neurodegenerative disease, loss of cognition, pain, fibromyalgia syndrome and chronic fatigue syndrome (see published patent application U.S. 2004/0204467). It is also known that the antagonists of the serotonin receptor type 3 are applicable for the prevention and treatment of bronchial asthma, bulimia nervosa, asthma sleep apnea, itching and migraine (see Costall and Naylor, Current Drug Targets - CNS &Neurological Disorders, 2004:3 27-37 and Israili, Current Med. Chem. - CNS Agents, 2001:1 171-199). It is also known that the antagonists of the serotonin receptor type 3 are applicable for the prevention and treatment of epilepsy. The use of such compounds for the treatment of epilepsy demonstrated in the international patent application PCT/GB2006/002733.

Detailed description of the invention

Throughout this description, the substituents have the meanings mentioned at the first mention, and retain their specified values.

In the first aspect of the invention relates to compounds of formula I, II or III:

In General, it was found that the compounds of the above formulas, t is Auda potent and selective inhibitors of the receptor 5-NT3. Each of the three connection types can be divided into two subtypes: 4-carboxamide (Ia, IIa and IIIa) and 7-carboxamide (Ib, IIb and IIIb):

In these compounds R4represents a saturated nitrogenous heterocycle or substituted stands saturated nitrogenous heterocycle, in which the nitrogen atom is tertiary. Nitrogen-containing heterocycle (also known as nitrogenous heterocycle is a heterocycle containing at least one nitrogen atom in the ring; it may contain additional nitrogen atoms, as well as other heteroatoms. Nitrogenous heterocycles include piperidine, methylpiperidine, tropan, 9-azabicyclo[3.3.1]nonan-3-one andin which X represents NCH3, O, S, SO or SO2. In some embodiments, the implementation of R4represents a

and

in which m is 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; Q represents N(CH3or-O - and R5represents hydrogen or methyl. For example, R4can be hinokitiol, tropanol, azabicyclo[3.3.1]nananom, methylisobutyl[3.3.1]nananom, dimethylbicyclo[3.3.1]nananom, methylpiperidino or methyl-3-oxa-9-azabicyclo[3.3.1]nananom.

In some embodiments, the implementation of R1, R2and R3not only is jut a hydrogen and the other one of R 1, R2and R3represents a halogen.

In some embodiments, the implementation of R10selected from the group consisting of hydrogen and (C1-C3)alkyl. In other embodiments, the implementation of type II R11represents N or CH3and R10selected from the group consisting of phenyl, substituted phenyl, (C1-C6)alkyl, 4-7-membered monocyclic nitrogen heterocycle containing 4-10 carbon atoms, a bicyclic nitrogenous heterocycle, 4-7-membered monocyclic nitrogen heterocycle, substituted by one or more (C1-C6)alkilani containing 4-10 carbon atoms, a bicyclic nitrogenous heterocycle, substituted by one or more (C1-C6)alkilani, dimethylamino(C1-C6)alkyl, 4-7-membered monocyclic nitrogen heterocyclic(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl and dialkylaminoalkyl(C1-C6)alkyl.

In other embodiments, implementation of R10and R11taken together form a nitrogenous heterocycle or substituted nitrogenous heterocycle. Examples include morpholine, piperazine, piperidine, diazepan, tetrahydroquinoxalin, azabicyclo[3.3.1]nonan, triazolopyridine, diazabicyclo[2.2.1]heptane, or any of the above is of heterocycles, substituted one, two or three substituents, independently selected from (C1-C6)alkyl, halogen(C1-C6)alkyl, (C1-C6)alkoxyphenyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

Compounds within the above group of compounds and its subgroups are applicable as inhibitors of 5-NT3. During the examination you may find that connections that are not currently excluded from the claims are patentable for the inventors in this application. In this case, the exception of individual compounds and subgroups of the claims should be regarded as unintentional defects in the proceedings, which do not reflect the idea and description by the authors of their inventions. The invention as object "substance" are all compounds of formulas I, II and III, except (a) those compounds, which are in the public domain, and (b) a specific compound of example 55 within subgroups IIa in which R10, R11and the nitrogen atom form a ring of the research and R4apparently (based on NMR)is endo-3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-yl. Such a connection does not show the level of activity that is set as the threshold for screening.

Op is adelene

It is assumed that the alkyl comprises an unbranched, branched or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to alkyl groups containing 1-6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec - and tert-butyl and the like. Preferred alkyl groups are alkyl groups With20or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon group with 3-8 carbon atoms. Examples cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, norbornyl and the like. Some groups require a precise definition. The assertion that the term alkyl is intended to include non-branched, branched or cyclic hydrocarbon structures and combinations thereof, means that the following combination unbranched and cyclic structural elements

(and such combinations as the "alkyl" group. With1-C20the hydrocarbon includes alkyl, cycloalkyl, alkenyl, aryl, and combinations thereof. Examples include phenethyl, cyclohexylmethyl, Campari and naphtalate.

Alkoxy or alkoxyl refers to groups with 1-8 carbon atoms, an unbranched, branched or cyclic structures and combinations of these, join the United to the "main" structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropylamine, cyclohexyloxy and the like. Lower alkoxy refers to groups containing one to four carbon atoms.

Oxaalkyl refers to alkyl residues in which one or more carbon atoms replaced by oxygen atoms. Examples include methoxypropane, 3,6,9-trioxadecyl and the like.

Acyl refers to groups with 1-8 carbon atoms, an unbranched, branched, cyclic structures, saturated, unsaturated and aromatic, and combinations of these, attached to the "main" structure through the carbonyl functional group. One or more of the carbon atoms in the acyl residue may be replaced by a nitrogen atom, oxygen or sulfur, while the place of connection to the "main" structure remains at the carbonyl. Examples include acetyl (AC), benzoyl, propionyl, isobutyryl, tert-butoxycarbonyl, benzyloxycarbonyl and the like. The lower acyl refers to groups containing one to four carbon atoms.

Aryl and heteroaryl mean 5 - or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N or S; a bicyclic 9 - or 10-membered aromatic system or heteroaromatic ring containing 0-3 heteroatoms selected from O, N or S; or tricycle the definition of a 13 - or 14-membered aromatic system or heteroaromatic rings, containing 0-3 heteroatoms selected from O, N or S. the Aromatic 6 to 14-membered carbocyclic rings include, for example, benzene, naphthalene, indan, tetralin and fluoran, and 5-10-membered aromatic heterocyclic rings include, for example, imidazole, pyridine, indole, thiophene, benzopyrane, thiazole, furan, benzimidazole, quinoline, isoquinoline, cinoxacin, pyrimidine, pyrazin, tetrazole and pyrazole.

Arylalkyl refers to the residue, in which the aryl part is attached to the "main" part of the molecule through the alkyl. Examples are benzyl, phenethyl and the like. Tolyl is not arylalkyl; tolyl is alkylaryl. Heteroaromatic means a heteroaryl residue, attached to the "main" part through alkyl. Examples of it include, for example, pyridinylmethyl, pyrimidinyl and the like.

A heterocycle means cycloalkenyl or aryl residue with rings from one to three, from one to four carbon atoms replaced by a heteroatom selected from the group consisting of N, O and S. the Heteroatoms nitrogen and sulfur may be optionally oxidized and the nitrogen heteroatom may be optionally quaternity. Examples of heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (usually referred to as methylenedioxyphenyl, when p is outstay as Deputy), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazol, dioxane, tetrahydrofuran and the like. Nitrogen heterocycles are heterocycles containing at least one nitrogen atom. They may additionally include other heteroatoms and multiple nitrogen atoms. Examples include Hinkley, tropan, piperidine, piperazine, morpholine, quinoline, benzo[b][1,4]oxazin, 1,2,4-triazolo[4,3-a]pyrazin, perhydrophenanthrene and thiazole. It should be noted that heteroaryl are a subgroup of heterocycles, in which the heterocycle is aromatic. Dihydropteroate are, as their name implies, heteroaryl residues, formally restored one mole of hydrogen. Example dihydrohelenalin residue is 2,3-dihydrobenzofuran.

Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refers to alkyl, aryl, cycloalkyl or heterocyclyl, where up to four atoms N in each residue are replaced with halogen, halogenation, hydroxy, lower alkoxy, carboxy, alkoxycarbonyl (COOR), oxo, carboxamido (-CONR2), sulfonamide (SO2NR2), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfonal, acylamino, amidino, phenyl, benzyl, heterocyclyl, heterocyclisation, phenoxy, gasoline is hydroxy or heteroaromatic. In the preceding list R represents hydrogen or alkyl.

The term "halogen" means fluorine atom, chlorine, bromine or iodine.

Some of the compounds described herein may contain one or more asymmetric centers and may thus be due to the existence of enantiomers, diastereomers, and other stereoisomeric forms that can be described in terms of absolute stereochemistry as (R)- or (S)-isomers. Have in mind that the present invention includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (R)- and (S)-isomers can be obtained using chiral synthons or chiral reagents, or the separation of mixtures using conventional methods. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, is meant that the compounds include both E and Z geometric isomers. Similarly mean that the compounds include all tautomeric forms. The configuration of any carbon-carbon double bond that is shown in them, selected for convenience only and do not assume that it means a specific configuration, so the carbon-carbon bond, pictured here arbitrarily as TRANS, can be Z-, E-configuration or a mixture of the boom configurations in any respect.

It should be clear that the compounds of this invention can exist in the form of radioisotope-labeled, i.e. the compounds may contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorus, fluorine, chlorine, and iodine include3H,14C,35S18F,36Cl125I, respectively. Compounds that contain radioisotopes and/or other isotopes of other atoms are within the scope of this invention. Radioisotopes tritium, i.e3N, and carbon-14, i.e14With, are especially preferred due to the ease of obtaining them and detectiveyoshi. Radioisotope-labeled compounds of this invention are usually obtained by methods well known to the person skilled in the art. Such radioisotope-labeled compounds can be obtained appropriately by carrying out the techniques described in the examples and schemes, replacing its radioactive isotope reagent readily available, radiolabelled reagent.

Terminology relating to "protection", "removing protection" and "protected" functional groups found throughout this application. This terminology is understandable to those skilled in about the region and its use in the context of ways, which include sequential processing of a number of reagents. In this context, the protective group refers to a group that is used to mask a functional group during the stage of the way in which it could otherwise react, but in which the reaction is undesirable. Protective group prevents reaction at this stage, but it can then be removed to obtain the original functional group. The removal of the protective group or "removing protection" takes place after completion of the reaction or reactions, which may prevent the mentioned functional group. Thus, when you specify the sequence of reagents, as is the case in the methods of the invention, the person skilled in the art can easily determine those groups that may be suitable as a "protective groups". Suitable groups for this purpose are discussed in standard textbooks in the field of chemistry, such as publishing Protective Groups in Organic Synthesis by T. W. Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference.

The term "prevention"as used here, refers to the administration of a medicinal product in advance to prevent or mitigate the attack. Specialist in the field of medicine (which includes the claims on the way) understands that the term "prevention" is e an absolute term. It is clear that in medicine it refers to the prophylactic administration of a medicinal product to significantly reduce the probability of occurrence or the severity of the condition, and this term has the sense assumed here. In fact, the publication 2006 publication of the Physician''s Desk Reference, which is a standard textbook in the field, used the term "prophylaxis" or "prevention" at least 10 times in his description of the criteria palonosetron.

Graphics racemic, ambisyllabic and solemny or enantiomerically pure compounds used here are taken from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate the exclusion of any stereochemical values that link, it represents, could form; a solid and clear broken lines are geometric descriptors indicating the relative configuration, but denoting racemic; and a wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. A simple solid line says nothing about stereochemistry. For example, in the illustration for example 2 the following table shows a solid line, but the connection p is the iMER actually is an individual enantiomer and S-configuration, and it can properly portray as

It is assumed, as should be clear to the person skilled in the art that used here, the term "connection" includes a salt, solvate and inclusion complexes of such compounds. The term "MES" refers to the compound of formula I in the solid state, in which molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic injection is physiologically tolerated when injected dose. Examples of suitable solvents for therapeutic injection are ethanol and water. When water is the solvent, the MES is called a hydrate. In General, the solvate is obtained by dissolving the compound in a suitable solvent and the release of MES cooling or application of antibacterial. MES is usually dried or subjected to azeotropic distillation in the environment. The inclusion complexes described in the publication Remington: The Science and Practice of Pharmacy 19th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly used of the inclusion complexes are complexes with cyclodextrins, and all complexes with cyclodextrins, natural and synthetic, in particular, included in the invention.

The term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically receiving the protected non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. When the compounds of the present invention is basic, salts may be obtained from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Suitable pharmaceutically acceptable acid additive salts of the compounds of the present invention include salts formed acetic acid, benzosulfimide (besylate), benzoic, camphorsulfonic, lemon, econsultancy, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate acid and the like. When the compounds contain acidic side chain, suitable pharmaceutically acceptable basic additive salts of the compounds of the present invention include metal salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts derived from lysine, N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine.

A complete list of abbreviations used by the specialists of organic chemistry, presented in the first issue of each volume of the Journal of Organic Chemistry. The list is to, which is usually present in the table entitled "Standard list of abbreviations", incorporated herein by reference.

Generalized synthetic scheme is shown below.

General methods of modification of the rings benzoxazole

Conditions: A) amine, the solvent; C) the basis hydroxide; (C) amine, EDCI, HOBt, DMF or HBTU, DMF; (D) HCl, MeOH or Et2O

General procedure (GP-A) amination ring benzoxazole

A mixture of the appropriate 2-chlorobenzoxazole,A1(1 EQ) and the appropriate amine (2 EQ) and an optional basis (For example, a2CO3, triethylamine, Diisopropylamine, 1,8-diazabicyclo[5.4.0]undecene or sodium hydride) in THF (or DME, DMF) is heated in the range 20-80°C for up to 24 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The crude product is purified column chromatography on silica gel (typical eluent include a mixture of 9:1 dichloromethane/methanol, ethyl acetate, hexane), thus obtaining the desired product, 2-aminobenzothiazole. The structure of the product is confirmed1H NMR or mass analysis.

General procedure (GP-B1) hydrolysis of the methyl ester

A mixture of methyl esterA22 N. NaOH and THF was stirred at room temperature for 12 hours. The reaction mixture is neutralized 2 N. HCl and then extragere the t dichloromethane. The combined organic layers are dried (Na2SO4), filtered and concentrated, thus obtaining the desired carboxylic acidA3. The structure of the product is confirmed or1H NMR, or mass analysis.

General procedure (GP-B2) hydrolysis of the methyl ester (carboxylate salt of lithium)

A mixture of methyl esterA2and monohydrate of lithium hydroxide (1-3 EQ) in methanol/water (3:1) was stirred at room temperature until completion of the reaction according to LC-MS. The solvent is removed in vacuum and the crude lithium saltA3dried under high vacuum and then used without further purification. The structure of the product is confirmed1H NMR or mass analysis.

General procedure (GP-B3) hydrolysis of the methyl ester

A mixture of methyl esterA2, monohydrate of lithium hydroxide (1-3 EQ) and methanol/water or THF/water (3:1 to 5:1) was stirred at room temperature until completion of the reaction according to LC-MS. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water, acidified (pH 1-5) 3n hydrochloric acid and concentrated to dryness. The solid is triturated in dichloromethane and the filtrate concentrated under reduced pressure, thus obtaining the desired carboxylic acidA3. The structure of the product is confirmed or1H NMR, or mass analysis.

<> General procedure (GP-C1) amidation

A mixture of carboxylic acids or carboxylate salts of lithiumA3(1 EQ), the appropriate amine (for example, dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.0]nonane (1 EQ), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2 EQ)and 1-hydroxybenzotriazole (2 equivalents) in DMF was stirred at room temperature for 5 min, then add triethylamine (2-4 EQ). The resulting reaction mixture is stirred at room temperature for 12 hours. The mixture is diluted with dichloromethane and then washed with saturated sodium bicarbonate solution. The aqueous layer was further extracted with dichloromethane. The combined organic layers are dried (Na2SO4), filtered and concentrated. The crude substance is purified by chromatography on silica gel (typical eluent: a mixture of ethyl acetate/hexane, ethyl acetate/methanol, dichloromethane, a mixture of dichloromethane/methanol or dichloromethane/methanol/concentrated ammonium hydroxide), while receiving the desired carboxamideA4. The structure of the product is confirmed1H NMR.

General procedure (GP-C2) amidation

A mixture of carboxylic acids or carboxylate salts of lithiumA3(1 EQ), the appropriate amine (for example, dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.0]nonane) (1 EQ)and HBTU (1.3 to 2 EQ) in DMF was stirred at room temperature for 5 is in then add triethylamine (2-4 EQ). The resulting reaction mixture is stirred at room temperature for 12 hours. The mixture is diluted with dichloromethane and then washed with saturated sodium bicarbonate solution. The aqueous layer was further extracted with dichloromethane. The combined organic layers are dried (Na2SO4), filtered and concentrated. The crude substance is purified by chromatography on silica gel (typical eluent: a mixture of ethyl acetate/hexane, ethyl acetate/methanol, dichloromethane, a mixture of dichloromethane/methanol or dichloromethane/methanol/concentrated ammonium hydroxide), while receiving the desired carboxamideA4. The structure of the product is confirmed1H NMR.

General procedure (GP-D1) transformations in salt HCl

It chilled with ice to a solution of the carboxamideA4(1 EQ) in dichloromethane and ethyl ether added hydrogen chloride (2 EQ) in methanol. The mixture is stirred at room temperature for 5 min and then diluted with anhydrous ethyl ether. The mixture was kept at room temperature for 2 hours and then the resulting precipitate is collected by filtration and washed with ethyl ether. The solid is dried under vacuum, thus obtaining the desired cleaners containing hydrochloride saltA4. The structure of the product is confirmed1H NMR.

General procedure (GP-D2) conversion into HCl salt

Chilled l is ω the solution of the BOC-protected carboxamide of the GP-C (1 EQ) is treated with excess or TFA, or HCl in diethyl ether, dioxane or methanol) in dichloromethane. The crude salt is diluted with methanol and loaded into a column of cation exchange resin (column 10 g isolute SCX-2). The column is washed with methanol (50 ml) and the product then elute 2 N. the ammonium hydroxide in methanol (50 ml). The solution is concentrated under reduced pressure. The crude substance is purified by chromatography on silica gel (typical eluent: a mixture of dichloromethane/methanol, dichloromethane/methanol/concentrated ammonium hydroxide), while receiving the desired carboxamide. Carboxamid then treated with HCl (1-2 equivalents) in dichloromethane and concentrated under reduced pressure. Amorphous cleaners containing hydrochloride salt lyophilized in a mixture of acetonitrile/water (6:1), thus obtaining the desired cleaners containing hydrochloride saltA4. The structure of the product is confirmed by analysis of the mass and1H NMR.

General procedure (GP-E) acylation of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

To ice a mixture of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide and triethylamine in CH2Cl2add a suitable acylchlorides, chloroformate or sulphonylchloride. The mixture allow to warm to ambient temperature and then stirred for up to an additional 4 hours. The reaction mixture was quenched with a mixture of CH3HE/saturated salt solution and the resulting mixture extracted with dichloromethane (2×). The combined organic layers are washed sequentially with 10% citric acid and saturated salt solution, then dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of column chromatography (silica gel, mixture of 9:1 CH2Cl2/CH3HE to a mixture of 90:9:1 CH2Cl2/CH3HE/NH4OH), gives the corresponding endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-arylpiperazine-1-yl)benzoxazole-4-carboxamide.

Obtaining methyl-2-chlorobenzoxazole-4-carboxylate

Conditions: (A) TMSCHN2; (B) O-ethylxanthate potassium, pyridine; (C) PCl5, POCl3.

Stage A: To a cooled ice slurry hydrobromide 2-amino-3-hydroxybenzoic acid (3.0 g, 12.8 mmol) in toluene (30 ml) and methanol (30 ml) is slowly added (trimethylsilyl)diazomethane (16.0 ml, 2 M solution in ethyl ether, 32,0 mmol), the mixture is then stirred at 0°C for 20 min In the reaction mixture at 0°C, add acetic acid (5 ml), the mixture is then stirred at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure and then the crude product is dissolved in ethyl acetate and washed with saturated solution of bi is carbonate sodium and saturated salt solution. The organic layer is dried (Na2SO4), filtered and concentrated. The crude product is purified column chromatography (silica gel, mixture 1:1 hexane/ethyl acetate), thus obtaining the desired ester (2,04 g, 95%) as a light brown solid.1H NMR (500 MHz, CDCl3) δ of 7.48 (DD, J=8,0, 1.5 Hz, 1H), for 6.81 (DD, J=7,5, 1.5 Hz, 1H), 6,50 (t, J=8.0 Hz, 1H), 5,80 (users, 2H), a 3.87 (s, 3H); MC (ESI+) m/z 168 (M+H).

Stage C. a Mixture of methyl 2-amino-3-hydroxybenzoate from the stage And (2,04 g, 12.2 mmol) and O-ethylxanthate potassium (1,37 g, 8,56 mmol) in pyridine (8 ml) is refluxed for 2 hours, then cooled to room temperature and poured into a mixture of ice-water (45 ml) and concentrated HCl (4.8 ml). The resulting precipitate is collected by filtration and washed with water, dried under vacuum, thus obtaining methyl-2-thioxo-2,3-dihydroisoxazole-4-carboxylate (1,33 g, 52%) as a light brown solid.1H NMR (500 MHz, CDCl3) the 10.40 δ (users, 1H), 7,82 (DD, J=8.0 a, 1.0 Hz, 1H), 7,49 (DD, J=8.0 a, 1.0 Hz, 1H), 7,28 (t, J=8.0 Hz, 1H), 4,01 (s, 3H); MC (ESI+) m/z 210 (M+H).

Stage C. the Mixture thione with stage (0.65 g, 3.11 mmol) and pentachloride phosphorus (0.65 g, 3.11 mmol) in phosphorus oxychloride (6 ml) is heated to 95°C for 2.5 hours. After cooling to room temperature the reaction mixture was concentrated and dried under vacuum, thus obtaining methyl-2-chlorobenzoxazole-4-carboxylate (0.66 g, quantitative yield) is the form of a brown solid. 1H NMR (300 MHz, CDCl3) δ with 8.05 (DD, J=8,1, 1.2 Hz, 1H), 7,72 (DD, J=8,1, 1.2 Hz, 1H), 7,45 (t, J=8,1 Hz, 1H), Android 4.04 (s, 3H); MC (ESI+) m/z 212 (M+H).

Obtaining methyl-2,6-dichlorobenzoate-4-carboxylate

Conditions: (a) O-ethylxanthate potassium, pyridine, (B) PCl5, POCl3.

Stage A. To a mixture of methyl 2-amino-5-chloro-3-hydroxybenzoate (4,00 g, 19,84 mmol) in anhydrous pyridine (30 ml) is added O-ethylxanthate potassium (3.50 g, 21,82 mmol) and the reaction mixture is heated to 125°C for 3 hours in nitrogen atmosphere. The warm solution is poured into a mixture of concentrated HCl (12 ml) and ice (120 ml), the formed precipitate was separated by filtration and dried under vacuum, thus obtaining methyl-6-chloro-2-thioxo-2,3-dihydroisoxazole-4-carboxylate (4,80 g, 99%) as a yellow solid:1H NMR (300 MHz, CDCl3) δ 8,10 (s, 1H), 7,81 (d, J=1.9 Hz, 1H), of 7.48 (d, J=1.9 Hz, 1H), 4,01 (s, 3H); MC (ESI+) m/z 244 (M+H).

Stage C. a Mixture of the product from step A (2.00 g, 8.20 mmol), POCl3(1.26 g, 8,21 mmol), and PCl5(1,71 g, 8,21 mmol) is heated to 125°C for 2.5 hours. The reaction mixture was dried in high vacuum for 24 hours, while receiving methyl-2,6-dichlorobenzoate-4-carboxylate (2.00 g, 99%) as a brown solid:1H NMR (300 MHz, CDCl3) δ of 8.04 (d, J=2.0 Hz, 1H), 7,72 (d, J=2.0 Hz, 1H), Android 4.04 (s, 3H); MC (ESI+) m/z 247 (M+H).

Obtaining methyl-2-chloro-7-fermentation-4-carboxylate

Conditions: (A) SOCl2, methanol; (C) 1,1'-thiocarbonyldiimidazole; (C) PCl5, POCl3.

Stage A: To a solution of 2-amino-4-fluoro-3-hydroxybenzoic acid (2,44 g, 9.7 mmol) in methanol (200 ml) is added thionyl chloride (3.8 ml, 50 mmol) at -78°C. the Mixture is stirred at the boiling solvent for 17 hours. The solvent is removed under reduced pressure; the residue is dissolved in methanol (200 ml). The solution is cooled to -78°C and treated with thionyl chloride (8 ml, 100 mmol). The mixture is stirred in boiling solvent within 48 hours. The solvent is removed under reduced pressure and the crude substance is purified column chromatography (silica gel, 0-70% ethyl acetate in hexano), while receiving methyl-2-amino-4-fluoro-3-hydroxybenzoate (1.5 g, 44%) as not quite white solid.1H NMR (300 MHz, CDCl3) δ of 7.48-the 7.43 (m, 1H), 6,40 (t, J=9,3 Hz, 1H), a 3.87 (s, 3H); MC (ESI+) m/z 186 (M+H).

Stage C. a Mixture of methyl 2-amino-4-fluoro-3-hydroxybenzoate (1.5 g, 8,11 mmol) and 1,1'-thiocarbonyldiimidazole (1,46 g, 8.2 mmol) in THF (30 ml) was stirred at ambient temperature overnight and at 50°C for 6 hours. The reaction mixture was cooled to ambient temperature and the solvent is removed under reduced pressure. The residue is washed with ether (3×50 ml) and dried, thus obtaining methyl-7-fluoro-2-thioxo-2,3-dihydroisoxazole-4-carboxylate (1.3 g, 70%) as a yellow solid matter what. 1H NMR (500 MHz, CDCl3) δ 7,82 for 7.78 (m, 1H), 6,40 (t, J=9.0 Hz, 1H), 4.00 points (s, 3H); (ESI+) m/z 228 (M+H).

Stage C. a Mixture of methyl 7-fluoro-2-thioxo-2,3-dihydroisoxazole-4-carboxylate (1.3 g, 5,72 mmol) and pentachloride phosphorus (1.2 g, 5,72 mmol) in phosphorus oxychloride (2,6 ml of 10.25 mmol) is heated to 95°C for 3.5 hours. After cooling to room temperature the reaction mixture was concentrated and dried under vacuum, thus obtaining methyl-2-chloro-7-fermentation-4-carboxylate (1.3 g, quantitative yield) as a brown solid.1H NMR (300 MHz, CDCl3) δ 8,08-of 8.04 (m, 1H), 7,21 (t, J=9,3 Hz, 1H), was 4.02 (s, 3H); MS (ESI+) m/z 229 (M+H).

In other embodiments, implement, where X is not an atom of hydrogen or halogen, the method of obtaining the above-mentioned compounds is similar to the method disclosed in the patent application U.S. 2006/183769, the full contents of which are incorporated herein by reference. In cases where there is an inconsistency in the nomenclature between the above-mentioned application and the present application, the nomenclature and definitions of this application have priority.

Example 1: Getting dihydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and 1-methylpiperazin converted into methyl-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxylate.1H NMR and MS is podtverjdayut the structure.

Stage C. According to the General method GP-B1 methyl-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxylate converted into 2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxylic acid.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 methyl-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxylate converted into 2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxylic acid. Acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane then condense with the receipt of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxamide, which in turn dihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 2: obtain the dihydrochloride of (S)-N-(Hinkley-8-yl)-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxamide

According to the General method GP-C1 condense 2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxamide, which in turn dihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 3: Obtaining hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(piperidine-1-yl)benzoxazole-4-carboxamide

Stage A. Methyl-2-(piperidine-1-yl)benzoxazole-4-carboxy is at synthesized according to the General method GP-A. 1H NMR and MS confirmed the structure.

Stage B. 2-(piperidine-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1, except that the reaction mixture is heated to 50°C for 12 h.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(piperidine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(piperidine-1-yl)benzoxazole-4-carboxamide, which in turn dihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 4: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-(piperidine-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-C1 condense a mixture of 2-(piperidine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-(piperidine-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 5: Receiving hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(phenylamino)benzoxazole-4-carboxamide

Stage A. Methyl-2-(phenylamino)benzoxazole-4-carboxylate synthesized by General methods the e GP-A. 1H NMR and MS confirmed the structure.

Stage B. 2-(Phenylamino)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1, except that the reaction mixture is heated to 50°C for 12 h.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(phenylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(phenylamino)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 6: obtain the hydrochloride of (S)-N-(Hinkley-8-yl)-2-(phenylamino)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-(phenylamino)benzoxazole-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-(phenylamino)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 7: Getting hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(dimethylamino)benzoxazole-4-carboxamide

Stage A. Methyl-2-(dimethylamino)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS is podtverjdayut the structure.

Stage B. 2-(dimethylamino)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(dimethylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(dimethylamino)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 8: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-(dimethylamino)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-(dimethylamino)benzoxazole-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-(dimethylamino)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 9: Getting hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-morpholinoethoxy-4-carboxamide

Stage A. Methyl-2-morpholinoethoxy-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage 2-Morpholinoethoxy-4-carboxylic acid synthesized according to the General method P-B1. 1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-morpholinoethoxy-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-morpholinoethoxy-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 10: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-morpholinoethoxy-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-morpholinoethoxy-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-morpholinoethoxy-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 11: Getting dihydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methyl-1,4-diazepan-1-yl)benzoxazole-4-carboxamide

Stage A. Methyl-2-(4-methyl-1,4-diazepan-1-yl)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage B. 2-(4-Methyl-1,4-diazepan-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. For about what her method GP-C1 condense a mixture of 2-(4-methyl-1,4-diazepan-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methyl-1,4-diazepan-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 12: Getting dihydrochloride (S)-N-(Hinkley-8-yl)-2-(4-methyl-1,4-diazepan-1-yl)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-(4-methyl-1,4-diazepan-1-yl)benzoxazole-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-(4-methyl-1,4-diazepan-1-yl)benzoxazole-4-carboxamide, which in turn dihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 13: Getting hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-methylthiotetrazole-4-carboxamide

Stage A. To a solution of methyl-2-thioxo-2,3-dihydroisoxazole-4-carboxylate (1.5 g, 7.2 mmol) in acetone (150 ml) is added potassium carbonate (4,00 g, 28.7 mmol) followed by the addition of iodomethane (0,89 ml, 14.0 mmol), the mixture is then stirred at room temperature for 12 hours. The reaction mixture is filtered through diatomaceous earth and washed with acetone, then concentrate under reduced pressure. The crude product is purified column chromatography (silica gel, mixture 3:1 hexane/EtOAc), thus obtaining the desired product is (1.4 g, 86%) as a pale yellow solid.1H NMR and MS confirmed the structure.

Stage B. 2-(Methylthio)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(methylthio)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-methylthiotetrazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 14: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-(methylthio)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-(methylthio)benzoxazole-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-(methylthio)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 15: Getting hydrochloride endo-N-(1-methylpiperidin-4-yl)-2-morpholinoethoxy-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-morpholinoethoxy-4-carboxylic acid and 4-amino-1-methylpiperidine, while receiving N-(1-methylpiperidin-4-yl)-2-morpholino isoxazol-4-carboxamid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 16: Getting dihydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(azetidin-3-ylamino)benzoxazole-4-carboxamide

Stage A. Methyl-2-(1-(tert-butoxycarbonyl)azetidin-3-ylamino)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage B. 2-(1-(tert-Butoxycarbonyl)azetidin-3-ylamino)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(1-(tert-butoxycarbonyl)azetidin-3-ylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving tert-butyl-3-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-ylamino)azetidine-1-carboxylate.1H NMR and MS confirmed the structure.

Stage D. To a cooled solution of tert-butyl 3-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-ylamino)azetidine-1-carboxylate (69 mg, 0.15 mmol) in CH2Cl2(5 ml) is added TFA (of 0.12 ml, 1.5 mmol). The reaction mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. General methods the e GP-D1 resulting TFA salt (73 mg, 0.15 mmol) is converted into the dihydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(azetidin-3-ylamino)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Example 17: Getting hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-[(2S,6R)-2,6-dimethylmorpholine]benzoxazole-4-carboxamide

Stage A. Methyl-2-[(2S,6R)-2,6-dimethylmorpholine]benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage B. 2-[(2S,6R)-2,6-Dimethylmorpholine]benzoxazol-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-[(2S,6R)-2,6-dimethylmorpholine]benzoxazol-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-[(2S,6R)-2,6-dimethylmorpholine]benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 18: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-((2S,6R)-2,6-dimethylmorpholine)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-[(2S,6R)-2,6-dimethylmorpholine]benzoxazol-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N(Hinkley-8-yl)-2-((2S,6R)-2,6-dimethylmorpholine)benzoxazol-4-carboxamid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 19: Obtaining hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-phenylmorpholine)benzoxazole-4-carboxamide

Stage A. Methyl-2-(3-phenylmorpholine)benzoxazole-4-carboxylate synthesized according to the General method GP-A, using triethylamine (1.5 EQ) as an optional basis.1H NMR and MS confirmed the structure.

Stage B. 2-(3-Phenylmorpholine)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(3-phenylmorpholine)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-phenylmorpholine)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1 and salt is isolated in the form of a mixture of enantiomers.1H NMR and MS confirmed the structure.

Example 20: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-(3-phenylmorpholine)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-(3-phenylmorpholine)benzoxazole-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(x is nuclein-8-yl)-2-(3-phenylmorpholine)benzoxazol-4-carboxamid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 21: Getting dihydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(piperazine-1-yl)benzoxazole-4-carboxamide

Stage A. Methyl-2-(4-(tert-butoxycarbonyl)piperazine-1-yl)benzoxazole-4-carboxylate synthesized according to the General method GP-A, except that the reaction is carried out at room temperature for 1 h before concentrating.1H NMR and MS confirmed the structure.

Stage B. 2-[4-(tert-Butoxycarbonyl)piperazine-1-yl]benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(1-(tert-butoxycarbonyl)azetidin-3-ylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving tert-butyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate.1H NMR and MS confirmed the structure.

Stage D. It chilled with ice to a solution of tert-butyl 4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate (73 mg, 0.15 mmol) in CH2Cl2(5 ml) is added TFA (0.16 ml, 2.0 mmol). The reaction mixture was stirred at on the th temperature for 12 h and then concentrated under reduced pressure. According to the General method GP-D1 resulting TFA salt (92 mg, 0.15 mmol) is converted into the dihydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(piperazine-1-yl)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Example 22: Obtaining dihydrochloride (S)-N-(Hinkley-8-yl)-2-(piperazine-1-yl)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-[4-(tert-butoxycarbonyl)piperazine-1-yl]benzoxazole-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, while receiving tert-butyl-4-[4-(Hinkley-8-ylcarbonyl)benzoxazol-2-yl]piperazine-1-carboxylate (85 mg, 0,19 mmol), to which is added TFA (0.17 ml, 2.3 mmol). The reaction mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. Salt TFA in turn dihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 23: obtain the dihydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methyl-2-phenylpiperazin-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and 1-methyl-3-phenylpiperazin converted into methyl-2-(4-methyl-2-phenylpiperazin-1-yl)benzoxazole-4-carboxylate, except that the reaction is carried out at room temperature for 1.5 h before concentrating.1NAMR and MS confirmed the structure.

Stage B. 2-(4-Methyl-2-phenylpiperazin-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(4-methyl-2-phenylpiperazin-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methyl-2-phenylpiperazin-1-yl)benzoxazole-4-carboxamide, which in turn dihydrochloride salt according to the General method GP-D1 and salt is isolated in the form of a mixture of enantiomers.1H NMR and MS confirmed the structure.

Example 24: Getting dihydrochloride (S)-N-(Hinkley-8-yl)-2-(4-methyl-2-phenylpiperazin-1-yl)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-[4-(tert-butoxycarbonyl)piperazine-1-yl]benzoxazole-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-(4-methyl-2-phenylpiperazin-1-yl)benzoxazole-4-carboxamide, which in turn dihydrochloride salt according to the General method GP-D1 and salt is isolated in the form of a mixture of diastereoisomers.1H NMR and MS confirmed the structure.

Example 25: obtain the dihydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-methylpiperazin-1-yl)benzoxazole-4-carboxamide

Stage A. Methyl-2-[4-(tert-b is oxycarbonyl)-2-methylpiperazin-1-yl]benzoxazole-4-carboxylate synthesized according to the General method GP-A. 1H NMR and MS confirmed the structure.

Stage B. 2-[4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl]benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense 2-[4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl]benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving tert-butyl-3-methyl-4-(endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate.1H NMR and MS confirmed the structure.

Stage D. It chilled with ice to a solution of tert-butyl 3-methyl-4-(endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate (120 mg, 0.24 mmol) in CH2Cl2(5 ml) is added TFA (to 0.29 ml, 3.6 mmol). The reaction mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. According to the General method GP-D1 resulting TFA salt converted into the dihydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-methylpiperazin-1-yl)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Example 26: Getting dihydrochloride (S)-N-(Hinkley-8-yl)-2-(2-methylpiperazin-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-C1 Conde is serout 2-[4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl]benzoxazole-4-carboxylic acid dihydrochloride and (S)-(-)-3-aminoquinuclidine, while receiving tert-butyl-3-methyl-4-(4-(Hinkley-8-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate.1H NMR and MS confirmed the structure.

Stage Century, chilled with ice to a solution of tert-butyl 3-methyl-4-(4-(Hinkley-8-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate (90 mg, 0,19 mmol) in CH2Cl2(5 ml) is added TFA (0.25 ml, 3.2 mmol). The reaction mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. According to the General method GP-D1 resulting TFA salt converted into the dihydrochloride (S)-N-(Hinkley-8-yl)-2-(2-methylpiperazin-1-yl)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Example 27: Obtaining dihydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(pyridine-4-ylamino)benzoxazole-4-carboxamide

Stage A. a Mixture of methyl-2-chlorobenzoxazole-4-carboxylate (350 mg, of 1.65 mmol), 4-aminopyridine (233 mg, 2.48 mmol), palladium(II) acetate (7.4 mg, 0,033 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (39 mg, 0,083 mmol), K2CO3(570 mg, 4,13 mmol) and tert-BuOH (4 ml) heated to 90°C for 40 min After cooling to room temperature the reaction mixture is filtered through diatomaceous earth and concentrated. The crude product is purified column chromatography (silica gel, mixture of 9:1 CH2Cl2/CH3IT), floor the tea methyl-2-(pyridine-4-ylamino)benzoxazole-4-carboxylate. 1H NMR and MS confirmed the structure.

Stage B. 2-(Pyridine-4-ylamino)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(pyridine-4-ylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(pyridine-4-ylamino)benzoxazole-4-carboxamide, which in turn dihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 28: Obtaining dihydrochloride (S)-N-(Hinkley-8-yl)-2-(pyridine-4-ylamino)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-(pyridine-4-ylamino)benzoxazole-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-(pyridine-4-ylamino)benzoxazole-4-carboxamide, which in turn dihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 29: obtain the dihydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3,4-dihydroquinoxaline-1(2H)-yl)benzoxazole-4-carboxamide

Stage A. Methyl-2-(3,4-dihydroquinoxaline-1(2H)-yl)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS on the confirm the structure.

Stage B. 2-(3,4-Dihydroquinoxaline-1(2H)-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(3,4-dihydroquinoxaline-1(2H)-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3,4-dihydroquinoxaline-1(2H)-yl)benzoxazole-4-carboxamide, which in turn dihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 30: obtain the hydrochloride of endo-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]non-7-yl)-2-(dimethylamino)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-(dimethylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-7-amino-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]non-7-yl)-2-(dimethylamino)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 31: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoxazole-4-carboxamide

Stage A. Methyl 2-((2-(dimethylamino)ethyl)(methyl)amino)benzoxazole-4-carboxylate synthetic is irout common method GP-A. 1H NMR and MS confirmed the structure.

Stage C. the Solution methylethyl-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoxazole-4-carboxylate (620 mg, 1.4 mmol) and the monohydrate of lithium hydroxide (130 mg, 3.0 mmol) in N2O (2.5 ml) and THF (15 ml) was stirred at room temperature for 17 hours. THF is removed under reduced pressure and the residue was diluted with H2About 150 ml and then loaded into a column anionoobmennika (Cl-form resin Bio Rad AG 1-X8, 2.6 mEq/g (dry), 5.5 g of resin (wet)). The column was washed with H2And then elute the product 0.1 G. of HCl (aqueous). Fraction of the product are combined and concentrated. The residue is treated CH3HE (3×15 ml) and then lyophilized, while receiving the dihydrochloride of 2-((2-(dimethylamino)ethyl)(methyl)amino)benzoxazole-4-carboxylic acid (273 mg, 58% (stage 2)in the form of a reddish-brown solid.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense the mixture of the dihydrochloride of 2-[(2-(dimethylamino)ethyl)(methyl)amino]benzoxazol-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-[(2-(dimethylamino)ethyl)(methyl)amino]benzoxazol-4-carboxamid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

u> Example 32: Getting trihydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2-(dimethylamino)ethylamino)benzoxazole-4-carboxamide

Stage A. Methyl-2-(2-(dimethylamino)ethylamino)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. a Solution of methyl 2-(2-(dimethylamino)ethylamino)benzoxazole-4-carboxylate (570 mg, 1.4 mmol) and the monohydrate of lithium hydroxide (130 mg, 3.0 mmol) in N2O (2.5 ml) and THF (15 ml) was stirred at room temperature for 17 hours. THF is removed under reduced pressure and the residue was diluted with H2About 150 ml and then loaded into a column anionoobmennika (Cl-form resin Bio Rad AG 1-X8, 2.6 mEq/g (dry), 3.5 g of resin (wet)). The column was washed with H2And then elute the product 0.1 G. of HCl (aqueous). Fraction of the product are combined and concentrated. The residue is treated CH3HE (3×15 ml) and then lyophilized, while receiving the dihydrochloride of 2-(2-(dimethylamino)ethylamino)benzoxazole-4-carboxylic acid (270 mg, 60% (stage 2)in the form of a reddish-brown solid.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense the dihydrochloride of 2-(2-(dimethylamino)ethylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-and bicyclo[3.3.1]nonan-3-yl)-2-(2-(dimethylamino)ethylamino]benzoxazol-4-carboxamid, which in turn trihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 33: Getting trihydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2-morpholinoethyl)benzoxazole-4-carboxamide

Stage A. Methyl-2-(2-morpholinoethyl)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. a Solution of methyl 2-(2-morpholinoethyl)benzoxazole-4-carboxylate (220 mg, to 0.72 mmol) and the monohydrate of lithium hydroxide (60 mg, 1.44 mmol) in N2O (1 ml) and THF (10 ml) was stirred at room temperature for 17 hours. THF is removed under reduced pressure and the residue was diluted with H2About 150 ml and then loaded into a column anionoobmennika (Cl-form resin Bio Rad AG 1-X8, 2.6 mEq/g (dry), 2.5 g of resin (wet)). The column was washed with H2And then elute the product 0.1 G. of HCl (aqueous). Fraction of the product are combined and concentrated. The residue is treated CH3HE (3×15 ml) and then lyophilized to give the hydrochloride of 2-(2-morpholinoethyl)benzoxazole-4-carboxylic acid (230 mg, 98%) as not quite white solid.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense the mixture of the hydrochloride of 2-(2-morpholinoethyl)benzoxazole-4-carboxylic acid and dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2-morpholinoethyl)benzoxazol-4-carboxamide, which in turn trihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 34: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(methylamino)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A mixture of methyl 2-chlorobenzoxazole-4-carboxylate and methylamine is heated to 80°C. in a sealed tube for 4 hours, thus obtaining methyl-2-(methylamino-4-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. 2-(Methylamino-4-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(methylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(methylamino)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 35: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-aminobenzothiazole-4-carboxamide

Stage A. To a solution of imidazole (13,63 g, 200 mmol) in CH 2Cl2(750 ml) was added CYANOGEN bromide at room temperature and the resulting mixture is refluxed for 45 minutes, the Reaction mixture was cooled to room temperature and the resulting solid substance produce by filtration. The filtrate is concentrated, while receiving di(1H-imidazol-1-yl)metonymy in the form of a white solid (10.5 g, 97%).1H NMR and MS confirmed the structure.

Stage b: synthesis of methyl 2-aminobenzoate-4-carboxylate. To a solution of di-(1H-imidazol-1-yl)methanamine (2,05 g of 12.26 mmol) in THF (60 ml) is added methyl 2-amino-3-hydroxybenzoate (1.98 g, of 12.26 mmol) at room temperature and the resulting reaction mixture is refluxed for 17 hours. The reaction mixture is cooled to room temperature, diluted with EtOAc (100 ml) and washed with H2About (3×100 ml), saturated ammonium chloride (2×100 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude substance is purified by recrystallization from diethyl ether, thus obtaining methyl-2-aminobenzothiazole-4-carboxylate (1.10 g, 50%) as a brown solid.1H NMR and MS confirmed the structure.

Stage C. a Mixture of methyl-2-aminobenzothiazole-4-carboxylate (750 mg, 3.9 mmol) and di-tert-BUTYLCARBAMATE (936 mg, the 4.29 mmol) in CH2Cl2(50 ml) paramashiva the t at room temperature for 17 hours. The reaction is quenched with saturated NaHCO3(25 ml) and then extracted with CH2Cl2(3×100 ml). The combined organic phase was washed with H2About (2×75 ml), saturated salt solution (1×50 ml) and dried (Na2SO4), filtered and concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 9:1 CH2Cl2/CH3IT), while receiving methyl-2-(tert-butoxycarbonylamino-4-yl)benzoxazole-4-carboxylate (930 mg, 82%) as a pale yellow solid.1H NMR and MS confirmed the structure.

Stage D. 2-(tert-Butoxycarbonylamino-4-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

The stage that a shared approach to GP-C1 condense 2-(tert-butoxycarbonylamino-4-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-aminobenzothiazole-4-carboxamide.1H NMR and MS confirmed the structure.

Stage F. To a solution of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-aminobenzothiazole-4-carboxamide (0.20 g, 0.48 mmol) in CH2Cl2(5 ml) is added TFA (4 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated and the crude substance clean preparati the Noah TLC (a mixture of 90:9:1 CH 2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-aminobenzothiazole-4-carboxamide (45 mg, 30%), which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 36: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-ethylmorpholino)benzoxazole-4-carboxamide

Stage A. To ice stirred suspension of sodium hydride (60% in oil, 1.6 g, 39,0 mmol) in toluene (50 ml) is added dropwise a solution of (S)-2-aminobutane-1-ol (1.5 g, 17,0 mmol) in toluene (36 ml). After complete addition, the reaction mixture is heated to room temperature and added dropwise a solution of ethylchloride (2.3 g, 19.0 mmol) in toluene (9 ml). The resulting mixture was then stirred at the boil under reflux for 20 h, cooled to room temperature and the reaction mixture is added solid ammonium chloride (2.0 g, of 38.7 mmol). The mixture is stirred for 20 min and then concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 95:5 CH2Cl2/CH3IT), thus obtaining (S)-5-ethylmorpholine-3-one (1.9 g, 88%) as not quite white semi-solid substances.1H NMR corresponds to the connection structure.

Stage Century. To obladenno is the ice THF (10 ml) add sociallyengaged (29.0 ml, 1.0 M solution in THF). After completion of adding dropwise during 20 min add a solution of (S)-5-ethylmorpholine-3-one (1.9 g, 15 mmol) in THF (10 ml). After complete addition, the ice bath removed and the reaction mixture is stirred at the boil under reflux for 20 hours. The reaction mixture was cooled in an ice bath and slowly dropwise (serial) add H2O (1.2 ml), 15% sodium hydroxide solution (1.2 ml) and N2O (1.2 ml). The resulting mixture was stirred at room temperature for 1 hour and then filtered, washing the solid EtOAc (50 ml). The filtrate is concentrated at room temperature and under reduced pressure, thus obtaining (S)-3-ethylmorpholine (1.6 g, 94%) as a clear, colorless oil.1H NMR corresponds to the connection structure.

Stage C. (S)-Methyl-2-(3-ethylmorpholino)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage d (S)-2-(3-Ethylmorpholino)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR corresponds to the connection structure.

The stage that a shared approach to GP-C2 condense a mixture of (S)-2-(3-ethylmorpholino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.]nonan-3-yl)-2-((S)-3-ethylmorpholino)benzoxazol-4-carboxamid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 37: Getting trihydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(9-methyl-9-azabicyclo[3.3.1]non-3-ylamino)benzoxazole-4-carboxamide

Stage A. Methyl-2-(3-amino-9-methyl-9-azabicyclo[3.3.1]nonan-3-ylamino)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. a Mixture of methyl 2-(3-amino-9-methyl-9-azabicyclo[3.3.1]nonylamine)benzoxazole-4-carboxylate (0,43 g of 1.74 mmol), monohydrate of lithium hydroxide (252 mg, 5,96 mmol) in a mixture of THF/N2About (2:1, 15 ml) was stirred at room temperature for 17 hours. the pH of the reaction mixture adjust to pH 10 6 N. NaOH. Formed precipitate was separated by filtration, thus obtaining 2-(3-amino-9-methyl-9-azabicyclo[3.3.1]nonylamine)benzoxazole-4-carboxylate sodium.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane and 2-(3-amino-9-methyl-9-azabicyclo[3.3.1]nonylamine)benzoxazole-4-carboxylate sodium condense with the dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylamino)benzoxazole-4-carboxamide, which is in turn trihydrochloride salt according to the General method GP-D1. 1H NMR and MS confirmed the structure.

Example 38: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2-methoxyethylamine)benzoxazole-4-carboxamide

Stage A. Methyl-2-(2-methoxyethylamine)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. a Mixture of methyl 2-(2-methoxyethylamine)benzoxazole-4-carboxylate (0,30 g, 1,19 mmol), trimethylsilanol potassium (330 mg, 2,63 mmol) and THF (15 ml) was stirred at room temperature for 48 hours, add additional trimethylsilanol potassium (75 mg, 0.59 mmol) and the mixture refluxed for 6 hours. The reaction mixture was cooled to 0°C and treated with HCl (1.0 M solution in diethyl ether, 3,57 ml of 3.57 mmol). The solvent is removed in vacuum and the crude 2-(2-methoxyethylamine)benzoxazole-4-carboxylic acid directly next turn without additional purification. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(2-methoxyethylamine)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2-methoxyethylamine)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and M is confirm the structure.

Example 39: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-methoxypropylamine)benzoxazole-4-carboxamide

Stage A. Methyl-2-chlorobenzoxazole-4-carboxylate and 3-methoxypropylamine converted into methyl-2-(3-methoxypropylamine)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. a Mixture of methyl 2-(3-methoxypropylamine)benzoxazole-4-carboxylate (0,30 g, 1.13 mmol), trimethylsilanol potassium (323 mg, 2,52 mmol) and THF (15 ml) was stirred at room temperature for 17 h, add additional trimethylsilanol potassium (72 mg, 0,56 mmol) and the mixture refluxed for 6 hours. The reaction mixture was cooled to 0°C and treated with HCl (1.0 M solution in diethyl ether, 3,39 ml, 3,39 mmol). The solvent is removed in vacuum and the crude 2-(3-methoxypropylamine)benzoxazole-4-carboxylic acid directly make further without additional purification. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(3-methoxypropylamine)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-methoxypropylamine)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and M is confirm the structure.

Example 40: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-hydroxypropylamino)benzoxazole-4-carboxamide

Stage A. Methyl-2-(3-hydroxypropylamino)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. 2-(3-Hydroxypropylamino)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of methyl 2-(3-hydroxypropylamino)benzoxazole-4-carboxylate dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-hydroxypropylamino)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Examples 41A and 41b: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-[(S)-2-methylpiperazin-1-yl]benzoxazole-4-carboxamide hydrochloride and endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-[(R)-2-methylpiperazin-1-yl]benzoxazole-4-carboxamide

Stage A. (S)- or (R)-methyl-2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. (S)- or (R)-2-(4-(tert-butoxycarbonyl the l)-2-methylpiperazin-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. 1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of (S)- or (R)-2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)benzoxazole-4-carboxylic acid and dihydrochloride salt of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-amine, while receiving (3S)- or (3R)-tert-butyl-3-methyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate. The solution of this substance in CH2Cl2(44 ml) at 0°C is treated with TFA (3,53 ml, 46 mmol) and stirred at room temperature for 12 hours. The mixture makes 2 main N. NaOH and the aqueous layer was extracted with CH2Cl2(3×150 ml). The combined organic layers are dried (MgSO4), filtered and concentrated. The crude substance is purified column chromatography (silica gel, mixture of 90:10:1 CH2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-[(S)-2-methylpiperazin-1-yl]benzoxazole-4-carboxamide and endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-[(R)-2-methylpiperazin-1-yl]benzoxazole-4-carboxamide. Both enantiomers turn in the appropriate cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 42: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4-(pyrimidine-2-yl)piperazine-1-yl)benzoxazole-4-carboxym is Yes

Stage A. Methyl-2-(4-(pyrimidine-2-yl)piperazine-1-yl)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage B. 2-(4-(Pyrimidine-2-yl)piperazine-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(4-(pyrimidine-2-yl)piperazine-1-yl)benzoxazole-4-carboxylic acid hydrochloride and endo-N-(9-methyl)-9-azabicyclo[3.3.1]nonan-3-amine, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4-(pyrimidine-2-yl)piperazine-1-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 43: obtain the hydrochloride of endo-N-(3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)-2-morpholinoethoxy-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-morpholinoethoxy-4-carboxylic acid and cleaners containing hydrochloride salt of endo-3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-amine, thus obtaining N-(3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)-2-morpholinoethoxy-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 44: obtain the hydrochloride of endo-N-(9-methyl-3-oxa-9-Isabel the lo[3.3.1]nonan-7-yl)-2-morpholinoethoxy-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-morpholinoethoxy-4-carboxylic acid hydrochloride and endo-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-amine, thus obtaining N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-2-morpholinoethoxy-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 45: obtain the hydrochloride of endo-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-2-(phenylamino)benzoxazole-4-carboxamide

According to the General method GP-C1 condense a mixture of 2-(phenylamino)benzoxazole-4-carboxylic acid hydrochloride and endo-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-amine, while receiving endo-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-2-(phenylamino)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 46: Obtaining hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3aS,6aS)-hexahydrofuro[3,4-b]pyrrol-5(1H)-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A mixture of methyl 2-chlorobenzoxazole-4-carboxylate and (3S),(4S)-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane converted into methyl-2-((1S),(4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure of the soybean is inane.

Stage C. 2-((1S),(4S)-5-(tert-Butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-((1S),(4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3aS,6aS)-hexahydrofuro[3,4-b]pyrrol-5(1H)-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 47: obtain the dihydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2-(dimethylamino)-2-oxoethylidene)benzoxazole-4-carboxamide

Stage A. According to the General method of GP-from a mixture of methyl-2-chlorobenzoxazole-4-carboxylate and 2-amino-N,N-dimethylacetamide get methyl-2-(2-(dimethylamino)-2-oxoethylidene)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. a Solution of methyl 2-(2-(dimethylamino)-2-oxoethylidene)benzoxazole-4-carboxylate (465 mg, 1,68 mmol) and monohydrate of lithium hydroxide (106 mg, 2,52 mmol) in N2About (3 ml) and THF (15 ml) was stirred at room temperature for 17 hours. THF is removed under reduced pressure, estato is diluted with N 2About 150 ml and then loaded into anion exchange cartridge (10 g isolute SAX). The cartridge was washed with N2And then elute the product 0.1 G. of HCl. Fraction of the product are combined and concentrated. The residue is treated CH3HE (3×15 ml) and then lyophilized in N2Oh, give the hydrochloride of 2-(2-(dimethylamino)-2-oxoethylidene)benzoxazole-4-carboxylic acid (280 mg, 56%).1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense the mixture of the hydrochloride of 2-(2-(dimethylamino)-2-oxoethylidene)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2-(dimethylamino)-2-oxoethylidene)benzoxazol-4-carboxamide, which in turn dihydrochloride salt common procedures GP-D1.1H NMR and MS confirmed the structure.

Example 48: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-isopropylaniline)benzoxazole-4-carboxamide

Stage A. To ice stirred suspension of sodium hydride (60% in oil, 1.3 g, 34,0 mmol) in toluene (45 ml) was added dropwise a solution of (S)-2-amino-3-methylbutane-1-ol (1.5 g, 15.0 mmol) in toluene (30 ml). After complete addition, the reaction mixture is heated to room temperature and added dropwise to the solution ethylchloride is (2.0 g, 16.0 mmol) in toluene (8 ml). The resulting mixture was then stirred at the boil under reflux for 20 h, cooled to room temperature and the reaction mixture is added solid ammonium chloride (1.8 g, 34,0 mmol). The mixture is stirred for 20 min and then concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 95:5, CH2Cl2/CH3IT), thus obtaining (S)-5-isopropylaniline-3-one (1.4 g, 67%) as a pale yellow solid.1H NMR and MS confirmed the structure.

Stage Century. To ice THF (6 ml) add sociallyengaged (1.0 M solution in THF and 18.0 ml, 18.0 mmol). When you are finished adding over 20 min added dropwise a solution of (S)-5-isopropylaniline-3-one (1.3 g, 9.0 mmol) in THF (6 ml). After complete addition, the ice bath removed and the reaction mixture is stirred at the boil under reflux for 18 hours. The reaction mixture was cooled in an ice bath and to it was added slowly N2About (0.75 ml), then 15% aqueous NaOH solution (0.75 ml) and then N2About (0.75 ml). The resulting mixture was stirred at room temperature for 1 hour and then filtered, washing the solid EtOAc (50 ml). The filtrate is concentrated at room temperature and reduced pressure, thus obtaining (S)-3-isopropylaniline (0.96 g, 83%) as a colorless transparent oil.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-A (S)-methyl-2-(3-isopropylaniline)benzoxazole-4-carboxylate and methyl 2-chlorobenzoxazole-4-carboxylate is transformed into (S)-methyl-2-(3-isopropylaniline)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage d (S)-2-(3-Isopropylaniline)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage F. According to the General method GP-C2 condense a mixture of (S)-2-(3-isopropylaniline)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-isopropylaniline)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 49: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-methylmorpholine)benzoxazole-4-carboxamide

Stage A. a Solution of (S)-(+)-2-amino-1-propanol (5.0 g, 67,0 mmol) in toluene (60 ml) is added dropwise at 0°C. to a stirred suspension of NaH (60% in mineral oil, 6.2 g, 145 mmol) in toluene (150 ml). The cooling bath removed and the reaction mixture was stirred at room temperature t is within 30 minutes Then dropwise at room temperature, add a solution of ethylchloride (8.0 ml, 73.8 mmol) in toluene (60 ml) and the resulting reaction mixture is refluxed for 20 hours. The reaction mixture is cooled to room temperature and the reaction mixture solid NH4Cl (5 g, 96.7 mmol). The reaction mixture was stirred for 20 min, filtered and the filtrate concentrated under reduced pressure. Purification of column chromatography (silica gel, mixture of 94:5:0.5 to CH2Cl2/CH3HE/NH4OH) gives (S)-5-methylmorpholin-3-one (6.5 g, 84%) as not quite white semi-solid substances.1H NMR and MS confirmed the structure.

Stage b: a Solution of (S)-5-methylmorpholin-3-one (6.9 g, was 59.9 mmol) in THF (40 ml) is added dropwise at 0°C. to a solution of LiAlH4(1.0 M solution in THF, 120,0 ml, 120 mmol) in THF (40 ml). The ice bath is removed and the reaction mixture refluxed for 18 hours. The reaction mixture was cooled in an ice bath and the excess hydride reagent is quenched carefully added dropwise N2O (5 ml), 15% aqueous NaOH (5 ml) and N2About (15 ml). The resulting mixture was stirred at room temperature for 1 hour and the reaction mixture is filtered through a layer of diatomaceous earth and a layer washed with EtOAc (100 ml). The filtrate is washed with saturated salt solution, dried over Na2SO 4, filtered and concentrated under reduced pressure, thus obtaining (S)-3-methylmorpholin in the form of a red oil. Because they imply that the products have high volatility, (S)-3-methylmorpholin used in the next stage without further separation or purification.

Stage C. (S)-Methyl-2-(3-methylmorpholine)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage D. a Solution of (S)-methyl-2-(3-methylmorpholine)benzoxazole-4-carboxylate (of 0.58 g, 2.1 mmol) in a mixture of 1,4-dioxane/CH3HE/H2About (2:2:1, and 8.5 ml)containing monohydrate of lithium hydroxide (150 mg, 6,30 mmol), stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the remaining N2About removed by azeotropic distillation with benzene (2×100 ml), thus obtaining (S)-2-(3-methylmorpholine)benzoxazole-4-carboxylate lithium in the form of a white solid, which is used in the next stage without further separation or purification.

The stage that a shared approach to GP-C2 condense a mixture of (S)-2-(3-methylmorpholine)benzoxazole-4-carboxylate lithium dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-methylmorpholine)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt total IU is the odik GP-D1. 1H NMR and MS confirmed the structure.

Example 50: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S*,6R*)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a cooled with ice to a solution of CIS-2,6-dimethylpiperazine (1.50 g, 13,13 mmol), di-tert-BUTYLCARBAMATE (3,15 g, accounted for 14.45 mmol) and 4-dimethylaminopyridine (1.60 g, 13,13 mmol) in CH2Cl2(20 ml) add diisopropylethylamine (2,17 ml, 13,13 mmol). The mixture is stirred for 10 minutes, then give her the opportunity to come to room temperature for 4 hours. The reaction mixture was quenched with saturated NaHCO3. The aqueous phase is further extracted with Et2O (2×20 ml). The combined organic phase was washed with saturated salt solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product is purified column chromatography (silica gel, 0-10% CH3HE in CH2Cl2), while receiving (3S*,5R*)-tert-butyl-3,5-dimethylpiperazine-1-carboxylate (2,18 g, 77%) as a clear oil.1H NMR and MS confirmed the structure.

Stage C. Methyl-2-((2S*,6R*)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. 2-((2S*,6R*)-4-(tert-Butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazol--the lithium carboxylate synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage d According to the General method GP-C1 condense 2-((2S*,6R*)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-lithium carboxylate (109 mg, 0.28 mmol) and the dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-(3S*,5R*)-tert-butyl-3,5-dimethyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Examples 51 and 52: Obtaining hydrochloride Exo-N-(3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)-2-(phenylamino)benzoxazole-4-carboxamide hydrochloride and endo-N-(3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)-2-(phenylamino)benzoxazole-4-carboxamide

According to the General method GP-C1 condense 2-(phenylamino)benzoxazole-4-carboxylic acid (140 mg, 0,551 mmol) and cleaners containing hydrochloride salt of 3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-amine (214 mg, 0,767 mmol)to give the hydrochloride Exo-N-(3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)-2-(phenylamino)benzoxazole-4-carboxamide and endo-N-(3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)-2-(phenylamino)benzoxazole-4-carboxamide that turn in their cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 53: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[.3.1]non-3-yl)-2-((S)-2-carbamoylation-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and (S)-prolinamide converted into (S)-methyl-2-(2-carbamoylation-1-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage Century To the ice slurry dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (93 mg, 0.41 mmol) in CH2Cl2(3 ml) was added trimethylaluminum (2n solution in toluene, 0.17 ml, 0.34 mmol) and the suspension stirred for 1 hour at room temperature. To the reaction mixture (S)-methyl-2-(2-carbamoylation-1-yl)benzoxazole-4-carboxylate (50 mg, 0,17 mmol) and the resulting reaction mixture is stirred at room temperature for 4 days. The reaction is quenched CH3HE (1 ml), pH adjust to the value 7 6 N. HCl and concentrated under reduced pressure. The crude substance is purified preparative TLC (mixture of 80:12:1,5 CH2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(S)-2-carbamoylation-1-yl)benzoxazole-4-carboxamide (35 mg, 50%) as a white solid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 54: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]Piras the n-7(8H)-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-a, except for the use of sodium hydride as the base, 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin and methyl-2-chlorobenzoxazole-4-carboxylate (243 mg, 1.15 mmol) is transformed into methyl-2-(3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. 2-(3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-(3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 55: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2,4-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. (S)-Methyl-2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure with the unity.

Stage C. (R)-2-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense (R)-2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-(3S)-(tert-butylbenzothiazole-2-yl)piperazine-1-carboxylate. The solution of this intermediate product in CH2Cl2(44 ml) at 0°C is treated with TFA (3,53 ml, 46 mmol) and stirred at room temperature for 12 hours. The mixture makes 2 main N. NaOH and the aqueous layer was extracted with CH2Cl2(3×150 ml). The combined organic layers are dried (MgSO4), filtered and concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 90:10:1 CH2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-methylpiperazin-1-yl)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Stage D. a Mixture of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-methylpiperazin-1-yl)benzoxazole-4-carboxamide (44 mg, 0.11 mmol), formaldehyde (37% aqueous solution, 4 ml, 49 mmol), acetic acid is (0.5 ml, 8,73 mmol) and cyanoborohydride sodium (14 mg, 0.22 mmol) in CH3HE (5 ml) was stirred at room temperature for 12 hours. The mixture is concentrated to dryness, make it basic to pH 12 2 N. NaOH and extracted with CH2Cl2(2×50 ml). The combined organic layers washed with saturated salt solution (5 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 90:10:1 CH2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2,4-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide in the form of an oil (45 mg, 99%).1H NMR and MS confirmed the structure.

The stage that a shared approach to GP-D1 endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2,4-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide in turn cleaners containing hydrochloride salt.1H NMR and MS confirmed the structure.

Example 56: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-oxo-2,3-dihydroisoxazole-4-carboxamide

Stage A. To a solution of methyl-2-chlorobenzoxazole-4-carboxylate (100 mg, 0.47 mmol) in THF (6 ml) add a solution of the monohydrate of lithium hydroxide (29,7 mg, 0.71 mmol) in N2About (3 ml). The reaction mixture was stirred at room temperature for 18 h and then concentrated to dryness, p is the best in this 2-oxo-2,3-dihydroisoxazole-4-lithium carboxylate (130 mg, 100%) as a yellow solid, which was directly used in the next stage without purification. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-oxo-2,3-dihydroisoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-oxo-2,3-dihydroisoxazole-4-carboxamide, which turns in cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 57: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((S)-2-methylpiperazin-1-yl)benzoxazole-4-carboxamide

Stage A. (S)-Methyl-2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-chlorobenzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. (S)-2-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-6-chlorobenzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense (S)-2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-chlorobenzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-ylcarbonyl)benzoxa the ol-2-yl)-(3S)-tert-butyl-4-(6-chloro-4-(3-methylpiperazin)-1-carboxylate. The intermediate product (410 mg, 0.79, which mmol) dissolved in CH2Cl2(10 ml) and treated with TFA (609 ml, 7.9 mmol) at 0°C. the Mixture is stirred at room temperature for 12 hours. The mixture makes 2 main N. NaOH and the aqueous layer was extracted with CH2Cl2(3×150 ml). The combined organic layers are dried (MgSO4), filtered and concentrated. The crude substance is purified column chromatography (silica gel, mixture of 90:10:1 CH2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((S)-2-methylpiperazin-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 58: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxamide

Stage A. Methyl-6-chloro-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxylate synthesized according to the General method GP-A, except that the reaction is carried out at ambient temperature for 12 hours.1H NMR and MS confirmed the structure.

Stage C. 6-Chloro-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense 6-chloro--(4-methylpiperazin-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-(4-methylpiperazin-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 59: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4-methoxybenzylamine)benzoxazole-4-carboxamide

Stage A. Methyl-2-(4-methoxybenzylamine)benzoxazole-4-carboxylate (oil) synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. 2-(4-Methoxybenzylamine)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense 2-(4-methoxybenzylamine)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4-methoxybenzylamine)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 60: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S*,5R*)-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and (±)-TRANS-1-allyl-2,5-dimethyl who piperazin converted into methyl-2-(4-allyl-(2R*,5S*)-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate. 1H NMR and MS confirmed the structure.

Stage C. 2-(4-Allyl-(2R*,5S*)-dimethylpiperazine-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-(4-allyl-(2R*,5S*)-dimethylpiperazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S*,5R*)-4-allyl-2,5-dimethylpiperazine-1-Il)benzoxazol-4-carboxamide.1H NMR and MS confirmed the structure.

Stage D. a Solution of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S*,5R*)-4-allyl-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (200 mg, 0.44 mmol), barbituric acid (337 mg, of 2.64 mmol) and tetrakis(triphenylphosphine)palladium(0) (25 mg/0,022 mmol, 5 mol.%) in a mixture of THF/DMF (2:1, 30 ml) is stirred for 17 h at 60°C in argon atmosphere. The mixture was poured into saturated NaHCO3(100 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is washed successively with a saturated salt solution (100 ml), N2O (100 ml), dried (Na2SO4), filtered and concentrated. The crude substance is purified double-column chromatography (silica gel, 100% CH2Cl2to a mixture of 20:76,5:3,5 CH2Cl2/CH3HE/NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan--yl)-2-((2S*,5R*)-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (34 mg, 17%) as a yellow film.1H NMR and MS confirmed the structure.

Stage E. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S*,5R*)-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide turn in dihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 61: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-hydroxybutylidene)benzoxazole-4-carboxamide

Stage A. To a solution of 2-hydroxyethylamine (4,00 g, 44,87 mmol) in anhydrous DMF (25 ml) is added tert-butyldiphenylsilyl (16,9 ml, 66,19 mmol) and imidazole (9,16 g, 13,46 mmol). The reaction mixture was stirred at room temperature for 2 days, then concentrated under reduced pressure and diluted with CH2Cl2(150 ml). The organic layer was washed with 5% aqueous solution of NaHCO3(50 ml), saturated salt solution (50 ml), dried (MgSO4), filtered and concentrated. The crude substance is purified column chromatography (0-100% EtOAc in hexane), thus obtaining 3-(tert-butyldiphenylsilyl)butane-1-amine (8.00 g, 54%) as a white solid.1H NMR and MS confirmed the structure.

Stage C. Methyl-2-(3-(tert-butyldiphenylsilyl)butylamino)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

The stage is. 2-(3-(tert-Butyldiphenylsilyl)butylamino)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage d According to the General method GP-C1 condense 2-(3-(tert-butyldiphenylsilyl)butylamino)benzoxazole-4-carboxylic acid and cleaners containing hydrochloride salt of endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-(tert-butyldiphenylsilyl)butylaminoethyl-4-carboxamide.1H NMR and MS confirmed the structure.

Stage E. To a solution of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-(tert-butyldiphenylsilyl)butylaminoethyl-4-carboxamide (553 mg, 0.89 mmol) in THF (10 ml) was added 1 M TBAF solution in diethyl ether (2.65 ml, to 2.65 mmol). The reaction mixture was stirred at room temperature for 24 h, then concentrated and diluted with CH2Cl2(250 ml). The organic layer was washed with saturated NH4Cl (50 ml) and saturated salt solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 90:10:1 CH2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-hydroxybutylidene)benzoxazol-4-carboxamid (342 mg, 99%) as a white TV is Gogo substances. 1H NMR and MS confirmed the structure.

Stage F. endo-N-2-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-(3-hydroxybutylidene)benzoxazol-4-carboxamid in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 62: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((S)-3-ethylmorpholino)benzoxazole-4-carboxamide

Stage A. To ice stirred suspension of NaH (60% in oil, 1.6 g, 39,0 mmol) in toluene (50 ml) is added dropwise a solution of (S)-2-aminobutane-1-ol (1.5 g, 17,0 mmol) in toluene (36 ml). After complete addition, the reaction mixture is heated to room temperature and added dropwise a solution of ethylchloride (2.3 g, 19.0 mmol) in toluene (9 ml). The resulting mixture was then stirred at the boil under reflux for 20 h, cooled to room temperature and the reaction mixture solid NH4Cl (2.0 g, of 38.7 mmol). The mixture is stirred for 20 min and then concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 95:5 methylene chloride/CH3IT), thus obtaining (S)-5-ethylmorpholine-3-one (1.9 g, 88%) as not quite white semi-solid substances.1H NMR and MS confirmed the structure.

Stage C. To the cooled THF (10 ml) add the LiAlH 4(29.0 ml, 1.0 M solution in THF). After completion of adding dropwise during 20 min add a solution of (S)-5-ethylmorpholine-3-one (1.9 g, 15 mmol) in THF (10 ml). After complete addition, the ice bath removed and the reaction mixture is stirred at the boil under reflux for 20 hours. The reaction mixture was cooled in an ice bath and slowly added dropwise (sequential) H2O (1.2 ml), 15% sodium hydroxide solution (1.2 ml) and N2O (1.2 ml). The resulting mixture was stirred at room temperature for 1 hour and then filtered, washing the solid EtOAc (50 ml). The filtrate is concentrated at room temperature and under reduced pressure, thus obtaining (S)-3-ethylmorpholine (1.6 g, 94%) as a clear, colorless oil.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-A condense (S)-3-ethylmorpholine and methyl-2,6-dichlorobenzoate-4-carboxylate, thus obtaining (S)-methyl-6-chloro-2-(3-ethylmorpholino)benzoxazole-4-carboxylate. MS corresponds to the connection structure.

Stage d (S)-6-Chloro-2-(3-ethylmorpholino)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

The stage that a shared approach to GP-C2 condense (S)-6-chloro-2-(3-ethylmorpholino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-the Mino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((S)-3-ethylmorpholino)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 63: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((S)-2,4-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl-2,6-dichlorobenzoate-4-carboxylate and N-BOC-(S)-4-methylpiperazin converted into (S)-methyl-2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-chlorobenzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. (S)-2-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-6-chlorobenzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C2 condense (S)-2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-chlorobenzoxazole-4-carboxylic acid and cleaners containing hydrochloride salt of endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine, while receiving endo-N-(3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-ylcarbonyl)benzoxazol-2-yl)-(3S)-tert-butyl-4-(6-chloro-4-(3-methylpiperazin)-1-carboxylate. This substance (410 mg, 0.79, which mmol) dissolved in CH2Cl2(10 ml) at 0°C, treated with TFA (609 ml, 7.9 mmol) and stirred at room temperature during the course the e 12 hours. The mixture makes 2 main N. NaOH and the aqueous layer was extracted with CH2Cl2(3×150 ml). The combined organic layers are dried (MgSO4), filtered and concentrated. The crude substance is purified column chromatography (silica gel, mixture of 90:10:1 CH2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((S)-2-methylpiperazin-1-yl)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Stage D. a Mixture of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((S)-2-methylpiperazin-1-yl)benzoxazole-4-carboxamide (60 mg, 0.14 mmol), formaldehyde (37% aqueous solution, 4 ml, 49 mmol), SPLA (0.5 ml, 8,73 mmol) and NaCNBH3(17 mg, 0.28 mmol) in CH3HE (5 ml) was stirred at room temperature for 12 hours. The mixture is concentrated to dryness, make it basic to pH 12 2 N. NaOH and extracted with CH2Cl2(2×70 ml). The combined organic layers washed with saturated salt solution (5 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 90:10:1 CH2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((S)-2,4-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt in General the second method GP-D1. 1H NMR and MS confirmed the structure.

Example 64: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2-methoxybenzylamine)benzoxazole-4-carboxamide

Stage A. Methyl-2-(2-methoxybenzylamine)benzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. 2-(2-Methoxybenzylamine)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.

Stage C. According to the General method GP-C1 condense 2-(2-methoxybenzylamine)benzoxazole-4-carboxylic acid dihydrochloride and endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2-methoxybenzylamine)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 65: Receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((R)-3-methylmorpholine)benzoxazole-4-carboxamide

Stage A. Ice SPLA (1.5 ml) is added dropwise at room temperature to a well stirred solution of (R)-(+)-2-amino-1-propanol (10.0 g, 133 mmol) and benzaldehyde (13,5 ml, 133 mmol) in CH3HE (260 ml). The reaction mixture was stirred at room temperature for 1.5 hours followed by the addition NaCNBH3(12,6 g, 200 mmol) and the reaction mixture is stirred at to matnog temperature throughout the night. The reaction mixture was concentrated under reduced pressure and the selected solid is dissolved in EtOAc (500 ml) and then the solution was washed with saturated bicarbonate (2×250 ml), N2O (250 ml) and saturated salt solution (250 ml). The organic phase is then dried over Na2SO4, filtered and concentrated, thus obtaining (R)-2-(benzylamino)propan-1-ol (19,8 g, 94%) as colorless oil: MS corresponds to the connection structure.

Stage Century. Chlorocatechol (to 11.6 ml, 120 mmol) is added dropwise at 0°C. to a solution of (R)-2-(benzylamino)propan-1-ol (19.9 g, 120 mmol) and triethylamine (30,5 ml) in toluene (600 ml). The cooling bath removed and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the selected solid is dissolved in EtOAc (500 ml) and then washed with saturated bicarbonate (2×250 ml), N2O (250 ml) and saturated salt solution (250 ml). The organic phase is then dried (Na2SO4), filtered and concentrated, thus obtaining (R)-2-(2-benzylamino)propoxy)acetylchloride: MS corresponds to the connection structure.

Stage C. (R)-2-(2-Benzylamino)propoxy)acetylchloride dissolved in tert-butanol (500 ml). Then in one portion add tert-piperonyl sodium (14.0 g, 125 mmol) and the reaction mixture is refluxed for 18 hours. The reaction is ionic mixture is cooled and concentrated under reduced pressure to remove solvent. The residue is dissolved in diethyl ether (300 ml) and then washed with 2 N. HCl (150 ml), N2O (150 ml) and saturated salt solution (100 ml). The organic phase is then dried (Na2SO4), filtered and concentrated under reduced pressure, thus obtaining a light yellow oil. Purification of column chromatography (silica gel, 10-50% EtOAc in heptane) gives (R)-4-benzyl-5-methylmorpholin-3-one (17,2 g, 63%) as a pale yellow oil.1H NMR and MS confirmed the structure.

Stage D. a Solution of (R)-4-benzyl-5-methylmorpholin-3-one (3.0 g, 14,22 mmol) in THF (10 ml) is added dropwise at 0°C. to a solution of sociallyengaged (1.0 M solution in THF, to 28.5 ml, 28.5 mmol) in THF (10 ml). The ice bath removed and the reaction mixture refluxed for 18 hours. The reaction mixture was cooled in an ice bath and the excess hydride reagent is quenched carefully added dropwise N2O (5 ml), 15% sodium hydroxide (5 ml) and N2About (15 ml). The resulting mixture was stirred at room temperature for 1 hour and the reaction mixture is filtered through a layer of celite and layer washed with EtOAc (100 ml). The filtrate is washed with saturated salt solution, dried (Na2SO4), filtered and concentrated under reduced pressure, thus obtaining (R)-4-benzyl-3-methylmorpholin (2.66 g, 95%) as a red oil.1H NMR and MS confirmed the structure.

Stage E. To a solution of (R)-4-benzyl-3-methylmorpholine (1.0 g, 5,07 mmol) in EtOAc (40 ml)containing a catalytic amount of HCl (4 M solution in 1,4-dioxane, 2 drops) is added 10% palladium on coal (400 mg) and the solution stirred in a Parr apparatus in an atmosphere of hydrogen (40 psi) for 18 hours. The reaction mixture was filtered through a layer of celite and the filter residue is washed with additional EtOAc. Careful concentration of the filtrate under reduced pressure gives (R)-3-methylmorpholin in the form of a yellow oil, which was used in the next stage without further separation or purification.

Stage F: synthesis of (R)-methyl-2-(3-methylmorpholine)benzoxazole-4-carboxylate. According to the General method GP-a, except for the use of triethylamine as the base, (R)-3-methylmorpholin and methyl-2-chlorobenzoxazole-4-carboxylate is transformed into (R)-methyl-2-(3-methylmorpholine)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage G. Synthesis of (R)-2-(3-methylmorpholine)benzoxazole-4-carboxylate lithium. According to the General method GP-B2 (R)-methyl-2-(3-methylmorpholine)benzoxazole-4-carboxylate is transformed into (R)-2-(3-methylmorpholine)benzoxazole-4-carboxylate lithium, which is used without further separation or purification. MS corresponds to the connection structure.

Stage N. According to the General method GP-C2 condense (R)-2-(3-methylmorpholine)benzoxazol-4-carb is xelat lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (0,856 g, 3,76 mmol), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((R)-3-methylmorpholine)benzoxazol-4-carboxamide. MS corresponds to the connection structure.

Stage I : To a solution of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((R)-3-methylmorpholine)benzoxazole-4-carboxamide (0,070 g, 0,175 mmol) in 1,4-dioxane (15 ml) was added dropwise HCl (4.0 M solution in 1,4-dioxane, 5.0 ml, 5.0 mmol). The resulting mixture was stirred at room temperature for 3 hours and then filtered. Selected hygroscopic solid is then dissolved in a mixture of acetonitrile/N2About (1:10, 10 ml) and lyophilized 3 times, while receiving a viscous oil. This substance is then dried in high vacuum for 72 h at 60°C in the presence of phosphorous pentoxide with the formation of a brown glassy solid, which is scraped from the walls of the flask, while receiving hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((R)-3-methylmorpholine)benzoxazole-4-carboxamide (0,050 g, 95%) as a hygroscopic brown solid.1H NMR and MS confirmed the structure.

Example 66: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-propiolactone)benzoxazole-4-carboxamide

Stage A. To ice stirred suspension of NaH (60% in oil, 1.9 grams, 46,0 mmol) in toluene (62 ml) is added dropwise races the thief (S)-2-aminoindan-1-ol (2.1 g, 20.0 mmol) in toluene (44 ml). After complete addition, the reaction mixture is heated to room temperature and added dropwise a solution of ethylchloride (2.7 g, 22,0 mmol) in toluene (12 ml). The resulting mixture was then stirred at the boil under reflux for 20 h, cooled to room temperature and the reaction mixture is added solid ammonium chloride (2.5 g, 46,0 mmol). The mixture is stirred for 20 min and then concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of from 98:2 CH2Cl2/CH3HE to 95:5 CH2Cl2/CH3IT), thus obtaining (S)-5-propylparaben-3-one (2.2 g, 76%) as a yellow oil. To ice THF (10 ml) add sociallyengaged (1.0 M solution in THF, 30 ml, 30 mmol). After completion of adding dropwise during 20 min add a solution of (S)-5-propylparaben-3-one (2.2 g, 15 mmol) in THF (10 ml). When you are finished adding bath removed and the reaction mixture is stirred at the boil under reflux for 20 hours. The reaction mixture was cooled in an ice bath and to it was added slowly N2O (1.2 ml), then 15% aqueous sodium hydroxide solution (1.2 ml) and then N2O (1.2 ml). The resulting mixture was stirred at room temperature for 1.5 hours and then filtered, washing the solid is emesto EtOAc (50 ml). The filtrate is concentrated at room temperature and under reduced pressure, thus obtaining (S)-3-propylparaben (1.9 g, 98%) as a pale yellow oil.1H NMR and MS confirmed the structure.

Stage C. (S)-Methyl-2-(3-propiolactone)benzoxazole-4-carboxylate synthesized according to the General method GP-A. MS corresponds to the connection structure.

Stage C. (S)-2-(3-Propiolactone)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage d According to the General method GP-C3 condense (S)-2-(3-propiolactone)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-propiolactone)benzoxazol-4-carboxamide, which in turn salt of hydrochloric acid according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 67: Getting hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-isobutylamino)benzoxazole-4-carboxamide

Stage A. To ice stirred suspension of NaH (60% in oil, 1.6 g, 39,0 mmol) in toluene (53 ml) is added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17,0 mmol) in toluene (37 ml). After complete addition, the reaction mixture is heated to room temperature and added dropwise the solution of ethylchloride (2.3 g, 19.0 mmol) in toluene (10 ml). The resulting mixture was then stirred at the boil under reflux for 20 h, cooled to room temperature and the reaction mixture is added solid ammonium chloride (2.1 g, from 39.0 mmol). The mixture is stirred for 20 min and then concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of from 98:2 CH2Cl2/CH3HE to 95:5 CH2Cl2/CH3IT), thus obtaining (S)-5-isobutylparaben-3-one (1.9 g, 70%) as a pale yellow oil. To ice THF (8 ml) add sociallyengaged (1.0 M solution in THF, 23,0 ml, 23,0 mmol). After completion of adding dropwise during 20 min add a solution of (S)-5-isobutylparaben-3-one (1.8 g, 12,0 mmol) in THF (7.0 ml). After complete addition, the ice bath removed and the reaction mixture is stirred at the boil under reflux for 20 hours. The reaction mixture was cooled in an ice bath and to it was added slowly N2O (1.2 ml), then 15% aqueous sodium hydroxide solution (1.2 ml) and then N2O (1.2 ml). The resulting mixture was stirred at room temperature for 1.5 hours and then filtered, washing the solid EtOAc (50 ml). The filtrate is concentrated at room temperature and under reduced pressure, thus obtaining (S)-3-isobutylparaben (1.6 g 95%) as a pale yellow oil. 1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-A (S)-3-isobutylparaben (0,38 g, 2.6 mmol) and methyl-2-chlorobenzoxazole-4-carboxylate is transformed into (S)-methyl-2-(3-isobutylamino)benzoxazole-4-carboxylate. MS corresponds to the connection structure.

Stage C. (S)-2-(3-Isobutylamino)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage d According to the General method GP-C1 condense (S)-2-(3-isobutylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-isobutylamino)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 68: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-tert-butylnitrone)benzoxazole-4-carboxamide

Stage A. To ice stirred suspension of NaH (60% in oil, 1.6 g, 39,0 mmol) in toluene (53 ml) is added dropwise a solution of (S)-2-amino-4,5-dimethylpentan-1-ol (2.0 g, 17,0 mmol) in toluene (37 ml). After complete addition, the reaction mixture is heated to room temperature and added dropwise a solution of ethylchloride (2.3 g, 19.0 mmol) in toluene (10 ml). The resulting CME is ü then stirred at the boil under reflux for 20 hours, cooled to room temperature and the reaction mixture is added solid ammonium chloride (2.1 g, from 39.0 mmol). The mixture is stirred for 20 min and then concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of from 98:2 CH2Cl2/CH3HE to 95:5 CH2Cl2/CH3IT), thus obtaining (S)-5-tert-butylboron-3-one (2.0 g, 74%) as a pale yellow oil. To ice THF (9 ml) was added LiAlH4(1.0 M solution in THF, 26,0 ml, 26.0 mmol). After completion of adding dropwise during 20 min add a solution of (S)-5-tert-butylboron-3-one (2.0 g, 13,0 mmol) in THF (8.0 ml). After complete addition, the ice bath removed and the reaction mixture is stirred at the boil under reflux for 20 hours. The reaction mixture was cooled in an ice bath and to it was added slowly N2O (1.2 ml), then 15% aqueous sodium hydroxide solution (1.2 ml) and then N2O (1.2 ml). The resulting mixture was stirred at room temperature for 1.5 hours and then filtered, washing the solid EtOAc (50 ml). The filtrate is concentrated at room temperature and under reduced pressure, thus obtaining (S)-3-tert-butylparaben (1.7 g, 97%) as a pale yellow oil.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-A (S)-3-tert-is ethylmorpholine (0,38 g, 2.6 mmol) and methyl-2-chlorobenzoxazole-4-carboxylate (0.28 g, 1.3 mmol) is transformed into (S)-methyl-2-(3-tert-butylnitrone)benzoxazole-4-carboxylate. MS corresponds to the connection structure.

Stage C. (S)-2-(3-tert-Butylnitrone)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage d According to the General method GP-C1 condense (S)-2-(3-tert-butylnitrone)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-tert-butylnitrone)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 69: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2R,6R)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a solution of dihydrochloride of ((2R,6R)-2,6-dimethylpiperazine (1.60 g, 8,55 mmol) in CH2Cl2(15 ml) at room temperature is added triethylamine (2,50 ml, 17,95 mmol) followed by addition of di-tert-BUTYLCARBAMATE (2,05 g, 9,40 mmol) and the reaction mixture left to stir at room temperature for 48 hours. The reaction mixture was partitioned between EtOAc (20 ml) and saturated NaHCO3(20 ml). The aqueous phase is further extracted with EtOAc (2×20 ml). Unite the military the organic phase is washed with saturated salt solution (20 ml) and dried (Na 2SO4). The crude product is purified column chromatography (silica gel, 3-10% of CH3HE in CH2Cl2), while receiving (3R,5R)-tert-butyl-3,5-dimethylpiperazine-1-carboxylate (1,17 g, 64%) as a clear oil.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-A, except that the reaction mixture is heated in DMF at 40°C, (3R,5R)-tert-butyl-3,5-dimethylpiperazine-1-carboxylate (500 mg, of 2.33 mmol) and methyl-2-chlorobenzoxazole-4-carboxylate is transformed into methyl-2-((2R,6R)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-B2 methyl-2-(2R,6R)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate converted into 2-((2R,6R)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium. MS corresponds to the connection structure.

Stage d According to the General method GP-C2 at 40°C condensation of 2-((2R,6R)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2R,6R)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage E. To a solution of endo-N-(methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2R,6R)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate (387 mg, 0,756 mmol) in a mixture of CH2Cl2/dioxane/CH3HE (2:1:1, 8 ml) is added HCl (4 M in dioxane, of 3.78 ml, 15,12 mmol) and the mixture is stirred at room temperature for 24 h, then concentrated under reduced pressure. Amorphous solid lyophilized in a mixture of acetonitrile/N2About (10:1, 22 ml), while receiving the dihydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2R,6R)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (361 mg, 98%) as a brown solid.1H NMR and MS confirmed the structure.

Example 70: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(cyclohexylamino)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and cyclohexylamin converted into methyl-2-(cyclohexylamino)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. Methyl-2-(cyclohexylamino)benzoxazole-4-carboxylate (220 mg, 0.80 mmol), monohydrate of lithium hydroxide (50 mg, 1.20 mmol) and a mixture of THF and N2About (10:1, 11 ml) was stirred at room temperature for 17 hours. The mixture is diluted with N2About and download in anion-exchange resin (column 10 g isolute SAX). The column was washed with H2About (50 ml) and elute the product 0.1 G. of aqueous HCl (50 ml). The solvent is removed under reduced pressure, thus obtaining hydroch Oric 2-(cyclohexylamino)benzoxazole-4-carboxylic acid (188 mg, 79%) as a pink solid.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense hydrochloride 2-(cyclohexylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(cyclohexylamino)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 71: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S)-2-isobutyl-4-benzylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a solution of (2S)-4-benzyl-2-isobutylpyrazine (100 mg, 0.52 mmol) in 1,2-dimethoxyethane (DME) (10 ml) at room temperature add NaH (21 mg, 0.52 mmol, 60% suspension in mineral oil) and the mixture is stirred for 1 hour. To the reaction mixture is added methyl-2-chlorobenzoxazole-4-carboxylate (110 mg, 0.52 mmol) and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was quenched CH3HE (10 ml), add silica gel (15 ml) and the solvent is removed under reduced pressure. The mixture was purified column chromatography (silica gel, 0-100% EtOAc in hexano), thus obtaining (S)-methyl-2-(4-benzyl-2-isobutylpyrazine-1-yl)benzoxazole-4-carboxylate (133 mg, 62%) as light is lo-yellow oil. 1H NMR and MS confirmed the structure.

Stage C. (S)-2-(4-Benzyl-2-isobutylpyrazine-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense (S)-2-(4-benzyl-2-isobutylpyrazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S)-2-isobutyl-4-benzylpiperazine-1-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 72: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-thioxo-2,3-dihydroisoxazole-4-carboxamide

Stage A. To a solution of methyl-2-thioxo-2,3-dihydroisoxazole-4-carboxylate (150 mg, to 0.72 mmol) in THF (6 ml) add a solution of the monohydrate of lithium hydroxide (45.1 mg, of 1.08 mmol) in N2About (3 ml). The reaction mixture is heated to 75°C. with stirring for 3 days, cooled to room temperature and concentrated under reduced pressure, thus obtaining 2-thioxo-2,3-dihydroisoxazole-4-lithium carboxylate (135 mg, 96,5%) as a yellow solid. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-thioxo-2,3-dihydroisoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-thioxo-2,3-dihydroisoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 73: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a solution of dihydrochloride of (2S,6S)-2,6-dimethylpiperazine (0,30 g, and 1.63 mmol) in CH2Cl2(10 ml) at room temperature is added triethylamine (of 0.48 ml of 3.42 mmol) followed by addition of di-tert-BUTYLCARBAMATE (0.39 g, to 1.79 mmol) and the reaction mixture left to stir at room temperature for 48 hours. The reaction mixture was partitioned between EtOAc (20 ml) and saturated NaHCO3(20 ml). The aqueous phase is further extracted with EtOAc (2×20 ml). The combined organic phase was washed with saturated salt solution (20 ml) and dried (Na2SO4). The crude product is purified column chromatography (silica gel, 3-10% of CH3HE in CH2Cl2), while receiving (3S,5S)-tert-butyl-3,5-dimethylpiperazine-1-carboxylate (0.34 g, 52%) as a clear oil.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-A, except that the reaction mixture is heated in DMF at 40°C, (3S,5S)-tert-butyl-3,5-dimethylpiperazine-1 carbox the lat (500 mg, of 2.33 mmol) and methyl-2-chlorobenzoxazole-4-carboxylate is transformed into methyl-2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. 2-((2S,6S)-4-(tert-Butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage d According to the General method GP-C2 at 40°C condensation of 2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate, which in turn cleaners containing hydrochloride salt according to the General method GP-D2.1H NMR and MS confirmed the structure.

Example 74: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S)-3-isobutylpyrazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a solution of 1-tert-butyloxycarbonyl-(2S)-2-isobutylpyrazine (384 mg, 1.6 mmol) in DME (10 ml) is added NaH (70 mg, 60% suspension in mineral oil, 1.6 mmol) and the mixture is stirred for 1 hour at room temperature. To the reaction mixture is added methyl-2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) and the formed suspension is stirred is at room temperature for 17 hours. The reaction mixture was quenched CH3HE (10 ml), add silica gel (15 ml) and the solvent is removed under reduced pressure. The mixture was purified column chromatography (silica gel, 0-80% EtOAc in CH2Cl2), while receiving methyl-2-(4-(tert-butoxycarbonyl)-(3S)-3-isobutylpyrazine-1-yl)benzoxazole-4-carboxylate (219 mg, 32%) as a clear oil.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-B3 methyl-2-(4-(tert-butoxycarbonyl)-(3S)-3-isobutylpyrazine-1-yl)benzoxazole-4-carboxylate converted into 2-(4-(tert-butoxycarbonyl)-(3S)-3-isobutylpyrazine-1-yl)benzoxazole-4-carboxylic acid. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-(4-(tert-butoxycarbonyl)-(3S)-3-isobutylpyrazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3S)-3-isobutyl-4-tert-butoxycarbonylmethyl-1-Il)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D2.1H NMR and MS confirmed the structure.

Example 75: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxamide

Stage A. To a solution of (3S,5S)-dimethylmorpholine (209 mg, 1.82 mmol) in 1,2-dimethoxyethane 10 ml) is added NaH (60% suspension in mineral oil, 146 mg of 3.64 mmol). After 10 min the reaction mixture was cooled to 0°C and in portions over 5 min add methyl-2-chlorobenzoxazole-4-carboxylate (500 mg, 2.36 mmol). After 10 min the reaction mixture is heated to ambient temperature and left to stir for 3 days. The reaction mixture was quenched CH3HE (10 ml) and then dry loaded onto silica gel (4.5 g). Purification by chromatography (silica gel, 0-20% EtOAc in hexano) gives a mixture of 1:1 methyl-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxylate and methyl-2-oxo-2,3-dihydroisoxazole-4-carboxylate (312 mg, 59%) as not quite white solid. MS corresponds to the connection structure.

Stage C. 2-((3S,5S) - for 3,5-Dimethylmorpholine)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2 and directly next turn without purification.

Stage C. According to the General method GP-C1 condense 2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 76: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-isopropylpiperazine-1-yl)benzox the evil-4-carboxamide

Stage A. To a solution of (2S)-4-benzyl-2-isopropylpiperazine (363 mg, of 1.66 mmol) in 1,2-dimethoxyethane (10 ml) at room temperature add NaH (80 mg, of 1.66 mmol, 60% suspension in mineral oil) and the mixture is stirred for 1 hour. To the reaction mixture is added methyl-2-chlorobenzoxazole-4-carboxylate (351 mg, of 1.66 mmol) and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was quenched CH3HE (10 ml), add silica gel (15 ml) and the solvent is removed under reduced pressure. The mixture was purified column chromatography (silica gel, 0-100% EtOAc in hexano), thus obtaining (S)-methyl-2-(4-benzyl-2-isopropylpiperazine-1-yl)benzoxazole-4-carboxylate (355 mg, 54%) as a pale yellow oil. MS corresponds to the connection structure.

Stage C. (S)-2-(4-Benzyl-2-isopropylpiperazine-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of (S)-2-(4-benzyl-2-isopropylpiperazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((4-benzyl-(S)-2-isopropylpiperazine-1-yl)benzoxazol-4-carboxamid, except that the product was then purified column chromatography (silica gel, 100% CH2Cl2 2Cl2/CH3HE/NH4OH).1H NMR and MS confirmed the structure.

Stage D. To a solution of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((4-benzyl-(S)-2-isopropylpiperazine-1-yl)benzoxazole-4-carboxamide (0,230 g, 0.44 mmol) in 1,2-dichloroethane (2 ml) was added 1-chloroethylphosphonic (0,12 ml, 1.10 mmol) and the mixture is stirred for 10 hours at room temperature and for 10 hours at 55°C. Add an additional 1-chloroethylphosphonic (0.1 ml, 0.8 mmol) and heating continued for 6 hours at 55°C. the Solvent is removed under reduced pressure and the residue is successively purified column chromatography (silica gel, mixture 10:1:0.1 to CH2Cl2/CH3HE/concentrated NH4OH) and preparative HPLC (Luna C18(2), 10% solution of CH3CN/0,05% TFA in H2About/of 0.05% TFA to 100% CH3CN/0,05% TFA over 20 min, the column was incubated for 15 min, I = 223 nm). The fractions containing the desired product are pooled and concentrated. The remainder of the turn in cleaners containing hydrochloride salt according to the General method GP-D2.1H NMR and MS confirmed the structure.

Example 77: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-isobutylpyrazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a solution of (S)-1-tert-butoxycarbonyl-2-isobutylpyrazine (973 mg, 4.0 mmol) in DME (15 ml) is added sodium hydride (60% suspen the Oia in mineral oil, 160 mg, 4.0 mmol) and the mixture stirred for 45 min at room temperature. To the reaction mixture add a solution of allylbromide (0.35 ml, 4.0 mmol) in DMF (5 ml) and the formed suspension was stirred at room temperature for 3 days. The solvent is removed under reduced pressure, thus obtaining a dark oil (1.06 g). The resulting oil was dissolved in CH2Cl2(10 ml) and treated with TFA (5 ml). The resulting solution was stirred at room temperature for 18 hours. The solvent is removed under reduced pressure, the residue is dissolved in CH2Cl2and the solution is extracted with saturated aqueous NaHCO3. The organic phase is washed with saturated salt solution, N2Oh, dried over Na2SO4and concentrate. The residue is dissolved in CH3HE (5 ml) and passed through a column of an ion exchanger SCX-2, while receiving (3S)-1-allyl-3-isobutylpyrazine (0,44 g, 60%).1H NMR and MS confirmed the structure.

Stage C. To a solution of (S)-1-allyl-3-isobutylpyrazine (442 mg, 2,42 mmol) in DME (10 ml) at room temperature add NaH (60% suspension in mineral oil, 100 mg, 2,42 mmol) and the mixture is stirred for 45 minutes To the reaction mixture is added methyl-2-chlorobenzoxazole-4-carboxylate (510 mg, 2,42 mmol) and the reaction mixture was stirred at room temperature for 17 hours. Reactio the ing the mixture is quenched CH 3HE (10 ml), add silica gel (15 ml) and the solvent is removed under reduced pressure. The mixture was purified column chromatography (silica gel, mixture 10:1:0.1 to CH2Cl2/CH3HE/concentrated NH4OH), while receiving methyl-2-(4-allyl-(S)-2-isobutylpyrazine-1-yl)benzoxazole-4-carboxylate (372 mg, 43%) as a yellow oil.1H NMR and MS confirmed the structure.

Stage C. 2-(4-Allyl-(S)-2-isobutylpyrazine-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage d According to the General method GP-C1 condense a mixture of 2-(4-allyl-(S)-2-isobutylpyrazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-isobutyl-4-arylpiperazine-1-yl)benzoxazol-4-carboxamide. MS corresponds to the connection structure.

Stage E. the Solution of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-isobutyl-4-arylpiperazine-1-yl)benzoxazole-4-carboxamide (180 mg, of 0.37 mmol), barbituric acid (284 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (40 mg, 0,037 mmol, 10 mol.%) in DMF (8 ml) is stirred for 17 h at 60°C in argon atmosphere. The mixture was poured into saturated NaHCO3(100 ml) and extracted with CH2Cl2(3×50 ml). The combined organic phase placentas is tion was washed with saturated salt solution (100 ml), H2O (100 ml), dried (Na2SO4), filtered and concentrated. The crude substance is purified preparative TLC (silica gel, mixture of 20:1:0.1 to CH2Cl2/CH3HE/saturated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-isobutylpyrazine-1-yl)benzoxazole-4-carboxamide (62 mg, 38%), which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 78: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-propylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a solution of 1-tert-butyloxycarbonyl-(S)-2-isopropylpiperazine (384 mg, 1.7 mmol) in DME (10 ml) is added NaH (70 mg, 60% suspension in mineral oil, 1.6 mmol) and the mixture is stirred for 1 hour at room temperature. To the reaction mixture is added methyl-2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) and the formed suspension was stirred at room temperature for 17 hours. The reaction mixture was quenched CH3HE (10 ml), add silica gel (15 ml) and the solvent is removed under reduced pressure. The mixture was purified column chromatography (silica gel, 0-80% EtOAc in CH2Cl2), while receiving methyl-2-(4-(tert-butoxycarbonyl)-(S)-3-isopropylpiperazine-1-yl)benzoxazole-4-carboxylate (255 mg, 39%) as a white foam.1H NMR and MS confirmed, p is the established levels of connection.

Stage C. 2-(4-(tert-Butoxycarbonyl)-(S)-3-isopropylpiperazine-1-yl)benzoxazole-4-carboxylic acid synthesized by the conversion of methyl-2-(4-(tert-butoxycarbonyl)-(S)-3-propylpiperazine-1-yl)benzoxazole-4-carboxylate according to General method GP-B2. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(4-(tert-butoxycarbonyl)-(S)-3-isopropylpiperazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-isopropyl-4-tert-butoxycarbonylmethyl-1-yl)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Stage D. a Solution of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-isopropyl-4-tert-butoxycarbonylmethyl-1-yl)benzoxazole-4-carboxamide (230 mg, 0.43 mmol) in CH2Cl2treated with TFA (0.33 ml, 4.3 mmol). The mixture is stirred at room temperature for 17 hours. The solvent is removed in vacuum and the residue is neutralized ion exchange chromatography (column 5 g SCX-2), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-isopropylpiperazine-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 79: obtain the hydrochloride of endo-N-(9-m is l-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)benzoxazole-4-carboxamide

Stage A. To a solution of NaH (60% dispersion in mineral oil, 0,130 g, 3.25 mmol) in THF (10 ml) is added 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin (0.33 g, a 2.71 mmol) and the reaction mixture is stirred for 10 minutes Add methyl-2-chlorobenzoxazole-4-carboxylate (478 mg, and 2.26 mmol) in THF (10 ml) and the reaction mixture stirred at room temperature for 17 hours. The reaction mixture was quenched CH3HE (3 ml) and adsorb on silica gel (2 g). The crude product is purified column chromatography (silica gel, 0.5 to 10% SN3HE in CH2Cl2), while receiving methyl-2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)benzoxazole-4-carboxylate (251 mg, 37%) as an orange oil.1H NMR and MS confirmed the structure.

Stage C. 2-(5,6-Dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)benzoxazole-4-lithium carboxylate (243 mg, 0.84 mmol) dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (229 mg, 1.01 mmol), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Primer: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-tert-butylnitrone)-6-chlorobenzoxazole-4-carboxamide

Stage A. To ice stirred suspension of NaH (60% in oil, 1.6 g, 39,0 mmol) in toluene (53 ml) is added dropwise a solution of (S)-2-amino-4,5-dimethylpentan-1-ol (2.0 g, 17,0 mmol) in toluene (37 ml). After complete addition, the reaction mixture is heated to room temperature and added dropwise a solution of ethylchloride (2.3 g, 19.0 mmol) in toluene (10 ml). The resulting mixture was then stirred at the boil under reflux for 20 h, cooled to room temperature and the reaction mixture is added solid ammonium chloride (2.1 g, from 39.0 mmol). The mixture is stirred for 20 min and then concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of from 98:2 CH2Cl2/CH3HE to 95:5 CH2Cl2/CH3IT), thus obtaining (S)-5-tert-butylboron-3-one (2.0 g, 74%) as a pale yellow oil. To ice THF (9 ml) add sociallyengaged (1.0 M solution in THF, 26,0 ml, 26.0 mmol). After completion of adding dropwise during 20 min add a solution of (S)-5-tert-butylboron-3-one (2.0 g, 13,0 mmol) in THF (8.0 ml). After complete addition, the ice bath removed and the reaction mixture is stirred at the boil under reflux for 20 hours. The reaction mixture was cooled in an ice bath and to it was added slowly N2On (,2 ml), then 15% aqueous NaOH solution (1.2 ml) and then N2O (1.2 ml). The resulting mixture was stirred at room temperature for 1.5 hours and then filtered, washing the solid EtOAc (50 ml). The filtrate is concentrated at room temperature and under reduced pressure, thus obtaining (S)-3-tert-butylparaben (1.7 g, 97%) as a pale yellow oil.1H NMR corresponds to the connection structure.

Stage C. To a solution of methyl-2,6-dichlorobenzoate-4-carboxylate (515 mg, of 2.09 mmol) in THF (15 ml) is added (S)-3-tert-butylparaben (600 mg, 4,19 mmol). The mixture is stirred at room temperature for 5 days. The reaction mixture is concentrated to dryness. The crude substance is purified column chromatography (silica gel, 2% EtOAc in hexane), thus obtaining the desired methyl-(S)-methyl-2-(3-tert-butylnitrone)-6-chlorobenzoxazole-4-carboxylate (149 mg, 20,2%) as a yellow solid. MS corresponds to the connection structure.

Stage C. According to the General method GP-B2 (S)-methyl-2-(3-tert-butylnitrone)-6-chlorobenzoxazole-4-carboxylate is transformed into (S)-2-(3-tert-butylnitrone)-6-chlorobenzoxazole-4-carboxylate lithium. MS corresponds to the connection structure.

Stage d According to the General method GP-C1 condense a mixture of (S)-2-(3-tert-butylnitrone)-6-chlorobenzoxazole-4-carboxylate lithium dihydrochloride 9-methyl-9-azabicyclo[3.3.1]nonan-3-amine, while receiving endo-N-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-tert-butylnitrone)benzoxazol-4-carboxamid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 81: obtain the hydrochloride of endo-N-(9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxamide

To endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazol-4-carboxamide (107 mg, 0.24 mmol) in CH2Cl2(3 ml) at 0°C. add 1,8-bis(dimethylamino)naphthalene (10 mg, 0,048 mmol) and 1-chloroethylphosphonic (of 0.21 ml, 1,90 mmol). After stirring at 0°C for 0.5 hour, the reaction mixture is refluxed. After 2 hours add additional 1,8-bis(dimethylamino)naphthalene (10 mg, 0,048 mmol). After another 0.5 hour add 1,8-bis(dimethylamino)naphthalene (10 mg, 0,048 mmol) and 1-chloroethylphosphonic (of 0.21 ml, 1,90 mmol). After 3 h the reaction mixture was cooled to ambient temperature and stirred over night. Then add additional 1,8-bis(dimethylamino)naphthalene (20 mg, 0,096 mmol) and 1-chloroethylphosphonic (of 0.21 ml, 1,90 mmol) and the reaction mixture is refluxed. After 7.5 hours, add another 1-chloroethylphosphonic (of 0.21 ml, 1,90 mmol) and the reaction mixture is refluxed over night. The reaction mixture was cooled to ambient temperature and concentrate under reduced pressure. Add Aut CH 3HE (5 ml) and the solution refluxed. After 1.5 h, the reaction mixture was concentrated and the resulting residue was dissolved in CH2Cl2(20 ml). The organic layer was washed with saturated NaHCO3(10 ml), saturated salt solution (10 ml), dried (Na2SO4) and concentrate under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 9:1 CH2Cl2/CH3HE to a mixture of 90:9:0,1 CH2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazol-4-carboxamide (62 mg). This substance is dissolved in a mixture of acetonitrile/N2About (1:4, 10 ml) and add HCl (1N in diethyl ether at 0.31 ml, 0.31 mmol). The solution lyophilized, while receiving hydrochloride endo-N-(9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxamide (71 mg, 68%) as a white powder.1H NMR and MS confirmed the structure.

Example 82: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(thiomorpholine-1,1-dioxide)benzoxazole-4-carboxamide

Stage A. a Solution of methyl-2-chlorobenzoxazole-4-carboxylate (1.0 g, 4.7 mmol) and thiomorpholine (1.4 ml, 14 mmol) in THF (20 ml) was stirred at ambient temperature for 1 hour. Then the reaction mixture was poured into EtOAc (100 ml) and the industry is up to 1 N. HCl (20 ml) and N2O (20 ml) and saturated salt solution (20 ml), dried (Na2SO4) and concentrate under reduced pressure. Purification by chromatography (silica gel, 5-50% EtOAc in hexano) gives methyl-2-timehelicobacter-4-carboxylate (1.1 g, 84%) as a yellow solid.1H NMR and MS confirmed the structure.

Stage Century methyl-2-timehelicobacter-4-carboxylate (500 mg, to 1.79 mmol) in CH3HE (10 ml) add peroxymonosulfate potassium (1,95 g of 5.39 mmol) in N2About (10 ml). The yellow suspension was stirred at ambient temperature for 2 h and then concentrated under reduced pressure. The residue is dissolved in N2O (30 ml) and extracted with chloroform (3×25 ml). The combined organic layers washed with N2O (20 ml), saturated salt solution (20 ml), dried (Na2SO4) and concentrated under reduced pressure, thus obtaining methyl-2-(thiomorpholine-1,1-dioxide)benzoxazole-4-carboxylate (528 mg, 95%) as a yellow solid.1H NMR corresponds to the connection structure.

Synthesis of 2-(thiomorpholine-1,1-dioxide)benzoxazole-4-carboxylate lithium: a shared approach to GP-B2 methyl-2-(thiomorpholine-1,1-dioxide)benzoxazole-4-carboxylate converted into 2-(thiomorpholine-1,1-dioxide)benzoxazole-4-carboxylate lithium, which is directly next turn without purification.

Stage C. In General the method GP-C1 condense a mixture of 2-(thiomorpholine-1,1-dioxide)benzoxazole-4-carboxylate lithium dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, except that after stirring at ambient temperature for 12 h the reaction mixture is heated at 50°C in oil bath for 6 hours. After the usual processing, the residue dissolved in CH2Cl2(5 ml) and add HCl (1 M solution in diethyl ether, 1.1 ml, 1.1 mmol). The mixture is concentrated under reduced pressure. The residue is dissolved in diethyl ether (10 ml) and the solution precipitated solid. The substance is additionally cleaned prepreparation HPLC (Luna C18(2), 10% solution of CH3CN/0,05% TFA in H2About/of 0.05% TFA to 100% CH3CN/0,05% TFA over 30 min, I = 223 nm). The desired fractions are combined and concentrated under reduced pressure. The residue is dissolved in CH2Cl2(35 ml) and the solution washed with saturated NaHCO3(20 ml), N2O (20 ml), saturated salt solution (20 ml), dried (Na2SO4) and concentrate under reduced pressure. To the residue add an excess of HCl (1 M solution in diethyl ether) and the solution concentrated under reduced pressure. Substance lyophilized in a mixture of acetonitrile/N2About (1:1, 6 ml)to give the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(thiomorpholine-1,1-dioxide)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Example 83: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-(ethyl(methyl)amino)benzoxazole-4-carbox the amide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and N-ethylmethylamine converted into methyl-2-(ethyl(methyl)amino)benzoxazole-4-carboxylate, except that the mixture was stirred at room temperature for 16 h and not heated. In addition, the crude substance is purified column chromatography (silica gel, 40% EtOAc in hexane). MS corresponds to the connection structure.

Stage C. 2-(Ethyl(methyl)amino)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(ethyl(methyl)amino)benzoxazole-4-carboxylate lithium dihydrochloride (S)-(-)-3-aminoquinuclidine and get (S)-N-(Hinkley-8-yl)-2-(ethyl(methyl)amino)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 84: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-ethylpiperazin-1-yl)benzoxazole-4-carboxamide

Stage A. 2-Benzylaminopurine (of 3.45 g of 22.8 mmol) are added to a solution of N-tert-BOC-α-aminobutyric acid (4.0 g, of 19.7 mmol) and carbonyldiimidazole (3,54 g and 21.8 mmol) in THF (100 ml) and the resulting mixture was stirred at room temperature for 17 hours. The solvent is removed in vacuo and the residue purified, colonos the Oh chromatography (silica gel, from 0 to 100% EtOAc in hexano), thus obtaining (S)-tert-butyl-1-(benzyl-(2-hydroxyethyl)amino)-1-oxobutyl-2-ylcarbamate (3 g, 45%) as a clear oil.1H NMR corresponds to the connection structure.

Stage C. TFA (10 ml) are added to (S)-tert-butyl-1-(benzyl-(2-hydroxyethyl)amino)-1-oxobutyl-2-ylcarbamate (3 g, of 8.92 mmol) in CH2Cl2(50 ml) at 0°C. the Mixture was stirred at 0°C for 1.5 hours followed by removal of solvent under reduced pressure. The residue is partitioned between CH2Cl2(300 ml) and 25% aqueous sodium hydroxide (100 ml). The aqueous fraction is then extracted with CH2Cl2(2×100 ml) and the combined organic fraction dried (Na2SO4), filtered and concentrated, thus obtaining (S)-2-amino-N-benzyl-N-(2-hydroxyethyl)butanamide in the form of a yellow oil (1.84 g, 87%).1H NMR corresponds to the connection structure.

Stage C. Diisopropylperoxydicarbonate (1,82 g, 9.3 mmol) are added to a solution of (S)-2-amino-N-benzyl-N-(2-hydroxyethyl)butanamide (1.84 g, 7.8 mmol) and triphenylphosphine (2,62 g, 10.0 mmol) in THF (50 ml). The reaction mixture was stirred at room temperature for 7 days. The solvent is removed under reduced pressure and the residue purified column chromatography (silica gel, 10% SN3HE EtOAc)to give (S)-1-benzyl-3-ethylpiperazin-2-he (0.8 g, 47%) as a clear oil.1H NMR according to the reecting the structure of the compound.

Stage D. LiAlH4(1 M solution in THF, 11 ml, 11.0 mmol) is added dropwise to a solution of (S)-1-benzyl-3-ethylpiperazin-2-she (0.8 g, 3,66 mmol) in THF (30 ml) at 0°C. the Reaction mixture was stirred at 65°C for 17 h, then cooled to 0°C. and quenched sequentially N2About (0.7 ml), 10% NaOH (1 ml) and N2About (1.5 ml). To the reaction mixture is added diethyl ether (100 ml) and stirring is continued for 1.5 hours. The solid is separated by filtration, the filtrate concentrated and dried in vacuum, thus obtaining (S)-1-benzyl-3-ethylpiperazine (0,67 g, 87%) as an oily solid.1H NMR and MS confirmed the structure.

Stage E. To a solution of (S)-1-benzyl-3-ethylpiperazine (650 mg, up 3.22 mmol) in DME (10 ml) at room temperature add NaH (60% suspension in mineral oil, 144 mg, 3.50 mmol) and the mixture is stirred for 45 minutes To the reaction mixture is added methyl-2-chlorobenzoxazole-4-carboxylate (510 mg, 2,42 mmol) and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was quenched CH3HE (10 ml), add silica gel (15 ml) and the solvent is removed under reduced pressure. The mixture was purified column chromatography (silica gel, 0-80% EtOAc in hexano), thus obtaining (S)-methyl-2-(4-benzyl-2-ethylpiperazin-1-yl)benzoxazole-4-carboxylate (0.87 g, 71%) as an oily solid.1The NMR and MS confirmed the structure.

Stage F. 2-(4-Benzyl-(S)-2-ethylpiperazin-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage G. By common procedures GP-C1 condense a mixture of 2-(4-benzyl-(S)-2-ethylpiperazin-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-ethyl-4-benzylpiperazine-1-yl)benzoxazol-4-carboxamide.1H NMR and MS confirmed the structure.

Stage N. To a solution of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-ethyl-4-benzylpiperazine-1-yl)benzoxazole-4-carboxamide (100 mg, 0.44 mmol) in 1,2-dichloroethane (10 ml) was added 1-chloroethylphosphonic (500 mg, 3.5 mmol) and Cs2CO3(0.5 g, 2 mmol) and the mixture is stirred for 5 hours at 55°C. the Solvent is removed in vacuo and the residue purified column chromatography (silica gel, mixture 10:1:0.1 to CH2Cl2:CH3HE:concentrated NH4OH), while receiving 31 mg (after aging in vacuum) of a transparent oil, MS (ESI+) m/z 312 (M+H). The resulting oil was dissolved in CH2Cl2(2 ml) and add HCl (1 M solution in ether, 0.3 ml, 0.3 mmol). The mixture is stirred at room temperature for 5 min, then diluted with ethyl ether (40 ml). The solvent is removed in vacuo and the residue dissolved in a mixture of N2About/ACET the nitrile (1:1, 10 ml) and lyophilized, while receiving hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-ethylpiperazin-1-yl)benzoxazole-4-carboxamide (20 mg, 21%) as a white powder.1H NMR and MS confirmed the structure.

Example 85: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-(isopropyl(methyl)amino)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and N-methylpropan-2-amine is transformed into methyl-2-(isopropyl(methyl)amino)benzoxazole-4-carboxylate, except that the mixture was stirred at room temperature for 16 h and not heated. MS corresponds to the connection structure.

Stage C. 2-(Isopropyl(methyl)amino)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(isopropyl(methyl)amino)benzoxazole-4-carboxylate lithium dihydrochloride and (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-(isopropyl(methyl)amino)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 86: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-oxopiperidin-1-yl)benzoxazole-4-carboxamide

Stage A. a Mixture of methyl-2-chlorbenzoyl the evil-4-carboxylate (750 mg, 3.54 mmol) and piperazine-2-it (780 mg, 7,79 mmol) in THF (60 ml) was stirred at ambient temperature over night. The reaction mixture was diluted with EtOAc (150 ml) and 1 N. HCl (25 ml). The aqueous layer is separated, do main 1 N. NaOH and extracted with EtOAc (6×50 ml). The combined organic extracts dried (Na2SO4) and concentrated under reduced pressure, thus obtaining methyl-2-(3-oxopiperidin-1-yl)benzoxazole-4-carboxylate (690 mg, 72%).1H NMR corresponds to the connection structure.

Stage C. 2-(3-Oxopiperidin-1-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2 and directly subjected to further transformation without any purification.

Stage C. According to the General method GP-C1 condense a mixture of 2-(3-oxopiperidin-1-yl)benzoxazole-4-carboxylate lithium dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-oxopiperidin-1-yl)benzoxazole-4-carboxamide, except that the reaction mixture is stirred at 40°C for 3 hours. The substance is purified column chromatography (silica gel, mixture of 9:1 CH2Cl2/CH3HE to a mixture of 90:9:1 CH2Cl2/CH3HE/concentrated NH4OH), followed by purification prepreparation HPLC (Luna C18(2), 10% CH3CN/0,05% TFA in H2O/0,05% TFA to 40% CH3CN/0,05% TFA in H2About/of 0.05% TFA in which the attachment 30 min, I = 223 nm). The desired fractions are concentrated under reduced pressure, thus obtaining TFA salt. The residue is dissolved in CH2Cl2(25 ml) and washed with 1 N. NaOH (10 ml), N2About (10 ml), saturated salt solution (10 ml), dried (Na2SO4) and concentrate under reduced pressure. The dried residue in turn cleaners containing hydrochloride salt according to the General method GP-D1, while receiving hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-oxopiperidin-1-yl)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Example 87: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S)-3-ethyl-5-methylmorpholine)benzoxazole-4-carboxamide

Stage A. a Mixture of (S)-2-aminobutane-1-ol (14.5 g, 0,163 mmol), 1-hydroxypropan-2-it (13.3 ml of € 0.195 mmol) and platinum oxide (IV) (100 mg, 0,440 mol) is stirred in hydrogen atmosphere (1 ATM). Later 30,5 hour, the reaction mixture was filtered through diatomaceous earth and the filtrate concentrated under reduced pressure. The residue is purified by distillation, thus obtaining (S)-2-(1-hydroxypropan-2-ylamino)butane-1-ol (17.5 g, 74%) as a colourless oil.1H NMR corresponds to the connection structure.

Stage Century. To (S)-2-(1-hydroxypropan-2-ylamino)butane-1-Olu (10.5 g, 0,071 mmol) in an ice bath at a temperature of 0°C. add concentrated portions H2SO4(7 ml) for 10 minutes SPU is tan 5 min the ice bath removed and the reaction mixture is heated on an oil bath at 180°C. Later 5,75 hour, the reaction mixture was cooled to ambient temperature and then poured onto portions in ice a solution of potassium hydroxide (16 g) in N2O (100 ml). The resulting solid is removed by vacuum filtration. To the filtrate add di-tert-BUTYLCARBAMATE (15.5 g, 0,071 mol) and the mixture was stirred at ambient temperature over night. The reaction mixture was extracted with diethyl ether (3×100 ml) and the combined organic extracts dried (Na2SO4) and concentrate under reduced pressure. The diastereomers separated column chromatography (silica gel, from hexanol to 10% solution of EtOAc in hexano), while receiving (3S,5S)-tert-butyl-3-ethyl-5-methylmorpholin-4-carboxylate (1,82 g, 11%) and (3R,5S)-tert-butyl-3-ethyl-5-methylmorpholin-4-carboxylate (1,32 g, 8.1 per cent).1H NMR corresponds to the connection structure.

Stage C. (3S,5S)-tert-Butyl-3-ethyl-5-methylmorpholin-4-carboxylate (1.8 g, 7.8 mmol) is dissolved in approximately 10 M of HCl in CH3HE and stirred at ambient temperature. After 2.5 hours the solution is concentrated under reduced pressure. To the residue add 1 N. NaOH (20 ml) and the mixture extracted with CH2Cl2(2×20 ml). The combined organic layers are dried (Na2SO4and carefully concentrated under reduced pressure, thus obtaining (3S,5S)-3-ethyl-5-methylmorpholine (1.0 g, quantity is the only exit). 1H NMR corresponds to the connection structure.

Stage C. a Mixture of methyl-2-chlorobenzoxazole-4-carboxylate (750 mg, 3.54 mmol) and (3S,5S)-3-ethyl-5-methylmorpholine (1,00 g of 7.75 mmol) in THF (40 ml) was stirred at ambient temperature over night. Then the reaction mixture is heated on an oil bath at 50°C for 4.5 hours. The reaction mixture was cooled to ambient temperature and most of the THF is removed under reduced pressure. The residue is dissolved in EtOAc (150 ml) and the solution washed with 0.5 N. HCl (25 ml), N2O (25 ml), saturated salt solution (25 ml), dried (Na2SO4) and concentrate under reduced pressure. The crude substance is purified column chromatography (silica gel, from hexanol to 10% EtOAc in hexano), while receiving methyl-2-((3S,5S)-3-ethyl-5-methylmorpholine)benzoxazole-4-carboxylate (540 mg, 50%) as a colourless oil.1H NMR corresponds to the connection structure.

Stage D. 2-((3S,5S)-3-Ethyl-5-methylmorpholine)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2 and without treatment directly subjected to further transformation.

The stage that a shared approach to GP-C1 condense a mixture of 2-((3S,5S)-3-ethyl-5-methylmorpholine)benzoxazole-4-carboxylate dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S)-3-ethyl-5-methylmorpholine)benzox the evil-4-carboxamid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 88: obtain the hydrochloride of endo-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxamide

Stage A. a Mixture of methyl-2-chlorobenzoxazole-4-carboxylate (620 mg, 2,96 mmol) and (3S,5S) - for 3,5-dimethylmorpholine (341 mg, 2,96 mmol) and potassium carbonate (1.0 g, 7.4 mmol) in DMF (15 ml) is stirred under heating at 35°C on an oil bath. After 17 h, the reaction mixture was cooled to ambient temperature, diluted with H2About (50 ml) and extracted with EtOAc (2×30 ml). The combined organic layers washed with N2About (3×20 ml), saturated salt solution (20 ml), dried (Na2SO4) and concentrate under reduced pressure. Methyl-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxylate (770 mg, 89%) was obtained as an amber oil.1H NMR corresponds to the connection structure.

Stage C. 2-((3S,5S) - for 3,5-Dimethylmorpholine)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2 and without treatment directly subjected to further transformation.

Stage C. According to the General method GP-C1, a mixture of 2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxylate dihydrochloride and endo-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-amine turn in endo-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-2-((3S,5S) - for 3,5-d is methylmorpholine)benzoxazol-4-carboxamid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 89: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4-methoxypiperidine-1-yl)benzoxazole-4-carboxamide

Stage A. To a solution of methyl-2-chlorobenzoxazole-4-carboxylate (210 mg, 0,99 mmol) in NMP (5 ml) is added 4-methoxypiperidine (230 mg, to 1.98 mmol) in NMP (5 ml) at room temperature. To the mixture in two portions over 5 min add NaH. The mixture is stirred at room temperature for 18 hours. The reaction is quenched by adding 10 ml of CH3HE followed by concentration to dryness. The crude substance is purified column chromatography (silica gel, 50% EtOAc in hexane), while receiving methyl-2-(4-methoxypiperidine-1-yl)benzoxazole-4-carboxylate (146 mg, 50%) as a yellow solid. MS corresponds to the connection structure.

Stage C. 2-(4-Methoxypiperidine-1-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-(4-methoxypiperidine-1-yl)benzoxazole-4-carboxylate lithium dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4-methoxypiperidine-1-yl)benzoxazole-4-carboxamide, which in turn hydrochloride the salt according to the General method GP-D1. 1H NMR and MS confirmed the structure.

Example 90: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxamide

Stage A. 2-((3S,5S) - for 3,5-Dimethylmorpholine)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2 and without treatment directly subjected to further transformation.

Stage C. According to the General method GP-C1 condense 2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxylate dihydrochloride and (S)-(-)-3-aminoquinuclidine, thus obtaining 2-((3S,5S) - for 3,5-dimethylmorpholine)-N-(Hinkley-8-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 91: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and 1,4-dioxa-8 azaspiro[4,5]decane converted into methyl-2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)benzoxazole-4-carboxylate, except that the mixture was stirred at room temperature for 3 days and not heated. MS corresponds to the connection structure.

Stage C. 2-(1,4-Dioxa-8 azaspiro[4,5]Decan-8-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Studies. According to the General method GP-C1 condense a mixture of 2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 92: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4-oxopiperidin-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and 1,4-dioxa-8 azaspiro[4,5]decane converted into methyl-2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)benzoxazole-4-carboxylate, except that the mixture was stirred at room temperature for 3 days and not heated. MS corresponds to the connection structure.

Stage C. 2-(1,4-Dioxa-8 azaspiro[4,5]Decan-8-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage C. According to the General method GP-C3 condense a mixture of 2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)benzoxazol-4-carboxamide.1

Stage D. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)benzoxazole-4-carboxamide (100 mg, 0.23 mmol) and PPTS (85 mg, 0.34 mmol) dissolved in acetone (1 ml) and N2O (1 ml). The reaction mixture was treated with microwave radiation at 170°C for 90 minutes the Solvent is removed under reduced pressure. The remaining oil was diluted with CH2Cl2(100 ml) and washed with H2About (3×25 ml). The organic layer is dried (MgSO4), filtered and concentrated to obtain crude product. The crude product is purified prepreparation HPLC (Luna C18(2), 10% CH3CN/0,05% TFA in H2About/of 0.05% TFA to 100% CH3CN/0,05% TFA over 25 min, I = 223 nm), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4-oxopiperidin-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 93: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-aminobenzothiazole-4-carboxamide

Stage A. To a solution of di-(1H-imidazol-1-yl)methanamine (2,05 g of 12.26 mmol) in THF (60 ml) is added methyl 2-amino-3-hydroxybenzoate (1.98 g, of 12.26 mmol) at room temperature and the resulting reaction mixture is refluxed for 17 hours. The reaction mixture is cooled to room temperature, diluted with EtOAc (100 ml) and washed with H2About(3×100 ml), saturated ammonium chloride (2×100 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude substance is purified by recrystallization from diethyl ether, thus obtaining methyl-2-aminobenzothiazole-4-carboxylate (1.10 g, 50%) as a brown solid.1H NMR and MS confirmed the structure.

Stage C. a Mixture of methyl-2-aminobenzothiazole-4-carboxylate (750 mg, 3.9 mmol), di-tert-BUTYLCARBAMATE (936 mg, the 4.29 mmol) in CH2Cl2(50 ml) was stirred at room temperature for 17 hours. The reaction is quenched with saturated NaHCO3(25 ml) and then extracted with CH2Cl2(3×100 ml). The combined organic phase was washed with H2About (2×75 ml), saturated salt solution (1×50 ml) and dried (Na2SO4), filtered and concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 9:1 CH2Cl2/CH3IT), while receiving methyl-2-(tert-butoxycarbonylamino-4-yl)benzoxazole-4-carboxylate (930 mg, 82%) as a pale yellow solid.1H NMR corresponds to the connection structure.

Stage C. 2-(tert-Butoxycarbonylamino-4-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B1.1H NMR and MS confirmed the structure.

Stage d According to the General method GP-C1 condense 2-(tert-butoxy is ebonyline-4-yl)benzoxazole-4-carboxylic acid, the dihydrochloride (S)-(-)-3-aminoquinuclidine (199 mg, 1.0 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, while receiving 4-(Hinkley-8-ylcarbonyl)benzoxazol-2-ylcarbamate (210 mg, 54%) as not quite white solid. MS corresponds to the connection structure.

Stage E. To a solution of tert-butyl 4-(Hinkley-8-ylcarbonyl)benzoxazol-2-ylcarbamate (0,210 g, 0.54 mmol) in CH2Cl2(5 ml) is added TFA (2 ml) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the crude substance is treated with an aqueous NaHCO3to regulate the pH to 7 and then extracted with CH2Cl2(5×50 ml). The combined organic phase is concentrated and purified preparative TLC (a mixture of 90:9:1 CH2Cl2/CH3HE/concentrated NH4OH), thus obtaining (S)-N-(Hinkley-8-yl)-2-aminobenzothiazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 94: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-(hydroxymethyl)morpholino)benzoxazole-4-carboxamide

Stage A. To a solution of (R)-methyl-2-amino-3-hydroxypropanoate (33 g, 212 mmol) in 2 N. NaOH solution (182 ml) was added benzaldehyde (32 ml, 318 mmol), the mixture is stirred at room temperature in ECENA 30 min and cooled to -5°C. Small portions during one hour add sodium borohydride (4,01 g, 106 mmol), added benzaldehyde (32 ml, 318 mmol) and the reaction mixture was stirred at room temperature for 30 min, then cooled to -5°C. in Small portions over one hour added NaBH4(4,01 g, 106 mmol) and the reaction mixture was stirred at room temperature for 12 hours. The solution is extracted with diethyl ether (500 ml) and acidified with concentrated HCl to pH 1. The precipitate was separated by filtration and dried in vacuum to give the hydrochloride of (R)-2-(benzylamino)-3-hydroxypropanoic acid (9.4 g, 23%) as a white solid.1H NMR corresponds to the connection structure.

Stage C. To a solution of hydrochloride of (R)-2-(benzylamino)-3-hydroxypropanoic acid (9.4 g, 48.2 mmol) and sodium hydroxide (to 2.57 g of 82.9 mmol) in N2O (30 ml) at 0°C is added dropwise chlorocatechol (4,9 ml, 62,1 ml) maintaining the temperature below 10°C. the Reaction mixture was then warmed to room temperature and stirred for 2 hours. The reaction mixture was extracted with CH2Cl2(2×250 ml) and the organic layer is dried (MgSO4), filtered and concentrated. The residue is purified flash chromatography (silica gel, 10-30% solution of CH3HE in CH2Cl2with 1% acetic acid)to give (R)-2-(N-benzo is l-2-chloroacetamido)-3-hydroxypropanoic acid (2.6 g, 20%) as a yellow foam.1H NMR corresponds to the connection structure.

Stage C. To a solution of (R)-2-(N-benzyl-2-chloroacetamido)-3-hydroxypropanoic acid (1,53 g, 5,63 mmol) in tert-butanol added tert-butanolate potassium and the reaction mixture is heated to 110°C for three hours, then cooled to room temperature and concentrated to dryness. The residue acidified with 1 N. HCl to pH 1 and the aqueous solution extracted with EtOAc (3×250 ml). The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure. The residue is purified flash chromatography (silica gel, 10-30% of CH3HE in CH2Cl2with 1% acetic acid)to give (R)-4-benzyl-5-exmortis-3-carboxylic acid (780 mg, 59%) as a yellow foam.1H NMR and MS confirmed the structure.

Stage D. To a solution of (R)-4-benzyl-5-exmortis-3-carboxylic acid (780 mg, of 3.32 mmol) and triethylamine (567 ml, 4,08 mmol) in anhydrous THF (15 ml) at 0°C. add the complex of borane-dimethyl sulfide for 15 minutes the Reaction mixture is heated to room temperature and refluxed for 6 hours, then cooled in an ice bath. To this mixture are added dropwise N2O (4 ml) for 30 min, then 2 N. NaOH (6 ml) and the mixture is concentrated to 30% vol. The residue is extracted with EtOAc (3×150 ml), the organic layer is dried (MgSO4) and concentrate. Statomat flash chromatography (silica gel, 0-5% CH3HE in CH2Cl2), thus obtaining (S)-(4-benzylmorphine-3-yl)CH3HE (470 mg, 68%) as a colourless oil.1H NMR and MS confirmed the structure.

Stage that is a Solution of (S)-(4-benzylmorphine-3-yl)CH3HE (450 mg, 2,17 mmol), tert-butylcholinesterase (392 mg, 2,60 mmol) and imidazole (370 mg, 5,42 mmol) in DMF (10 ml) was stirred at room temperature for 18 hours. The reaction mixture was diluted with CH2Cl2(2×50 ml), washed with 5% solution of NaHCO3(50 ml) and saturated salt solution (3×20 ml) and the organic layer is dried (MgSO4) and concentrate. The residue is purified flash chromatography (silica gel, 10-30% of CH3HE in CH2Cl2), thus obtaining (R)-4-benzyl-3-((tert-butyldimethylsilyloxy)methyl)morpholine (576 mg, 82%) as a colourless foam.1H NMR and MS confirmed the structure.

Stage F. Suspension of (R)-4-benzyl-3-((tert-butyldimethylsilyloxy)methyl)research (576 mg, to 1.79 mmol) and 10% palladium on coal in EtOAc (20 ml) is placed in a vibrator Parra and hydronaut when the hydrogen pressure of 45 psi for 48 hours. The heterogeneous mixture is filtered through a layer of diatomaceous earth, washed with CH3HE (200 ml) and concentrated, thus obtaining (R)-3-((tert-butyldimethylsilyloxy)methyl)morpholine (414 mg, quantitative yield) as a colorless oil. MS corresponds to the connection structure.

With the adiya G. According to the General method GP-A (R)-3-((tert-butyldimethylsilyloxy)methyl)morpholine and 2-chlorobenzoxazole-4-carboxylate is transformed into (R)-methyl-2-(3-((tert-butyldimethylsilyloxy)methyl)morpholino)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage N. To a solution of LiI (298 mg, 2.22 mmol) in boiling under reflux in anhydrous pyridine (50 ml) is added (R)-methyl-2-(3-((tert-butyldimethylsilyloxy)methyl)morpholino)benzoxazole-4-carboxylate (226 mg, 0.55 mmol) and the reaction mixture is refluxed for 24 hours. The mixture is cooled to room temperature, concentrated to dryness and dried under vacuum, thus obtaining (R)-2-(3-((tert-butyldimethylsilyloxy)methyl)morpholino)benzoxazole-4-carboxylate lithium in the form of a yellow oil which is used without further purification. MS corresponds to the connection structure.

Stage I. General method GP-C1 condense (R)-2-(3-((tert-butyldimethylsilyloxy)methyl)morpholino)benzoxazole-4-carboxylate dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonan, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((R)-3-((tert-butyldimethylsilyloxy)methyl)morpholino)benzoxazol-4-carboxamide.1H NMR and MS confirmed the structure.

Stage J. a Solution of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((R)-3-((tert-butyldimethylsilyloxy)methyl)morpholino)benzo is xazal-4-carboxamide (293 mg, 0.55 mmol) and tetrabutylammonium fluoride (1.7 ml, 1 M solution in THF) in anhydrous THF (80 ml) was stirred at room temperature for 12 hours. The reaction mixture is concentrated to dryness and the residue is again dissolved in CH2Cl2(100 ml), washed with a saturated solution of ammonium chloride (2×25 ml), saturated salt solution (25 ml) and the organic layer is dried (MgSO4) and concentrate. The crude substance is purified column chromatography (silica gel, 100% CH2Cl2to a mixture of 90:10:1 CH2Cl2/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-(hydroxymethyl)morpholino)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 95: Getting hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-methylpiperazin-1-yl)benzoxazole-4-carboxamide

Stage A. To a solution of tert-butyl 2-methylpiperazine-1-carboxylate (340 mg, 1.70 mmol) in THF (5 ml) is added sodium hydride (60%, 82 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 5 min, then the reaction mixture is added methyl-2-chlorobenzoxazole-4-carboxylate (300 mg, of 1.41 mmol) in THF (5 ml). The reaction mixture was stirred at room temperature for 19 hours. The mixture is concentrated PR is the reduced pressure and the resulting residue is purified column chromatography (silica gel, 20% EtOAc in hexane), while receiving methyl-2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)benzoxazole-4-carboxylate (336 mg, 63%) as a yellow solid. MS corresponds to the connection structure.

Stage C. 2-(4-(tert-Butoxycarbonyl)-3-methylpiperazin-1-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)benzoxazole-4-carboxylate lithium and the dihydrochloride 9-methyl-9-azabicyclo[3.3.1]nonan-3-amine, while receiving tert-butyl-2-methyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate. MS corresponds to the connection structure.

Stage D. To a solution of the obtained tert-butyl-2-methyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate (138 mg, 0.27 mmol) in CH2Cl2(2 ml) is added TFA (2 ml) at 0°C. the Reaction mixture was stirred at 0°C for 1.5 h and concentrated to obtain crude product. The crude product was purified preparative TLC (silica gel, mixture of 80:19:1 chloroform/CH3HE/concentrated NH4OH), while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(3-methylpiperazin-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1N Amri MS confirmed the structure.

Example 96: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-tert-butylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. Sociallyengaged (1 M solution in THF, 40 ml, 40.0 mmol) is added dropwise to a solution of (S)-2-tert-butylpiperazine-3,6-dione (1.5 g, 8,82 mmol) in THF (50 ml) at 0°C. the Reaction mixture was stirred at room temperature for 7 days and at 65°C for 17 h, then cooled to 0°C. and quenched sequentially N2About (1.7 ml), 10% NaOH (2.2 ml) and N2(3.4 ml). To the reaction mixture add a simple ether (100 ml) and stirring is continued for 1.5 hours. The solid is separated by filtration, the filtrate concentrated and purified column chromatography (silica gel, 33% EtOAc in hexano), thus obtaining (S)-2-tert-butylpiperazine (0.64 g, 52%) as a clear oil.1H NMR and MS confirmed the structure.

Stage Century. To (S)-2-tert-butylpiperazine (0.5 g, to 3.49 mmol) in CH2Cl2(15 ml) at room temperature is added triethylamine (0.5 ml, 3,59 mmol) followed by addition of di-tert-BUTYLCARBAMATE (0,83 g, with 3.79 mmol) and the reaction mixture stirred at room temperature for 17 hours. The solvent is removed in vacuo and the residue purified column chromatography (silica gel, mixture 10:1:0.1 to CH2Cl2/CH3HE/concentrated NH4OH), thus obtaining (S)-4-t the et-butyloxycarbonyl-2-tert-butylpiperazine (0,59 g, 69%) as a clear oil.1H NMR corresponds to the connection structure.

Stage back To (S)-4-tert-butyloxycarbonyl-2-tert-butylpiperazine (640 mg, 2,60 mmol) in DME (10 ml) at room temperature add NaH (60% suspension in mineral oil, 115 mg, 3.50 mmol) and the mixture is stirred for 45 minutes To the reaction mixture is added methyl-2-chlorobenzoxazole-4-carboxylate (780 mg, of 3.69 mmol) and the mixture is stirred at room temperature for 3 days at 55°C for 24 hours. The reaction mixture was quenched CH3HE (10 ml), add silica gel (15 ml) and the solvent is removed under reduced pressure. The residue is purified column chromatography (silica gel, 33% EtOAc in hexano), thus obtaining (S)-methyl-2-(4-tert-butyloxycarbonyl-2-tert-butylpiperazine-1-yl)benzoxazole-4-carboxylate (0,42 g, 39%) as a yellow solid.1H NMR and MS confirmed the structure.

Stage d According to the General method GP-B3 (S)-methyl-2-(4-tert-butyloxycarbonyl-2-tert-butylpiperazine-1-yl)benzoxazole-4-carboxylate is transformed into (S)-2-(4-tert-butyloxycarbonyl-2-tert-butylpiperazine-1-yl)benzoxazole-4-carboxylic acid. MS corresponds to the connection structure.

The stage that a shared approach to GP-C1 condense (S)-2-(4-tert-butyloxycarbonyl-2-tert-butylpiperazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]but the Academy of Sciences, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-tert-butyl-4-tert-butyloxycarbonyl-1-yl)benzoxazole-4-carboxamide. MS corresponds to the connection structure.

Stage F. TFA (1 ml) are added to endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-tert-butyl-4-tert-butyloxycarbonyl-1-yl)benzoxazole-4-carboxamide (100 mg, 0.18 mmol) in CH2Cl2(1 ml) and the mixture is stirred for 1 hour at room temperature. The solvent is removed in vacuum and the residue is neutralized ion exchange chromatography (column 5 g SCX-2), while receiving 29 mg of a clear oil. The oil obtained is transformed into cleaners containing hydrochloride salt according to the General method GP-D1, while receiving hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-tert-butylpiperazine-1-yl)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Example 97: Getting hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxamide

Stage A. a Mixture of methyl-2-chlorobenzoxazole-4-carboxylate (970 mg, 4,58 mmol) and (3S,5S)-1-benzyl-3,5-dimethylpiperazine-2-it (1,00 g, 4,58 mmol) in DMF (20 ml) is stirred at an oil bath at 35°C. After 16 h the reaction mixture is heated to 55°C. After 3 hours add potassium carbonate (630 mg, 4,58 mmol). The reaction mixture is stirred for 2 caspri 55°C and then at room temperature for 17 hours. The reaction mixture was diluted with H2About (50 ml) and extracted with EtOAc (2×50 ml). The combined organic layers washed with 0.5 N. HCl (25 ml), N2O (25 ml), saturated salt solution (25 ml), dried (Na2SO4) and concentrate under reduced pressure. Purification by chromatography (silica gel, 10-80% solution of EtOAc in hexano) gives methyl 2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate (1.08 g, 60%).1H NMR corresponds to the connection structure.

Stage C. 2-((2S,6S)-4-Benzyl-2,6-dimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2 and without treatment directly subjected to further transformation.

Stage C. According to the General method GP-C1 condense 2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate lithium and the dihydrochloride endo-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-amine, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 98: Getting hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-methyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxamide

Stage A. a Mixture of methyl-2-chlorobenzoxazole-4-carboxylate (370 mg, about 1.75 mmol), (S)-3-methylpiperazin-2-it (00 mg, a 1.75 mmol) and K2CO3(605 mg, of 4.38 mmol) in DMF (15 ml) was stirred at ambient temperature for 17 hours. The reaction mixture was diluted with H2O (30 ml) and extracted with CH2Cl2(2×50 ml). The combined organic layers washed with N2About (3×20 ml), saturated salt solution (20 ml), dried (Na2SO4). The product is concentrated under reduced pressure, thus obtaining (S)-methyl-2-(2-methyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate (500 mg, 73%) as a yellow oil.1H NMR corresponds to the connection structure.

Stage Century. To (S)-methyl-2-(2-methyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate (118 mg, 0,407 mmol) in THF (3 ml) add trimethylsilanol potassium (58 mg, 0,407 mmol). Formed yellow precipitate, and after 1.5 hours, add additional trimethylsilanol potassium (58 mg, 0,407 mmol). After 1 hour the reaction mixture is refluxed. After 1.5 h, the reaction mixture was cooled to ambient temperature. The solid is collected by vacuum filtration and washed with diethyl ether, thus obtaining the crude (S)-2-(2-methyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate potassium.1H NMR corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of (S)-2-(2-methyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate and potassium dihydrochloride endo-9-mate the-3-oxa-9-azabicyclo[3.3.1]nonan-7-amine, while receiving hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-2-methyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxamide according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 99: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. 2-((2S,6S)-4-(tert-Butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium dihydrochloride and (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. To a solution of (S)-N-(Hinkley-8-yl)-2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate (245 mg, 0.51 mmol) is added HCl (1.25 M solution in CH3HE, of 8.2 ml, 10,13 mmol) and the mixture was stirred at 35°C for 17 h, then concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, 100% mixture of 9:1 CH2Cl2/CH3IT is up to 100% of a mixture of 90:9:1 CH2Cl2/CH3HE/concentrated NH4O) thus the (S)-N-(Hinkley-8-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 100: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(6,9-diazaspiro[4.5]Decan-6-yl)benzoxazole-4-carboxamide

Stage A. To a solution of tert-butyl-6,9-diazaspiro[4.5]decane-9-carboxylate (192 mg, 0.80 mmol) in DME (10 ml) is added NaH (60%, 96 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 10 min followed by the addition of methyl-2-chlorobenzoxazole-4-carboxylate (186 mg, 0.88 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction is quenched by adding 5 ml of N2Oh and the mixture extracted with EtOAc (2×30 ml). The organic layer was washed with saturated salt solution, dried over Na2SO4filter and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel, 50-100% chloroform in hexane), while receiving methyl-2-(9-(tert-butoxycarbonyl)-6,9-diazaspiro[4,5]Decan-6-yl)benzoxazole-4-carboxylate (61,4 mg, 18,5%) as a yellow oil. MS corresponds to the connection structure.

Stage C. According to the General method GP-B2 methyl-2-(9-(tert-butoxycarbonyl)-6,9-diazaspiro[4,5]Decan-6-yl)benzoxazole-4-carboxylate of preures the Ute 2-(9-(tert-butoxycarbonyl)-6,9-diazaspiro[4,5]Decan-6-yl)benzoxazole-4-carboxylate lithium. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-(9-(tert-butoxycarbonyl)-6,9-diazaspiro[4,5]Decan-6-yl)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving tert-butyl-6-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)-6,9-diazaspiro[4,5]decane-9-carboxylate (25 mg, 52%) as a yellow solid. MS corresponds to the connection structure.

Stage D. tert-butyl-6-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)-6,9-diazaspiro[4,5]decane-9-carboxylate (25 mg, 0.05 mmol) in CH2Cl2(1 ml) is added TFA (1 ml) at 0°C. the Reaction mixture was stirred at 0°C for 30 min, then at room temperature for 30 minutes, the Reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in CH2Cl2(50 ml). The organic phase is treated with an aqueous saturated solution of NaHCO3(25 ml). The organic layer is separated, dried over MgSO4, filtered and concentrated under reduced pressure, thus obtaining endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(6,9-diazaspiro[4,5]Decan-6-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 101: obtain the hydrochloride of N-(8-methyl-8-sabillo[3.2.1]Octan-3-yl)-2-(3S,5S) - for 3,5-dimethylmorpholine-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and (3S,5S) - for 3,5-dimethylmorpholine converted into methyl-2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxylate.1H NMR corresponds to the connection structure.

Stage C. 2-((3S,5S) - for 3,5-Dimethylmorpholine)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-((3S,5S) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxylic acid dihydrochloride and 8-methyl-8-azabicyclo[3.2.1]Octan-3-amine, thus obtaining N-(8-methyl-8-azabicyclo[3.2.1]Octan-3-yl)-2-(3S,5S) - for 3,5-dimethylmorpholine)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 102: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2,2-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a cooled with ice to a solution of 2,2-dimethylpiperazine (1.0 g, 8,76 mmol) in methanol (200 ml) is added di-tert-BUTYLCARBAMATE (1,91 g, 8,76 mmol) and triethylamine (2.67 g, 26,27 mmol). The reaction mixture was stirred at room temperature for 20 hours. The solvent is removed under reduced pressure and the remaining oil is extracted with CHCl3(3×60 ml). The organic phase is concentrated under reduced pressure, while receiving tert-butyl-3,3-dimethylpiperazine-1-carboxylate (662 mg, 35%) as a yellow oil. MS corresponds to the connection structure.

Stage C. According to the General method GP-A tert-butyl-3,3-dimethylpiperazine-1-carboxylate and methyl 2-chlorobenzoxazole-4-carboxylate is transformed into methyl-2-(4-(tert-butoxycarbonyl)-2,2-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. 2-(4-(tert-Butoxycarbonyl)-2,2-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage d According to the General method GP-C1 condense 2-(4-(tert-butoxycarbonyl)-2,2-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving tert-butyl-3,3-dimethyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate. MS corresponds to the connection structure.

Stage E. To a solution of tert-butyl-3,3-dimethyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate (63 mg, 0.12 mmol) in CH2Cl2(1 ml) is added TFA (1 ml) at 0°C. the Reaction mixture was stirred at 0°C for 30 min, then at room temperature for 30 minutes, the Reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in CH2Cl2(50 ml) and the solution washed with water feast upon the s ' solution of NaHCO 3(25 ml). The organic layer is separated, dried over MgSO4, filtered and concentrated under reduced pressure, thus obtaining endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2,2-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (28.5 mg, 56%) as a white solid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 103: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-amino-6-chlorobenzoxazole-4-carboxamide

Stage A. To a solution of di-(1H-imidazol-1-yl)methanamine (1,74 g, 10,83 mmol) in tetrahydrofuran (50 ml) is added methyl 2-amino-3-chloro-3-hydroxybenzoate (1.75 g, 8,66 mmol) at room temperature and the resulting reaction mixture is refluxed for 17 hours. The reaction mixture is cooled to room temperature and concentrate under reduced pressure. The residue is dissolved in CH2Cl2(100 ml) and washed with H2About (1×100 ml), saturated aqueous NH4Cl (3×100 ml), saturated salt solution (1×100 ml), dried over Na2SO4filter and concentrate under reduced pressure. The crude substance is cleaned by rubbing with EtOAc, while receiving methyl-2-amino-6-chlorobenzoxazole-4-carboxylate (1,05 g, 54%) as a light brown solid.1H NMR and MS confirmed the structure.

Stage C. the Mixture METI the-2-amino-6-chlorobenzoxazole-4-carboxylate (1,05 g, the 4.65 mmol) and di-tert-BUTYLCARBAMATE (3,15 g, 3.25 mmol) in CH2Cl2(50 ml) was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. The crude substance is purified column chromatography (mixture of 99:1 CH2Cl2/CH3IT), while receiving methyl-2-(tert-butoxycarbonylamino)-6-chlorobenzoxazole-4-carboxylate (720 mg, 36%) as a pale yellow solid.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-B3 methyl-2-(tert-butoxycarbonylamino)-6-chlorobenzoxazole-4-carboxylate converted into 2-(tert-butoxycarbonylamino-4-yl)benzoxazole-4-carboxylic acid. MS corresponds to the connection structure.

Stage d According to the General method GP-C1 condense 2-(tert-butoxycarbonylamino-4-yl)benzoxazole-4-carboxylic acid dihydrochloride and (S)-(-)-3-aminoquinuclidine, while receiving tert-butyl-6-chloro-4-(Hinkley-8-ylcarbonyl)benzoxazol-2-ylcarbamate. MS corresponds to the connection structure.

Stage E. To a solution of tert-butyl 6-chloro-4-(Hinkley-8-ylcarbonyl)benzoxazol-2-ylcarbamate (71 mg, 0,17 mmol) in CH2Cl2(1 ml) is added TFA (1 ml). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the crude substance is treated with concentrated Ki is roxicam ammonium for regulating the pH to 7. The mixture is concentrated under reduced pressure and the crude substance is purified preparative TLC (a mixture of 90:9:1 CH2Cl2/CH3HE/concentrated NH4OH), thus obtaining (S)-N-(Hinkley-8-yl)-2-amino-6-chlorobenzoxazole-4-carboxamide (21 mg, 38%) as a white solid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 104: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-ethylaminoethanol-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and ethylamine converted into methyl-2-(ethylamino)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. 2-(4-(tert-Butoxycarbonyl)-2,2-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-(ethylamino)benzoxazole-4-carboxylic acid dihydrochloride and (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-ethylaminoethanol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 105: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-ethylbenzamide-4-carboxamide

what about the common procedures GP-C1 condense 2-(ethylamino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-ethylbenzamide-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 106: Getting hydrochloride endo-6-chloro-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-methylmorpholine)benzoxazole-4-carboxamide

Stage A. a Solution of (S)-(+)-2-amino-1-propanol (5.0 g, 67,0 mmol) in toluene (60 ml) is added dropwise at 0°C. to a stirred suspension of NaH (60% in mineral oil, 6.2 g, 145 mmol) in toluene (150 ml). The cooling bath removed and the reaction mixture was stirred at room temperature for 0.5 hour. Then at room temperature is added dropwise a solution of ethylchloride (8.0 ml, 73.8 mmol) in toluene (60 ml) and the resulting reaction mixture is refluxed for 20 hours. The reaction mixture is cooled to room temperature and added to the mixture of solid ammonium chloride (5 g, 96.7 mmol). The reaction mixture was stirred for 20 min, filtered and the filtrate concentrated under reduced pressure, thus obtaining a yellow syrup. Purification of column chromatography (silica gel, mixture of 94.5:5:0.5 to CH2Cl2/CH3HE/NH4OH) gives (S)-5-methylmorpholin-3-one (6.5 g, 84%) as not quite white semi-solid substances.1H NMR and MS confirmed the structure

Stage C. a Solution of (S)-5-methylmorpholin-3-one (6.9 g, was 59.9 mmol) in tetrahydrofuran (40 ml) at 0°C is added dropwise to a solution of hydride LiAlH4(1.0 M solution in THF, 120,0 ml, 120 mmol) in tetrahydrofuran (40 ml). The ice bath is removed and the reaction mixture refluxed for 18 hours. The reaction mixture was cooled in an ice bath and the excess hydride reagent is quenched carefully by adding dropwise water (5 ml), 15% sodium hydroxide (5 ml) and water (15 ml). The resulting mixture was stirred at room temperature for 1 hour and the reaction mixture is filtered through a layer of celite and layer washed with ethyl acetate (100 ml). The filtrate is washed with saturated salt solution, dried over Na2SO4, filtered and concentrated under reduced pressure, thus obtaining (S)-3-methylmorpholin in the form of a red oil. Since it is assumed that the products have high volatility, (S)-3-methylmorpholin used in the next stage without further separation or purification.

Stage C. According to the General method GP-A 2,6-dichlorobenzoate-4-carboxylate hydrochloride and (S)-3-methylmorpholine converted into (S)-methyl-6-chloro-2-(3-methylmorpholine)benzoxazole-4-carboxylate.1H NMR corresponds to the connection structure.

Stage d (S)-methyl-6-chloro-2-(3-methylmorpholine)benzoxazole-4-carboxylate (390 mg, 1.25 mmol) in tetrahydrofuran (20 ml) is added t ematiciens potassium (178 mg, 1.25 mmol). The reaction mixture is refluxed for 45 minutes Then add additional trimethylsilanol potassium (178 mg, 1.25 mmol). After 30 min the reaction mixture was cooled to ambient temperature. The solid is collected by vacuum filtration, washed with diethyl ether and dried, thus obtaining the crude (S)-6-chloro-2-(3-methylmorpholine)benzoxazole-4-carboxylate potassium (454 mg, quantitative yield), which is directly next turn without purification.1H NMR corresponds to the connection structure.

The stage that a shared approach to GP-C2 condense (S)-6-chloro-2-(3-methylmorpholine)benzoxazole-4-carboxylate potassium and dihydrochloride endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving 6-chloro-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-methylmorpholine)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt common procedures GP-D1.1H NMR and MS confirmed the structure.

Example 107: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)-7-fermentation-4-carboxamide

Stage A. Methyl 2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)-7-fermentation-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-B3 methyl-2-((2S,6S)-4-(Tr is t-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)-7-fermentation-4-carboxylate converted into 2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)-7-fermentation-4-carboxylic acid. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)-7-fermentation-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-tert-butoxycarbonylmethyl-1-yl)-7-fermentation-4-carboxamide. MS corresponds to the connection structure.

Stage D. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-tert-butoxycarbonylmethyl-1-yl)-7-fermentation-4-carboxamide dissolved in 3 ml of 50% solution of TFA in CH2Cl2and stirred for 3.5 hours at ambient temperature. The solvent is removed in vacuum and the residue is neutralized ion exchange chromatography (column 5 g SCX)to give the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)-7-fermentation-4-carboxamide (62 mg) as a clear oil, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 108: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-6-chloro-2-(dimethylamino)benzoxazole-4-carboxamide

Stage A. Methyl-2-(dimethylamino)-6-chlorobenzoxazole-4-carboxylate synthesized according to the General method GP-A. MS corresponds to the connection structure./p>

Stage C. 2-(Dimethylamino)-6-chlorobenzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2. MS corresponds to the connection structure.

Stage d According to the General method GP-C1 condense 2-(dimethylamino)-6-chlorobenzoxazole-4-carboxylate lithium dihydrochloride and (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-6-chloro-2-(dimethylamino)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 109: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-(2,2,2-triptoreline)benzoxazole-4-carboxamide

Stage A. Methyl-2-(2,2,2-triptoreline)benzoxazole-4-carboxylate synthesized according to the General method GP-A. MS corresponds to the connection structure.

Stage C. 2-(2,2,2-Triptoreline)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense 2-(2,2,2-triptoreline)benzoxazole-4-carboxylic acid dihydrochloride and (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-(2,2,2-triptoreline)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 110: obtain the hydrochloride of endo-N-(9-methyl-9-AZ the bicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-acetyl-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a cooled with ice to a solution of (2S,6S)-2,6-dimethylpiperazine (712 mg, 6,24 mmol) in CH2Cl2(28 ml) is added di-tert-BUTYLCARBAMATE (1.50 g, 6,86 mmol), triethylamine (1,33 g to 13.09 mmol) and N,N-dimethylpyridin-4-amine (38,1 mg, 0.31 mmol). The reaction mixture was stirred at 0°C for 15 min, then warmed to room temperature and stirred for 20 hours. The solvent is removed under reduced pressure. The residue is dried, thus obtaining (3S,5S)-tert-butyl-3,5-dimethylpiperazine-1-carboxylate (1,79 g, 100%) as a white solid. MS corresponds to the connection structure.

Stage C. Methyl-2-(4-(tert-butoxycarbonyl)-2S,6S-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate synthesized according to the General method GP-A. MS corresponds to the connection structure.

Stage C. It chilled with ice to a solution of methyl 2-(4-(tert-butoxycarbonyl)-2S,6S-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate (360,1 mg, 0,924 mmol) in CH2Cl2(5 ml) is added TFA (0,343 ml, to 4.62 mmol). The reaction mixture was stirred for 18 h under nitrogen atmosphere while gradually warming to room temperature. The reaction is quenched with saturated aqueous sodium bicarbonate (15 ml). The organic layer is separated, washed with saturated salt solution (10 ml), dried (Na2SO4), filtered and concentrated under reduced pressure, thus obtaining methyl-2-((2S,6S)-2,6-dim teleperson-1-yl)benzoxazole-4-carboxylate in the form of oil (285 mg, >99%). This substance is transferred to the next stage without characterization.

Stage D. It chilled with ice to a solution of methyl 2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate (273 mg, 0,943 mmol) in CH2Cl2(5 ml) is added pyridine (0,114 ml of 1.41 mmol) followed by the addition of acetylchloride (0.100 ml, of 1.41 mmol) under nitrogen atmosphere. The mixture is stirred for 18 hours while gradually warming to room temperature. The reaction mixture was diluted with CH2Cl2(10 ml) and washed with saturated aqueous NaHCO3(10 ml), 1 N. HCl solution (10 ml) and saturated salt solution (10 ml). The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (0%-50% solution of a mixture of 95:15:1,5 CH2Cl2/CH3HE/concentrated NH4OH in CH2Cl2), while receiving methyl-2-((2S,6S)-4-acetyl-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate in the form of oil (62,1 mg, 20%).1H NMR and MS confirmed the structure.

The stage that a shared approach to GP-B2 methyl-2-((2S,6S)-4-acetyl-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate is subjected to interaction with the monohydrate of lithium hydroxide, thus obtaining 2-((2S,6S)-4-acetyl-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium.1H NMR and MS confirmed the structure is ur connection.

Stage F. According to the General method GP-C2 condense 2-((2S,6S)-4-acetyl-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium and the dihydrochloride 9-methyl-9-azabicyclo[3.3.1]nonan-3-amine, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-acetyl-2,6-dimethylpiperazine-1-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 111: Getting hydrochloride endo-2-amino-6-chloro-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)benzoxazole-4-carboxamide

Stage A. 2-Amino-6-chlorobenzoxazole-4-carboxylic acid synthesized according to the General method GP-B2.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense 2-amino-6-chlorobenzoxazole-4-carboxylic acid dihydrochloride and 9-methyl-9-azabicyclo[3.3.1]nonan-3-amine, while receiving endo-2-amino-6-chloro-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 112. Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-amino-7-fermentation-4-carboxamide

Stage A. a Mixture of methyl 2-chloro-7-fluoro-2,3-dihydroisoxazole-4-carboxylate (720 mg, 3.14 mmol), o-NITROPHENOL (660 mg, 4,71 mmol) and K2CO3(0.96 g, 7.0 mmol) in THF (10 ml) per mesilat at ambient temperature for 2.5 hours. The reaction mixture was filtered through mother solution bubbled ammonia gas for 10 minutes Formed precipitate was separated by filtration and washed with THF (20 ml). Combined fractions in THF concentrated and the resulting residue crystallized from methanol, thus obtaining methyl-2-amino-7-fermentation-4-carboxylate (173 mg, 26%) as a pale yellow solid.1H NMR and MS confirmed the structure.

Stage C. 2-Amino-7-fermentation-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense 2-amino-7-fermentation-4-carboxylic acid dihydrochloride and (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-amino-7-fermentation-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 113. Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-methylaminoethanol-4-carboxamide

Stage A. Methyl-2-methylaminoethanol-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. 2-Methylaminoethanol-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage With. what about the common procedures GP-C1 condense 2-methylaminoethanol-4-carboxylic acid dihydrochloride and (S)-(-)-3-aminoquinuclidine, thus the (S)-N-(Hinkley-8-yl)-2-methylaminoethanol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 114: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. Methyl 2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)-6-chlorobenzoxazole-4-carboxylate synthesized according to the General method GP-A.1H NMR and MS confirmed the structure.

Stage C. 2-((2S,6S)-4-(tert-Butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)-6-chlorobenzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense 2-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)-6-chlorobenzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Stage D. To a solution of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (294 mg, of 0.53 mmol) in CH2Cl2(10 ml) is added TFA (3.0 ml, 38,90 mmol) and the mixture peremeci is up at room temperature for 2 hours, then concentrate under reduced pressure. The crude substance is purified preparative TLC (silica gel, 100% mixture of 9:1 CH2Cl2/CH3IT is up to 100% of a mixture of 90:9:1 CH2Cl2/CH3HE/concentrated NH4OH), followed by purification prepreparation HPLC (Luna C18(2), 10% solution of CH3CN/0,05% TFA in H2About/of 0.05% TFA to 100% CH3CN/0,05% TFA over 30 min, I = 223 nm). The desired fractions are first treated with 10% aqueous K2CO3to achieve pH = 9 and then the aqueous phase is concentrated to 1/3 of its original volume under reduced pressure and the aqueous phase extracted with ethyl acetate (2×25 ml). The combined organic phase was washed with saturated salt solution (10 ml), dried (Na2SO4) and concentrated under reduced pressure, thus obtaining endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 115. Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-diethylaminobenzoate-4-carboxamide

Stage A. 2-(Diethylamino)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C2 condense 2-(diethylamino)benzoxazol-4-carbox the lat lithium dihydrochloride and (S)-(-)-3-aminoquinuclidine, receive (S)-N-(Hinkley-8-yl)-2-diethylaminobenzoate-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 116. Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-amino-6-fermentation-4-carboxamide

Stage A. To a solution of fuming nitric acid (18 ml) and glacial acetic acid (36 ml), preheated to 55°C add in portions of 3-fluoro-5-methoxybenzoic acid (3.00 g, 17,63 mmol) over 5 minutes the Mixture was incubated at 55°C for an additional 90 minutes, the Reaction mixture was cooled to ambient temperature and poured into a mixture of ice-water (200 ml). the pH of the solution is regulated to 2 using aqueous NaHCO3. Formed precipitate was separated by filtration and washed with hexane (100 ml), while receiving 5-fluoro-3-methoxy-2-nitrobenzoic acid (2,52 g, 66%) as a white solid.1H NMR and MS confirmed the structure.

Stage C. 5-fluoro-3-methoxy-2-nitrobenzoic acid (2,78 g, 12,92 mmol) is suspended in a mixture of 48% aqueous Hydrobromic acid/glacial acetic acid (7:2, 90 ml) and the suspension heated at 135°C for 41 hours. The solvent is removed under reduced pressure, the crude 5-fluoro-3-hydroxy-2-nitrobenzoic acid (2,60 g) directly expose to build the structure without additional characterization/purification. MS corresponds to the connection structure.

Stage C. the Crude 5-fluoro-3-hydroxy-2-nitrobenzoic acid (2,60 g, 12,92 mmol) suspended in CH3HE (50 ml) and cooled to 0°C. dropwise at 0°C, add thionyl chloride (9.4 ml, 129,26 mmol). The mixture allow to warm to ambient temperature, then refluxed for 17 hours. The reaction mixture allow to cool to room temperature and the solvent is removed under reduced pressure. The crude substance is purified column chromatography (silica gel, 0-20% CH3HE in CH2Cl2), while receiving methyl-5-fluoro-3-hydroxy-2-nitrobenzoate (1,15 g, 41%) as a white solid.1H NMR and MS confirmed the structure.

Stage D. To a solution of methyl 5-fluoro-3-hydroxy-2-nitrobenzoate (1,15 g of 5.34 mmol) in a mixture of CH3HE and glacial acetic acid (3:1, 40 ml) is added 10% palladium on charcoal (0.20 g, 17% wt.). The suspension is placed in an apparatus for the hydrogenation Parra in the atmosphere of H2at a pressure of 50 psi for 1.5 hours. The suspension is filtered through diatomaceous earth, elwira a mixture of CH2Cl2/CH3HE (9:1, 100 ml). Purification of column chromatography (silica gel, 5-100% EtOAc in hexano) for methyl-2-amino-5-fluoro-3-hydroxybenzoate (0,80 g, 83%) as a white solid.1H NMR and Spottersday the structure.

Stage E. To a solution of di-(1H-imidazol-1-yl)methanamine (1,05 g of 6.52 mmol) in THF (30 ml) is added methyl 2-amino-5-fluoro-3-hydroxybenzoate (0.96 g, with 5.22 mmol) at room temperature and the resulting reaction mixture is refluxed for 6 hours. The reaction mixture is cooled to room temperature and concentrate under reduced pressure. The residue is dissolved in EtOAc (200 ml) and the solution washed with N2About (4×100 ml), saturated aqueous ammonium chloride (2×100 ml), saturated salt solution (2×100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure, thus obtaining methyl-2-amino-6-fermentation-4-carboxylate (0.95 g, 87%) as a yellow solid.1H NMR and MS confirmed the structure.

Stage F. 2-Amino-6-fermentation-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR corresponds to the connection structure.

Stage G. By common procedures GP-C1 condense 2-amino-6-fermentation-4-carboxylic acid dihydrochloride and (S)-(-)-3-aminoquinuclidine obtaining (S)-N-(Hinkley-8-yl)-2-amino-6-fermentation-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 117: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-benzoyl-2,6-dimethyle the Razin-1-yl)benzoxazole-4-carboxamide

Stage A. a Mixture of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (of 81.4 mg, 0,19 mmol) of benzoyl chloride (34 ml, 0.30 mmol) and triethylamine (55 ml, 0.40 mmol) in CH2Cl2(5 ml) was stirred at ambient temperature for 6 hours. The reaction mixture was quenched with saturated NaHCO3(10 ml) and extracted with CH2Cl2(2×30 ml). The combined organic layers washed successively 1 N. HCl (30 ml), saturated salt solution (25 ml), dried (Na2SO4) and concentrate under reduced pressure. Purification of column chromatography (silica gel, mixture of 9:1 CH2Cl2/CH3HE to a mixture of 90:9:1 CH2Cl2/CH3HE/NH4OH) gives endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4-benzoyl-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (36 mg, 35%) as a white solid.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-D1 endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-benzoyl-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide in turn cleaners containing hydrochloride salt.1H NMR and MS confirmed the structure.

Example 118: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)-7-fermentation-4-carboxamide

Stage A. According to the General method GP-C1 condense a mixture of 2-((2S,6S)-4-(tert-b is oxycarbonyl)-2,6-dimethylpiperazine-1-yl)-7-fermentation-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine obtaining (S)-N-(Hinkley-8-yl)-2-((2S,6S)-2,6-dimethyl-4-tert-butoxycarbonylmethyl-1-yl)-7-perbenzoate-4-carboxamide. Carboxamide dissolved in 3 ml of 50% TFA in CH2Cl2and the solution is stirred for 2 hours at ambient temperature. The solvent is removed in vacuum and the residue is neutralized ion exchange chromatography (column 2 g SCX-2), thus obtaining a clear oil (to 15.4 mg). Cleaners containing hydrochloride salt get a shared approach to GP-D1.1H NMR and MS confirmed the structure.

Example 119: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(cyclopropylmethyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. a Mixture of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (51 mg, 0.12 mmol), cyclopropanecarboxaldehyde (28 ml of 0.37 mmol) and NaBH(OAc)3(79 mg, and 0.37 mmol) in a mixture of CH2Cl2/SPLA (100:1, 10.1 ml) was stirred at ambient temperature for 17 hours. The reaction mixture was diluted with saturated NaHCO3(10 ml) and extracted with a mixture of EtOAc/CH2Cl2(1:1, 2×20 ml). The combined organic layers washed with saturated salt solution (25 ml), dried (Na2SO4) and concentrate under reduced pressure. Purification preparative TLC (silica gel, mixture of :9:1 CH2Cl2/CH3HE/NH4OH) gives endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(cyclopropylmethyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide to 35.8 mg, 62%) as a white foam.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-D1 endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(cyclopropylmethyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide in turn cleaners containing hydrochloride salt.1H NMR and MS confirmed the structure.

Example 120: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxamide

Stage A. To a cooled to -30°C. a solution of N-tert-BOC-L-alanine (20,0 g, 0,106 mol) and triethylamine (16,8 ml, 0,119 mol) in THF (300 ml) is added dropwise isobutylparaben (15.0 ml, 0,114 mol). The reaction mixture is heated to ambient temperature for 1.25 hours and then stirred for 3.5 hours. The reaction mixture was cooled to 0°C and added dropwise a solution of N-methylbenzylamine (14,3 ml, 0,111 mmol) and triethylamine (18.8 ml, 0,134 mol) in THF (60 ml). The reaction mixture allow to warm to ambient temperature. After 16 h add saturated NaHCO3(200 ml) and most of the THF is removed under reduced pressure. The remaining aqueous layer was extracted with EtOAc (2×250 ml). The combined organic layers washed with saturated salt solution (100 ml), dried (Na2SO4) and concentrate under reduced pressure. Cleaning the column chromatographie is (silica gel, 10% solution of EtOAc in hexano up to 40% solution of EtOAc in hexano) gives (S)-tert-butyl-1-(benzyl(methyl)amino)-1-oxoprop-2-ylcarbamate (26,3 g, 85%) as a colourless oil.1H NMR corresponds to the connection structure.

Stage Century, chilled with ice to a solution of (S)-tert-butyl-1-(benzyl(methyl)amino)-1-oxoprop-2-ylcarbamate (26,3 g 0,090 mol) in CH2Cl2(100 ml) was added dropwise TFA (100 ml). The reaction mixture is heated to ambient temperature. After 18.5 hours, the reaction mixture was concentrated under reduced pressure. The residue is partitioned between CH2Cl2(250 ml) and saturated NaHCO3(250 ml). The aqueous layer was separated and do basic to pH 9-10 1 N. NaOH and again extracted with CH2Cl2(100 ml). The combined organic layers washed with saturated NaHCO3(100 ml), N2O (100 ml), saturated salt solution (100 ml), dried (Na2SO4) and concentrated under reduced pressure, thus obtaining (S)-2-amino-N-benzyl-N-methylpropanamide (14,7 g, 85%) as an amber oil.1H NMR corresponds to the connection structure.

Stage C. It chilled with ice to a solution of (S)-2-amino-N-benzyl-N-methylpropanamide (1.70 g, 8,80 mmol) in THF (25 ml) added dropwise sociallyengaged (18 ml of a 1.0 M solution in THF, 17.6 mmol). The reaction mixture is refluxed for 2 hours. After cooling to 0°C. the reaction mixture ha is Yat added dropwise N 2About (0.7 ml), 15% sodium hydroxide (0.7 ml) and N2Of (2.1 ml). During blanking add diethyl ether (25 ml). The mixture is filtered through celite and the layer celite washed with diethyl ether. The filtrate is concentrated under reduced pressure, thus obtaining (S)-N-1-benzyl-N-1-methylpropan-1,2-diamine (1.3 g, 82%) as a colourless oil.1H NMR corresponds to the connection structure.

Stage D. It chilled with ice to a solution of (R)-(+)-lactate (0,91 g, 8,7 mmol) in CH2Cl2(40 ml) add Tf2O (1.5 ml, 8,7 mmol). After 10 minutes add a solution of 2,6-lutidine (1.2 ml, 10 mmol) in CH2Cl2(3 ml). After another 10 minutes add a solution of (S)-N-1-benzyl-N-1-methylpropan-1,2-diamine (1.3 g, 7,3 mmol) and triethylamine (1.6 ml, 12 mmol) in CH2Cl2(10 ml). The reaction mixture allow to warm to ambient temperature. Later 15,25 hour, the reaction mixture was partitioned between saturated NaHCO3(100 ml) and CH2Cl2(100 ml). The aqueous layer was separated and again extracted with CH2Cl2(20 ml). The combined organic layers washed with N2About (50 ml), saturated salt solution (50 ml), dried (Na2SO4) and concentrate under reduced pressure. Purification of column chromatography (silica gel, EtOAc) to give (S)-methyl-2-((S)-1-(benzyl(methyl)amino)propan-2-ylamino)propanoate (0,98 g, 50%, which contains 2,6-lutidine in the amount of approximately 2:product:2,6-lutidine). 1H NMR corresponds to the connection structure.

Stage E. (S)-Methyl-2-((S)-1-(benzyl(methyl)amino)propan-2-ylamino)propanoate (0,98 g, 3.7 mmol), concentrated HCl (ml) and 10% Pd on coal (200 mg) are mixed in ethanol (25 ml). The reaction mixture was shaken on the Parr apparatus in a hydrogen atmosphere (15 psi). Through 16,75 hours, the reaction mixture was filtered through celite and the layer celite washed with CH3HE and CH2Cl2. The filtrate is concentrated under reduced pressure, thus obtaining (S)-methyl-2-((S)-1-(methylamino)propane-2-ylamino)propanoate, which is directly used in the next reaction. MS corresponds to the connection structure.

Stage F. the Crude (S)-methyl-2-((S)-1-(methylamino)propane-2-ylamino)propanoate dissolved in ethanol (30 ml) and add n-toluensulfonate acid (175 mg). The reaction mixture was refluxed for 18 h, then concentrated under reduced pressure. The residue is partitioned between CH2Cl2(40 ml) and saturated NaHCO3(20 ml). The aqueous layer was separated and again extracted with CH2Cl2(20 ml). The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure, thus obtaining (3S,5S)-1,3,5-trimethylpyrazine-2-he (230 mg, 43%, contains 2,6-lutidine in the amount of approximately 2:1 product:2,6-lutidine) as an amber oil.1H NMR corresponds to p is the established levels of connection.

Synthesis of methyl-2-(2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate. A mixture of methyl-2-chlorobenzoxazole-4-carboxylate (342 mg, of 1.62 mmol), (3S,5S)-1,3,5-trimethylpyrazine-2-she (230 mg, of 1.62 mmol) and potassium carbonate (670 mg, is 4.85 mmol) in DMF (10 ml) was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (2×40 ml). The combined organic layers washed with 0.5 N. HCl (10 ml), N2About (10 ml), saturated salt solution (10 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is triturated with diethyl ether and the solid is removed by filtration. The filtrate is concentrated and purified column chromatography (silica gel, 10% CH2Cl2in EtOAc to 100% EtOAc), while receiving methyl-2-(2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate (98 mg, 19%).1H NMR corresponds to the connection structure.

Stage G. By common procedures GP-B3 methyl-2-((2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate converted into 2-((2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylic acid, which is directly next turn without purification.

Stage N. According to the General method GP-C2 condense 2-((2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]Nona is and obtaining hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 121: Getting hydrochloride endo-2-amino-6-fluoro-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)benzoxazole-4-carboxamide

Stage A. To a solution of di-(1H-imidazol-1-yl)methanamine (1,05 g of 6.52 mmol) in THF (30 ml) is added methyl 2-amino-5-fluoro-3-hydroxybenzoate (0.96 g, with 5.22 mmol) at room temperature and the resulting reaction mixture is refluxed for 6 hours. The reaction mixture is cooled to room temperature and concentrate under reduced pressure. The residue is dissolved in EtOAc (200 ml) and washed with H2About (4×100 ml), saturated aqueous ammonium chloride (2×100 ml), saturated salt solution (2×100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure, thus obtaining methyl-2-amino-6-fermentation-4-carboxylate (0.95 g, 87%).1H NMR and MS confirmed the structure.

Stage C. 2-Amino-6-fermentation-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense 2-amino-6-fermentation-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane with obtaining endo-2-amino-6-fluoro-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)benzoxazol the-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 122: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,4,6-trimethylpyrazine-1)benzoxazole-4-carboxamide

A mixture of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (80 mg, 0,19 mmol), formaldehyde (37% aqueous solution of 6.0 ml, 76.9 mmol) and NaCNBH3(25 mg, 0,39 mmol) in a mixture of CH3HE/SPLA (10:1, 5.5 ml) was stirred at ambient temperature for 24 hours. The reaction mixture was concentrated, diluted with saturated ammonium chloride (5 ml) and extracted with CH2Cl2(2×25 ml). the pH of the aqueous phase to regulate 8 and extracted with CH2Cl2(2×25 ml) and the combined organic phase was washed with saturated salt solution (10 ml), dried (Na2SO4) and concentrated under reduced pressure, thus obtaining endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,4,6-trimethylpyrazine-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 123: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S)/(3R,5R) - for 3,5-dimethylmorpholine-1,1-dioxide)benzoxazole-4-carboxamide

Stage A. To a solution of souperen the frame of chloroacetone (31.0 g, 0.33 mol) in ethanol (335 ml) at 75°C in an atmosphere of N2added dropwise a solution of Na2S·N2On (40,2 g to 0.17 mol) in N2On (110 ml). After complete addition, the reaction mixture is heated for an additional 45 min before she is granted the opportunity to cool down to ambient temperature. The reaction mixture is concentrated to approximately half volume under reduced pressure and then partitioned between EtOAc (400 ml) and saturated salt solution (200 ml). The layers are separated and the organic layer was washed with saturated salt solution (200 ml) and dried over Na2SO4before concentrating under reduced pressure. The remaining orange oil is distilled under high vacuum (140°C <1 mm Hg), while receiving 1,1'-thiodipropanol-2-he (10.3 g, 42%).1H NMR and MS confirmed the structure.

Stage C. To the mixed solution of diphenylmethylene (2,36 ml, 13.7 mmol), SPLA (0,86 ml, 15.1 mmol) and potassium hydroxide (0,19 g, 3.4 mmol) in CH3HE (25 ml), cooled to 0°C., add a solution of 1,1'-thiodipropanol-2-she (2.0 g, 13.7 mmol) in CH3HE (10 ml). Then add NaCNBH3(0,86 g, 13.7 mmol) and the reaction mixture stirred at ambient temperature for 16 hours. Add an additional portion of NaCNBH3(0,43 g, 6,9 mmol) and the reaction mixture is stirred for another 4 hours. The reaction mixture RA is predelay between EtOAc (150 ml) and N 2O (150 ml) and the layers separated. The organic layer was washed with H2O (150 ml), saturated salt solution (150 ml), then dried over Na2SO4. After concentration under reduced pressure the resulting residue is purified column flash chromatography (silica gel, 10-50% EtOAc in hexano), while receiving (3S,5S)/(3R,5R)-4-benzhydryl-3,5-dimethylmorpholine (0.52 g, 13%).1H NMR corresponds to the connection structure.

Stage C. a Mixture of (3S,5S)/(3R,5R)-4-benzhydryl-3,5-dimethylmorpholine (0.52 g, a 1.75 mmol), triethylsilane (1,12 ml of 7.00 mmol) and TFA (20 ml) is refluxed for 20 hours. After cooling to ambient temperature the reaction mixture was concentrated under reduced pressure and the residue partitioned between 1 N. HCl (10 ml) and Et2O (20 ml). The aqueous layer was separated and lyophilized, while receiving hydrochloride (3S,5S)/(3R,5R) - for 3,5-dimethylmorpholine (285 mg, 97%).1H NMR and MS confirmed the structure.

Stage D. a Mixture of methyl-2-chlorobenzoxazole-4-carboxylate (360 mg, 1.70 mmol), hydrochloride (3S,5S)/(3R,5R) - for 3,5-dimethylmorpholine (270 mg, of 1.62 mmol) and potassium carbonate (672 mg, a 4.86 mmol) in DMF (5 ml) was stirred at ambient temperature for 6 hours. The reaction mixture was then heated at 55°C for 2 h before it was diluted with H2O (20 ml) and extracted with EtOAc (2×40 ml). The combined organic layers industry is saturated with a salt solution, dried (Na2SO4) and concentrate under reduced pressure. The crude methyl ester retained for further purification. The remaining aqueous phase is then acidified to pH 5 by addition of 1 N. HCl and extracted with CH2Cl2(2×40 ml). The combined organic extracts dried (Na2SO4) and concentrate under reduced pressure to get crude (3S,5S)/(3R,5R) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxylic acid (70 mg, 15%), which is directly next turn without purification.

Stage E. To a solution of (3S,5S)/(3R,5R) - for 3,5-dimethylmorpholine)benzoxazole-4-carboxylic acid (68 mg, 0.23 mmol) in CH3HE (3 ml) and dioxane (0.5 ml) add a solution oxone (215 mg, 0.35 mmol) in N2About (1.5 ml). The resulting suspension stirred at ambient temperature for 2 h, then partitioned between CH2Cl2(50 ml) and N2About (50 ml). The layers are separated and the aqueous phase is extracted with next CH2Cl2(50 ml). The combined organic extracts washed with saturated salt solution, dried over Na2SO4and concentrate under reduced pressure, thus obtaining the crude 2-((3S,5S)/(3R,5R) - for 3,5-dimethylmorpholine-1,1-dioxide)benzoxazole-4-carboxylic acid, which is directly next turn without purification.1H NMR corresponds to the connection structure.

Stage F. According to the General method GP-C1 condenser the Ute 2-((3S,5S)/(3R,5R) - for 3,5-dimethylmorpholine-1,1-dioxide)benzoxazole-4-carboxylic acid dihydrochloride and endo-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-amine with obtaining endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S)/(3R,5R)for 3,5-dimethylmorpholine-1,1-dioxide)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 124: obtain the hydrochloride of N-(Hinkley-8-yl)-2-((2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A mixture of methyl 2-chlorobenzoxazole-4-carboxylate and (3S,5S)-1,3,5-trimethylpyrazine-2-it is transformed into methyl-2-((2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylate.1H NMR corresponds to the connection structure.

Stage C. According to the General method GP-B3 get 2-((2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylic acid, which is directly next turn without characterization.

Stage C. According to the General method GP-C2 condense 2-((2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylic acid (237 mg, 0.78 mmol) and the hydrochloride of (S)-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane with obtaining N-(Hinkley-8-yl)-2-((2S,6S)-2,4,6-trimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxamide that in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 125: Getting hydrochloride endo-(3S,5S)-methyl-3,5-dimethyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate

Stage A. To ice a mixture of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (222,1 mg, 0.54 mmol) and triethylamine (82,1 ml, 0.59 mmol) in CH2Cl2(5 ml) add methylchloroform (45.1 ml, 0.59 mmol), the mixture is stirred and give her the opportunity to warm to ambient temperature and stirred for additional 20 hours. The reaction mixture was quenched with a mixture of CH3OH/saturated salt solution (1:2, 15 ml) and extracted with CH2Cl2(2×30 ml). The combined organic layers washed successively 1 N. aqueous HCl (30 ml), saturated salt solution (25 ml), dried (Na2SO4) and concentrate under reduced pressure. Purification of column chromatography (silica gel, mixture of 9:1 CH2Cl2/CH3HE to a mixture of 90:9:1 CH2Cl2/CH3HE/NH4OH) gives (3S,5S)-methyl-3,5-dimethyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate (51,2 mg, 20%) as not quite white solid.1H NMR and MS confirmed the structure.

Stage C. 3,5-Dimethyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbonyl)benzoxazol-2-yl)piperazine-1-carboxylate in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 126: Getting dihydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((4aS,8aS)-octahydrophenanthrene-1(2H)-yl)benzoxazole-4-carboxamide

Stage A. To a cooled with ice to a solution of (1S,2S)-()-1,2-diaminocyclohexane in N 2(120 ml) was added Chloroacetic acid (3,31 g, 35,02 mmol) and knso3(3.51 g, 35,02 mmol). The mixture is stirred at room temperature for 16 h, then heated at 90°C for 4 hours. The mixture is cooled to room temperature and concentrated under reduced pressure, thus obtaining (4aS,8aS)-octahydrophenanthrene-2(1H)-he (8,82 g, >99%).

Stage C. a Mixture of (4aS,8aS)-octahydrophenanthrene-2(1H)-she (8,82 g, 57,19 mmol), 2,4-dimethoxybenzaldehyde (9,50 g, 57,19 mmol) and triacetoxyborohydride sodium (36,31 g, 171,57 mmol) in 1% of the SPLA in CH2Cl2(250 ml) was stirred at room temperature for 16 hours. The mixture is neutralized with a saturated aqueous solution of NaHCO3(200 ml). The organic layer is separated and washed with N2O (100 ml), saturated salt solution (100 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the residue column chromatography (silica gel, 0% to 100% solution of a mixture of 90:9:1 CH2Cl2/CH3HE/NH4OH in CH2Cl2) gives (4aS,8aS)-4-(2,4-dimethoxybenzyl)octahydrophenanthrene-2(1H)-he (1.10 g, 11.1% two steps).1H NMR and MS confirmed the structure.

Stage back To ice 1.0 M solution of LiAlH4in THF (4,10 ml, 4,10 mmol) is added a solution of (4aS,8aS)-4-(2,4-dimethoxybenzyl)octahydrophenanthrene-2(1H)-he (500 mg, of 1.64 mmol) in THF (10 ml). The mixture is boiled with britishtelecom within 8 hours. The reaction mixture was cooled to 0°C and carefully quenched with EtOAc (50 ml) and 1 N. NaOH solution (20 ml). The mixture is stirred for 30 min and the layers separated. The organic layer was washed with saturated salt solution (20 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the residue column chromatography (silica gel, 0%to 60% solution of a mixture of 90:9:1 CH2Cl2/CH3HE/NH4OH in CH2Cl2) gives (4aS,8aS)-1-(2,4-dimethoxybenzyl)decahydroquinoline (120,1 mg, 25.4 per cent).1H NMR and MS confirmed the structure.

Stage d According to the General method GP-A (4aS,8aS)-1-(2,4-dimethoxybenzyl)decahydroquinoline (120,1 mg, 0.41 mmol) and methyl-2-chlorobenzoxazole-4-carboxylate is transformed into methyl-2-((4aS,8aS)-4-(2,4-dimethoxybenzyl)octahydrophenanthrene-1(2H)-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage E. 2-((4aS,8aS)-4-(2,4-Dimethoxybenzyl)octahydrophenanthrene-1(2H)-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage F. According to the General method GP-C2 condense 2-((4aS,8aS)-4-(2,4-dimethoxybenzyl)octahydrophenanthrene-1(2H)-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane with obtaining endo-2-((4aS,8aS)-4-(2,4-dimethoxybenzyl)octahydrophenanthrene-1(2H)-yl)-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)benzo is xazal-4-carboxamide. MS corresponds to the connection structure.

Stage G. a Mixture of endo-2-((4aS,8aS)-4-(2,4-dimethoxybenzyl)octahydrophenanthrene-1(2H)-yl)-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)benzoxazole-4-carboxamide (200 mg, 0.34 mmol), 10% palladium on coal (25 mg, 0.04 mmol) in CH3HE (10 ml) is kept in the atmosphere of hydrogen gas at a pressure of 30 psi at room temperature for 7 hours. The mixture is filtered and the filter residue is washed with CH3HE. The filtrate is concentrated under reduced pressure. Purification of the residue column chromatography (silica gel, 0%-100% solution of a mixture of 90:9:1 CH2Cl2/CH3HE/NH4OH in CH2Cl2gives endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((4aS,8aS)-octahydrophenanthrene-1(2H)-yl)benzoxazole-4-carboxamide (25.1 mg, 16.9 per cent).1H NMR and MS confirmed the structure.

Stage N. According to the General method GP-D1 endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((4aS,8aS)-octahydrophenanthrene-1(2H)-yl)benzoxazole-4-carboxamide turn in dihydrochloride salt.1H NMR and MS confirmed the structure.

Example 127. Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-amino-6-methylbenzothiazol-4-carboxamide

Stage A. To a solution of methyl 2-amino-3-methoxybenzoate (13,0 g, 71,8 mmol) in DMF (30 ml) is added NBS (14,38 g, 80,8 mmol) at room temperature and the resulting reaction mixture is stirred in ECENA 17 hours. The reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel, 2%-5% EtOAc in hexano), while receiving methyl-2-amino-5-bromo-3-methoxybenzoate (13,7 g, 73%).1H NMR corresponds to the connection structure.

Stage C. a Mixture of methyl 2-amino-5-bromo-3-methoxybenzoate (6.50 g, 25 mmol), methylboronic acid (3.0 g, 50 mmol), potassium fluoride (5.8 g, 100 mmol) and tetrafluoroborate three-tert-butylphosphine (0.87 g, 3.0 mmol) in THF (200 ml) deoxygenated and then filled with argon. Add Tris(dibenzylideneacetone)dipalladium(0) (1,43 g, 1.5 mmol) and the mixture is heated at 70°C for 17 hours in an argon atmosphere. The reaction mixture was concentrated and the residue purified column chromatography (silica gel, 0%-5% solution of EtOAc in hexano), while receiving methyl-2-amino-5-methoxy-3-methylbenzoate (3.55 g, 73%).1H NMR corresponds to the connection structure.

Stage C. a Mixture of methyl 2-amino-5-methoxy-3-methylbenzoate (2,96 g, 15,21 mmol), 48% HBr (25 ml) and the SPLA (2.5 ml) is refluxed for 8 hours. The reaction mixture is cooled to room temperature with the formation of the suspension. The solid is isolated and dried in a high vacuum, thus obtaining the desired hydrobromide 2-amino-3-hydroxy-5-methylbenzoic acid (2,32 g, 61%).1H NMR corresponds to the structure of the is to be placed.

Stage D. To a solution of the hydrobromide of 2-amino-3-hydroxy-5-methylbenzoic acid (2.65 g, is 10.7 mmol) in anhydrous CH3HE (50 ml) is added thionyl chloride (3.9 ml, with 53.4 mmol) at -78°C. the Resulting reaction mixture was allow to warm to room temperature and then refluxed for 17 hours. The reaction mixture is cooled to room temperature and concentrate under reduced pressure. The residue is treated with saturated aqueous NaHCO3to establish the pH to 7 and then extracted with EtOAc (4×100 ml). The combined organic phase was washed with H2Oh, saturated salt solution, dried (Na2SO4), filtered and concentrated under reduced pressure, thus obtaining methyl-2-amino-3-hydroxy-5-methylbenzoate (1.40 g, 72%).1H NMR corresponds to the connection structure.

Stage E. To a solution of di-(1H-imidazol-1-yl)methanamine (1.56 g, 9,67 mmol) in THF (30 ml) is added methyl 2-amino-3-hydroxy-5-methylbenzoate (1.40 g, 7,73 mmol) at room temperature and the resulting reaction mixture is refluxed for 6 hours. The reaction mixture is cooled to room temperature and concentrate under reduced pressure. The residue is dissolved in CH2Cl2(100 ml), treated with saturated aqueous ammonium chloride (25 ml) and then extracted with CH2Cl2(2×100 ml). Unite the military the organic phase is washed with saturated salt solution (2×100 ml), dried (Na2SO4), filtered and concentrated under reduced pressure, thus obtaining a yellow solid. The solid is triturated with CH3HE obtain methyl 2-amino-6-methylbenzothiazol-4-carboxylate (0,717 g, 45%).1H NMR and MS confirmed the structure.

Stage F. According to the General method GP-B3 methyl-2-amino-6-methylbenzothiazol-4-carboxylate is transformed into 2-amino-6-methylbenzothiazol-4-carboxylic acid.1H NMR and MS confirmed the structure.

Stage G. By common procedures GP-C1 condense 2-amino-6-methylbenzothiazol-4-carboxylic acid (0.35 g, to 1.79 mmol) and the hydrochloride of (S)-(-)-3-aminoquinuclidine obtaining (S)-N-(Hinkley-8-yl)-2-amino-6-methylbenzothiazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 128: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-amino-5-perbenzoate-4-carboxamide

Stage A. a Solution of sodium persulfate (15,4 g, and 64.5 mmol) in N2O (160 ml) is added dropwise to a solution of 2-amino-6-fermenting acid (10 g, and 64.5 mmol) in 2 N. NaOH (60 ml) for 3 hours. The resulting black mixture is stirred for 2 days at ambient temperature and extracted successively with ether (3 l) and EtOAc (1 l). The aqueous layer was concentrated under pengendalian and the resulting residue is suspended in CH 3HE (1 l) and stirred over night at ambient temperature. The precipitate was separated by filtration, the mother liquor is concentrated to 1/3 of the initial volume, cooled to -78°C and treated with SOCl2(15 ml, 128 mmol). The mixture allow to warm to room temperature, then refluxed for 16 hours. The mixture is concentrated under reduced pressure and the resulting residue suspended in EtOAc (1 l) and extracted with saturated aqueous NaHCO3(300 ml). The organic fraction was washed with saturated salt solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is purified column chromatography (silica gel, mixture 1:3 EtOAc/hexane), while receiving methyl-2-amino-6-fluoro-3-hydroxybenzoate (0.4 g, 3.3 per cent).1H NMR and MS confirmed the structure.

Stage C. To a solution of methyl 2-amino-6-fluoro-3-hydroxybenzoate (0.4 g, 2.2 mmol) in THF (10 ml) is added di(1H-imidazol-1-yl)metonymy (0,44 g, a 2.75 mmol) at room temperature and the resulting reaction mixture is refluxed for 16 hours. The reaction mixture is cooled to room temperature and concentrate under reduced pressure. The residue is dissolved in CH2Cl2(100 ml) and the solution is treated with saturated aqueous ammonium chloride (25 ml). The organic layer is separated and the aq is th layer is extracted with additional CH 2Cl2(2×100 ml). The combined organic phase was washed with saturated salt solution (2×100 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain yellow solid. The solid is triturated with ether, thus obtaining methyl-2-amino-5-perbenzoate-4-carboxylate. MS corresponds to the connection structure.

Stage C. 2-Amino-5-perbenzoate-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage d According to the General method GP-C1 condense a mixture of 2-amino-5-perbenzoate-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-amino-5-perbenzoate-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 129: Getting hydrochloride endo-2-amino-6-methyl-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)benzoxazole-4-carboxamide

According to the General method GP-C1 condense 2-amino-6-methylbenzothiazol-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-2-amino-6-methyl-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS is podtverjdayut the structure.

Example 130: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-evaluieren-1-yl)benzoxazole-4-carboxamide

According to the General method GP-C1 condense endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide and pivaloyloxy, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-evaluieren-1-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 131: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(methylsulphonyl)piperazine-1-yl)benzoxazole-4-carboxamide

According to the General method GP-S condense endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide and methansulfonate, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(methylsulphonyl)piperazine-1-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 132: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(cyclohexanecarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

According to the General method GP-E. condenser the t endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide and cyclohexanethiol, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(cyclohexanecarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 133: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(cyclopentanecarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

According to the General method GP-S condense endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide and cyclopentanethiol, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(cyclopentanecarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 134: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-propenylbenzene-1-yl)benzoxazole-4-carboxamide

According to the General method GP-S condense endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide and propionitrile, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-propenylbenzene-1-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt about is her method GP-D1. 1H NMR and MS confirmed the structure.

Example 135: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-isobutyryl-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

According to the General method GP-S condense endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide and isobutyrate, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-isobutylpyrazine-1-yl)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 136: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(dimethylcarbamoyl)piperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a solution of methyl 2-((2S,6S)-2,6-dimethyl-4-piperazine-1-yl)benzoxazole-4-carboxylate (235 mg, 0.81 mmol) and diisopropylethylamine (339 ml of 1.95 mmol) in CH2Cl2(5 ml) was added 1-dimethylcarbamodithioato (163 ml, to 1.79 mmol). The reaction mixture was stirred at ambient temperature for 90 min, then partitioned between CH2Cl2(50 ml) and 0.5 M citric acid (20 ml). The organic layer was washed with saturated salt solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude substance cleanse kolonochnoi chromatography (silica gel, dichloromethane and then a mixture of 90:9:1 CH2Cl2/CH3HE/concentrated NH4OH), while receiving methyl-2-((2S,6S)-2,6-dimethyl-4-(dimethylcarbamoyl)piperazine-1-yl)benzoxazole-4-carboxylate as a colorless oil (270 mg, 92%).1H NMR and MS confirmed the structure.

Stage C. To a solution of methyl 2-((2S,6S)-2,6-dimethyl-4-(dimethylcarbamoyl)piperazine-1-yl)benzoxazole-4-carboxylate (265 mg, of 0.74 mmol) in pyridine (5 ml) was added LiI (984 mg, of 7.35 mmol). The mixture is heated at 110°C for 14 hours and give her the opportunity to cool down to ambient temperature. The reaction mixture was partially concentrated under reduced pressure before distribution between a mixture of 9:1 CH2Cl2/2-propanol (50 ml) and 1 N. HCl (20 ml). The organic layer was washed with saturated salt solution, dried (Na2SO4) and concentrated under reduced pressure, thus obtaining the crude 2-((2S,6S)-2,6-dimethyl-4-(dimethylcarbamoyl)piperazine-1-yl)benzoxazole-4-carboxylic acid as an orange oil, which is directly next turn without purification.

Stage C. According to the General method GP-C1 condense 2-((2S,6S)-2,6-dimethyl-4-(dimethylcarbamoyl)piperazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(dimethylcarbamoyl)piperazin the-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 137: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(2,2,2-triptorelin)piperazine-1-yl)benzoxazole-4-carboxamide

To a mixture of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide (150 mg, 0.36 mmol) and pyridine (65 ml, 0.80 mmol) in N,N-dimethylformamide (10 ml) was added 2,2,2-triftoratsetilatsetonom (115 ml, 0.80 mmol) and the mixture is heated to 110°C for 20 hours. The reaction is quenched with saturated ammonium chloride (10 ml) and extracted with CH2Cl2(2×30 ml). The combined organic layers washed successively NaHCO3(10 ml) and saturated salt solution (25 ml) and then dried (Na2SO4), filtered and the solution concentrated under reduced pressure. Purification of column chromatography (silica gel, mixture of 9:1 CH2Cl2/CH3HE to a mixture of 90:9:1 CH2Cl2/CH3HE/NH4OH) gives endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(2,2,2-triptorelin)piperazine-1-yl)benzoxazole-4-carboxamide (52 mg, 29%), which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 138: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]n the NAS-3-yl)-2-((2S,6S)-4-(isobutoxide)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a solution of lithium iodide (185 mg, 1.38 mmol) in boiling under reflux in anhydrous pyridine (10 ml) is added methyl-2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate (100 mg, 0,346 mmol) and the reaction mixture is refluxed for 24 hours. The mixture is cooled to room temperature, concentrated to dryness and dried under vacuum, thus obtaining 2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium in the form of a solid substance, which is used without further purification. MS corresponds to the connection structure.

Stage C. To the vigorously stirred suspension of 2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-lithium carboxylate (97 mg, 0,346 mmol) and NaHCO3(87 mg, 1,037 mmol) in chloroform (6 ml) and N2O (6 ml) was added dropwise isobutylparaben (54 ml, 0,415 mmol). The reaction mixture was stirred at room temperature for 2 hours, then neutralized 1 N. aqueous HCl and concentrated under reduced pressure, thus obtaining 2-((2S,6S)-4-(isobutoxide)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylic acid. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense a mixture of 2-((2S,6S)-4-(isobutoxide)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo--(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(isobutoxide)-2,6-dimethylpiperazine-1-Il)benzoxazol-4-carboxamid, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 139: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-amino-5-perbenzoate-4-carboxamide

According to the General method GP-C2 condense 2-amino-5-perbenzoate-4-carboxylic acid dihydrochloride and (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-amino-5-perbenzoate-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 140: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(pyrrolidin-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-E condense methyl-2-((2S,6S)-2,6-dimethyl-4-piperazine-1-yl)benzoxazole-4-carboxylate and 1-pyrrolidinecarbonyl, while receiving methyl-2-((2S,6S)-2,6-dimethyl-4-(pyrrolidin-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxylate.1H NMR and MS confirmed the structure.

Stage C. To a solution of methyl 2-((2S,6S)-2,6-dimethyl-4-(pyrrolidin-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxylate (200 mg, 0.52 mmol) in pyridine (2 ml) is added lithium iodide (550 mg, 4,11 mmol). The mixture is heated at 110°C for 18 h and then give her the opportunity to cool down to ambient temperature before the distribution is observed between the mixture of 9:1 dichloromethane and isopropanol (100 ml) and 1 N. HCl (50 ml). Inhomogeneous organic layer was washed with saturated salt solution and concentrate under reduced pressure. The residue is treated with a mixture of 9:1 toluene/methanol (100 ml) and concentrate under vacuum, thus obtaining the crude 2-((2S,6S)-2,6-dimethyl-4-(pyrrolidin-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxylic acid as a brown solid, which is directly next turn without purification.

Stage C. According to the General method GP-C1 condense a mixture of 2-((2S,6S)-2,6-dimethyl-4-(pyrrolidin-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(pyrrolidin-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxamide, except that the reaction mixture is extracted with a mixture of CH2Cl2/2-propanol (9/1). Carboxamid turn in dihydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 141: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(piperidine-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-E condense methyl-2-(2S,6S)-2,6-dimethyl-4-piperazine-1-yl)benzoxazole-4-carboxylate and 1-piperidinecarboxylate, while receiving methyl-2-((2S,6S)-2,6-dimethyl-4-(Pipa is one-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxylate. 1H NMR and MS confirmed the structure.

Stage C. To a solution of methyl 2-((2S,6S)-2,6-dimethyl-4-(piperidine-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxylate (200 mg, 0.52 mmol) in pyridine (2 ml) is added lithium iodide (495 mg, 3,70 mmol). The mixture is heated at 110°C for 18 h and give her the opportunity to cool down to ambient temperature before distribution between a mixture of 9:1 dichloromethane/2-propanol (100 ml) and 1 N. HCl (50 ml). Inhomogeneous organic layer was washed with saturated salt solution and concentrated in vacuo. The residue is treated with a mixture of 9:1 toluene and methanol (100 ml) and concentrate under reduced pressure, thus obtaining 2-((2S,6S)-2,6-dimethyl-4-(piperidine-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxylic acid as a brown solid, which is directly next turn without purification.

Stage C. According to the General method GP-C1 condense a mixture of 2-((2S,6S)-2,6-dimethyl-4-(piperidine-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(piperidine-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxamide, except that the reaction mixture is extracted with a mixture of 9:1 CH2Cl2/2-propanol (9:1). Carboxamid in turn cleaners containing hydrochloride salt according to the General method GP-D1. 1H NMR and MS confirmed the structure.

Example 142: Obtaining hydrochloride (S)-N-(Hinkley-8-yl)-2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxamide

Stage A. 2-((2S,6S)-4-Benzyl-2,6-dimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3.1H NMR corresponds to the connection structure.

Stage C. According to the General method GP-C2 condense a mixture of 2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxylic acid dihydrochloride (S)-(-)-3-aminoquinuclidine, thus obtaining (S)-N-(Hinkley-8-yl)-2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperidin-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 143: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(isopropoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a vigorously stirred suspension of 2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-lithium carboxylate (208 mg, 0,743 mmol) and NaHCO3(187 mg, of 2.23 mmol) in chloroform (12 ml) and N2About (2 ml) is added dropwise isopropylcarbamate (1 M solution in toluene, 892 ml, 0,891 mmol). The reaction mixture was stirred at room temperature for 2 hours, then neutralized 1 N. aqueous HCl. Mixture to the will centerour under reduced pressure, thus obtaining 2-((2S,6S)-4-(isopropoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium. MS corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-((2S,6S)-4-(isopropoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(isopropoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 144: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(etoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. To a vigorously stirred suspension of methyl 2-((2S,6S)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate (208 mg, 0,743 mmol) and NaHCO3(187 mg, of 2.23 mmol) in chloroform (12 ml) and N2About (2 ml) is added dropwise ethylchloride (85 ml, 0,891 mmol). The reaction mixture was stirred at room temperature for 2 hours, then neutralized 1 N. aqueous HCl and concentrated under reduced pressure, thus obtaining 2-((2S,6S)-4-(etoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium. MS corresponds to the connection structure.

Stage C. General methods the e GP-C1 condense 2-((2S,6S)-4-(etoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-(etoxycarbonyl)-2,6-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 145: Obtaining N-((4-methyl-1H-imidazol-5-yl)methyl)-2-amino-6-chlorobenzoxazole-4-carboxamide

Stage A. a Solution of 5-(chloromethyl)-4-methyl-1-trityl-1H-imidazole (1,00 g, 2.68 mmol) in ammonia (7n in CH3HE, 4 ml, 28 mmol) is heated to 50°C. in a sealed vial for 16 h. The reaction mixture was concentrated under reduced pressure and the crude substance is purified column chromatography (silica gel, 100% CH2Cl2up to 50% of CH3IT), while receiving (4-methyl-1-trityl-1H-imidazol-5-yl)methanamine (250 mg, 26%).1H NMR corresponds to the connection structure.

Stage C. a Solution of (4-methyl-1-trityl-1H-imidazol-5-yl)methanamine (250 mg, 0.07 mmol) in glacial acetic acid (50 ml) is refluxed for 2 hours. The reaction mixture is cooled to room temperature and concentrated to dryness, thus obtaining (4-methyl-1H-imidazol-5-yl)methanamine (79 mg, quantitative yield).1H NMR and MS confirmed the structure.

Stage C. According to the General method GP-C1 condense 2-amino-6-chlorobenzoxazole-4-carboxylic acid and (4-methyl-1H-imidazol-5-yl)meta is Amin, while receiving N-((4-methyl-1H-imidazol-5-yl)methyl)-2-amino-6-chlorobenzoxazole-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 146: obtain the hydrochloride of endo-N-(9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(pyrrolidin-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxamide

Endo-N-(9-Azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-2,6-dimethyl-4-(pyrrolidin-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxamide unexpectedly produce as a by-product when or 2-((2S,6S)-2,6-dimethyl-4-(pyrrolidin-1-carbonyl)piperazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (see example 141) according to the General method GP-C1, except that the reaction mixture is extracted with a mixture of CH2Cl2/2-propanol (9/1). Carboxamid in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 147: Getting dihydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S*,5R*)-4-allyl-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate and (±)-TRANS-1-allyl-2,5-dimethylpiperazine converted into methyl-2-((2S*,5R*)-4-allyl-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxylate.1H NMR and M is confirm the structure.

Stage C. 2-((2S*,5R*)-4-Allyl-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3 and then used without further purification. MS corresponds to the connection structure.

Stage C. 2-((2S*,5R*)-4-Allyl-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane condense on common procedures GP-C1, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S*,5R*)-4-allyl-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide.1H NMR and MS confirmed the structure.

Stage d According to the General method GP-D1 endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S*,5R*)-4-allyl-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide converted into the dihydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S*,5R*)-4-allyl-2,5-dimethylpiperazine-1-yl)benzoxazole-4-carboxamide, except that the product is recovered from aqueous solution by lyophilization.1H NMR and MS confirmed the structure.

Example 148: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-benzyl-2,6-dimethylpiperidin-1-yl)benzoxazole-4-carboxamide

Stage A. According to the General method GP-A, methyl 2-chlorobenzoxazole-4-carboxylate is treated with potassium carbonate and (3S,5S)-1-benzyl-3,5-dimethylpiperazine in N,N-dimethylformamide at 40°C for 60 hours while atomatic-2-((2S,6S)-4-benzyl-2,6-dimethylpiperidin-1-yl)benzoxazole-4-carboxylate. 1H NMR and MS confirmed the structure.

Stage C. 2-((2S,6S)-4-Benzyl-2,6-dimethylpiperidin-1-yl)benzoxazole-4-carboxylate lithium synthesized according to the General method GP-B2.1H NMR corresponds to the connection structure.

Stage C. According to the General method GP-C1 condense 2-((2S,6S)-4-benzyl-2,6-dimethylpiperidin-1-yl)benzoxazole-4-carboxylate lithium dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane, while receiving endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2S,6S)-4-benzyl-2,6-dimethylpiperazine-1-Il)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 151: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2R)-3-ethylmorpholino)benzoxazole-4-carboxamide

Stage A. To ice stirred suspension of sodium hydride (60% in oil, 2.1 g, with 52.0 mmol) in toluene (65 ml) to the aqueous phase add a solution of (R)-2-aminobutane-1-ol (2.0 g, 22,0 mmol) in toluene (48 ml). After complete addition, the reaction mixture is heated to room temperature and added dropwise a solution of ethylchloride (3.0 g, 25,0 mmol) in toluene (12 ml). The resulting mixture was then stirred at the boil under reflux for 20 h, cooled to room temperature and the reaction mixture is added solid ammonium chloride (2.7g, with 52.0 mmol). The mixture is stirred for 20 min and then concentrated under reduced pressure. The crude substance is purified column chromatography (silica gel, mixture of 95:5 dichloromethane/methanol)to give (R)-5-ethylmorpholine-3-one (2.0 g, 70%) as a pale yellow solid. To ice the tetrahydrofuran (10 ml) add sociallyengaged (1.0 M solution in tetrahydrofuran, was 31.0 ml, was 31.0 mmol). When you are finished adding over 20 min added dropwise a solution of (R)-5-ethylmorpholine-3-one (2.0 g, 16 mmol) in tetrahydrofuran (10 ml). After complete addition, the ice bath removed and the reaction mixture is stirred at the boil under reflux for 20 hours. The reaction mixture was cooled in an ice bath and slowly add water (1.3 ml), then 15% aqueous sodium hydroxide solution (1.3 ml) and then water (1.3 ml). The resulting mixture was stirred at room temperature for 1.5 hours and then filtered, washing the solid with ethyl acetate (50 ml). The filtrate is concentrated at room temperature and under reduced pressure, thus obtaining (R)-3-ethylmorpholine (1.6 g, 90%) as a pale yellow oil.1H NMR and MS confirmed the structure.

Stage C. (R)-Methyl-2-(3-ethylmorpholino)benzoxazole-4-carboxylate synthesized according to the General method GP-A. MS corresponds to the connection structure.

The Study Is S. (R)-2-(3-Ethylmorpholino)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the connection structure.

Stage d According to the General method GP-C2 condense (R)-2-(3-ethylmorpholino)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane with obtaining endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2R)-3-ethylmorpholino)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

Example 152: obtain the hydrochloride of endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2R)-3-isopropylaniline)benzoxazole-4-carboxamide

Stage A. To a cooled with ice, stirred suspension of sodium hydride (60% in oil, 1.6 g, 40.0 mmol) in toluene (52 ml) drops is added to a solution of (R)-2-amino-3-methylbutane-1-ol (1.8 g, 17,0 mmol) in toluene (38 ml). After complete addition, the reaction mixture is heated to room temperature and added dropwise a solution of ethylchloride (2.3 g, 19.0 mmol) in toluene (8 ml). The resulting mixture was then stirred at the boil under reflux for 20 h, cooled to room temperature and the reaction mixture is added solid ammonium chloride (2.1 g, 40.0 mmol). The mixture is stirred for 20 min and then concentrated under reduced pressure. The crude substance cleanse kolonochnoi chromatography (silica gel, a mixture of 95:5 dichloromethane/methanol)to give (R)-5-isopropylaniline-3-one (1.7 g, 68%) as a pale yellow solid.

To ice the tetrahydrofuran (8.0 ml) add sociallyengaged (1.0 M solution in tetrahydrofuran, 23,0 ml, 23,0 mmol). When you are finished adding over 20 min added dropwise a solution of (R)-5-isopropylaniline-3-one (1.7 g, 12 mmol) in tetrahydrofuran (8 ml). After complete addition, the ice bath removed and the reaction mixture is stirred at the boil under reflux for 20 hours. The reaction mixture was cooled in an ice bath and slowly add water (1.0 ml), then 15% aqueous sodium hydroxide solution (1.0 ml) and then water (1.0 ml). The resulting mixture was stirred at room temperature for 1.5 hours and then filtered, washing the solid with ethyl acetate (50 ml). The filtrate is concentrated at room temperature and under reduced pressure, thus obtaining (R)-3-isopropylaniline (1.4 g, 93%) as a pale yellow oil.1H NMR corresponds to the connection structure.

Stage C. (R)-Methyl-2-(3-isopropylaniline)benzoxazole-4-carboxylate synthesized according to the General method GP-A. MS corresponds to the connection structure.

Stage C. (R)-2-(3-Isopropylaniline)benzoxazole-4-carboxylic acid synthesized according to the General method GP-B3. MS corresponds to the structure connected to the I.

Stage d According to the General method GP-C2 condense (R)-2-(3-isopropylaniline)benzoxazole-4-carboxylic acid dihydrochloride and endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane with obtaining endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((2R)-3-isopropylaniline)benzoxazol-4-carboxamide, which in turn cleaners containing hydrochloride salt according to the General method GP-D1.1H NMR and MS confirmed the structure.

In other embodiments, the implementation, where R2not an atom of hydrogen or halogen, the method of obtaining the above-mentioned compounds is similar to the methods presented in the application for U.S. patent 2006/183769, the full contents of which are incorporated herein by reference. In cases in which there may be inconsistency in the nomenclature between the above-mentioned application and the present application, the nomenclature and definitions of this application have priority.

The affinity of compounds in respect of the receptor 5-NT3 person (analysis A)

Compounds were tested MDS Pharma Services - Taiwan Ltd., 158 Li-The Road, Peitou, Taipei, Taiwan 112 R.O.C. To evaluate the relative affinity of various compounds in respect of the receptor 5-NT3 person has developed a cell line N1E-155 for expression of the protein target. To link these cells are homogenized, centrifuged and washed with buffer (20 mm HEPES, 150 mm NaCl, pH 7.4), then suspended in 0.5 ml buffer and we use the and [ 3H]-GR6530 at a concentration of 3.5×10-10M was Then added to the test compound during the initial uniform concentration of 10-7M. Incubation was carried out at room temperature for 60 minutes at 25°C, then stopped by rapid destruction of the environment for incubation. Radioactivity was assessed using a liquid scintillation spectrometry after exposure of scintillation cocktail account for at least three hours. The compounds exhibiting more than 75% inhibition of binding of radioligand at 10-7M, then analyzed on the above Protocol with the use of a range of concentrations of the test compounds: 10-9M, 10-8M, 3×10-8M, 10-7M, 3×10-7M and 10-6M Then built competition curves and determination of IC50 were performed using nonlinear regression analysis. The Ki values were then calculated from the equation of Cheng-Prusoff. In all the above studies of non-specific binding determinant was MDL-72222 (1,0 µm).

The affinity of compounds in respect of the receptor 5-NT3 person (analysis)

The relative affinity of various compounds in respect of the receptor 5-NT3 man was measured by analysis of binding of radioligand using format scintillation proximal analysis (SPA). Compound was dissolved to a concentration of 10 is M in 100% DMSO, then serially diluted at concentrations for the analysis of 10× in 100% DMSO in 96-well polypropylene tablets and further diluted to concentrations for analysis 4× buffer for analysis. Samples were incubated in 50 mm Tris-HCl, pH 7.5, 3 mm MgCl2, 1 mm EDTA and 10% DMSO with 10 nm [9-methyl-3H]BRL-43694 (Perkin Elmer), 3 μg of membranes with receptor 5-NT3 person (Perkin Elmer) and 0.5 mg/ml granules for SPA (WGA PVT, Amersham Biosciences) in a final volume of 0.2 ml binding assays were performed in the wells PicoPlates-96 (Perkin Elmer) by consistently adding 50 µl of each of the competing compounds or buffer, pellets SPA, radioligand and membrane receptor 5-NT3. After incubation for 60 min at room temperature on a Nutator mixer the plates were centrifuged for 15 min at 1500 rpm, followed by incubation in the dark for 30 minutes, the Radioactivity was counted by a counter for microplate TopCount (Perkin Elmer) for 5 minutes Total binding control containing only buffer; nonspecific binding was determined in the presence of 30 μm MDL-72222. Specific binding was determined by subtracting nonspecific binding from total binding. All experiments were performed in duplicate using ten concentrations of competing ligand, and ondansetron was included as a control in each experiment. IC50 values were determined from the data of specific binding with the application of the m software build curves XLfit4.1 from IDBS Ltd. The Ki values were then calculated from the equation of Cheng-Prusoff.

The affinity of compounds in respect of the receptor 5-NT3 mice (analysis)

Compounds were tested by Novoscreen Biosciences Corporation, 7170 Standard Drive, Hanover, Maryland in the analysis of binding of radioligand using murine receptor 5-NT3 obtained from cells for neuroblastoma mice, and [3H]-GR65630 (ligand). Determinant of nonspecific binding was MDL-72222. Compounds were tested at a single concentration of 100 nm in two replications. Specifies the percentage inhibition. To evaluate the relative affinity of various compounds in respect of the receptor 5-NT3 developed cell line N1E-155 for expression of the protein target. To link these cells are homogenized, centrifuged and washed with buffer (20 mm HEPRS, 150 mm NaCl, pH 7.4), then suspended in 0.5 ml of buffer was added [3H]-GR65630 at a concentration of 3.5×10-10M was Then added to the test compound during the initial uniform concentration of 10-7M. Incubation was carried out at room temperature for 60 minutes at 25°C., and then the incubation was stopped by rapid destruction of the environment for incubation. Radioactivity was assessed using a liquid scintillation spectrometry after exposure of scintillation cocktail account for at least three hours. The compounds exhibiting more than 75% in the euromania binding radioligand at 10 -7M, then analyzed on the above Protocol using the following range of concentrations of the test compounds: 10-9M, 10-8M, 3×10-8M, 10-7M, 3×10-7M and 10-6M Then built competition curves and determination of IC50 were performed using nonlinear regression analysis. The Ki values were then calculated from the equation of Cheng-Prusoff. In all the above studies of non-specific binding determinant was MDL-72222 (1,0 µm).

The following table shows an analysis in which data were obtained (as a, b or C), together with the data. Presents data received basis unless otherwise specified.

StructureEtc.Data of NMR and MSKi5-HT3(nm)
11H NMR (500 MHz, DMSO-d6) δ 11,49 (users, 1H), 10,48 (users, 0,4H), 9,71 (users, 0,6N), 9,11 (d, J=5.5 Hz, 0,4H), 8,86 (d, J=5.5 Hz, 0,6N), 7,81-to 7.77 (m, 1H), 7,69-the 7.65 (m, 1H), 7.23 percent-to 7.18 (m, 1H), 4,60-4,50 (m, 0,6N), to 4.38-4.25 in (m, 2,4H), and 3.72 (t, J=12,5 Hz, 2H), 3,63 (d, J=9.5 Hz, 1H), to 3.58-to 3.50 (m, 3H), 3,30-3,18 (m, 2H), 2,86 is 2.75 (m, 6N), 2,72-of 2.58 (m, 2H), 2,25 (d, J=6.0 Hz, 1H), 2,18-2,05 (m, 2H), 1.85 to to 1.70 (m, 3H), 1.60-to of 1.42 (m, 2H); MS (ESI+) m/z 398 (M+H).85
21H NMR (500 MHz, DMSO-d6) to 11.56 δ (users, 1H), accounted for 10.39 (users, 1H), 9,23 (d, J=6,5 Hz, 1H), to 7.77 (DD, J=8.0 a, 1.0 Hz, 1H), 7,69 (DD, J=8.0 a, 1.0 Hz, 1H), 7,21 (t, J=8.0 Hz, 1H), 4,45 is 4.36 (m, 1H), 4,30 (d, J=14,0 Hz, 2H), 3,78-3,63 (m, 3H), 3,54 (d, J=11.5 Hz, 2H), 3,40-of 3.31 (m, 1H), 3,30-3,18 (m, 6N), 2,80 (s, 3H), of 2.23 (DD, J=6,0, 3.0 Hz, 1H), 2,10-2,02 (m, 1H), 1,98-of 1.85 (m, 3H); MS (ESI+) m/z 370 (M+H).382
31H NMR (500 MHz, DMSO-d6) δ 10,37 (users, 0,4H), 9,70 (users, 0,6N), 9.28 are (d, J=6.0 Hz, 0,4H), 9,03 (d, J=6.0 Hz, 0,6N), 7,76-7,72 (m, 1H), to 7.59-EUR 7.57 (m, 1H), 7,13-to 7.09 (m, 1H), with 4.64 is 4.45 (m, 0,6N), to 4.38-4,30 (m, 0,4H), 3,68 (users, 4H), 3,63-to 3.50 (m, 2H), 2,85-2,82 (m, 3H), 2,72-2,60 (m, 2H), 2,32-of 2.08 (m, 3H), 1.85 to 1,72 (m, 3H), 1,65 (users, 6N)and 1.51 (t, J=11,0 Hz, 2H); MS (ESI+) m/z 383 (M+H).10,4

41H NMR (500 MHz, DMSO-d6) δ 10,34 (users, 1H), 9,42 (d, J=6,5 Hz, 1H), 7,71 (DD, J=9,0, 1.0 Hz, 1H), 7,60 (DD, J=9,0, 1.0 Hz, 1H), 7,12 (t, J=8.0 Hz, 1H), 4,40-4,32 (m, 1H), 3,74 (t, J=12,5 Hz, 1H), 3,68 (users, 4H), 3,29 (t, J=8.0 Hz, 2H), 3,23 (t, J=8.0 Hz, 2H), 3,12 (DD, J=13,5, 4.0 Hz, 1H), 2,27-2,22 (m, 1H), 2,14-of 2.08 (m, 1H), 1,98-of 1.88 (m, 3H), 1,66 (users, 6N); MS (ESI+) m/z 355 (M+H).34,2
51H NMR (500 MHz, DMSO-d6) δ of 11.15 (s, 0,8H), 11,10 (s, 0,2N), 10,29 (users, 0,2N), for 9.47 (users, 0,8H), 9,04 (d, J=6.0 Hz, 0,2N), of 9.00 (d, J=6.0 Hz, 0,8H), the 7.85-the 7.65 (m, 4H), 7,45-7,38 (m, 2H), 7,24 (t, J=8.0 Hz, 1H), 7,13 (t, J=8.0 Hz, 1H), 4,69-to 4.62 (m, 0,8H), to 4.41 is 4.35 (m, 0,2N), 3,70 (d, J=9.5 Hz, 1,6N), 3,61 (d, J=9.5 Hz, 0,4H), 2,88-2,82 (m, 3H), 2,78-2,60 (m, 2H), 2,16-of 1.97 (m, 3H), 1,80 is 1.70 (m, 2H), 1,68-of 1.40 (m, 3H); MS (ESI+) m/z 391 (M+H).6,25
61H NMR (500 MHz, DMSO-d6) δ 11,14 (s, 1H), 10,24 (users, 1H), 9,23 (d, J=6.0 Hz, 1H), 7,79 (DD, J=8.0 a, 1.0 Hz, 1H), 7,72 (DD, J=8.0 a, 1.0 Hz, 3H), 7,43 (DD, J=8,5, 7.5 Hz, 2H), 7,26 (t, J=8.0 Hz, 1H), 7,13 (t, J=7.5 Hz, 1H), 4,45 is 4.35 (m, 1H), 3,79 (t, J=11.5 Hz, 1H), 3,30-of 3.12 (m, 5H), 2,31-of 2.28 (m, 1H), 2,20-2,10 (m, 1H), 2,02-of 1.85 (m, 3H); MS (ESI+) m/z 363 (M+H).8,1
71H NMR (500 MHz, DMSO-d6) δ 10,27 (users, 0,4H), being 9.61 (users, 0,6N), to 9.32 (d, J=6.0 Hz, 0,4N), which is 9.09 (d, J=6.0 Hz, 0,6N), 7,76-7,72 (m, 1H), 7,60-7,58 (m, 1H), 7,12-was 7.08 (m, 1H), 4,55-4,47 (m, 0,6N), to 4.38-4,30 (m, 0,4H), 3,67-3,52 (m, 2H), 3.25 to 3,18 (m, 6N), 2,86-and 2.83 (m, 3H), 2,75-2,60 (m, 2H), 2,30-of 2.08 (m, 3H), 1,83-1,72 (m, 3H), 1.60-to the 1.44 (m, 2H); MS (ESI+) m/z 343 (M+H).6,1

81H NMR (500 MHz, DMSO-d6) δ 10,06 (users, 1H), 9,51 (d, J=6,5 Hz, 1H), 7,72 (DD, J=8.0 a, 1.0 Hz, 1H), to 7.61 (DD, J=8.0 Hz, 1.0 Hz, 1H), 7,11 (t, J=8.0 Hz, 1H), 4,42-4,37 (m, 1H), 3,75 (t, J=11.5 Hz, 1H), 3,35-3,20 (m, 10H), 3,13 (d, J=13,0 Hz, 1H), 2,28-of 2.21 (m, 1H), 2,18-of 2.08 (m, 1H), 1,98-of 1.88 (m, 3H); MS (ESI+) m/z 315 (M+H).18,1
91H NMR (500 MHz, DMSO-d6) δ 10,53 (users, 0,4H), 9,80 (users, 0,6N), 9,20 (d, J=5.8 Hz, 0,4H),to 8.94 (d, J=6,6 Hz, 0,6N), 7,78-7,74 (m, 1H), 7,65-of 7.60 (m, 1H), 7.18 in for 7.12 (m, 1H), 4,56-4,50 (m, 0,6N), 4,30-of 4.25 (m, 0,4H), of 3.80-3.75 to (m, 4H), 3.72 points-3,66 (m, 4H), 3,65-of 3.60 (m, 1,2N), 3,55-3,50 (m, 0,8H), 2,85 is 2.80 (m, 3H), 2,70-to 2.65 (m, 2H), 2,30-of 2.20 (m, 1H), 2,15-2,05 (m, 2H), 1.85 to 1,72 (m, 3H), 1,55-of 1.45 (m, 2H); MS (ESI+) m/z 385 (M+H).42
101H NMR (500 MHz, DMSO-d6) δ 12,64 (users, 1H), 9,36 (d, J=7.2 Hz, 1H), 7,74 (DD, J=8.0 a, 1.0 Hz, 1H), to 7.64 (DD, J=8.0 a, 1.0 Hz, 1H), 7,16 (t, J=7.9 Hz, 1H), 4,42 is 4.35 (m, 1H), 3,78-3,70 (m, 4H), 3,78-the 3.65 (m, 4H), 3,35-of 3.32 (m, 5H), 3,12 (DD, J=14,1, 4,2 Hz, 1H), 2,30-of 2.20 (m, 1H), 2,18 is 2.10 (m, 1H), 2.00 in 1,90 (m, 3H); MS (ESI+) m/z 357 (M+H).164
111H NMR (500 MHz, DMSO-d6) δ 11,10 (ears is .c, 0,6N), 10,98 (users, 0,4H), 10,34 (users, 0,4H), being 9.61 (users, 0,6N), 9,19 (users, 0,4H), 8,98 (d, J=3.5 Hz, 0,6N), 7,79-7,63 (m, 2H), 7,17-7,13 (m, 1H), 4,58-4,47 (m, 0,6N), to 4.38-4,30 (m, 0,4H), 4,22-4,10 (m, 1H), 4.00 points of 3.75 (m, 3H), 3,65-3,55 (m, 2H), 3,40-of 3.25 (m, 3H), 3,05-2,95 (m, 1H), 2,85 is 2.75 (m, 6N), 2,72-2,60 (m, 3H), 2,30-of 2.15 (m, 2H), 2,14-2,05 (m, 2H), 1,82 is 1.70 (m, 3H), 1.60-to of 1.42 (m, 2H); MS (ESI+) m/z 412 (M+H).89,6

121H NMR (500 MHz, DMSO-d6) of 11.26 δ (users, 1H), 10,35 (users, 1H), 9,39 (users, 1H), of 7.75 (d, J=8.0 Hz, 1H), 7,66 (d, J=8.0 Hz, 1H), 7,16 (t, J=8.0 Hz, 1H), 4,45-4,32 (m, 1H), 4,28-4,10 (m, 1H), 4,00-3,70 (m, 4H), 3,55 are 2.98 (m, N), 2,80-2,70 (m, 4H), 2,30-of 1.85 (m, 6N). MS (ESI+) m/z 384 (M+H).317
131H NMR (500 MHz, DMSO-d6) δ 10,20 (users, 0,3H), 9,45 (users, 0,7H), of 8.95 (d, J=6,5 Hz, 0,3N), a total of 8.74 (d, J=6,5 Hz, 0,7H), 7,92-7,86 (m, 2H), 7,47-7,42 (m, 1H), 4.63 to-4,55 (m, 0,7H), 4,40-4,32 (m, 0,3H), 3,70-to 3.52 (m, 2H), 3,88-2,82 (m, 6N), 2,72-of 2.54 (m, 2H), 2,20-2,04 (m, 3H), 1.85 to about 1.75 (m, 3H), 1.60-to of 1.42 (m, 2H); MS (ESI+) m/z 346 (M+H).4,6 (A)
141H NMR (500 MHz, DMSO-d6) δ 10,11 (users, 1H), 9,12 (d, J=6,5 Hz, 1H), of 7.90-7,86 (m, 2H), 7,46 (t, J=8.0 Hz, 1H), 4,45 is 4.36 (m, 1H), 3,74 (t, J=11,0 Hz, 1H), 3,30-and 3.16 (m, 5H), 2,85 (s, 3H), 2,30-of 2.27 (m, 1H), 2,20-2,10 (m, 1H), 1,98-of 1.85 (m, 3H); MS (ESI+) m/z 318 (M+H).2,6 (A)
151H NMR (500 MHz, DMSO-d6) δ 10,27 (users, 0,2N), 10,12 (users, 0,8H), 9,10 (users, 0,2N), of 8.95 (d, J=7,0 Hz, 0,8H), 7,74 (d, J=7.5 Hz, 1H), to 7.61 (d, J=7.5 Hz, 1H), 7,14 (t, J=7.5 Hz, 1H), 4,21-4,18 (m, 0,2H), 4.09 to 4,00 (m, 0,8H), 3,79 of 3.75 (m, 4H), 3,70-the 3.65 (m, 4H), of 3.45 (d, J=11.5 Hz, 2H), 3,12 (t, J=11.5 Hz, 2H), 2,75 (s, 3H), 2,18 (d, J=12,5 Hz, 2H), 1.85 to about 1.75 (m, 2H); MS (ESI+) m/z 345 (M+H).87 (C)
161H NMR (500 MHz, DMSO-d6) δ 9,52 (users, 1,2N), 9,50-9,40 (m, 1H), 9,16 (users, 0,8H), 9,07 (d, J=6.0 Hz, 0,4H), 8,89 (d, J=6.0 Hz, 0,6N), 7,76-7,73 (m, 1H), 7,65-of 7.60 (m, 1H),7,19-to 7.15 (m, 1H), of 5.05-4,51 (m, 2H), to 4.38-was 4.02 (m, 4H), 3,70-3,62 (m, 2H), 3,10-of 2.93 (m, 1H), 2,85 is 2.80 (m, 3H), 2,75-2,60 (m, 3H), 2,18-2,02 (m, 2H), 1,90-1,72 (m, 3H), 1,65 of 1.50 (m, 2H); MS (ESI+) m/z 370 (M+H).179

171H NMR (500 MHz, DMSO-d6) δ 10,32 (users, 0,4H), RS 9.69 (users, 0,6N), 9,23 (d, J=6.0 Hz, 0,4H), of 9.02 (d, J=6.0 Hz, 0,6N), 7,79-7,74 (m, 1H), to 7.61-of 7.60 (m, 1H),7,16 for 7.12 (m, 1H), 4.53-in is 4.45 (m, 0,6N), to 4.38-4,30 (m, 0,4H), 4,10-4,00 (m, 2H), 3,70 at 3.69 (m, 2H), 3,65-to 3.50 (m, 2H), 2.95 and is 2.80 (m, 5H), 2,72-2,60 (who, 2H), 2,35-2,05 (m, 3H), 1,86 is 1.70 (m, 3H), 1.60-to a 1.45 (m, 2H), 1,20-of 1.13 (m, 6N); MS (ESI+) m/z 413 (M+H).54,2
181H NMR (500 MHz, DMSO-d6) δ 10,11 (users, 1H), 9,39 (d, J=7,0 Hz, 1H), 7,73 (DD, J=8.0 a, 1.0 Hz, 1H), 7.62mm (DD, J=8.0 a, 1.0 Hz, 1H), 7,16 (t, J=8.0 Hz, 1H), 4,42-4,37 (m, 1H), 4,08-4,01 (m, 2H), 3,78-3,70 (m, 3H), 3,35-up 3.22 (m, 4H), 3.15 in (DD, J=a 13.5 and 4.5 Hz, 1H), 2,97-is 2.88 (m, 2H), 2,28-of 2.21 (m, 1H), 2,18-of 2.08 (m, 1H), 1,98-1,89 (m, 3H), of 1.17 (d, J=6.0 Hz, 6N); MS (ESI+) m/z 385 (M+H).443
191H NMR (500 MHz, DMSO-d6) δ 10,12 (users, 0,4H), for 9.47 (users, 0,6N), 9,10 (d, J=6.0 Hz, 0,4H), 8,88 (d, J=6.0 Hz, 0,6N), 7,79-7,74 (m, 1H), 7.68 per-of 7.60 (m, 1H), 7,50-7,30 (m, 5H), 7,19 for 7.12 (m, 1H), 5.40 to to 5.35 (m, 1H), 4.53-in is 4.45 (m, 1H), to 4.38-4.25 in (m, 1H), 4,10-3,95 (m, 3H), 3,80 at 3.69 (m, 1H), 3,65 is-3.45 (m, 3H), 2,85-2,78 (m, 3H), 2,70 is 2.55 (m, 2H), 2,12-of 1.93 (m, 3H), 1,80-of 1.52 (m, 3H), 1,47 to 1.37 (m, 2H); MS (ESI+) m/z 461 (M+H).17
201H NMR (500 MHz, DMSO-d6) δ 10,10 (users, 1H), 9,27-9,23 (m, 1H), 7,74 (d, J=8.0 Hz, 1H), 7,65 (d, J=8.0 Hz, 1H), 7,50-7,28 (m, 5H), 7,20-7,14 (m, 1H), 5.40 to-5,33 (m, 1H), 4,45-4,27 (m, 2H), 4,10-of 3.96 (m, 3H), 3,80-to 3.52 (m, 3H), 3.25 to 3.00 for (m, 5H), 2,25-2,03 (m, 1H), 1.93 and-of 1.62 (m, 4H); MS (ESI+) m/z 433 (M+H).34,4

211H NMR (500 MHz, DMSO-d6) δ 10,48 (users, 0,4H), 9,72 (users, 0,6N), 9,56 (users, 2H), 9,11 (d, J=5.5 Hz, 0,4H), 8,86 (d, J=5.5 Hz, 0,6N), 7,80-7,74 (m, 1H), 7.68 per to 7.62 (m, 1H), 7,22-to 7.15 (m, 1H), 4,60-4,51 (m, 0,6N), to 4.38-4,30 (m, 0,4H), 3,98-3,88 (m, 4H), 3,63 (d, J=9.0 Hz, 2H), 3,35-of 3.27 (m, 4H), 2,85 is 2.80 (m, 3H), 2,75-2,60 (m, 2H), 2.40 a-2,05 (m, 3H), 1.85 to 1,72 (m, 3H), 1.60-to a 1.45 (m, 2H); MS (ESI+) m/z 384 (M+H).74,6
221H NMR (500 MHz, DMSO-d6) δ 10,35 (users, 1H), 9,59 (users, 2H), 9,25 (d, J=6,5 Hz, 1H), 7,76 (d, J=8.0 Hz, 1H), 7,66 (DD, J=8.0 a, 1.0 Hz, 1H), 7,19 (t, J=8.0 Hz, 1H), 4,42-4,37 (m, 1H), 3,94 (t, J=5.0 Hz, 4H), 3,74 (t, J=11,6 Hz, 1H), 3,36-3,20 (m, 8H), 3.15 in (DD, J=13,4, 4,2 Hz, 1H), 2,27-of 2.20 (m, 1H), 2,10-2,02 (m, 1H), 1,98 of-1.83 (m, 3H); MS (ESI+) m/z 356 (M+H).321
231H NMR (500 MHz, DMSO-d6) δ 11,67 (users, 0,2N), 10,52 (users, 0,4H), 10,10-9,56 (m, 1,4H), 9,03-charged 8.52 (m, 1H), 7,88-to 7.61 (m, 2H), of 7.48-7,29 (m, 5H), 7,20-to 7.15 (m, 1H), 5,94 (users, 0,8H), 5,55 lower than the 5.37 (m, 0,2N), 4,60-4.26 deaths (m, 3H), 3,82-3,25 (m, 6N), 2,98 is 2.80 (m, 6N), was 2.76-2,52 (m, 2H), 2,07-1,90 (m, 3H), 1,81-1,20 (m, 5H); MS (ESI+) m/z 474 (M+H).25,2
24 1H NMR (500 MHz, DMSO-d6) δ 11,81 (users, 0,2N), 10,70-10,45 (m, 1H), 10,17 (users, 0,8H), 9,20-8,97 (m, 1H), 7,80-7,73 (m, 2H), 7,42-of 7.23 (m, 5H), 7.18 in-was 7.08 (m, 1H), 6,02-of 5.50 (m, 1H), 4,71-to 4.15 (m, 3H), 3,84-3,20 (m, 5H), 3,18-of 2.81 (m, 8H), 2,18-of 1.45 (m, 5H); MS (ESI+) m/z 446 (M+H).103

251H NMR (500 MHz, DMSO-d6) δ of 10.58 (users, 0,4H), 9,85 (users, 1,6N), 9,49 (users, 1H), 9,11 (d, J=7,0 Hz, 0,4H), 8,89 (d, J=7,0 Hz, 0,6N), 7,80-7,74 (m, 1H), 7.68 per to 7.62 (m, 1H), 7,22-to 7.15 (m, 1H), 4,65-4,58 (m, 1H), 4,55-4,47 (m, 0,6N), to 4.38-to 4.28 (m, 0,4H), 4,20-4,12 (m, 1H), 3,68-of 3.60 (m, 2H), 3,52 is 3.25 (m, 4H), 3,18-is 3.08 (m, 1H), 2,85 is 2.80 (m, 3H), 2,75-2,60 (m, 2H), 2,32-2,05 (m, 3H), 1,80-1,72 (m, 3H), 1.60-to a 1.45 (m, 5H); MS (ESI+) m/z 398 (M+H).27,5
261H NMR (500 MHz, DMSO-d6) δ 10,49 (users, 1H), to 9.91 (d, J=10.0 Hz, 1H), at 9.53 (d, J=9.0 Hz, 1H), 9,29 (d, J=6,5 Hz, 1H), 7,76 (d, J=8.0 Hz, 1H), 7,66 (d, J=8.0 Hz, 1H), 7,17 (t, J=8.0 Hz, 1H), 4,68-4,59 (m, 1H), to 4.41-4,32 (m, 1H), 4,18 (d, J=14,0 Hz, 1H), and 3.72 (t, J=12.0 Hz, 1H), 3,61 (t, J=12.0 Hz, 1H), 3,40 was 3.05 (m, N), 2,27-of 2.20 (m, 1H), 2,10-2,02 (m, 1H), 1,98 of-1.83 (m, 3H), 1,50-of 1.45 (m, 3H); MS (ESI+) m/z 370 (M+H).241
271H NMR (500 MHz, DMSO-d6) δ 10,38 users, 0,2N), 9,54 (users, 0,8H), 8,72 (d, J=6,5 Hz, 2,2H), 8,61 (d, J=6,5 Hz, 0,8H), 8,18-with 8.05 (m, 2H), 7,88-7,80 (m, 2H), 7,43 and 7.36 (m, 1H), 4,73-4,63 (m, 0,8H), 4,42-to 4.38 (m, 0,2N), and 3.72-3,55 (m, 2H), 2,87-2,82 (m, 3H), 2,78 of $ 2.53 (m, 3H), 2,20-2,05 (m, 3H), 1,86-of 1.45 (m, 5H); MS (ESI+) m/z 392 (M+H).4,5
281H NMR (500 MHz, DMSO-d6) δ 10,48 (users, 1H), 8,89 (d, J=6.0 Hz, 1H), 8,80 (d, J=7,0 Hz, 2H), 8,17 (d, J=7,0 Hz, 2H), 7,89 (DD, J=8.0 a, 1.0 Hz, 1H), to 7.84 (DD, J=8.0 a, 1.0 Hz, 1H), 7,43 (t, J=8.0 Hz, 1H), 4,42 (d, J=5.5 Hz, 1H), 3,78 (t, J=to 11.0 Hz, 1H), 3,38 is 3.15 (m, 6N), 2,38-of 2.34 (m, 1H), 2,20-2,10 (m, 1H), 2,01-to 1.87 (m, 3H); MS (ESI+) m/z 364 (M+H).5,3

291H NMR (500 MHz, DMSO-d6) δ 10,70 (users, 0,3H), 9,77 (users, 0,7H), 9,17 (d, J=5.5 Hz, 0,3H), 9,01 (d, J=7,0 Hz, 0,7H), to 7.84 (d, J=8.0 Hz, 1H), 7,79 (d, J=7.5 Hz, 1H), 7,69 (d, J=7.5 Hz, 1H), 7,21 (t, J=8.0 Hz, 1H), of 6.96 (t, J=7.5 Hz, 1H), 6.73 x (d, J=8.0 Hz, 1H), 6,63 (d, J=7.5 Hz, 1H), 4,65-4,55 (m, 0,7H), 4,40-4,30 (m, 0,3H), 4,08-and 4.40 (m, 2H), 3,64 (d, J=9.0 Hz, 1,3H), 3,60-3,50 (m, 0,7H), 3,48-of 3.42 (m, 2H), 2,86-2,80 (m, 3H), 2,70-of 2.58 (m, 2H), 2,20-a 1.96 (m, 3H), 1,80-to 1.60 (m, 2H), 1.56 to 1,50 (m, 1H), 1,48-of 1.36 (m, 2H); MS (ESI+) m/z 432 (M+H).3,6
301H NMR (500 MHz, DMSO-d679
311H NMR (500 MHz, DMSO-d6) δ 11,02-10,96 (m, 1H), 10,79 (users, 0,3H), 9,85 (users, 0,7H), the remaining 9.08 (users, 0,3H), 8,81 (users, 0,7H), 7,78 to 7.75 (m, 1H), 7.62mm (DD, J=7,9, 0.8 Hz, 1H), 7,15 for 7.12 (m, 1H), 5,95 (users, 3H), 4,69-to 4.62 (m, 0,7H), to 4.38-4.35 the (m, 0,3H), 4,07-4,00 (m, 2H), 3,65-3,62 (m, 1,5H), 3,56-to 3.52 (m, 0,5H), 3,47-of 3.42 (m, 2H), 3,25 (s, 3H), 2,85-2,82 (m, N), 2,69-to 2.57 (m, 2H), 2,31-2,05 (m, 3H), 1,82-of 1.73 (m, 3H), 1,53 is 1.48 (m, 3H); MS (ESI+) m/z 400 (M+H).107

321H NMR (500 MHz, DMSO-d6) δ 10,95 (users, 0,7H), 10,86 (users, 0,3H), 10,50 (users, 0,3H), 9,72 (users, 0,7H), 9,15 (users, 0,3H), 8,93-of 8.90 (m, 1,7H), 7,76-7,73 (m, 1H), 7,60-7,58 (m, 1H), 7,16 FOR 7.12 (1H), with 4.64-4,55 (m, 0,8H), 4,36-4,32 (m, 0,2N), 4,21 (users, 6N), a 3.87-of 3.77 (m, 2H), 3,65-3,62 (m, 1,4H), 3,55-to 3.52 (m, 0,6N), 3,40-to 3.35 (m, 2H), 2,84-2,82 (m, N), 2,69-257 (m, 2H), 2,29-2,05 (m, 3H), 1,84-1,71 (m, 2,6N), 1,57-1,49 (m, 2,4H); MS (ESI+) m/z 386 (M+H).234
331H NMR (500 MHz, DMSO-d6) δ of 11.45 (users, 0,7), 11,18 (users, 0,3H), 10,32 (users, 0,3H), to 9.57 (users, 0,7H), 9,16 (users, 0,3H), 8,93-of 8.90 (m, 1,7H), 7,76-7,73 (m, 1H), to 7.59 (d, J=7.9 Hz, 1H), 7,16 for 7.12 (m, 1H), br4.61-to 4.52 (m, 0,6N), 4,35-or 4.31 (m, 0,4H), 3,99-a-3.84 (m, 3,5H), 3,66-of 3.43 (m, 3,5H), 3,17-3,13 (m, 1H), 2,85-of 2.81 (m, 3H), 2,67 at 2.59 (m, 3H), 2,22-2,05 (m, 3H), 1,87-1,71 (m, 4H), 1.56 to 1,50 (m, 2H), 0,89-of 0.62 (m, 2H); MS (ESI+) m/z 428 (M+H).168
341H NMR (500 MHz, DMSO-d6) δ 10,46 (users, 0,4H), 9,81 (users, 0,6N), 9,42 (d, J=5,9 Hz, 0,4H), 9,17 (d, J=6,5 Hz, 0,6N), 8,55-to 8.45 (m, 1H), 7,75-7,66 (m, 1H), EUR 7.57-to 7.50 (m, 1H), 7,10? 7.04 baby mortality (m, 1H), 4,55 is 4.45 (m, 1,2N), 4,35-of 4.25 (m, 0,8H), 3,65 is 3.57 (m, 1,2N), 3,55-3,50 (m, 0,8H), to 3.02 vs. 2.94 (m, 3H), 2,88 is 2.80 (m, 3H), 2,74-2,70 (m, 2H), 2,30-of 2.20 (m, 1H), 2,15-2,05 (m, 2H), 1,84-1,72 (m, 3H), 1.60-to a 1.45 (m, 2H); MS (ESI+) m/z 329 (M+H).5,3
351H NMR (500 MHz, DMSO-d6) δ 10,54 (users, 0,3H), 9,81 (users, 0,7H), 9,37 (d, J=5.5 Hz, 0,3H), 9,03 (d, J=7,1 Hz, 0,7H), 8,30 (users, 1,4H), 8,18 (users, 0,6N), 7,78-of 7.70 (m, 1H), 7,60 is 7.50 (m, 1H), 7,15-7,05 (m, 1H), 4,65-4,55 (m, 0,7H), 4,35-of 4.25 (m, 0,3H), 3,70-to 3.50 (m, 2H), 2,90 is 2.80 (m, 3H), 2,72 is 2.55 (m, 2H), 2,15-2,05 (m, 3H), 1,90 is 1.70 (m, 3H), 1,54-of 1.45 (m, 2H); MS (ESI+) m/z 315 (M+H).9,1

361H NMR (500 MHz, DMSO-d6) δ 10,69 (users, 0,4H), 9,89 (users, 0,6H), 9,15-9,14 (m, 0,4H), 8,96-8,95 (m, 0,6H), to 7.77-7,74 (m, 1H), to 7.61-to 7.59 (m, 1H), 7,15-7,11 (m, 1H), 4,57-a 4.53 (m, 0,6H), 4,34-to 4.33 (m, 0,4H), 4.04 the-a 4.03 (m, 1H), 3,94-a-3.84 (m, 3H), 3,68-of 3.46 (m, 5H), 2,83-of 2.81 (m, 3H), 2,68-2,62 (m, 2H), 2,27 was 2.25 (m, 1H), 2,12-2,10 (m, 2H), 1.91 a-1,74 (m, 5H), 1,53 to 1.47 (m, 2H), 0,93 is 0.86 (m, 3H); MC (ESI+) m/z 413 (M+H).the 4.7
371H NMR (500 MHz, DMSO-d6) δ 11,35-of 11.15 (m, 0,8H), 10,96-10,85 (m, 0,2H), to 10.62 (c, 0,2H), 10,00-9,60 (m, 0,8H), 9,18-9,06 (m, 0,5H), 8,98 (d, J=7,0 Hz, 0,5H), a total of 8.74-8,66 (m, 1H), 7,80-of 7.70 (m, 1H), 7,60-rate of 7.54 (m, 1H), 7.18 in-7,12 (m, 1H), 4,96-4,82 (m, 1H), 4,68-4,60 (m, 0,6H), 4,40-4,24 (m, 0,4H), 3,66-to 3.50 (m, 4H), 2,90-to 2.74 (m, 6H), 2,70-2,60 (m, 3H), 2,36-of 2.20 (m, 2H), 2,16-2,00 (m, 5H), 1,94-of 1.88 (m, 1H), 1,86 is 1.70 (m, 2H), 1,68 of 1.46 (m, 5H); MC (ESI+) m/z 452 (M+H).243
381H NMR (500 MHz, DMSO-d6) δ 10,77 (c, 0,4H), of 10.05 (c, 0,6N), of 9.30 (d, J=5.5 Hz, 0,4H), 9,12 (d, J=6,5 Hz, 0,6N), 8,77 (c, 1H), 8.30 to-7,80 (users, 1H), 7,74-7,71 (m, 1H), 7,55 (DD, J=8.0 a, 1.0 Hz, 1H), 7,10 (apparent t, J=8.0 Hz, 1H), 4,56-4,48 (m, 0,6H), to 4.38-4,30 (m, 0,4H), 3,64-to 3.50 (m, 6H), 3,30 (d, J=3.5 Hz, 3H), 2,84 is 2.80 (m, 3H), 2,74-2,62 (m, 2H), 2,38-of 2.24 (m, 1,2H), 2,11 (d, J=6,5 Hz, 1,8H), 1,82 is 1.70 (m, 3H), 1.50 is of 1.46 (m, 2H); MC (ESI+) m/z 373 (M+H).7,5

391H NMR (500 MHz, DMSO-d6) δ 10,70 (c, 0,4H), 9,99 (c, 0,6N), 9,34 (d, J=5.5 Hz, 0,4H), 9,16 (d, J=6,5 Hz, 0,6H), 8,73-8,66 (m, 1H), of 7.90-7,50 (users, 1H), 7,80-7,66 (m, 1H), 7,56-7,53 (m, 1H), 7,09 (apparent t, J=8.0 Hz, 1H), 4,56-4,50 (m, 0,6H), 4,36-4,30 (m, 0,4H), 3,61 (d, J=9.0 Hz, 1H), 3,53 (users, 1H), 3.46 in-to 3.38 (m, 4H), 3,23 (d, J=1.0 Hz, 3H), 2,82 (DD, J=8,5, 5.0 Hz, 3H), 2,75-2,62 (m, 2H), 2,16-of 2.08 (m, 1,2H), 2,12 (d, J=7,0 Hz, 1,8H), 1,92-to 1.82 (m, 2H), 1,80 is 1.70 (m, 3H), 1.60-to the 1.44 (m, 2H); MC (ESI+) m/z 387 (M+H).13,2
401H NMR (500 MHz, DMSO-d6) δ 10,76 (c, 0,4H), there is a 10.03 (c, 0,6H), 9,36 (d, J=6.0 Hz, 0,4H), 9,20 (d, J=6.0 Hz, 0,6H), 8,70-to 8.62 (m, 1H), of 7.90-7,50 (users, 1H), 7,80-of 7.70 (m, 1H), 7,60-7,52 (m, 1H), 7,10 (apparent t, J=8.0 Hz, 1H), 4,60-4,50 (m, 0,6H), 4,40-4,30 (m, 0,4H), 3,61 (d, J=9.0 Hz, 1H), 3,54-to 3.50 (m, 2H), 3,49 is 3.40 (m, 2H), 2,85 is 2.80 (m, 2H), 2,74-2,60 (m, 2H), 2,38-of 2.28 (m, 1H), 2,16-of 2.08 (m, 2H), 1,82 is 1.70 (m, 4H), 1.60-to of 1.46 (m, 2H); MC (ESI+) m/z 373 (M+H).7,8
41a1H NMR (500 MHz, DMSO-d6) δ 10,47 (users, 0,4H), 9,50-to 9.57 (m, 1,6H), 9,41 (users, 1H), 9,10 (c, 0,4H), 8,89 (c, 0,6H), 7,88-7,72 (m, 1H), 7,65 (c, 1H), 7,32-7,06 (m, 1H), with 4.64 (users, 1H), 4,54 figure-4.49 (m, 1H), 4,27-4.09 to (m, 1H), 3.75 to 3,56 (m, 2H), 3,53 (c, 1H), 3,34-up 3.22 (m, 3H), 3,22-a 3.01 (m, 1H), 2,84 (c, 3H), 2,72-2,60 (m, 2H), 2.26 and (c, 1H), 2,11 (c, 2H), 1.93 and-of 1.64 (m, 3H), 1,63-of 1.33 (m, 5H); MC (ESI+) /z 398 (M+H). 14,2

41b1H NMR (500 MHz, DMSO-d6) δ 10,47 (users, 0,4H), 9,50-to 9.57 (m, 1,6H), 9,41 (users, 1H), 9,10 (c, 0,4H), 8,89 (c, 0,6H), 7,88-7,72 (m, 1H), 7,65 (c, 1H), 7,32-7,06 (m, 1H), with 4.64 (users, 1H), 4,54 figure-4.49 (m, 1H), 4,27-4.09 to (m, 1H), 3.75 to 3,56 (m, 2H), 3,53 (c, 1H), 3,34-up 3.22 (m, 3H), 3,22-a 3.01 (m, 1H), 2,84 (c, 3H), 2,72-2,60 (m, 2H), 2.26 and (c, 1H), 2,11 (c, 2H), 1.93 and-of 1.64 (m, 3H), 1,63-of 1.33 (m, 5H); MC (ESI+) m/z 398 (M+H).125
421H NMR (500 MHz, DMSO-d6) to 8.41 δ (c, 2H), 7,84 (c, 1H), 7,62-7,47 (m, 1H), 7,28-7,05 (m, 1H), for 6.81-of 6.61 (m, 1H), 4,66-the 4.29 (m, 1H), 4,17-of 3.97 (m, 4H), 3.96 points-of 3.78 (m, 4H), 3,78-to 3.58 (m, 2H), is 3.08-2.91 in (m, 311), 2,91-2,62 (m, 2H), 2,37-2,11 (m, 3H), 2,11 is 1.91 (m, 2,5H), 1,80-to 1.59 (m, 2,5H); MC (ESI+) m/z 462 (M+H).11
431H NMR (500 MHz, DMSO-d6) δ 9,14-8,93 (m, 0,5H), the 7.85-the 7.65 (m, 0,8H), 7,65-7,53 (m, 0,8H), 7,25-6,99 (m, 0,9H), 5,39-5,00 (m, 1H), 4,74-3,98 (m, 6H), 3,86-3,39 (m, 9H), 3,29-of 2.58 (m, 6H), 2,48-of 1.93 (m, 5H); MC (ESI+) m/z 400 (M+H).480
441H NMR (500 MHz, CD3OD) δ of 10.21 (users, 1H), 7,94-to 7.68 (m, 1H), 7,56-,38 (m, 1H), 7,26-of 6.96 (m, 1H), 4,81-4,63 (m, 1H), 4,11-to 3.89 (m, 2H), 3,88-3,70 (m, 10H), 2,85-to 2.67 (m, 2H), 2,68-2,48 (m, 5H), 1,71-is 1.51 (m, 2H); MC (ESI+) m/z 387 (M+H).323
451H NMR (500 MHz, DMSO-d6) δ 10,91-10,88 (m, 0,6H), 10,86-10,53 (m, 0,4H), 10,53-10,10 (m, 0,2H), 9,42-9,13 (m, 0,8H), 7,98-7,79 (m, 1H), 7,79-of 7.60 (m, 3,9H), 7,58-7,34 (m, 2H), 7,34-7,17 (m, 1H), 7,15-6,98 (m, 1H), 4,79-4,51 (m, 1H), 4,35-4,12 (m, 0,9H), 4,12-3,90 (m, 2,4H), 3,90-the 3.65 (m, 1H), 3,65 is 3.40 (m, 2,3H), 3,10-2,96 (m, 1,3H), 2,96-2,84 (m, 1,8H), 2,84-2,62 (m, 2,4H), 2,17-of 1.97 (m, 0,8H), 1,95-of 1.73 (m, 1,2H); MC (ESI+) m/z 393 (M+H).22,6

461H NMR (500 MHz, DMSO-d6) δ 10,56 (users, 0,5H), 10,07 (c, 0,5H), 10,01 (c, 0,5H), 9,52 (c, 1H), which 9.22 (d, J=5.5 Hz, 0,4H), 8,99 (d, J=5.5 Hz, 0,6H), 7,78 (t, J=7.5 Hz, 1H), to 7.67 (d, J=8.0 Hz, 1H), 7,19-7,16 (m, 1H), 4,91 (c, 0,5H), 4,87 (c, 0,5H), 4,34-or 4.31 (d, J=10.5 Hz, 1H), 3,79 is 3.76 (m, 1H), 3,62-3,59 (m, 1H), 3,52 (c, 1H), 3,42 (c, 1H), 3,34-of 3.32 (m, 1H), 2,89-and 2.83 (m, 3H), 2,78-2,62 (m, 2H), 2,30-of 2.23 (m, 2H), 2,17-2,08 (m, 1H), 2,05 (d, J=10.0 Hz, 1H), 1,83-of 1.78 (m, 3H), 1,63 is 1.58 (m, 1H), 1,51-1,49 (m, 1H); MC (ESI+) m/z 396 (M+H).284
471H NMR (500 MHz, DMSO-d6) the 10.40 δ (users, 1H), 9,62 (users, 1H), of 9.21-9,20 (m, 0,3H), remaining 9.08-9,06 (m, 0,7H), 8,75 (users, 0,7H), 8,67-8,65 (who, 0,3H), 7,74-7,71 (m, 1H), 7,58 (d, J=7.8 Hz, 1H), 7,13-to 7.09 (m, 1H), 4,80 (users, 4H), or 4.31 (m, 2,5H), 3,65-3,63 (m, 1,5H), 3,54 (users, 0,5H), 3,03 (c, 3H), 3.00 and (c, 1H), 2,87 is 2.80 (m, 6N), 2,70 at 2.59 (m, 2H), 2,20 (users, 0,8H), 2,11-of 2.09 (m, 2,2H), 1,78-of 1.74 (m, 3H), 1,53-1,45 (2,5H); MC (ESI+) m/z 400 (M+H).137
481H NMR (500 MHz, DMSO-d6) δ 10,77 (users, 0,4H), 9,98 (users, 0,6N), 9,14-9,13 (m, 0,4H), 8,98-8,97 (m, 0,6H), to 7.77-7,74 (m, 1H), 7,60-7,58 (m, 1H), 7,14-7,10 (m, 1H), 4,58-4,51 (m, 0,6N), 4,34-to 4.33 (m, 0,4H), 4.04 the-3,91 (m, 3H), 3,76-3,71 (m, 1H), 3,68-3,44 (m, 5H), 2,83-2,77 (m, 3H), 2,73-of 2.64 (m, 2H), 2,46 to 2.35 (m, 1H), 2,32-to 2.18 (m, 1H), 2,12-of 2.08 (m, 2H), 1,80-of 1.73 (m, 3H), 1,54-of 1.45 (m, 2H), 1,07 is 0.99 (m, 3H), 0,91 is 0.81 (m, 3H); MC (ESI+) m/z 427 (M+H).6,0

491H NMR (500 MHz, DMSO-d6) δ 10,59 (users, 0,4H), 9,89 (users, 0,6H), 9,18-9,17 (m, 0,4H), 8,98-8,98 (m, 0,6H), to 7.77-7,74 (m, 1H), 7,62-to 7.61 (m, 1H), 7,16 for 7.12 (m, 1H), 5,50-5,00 (users, 4H), 4,57-a 4.53 (m, 0,6H), 4,34-to 4.33 (m, 0,4H), Android 4.04-of 1.03 (m, 1H), 3,95 (m, 1H), 3,86 (m, 1H), 3,74-and 3.72 (m, 2H), 3,60-3,51 (m, 4H), 2,83-of 2.81 (m, 3H), 2,68-2,62 (m, 2H), 2,27 was 2.25 (m, 1H), 2,12-2,10 (m, 2H), 1,80-of 1.78 (m, 3H), 1,53 to 1.47 (m, 2H), 1,36 is 1.34 (m, 3H); MC (ESI+) m/z 399 (M+H).10,9
501H NMR (500 MHz, DMSO-d6) δ 0.70 and (c, 0,4H), 10,49 (c, 1H), 9,99 (c, 0,6H), 9,80-9,60 (m, 1H), 9,07 (d, J=5.5 Hz, 0,5H), 8,98 (d, J=6.0 Hz, 0,5H), 7,78 (DD, J=11,0, 8.0 Hz, 1H), to 7.67 (d, J=8.0 Hz, 1H), 7,17 (apparent t, J=8.0 Hz, 1H), 4,60-4,55 (m, 3H), 4,54 figure-4.49 (m, 1,5H), to 4.38-to 4.28 (m, 0,5H), 3,66-to 3.58 (m, 1,2H), 3,56-of 3.48 (m, 0,8H), 3,38-up 3.22 (m, 4H), 2,88-2,78 (m, 3H), 2,74-of 2.64 (m, 2H), 2,38-to 2.18 (m, 1,2H), 2,16-to 2.06 (m, 1,8H), 1,82-1,72 (m, 3H), 1.60-to of 1.46 (m, 6H); MC (ESI+) m/z 412 (M+H).13,6
511H NMR (500 MHz, DMSO-d6) δ 11,0-10,71 (m, 1H), accounted for 10.39 (users, 0,8H), 10,01-9,73 (m, 0,8H), 7,89-7,56 (m, 4H), 7,56 and 7.36 (m, 2H), 7,26-7,17 (m, 1H), 7,17-6,98 (m, 1H), 4,62-to 4.33 (m, 1H), 3,60-to 3.35 (m, 2,5H), 3,32-3,10 (m, 1H), 2,98-2,73 (m, 5,5H), 2,73-2,62 (m, 1,6H), 2,62 of $ 2.53 (m, 2H), 2,09-to 1.59 (m, 4,8H); MC (ESI+) m/z 406 (M+H).212
521H NMR (500 MHz, DMSO-d6) δ 11.30 on-11,00 (m, 1H), is 10.68 (users, 0,5H), 8,81 (users, 0,5H), 8,97-8,66 (m, 1H), 7,93-7,63 (m, 4H), 7,62-7,37 (m, 2H), 7,34-7,19 (m, 1H), 7,19-7,02 (m, 1H), 5,47-5,10 (m, 1H), 3,85-3,62 (m, 3H), 3.27 to 3,03 (m, 2H), 3,03-of 2.86 (m, 4H), 2,86-2,61 (m, 2H), 2,43-of 1.93 (m, 6H); MC (ESI+) m/z 406 (M+H). Exo27,6

531H NMR (500 MHz, DMSO-d6) δ 10,15 (users, 0,3H), 9,40 (users, 0,7H), 9,14 (users, 1H), 7,76-7,73 (m, 1H), 7,69 (c, 1H), 7,63 (d, J=6.3 Hz, 1H), 7,22 (ears is .c, 1H), 7,14-to 7.09 (m, 1H);4,54-4,32 (m, 4H), 3,83-of 3.54 (m, 4H), 2,84-2,82 (m, 3H), 2,73-2,52 (m, 2H), 2,38-of 2.30 (m, 1H), 2,12-of 1.95 (m, 5H), 1,80 by 1.68 (m, 2H), 1,55-of 1.45 (m, 2H); MC (ESI+) m/z 412 (M+H).212
541H NMR (500 MHz, DMSO-d6) δ 10,32 (c, 0,4H), 9,63 (c, 0,6H), 9,07 (d, J=6.0 Hz, 0,4H), 8,88 (d, J=6.0 Hz, 0,6H), 7,78 (DD, J=8.0 a, 1.0 Hz, 1H), of 7.70 (d, J=8.0 Hz, 1H), 7.24 to to 7.18 (m, 1H), 5,20 (d, J=12.0 Hz, 2H), 4,58-4,50 m, 0,6H), 4,40-4,34 (m, 2,4H), 4,25-4,20 (m, 2H), 3,64 (d, J=9.0 Hz, 2H), 2,85-2,84 (m, 3H), 2,73-2,60 (m, 2H), 2,32-2,22 (m, 1H), 2,20-of 2.08 (m, 2H), 1,90-of 1.78 (m, 2H), 1.60-to of 1.46 (m, 2H); MC (ESI+) m/z 490 (M+H).118
551H NMR (500 MHz, DMSO-d6) δ 11,02-10,84 (m, 0,7H), 10,29-10,17 (m, 0,3H), being 9.61-9,46 (m, 0,5H), 9,10-9,00 (m, 0,4H), 8,90-8,80 (m, 0,6N), 7,84-7,71 (m, 1H), 7,71-7,58 (m, 1H), 7,26-7,07 (m, 1H), 4,79 with 4.65 (m, 1H), 4,59-of 4.44 (m, 0,7H), 4,39-4,20 (m, 1,5H), 3,79-3,59 (m, 2,5H), 3,59 is-3.45 (m, 3H), 3,26-to 3.09 (m, 1,2H), 2,88-2,78 (m, 6,3H), 2,75-to 2.57 (m, 2,5H), 2,29-of 2.15 (m, 1,5H), 2,14 is 2.01 (m, 2H), 1,86 by 1.68 (m, 3H), 1,59-1,40 (m, 4H); MC (ESI+) m/z 412 (M+H).28,8
561H NMR (500 MHz, DMSO-d6) δ 11,7-of 8.47 (osirm, 2,5H), of 7.70 (d, J=8,1 Hz, 1H), 7,44 (d, J=7.8 Hz, 1H), 7,16 (t, J=8.0 Hz, 1H), 4,73-4,12 (osirm, 1H), 3,60 (d, J=9.0 Hz, 2H), 3,17 (c, 1H), 2,81 (c, 3H), 2,42 (users, 2H), 2,25-2,07 (m, 3H), of 1.87 (t, J=11,9 Hz, 2H), 1.70 to about 1.35 (m, 3H); MC (ESI+) m/z 316 (M+H).72

571H NMR (500 MHz, DMSO-d6) δ 10,43-10,14 (m, 0,3H), 9,86-9,63 (m, 0,7H), 9,60-9,48 (m, 0,5H), 9,48-9,16 (m, 0,8H), 9,07-to 8.94 (m, 0,4H), cent to 8.85-to 8.62 (m, 0,7H), 7,94-7,81 (c, 1H), 7,80-7,53 (c, 1H), 4,71-4,56 (m, 1H), 4,56-4,43 (m, 0,7H), 4,40-4,37 (m, 0,5H), 4,27-was 4.02 (m, 1H), 3,76-to 3.58 (m, 2,5H), to 3.58 is-3.45 (m, 1H), 3,21-3,03 (m, 1,4H), 2.95 and was 2.76 (m, 3,4H), was 2.76-of 2.56 (m, 2,7H), 2,32-to 1.98 (m, 3,4H), 1,98-of 1.64 (m, 3H), 1,63 is 1.34 (m, 6H); MC (ESI+) m/z 432 (M+H).11,4
581H NMR (500 MHz, DMSO-d6) δ 10,54-10,34 (m, 0,3H), 9,79-at 9.53 (m, 0,6N), 9,11-to 8.94 (m, 0,4H), 8,87-to 8.62 (m, 0,6H), 7,95-7,81 (c, 1H), 7,80-to 7.67 (c, 1H), 4,66-of 4.44 (m, 0,6H), of 4.44-4,10 (m, 2,4H), 3,83-to 3.49 (m, 6H), 3,28-3,09 (m, 2,5H), 2.91 in is 2.75 (m, 6H), 2,74-of 2.54 (m, 2,5H), 2,35-2,17 (m, 1H), 2,17-of 1.97 (m, 2H), 1,87-1,71 (m, 3H), 1.60-to of 1.41 (m, 2H); MC (ESI+) m/z 432 (M+H).11,9
591H NMR (500 MHz, DMSO-d6) δ br11.01-10,91 (m, 0,7H), 10,91-10,84 (m, 0,2N), 10,34-10,08 (m, 0,2H), 9,60-9,40 (m, 0,7H), 9,16-9,00 (m, 1H), 7,86 is 7.50 (m, 4H), 7,31-7,16 (m, 1H), 7,06-6,85 (m, 2H), 4.72 in figure-4.49 (m, 0,7H), 4,48-4.26 deaths (m, 0 2N), a 3.87-and 3.72 (m, 3H), 3.72 points-to 3.52 (m, 2H), 2,94-2,78 (m, 3H), 2,78 at 2.59 (m, 1,5H), 2,23-1,89 (m, 3H), 1,89-1,32 (m, 5H); MC (ESI+) m/z 421 (M+H).7,6
601H NMR (500 MHz, DMSO-d6) δ 10,63 (c, 0,4H), 9,87 (users, 1,6H), 9,67 (d, J=10.0 Hz, 1H), 9,07 (d, J=6,50 Hz, 0,4H), of 8.90 (d, J=6,50 Hz, 0,6H), 7,79 to 7.75 (m, 1H), 7,65 (d, J=8.5 Hz, 1H), 7,19-7,16 (m, 1H), 4,57-4,50 (m, 1,6H), 4,34-4,32 (m, 0,4H), 3,91-with 3.79 (m, 2H), 3,70-3,62 (m, 2H), 3,53 is-3.45 (m, 2H), 3,16-3,13 (m, 1H), and 2.83 (t, J=5,2 Hz, 3H), 2,73-2,61 (m, 2H), 2,30-of 2.23 (m, 1H), 2,18-to 2.06 (m, 2H), 1,79 by 1.68 (m, 3H), 1.56 to 1,42 (m, 5H), 1,37 is 1.34 (m, 3H). MC (ESI+) m/z 412 (M+H).10,5

611H NMR (500 MHz, DMSO-d6) δ of 10.25-there is a 10.03 (m, 0,5H), 9,52-of 9.09 (m, 1H), of 9.30-of 9.09 (m, 0,5H), 8,66-of 8.47 (m, 1H), 7,79-the 7.65 (m, 1H), 7,65-7,46 (m, 1H), 7,15-7,03 (m, 1H), br4.61-to 4.41 (m, 1H), to 4.41-4.25 in (m, 0,5H), 3,84-3,61 (m, 2H), 3,61-to 3.52 (m, 1H), 3.25 to 3,03 (m, 0,75H), 2,94-2,78 (m, 2,75H), 2,78 is 2.55 (m, 2H), 2,35-of 1.94 (m, 3H), 1,90-of 1.62 (m, 5H), 1,62 to 1.37 (m, 3H), 1,37-to 1.21 (m, 0,5H), 1,19 is 0.99 (m, 3H), 0,99-of 0.82 (m, 0,5H); MC (ESI+) m/z 387 (M+H).to 19.9
621H NMR (500 MHz, DMSO-d6) δ 10,43 (users, 0,35H), 9,65 (users, 0,65H), 9,05-9,04 (m, 0,35H), cent to 8.85-8,83 (m, 0,65H), 7,81 (apt c, 1H), 7,71-to 7.64 (m, 1H), 4,58-4,50 (m, 0,7H), 4,35-4,32 (m, 0,3H), 4,03-4,00 (m, 1H), 3.95 to of 3.80 (m, 3H), 3.72 points-3,44 (m, 5H), 2,83-2,82 (m, 3H), 2.71 to figure 2.54 (m, 2H), 2,24-2,17 (m, 1H), 2.13 and is 2.01 (m, 2H), 1.93 and-of 1.74 (m, 5H), 1,58-of 1.44 (m, 2H), 0,94 is 0.86 (m, 3H); MC (ESI+) m/z 447 (M+H).6,3
631H NMR (500 MHz, DMSO-d6) δ 9,58-to 8.62 (m, 1H), 7,94-to 7.77 (m, 1H), to 7.77-7,58 (m, 1H), 4,81-4,58 (m, 0,3H), 4,56-4,06 (m, 2H), 4,06-a 3.83 (m, 0,8H), 3,83-3,59 (m, 1,5H), 3,55-3,39 (m, 2H), 2,92-and 2.79 (m, 4,5H), 2,79-of 2.56 (m, 3,5H), 2,40-of 1.93 (m, 7,3H), 1,86-of 1.65 (m, 2,8H), 1,61-1,17 (m, 5,5H); MC (ESI+) m/z 446 (M+H).16,1
641H NMR (500 MHz, DMSO-d6) δ 10,32-10,24 (m, 1H), to 10.09-9,89 (m, 0,25H), 9,38-9,20 (m, 0,75H), 9,20-9,10 (m, 0,25H), 9,10-8,91 (m, 0,75H), 8,09-to 7.95 (m, 0,75H), 7,87-to 7.59 (m, 1,25H), 7,72-of 7.60 (m, 1H), 7,31-was 7.08 (m, 3H), 7,08-6,86 (m, 1H), 4,71 is 4.45 (m, 0,75H), to 4.41-4,22 (m, 0,25H), 3,97-with 3.79 (m, 3H), 3,76-3,59 (m, 1,5H), 2,92-and 2.79 (m, 3H), 2,74 of $ 2.53 (m, 2H), 2,20-of 1.78 (m, 3H), 1,78-1,19 (m, 5H); MC (ESI+) m/z 421 (M+H).16,2

651H NMR (500 MHz, DMSO-d6) δ 10,59 (users, 0,4H), 9,89 (users, 0,6H), 9,18-9,17 (m, 0,4H), 8,98-8,98 (m, 0,6H), to 7.77-7,74 (m, 1H), 7,62-to 7.61 (m, 1H), 7,16 for 7.12 (m, 1H), 4,60-4,20 (m, 2H), 3,95 (m, 1H), 3,74-and 3.72 (m, 1H), 3,56-of 3.46 (m, 4H), 2,83-of 2.81 (m, 3H), 2,68-2,62 (m, 2H), 2,27 was 2.25 (m, 2H), 2,12-2,10 (m, 2H), 1,80-of 1.78 (m, 3H), 1,53 to 1.47 (m, 3H), 1,36 is 1.34 (m, 3H); MC (ESI+) m/z 399 (M+H).89
664,1
671H NMR (500 MHz, DMSO-d6) δ 10,67 (users, 0,3H), 9,73 (users, 0,7H), 9,10-of 9.09 (m, 0,3H), 8,82-8,81 (m, 0,7H), to 7.77-7,72 (m, 1H), to 7.61-to 7.59 (m, 1H), 7,15-7,11 (m, 1H), 4.63 to-4,60 (m, 0,7H), 4,37 is 4.35 (m, 0,3H), 4,27-4,20 (m, 1H), 3,94-3,90 (m, 2H), 3,83-of 3.78 (m, 1H), 3,71-to 3.64 (m, 2H), 3,60-to 3.49 (m, 3H), 2,87-2,77 (m, 3H), 2,74-of 2.54 (m, 2H), 2,36-2,17 (m, 1H), 2,13-2,00 (m, 2H), 1,86 to 1.37 (m, 8H), 1,02-to 0.89 (m, 6H); MC (ESI+) m/z 441 (M+H).a 3.9
681H NMR (500 MHz, DMSO-d6) δ 10,76 (users, 0,35H), 9,87 (users, 0,65H), 9,13-9,12 (m, 0,35H), 8,98-8,97 (m, 0,65H), 7,79-of 7.70 (m, 1H), 7,63-to 7.59 (m, 1H), 7,16-to 7.09 (m, 1H), br4.61-4,59 (m, 0,65H), to 4.38-to 4.33 (m, 0,35H), 4,25-to 4.14 (m, 1H), 4,13-was 4.02 (m, 1H), 3.95 to of 3.77 (m, 2H), 3.72 points-to 3.36 (m, 5H), 2,87-2,78 (m, 3H), 2.77-to of 2.58 (m, 2H), 2,41-of 1.95 (m, 3H), 1.77 in is 1.70 (m, 3H), 1.56 to about 1.36 (m, 2H), 1,09-a 1.08 (m, 9H); MC (ESI+) m/z 441 (M+H).2,0

69 1H NMR (500 MHz, DMSO-d6) δ 10,79 (users, 0,2N), 10,20-9,95 (m, 2H), 9,05-8,90 (m, 0,8H), 7,84-to 7.77 (m, 1H):7,72-the 7.65 (m, 1H), 7,15-7,05 (m, 1H), 6,80 (users, 1H), 4,60 is 4.45 (m, 0,5H), to 4.41-4,32 (m, 2H), 3,60 is 3.40 (m, 4,5H), 3,39-3,17 (m, 2H), 2,82 (c, 3H), 2,73-2,62 (m, 2H), 2,28-2,22 (m, 0,6H), 2,20-2,00 (m, 2H), 1,80-of 1.62 (m, 2,4H), 1.60-to of 1.20 (m, 8H); MC (ESI+) m/z 412 (M+H).32,7
701H NMR (500 MHz, DMSO-d6) δ 10,56 (c, 0,4H), 9,79 (c, 0,6H), 9,25 (d, J=5.5 Hz, 0,4H), of 9.21 (d, J=5.5 Hz, 0,6H), 8,60 are 8.53 (m, 1H), 7,73-to 7.68 (m, 1H), 7,55 is 7.50 (m, 1H), 7,07 (apparent t, J=8.0 Hz, 1H), 4,54 ñ 4.50 (m, 1H), 3,60-3,52 (m, 3H), 2,90 is 2.80 (m, 3H), 2,75-to 2.65 (m, 2H), and 2.27 (c, 1H), 2,22-of 1.97 (m, 4H), 1,75-to 1.60 (m, 5H), 1,57 of 1.46 (m, 4H), 1,37-of 1.26 (m, 4H); MC (ESI+) m/z 397 (M+H).19,2
711H NMR (500 MHz, DMSO-d6) the 10.40 δ (c, 0,3H), 9,52 (c, 0,7H), 8,96 (c, 0,4H), 8,61 (c, 0,6H), 7,78 (d, J=7.5 Hz, 1H), 7,69 (users, 2H), 7,63 (d, J=7.5 Hz, 1H), 7,44 (users, 3H), of 7.36 (c, 1H), 7.18 in-to 7.15 (m, 1H), 4,71-to 4.52 (m, 1H), 4,50-to 4.38 (m, 1H), 4,34-4,27 (m, 2H), 3,84-3,70 (m, 1H), 3,65 (d, J=9.0 Hz, 2H), 3,54 (users, 1H), 3,32-3,30 (m, 1H), 3.25 to the 3.11 (m, 1H), 2,84-2,82 (m, 3H), 2,75-2,62 (m, 1H), 2,60-2,52 (m, 2H), 2,30 with 2.14 (m, 1H), 2,11-to 2.06 (m, 3H), 1.91 a and 1.80 (m, 1H), 1,72-of 1.62 (m, 3H), 1,53-of 1.35 (m, 3H), 1.30 and of 1.23 (m, 1H), 0,95-to 0.89 (m, 6H); MC (ESI+) m/z 530 (M+H).48,6
721 H NMR (500 MHz, DMSO-d6) δ 9,59-to $ 7.91 (osirm, 2H), 7,58-7,49 (m, 1H), 7,26 (d, J=7,6 Hz, 1H), 6,95 (t, J=7.8 Hz, 1H), 5,76-to 4.52 (osirm, 1H), 3,62 (users, 2H), 3,32 (users, 1H), 2,82 (users, 3H), 2.57 m (users, 2H), 2,09 (users, 3H), 1,72 (users, 2H), 1.55V (users, 3H); MS (ESI+) m/z 332 (M+H).30,8

731H NMR (500 MHz, DMSO-d6) δ 10,69 (users, 0,2H), 10,00-9,70 (m, 2H), 9,10-8,90 (m, 0,8H), 7,84-7,76 (m, 1H), 7,70-to 7.68 (m, 1H), 7,20-7,14 (m, 1H), 5,20 (users, 1H) 4,60 is 4.45 (m, 0,6H), to 4.41-4,32 (m, 2,4H), 3,66-of 3.42 (m, 4H), 3,32-3,20 (m, 2H), 2,85 (c, 3H), 2,80-2,60 (m, 2H), 2,30-2,00 (m, 3H),1,80-of 1.62 (m, 2H), 1.60-to of 1.20 (m, 9H); MC (ESI+) m/z 412 (M+H).2,2
741H NMR (500 MHz, DMSO-d6) δ 10,35 (c, 0,4H) 9,85-9,78 (m, 1H), being 9.61-9,56 (m, 1,6H), 9,05 (d, J=5.8 Hz, 0,4H), cent to 8.85 (d, J=7,1 Hz, 0,6H), 7,80-to 7.77 (m, 1H), to 7.67-to 7.64 (m, 1H), 7,21-to 7.15 (m, 1H), 4.63 to-4,56 (m, 0,7H), 4,40-4,56 (m, 1H), 4,23 (t, J=9,2 Hz, 1,3H), of 3.73-to 3.64 (m, 3H), 3,56 (users, 1H),3,52-to 3.35 (m, N), 3,27 is 3.23 (m, 1H), 2,84 is 2.80 (m, 3H), 2,73-2,63 (m, 1H), 2,62-of 2.58 (m, 2H), 2,28-2,22 (m, 1H), 1,87-1,72 (m, 4H), 1,61-is 1.51 (m, 3H), of 1.45 (t, J=12.0 Hz, 2H), 0,95-of 0.93 (m, 6H); MC (ESI+) m/z 440 (M+H).72,9
751H NMR (500 MHz, CD3OD) δ 7,89-to 7.84 (m, 1H), EUR 7.57-of 7.55 (m, 1H), 7.23 percent-7,20 (m, 1H, 4,60 is 4.45 (m, 1H), 4,19-to 4.15 (m, 2H), 3,97-3,93 (m, 2H), 3,76-the 3.65 (m, 2H), 3,64-of 3.60 (m, 2H), 3,02 (c, 0,75H), 2,98 (c, 2,25H), 2,90-2,70 (m, 2H), 2,30-2,10 (m, 3H), 1,97 is 1.86 (m, 2,5H), 1,73 is 1.60 (m, 2,5H), 1,49 of 1.46 (m, 6N); MC (ESI+) m/z 413 (M+H).0,59

761H NMR (500 MHz, DMSO-d6) δ 10,50 (c, 0,3H), 9,75 (c, 0,7H), 9,76 (d, J=5.0 Hz, 1H), at 9.53-9,43 (m, 1H), 9,04 (d, J=5.5 Hz, 0,4H), 8,91 (d, J=5.5 Hz, 0,6H), 7,80 to 7.75 (m, 1H), of 7.64 to 7.62 (m, 1H), 7.18 in-7,14 (m, 1H), 4,57-to 4.52 (m, 0,6H), 4,40-4,22 (m, 1,4H), 4,08 (DD, J=10,0, 3.0 Hz, 0,7H), Android 4.04 (DD, J=10,0, 3.0 Hz, 0,3H), 3,81-3,61 (m, 5H), 3,66-of 3.48 (m, 3H), 3,34-up 3.22 (m, 2H), 3,20-is 3.08 (m, 1H), 2,87-2,82 (m, 3H), 2,75-2,62 (m, 3H), 2,25-of 2.21 (m, 1H), 2,18 with 2.14 (m, 1H), 1,81-1,72 (m, 2H), 1,55-of 1.45 (m, 2H), 1,07-of 1.03 (m, 3H), 0,89 is 0.86 (m, 3H); MS (ESI+) m/z 426 (M+H).9,8
771H NMR (500 MHz, DMSO-d6) δ 10,56 (c, 0,4H) 9,82 (d, J=7.5 Hz, 1H), 9,68 (m, 0,7H), 9,42 (d, J=7.5 Hz, 1H), 9,00 (d, J=6.0 Hz, 0,3H), up 8.75 (d, J=7,0 Hz, 0,6H), 7,79-to 7.77 (m, 1H), 7,65-7,63 (m, 1H), 7,17 (t, J=8.0 Hz, 1H), with 4.64-br4.61 (m, 1H), 4,55 (c, 0,5H), 4,35 (c, 0,5H), 4,24-4,19 (m, 1H), 3,70-of 3.53 (m, 3H), 3,40 of 3.28 (m, 2H), 3,18 was 3.05 (m, 1H), 2,80 (c, 3H), 2,75-to 2.65 (m, 1H), 2,62 is 2.55 (m, 2H), 2,35-of 2.20 (m, 1H), 2,15-to 1.98 (m, 2H), 1,97-of 1.78 (m, 2H), 1,75-to 1.63 (m, 2H), 1.60-to 1,50 (m, 2H), and 1.56 (t, J=13.5 Hz, 2H), 1.00 and is 0.86 (m, 6H); MS (ESI+) m/z 440 (M+H).6,4
781H NMR (500 MHz, DMSO-d6) δ 10.30 a.m (c, 0,3H), 9,70-9,52 (m, 1H), 9,44 (users, 0,7H), 9,35 (c, 1H), 9,03 (d, J=6.0 Hz, 0,3H), 8,87 (d, J=6.0 Hz, 0,7H), 7,80-to 7.77 (m, 1H), 7,70-to 7.64 (m, 1H), 7,21-7,17 (m, 1H), with 4.64-4,56 (m, 0,7H), 4,42-4,37 (m, 1H), 4.26 deaths (d, J=12,5 Hz, 1,3H), 3.72 points-3,62 (m, 2H), 3,51 (users, 1H), 3,48-to 3.41 (m, 2H), 3,40-of 3.25 (m, 2H), 2,88 (c, 3H), 2,72-of 2.64 (m, 1H), 2,62-of 2.54 (m, 1H), 2,28-to 2.18 (m, 1H), 2,10-of 1.97 (m, 3H), 1,82-of 1.65 (m, 2H), 1,58-1,49 (m, 1H), 1,42 (t, J=15,0 Hz, 2H), 1,21-of 0.95 (m, 6N); MS (ESI+) m/z 426 (M+H).25,8

791H NMR (500 MHz, DMSO-d6) the 10.40 δ (c, 0,4H), 9,60 (c, 0,6H), remaining 9.08 (d, J=5.5 Hz, 0,4H), 8,86 (d, J=5.5 Hz, 0,6H), 7,85 for 7.78 (m, 1H), 7,75-7,66 (m, 3H), 7,26-7,20 (m, 1H), 5.25 to further 5.15 (m, 2H), 4,62-4,50 (m, 0,7H), 4,40-4,30 (m, 2,3H), 4,25-to 4.15 (m, 2H), 3.72 points-to 3.64 (m, 1,5H), 3,60-of 3.48 (m, 1H), 2,85 (c, 3H), 2,80-2,62 (m, 2,5H), 2,32-of 2.24 (m, 1H), 2,15-2,05 (m, 2H), 1,88 and 1.80 (m, 2,7H), 1,64-and 1.54 (m, 2,3H); MS (ESI+) m/z 421 (M+H).29,3
801H NMR (500 MHz, DMSO-d6) δ is 10.68-9,74 (osirm, 1H), 9,02-8,86 (osirm, 1H), 7,82-7,80 (m, 1H), 7,69-to 7.61 (m, 1H), 4,59 (users, 1H), 4,18 (d, J=12,4 Hz, 2H), 4,07 (users, 1H), 3,95 (d, J=9,3 Hz, 1H), 3.72 points-3,55 (m, 5H), 2,82 (d, J=4.3 Hz, 3H), 2,73-2,59 (m, 2H), 2,29-of 2.23 (m, 1H), 2,15-2,05 (m, 2H), 1,80-of 1.65 (m, 3H), 1,55-of 1.53 (m, 1H), 1,47-of 1.40 (m, 1H), 1,31-of 1.18 (m, 1H), 1,10-of 1.07 (m, 8H); MS (ESI+) m/z 475 (M+H).29,4
811H NMR (500 MHz, CD3OD) δ 7,86-to 7.84 (m, 1H), EUR 7.57-7,56 (m, 1H), 7,21 (apparent t, J=8.0 Hz, 1H), of 4.44 is 4.35 (m, 1H), 4,19-4,16 (m, 2H), 3.96 points-3,90 (m, 4H), 3,64-of 3.60 (m, 2H), 2,69-2,61 (m, 2H), 2,17-to 2.06 (m, 1H), 1,96-1,90 (m, 2H), 1,79-1,67 (m, 5H), for 1.49 (d, J=6.5 Hz, 6H); MS (ESI+) m/z 399 (M+H).16,8
821H NMR (500 MHz, CD3OD) δ 7,88-to 7.84 (m, 1H), 7,58-7,56 (m, 1H), 7.23 percent-7,19 (m, 1H), 4,57-4,51 (m, 0,7H), 4,47-4,43 (m, 0,3H), or 4.31-the 4.29 (m, 4H), 3,74-to 3.67 (m, 2H), 3,36-of 3.32 (m, 4H), 3.00 and are 2.98 (m, 3H), 2,88 is 2.80 (m, 0,6H), 2,77-2,70 (m, 1,4H), 2,43 with 2.14 (m, 3H), 2,03-of 1.93 (m, 2,5H), 1.70 to of 1.62 (m, 2,5H); (ESI+) m/z 433 (M+H).132

831H NMR (500 MHz, DMSO-d6) δ accounted for 10.39 (users, 1H), 9,52 (d, J=6,6 Hz, 1H), 7,73-7,71 (m, 1H), to 7.61-of 7.60 (m, 1H), 7,11 (t, J=7.9 Hz, 1H), 4,37 (users, 1H), 3,78-3,70 (m, 1H), 3,65-of 3.60 (m, 2H), 3,29 (t, J=8,1 Hz, 2H), 3,23 (t, J=8,1 Hz, 2H), 3,20 (c, 3H), 3,12-of 3.07 (m, 1H), 2,25-of 2.23 (m, 1H), 2,18-to 2.06 (m, 1H), 1,97-1,90 (m, 3H), of 1.23 (t, J=7,1 Hz, 3H); MS (ESI+) m/z 329 (M+H).6,8
841H NMR (500 MHz, DMSO-d6) a 10.74 δ (c, 0,4H) to 9.93-9,87 (m, 1,6H), 9,59-at 9.53 (m, 1H), 9,06 (d, J=5.5 Hz, 0,4H), 8,88 (who, J=5.5 Hz, 0,6H), 7,76 (t, J=8.0 Hz, 1H), to 7.64 (d, J=7.5 Hz, 1H), 4,62 was 4.42 (m, 4H), to 4.41-4.25 in (m, 2H), 4,23 (t, J=13,0 Hz, 1H), 3,70-of 3.48 (m, 3H), 3,42-up 3.22 (m, 3H), 3,20 was 3.05 (m, 1H), 2,83-of 2.81 (m, 3H), 2,72-2,61 (m, 2H), 2,32-of 2.27 (m, 1H), 2,20-a 2.01 (m, 3H), 2.00 in to 1.86 (m, 1H), 1.85 to of 1.65 (m, 3H), 1.60-to of 1.40 (m, 2H), 0,93-to 0.88 (m, 3H); MS (ESI+) m/z 412 (M+H).11,3
851H NMR (500 MHz, DMSO-d6) δ 10,44 (users, 1H), 9,52 (d, J=6,6 Hz, 1H), 7,72-7,71 (m, 1H), to 7.61-to 7.59 (m, 1H), 7,11 (t, J=7.9 Hz, 1H), to 4.52-4,43 (m, 1H), 4,40-4,32 (m, 1H), of 3.77-and 3.72 (m, 1H), 3,29 (t, J=8.0 Hz, 2H), 3,23 (t, J=7.9 Hz, 2H,), is 3.08 (c, 3H), 2,25-of 2.23 (m, 1H), 2,16-of 2.08 (m, 1H), 1,97-of 1.94 (m, 3H), 1,28-of 1.26 (m, 6H), 0,99 (c, 1H); MS (ESI+) m/z 343 (M+H).28,9
861H NMR (500 MHz, CD3OD) δ 7,88-to 7.84 (m, 1H), 7,58-7,56 (m, 1H), 7,21-to 7.18 (m, 1H), 4,73-to 4.46 (m, 1H), to 4.38 (c, 2H), 4,35 (c, 1H), 4,01-of 3.97 (m, 2H), 3,74-3,71 (m, 1,4H), 3,69-the 3.65 (m, 0,6H), 3,55-of 3.53 (m, 2H), 3,01 (c, 1H), 2,99 (c, 2H), 2,89-of 2.81 (m, 0,6H), 2,78-of 2.72 (m, 1,4H), 2,49-of 2.56 (m, 0,3H), 2,30 with 2.14 (m, 2,7H), 2.05 is is 1.96 (m, 2,5H), 1,75-of 1.64 (m, 2,5H); MS (ESI+) m/z 398 (M+H).66,2

871H NMR (500 MHz, CD3OD) δ 7,89-7,83 (m, 1H), EUR 7.57-7,53 (m, 1H), 7.23 percent-7,16 (m, 1H), with 4.64 figure-4.49 (m, 1H), 4.09 to a 4.03 (m, 2H), 4,01-3,93 (m, 1H), 3,91-to 3.89 (m, 2H), of 3.77-to 3.73 (m,2H), 3,55-of 3.48 (m, 1H). to 3.02 (c, 0,6H), 2,97 (c, 2,4H), 2,90 of 2.68 (m, 2H), 2,30 by 1.68 (m, N), 1,57-of 1.52 (m, 4H), 1,01-of 0.94 (m, 3H); MS (ESI+) m/z 427 (M+H).1,0
881H NMR (500 MHz, CD3OD) δ 9,96 (users, 1H), 7,89 (DD, J=8,0, 0.9 Hz, 1H), 7,52 (DD, J=8,0, 0.9 Hz, 1H), 7,17 ( apparent t, J=8.0 Hz, 1H), of 4.44-4,30 (m, 1H), 4,24-4,19 (m, 3H), 4,12-of 4.05 (m, 1H), was 4.02-3,93 (m, 3H), of 3.60 (DD, J=11,6, a 5.4 Hz, 2H), 3,56-of 3.48 (m, 2H), 3,20-to 3.02 (m, 3H), 2,90-2,70 (m, 2H), 2,24-2,22 (m, 1H), 2,02 is 2.00 (m, 1H), 1,44 (DD, J=6,5 Hz, 6N); MS (ESI+) m/z 415 (M+H).to 19.9
891H NMR (500 MHz, DMSO-d6) δ 10,61-9,92 (osirm, 1H), 9,26-9,00 (osirm, 1H), 7,76-7,73 (m, 1H), 7,60-7,58 (m, 1H), 7,14-7,10 (m, 1H), to 4.52-to 4.33 (m, 1H), 3,92-3,86 (m, 2H), 3,61 (d, J=8.5 Hz, 1H), 3,57-to 3.49 (m, 4H), 3,30 (c, 3H), 2,84-of 2.81 (m, 3H), 2,72-of 2.64 (m, 2H), to 2.29 (d, J=6.3 Hz, 1H), 2,18-of 2.08 (m, 2H), 1,99-of 1.95 (m, 2H), 1,84 is 1.75 (m, 3H), 1,64-of 1.57 (m, 2H), 1,53 is 1.48 (m, 2H); MS (ESI+) m/z 413 (M+H).36,9
901H NMR (500 MHz, DMSO-d6) δ 10,0 (users, 1H), of 9.30 (d, J=6,4 Hz, 1H), to 7.77 (DD, J=8,0, 0.8 Hz, 1H), 7,68 (DD, J=8,0, 0.7 Hz, 1H), 7,21 (apparent t, J=8.0 Hz, 1H), to 4.41 is 4.35 (m, 1H), 4,11-4,08 (m, 2H), 3,90 (DD, J=11,6, 3.6 Hz, 2H), 3,80-3,74 (m, 1H), of 3.56 (DD, 3=11,6, a 5.4 Hz, 2H), 3,30 is 3.23 (m, 4H), 3,18-of 3.12 (m, 1H), 2.21 are 2,19 (m, 1H),2,12-2,05 (m, 1H), 1,97-of 1.88 (m, 3H), 1,38 (DD,J=6,5 Hz, 6H); MS (ESI+) m/z 385 (M+H).6,8

911H NMR (500 MHz, DMSO-d6) δ 10,52-9,84 (osirm, 1H), 9,24-8,99 (m, 1H), 7,76-7,73 (m, 1H), 7,60-7,58 (m, 1H), 7,14-7,11 (m, 1H), to 4.52-to 4.33 (m, 1H), 3,95 (c, 3H), 3,79 is 3.76 (m, 4H), 3,61 (d, J=8.5 Hz, 1H), 3,53-of 3.46 (m, 5H), and 2.83 (t, J=5,5 Hz, 2H), 2,73-2,63 (m, 2H), 2,28-of 2.26 (m, 1H), 2,15-of 2.08 (m, 1H)and 1.83-1.77 in (m, 6H), 1,54 to 1.47 (m, 2H); MS (ESI+) m/z 441 (M+H).14,5
921H NMR (500 MHz, DMSO-d6) δ 10,37-RS 9.69 (osirm, 1H), 9,24-8,99 (m, 1H), 7,79-7,76 (m, 1H), 7,66-to 7.64 (m, 1H), 7.18 in-7,14 (m, 1H), 4.53-in-4,34 (m, 1H), 4,05-4,01 (m, 4H), 3,62 (d, J=8.5 Hz, 1H), 3,49 (users, 1H), 3,32 (c, 3H), and 2.83 (t, J=4.4 Hz, 3H), 2,72-of 2.58 (m, 6H), 2,36-2,22 (m, 1H), 2,17-of 2.08 (m, 2H), 1.85 to about 1.75 (m, 2H), 1,53-1,49 (m, 2H); MS (ESI+) m/z 397 (M+H).of 21.2
931H NMR (500 MHz, DMSO-d6) δ 10,33 (c, 1H), 9,50 (d, J=6,6 Hz, 1H), 8,09 (users, 2H), 7,69 (d, J=7.9 Hz, 1H), 7,54 (d, J=7.9 Hz, 1H), to 7.09 (t, J=7.9 Hz, 1H), 4,40-of 4.35 (m, 1H), 3,74 (t, J=11,4 Hz, 1H), 3,31-3,20 (m, 4H), 3,10-3,03 (m, 1H), 2,25-of 2.16 (m, 2H), 1,97-of 1.85 (m, 3H); MS (ESI+) m/z 287 (M+H).12,1
94 1H NMR (500 MHz, DMSO-d6) δ 9,20 (users, 0,5H), cent to 8.85 (users, 1H), 7,73 (d, J=1.9 Hz, 1H), 7,56 (d, J=7.9 Hz, 1H), 7,11 (d, J=7.9 Hz, 1H), 5,09-4,96 (m, 1H), 4.53-in-4,22 (m, 1H), 4,21-was 4.02 (m, 2H), was 4.02-3,81 (m, 3H), 3,81-3,39 (m, 5H), 3,26-3,14 (m, 1,5H), 3,13-2,87 (m, 1,5H), 2,48-2,22 (m, 3H), 2,22-0,75 (m, 8H); MS (ESI+) m/z 415 (M+H).27,5
951H NMR (500 MHz, DMSO-d6) δ 8,96 (users, 1H), 7,74 (DD, J=8,0, 0.8 Hz, 1H), 7,58 (DD, J=7,9, 0.8 Hz, 1H), 7,12 (t, J=8.0 Hz, 1H), to 4.38-4,32 (m, 1H), 4,07 (d, J=9.9 Hz, 2H), 3,38-3,20 (m, 7H), 3,13 (d, J=12,4 Hz, 1H), 2,99 (d, J=7.7 Hz, 2H), 2,98-to 2.85 (m, 1H), 2,60 (users, 3H), 2,15-2,02 (m, 3H), 1,58-of 1.45 (m, 3H), 1,35-1,20 (m, 2H), 1,13 (d, J=5.3 Hz, 3H); MS (ESI+) m/z 398 (M+H).52,4

961H NMR (500 MHz, DMSO-d6) δ 10,49 (c, 0,4H), for 9.64 (users, 1,6H), 9,15 (c, 1H), 9,00 (c, 0,3H), 8,93 (d, J=5.0 Hz, 0,7H), 7,83 to 7.75 (m, 1H), to 7.67-7,63 (m, 1H), 7.23 percent-7,14 (m, 1H), 4,67-of 4.57 (m, 1H), to 4.41-4.25 in (m, 2H), 3,68-3,63 (m, 2H), 3,56 (c, 1H), 3,48-of 3.32 (m, 2H), 3,26 (users, 2H), 2,83 (c, 3H), 2,75-2,61 (m, 2H), 2,27-to 2.18 (m, 1H), 2,15 for 2.01 (m, 2H), 1,82-of 1.62 (m, 3H), 1,58-of 1.53 (m, 1H), 1,50-to 1.38 (m, 1H), 1,04 is 0.99 (m, 9H); MS (ESI+) m/z 440 (M+H).7,5
971H NMR (500 MHz, CD3OD) δ a 7.85-7,83 (m, 1H), 7,56 to 7.4 (m, 1H), 7,38-7,31 (m, 5H), 7,18 (apparent t, J=8.0 Hz, 1H), 4,76-4,63 (m, 3H), to 4.52-4,47 (m, 2H), 3,91 (DD, J=13,7, 3.5 Hz, 1H), 3,64-3,61 (m, 2H), 3,41-3,37 (m, 1H), 2,92 (c, 3H), 2,82-a 2.71 (m, 2H), 2.23 to-2,19 (m, 3H), 1,90-of 1.88 (m, 2H), 1,73 is 1.60 (m, 6H), of 1.13 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 516 (M+H).0,40
981H NMR (500 MHz, CD3OD) δ 7,87-7,83 (m, 1H), 7,56-rate of 7.54 (m, 1H), 7,20-7,16 (m, 1H), 4,79 was 4.76 (m, 1H), 4,54-to 4.41 (m, 1H), 4,30-of 4.25 (m, 1H), 3,78-the 3.65 (m, 3H), 3,62-3,55 (m, 1H), 3,48-of 3.42 (m, 1H), 3,01-2,99 (m, 3H), 2,90 is 2.80 (m, 0,7H), 2,80-of 2.72 (m, 1,3H), 2,50-is 2.37 (m, 0,3H), 2,30 with 2.14 (m, 2,7H), 2,04-of 1.94 (m, 2,5H), 1,75-to 1.61 (m, 5,5H); MS (ESI+) m/z 412 (M+H).14,6
991H NMR (500 MHz, DMSO-d6) δ 9,70 (users, 2H), was 9.33 (d, J=6,5 Hz, 1H), 7,76 (d, J=8.0 Hz, 1H), to 7.67 (d, J=8.0 Hz, 1H), 7,18 (apparent t, J=8.0 Hz, 1H), 4,40-4,30 (m, 3H), 3,76-to 3.73 (m, 1H), 3,42-3,00 (m, 10H), 2,20 (users, 1H), 2,18-2,05 (m, 3H), to 1.48 (d, J=6.5 Hz, 3H), of 1.44 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 384 (M+H).13,2

1001H NMR (500 MHz, DMSO-d6) δ accounted for 10.39-9,56 (osirm, 1H), 8,87-8,65 (m, 1H), 7,81 for 7.78 (m, 1H), 7,71-7,66 (m, 1H), 7.24 to 7,19 (m, 1H), 4.72 in-4,37 (m, 1H), 4,00-3,98 (m, 2H), 3,68-to 3.58 (m, 2H), 3,28-of 3.25 (m, 4H), 3,17 (c, 1H), 2,85-and 2.83 (m, 3H), 2,75-to 2.54 (m, 2H), 2,46-of 2.27 (m, 2), 2,23-2,10 (m, 3H), 2,07 (c, 1H), 2,03-of 1.94 (m, 1H), 1,91-of 1.84 (m, 2H), 1,72-of 1.62 (m, 4H), 1,59-of 1.53 (m, 1H), 1,45 (d, J=13,8 Hz, 2H); MS (ESI+) m/z 438 (M+H).11,4
1011H NMR (500 MHz, DMSO-d6) δ 10,89 (c, 1H), 8,95 (d, J=7,0 Hz, 1H), 7,76 (d, J=8.0 Hz, 1H), 7,63 (d, J=8.0 Hz, 1H), 7,18 (t, J=8.0 Hz, 1H), 4,37-to 4.33 (m, 1H), 4,15-4,08 (m, 2H), 3,90 (users, 2H), 3,86 (DD, J=11,5, 0.5 Hz, 2H), 3,57-3,52 (m, 2H), 3.33 and (users, 3H), 2,66 (d, J=5.0 Hz, 1H), 2,28-of 2.21 (m, 2H), 2,20-2,10 (m, 4H), 2,04 of 1.99 (m, 2H), 1.41 to to 1.39 (m, 6H); MS (ESI+) m/z 399 (M+H).2,6
1021H NMR (500 MHz, DMSO-d6) δ 8,94-8,89 (osirm, 1H), 7,78 (DD, J=7,9, 0.6 Hz, 1H), 7,66 (DD, J=7,9, 0.7 Hz, 1H), 7,20 (t, J=8.0 Hz, 1H), to 4.52 (users, 1H), a 3.87 (t, J=5.4 Hz, 2H), to 3.58-to 3.52 (m, 2H), 3,31 (users, 3H), up 3.22 (t, J=5.4 Hz, 2H), 3,11 (users, 2H), 2,78 (users, 3H), 2,67-2,61 (m, 2H), 2,12 is 2.01 (m, 3H), 1,65 (c, 6H), 1,61-of 1.52 (m, 2H), 1,50-of 1.40 (m, 2H); MS (ESI+) m/z 412 (M+H).15,8
1031H NMR (500 MHz, DMSO-d6) δ 10,22 (c, 1H), 9,38 (d, J=6,7 Hz, 1H), 8,27, (users, 2H), 7,76 (d, J=2.0 Hz, 1H), 7.62mm (d, 7 = 2.0 Hz, 1H), 4,37-to 4.33 (m, 1H), of 3.73 (t, J=11,4 Hz, 1H), 3,30-3,20 (m, 4H), 3,10-of 3.06 (m, 1H), 2,22-2,12 (m, 2H), 1,97-of 1.85 (m, 3H); MS (ESI+) m/z 321 (M+H).5,1

1041H NMR (500 MHz, DMSO-d6) δ 10,51 (c, 1H), to 9.57 (d, J=7,0 Hz, 1H), 8,71-8,69 (m, 1H), 7,69 (DD, J=7,0, 1.0 Hz, 1H); 7,56 (DD, J=7,0, 0.7 Hz, 1H), 7,10 (t, J=8.0 Hz, 1H), 4.75 in (users, 2H), 4,37 (c, 1H), 3,74 (t, J=6.0 Hz, 1H), 3,42-3,38 (m, 2H), 3.33 and is 3.23 (m, 2H), 3,21-3,17 (m, 2H), 3,09 (d, J=12.0 Hz, 1H), 2,24-2,22 (m, 1H), 3,18-is 3.08 (m, 1H), 1,97-of 1.94 (m, 3H), 1,24 (t, J=7.5 Hz, 3H); MS (ESI+) m/z 315 (M+H).13,5
1051H NMR (500 MHz, DMSO-d6) δ 10.30 a.m. (c, 04H), 9,65 (c, 0,6H), 9,35 (d, J=6.0 Hz, 0,4H), 9,17 (d, J=6.0 Hz, 0,6H), 8,60-8,58 (m, 1H), 7,73-to 7.68 (m, 1H), 7,55 (d, J=7.5 Hz, 1H), 7,10-7,05 (m, 1H), 4,60-4,48 (m, 1,5H), 4,40-4,30 (m, 0,5H), 3,70-of 3.60 (m, 1H), 3,59-to 3.52 (m, 1H), 3.45 points-of 3.33 (m, 2H), 2,83 (c, 3H), 2,80-2,60 (m, 2H), 2,30-of 2.20 (m, 1H), 2,18-2,05 (m, 2H), 1.60-to of 1.40 (m, 3H), 1,28-of 1.15 (m, 3H); MS (ESI+) m/z 343 (M+H).3,3
1061H NMR (500 MHz, DMSO-d6) δ 9,67 (users, 0,35H), 9,18 (users, 0,65H), 9,07 (d, J=5.3 Hz, 0,35H), 8,84 (d, J=6,7 Hz, 0,N), 7,83 (d, J=2.0 Hz, 1H), 7,70-to 7.67 (m, 1H), 4,49-of 4.25 (m, 2H), 3,98-3,95 (m, 1H), 3,85-to 3.52 (m, 7H), 2,86-2,83 (m, 3H), 2,72-2,52 (m, 2H), 2,14-2,05 (m, 3H), 1,82-of 1.78 (m, 3H), 1,53 to 1.47 (m, 2H), of 1.36 and 1.33 (m, 3H); MS (ESI+) m/z 433 (M+H).12,6
107 1H NMR (500 MHz, DMSO-d6) δ 10,38 (c, 0,3H), 9,86 (c, 2H), 9,58 (c, 0,7H), 8,83 (d, J=5.5 Hz, 0,4H), up 8.75 (d, J=5.5 Hz, 0,6H); 7,82-to 7.77 (m, 1H), 7,16 for 7.12 (m, 1H),4,60-to 4.52 (m, 0,7H), 4,45-and 4.40 (m, 2H), 4,36 (users, 0,3H), 3,66-3,62 (m, 1H), 3,55 (users, 1H), 3,52-of 3.43 (m, 2H), 3,28-up 3.22 (m, 3H), 2,86 (c, 3H), was 2.76-2.71 to (m, 1H), 2,70-of 2.58 (m, 1H), 2,28 is 2.00 (m, 3H), 1,82-of 1.65 (m, 3H), 1.60-to of 1.39 (m, 8H); MS (ESI+) m/z 430 (M+H).14,2

1081H NMR (500 MHz, DMSO-d6) δ is 10.68-9,74 (osirm, 1H), 9,02-8,86 (osirm, 1H), 7,82-7,80 (m, 1H), 7,69-to 7.67 (m, 1H), 4,59 (users, 1H), 4,18 (d, J=12,4 Hz, 2H), 4,07 (users, 1H), 3,95 (d, J=9,3 Hz, 1H), 3.72 points-3,55 (m, 5H), 2,82 (d, J=4.3 Hz, 3H), 2,73-2,59 (m, 2H), 2,29-of 2.23 (m, 1H), 2,15-2,05 (m, 2H), 1,80-of 1.65 (m, 3H), 1,55-of 1.53 (m, 1H);1,47-of 1.40 (m, 1H), 1,31-of 1.18 (m, 1H), 1,10-of 1.07 (m, 8H); MS (ESI+) m/z 349 (M+H).14.4V
1091H NMR (500 MHz, DMSO-d6) δ 10,33 (users, 1H), 9,50-9,39 (m, 1H), was 9.33 (d, J=6,7, 1H), of 7.75 (DD, J=8,2, 0.8 Hz, 1H), 7,65 (DD, J=8,0, 0.8 Hz, 1H), 7,19 (t, J=8.0 Hz, 1H), 4,47-4,07 (m, 3H), and 3.72 (t, J=to 11.0 Hz, 1H), or 3.28 (t, J=8,4 Hz, 2H,), 3,24 (t, J=8,4 Hz, 2H), 3,19-3,10 (m, 1H), 2,24-2,22 (m, 1H), 2,17-to 2.06 (m, 1H), 1,97-of 1.93 (m, 2H), 1,92-to 1.82 (m, 1H); MS (ESI+) m/z 369 (M+H).47,9
1101H NMR(500 MHz, DMSO-d6) δ 9,90 (osirm, 0,4H), 9,16 (osirm, 0,6N), 7,78 (DD, J=7,9, 0.6 Hz, 1H), 7,66 (d, J=7,9, 1H), 7,16 (t, J=8.0 Hz, 1H), 4,39 (osirm, 3H), with 3.89 (m, 2H), 3,68-to 3.34 (m, 4H), of 2.86 (m, 3H), 2,85 is 2.51 (m, 3H), 2,12-2,08 (m, 3H), 1,48 is 1.23 (m, 8H); MS (ESI+) m/z 454 (M+H).2,2
1111H NMR (500 MHz, DMSO-d6) δ 10.30 a.m. (users, 0,25H), 9,58 (users, 0,75H), 9,26 (d, J=5.8 Hz, 0,25H), 8,91 (d, J=5.8 Hz, 0,75H), 8,28 (users, 2H), of 7.75 (d, J=2.0 Hz, 1H), 7,63 (d, J=2.0 Hz, 1H), with 4.64-4,59 (m, 0,75H), 4,35-of 4.25 (m, 0,25H), to 3.64 (d, J=9,2 Hz, 1,2H), 3,60-3,55 (m, 0,25H), 2,85 is 2.80 (m, 3H), 2,72-of 2.54 (m, 2H), 2,27 is 2.10 (m, 3H), 2,85-to 2.65 (m, 3H), 1.60-to of 1.42 (m, 2H); MS (ESI+) m/z 349 (M+H).2,0

1121H NMR (500 MHz, DMSO-d6) δ 10,00 (c, 1H), of 9.30 (d, J=6,6 Hz, 1H), 8,32 (c, 2H), 7,71-to 7.68 (m, 1H),? 7.04 baby mortality (t, J=8.0 Hz, IH), 4,40-to 4.28 (m, 1H), 3,80-3,70 (m, 1H), 3,35-3,26 (m, 2H), 3.25 to 3,20 (m, 2H), 3,10-to 3.02 (m, 1H), 2,28-2,22 (m, 1H), 2,18 is 2.10 (m, 1H), 1,98-of 1.92 (m, 3H); MS (ESI+) m/z 305 (M+H).33,3
1131H NMR (500 MHz, DMSO-d6) δ 10,33 (users, 1H), being 9.61 (d, J=6,8 Hz, 1H), 8,55-charged 8.52 (m, 1H), of 7.70 (DD, J=8,1, 0.9 Hz, 1H), 7,65 (DD, J=8,1, 1.0 Hz, 1H), 7,10 (t, J=8.0 Hz, 1H), 4,39-4,37 (m, 1H, in), 3.75 (t, J=11,4 Hz, 1H), and 3.31 (t, J=7,3 Hz, 2H), 3,24 (t, J=8,8 Hz, 2H), 3,5-3,11 (m, 1H), 2,97 (c, 3H), 2,24-of 2.23 (m, 1H), 2.21 are of 2.16 (m, 1H), 1,97-1,90 (m, 3H); MS (ESI+) m/z 301 (M+H).14,5
1141H NMR (500 MHz, CD3OD) δ to 9.15 (d, J=6.0 Hz, 0,3H), remaining 9.08 (d, J=6.0 HZ, 0,3H), 7,84-of 7.82 (m, 1H), 7,66 (d, J=1.5 Hz, 1H), 4,62-to 4.46 (m, 3H), 3,82-of 3.60 (m, 4H), 3,44-to 3.38 (m, 2H), 3,01-of 2.97 (m, 3H), 2,92-2,70 (m, 2H), 2,32-2,16 (m, 3H), 2.00 in to 1.82 (m, 3H), 1,72-of 1.64 (m, 1H), and 1.63 (d, J=7,0 Hz, 6H); MS (ESI+) m/z 446 (M+H).6,6
1151H NMR (500 MHz, DMSO-d6) of 9.55 δ (osirm, 1H), 7,73 (d, J=7.9 Hz, 1H), 7.62mm (d, J=7.9 Hz, 1H), 7,12 (t, J=7.9 Hz, 1H), 4,29 (osirm, 1H), 3,65 (m, 5H), of 3.12 (m, 4H), 2,99 (m, 1H), 2,15 (m, 2H), 1,87 (m, 3H), of 1.23 (t, J=3,6 Hz, 6H); MC (ECI+) m/z 343 (M+H).4,8
1161H NMR (500 MHz, DMSO-d6) δ 9,39 (d, J=7.2 Hz, 1H), 8,10 (users, 2H), 7,60 (DD, J=8,1, 2.7 Hz, 1H), 7,40 (DD, J=8,1, 2.7 Hz, 1H), 4,23-4,06 (m, 1H), 3,55 is-3.45 (m, 1H), 3,09-2,95 (m, 4H), and 2.79 (DD, J=a 13.5 and 4.5 Hz, 1H), 2,10-1,90 (m, 2H), 1,82-of 1.64 (m, 3H); MS (ESI+) m/z 305 (M+H).9,4

1171H NMR (500 MHz, DMSO-d6) δ 9,90-9,80 (who, 0,25H), 9,40-9,00 (m, 1,5H), 7,74 (d, J=8.0 Hz, 1H), 7,65 (d, J=8.0 Hz, 1H), 7,55-of 7.48 (m, 5H), 7,13 (d, J=8.0 Hz, 1H), 4.53-in-4,20 (m, 2H), 4,05-of 3.85 (m, 3H), 3,70-of 3.42 (m, 2H), 2,85 is 2.75 (m, 2,5H), 2,70-to 2.40 (m, 4,25H), 2,16-1,90 (m, 3H), 1,88-of 1.62 (m, 2,5H), 1.60-to of 1.40 (m, 5H), 1,28-1,20 (m, 4H); MS (ESI+) m/z 516 (M+H).2,3
1181H NMR (500 MHz, DMSO-d6) δ 10,08-9,90 (users, 1H), 9,78-9,60 (users, 2H), 9,10 (d, J=6,8 Hz, 1H), 7,80-to 7.77 (m, 1H), 7,17-7,13 (m, 1H), of 4.44-and 4.40 (m, 3H), 3,80 of 3.75 (m, 1H), 3,51-3,47 (m, 2H), 3,38-3,20 (m, 6H), 3,17-is 3.08 (m, 1H), 2,62-2,60 m, 0,5H), 2,38-of 2.36 (m, 0,5H), 2,19-to 2.18 (m, 1H), 2,10-2,00 (m, 1H), 1,98-of 1.85 (m, 3H), 1,52-1,49 (m, 6H); MS (ESI+) m/z 402 (M+H).26,8
1191H NMR (500 MHz, DMSO-d6) δ 11,20-11,00 (m, 1H), 10,32 (users, 0,3H), 9,50 (c, 0,7H), 9,00-of 8.90 (m, 1H), 7,86-7,80 (m, 1H), 7,72-to 7.68 (m, 1H), 7,26-to 7.18 (m, 1H), 4,86-4,74 (m, 1H), 4,68-4,58 (m, 0,7H), 4,40-4,32 (m, 0,3H), 4,28-4,20 (m, 1H), 3,70 of 3.56 (m, 4H), 3,20-3,00 (m, 3H), 2,86 (c, 3H), 2.40 a-1,92 (m, 3H), 1,80-1,72 (m, 6H), 1.70 to and 1.54 (m, 4H), 1,50-of 1.40 (m, 2H), 1.30 and of 1.18 (m, 1H), 0.70 to to 0.60 (m, 2H), from 0.50 to 0.30 (m, 2H); MS (ESI+) m/z 466 (M+H).6,6
1201H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ 9,95 (users, 0,35H), 9,34 (users, 0,65H), the remaining 9.08 (d, J=5.4 Hz, 0,35H), 9,01 (d, J=6,9 Hz, 0,65H), 7,80-7,66 (m, 2H), 7,19-7,14 (m, 1H), 4,55-4,34 (m, 3H), 3,97-3,93 (who, 1H), 3,67-to 3.58 (m, 2H), 3,39-to 3.36 (m, 1H), 3.00 and (c, 3H), 2,285 (d, J=4,6 Hz, 3H), 2,73-2,61 (m, 2H), 2,15-to 2.06 (m, 3H), 1,80 was 1.69 (m, 3H), 1,59 of 1.46 (m, 5H), 1.30 and of 1.23 (m, 3H); MS (ESI+) m/z 440 (M+H).1,9

1211H NMR (500 MHz, DMSO-d6) δ 10.30 a.m. (users, 0,25H), 9,58 (users, 0,75H), 9,26 (d, J=5.8 Hz, 0,25H), 8,91 (d, J=5.8 Hz, 0,75H), 8,28 (users, 2H), of 7.75 (d, J=2.0 Hz, 1H), 7,63 (d, J=2.0 Hz, 1H), with 4.64-4,59 (m, 0,75H), 4,35-of 4.25 (m, 0,25H), to 3.64 (d, J=9,2 Hz, 1,2H), 3,60-3,55 (m, 0,25H), 2,85 is 2.80 (m, 3H), 2,72-of 2.54 (m, 2H), 2,27 is 2.10 (m, 3H), 2,85-to 2.65 (m, 3H), 1.60-to of 1.42 (m, 2H); MS (ESI+) m/z 333 (M+H).9,0
1221H NMR (500 MHz, DMSO-d6) δ 11,20-11,00 (m, 1H), 10,36 (users, 0,25H), 9,51 (users, 0,75H), 7,82-7,76 (m, 1H), 7,70-to 7.68 (m, 1H), 7,25-7,20 (m, 1H), 4,76-4,70 (m, 1H), 4,62-4,58 (m, 0,7H), 4,40-4,30 (m, 0,3H), 4,20-4,10 (m, 1H), 3,70 is-3.45 (m, 2H), 3,10-to 3.02 (m, 1H), 2,95-to 2.85 (m, 5H), of 2,75 2,50 (m, 7H), 2,30-of 1.85 (m, 3H), 1,80-to 1.38 (m, 10H); MS (ESI+) m/z 426 (M+H).2,3
1231H NMR (500 MHz, CD3OD) δ a 7.85-a 7.92 (m, 1H), to 7.59 (d, J=7.8 Hz, 1H), 7,24 (t, J=8.0 Hz, 1H), 4,47-4,60 (m, 1H), 3,68-of 3.77 (m, 2H), 3,40-to 3.58 (m, 6H), 3,12 (c, 0,75H), 2,97 (c, 2,25), 2,72-of 2.86 (m, 2H), 2,08-is 2.37 (m, 3H), 1,60-2,00 (m, 12H); MS (ESI+) m/z 461 (M+H).57
1241H NMR (500 MHz, DMSO-d6) δ 10,22 (users, 1H), 9,39 (d, J=6,9 Hz, 1H), 7,76 (DD, J=7,9, and 0.9 Hz, 1H), 7,69 (DD, J=7,9, and 0.9 Hz, 1H), 7,17 (apparent t, J=7.9 Hz, 1H), 4,49-and 4.40 (m, 3H), 3,93 (DD, J=13,7, 3.3 Hz, 1H), 3,76-and 3.72 (m, 1H), 3,39-to 3.36 (m, 1H), 3,34-3,30 (m, 2H), 3,26 is 3.23 (m, 2H), 3,19 is 3.15 (m, 1H), 3,01 (c, 3H), 2,22-of 2.20 (m, 1H), 2,19-of 2.15 (m, 1H), 1,98 is 1.91 (m, 3H), 1,53 (d, J=6.9 Hz, 3H), of 1.28 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 412 (M+H).17,7
1251H NMR (500 MHz, DMSO-d6) δ 9,89 (m, 0,3H), 9,23 (1H, 0,7H), 7,78 (m, 1H), 7,63 (m, 1H), 7,15 (m, 1H), to 4.52 (m, 0,3h), of 4.44 (m, 2,7H), a 3.87-to 3.52 (m, 9H), 2,90 (c, 3H), 2.77-to to 2.65 (m, 2H), 2,36 is 2.10 (m, 3H), 1,87 to 1.31 (m, 11H); MS (ESI+) m/z 470 (M+H).2,1

1261H NMR (500 MHz, DMSO-d6) δ 9,85-of 9.30 (m, 2H), 9,00 cent to 8.85 (m, 1H), 7,80 (m, 1H), 7,68 (m, 1H), 7,16 (m, 1H), br4.61 (m, 0,8H), 4,33 (m, 0,2H), 4.16 the (m, 1H), 3.96 points is 3.40 (m, 6N), 2,84 (c, 3H), 2,72-of 2.56 (m, 3H), 2,39-of 1.41 (m, 19H); MS (ESI+) m/z 438 (M+H).16,5
1271H NMR (500 MHz, DMSO-d6) δ 10,31 (users, 1H), 9,44 (d, J=6,7 Hz, 1H), 7,97 (users, 2H),7,51 (c, 1H), 7,39 (c, 1H), 4,40-4,30 (m, 1H), 3,74 (t, J=11,6 Hz, 1H), 3,55-3,20 (m, 4H), 3,05-a 3.01 (m, 1H), is 2.37 (s, 3H), 2,22-2,12 (m, 2H), 1,95-of 1.85 (m, 3H); MS (ESI+) m/z 301 (M+H).20,0
1281H NMR (500 MHz, DMSO-d6) δ 10.20 to (c, 0,2H), 9,42 (c, 0,8H), 8,93 (d, J=7.5 Hz, 0,2H), 8,65 (d, J=7.5 Hz, 0,8H), 7,85 (c, 2H), 7,43-7,39 (m, 1H), 6,84-6,79 (m, 1H), br4.61-of 4.44 (m, 0,8H), or 4.31-4,18 (m, 0,2H), 3,63-3,55 (m, 2H), 2,82-of 2.81 (m, 3H), 2,66-of 2.54 (m, 1H), 2,47-to 2.42 (m, 1H), 2,19-of 1.92 (m, 3H), 1,74 by 1.68 (m, 3H), 1,58-1,49 (m, 1H), 1,47-of 1.36 (m, 2H); MS (ESI+) m/z 333 (M+H).124
1291H NMR (500 MHz, DMSO-d6) δ 10.30 a.m. (users, 0,3H), 9,42 (users, 0,7H), to 9.32 (d, J=5.7 Hz, 0,3H), of 8.95 (d, J=5.7 Hz, 0,7H), 7,88 (users, 1,4H), 7,86 (c, 0,6H), 7,52 (c, 0,7H), 7,51 (c, 0,3H), 7,37 (c, 1H), 4,60-4,55 (m, 0,7H), 4,35-of 3.25 (m, 0,3H), of 3.65 (d, J=8,9 Hz, 1,4H), 3,60-3,55 (m, 0,3H), 2,85 is 2.80 (m, 3H), 2,75-to 2.55 (m, 2H), is 2.37 (s, 3H), 2,20-2,00 (m, 3H), 1.85 to of 1.65 (m, 3H), 1.60-to of 1.40 (m, 2H); MS (ESI+) m/z 329 (M+H).10,7
1301H NMR (500 MHz, DMSO-d6) δ 10,20-10,10 (m, 0,4H), 9,50-9,40 (m, 0,6H), 9,18-9,06 (m, 1H), 7,84-7,74 (m, 1H), 7,66 (d, J=8.0 Hz, 1H), 7,13 (dt, J=8,0, 2.0 Hz, 1H), 4,54-4,50 (m, 0,7H), 4,42-4,30 (m, 2,3H), 3.96 points-3,86 (m, 2H), 3,82-3,68 (m, 2H), 3,64-to 3.50 (m, 2H), 2,85 (m, 3H), was 2.76-2,52 (m, 2H), 2,12-1,90 (m, 2H), 1,82-of 1.42 (m, 5H), 1,40-of 1.30 (m, 6H), 1,25 (c, 9H); MS (ESI+) m/z 496 (is+H). 2,8

1311H NMR (500 MHz, DMSO-d6) the 10.40 δ (c, 0,4H), for 9.64 (c, 0,6H), 9,12-9,00 (m, 1H), 7,82-7,74 (m, 1H), 7,65 (DD, J=8,0, 2.0 Hz, 1H), 7,17 (apparent t, J=8.0 Hz, 1H), 4,60-of 4.54 (m, 0,6H), 4,42-4,32 (m, 2,4H), 3,70-to 3.36 (m, 8H), to 3.02 (c, 3H), 2,84 (c, 1H), 2,80-of 2.58 (m, 2H), 2,30-to 1.98 (m, 2H), 1,80 by 1.68 (m, 2H), 1.60-to of 1.52 (m, 1H), 1,50-to 1.38 (m, 7H); MS (ESI+) m/z 490 (M+H).1,0
1321H NMR (500 MHz, DMSO-d6) δ 10.30 a.m.-10,10 (m, 0,4H), 9,80-of 9.30 (m, 0,6H), of 7.75 (d, J=8.0 Hz, 1H), to 7.64 (d, J=8.0 Hz, 1H), 7,13 (apparent t, J=8.0 Hz, 1H), 4,60-4,30 (m, 3H), 3.96 points-3,90 (m, 2H), 3,86-of 3.78 (m, 1H), 3,60-of 3.46 (m, 3H), 2,80 (c, 3H), 2,64 is 2.55 (m, 3H), 2,30-2,00 (m, 3H), 1,80-to 1.60 (m, 7H), 1.60-to 1,10 (m, 14H); MS (ESI+) m/z 522 (M+H).1,9
1331H NMR (500 MHz, DMSO-d6) δ 9,60-of 9.30 (m, 0,2H), 9,20-9,02 (m, 0,8H), of 7.75 (d, J=7.5 Hz, 1H), to 7.64 (d, J=8.0 Hz, 1H), 7,13 (apparent t, J=8,0 Hz, 1H), 4,54-4,30 (m, 3H), 4,00-3,82 (m, 3H), 3,70 is 3.40 (m, 2H), 3,38-3,26 (m, 6H), 3,02-2,96 (m, 1H), 2,90-of 2.50 (m, 4H), 2.40 a-1,90 (m, 3H), 1,88-of 1.40 (m, 10H), 1,40-of 1.30 (m, 6H); MS (ESI+) m/z 508 (M+H).1,8
134 1H NMR (500 MHz, DMSO-d6) of 10.05 δ (c, 1H), 7,76 (d, J=8.0 Hz, 1H), 7.62mm (d, J=8.0 a, 2.0 Hz, 1H), 7,12 (apparent t, J=8.0 Hz, 1H), 4,50-4,34 (m, 3H), of 3.96 (DD, J=13, 1.5 Hz, 1H), 3,88 (DD,J=13,5, 4.0 Hz, 1H), of 3.73 (DD, J=13, 1.5 Hz, 1H), 3,51 (DD, J=13,5, 4.0 Hz, 1H), 3,32-of 3.27 (m, 5H), 2,60-of 2.30 (m, 3H), 2,15-of 1.85 (m, 3H), 1.60-to of 1.30 (m, 9H), 1,15-of 1.05 (m, 3H); MS (ESI+) m/z 468 (M+H).1,7

1351H NMR (500 MHz, DMSO-d6) δ 9,16-8,96 (m, 1H), of 7.75 (d, J=8.0 Hz, 1H), 7,63 (d, J=8.0 Hz, 1H), 7,12 (apparent t, J=8.0 Hz, 1H), 4,50-4,30 (m, 2H), 3.96 points-3,90 (m, 2H), 3,86-of 3.80 (m, 1H), 3,60-of 3.46 (m, 2H), 3,30-3,26 (c, 6H), 2,96 is 2.80 (m, 2H,), 2,20-1,90 (m, 3H), 1.70 to of 1.20 (m, 9H), 1,16-a 1.08 (m, 6H). MS (ESI+) m/z 482 (M+H).2,0
1361H NMR (500 MHz, CD3OD) δ 7,80-7,87 (m, 1H), 7,55-to 7.61 (m, 1H), 7,17-7,25 (m, 1H), of 4.44-4,69 (m, 3H), 3,90-of 3.97 (m, 2H), 3,67-of 3.77 (m, 2H), 3,42-3,47 (m, 2H), 2,97-3,03 (m, 3H), 2,89 (c, 6H), 2,69-2,82 (m, 2H), 2,15-to 2.42 (m, 3H), 1,87-2,02 (m, 2,5H), 1,59 is 1.75 (m, 2,5H), 1,47-of 1.53 (m, 6H); MS (ESI+) m/z 483 (M+H).2,6
1371H NMR (500 MHz, DMSO-d6) δ 8,96-8,80 (c, 1H), 7,76 (d, J=8.0 Hz, 1H), 7.62mm (d, J=8.0 Hz, 1H), 7,18 (apparent t, J=8.0 Hz, 1H), 4,40-4,24 (m, 1H), 4,20-to 4.14 (m, 2 H), 3,36-up 3.22 (m, 6H), 3,16-is 2.88 (m, 3H), 2,72-262 (m, 2H), 2,60-of 2.34 (m, 3H), 2,12-of 1.88 (m, 3H), 1.60-to of 1.40 (m, 8H), 1,38-to 0.88 (m, 3H);19F {1H}NMR (282 MHz, DMSO-d6), δ 64,02; MS (ESI+) m/z 494 (M+H).1,8
1381H NMR (500 MHz, CD3OD) δ of 7.90-7,72 (m, 1H), to 7.59 was 7.45 (m, 1H), 7,25-7,03 (m, 1H), 4,59-4,34 (m, 3H), 4,07-3,88 (m, 2H), 3,88-to 3.67 (m, 4H), 3,50-to 3.36 (m, 2H), 2,83-of 2.54 (m, 5H), 2,22-to 2.06 (m, 3H), 2.06 to to 1.87 (m, 1H), 1,80 is 1.58 (m, 3H), 1,58-of 1.36 (m, 8H), 1,08-of 0.91 (m, 6H); MS (ESI+) m/z 513 (M+H).2,4
1391H NMR (500 MHz, DMSO-d6) δ 10,24 (c, 1H), 9,04 (d, J=6,5 Hz, 1H), 7,93 (c, 2H), 7,45-7,42 (m, 1H), 6,85-for 6.81 (m, 1H), 4,33-or 4.31 (m, 1H), 3,69-the 3.65 (m, 1H), 3.25 to 3,19 (m, 4H), 3,06 are 2.98 (m, 2H), 2,24-of 2.08 (m, 2H), 1,92-1,89 (m, 2H), 1,81-1,71 (m, 1H); MS (ESI+) m/z 305 (M+H).67,4

1401H NMR (500 MHz, CD3OD) δ 7,82-7,87 (m, 1H), 7,55-to 7.61 (m, 1H), 7,16-7,24 (m, 1H), 4,45-4,63 (m, 3H), 3,92 (DD, J=13,0, 3.3 Hz, 1H), 3,67-of 3.78 (m, 2H), 3.49 points of 3.56 (m, 4H), 3,30-to 3.38 (m, 2H), 3,02 (c, 1H), 2,97 (c, 2H), 2,72-only 2.91 (m, 2H), 2,15 is 2.43 (m, 3H), 1.60-to 2,02 (m, 9H), 1,47-of 1.53 (m, 6H); MS (ESI+) m/z 509 (M+H).2,2
141 1H NMR (500 MHz, CD3OD) δ 7,82-7,87 (m, 1H), 7,53-EUR 7.57 (m, 1H), 7,15-7,20 (m, 1H), 4,43-4,58 (m, 3H), 3,90-of 3.96 (m, 2H), 3,67-of 3.78 (m, 2H), 3,44 (DD, J=13,1, and 2.3 Hz, 2H), 3,17-of 3.25 (m, 2H), 3,02 (c, 0,75H), 2,97 (c, 2,25H), 2,72-of 2.92 (m, 2H), 2,13-to 2.42 (m, 3H), 1,86-2,02 (m, 2H), 1,46-1,75 (14H); MS (ESI+) m/z 523 (M+H).1,8
1421H NMR (500 MHz, CD3OD) δ to 7.84 (DD, J=8.0 a, 1.0 Hz, 1H),EUR 7.57 (DD, J=8,0, 0.9 Hz, 1H), 7,39-to 7.32 (m, 5H), 7,19 (apparent t, J=8.0 Hz, 1H), 4,77 with 4.65 (m, 3H), 4,55 is 4.45 (m, 2H), 3,93-to 3.89 (m, 2H), 3,48-to 3.38 (m, 5H), 3,30-of 3.25 (m, 1H), 2,38-of 2.36 (m, 2H), 2,17-2,12 (m, 3H), 1,67 (d, J=7,0 Hz, 3H), of 1.12 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 488 (M+H).11,5
1431H NMR (500 MHz, CD3OD) δ of 7.90 for 7.78 (m, 1H), EUR 7.57-7,49 (m, 1H), 7,21 for 7.12 (m, 1H), 5,04-4,89 (m, 1H), 4,58-to 4.41 (m, 3H), a 3.87-3,66 (m, 6H), 3.00 and (c, 3H), 2,92-to 2.65 (m, 2H), 2,47 is 1.58 (m, 8H), 1,53 was 1.43 (m, 6H), 1,36-1,22 (m, 6N); MS (ESI+) m/z 498 (M+H).1,4
1441H NMR (500 MHz, CD3OD) δ 7,89-7,80 (m, 1H), 7,60-7,49 (m, 1H), 7,20 for 7.12 (m, 1H), br4.61-to 4.41 (m, 3H), 4,30-4,16 (m, 2H), 3,91-3,63 (m, 6H), 3,06-2,95 (m, 3H), 2,90-2,69 (m, 2H), 2,38-of 1.53 (m, 8H), 1,53-of 1.36 (m, 6H), 1,36 is 1.23 (m, 3H); MS (ESI+) m/z 484 (M+H).1,0
1451H NMR (500 MHz, CD3OD) δ 8,20 (c, 1H), 7,76 (c, 1H), of 7.48 (c, 1H), br4.61 (c, 2H), 2,35 (c, 3H); MS (ESI+) m/z 306 (M+H).127

1461H NMR (500 MHz, CD3OD) δ of 7.82 (d, J=8.0 Hz, 1H), 7,54 (d, J=7.9 Hz, 1H), 7,15 (t, J=8.0 Hz, 1H), 4,43-to 4.52 (m, 2H), 4,33 was 4.42 (m, 1H), 3,88-3,93 (m, 4H), 3,48-3,55 (m, 4H), 3,30-to 3.35 (m, 2H), 2,62-of 2.72 (m, 2H), 2,10-2,22 (m, 1H), 1,65-2,02 (m, 11H), of 1.52 (d, J=6,7 Hz, 6H); MS (ESI+) m/z 495 (M+H).32,2
1471H NMR (500 MHz, DMSO-d6) δ the 10.40-10.30 a.m. (m, 0,4H), 9,60-at 9.53 (m, 0,6H), 9,10-9,00 (m, 0,4H), 8,89-8,83 (d, J=6.0 Hz, 0,6H), 7,80-7,76 (m, 1H),7,65 (d, J=10 Hz, 1H), 7,20-7,17 (m, 1H), 6,26-6,16 (m, 0,8H), 6,07-of 6.02 (m, 0,2H), 5,61-of 5.50 (m, 2H), and 4.68 (d, J=6.0 Hz, 1H), 4,60-4,48 (m, 1H), 4,32-4,30 (m, 0,5H), 4,16-of 4.05 (m, 1H), was 4.02-3,98 (m, 1H);3,60-of 3.54 (m, 2H), 3,52-of 3.48 (m, 1H), 3.46 in-and 3.16 (m, 5H),2,85 (c, 3H), 2,75-to 2.55 (m, 2H), 2,27-to 2.18 (m, 1H), 2,12-2,05 (1H, 2H), 1,78 by 1.68 (m, 3H), 1.60-to of 1.40 (m, 2H), 1,30-1,22 (m, 3H); MS (ESI+) m/z 452 (M+H).10,8
1481H NMR (500 MHz, DMSO-d6) δ are 11.62-11,44 (m, 1H), the 10.40-10,32 (m, 0,3H), 9,58-9,50 (m, 0,7H), 8,96-8,78 (m, 1H), 7,84-to 7.64 (m, 4H), 7,54-7,30 (m, 3H), 7,22-to 7.18 (m, 1H), 4.80 to 4.72 in (m, 1H), 4,68-4,58 (m, 1H), 4,56-to 4.46 (m, 1H), 4,40-4,22 (m, 2), 3,90-3,50 (3H), 3,42-3,30 (m, 1H), 3,22-of 3.12 (m, 2H), 2,86 (c, 3H), 2,78-2,62 (1H, 2H), 2,20-1,90 (m,3H), 1,76 is 1.60 (m, 5H), 1.56 to the 1.44 (m, 6H); MC (ESI+) m/z 502 (M+H).1,6
1511H NMR (500 MHz, DMSO-d6) δ 10,66 (users, 0,4H), 9,86 (users, 0,6H), 9,16 is 9.15 (m, 0,4H), 8,96-8,95 (m, 0,6H), to 7.77-7,72 (m, 1H), to 7.61-EUR 7.57 (m, 1H), 7,15-7,11 (m, 1H), 4,59-4,51 (m, 0,6H), 4,36-or 4.31 (m, 0,4H), 4,06-a 4.03 (m, 1H), 3,95-a-3.84 (m, 3H), 3,68-of 3.46 (m, 5H), 2,83-of 2.81 (m, 3H), 2,75-2,62 (m, 2H), 2,31-2,19 (m, 1H), 2,11-of 2.09 (m, 2H), 1,94-of 1.74 (m, 5H), 1,58-of 1.45 (m, 2H), of 0.93-0.87 (m, 3H); MS (ESI+) m/z 413 (M+H).34

1521H NMR (500 MHz, DMSO-d6) δ 10,66 (users, 0,4H), 9,84 (users, 0,6H), 9,14-9,13 (m, 0,4H), 8,98-8,97 (m, 0,6H), to 7.77-7,73 (m, 1H), 7,60-7,58 (m, 1H), 7,14-7,10 (m, 1H), 4,58-4,50 (m, 0,6H), 4,36-or 4.31 (m, 0,4H), 4.04 the-3,91 (m, 3H), 3,76-3,71 (m, 1H), 3,63-3,44 (m, 5H), 2,83-of 2.81 (m, 3H), 2,73-2,62 (m, 2H), 2,46-of 2.36 (m, 1H), 2.26 and-to 2.18 (m, 1H), 2,12 is 2.01 (m, 2H), 1,81-of 1.73 (m, 3H), 1,54-of 1.45 (m, 2H), 1,09 is 0.99 (m, 3H), 0,95-of 0.85 (m, 3H); MS (ESI+) m/z 427 (M+H).75

Analysis of the Bezold-Jarisch in vivo. To demonstrate the functional antagonism of receptors 5-HT3connection (see below) was assessed by their ability to inhibit induced serotonin bradycardia in vivo in mice [Saxena, P.R. and Lawang, A. A comparison of cardiovascular and smooth muscle effects of 5-hydroxytryptamine'an 5-carboxamidotryptamine, a selective agonist of 5-HT1receptors. Arch. Int. Pharmacodyn. 277: 235-252, 1985]. Each of the tested substances and the filler [2% tween 80] was administered orally (0.3 to 3 mg/kg) group 5 male or female mice CD-1 (Crl.), each weighing 24±2 g were Used, the dose volume of 10 ml/kg sixty minutes-induced 5-HT (0.1 mg/kg, intravenously) bradycardia was detected in the animals shot by urethane (2225-2500 mg/kg, intraperitoneally introduced for 10 minutes before the introduction of 5-HT).

5-HT3-antagonism in vivo mouse (reflex bradycardia)

ConnectionExample% inhibition at the dose of the test compounds (oral administration)
883% @ 0.3 mg/kg

4986% @ 1 mg/kg
7598% @ 1 mg/kg
5080% @ 3 mg/kg
9385% @ 3 mg/kg
10397% @ 3 mg/kg
11297% @ 3 mg/kg

Compounds of the invention can be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg / day. The dose range for adult humans is generally from 0.005 mg to 10 g/day. Tablets or other formulation, presented in the form of discrete units may appropriately contain a number of compounds of the invention that is effective at this dose or several doses, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg of the Exact number of connections, input patient, determined by the attending physician of the hospital. However, the dose administered will depend on a number of factors, including the age and sex of the patient, a particular disorder being treated and its severity. In addition, the route of administration can vary depending on the condition and its severity.

Although the compounds of formulas I and II can be entered as individual chemical compounds, it is preferable to present them as pharmaceutical compositions. is according to the next aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula I or II or its pharmaceutically acceptable salt or MES together with one or more of its pharmaceutical carriers, and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense that it is compatible with other ingredients of the formulation and is not harmful to the recipient.

Preparative forms include forms suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and local (including skin, transbukkalno, sublingual and intraocular) administration. The most suitable way may depend on the condition and disorder of the recipient. Preparative forms can suitably be present in the dosage form and can be obtained by any of the methods well known in the field of pharmacy. All methods include the stage of combining (mixing) the compounds of formula I or II or its pharmaceutically acceptable salt or MES ("active ingredient") with the carrier which comprises one or more accessory ingredients. In General, the formulation will receive a uniform and tight mixing active and is gradient with liquid carriers or finely ground solid carriers or both and then, if necessary, shaping the product into the desired formulation form. Preferred dosage forms are pharmaceutical form containing an effective dose, or an appropriate part of the effective dose of the active ingredient.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets, each of which contains a defined amount of the active ingredient; as a powder or granules; as solution or suspension in an aqueous liquid or non-aqueous liquid or in the form of a liquid emulsion of the type oil-in-water or a liquid emulsion of the type water-in-oil. The active ingredient may also be presented in the form of a bolus, electuary or paste.

A tablet may be made by extrusion or molding, optionally with one or more accessory ingredients. Molded tablets can be obtained by compressing in a suitable machine the active ingredient in granular form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of powdery compounds, HC is Ananova inert liquid diluent. The tablets may optionally be covered with membrane or to put on them risks and can be made to provide steadfastly supported, slow or controlled release of the active ingredient.

Preparative forms for parenteral administration include aqueous and non-aqueous sterile solutions for injection, which may contain antioxidants, buffers, bacteriostatic and dissolved substances, which make the preparative form is isotonic with the blood of the intended recipient. Preparative forms for parenteral administration include aqueous or non-aqueous sterile suspensions, which include suspendresume agents and thickening agents. Preparative form can be represented in containers with a single dose or multiple doses, for example, sealed ampoules and vials, they can be stored in a freeze dried (liofilizirovannom) condition, which requires only the addition of sterile liquid carrier, such as saline, phosphate-saline buffer solution (PBS) or the like, immediately before use. "Makeshift solutions or suspensions for injection can be obtained from sterile powders, granules and tablets of the previously described type.

Preparative forms for rectal injection can be presented in the form of suppose the thorium conventional carriers, such as cocoa butter or polyethylene glycol.

Preparative form for the local introduction into the oral cavity, for example transbukkalno or sublingually, include pellet, containing the active ingredient in the base with a pleasant taste and smell, such as sucrose and the Arabian gum or tragakant, and tablets containing the active ingredient in such manner as gelatin and glycerin or sucrose and Arabian gum.

It should be clear that in addition to the ingredients specified above, the formulations of this invention may include other agents conventional in this field and related to the type of question formulation, for example, preparative forms suitable for oral administration may include corrigentov.

Although this invention is described in detail for purposes of illustration, the specialist in this area should be immediately obvious that there may be changes or modifications not beyond the scope of the invention described here.

1. The compound of formula II:

where
R1, R2and R3independently selected from the group consisting of hydrogen,
halogen and lower alkyl containing 1-6 carbon atoms;
R4represents a residue selected from the group consisting of

and where m is 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
Q represents N(CH3or-O - and
R5represents hydrogen or methyl; and
R10selected from the group consisting of
(i) hydrogen;
(ii) (C1-C10) alkyl;
(iii) (C1-C10)alkyl, substituted by one or more substituents independently selected from the group consisting of-N(CH3)2, morpholinyl, (C1-C4)alkoxy, hydroxyl, -CON(CH3)2and halogen;
(iv) a monocyclic (C3-C8)cycloalkyl containing one N heteroatom;
(v) 9-methyl-9-azabicyclo[3.3.1]nonane;
(vi) phenyl, and
(vii) phenyl, substituted by one or more (C1-C4)alkoxy;
R11selected from the group consisting of hydrogen and (C1-C10)alkyl;
or
R10, R11and the nitrogen atom to which they are attached, together form a nitrogenous heterocycle or substituted nitrogenous heterocycle selected from the group consisting of the research, piperazine, piperidine, diazepan, tetrahydroquinoxaline, triazolopyridine, 6,9-diazaspiro[4.5]decane, 1,4-dioxa-8 azaspiro[4.5]decane, 3-oxopiperidine, thiomorpholine-1,1-dioxide, or any of the above heterocycles, substituted one, two or three substituents, independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)ha is hogenakkal, (C1-C6)alkoxyalkyl, phenyl, pyrimidinyl, (C1-C4)alkylsulphonyl, benzoyl, (C5-C6)cycloalkylcarbonyl, carboxamido and (C1-C4)alkoxycarbonyl.

2. The compound according to claim 1 of the formula IIa or IIb

3. The compound according to claim 1, where R4selected from hinoklidina, tropane, azabicyclo[3.3.1]nonane, methylisobutyl[3.3.1]nonane, dimethylbicyclo[3.3.1]nonane, methylpiperidine and methyl-3-oxa-9-azabicyclo[3.3.1]nonane.

4. The compound according to claim 1, where R1, R2and R3represent hydrogen.

5. The compound according to claim 1, where one of R1, R2and R3represents a halogen.

6. The compound according to any one of claims 1 to 5, where R10selected from the group consisting of hydrogen and (C1-C3)alkyl.

7. The compound according to claim 1, where R11represents N or CH3.

8. The compound according to any one of claims 1 to 5, where R10selected from the group consisting of phenyl, phenyl substituted by one or more (C1-C4)alkoxy, (C1-C6)alkyl, monocyclic (C4-C7)cycloalkyl containing one heteroatom N, 9-methyl-9-azabicyclo[3.3.1]nonane, dimethylamino(C1-C6)of alkyl, morpholinyl(C1-C6)alkyl, (C1-C4)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl and dimethylamine is carbonyl(C 1-C6)alkyl.

9. The compound according to claim 1, where R10and R11taken together form a nitrogenous heterocycle or substituted nitrogenous heterocycle selected from the group consisting of the research, piperazine, piperidine, diazepan, tetrahydroquinoxaline, triazolopyridine, 6,9-diazaspiro[4.5]decane, 1,4-dioxa-8 azaspiro[4.5]decane, 3-oxopiperidine, thiomorpholine-1,1-dioxide, or any of the above heterocycles, substituted one, two or three substituents, independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)halogenoalkane, (C1-C6)alkoxyalkyl, phenyl, pyrimidinyl, (C1-C4)alkylsulphonyl, benzoyl, (C5-C6)cycloalkylcarbonyl, carboxamido and (C1-C4)alkoxycarbonyl.

10. The compound according to claim 1 which is a hydrochloride (S)-N-(Hinkley-8-yl)-2-(dimethylamino)benzoxazole-4-carboxamide.

11. The compound according to claim 1 which is a hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-3-methylmorpholine)-benzoxazol-4-carboxamide.

12. The compound according to claim 1 which is a hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((3S,5S) - for 3,5-dimethyl-morpholino)benzoxazole-4-carboxamide.

13. The compound according to claim 1 which is a hydrochloride endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2((2S*,6R*)-2,6-dimethyl-piperazine-1-yl)benzoxazole-4-carboxamide.

14. The compound according to claim 1 which is a hydrochloride (S)-N-(Hinkley-8-yl)-2-aminobenzothiazole-4-carboxamide.

15. The compound according to claim 1 which is a hydrochloride (S)-N-(Hinkley-8-yl)-2-amino-6-chlorobenzoxazole-4-carboxamide.

16. The compound according to claim 1 which is a hydrochloride (S)-N-(Hinkley-8-yl)-2-amino-7-fermentation-4-carboxamide.

17. Pharmaceutical composition having the ability to modulation of the serotonin receptor type 3 containing a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 1 to 16.

18. A method of treating disorders which depends on the modulation of the serotonin receptor type 3, comprising administration to a patient in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to 16.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .

EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: pharmacology.

SUBSTANCE: invention refers to the compound of formula(I) or to is salt where R1 is -H or C1-6 alkyl; R2 is bridged aza-ring chosen out of group including formula and where ring hydrogen atom in bridged aza-ring may be substituted by one or several groups of R22; m, n and p have respective values 1 or 2; r has the value 0 or 1; R21 is C1-6 alkyl, -C1-6 alkyl-O-phenyl or -C1-6 alkyl-phenyl; R22 is C1-6 alkyl-cycloalkyl or -C1-6 alkyl-phenyl; R2 is thienyl, phenyl, pyridyl, pyranzinyl, thiazolyl or pyrazolyl, each of which can be substituted by one or several R31; R31 is the halogen, -OH, -CN, -CF3, C1-6 alkyl or -O-C1-6 alkyl; ring A is the group consisting of thiophene, thiazole, isothiazole, thidiazole, oxazole, isooxazole, cyclohexan, norboran, benzothiophene and 5,6-dihydro-4H-cyclopentathiophene, each of which can be substituted by the group chosen out of the group consisting out of one or several RA1; where RA1 is a halogen, -CN, -NH2, C1-6 alkyl, -O-C1-6 alkyl, CONH2, - HN-C1-6 alkyl, -HN-C1-6 alkyl-O-C1-6 alkyl-phenyl, -HN-C1-6 alkyl-phenyl or -HN-C1-6 alkyl-OH where C1-6 alkyl can be substituted with one or several halogen atoms; V is -NH- or -O-; W is -(CH2)q-; q has the value 0.1 or 2; X is the counteranion and is an ordinary bond; on condition when in case ring A is cyclohexane, R3 is phenyl which can be replaced with one or several R31. The invention also refers to pharmaceutical composition that has antagonistic effect on muscarine receptor M3, on the basis of said compound.

EFFECT: production of new compound and pharmaceutical composition on its basis, which can be applied in the medicine as an active substance for preventive and/or therapeutic drug for treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like.

14 cl, 60 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 1-azabicyclo[2.2.2]oct-3(R)yl ether of 2-hydroxy-2,2-dithien-2-ylacetic acid and 3-phenoxypropyl bromide, where the reaction takes place in a solvent or mixtures of solvents, having boiling point ranging from 50 to 210°C and selected from a group comprising ketones and cyclic ethers, preferably in acetone, dioxane and tetrahydrofuran.

EFFECT: efficient method of obtaining the compounds.

12 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (R)- quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate or salt thereof, involving: 1) converting a compound which is 4-amino-3-methoxypiperidine-1-carboxylate to a salt; 2) converting the ethyl 4-amino-3-methoxypiperidine-1-carboxylate salt into ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate 3) treating ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate with hydroxide or hydride of an alkali metal to obtain 3-methoxy-N,N-diphenylpiperidine-4-amine 4) obtainijng a chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine by bringing 3-methoxy-N,N-diphenylpiperidine-4-amine into contact with a chiral splitting agent and extracting the obtained chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine; optional recrystalisation of product 4; converting product 4 or 5 to a base to obtain product 4 or 5 in form of a free base; 7) bringing product 6 into contact with ethyl 6-bromohexanoate to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 8) esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate using (R)-quinuclidin-3-ol with a Lewis acid to obtain (R)- quinuclidin-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 9) removing protection from the 4-amine group of product 8 to obtain (R- quinuclidin-3-yl 6- [(3S,4R)-4-amino-3-methoxypiperidin-1-yl)hexanoate; 10) acylation of product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)- quinuclidin-3-yl 6-((38,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate; 11) optional conversion of product 10 into a salt.

EFFECT: method increases output of the end product and reduces content of impurities.

7 cl, 3 ex, 6 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I where X1-X4 each independently represent CR1, B represents -C(O)-O- or -C(O)-NH-CH2-, Y represents S or NH, R1 represents H, C1-C4alkoxy, unsubstituted or substituted by once or several times with F, or Het, and Het stands for heterocyclic group, fully saturated, partly saturated or fully unsaturated, containing in cycle 5-10 atoms, of which at least one atom represents N, O or S, unsubstituted or substituted once or several times with C1-C8alkyl, or to its pharmaceutically acceptable salt.

EFFECT: obtaining pharmaceutical composition for selective activation/stimulation of nicotine receptors α7 on the basis of said compound, as well as to their application for treatment of patient, suffering from psychotic disease, neurodegenerative disease, including cholinergic system dysfunction and/or condition of memory failure and/or failure of cognitive abilities.

52 cl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , in which A denotes hydrogen, B denotes methyl or B is in a trans-position relative oxygen; X denotes CH2; Y denotes a group of formula , , ,

, or ;

, in which the left-hand bond is to an oxygen atom, and the right-hand bond is to the group R; R denotes 5-indolyl; in form of a free base or an acid addition salt. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-7, to a method of preventing and treating psychiatric and neurodegenerative disorders in a person, as well as a method of treating and preventing diseases or pathological condition in which α7 nAChR activation plays a role.

EFFECT: obtaining novel biologically active compounds having α7 nAChR agonist activity.

16 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I

in form of a salt, where R1 and R2 each independently denotes phenyl, where one or both R1 and R2 are substituted in one, two or three positions by the following groups: halogen, C1-C8alkyl or C1-C8alkoxy, and R3 is hydroxy, or R1 and R2 each denotes an unsubstituted phenyl, and R is hydrogen, C1-C8alkyl, C1-C8alkoxy or C1-C8alkylthio, or R1 is C3-C8cycloalkyl and R2 is phenyl or a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes oxygen and sulphur, and R3 is hydroxy, or -CR1R2R3 denotes 9-hydroxy- 9H-fluoren-9-yl or 9-hydroxy-9H-xanthen-9-yl, and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, optionally substituted with phenyl, or R1 and R2 each denotes an unsubstituted phenyl, and R3 is hydroxy and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is 5-methyl-3-isoxazolyl or R1 and R2 each denote unsubstituted phenyl, and R3 is hydroxy and R4 is 1-ethyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen, R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, provided that the formula I compound is not (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrazin-2-ylcarbamoylmethy)-1-azoniumbicyclo[2.2.2]octane, (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide or (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-8, as well as to methods for synthesis of formula I compounds.

EFFECT: obtaining new biologically active compounds which have M3 muscarinic receptor mediated activity.

14 cl, 254 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat diseases mediated by the nicotinic acetylcholine receptor, such as derangement of memory. In general formulae , and A is an indazolyl, benzothiazolyl or isobenzothiazolyl group which corresponds to structural formulae a) to c) respectively or X is O; R1 is H, F, Cl, Br, I, cycloalkyl containing 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; ; R2 is H; R3 is H; R4 is H, F, Cl, Br, I, cycloalkyl which contains 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; R5 is H; Ar is an aryl group containing 6 carbon atoms which is unsubstituted or substituted once or several times with halogen; and Het is a 5- or 6-member heteroaromatic group containing a heteroatom in the ring which is selected from N, O and S, or a 6-member saturated heterocyclic group which contains a heteroatom in the ring which is selected from N and O; and their pharmaceutically acceptable salts, where, if the said compound has formula I, the indazolyl group of group A is bonded through its 3rd, 4th or 7th position, the benzothiazole group of group A is bonded through the 4th or 7th position, the isobenzothiazole group of group A is bonded through the 3rd, 4th or 7th position.

EFFECT: obtaining compounds with properties of nicotinic acetylcholine receptor (nAChR) ligands, and pharmaceutical compositions based on the said compounds.

53 cl, 95 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where B represents a hydrogen atom or a group selected from -R1, -OR1, hydroxy, - O(CO)R1, cyano and non-aromatic heterocycle which is a saturated or unsaturated C3-C10carbocyclic ring in which one or more carbon atoms, preferably 1 or 2 carbon atoms, are substituted with oxygen atoms as heteroatoms, where R1 is selected from a group containing hydrogen atoms, C1-C8alkyl, C2-C8alkenyl and C3-C8cycloalkyl, where the alkyl group is unsubstituted or substituted with one or more substitutes selected from halogen atoms and C1-C4alkyl, and where the alkenyl group is unsubstituted or substituted with one or more substitutes selected from C1-C4alkyl, n equals an integer from 0 to 4, A is selected from a group containing -CH2-, -CH=CR3-, -CR3=CH-, -CR3R4-, -O-, -CO-, -O-(CH2)2-O-, where R3 and R4 each independently represents a hydrogen atom or C1-C8alkyl, m equals an integer from 0 to 8, p equals 2, and the bicyclic azonium ring contains a substitute on position 3, including all possible configurations of asymmetrical centres, D is selected from a group containing: or where R5 is selected from a group containing phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, R6 is selected from a group containing 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, C3-C8cycloalkyl, C1-C8alkyl, C2-C8alkenyl and phenylethyl, R7 represents a hydrogen atom or a group selected from hydroxyl, hydroxymethyl and methyl, Q represents a single bond or a group selected from -CH2-, -CH2CH2-, -O-, -O-CH2-, equals an integer from 0 to 3, X represents a pharmaceutically acceptable anion of mono- or polybasic acid, under the condition that the B-(CH2)n-A-(CH2)m- group does not represent a straight C1-4alkyl and that the following compounds are excluded: 1-allyloxycarbonylmethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-azoniumbicyclo[2.2.2]octane and 1-carboxymethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-azoniumbicyclo [2.2.2]octane. The invention also relates to a method of producing formula (I) compounds, to a pharmaceutical composition, to use of compounds in any of paragraphs 1-14, as well as a combined product.

EFFECT: obtaining novel biologically active compounds with antagonistic activity towards muscarine receptors M3.

21 cl, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azabicyclic alkane derivatives which are substituted with a condensed bicycloheterocycle of formula or pharmaceutically acceptable salt thereof, ester, amide or prodrug, where n equals 1, 2 or 3; A denotes N or N+-O-; R denotes hydrogen, alkyl, cycloalkylalkyl and arylalkyl; L is selected from a group consisting of O, S and -N(Ra)-; Ar1 denotes a 6-member aryl or a 6-member heteroaryl; and Ar2 denotes a bicyclic heteroaryl; and Ra is selected from a group consisting of hydrogen, alkyl and alkylcarbonyl; provided that if Ar1 is represented by formula then L denotes O or S; compositions containing such compounds, and methods of treating conditions and disorders using said compounds and compositions.

EFFECT: improved properties of the derivatives.

19 cl, 66 ex

The invention relates to a method for producing the intermediate product to obtain with antiholinergicescuu activity of substances derived tropovoy acid, more specifically to a method of obtaining pure enantiomers esters (+) or (-) tropovoy acid with aminoalcohols

The invention relates to new esters of carboxylic acids with valuable properties, in particular the esters taylorbow acids and aminoalcohols of General formula (I)

< / BR>
where a group

< / BR>
where m and n are independent of each other represent 1 or 2,

Q group of formulae

< / BR>
Q' группаNR, where R denotes hydrogen or alkyl with 1 to 4 carbon atoms, unsubstituted or substituted with halogen or hydroxyl, or a group NRR', where R' is alkyl with 1 to 4 carbon atoms, or R and R' together form alkylene with 4 to 6 carbon atoms, and in the case of the fourth connection to the positive charge of the nitrogen atom is the equivalent of the anion (X),,

R1thienyl, phenyl, furyl, cyclopentyl and cyclohexyl, unsubstituted or substituted stands, and thienyl and phenyl may be substituted by fluorine or chlorine,

R2hydrogen, alkoxy 1 to 4 carbon atoms or alkyl with 1 to 4 carbon atoms,

Rahydrogen, fluorine, chlorine or methyl, provided that when a represents 3-tropanol, R1hydroxyl and R

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel indazole-carboxamide compounds of formula ,

in which radicals and groups are as defined in claim 1 of the formula of invention. Present invention also relates to pharmaceutical compositions containing said compounds, to methods of using such compounds to treat 5-HT4-receptor mediated diseases.

EFFECT: said compounds are 5-HT4-receptor agonists.

16 cl, 10 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) , where Z means where R means hydrogen, C4-C6cycloalkyl group attached either through one of ring carbon atoms, or through a lower alkylene group attached to the ring, or a linearly chained or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or a phenyl(lower alkyl) group optionally substituted with 1-2 substitutes chosen from lower alkyl, lower alkoxy, halogen and hydroxy, or heteroaryl(lower alkyl)group where heteroaryl is chosen from the group consisting from thienyl, substituted with lower alkyl group, imidazolyl, and thiazolyl substituted with the lower alkyl group; n means 0 or 1; or Z means a group where R means the lower alkyl group; X1 means methylene or NH group; and X2 means methylene; or X1 means methylene and X2 means methylene or a bond; or X1 means methylene, and X2 means O, S or a bond; Y1 means methylene, and Y2 means methylene, vinylene, ethylene, or a bond; Ar1 means unsubstituted or substituted phenyl; Ar2 means unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted furyl, unsubstituted or substituted pyridyl; and when Ar1 and Ar2 are substituted, each Ar1 and Ar2 are independently substituted with one or more substituted chosen from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di- and trihaloalkyl, di- and trihaloalkoxy, mono- and dialkylamino, alkilthio, alkyl ester and nitro; provided that Ar1 and Ar2 do not simultaneously mean unsubstituted phenyl; W means oxygen or sulphur; or to their pharmaceutically acceptable salts; provided those specified in cl. 1 of the patent claim. Besides the invention concerns the compounds chosen from the group, to compounds of formula (I), to pharmaceutical compositions, to a method of inhibition of monoamine receptor activity, to a method of inhibition of monoamine receptor activation, to a method of treating a diseased state associated with serotonin receptor, to a method of treating schizophrenia, to a method of treating migraine, and also to a method of treating psychosis.

EFFECT: preparation of the new biologically active compounds capable to inhibit monoamine receptor activity.

65 cl, 140 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: in new compounds of the formula R1 represents hydrogen, halogen; R2 represents C3-4 alkyl, or C3-6 cycloalkyl; R3 represents hydrogen or C1-3 alkyl; R4 represents -S(O)2R6, or -C(O)R7; R5 represents hydrogen, C1-3 alkyl, C2-3 alkyl substituted with -OH or C1-3alkoxy, or -CH2-pyridyl; R6 represents C1-3 alkyl, or R5 and R6 taken together form a C3-4 alkylenyl; and R7 represents hydrogen, C1-3 alkyl or pyridyl; or their pharmaceutically acceptable salts or solvates or stereoisomers. The invention also refers to pharmaceutical composition, to compounds application, to method for treating mammals, to method for treating disorders of reduced motor activity of gastrointestinal tract in a mammal, to method for obtaining compounds according to any of Clauses 1-12, to method for obtaining compounds of formula (I'), as well as to compounds of formula (III).

EFFECT: obtaining new biologically active compounds having activity as 5-NT4 receptors.

24 cl, 29 ex, 4 tbl

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