Oxa- and thiazole derivatives as antidiabetic agents and anti-fat agents

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

 

The technical field

The present invention relates to new substituted derivatives of acids that modulate the level of blood glucose, triglyceride levels, insulin levels and the level neeterificirovannah fatty acids (NEFA) and, therefore, particularly useful for the treatment of diabetes and obesity, as well as to a method of treating diabetes, especially type 2 diabetes, as well as hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, atherosclerosis and related diseases, the application of such substituted derivatives of acids alone or in combination with another antidiabetic agent and/or a hypolipidemic agent.

Description of the invention

In accordance with the present invention proposed substituted derivatives of acids of formula I

where x has a value of 1, 2, 3 or 4; m is 1 or 2; n is 1 or 2;

Q represents C or N;

And represents O or S;

Z represents O or a bond;

R1represents lower alkyl;

X represents CH;

R2represents N;

R2a, R2band R2cmay be the same or different and are selected from H, alkoxy, halogen;

R3is aryloxyalkyl, allyloxycarbonyl, alkyl(halogen)aryloxyalkyl, alkyloxy(halogen)aryloxy arbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarboxamide, alkylsulfonyl, cyclohexanecarbonyl, heteroaromatic, alkoxycarbonyl, arylalkylamines, alkylaminocarbonyl, halogenocarboxylic, alkoxycarbonylmethyl, arylalkylamines, aryloxyalkanoic, arylalkylamines, heteroarylboronic, arylsulfonyl, arylalkylamines, allakariallak, heteroepitaxial;

cycloalkyl denotes a saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing from 1 to 3 rings, including monocyclohexyl, bicycloalkyl and tricyclohexyl containing in total from 3 to 20 carbons forming the rings, preferably 3 to 10 carbon atoms forming a ring;

aryl refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbon atoms in the ring selected from phenyl or naphthyl including 1-naphthyl and 2-naphthyl, and may optionally include one to three additional rings condensed with carbocyclic or heterocyclic ring selected from aryl, cycloalkyl, heteroaryl or cyclogeranyl ring;

heteroaryl denotes a 5 - or 6-membered aromatica is some ring, which contains 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur, and such rings fused with an aryl ring;

cyclogeranyl denotes cyclogeranyl group, 5 - or 6-membered saturated or partially unsaturated heterocyclic ring which contains 1, 2 or 3 heteroatoms selected from N, O or S, connected through an atom or heteroatom with (CH2)pchain; p is 0 or 1;

heteroaromatic denotes a heteroaryl group linked via an atom or heteroatom with alkylene or Alcanena;

Y represents CO2R4where R4represents H or alkyl,

where in all of these alkyl groups is a1-8alkyl, alkenyl represents a C2-8alkenyl, alkylene represents a C1-8alkylen, albaniles represents a C2-8albaniles,

including all stereoisomers and pharmaceutically acceptable salts, with the proviso that if a represents Oh, then R3is not aryloxyalkyl or alkoxycarbonyl.

The compounds of formula I according isobutene can have the structure

or

Preferred are the compounds of formula I according to the invention, having the structure

More preferred are the compounds of formula I according to the invention, having the structure

In the above compounds most preferably, when R2Arepresents alkoxy, but more preferably N, Z represents a bond, but more preferably Oh, (CH2)xrepresents CH2, (CH2)2, (CH2)3or, (CH2)mrepresents CH2or(where Ra is an alkyl, such as methyl, or alkenyl, such asor, (CH2)nrepresents CH2, R1represents lower alkyl, preferably-CH3, R2represents H, R2arepresents H, R4represents H, X represents CH and R3is arylalkylamines, arylheteroacetic, aryloxyalkyl, arylalkyl, aryloxyalkyl, halogenoalkanes, alkoxycarbonyl, alkylaminocarbonyl, aryloxyalkanoic, heteroepitaxial, heteroarylboronic, aryloxyalkanoic, arylalkylamines, cycloalkylcarbonyl, arylalkylamine is of IMT, heteroaryl-heteroallyl, cycloalkylcarbonyl, heteroaryl-heteroarylboronic, alkylaminocarbonyl, arylalkylamines, arylalkylamines, alkoxyalkyl, aristochromis, cyclohexanecarbonyl, cyclohexanecarbonyl or polyhalohydrocarbon, where the above preferred groups may be optionally substituted.

Preferred compounds according to the invention include the following:

Detailed description of the invention

The compounds of formula I of the present invention can be obtained in accordance with the following General synthesis schemes, as well as in the published literature relevant methods that use specialists Dunn the level of technology. Examples of the reagents and methods of these reactions are described hereafter, as well as in the working examples. Protect and unprotect in the diagrams below, can be carried out by methods well known in the prior art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3rdEdition, 1999 [Wiley]).

Scheme 1 describes a General synthesis of amino acids described in the present invention. Alcohol II (R5(CH2)xOH) (most preferred is 2-phenyl-5-methoxazole-4-ethanol) condense with hydroxyaryl or heteroanalogues III (preferably 3 - or 4-hydroxybenzaldehyde) in a standard reaction conditions Mitsunobu (Mitsunobu) (for example, Mitsunobu, O., Synthesis, 1981, 1). The resulting aldehyde IV is then subjected to reductive aminating using methods known from the prior art (for example, Abdel-Magid, etc., J. Org. Chem. 1996, 61, 3849), hydrochloride α-aminoether V. PG in figure 1 indicates the preferred protective group for carboxylic acids, such as methyl or tert-butyl methyl ether. The resulting secondary aminoether VI then subjected to repeated recovery aminating using methods known from the prior art (for example, Abdel-Magid, etc., J. Org. Chem. 1996, 61, 3849), with R3athe aldehyde VII. The final removal of the protective groups with ether carboxylic acid under standard conditions known from the prior art (Grene), when using basic conditions (for methyl esters) or acidic conditions (tert-butyl esters) then leads to the production of desired products, which are amino acids ID.

An alternative path to the aldehyde IV is shown in scheme 1A. Alcohol II (R5(CH2)xIT) (of which the most predpochtitelnei is 2-[2-phenyl-5-methoxazole-4-yl]ethanol) treated with methanesulfonamide to obtain the corresponding nelfinavir VIII. Mesilate then alkylate the standard basic conditions using hydroxyaryl or hydroxycitronellal III with obtaining aldehyde IV.

An alternative route to amino acids IF shown in scheme 2. Secondary aminoether VI remove a protective group under standard conditions (basic conditions, if the protecting group (PG) is methyl; acidic conditions, if PG is tert-bootrom) to obtain the corresponding amino acids IE. Reductive amination with R3aaldehyde under similar conditions as described in scheme 1, results in the desired tertiary products of amino acids IF the quality of the products.

Alternatively, as shown in figure 3, the tertiary amino acids IF can also be obtained by alkylation of the secondary aminoether alkylating agent VI IX (with a suitable leaving group (LG)such as halogen, mesilate or tosylate) in standard the x terms known from the prior art, with the subsequent standard by removing the protective groups, ether carboxylic acids X to obtain amino acids IF.

As shown in figure 4, the tertiary amino acid IF it can be formed via reductive amination first R3aaldehyde XI with a suitable hydrochloride aminoether V. the Resulting secondary aminoether XII then subjected to reductive aminating with a suitable aldehyde alkyl, aryl or heteroaryl IV (scheme 1), followed by removing the protective groups of an ether carboxylic acid to obtain the desired analogues of amino acids IF.

Further amino acid substitution is shown in the General scheme of the synthesis of 5. Reductive amination of the appropriate amine XIII aryl - or heteroanalogues XIV in standard conditions leads to the corresponding secondary amine XV, which is then subjected to reaction with halogenation XVI (for example, tert-butylbromide) to obtain the corresponding α-aminoether XVII. I received aminoether XVII then remove the protective group under standard conditions to obtain the desired analogues of amino acids IF.

The method of synthesis in scheme 5 also shows a General scheme of the synthesis of the corresponding aminophosphonic acids IFA, as shown in figure 5A. Secondary amine XV is subjected to reaction with an appropriate protected halogeno the atom XVIA to obtain the corresponding aminophosphate ether XVIIA, which then remove the protective group under standard conditions (Greene & Wuts with getting aminophosphonic acid IFA. In the diagram 5b shows the synthesis aminophosphinic acids IFB, which also include the reaction of suitably protected halogenosilanes ether XVIB with a secondary amine XV. Removing the protective groups formed aminophosphonates ether then leads to the production of phosphine acid IFB.

An alternative method to the sequence in scheme 5 shown in scheme 6. Hydroxyaryl or heteroaryl XVIII selectively protect the nitrogen of obtaining protected amine XIX. Preferred R5(CH2)nOH (II) is then subjected to reaction with XIX under the reaction conditions Mitsunobu (Mitsunobu) to obtain the corresponding simple ether, followed by removal of the protective groups of the amine, to obtain the free amine XX. The free amine XX then trigger standard trigger group (2,4-dinitrobenzenesulfonic; .Fukuyama and others, Tetrahedron Lett. 1997, 38, 5831) and then treated α-halogenation XVI, as shown in scheme 5. With 2,4-dinitrobenzenesulfonic XXI remove a protective group under conditions known from the prior art (T. Fukuyama and others, Tetrahedron Lett., 1997, 38, 5831) obtaining secondary α-aminoether XXII, which is then subjected to reductive aminating with R3athe aldehyde XI with subsequent removal of the protective groups with ether X with the teachings of the desired analogues IF.

Scheme 7 describes an alternative way to analogs of amino acids IG. Hydroxyaryl or wateroriented III is subjected to normal conditions of reductive amination with a suitable hydrochloride aminoether V. the Resulting secondary aminoether XXIII functionalitywith in this case, repeated by reductive amination with R3athe aldehyde VII to obtain the corresponding tertiary hydroxylaminopurine XXTV. It can be subjected to reaction Mitsunobu with the corresponding alcohol II (R5(CH2)nOH), followed by removing the protective groups of the ester XXV, which results in obtaining the desired analogues IG.

Scheme 8 describes a General synthesis of diaryl - and allgemeinmedizin analogues of amino acids IH. Secondary aminoether XXII subjected to reductive aminating with suitably substituted formylphenylboronic acid XXVI under standard conditions to obtain the corresponding tertiary aminoethers Bronevoy acid XXVII. Arylboronic acid XXVII can then undergo condensation Suzuki (Suzuki) (for example, conditions described in Gibson, S.E., Transition Metals in Organic Synthesis, A Practical Approach, pp.47-50, 1997) with aryl - or heteroarylboronic XXVIII (especially bromine) with a suitable mirandamiranda dialling products XXIX. Removing the protective groups from aminoether XXIX results in the desired analogues amino is islote IH.

Scheme 9 describes the total synthesis of diaryl - and arylheteroalkanecarboxylic analogues of amino acids IJ. Tertiary aminoethyl Bronevoy acid XXVII, which is described in scheme 8, can be powerget condensation with a suitably substituted phenols XXX under conditions known from the prior art (D.A.Evans and others, Tetrahedron Lett., 1998, 39, 2937) to obtain the corresponding diaryl - or arylheteroacetic XXXI, which after removing the protective groups lead to amino acid analogues IJ.

Alternatively, as shown in scheme 10, reductive amination of secondary aminoether XXII with a suitably substituted hydroxyaryl or hydroxymatairesinol XXXII leads to the corresponding tertiary femalemanaegre XXXIII. Phenol XXXIII may further be subjected to binding with the appropriate aryl or heteroaryl boronowski acids XXXIV under conditions known from the prior art (D.A.Evans and others, Tetrahedron Lett., 1998, 39, 2937) to obtain the corresponding diaryl - or arylethanolamine esters XXXI. The desired analogues IJ can then be obtained by removing the protective groups aminoether XXXI.

Figure 11 shows the synthesis carbonatation analogues IK. Secondary aminoether XXII can respond with the appropriate chloroformate XXXV under conditions known from the prior art (optimally in CH2Cl2or CHCI3in the presence of the basis of the Oia, such as Et3N) the corresponding carbonatation. The desired analogues IK then get after removing the protective groups from carbamaaepine. Alternatively, the secondary aminoether XXII may react with phosgene to obtain the corresponding carbamoylated XXXVI. Specified intermediate carbamoylated XXXVI can react with R3a-OH (XXXVII) (optimally substituted phenols) to give the corresponding carbamate-acid IK after removing the protective groups.

Figure 12 shows further functionalization of aryl carbonatation analogues IK. Secondary aminoether XXII subjected to reaction with arillotta XXXVIII (containing a protected hydroxy-group) obtaining XXXIX. With a hydroxyl group is then selectively removed protection in the presence of an ether with obtaining XL, then alkylate suitable R6-LG (XLI) (where LG is Galand, mesilate or toilet and R6is the most preferable CHF2or CH3CH2-) in the presence of a base. Removing the protective groups with ether then results in the desired carbonatation analogues IL.

Secondary aminoether XXIIA can be funktsioniroval substituted aryl or aliphatic carboxylic acids XLII, in standard conditions for peptide as shown in scheme 13. The formation of the amide bound and carried out in accordance with the standard methods of obtaining peptide, known from the prior art. Optimally, the reaction is carried out in a solvent such as DMF, at a temperature of from 0°to room, using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC or EDCI or WSC), 1-hydroxybenzotriazole (NOVT) or 1-hydroxy-7-asobancaria (NEAT) and a base, such as base Janiga (Hunig) (diisopropylethylamine), N-methylmorpholine or triethylamine. Removing the protective groups from amidoamine then results in the desired aminokislotnykh analogues IM.

Secondary aminoether XXIIA can also react with the aliphatic or aryl isocyanates XLIII with obtaining appropriate urea-ethers. Removing the protective groups of the urea-ethers results in the desired urea-acid analogues IN as shown in figure 14. Alternatively, as shown in scheme 15, the intermediate carbamoylated XXXVI described in scheme 11, can react with suitable aliphatic or ariline amines XLIV in the presence of tertiary amine (for example, Et3N) to obtain the three - or Tetra-substituted mechelininkatu analogues IO or IP after removing the protective groups from the air.

Secondary aminoether XXIIA may also respond with appropriate sulphonylchloride XL VI under standard conditions known from the literature (optimally in the presence of a base, such as pyridine, pure or in mixture with chloroform as Sora is the solvent), with the subsequent removal of the protective groups to obtain the corresponding sulfonamidnuyu acids IQ, as shown in scheme 16.

The substitution of a functional group of carboxylic acid in these analogues on tetrazol can be carried out as shown in scheme 17. Acid analogue IK condensed with the amine (containing a suitable tetrazolo protective group) XLVII (preferably 3-aminopropionitrile) under standard conditions to obtain the peptide. The resulting secondary amide XLVIII then subjected to reaction Mitsunobu under standard conditions with trimethylsilylacetamide (TMSN3) to obtain the protected tetrazole XLIX. Removing the protective groups with cyanoethylene group carried out preferably in the presence of base to give the desired free analog tetrazole IR.

Scheme 18 describes the total synthesis hydrazinoacetate analogues IS. Substituted arylcarbamoyl acid 1 is treated with methanesulfonamide in the presence of a base; an intermediate connection then subjected to reaction with the protected hydrazinolysis VA to obtain the corresponding acylated hydrazine 1A (see Synthesis, 1989, 745-747).

Acylhydrazone 1A condense with a suitable substituted arilaldegidov IV under conditions of reductive amination to obtain the corresponding protected hydrazide ester 3 (see Can. J. Chem., 1998, 76, 1180-1187).

Removing the protective groups from the Fira 3 then yields a hydrazide-acid analogues IS.

Alternative synthesis related to hydrazinoacetate IS shown in figure 19. Killdevil IV can be restored to the corresponding alcohol under standard conditions (e.g., NaBH4), This alcohol is then converted into the corresponding bromide 4 using standard conditions (e.g., Ph3R/CBr4or PBr3). Bromide 4 then subjected to reaction with hydrazinium 1A (see Tetrahedron Lett., 1993, 34, 207-210) to obtain the protected Herzegovina 3, which then remove the protective group to obtain hydrazinoacetate analogues IS.

Different approaches to obtain analogs α-alkylbenzenesulfonate and carbamate-acid IT and IU are presented on the following synthesis schemes. Figure 20 suitable substituted killdevil IV is treated with a suitable ORGANOMETALLIC reagent (for example, a Grignard reagent R10MgBr) under standard conditions to obtain the corresponding secondary alcohol, which is then oxidized under standard conditions (for example, Swern oxidation with (COCl)2/DMSO/Et3N or using Chloramin pyridinium) to obtain the corresponding ketone 5. Reductive amination of ketone 5 with a suitably substituted aminoethanol 6 leads to the corresponding α-alkylbenzenesulfonic 7. It is clear that in aminoether 6 balancenot necessarily represent the possessing a two repeating units.

Acylation of aminoether 7 with a suitable substituted aryl - or heteroarylboronic XXXV, followed by removing the protective groups yields a racemic carbonatation analogues of IT. Reductive amination of alkylbenzenesulfonic 7 arilaldegidov VII, followed by removing the protective groups yields a racemic amino acid analogues IU.

Alternatively, as shown in scheme 21, asymmetric recovery (for example, using the method oxazaborolidine recovery Corey; see E.J. Corey & S. Helal, Angew. Chem. bit. Ed. Engl., 1998, 37, 1986-2012) arylketones 5 results in any desired enantiomeric alcohols 8 (although only one enantiomer is shown in the diagram). Processing chiral alcohol 8 azide in the reaction, such reaction Mitsunobu (see A.S. Thompson et. al, J. Org. Chem. 1993, 58, 5886-5888), leads to the corresponding chiral azide (with the handling of stereochemistry with respect to the source of the alcohol). Azide is then converted into the amine 9 standard recovery techniques (e.g., gidrogenizirovanii or Ph3R/THF/H2About). Processing chiral amine 9 ether XVIA (containing a suitable leaving group) results secondary aminoether 10. Acylation of aminoether 10 aryl - or heteroarylboronic XXXV, followed by removing the protective groups leads to the production of chiral carbama kislotnyh analogues ITa (which can be any enantiomers, depending on the stereochemistry of compound 8). Reductive amination of alkylamidoamines 10 arelargely VII, followed by removing the protective groups leads to the production of chiral amino acid analogues IIIa (which can be Lubimy the enantiomers depending on the stereochemistry of compound 8).

An alternative path to the circuit 21 shown in scheme 22. Suitably protected oxicillin 11 is subjected to an asymmetric recovery with obtaining chiral alcohol 12. It transformed into a chiral amine 13 in accordance with methods similar to those described in scheme 21 (via chiral azide). Processing chiral amine 13 ether XVIA (LG = halogen or mesilate) leads to the corresponding secondary aminoether 14. The acylation 14 aryl - or heteroarylboronic XXXV yields a corresponding carbamaaepine. Selective removal of the protective groups results in a free finalternatives 15. Alkylation of phenol 15 halide or mesilate VIII, followed by removing the protective groups results in carbonatation analogues ITa. A similar sequence involving reductive amination of secondary aminoether 14 aryl - or heteroanalogues VII, then selective removal of the protective groups, alkylation with the eighth and final removal of the protective groups) results in amino acid analogues IUa.

Obviously, Thu is (R)- or (S)-enantiomers ITa or IIIa can be obtained in accordance with circuits 21 and 22 depending on the chirality used restorative agent.

The fourth sequence of the synthesis shown in scheme 23. Substituted aldehyde IV condense hydrochloride aminoether 6 to obtain the corresponding imine 16, which is then treated in situ with a suitable substituted allergologicum 17 in the presence of metal India (see Loh, T.-P. and others, Tetrahedron Lett., 1997, 38, 865-868) obtaining α-allianceandempire 18. Acylation of amine 18 aryl - or heteroarylboronic XXXV, followed by removing the protective groups results in carbonatation analogues I. Reductive amination of alkylamidoamines 18 aryl - or heteroanalogues VII, followed by removing the protective groups results in amino acid analogues IW.

Figure 24 shows the desired intermediate 2-aryl-5-methoxazole-4-iletileri 21 (following the General procedure described in Malamas, .S. etc., J. Med. Chem., 1996, 39, 237-245). Substituted killdevil 19 condense with butane-2,3-daemonversion in acidic conditions to obtain the corresponding oxazol-N-oxide 20. Deoxyadenosine oxazol-N-oxide 20 with a concomitant chlorination results in the desired hermeticallysealed 21. Hydrolysis of chlormethiazole 21 in the basic conditions leads to the receipt of oxazolidinone 22. Oxidation of the alcohol 22 to the corresponding aldehyde is carried out with subsequent transformation into with the relevant dibromsalan 23 (for example, Ph3R/CBr4). Dibromide 23 turn in the appropriate alkyllithium balance (use organolithium reagent, such as n-BuLi), which can be subjected to reaction in situ with a suitable electrophile, such as formaldehyde, to obtain the corresponding acetylenic alcohol (see Corey, E.J., and others, Tetrahedron Lett. 1972, 3769, or Gangakhedkar, K.K., Synth. Commun. 1996, 26, 1887-1896). The specified alcohol can then be converted into the corresponding mesilate 24 and is alkylated with a suitable phenol 25 obtaining analogues 1X. Further stereoselective reduction (for example. H2/Lindlar catalyst) results in E - or Z-albanianlove IV.

Scheme 25 describes the total synthesis aminobenzotriazole analogues IZ (reference: Sato, Y. and others, J. Med. Chem. 1998, 41, 3015-3021). Suitable substituted ortho-aminophenol 26 is treated with CS2in the presence of a base to obtain the corresponding mercaptobenzoxazole 27. Processing the received thiol 27 appropriate gloriouse agent (e.g., DCS) leads to the production of a key intermediate chlorobenzoxazole 28, which is subjected to reaction with a secondary aminoether VI obtaining, after removing the protective groups, aminobenzonitrile analogues IZ.

TietoEnator IZa synthesized in accordance with the General scheme of the synthesis shown in scheme 26 (see Collins, J.L., and others, J. Med. Chem. 1998, 41, 5037). Secondary is th aminoether XXIII subjected to reaction with aryl - or heteroarylboronic XXXV in the presence of a suitable base (for example, pyridine or triethylamine) to obtain the corresponding hydroxycarbamoyl 29. Hydroxyaromatic 29 then subjected to reaction with suitable substituted α-brompheniramine 29A (S3=CH3for example, Weyerstahl, P., and others, Flavour Fragr. J., 1998, 23, 177, or Sokolov, N. A. and others, Zh. Org. Khim., 1980, 16, 281-283) in the presence of a suitable base (For example, a2CO3) to obtain the corresponding adduct reaction Michael, α-brancheorganisatie 30. α-Bratton 30 then subjected to the condensation reaction with suitable substituted arylamido 31 (=O) or arylthioureas 31 (A=S) and receiving the corresponding oxazole (amide) or thiazole (from thioamide) (see Malamas, M. S., and others, J. Med. Chem., 1996, 39, 237-245). Finally, removing the protective groups of the esters 31 then leads to the production of substituted oxazol and thiazolecarboxamide analogues IZa.

It is obvious that in the following diagrams, where get carbonatation counterparts, the corresponding analogues of amino acids can also be obtained by substitution reaction with CHLOROFORMATES on the aldehyde in the recovery aminating (as in figure 20 with the intermediate amine 7).

Scheme 27 describes the total synthesis of acids IZb and IZc. Halogensubstituted killdevil 32 (preferably iodide or bromide) is subjected to reductive aminating, using the technique known from the prior art (for example, Abdel-Magid and the RV, J. Org. Chem. 1996, 61, 3849) with hydrochlorot α-amino acid ester V. the Resulting secondary aminoether 33 then subjected to reaction with aryl - or heteroarylboronic XXXV in the presence of a suitable base (e.g. pyridine or triethylamine) to obtain the corresponding halogenerator 34. Aryl halides 34 are then subjected to reaction with an appropriate aryl - or heteroarylboronic acetylene 35 (preferred acetylene is 5-phenyl-2-methoxazole-4-ylmethylamino) in the presence of a suitable palladium catalyst (for example, (Ph3R)2PdCl2and salts of copper (I) (e.g., Cul) in the condensation reaction by Sonogashira (Sonogashira) (see Organocopper Reagents, a Practical Approach, R. J. K. Taylor, Ed., Chapter 10, pp 217-236, Campbell, I.B., Oxford University Press, 1994) to obtain the key intermediate arylacetylenes ether 36.

With arylacetylenes ether 36 remove a protective group to obtain the corresponding arylacetylenes analogues IZb. Acetylene group 36 may be recovered by standard methods (for example, hydrogenomonas, see M. Hudlicky, Reductions in Organic Chemistry, 2ndEdition, ACS, 1996, Chapter 1) to obtain the corresponding fully saturated alkylarylsulphonates ether, which then remove the protective group to obtain alkylarylsulfonate analogues IZc. Stereoselective recovery of acetylene ether is 36 by standard methods (for example, the Lindlar catalyst; see Preparation of Alkenes, A Practical Approach, J.J. Williams, Ed., Chapter 6, pp 117-136, Oxford University Press, 1996) can be performed to obtain the corresponding CIS-alkariaribinnatencvr, which then remove the protective group to obtain Z-alkenylzirconocene analogues IZd (scheme 28). Alternatively, this sequence can be reversed, i.e. the initial step is the removal of the protective groups with acetylene ether 36 obtaining acetylene acid with subsequent stereoselective recovering acetylene group with obtaining Z-ascencion analogues IZd.

The corresponding TRANS-alkenylsilanes acid IZe can be obtained in accordance with the General method of scheme 29. Aryl - or heterogenisation 35 (preferred group again is 5-phenyl-2-methoxazole-4-ylmethylamino) halogenous under standard conditions (see Boden, S. D. J., and others, J. Chem. Soc. Perkin Trans. I, 1996, 2417, or Lu, W. et. al., Tetrahedron Lett. 1998, 39, 9521) to obtain the corresponding halogenation, which is then converted into the corresponding TRANS-alkenylsilanes 37 (see Boden, S. D.J., J. Chem. Soc., Perkin Trans. I, 1996, 2417). The resulting aryl - or heteroarylboronic TRANS-alkenylsilanes 37 then associated with halogenoalkanes ether 34 in the standard combination of condensation on Still (Stille) (see Farina, V. E., and others, "The Stille Reaction", Organic Reactions, 1997, 50, 1) obtaining from the relevant TRANS-alkenylsilanes ester 38. With the specified carbamaaepine then remove the protective group under standard conditions to obtain the desired TRANS-alkenylzirconocene analogues IZe.

Appropriate cyclopropyl analogues IZf and IZg receive in accordance with the Scheme 30. For CIS - or (Z) cyclopropyl analogues using stereoselective reduction (N2/ Lindlar catalyst) alkenylphenol group interim akinrinola ether 36 (as analogues for IZd) with subsequent cyclopropylamine under standard conditions (Zhao, Y. and others, J. Org. Chem. 1995, 60, 5236-5242), and then removing the protective groups leads to the production of CIS-cyclopropanecarbonitrile analogues IZf. For TRANS-cyclopropyl analogues IF used a similar cyclopropylamine E-alkinoos group intermediate connection 38 with the subsequent removal of the protective groups, resulting in TRANS-cyclopropanecarboxylate analogues IZg.

Scheme 1

In this and the following reaction schemes

An alternative scheme 1A to obtain the aldehyde IV

Scheme 1A

Scheme 2

(S1=H, alkyl, halogen, alkoxy, alkylthio, alkylamino, aryloxy, aryl, heteroaryl, alkoxycarbonyl, alkylaminocarbonyl; S2=H, alkyl, halogen, alkoxy, alkylthio, alkylamino, aryloxy, aryl, heteroaryl, alkoxycarbonyl, alkylaminocarbonyl)

Scheme 11

Unless otherwise specified, the term "lower alkyl", "alkyl" or "ALK"as used here by itself or as part of another group includes linear and branched the s-chain hydrocarbons, containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms in the normal chain, and may optionally include an oxygen or nitrogen in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched isomers, and the like, as well as such groups, which include 1 to 4 substituents such as halogen, for example F, Br, Cl or I or CF3, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylation, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaromatic, cyclogeranyl, Allgeier, arylethoxysilanes, heteroallyl, heteroaromatics, aryloxyalkyl, aryloxyalkyl, alkylamino, alkanolamine, arylcarboxamide, nitro, cyano, thiol, halogenated, trihalomethyl and/or alkylthio and/or any of R3groups.

Unless otherwise specified, the term "cycloalkyl"which is used herein by itself or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing from 1 to 3 rings, including monocyclohexyl, bicycal the sludge and tricyclohexyl, containing in total from 3 to 20 carbons forming the rings, preferably 3 to 10 carbon atoms forming the ring and which may be condensed with 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

,,,,,

any of these groups can be optionally substituted by 1-4 substituents, such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamino, alkanolamine, oxo, acyl, arylcarboxamide, amino, nitro, cyano, thiol and/or alkylthio and/or any of the substituents for alkyl.

The term "cycloalkenyl"which is used herein by itself or as part of another group, refers to a cyclic hydrocarbon containing from 3 to 12 carbon atoms, preferably from 5 to 10 carbon atoms, and 1 or 2 double bonds. Examples cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, cyclohexadienyl and cycloheptadiene, which may be optionally substituted as defined for cycloalkyl.

The term "cycloalkyl", which is here used is:, means cycloalkyl group, which includes free links and, therefore, is a linker group, such as,and the like, and may optionally be substituted as indicated above for the "cycloalkyl".

The term "alkanoyl"which is used herein by itself or as part of another group refers to alkyl associated with the carbonyl group.

Unless otherwise specified, the term "lower alkenyl" or "alkenyl"which is used herein by itself or as part of another group, refers to linear or branched radicals containing from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms and more preferably from 2 to 8 carbon atoms in the normal chain, which include one to six double bonds in the normal chain, and may optionally include an oxygen or nitrogen in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenal, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecanoyl and the like, and which may be optionally substituted from 1 to 4 substituents, namely, halogen, halogenation, alkyl, alkoxy, alkenyl, quinil, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cyclo what heteroalkyl, alkanolamine, alkylamine, arylcarboxamide, nitro, cyano, thiol, alkylthio and/or any Deputy for alkyl above.

Unless otherwise specified, the term "lower quinil" or "quinil"which is used herein by itself or as part of another group, refers to linear or branched radicals containing from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms and more preferably from 2 to 8 carbon atoms in the normal chain, which include one triple bond in the normal chain, and may optionally include an oxygen or nitrogen in the normal chain, such as 2-PROPYNYL, 3-butynyl, 2-butynyl, 4-pentenyl 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4 - heptenyl, 3-octenyl, 3-nonenal, 4-decenyl, 3-undecenyl, 4-dodecenyl and the like, and which may be optionally substituted by 1-4 substituents, namely, halogen, halogenation, alkyl, alkoxy, alkenyl, quinil, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cyclogeraniol, hydroxy, alkanolamine, alkylamine, arylcarboxamide, nitro, cyano, thiol and/or alkylthio and/or any of the substituents for alkyl above.

The terms "arylalkyl and arylalkyl", which are used by themselves or as part of another group, refers to alkenyl and alkynylaryl groups, as described above, with the arilje the first Deputy.

Where the alkyl groups defined above are simple for connection to other groups and two different carbon atoms, they are called "alkylene group, and can optionally be substituted as indicated above for "alkyl".

Where alkeneamine group, as defined above, and alkyline group, as defined above, respectively, are simple for connection to two different carbon atoms, they are called "alkenylamine group" and "alkenylamine groups, respectively, and may optionally be substituted as indicated above for the "alkenyl" and "quinil".

(CH2)x, (CH2)m, (CH2)nor (CH2)yincludes alkylene, alltel, albaniles or alkenylamine group, as here defined, each of which may optionally include oxygen or nitrogen in the normal chain, which may optionally include 1, 2, or 3 substituent which include alkyl, alkenyl, halogen, cyano, hydroxy, alkoxy, amino, thioalkyl, keto,3-C6cycloalkyl, alkylcarboxylic or alkylcarboxylic; alkyl Deputy may be Allenova group with 1-4 carbon atoms that may join one or two carbon atoms in (CH2)xor (CH2)mor (CH2)nthe group with the formation of cycloalkenes.

Examples (CH2)x, (CH2)m, (CH2)n, (CH2)y, alkylene, Alcanena and akinlana include

,,,,

,,,

,,,,,

,,,,,

,,,,,

,,,,

,,,,

,,,

,,,

,,,,

,,or.

The term "halogen" or "halo"as used here by itself or as part of another group refers to chlorine, bromine, fluorine and iodine, as well as CF3, preferably chlorine or fluorine.

The term "metal ion" refers to ions of alkali metals such as sodium, potassium or lithium, and alkaline-earth metals such as magnesium or calcium, zinc and aluminum.

Unless otherwise specified, the term "aryl"as used here by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbon atoms in the ring (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and may optionally include one to three additional rings condensed with carbocyclic or heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheptatriene rings, for example

,,,,,

, ,,,

,,,,

and they can be optionally substituted through an acceptable carbon atoms 1, 2, or 3 groups selected from hydrogen, halogen, halogenoalkane, alkyl, halogenoalkane, alkoxy, halogenoalkane, alkenyl, trifloromethyl, triptoreline, quinil, cycloalkyl-alkyl, cyclogeranyl, cyclohexanoltramadol, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, Allakaket, alkoxycarbonyl, arylcarbamoyl, arylalkyl, aminocarbonylmethyl, aaltio, arylsulfonyl, arylazo, heteroallyl, heteroallyl, heteroarylboronic, heteroaromatic, hydroxy, nitro, cyano, amino, substituted amine, where the amine includes 1 or 2 Deputy (which are alkyl, aryl or any of the other aryl compounds mentioned in the description in the section "definitions"), thiol, alkylthio, aaltio, heteroaromatic, alltoall, alkoxyaryl, alkylcarboxylic, arylcarbamoyl, alkylaminocarbonyl, arylenecarborane, alkoxycarbonyl, aminocarbonyl, alkylcarboxylic, arylcarboxylic, alkylcarboxylic, arylcarboxamide, arylsulfonyl, arylsulfonyl, arylsulfonyl or arylsulfonyl and/or is any substituent for alkyl, specified here.

Unless otherwise specified, the term "lower alkoxy", "alkoxy", "aryloxy" or "arakaki"which is used herein by itself or as part of another group includes any of the above alkyl, aracelio or aryl group linked to the oxygen atom.

Unless otherwise specified, the term "substituted amino"as used here by itself or as part of another group, refers to an amine substituted by one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroaromatic, cyclogeranyl, cyclohexanoltramadol, cycloalkyl, cycloalkenyl, halogenated, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted by carboxylic acid and/or any Deputy for alkyl above. In addition, aminosalicylic can be taken together with the nitrogen atom to which they are attached, with the formation of 1-pyrrolidinyl, 1-piperidinyl, 1-azepine, 4-morpholinyl, 4-thiomorpholine, 1-piperazinil, 4-alkyl-1-piperazinil, 4-arylalkyl-1-piperazinil, 4-varilly-1-piperazinil, 1-pyrrolidinyl, 1-piperidinyl or 1-azepine, optionally replaced by alkyl, alkoxy, alkylthio, halogen, trifluoromethyl or hydroxy.

Unless otherwise specified, the term "lower alkylthio", alkylthio", "aryl is IO" or "Uralkali", used here by itself or as part of another group includes any of the above alkyl, aracelio or aryl group associated with the sulfur atom.

Unless otherwise specified, the term "lower alkylamino", "alkylamino", "arylamino" or "arylalkylamine"which is used herein by itself or as part of another group includes any of the above alkyl, aryl or arylalkyl groups connected to the nitrogen atom.

Unless otherwise specified, the term "acyl", which is used by itself or as part of another group, as defined here, refers to an organic radical linked to a carbonyl () group; examples of acyl groups include any R3group attached to a carbonyl, such as alkanoyl, alkanoyl, aroyl, arkanoid, heteroaryl, cycloalkenyl, cyclohexanol and the like.

Unless otherwise specified, the term "cyclogeranyl"which is used herein by itself or as part of another group denotes a 5-, 6 - or 7-membered saturated or partially unsaturated ring which includes 1 to 2 heteroatoms, such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p(where p denotes 1, 2 or 3), such as

,,,,

,,,,

,,,

,,,

and like them. The above groups may include 1 to 4 substituents such as alkyl, halogen, oxo and/or any of the substituents for alkyl or aryl, shown here. In addition, any of cyclogeranyl rings may be condensed with cycloalkyl, aryl, heteroaryl or cyclogeranyl ring.

Unless otherwise specified, the term "heteroaryl"which is used herein by itself or as part of another group denotes a 5 - or 6-membered aromatic ring which contains 1, 2, 3 or 4 heteroatoms, such as nitrogen, oxygen or sulfur, and such rings fused with aryl, cycloalkyl, heteroaryl or cyclogeranyl ring (for example, benzothiophene, indolyl), and includes possible N-oxides. Heteroaryl group may optionally include 1 to 4 substituents such as any of the substituents for the alkyl is any aryl, above.

Examples of heteroaryl groups include the following:

,,,,

,,,,,,

,,,,,,

,,,,,

and similar to them.

The term "cyclohexanoltramadol"which is used herein by itself or as part of another group, refers to cyclogeranyl groups as defined above linked via an atom or heteroatom with (CH2)pchain.

The term "heteroaromatic" or "heteroaromatic"which is used herein by itself or as part of another group, refers to a heteroaryl group as defined above linked via an atom or heteroatom -(CH2)p- chain, alkylene or Alcanena, as defined above.

The term "polylog alkyl", which is used here, refers to "alkyl" group as defined above which includes from 2 to 9, preferably from 2 to 5 halogen substituents, such as F or Cl, preferably F, such as CF3CH2, CF3or CF3CF2CH2.

The term "polygalacturonic", which is used here, refers to a group "alkoxy" or "alkyloxy"as defined above which includes from 2 to 9, preferably from 2 to 5 halogen substituents, such as F or Cl, preferably F, such as CF3CH2O, CF3On or CF3CF2CH2O.

The term "Proletarskoye esters", which is used here, includes proletarienne essential forms, which are known from the prior art for esters of carboxylic and phosphoric acids, such as methyl, ethyl, benzyl and the like. Other examples procarcinogen ether R4include the following groups:

(1 alkanoyloxy)alkyl, such as

or

where Ra, Rband Rcrepresent H, alkyl, aryl or arylalkyl;

however, RaO may not be BUT.

Examples of such proletarienne esters R4include

,,or

.

Other examples of suitable proletarienne esters R4include

,,,,

,

where Randcan be H, alkyl (such as methyl or tert-butyl), arylalkyl (such as benzyl) or aryl (such as phenyl); Rdrepresents H, alkyl, halogen or alkoxy, Rerepresents alkyl, aryl, arylalkyl or alkoxy and n1is 0, 1 or 2.

Where compounds of structure I are in the acid form, they can form pharmaceutically acceptable salt, such as alkali metal salts, such as lithium, sodium or potassium, salts of alkaline-earth metals such as calcium or magnesium, as well as salts of zinc or aluminum and other cations such as ammonium, choline, diethanolamine, lysine (D or L), Ethylenediamine, t-butylamine, tert-octylamine, Tris-(hydroxymethyl)aminomethan (TRIS), N-methylglucamine (NMG), triethanolamine and dehydroabietylamine.

All stereoisomers of the compounds of the present invention refers to either in a mixture or in pure or nearly pure form. Compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one or R Zam is stately. Therefore, the compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures. Methods of obtaining can use the racemates, enantiomers or diastereomers as starting materials. Upon receipt of the diastereomeric or enantiomeric products they can be separated by conventional methods such as chromatography or fractional crystallization.

Optionally, compounds of structure I may be used in combination with one or more hypolipidemic agents or lipid-lowering agents and/or one or more other types of therapeutic agents, including anti-diabetic agents, agents against obesity, antihypertensive agents, platelet aggregation inhibitors and/or anti-osteoporosis agents that can be administered orally at the same dose form, in a separate oral dose form or by injection.

The hypolipidemic agent or lipid-lowering agent, which may optionally be used in combination with compounds of the formula I according to the invention may include 1, 2, 3 or more MTP inhibitor, an inhibitor of HMG COA reductase inhibitor salanova synthetases, an inhibitor of fibrin derivatives acids, ACAT inhibitors, lipoxygenase inhibitor, an inhibitor of cholesterol absorption, inhibitor iliac cotransporter Na+/alcinoe acid, the regulator of the activity of the LDL receptor, substances that increase the excretion of bile acid and/or nicotinic acid and derivatives thereof.

MTP inhibitors, applicable here include MTP inhibitors, is described in US 5595872, US 5739135, US 5712279, US 5760246, US 5827875, US 5885983 and request US 09/175180 filed 20.10.1998, currently US 5962440. Preferred are any of the preferred MTP inhibitors, is described in each of the above patents and applications.

All of the above US patents and applications listed here as references.

The most preferred MTP inhibitors, applicable in accordance with the present invention include the preferred MTP inhibitors, which are described in US 5739135, 5712279 and US 5760246.

The most preferred MTP inhibitor is 9-[4-[4-[[2-(2,2,2-triptoreline)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-triptorelin)-N-fluoren-9-carboxamide

The hypolipidemic agent may be an inhibitor of HMG COA reductase, which includes, but is not limited to such compounds as mevastatin and related compounds, which are described in US 3983140, lovastatin (mevinolin) and related compounds, which are described in US 4231938, pravastatin and related compounds, which are described in US 4346227, simvastatin and related compounds, which are described in US 4448784 and 4450171. Other HMG inhibitors Zoaretz, can be used include, but are not limited to, fluvastatin, described in US 5354772, tseriwastatina described in US 5006530 and 5177080, atorvastatin, described in US 4681893, 5273995, 5385929 and 5686104, itavastatin (Nissan/Sankyo nicastrin (NK-104)described in US 5011930, Shionogi-Astra/Zeneca visitation (ZD-4522), described in US 5260440, and related compounds statin described in US 5753675, pyrazol analogues mevalonate derivatives, which are described in US 4613610, indene analogues derivatives mevalonate that described in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)alkyl)Piran-2-ones and their derivatives, which are described in US 4647576, Searle SC-45355 (3-substituted derivative of pentanedionato acid), dichloromethane, imidazole analogues of mevalonate, which are described in PCT application WO 86/07054, derivatives of 3-carboxy-2-hydroxypropanesulfonic acid, which is described in FR 2596393, 2,3-disubstituted pyrrole, furan and thiophene derivatives, which are described in the application EP 0221025, raftiline analogues of mevalonate, which are described in US 4686237, octahydronaphthalene, such as described in US 4499289, ketoanalogue of mevinolin (lovastatin), which are described in the application EP 0142146 A2, and quinoline and pyridine derivatives described in US 5506219 and 5691322.

In addition, the compounds of phosphinic acid, are useful for inhibiting HMG COA reductase, suitable for use here, description is by GB 2205837.

Inhibitors salanova synthetases, suitable for use here include, but are not limited to, α-phosphosulfate described in US 5712396 described Biller and others, J. Med. Chem., 1988, Vol.31, No.10, pp 1869-1871, including isoprenoid (povinelli)phosphonates, as well as other known inhibitors salanova synthetases, such as that described in US 4871721 and 4924024 and Biller, S.A., Neuenschwander, K., Ponpipom, M.M. and Poulter, C.D., Current Pharmaceutical Design, 2, 1-40 (1996).

In addition, other synthetase inhibitors suitable for use in accordance with the invention, include terpenoid pyrophosphates described R. Ortiz de Montellang etc., J. Med. Chem., 1977, 20, 243-249, diphosphates similar farnesyl and Paskaleva pyrophosphate (PSQ-PP) analogues, which are described Soju and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, fashinistas described McClard, R.W., and others, J.A.C.S., 1987, 109, 5544, and cyclopropanes described Capson, T.L., PhD dissertation, June. 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary.

Other lipolipidemicescoe agents suitable for use here include, but are not limited to, derivatives of fibrin acid, such as fenofibrate, gemfibrozil, clofibrate, bezafibrat, ciprofibrate, clinofibrate and the like, probucol and related compounds, which are described in US 3674836, probucol and gemfibrozil, are the preferred substances that increase the excretion of bile acids, such as cholestyramine stake is tipol and DEAE-Sephadex (Secholex® , Policexide®) and cholestagel (Sankyo/Geltex), as well as LIPOSTABIL (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derived), manickal (NOAH-402), tetrahydrolipstatin (THL), stigmastadienol (SPC, Roche), aminocyclohexane (Tanabe Seiyoku), Ajinomoto AJ-814 (Aslanova derived), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277082 and CL-283546 (disubstituted urea derivatives), nicotinic acid (Niacin), acipimox, acifran, neomycin, n-aminosalicylic acid, aspirin, a derivative of poly(diallylmethylamine), such as that described in US 4759923, Quaternary amine poly(diallyldimethylammoniumchloride) and ionene, such as described in US 4027009, and other known agents that reduce the level of cholesterol in the plasma.

The hypolipidemic agent may be an ACAT inhibitor, such as described in Drugs of the Future 24, 9-15 (1999), (Avasimibe); "The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters", Nicolosi and others, Atherosclerosis (Shannon, Irel) (1998), 137 (1), 77-85;

"The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB 100-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16 (1), 16-30; "RP 73163: a bioavailable alkylsulfinil-diphenylimidazole ACAT inhibitor". Smith, C. and others, Bioorg. Med. Chem. Lett. (1996), 6 (1), 47-50; "ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals", Krause and others, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovic and others, Curr.Med. Chem. (1994), 1 (3), 204-25; "Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). Development of a series of substituted N-phenyl-N'-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity. Stout and others, Chemtracts: Org. Chem. (1995), 8 (6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd.

The hypolipidemic agent may be a regulator of the activity of the receptor LD2 such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eh Lilly).

The hypolipidemic agent may be an inhibitor of cholesterol absorption, preferably Schering-Plough's SCH48461, as described in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

The hypolipidemic agent may be an inhibitor iliac cotransporter Na+/bile acid, such as described in Drugs of the Future, 24, 425-430 (1999).

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, tseriwastatina, itavastatin and visitation.

The above US patents are listed here as references. The applied quantity and dose will be the same as specified in Physician''s Desk Reference and/or in the patents listed above.

The compounds of formula I according to the invention are used in mass ratio with lipid-lowering agent (the audience), which lies in the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

Enter the dose should be carefully on what the elected in accordance with age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

Doses and compositions for lipid-lowering agent are as described in various patents and applications described above.

The doses and formulations used for other lipid-lowering agents, where possible, are as described in the latest edition of the Physicians' Desk Reference.

In the case of oral administration a satisfactory result can be obtained when using MTP inhibitor, taken in an amount ranging from about 0.01 mg to about 500 mg, and preferably from about 0.1 mg to about 100 mg, one to four times daily.

Preferred oral dose form, such as tablets or capsules, may contain MTP inhibitor, taken in an amount from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.

For oral administration can be obtained a satisfactory result using an inhibitor of HMG COA reductase inhibitor such as pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or tseriwastatina in the dosage used, which are listed in Physician''s Desk Reference, in a number ranging from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.

Inhibitor salanova synthetases can is t be used in doses in amounts ranging from about 10 mg to about 2000 mg, and preferably from about 25 mg to about 200 mg

Preferred oral dose form, such as tablets or capsules, may contain an inhibitor of HMG COA reductase in an amount of from about 0.1 to about 100 mg, preferably from about 0.5 to about 80 mg, and more preferably from about 1 to about 40 mg

Preferred oral dose form, such as tablets or capsules, may contain an inhibitor salanova synthetases in the amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg

The hypolipidemic agent may be an inhibitor of lipoxygenase, including the inhibitor of 15-lipoxygenase (15-LO), such as benzimidazole derivatives, which are described in WO 97/12615, 15-LO inhibitors, which are described in WO 97/12613, isothiazolone, which are described in WO 96/38144, and 15-LO inhibitors, which are described Sendobry and other "Attenuation of dietret-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase ingibitor lacking significant antioxidant properties", Brit. J. Pharmacology (1997) 120, 1199-1206, and Comicelli and others, "15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease", Current Pharmaceutical Design, 1999,5,11-20.

The compounds of formula I and hypolipidemic agent may be used together in a single oral dose form or in separate oral dose forms taken at the same time.

The compositions described above may be administered in dosage forms as described above in single or divided doses one to four times daily. It is advisable to start treatment p is the consistent with a person with a low dose combination and gradually to achieve high-dose combination.

The preferred lipid-lowering agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or tseriwastatina, as well as Niacin and/or cholestagel.

Antidiabetic agent, which may optionally be used in combination with the compound of the formula I may represent 1, 2, 3 or more antidiabetic agents or antihyperglycemic agents, including substances that increase insulin secretion or insulinemia sensitizing substances, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPAR γ agonists, such as preparations of thiazolidinediones, or inhibitors, PPAR α/γ dual agonists, dipeptidyl peptidases IV (DP4) inhibitors, SGLT2 inhibitors and/or meglitinides, as well as insulin, and or like peptide-1 (GLP-1).

Anti-diabetic agent may be administered orally with antihyperglycemic agent, preferably biguanides, such as Metformin or phenformin or their salts, preferably Metformin HCl.

Where antidiabetic agent is biguanidine, the compounds of structure I may be used in a mass ratio with biguanidines, which is in the range from about 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.

Antidiabetic agent may also be preferably a sulfonylurea, such that the AK gliburid (also known as glibenclamide), glimepiride (described in US 4379785), glipizide, gliclazide or hlorpropamid, other known sulfonylureas or other antihyperglycemic agents, which act on the ATP-dependent channel of the P-cells are preferred gliburid and glipizide, which can be entered in one or in different oral dose forms.

Compounds of structure I may be used in a mass ratio with sulfonylurea, which lies in the range from about 0.01:1 to about 100:1, preferably from about 0.02:1 to about 5:1.

Oral input antidiabetic agent may also be a glucosidase inhibitor such as acarbose (described in US 4904769) or miglitol (described in US 4639436)that can be entered in one or in separate oral dose forms.

Compounds of structure I may be used in a mass ratio with the glucosidase inhibitor, which is in the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 10:1.

Compounds of structure I may be used in combination with a PPAR γ agonist, such as thiazolidinedione oral anti-diabetic agent or other insulin sensitizing substance (which have insulin-sensitive effect in NIDDM patients)such as troglitazone (Warner-Lambert's Rezulin®described in US 4572912), rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555 (described in US5594016), Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isopetasin (MIT/J&J), JTTPET-501 (JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN) or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.

Compounds of structure I may be used in a mass ratio with thiazolidinedione in an amount which ranges from about 0.01:1 to about 100:1, preferably from about 0.05 to about 10:1.

The sulfonylurea and thiazolidinedione in the amount of less than about 150 mg oral antidiabetic agent may be incorporated in a single tablet with compounds of structure I.

Compounds of structure I may also be used in combination with antihyperglycemic agent such as insulin or with glycohaemoglobin peptide-1 (GLP-1) such as GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (7-37) (which are described in US 5614492 Habener, described here as a reference), as well as AS (Amylin) and LY-315902 (Lilly), which can be administered by injection, intranasal, inhalation, or via transdermal or buccal devices.

Where Metformin, sulfonylureas, such as gliburid, glimepiride, glipizide, glipizide, hlorpropamid and gliclazide, and glucosidase inhibitors, acarbose or miglitol or insulin (injection, intra-lungs, buccal or oral) can be used in the compositions defined above, and count is the number and dose as indicated in Physician''s Desk Reference (PDR).

Where Metformin or its salt, it can be used in amounts lying in the range from about 500 to about 2000 mg per day, which can be entered in one or divided doses one to four times daily.

Where there is thiazolidinedione antidiabetic agent, it can be used in amounts lying in the range from about 0.01 to about 2000 mg/day, which may be given in one or two doses one to four times daily.

Where insulin is present, it can be used in the compositions, the number and doses as stated in Physician''s Desk Reference.

Where GLP-1 peptides, they can be administered orally in the buccal compositions, nazalnam introduction or parenterally as described in US 5346701 (TheraTech), 5614492 and 5631224 listed here as references.

Antidiabetic agent may also be a PPAR α/γ dual agonist such as AR-H039242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck)as well as those described Murakami and others, "A Novel Insulin Sensitizer Acts As a Coligand for Peroxusome Proliferation-Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats", Diabetes 47, 1841-1847 (1998).

Antidiabetic agent may be an SGLT2 inhibitor, such as described in US application 60/158773 published 12.10.1999 (attorney file LA49), using doses that are shown there. Predpochtite lname are compounds listed as preferred in the application.

Anti-diabetic agent may be an inhibitor, such as described in application US 09/391053 published 7.09.1999, US 60/127,745, published 05.04.1999 (attorney file LA27*), using doses that are shown there. Preferred are the compounds indicated as preferred in this application.

Anti-diabetic agent may be a DP4 inhibitor, such as described in the application 60/188,555, published 10.03.2000 (attorney file LA50), WO 99/38501, WO 99/46272, WO 99/67279 (PROBIODRUG), WO 99/67278 (PROBIODRUG), WO 99/61431 (PROBIODRUG), NVP-DPP728A (1-[[[2-[(5-cyano-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis) (preferred), as described by Hughes and other, Biochemistry, 38 (36), 11597-11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (described Yamada and others, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540, 2-cyanopyrrolidine and 4-cyanopyrrolidine described Ashworth and others, Bioorg. & Med. Chem. Lett., Vol.6, No.22, pp. 1163-1166 and 2745-2748 (1996), using doses that are listed in the references.

Meglitinides, which can optionally be used in combination with the compound of the formula I according to the invention can be Repaglinide, nateglinide (Novartis) or KADI 229 (PF/Kissei), preferably Repaglinide.

The compound of the formula I can be used in a mass ratio with meglitinide, PPAR γ agonist, PPAR α/γ dual agonist, an inhibitor, a DP4, inhibitor is or SGLT2 inhibitor, which is in the range from about 0.01:1 to about 100:1, preferably from about 0.05 to about 10:1.

Another type of therapeutic agent, which may optionally be used with the compound of the formula I, may be 1, 2, 3 or more agents, anti-obesity, including beta-3 adrenergic agonist, a lipase inhibitor, an inhibitor of serotonin (and dopamine), ar inhibitor, agonist thyroid receptor and/or anorectics agent.

Beta-3 adrenergic agonist, which may optionally be used in combination with the compound of the formula I, can be AJ9677 (Takeda/Dainippon), L750355 (Merck) or SR (Pfizer) or other known beta 3 agonists, which are described in US 5541204, 5770615, 5491134, 5776983 and 5488064, preferred are AJ9677, L750355 and SR.

A lipase inhibitor, which can optionally be used in combination with the compound of the formula I, can be orlistat or ATL-962 (Alizyme), preferred is orlistat.

Inhibitor of serotonin (and dopamine), which can optionally be used in combination with the compound of the formula I, can be sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), preferred are sibutramine and topiramate.

Agonist thyroid receptor, which may optionally be used in combination with the compound of the formula I, may be the ligand of thyroid receptor, which is described in WO 97/21993 (U. Cal SF), WO 99/00353 (KaoBio), GB 98/284425 (KaroBio) and request US 60/183223 published 17.02.2000, preferred are compounds KaroBio applications and specified US application.

Anorectics agent, which may optionally be used in combination with the compound of the formula I, can be dexamfetamine, phentermine, phenylpropanolamine or mazindol, it is preferable to dexamfetamine.

Various agents against obesity, described above, can be used in the same dosage form with the compound of the formula I or in different dosage forms, doses, and modes, which are well known from the prior art or of the PDR.

Antihypertensive agents that may be used in combination with the compound of the formula I according to the invention include ACE inhibitors, receptor antagonists angiotensin II, NEP/ACE inhibitors, as well as calcium channel blockers, β-adrenergic blockers and other antihypertensive agents, including diuretics.

Inhibitor angiotensinconverting enzyme, which can be used here, includes containing mercaptopropyl (S), such as substituted prolinnova derivatives, such as described in US 4046889 Ondetti and others, mentioned above, it is preferable captopril, which is 1-[(2S)-3-mercapto-2-methylpropionyl]-L-Proline and mercaptopurine derivatives substituted prolinol, such as any of the OPI is data in the US 4316906, preferred is zofenopril.

Other examples mercaptoacetic ACE inhibitors that may be used include renipril (pentopril, Santen), described in Clin. Exp. Pharmacol. Physiol. 10: 131 (1983); as well as pivotal and YS980.

Other examples of inhibitors of angiotensin-transforming enzyme that may be used include any of the features described in US 4374829 mentioned above, preferred is N-(1-etoxycarbonyl-3-phenylpropyl)-L-alanyl-L-Proline, or enalapril, any of phosphonates substituted amino or aminocyclo or salts described in US 4452790 is preferred (S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-Proline or (ceronapril), phosphinylacetohydrazide described in US 4168267 above, it is preferable to fosinopril, any of fosforilirovannyh of prolinol described in US 4337201, and phosphoramidate described in US 4432971 above.

Other examples of ACE inhibitors that may be used include Beecham's BRL 36378, which are described in EP 80822 and 60668; Chugai's MC-838 described in SA 102:72588V and Jap. J. Pharmacol. 40:373 (1986); Ciba-Geigy''s CGS 14824 (3-([1 - etoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepin-1 acetic acid HCl), described in UK 2103614 and CGS 16617, (3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-ethanoic acid is), described in US 4473575; Cetaphil (alacepril, Dainippon), described in Eur. Therap. Res. 39:671 (1986); 40:543 (1986); ramipril (Hoechst), described in EP 79-022 and Curr. Ther. Res. 40:74 (1986); Ru 44570 (Hoechst), described in Arzneimittelforschung 34: 1254 (1985), cilazapril (Hoffman-LaRoche), described in J. Cardiovasc. Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche), described in FEBS Lett. 165: 201 (1984); lisinopril (Merck), inaapril (delapril), described in US 4385051; indonepal (Schering), described in J. Cardiovasc. Pharmacol. 5:643655 (1983), spirapril (Schering), described in Acta. Pharmacol. Toxicol. 59 (Supp.5):173 (1986); perindopril (Servier), described in Eur. J. Clin. Pharmacol. 31:519 (1987); quinapril (Warner-Lambert), described in US 4344949 and S (Warner-Lambert) ([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxyacetylene)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-izohinolinove acid HCl), described in Pharmacologist 26:243, 266 (1984), WY-44221 (Wyeth), described in J. Med. Chem. 26:394 (1983).

Preferred ACE inhibitors are captopril, fosinopril, enalapril, lisinopril, quinapril, benazepril, pentopril, ramipril and moexipril.

NEP/ACE inhibitors, which can also be used here include those that possess inhibitory activity of neutral endopeptidase (NEP) and inhibitory activity angiotensinconverting enzyme (ACE). Examples of NEP/ACE inhibitors suitable for use here include described in US 5362727, 5366973, 5225401, 4722810, 5223516, 4749688, US 5552397, US 5504080, US 5612359, US 5525723, EP 0599444, 0481522, 0599444, 0595610, EP 0534363 A2, 534396 and 53492, and E 0629627 A2.

Preferred are those NEP/ACE inhibitors and their dosages, which are indicated as preferred in these patents/applications US here as links; most preferred is omapatrilat, BMS 189921 ([S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepin-1-acetic acid (gemopatrilat)) and CGS 30440.

Receptor antagonist of angiotensin II (also referred to here as the antagonist of angiotensin II or AII antagonist), suitable for use here includes, but is not limited to, irbesartan, losartan, valsartan, candesartan, telmisartan, tasosartan or eprosartan, are preferred irbesartan, losartan or valsartan.

A preferred oral dosage form, such as tablets or capsules, may contain the ACE inhibitor or AII antagonist in an amount which ranges from about 0.1 to about 500 mg, preferably from about 5 to about 200 mg, and more preferably from about 10 to about 150 mg

For parenteral administration of the ACE inhibitor, antagonist of angiotensin II or NEP/ACE inhibitor can be used in an amount which ranges from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.01 mg/kg to about 1 mg/kg

With the introduction of intravenous drug means it can find the I in the usual solvent, such as distilled water, brine, saline solution, ringer's solution or other conventional media.

Considered that the preferred dose of ACE inhibitor and an AII antagonist, as well as other antihypertensive agents described herein may be such as specified in the latest edition Physician''s Desk Reference (PDR).

Other examples of preferred antihypertensive agents suitable for use here include omapatrilat (Vanlev®), amlodipine, besilate (By®), prazosin HCl (Minipress®), verapamil, nifedipine, nadolol, diltiazem, felodipine, nisoldipine, isradipine, nicardipine, atenolol, carvedilol, sotalol, terazosin, doxazosin, propranolol and clonidine HCl (Catapres®).

Diuretics, which can be used in combination with compounds of the formula I, include hydrochlorothiazide, torsemide, furosemide, spironolactone and indapamide.

Antithrombotic agents that can be used in combination with compounds of the formula I according to the invention include aspirin, clopidogrel, ticlopidine, dipyridamole, abciximab, tirofiban, eptifibatide, anagrelide and petrobas, are preferred clopidogrel and aspirin.

Antithrombotic drugs may be used in amounts specified in the PDR. Petrobas can be used in amounts as indicated in US 5100889.

Antiosteoporosis agents suitable on what I use here, in combination with the compounds of the formula I according to the invention, include partiality hormone or bisphosphonates, such as MK-217 (alendronate) (Fosamax®). The applied dose can be such as specified in the PDR.

In the process according to the invention used in the pharmaceutical composition, which contains compounds of structure I, with or without other therapeutic agent, in combination with a pharmaceutical carrier or diluent. The pharmaceutical composition can be prepared using conventional solid or liquid fillers or solvents and pharmaceutical additives of the appropriate type for the method of the desired injection. The compounds can be administered to mammals, including humans, monkeys, dogs, etc., oral route, for example, in the form of tablets, capsules, granules or powders, or they can enter parenterally in the form of injectable preparations. The dose for injection is preferably between 50 and 2000 mg per day and can be entered in one dose or in the form of individual doses from 1-4 times a day.

A typical capsule for oral administration include compounds of structure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60-cell sieve and placed in a gelatin capsule No. 1.

A typical injectable receive aseptic filling 250 mg of the compounds of structure I in a vial, aseptic freeze-drying and zapaivanie the m To use the contents of the vials are mixed with 2 ml of saline brine with obtaining injectable.

The following examples represent preferred embodiments of the invention.

In the examples the following abbreviations are used:

Ph=phenyl

Bn=benzyl

tert-Bu=tert-butyl

Me=methyl

Et=ethyl

TMS=trimethylsilyl

TMSN3=trimethylsilylmethyl

TBS=tert-butyldimethylsilyl

FMOC=fluorenylmethoxycarbonyl

Boc=tert-butoxycarbonyl

Cbz=carbobenzoxy or carbobenzoxy or benzyloxycarbonyl

THF=tetrahydrofuran (THF)

Et2O=diethyl ether

hex=hexane

EtOAc=ethyl acetate

DMF=dimethylformamide

Meon=methanol

EtOH=ethanol

i-D=isopropanol

DMSO=dimethyl sulfoxide (DMSO)

DME=1,2-dimethoxyethane

DCE=1,2-dichloroethane

NMRA=hexamethylene phosphoric acid

The SPLA or the Asón=acetic acid

TFA=triperoxonane acid

i-Pr2NEt=diisopropylethylamine

Et3N=triethylamine

NMM=N-methylmorpholine

DMAP=4-dimethylaminopyridine

NaBH4=borohydride sodium

NaBH(SLA)3=triacetoxyborohydride sodium

DIBALH=diisobutylaluminum

LiAlH4=socialogical

n-BuLi=n-utility

Pd/C=palladium on coal

PtO2=platinum oxide

KOH=potassium hydroxide

NaOH=sodium hydroxide

LiOH=lithium hydroxide

To2 CO3=potassium carbonate

NaHCO3=sodium bicarbonate

DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

EDC (or EDC·HCl) or EDCI (or EDCI·HCl) or EDAC=3-ethyl-3'-(dimethylamino)propylbromide hydrochloride (or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)

NOT or HOBT·H2O=1-hydroxybenzotriazole hydrate

BOAT=1-hydroxy-7-asobancaria

THIEF reagent=benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium hexaflurophosphate

NaN(TMS)2=hexamethyldisilazide or sodium bis(trimethylsilyl)amide sodium

Ph3P=triphenylphosphine

Pd(OAc)2=palladium acetate

(Ph3P)4Pd=tetranitropentaerithrite

DEAD=diethylazodicarboxylate

DIAD=diisopropylsalicylic

Cbz-Cl=benzylchloride

CAN=cerium ammonium nitrate

SAX=strong aminoalkenes

SCX=strong cation-exchanger

Ar=argon

N2=nitrogen

min=minute(s)

h or hr=hour(s)

L=liter

mL=milliliter

μL=microliter (μl)

g=gram(s)

mg=milligram(s)

mol=moles

mmol=millimoles(and) (mmol)

meq=milliequivalent

RT=room temperature

sat or sat'd=saturated

aq.=water

TLC=thin layer chromatography

HPLC=high performance liquid chromatography

LC/MS=high performance liquid chromatography/mass spectrometry

MS or Mass Spec=mass spectrometry

NMR=the poison is but magnetic resonance imaging

NMR spectral data: s(s)=singlet; d(l)=doublet; m(m)=multiplet; br=fuzzy; t(t)=triplet

mp=melting point (TPL)

Example 1

To a cooled to 0°With the solution of 4-hydroxybenzaldehyde (1.70 g, 12.3 mmol), 5-phenyl-2-methoxazole-4-ethanol (Maybridge; 2.50 g, 14.0 mmol) and Ph3R (4.20 g, 16.0 mmol) in dry THF (30 ml) is added dropwise DEAD (3.20 g, 15.0 mmol). The solution was stirred at 0°C for 0.5 h, then allowed to warm to room temperature and stirred over night. Orange-red solution is evaporated in vacuum and the residue chromatographic (gradual gradient from 5:1 to 5:2, hexane:EtOAc) to give the compounds, part a (2.47 g, 65%) as a clear light yellow viscous oil.

A1. An alternative way to obtain aldehyde, part A.

To a cooled to -5°With a solution of 5-phenyl-2-methoxazole-4-ethanol (20.00 g, 0.098 mol) in CH2Cl2(100 ml) in one portion add methanesulfonanilide (12.40 g, 0.108 mol) (exothermic reaction). After re-cooling to -5°slowly add Et3N (11.1 g, 0.110 mol) over 30 minutes (the internal temperature <3°). The reaction mixture is allowed to warm to room temperature and stirred for 1 hour (the reaction is followed by means of analytical HPLC), after which the source is, the product disappears. The reaction mixture was washed with aqueous solution of HCl (2×50 ml of a 3 n solution). The combined aqueous layers are extracted with CH2Cl2(50 ml). Received the combined organic extracts are successively washed with saturated aqueous NaHCO3and brine (50 ml each), dried (Na2SO4) and concentrate to a volume of ˜Add 30 ml of methyl tert-butyl ether (120 ml) and the mixture is stirred; the formed white solid. The mixture is cooled to -20°to complete the crystallization. The product is filtered and dried under vacuum, giving mesilate (23.3 g, 85%) as a white solid. The mother liquid is concentrated under vacuum and recrystallized from methyl tert-butyl ether(MTBE)/heptane, which gives the second portion of the product, such as mesilate (3.3 g, 12%; total yield 97%).

The mixture obtained above nelfinavir (13.6 g, 0.048 mol), 4-hydroxybenzaldehyde (7.09 g, 0.058 mol) and K2CO3(9.95 g, 0.072 mol) in DMF (110 ml) was heated to 100°C for 2 hours (the reaction is complete, as shown by analytical HPLC). The mixture is allowed to cool to room temperature, then poured into ice water (400 ml) and stirred for 30 minutes. The obtained solid is filtered, washed with ice water (3×25 ml) and dried under vacuum at 50-60°With during the night. Cheese is the first product is crystallized from MTBE-hexane, that gives (12.2 g, 82%; 2 servings) of aldehyde (compound, part A1 ) in the form of a white solid.

To a solution of N-benzylpyrimidines ester (43 mg; 0.22 mmol) and the compound from part A1 (52 mg; 0.17 mmol) in DCE (10 ml) is added NaBH(OAc)3(56 mg; 0.26 mmol). The reaction mixture was vigorously stirred overnight (12 hours). Add saturated aqueous solution of NaHCO3(10 ml) and the mixture extracted with EtOAc (3×10 ml). The combined organic extracts washed with brine, dried (Na2SO4), concentrated under vacuum and chromatographic (hexane:EtOAc, 4:1), giving the compound of part b (45 mg, 55%) as a pale yellow oil, besides the original product (14 mg, 27%).

To a solution of compound from part b (45 mg) in CH3HE (2 ml) is added aqueous NaOH solution (3 ml of 1 M solution). The solution is stirred over night 14 hours and then acidified to pH 5 with excess of aqueous HCl (1 M solution). The mixture is extracted with EtOAc (2×10 ml); the combined organic extracts washed with brine, dried (Na2SO4), concentrated under vacuum, giving the desired acid which has been contaminated source material. This mixture was dissolved in CH3HE (2 ml) and aqueous NaOH solution (3.0 ml of 1 M solution), the resulting solution is heated with reverse holodilniki is within 1.5 hours. Extractive treatment with acid as described above gives the desired titled compound as a colorless solid (28 mg; 71%). [M+H]+=457.2

Example 2

To a solution of compound from example 1, part a (147 mg, 0.479 mmol) and hydrochloride glycinamido ester (73 mg; 0.52 mmol) in DCE (2 ml) was added Et3N and NaBH(OAc)3(156 mg; 0.74 mmol), the reaction mass is stirred over night at room temperature. Flash chromatography (gradual gradient from 7:3 to 2:3 hexane:EtOAc) to give 35 mg (21%) dibenzylamino ester (compound according to example 2, part a). In addition, get 127 mg (67%) monumentalizing ester (compound according to example 3, part a).

A solution of compound of example 1, part a (35 mg; 0.051 mmol) in CH3HE (2 ml) and aqueous NaOH solution (3 ml of 1 M solution) is heated at the boil under reflux for 12 hours. The solution is brought to pH 5 aqueous solution of 1 M HCl and an aqueous solution of 1 M NaOH, then extracted with EtOAc (3x). The combined organic extracts washed with brine, dried (Na2SO4) and concentrate under vacuum, giving the named compound (13 mg) as colorless solids. [M+H]+=658.2

Example 3

To a solution of compound of example 1, part a (147 mg, 0.479 mm is l) and hydrochloride glycinamido ester (73 mg; mmol) in DCE add Et3N and NaBH(SLA)3(156 mg; 0.74 mmol). Flash chromatography (gradual gradient from 7:3 to 2:3, hexane:EtOAc) to give 127 mg (67%) of the named compound. In addition, as a by-product obtain 35 mg (21%) bisbenzylisoquinoline ester (example 2,part a).

A solution of compounds, part a (72 mg; 0.18 mmol) in aqueous NaOH solution (2 ml of 1 M solution) and methanol (2 ml) is heated obratnim refrigerator for 3 hours. The reaction mass was adjusted to pH 5 aqueous solution of 1 M HCl and the solid is filtered off. The filtrate is extracted with EtOAc (3x). The combined organic extracts washed with brine, dried (Na2SO4) and concentrate under vacuum, giving a colourless solid, which was purified preparative HPLC (using a YMC S5 ODS 20 mm × 100 mm column with a continuous gradient from 70% A: 30% to 100% b for 10 minutes at a flow rate of 20 ml/min, where A=90:10:0.1 H2O:methanol:TFA and where a=90:10:0.1 methanol:N2O:TFA), which gives the named compound(10 mg; 15%) as a colourless solid. [M+H]+=367.2

Example 4

A solution of amino-tert-butyl ester (0.040 g, 0.095 mmol; it is produced as disclosed in example 7, part C, except that the aldehyde used in the recovery aminating, taken from approx the RA 1, part a, but not from example 7, part a)

and propylbromide (0.014 g, 0.120 mmol), and DBU (0.5 ml, 2.96 mmol) in DCE (1 ml) was stirred at 0°C for 5 hours. TECH (thin-layer liquid chromatography shows that the reaction at this point is completed. Add EtOAc (10 ml), the organic phase is washed with N2O and concentrated in vacuo. The remaining oil was dissolved in CH2Cl2/TFA (1:1.1 ml) and stirred at room temperature for 5 hours, then concentrated under vacuum. The residue is purified preparative HPLC (YMC S5 ODS 30 mm × 250 mm column with reversed phase; flow rate 25 ml/min; 30 min continuous gradient from 70:30 a:100% B; where A=90:10:0.1 H2O:methanol:TFA (triperoxonane acid) and where a=90:10:0.1 methanol:N2O:TFA), which gives the named compound (34 mg, 92%) as oil. LC/MS (Electronista) gives the exact value of [M+H]+=405.2 for these compounds.

Example 5

A solution of 2-chlorobenzoxazole (20 mg, 0.131 mmol), secondary aminomethylated ester (52 mg; 0.146 mmol)

(get as disclosed in example 3, part a, except that glycemically ester HCl substitute for glycemically ether·HCl and apply the aldehyde from example 7, part a) and an excess of Et3N (0.5 ml) in THF (2.0 ml) is heated is 100° With in a tightly closed tube and the reaction is followed by means of LC/MS. After 4 days starting amine completely reacts. The reaction mixture is cooled to room temperature and the solution was added an aqueous LiOH solution (0.50 ml of 1 M solution). The resulting solution was stirred at room temperature for 5 hours, after which the hydrolysis is completed. The mixture is concentrated under vacuum giving the crude acid in the form of oil, which is purified preparative HPLC (30 min continuous gradient from 70:30 a:100% b, where A=90:10:0.1 H2O:methanol:TFA and B=90:10:0.1 methanol:H2O:TFA; flow rate=25 ml/min; YMC S5 ODS 30×250 mm column with reversed phase ), which gives titled compound (52 mg; 82%) as a solid after lyophilization from (methanol/N2About). [M+H]+=484.2.

Example 6

The named compound (13 mg; 21%) are obtained by analogy with the method of example 5 using the appropriate secondary aminomethane ether.

(the specified connection receive, as disclosed in example 3, part a, except that glycemically ester HCl replace glycemically ether·HCl). [M+H]+=484.2.

Example 7

To a cooled to 0°With the solution of 3-hydroxybenzaldehyde (3.00 g, 24.6 mmol), 2-phenyl-5-meth is oxazol-4-ethanol (5.00 g; 24.6 mmol) and Ph3R (7.10 g, 27.1 mmol) in dry THF (75 ml) is added dropwise DEAD (4.27 ml, 27.1 mmol) over 10 minutes. Brown-orange solution was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solution is concentrated under vacuum and chromatographic (SiO2; gradual gradient of 100% hexane to hexane:EtOAc, 3:1), which gives the connection, part a, in the form of a pale yellow viscous oil (4.01 g; 53%).

A.1. An alternative process to obtain the aldehyde, part A.

To a solution of 3-hydroxybenzaldehyde (9.1 g; 0.074 mmol) in CH3CN (206 ml) is added To a2CO3(10.3 g). The mixture is heated to 90°C in an oil bath and stirred for 18 hours at 90°With (at this point the reaction is complete, as shown by analytical HPLC). The reaction mass is then cooled to room temperature, then diluted with EtOAc (500 ml), washed with H2Oh, aqueous solution of NaOH (2×100 ml of 1 M solution) and brine. The organic phase is dried (MgSO4) and concentrate under vacuum. The remaining oil chromatographic (SiO2; hexane:EtOAc from 9:1 to 4:1), which gives the aldehyde, part a (12.7 g; 67%) as a viscous transparent pale yellow oil.

Century

Solution connection part A1 (4.00 g; 13.0 mmol), hydrochloride of glycine tert-butyl ester (.40 g; 14.3 mmol) and Et3N (2.18 ml, 15.7 mmol) in methanol (30 ml) was stirred at room temperature for 6 hours and then cooled to 0°C. To a solution of NaBH4(594 mg, 15.7 mmol) in methanol (10 ml) is added by portions at 0°With a solution of crude imine for more than 15 minutes. The solution was stirred at 0°C for 3 hours, then at room temperature for 3 hours, then concentrated under vacuum without heating to remove the methanol. The remainder is divided between saturated aqueous NaCl and EtOAc (50 ml each). The aqueous layer was extracted with EtOAc (2×50 ml). The combined organic extracts dried (Na2SO4) and concentrate under vacuum, giving a yellow oil, which chromatographic on SiO2(gradual gradient; hexane:EtOAc from 4:1 to 2:3) and get a connection, part b, in the form of a viscous pale yellow oil (4.82 g; 88%).

C.

To a solution of compounds, part b (0.400 g; 0.95 mmol) and 4-phenoxybenzaldehyde (0.216 g; 1.09 mmol) in DCE (5 ml) is added NaBH(OAc)3(0.300 g, 1.42 mmol), and then the SPLA (25 μl). The reaction mass was stirred at room temperature for 24 hours. As shown by analytical HPLC 10% unreacted starting amine still present. Enter the additional amount of the aldehyde (30 mg) and NaBH(SLA)3(60 mg) and the reaction stirred at room temperature the next 18 hours, then it ends. The solution is shared between the aqueous solution of NaHCO3(50 ml of 10% solution) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2×25 ml). The combined organic extracts washed with aqueous solution of NaHCO3(2×15 ml of 10% solution), dried (Na2SO4) and concentrate under vacuum, giving a connection part (521 mg, crude product) as a colorless transparent oil.

D.

The connection part With, dissolved in CHCl3(2 ml) and TFA (1.5 ml) and the solution stirred at room temperature for 24 hours. The solution is concentrated under vacuum and the residue purified preparative HPLC (YMC S5 ODS 20×250 mm column; continuous gradient from 40:60 solvent A:In to 100% solvent b, where solvent A=90:10:0.1 H2O:methanol:TFA; solvent B=90:10:0.1 methanol:H2O:TFA). The purified product lyophilized from methanol/N2Oh, that gives the named amino acid (312 mg; 48% in stage 2) as its TFA salt (off-white lyophilic). [M+H]+(Electronista)=549.3.

Example 8

A mixture of aminoether (39 mg, 0.092 mmol)

(get as disclosed in example 4), 2-naphthaldehyde (29 mg; 0.185 mmol) and NaBH(OAc)3(100 mg, 0.472 mmol) in DCE (1.5 ml) was stirred at room temperature for 16 hours. Then to the mixture until ablaut TFA (1.0 ml) and stirred at room temperature for further 12 hours. Volatile products are removed under vacuum. The obtained residue was diluted with methanol (1.5 ml), filtered and purified preparative HPLC (YMC S5 ODS 30 mm × 250 mm column; continuous 30 min gradient @ 25 ml/min from 100% a to 100% B; solvent A=90:10:0.1 H2O:methanol:TFA; B=90:10:0.1 methanol:H2O:TFA), which gives the desired titled product (39 mg; 68%) as a clear viscous oil. [M+H]+=507.3.

Example 9

A solution of tert-butyl methyl ether amino acid (1.8 g, 4.27 mmol)

(get as disclosed in example 7, part b) and TFA (20 ml) in CH2Cl2(40 ml) was stirred at room temperature overnight. The solution is concentrated under vacuum and the residue dissolved in CH2Cl2and then elute through solid NaHCO3(to remove excess TFA) excess of CH2Cl2. The combined filtrates are concentrated under vacuum, which provides the desired amino acid, part a (1.48 g; 95%). [M+H]+=457.2.

Century

A named connection receive as part of the library in the stream-soluble phase, using the following exemplary process.

To a solution of amino acids, part a (27 mg, 0.074 mmol; 2 ml of CH2Cl2)

add (4 chlorophenoxy)-3-benzaldehyde (86 mg; 0.37 mmol), NaBH(OAc)3(79 mg, 0.37 mmol) and the SPLA (0.1 ml). Rea the traditional mass was stirred at room temperature for 15 hours.

The product was then purified using solid phase extraction using a Varian SAX cartridge (3 g of sorbent in 6 ml column, 0.3 meg/g) using the process described below:

1) the column is filled with methanol (10 ml) and CH2Cl2(20 ml);

2) the reaction mixture is loaded into a SAX column;

3) the column was washed with CH2Cl2(10 ml);

4) the column is washed with 1% TFA in methanol (3 ml);

5) elute the product with 1% TFA in methanol (20 ml).

The solution of the reaction products (combine fractions after 5 stages) concentrated using a Speed Vac (high vacuum) for 16 hours, resulting crude product (25 mg, 49%) as a solid. Analysis of HPLC with reversed phase (YMC S5 ODS 4.6×33 mm column, continuous gradient from 100% a to 100% b for 2 min at a flow rate of 5 ml/min [solvent A=10% methanol/90% H2O/0.2% of N3PO4; solvent B=90% methanol/10% H2O/0.2% of N3PO4]) shows that the purity of the product is 92%. In addition, LC/MS (Electronista determine the exact molecular ion [(M+N)+=583] for these compounds.

Example 10 (a process that uses a heterocyclic aldehyde)

A named connection receive as part of the library in the stream-soluble phase, using the following exemplary process. The mixture of amino acids (14 mg, 0.038 mmol)

(get as disclosed in example 9, part a), 5-(4-chlorophenyl)-2-furfural (16 mg; 0.076 mmol) and NaBH(OAc)3(72 mg, 0.34 mmol) in DCE (1.5 ml) was stirred at room temperature for 16 hours. Then to the mixture is added TFA (1.0 ml), which was stirred at room temperature for further 12 hours. Volatile products are removed under vacuum. The remaining residue is diluted with methanol (1.5 ml), filtered and purified preparative HPLC (YMC S5 ODS 30 mm × 250 mm column; continuous 30-minute gradient @ 25 ml/min from 100% a to 100% B; solvent A=90:10:0.1 H2O:methanol:TFA; B=90:10:0.1 methanol:H2O:TFA), which gives the desired titled product (39 mg; 68%) as a clear viscous oil.

Example 10A

Alternative cleaning process preparative HPLC is used as follows.

The crude product reductive amination is cleaned by solid phase extraction using SAX cartridge (United Chemicals; 3 g of sorbent in 6 ml column, 0.3 meg/g) using the process disclosed below:

1) the column is filled with methanol (5 ml) and CH2Cl2(5 ml);

2)the reaction mixture was diluted with 2 ml of CH2Cl2download SAX column;

3) the column was washed with CH2Cl2(8 ml);

4) elute the product with 1% TFA in methanol (20 ml).

Containing the product fractions are concentrated under in the cosmology vacuum using Speed Vac for 16 hours, giving a crude product. It is dissolved in CH2Cl2:methanol (95:5) and upload to silikagelya cartridge (1.5 g SiO2), and then elute the product with the help of CH2Cl2:methanol (95:5; 8 ml). The product containing fractions are concentrated under vacuum, using a Speed Vac, giving the desired product named.

Analysis of HPLC with reversed phase (YMC S5 ODS 4.6×33 mm column, continuous gradient from 100% a to 100% b for 2 minutes at a flow rate of 5 ml/min [solvent A=10% methanol/90% H2O/0.2% of N3PO4; solvent B=90% methanol/10% H2O/0.2% of N3PO4]) shows that the purity of the product is 92%. In addition, LC/MS (Electronista determine the exact molecular ion [(M+N)+=583] for these compounds.

Example 11

To a mixture of amino-tert-butyl ether (0.339 g, 0.80 mmol)

(get as disclosed in example 7, part b, 4-hydroxybenzaldehyde (0.127 g, 1.03 mmol) and NaBH(SLA)3(0.510 g, 2.4 mmol), add 7 drops of the SPLA. The reaction mass was stirred at room temperature for 16 hours. The mixture is diluted with EtOAc, then washed with aqueous solution of NaHCO3. The organic phase is dried (MgSO4) and concentrate under vacuum. The crude product chromatographic (SiO2; g is Xan/EtOAc, 3:1 to 1:4), which provides 4-hydroxyethylaminomethyl named connection (0.381 g, 90%).

A named connection receive as part of the library in the stream-soluble phase, using the following exemplary process.

To a solution of phenolic compounds, part a (30 mg, 0.057 mmol) in CH2Cl2(1 ml) is added 3-ftorhinolonovy acid (12 mg, 0.086 mmol) and 4Å molecular sieves (pre-dried at 400°overnight) at room temperature.

After stirring for 5 minutes, to the mixture of Cu(SLA)2(1 equiv), Et3N (5 EQ) and pyridine (5 EQ). The vessel open and allow air to pass through the reaction mass. Then it is stirred at room temperature for 60 hours, after which the reaction is completed, as shown by analytical HPLC and LC/MS. (For other reactions that are not completed during this time, introduce additional Bronevoy acid (1.5 EQ)to form additional desired product). The reaction mixture was filtered and concentrated under vacuum. The product was then purified using solid phase extraction using United Technology SCX column (2 g sorbent in 6 ml column) using the process disclosed below:

1) the column is filled with methanol (10 ml) and CH2Cl2(10 ml);

2) the residue is dissolved in a minimum amount of CH2Cl 2and loaded into the SCX column;

3) the cartridge sequentially washed with CH2Cl2(20 ml); CH2Cl2/methanol (20% methanol, 20 ml) and methanol (20 ml);

4) elute the product with a solution of 0.5 N. NH3in methanol.

Containing the product fractions are concentrated under vacuum, giving the desired tert-butyl ether. (Some incomplete reactions require chromatography (SiO2) the crude product, which gives the desired esters of purity). tert-Butyl ether is treated with a solution of 30% TFA in CH2Cl2throughout the night. Volatile products were removed and the residue again dissolved in CH2Cl2(1 ml) and concentrate under vacuum in a Speed Vac (quick vacuum), which allows to obtain the desired titled product (30 mg; 77%). Analysis of HPLC with reversed phase shows that the purity of the product is 90%. In addition, LC/MS exact molecular ion [(M+N)+=567] named for the desired connection.

Example 12

To a solution of secondary amino-tert-butyl ester (110 mg, 0.26 mmol)

(get as disclosed in example 7, part b) in 1,2-dichloroethane (4 ml) was successively added 4-formylphenylboronic acid (47 mg; 0.31 mmol) and NaBH(SLA)3(165 mg, 0.78 mmol). The mixture is stirred at room temperature for 3 hours Analysis of HPLC and LC/MS shows that the reaction is complete at this moment. Volatile products are removed under vacuum and the residue chromatographic (SiO2; gradual gradient from 3:1 to 1:1, hexane:EtOAc)that provides the named compound (133 mg; 91%) as a white foam.

A named connection receive as part of the library in the stream-soluble phase, using the following process. To a solution of compound Bronevoy acids, part a (40 mg, 0.072 mmol) in CH2Cl2(1 ml) was added meta-cresol (23 mg; 0.22 mmol) and 4Å molecular sieves (150 mg, previously dried at 400°during the night). After stirring for 5 minutes, to the mixture of Cu(SLA)3(1 equiv), Et3N (5 EQ) and pyridine (5 EQ). The vessel is opened and air allowed to enter into the reaction mass, after which it was stirred at room temperature for 24 hours. The reaction mixture was filtered through a bed of Celite and concentrate under vacuum. The product was then purified using solid phase extraction using United Technology SCX column (2 g sorbent in 6 ml column) using the process described below:

1) the column is filled with methanol (10 ml) and CH2Cl2(10 ml);

2) the residue is dissolved in a minimum volume of CH2Cl2and loaded into the SCX column;

3) the cartridge sequentially washed with CH2Cl2(20 ml) and methanol (20 ml);

4) elute the product with a solution of 0.5 N. NH3in methanol;/p>

5) containing the product fractions are concentrated under vacuum;

6) the residue is dissolved in a minimal amount of CH2Cl2and upload to silikagelya cartridge (2 ml);

7) cartridge, elute with hexane:EtOAc (3:1; 20 ml);

8) containing the product fractions are collected and concentrated under vacuum, giving a purified tert-butyl ether.

tert-Butyl ether is treated with solution (1:1) TFA in CH2Cl2throughout the night. Volatile products were removed and the residue again dissolved in CH2Cl2(1 ml) and concentrate under vacuum in a Speed Vac that will give the desired titled product (25 mg, 48%) as a slightly yellowish oil. Analysis of HPLC with reversed phase shows that the purity of the product is 91%. In addition, LC/MS exact molecular ion [(M+H)+=563.2] for the desired connection.

Example 13

A named connection receive as part of the library in the stream-soluble phase, using the following exemplary process.

To a solution of 3-bromopyridine (32 mg; 0.2 mmol) in DME (1 ml) are successively added (Ph3R)4Pd (5 mg; 0.05 mol EQ) and example 12, part a, baronova acid (50 mg; 0.09 mmol)

At the end add an aqueous solution of Na2CO3(19 mg in 0.3 ml of N2O) and the mixture is heated on an oil bath at 85°With out within 5 hours; LC/MS shows that at this point the reaction is complete.

The reaction mixture is filtered and the filtrate chromatographic on silicagel cartridge (2 ml; EtOAc). Containing the product fractions are concentrated under vacuum and the residue chromatographic on another silicagel cartridge (2 ml; gradual gradient of hexane, hexane:EtOAc 3:1 and EtOAc). Containing the product fractions are concentrated under vacuum and the residue elute through SCX (2 g) cartridge (20 ml each CH2Cl2and methanol; the product is then elute with 2 M ammonia in methanol). Containing the product fractions are concentrated under vacuum, giving the desired biaryl amino - tert-butyl ester as the reaction product. It is treated with a solution of CH2Cl2/TFA (7:3; 1 ml) during the night of 14 hours. Volatile products are removed, which gives the named compound (39 mg; 67%) as oil. [M+H]+=534.3.

Examples 14 to 124

Following one of the above processes, you receive the following compounds according to the invention is:

Table 1
Example No.R3[M+H]+
14457.3
15 471.3
16485.3
17617.2
18549.3
19533.3
20557.3
21617.3
22562.7
23579.3

/tr>
Example No.R3[m+h]+
24559.4
25615.3
26503.4
27563.4
28596.3
29555.3
30473.4
31475.4
32599.3

Example No.R3[M+H]+
33517.4
34507.1
35507.1
36496.1
37557.1
38591.2
39568.2
40625.2
41591.2
42568.2
43 622.3

Example No.R3[M+H]+
44601.2
45557.2
46519.2
47675.2
48519.2
49600.3
50564.2
51545.3
52625.2
53563.3

Example No.R3[M+H]+
54632.3
55556.3
56 563.3
57593.2
58562.2
59582.2
60582.2
61593.2
62593.2
63571.2
64611.2

Example No.R3[m+h]+
65537.3
66537.3
67636.2

Table 2

Example No.R3 [M+H]+
68534.2
69547.2
70465.4
71533.3
72473.3

82
Example No.R3[M+H]+
73507.3
74587.4
75517.3
76549.3
77549.3
78583.2
79617.2
80563.2
81559.2
615.2
83629.1
84605.3
85563.2

Example No.R3[M+H]+
86596.2
87549.3
88635.3
89639.2
90583.2
91563.2
92635.3
93583.2
94617.2
95617.1
96 567.2
97555.1
98595.3

Example No.R3[M+H]+
99555.2
100617.2
101594.2
102548.2
103523.3
104534.4
105576.2
106601.1
107563.2
108609.2
109551.2
110 523.2
111539.2

Example No.R3[M+H]+
112579.3
113594.4
114563.3
115583.2
116579.3
117583.2
118594.3
119594.3
120537.3
121537.3
122535.2
123535.2
124496.1

Example 125

A solution of the aldehyde from example 7, part a (60 mg; 0.20 mmol) and (S)-α-methylbenzylamine (30 mg; 0.24 mmol) in methanol (1 ml) was stirred at room temperature for 6 hours. The solution is cooled to 0°and add portions of the prior solution of NaBH4(9 mg; 0.24 mmol) in methanol (0.5 ml). The reaction mass was stirred at room temperature overnight, then concentrated under vacuum without heating. The remainder is shared between the aqueous solution of NaHCO3and EtOAc (5 ml each). An aqueous solution (layer), extracted with EtOAc (2×5 ml). The combined organic extracts dried (Na2SO4) and concentrate under vacuum, giving a named connection in the form of an orange-yellow oil (81 mg, crude).

A solution of compound from part a (70 mg, 0.17 mmol), tert-butylbromide (66 mg; 0.34 mmol) and ISO-Pr2NEt in DMF (0.5 ml) was stirred at room temperature for 2 days. LC/MS shows that the reaction is complete and has passed completely.

The crude reaction mixture is divided between the H2O (30 ml) and EtOAc (20 ml). The aqueous layer was extracted with Et2O (2×10 ml); the combined organic extracts dried (MgSO4) and concentrated under vacuum giving the crude amino-tert-butyl ether.

The resulting crude product per mesilat in solution (1:1) CHCl 3and TFA (2 ml) for 18 hours at room temperature. Then the solution is concentrated under vacuum and purified preparative HPLC with reversed phase (as in example 10). The purified material lyophilized from methanol-H2O that gives the named compound (71 mg; 71%) as a white Lopilato. [M+H]+=471.2.

Example 126

The named compound is synthesized following the same process that disclosed above in example 125 except that (S)-α-methylbenzylamine replace (R)-α-methylbenzylamine in the synthesis of compounds, part A. the Named compound are obtained from 67% overall yield (66 mg). [M+H]+=471.2.

Example 127

The mixture of compounds from example 7, part a (30 mg, 0.098 mmol), hydrochloride tert-butyl ester of D-alanine (23 mg; 0.127 mmol), Et3N (5 drops) and 4Å molecular sieves in methanol (2 ml) was stirred at room temperature for 4 hours. Enter NaBH4(12 mg, 0.0294 mmol) and again stirred at room temperature for 30 minutes. Then the reaction mixture is concentrated under vacuum, diluted with CH2Cl2(2 ml) and filtered through cloth. To the filtrate is again added TFA (1 ml) and the reaction mass stirred at room temperature overnight. Then it is concentrated under vacuum, diluted with EtOAc, washed several the times specified in an aqueous solution of NaHCO 3and then brine. The organic phase is dried (MgSO4) and concentrate under vacuum. The residue is purified preparative HPLC (YMC ODS 30 mm × 250 mm column with reversed phase; flow rate 25 ml/min; 30 min continuous gradient from 50:50 a:100% b, where A=90:10:0.1 H2O:methanol:TFA and B=90:10:0.1 methanol:H2O:TFA), which provides the named compound (7.8 mg, 21%) as a white Lopilato. [M+H]+=381.1.

Example 128

A named connection (20% of total output) are synthesized by following the same process described in example 125 using hydrochloride tert-butyl ester of D-phenylalanine instead hydrochloride tert-butyl ester of D-alanine. [M+H]+=457.2.

Example 129

The mixture of compounds from example 7, part a (40 mg, 0.13 mmol), hydrochloride tert-butyl ester of D-alanine (31 mg, 0.17 mmol), Et3N (6 drops) and 4Å molecular sieves in methanol (2 ml) was stirred at room temperature for 4 hours. Enter NaBH4(15 mg, 3 EQ) and the mixture is stirred at room temperature for 30 min, then concentrated under vacuum. The residue is dissolved in CH2Cl2(2 ml) and filtered. In the tube with the filtrate add 4-phenoxybenzaldehyde (77 mg, 0.39 mmol) and NaBH(SLA)3(138 mg, 0.65 mmol). The reaction mass was stirred at room temperature for the of 18 hours. After that, the obtained reaction mixture chromatographic on SiO2using hexane/EtOAc(9:1 - 4:1), to obtain pure tert-butyl ether. The specified product is dissolved in CH2Cl2(2 ml) and added slowly TFA (1 ml). The solution was stirred at room temperature overnight, then concentrated under vacuum. The residue is again dissolved in CH2Cl2and filtered through solid NaHCO3to remove residual TFA. This solution is further diluted with CH2Cl2, washed with 1 M aqueous solution of NaHSO4and brine, dried (MgSO4), filtered and concentrated under vacuum to obtain the titled compound (9.1 mg, 12%). [M+H]+=563.2.

Example 130

A named connection (13% of total output) are synthesized by following the same process, which is disclosed in example 127, using hydrochloride tert-butyl ester of D-phenylalanine instead hydrochloride tert-butyl ester of D-alanine. [M+H]+=639.2.

Examples 131 135

Other analogues in this series received the same processes described in the following table.

Table 3

Example No.R3c[M+H]+
131 3563.2
132639.3
133591.4
134579.3
135635.4

Example 136

Solution secondary aminoethylamide ester (72 mg, 0.183 mmol)

(get as disclosed in example 3, part a) in methanol (2 ml) and aqueous NaOH solution (2 ml of 1 M solution) is heated at the boil under reflux for 12 hours. The pH value of the solution was adjusted to 5 ( an aqueous solution of 1 M NaOH and 1 M HCl), and then colorless solid precipitates. It is filtered off and the filtrate is extracted with EtOAc (3x), the combined organic extracts dried (Na2SO4) and concentrate under vacuum, giving called crude amino acid as colorless solid (97 mg).

B.

To a solution of amino acids, part a (15 mg, 0.04 mmol) in dioxane:H2O (1:1, 8 ml) is added To a2CO3(22 mg, 0.16 mmol), and then benzylchloride (15 mg; 0.09 mmol)Reaktsionnuyu mass is stirred overnight, then concentrated under VA what womam and acidified with excess aqueous 1 M HCl. The extraction is carried out EtOAc (3x), the combined organic extracts washed with brine, dried (Na2SO4) and concentrate under vacuum, giving the named compound (13 mg; 63%) as a colourless solid. [M+H]+=501.3.

Example 137

To a cooled to 0°With a solution of amino-tert-butyl ester (75 mg, 0.18 mmol)

(get as disclosed in example 7, part b) in CH2Cl2(1 ml) was added CbzCl (28 μl; 0.20 mmol), then Et3N (54 μl; 0.39 mmol). The reaction mixture is allowed to warm to room temperature and then stirred at this temperature overnight (18 hours). Add an aqueous solution of NaHCO3(2 ml of 10% solution) and the aqueous layer was extracted with EtOAc (2×2 ml). The combined organic extracts dried (Na2SO4) and concentrate under vacuum. Crude carbamates dissolved in CHCl3(3 ml) and TFA (1 ml); the solution was stirred at room temperature for 24 hours, then concentrated under vacuum. Raw carbonatation purified preparative HPLC with a reversed phase C-18 column (continuous gradient of more than 14 min; 4 min exposure time; flow rate=20 ml/min, 1:1 (a:100% B; solvent A=90:10:0.1 H2O:methanol:TFA; solvent B=90:10:0.1 methanol:H2O: TFA). Product lyophilized from MeOH/H2 O that gives the named compound as a white Lopilato. [M+H]+=501.3.

Example 138

A. Required allpharmacy (if they are not commercially available) are obtained according to the following General process disclosed in example of synthesis 2-methoxyphenylpiperazine.

A solution of 2-methoxyphenol (2 g, 16.1 mmol), N,N-dimethylamine (1.95 g, 16.1 mmol), phosgene (8.34 ml of a 1.93 M solution in toluene, 16.1 mmol) and catalytic amount of DMF in chlorobenzene (5 ml) is stirred into the tube under pressure for 2 hours at a temperature of 80°C. the Organic layer is separated and concentrated in vacuo. The residue is distilled (Buchi Kugelrohr; BP.=115°C @ 10 mm Hg)to obtain 2-methoxyphenylalanine (1.5 g, 50%) as a clear oil.

B.

A solution of amino-tert-butyl ester (20 mg, 0.05 mmol)

(prepared as described in example 7, part b, 2-methoxyphenylacetate (8 mg, 0.05 mmol) obtained above, and pyridine (Aldrich; 16 mg, 0.3 mmol) in CH2Cl2(1 ml) is stirred for 30 min at room temperature. Add the amino WA21J (Supeico; 200 mg) and the mixture is again stirred at room temperature for 30 min to remove unreacted chloroformate. The reaction mass is filtered and conc is tryout in vacuum, that will give the desired 2-methoxyphenylacetate the ether.

The ether is treated with a solution of 30% TFA in CH2Cl2(5 ml) over night. Volatile products are removed in vacuo, giving crude acid. This product was then purified using solid phase extraction using column anionoobmennika (CHQAX13M6 column; United Technologies; 3 g of sorbent in 6 ml column) according to the process described below:

1) the column is filled with methanol (10 ml) and CH2Cl2(10 ml);

2) crude acid is dissolved in the minimum volume of CH2Cl2and download SAX column;

3) the cartridge was washed with CH2Cl2(10 ml), CH2Cl2/methanol (10 ml of 4:1 CH2Cl2:CH3HE solution);

4) elute the product with the help of CH2Cl2/CH3HE (10 ml 4:1 CH2Cl2:CH3IT). Containing the product fraction was concentrated in vacuo on a Speed Vac, allowing you to obtain the titled compound in the form of oil. Analytical HPLC with reversed-phase (standard conditions) determines the purity of the product as 90%. In addition, LC/MS exact molecular ion [(M+N)+=517.3] named for the desired connection.

Example 139

A.

Phosgene (0.21 ml of a 1.93 M solution in toluene; 0.40 mmol) was added dropwise to a solution of amino-tert-butyl ester (100 mg, 0.24 mmol)

(the floor is up, as disclosed in example 7, part b) and Et3N (30.3 mg; 0.30 mmol) in 3 ml of CH2Cl2at -5°C. the Reaction mixture was stirred at room temperature for 2 hours. The mixture is concentrated under vacuum giving the crude product, which chromatographic (SiO2; hexane/EtOAc, 1:5), which provides the named compound (0.105 g, 91%).

B.

A named connection receive as part of the library in the stream-soluble phase, using the following exemplary process.

A mixture of carbamoylated, part a (20 mg, 0.045 mmol), 3,5-dichlorphenol (16 mg, 0.07 mmol) and pyridine (0.5 ml) was stirred at 80°C for 16 hours. The pyridine is removed under vacuum and the residue purified using solid phase extraction using CHQAX1 cartridge (2 g sorbent in 6 ml column, 0.3 mg/g), using the process described below:

1) the column is filled with methanol (10 ml) and CH2Cl2(20 ml);

2) the reaction mixture in CH2Cl2download SAX column;

3) elute the product with the help of CH2Cl2(10 ml).

Containing the product fractions are concentrated under vacuum, using a Speed Vac for more than 16 hours, which gives a net arylcarbamoyl-tert-butyl ester, which is treated with a solution of 30% TFA in CH2Cl2throughout the night. Volatile products are removed using a Speed Vac for 16 hours, giving a crude KIS the GTC as a final product. The product is first purified using solid phase extraction using a Varian SAX cartridge (2 g sorbent in 6 ml column, 0.3 meg/g), using the process described below:

1) the column is filled with methanol (10 ml) and CH2Cl2(20 ml);

2) the reaction mixture in CH2Cl2download SAX column;

3) the column was washed with CH2Cl2(10 ml);

4) the column was washed with 10% methanol in CH2Cl2(10 ml);

5) elute the product with 2% TFA in CH2Cl2(10 ml).

Containing the product fractions are concentrated under vacuum, using a Speed Vac, 16 hours, giving the purified product (20 mg, 80%) as a solid. Analysis of HPLC with reversed phase (YMC S5 ODS 4.6×33 mm column, continuous gradient from 50% a to 100% b for 2 min at a flow rate of 5 ml/min [solvent A=10% methanol/90%H2O/0.2% of N3PO4; solvent B=90% methanol/10% H2O/0.2% of N3PO4]) shows that the purity of the product is 96%.

In addition, LC/MS exact molecular ion [(M+N)+=555.2] (Electronista) for these compounds.

Example 140

Benzylchloride synthesized in accordance with the following General process, as shown in the example of methoxybenzonitrile.

A.

To a solution of 3-methoxybenzylamine sleep is one (2.0 g; 7.24 mmol), N,N-dimethylaniline (0.877 g, 7.24 mmol) in anhydrous ether (5 ml) is added dropwise phosgene (3.8 ml of a 1.93 M solution in toluene; 7.3 mmol) at 0°C. the Reaction mixture was stirred at 0°C for 2 hours, then the solid is filtered off. The filtrate is concentrated under vacuum at room temperature. Crude chloroformate distilled from anhydrous Et2O (2×2 ml) and used without further purification in the next reaction. Consistently receive other chloroformiate, using the standard process.

B.

A named connection receive as part of the library soluble phase, which is distilled using the following standard process.

To a suspension of amino acids (alttc) example 3

(25 mg, 0.05 mmol) in CH2Cl2(1 ml) add connection, part a (10 mg; 0.05 mmol) and ISO-Pr2NEt (19.4 mg; 0.15 mmol). After stirring for 30 min at room temperature, the reaction mixture was concentrated under vacuum.

The product was then purified using solid phase extraction using a Varian CHQAX13M6 (anion exchange) column (3 g of sorbent in 6 ml column) using the process disclosed below:

1) the column is filled with methanol (10 ml) and CH2Cl2(10 ml);

2) the residue is dissolved in a minimum volume of CH2Cl 2and download SAX column;

3) the cartridge is washed successively CH2Cl2(10 ml), 20% methanol/CH2Cl2(10 ml);

4) elute the product with a solution of 20% methanol/CH2Cl2(10 ml).

Containing the product fractions are concentrated under vacuum, using a Speed Vac, allowing you to get a named connection. Analysis of HPLC with reversed phase using the standard indicates that the purity of the product is 90%. In addition, LC/MS (Electronista determine the exact molecular ion [(M+N)+=531.3] named for the desired connection.

Example 141

A solution of 4-(benzyloxy)phenol (2.0 g, 9.99 mmol), N,N-dimethylaniline (1.21 g, 9.99 mmol), phosgene (5.2 ml 1.95 M solution in toluene; 10 mmol) and catalytic amount of DMF in chlorobenzene (5 ml) is heated to 80°in the tube under pressure for 2.5 hours. The mixture is allowed to cool to room temperature. The upper clear solution was separated and concentrated under vacuum giving the crude named allglorious in the form of crystals (2 g crude product).

B.

To a mixture of chloroformiate, part a (184 mg, 0.70 mmol) in CH2Cl2(5 ml) and pyridine (Aldrich; 315 mg, 1 mmol) is added a solution of amino-tert-butyl ester (280 mg, 0.66 mmol)

(get as disclosed in example 7, part b) in CH2Cl2(5 ml). The reaction mass was stirred at room temperature for 15 minutes To this mixture associated with resin-amine (WA21J, Supeico; 150 mg). The reaction mixture is stirred for another 15 minutes. Associated with the amine resin and polyvinylpyridine filtered and the filtrate concentrated under vacuum giving the crude product. It chromatographic (SiO2; hexane/EtOAc, 1:4), which provides the named compound (0.30 g, 70%).

C.

A solution of compounds, part b (75 mg; 0.42 mmol) in 20 ml of methanol hydronaut in the presence of 20 mg of 10% Pd/C in an atmosphere of H2(balloon) for 24 hours.

The palladium catalyst was removed by filtration and the filtrate concentrated under vacuum giving the crude named tert-butyl ester (240 mg, 90%), which is used without further purification in the next stage.

A solution of phenol-tert-butyl ether, a portion (50 mg, 0.089 mmol), catalytic amounts Bu4NBr (1.5 mg, 0.0047 mmol), aqueous NaOH (0.7 ml of 1 M solution) and isopropanol (2 ml) in a tube under pressure is cooled to -50°C. In the solution for 1 min propulsive freon. The tube is sealed and heated to 80°C for 12 hours. The mixture is extracted with EtOAc (3×10 ml). The combined organic e is stricty washed with brine, dried (Na2SO4) and concentrate under vacuum, giving an oil, which is then treated with a solution of 30% TFA in CH2Cl2throughout the night. Volatile products are removed under vacuum and the residue purified using preparative HPLC (YMC S5 ODS 30×250 mm column with reversed phase; 30 min continuous gradient from 70:30 a:100% b, where A=90:10:0.1 H2O:methanol:TFA and B=90:10:0.1 methanol:H2O:TFA), which leads to the desired titled product (14 mg; 28%). Analysis of HPLC with reversed phase shows that the purity of the product was 97%. In addition, LC/MS (Electronista determine the exact molecular ion [(M+N)+=553.1] for the desired connection.

Example 142

The following example 142 discloses a process of obtaining similar compounds [(M+H)+=553.2].

Intermediate compounds corresponding to example 141 parts b and C, remove protection using the same TPA/CHCl3the process as described above, and purified as usual, which gives the following equivalents:

Example 143: [M+H]+=593.4

Example 144: [M+H]+=503.1

Examples 145 305.

The following analogs of carbonatation, summarized in tables 4 and 5, are synthesized according to one of the above methods.

Table 4

Example No.R3d[M+h]+
145487.2

Example No.R3d[M+H]+
146539.3
147593.2
148449.3
149501.3
150517.2
151532.2
152589.3
153546.3
154532.2
155579.2
156593.2
157 593.3
158579.2

Example No.R3d[M+H]+
159579.2
160531.2
161527.2
162525.2
163515.2
164529.2
165527.2
166519.3
167517.3
168547.3
169577.3
170531.3
171 531.3
172545.3

Example No.R3d[M+H]+
173531.3
174571.2
175567.3
176547.3
177545.3
178579.2
179591.2
180535.2
181505.2
182521.1
183566;588
184571.1

Example No. R3d[M+H]+
185505.2
186521.1
187566;588
188545.2
189529.1
190529.1
191543.1
192571.2
193503.3
194501.3

Example No.R3d[m+h]+
195529.4
196531.3
197561.3
198 555.3
199513.3
200557.4
201543.3
202571.4
203572.3
204541.3
205543.4

Example No.R3d[m+h]+
206529.4
207515.3
208515.3
209515.3
210543-3
211529.4
212 577.3
213515.3
214529.3
215527.3
216531.3
217557.3

Example no.R3d[M+H]+
218573.1
219519.2
220535.2
221585.2
222519.2
223535.2
224585.2
225561.2

Table 5br>
Example no.R3d[M+H]+
226545.2

579.2
Example No.R3d[m+h]+
227593.1
228449.2
229501.2
230517.2
231532.2
232487.3
233546.3
234532.2
235579.2
236593.2
237593.3
238
239579.2
240531.2

td align="center"> 253
Example No.R3d[m+h]+
241527.2
242525.2
243515.2
244529.2
245527.2
246517.3
247517.3
248547.3
249577.3
250543.1
251531.3
252545.3
531.3

Example No.R3d[M+h]+
254571.2
255567.3
256547.3
257545.3
258593.4
259503.2
260579.2
261505.2
262521.1
263566/567

Example No.R3d[m+h]+
264571.1
265 505.2
266521.1
267566/567 .0
268523.3
269501.3
270539.2
271529.3
272549.2
273523.2
274513.3

Example No.R3d[M+H]+
275519.2
276539.2
277547.3
278552.3
279541.3
280563.3
281555.3
282543.3
283529.3
284515.3
285515.3

Example No.R3d[M+h]+
286515.3
287535.2
288529.2
289577.3
290515.2
291529.2
292527.3
293537.3
29 531.3
295555.2
296571.3
297573.2

Example No.R3d[M+H]+
298531.3
299519.3
300535.2
301585.2
302519.2
303535.2
304585.2
305561.2

Example 149

To a solution of secondary aminoether (2.1 g, 5.52 mmol)

in CH2Cl2(10 ml) is added 4-methylphenyl format (0.79 ml; 5.52 mmol) and polyvinylpyridine (Aldrich; 1.74 g; 16.5 mmol). The mixture is stirred at room temperature for 15 minutes, at which time TLC shows that the original product came in reaction. The solution is filtered, concentrated under vacuum and the residue chromatographic (SiO2; hexane:EtOAc, 4:1), which provides a clean carbamates (2 g). It dissolved in a mixture of THF (10 ml), methanol (1 ml) and aqueous LiOH (8 ml of 1 M solution). The solution was stirred at room temperature overnight, then acidified to pH 3 with excess aqueous 1 M HCl. The solution is extracted with EtOAc (2×50 ml). The combined organic extracts washed with H2O (2×50 ml) and brine (50 ml), dried (Na2SO4) and concentrate under vacuum, allowing the named compound as a white solid (1.75 g; 63%). [M+H]+=501.2.

[M+H]+=501.2.

1H NMR (400 MHz; CDCl3): δ 7.93-7.99 (m, 2H), 7.38-7.43 (m, 3H), 7.23 (q, 1H, J=8 Hz), 7.02-7.12 (m, 3H), 6.98-7.02 (m, 2H), 6.82-6.89 (m, 2H), 4.71 (s, 1H), 4.64 (s, 1H), 4.25 (t, 2H, J=7 Hz), 4.07 (s, 2H), 2.90-2.98 (m, 2H), 2.37 (s, 3H), 2.29 (C. 3H).

Example 230

To a cooled to 0°With a solution of secondary amine (3.0 g, 7.9 mmol)

in CH2Cl2(45 ml) was successively added pyridine (0.8 ml, 9.9 mmol) and 4-methoxyphenylalanine (1.3 ml, 8.7 mmol). The reaction is stirred PR is 0° C for 3 hours, to atota the time the original product came in reaction (analytical HPLC). The reaction solution was washed with aqueous solution of HCl (2×25 ml of 1 M solution), brine (2x), dried (Na2SO4) and concentrate under vacuum. The crude product chromatographic (SiO2; gradual gradient from 4:1 to 3:7 hexane:EtOAc)that provides the desired carbamates (4.2 g; 100%). The ether is dissolved in a mixture of THF:methanol:H2O (50 ml, 3:1:1 solution) and added LiOH·H2O (0.5 g; 11.9 mmol). The solution is stirred over night at room temperature. The original product is still present, as shown by HPLC. Enter additional number of LiOH.H2O (0.2 g; 4.8 mmol) and the mixture gently heated to solubilize LiOH, then stirred at room temperature for 4 hours. The reaction is finished at this moment and the mixture is acidified to pH 3 with excess aqueous 1 M HCl, then the organic solvent is removed under vacuum. The remaining aqueous phase is extracted with EtOAc (3×50 ml). The combined organic extracts are successively washed with H2O and brine (50 ml each), dried (Na2SO4), filtered and concentrated under vacuum, giving the named compound as a colourless solid (3.07 g; 75%). [M+H]+=517.2.

1H NMR (400 MHz; CDCl3): δ 7.96-7.98 (m, 2H), 7.4-7.45 (m, 3H), 7.2-7.3 (m, 2H), 7.07.1 (m, 2H), 6.8-7.0 (m, 4 H), 4.65 (s, 1H), 4.55 (s, 1H), 4.20-4.24 (m, 2H), 4.02 (s, 2H), 3.77 (s, 3H), 3.00 (s, 2H), 2.38 (s, 3H).

Compounds in the following examples(167, 187, 216, 229, 247 and 263) synthesized according to the procedures disclosed in examples 149 and 230.

Example 167

1H NMR (DMSO-d6; 500 MHz): δ 2.37 (s, 3H), 2.94 (m, 2H), 3.73 (2s, 3H), 4.06 (d, J=4.8 Hz, 2H), 4.25 (t, J=7.2 Hz, 2H), 4.66 (2s, 2H), 6.71 (m, 3H), 6.85 (m, 2H), 7.06 (d, J=16 Hz, 1H), 7.22 (m, 2H), 7.39 (m, 3H), 7.96 (m, 2H).

Example 187

1H NMR (DMSO-d6; 500 MHz): δ 2.36 (s, 3H), 2.93 (t, J=6.6 Hz, 2H), 4.02 (2s, 2H), 4.21 (t, J=6.6 Hz, 2H), 4.55 (2s, 2H), 6.94 (m, 3H), 7.48 (m, 8H), 7.90 (m, 2H).

Example 216

1H NMR (CDCl3; 400 MHz): δ 1.3-1.4 (m, 3H), 2.39 (s, 3H), 2.9-3.05 (m, 2H), 3.9-4.05 (m, 2H), 4.06 (advanced s, 2H), 4.25 (t, J=7.0 Hz, 2H), 6.85 (DD, J=11.4, 8.8 Hz, 2H), 6.99 (DD, J=15.8, 8.8 Hz, 2H), 7.18 (DD, J=8.4, 2.6 Hz, 2H), 7.38-7.50 (m, 5H), 7.99 (extended d, J=7.9 Hz, 2H).

Example 229

1H NMR (CDCl3; 400 MHz): δ 2.30 (2 peak, 3H), 2.38 (2 peak, 3H), 3.03 (DD, J=5.7, 5.7 Hz, 2H), 3.99 (s, 2H), 4.21 (DD, J=6.1, 6.1 Hz, 2H), 4.63 (2 peaks, 2H), 6.82-6.87 (m, 2H), 6.96-7.01 (m, 2H), 7.09-7.14 (m, 2H), 7.18-7.20 (m, 2H), 7.43-7.45 (m, 3H), 7.96-7.98 (m, 2H).

Example 247

1H NMR (DMSO-d6; 500 MHz): δ 2.36 (s, 3H), 2.93 (t, J=6.6 Hz, 2H), 3.74 (s, 3H), 3.96 (2s, 2H), 4.20 (t, J=6.6 Hz, 2H), 4.55 (2s, 2H), 6.65 (m, 2H), 6.94 (m, 3H), 7.27 (m, 3H), 7.48 (m, 3H), 7.91 (d, J=6.1 Hz, 2H).

Note the p 263

1H NMR (CDCl3; 400 MHz): δ 2.42 (2s, 3H); rotamer); 3.0-3.5 (m, 2H), 3.99 (advanced s, 2H), 4.15-4.25 (m, 2H), 4.57 (AB doublet, J=38.2 Hz, 2H), 6.85 (DD, J=11.4, 8.8 Hz, 2H), 6.99 (DD, J=15.8, 8.8 Hz, 2H), 7.18 (DD, J=8.4, 2.6 Hz, 2H), 7.38-7.50 (m, 5H), 7.99 (extended d, J=7.9 Hz, 2H).

Example 306

The solution monoacetate of resorcinol (2 g, 13.14 mmol), N,N-dimethylaniline (1.6 g, 13.14 mmol), phosgene (6.8 ml 1.95 M solution in toluene; 13.1 mmol) and catalytic amount of DMF in chlorobenzene (5 ml) is heated at 80°in the tube under pressure for 2.5 hours and then allowed to cool to room temperature. Transparent supernatant the solution is separated and concentrated under vacuum. The residue is purified by distillation under vacuum (140-150° @ 1.0 mm Hg), which gives a named connection in the form of a transparent oil (2 g; 71%).

B.

To a mixture of chloroformiate, part a (50 mg, 0.237 mmol)and pyridine (PVP) (75 mg, 0.70 mmol) adds CH2Cl2solution (2 ml) amino-tert-butyl ester (100 mg, 0.237 mmol),

(get as disclosed in example 7, part b).

The reaction mass was stirred at room temperature for 15 minutes Associated with resin-amine (WA21J, Supeico; 150 mg) is added to the mixture. The reaction mixture is stirred for an additional 15 minutes. SV is connected with the amine resin and PVP is removed by filtration and the filtrate is concentrated under vacuum, that gives the crude product. The crude product chromatographic (SiO2; hexane/EtOAc, 1:4), which provides the named compound (0.1 g, 70%).

C.

A solution of phenol-tert - butyl ether, part b (60 mg; 0.10 mmol), Bu4NBr (0.32 mg, 0.001 mmol), aqueous NaOH (0.5 ml of 1 M solution; 0.5 mmol) and isopropanol (1 ml) in a tube under pressure is cooled to -50°C. Through the solution for 1 minute propulsive gaseous freon. The tube is sealed and heated to 80°C for 12 hours. The mixture is extracted with EtOAc (3×10 ml). The combined organic extracts washed with brine, dried (Na2SO4) and concentrate under vacuum, which makes difficult the raw deformedarse-tert-butyl simple ether in the form of oil. The crude ester is then treated with a solution of 30% TFA in CH2Cl2throughout the night. Volatile products are removed under vacuum and the residue purified using preparative HPLC with a reversed phase (as in example 127, except that they use a continuous gradient from A:70:30 to 100%) to obtain two products, the desired named deformatsiei acid (13 mg, 23%) and phenol-acid defined below (32 mg; 63%). Analysis of HPLC with reversed phase, using standard conditions shows that the purity of the product is >92%. In addition, LC/MS (Electronista) determines the exact mo is egularly ion [(M+N) +=553.2 and 503.2 respectively] for the two compounds.

Examples 307 and 308

Following the General process described above in example 306, receive the following connections:

Example 309

To a mixture of penishealthinformation (11 mg, 0.063 mmol) and triethylamine (6.5 mg, 0.063 mmol) is added a solution of amino-tert-butyl ester (20 mg, 0.053 mmol),

(get as disclosed in example 7, part b) in CH2Cl2(1 ml). The reaction mass was stirred at room temperature for 15 minutes and the mixture is concentrated under vacuum giving the crude thionocarbamate tert-butyl ether. The specified product is dissolved in aqueous LiOH solution (0.50 ml, 1.0 M solution) and THF (2 ml) and stirred at room temperature for 5 hours. The solution is concentrated under vacuum giving the crude acid in the form of oil. The crude product is purified using preparative HPLC to obtain the desired titled product (10 mg, 38%). [M+H]+=503.2.

Example 310

The corresponding THIOCARBAMATE 1.4 series get the technique which is disclosed in example 309.

Example 311

To a mixture of amino-tert-butyl ester (30 mg, 0.73 mmol)

(get as disclosed in example 7, part b) and p-phenoxybenzoic acid (220 mg; 1.02 mmol; 1.4 EQ) in CH3CN (20 ml) is added a THIEF reagent (372 mg, 0.84 mmol, 1.15 EQ) in one portion, and then ISO-Pr2NEt (0.5 ml; 2.9 mmol; 3.9 EQ) dropwise. The reaction mass is stirred over night at room temperature, after which the volatile products are removed under vacuum. The residue is dissolved in EtOAc and washed with aqueous solution of 1 N. HCl. An aqueous solution (layer), extracted with EtOAc (2x) and the combined organic extracts washed with H2O, saturated aqueous NaHCO3and brine, dried (Na2SO4) and concentrate under vacuum, giving the desired product. The resulting crude amidoethyl use in the next stage without further purification.

A solution of crude amidoamine in 40% TFA - CH2Cl2(25 ml) is stirred for 5 hours at room temperature. Volatile products are removed under vacuum and the crude acid is purified preparative HPLC (YMC S5 ODS 30 mm × 250 mm column with reversed phase; flow rate=25 ml/min; 30 min continuous gradient from 70:30 a:100% B; solvent A=90:10:0.1 H2O:methanol:TFA; solvent B=90:10:0.1 methanol:H2O:TFA)to give the named compound (238 mg; 58% yield after 2 stages) as a white solid. Analysis of HPLC with reversed phase: BP the two delay=7.53 min (continuous gradient solvent system: from 50% A:50% to 0% A:100% B (A=90% H 2O/10% methanol/0.2% N3PO4; B=90% methanol/10% H2O/0.2% of N3PO4) for 8 min; determining at 220 nm; YMC S3 ODS 4.6×50 mm column). [M+H]+=563.3.

Example 311 And

(alternative synthesis)

To a solution of secondary amino-tert-butyl ester (35 mg, 0.083 mmol), (produced as described in example 7, part b).

4-phenoxybenzoic acid (30 mg, 0.14 mmol) and NEAT (30 mg, 0.22 mmol) in THF/DMF (1 ml/0.05 ml) is added EDCI (20 mg, 0.10 mmol) and the mixture is stirred at room temperature overnight. The reaction mass was diluted with EtOAc, washed with aqueous solution of 1 N. HCl, H2O, saturated aqueous NaHCO3and brine, dried (Na2SO4) and concentrate under vacuum. The crude amide-tert-butyl ether is dissolved in TFA/CH2Cl2(5 ml, 1:1 solution). Received pink solution is stirred overnight and concentrated under vacuum, which provides crude amide acid as a dark brown oil. The crude product is purified preparative HPLC (YMC S5 ODS 20×100 mm column, 10 min continuous gradient from 60:40 a:100% B; solvent A=90:10:0.1 H2O:methanol:TFA; solvent B=90:10:0.1 methanol:H2O:TFA; flow rate 20 ml/min), which provides the named compound (32 mg, 69%). [M+H]+=563.3.

Example 312

1) To a solution of secondary amino-tert-butyl ester (25 mg; 006 mmol)

(get as disclosed in example 7, part b) in THF (0.5 ml) is added 2-naphthaleneboronic acid (25 mg; 0.15 mmol; 2.5 EQ);

2) add NEAT (48 mg; 0.35 mmol; 5.8 EQ);

3) add DMF (50 μl);

4) is added EDCI (20 mg, 0.1 mmol, 1.8 mEq);

5) the reaction vessel for 24 hours at room temperature;

6) the reaction is diluted with methanol (2 ml) and filtered;

7) amide-tert-butyl ether purified preparative HPLC (YMC S5 ODS 20×100 mm column; flow rate 25 ml/min; 10 min continuous gradient from 70:30 a:100% B; solvent A=90:10:0.1 H2O:methanol:TFA; solvent B=90:10:0.1 methanol:H2O:TFK);

8) the fractions containing the purified aminoether, treated with a solution of TFA in CH2Cl2(0.5 ml, 1:1 solution) during the night. The reaction mass is concentrated under vacuum (Speed Vac), which gives titled compound (8 mg; 25%). Analysis of HPLC with reversed phase shows that the purity is >88%; LC/MS (Electronista) determines the exact ion [M+H]+=521.2 for these compounds.

Example 313

A mixture of aminoether (20 mg, 0.0474 mmol)

(get as disclosed in example 7, part b), thiophene-2-carboxylic acid (9.1 mg, 0.71 mmol), EDCI (26 mg, .4 mmol) and DMAP (catalytic amount) was dissolved in CH 2Cl2(2 ml) and stirred at room temperature overnight. The reaction solution is successively washed with an aqueous solution of 1 N. HCl (2 ml) and saturated aqueous NaHCO3(2 ml). To the organic phase then add 0.5 g of anhydrous Na2SO4and 0.2 g WA21J aminomethane resin (Supeico). The mixture is shaken for 0.5 hours and the solid is filtered off. TFA (2.0 ml) is added to the filtrate and the solution is shaken at room temperature overnight. The reaction solution is concentrated under vacuum, using a Speed Vac for 16 hours, allowing you to obtain the titled compound as a yellow oil. Analysis of HPLC with reversed phase (YMC S5 ODS 4.6×33 mm column, continuous gradient from 100% A to 100% B for 2 min at a flow rate of 5 ml/min [solvent A=10% methanol/90% H2O/0.2% of N3PO4; solvent B = 90% methanol/10% H2O/0.2% of N3PO4]) shows that the purity of the product is 92.7%. In addition, LC/MS (Electronista) gives the exact molecular ion [(M+N)+=477.2] named for the desired connection.

Example 314

Another method of purification using aminomethane resin to amicability, illustrated by the following synthesis.

To a mixture of aminoether (20 mg, 0.0474 mmol)

(get as disclosed the example 7, part b) and 3.5-dimethoxybenzoic acid (13 mg, 0.071 mmol) in anhydrous CH3CN (0.5 ml) add a solution THIEF reagent (31 mg, 0.071 mmol) in CH3CN (0.5 ml), and then DIEA (41 μl, 0.23 mmol) in CH3CN (0.5 ml). The reaction mass is shaken at room temperature overnight. Volatile products are removed under vacuum using a Speed Vac, and add CH2Cl2(2 ml). The solution is washed successively with an aqueous solution of 1 N. HCl (2 ml) and saturated aqueous NaHCO3(2 ml). In the organic phase is added 0.5 g anhydrous Na2SO4and 0.2 g WA21J associated with resin-amine (Supeico). The mixture is shaken for 0.5 hours and the solid is filtered off. Then to the filtrate is added TFA (2 ml) and the solution is shaken at room temperature overnight. The reaction solution is concentrated under vacuum, using a Speed Vac, 16 hours, which allows to obtain the final product as a yellow resin. Analysis of HPLC with reversed phase (YMC S5 ODS 4.6×33 mm column, continuous gradient from 100% A to 100% b for 2 min at a flow rate of 5 ml/min [solvent A=10% methanol/90% H2O/0.2% of N3PO4; solvent B=90% methanol/10% H2O/0.2% of N3PO4]) shows that the purity of the product is 90%. In addition, LC/MS (Electronista determine the exact molecular ion [(M+N)+=531.3] for named connection is of high value.

Examples with 315 on 391

Following the above processes, you receive the following compounds are summarized in tables 6 and 7 according to the invention.

Table 6: (amicability)

Example No.R3e[M+H]+
315521.2
316507.3
317563.1
318561.2
319499.3
320559.2
321491.1
322522.2
323491.2
324543.3

Example No.R3e[M+H]+
325515.3
326535.3
327499.3
328485.3
329503.3
330517.3
331513.3
332527.3
333519.3
334515.3
335515.3
336529.3

Example No.R3e[M+H]+
337477.2
338471.2
339 501.3
340489.2
341539.2
342529.3
343515.3
344485.3
345501.3
346505.2
347505.2
348527.3
349539.2

Example No.R3e[M+H]+
350489.3
351523.2
352515.3
353 511.2
354523.1
355499.2
356503.2
357521.2
358529.2
359529.2
360530.2
361530.2

Table 7 (amicability)

Example No.R3[M+H]+
362499.2
363547.2
364563.2
365561.1
366 595.1
367593.1
368595.1
369597.1

Example No.R3[M+H]+
370563.1
371547.2
372563.1
373577.2
374561.2
375561.2
376536.2
377577.2
378577.2
379615.3
38049.3

Example No.R3[M+H]+
381519.3
382507.3
383539.2
384505.2
385505.2
386522.7
387513.3
388527.3
389529.3
390527.3
391523.1

Example 392

A.

To a solution of amine (47 mg, 0.12 mmol)

(get as disclosed in example 3, part a) in CH3Cl2(5 ml) was added ISO-Pr2NEt (0.1 ml, 0.57 mmol) and DMAP (14 mg; 0.12 mm is l), and then benzylsuccinic (24 mg, 0.18 mmol). The reaction mass is stirred for 14 hours, then passed through an SCX cartridge [3 g; SCX cartridge pre-washed sequentially with methanol (10 ml) and CH2Cl2(5 ml)], elwira CH2Cl2(15 ml). The filtrate is concentrated under vacuum giving the crude urea, compound, part a (53 mg; 84%), which is essentially pure and can be used in the next stage without further purification.

B.

The crude solution of urea-ethyl ester (53 mg) and LiOH.H2O (12 mg) in THF:methanol:H2About (3:1:1; 5 ml) was stirred at room temperature for 2 days. The solution is acidified to pH 3 with an aqueous solution of 1 M HCl, concentrated under vacuum and purified preparative HPLC (using a YMC S5 ODS 20 mm × 100 mm column; continuous gradient from 70% A:30% to 100% b for 10 minutes, flow rate 20 ml/min, where a 90:10:0.1 H2O:methanol:TFA and where a=90:10:0.1 methanol:H2O:TFA), which gives the named compound (12 mg; 24%) as off-white solid. [M+H]+=500.2.

Example 393

A.

To a solution of amine (0.25 g, 0.66 mmol)

(get as disclosed in Example 6) in CH2Cl2(5 ml) in one portion add 4-methoxyphenyl oceanet (0.20 g, 1.32 mmol) and the resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then concentrated under vacuum, giving an oil, which chromatographic (SiO2; 1.5% methanol/CH2Cl2)that provides the named compound (0.34 g; 97%) as a colourless oil.

B.

A solution of compounds, part a (0.14 g, 0.26 mmol) and LiOH (0.1 g, 4.3 mmol) in H2O/THF (5 ml, 40:60 solution) is stirred for 12 hours at 25 °C. the Reaction mixture is acidified with SPLA and extracted with EtOAc (2x). The combined organic extracts dried (MgSO4) and concentrate under vacuum, allowing the named compound (0.12 g, 90%) as a colourless oil. [M+H]+=516.

1H NMR (CD3OD): δ 7.94 (m, 2H), 7.45 (m, 3H), 7.23 (m, 3H), 6.80 (m, 2H), 6.80 (m, 3H), 4.58 (s, 2H), 4.23 (t, J=7.9 Hz, 2H), 3.81 (s, 2H), 3.73 (s, 3H), 2.98 (t, J=7.9 Hz, 2H), 2.36 (s, 3H).

Example 394

A.

The solution previously described carbamylcholine (connection example 139, part a; 0.15 g, 0.34 mmol)

N-methyl-p-anisidine (0.14 g, 1.0 mmol) and K2CO3(0.15 g, 1.1 mmol) in 5 ml of acetone is stirred at 25°C for 12 hours. The reaction mixture is concentrated under vacuum, resulting in an oily residue, which chromatographic(SiO 2; 1.5% methanol/CH2Cl2), which, in turn, provides the named compound (0.12 g, 65%) as a colourless oil.

Century

A solution of compounds, part a (0.12 g, 0.22 mmol) and LiOH (0.050 g, 2.1 mmol) in H2O/THF (5 ml of a 40:60 mixture) was stirred at room temperature for 12 hours. The reaction mixture is concentrated under vacuum, resulting in an oily residue, which was purified preparative HPLC (YMC S5 ODS 30×250 mm column; flow rate 25 ml/min 30 min continuous gradient from a:B=50:50 to 100% B; solvent A=90:10:0.1 H2O:methanol:TFA; solvent B=90:10:0.1 methanol:H2O:TFA), which provides the named compound (59 mg, 50%) as a colourless oil. [M+H]+=530.3.

1H NMR (CDCl3): 7.99 (d, 6.2 Hz, 2H), 7.45 (m, 3H), 7.24 (m, 3H), 6.82 (d, 6.2 Hz, 2H), 6.79 (m, 1H), 6.63 (m, 1H), 6.55 (s, 1H), 4.24 (s, 2H), 4.16 (t, 7.8 Hz, 2H), 3.72 (s, 3H), 3.59 (s, 2H), 3.16 (s, 2H), 3.02 (t, 7.8 Hz, 2H), 2.40 (s, 3H).

Examples 395 at 409

Using the above processes, synthesize analogues are summarized in tables 8 and 9.

Table 8: (urea-acid)

Example No.R3f[M+H]+
395562.3
396 546.3
397554.2
398532.3
399522.3
400546.3
401516.3

Table 9 (urea-acid)

Example No.R3f[M+H]+
402562.3
403546.3
404554.2
405532.3
406522.3
407546.3
408516.3
409 516.3

Example 410

A named connection receive as part of the library in the stream-soluble phase, using the following process.

A.

To a mixture of 1-attilalongoria (26.8 mg, 0.12 mmol) and DMAP (2 mg, 0.016 mmol) in pyridine (2 ml) add a solution of amino-tert-butyl methyl ether

(get as disclosed in example 8) (20 mg, 0.05 mmol) in pyridine (0.6 ml). The reaction mass was stirred at room temperature for 20 hours. Associated with resin-amine (WA21J, Supeico; 5.8 mmol/g loading; 150 mg) is added to the mixture. The reaction mass is stirred for further 4 hours. The resin is filtered off and the filtrate concentrated under vacuum giving the crude product, which chromatographic (CUSIL12M6 column; United technology; 2 g of sorbent in 6 ml column) using the following process:

1) the column is filled with hexane (20 ml);

2) the residue is dissolved in minimum amount of EtOAc and loaded into a column of silica gel;

3) cartridge, elute with hexane/EtOAc (3:1), hexane/EtOAc (1:1). The desired fraction (identified by TLC) is collected and concentrated, giving a named connection in the form of viscous oils, which are used in the next stage without additional purification.

B.

Et3N (0.3 ml of 1 M solution in CH2Cl2) and TMSI (0.3 ml of 1 M solution in CH2Cl2) successively added to a solution of compound from part a in CH2Cl2. The reaction mixture was stirred at room temperature for 12 hours and then concentrated under vacuum giving the crude product. The product was then purified by solid-phase extraction using CHQAX12M6 column (United technology; 2 g of sorbent in 6 ml column) using the following process:

1) the column is filled CH2Cl2(25 ml);

2) the residue is dissolved in a minimum volume of CH2Cl2and download SAX column;

3) the cartridge is washed successively CH2Cl2(25 ml), CH2Cl2/methanol (5% methanol, 15 ml), CH2Cl2/methanol (50% methanol, 15 ml), methanol (20 ml);

4) elute the product with a solution of 1% TFA in methanol (20 ml).

The final product containing fractions are collected and concentrated under vacuum using a Speed Vac that allows you to receive BMS-329075 (16 mg; 62%). Analysis of HPLC with reversed phase shows that the purity of the product is 90%. In addition, LC/MS (Electronista determine the exact molecular ion [(M+N)+=557.1] for the desired connection.

Example 411

A.

X = halogen, alkyl, CF3, CF3About etc.

Following the General process used to prepare rebbekah substituted benzalconihlorida.

Gaseous Cl2miss cooled to 0°With a solution of 4-verbesserten (1.0 g, Lancaster) in glacial acetic acid (100 ml) and H2O (5.0 ml) for 1 hour. The reaction mixture was then poured into a mixture of ice-N2On and immediately extracted with CH2Cl2(200 ml); the organic phase is thoroughly washed sequentially H2O (200 ml), aqueous solution of saturated NaHCO3(2×100 ml) and finally brine (200 ml). The organic phase is dried (MgSO4) and concentrate under vacuum, resulting in 4-forbindelsesfaneblad in the form of a colorless solid (1.3 g; 89%).

B.

To a solution of secondary aminomethylated ester (25 mg, 0.066 mmol)

(get as disclosed in example 6) in pyridine (0.8 ml) is added 4-forbindelsesfaneblad (68 mg; 0.33 mmol; 5 EQ).

The mixture is heated to 75°C, stirred overnight at 75°and then concentrate under vacuum. The black residue is treated with an aqueous LiOH solution (1.0 ml of a 0.3 M solution) in H2O/methanol/THF for 18 hours, then concentrated under vacuum. The residue is acidified with 1.0 M aqueous solution of HCl to pH=1-2 and extracted with EtOAc (2x), dried (Na2SO4) and concentrated under vacuum giving the crude product. Purification preparative HPLC (YMC S5 CDS 20 mm × 250 mm column with education the military phase; 15-min continuous gradient from 60:40 a:up to 100% In 10-minute exposure time, where A=90:10:0.1 H2O:methanol:TFA and B=90:10:0.1 methanol:H2O:TFA; flow rate 25 ml/min) to give the named compound (12 mg; 34%) as a white solid. [M+H]+(LC/MS)=539.1.

Examples 412 on 456

Using the above processes, synthesize analogues are summarized in tables 10 and 11.

Table 10: (sulfonamide acid)

Example No.R3g[M+H]+
412507.3
413575.2
414525.2
415521.2
416533.2
417513.2
418535.3
419575.2
420 581.1
421590.3
422589.2

Example No.R3g[M+H]+
423535.3
424539.1
425541.2
426589.0
427573.2
428555.2
429555.3
430589.2
431535.3
432605.3
433577.4

Table 11 (sulfonamide acid)

Example No.R3g[M+H]+
434549.4
435557.3
436506.3
437549.3
438541.2
439521.3
440533.3
441535.4
442575.3
443678.3

Example No.R3g[M+H]+
444597.4
445589.2
446 535.3
447539.1
448539.1
449589.0
450573.2
451555.2
452555.3
453589.2
454535.3
455605.3
456577.4

Example 457

A.

To a cooled to 0°With a solution of methyl-2-hydroxypyridine-5-carboxylate (0.2 g, 1.3 mmol), 2- (5-methyl-2-phenyloxazol-4-yl)ethanol (0.32 g, 1.56 mmol) and Ph3R (0.38 g, 1.56 mmol) in CH2Cl2(10 ml) is added DEAD (0.2 ml, 1.95 mmol) dropwise and the reaction mass stirred at 25°C for 12 hours. The solution is concentrated under vacuum and chromatographic on SiO2/sub> (4:1, hexane:EtOAc)that provides the named compound (0.28 g, 63%) as oil.

B.

To a cooled to -78°With the solution of compound from part a (0.28 g, 0.82 mmol) in THF (10 ml) was added DIBALH (2.0 ml of 1 M solution in CH2Cl2; 1.95 mmol) and the reaction stirred at -78°C for 4 hours. TLC of an aliquot of the reaction mixture shows the presence of the corresponding aldehyde and alcohol. The reaction mass is heated to 25°and stirred at room temperature for 1 hour, after which TLC see only the alcohol. The reaction zakolerovat water and diluted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo before the formation of these compounds in the form of oil. The resulting crude product is used in the next reaction without further purification.

C.

To a cooled to -78°With the solution oxalicacid (0.22 ml, 2.6 mmol) and DMSO (0.37 ml, 5.2 mmol) in CH2Cl2(15 ml) added dropwise a solution of compound from part b (0.42 g of the crude product in 5 ml of CH2Cl2). The reaction mixture is stirred for 2 hours at -78°and then (1 ml) is added dropwise Et3N. the Reaction mixture was stirred for an additional 0.5 hours at -78°and then slowly heated to 25°C. Then the reaction mixture is izbavlyayut EtOAc (200 ml) and washed sequentially with an aqueous solution NaHCO 3and brine. The organic layer is dried (MgSO4), then concentrated under vacuum, allowing the named compound (0.40 g; 95%) in the form of oils, which are used in the next stage without further purification.

D.

A mixture of compounds, some With (<0.82 mmol), hydrochloride licensedialog ester (0.5 g, 4.0 mmol), NaBH(OAc)3of 0.85 g, 4.0 mmol) and DCE (10 ml) was stirred at 25°C for 12 hours. The reaction mixture was then diluted with EtOAc (50 ml) and washed sequentially with an aqueous solution NaHCO3and brine. The organic layer is dried (MgSO4), then concentrated under vacuum, giving a named connection (0.31 g; 82%) as oil (>95% purity, as shown by analytical HPLC with reversed phase), which is used in the next stage without further purification.

E.

A mixture of compounds, part D (0.050 g, 0.13 mmol), 4-phenoxybenzaldehyde (0.048 g; 0.26 mmol), NaBH(SLA)3(0.082 g; 0.39 mmol) in DCE (10 ml) was stirred at 25°C for 12 hours. The reaction mixture was diluted with EtOAc (50 ml) and washed sequentially with an aqueous solution NaHCO3and brine. The organic layer is dried (MgSO4), then concentrated under vacuum, giving tertiary aminomethane ester as an oily residue. To the specified residue is added LiOH (0.050 g) and H2O/THF (2 ml:40 solution) and the reaction mass stirred at room temperature for 12 hours. Preparative HPLC (YMC S5 ODS 30×250 mm column, a continuous gradient over 30 min; flow rate 25 ml/min, 30:70 a:100% B; A=90:10:0.1 H2O:methanol:CF3CO2N; B=90:10:0.1 methanol:H2O:CF3CO2H) ensure that the named compound (0.021 g; 30%) as a TFA salt.

1H NMR (CDCl3): δ 8.18 (s, 1H), 7.94 (d, 6.6 Hz, 2H), 7.86 (D. 8.8 Hz, 1H), 7.45 (m, 3H), 7.34 (m, 3H), 7.14 (t, 7.4 Hz, 1H), 7.02-6.92 (m, 5H), 6.81 (t, 8.8 Hz, 1H), 4.51 (m, 6N), 3.59 (s,2H), 3.06 (t, 6.2 Hz, 2H).

Example 458

A.

A mixture of 2-hydroxypyridine-6-carboxylic acid (1.30 g, 9.4 mmol), concentrated H2SO4(0.5 ml) and methanol (20 ml) is heated at boiling with obratnim refrigerator for 12 hours. The reaction is finished at this moment, as shown by analytical HPLC. The reaction mixture is concentrated under vacuum, giving a light yellow oil, which was diluted with EtOAc and washed with aqueous solution of NaHCO3. The organic phase is dried (MgSO4) and concentrate under vacuum to obtain the titled compound as a solid (0.43 g, 30%).

B.

To a solution of compounds, part a (0.43 g, 2.8 mmol), 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (0.68 g, 3.3 mmol) and Ph3P (1.0 g, 4.07 mmol) in THF (10 ml) is added DEAD (0.66 ml, 4.2 mmol) and the reaction mixture was stirred at room temperature is within 12 hours. The solution is concentrated under vacuum and the residue chromatographic (SiO2; 20% acetone in hexane), which provides a named connection in the form of oil (0.92 g; 97%).

C.

To a solution of compounds, part b (0.92 g, 2.7 mmol) in THF (50 ml) is added LiAlH4(5 ml, 1.0 M solution in THF, 5 mmol) dropwise at -78°and the final reaction mass is heated to 0°C for 2 hours. Then the reaction zakolerovat, adding to the mixture a few pieces of ice. Then the reaction mixture was separated between EtOAc (200 ml) and brine (50 ml). The organic phase is dried (MgSO4) and concentrate under vacuum, giving the oil (0.92 g; 95%) which was used in the next reaction without further purification.

D.

To a solution of oxalicacid (0.47 ml, 5.4 mmol) and DMSO (0.36 ml, 10.8 mmol) in CH2Cl2(15 ml) is added dropwise a solution of the connection part (0.92 g; >2.7 mmol) in CH2Cl2(10 ml) at -78°C. the Reaction mixture is stirred for 2 hours and then added dropwise Et3N (1 ml). The reaction mixture is allowed to mix for an additional 0.5 hours at -78°and then slowly heated to 25°C. the Reaction mixture was then diluted with EtOAc (200 ml) and washed sequentially with an aqueous solution NaHCO3and brine. The organic layer is dried (MgSO4and then conc the Ute under vacuum, to obtain the titled compound (0.90 g; purity >90%,1H NMR analysis) in the form of oil. The resulting product is then used without further purification.

E.

To a solution of compounds, part D (0.90 g, 2.7 mmol), hydrochloride licensedialog ether (1.7 g, 13.5 mmol) in 1,2-dichloroethane (10 ml) is added NaBH(SLA)3(1.7 g, 8.1 mmol) in one portion. The resulting solution was stirred at 25°C for 12 hours. The reaction mixture is concentrated under vacuum, giving an oil, which chromatographic (SiO2; 30% acetone in hexane), which provides the named compound (0.86 g; 83%) as a colourless oil.

F.

Solution connection, part E (0.040 g, 0.1 mmol), 4-phenoxybenzaldehyde (0.030 g, 0.15 mmol) and NaBH(OAc)3(0.060 g, 0.3 mmol) in DCE (10 ml) was stirred at room temperature for 12 hours. The reaction mixture is concentrated under vacuum and the oily residue chromatographic (SiO2; 30% acetone in hexane), which provides aminoethane titled compound (56 mg, >95%) as a colourless oil.

G.

Solution connection, part F (56 mg; 0.1 mmol) and LiOH (0.050 g, 0.21 mmol) in H2O/THF (2 ml of 6:4 solution) was stirred at room temperature for 12 hours. The reaction mixture is concentrated under vacuum, giving a white solid fuel is the substance, which is dissolved in methanol and purified preparative HPLC (YMC S5 ODS 30×250 mm column; continuous gradient over 30 min; flow rate 25 ml/min, 30:70 a:100% B; A = 90:10:0.1 H2O:methanol:TFA; B=90:10:0.1 methanol:H2O:TFA). The named compound (41 mg; 72%) was obtained as TFA salt.

1N Yarm (methanol-D4): 7.90 (m, 2H), 7.71 (t, 8.4 Hz, 1H), 7.51 (d, 8.7 Hz, 2H), 7.44 (m, 3H), 7.36 (t, 8.7 Hz, 2H). 7.17 (t, 8.4 Hz, 1H), 6.96 (m, 5H), 6.82 (d, 8.4 Hz, 1H), 4.62 (t, 6.2 Hz, 2H), 4.56 (s, 2H), 4.50 (s, 2H), 4.17 (s, 2H), 3.00 (t, 6.2 Hz, 2H), 2.36 (s, 3H). With34H31N3O5. 550.23 (M+H+) LC/MS (Electronista).

Example 459

A.

To a cooled to 0°With the solution of 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (1.07 g, 5.25 mmol), Ph3R (1.38 g, 5.25 mmol) and N-Boc-4-hydroxyphenylethylamine (1.24 g, 5.25 mmol) in THF (36 ml) is added DEAD (0.83 ml, 5.25 mmol), allowed to warm to room temperature and stirred for 15 hours. The reaction mixture is concentrated under vacuum and the residue chromatographic (SiO2; gradual gradient from 95:5 to 4:1, hexane:EtOAc) to obtain the titled compound (1.43 g, 65%).

Century

A solution of compounds, part a (1.01 g, 2.37 mmol) and TFA (8 ml) in CH2Cl2(30 ml) was stirred at room temperature for 4.5 hours. The solution is concentrated under vacuum and the residue dissolved in CH2l 2and then filtered through a pillow of solid To2CO3. The filtrate is concentrated under vacuum, giving the corresponding crude amine. To a solution of the crude amine in THF (11.9 ml) is added pyridine (0.383 ml, 4.74 mmol) and 2,4-dinitrobenzenesulfonyl (0.85 g, 3.19 mmol) and the solution stirred at room temperature for 15 hours. Because at this point there is still a certain amount of the original product, introduce additional number of sulphonylchloride (0.32 g, 1.2 mmol). After a further 4 hours, HPLC analysis indicates that the entire original product came in reaction. The reaction mixture was diluted with Et2O, washed with 1 N. aqueous HCl, saturated aqueous NaHCO3and brine, dried (MgSO4), filtered and concentrated under vacuum, which provides a crude 2,4-dinitrobenzenesulfonic.

To a solution of crude 2,4-dinitrobenzenesulfonic in CH3CN (3 ml) is added To a2CO3(excess) and tert-butyl bromoacetate (7.11 mmol). The reaction mass was stirred at room temperature overnight. HPLC analysis shows that the ratio of product and starting material is 2:1. To the reaction mixture an additional amount of DMF (3 ml), K2CO3and tert-butylbromide. The reaction is complete in 2 hours. The reaction mixture Et 2O, washed with 1 N. aqueous solution of HCl, a saturated solution of NaHCO3and brine, dried (MgSO4) and concentrate under vacuum, which provides a crude tert-butyl ether. Specified the crude product chromatographic (SiO2; hexane/EtOAc; gradual gradient from 9:1 to 2:1), giving a named connection (0.663 g, 42% overall).

C.

To a solution of compounds, part b (0.663 g, 0.995 mmol) in THF (2.5 ml) was added Et3N (0.208 ml, 1.49 mmol) and mercaptohexanol acid (0.090 ml, 1.29 mmol). The reaction mass was stirred at room temperature overnight. The reaction mixture was then diluted with Et2O, washed with 1 N. aqueous solution of HCl, a saturated solution of NaHCO3and brine, dried (MgSO4) and concentrate under vacuum. The remainder chromatographic (SiO2; hexane/EtOAc; gradual gradient from 9:1 to 2:1), which gives the named compound (0.265 g, 61%).

D.

To a solution of the connection part (0.015 g, 0.0344 mmol) in DCE (1 ml) is added 4-phenoxybenzaldehyde (0.103 mmol) and NaBH(SLA)3(0.0365 g, 0.172 mmol). The reaction mass was stirred at room temperature for 15 hours. Then it is filtered through a fabric cushion that gives a clear solution, which was diluted with CH3Cl2and washed with a saturated aqueous solution of NaHCO3and brine, dried (MgSO4 ) and concentrate under vacuum. The crude product is purified preparative HPLC (YMC S5 ODS 30×250 mm column; flow rate 25 ml/min, gradient from 20% to 100% over 25 min, 100%, exposure for 15 min delay time=29.1 min)to obtain tert-butyl ether. The resulting ester was dissolved in CH2Cl2(1.3 ml) and added slowly TFA (0.5 ml). The reaction mass was stirred at room temperature overnight and then concentrated under vacuum. The residue is then dissolved in CH2Cl2, washed with H2O, saturated aqueous NaHCO3and brine, dried (MgSO4) and concentrate under vacuum, giving a named connection (0.012 g, 61%). LC/MS gives the correct [M+H]+=563.3.

Other analogues (as shown in the table) are synthesized by the same process of reductive amination, as described in example 459, part D using the connection for example 459, part With, and different aromatic aldehydes in Addition, carbonatation, such as described in example 461, also synthesized using the General process disclosed previously for the synthesis of the compound from example 136.

Table 12

Example No.R3[M+H]+
460 571.3
461515.3
462471.3

Example 463

A.

To a solution of the acid from example 230 (240 mg, 0.47 mmol) in DMF (2.0 ml) add NEAT (68 mg, 0.49 mmol), EDAC (94 mg, 0.49 mmol) and 2-cyanoethylene (34 mg, 0.49 mmol). The solution was stirred at room temperature for 18 hours; the analysis of the reaction by LC/MS shows that the original product is still present. The reaction mass is injected additional 2-cyanoethylene (34 mg, 0.49 mmol) and stirred at room temperature for 48 hours. Volatile products are removed under vacuum and the residue dissolved in CH2Cl2(40 ml)and then washed successively with water (2×30 ml) and brine (30 ml). The organic phase is dried (MgSO4) and concentrate under vacuum. The obtained white residue is dissolved in a minimal amount of CH2Cl2(3 ml) and planted by careful addition of EtOAc, the resulting amide, which is called compound (184 mg; 70%) as a white solid.

B.

To a cooled to 0°With the solution of the compounds, part a (180 mg; 0.32 mmol) in CH2Cl2(1.5 ml) are successively added Ph3the (83 mg; 0.32 mmol), DEAD (100 μl, 0.64 mmol) and TMSN3(85 μl, 0.64 mmol). The reaction mixture was stirred at room temperature for 24 hours. LC/MS analysis shows that there is still enough of the original product. The reaction mixture was then concentrated under vacuum to 2/3 of the original volume and introduce an additional amount of Ph3P, DEAD and TMSN3(1 equivalent of each reagent). The reaction mixture was stirred at room temperature for another 24 hours and then diluted with EtOAc (40 ml). The solution is treated with 5% aqueous solution of CAN (10 ml) and stirred for 15 minutes. The reaction solution was washed with water (30 ml) and brine (30 ml), dried (MgSO4) and concentrate under vacuum. The remainder chromatographic (SiO2; simple ester: CH2Cl2, 3:7), which gives the named compound (100 mg; 53%) as a white solid.

C.

To a solution of compounds, part b (100 mg, 0.17 mmol) in THF/1,4-dioxane (6:1, 1.4 ml) is added aqueous NaOH solution (0.6 ml, 1.0 M solution, 3.5 EQ). The mixture is stirred at room temperature for 14 hours and then acidified to pH ˜2 with 1.0 M aqueous solution of N3PO4. EtOAc (30 ml) is added and the organic phase washed with water (15 ml) and brine (15 ml), dried (MgSO4) and concentrate under vacuum. The remainder of chromatography the Ute (SiO 2; 4% methanol/CH2Cl2), which gives these tetrazole (35 mg, 38%) as a white foam. LC/MS (Electronista) gives the correct molecular ion: [M+H]+=541.3.

Example 464

A.

A mixture of 2-hydroxybenzaldehyde (500 mg, 4.09 mmol), hydrochloride licensedialog ether (544 mg, 4.09 mmol) and Et2N (495 mg, 4.9 mmol) in dry methanol (5 ml) was stirred at room temperature for 3 hours. Then with three portions added NaBH4(155 mg, 4.09 mmol). The reaction mass was stirred at room temperature for another 30 minutes. A saturated aqueous solution of Na2CO3(1 ml) is added to destroy the remaining NaBH4,and then add an aqueous solution of HCl (10 ml of 1 n solution). The aqueous phase washed with EtOAc (3×20 ml), then gently alkalinized 1 N. aqueous NaOH solution to pH 7-8. The aqueous phase is then extracted with EtOAc (3×20 ml). Red-orange solution is concentrated under vacuum, giving the named compound as a yellow viscous oil.

B.

Connection, part a (38 mg, 0.195 mmol), 4-methoxyphenylalanine and pyridine (39 mg, 5 mmol) dissolved in 0.1 ml of CH2Cl2within 5 minutes. The reaction mixture is then washed with an aqueous solution of HCl (2×2 ml of 1 n solution). The organic phase is washed with brine, dried (Na SO4), concentrated under vacuum and chromatographic (SiO2; hexane:EtOAc, 7:3), which gives the named compound (40 mg; 59%) as a pale yellow oil.

C.

To a solution of compounds, part b (40 mg, 0.116 mmol), 2-[2-phenyl-5-methoxazole-4-yl]ethanol (Maybridge; 24 mg, 0.116 mmol) and Ph3R (40 mg, 0.151 mmol) in dry THF (3 ml) is added dropwise DEAD (26 mg, 0.151 mmol). The solution was stirred at room temperature overnight. Red-orange solution was concentrated under vacuum and the residue purified preparative HPLC (continuous gradient from 50% A : 50% to 100%B; A = 90% H2A:10% methanol+0.1% TFA); B=90% methanol/10% H2O+0.1% TFA) for 10 min; YMC SH-343-5 ODS 20×100 mm (5 μm) column)that provides the named compound (30 mg, 47%) as a yellow viscous oil.

D.

The compound from part C was dissolved in methanol (3 ml) and H2O (0.3 ml). To the resulting solution was added LiOH (3 mg) and the reaction stirred at room temperature for 3 hours. Volatile products are removed under vacuum and the solution acidified with 1 N. aqueous solution of HCl to pH 3-4. The aqueous phase is extracted with EtOAc (3×10 ml). The combined organic extracts washed with brine, dried (Na2SO4) and concentrate under vacuum, giving a named connection in the form of a white solid (18 mg; 64%). LC/MS (elec is readiline) provides the exact molecular ion [(M+N) +=516].

1H NMR: δ 2.27-2.32 (m, 3H), 2.96-2.98 (m, 2H), 3.65-3.69 (d, 3H), 4.06-4.20 (m, 4H), 4.55-4.63 (d, 2H), 6.74-6.93 (m, 4H), 7.19-7.35(m, 2h), 7.88-7.90 (m, 2H).

Example 465

A.

A mixture of the hydrochloride of p-alaninemia ester (51 mg, 0.363 mmol), Et3N (50 μl; 0.363 mmol) and aldehyde (100 mg; 0.33 mmol)

in methanol (1 ml) was stirred at room temperature for 3 hours. Added NaBH4(14 mg, 0.363 mmol) and the reaction stirred at room temperature for another 1 hour. Volatile products are removed under vacuum and the residue is divided between saturated aqueous Na2CO3and EtOAc (20 ml each). The organic phase is concentrated under vacuum, giving a connection, part a, in the form of a yellow oil, which was used in the next stage without further purification.

B.

To a solution of compound from part a (20 mg, 0.050 mmol) and pyridine (0.50 ml) in CH2Cl2(2 ml) is added 3-chlorophenylalanine (14 mg, 0.070 mmol). The reaction mass was stirred at room temperature for 2 hours, then the volatile products are removed under vacuum. The residue is purified preparative HPLC (YMC S5 ODS 20×75 mm column with reversed phase; continuous gradient from 50:50 a:100% b, where A=90:10:0.1 H2O:methanol:TFA and B=90:1:0.1 methanol:H 2O:TFA), which gives the connection part of the Century

C.

A solution of compound from part b and LiOH·N2About (5 mg) in THF:H2O (4:1) was stirred at room temperature for 1 hour. The reaction solution is acidified to pH 3 with an aqueous solution of HCl, then extracted with EtOAc. The combined organic extracts are concentrated under vacuum, giving a named connection (5 mg, 18%) as a white solid. [M+H]+=535.2; 537.2.

Example 466

The named compound is synthesized using the same sequence as that in example 465, except that the use of aldehyde

[M+H]+= 535.2; 537.2.

Following the processes disclosed above, get connection examples with 467 in 472.

Examples 467 on 469

Example No.R3[m+h]+
467501.3
468563.3
469515.3

Examples 470 through 472

Example No.R3[M+H]+
470501.3
471563.3
472515.3

Example 473

A.

A mixture of 3-itfinal (2.0 g, 9.1 mmol), acetic anhydride (4.6 g, 45.5 mmol) and pyridine (3.6 g, 45.5 mmol) is stirred in CH2Cl2(20 ml) for 3 hours. The resulting mixture was washed with saturated aqueous NH4Cl (3×100 ml), dried (MgSO4) and concentrate under vacuum, giving the compound of part a (2.30 g; 97%) as a yellow oil.

B.

A mixture of compound from part a (1.00 g, 4.0 mmol), trimethylsilylacetamide (780 mg; 8 mmol), CuI (15 mg, 0.08 mmol) and (Ph3R)2Pd2Cl2(28 mg, 0.04 mmol) in diethylamine (10 ml) was stirred at room temperature for 3 hours. Volatile products are removed under vacuum and the residue chromatographic (SiO2; hexane:EtOAc, 4:1), which gives the crude compound from part b, which is used in the next stage without further purification.

C.

To a solution of crude compound from part b in CH2Cl2(2 ml) is added pyridine (3 ml, 37 mmol) and acetic anhydride (4 ml, 42 mmol). The reaction mass was stirred at room temperature for 2 hours, then divide between saturated aqueous NH4Cl (30 ml) and CH2Cl2. The organic phase is washed dopolnitelnim the amount of saturated aqueous solution of NH4Cl (30 ml) and H2O (100 ml), dried (Na2SO4) and concentrate under vacuum, giving a connection part, which is used in the next stage without further purification.

D.

A solution of crude compound, part With, and Bu4NF (1.1 g; 12 mmol) in THF (10 ml) was stirred at room temperature for 1.7 hours, after which the entire original product reacts. The reaction solution was washed with H2O add Celite® (Celite) and the volatile products are removed under vacuum. Solid chromatographic (SiO2; hexane:EtOAc, 9:1), which gives the connection, part D (400 mg; 63% for 3 stages).

E.

A mixture of compound from part D (400 mg; 2.5 mmol) and the catalyst Pd/caso3/Pb (40 mg; Aldrich) in methanol (20 ml) stirred in an atmosphere of H2within 30 minutes. The mixture is filtered through Celite® and the filtrate concentrated under vacuum. The remainder chromatographic (SiO2/sub> ; hexane:EtOAc, 95:5), which gives the connection part E (310 mg; 77%) as a colourless oil.

F.

To a cooled to 0°With the solution of compound from part E (310 mg; 1.9 mmol) in DCE (10 ml) was sequentially added dropwise clean diethylzinc (491 μl; 4.8 mmol; Aldrich) and ICH2Cl (700 μl; 9.6 mmol). The reaction mixture is allowed to warm to room temperature and then stirred at room temperature for 3 hours, after which it is divided between saturated aqueous NH4Cl and EtOAc (50 ml each). The organic phase is washed with saturated aqueous NH4Cl and H2O (50 ml each) and concentrated under vacuum. The remainder chromatographic (SiO2; hexane:EtOAc, 9:1), which leads to the connection part F (230 mg; 69%) as a colourless oil.

G.

A mixture of compound from part F (100 mg; 0.57 mmol) and K2CO3(157 mg; 1.1 mmol) in methanol (5 ml) was stirred at room temperature overnight (no reaction). Add an aqueous solution of Li HE (1.1 ml of 1 M solution; 1.1 mmol) and the solution stirred at room temperature overnight. Volatile products are removed under vacuum and the residue partitioned between an aqueous solution of 1 M HCl and EtOAc. The organic phase is concentrated under vacuum and the residue chromatographic (SiO2; hexane:EtOAc, 4:1), which leads to the connection of the structure, part G (70 mg; 92%) as a yellow oil.

H.

To a solution of compound from part G (6 mg; 0.045 mmol) in DMF (0.2 ml) is added tert-butyl potassium (5 mg; 0.05 mmol). The reaction is stirred for 2 min at room temperature, then add carbamoylated (20 mg, 0.045 mmol)

and the reaction mass stirred at room temperature for further 15 minutes. Volatile products are then removed under vacuum and the residue chromatographic (SiO2; hexane:EtOAc, 7:3), which leads to the connection part N (11 mg; 45%) as a yellow oil.

I.

To a solution of compound from part H and LiOH·H2O in methanol/H2O (10 ml, 9:1 mixture) was stirred at room temperature overnight. Then the solution is acidified to pH ˜3 aqueous solution of HCl and extracted with EtOAc. The combined organic extracts concentrated in vacuo and purified preparative HPLC, giving the named compound (10.1 mg, 95%) as off-white Lopilato. [M+H]+=527.3.

Example 474

A.

A mixture of 3-benzyloxybenzaldehyde (2.00 g; 1.0 mmol), ethylbromoacetate (1.67 g; 1.0 mmol) and Cs2CO3(3.25 g; 1.0 mmol) in DMF (20 ml) was stirred at room temperature for 8 hours is. The reaction mixture is divided between the H2O (300 ml) and EtOAc (100 ml). The aqueous phase is extracted with EtOAc (2×100 ml). The combined organic extracts washed with brine, dried (Na2SO4) and concentrate under vacuum. The remainder chromatographic (SiO2; 85:15, hexane:EtOAc)to obtain the compound of part a (3.48 g; >100%) as a colourless oil.

B.

To a solution of compound from part a (3.4 g; 11.9 mmol) in dry THF (50 ml) in an argon atmosphere add LiAlH4(36 ml, 0.5 M solution in THF; 17.8 mmol) dropwise. The reaction mass was stirred at room temperature for 1 hour. The reaction zakolerovat, slowly adding saturated aqueous solution of NH4Cl (1 ml). Volatile products are removed under vacuum and the residue separated between EtOAc (100 ml) and 1 M aqueous HCl solution. The organic phase is dried (Na2SO4) and concentrate under vacuum, giving a connection part In (2.4 g; 98%) as a white solid.

C.

To a solution of compound from part b (2.4 g; 9.8 mmol) and Ph3P (3.1 g; 14.7 mmol) in CH2Cl2add CBr4(4.80 g; 14.7 mmol). The reaction mass was stirred at room temperature overnight, then concentrated under vacuum. The remainder chromatographic (SiO2; 95:5, hexane:EtOAc), which gives the connection part With (2.8 g; 93%) in the de white solid.

D.

A mixture of compound from part C (310 mg; 1.0 mmol) and of potassium tert-butylate (113 mg; 2.0 mmol) in toluene (20 ml) is heated to 105°C for 20 minutes. Enter additional number of KO-t-Bu (56 mg; 1.0 mmol) and the reaction heated at 105°C for another 10 minutes. The mixture is cooled to room temperature and divide between H2O (100 ml) and EtOAc (100 ml). The organic phase is washed with H2O (2×100 ml), dried (Na2SO4) and concentrate under vacuum. The reaction is repeated with an additional number of connections, part C (500 mg; 1.63 mmol) and KO-t-Bu (182 mg, 16 mmol). The combined crude reaction products chromatographic (SiO2; hexane), which gives the connection, part D (590 mg; 89%) as a colourless oil.

E.

To a cooled to 0°With the solution of compound from part D (1.4 g; 62 mmol) in DCE (100 ml) is added dropwise pure diethyl zinc (1.6 ml, 16 mmol), and then ICH2Cl (5.46 g; 31 mmol)Reaktsionnoi mixture is allowed to warm to room temperature and stirred at room temperature overnight, then washed with 1 M aqueous HCl solution. The organic phase is dried (Na2SO4) and concentrate under vacuum. The crude residue chromatographic twice (SiO2; hexane), which gives the connection part E (510 mg; 30%), in addition, produce the original product connection part D (250 mg; 18%).

F.

To a cooled to -78°With the solution of compound from part E (510 mg; 2.2 mmol) in liquid NH3(30 ml) was added Na (500 mg, 22 mmol). Dark blue solution was stirred at -78°C for 4 hours, then allowed to warm to room temperature over night. The resulting solid residue is divided between 1 M aqueous solution of HCl and EtOAc (50 ml each). The organic phase is dried (Na2SO4) and concentrate under vacuum. The crude product chromatographic (SiO2; 9:1, hexane:EtOAc), which gives the connection part F (240 mg, 75%) as a yellow oil.

G.

To a solution of compound from part F (150 mg; 1.0 mmol) in DMF (10 ml) was successively added KO-t-Bu (112 mg; 1.0 mmol) and a solution of carbamylcholine (44 mg; 1.0 mmol) in DMF (0.5 ml).

(get as disclosed in examples 5 and 139).

The reaction mass was stirred at room temperature for 15 min, after which HPLC analysis shows that all of the original product came in reaction. The mixture is divided between the H2O and EtOAc (100 ml each). The organic phase is washed with H2O (2×100 ml), dried (Na2SO4) and concentrate under vacuum. The crude product chromatographic (SiO2; 9:1, hexane:EtOAc), which gives the connection, part G, with impurities in the form of a yellow oil.

N.

A solution of compound from part G (556 mg; 1.0 mmol) and LiOH·H2O (116 mg; 2.8 mmol) in (10:1) methanol: H2About (10 ml) was stirred at room temperature for 2 hours. Volatile products are removed under vacuum and the residue is acidified to pH 2 with an aqueous solution of 1 M HCl, then extracted with EtOAc (3×40 ml). The combined organic extracts dried (Na2SO4) and concentrate under vacuum. The crude product is purified preparative HPLC (YMC S5 ODS 50×250 mm column; flow rate 25 ml/min; continuous 20 min gradient from 70:30 B:a to 100% b, where A=90:10:0.1 H2O:methanol:TFA and B=90:10:0.1 methanol:H2O:TFA), which gives the product (120 mg; 30% for 2 steps) as a colourless oil. [M+H]+=543.2.

Example 475

The named compound synthesized from the compound of example 474, part F (150 mg; 1.0 mmol) and carbamylcholine (440 mg; 1.0 mmol)

(get as disclosed in examples 6 and 139), followed by hydrolysis with LiOH·H2O analogously to example 474. A named connection produce, purify and receive in the form of a colorless oil (340 mg; 92% over 2 stages). [M+H]+=543.3.

Following the processes disclosed above, get connection examples with 476 in 494.

Examples from 476 in 484

Example No.R3h[M+H]+
476519.1
477535.1
478579.1; 581.0
479535.3
480551.3
481595.3; 597.3
482529.3
483527.3
484543.4

Examples 485 494

Example No.R3h[M+H]+
485519.1
486535.1
487579.1; 581.0
488535.3
489551.3
490595.2; 597.2
491529.3
492527.3
493527.3
494543.3

Example 492

Connection example 492 synthesized according to the processes disclosed above.

1H NMR (CDCl3; 400 MHz): δ 0.68 (t, J=4.4 Hz, 2H), 0.94 (t, J=4.4 Hz, 2H), 1.87 (m, 1H), 2.42 (s, 3H), 3.06 (s, 2H), 4.02 (t, J=5.2 Hz, 2H), 4.22 (t, J=5.2 Hz, 2H), 4.60 (2 peaks, 2H), 6.84-6.89 (m, 4H), 7.15-7.26 (m,, 4H), 7.40-7.47 (m, 3H), 7.98-8.00 (m, 2H).

Required (not commercially available) phenols and chloroformiate for the synthesis of analogues of carbonatation obtained as follows.

3-Fluoro-4-methylphenylphosphinic

A.

A mixture of 5-methoxy-2-methylaniline (5.0 g, 36 mmol), HCl (7.6 ml of a 12 M solution; 91 mmol) and H2O (11 ml) heated to 60°C for 15 min until terminated complete dissolution. The reaction is cooled to 0°C and d is billaut dropwise an aqueous solution of NaNO 2(2.5 g; 36 mmol) (internal temperature <7°). Stirred at 0°C for 30 min and carefully add cooled to 0°With solution HBF4(5.3 ml of a 48% solution; 40 mmol). The reaction was stirred at 0°C for 20 min and the resulting brown solid was filtered, washed with ice water (3×10 ml) and H2O (2×10 ml). The solid is dried under high vacuum for 20 hours, then heated (heat gun)until the allocation BF3(white smoke) does not stop. The obtained brown oil separated between EtOAc and H2O. the Organic phase is dried (Na2SO4), concentrated under vacuum and distilled (Kugelrohr), which gives 3-fluoro-4-methylanisole (1.6 g; 31%) as a colourless oil.

B.

To a cooled to -70°With the solution of 3-fluoro-4-methylanisole (1.62 g; 11.6 mmol) in CH2Cl2(10 ml) is added dropwise BBr3(10 ml; 12 mmol). The reaction mixture was stirred at -70°C for 10 min, then allowed to warm to 0°C and stirred at 0°C for 2 hours. The reaction allowed to warm to room temperature and concentrate under vacuum, and the residue is divided between the H2O and EtOAc. The organic phase is washed with H2O, dried (Na2SO4) and concentrate under vacuum, which gives 3-fluoro-4-METHYLPHENOL (1.1 g; 75%) as oil.

C.

A solution of 3-fluoro-4-METHYLPHENOL (1.1 g, 8.7 mmol), phosgene (5.9 ml of a 1.93 M solution in toluene; 8.7 mmol), DMF (10 μl) and N,N-dimethylaniline (1.27 g; 8.7 mmol) in chlorobenzene (10 ml) in a tightly closed tube was stirred at room temperature for 2 hours, then at 80°C for 2 hours, cooled to room temperature, stirred at room temperature for 1 hour, then concentrated under vacuum. The residue is distilled on a Kugelrohr to obtain 3-fluoro-4-methylenechloride (800 mg; 49%) as a clear oil.

3-Chloro-4-methylphenylphosphinic

3-Chloro-4-methylenechloride (600 mg; 45% of the total for 2 stages) synthesized from 3-chloro-4-methylanisole (1.0 g), using the same path (BBr3-initiated cleavage of the methyl ester, followed by treatment with phosgene as described above.

3-Bromo-4-methylphenylphosphinic

To a cooled to 0°With a mixture of 3-bromo-4-methylaniline (5 g; 27 mmol) and N2SO4(5.5 ml 16 M solution) in H2O (7.5 ml) is added dropwise an aqueous solution of NaNO2(1.93 g; 28 mmol per 7.5 ml of H2O). The reaction mass is stirred at 0°C for 30 minutes, then heated to 50°C for 2 hours, then cooled to room temperature and extracted with EtOAc (2x). The combined organic extracts are washed with the H 2O, dried (Na2SO4) and concentrate under vacuum, which gives 3-bromo-4-METHYLPHENOL (1.72 g; 34%) as oil. The resulting phenol is converted into 3-bromo-4-methylenechloride (1.9 g; 82%), following the same process (phosgene/dimethylaniline/heated)and 3-fluoro-4-methylenephosphonate above.

2-Methoxyphenylalanine (1.5 g) and 3-methoxyphenylalanine (1.5 g), both synthesized in the same way that 3-fluoro-4-methylenechloride (phosgene/dimethylaniline/heated) 2-methoxyphenol (2 g) and 3-methoxyphenol (2 g), respectively.

3-Chloro-4-methoxyphenol

To a cooled to 0°With the solution of 3-chloro-4-methoxyaniline (1.0 g, 6.4 mmol) in (1:1) H2O: conc. H2SO4(100 ml) is added slowly a solution of NaNO2(0.5 g; 7.6 mmol) in H2O (10 ml). Appears thick yellow smoke and the black solution is then heated to boiling with obratnim fridge for 30 minutes the Mixture is extracted with EtOAc (4×50 ml) and the combined extracts are concentrated under vacuum. The remainder chromatographic (SiO2; 4:1, hexane:EtOAc)to obtain 3-chloro-4-methoxyphenol (300 mg; 30%) as a yellow oil.

3-Fluoro-4-methoxyphenol

A solution of 3'-fluoro-4'-methoxyacetophenone (10 g, 59 mmol) and meta-chloroperbenzoic acid (50% purity; 30 g, 89 mmol) in CH2Cl2(300 ml) paramashiva the t at room temperature over night. The solution was washed with saturated aqueous Na2CO3, then filtered through a bed of SiO2(CH2Cl2as eluent) and finally chromatographic (SiO2; hexane:EtOAc, 4:1), which gives the crude product (3'-fluoro-4'-methoxyphenylacetate; 63 g). The solution indicated the crude product and LiOH.H2O (5 g; 120 mmol) in methanol:H2O (100 ml, a mixture of 9:1) was stirred at room temperature overnight. Volatile products are removed under vacuum and the residue is divided between excess aqueous 1 M HCl and EtOAc (aqueous solution (layer) pH˜3). The aqueous phase is extracted with EtOAc (2x). The combined organic extracts dried (Na2SO4) and concentrate under vacuum, which gives 3-fluoro-4-methoxyphenol (6.1 g; 72%) as oil.

3-Bromo-4-methoxyphenol (4.39 g; 47% for 2 stages) are synthesized using essentially the same sequence, on the basis of 3-bromo-4-methoxybenzaldehyde.

3-Propylene

A.

A mixture of 3-yoganidra (2 g, 8.5 mmol), trimethylsilylacetamide (1.67 g; 17 mmol), Cul (32 mg, 0.17 mmol) and (Ph3R)2PdCl2(59 mg; 0.085 mmol) in diethylamine (10 ml) was stirred at room temperature for 1 hour. Volatile products are removed under vacuum and the residue separated between EtOAc and brine. The organic phase is washed with brine (2×10 ml) and then filter the display through the bed of SiO 2. Volatile products are removed under vacuum giving the crude product (3-trimethylsilylethynyl) as a pale yellow oil. The solution indicated the crude product and tetrabutylammonium (6.6 g; 26 mmol) in THF (10 ml) was stirred at room temperature for 15 minutes. Volatile products are removed under vacuum and the residue chromatographic (SiO2; 9:1, hexane:EtOAc), which leads to the compound from part a (1.0 g; 89%) as a yellow oil.

B.

To a cooled to 0°With the solution of compound from part a (1.0 g; 7.6 mmol) in anhydrous THF (5 ml) is added dropwise n-BuLi (4.5 ml of a 2.0 M solution in hexane; 9.1 mmol). The obtained yellow solution was stirred at 0°C for 30 minutes. Then add methyliodide (1.6 g; 11.4 mmol) and allowed to warm to room temperature, and then stirred at room temperature for 30 minutes, Volatile products are removed under vacuum and the residue is divided between water solution of 1 N. HCl and EtOAc. The aqueous phase is extracted with EtOAc (3×20 ml), the combined organic extracts dried (MgSO4) and concentrate under vacuum, giving a connection, part b (1.0 g; 92%) as a yellow oil.

C.

A solution of compound from part b (1.0 g) in methanol (5 ml) is stirred over 10% Pd/C (10 mg) in an atmosphere of H2throughout the night. The catalyst is removed filter is receiving through the pillow Celite® and the filtrate is concentrated under vacuum, giving the connection part C (1.0 g; 100%) as a yellow oil.

D.

To a cooled to -78°With the solution of the compound from part C (1.0 g; 6.6 mmol) in CH2Cl2(10 ml) was added BBr3(4.8 ml of 1 M solution in CH2Cl2), allowed to warm to room temperature and stirred at room temperature for 3 hours, then carefully divide between aqueous solution of 1 M HCl and CH2Cl2. The organic phase is washed with aqueous solution of NH4Cl, dried (MgSO4) and concentrate under vacuum, giving 3-propylene (900 mg; 100%) as a yellow oil.

Example 495

A.

A mixture of benzoic acid (1.22 g, 10 mmol); methanesulfonanilide (1.15 g; 10 mmol), K2CO3(5.52 g, 40 mmol) and benzyltriethylammonium (0.23 g, 1 mmol) in toluene was stirred at 80°C for 2 hours. Then add utilization.therefore (1.55 g; 10 mmol) and the reaction mass is then cooled for 30 min, then cooled to room temperature. The solid is filtered off and the filtrate concentrated under vacuum. The remainder chromatographic (SiO2; gradual gradient from 3:1 to 1:1, hexane:EtOAc), giving the compound of part a (350 mg; 16%) as a white solid.

B.

To a cooled to 0°With the solution of compound from part a (49 mg; 0.22 mmol) and aldehyde (50 mg; 010 mmol)

in DCE (3 ml) is added NaBH(SLA)3(30 mg; 0.42 mmol), allowed to warm to room temperature, and then stirred at room temperature for 2 hours, then at 60°C for 18 hours. The mixture is cooled to room temperature and concentrate under vacuum. The residue is purified preparative HPLC (YMC S5 ODS 30×250 mm column; flow rate 25 ml/min; 20 min continuous gradient from 70:30 B:a to 100% b, where solvent A=90:10:0.1 H2O:methanol:TFA and solvent B=90:10:0.1 methanol:H2O:TFA), which gives the connection part of the Century

C.

A solution of crude compound from part b in THF (1 ml) and aqueous LiOH solution (0.3 ml of 1 M solution; 0.3 mmol) was stirred at room temperature for 3 hours, then acidified to pH ˜3 aqueous solution of 1 M HCl. The aqueous phase is extracted with EtOAc (2x), the combined organic extracts are concentrated under vacuum. The residue is purified preparative LDCs (YMC S5 ODS 30×250 mm column; flow rate 25 ml/min; 22 min continuous gradient from 70:30 B:a to 100% b, where solvent A=90:10:0.1 H2O:methanol:TFA and solvent B = 90:10:0.1 methanol:H2O:TFA), which gives the named compound (26 mg; 33% yield after 2 stages) in the form of a white solid which substances. [M+H]+=486.3.

Example 496

A.

To a cooled to 0°With the solution of the aldehyde (200 mg, 0.65 mmol)

in methanol (2 ml) is added by portions NaBH4(24 mg; 0.65 mmol), after which the reaction allowed to warm to room temperature, and then stirred at room temperature for 1 hour. Volatile products are removed under vacuum and the residue is divided between the H2O and EtOAc. The organic phase is dried (Na2SO4) and concentrate under vacuum, giving the intermediate alcohol in the form of oil. A solution of alcohol in CH2Cl2(2 ml) and PBr3(1 ml of 1 M solution in CH2Cl2) was stirred at room temperature for 30 minutes. Volatile products are removed under vacuum and the residue is divided between saturated aqueous NaHCO3and EtOAc. The organic phase is washed with H2O, dried (Na2SO4) and concentrate under vacuum, giving the compound of part a (150 mg; 62%) as oil.

B.

A solution of compound from part a (42 mg; 0.11 mmol) of example 500, the compound of part a (25 mg; 0.11 mmol) and K2CO3(100 mg; 0.71 mmol) in DMF (1 ml) was stirred at room temperature for 3 days. The reaction mixture was separated between EtOAc and H2O. the Organic phase was washed with H2O (2) and concentrate under vacuo the om. The remaining oil is dissolved in THF (1 ml) and added aqueous LiOH solution (0.3 ml of 1 M solution). The reaction mass was stirred at room temperature for 3 hours, then acidified to pH ˜3 aqueous solution of 1 M HCl. The aqueous phase is extracted with EtOAc (2x), the combined organic extracts are concentrated under vacuum. The residue is purified preparative LDCs (YMC S5 CDS 30×250 mm column; flow rate 25 ml/min; 20 min continuous gradient from 70:30 B:a to 100% b, where solvent A=90:10:0.1 H2O:methanol:TFA and solvent B=90:10:0.1 methanol:H2O:TFA), which gives titled compound (15 mg; 27% yield after 2 stages) as a white solid. [M+H]+=486.4.

Example 497

A.

A mixture of 3-hydroxyacetophenone (650 mg, 4.78 mmol), K2CO3(660 mg, 4.78 mmol) and 2-phenyl-5-methyl-4-oxazolidinedione (1.12 g, 3.98 mmol)

in MeCN (40 ml) is heated under reflux during the night. Volatile products are removed under vacuum and the residue separated between EtOAc (100 ml) and 1.0 M aqueous NaOH solution (80 ml). The organic phase is washed with brine (100 ml), dried (MgSO4) and concentrate under vacuum. The remainder chromatographic (SiO2; hexane:EtOAc, 3:1), giving the compound of part a (850 g; 67%) as a yellow solid.

B.

To a solution of the compound from part a (850 mg, 2.65 mmol) in DCE (15 ml) was successively added hydrochloride licensedialog ester (333 mg, 2.65 mmol), Et3N (554 μl, 4.0 mmol), NaBH(SLA)3(786 mg; 3.7 mmol) and acetic acid (152 μl; 2.65 mmol). The reaction mixture was stirred at room temperature for 6 days, then divide between aqueous solution of 1 M NaOH and CH2Cl2. The aqueous phase was washed with H2O, then concentrate under vacuum. The remainder is divided between EtOAc and 1 M aqueous HCl solution. The organic phase is washed with brine, dried (MgSO4) and concentrate under vacuum, giving back your original product (the compound of part a). The pH value of aqueous HCl phase was adjusted to 10 with an excess of solid NaOH. The resulting aqueous phase is extracted with EtOAc (60 ml). The organic extract was washed with brine (60 ml), dried (MgSO4) and concentrated under vacuum giving the crude compound, part b (400 mg; 39%) in the form of oils, which are used in the next stage without further purification.

C.

To a solution of compound from part b (29 mg; 0.074 mmol) in pyridine (1.0 ml) is added 4-taylhardat (14 μl; 0.089 mmol) and DMAP (10 mg). The solution is heated to 61°for chasov, then cooled to room temperature and concentrated under vacuum giving the crude connection part (36 mg) as a syrup.

D.

A solution of crude compound from part C (36 mg; 0.68 mmol) and LiOH·H2O (12 mg; 0.28 mmol) in THF:methanol:H2O (1 ml of 1:1:1 solution) was stirred at room temperature for 2 hours. Volatile products are removed under vacuum and the residue is acidified to pH 2 with an aqueous solution of 1 M HCl, then extracted with EtOAc (3×40 ml). The combined organic extracts dried (Na2SO4) and concentrate under vacuum. The crude product is purified preparative HPLC (YMC S5 ODS 50×250 mm column; flow rate 25 ml/min; continuous 20 min gradient from 70:30 B:a to 100% b, where A=90:10:0.1 H2O:methanol:TFA and B=90:10:0.1 methanol:H2O:TFA), which gives the named compound (28 mg; 72% after 2 stages) as a white solid. [M+H]+=515.3.

Example 498

A.

A solution of (S)-1-(4-methoxyphenyl)ethylamine (11.9 g, 79 mmol), methylpropanoate (11.5 g; 75 mmol) and Et3N (12.6 ml, 90 mmol) in THF (156 ml) was stirred at room temperature for 15 hours. The reaction mass is divided between EtOAc and H2O. the Organic phase is washed with brine, dried (MgSO4) and concentrated under vacuum giving the crude compound, which was used in the next stage without additional purification.

B.

To a cooled to 0°With the solution shyrokoseredynnye, part a, obtained above, in CH2Cl2(198 ml) is slowly added dropwise BBr3(12.0 ml, 127 mmol), stirred at 0°C for 3 hours, then poured carefully cooled to 0°With a mixture of saturated aqueous solution of NH4Cl and EtOAc. The aqueous phase is neutralized by slowly adding solid NaHCO3, then extracted with EtOAc (2x). The combined organic extracts washed with brine, dried (MgSO4) and concentrate under vacuum, which leads to the connection part (7.29 g; 44% after 2 stages).

C.

To a solution of compound from part b (6.13 g, 29.3 mmol) in dioxane:H2O (98 ml of 1:1 solution) successively added NaHCO3(3.2 g; 38 mmol) and 4-methoxyphenylalanine (3.92 ml, 26.4 mmol). The reaction mass was stirred at room temperature for 2 hours, then divide between EtOAc and H2O. the Organic phase is washed with brine, dried (MgSO4) and concentrated under vacuum giving the crude compound, a portion (10.0 g; 95%).

D.

To a solution of compound from part C in MeCN (59 ml) are successively added To a2CO3(2.43 g; 17.6 mmol) and mesilate (4.93 g; 17.6 mmol).

The mixture is heated to 90°C for 20 hours, then cooled to room temperature. The mixture is divided between tOAc and H 2O. the Organic phase is washed with brine, dried (MgSO4) and concentrate under vacuum. The remainder chromatographic (SiO2; gradual gradient from 8:1 to 3:1 to 1:1, hexane:EtOAc), which gives the connection, part D (3.4 g; 36%).

E.

To a solution of compound from part D (3.4 g, 6.25 mmol) in THF:H2O (31 ml of a 2:1 solution) is added LiOH·HiO (0.525 g; 125 mmol). The reaction mass was stirred at room temperature overnight (14 hours). Add EtOAc and the solution acidified with 1 N. HCl solution to pH ˜2. The organic phase is washed with brine, dried (MgSO4) and concentrate under vacuum. The residue is purified preparative HPLC (YMC S5 ODS 30×250 mm column; flow rate 25 ml/min; 22 min continuous gradient from 70:30 B:a to 100% b, where solvent A=90:10:0.1 H2O:methanol:TFA and solvent B=90:10:0.1 methanol:H2O:TFA; delay time=17.8 min), which gives titled compound (2.1 g; 63% yield) as a white solid. [M+H]+=531.3.

1H NMR (DMSO-d6; 400 MHz): δ 1.50 (2D, J=6.6 Hz, 3H), 2.37 (s, 3H), 2.94 (t, J=7.0 Hz, 2H), 3.74 (s, 3H), 3.81 (m, 2H), 4.21 (t, J=6.2 Hz, 2H), 5.36 (m, 1H), 6.93 (m, 6N), 7.28 (m, 2H), 7.50 (m, 3H), 7.91 (m, 2H).

Example 499

The synthesis of these compounds is carried out, using the same sequence, which is disclosed in example 498, except that (R)-4-methoxy-α-methylbenzo the amine is used instead of (S) isomer. [M+H]+=531.3.

1H NMR (DMSO-d6; 400 MHz): δ 1.50 (2D, J=7.0 Hz, 3H), 2.37 (s, 3H), 2.94 (t, J=6.6 Hz, 2H), 3.74 (s, 3H), 3.84 (m, 2H). 4.21 (t, J = 6.6 Hz, 2H), 5.35 (m, 1H), 6.93 (m, 6N), 7.29 (m, 2H), 7.50 (m, 3H), 7.91 (m, 2H).

Example 500

A.

A mixture of 4-hydroxyphenylethylamine (2.50 g; 14.0 mmol), 2-phenyl-5-methoxazole-4-ethanolgasoline (3.30 g; 11.7 mmol) and K2CO3(1.94 g; 14.0 mmol) in acetonitrile (50 ml) is heated under reflux in an atmosphere of Ar for 18 hours. Volatile products are removed under vacuum and the residue is divided between the H2O and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic extracts washed with aqueous solution of 1M NaOH and H2O, dried (MgSO4) and concentrate under vacuum. The remainder chromatographic (SiO2; gradual gradient from 3:1 to 9:1, hexane:EtOAc), giving the compound of part a (3.42 g; 80%) as a white solid.

B.

A mixture of compound from part a (3.42 g, 9.42 mmol), glycemically ester, HCl salt (1.18 g, 9.42 mmol), Et3N (1.97 ml, 14.1 mmol), NaBH(OAc)3(2.80 g; 13.2 mmol) and the SPLA (0.54 ml, 9.42 mmol) in DCE (20 ml) was stirred at room temperature for 6 days. During this time, the reaction is not yet complete, but does not proceed further. It zakolerovat saturated aqueous NaHCO3(6 ml), then concentrated under vacuum. About who headed the remainder of the divide between saturated aqueous NaHCO 3and EtOAc. The organic phase is washed with saturated aqueous NaHCO3and H2O, then extracted with 1 M aqueous HCl solution (unreacted original product remains in the organic phase). The aqueous phase is alkalinized with NaOH, then extracted with EtOAc. The organic phase is washed with H2O and brine, dried (MgSO4) and concentrate under vacuum, giving a connection part (365 mg; 9%) in the form of oil.

C.

To a solution of compound from part C (50 mg; 0.11 mmol) in pyridine (1 ml) is added 4-methoxyphenylalanine (40 μl) and DMAP (5 mg). The reaction mixture is heated to 60°C for 6 hours, then cooled to room temperature and the volatile products are removed under vacuum. The residue is dissolved in THF/methanol/H2O (1 ml, 2:2:1 mixture) and add LiOH (30 mg). The reaction mass was stirred at room temperature for 18 hours, then acidified with aqueous solution of 1 M HCl to pH 2. The mixture is extracted with EtOAc (30 ml), washed with H2O and brine (15 ml each), dried (MgSO4) and concentrated under vacuum giving the crude product. Its clear preparative HPLC (YMC S5 ODS 30×250 mm column; continuous gradient from 60:40 a:up to 100% In 30 min), which gives, after lyophilization from methanol/H2O titled compound (52 mg; 79%) as a white solid. [M+H]+=573.3.

Example 501

A.

A mixture of the hydrochloride licensedialog ester (245 mg; 1.95 mmol), Et3N (271 μl; 1.95 mmol), aldehyde

(400 mg; 1.3 mmol) and anhydrous MgSO4(200 mg) in THF (4 ml) was stirred at room temperature overnight, then filtered. The filtrate is concentrated under vacuum giving the crude compound from part a, which is used in the next stage without further purification.

B.

The mixture of metal India (448 mg; 3.9 mmol) and allylbromide (334 μl; 3.9 mmol) in anhydrous DMF (2 ml) stirred at 0°C for 50 minutes, Add a solution of crude compound from part a above) in anhydrous DMF (2 ml) to this mixture and the reaction vigorously stirred at room temperature for 3 hours. Analysis of the HPLC/MS shows that the reaction is complete at this moment. The reaction mass is divided between saturated aqueous NH4Cl and EtOAc. The organic phase is washed with H2O (emulsion is formed) and brine, dried (MgSO4) and concentrated under vacuum giving the crude compound, part b (300 mg; 55% for 2 stages). This product is used in the next stage without further purification.

C.

To a cooled to 0°With the solution of compound from part b (150 mg, 0.36 mmol) and Et3N (51 μl; 0.36 mmol) in CH2Cl2/sub> (4 ml) is added dropwise 4-methoxyphenylalanine (53 (ál; 0.36 mmol), allowed to warm to room temperature and then stirred at room temperature for 1 hour and then concentrated under vacuum. The remainder chromatographic (SiO2; hexane:EtOAc, 2:1), which gives the connection part (200 mg; 98%) as oil.

D.

A solution of compound from part C (100 mg, 0.18 mmol) and LiOH·H2O (30 mg, 0.72 mmol) in THF:methanol:H2O (1 ml, 1:1:1 solution) was stirred at room temperature for 2 hours. The reaction mixture was then acidified to pH˜2 aqueous solution of 1 N. HCl. The aqueous phase is extracted with EtOAc (2x). The combined organic extracts dried (Na2SO4), concentrated under vacuum and lyophilized of dioxane, which provides the named compound (80 mg, 82%) as a white solid. [M+H]+=557.2.

Example 502

A.

A solution of the compound from example 501, part C (100 mg; 0.18 mmol) in methanol (10 ml) in the presence of 10% Pd/C (50 mg) is stirred in an atmosphere of H2for 2 hours at room temperature. Then the catalyst is filtered off using a pad of Celite®. The filtrate is concentrated under vacuum, giving the compound of part a (100 mg; 100%) as oil.

B.

The named compound (87 mg; 90%; white solid lyophilic) is produced from compound from part a as in example 501, a compound synthesized from the compound in example 501, part C. [M+H]+=559.2.

Example 503

A.

To a solution of 5-methyl-2-phenylthiazol-4-retinol (50 mg; 0.23 mmol) in CH2Cl2(3 ml) was successively added Et3N (50 μl; 0.36 mmol) and methanesulfonamide (20 ml; 0.26 mmol). The reaction mass was stirred at room temperature for 2 hours, then divide between CH2Cl2and an aqueous solution of 1 M HCl. The organic phase is washed with brine, dried (Na2SO4) and concentrate under vacuum, giving the compound of part a (68 mg; 100%) as a colourless oil. This product is used in the next stage without further purification.

B.

A mixture of phenol (get, using the same process as disclosed in example 498 for the synthesis of compounds, part C, except that ethylbromoacetate used instead of methylpropanoate)

(18 mg; 0.048 mmol) and K2CO3(30 mg; 0.22 mol) in MeCN (2 ml) heated to 60°C overnight, then cooled to room temperature and separated between EtOAc and excess aqueous 1 M HCl. The aqueous phase is extracted with EtOAc (2x), the combined body of the economic extracts dried (Na 2SO4) and concentrate under vacuum. The residue is purified preparative HPLC (as described in example 498), which provides a connection part (12 mg; 43%).

C.

A solution of compound from part b (12 mg, 0.02 mmol) and LiOH·H2O (10 mg; 0.24 mmol) in THF (2 ml) and H2O (1 ml) was stirred at room temperature for 4 hours. The reaction mixture is acidified with excess aqueous 1 M HCl and extracted with EtOAc (3x). The combined organic extracts dried (Na2SO4) and concentrated under vacuum; the residue is purified preparative HPLC (as described in example 498), which gives the named compound (3 mg, 26%) as a colourless oil. [M+H]+=547.2.

Example 504

A named connection receive exactly the same way as described in example 503, except that [S]-enantiomer of the compound a (100 mg; 47%) was obtained as oil. This product is used in the next stage without further purification.

B.

A solution of compound from part a (100 mg; 0.61 mmol), methylpropanoate (103 mg; 0.67 mmol) and Et3N (102 μl; 0.73 mmol) in THF was stirred at room temperature for 16 hours. The reaction mixture was separated between EtOAc and H2O. the Organic phase is washed with brine, dried (MgSO4) and concentrate on the vacuum. The remainder chromatographic (SiO2; CH2Cl2:methanol, 9:1), which gives the connection part (90 mg, 62%) as oil.

C.

To a cooled to 0°With the solution of compound from part b (90 mg, 0.38 mmol) in CH2Cl2(12.7 ml) slowly add clean BBr3(82 μl; 0.87 mmol). The reaction mass is stirred at 0°C for 3 hours, then divide between ice saturated aqueous NH4Cl and EtOAc. The organic phase is separated and the aqueous layer was neutralized by adding NaHCO3, then extracted with EtOAc (2x). The combined organic extracts washed with brine, dried (MgSO4) and concentrate under vacuum, giving a connection part (50 mg; 59%).

D.

A mixture of compound from part C (50 mg; 0.22 mmol), 4-methoxyphenylalanine (33 mg; 0.22 mol) and NaHCO3(25 mg; 0.29 mmol) in (1:1) aqueous solution of dioxane (7.5 ml) was stirred at room temperature for 2 hours. The reaction mixture was separated between EtOAc and H2O. the Organic phase is washed with brine, dried (MgSO4) and concentrate under vacuum, giving a connection, part D (45 mg; 52%).

E.

A mixture of compound from part D (45 mg; 0.12 mmol), K2CO3(30 mg; 0.22 mol) and mesilate (33 mg; 0.12 mmol)

in MeCN (4 ml) heated to 90°C for 20 hours. The reaction mass is then cooled to room temperature and separated between EtOAc and H2O. the Aqueous phase is extracted with EtOAc (2x), the combined organic extracts dried (MgSO4) and concentrate under vacuum. The remainder chromatographic (SiO2; gradual gradient from 9:1 to 1:1, hexane:EtOAc)that provides connectivity, part E (42 mg; 65%).

F.

A solution of compound from part E (42 mg; 0.08 mmol) and LiOH·H2O (6 mg; 0.15 mmol) in THF:H2O (3.8 ml, 2:1) was stirred at room temperature overnight. The reaction mixture is acidified to pH 2 with excess aqueous 1 M HCl and extracted with EtOAc (2x). The combined organic extracts dried (Na2SO4) and concentrated under vacuum; the residue is purified preparative HPLC (as described in example 498), which gives the named compound (28 mg; 68%) as a colourless oil. [M+H]+=543.2.

Following the processes disclosed above, get connection examples with 506 at 518.

Example No.Ra[M+H]+
506(±) Me515.3
507(±) n-Bu557.4
Example No.Ra[M+H]+
508(±) Me531.3
509(±) Et545.1
510(±) i-Bu573.3
511(±)571.3

Example 506

1H NMR (DMSO-d6; 400 MHz): δ 1.47 and 1.54 (2D, J=7.5 Hz, 3H), 2.29 (s, 3H), 2.37 (s, 3H), 2.93 (t, J=6.6 Hz, 2H). 3.81 (2D, J=18 Hz; 2H), 4.21 (t, J=6.6 Hz, 2H), 5.3 (m, 1H), 6.94 (m, 4H), 7.18 (d, J=8.4 Hz, 2H), 7.31 (m, 2H), 7.49 (m, 2H).

Example 508

1H NMR (DMSO-d6; 400 MHz): δ 1.47 and 1.54 (2d, J=Hz; 3H), 2.37 (s, 3H), 2.94 (t, J=6.6 Hz, 2H), 3.74 (s, 3H), 3.81 (m, 2H), 4.21 (t, J=6.6 Hz, 2H), 5.36 (m, 1H), 6.94 (m, 4H), 7.29 (m, 2H), 7.49 (m, 3H), 7.91 (m, 2H).

Example No.Structure[M+H]+
512< / br>
(±)
531.3

In the synthesis examples 513-518 included ispolzovanie connection example 541, part b, as alkylating agent.

Example No.Structure[M+H]+
513517.2
514517.2
515501.2

Example No..Structure[M+H]+
516501.2
517517.2
518517.2

Example 519

A mixture of the hydrochloride of methyl-α-aminoisobutyrate (108 mg; 0.7 mmol), Et3N (146 μl; 111 mmol), NaBH(SLA)3(222 mg, 11 mmol) and aldehyde (215 mg; 07 mmol)

in DCE (5 ml) was stirred at room temperature for 21 hours. Is a certain amount of the original product, so it is heated up to 55°C for 4 hours (the reaction does not proceed). Add saturated aqueous solution of NaHCO3and volatile products are removed under vacuum. The remainder is shared between the H2O and EtOAc. the same phase is further extracted with EtOAc (2x). The combined organic extracts washed with brine and extracted with an aqueous solution of 1 M HCl. The aqueous phase is alkalinized solid NaOH and extracted with EtOAc (2x). The organic extracts are dried (Na2SO4) and concentrated under vacuum giving the crude compound from part a (174 mg; 61%).

B.

A solution of compound from part a (120 mg, 0.29 mmol), an aqueous solution of LiOH (2.0 ml of a 0.3 M solution of 1:1:1 mixture of THF:methanol:H2O) is stirred at room temperature overnight. The reaction is acidified to pH˜2 aqueous solution of 1 M HCl, then concentrated under vacuum and purified preparative HPLC (YMC S5 ODS 30×250 mm column; flow rate 25 ml/min; continuous gradient from 40:60 V:a to 100% b over 30 min, where solvent A=90:10:0.1 H2O:methanol:TFA; solvent B=90:10:0.1 methanol:H2O:TFA)to obtain a connection, part b (60 mg, 53%) as syrup.

C.

A solution of compound from part b (25 mg; 0.06 mmol), 4-methoxyphenylacetate (20 μl) in pyridine (1 ml) heated to 60°C for 6 hours. Volatile products are removed under vacuum and the residue separated between EtOAc (2 ml) and an aqueous solution of 1 M HCl (1 ml). The organic phase is concentrated under vacuum and the residue purified preparative HPLC (YMC S5 ODS 30×250 mm column; flow rate 25 ml/min; continuous gradient is t 40:60 V:a to 100% b over 20 min, where solvent A=90:10:0.1 H2O:methanol: TFA; solvent B=90:10:0.1 methanol:H2A: TFA)to obtain the titled compound (4 mg, 12%) as a white foam. [M+H]+=545.3.

Following the processes opisannym get connection in the following examples with 520 through 535.

Examples from 520 to 535

Example No.Structure[M+H]+
520543.4
521527.3
522531.2
523515.2

Example No.Structure[M+H]+
524531.2
525515.2
526515.2

Example No.Structure[M+H]+
527543.3
528527.3
529545.3

Example No.Structure[M+H]+
530531.2
531515.2
532515.2
533531.2
534