 Method of producing cephalosporin derivatives or their additive salts with trifluoroacetic acid
专利摘要:
La présente invention concerne des dérivés de la famille des céphalosporines de formule: dans laquelle: le groupe COOA en position 4 est un radical acide, ou un sel alcalin ou alcalino-terreux, ou un sel d'amino-acide ou d'amine, par exemple la triéthylamine ou les éthanolamines, ou un radical ester facilement hydrolysable ou métaboliquement labile et pharmaceutiquement acceptable, X désigne un atome d'oxygène ou un atome de soufre, n est 0 ou 1, R1 et R2 désignent chacun indépendamment l'hydrogène ou un groupe alkyle inférieur, de préférence un groupe méthyle, ou R1 et R2 pris ensemble avec l'atome de carbone auquel ils sont liés forment un noyau cyclobutyle ou cyclopentyle. B est le reste d'une amine primaire ou secondaire. Application: composés antibiotiques. 公开号:SU1282817A3 申请号:SU843749939 申请日:1984-05-25 公开日:1987-01-07 发明作者:Сали Али；Олльеро Доминик 申请人:Санофи (Фирма)； IPC主号:
专利说明:
NCC - 0 (0) -NH CH-CH-S (-0) -CH ,,,, And II "I (,. I ( H N-C-S-CH N-0- (R) C (R2) -C (0) OH 0 C-N-C (COOH) C-CH, -X-C (0) - (CH2) p-Cs as syn-isomers, where Rj and Rj are the same or different, H or lower alkyl, preferably CH, or R and RJ together with C, to which they are bound, is cyclobutyl; X - S; p O or 1; Rj-rpynna -Z.-NH-Ff, where Zj is a straight or branched Cj -C-alkylene, possibly interrupted by the S atom and unsubstituted or substituted by OH, NHg, cNsC (o) 1ha, NHjCG, CgHg, HO-Cg H, or imidazolol, or Zj, -cyclopentylidene or cyclohexylidene; R is H or kil, or R is Zj-Alk-HN-R4, where Zj is 1,3- or 1,4-СеН, unsubstituted or substituted by monohalogen, mono- or di-CH O- or MONO-, di- or tri-CH, or Zg is 1,4-cyclohexylene; Alk - straight or branched C, -C5-alkylene; or R is a group. (R5) -C (0) - —Y — NH — Re, where Z is 1,3- or 1, unsubstituted or substituted with monohalogen, or mono- or di-SND; B and Rg are the same or different - H or Y is Cj-C-alkylene or Y-4-piperidyl; or R is a group where Z is 1,3- or 1,4-cyclohexylene, or RS - group-C-S-CK CH7 where K - - C (o) p - Alk - p O or 1; Alc is specified; or y, -2-, 3-wjm 4-piperidyl, unspecified or substituted by the N atom of piperidyl-4-СО or Ш2-Alk-CO, or their additive salts with CFjCOGH, which can be used in medicine . In order to detect activity with increased antimicrobial efficacy, new derivatives of I were obtained by punching individual strains of microorganisms. Synthesis is carried out by replacing bromine in 3-bromomethylcephalosporine with an appropriate substituent, and all NH and COOH groups in the starting products are protected. The protecting groups are then removed and the I is liberated in free form or as addition salts with CFgCOOH. Compounds I have a low toxicity and a stronger antimicrobial effect than the known cephalosporins, 5 tab. WITH N9 00 00 CH The invention relates to a process for the preparation of new derivatives of cephalosporin or their trifluoroacetic acid addition salts, which are antibiotics and can be used in medicine. The aim of the invention is to obtain new cephalosporinic antibiotics, showing enhanced activity against individual strains of microorganisms. Since, basically, the products according to the proposed method do not have melting points, but have only decomposition points that do not allow them to be characterized, they are characterized by NMR spectra taken at 60 or 250 MHz using hexamethylsiloxane as an internal standard. The spectra are recorded in de-primed dimethyl sulfoxide, except for the exceptions indicated in the description of the spectrum: 50-mg product in 0.5 ml of solvent at 60 MHz and 10 mg in 0.5 ml at 250 MHz, Himsdvigi yzme-. ryut with accuracy, 01., the binding constant - with an accuracy of +0.5 Hz, isiH-in sAiss about S s-s-f-rg i -N-O N CH2 00-C-COOtBu where t-Bu and Tr are as indicated; " Voye - tert-butoxycarbonyl group. To a solution of 1.38 g of syn-isomer 4-tert-butyl-3-1-Lxd-7-2- (2- -triphenylmethyl-4-thiazolyl) -2- (2-tert-butoxycarbon1-2-propyloxyimino) α-β-acetamido-3-bromomethyl-3-cephemcarboxylate in 1 ml of 1-tert-butyloxycarbonyl-4-piperidyl-carboxylic acid and 1.5 g of potassium bicarbonate are added to 20 ml of anhydrous dimethylformamide. After 17 hours of stirring at room temperature (20-25 ° C), the reaction mixture is taken up in 200 ml of ice-cold water. After vigorous stirring, the crystals are filtered and washed with water. Then treated with 70 ml of dichloromethane. The organic phase is then mixed with saturated fO five and 25. 828172 In addition, in each case carried out elemental microanalysis, which corresponds to the specified formulas. The IR spectra are taken in the DOOO-600 cm interval using KBr tablets containing a product at a concentration of about 2%, if the spectrum is taken in a 1% solution in a chlorinated solvent, the nature of the latter is indicated. Note the shift in the frequency of vibrations of the carbonyl groups of the molecule (l co Example 1. Trifluoroacetate S-1-oxide (syn-isomer) (2-amino-4-thiazolyl) -2- (2-carboxy-2-propyloxyimo) acetamido-4-piperidylcarbonyl-3-hydroxymethyl-3-cephem-4-carboxylic acid, SP 4 862, A 4-tert-butyl-1 -B-oxide-7-f2 - {2 triphenylmethylamino-4-thiazolyl) - -2- (2-tert-butoxycarbonyl-2-pro-1-hydroxyimino) acetamido - (1-ter -butoxycarbonyl-4-piperidinyl) -carbonyl-3-oxymethyl-3-cephemcarboxylate (syn-isomer) 15 20 (BUT) sodium chloride solution, dried over magnesium sulphate and evaporated. The product obtained is chromatographed on a column of 50 g of silica ;, a mixture of dichloromethane and ethyl acetate 90:10 (v / v) is eluted. After evaporation of the fractions containing the compound and trituration in hexane, 1.3 g of the expected compound are recovered. IR spectrum of RSO cm-11805 (C O in 8p-lactam); 1735 (C O complex 1 tert-butyl esters and complex, ester in position 3); 1695 (amide at position 7 and t-butoxy carbonyl protecting group of piperidine). NMR spectrum at 250 MHz, ppm: W at 8.75 (C, W, Tg); 1H at 8.10 (D, J 9 Hz, CONU); 15H at 7.25 (M, H aromatic); W at 6.73 (s, H triazole); 1H at 5.8 (M, NuB 1H at 5.25 (D, Hz, CHjOCO); 1H at 4.94 (D, Hz, Hgl; 1H at 4.55 (D, Hz, CHjOCO); IH at 5.90- (D, Hz, ClJgRO); 2H at 3.79 (D, Hz, HCN Boe equatorial); 1H at 3.53 (D, Hz, CHgSO); 2H at 2.75 (M, HCN Baugh axial); 1H at 2.50 (M, AND CCOj); 2H at, 75 (D, Hz, HCHCHO equatorial); 9H at 1.46 (s, COj tert-butyl), 2H at 1.40 (M, HNSSNO axial); 6H at 1, 39 (C, (CH) C); 9H at 1.36 (s, CO tert-butyl); 9H at 1.29 (s, Baugh, N). B. SR 41 862 . 0.8 g of the obtained compound is dissolved in 10 MP of trifluoroacetic acid. After 45 minutes at 23 ° C, the acid is evaporated under vacuum without heating and the oily residue is crystallized by the addition of 50 ml of diisopropyl ether. The crystals are filtered and washed with diisopropyl ether, and then with hexane. After that, they are exhausted under vacuum over phosphoric anhydride. 0.66 g of the expected product is obtained. IR spectrum 1795 (at position 8 f-lactam); 1735 (an ester in position 3); 1680 (wide band: acid molecule amide at position 7, ions СРз СО) NMR spectrum at 250 MHz, mode,: 2H at 8.60 (SU, p); 1H at 8.50 (D, Hz, sor); ZN at 8.40 (SU, p); .1H at 6.68 (s, H thiazole); 1H at 6.0 (D – D, Hz, Hz, N,); 1H, at 5.16 (D, Hz,); . 1H at 4.97 (D, Hz, U); IH at 4.60 (D, Hz, CHjOCO); 1H at 3, 90 (D, Hz,); 1H at 3.55 (D, Hz, SNgR-O); 2H at 3.23 (M, SNgKN); 2H at 2.90 (m,); 1H at 2.66 (M, CH COj); 2Н5, at 1.90 (m,); 2H at 1.70 (m); 6H at 1.44 (2C, (sn)., c). Example 2. The syn-isomer-oxide-trifluoroacetate-7- 2- (2-amino-4-thiazolyl) -2- (2-carboxy-2-propyl-oxyimino) -acetamido - (3-amino-pro pionyl) -3-thiomethyl-3-cephem-4-carboxylic acid. SR 41,884. A, 3-tert-Butoxycarbonylamino-thiopropionic acid, 1.8 g of 3-tert-butoxycarbonylamino-propionic acid is dissolved in 0 five about 0 50 ml of anhydrous dichloromethane. A three-necked flask was supplied with calcium chloride tube and cooled in a bath of water and ice. 1.4 ml of triethylamine and 1.3 ml of isobutyl chloroformate were added successively to the flask. After stirring for 20 minutes in the cold, 1.5 ml of triethylamine are added and a stream of hydrogen sulfide is passed in for 15 minutes. The mixture is then stirred in the cold for 45 minutes until it is evaporated to dryness. 150 ml of sulfate buffer (pH 2) are added and the thioxylate is extracted twice with 70 ml of dichloromethane. The combined organic phases are over magnesium sulfate and evaporated. An oily product is obtained. B. (4-tert-Butyl-1 -8-oxide) - (2-triphenylyethylamino-4-thiazolyl) -2- - (2-tert-butoxycarbonyl-2-propyloxyimino) -acetamido - (3-tert- butoxycarboxylaminopropionyl) -3-thiomethyl-3-cef.em-1-carboxylate, syn-isomer. To a solution of 0.46 g of the syn-isomer (4-tert-butyl-S-1p-oxide) (2-triphenylmethylamino-4-thiazolyl) -2- (2-tert-butoxycarbonyl-2-propyl-hydroxyimino ) -α-acetamido-3-bromomethyl-3-cefemcarboxylate in 10 ml of tetrahydrofuran is added 0.4 g of the described thio-acid as well as 0.6 g of potassium bicarbonate. After stirring for 4 hours at room temperature, the solvent is evaporated and the residue is treated with 100 ml of water and 50 ml of dichloromethane. After decantation, the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are combined, dried over magnesium sulphate and evaporated. Thus, the resulting lacquer chromatographic on a column of silica (40 g), elute with a mixture of dichloromethane with ethyl acetate 90:: 10 (by volume). IR spectrum, 1805 (in the 8p-lactam position); 1720 (tr-butyl esters); 1690 (amide in position 7, complex thioether in position 3 and tert-butoxycarbonyl protecting group of amine) .. NMR spectrum at 250 MHz (CDCl1), M.D .: 1H at 7.75 (D, Hz, SOIN); 15H at 7.27 (M, H aromatic triphenylmethyl); 1H at 6.95 (SU, NH triphenylmethyl); 1H at 6.63 (C, H thiazole); 1H at 6.21 (DD, l with 1785 51 Hz,, N); 1H at 4.85 (SU, NH-BOC); 1 ° at 4.50 (D, J 4 Hz, Hg); 1H at 4.29 (D, J 13 Hz, CHj, SCO); 1H at 3.75 (D, Hz,); W at 3.58 (A of AB, 17 Hz,); 2H at 3.36 (M, CHjNH Bos); W at 3.22 (in from AB, J 17 Hz, CHgSO); 2H at 2.75 (T, J 6 Hz, CHg-COS); 15H at 1.52 (s, Bosh III and (CHjijC); 18H at 1.39 (2C, SOT-tert-bootyd), B.S.P. 41,884. The entire amount of the obtained compound is dissolved in 10 ml of trifluoroacetic acid. After 45 minutes' incubation, the acid is evaporated under vacuum without heating, and the oily residue is crystallized by the addition of 50 ml of diisopropyl ether. The crystals are filtered and washed with diisopropyl ether, then with hexane. After that, they are dried under vacuum over phosphoric anhydride. 0.37 g of the expected product is obtained. IR spectrum in position 8f-lactam); 1680 (wide band: acid molecule, amide at position 7, complex thioether, ions. NMR spectrum at 250 MHz, m, d, ... W at 8.40 (D, Hz, CONH); 3H at 7.80 (SU, NHf); ZN at 7.30 (SU, NHf); 1H at 6.78 (C, H thiazol); 1H at 5.95 (D-D, Hz, Hz, N-,); W at 4.92 (D, J 4Hz, Hj; 1H at 4.18 (D, J 13 Hz, CHjSCO); at 3.79 (D, J 13 Hz); 2H at 3.66 (C, CHjSO ); 2H at 3.0 (M, 2H at 2.92 (M, CHgCOS); 6 at 1.44 (s, (CH3) gC). Example 3 ,, S-l-Oxydrifluoroacetate (syn-isomer) (2-amine ABOUT S C-MH-t-Rt O T Y CH2-0-C- (CH2) nBs COOH o -TFA c-soon I R2 81 five 0 five 0 five 0 76 -4-thiazolyl) -2- (2-carboxy-2-propyl-oxyimino) -acetamido - (3-aminopropionyl) -3-thiomethyl-3-cephem carboxylic acid. SR 41 884, A, (4-tert-Butyl-3-1-oxide) - (2-triphenylmethyl-amino-4-thiazolyl) -2 -2 (2-tert-butoxycarbonyl-2-propyl-hydroxyimino) -acetamido- (3 tert-butoxycarbonylaminopropionyl) -3-thiomethyl- -3-cephemcarboxylate, syn-isomer, To 0.46 g of 4-tert-butyl-3-1-oxide- (2-triphenylmethylamino-4-thiazolyl) -2- (2-tert-butoxycarbok power-2-propyloximino) -acetamido-3-bromo - methyl 3-cephemcarboxylate, syn-isomer, 0.4 g of 3-tert-butoxycarbonyl-aminothiopropionic acid, 0.6 g of sodium bicarbonate and 0.25 g of sodium iodide are added in 10 ml of anhydrous acetone, After stirring for 2 hours at room temperature, the solvent is evaporated to dryness. The residue is treated with 1UO ml of water and extracted with 50 ml of dichloromethane. The organic phase is separated and the aqueous phase is again extracted with 50 ml of dichloromethane. The organic extracts are combined, dried over magnesium sulphate and evaporated to dryness. The product obtained is chromatographed on a silica column, eluting with a 90:10 mixture (dichloromethane: ethyl acetate) (volume by volume). Get the product (IR spectrum and NMR spectrum), identical to the product of example 2B, B, SR 41884, The removal of the protecting groups is carried out, as indicated in Example 2B, Work as in Example 1, the compounds according to the proposed method are obtained in the form of trifluoroacetate, described in Table 1 41730 x 41855 O Table 13 1282817 14 Continued table. R 21 1282817 22 Continued table.) Note. AcOEt - ethyl acetate; Meon -, 29 In Table 1, acid E - (CH), - COOH, which is reacted with compound (I) to produce compound (iV), is the amino acid L- or D-row or racemic. The solvent for chromatography, which serves to isolate compound (IV), is also indicated, the latter is an intermediate before deblocking the acid and amine functions of the molecule. This intermediate (IV) is characterized by an IR spectrum, a length of bands that correspond to the shift of the vibrational frequencies of carbonyl in position 8b-lactam, tert-butyl esters and ester in position 3, the amide in position 7 and the carbamate protecting group of the amine. When only two waves are indicated, the second corresponds to a broadened band that covers the offset of the vibrational frequencies of all the esters, amide and carbamate amine protecting group, The NMR spectra of the compounds listed in table. 1, removed at 60 MHz (a) and at 250 MHz (); if there are two diastereoisomers in the molecule, then split doubles, the signals are indicated by the index. NMR spectrum, MD: 1 (b): 1H at 8.44 (D Hz, SOKN) at 7.90 (SU, 3N with 7.50 (NHg); 1H at 6.78 tC, H thiazol); 5.97 (D-D, Hz, J 4 Hz, N); 1H at 5.18 Cfl, J 13 Hz,); 1H at 4.94 (D, Hz, Hg); 1H at 4.64 (D, J 13 Hz, CHjOCOl; W at 3.90 (D, Hz, SNDCO); 1H at 3.58 (D, Hz, CHj, SO); 2H at 3.00 (M, ); 2H at 2.6P (M,); 6H at 1.44 (C, (CH3) oC). 2 (b): 4H at 8.45 (M, NNz, SOKN); ZN at 7.35 (SU, KHt); 5H at 7.25 (M, H aromatic); W at 6.82 (s, H thiazole); 1H at 6.0 (D-D, J 9 Hz, Hz, C); 1H at 5.20 (D, Hz, SN.OSO); W at 4.92 (D, Hz, Hb H at 8 (D, Hz, Sigoso); 1H at 4.31 (SU, CpH); 1H at 3.50 (D, J 17 G1 CHjPO); 1H at 3.30 (D, Hz, CHjSO); 2H at 3.10 (M, CHj CsHjh 6H at 1, .44 (2C, CH3) 2C). 3 (b): 5H at 8.45 (SU. NPg, OH, CONH); ZN at 7.50 (SU, NHg); 2H at 6.95 (D, Hz, H meta-OH); 1H at 128 UN E o- .. , five . j 20 25 zo 281730 , 6.78 (s, H thiazole); 2H at 6.68 (D, Hz, U ortho-OH); 1H at 6.0 (DD, Hz, N-,); 1H at h 1 A In 11 T,. fu. 1 U „ V d d j -. . . . SI -) 5.16 (D, 13 Hz, CHjOCO); 40 e, 1o (, d, and HZ, uiijUuy ;; IH at 4.92 (D, Hz, Hg); 1H at 4.74 (D, Hz,); 1H at 4.19 (M, CHNHj); 1H , at 3.66 (D, .1 17 Hz CHgSO); 1H at 3.34 (D, Hz,); 2H at 2.93 M, CHj-CH-KHj); 6H at 1.44 (2C, (CHj) jC), 4 (b); 1H at 8.50 (D, Hz, juices); ZN at 8.40 (SU, NHp; ZN at 7.60 (SU, NHj); 1H at 6.79 (C, H thiazole.); 1H at 6.00 (D-D, Hz, Hz, HT) ; 1H at 5.45 (D, J 13 Hz,); W at 4.97 (d, J 4 Hz, Hg); 1H at 4.80 (d, J 13 Hz, CHjOCO); 1H at 4.08 (M, CHNHj); 1H at 3.92 (D, Hz, CHjSO); 1H at 3.58 (D,. Hn,); 6H at 1.44 (C, (CH) C); 3H at 1, 34 (D, Hz, CHjCH). 5 (b): 1H at 8.45 (D, Hz, CONH); ZN at 8.40 (SU, NHp; ZN at 7.60 (SU, NF); 1H at 6.78 (C, H thiazole); 1H at 6.0 (D-D,, Hz, H,); W at 5.25 (D, J 13 Hz ,. CHjOCO); IH at 4.95 (D, - J 4 Hz, Hg); 1H at 4.82 (D, Hz, CHjOCO); 2H at 3.92 (M, CHNH, and); 1H at 3.56 (D, Hz, CH); iH at 2.11 (M, CH (CH3) 2); 6H at 1.44 (20, (CH3) 2C); 6H at 0.9 (d, Hz, (CH,) 2CH). 6 (b): 1H at 8.45 (D, Hz, CONH); ZN at 8.35 (SU, 4H. At 7.40 (SU, CONHj, IH at 6.92 (SU, CONHj); 1H at 6.76 (C, H thiazole); 1H at 6.0 (D- D, Hz, Hz, C); W at 5, .25 (D, J 13 Hz,.); W at 5, 00 (D, J 4 Hz, Hg); 1H at 4.82 (D, Hz, CHjOCO); 1H at 4.00 (M,. CHNH g); Gn at 3.95 (d, Hz, CEjSO); 1H at 3.56 (d, Hz, CHjSO); 2H at 2.20 (N, CHj-CONHj) -, 2H at 1.95 (M, CH, j-CH.); 6H at 1.44 (2C, (CH3) gC) - 7 (b): 1H at 8.50 (D. gp, CONH); ZN at 8.40 (SU, ZN at 7.40 (SU, NHj); 1H at 6.76 (s, u, thiazole); 1H at 6.0 (D-D, Hz, Hz, N); W at 5.25 (d, Hz,); W at 4.92 (D, Hz, Not); 1H at 4.82 (D, Hz,); 1H at 4.16 (M, CgNHj); IH at 3 , 95 (D,, Hz, CHjSO); 1H at 3.8 (A from AB, J 13 Hz,); 1H at 3.69 (B from AB, Hz, CH2, OH); 1H at 3.55 CH, PO); 6H at 1.44 (D, Hz, CH (2C, (CHj) 2C). 7 (a): 8H at 5.5-8.5 (wide signal, NHj, С02Н, trifluoroacetate); 1H at 8.40 (D, Hz, CONH); 1H cry 6.82 {s, H thiazole); 1H at 6.0 (D – D, Hz, Hz, N,); 1H at 5.15 {A of AB, Hz, CH, AOC); 1H at 5.0 (D, Hz,); 1H at 4.67 (B of AB, Hz, 3.85 (A from AB, J j „, О .0 f п to 6.90 (s, H thiazole); 1H at 6.0 (Hz, Hz, H-j); 1H at 5.30 of AB, Hz, CHjOCO); 1H at 5 (D, Hz, HghlH at 4.80 (B from Hz, CHjOCO); 1H at 3.92 (A and AB, Pg,); 1H at 3.67 from AB, Hz, CH, SO); 12H at 1 (C, (CH,), j C-COjH, (CHj) jCNH2). 13 (a); 8H at 6.5-9.5 (signal broadened,, NH2, trifluoroacetate) 1H at 8.5 (D, Hz, CONH); 1H Yu (C, H thiazole); IH at 6 CH2.0CO); 1H at 3.85 (A from AB, J y ри ri 8.5 (D, Hz, CONHj; 1 H 17 Hz, CH2, SO); H at 3.62. (B from ри ri 6.90 (C, H thiazole); IH at 6 AB, Hz,); 2H at 2.80 (M, (Hz. Hz, HJ; 1H at); 2H at 2.40 (M,); 5.30 (A of AB, Hz7 CH, CCA); 2H at 1.80 (m, CH CHjCH); 6H at. / „. , „„ F.,. . 1.43 (C, (CH3) 2C). 9 (a): 8H at 5.5-8.7 (broad signal, CO ,, H, NHj,. rifluoroacetate) ;, „. 1H at 8.40 (D, Hz, CONH); 1H (s,) s), 6H at 0.85 (D, J 7 (p. N ti o.p) 1N ppi20 / Xtg ii.-ti L 9 (sec) 2CH) Nal, Ngj, C02H, trifluoroapatate}; 1H at 8.50 (D, Hz, CONH); W at 6.90 (s, and thiazole); 1H at 6.08 , G „. , Gtt. H 1 - ii thiazyl, in IJJJM o, io at J, oj VA IZ lv, CJ-1 / u, (; i 5 (Hz, Hz, H,); W P & W at 3.60 (in from AB Hz, 5.30 (A from AB, Hz, CH, CCA); 1H ); 2H at 2., 80 (M, CBjNHj); 2Hr and 5.05. (D, Hz, H,); 1H at „„ „9 n (rn. .On„. „1 /. (G g CH.OCO); 3N at 3.90 (M, CH, SO, and CHCH,); IH at 30 1.80 (M, CH 2 CH 2 Td; 6H at 1.45 (C, (); 2H at 1.30 (k, CH 2 CH 3); and P OO IL-r4J - G "O 1H at 3.60 (E from AB, J); 2H at 2., 80 (M, at 2.30 (M,); 12H at 1.45 (SU, (CH) C and CH2 (CHg) 3 CH2). 10 (aU: 8H at 5.5–8.0 (broadened signal. NH. SOCHN and TOLovuk10 (a): 8H at 5.5–8.0 (wider signal, U, COgH, trifluoroxy KHCJjOTa} ; 1H at 8.45. (D,. Hz, CONH); 1H at 6.87 (C, H thiazole); 1H at 6.0 (D-D, Hz, Hz, Nt); 1H at 5.15 (A of AB, Hz, CHjOCO); W at 5.0 (D, J 4 Pd, Hg); W at 4.65 (W of AB, Hz7); W at 3.85 (A AR .t 1-7 gtt gn. G1 IN, (); 2H at 1.30 (к, СНгСНз бН at 0.88 (М, and CHjCH). 15 (b): W at 8.5 (D, Hz, 35 of 15 (b): W at 8.5 (D, Hz, CONH); ZN at 8.30 (SU, NH); ZN at 7.40 (SU, NH); W at 6,76 (C, H thiazole); 1H at 6.0 (D – D, Hz, Hz, HT;); 1H at 5.24 (D, Hz IHgiOCO); W at 4.92 (D, Hz, Hg) H at 4.84 (D, Hz, CH2.0SO); 1H 4.10 (M, CH-NHj); IH at 3.97 CH-OH); W at 3.94 (D, J 17iru, ,five); 1H at o, j m 0-7 I c, CONH); ZN at 8.40 (SU, NH |); 1H at -} IH TTT1LJ 7 Sn frV and Ya.4P SSU. NMtb 1H iip ;; lp at o, chi i / a, wnj ;; in at 7.66 (C, CONgj); ZN at 7.50 (SU, -r-,, -... .L,. .4, jift - /, NHt); IH at 7.22 (s, CONIii); lH at 1H, at 4.98 (D, Hz, H); (C, H thiazole); 1H at 6.0 (DD, at 4.90 (V of AB,,) ;, 0 Hz, Hz, H,); 1H at 5.29. (D, ZN at 4.30 M, CH NHCOCH ,, CHNI) -, j, 3 ri, CH, CCA) G 1H at 4.92 (D, 1H at 4.00 (A from AB, J.-17 Hz, Hz, He); "N at 4.79 (D, Hz, O1L 1 tl «-. 1 l 1 P g p AI-Tggl., ". - Г, "л - f г ntTATTJ 1 U ); 1N.PRI 3.65 (B of AB,); 1H at 4.26 (W, .CHNHj); li 17 Hz,); 2H at 3.0 (M,): at 3.92 (D, Hz,); 1H at 3N at 1.80 (s, CHjCONH); bN at 55 3.52 (D, Hz, CHjSG.); 2H at 1.45 (s, (CH3) 2C) .2.71 (M, CH CONHj); 6H at 1.44 (C, T2 (a): 8H at 6.5-9.0 (broad (CH3), C). signal, trifluoroacetate, NH); 17 {b): W at 8.50 (D, Hz, 1H at 8.5 (d, Hz, CONH); W when CONH); ZN at 8.45 (SU, NHp; ZN at 281732 to 6.90 (s, H thiazole); 1H at 6.0 (D – D, Hz, Hz, H – j); 1H at 5.30 (A from AB, Hz, CHjOCO); 1H at 5.0 (D, Hz, HghlH at 4.80 (B from AB, Hz, CHjOCO); 1H at 3.92 (A from AB, Pg,); 1H at 3.67 (B from AB, Hz , CH, SO); 12H at 1.45 (C, (CH,), j C-COjH, (CHj) jCNH2). 13 (a); 8H at 6.5-9.5 (broad signal,, NH2, trifluoroacetate); 1H at 8.5 (D, Hz, CONH); 1H Yu (C, H thiazole); IH at 6.05 yu ry 8.5 (D, Hz, CONHj; 1H ry; 6.90 (C, H thiazole); IH at 6 (Hz. Hz, HJ; 1H at 5.30 (A of AB, Hz 7 CH, CCA); (SC, s), 6H at 0.85 (D, J / Htg ii.-ti L 9 (sec) 2CH) 14 (a): 8H at 7-9 (broad sig-, N112, CO2H, trifluoroapetate); IH 8.50 (D. Hz. CONH); Sh Nal, Ngj, C02H, trifluoroapatate}; 1H at 8.50 (D, Hz, CONH); W at 6.90 (s, and thiazole); 1H at 6.08 , G „. , Gtt. H 1 - ii thiazyl, in IJJJM o, io (Hz, Hz, H,); W PRE 5.30 (And from AB, Hz, CH, CCA); 1H at 3.90 (M, CH, SO, and CHCH,); IH at 30 1.80 (M, CH 2 CH 2 Td; 6H at 1.45 (C, (); 2H at 1.30 (k, CH 2 CH 3); and P OO IL-r4J - G "O (); 2H at 1.30 (к, СНгСНз бН at 0.88 (М, and CHjCH). 15 (b): W at 8.5 (D, Hz, 35 s 15 (b): W at 8.5 (D, Hz, CONH); ZN at 8.30 (SU, NH); ZN at 7.40 (SU, NH); W at 6,76 (C, H thiazole); 1H at 6.0 (D – D, Hz, Hz, HT;); 1H at 5.24 (D, Hz, IHgiOCO); W at 4.92 (D, Hz, Hg); H at 4.84 (D, Hz, CH2.0SO); 1H 4.10 (M, CH-NHj); IH at 3.97 CH-OH); W at 3.94 (D, J 17iru, L1. l HAVCH L L 1 i. Iij. (m, CH-OH); W pry 3.94 (D, J 17iru, CHjSoT; Tn at 3.65 (D, Hz, CHjSO); 6H at 1.44 (C, (CE); ZN pty t 1Л / П .7 7 Гтт rH-rHl CHSO); 6H at 14 (D, J ,five); 1H at o, j m 0-7 I c, CONH); ZN at 8.40 (SU, NH |); 1H at -} IH TTT1LJ 7 Sn frV Hjso); 6H at 1.44 (C, (CH at 1.14 (D, Hz, SNdCH), 1b (b): W at 8.5 (D, Hz, and Ya.4P SSU. NMtb 1H iip ;; lp at o, chi i / a, wnj ;; in at 7.66 (C, CONgj); ZN at 7.50 (SU, /, NHt); IH at 7.22 (s, CONIii); lH at --- ly, j IH at 3.92 at 3.10 fO 1RI 4.1J P, UlJi ilj / 5 D, Hz,); IH at 3.10 (D, Hz, SNGZO); 1H at 2.50 (M,); 5H at 2.0 (M, CHjS and CH ,, - -CHj-S); 6H at 1.44 (C, (3) 2). 18 (b): 4H at 8.50 (M, CONHjNHg); ZN at 7.80 (SU, NHj); ZN at 7.50 (SU, NHj); 1H at 6.79 (s, H thiazole); 1H at 6.0 (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.24 (D, Hz,); 1H at 4.97 (D, Hz, Nb); 1H at 4.82 (D, Hz, CHjOCO); 1H at 3.97 (K, CHNHj); W at 3.92 (D, Hz, SNGZO); 1H at 3.60 (D, Hz, CH); 2H at 2.75 ° (M,); 1I at 1.75 (M, CH2.CH); . 11H at 1.40 (SU, (CH3) 2C, f g. H-TJTT ™. 22 (a): 8H at 6-9 (broad sial, trifluoroacetate, fili, COjIj); IH 5 at 8.42 (D, ..., 1 9 Hz, CONli); 1H at - --- at 6.05 6 (D - 5.30 85 (s, H thiazole); 1H at 6.05 LC, Hz, H-,); 1H at 5.30 (A from AB. Hz,); 1H at 5.05 (D, Hz, Hg); 1H at 4.68 (in from AB, Hz, CHjOCO); 1H cri-4.0 (A of AB, Hz, SISG-O); at-4.0 (A from AB,, 1H at 3.65 (in from AB, Hz, CH, RO); 8H at l, 75 (M, H hyclophene 1-, 45 (C, (СНз) 2С ). -7 1G /. tang); 6H at 1., 45 (C, (CH3) 2C). 23 (a): 8H at 7-10 (broad signal, trifluoroacetate, NK2,); Ш сри 8.50 (D, Hz, CONH); 1H at 6.92 (s, H thiazole); 1H at 6.10 D-D, Hz, Hz, N-,): 1H at 19 (6): on at 8, about V UJ, i rij /; in (D, Hz, CONH); IH y of H, imidazole); ZN at 7.30 (SU, NHj); 1H at 6.79 (C, H thiazole); 1H at 6.0 (D-D, Hz, Hz, N); 1H at 5.22 (D, Hz,); W at 4.97 (D, Hz, H.) ;. H at 4.90 (D, J 13 Hz, CHjOCO); 1H at rtiMU I IL 1-GT-1TD 7 to {nt ,, 4 V- T1 9 Hz, CONH); 1H azole); 1H with f 1-D, Hz, Hz, H-f); 1H at 35 (A from AB, Hz,); 1H .. and 5.0 (D, Hz, Hg); 1H at 4.75 (in from AB, Hz, CHjOCO); 1H at 4.0 (A 3 AB, Hz, SNZZO); 1H 1-glt,; 7P with R «about ATI. 7 GTT rV (G 1 111 with I, -tu (CHi) 3C-)., -., .. -. , 19 (6): IH at 9 (C, Hj ynidazole; at 3.70 (B from AB, Hz, CHjO); MN at 8.6 (SU, MKZ); 1H at 8.5 16H at 1-2 , 3 (And, (CHj) 2C, and cyclopri 7.40 (s, hexane). (A): 9H at 8-10 (broad signal, NH, OH, trifluoroacet.); 1H at 8.55 (D, Hz, CONH); -, i in (Ti, Tat.) 17 Hz,); W at 3., 52 (D, J 17 Hz, CH2SO); 2H ryr 3.20 (M,); 6H at 1.44 (C, (CHD) C). 0 (6): W at 8.50 (D, Hz, :); ZN at 7.40 (SU, NH); SN 7.40 (SU, J4H); H at 6.77. (C, C thiazole); 1H at 6.0 (D-D, Hz, Hz, HT); 1H at 5.76 (D, Hz, CHjOCO); W at 4.95 (d. Hz, Hg); W at 4.81 (D, rti GN-nr.nl- Sh ppi L ( +, 7U M, o- ij AC, V. lipri 4.40 (M, CHNH2); IH at 3.89 (D, J 1 / Hz,); n /. 17 Hz, CH2SO); ); 6H at 1.44 iC, ICHg) Cj. 20 (b): IH at 8.50 (D, Hz, CONg); ZN at 7.40 (SU, NH); ZN at 7.40 (SU. M,); H at 6.77. . C G J (D, 1C, Hg ;; 1H at, i d, Hz, CHjOCO); 1H at 4.06 (M, CHNHj); W at 3.95 (D, Hz,); 6H at 1.44 (C, (CH3), C), 3N at 1.36 (D, Hz, CHjCH). 21 (a): 8H at 6.5-9.0 (signal extended NHj, CO2H, trifluoroacetic acid); 1H at 8.35 (D, J = 9 Hz, CONH); 1H at 6.80 (C, and thiazole); 1H at 6.0 (D-D, Hz, Hz, N-,); 1H at 5.15 (A from AB, Hz, CH, CCA); 1H at 5., 0 (D, J 4 Hz, Hg); W at 4.65 (in a of AV, Hz CH-CCA); 1H at 3.95 (A from AB, Hz, W at 3.65 (in from AB, Hz, CH2, SO); 2H at 2.80 (M,); 2.35 ( 40 45 1H with :), U; i 1, D, 4.80 (in from AB, 1c, loHjUbu ;; in at 4.30 (N, SNR); 2H at 3.70 (M,); 2H at 3.0 (M, CHj-CgH OH) 6H at 1.46 (C, (CH5) 2C), 25 (a): YUN at 6.5-9.5 (broad signal, NH2, 002Н, trifluoroacetate); 1H at 8.40 (D, Hz, CONH); W at 6.85 (s, H thiazole); 1H at 6.05 (D-D, Hz, Hz, N-,); 1H at 5.30 (A from AB, Hz,); 1H at 5.0 (D, Hz, Hg); 1H at 4.85 (in from AB, Hz, CH20CO); 1H at 4.20 (M, CpHg); 2H at 3.80 (M,); 2H — at 2.95 (m, CHjNHj); 2H 50 at 2.20 (m, SrgN CH); 6H at 1.45 (C, (CH,) C). 26 (b): ZN at 8.60 (SU, NHg); 1H at 7.44 (D,. Hz, CONH); Tn at 6.78 (s, H thiazole); 1H at 6.0 (DD, 55 Hz, Hz, H); 1H at 5.16 (2D, Hz.) 1H Poi 4. Hz, Hz, H-); 1H at 5.16 Hz, CHjOCO) 1H at 4.97 (D, Hz, Hg); 1H at 4.66 (2D, J 13 Hz, CH, CCA); 1H at 3.92 (D, 17 Hz, CH, SO); W at 3.56 (D. J 11 f J f- Mj at 3.56 (D, J J 82817 BEHIND fO ,; ,; °; ); YUN with 1.45 (SU, (SIS) 2C + + CH., (CHJ2C). 22 (a): 8H at 6-9 (broad sial, trifluoroacetate, fili, COjIj); IH 5 at 8.42 (D, ..., 1 9 Hz, CONli); 1H at - --- at 6.05 sig6 (D - 5.30 85 (s, H thiazole); 1H at 6.05 LC, Hz, H-,); 1H at 5.30 (A from AB. Hz,); 1H at 5.05 (D, Hz, Hg); 1H at 4.68 (in from AB, Hz, CHjOCO); 1H cri-4.0 (A of AB, Hz, SISG-O); at-4.0 (A from AB,, 1H at 3.65 (in from AB, Hz, CH, RO); 8H at l, 75 (M, H hyclophene 1-, 45 (C, (СНз) 2С ). -7 1G /. tang); 6H at 1., 45 (C, (CH3) 2C). 23 (a): 8H at 7-10 (broad signal, trifluoroacetate, NK2,); Ш сри 8.50 (D, Hz, CONH); 1H at 6.92 (s, H thiazole); 1H at 6.10 D-D, Hz, Hz, N-,): 1H at ,, 4 V- T1 9 Hz, CONH); 1H azole); 1H with f 1-D, Hz, Hz, H-f); 1H at 35 (A from AB, Hz,); 1H .. and 5.0 (D, Hz, Hg); 1H at 4.75 (in from AB, Hz, CHjOCO); 1H at 4.0 (A 3 AB, Hz, SNZZO); 1H 1-glt,; 7P with R «about ATI. 7 GTT rV (G , -., .. -. , ; at 3.70 (B of AB, Hz, CHjO); 16H at 1-2.3 (And, (CHj) 2C and cyclosign m.) Tat.) 0 five 1H with :), U; i 1, D, 4.80 (in from AB, 1c, loHjUbu ;; in at 4.30 (N, SNR); 2H at 3.70 (M,); 2H at 3.0 (M, CHj-CgH OH) 6H at 1.46 (C, (CH5) 2C), 25 (a): YUN at 6.5-9.5 (broad signal, NH2, 002Н, trifluoroacetate); 1H at 8.40 (D, Hz, CONH); W at 6.85 (s, H thiazole); 1H at 6.05 (D-D, Hz, Hz, N-,); 1H at 5.30 (A from AB, Hz,); 1H at 5.0 (D, Hz, Hg); 1H at 4.85 (in from AB, Hz, CH20CO); 1H at 4.20 (M, CpHg); 2H at 3.80 (M,); 2H — at 2.95 (m, CHjNHj); 2H 0 at 2.20 (m, SrgN CH); 6H at 1.45 (C, (CH,) C). 26 (b): ZN at 8.60 (SU, NHg); 1H at 7.44 (D,. Hz, CONH); Tn at 6.78 (s, H thiazole); 1H at 6.0 (DD, 5 Hz, Hz, H); 1H at 5.16 (2D, Hz.) 1H Poi 4. Hz, Hz, H-); 1H at 5.16 Hz, CHjOCO) 1H at 4.97 (D, Hz, Hg); 1H at 4.66 (2D, J 13 Hz, CH, CCA); 1H at 3.92 (D, 17 Hz, CH, SO); W at 3.56 (D. J 11 f J f- Mj at 3.56 (D, J J 17 Hz, CHSO); 5H at 2.5-3.5 (M, - and CHCOj); 4H at 1.5-2.0 (M, (CH)); 6H at 1.44 (C, (. 27 (6): ZN at 8.50 (SU, U) ;. 1H t 4.44 (D, Hz, sor); ZN at -5 U SSU, NHp; 3H at 7130 {SU, NHp; THAT .. 1TI at h, hh m J-: 1 C, 7.80 SSU, NHp; 3H with ,, v. , , .... 1H at 6.78 (s, H thiaeola); 1H at 6.0 (D-D, Hz; J 4 Hz, N.); 1H at 5.26 (D, Hz, CH „TOC); 1H at 4.97 (D, Hz, He); W at 4.84 (D, Hz, CHgOCn); 1H at 4.08 (q, CHCOj); W at 3.94 (D, Hz,); 1H at 3.66 (D, Hz, CH,); 2H at 2.80 (M,); AN at 1.60 (M, (CH) CH2NH2); 6H at T, 2G4 (C (Syz) 2C). - 28 (6): 1Н at 8.37 (D, Hz, ЗН Poi 7.90 (SU, NH); ЗН at 1Н Гтпн ft. 7fi f P. TT TT - -. Sh 15 - h 1C, n-j, in when J ,,. O -1J: СНгОСО) Т Ш at 4.97 (D, Hz, Н, Ш at 4.66 (Д, Гц, CHjOCO); 1Н at 3.92 (Д, Гц,); 1Н at 3.58 (Д, Гц, 1 CH, BO); 1H pr 3.50 (M,); 2H at 2.56 {K, CH SNCH); 6H at 1.44 {C, (CH, a) g) ZN at 1, J6 (D, Hz, CHjCH). 29 (b): .Sh at 8.44 (D, Hz, CONH); ZN at 7.95 (SU, NH |); ZN at 7.50 (SU, SCHR; W at 6.78 (C g of thiazole); 1H at 6.0 (, G Hz, N); W at 5.20 (2D, J 13 Hz, SN.OSO) ; 1H at 4.95 (M, Hg); 1H at 4.62 (2D, Hz,); 1H at 3.94, (D, 7 Hz, SC, 80); W at 3.58 (D, Hz, lt sg. 1U p "., In (1 gchsh / l. Pts 1P with J, jo VM, and -1/1 c, CHSO); 1H at 3.0 (M, SCSE); 2H tggt O / M PH. JSC „1 /./. Uhjbu ;; IH at J, u ut, i at 2.75 (k, CHgNHz); 6H with i, 44 (M, (CH3) C); ZN at 1.10 (D, J 17 Hz, CHjCH). 30. (b): 4H at 8.45 (M, Ng, secondary school); 8H at 7.35 (M, NH, H armature); 1H at 6.78 (s, H thiazole); 1H at 6.0. (M, H-J); 1H at 5.05 (2Д, Hz, СНЗОСО); W at 4.94 (2D, Hz, Hg); W at 4.60 (M, Cr Hg); 1H at 3.66 (2D, Hz,); 1H at 3.40 (2D, Hz,); 2H at 3.0 (M, (); 6H at 1.44 (C, (CHj) jC). at 8.40 (D, J 9 Hz -t 41. t p V wrr -five Sh (M, Cg CHNHi); W at 1.61 (M, CHj.CHNHj); 6H at 1.44 (2C, (CH) .C); 1H at 1.1 (D, J 7 Hz, CHj-CH). 32 (a): 7H at 7-9 (W, W, trifluoroacetate); 1H at 8.50 (D, J 9 Hz, CONH); 1H at 6.90 (C, H of the ti-pola); 1H at 6.05 (D-D, J 9 Hz, 4 Hz, N); 1H at 5.15 (A of AB, 1 About G. OUT. 1 game - e / t 15 azole ;; in with o, 1; e D-D t - U C J 4 Hz, N); 1H at 5.15 (A from AB J 13 Hz, CH20CO); W at 5.0 (D, t 4 Hz, Hg); 1H at 4.70 (in of AB, 17 Hz,); 1H at 3.65 (V 25 thirty 35 SIGN SLEEP) ,,, 40 J 17 Hz,); IH at 3.65 (l from AB, J 17 Hz, CH 3 SO); 2H at 2.90 (M, CHjNH); ZN at 2.45 (D, J 6 Hz,); 2H at 2.4 (M,); 2H at 1.70 (M, CHgCHjCHj); 6H at 1.42 (C, (). 33 (a): 7H at 7-9.5 (KN, NH, CO, H, trifluoroacetic acid); 1H at 8.46 (D, J 9 Hz, CONH); W at 6.90 (C, H thiazole); W at 6.05 (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.15 (A from AB, J 13 Hz, CH, CCA); W at 5.0 (d, J 4 Hz, Hg); IH at 4.70 (B of AB, J 13 Hz, CH, CCA); 1H at 3.90 (A of AB, J 17 Hz,); 1H at 3.65 (in from AB, J 17 Hz, SNGZO); 2H at 2.75 (M, CHjNHCHj); 5H at 2.45 (M, CHjNH and); YUN at 1.45 (C Y, (CH3) 2C and CH2 (CHj) CHg). 34 (a): 8H at 6-9 (broadened signal, NH, trifluoroacetate, OH H); 8.47 (D, J 9 Hz,: 1N ppi 6.90 (p. H 45 0 five , .Kj-.A- J .. | Ц Ц у CONH); W at 6.90 (s, H thiazole); 1H at 6.16 (D-D, J 9 Hz, J 4 Hz, N-,); W at 5.35 (AB, J 13 Hz, CHgOCO); W at 5.0 (D, J 4 Hz, Hg); 1H at 4.85 (B of AB, J 13 Hz, CH20CO); 4H at 3.95. (M, CHSO, ZION and CpH); 6H at 1.45 (s, (SNLS); 3N at 1.20 (D, J = 7 Hz, CH 2 CH 2), 35 (b): 1H at 8.50 (D, J 9 Hz, CONH); ZN at 8.35 (C Y, NHp; 2H at 7.94 (D, J 8 Hz, H ortho CO); 2H at 7.55 (D, J 8 Hz, N meta CO); W at 6.84 (s, H thiazole); 1H at 6.0 (D-D, J 9 Hz, - J 4 Hz, HT); H at 5.44 (D, J 13 Hz, CHjOCO); 1H at 4.99 ( D, 4 Hz, HgT; W at 4.86 (D, J 13 Hz, CH2, CCA); 3N PPI 4.1 (M, ,, CHjSoT; IH at 37 128281 3.72 (D, J 17 Hz, CH); 6H at 1.44 (2С, (СН,)) „ 36 (a): ZN at 9.30 (C Y, NHp; 38 CHjNHj); IH at 1.52 (M, CHCQ,); W at 1.84 (M, CH, CH); 1H at 1.56 36 (a): 9.30 (C Y, U); (M, CH5, CH); 1.44 (C, (CH) C); 1H at 8.55 (D, J 9 Hz, CONH); ZN ZN at 1.06 (D, J 7 Hz, SNSN). at 8.05 (with U ShL; W at 6.92 (C, 5 40 (a): 1H at 8.45 (D, J 9 Hz, H thiazole); 1H at 6.05 (D-D, J CONH); ZN at 7.30 (C Y, NH,); 9 Hz, J 4 Hz, H); 1H at 5.30 IH gt ,,;, f, p / t n ,, l. IH g, „ (And from AB. J 13 Hz. SN.OSO); 1H: fO 9 Hz, J 4 Hz, H); 1H at 5.30 (A of AB, J 13 Hz,); 1H at 5.05 (D, J 4 Hz, Hg); 1H at 4.70 (in from AB, J 13 Hz, CHjOCO); 1H at, 3.95 (A from AB, J = 17 Hz, CH 3 SO); 1H at 3.65 (B of AB, J 17 Hz,); 2H at H., 0 (C Y, at 1.45 (s, (CH3) C-ON); 6H at 1.17 (s, (CHj) ,, C02CH2) o 37 (b): 8H at 6-9 (broad sig-, trifluoroacetate, NH); 1H p (n., t q qmt comb IH CONH); ZN at 7.30 (SU, NH, IH at 6.80 (C, H thiazole); 1H at 6.0 (M, H); W at 5.20 (A of AB, J 13 Hz,); W at 4.90 (V MO AR L 1 - Ttt G.N. nrn ZN (C, U inci3ujici / in with. U, u V.14, P- / , 3t Vw "J - 1Ц v njDuj; in at, 6 (M, CH.KHj); IH at 2.25 (T, 12 Hz, SNCO); 4H at 1.84 (M, N. CHCHO); 6H at 1.45 (C, (CH3) 2C); ZN at 1.25 (M, CHjCHCO); 6H at 1.45 (s, (CH3) gC); ZN at 1.25 (M, - and CH KCHCH NHj); 2H-PRI 0.95 (M,) 38 (b): - 1Npri 8.37 (D, J 9 Hz, SOSH); ZN at 7.90 (C y, .N | j |); ZN at 7.40 (with Y, Ifflt); 1H at 6.79 35 (s, And thiazole); lit at 6, Oy (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.11 (2D, J 13 Hz,); W at 4.98 (d, J. 4 Hz, H); 1H at 4.61 (2D, J 13 Hz,); W at 3.90 (d, J 17 Hz,); W at 3.59 (D, .J J7 Hz, CHgSO); W at 3.0 (with U,. SNS); W at 2.40 Tiyi, CHCpi); W at 2.10 (M, CHN ;,); ZN at 1.80 (M,); 8H at 1.44 (2C, (CHjLc); 4H at 1-rl, 5 (M, CH.jCH CHCOi} o 39 (b): W at 8.5 (D, J 9 Hz, SOC)}; 6H at 7-8 (broad signal, NH, trifluoroacetyl); W at 6.81 (C, H Thiazole); 1H at 6.0 (DD, J 9 Hz, J - .4 Hz, HT); W at 5.15 (2D, J - 13 Hz, CH, CCA); 1H at 5.0 (D, J - 4 Hz, Hg); W at 4.63 (2D, J, 5 13 Hz, CH-CCA); 1H at 3.78 (D, J - 17 Hz, CH jSO); 1H at 3.56 (D, J 17 Hz, CH, SO); 1H at 3.56 (D, J 17 Hz,); 2H at 2.77 (M, 40 45 38 40 (a): 1H at 8.45 (D, J 9 Hz CONH); ZN at 7.30 (C Y, NH,) IH rm ,,;, f, p / t n ,, l. IH g, „ CONH); ZN at 7.30 (SU, NH, IH at 6.80 (C, H thiazole); 1H at 6.0 (M, H); W at 5.20 (A of AB, J 13 Hz,); W at 4.90 (V MO AR L 1 - Ttt G.N. nrn 0 25 - 35 , five ZN (C, U inci3ujici / in with. U, u V.14, P- / IH at 5.15 (A from AB), J 13 Guy, CHjOCO); W at 4.96 (D, J - 4 Hz, W at 4.65 (B from AB, J 13 Hz, CHjOCO); W at 3.90 (A from AB, J 17 Hz, CJ280); W at 3 , 65 (B from AB, J 17 Hz, CHjSO); 2H at 3.00 (M,); 5H at 2.50 (M,, CHjCO); 6H at 1.42 (C, (CH3) 2C). 42 (a): 7H at 9.4 (C Y, U, U, NH, COgH); W at 8.45 (D, J .9 Hz, CONp); 1H at 6.85 (C, H thiazole); W at 6.00 (M, H); W at 5.00 (D, J 4 Hz, Hg); W (A of AB, J 1 rm. GN.-PG.P 1N ppm l ACh fV. (D, J 4 Hz, Hg); W (A from AB, J Hz, CHj-OCO); 1H at 4.65 (V from AB, J 1z Hz, CHjOCO); 1H with fA from AB. J 17 Guy. CH.SO): of AB, J 13 Hz, CHjOCO); 1H at 3.85 (A from AB, J = 17 Hz, CH2, SO); 1H at 3i60 (B of AB, J 17 Hz,); 4H at 2.85 (M,); 2H at 2.40 (C, CH, CCA); 2H at 1.80 (M, CH CHjCHjNH); 6H at, 1.45 (C, (CH3) C); ZN at 1.10 (T, J 7 Hz, CHjCHjNH). 40 CHjCHjNH). 45 43 (a): 2H at 8.50 (C T, NHp; W at 8.40 (D, J 9 Hz, CONH); 7.00 (C Y, NHp; 1H at 6.76 azazole); 1H at 5.95 (M, H), ZN at AA / j - 4 1/9 9 (C, H thiazole); W at 5.95 (M, H 1H at 5.10 (A of AB, J 13 Hz7); 1H at 5.0 (D, J 4 Hz, H); 1H at 4.65 (B of AB, J 13 Hz, SN.OSO); 1H at 3.85 (A mch AV. L 17 Gi. SNLBO); W when 3.50 (V 3 Hz, SN.OSO); W at j, a :) I.A AB, J - 17 Hz,); W when) 0 (B of AB, J - 17 Hz, CHjSO); IH at 3.30 (M, CHNH); 5H at 2.45 (M, CHjNH and CHjpCO); 2H at 1.80 (M, iCHjCH20CO); 6H at 1.45 (C, CH3) j, C); ZN at 1.10 (D, J = 7 Hz, СНзСН). 44 (a): 1H at 8.40 (D, J 9 Hz, CONH); 7H at 7.80 (SU, U, N, NH,); W at 6.80 (C, H thiazole); of 85 IH at 6.00 (M, H); 1H at 5.00 (M, H); 1H at 5.00 (A of AB, J 13 Hz,); 1H at 4.65 (V AB, J 13 Hz, CH2, CCA); 1H at 3.85 (A of AB, J 17 Hz, CH ,, SO); H at 3.65 (V of AB, J 17 Hz,); 2H at 2.80 (M, Cy2-NH); 5H at 2.40 (M, CHjNH,); 12H at 1.45 (C Y, (CH3) jC and)). 45 (b): 1H at 8.75 (D.J. 9 Hz, CONH); 1H at (C U, F); 1H, 40 (C Y, NH); ЗН at 7.30 (С У, Ш); 1H at 6.78 (C, H thiazol); 1H at 5.91 (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.13 (D, J 13 Hz, CHjOCO); 1H at 4.95 (D, J 4 Hz, Hg); 1H at 4.61 (D, J 13 Hz,); 2H at 4.55 (C, CHjON); 1H with 3.84 (A of AB, J 1-7 p „OU., 3.55 (B of ABOUT); 2H at 3.20 1282817 40 ten 48 (b): 1H at 8.75 (D, J 9 Hz CONH); ЗН at 8.30 (С У, Ш,); 2H at 7.95 (D, J 8 Hz, H ortho CO); 2H at 7.55 (D, JJ 8 Hz, H metha CO ZN at 7.30 (C Y, Crz); 1H at 6.78 (C, H thiazole); 1H at 5.95 (D-D, J 9 Hz, J 4 Hz, ... H); 1H at 4.44 (D, J 13 Hz, CH20SO); 1H at 4.98 (D, J 4 Hz, Hg); 1 at 4.98 (D, J 4 Hz, Hg); 1H at 4.81 (D, J 13 Hz,); IH at 4.10 (C Y, CH2NH2); 1H at 4.05 (A of AB, J = 17 Hz, CH 3 SO); IH at 3..71 (B of AB, J 17 Hz, CH, 0); 15 I 4H at 2.40 (M, CHj —C — CbgH); 2H at CHj Oh - 1/1 q, j 1 AD, J 17 Hz, SNO j J) ill iipn, i, kj 2.90 (M,) 20 CH, 0 . . 1.85 (M, V) CH. CO H (M,); 2H at 2.90 (M,); IH at 2.64 (M,; 2H at 1.95. Ijy gj: IH at a, /: e tA, J At Hz. (M, CH CHgNH); 2H at 1.66 (M, CONH); 3H at 7.70 (C Y, NHJ; 3N - at 7.30 (C Y, fej); IH at 6.82 (C, H thiazole); 1H at 5.90 49 (b): 1H at 8.75 (D, J 9 Hz ); 2H at 1, 66 (M, CHjCHjNH). 46 (b): 1H at 8.75 (D J 9 Hz, CONH); W at 8.60 (C Y, NH «); 1H at 8.40 (dU, NHj); ZN at 7.30 (SU, W); 1H at 6.78 (C, H thiazole); 1H at (D-D, J 9 Hz, J 4 Hz, C-,); 5.94 (D-D, J 9 Hz, o - -, X ..., W at 5.13 (D, J 13 Hz,); W at 4.95 (D, J 4 Hz, Hg); W at 4.61 (D, J 13 Hz,); 1H at 3.90 (A of AB, J 1H at) i (M,); Sh 17 ), 111 Hz, CH)); H J, ifu. L from Lee, about 1 at 3.55 (B from AB, J 17 Hz, 0); 2H at 3.20 (M, CHjNH); 2H 7 QO mi 1U at L. and about at J - I / i-0 - / U 3.55 (B of AB, J = 17 Hz,); ,, 2H at 2.76 (M,); 2H at 2.40 (M, CH, C02); 2H at 1.72 (C, -CHjNHj). with jc, and ui --Uj. iif 2.64 (M, CH COj,); 4H at 2.40 (M, 0 C-fCO.H); 6H at 1.5-2 and CHj CHjNH) CH (CH, .0 COgH 2 47 (6): IH at 8.79 (D.J. 9 Hz, NH); ZN at 8.30 (C Y, NHj) J 2H -CHjNHj). 50 (b): IH at 8.75 (D.J. 9 Hz, CONH); ZN at 7.75 (C Y, NHj); ZN 40 at 7.23 (C Y, Schd); 1H at 6.77 (C, H thiazole); W at 5.94 (D-D, J - Hz, J 4 Hz, H,); 1Nat 5.11 h, Guy PGPL. 1U g, tx ,, 4 95 YES h / (.o;: 1H at o, / y c. j s i NH); ZN at 8.30 (C Y, NHj) J 2H, 97 (D, J 8 Hz, H ortho CO); at 7.55 (D, J 8 Gu, N meta); ЗН at 7.39 (С У,, 1Н ni CONH) at 2H with /, 53 1Д, J о 1U, n met CO); ZN at 7.39 (C Y, NHj); 1H at 6.84 (C, H thiazole); W at 5.92 (D-J. J 9 Hz, J 4 Hz, C); W at 5.40 (D, J 13 Hz, CHjOCO); 1H at 4.95 (D, J 4 Hz, Hg); 1H at 4.84 (D, J 13 Hz,); 2H at 4.56 (C,); W at 4.08 (M, CH2NH,); 1H at 4.00 (A of AB, J 17 Hz,); 1H at 3.71 (B of AB, J 17 Hz,). 9 Hz, J 41 C, H, ;; 1H at 5, ii (D, J 13 Hz, CH5, CCA); 1H at 4.9 (D, J 4 Hz, Hg); IH at 4.55 (D 45 J 53 Hz, CHjOCO); 1H at 3.89 O of AB, J 17 Hz, CH SO); 1H at 3.55 (B from AB J Tf Hz, 2H at 2.78 (M, CHjNHz); 6H at O 50 2.40 (M, CH f-CO H); 4H with CH 1.85 (M, CHjCHjNH, CHj 55 51 (b): 1H at 8.75 (D, J 9 Hz, CONH); ZN at 7.60 (C Y,); ZN 1282817 40 ten 48 (b): 1H at 8.75 (D, J 9 Hz, CONH); ЗН at 8.30 (С У, Ш,); 2H at 7.95 (D, J 8 Hz, H ortho CO); 2H at 7.55 (D, J J 8 Hz, N meta CO); ZN at 7.30 (C Y, Krz); 1H at 6.78 (C, H thiazole); 1H at 5.95 (D-D, J 9 Hz, J 4 Hz, ... H); 1H at 4.44 (D, J 13 Hz, CH20CO); 1H at 4.98 (D, J 4 Hz, Hg); one at 4.98 (D, J 4 Hz, Hg); 1H at 4.81 (D, J 13 Hz,); IH at 4.10 (C Y, CH2NH2); 1H at 4.05 (A of AB, J = 17 Hz, CH 3 SO); IH at 3..71 (B of AB, J 17 Hz, CH, 0); I 4H at 2.40 (M, CHj —C — CbgH); 2H at CHj Oh CH, 0 . . 1.85 (M, V) CH. CO H ijy gj: IH for a, /: e tA, J In Hz (H); 3H at 7.70 (C Y, NHJ; 3N 49 (b): 1H at 8.75 (D, J 9 Hz, L. and about at J - I / i-0 - / U 3.55 (B of AB, J = 17 Hz,); 2H at 2.76 (M,); 2H at 2.40 (M, CH, C02); 2H at 1.72 (C, -CHjNHj). -CHjNHj). 50 (b): IH at 8.75 (D.J. 9 Hz, CONH); ZN at 7.75 (C Y, NHj); ZN at 7.23 (C Y, Schd); 1H at 6.77 (C, H thiazole); W at 5.94 (D-D, J - Hz, J 4 Hz, H,); 1Nat 5.11 h, Guy PGPL. 1U g, tx ,, 4 95 YES 9 Hz, J 41 C, H, ;; 1H at 5, ii (D, J 13 Hz, CH5, CCA); 1H at 4.9 (D, J 4 Hz, Hg); IH at 4.55 (D J 53 Hz, CHjOCO); 1H at 3.89 O of AB, J 17 Hz, CH SO); 1H at 3.55 (B from AB J Tf Hz, 2H at 2.78 (M, CHjNHz); 6H at O 2.40 (M, CH f-CO H); 4H at CH 1.85 (M, CHjCHjNH, CHj 51 (b): 1H at 8.75 (D, J 9 Hz, CONH); ZN at 7.60 (C Y,); ZN HII at 7.30 (C Y,% h) 5 R (C, H thiazole); W at 5.87 (D-D, J 9 Hz, J 4 Hz, HI); 1H at 5.61 (D, J 13 Hz, CH, jOCO); 1H at 4.92 (D, J 4 Hz, Hg); 1H at 4.58 (D, J 13 Hz, CHj, SO); 1H at 3.55 (B of AB, J 13 Hz, CHjSO); 2H at GN 9H lpm 9 41 (M, СН СОЗ + СН ,,} СО Н); 2H at Schg 1.85 CH X , 0 sleep 4H at 1.50 2 2 (M, CH, CH2: CH, j, -C02). 53 (b): 1H at 8.80 (D, J 9 Hz, CONH); ZN at 8.40 (C Y, NH); ЗН prn 7.40 (С У,); 1H at 6.78 (C, H thiazole); W at 5.95 (D-D, J 9 Hz, J 4 Hz, N); W at 5.25. (D, J 13 Hz,) ,; W at 4.95 (D, J 4 Hz, HgT; 1H at 4.78 (D, J 13 Hz, CHjOCO); 1H at 4.08 (M, CHNHj) -, 1N.PRI 3.95 (A of AB, J 17 Hz, CHjSO); W at 3.60 (B of AB, J 17 Hz, CHgSO); 4H at ); 2H at 1.90 thirty about (M, CHjCH-CHj 35 (CH3) 2C). ); 6H at 1, 14 (C, 9 Hz ° 4.9; 2.40 (M, CH "fCO-H); 2H at C2D, CH45 3.90 1H p 56 (b): W at 8.75 (D. J 9: CONH); ZN at 7.75 (C Y, NHj); ZN at 7.30 (C Y,); W at 6.80 40 (C, H thiazole); 1H at 5.95 (D-D, J 9 Hz, J 4 Hz, H-j); | H at 5.1 C2D, J 13 Hz,); W at 4.95 (D, J 4 Hz, Hg); 1H at 4.60 C2D, J. 13 Hz,); W at 3.90 SA ich AR- l 17 Gtt. G.NP 1.80 (M, CH CHj 1.36 (D, J = 7 Hz, CH, CH). 54 (b): 1H at 8.75 (D CONH); ZN at (S U, YN); ZN at, 30 (C Y, NH3); 1H at 6.78 (C, H thiazole); W at 5.95 (DD, t, o G. r tt rTt H 1 N ttpm J- 13 Hz,); 1H at 45 3.90 (A from AB, J 17 Hz,); 1H at 3.56 (B of AB, J = 17 Hz, CH = SO); 2H at 2.74 (M.) .; 1N ЗН at pripri 2.50 (M, SNSO); 4H at 2.40 ABOUT J 9 Hz, 50 (C,); ZN at 1.90 CH, about and (55 tM, CH — COgH and); Sh Sh at 282817 42 .- 3.92 (A from AB, J = 17 Hz,); 1H at 3.55 (B of AB, J 17 Hz,); 1H at 3.0 (M, CH, COp; 2H at 2.80 (M, CH, NH2); 4H at 2.40 O (M, CH - | --COHN); 2H at 1.80 fO (M, ; ZN at 1.08 t (D, J 7 Hz,) J 7 Hz,). 55 (b): 1H at 8.75 (D.J. 9 Hz, CONH); ZN at 7.80 (C Y,); ZN at 7.30 (C Y, NHj); W at 6.80 fr U "t,. IU - / 9 j J) iiiJri J} (C, H thiazole); Tn at 5.95 (M, H-j,); IH at 5.20 (D, J 13 Hz,); 1H at 4.95 (C O. And,); 1H at 4.63 v 1n with: s, and VM J iJ C, (; 1H at 4.95 (C Y, PJ); 1H at 4.63 (D, J 13 Hz,); 1H at 3.90. (And from AB, J 17 Hz, CHjSO); 1H at 3.58 (B-from AB, J = 17 Hz, CHjiSO); 5 2H at 2.93 (M,); 4H at 2.40 O ); 2H at 1.90 thirty about (M, CHjCH-CHj 5 (CH3) 2C). ); 6H at 1, 14 (C, 9 Hz 4.9; S2d 45 3.90 56 (b): W at 8.75 (D. J 9: CONH); ZN at 7.75 (C Y, NHj); ZN at 7.30 (C Y,); W at 6.80 0 (C, H thiazole); 1H at 5.95 (D-D, J 9 Hz, J 4 Hz, H-j); | H at 5.15 C2D, J 13 Hz,); W at 4.95 (D, J 4 Hz, Hg); 1H at 4.60 C2D, J. 13 Hz,); W at 3.90 SA ich AR- l 17 Gtt. G.NP J- 13 Hz,); 1H at 45 3.90 (A from AB, J 17 Hz,); 1H at 3.56 (B of AB, J = 17 Hz, CH = SO); 2H at 2.74 (M.) .; 1H at 2.50 (M, CH 2 O); 4H at 2.40 50 (C,); ZN at 1.90 CH, about and CH - COgH and); Sh CH2-CH2 1.55 (M, CHjCHjNHj); ZN at 1.08 J 7 Hz, CHjCH), 57 CONH) at 7 (C, H J 9 (D, J (D, J J 1 of AB 3.61 (b): W at 8.80 (D, J 9 Hz,; ЗН at 8.40 (С У, И Н); ЗН, 40 (С У, И Hj); Ш at 6.79 I thiazole); 1H at 5.95- (DD, Hz, J 4 Hz, H-,); 1H at 5.28 13 Hz, CHjOCO); 1H at 4.95 4 Hz, Hg); 1H at 4.75 (D, 3 Hz,); W at 3.95 (, J 17 Hz, CHjSO; W at (H of AB, J 77 Hz, CHjSO; O 12 4H at 2.40 (M, CH WITH, AND); 2H 2.10 (M, CH cyclopentane); 2H O 1.90 (M,; 6H at 1.80 gi-gn СН „- СН, 61 (b): 1H at 8.70 (2D, J 9 G ZN at, 70 (C Y, NHj); 3N at 7.30 (C Y, NHj); 1H at 6.82 (2C, H thiazole) -; W at 5.95 (D-D, J 9 Hz, J 4 Hz, N); W at 5.18 (D, J 13 Hz, CH, CC); 1H at 4.94 (2D, Hg) ; 2H at 4.60 (M, HCOn, and); 1H at 3.86 (A of AB, J - -O iit -t 5 v-); 1H at 3.86 (A of AB, J 17 Hz, CH, SO); W at 3.65 (V of AB, J 17 Hz,); 2H at 2.75 (M, CH2NH2); 2H at 2.31 (M,) 4H at 1.50 (M, .CH, jNHj); ZN Poi 1.45 joint venture. J 7 Guy. SN.CH). 4H with i, ju (, p, (, L; H riHj;; 1.45 (D, J 7 Hz,). 61 i 2H pi 8.fin, M. CnWH. i t (M, CE cyclopentane). 58 (b): 1H at 8.75 (D. 9 Hz, CONH); ZN at 2.70 (C Y, NH); ZN, 30 (C Y, Shr; W at 6.84 (C, L of thiazole); 1H at 5.89 (DD, J 9 Hz, J 4 Hz, H); 1H at 5.13 (D, J 13 Hz, SC CCA); 1H at 3N at 1.45 (D, J 7 Hz,). 4.95 (D, J 4 Hz, 1L); ZN at 4.55. 62 (b): 2H at 8.60 (M, CONH, (M, СН "0№ and); 1H at 3.82 U); 1H at 8, - | 0 (S U, YN); ZN (And from AB, J 17 Hz,); W at 30 Pu 7.30 (C Y, NHj); 1H at 6.82 3.55 (B of AB, J = 17 Hz, CHgSO); C2C, H thiazole): 1H reg 5,95 (D-D, 2H at 2.60 (M,); IH at 2.21 (M, CHCOj); 4H at 1.80 (M, CH cyclohexane); 1H at 1.45 (M,); 2H at 1.25 (M, CHj cyclohexane); 2H at 0.90 (M, CH cyclohexane). 59 (b): W at 8.67 (D. J 9 Hz, CONH); ZN at (SU, Shd); ZN, 30 (C Y, NHj); W, 82, (C, H - thiazole); W at 5.94 (D-D, J 9 Hz, Hz, CR; 1 Npri 5.13 (D, J 13 Hz, CH.J.OC6); 1H at 4.95 TD, J 4 Hz, Hg); 1H at 4.56 (D, J 13 Hz, SN.OCO); 1H at 3.87 (A (2C, H thiazole), ..., .g „, J 9 Hz, J 4 Hz, K); | H at .5,14 (D, J 13 Hz, ell CCA); 1P at 4.95 (2D, Hg); 2H at 4.60 (M, “CHON, and); 1H at 3.88 (2D, J 17 Hz,); W at 3.55 (D, J 17 Hz, CHjSG); 2H at 3.20, 2 at 2.95 (M, CH NHCHj); W at 2, 2Н 66 hl J-1,) X, y 11 at 2.95 (M, CH NHCHj ;; 1H at 2 (M, CHCOj); 2H at 7.95 and 2H at 2 1.70 (M, -:); ZN at 1.45 . sn (D, J 7 Hz,). at 0.90 ppm (M, SSCH CH2 Av OS II about 282817 CONH) at hh 60 (b): 1H at 8.60 (2D, J 9 Hz, H); ZN at, 70 (S Y, Sh); ZN at 7.30 (C Y, NHj); IH at 6.82 (2C, H thiazole) j W at 5.95 (D-D, -. J-9 Hz, J 4 Hz, H); Shiri 5, 13 (d, J 13 Hz, CHjOCO); 1H at 4.95 (2D, Hg); 2H at 4.60 (M, + CHON); W at (2D, J 17 Hz, CH, 0); 1H at 3.56 (2D, J 1-7 Hz,); 2H at 2.75 (M, CH, CNZ.); 2H at 2.40 (T, J = 7 Hz,); 2H at 1.75 (C,); ZN at 1.39 (D,. Гч ГН ГН (C, J 7 Hz, SYZCH). 61 (b): 1H at 8.70 (2D, J nUV. lU n "Ti h G fr V 9 Hz 61 (b): 1H at 8.70 (2D, J 9 G ZN at, 70 (C Y, NHj); 3N at 7.30 (C Y, NHj); 1H at 6.82 (2C, H thiazole) -; W at 5.95 (D-D, J 9 Hz, J 4 Hz, N); W at 5.18 (D, J 13 Hz, CH, CC); 1H at 4.94 (2D, Hg) ; 2H at 4.60 (M, HCOn, and); 1H at 3.86 (A of AB, J - -O iit -t 5 v-); 1H at 3.86 (A of AB, J 17 Hz, CH, SO); W at 3.65 (V of AB, J 17 Hz,); 2H at 2.75 (M, CH2NH2); 2H at 2.31 (M,); 4H at 1.50 (M, .CH, jNHj); ZN Poi 1.45 joint venture. J 7 Guy. SN.CH). 4H with i, ju (, p, (, L; H riHj;; 1.45 (D, J 7 Hz,). 61 i 2H pi 8.fin, M. CnWH. ZN at 1.45 (D, J 7 Hz,). . 62 (b): 2H at 8.60 (M, CONH, 0 Pu 7.30 (C Y, NHj); 1H at 6.82 C2C, H thiazole): 1H reg 5,95 (D-D, (2C, H thiazole), ..., .g „, J 9 Hz, J 4 Hz, K); | H at .5,14 (D, J 13 Hz, ell CCA); 1P at 4.95 (2D, Hg); 2H at 4.60 (M, “CHON, and); 1H at 3.88 (2D, J 17 Hz,); W at 3.55 (D, J 17 Hz, CHjSG); 2H at 3.20, 2 at 2.95 (M, CH NHCHj); W at 2, 2Н 66 hl J-1,) X, y 11 at 2.95 (M, CH NHCHj ;; 1H at 2 (M, CHCOj); 2H at 7.95 and 2H at 2 1.70 (M, -:); ZN at 1.45 . sn (D, J 7 Hz,). 2H at 7.95 (D, H ortho CO,); 2H at 7.55 (D, J a, H meta CO); ZN at 7.30 (C Y, NHj); W at 6.82 (2C, H thiazole); W at 5.95 (D-D, J 9 Hz, J 4 Hz, N-); 1H at 5.44 (D, J 13 Hz, CH „CCA); 1H at 4.96 (2D, W, 84 (D, J 13 Hz, , j CH., CCA); W at 4-, 60 (K, J 7 Hz, GPPM h /. tn / M li mi N. Itl 12 9 Hz five 64 (b): 1H at 8.60 (2D. J 9: CONH); ЗН at 7.70 (С У, Щ); W at 6.80 (2C, H thiazole); 1H at 5.95 (D-D, J 9 Hz, J 4 Hz, N,); 5H at 4-6 (C Y, NHj,); 1H at 5.13 (D, J 13 Hz; CHjOCO); 1H at 4.95 (2D, 2H at 4.60 (M, t, „from, t, h , “Dz 1 and "... Q tt; 13 ,," t, 7J, 1 with T, uvj vn, and CHON) -i IH at 3.86 (A of AB J 17 Hz, CHjSO); IH at 3.65 (B from AB, J 17 Hz, CH, SO); 2H at 2.61 (M, CH, NH,); IH at 2.21 (M, CH 2 O, -); I - I - RTT pTT 4H at 180 (M, -i ЗН at 1.45 (D PTT g - I L 7 Hz,); 2H at 1.25 and /% - CH at 0.90 (M ,. 2H DO o ;: in with o, oi (.M, yJ U AC CONH); ZN at 8.05 (C Y,); 1H at 6.95 (C, H thiazole); 1H at 6.00 (DD, L 9 Hz, L 4 Hz, H); 1H at 5.20 C2D superimposed, L 13H SN.OCO); 1H at 5.10 (2D, L 4 Hz, H,); W at 4.56 (2D-imposed, L 13 Hz,); 4H at 3.90 (M, CH, SO and); ЗН at 2., 80 (М, еЙСО, CHCHgbfHj and Н equatorial in d-position to СО); 1H at 2.00 (M, H axial in the S-position to CO) -; 6H at 1.50 (2C, CCH) C); 6H at 1.20-1.80 (M, 3 CHj, the remaining pH of cyclohexane) ,. 67 (b): NR at 8.50 CM, NH2 and lu. Oi g., 7 s; n fr V t 817 sn sn five , 0); W at 3.58 (D, L 17 Hz, 50); W at 3.36 M, CpNHj); 1H at 3.25 (M,: CH2, NHG); 1H at - 2.95 (M, CHjJlI H); 2H at 2.60 C2D superimposed,); ZN at 1.70 (M, H piperidine); 6H at 1.48 (2C, (CH3)) | ZN at 1.45 (M, H piperidine). 68 (b): W at 8.60 (C Y, MN, piperidine); 1H at 8.45 (C Y, NH piperidine); 1H at 8.45 (D, L 9 Hz, CONH); W at 7.50 (C Y, NH thiazole); 1H at 6.70 CC, H thiazole); W at 5.97 (DD, -L 9 Hz, L 4 Hz, T1. "T c 1 / at 5.97 (D-D, -L 9 Hz, L 4 Hz,); W at 5,10 (D, L 13Tts, CHgOCO); 1H at 4.97 (D, L 4 Hz, BH); 1H at 4.63 (D, L 13 Hz,); 1H at 3.90 (D, L 17 Hz, SjSO); W at 3.57 (D, L 17 Hz,; U2SO); 2H at 3.20 M, cHjSNHj); Iu,. about 1 {(I rV h. 9U rrm. (JD, "-Aig - - / at h (D, l 17 G1); W at 3.75 (M, C0-Sa, -Shz and SNGZOGbN at 1.47 (2C, (SNZ) 2C) .. 70 (b): W at 8.70 (D, L 9 Hz ZN at 8.50 (C Y,); at 1H at /, J4 VA, J / 1C and Ag-e ;; 1H at b, 95 (C, C thiazole); 1H at 6.00 (DD, l 9 Hz, L 4 Hz, N,); GN at 5.45 (D, L 13 Hz,); W 4 Hz, d); W when Itt j, / JVM, o - II 1C, Vjnj U ZN at 2.36 (C, 6H at 1.47 (2C, (CHJjC). 72 (b): 1H at 8.70 (D, J 9 Hz, rnWH - 9N gtp 7 OC GP T 8 Hz, 6.92 (C, C thiazole); 1H at 1-D, J 9 Hz, J 4 Hz, N)} 5.37 (D, J 13 Hz, SNgOSO); 1H at 5.00 (D, J 4 Hz. H); 1H at 4.84 (D, J 13 Hz,); ZN at 4.10 (M, and CHjSO); 1H at 3.75 (D, j = 17 Hz, CH); ZN at 2.40 (C, CHj aromatic); 6H at 1.47 (2C (CH3) 2C). 76 (b): 1H at 8.62 (D, / Z (.o;: in with o, / and w j y i CONH); 2H at 7.95 (D, J 8 Hz, N Ar-2, 6); 2H at 7.67 (D, J 8 Hz, N Ar-3, 5); 1H at 6.95 (C, H thiazole); W at 6.00 (D-D, J 9 Hz, J 4 Hz, I-,); W at 5.45 (D, J 13 Hz,); W at 5.00 (D, J 4 Hz, Hg); W at 4.92 (D. J 13 Hz. SN "CCA): 2N pr CONH) 1H at 1H at 1H at 6, , s- w vi m - J C 1H at 5.27 (D, J 13 Hz,); 1H at 5.00 (D, J 4 Hz, Hg); 1H at. 4.92 (D, J 13 Hz, CHjOCO); ZN at 4.00 (M, SNHSD and CH); 1H at , 92 (D, J 13 Hz,); 2H at ° 3.64 (D, J 17 Hz,); 6H at, 16 (M, Ar CHj NHCHj); 1H at 4.08 2.18 (C,); 6H at 1.48 (2C, D, J 17 Hz, CHjSG); W at 3.78 SSN:) 2 C), 77 (b): 1H at 8.65 (D, J. 9 Hz, 25 CONH); ZN at 7.90 (C Y,); 1H at 7.00 (C, H Ar); 1H at 6.90 (C, B thiazole); GN at 6.00 (D-D, J 9 Hz, J 4 Hz, N); IH at 5.25 (D, J 13 Hz, CHjOCO); 1H at 5.00 U (D, J 4 Hz, Hg); IH at 4.92 (D, J 13 FHC,); ZN at 4.00 (M, A, Cb2.NH3 and CHjSO); 1H at 3.65 (D, J 17 Hz, CHzSO); ZN at 2.31 (c. Mon. PPI 7.7S (C. G. H. Ar; with J, uu w. J + 1C in at 4.92 (D, J 13 Hz,); 2H at 4.16 (M, Ar); 1H at 4.08 (D, J 17 Hz,); W at 3.78 (D, J 17 Hz,); ZN at 2.43. (C, SNM); 6H at 1.48 (2C, () 73 (b): W at 8.70 (D, J 9 Hz, CONH); 2H at 7.95 (D, J 8 Hz, H Ar-2,6); 4H at 7.67 (D, -J 8 Hz, N Ar-3, 50; N at 6.92 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, H-,); W at 5.43 (D, J 13 Hz,); 1H at 5.00 (D, J 4 Hz, Hg); 1H at 4.82 (D, J 13 Hz, CH, CCA ); 2H at 4.18 (M, I - n 1 and, iJg chup t, ui, o - 13 Hz, SN, CCA); 2H at 4.18 (M,); W at 4,10 (D, J 17 Hz,); 1H at 3.76 (D, J 17 Hz,); 2H at 2.90 (M, CHgCH NH); 6H at 1.47 (2C, (CH3) gC); ZN at 1, 16 (T, J 7 Hz,,). 74 (b): 1H at 8.70 (D, J 9 Hz, lhttt. OTIt PS / gt t - o tch- (D, J 17 Hz, CHjSO); ZN at 2.31 (C, CHjAr); ZN at 2.25 (C,); ZN at 2.14 (C, CHdAg); 6H at 1.45 35 (2C, (CH3) iC). 78 (b): 1H at 8.70 (D, 3 9 Hz, CONH); ZN at 8.00 (C Y, CHjNHg) 40 1H 2H / - about - 78 (b): 1H JH); ZN at 8.00 (., ,,, at 7.45 (D, J = 7 Hz, and Ar-4); AI at 6.92 (M, H thiazole and C Ar-5); 1H at 6.00 (D-dT J 9 Hz, J 4 Hz, HT); W at 5.42 (D, J 13 Hz, m CHjOCO); 1H lri 5.00 (D, J 4 Hz, Hg); W at 4.84 (D, J 13 Hz, at 7.45 (D, J = 7 Hz, and Ar-4); AI at 6.92 (M, N thiazole and C Ar-5 1H at 6.00 (D-dT J 9 Hz, J 4 G HT); W at 5.42 (D, J 13 Hz, m CHjOCO); 1H lri 5.00 (D, J 4 Hz, Hg); W at 4.84 (D, J 13 Hz, (C, H thiazole); W at 6.00 (D-D, N); W at 4.84 (D, J 13 Hz, J 9 rif, J 4 Hz, IH at 5.45 hp); ZN at 3.95 (M, and (D, J 13 Hz,); 1H at 5.00); ZN at 3.78 (C, OCHj); ZN (D, J 4 Hz, Hg); 1H at 4.82 (D, P, 73 (C, OCHj); W at 3.58 (D, J 13 Hz, CHjOCO); 2H at 4.16 (M, J 17 Hz,); 6H at 1, 47 (2C, VM in with J 13 Hz, CHjOCO); 2H at 4.16 Ar-CH2N-file); W at 4.08 (D, J 17 Hz,); W at 3.78 (D, J 17 Hz, CH); 1H at 3.20 (M, LH-CH (CH3) 2); 6H at 1.48 C2C, (CH3) gC); 6H at 1.26 (D, L 7 Hz, (OH,). CH). 50 4f) / t. . y t at 3.73 (C, OCHj); 1H at 3.58 (D, J 17 Hz, CH5, SO); 6H at 1.47 (2C, (CHj) C). 79 (b): W at 8.62 (D, J 9 Hz, CONH); 5H at 8.00 (M, CHgNgj and H Ar-2, 6); 1H at 7.20 (D, J = 7 Hz, and Ar-5); 1H at 6.95 (C, H thiazole); W at 6.00 (D-D, J 9 Hz, J 4 Hz, N,); W at 5.45 (D, J 13 Hz ,. SN.OSO); W at 5.00 (D, J 4 Hz, Hg); 1H at 4.82 (D, J 13 Hz,); ZN at 4.00 (M, CHgNH ,, and SNGZO); ZN at 3.88 (C, 282817 IN at 6.00 (D 1H at 5 5 A 6.92 (C, C thiazole); 1H at 1-D, J 9 Hz, J 4 Hz, N)} 5.37 (D, J 13 Hz, SNgOSO); 1H at 5.00 (D, J 4 Hz. H); 1H at 4.84 (D, J 13 Hz,); ZN at 4.10 (M, and CHjSO); 1H at 3.75 (D, j = 17 Hz, CH); ZN at 2.40 (C, CHj aromatic); 6H at 1.47 (2C (CH3) 2C). 76 (b): 1H at 8.62 (D, CONH) 1H at 1H at 1H at 6, , s- w vi m - J C 1H at 5.27 (D, J 13 Hz,); 1H at 5.00 (D, J 4 Hz, Hg); 1H at. 4.92 (D, J 13 Hz, CHjOCO); ZN at 4.00 (M, SNHSD and CH); 1H at 77 (b): 1H at 8.65 (D, J. 9 Hz, 5 CONH); ZN at 7.90 (C Y,); 1H at 7.00 (C, H Ar); 1H at 6.90 (C, B thiazole); GN at 6.00 (D-D, J 9 Hz, J 4 Hz, N); IH at 5.25 (D, J 13 Hz, CHjOCO); 1H at 5.00 (D, J 4 Hz, Hg); IH at 4.92 (D, J 13 FHC,); ZN at 4.00 (M, A, Cb2.NH3 and CHjSO); 1H at 3.65 (D, J 17 Hz, CHzSO); ZN at 2.31 (c. Mon. PPI 7.7S (C. G. H. Ar; (D, J 17 Hz, CHjSO); ZN at 2.31 (C, CHjAr); ZN at 2.25 (C,); ZN at 2.14 (C, CHdAg); 6H at 1.45 5 (2C, (CH3) iC). 78 (b): 1H at 8.70 (D, 3 9 Hz, CONH); ZN at 8.00 (C Y, CHjNHg) 0 1H 2H / - about - 78 (b): 1H JH); ZN at 8.00 (., ,,, at 7.45 (D, J = 7 Hz, and Ar-4); AI at 6.92 (M, H thiazole and C Ar-5); 1H at 6.00 (D-dT J 9 Hz, J 4 Hz, HT); W at 5.42 (D, J 13 Hz, m CHjOCO); 1H lri 5.00 (D, J 4 Hz, Hg); W at 4.84 (D, J 13 Hz, H); W at 4.84 (D, J 13 Hz, with ); ZN at 3.95 (M, and); ZN at 3.78 (C, OCHj); ЗН Р, 73 (С, OCHj); W at 3.58 (D, J 17 Hz,); 6H at 1.47 (2C, ls); ZN at 3.95 (M, and); ZN at 3.78 (C, OCHj); ЗН Р, 73 (С, OCHj); W at 3.58 (D, J 17 Hz,); 6H at 1.47 (2C, 50 55 4f) / t. . y t at 3.73 (C, OCHj); 1H at 3.58 (D, J 17 Hz, CH5, SO); 6H at 1.47 (2C, (CHj) C). 79 (b): W at 8.62 (D, J 9 Hz, CONH); 5H at 8.00 (M, CHgNgj and H Ar-2, 6); 1H at 7.20 (D, J = 7 Hz, and Ar-5); 1H at 6.95 (C, H thiazole); W at 6.00 (D-D, J 9 Hz, J 4 Hz, N,); W at 5.45 (D, J 13 Hz ,. SN.OSO); W at 5.00. (D, J 4 Hz, Hg); 1H at 4.82 (D, J 13 Hz,); ZN at 4.00 (M, CHgNH ,, and SNGZO); ZN at 3.88 (C, 49 128 v OCHj.); IH at 3.72 (D, J 17 Hz, CH, 50); ZN at 1.48 C, (CH) HS); ZN at .1.47 h (C (CH3) 2C); 80 (b): W at 8.66 (D, J 9 Hz, CONH); ZN at 8.05 (S Y): ZN at 7.50 (M, H Ar); 1H at 6.95 (C, H thiazole); IH at 6.00 (D-D, J 9 Hz, J 4 Hz, N,); 1H at 5.45 DM, J 13 Hz,); 1H at 5.00 (D, J 4 Hz, Hg); 1H at 4.84 (D, J J3 Hz,); ZN at 4.00 (M, CHjiNHg, and); ZN at 3.86 (C, CHjO Ar); W at 3.75 (D, J 17 Hz, CH); ZN at 1.48 (C, (CHj) 2C); ZN at 1.47 (C, (CH3,) HS). 7.69 (D, J 7 Hz, H Ar-4); 1H at 7.55 (T, J = 7 Hz, H Ar-5); W at 6.95 (C, H thiazole); W at 6.00 (D-D, J 9 Hz, J 4 Hz, N-,); W at 5.48 (D, J 13 Hz,); W at 5.00 (D, J 4 Hz, Hg); W at 4.86 (D, J f13. Hz, CJJJOCO); ZN at 4,05- (M,. And); 1H at 3.75 (D, J 17 Hz, CH2.SO); 4H at I-sa 2.40. (M, CH, 2H at 1.90 cm. with W at 8.82 (D, LF 9 Hz, 1 at 8.20 (C Y, CHjNHj); 2H (M, H Ar-2, 6); W at J 1 Hz, N Ar-5); 1H with H-thiazole); W at 5.97 9 Hz, J 4 Hz, H); 1H (D, 40 - 1 U ,, -f 14 J 13 Hz, CBjiOCO); 1H (D, J 4 Hz, Not); 1H at J LZ Hz, CH ,, CCA); ZN with CHjNHa and); W when - T-t. to 45 (6); ZN, 80 (D, (C, J, 45, 00 (D, (M, (D, (M, L-BjiNHj and; IH with - --as; J 17 Hz, CH, SO); 4H at Hz, SNGI); . z 50 J -17 Hz, CH (SO); ABOUT ); ZN at 2.34 ST, J 8 Hz, N Ar (C, H thiazole); 1H J 9 Hz, J 4 Hz (D, J 13 Hz, SNGO (D, J 4 Hz, Hg); J 13 Hz, CHjOCO) J 17 Hz,); J 17 Hz, CHgSO); J 7 Hz, (T, J 7 Hz. CHjCH 1.47 (2C, (CH3) 1C). 85 (b): 1H with CONH); 4H at 8.20 thiazole in position (C, H thiazole); W J 9 Hz, J 4 Hz (D, J 13 Hz, CH20 (D, J 4 Hz, Hg); J 13 Hz, CHjOCO) J 17 Hz,); j 7 Hz, SNg,); J. 17 Hz, CHSO); (C, CHj aromatic); 2H at 1.90 ,, (M, 1282817 v 50 83 (b): 1H at 8.97 (D, L 9 Hz. CONH) ;: 2H at 8,, 79 (C Y, CH); 2H at 8.00 (D, J 8 Hz, N Ar-2, 2N at 7.58 (D, L 8 Hz, N); W at 6.95 (C, H thiazole); 1H at B) 2Npri / 5 "(D, J 8 Hz, N Ar-3, 5 W at 6.95 (C, H thiazole); 1H at 5.97 (D-D, J 9 Hz, J 4 Hz, N- .); W at 5.45 (D, J 13 Hz, SigrSO); 1H at 5.00 (D, J 4 Hz, Hg); 1H at 4.84 (D, J 13 Hz, CH TOC); 2H at 4.19 (M, Ca2MH2-CH3); W at 4.08 (D, J 17 Hz,); 1H at 3.75 (D, J L7 Hz,); ZN at 2.50 (M, -CH 4H with 2.40 ICHj (M,); 2H at 1.90 t CH : q-o). 0 35 40 45 - --as; Hz, SNGI); 50 J -17 Hz, CH); CT, J 8 Hz, N Ar5); 1H at 6.92 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, Ny); 1H at 5.45 (D, J 13 Hz, SNgOCO); GN at 5.00 (D, J 4 Hz, Hg); 1H at 4.84 (D, J 13 Hz, CHjOCO); H at 4.00 (D, J 17 Hz,); 1H at 3.75 (D, J 17 Hz, CHgSO); 2H at 3.05 (K, J = 7 Hz); 2H at 2.70 (T, J = 7 Hz. CHjCHjNH); 6H at 1.47 (2C, (CH3) 1C). 85 (b): 1H at 8.80 U.J 9 Hz, CONH); 4H at 8.20 (M, CH, CN and H thiazole in position 3); 1H at 6.95 (C, H thiazole); W at 6.00 (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.38 (D, J 13 Hz, CH20CO); W at 4.98 (D, J 4 Hz, Hg); 1H at 4.78 (D, J 13 Hz, CHjOCO); 1H at 3.98 (D, J 17 Hz,); 2H at 3.82 (K, j 7 Hz, SNg,); 1H at 3.66 (D, J. 17 Hz, CH jSO); 6H at 1.49 (2C, 51 IH at 4.98 (D, J 4 Hz, Hg); IH at 4.80 (D, J 13 Hz,); W at 4.05 (D, J 17 Hz, CH); ZN at 3.80 (M, CHg, 0 and); 6H at 1.48 (2C, (CH3) 2C). 87 (b): 1H at 8.75 (D, J 9 Hz, & 1282817 52 five /Not ); 1H at 4.60 (D, J 13 Hz, CYGOSO); HI at 3.89 (D, J 17 Hz, CH); W at 3.58 (D, J 17 Hz,); 2H at 3.18 (M, H in the 1-position, Ifflj of piperidine); 2H at 2.81 (M, H in the l-position, NH piperidine) -sn. CONg); 1H at 8.50 (C U, W piperidine); W at 8.40 (C U, IH piperi- / n L1 p oi dina); 2H at 7.40 (C Y NH / thiazole); , о Р «2.40 (M, СН, - | 0); 2H at 1H poi6.78 fC. N ti cho. P): 1H Dina); 2H at 7.40 (C y NH thiazole) 1H at 6.78 (C, H thiaole); 1H at 5.95 (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.16 (2D, J 13 Hz, SNOOOSO); 1H at 4.95 (D, J 4 Hz, Hg); 1H at 4.68 (D, J 13 Hz, SNg, CCA); 1H at 3.92 (D, J 17 Hz, CHjSQ) ;; IH at 3.60, J = 17 Hz, CHjSO) j., 3 JtO (M, cn Y); Syringe 3, N. 1 U Z.i О ЯО М. CH 4H at 2.40 ); CO 2.28 (D, J 7 Hz,); 5H at GCHU 15 Oh, SNSNGSOO, 2H in Syringe JtO (M, CH III); Spra (M, C, U 1H at 2.89 (M, 2H at 2.60 (2D imposed, J 20 7 Hz,); ICH, CM, SI, - o; 5H at 1.85 WITH (M, ZN, piperidine and YU ZN at 1.45 (M, PZ piperidine). 88 (b): W at 8.80 (D. J 9 Hz, 1n T7GMT I lp sg V gan pil- 35 00 (.0): n for o, oi, ws - ei c, CONH); 1H at 8.60 (SU,% piperidine); 1H at 8.45 (SU, NHj. Piperidine); 2H at 7.25 (C Y, Shch thiazole); W at 6,79 (C, H thiazole); 1H PR 6.00 (D-D, J 9 Hz, J 4 Hz, N); W at 5.16 (D, J 13 Hz, CHgOCO); 1H at 5.00 (D, J 4. Hz, Hg); 1H at 4.69 (D, J 13 Hz,); 1H at 3.90 (D, J 17 Hz,); 1H at 3.60 (D, J 17 Hz,); 2NFPRI 3.24 (M, CHg in the dk-position, NHg of piperidine); 2H at 2.70 (M, CHj, in the ok position, Ifflj pipa (SI. I I 45 Ridin); 6H at 2.40 (M, SN.SO and); 6H at 1.5-2.2 (M, - O of piperidine). . 2817 52 five /Not ); 1H at 4.60 (D, J 13 Hz, CYGOSO); HI at 3.89 (D, J 17 Hz, CH); W at 3.58 (D, J 17 Hz,); 2H at 3.18 (M, H in the 1-position, Ifflj of piperidine); 2H at 2.81 (M, H in the l-position, NH piperidine); -sn. / n L1 p oi P “2.40 (M, CH, - | 0); 2N pr CO 2.28 (D, J 7 Hz,); 5H at GCHU 15 Oh, SNSNGSOO, 2H in ); ); 2 25 five five 0 wv-iv / / J 11 -Tj ViM9 - - M Hg); IH at 4.61 (D, J 13 Hz, CHjOCO); IH at 3.89 (D, J 17 Hz,); IH at 3.58 (D, J 17 Hz,); 211 at 3.21 (M, CH in o-position, NHg piperidine); 2H at 2.81 (M, SC, o-position, NHp piperidi. In the position,, at 2,2 ); Sh with Oi ",. 1 71; , 12 piperidine); 2H at 2.27 (D, J 7 Hz, 1.95 (M,); PH and rJ tr MN gtchggt aly - ); W at 1.95 (M,); 2H at 1.75 (M, CHg in o (k NHj of piperidine); 6H at 1.47 (2C, (CH32gC); 2H at 1.40 (M, CHj in RN to piperidine III) 91 (6): 2H at 8.70 (C Y, CH NHgCHj); H at 8.60 (D, J 9 Hz, CONH); W at 8.10 (C Y, H Ar-2); 1H at 7.96 (D, J 8 Hz, H Ar-6V); 1H at 7.75 (D, J 8 Hz, N Ar-4); W at 7.56 (T, J 8 Hz, N.Ag-5); 1H at 6.92 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.45 (D, J 13 Hz, SigOSO); W at 5.00 (D, J 4 Hz, Nb); W at 4.87 (D, J,); 2H at 4.1b (M, Ar); W at 4.05 (D, J 17 Hz, CH); 1H at 3.75 (D, J 17 Hz, cH250); ZN at 2.50 (M, CH ShgSNg); .6H at 1.45 (2C, (CHj) jj C) ... 92 (6): 2H at 8.70 (C Y, - CHj, l% CH2CHj); - An / p. t sh. about city .. GLNCH i, J - about 1C, p. (C, H thiazole); W at 9 Hz, J 4 Hz, N- (D, J 13 Hz, CHjOCC (D, J 4 Hz, i3g); 1H. T P Gtt. NH.nr.n i; J one : 1c, J - 4 Hz, Ng); , J 13 Hz, CHjOCO); J 4 Hz, i3g); IH about 13 Hz, CHjOCO); ZN A, and CH.SO); (R, j 17 Hz,) (C, CIZAg); 4H at 2, ABOUT); 2H at 1.90 (M GNG, .80); j 50 W at (M 35 -5 W N CH Hg inn 45 IH pr (M 6, (D j 97. (b): 1H at 10.30 (C, ArNHCO); W at 8.70 (D, J 9. Hz, CONH); 1H at 8, for (C Y, H Ar-2); ZN at 8.05 (M, CH, No. Ij); 2H at 7.70 (M, H Ar - -5.6); 1H at 6.95 (C, H thiazole); W at 6.00 (D-D, J 9 Hz, J 4 Hz N); 1H at 5.45 (D, J 13 Hz,); 1H at 4.97 (D, J 4 Hz, Hg); 1H at 4.80 (D, J 13 Hz, inn.nnn i - 1n pg, “l m g g t 17 Hz w vv, Ag NH 9 Hz, CONH); Ih 70 1.4 / v, /., Vbnj ;; ji, 98 (6): IH at 9.90 (C, AL mp 5 IH at 8.66 (D, J 9 Hz, CONH); at 8.28 ( C, H Ar-2) at 7, (M, H Ar-5, b and CHjNH); GN at 6.95 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, H-,); 1H ppm h LTs P t p 14 GTT .P at 5.45 (D, J = 13 Hz, CHgOCO); 11 at 5.00 (D, J 4 Hz, Hj); 1H at 4.84 (D, J 13 Hz,); W at 4.03 (D, J 17 Hz, CHg.SO); 1H at 3.68 (D, J 17 Hz, CHj, SO); 2H five at 3.68 (D, J 17 rn, CHj, SO); 2H at 3.05 (M, CO — CH CH NHj); 2H at 2.75 (T, J = 7 Hz, CO — CH CH2, n113); 6H at 1.46 (2C (CH3)). 99 (6): 1H at 10.5 (C, Ar NHCe); 99 (6). . „1H npif 8.56 (D 1H at o, 5 (C, Ag NHCe); J 9 Hz, CONH); 2H 33 at 7.89 (D, J 9 Hz, H Ar-2, 6); 2H at 7.70 (D, J 8 Hz, N Ar-3, 5); ZN at 7.70 (C Y, (CE liHj); 1H at 6.95 (C, H, thiazole); - 1H at , 98 (D-D, J 9 Hz, J 4 Hz, N,); H at 5.40 (D, J 13 Hz, CHgOCO); ITtf -rt-g / "- 1lt -11T 1H at 4.98 (D, J 4 Hz, Ug); 1H at 4.79 (D, J 13 Hz, SNHOSO); W at 4.05 (D, J 17 Hz,); 1H at 3.75 (D, J 17 Hz,); 2H at 3.06 (M, CO-CH, CNHKNz); 2H at 2.70 (M, CO-CHgCH NHj); 6H at, 45 C2C, (SIS) GS). 100 (b): 1H at 12.75 (C Y, thiazol SCHSO); 1H at 8.90 (D, J 9 Hz CONH); 4H at 8.15 (M, and H thiazole at position 3); 1H at 6.96 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, N.); 1H at 5.40 (D, J 13 Hz,); 1H at 4.98 (D, J 4 Hz, Hg); 1H at 4.81 DM, J 13 Hz,); 1H at 4.0 (D, J in Hz, CH); 2H at 3.86 (M, GBSH NH); JH at 3.66 (D, J .17 Hz, CHjSO); 4H at 2.5 (M, -. 2H at 1.90 (M, sn 101 (b) g 1H at 8.95 (D, J : 1H at 10.8 (C, ArNfi CO) 5 (P. J 9fHz, CONH;: 1H at 8.95 DM, J 9fHz, CONH; : ZN at 8.15 (C Y,); 2H at 7.90 (D, J 8 Hz, N Ar-2, 6); 2H at 7.70 (D, J 8 Hz, N Ar-3, -5); 1H at 6.97 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.36 (D, J 13 Hz, SNgOCO); 1H at 5.00 (D, J 4 Hz, Hg); 1H at 4.82 (D, J 13 Hz, SNgOCO); 1H at 4.05 (D, J d17 Hz,); . ZN at 3.8 (M, CJ5, NH3 and CH, SO); 4H 1 - - / -BH I 2 at 2.40 CM, SNg-O); 2H at 1.90 (m, 102 (b): 1H at 8.45 (D, J 9 Hz, CONH); ZN at 8.0 (C Y, CHjNHj); W at 6,79 (C, and thiazole); W at 5.98 (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.15 (2D, J 13 Hz, CHgOCO); W at 4.97 (D, J 4 Hz, Hg); IH at 4.62 (D, J 13 Hz, CBjOCO); 1H 28281756 at 4.15 (D Y, J 12 Hz, Ng equiv., - -. - - ten 15 20 25 thirty ); at 4.15 DM, J 12 Hz, Ig eq. piperidine); ZN at 3.84 (M, CHj, 1 and); 2H at 3.58 (M, and Hg equiv. Of piperidine); W at 3.05 (TU, J 12 Hz, not ax. Piperidine); 1H at 2.60 (M, CH COj); 2H at 1.84 (M, Hj and Hg of piperidine); 2H at 1.50 (M, Hj and Hj piperidine); 6H at 1.45 C2D, CCH5)., C). 103 (b): W at 8.72 (D, |, 9 Hz, CONH); ZN at 8.25 (C Y, CHgNHj); ZN at 7.75 (M, H Ar); 1H at 6.97 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, N-); W at 5.45 (D, J., 13 Hz,); W at 5.00 (D, J 4 Hz, Hg); W at 4.84 (D, J 13 Hz,); ZN at 4.05 (M, and CHjSO); W at 3.75 (D, J 17 Hz, CH2SO); 6H at 1.45 (2C, (SND) 2C). 104 (6): 2H at 8.80 (C Y, --- CH ,, No. jCHj); W at 8.77 (D, J 9 Hz, CONH); ZN at 7.75 (M, H Ar); Ih at 6.95 (C, H thiazole); 1H at (6.00 (D-D, J 9 Hz, J 4 Hz, HT); 1H at 5.45 (D, J 13 Hz,); 1H at 5.00 (D, J 4 Hz, Hg) ; Ih at 4.86 (D, J 13 Hz, CHjOCO); 2H at 4.25 (M, CHjfcHg); iH at 4.10 (D, J 17 Hz, CH); 1H at 3.74 (D, J 7 Hz,); ZN at 2.58 (M, CHjNHj-CHj); 6H at 1.45 (2C, (CH) C). 105 (b): W at 10.70 (C, A, five (T, J 8 Hz, N Ar-5); 1H at 6.95 (C, H thiazole); 1H. at 6.00 (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.45 (D, J 13 Hz, CH2, CCA); W at 5.00 (D, J 4 Hz, Hg); W at 4.82 (D, J 13 Hz,); W at 4.02 (D, J 17 Hz, CHj, SO); 2H at 3.90 (M, CH NH-CHj); 1H at 3.74 (D, J 17 Hz, CH2SO); 3H at 2.60 (M, CHj, NK2CH3); 6H at 1.45 (2C, () 106 (b): W at 10.80 (C, ArNHCO); 3N at 8.70 (M, CH j lfflji CHa and CO NH); 2H at 7.92 (D, J 8 Hz, N Ar-2, 6); 2H at 7.69 (D, J 8 Hz, N Ar-3, 5); 1H at 6.95 (C, H thiazole); W at 6.00 (D -D, J 9 Hz, .J. 4 Hz, HT.); 1.H at 5.42 (D, J 13 Hz, CHjOCO); 1H at 5.00 (D, J 4 Hz, Hb) H at 4.81 (D, J 57 128 e / 13 Hz,); 1H at 4.05 (D, J 17 Hz, CH); 2H at 3.95 (M, CHjNHgCHg); 1H at 3.75 (D, J 17 Hz, CH); ZN at 2.62 (M,); 6H at 1.45 C2C, (CH3) 2C), 107 (b): 1H at 9.95 (M, AgMa CO); 1H at 8.75 (D, J 9 Hz, CONH); ZN at 8.05 (C Y, Sh. Shd); 1H at 7.61 (D, J 8 Hz, N Ar-6); 1H at 7.52 (D, J 8 Hz, N Ar-4) i 1H at 7.31 (T, J 8 Hz, H Ar-6); W at 6.96 (C, H thiazole) J 1H at 6.00 (D-D, .J 9 Hz, J A Hz, N); W at 5.40 (D, J 13 Hz,); W at 5.0 (D, J 4 Hz, Hg); W at 4.81 (D, J 13 Hz,); W at 4.05 (D, J gl7 Hz,), 2H at 3.81 (M, SNL, Shz); 1H at 3.72 (D, J 17 Hz,); ZN at 2.28 (C, AgS%); 6H at 1.45 (2C, (CH3) 2C). 108 (b): W at 9.75 (C, ArNH.CO); ITT O J f frr t Pi--. . , -,, and Hz, H, AG-: E); w at 6.95 (C, H thiazole); 1H at 6.00 (DD, - J 9 Hz, J 4 Hz, N); W at 5.39 (D, J 13 Hz, CH20SO; 1H at 5.00 (D, J 4 Hz, N); W at 4.82 (D, J 13 Hz,); 1H at 4.05 (D , J 17 Hz,); lH at 3.7.2 (D, J 17FHC,); 2H at about l 1 / XTIT h. otto fiQ 9 J - t J 1C, in iipK I, J 17 Hz,); lH at j, /. HD, J 17FHZ,); 2H at 3.02 CM, ,, Shz) at 2.69 (T, J 7 Hz, CH CHgNHj); ZN at 2.29 .. (C, Ar, CH3); 6H at 1.45 (2C, (Ca) pC). (saz) 2C). 109 (b): 1H at 12.7 (C Y, NHCO thiazole) at 8.79 (D, J 9 Hz, CONH); W at 8.08 (C, H thiazole in position 3); ZN at 7.75 (C Y, CH 2) at 6.98. (C, C thiazole); W at 6.00 (D-D, J 9 Hz, J 4 G H); W at 5.37 (D, J 13 Hz, CH, jOCO); 1H at 5.00 (D, J 4 Hz, and. 1N TTG.M D Ya1 fn L tT GTT. CH, jOCO); 1H at 5.00 (D, J 4 Hz, He); w at 4.81 (D, J 13 Hz,); W at 4.03 (D, J 17 Hz, CH); W at 3.68 (D, J 17dHz,); 2H at 3.06 (M, CHg CH., NH); gi at 2.77 (T, J 7 Hz, CHjCHgNHj jH poi 1, 45 (2C. (SNL C). fO five ; 58 15 J 4 Hz, Nb.); IH at 4.84 (D, J 13 Hz, CHjOCO); IH at 4.06 (D, J 17 Hz, CHjSD); IH at 3.74 (D, J Hz,); 2H at 3.55 (C Y,); ZN at 3.25 (C Y, KSNz); 6H at 1.45 (2C, (CH3) 2C). ,,,. ,,. . , 5 (S U, Ar 9 Hz, 3 Hz, , l 9 / u “-.i j.i r y / j, u u j 8, Hz, H Ar-3, 5); 1H at 6.96 (C, H thiazole); W at 5.98 (D-D, J 9 Hz, J 4 Hz, N-,); 1H at 5.42 (D, J 13 Hz, ... CHjOCO); W at 5.00 (D, J 4 Hz, Hg); 1H at 4.80 (D, J 13 Hz,); 1H at 4.05 (D, J 17 Hz,); 1H at 3.75 (D, J),); 2H at 3.05 (M, CH5, CH2.Shz); 2H at 2.70 (T, J = 7 Hz, CHiCH-jlfe); 4H at 2.40 (M, Mr. BUT ); 2H at 1.90 CM, sn, -ABOUT). five five 112 (b): 1H at 8.80 (D, J 9-fHz, CONy); ZN at 7.90 (C Y,); W at 6.80 CC, C thiazole); W at 5.95 SD-D, J 9 Hz, J 4 Hz, N); -Sh at 5.17 S2D, J Hz Hz,); 1H at 4.96 DM, J 4 Hz, 06,); W at 4.60 DM, J 13 Hz, CH, CCA); W at 4.18 (M. H, eq, pi „-,. -R, V - h chl, WJ 1 -V l and,, ); w at 4.18 CM, Hj equiv, pi peridine); ZN at 3.90 (M, CH211H3 and CHgSO); 2H at 3.58 CM, and H eq, piperidine); W at 3.06 CM Hj ax. piperidine); 1H at 2.75 CM, Hg ax. piperidine); W at 2.60 (M, Nc piperidine); 4H at 2.40 O. (M, SO); 4H at 1.80 0 ABOUT and 2H at 1.50 G (° and and No. 5 piperidine). 113 Sat): 1H at 8.75 (D, J Gt1 ch TTTiTi lp fr v 9 / c CH NH W when J VD; : in with a, / 5 “.D, J c, CGNH); ZN at 8.40 (C Y,: 1h); 1H at 8.13 CC, H Ar-6); ri 8.00 (D, J 8 Hz, B Ar-2); W at 7.64 DM, J 8 Hz, H Ar-J); 1H at 6.97 CC, H thiazole); W at .6,00 CD-D, J 9 Hz, J 4 Hz, ND; W at 5.45 DM, J 13 Hz, CHaGCG); W at 5.00 SD, J 4 Hz, IB); 1H 59 at 4.86 (D, J = 13 Hz, CHgOCO); 2H at 4.19 (M-, CHjNHa); 1H at 4.10 (D, J 17 Hz, CH SO); W at 3.76 (D., J .17 Hz, CH, SO); 6H at 1.45 (2C, (CHj) jC) eleven/. K 1TT LIJ, F SuGut LL Lt g ± - . ,) 2H at, .. (M, CHgNHj); 1H at 4.06 (D, J 17 Hz,); W at 3.78 (D, J 17 Hz, CH); 6H at 1.45 (2C, (CH) C). 115 (b): 1H at 10.20 (C Y, Ar: NHCO); 1H at 8.70 (D, J 9 Hz, CONH); 1H at 8.16 (C Y, H Ar-2); 1H at 7.84 (D, J 8 fHz, n Ar-6)} CHN GGG.M 7 f, f (G. V r.H-NH. G 118 (b): 1H at 12.7 (C Y, NH CO thiazole); 1H at 8.65 (D, J CONH); ZN at 8.20 (C Y,) ,; 1H at 6.93 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, N); 5 1H at 5.45 (D, J 13 Hz,); 1H at 5.02 (D, J 4 Hz, He); 1H at 4.75 (D, J 13 Hz,); W at 4.02 (D, J 17 Hz,, 80); 1H at 7.84 (D, J 8fHz, N. ZN at 7.66 (C Y, CH, CNH); 11 7.60 (D, J 8 Hz, H Ar-4); ... 7, 45 (T, J 8 Hz, B Ar-5); 1H 6.97 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, B7); 1H at 1H at 1H at 20 25 lit -t, / j, o W at 4.02 (D, 2H at 3.90 (M, 1 p -1 -li ;; i 3.70 (D, J 1.7 Hz,); . SN, thiazole: 6H at 1.45 h, (, d, J I / I c, 2H at 3.90 (M,); 1H at .D, J 1.7 Hz,); ZN at 2.50 (C, CHj thiazole) С2С, (СНз) 2С). 19 (b): 1H at 8.45 (D, 9 Hz,); ZN at 7.80 (C Y, CH-NH.); -. D Qf / T and n ,, - lU N .. at 5.00 (D, J 4 Hz, Hg); 4.84 (D, J 13 Hz,); 4.05 (D, J 17 Hz,); 3.75 (D, J 1717 Hz, CH SO); 2.81 (M, CHjNHj); 2H at 2, t, CONH); ZN at 7.80 (C Y, CH-NH.); 1H at 6.80 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, I,); H at 5.10 (D, J 13 Hz,); 1H at 4.95 (D, J 4 Hz, Hg); Sh / g C f ht t. t 4 t t 1 "t C, J 9 Hz, J 4 Hz, B7); 1H at 5.45 (D, J 13 Hz,); 1Н Jn 1, И- VM, J - - i × iis at 5.00 (D, J 4 Hz, Hg); 1H at at 4.58 (D, J 13 Hz,) 1, J 13 Hz,); W at 3.90 (D, J 17 Hz,); g t 17 g, t g c: n. IH gtu at 3.56 (D, J 17 Hz,); Poi 3.00S2M. CHNH,: 1N Poi 2. 1H 1H 1H .d, J N 1C, PD; I, J 13 Hz,); J 17 Hz, CH, jSO); at 3.56 (D, J 17 Hz,); 1 at 3.00 (2M, CHNHj); 1H at 2.25 CM, CH CO); 4H at 1.80 and 4H at 1.40 (M, cyclohexane CH); 6H at 1.44 C2C, (SBz) 2C). 1H at , ,, , -,, 2H at 2.81 (M, CHjNHj); 2H at 2.40 (T, J = 7 Hz, CHjCO); 2H at 1.82 (M, CHjCHjCOj); 6H at 1.45 C2C, (CH3) gC). 35 116 (b): 1H at 10.3 (S U, Agi / and {, o ;: w at b, / 5 (d, J UHz, NH CO); 1H at 8.70 (D, J 9 Hz, CONH); 2H. at 7.80 (C Y, N Ar-2,. CONH); 2H at 7.90 (D, J 8 Hz, 6); ZN at 7.65 (C Y, CH, NL3); Sh H Ar-2, 6); - 1H at 7.67 (D, J at 7.57 (D, J. 8 Hz, B Ar-4); IH 8 Hz, H-Ar-3, 5); ЗН at 7.60 (С У, СН, Н,); 1H at 6.95 (C, H 120 (b): 1n at 8.75 (D 40 at 7.57 (D, J. 8 Hz, V AG-. ,, - 8 Hz, V. Ag-5); Sh 00 l.l.t.f h. I - Xf -S J W - ..- / at 7.47 (T, J = 8 Hz, B .Ar-5); I at 7.00 (C, H thiazole); 1H at 6, (D-D, J 9 Hz, J 4 Hz, N,); 1H pr 5.45 (D, J 13 Hz,); 1H at 4.98 (D, J 4 Hz, HS); IH at 4.82 (D, J 13 Hz, SNgOCO); 1H at 4.05 (D, J 17 Hz,); 1H at 3.75 (D, J 17 Hz, CH); ZN at 3.00 (M, Ca (CH3).); 6H at 1.50 (2C, Hz) 2C); ZN at 1.20 (D, J = 7 Hz, CHgNHi. Hz,); W at 4.06 ( j Hz, N at 3.75 (D, J 17 Hz,); 2H at 2.79 (M, CH-NHj); 2H at 2.42 (M, CH, CO, UN); 2H at 1.84 (M, vCHgCH NHj); tu „r. I l G9G SGN H r about Ar); 2H at 1, 04 .p, np2 6H at 1, 48 (2C, (Sise) 2C). 117 - (b): W at 10.30 (C, Y, Ar NH NH CO); 1H at 8.75 (D, J 9 Hz, CO); 2H at 7.04 (D, J 8 Hz, 50 at 7.47 (T, J = 8 Hz, B .Ar-5); I at 7.00 (C, H thiazole); 1H at 6, (D-D, J 9 Hz, J 4 Hz, N,); 1H pr 5.45 (D, J 13 Hz,); 1H at 4.98 (D, J 4 Hz, HS); IH at 4.82 (D, J 13 Hz, SNgOCO); 1H at 4.05 (D, J 17 Hz,); 1H at 3.75 (D, J 17 Hz, CH); ZN at 3.00 (M, Ca (CH3).); 6H at 1.50 (2C, Hz) 2C); ZN at 1.20 (D, J = 7 Hz, CHgNHi. (CH / 2 i / SN SNGS si 55 121 (b): 1H at 10.0 (C U, ArNH CO); 1H at 8.85 (D, 4 9 Hz, CONH); ZN at 8.05 (C Y,); W at 7.45 (C, H Ar-.b); W at 7.30 (C, /, -.one. ., v, v, H Ar-4); 1H at 7.00 (s, H thiazole); .U Y, N at 9 (- I ti-Tn at 6.00 (D-D, J 9 Hz, J 4 Hz, azole); 1H at 6.00 (D-D, J 9 Hz, H ,. ); W - at 5.43 (D, J 13 Hz, NHCO); 2H with y H Ar-2, 6); 2 n at 7.72 (D, J 8 Hz, B / g-3, 5); ZN at 7.60 / f t HCH1 thai. 1 U ". O7 fr (C y 282817 60 ai J 4 Hz, N); lH - at 5.40 (D, J 13 Hz, CUgOCO); 1H at 4.90 (D, J 4 Hz, Hg); IH at 4.78 (D, J 13 Hz, CH, CCA); W at 4.05 (D ,. J 17 Hz, CH); 1H at 3.75 (D, J 17 Hz,); 2H at 2.75 (M, CHjNHj); 2H at 2.36 (M, Ar); 4H at 1.58 (M, COCH-g (Clij) jiCH NHj); 6H at 1, 45 (2C, () 2 C). 118 (b): 1H at 12.7 (C Y, NH CO thiazole); 1H at 8.65 (D, J CONH); ZN at 8.20 (C Y,) ,; 1H at 6.93 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, N); 5 1H at 5.45 (D, J 13 Hz,); 1H at 5.02 (D, J 4 Hz, He); 1H at 4.75 (D, J 13 Hz,); W at 4.02 (D, J 17 Hz,, 80); 20 25 lit -t, / j, o W at 4.02 (D, 2H at 3.90 (M, 1 p -1 -li ;; i 3.70 (D, J 1.7 Hz,); . SN, thiazole: 6H at 1.45 h, (, d, J I / I c, 2H at 3.90 (M,); 1H at .D, J 1.7 Hz,); ZN at 2.50 (C, CHj thiazole) С2С, (СНз) 2С). 19 (b): 1H at 8.45 (D, 9 Hz,); ZN at 7.80 (C Y, CH-NH.); -. D Qf / T and n ,, - lU N .. CONH); ZN at 7.80 (C Y, CH-NH.); 1H at 6.80 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, I,); H at 5.10 (D, J 13 Hz,); 1H at 4.95 (D, J 4 Hz, Hg); Sh / g C f ht t. t 4 t t 1 "t Jn 1, AND- VM, J - - i × iis at 4.58 (D, J 13 Hz,) at 3.90 (D, J 17 Hz,); at 3.56 (D, J 17 Hz,); Poi 3.00S2M. CHNH,: 1N Poi 2. 1H 1H 1H .d, J N 1C, PD; I, J 13 Hz,); J 17 Hz, CH, jSO); at 3.56 (D, J 17 Hz,); 1 at 3.00 (2M, CHNHj); 1H at 2.25 CM, CH CO); 4H at 1.80 and 4H at 1.40 (M, cyclohexane CH); 6H at 1.44 C2C, (SBz) 2C). . 35 i / and {, о ;: ш when ь, / 5 (d, J UHz, CONH); 2H. at 7.80 (C Y, N Ar-2,. 120 (b): 1n at 8.75 (D 6); ZN at 7.65 (C Y, CH, NL3); Sh at 7.57 (D, J. 8 Hz, B Ar-4); Ih at 7.57 (D, J. 8 Hz, V AG-. ,, - 8 Hz, V. Ag-5); Sh 00 l.l.t.f h. I - Xf -S J W - ..- / at 7.47 (T, J = 8 Hz, B .Ar-5); I at 7.00 (C, H thiazole); 1H at 6, (D-D, J 9 Hz, J 4 Hz, N,); 1H pr 5.45 (D, J 13 Hz,); 1H at 4.98 (D, J 4 Hz, HS); IH at 4.82 (D, J 13 Hz, SNgOCO); 1H at 4.05 (D, J 17 Hz,); 1H at 3.75 (D, J 17 Hz, CH); ZN at 3.00 (M, Ca (CH3).); 6H at 1.50 (2C, Hz) 2C); ZN at 1.20 (D, J = 7 Hz, CHgNHi. (CH / 2 i / SN SNGS si 55 61 1.282817 ); IH at 5.00 (D, J 4 Hz, Hg); W at 4.78 (D, J 13 Hz,); 1H at 4.05. (D, J 17 Hz,); 2H at 3.80 (M, CH2.-Gly); 1H at 3.75 (D, J 17 Hz, C0r80); 6H at 2.25 (2C, CHjAr); 6H at 1.50 (2C, (CHj) 2 C). 122 (6): 1H at 10.45 (C Y, A, NH CO); 1H at 8.70 (D, J 9 Hz,. "CONH); W at 8.50 (C Y, UH, piperidine); 1H at 8.20 (C Y, NH2, piperidine); 2H at 7.84 (D, J 8 Hz, N Ar-2,6); 2H at 7.70 (D, J 8 Hz, N Ar-3, 5); 1H at 6.88, 5 (C, H thiazole); W at 6.00 (D-D, J g 9 Hz, J 4 Hz, C); 1H at 5.42 (D, J 13 Hz, CH20CO); 1H at 4.98 (D, J 4 Hz, Hg); 1H at 4.78 (D, J 13 Hz,); 1H at 20 4.05 (D, J 17 Hz, CH jSO); W at 3.75 (D, J 17 Hz, CH2.SO) at 3.30 (M, CHj in the 1 1-position NH pipet-mptlia 7H ghpm H PE M M G. 62 13 Hz, CH2.0CO); 1H at 5.00 (D, J 4 Hz, Hg); 1H at 4.80 (D, J 13 Hz,); 2H at 4.00 (M, H in the "position of Ala and CH2SO); 1H at 3.75 (D, J 17 Hz, CHgSO); 6H at 1.50 (2C, (CH3) 2C); ZN at 1.42 (D, J 7 Hz,). (D, 7, at , ,, J- TA, i / Jt and L 5.45 (D, J 13 Hz, in demand); 1H at 5.00 (D, J 4 Hz, Hg); 1H at 4.80 (D, J 13 Hz, CHjOCO); 2H at 4.00 (M, NLALA and); 1H at 3.75 (D, 17 Hz, CH-, SO); 4H at 2.40 (M,% sn, -,. ); 3 on / M giiSC, 2H at 1.80 (M, 3.30 cm, CHj in the o1-position NHj is pip-. -i i. readin); 2H at 3.30 (M, CHj b1-PN at 4.43 (D, J 7 Hz, CHjAna). NHj position of piperidine); 2H at 25,126 (b): 1H at 8.45 DD, J 9 Hz, 2.90 M, CHj in about (-position U, pi-CONy); ZN at 8.00 (SU, NN Ala); Peridine ZN); W at 2.66 (M, SAT CONH); at 7.80 (SU, thiazole); 1H at 411 at 1.80 (M, CHj. In.-Position 6.80 (C, H thiazole); W at 6.00 WHj piperazine; 6H at 1.45 (2C, CCH) 2C) .30 123 (b): W at 10.25 (C U, Ar N N CO); W at 8.70 (P, 9 Hz, CONH); 1H at 8.50 (C Y, tfflj of pip-. Hydride); 1H at 8.25 (C Y, U of piperidine); 1H at 8.19 (with Y, H Ar-2i. „: 1H at 7.86 (D, J 8 Hz, .n Ar-6); W at 7.60 (D, J 8 Hz, Ar-4 ); W at 7.42 (T, J 8 Hz, C Ar-5); W at 6.95 (C, H thiazole); W at 6.00 (D-D, J 9 Hz, J 4 Hz, N); 40 W at 5.45 (D, J 13 Hz,); W at 5.00 (D, J 4 Hz, Hg); 1H at 4.81 (D, J 13 Hz,); 1H at 4.05 (d, J 1 Hz,); 1H at 3.71 (D, J 17 Hz,); 2Н 45 at 3.30 (С, СН in d-position to Шг of piperidine) at 2.90 (М, CHj in «- (Position to NHj of piperidine); 1Н at 2.66 (М, СН CONH); 4Н at 1.80, (M, CHg in the p-position to the NHj of piperindridine); 6H at 1.45 (2C, (). 124 (b): 1H at 10.75 (C U, ArNH CO); 1H at 8.80 (D, J 9 Hz,, CONH); ZN at 8.20 (C Y, CH%); 2H at 7.92 (D, J 8 Hz, N Ar-2, 6); 2H at 7.70 (D, J 8 Hz, N Ar-3, 5); 1H at 7.00 (C, H thiazole); 1H at 6.00 (D-D, J 5 Hz, J 4 Hz, N-,); 1H at 5.45 (D, J with 1,: (, (, (.nz; 2 - -J with J (2D, CHjCH. 127 (b): 1H at 8.43 (D, J 9 Hz, secondary school); 6H at 7.50 (SU, N H); W at 6.80 (C, H thiazole); 1H at 6.00 (DD, -J 9 Hz, J 4 Hz, Nt); 1H at 5.16 (2D, J 13 Hz,); W at 4.95 (D, J 4 Hz, Nb) H at 4.58 (D, J 13 Hz, SSCHOSO); 1H at 4.20 (M, H equiv. Of piperidine); 1H at 3.90 (D, J 17 Hz, CHgSO) W at 3.64 (M, Hg eq. Piperidine); 1H at 3; 57 (D, J 17 Hz, CH); W at 3.07 (M, N. pipervdina); 2H at 2.96 (M,); 1H at 2.75 (M, Hg piperidine); 3N at 3.65 (M CHCOg and CH; jCON); 2H at 1.80 and 2H at 1.50 (H, and H5-,. Yiperidine); 6H at 1.45 (2C, (CH3) 2C). 128 (b): W at 8.45 (D, J 9 Hz, CONH); 6H at 7.70 (SU,); | H at 6.80 (C, H thiazole); 1H at 5.98 (D-D, J 9 Hz, J 4 Hz, 1.282817 62 13 Hz, CH2.0CO); 1H at 5.00 (D, J 4 Hz, Hg); 1H at 4.80 (D, J 13 Hz,); 2H at 4.00 (M, H in the "position of Ala and CH2SO); 1H at 3.75 (D, J 17 Hz, CHgSO); 6H at 1.50 (2C, (CH3) 2C); ZN at 1.42 (D, J 7 Hz,). (D, 7, at , ,, J- TA, i / Jt and L 5.45 (D, J 13 Hz, in demand); 1H at 5.00 (D, J 4 Hz, Hg); 1H at 4.80 (D, J 13 Hz, CHjOCO); 2H at 4.00 (M, NLALA and); 1H at 3.75 (D, 17 Hz, CH-, SO); 4H at 2.40 (M,% sn, -,. ); SC, 2H at 1.80 (M, -i i. with 1,: (, (, (.nz; 2 - -J with J (2D, CHjCH. 127 (b): 1H at 8.43 (D, J 9 Hz secondary school); 6H at 7.50 (SU, N H); W at 6.80 (C, H thiazole); 1H at 6.00 (DD, -J 9 Hz, J 4 Hz, Nt); 1H at 5.16 (2D, J 13 Hz,); W at 4.95 (D, J 4 Hz, Nb) H at 4.58 (D, J 13 Hz, SSCHOSO); 1H at 4.20 (M, H equiv. Of piperidine); 1H at 3.90 (D, J 17 Hz, CHgSO) W at 3.64 (M, Hg eq. Piperidine); 1H at 3; 57 (D, J 17 Hz, CH); W at 3.07 (M, N. pipervdina); 2H at 2.96 (M,); 1H at 2.75 (M, Hg piperidine); 3N at 3.65 (M CHCOg and CH; jCON); 2H at 1.80 and 2H at 1.50 (H, and H5-,. Yiperidine); 6H at 1.45 (2C, (CH3) 2C). 128 (b): W at 8.45 (D, J 9 Hz CONH); 6H at 7.70 (SU,); | H at 6.80 (C, H thiazole); 1H at 5.98 (D-D, J 9 Hz, J 4 Hz, 12828 Uj HT); IH at 5.20 (2D, J 13 Hz,); IH at 4.96 (D, J 4 Hz, g); IH at 4.58 (D, J 13 Hz,); IH at 4.18 (Hj equiv. Of piperidine); W at 3.90 (D, J 17, Hz, 5) -; IH at 3.75 (M, Hg equiv. Of piperidine); 1H at 3.55 (D, J 17 Hz, CHj.SO), 1H at 3.00 (M, Hj ax. Piperidine); 4H at 2.65 (M, CHjNHj, Hg aks. And H piperidine); 2H at 2.40 (T, CHjCON); 4H at 1.70 (M, SI sschsnd NNZ, Hj and U; piperidine); 2H at 1.50 (M, Hj and Hfj of piperidine; 2H at 1.50 (M, Ultrasound and Hj of piperidine); 6H at 1.44 (2C, (CUy, C). 129 (b): 1H at 8.50 (SU, pyrididini); 1H at 8.45 (D, 9 Hz, Secondary School); 1H at 8.25 (SU, piperidini); ZN at 7.40 (SU, N N thiazole); W at 6.80 (C, C thiazole); W at 6.00 (D-D, J 9 Hz, J 4 Hz, N,); 1H at 5.16 (D, J 13 Hz,); IH at 4.15 (M, Hj equiv. Pi peridine); 2H at 3.90 (M, Hg equiv. Of piperidine and CH; O); W at 3.55 (D, J 17 Hz, CHjSG); 2H at 3.25 (M, j equiv. And H equiv. Piperidini); W at 3.15 (M, Hj ax. Piperidine); ZN at 2.85 (M, Hg aks. Piperidine and H 30 aks. And Tsv aks. Piperidini); 2H at 20 pi-eq. 25 J 9 Hz, J 4 Hz, H-,); W when. 5.42 (D, J 13 Hz,); 1H at 5.00 (D, J 4 Hz, He); 1H at 4.80 (D, J 13 Hz, CHjOCO); ZN at 4.00 (M, CHjN From and CHjSO); W at 3.75 (D. J 17 Hz, SI, SO); ZN at 2.45 (C, CH Ar); 6H at 1.45 (2C, (CH, C 131 (b): W at 8.85 (D, J 9 Hz, SOSH); ZN at 8.20 (SU,); W at 7.80 (D, J 8 Hz, B Ar-6); 2H at 7.45 (M, H Ar-3, 5); W at 6.95 (C, H thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, H,); 1H at 5.45 (D, J 13 Hz, CHjOCO); W at 5.00 (D, J 4 Hz, Hg); H at .4,80 (D, J 13 Hz,); ZN at 4.00 (M, CHjNHj and CHjSO); W at 3.73 (D, J 17 Hz, CHgSO); ZN at 2.50 (C, CHgAr); 4H at 2.40 ( M, 1282817 64 5 q; ; -); c, and, H 30 20 and- 25 00 45, 50 55 ABOUT ), 9 Hz CD CH, - | 0); 2H at 1.80 (C, d1-drii Wj, 132 (b): 1H at 8.80 (D, J 9 Hz, CONH); 3N at 8.10 (SU, SNg. C); W at 7, 55 (C, B Ar); 1H at 7.45 (C, H Ar); 1H at 7.00 (C, H thiazole); 7n at 6.00 (D-D, J 9 Hz, J 4 Hz, H,); 1H at 5.40 (D, J 13 Hz, CH, CCA); 1H at 5.00 (D, J 4 Hz, Hg); W at 4.83 (D, J 13 Hz, CHgOCO) ; ZN at 3.70 (M, and CHgSO); 1H at 3.70 (D, J 17 Hz, n G1G. OiT -, O L / L / g A “L. HE CHgSO); 1H with,., -. -, CH2SO); ZN at 2.40 (C, SNzAg); ZN at 2.34 (C); 6H at 1.45 (2C (CUjJ C). 133 (b): 1H at 12.5 (SU, AgSChSO); phi 8.78 (D, J 9 - 8.30 (SU, CH (CH3) 133 (b): 1H at 12.5 (SU, AgSChSO III at 8.78 (D, J 9 Hz, Sonn); ZN at 8.30 (SU, CH (CH3) N®Hj), W at 8, 20 (C, H thiazole in position 3); W at 7.00 (C, H thiazole); W at 6.00 (D-D, J 9 Hz, J 4 Hz, H); H at 5.42 ( 2D, J 13 Hz,); W at 5.00 (D, J 4 Hz, Not); W at 4.90 (D, J 13 Hz,); W at 4.15 (M, CHCHj - NTIj); W at 4.00 (D, J 17 Hz,); W at : 3.76 (D, J 17 Hz, CH); 6H at 1.44 (2C, (); 3N at 1.40 (D, J 7 Hz,). 134 (b): W at 8.85 (D, J 9, Hz, CONH); 1H at 8.50 (C, B thiazole at position 3); ZN at 7.90 (SU, CHj); W at 7.00 (C, C thiazole); 1H at 6.00 (D-D, J 9 Hz, J 4 Hz, OI; 1H at 5.42 (D, J J 4 Hz, And,); 1H at 5.42 (D, „13 Hz, CH, CCA); 1H at 4.99 (D, J 4 Hz, Not); W at 4.84 (D, J 13 Hz, CHjOCO); 1H at 4.00 (D, J 17 Hz, CHgSO); W at 3.75 (D, CH, h a tJ t.n yIilA r y B / V / G E 17 Hz, CHgSO); W at 3.75 (D, 17 Hz, CH); 4H at 3.20 (M, ijCas-N Hz); 6H AT 1.45 (2C, (CBj) j, C). 135 (b): W at 8.80 (D, J 9 Hz, SOC); W at 8.57 (C, H thiaeol in position 3); ZN at 8.50 (cy, H: 1H at 7.00 (C, H thiazole); 1H at / 6.00 (D-D, J - 9 Hz, J 4 Hz, nr; W at 5.40 (D, J 13 Hz, CHjOCO); W at 5.00 (D, J 4 Hz, Bg); W at 4.90 (D, J 13 Hz, CHgOCO); 2H at 4.45 (M,); W at 4.00 (D, J 17 Hz,); 1H at 3.7: 2 (D, J “17 Hz,); 6H at 1.45 (2C, (CH3), C). 136 (b): 1H at 8.90 (D, J 9 Hz ,: SOC); W at 6.60 (C, H thiazole in position 3); 1H at 8.50 (SU, CH, and Cs); 1H at 6.98 (C, H thiazo-, 65 12828 la); IH at 6.00 (D-D, J 9 Hz, J i 4 Hz, N,); W at 5.42 (D, J 13 Hz, CH2.0SO); W-5.00 (D, J 4 Hz,); 1H at 4.84 (D, J 13 Hz, SNaOCO); 2H at 4.45 (M,); 1H at 4.00 (D, J 17 Hz, ClJgSO); W at 3.72 (D, J, 17 Hz, SCSS); 4H at 2.40 (M, CHz4-CO); rt --- ®dH 2H at 1.86 (M, g CHj fO -00). 137 (b): W at 8.90 (T, J 8 Hz; IHCHj); W at 8.75 (D, J 9 Hz, U); ZN at 8.00 (SU, Hj); 2H, 41971 66 at 7.88 (D, .J 2H at 7.40 (D, Sh at 6.96 (C, 6.00 (D-D, J Sh at 5.44 (D, 1H at 4.98 SD, 4 , 80 (D, J 13 4.40 (D, J 8: 4.06 and 1H with 3 CH, SO); 2H with 2H with 1,, 47 (2C 8 Hz, H Ar-2,6); J 8 Hz, N Ar-3, 5); H thiazole); 1H at 9 Hz, J 4 Hz, C,); J 13 Hz, CigOSO); J 4 Hz, Not); W at I Hz, CHjOCO); 2H with Hz, ArgSdMN); .1H at (, 70 (D, J 17 Hz, 3.57 (M, OCCHjN H,);:, (CH3) gS). Working as in Example 2 or 3, compounds according to the invention are obtained in the form of trifluoroacetates described in Table. 2 table 2 Continued table. 2 g N o I I J-C-C- 1H l 0 -rrfS Y CH2SC- (CH2) FA 0- {jI-COOH COOH HI These compounds are identified by a standard number. Chromatography eluent is indicated which serves to isolate the compound (IV), which is the last intermediate product before deblocking the acid and amine functions of the molecule. This intermediate product (IV) is characterized by an IR spectrum, and the wavelengths correspond to the mixing order of the vibrational frequencies of carbonyl at position 8, β-lactam, tert-butyl esters, and thiofiber in position 3, amide in position 7, and protective amine carbamate. When only two wavelengths are indicated, the second corresponds to a broadened band, which gives the shift of the vibrational frequencies of both the ester, amide and carbamate protection of the amine and the thioether. „ For some products, the frequency of the thioester has the same wavelength as the tert-butyl ester. This is indicated in the table. designation + COS from the corresponding vibrational frequency. The NMR spectra are listed in table. 2 connections registered at 60 MHz (a), or at 250 MHz (b); when there are two diastereoisomers in the molecule, the split signals are labeled V NMR spectrum, MD: 1 (a): 8H at 6-9 (broad signal, CHg, trifluoroacetate, COjjH); 1H at 8.40 (D, J = 9 Hz, SOIN) G fH at 6.86 (C, H thiazole); W at 6.00 (dd, J 9 Hz, J 4 Hz. a); Jh at 4.97 (D, J 4 Hz, He); 1H at 4.20 (AB, J 13 Hz, CHaSCO); ZN at 3.70 (M, CHjSCO and CHjSO); 4H at 2.75 (M, and CHjCOS); 2H at 1.77 (M, CHjCH-CH); 6H at 1.45 (C, (s) 2 C). 2 (a): HV at 6.5–9 (broad signal,, trifluoroacetate, III); W at 8.40 (D, J 9 Hz, SOad); Sh at 6.88 (C, and thiazole); 1H at 6.0 (D-D, J 9 Hz, J 4 Hz, N); 1H at 5.0 (D, J 4 Hz, Hg); W at 4.20 (A of AB, -J 13 Hz, SNGVSO); ZN at 3.80 (M, CHj O and); 4H I at 8.40 (D, J 9 Hz, CONa); 1H and 6.87 (C, H thiazole); 1H at 6.0 Y – D J 9 Hz, J 4 Hz, N); 1H at 5.0 (D, J 4 Hz, Hg); 1H at 4.20 (A of AB, J 13 Hz,); ZN -G-PTH 3 7 f / TLfr tl. /.It at (D 4 (a): 7H at 6.5-9.5 (broad signal, NH, III,, trifluoroacetate); 1H at 8.40 (D, J 9 Hz, CONH); W at 6.90 (C, H thiazole); W at 6.0 (D-D, J 9 Hz, J 4 Hz, Not); W at 5.0 (D, J .4 Hz, N); W at 4,20 (And from AB, J 13 Hz, SNgZSO); ZN at 3.70 (M, CH2.SCO and); - 5H at 3.0 (M, CHzN and CHCOS); 4H at 1.90 (M, SyngSng); 6H at 1.45 (C, (CH3) gC). 5 (b): 5H at 7-9 (broad signal, Shg, trifluoroacetate, U); 1H at 8.34 (2D, J 9 Hz, CONH); 1H at 6.8 (C, H thiazole); 1H at 5.97 (D-D, J 9 Hz, J .- 4 Hz, I); 1H at (p. t A Gtg N L 1N rrnw L Hz, J .- 4 Hz, I); 1H at 4.95 (D, J 4 Hz, Well); W at 4.16 (2D, J 13 Hz, CH, jSCO); 1H at 3, (D, J 13 Hz, CHj.SCO); 2H at 3.66 (C, .CH2.SO); 1H at 3.4, 1H at 3.16 , w otr, -, o PS / - “tr m. 1 rt o o jn with /, oi, P O, OE (C, C thiazole); 1H at 6.00 (D-D, J. 9 Hz, J A Hz, e) 5 W at 5.00 (D, J 4 Hz, HS): W at 4.15 (A from AB, J 13 Hz , CHjSCO); 1H at 3.80 (B of AB, J 13 Hz, CHaSCO); 2H at 3.70 (SU, CJi2, SO); 7H with 128281776 (M, СЫ, NH, СНгЖ,); 2I with (M, SP., NH and CU COS); 2H at 1.95 and , 30 (M, CH2CH5CH2NH); 6H at 1.452H at 1.65 (M, CHjCH NH), 19 9I-I ppm and AP I M (J M, SI, NH, UHzNIl, f-iil lJUbj; / and 1.30 (M, CHjCHjCHjNH); 6H at (2C, (CH) 2C). 7 (a): 8.35 (D, J 9 Hz, CONU); HH at 6.5-10 (COj.H, NH2, trifluoroace-5 tat); W at 6.82 (C, H thiazole); ) N at 6.00 (D-D, J 9 Hz, J 4 Hz, at 2.60 (M,); 1H at 2.45 (M, CHCOS); 4H at 1.84 (M, CHjCHCOS) 6H at 1.44 (2C, (CH3) 2C); 2H at 1.40 and 2H at 1.0 (M,). 9 (b): W at 8.36 (D, J 9 Hz, NHCO); ZN at 8.30 (SU, U); 2H at. 7.94 (D, J 8 Hz, H ortho CO); 2H at 7.55 (D, J 8fHz, p meta CO); y 2.40 (M, 3N at 7.40 (SU, NMj); 1H at 6.76 (C, H thiazole); 1H at 5.95 (D-D, J 9 Hz, J 4 Hz, N); 1H at 4.95 (D, J 4 Hz, Not); 1H at 4.40 (D,. J 13 Hz, SN SW); 2H at 4.10 (M, CH, NH,); 1H at 3.90 (D, J 13 Hz, 1 (6) 1H at 8.65 (D, J 9 Hz.); 2H at 3.74 (C, CH, SO); 6H SOCh); ZN at 8.20 Hz (SU, NH); 2N YY. 1 lo / ol. f. at 7.92 (D, J 8 Hz, H ortho CO); 2H at 7.56 (D, J 8 Hz, N meta CO); ZN at 7.30 (SU. W,); W at 6.82 ); 6H at (M, SI-4-SO. H and sco .. I CH, SNG CH, SCO); 2H at 3.7 hours at 1.42 (2C, (CH3) 2C). - when 10 (a): W at 8.30 (D.J. 9 Hz, 2H at 7.56 (D, J 8 Hz, N meta C SOSH); 8H at 6.5-9 (SU, N,);. d ZN at 7.30 (SU, NHj); W at 6.82 1H at 6.80 (C, H thiazole); W at (C, H thiazole); 1H at 5.88 (DD, 5.95 (M, I); 1H at 4.90 (D, J J 9 Hz, J 4 Hz, N); HI at 4, 4 Hz, Hg); W at 4.25 (A from AB, (D J 4 Hz, Hv); 2H at 4.55 (C, J 13 Hz, SNGHO); 1H at 3.90 (); W at 4.37 (D, J 13 Hz, MO DP L 1 Hz. GN-.CHG.OCH: 92 4 Hz, Hg); W at 4.25 (A from AB, (.D, J 1c, N p J 13 Hz, SNHXO); 1H at 3.90 (V.); W at 4.37 (D, from AB, J 13 Hz , CH2.5CO); 2H with |,); 2H at 4.13 (M, 3.65 (SU, CHjSO); iOH at 1-2.3 (M, 1H at 4.42 (D, J 13 QQ2H at 3.74 (C, CHjSO). (.C.L f, H ppi 1.43 (C. (). - / J at 4.37 (D, 4.13 (M,); t 13 Hz7 CHjjSCO); CH ,,); 6H at 1.43 (C, (CH3) gS) - N P2 ); 6H at H and sco .. 2 92 c, hb); 2H at 4.55 (C, at 4.37 (D, J 13 Hz, c, N p at 4.37 (D, at 4,13 (M, (D, J 13 (C, CHjSO). - / J at 4.37 (D, 4.13 (M,); t 13 Hz7 CHjjSCO); 28281 / /12 CHjSCO); 2H at 3.75 (C, OCGZO); ZN at 1.45 (D, J 7 Hz,). 16 (b): 1H at 8.61 (JL, J 9 Hz, CONH); 5H at 8.40 (SU, W, SOGN); 2H at 7.95 (D, J 8 Hz, Y ort.o WITH); 5 2H at 7.61 (D, J 8 Hz, N meta CO); ZN at 7.30 (SU, Shz); 1H at 6.76 (, C, H thiazole); 1H at 5.92 (, R-R, J 9 Hz, J 4 Hz, H); 1H at 4.93 D, J 4 Hz, Hg); 1H at 4.42 (D, O J 13 Hz, CH2.SCO); 2H at 4.10 (SU, CHjNHg); 1H at 3.92 (D, J 13 Hz, CH2.SCO); 2H at 3.74 (C,); 4H 15 at 2.35 (M, CH - —C02H); 2H at CHg 1.85 (M, CH4 | XO, HB 17 (b): W at 8.62 (D, J 9 Hz, CONH); ZN at 8.20 (SU,); W at 8.00 (SU, H Ar-2); 1H at 7.90 (D, J 8 Hz, N Ar-6); W at 7,72 (D, J 8 Hz, N Ar-4); W at 7.55 (T, J 8 Hz, N Ar-5); 1H at 6.93 5 (C, H thiazole); 1H at 5.95 (D-D, J 9 Hz, J 4 Hz, N); W at 4.93 (D, J 4 Hz, Hg); 1H at 4.43 (D, J 13 Hz); 2H at 4.10 (K, J 7 Hz,); 1H at 3.94 (D,, J 13 Hz, CHjCO); 2H at 3.75 (SU, CHjSC); 6H at 1.45 (2C, (CH3) 2C). 18 (b): W at 8.80 (D, J 9 Hz, SOC); ZN at 8.20 (SU,); 1H at 8.00 (SU, And Ar-2); W at 7.80 (D, J 8 Hz, N Ar-6); W at 7,72 (D, J 8 Hz, And Ar-4); 1H at 7.55 (T, J 8 Hz, H Ar-5); W at 6.92 (C, And thiazole); 1H 5.94 (DD, J WITH ABOUT ); 2H at 1.9 (.1, J "Hz, H Ar-: h ;; 1H with b, Y (C, H thiazole); W with 5.95 (D-D, J 9 Hz, J 4 Hz, Yy); 1H with 4.9 (D, L 4 Hz, Hg); HI at 4.39 (D, J 13 Hz,); 2H at 4.07 (M, Ar CHJ N); 1 N at 3.90 (D, J 13 Hz,); 2H at 3.78 (C,); ZN at 2.26 (C,); 6H at 1.45 (2C, (Caz) 2C) P tTT P P f t, J 8 Hz, H AG-5 ;; H with b, Y / -Ag-4, 6); W when (C and thiazole); 1H 5 94 (D-D, J (T, J 8 Hz, N Ar-5 -); W etc. 9 Hz, J 4 4 Hz, H,); 1H at 4.96. „,; os about ich itrs g with (H,); W @ 4,4 (D J 13 Hz, B thiazole); W at 5.95 CH SCO; 2N CR 4.10 (K, J 7 Hz, (D D Hz, B,); W ); n at 3.94 (D, J 13 Hz ,. P 5; °° D HZ ib); w when 2.3f „-)„ „„, Д .40 (п. Л. 1 Гтт. ПН ЯГ.П 7Н ттг, г Vtjg / y -.-. fff, -. . y . ,,, - ij - ", ); 2H at 4.10 (K, J 7 Hz, Sa2. №1z); 1H at 3.94 (D, J 13 Hz,); 2H at 3.77 (SU, CHjSO); 4H at 2.40 (M, 1.90 (M, Lf | -sn 0); 2H at gth with 0)., 45 at 5, IO (D, J 4 Hz, Hg); 1H at 4.40 (D, J,); 2H at 4.05 (M, A, CHjNH); Tn at 3.90 (D, J 13 Hz,); 2H at 3.79 (C,); AN at 2.40 (M, About UHL - I-CO); ZN at 2.25 (C ,. sn 19 (b): 2H at 8.80 (SU,); W at 8.60 (D, J 9 Hz, Secondary School); 2H at 7.95 (D, J 8 Hz, N Ar-2, 6); 2H at 7.60 (D, J 8 Hz, Ar-3, 5); 1H at 6.94 (C, H thiazole); 1H at 5.95 (D-D, J, J 4 Hz, N); 1H at 4.95 (D, J 4 Hz, N); Pu 4.95 (D, J 4 Hz, H (j); W 4.42 (D, J 23 Hz,); 2H 4.16 (T, J 7 Hz, CH j lfflj CH,); with, -g- x „, at 4.16 (T, 2 WITH ABOUT ); 2H at 1.90 (.1, J "Hz, H Ar-: h ;; 1H with b, Y (C, H thiazole); W with 5.95 (D-D, J 9 Hz, J 4 Hz, Yy); 1H with 4.96 (D, L 4 Hz, Hg); HI at 4.39 (D, J 13 Hz,); 2H at 4.07 (M, Ar CHJ N); 1 N at 3.90 (D, J 13 Hz,); 2H at 3.78 (C,); ZN at 2.26 (C,); 6H at 1.45 (2C, (Caz) 2C) P tTT P P f In thiazole); W at 5.95 (D D Hz, B,); Sh R 5; °° D HZ yb); w when D .40 (p. L. 1 Гтт. ПН ЯГ.П 7Н ттг, г at 5, IO (D, J 4 Hz, Hg); 1H at 4.40 (D, J,); 2H at 4.05 (M, A, CHjNH); Tn at 3.90 (D, J 13 Hz,); 2H at 3.79 (C,); AN at 2.40 (M, About UHL - I-CO); ZN at 2.25 (C ,. sn SS); 2H at 1.90 (M, oi 23 (b): W at 8.64 (D, l 9 Hz, CONH); ZN at 8.14 (SU, CHNHj); 1H at 7.95 (C, H Ar-2); 1H at 7.60 (D, J 8 Hz, N Ar-6 "); 1H at 7.39 D, J 8 Hz, N Ar-5); 1H at 6.95 (C, L of thiazole); 1H at 5.95 (D-D, J 9 Hz, J 4 Hz, U); 1H at 4.96 79 1282817 80 Ih / Uu (D, J 4 Hz, Hg); IH at 4.37 (D, (D, J 8 Hz, and Ar-2, 6); 2I with J f13 Hz, CHjSCO); 2H at 4.08 (M, 7.7 A (D, J 8 Hz, H Ar-3, 5); 1H); 1H at 3.94 (D, J 13 Hz, at 6.96 (C, H thiazole); 1H at 5, CH, SCO) ,; 2H at 3.74 (SU,); ZN - - / - - at 2.37 (C, ArCHj); 6H at 1.45 (2C, .5 (). 24 (b): 1H at 8.80 (2D, J 9 Hz, CONH); ZN at 8.20 (SU,); 1H, “,,„. about. h, j at 7.39 ° with 6.95 , 94 (JD 95 uUiSH ;; JH with at, / and (, and, uhj , 94 (C, H Ar-2); 1H i (D, J 8 Hz, N Ar-B1); Sh (D, J 8 Hz, N Ar-5); 1H at o, 5-. (2C, H thiazole; 1H at 5.94 (D-D, J 9 Hz, J 4 Hz, H); W at 4.95 (2D, J 4 Hz, Hj); W at 4.70 (M, (d, j about y, l lg-j, j-; i m with CHgCBON); W at 4.37 (2D, Jg 13 Hz, 6.95- (C, H giazola); W at 5.94 CHjSCO); 2H at 4.08 (M, SNGS) (D-J. J 9 Hz, J 4 Hz, BT); 1H at 3.94 (D, J 13 Hz,); 2H - / about fn tl g. And l. sh „™ at 3.73 (SU,); ZN at 2.36 H D M, j /, - with j, VM J and 1c, oops ;; p at 4.95 (D, J 4 Hz, Hg); 1H at 3.73 (SU,); ZN at 2.36 4.45 (D, J 13 Hz, CHjSCO); Ш when (С, АССН); ZN at 1.42 (D, J 7 Hz, 3.87 (D, J 13 Hz,); 4H with CHjCHGN). 3.80 (M, CHjSO, and); 4H at 2.40 ph. 1282817 80 / Uu 95 Ih ri 1H 5, H J 4 Hz, Hg); 1H at 13 Hz, CHjSCO); W at 13 Hz,); 4H with jSO and); 4H at 2, ph. ), 2H at 1.90 (M, 2828 groom's I i o marriages x 3 and 5 piperidine); 6H at 1.45 (M, H at positions 3 and 5 of piperidine); 6H at 1.45 (2C, (%) 2C). 32 (b): 1H at 8.66 (D, J 9 Hz, CONH); ZN at 7.90 (SU, CHjNH); ZN 5 at 4, Y.d, J 1-c, w at 4.26 (DU, J 12 Hz, Hj, eq. piperidine); 1H at 4.16 (D, J 13 Hz,); 2H at 3.82 (M, CH Gly); W at 3.74 D, J 13 Hz,); ZN at 3.63 (SU, CH, SO, and Y equiv. Pi peridine); 1H at 3.05 (TU, J 13 Hz, Hj ax. Piperidine); 1H at 2.87 (TU, J 12 Hz, S-CO-CH); 1H at 2.75 (TU, J 12 Hz, H ax. Piperidine); 4H at 2.44 (C, ABOUT -) - WITH); 4H at 1.90 (M,. SNG SNG CE WITH O and N equiv. piperidine); 2H Uh 25 thirty 36 (b): W at 8.70 (D, J 9 Hz SOC); ZN at 8.20 (SU, N); W at 7.75 (D, J 8 Hz, N Ar-6); 2H at 7.43 (M, H Ar-3, 5); 1H at 6.98 (C. U, H thiazole); 1H at 6.00 (Dg-D, J 9 Hz, J 4 Hz, N,); W at 4.97 (D, J 4 Hz, Hg); W at 4.34 (D, J 13 Hz, CHjSCO); 2H at 4.00 (M, CHjN H); 1H at 3.90 (D, J 13 Hz, CHjSCO); 2H at 3.77. (SU SNGZO); W at 2.34 (C,); 6H at 1.46 (2C, (CH C). 37 (b): W at 8.80 (D, J 9 Hz, h oi ™ ,. about 1C / GCH / - GT fcTtr. III V / v at 1.50 (M, H ax. and Hj ax. piperidine). 33 (b): W at 10.70 (C, ArNHCO); 1H at 8.70 (D, J 9 Hz, CONH); W at 8.30 (C, H Ar-2); ZN at 8.1037 Sa Sh 80 P T - Ch Gu . t gp. ssh; Zn p and 8J5 (with y, sh,.,;) Sh f 1 m P «72 (D, J 8 Hz, N Ar-6) 2H - f I w w fof g ,. R “(M, H Ar-3, 5); W when J 8 Hz, N Ar-5); W at 6.95 (C, 35 95 (C, H thiazole); 1H at 5.95 N thiazole); IH at 5.95 (D-D, J. „„ T about Gp J 4 Gp N L 1H ; „; f; . ; G ". - rS. S;) M5ip, J 4 Hz, Hg); IH at 4.45 (D, /. N / / g, -,, -, ,, ,, ,, o, 13 Hz, CHjjSCO); W at 3.90 (D, (D 40 J 13 Hz, CHjjSCO); W at 3.90 (D, J 13 Hz, CHjSCO); 4H at 3.75 (M, and CHj Gly); 6H at 1.45 (2C, (CH3) C). 34 (b): W at 10.65 (SU, ArNHCO); at 8.80 (D, J 9 Hz, MISO); 1H and 8.25 (SU, H Ar-2); ZN at 8.05 / 1 TTT TS / GTT 1H at at 4.93 (D, J 4 Hz, Hg); 1H at 4.34 (D, J 3 Hz, CH2, SCO); 2H at 4.00 (M, CH ,, NH3); 1H at 3.90 (D, J 13 Hz,); 2H at 3.78 (SU,); 2H at 2.34 (C,); 4H O - at 2.30 (M, CHj-f-CO), 2H at CHi 1.80 (M, CO). J 8 Hz, N Ar-4); W at J 8; Hz, H Ar-5); W at 6.95 (C H thiazole); W at 5.95 (D-D, J 9 Hz, J 4 Hz, N-); W at 4.95 n J 4 Hz, Hg); 1H at 4.45 (D, N srp 1n tglm on fn (D -J + l C UQ / f J 13 Hz, CHjSCO); J 13 Hz, CHj, SCO); 4H at 3.75 and); 4H at 2.40 (M, h SS -f --- y - (- 17 W at 3.90 (D, 4H at 3.75 (M, ABOUT ); 2H at 1.90 (M, 282817 i o 82 ABOUT 0 0 five 0 WITH 35 (b): 1H at 8.40 (D, J 9 Hz, CONH); 6H at 7.60 (SU, HHj); 1H at 6.80 (C, H thiazole); 1H at 5.95 (D-D, J 9 Hz, J 4 Hz, N); 1H at 4.95 (D, J 4 Hz, Hg); 1H at 4.30 (C, H2 equiv. Of piperidine); 1H at 4.16 (D, J 13 Hz, CHjSCO); W at 3.75 (D, J 13 Hz, CHgSCO): 2H at 3.60 (C, CHjSO); W at 3.55 (M, H equiv. Piperidine); 4H at 2.90 (M, H2 ax. And Hg ax. Piperidine); ZN at 2.60 (M, CHjCH NHj and Hc-piperidine); 2H at 1.80 and 2H at 1.50 (2M, Nd, and Yy of piperidine); 6H at 1.45 (2C, (CH3 C), 36 (b): W at 8.70 (D, J 9 Hz, SOC); ZN at 8.20 (SU, N); W at 7.75 (D, J 8 Hz, N Ar-6); 2H at 7.43 (M, H Ar-3, 5); 1H at 6.98 (C. U, H thiazole); 1H at 6.00 (Dg-D, J 9 Hz, J 4 Hz, N,); W at 4.97 (D, J 4 Hz, Hg); W at 4.34 (D, J 13 Hz, CHjSCO); 2H at 4.00 (M, CHjN H); 1H at 3.90 (D, J 13 Hz, CHjSCO); 2H at 3.77. (SU, SNGZO); W at 2.34 (C,); 6H at 1.46 (2C, (CH C). 37 (b): W at 8.80 (D, J 9 Hz, h oi ™ ,. about 1C / GCH / - GT fcTtr. III 37 Sa Sh 80 P T - Ch Gu ssh; Zn p and 8J5 (with y, sh,.,;) Sh ". - rS. S;) M5ip, /. n / / g, -,, -, ,, ,,.. about,. 0 0 five at 4.93 (D, J 4 Hz, Hg); 1H at 4.34 (D, J 3 Hz, CH2, SCO); 2H at 4.00 (M, CH ,, NH3); 1H at 3.90 (D, J 13 Hz,); 2H at 3.78 (SU,); 2H at 2.34 (C,); 4H O - at 2.30 (M, CHj-f-CO), 2H at CHi 1.80 (M, CO). 38 (b): 1H at 8.60 (D, J 9 Hz, CONH); 7H at 7.70 (M, H Ar and 1H at 6.98 (C, H thiazole); W at 5.98 (D-D, J -, J 4 Hz, N); W at 4.96 (D , J 4 Hz, Hg); W at 4.38 (D, J 13 Hz,); IH at 3.94 (D, J 13 Hz,); 2H at 3.75 (SU,); 3N at 3, 00 (.М, СН .j); 6Н at 1.47 (2С, (CHj) C), ЗН at 1.19 (Д, J 7 Hz, СЩСН). 83 Table 3 89 1282817 90 Continuation of table 3 91 To assess the stability of these areas, producing and not producing products in relation to the β-lactamase 25 β-β-lactamase. determine their CMI on isogenic strains. The results are presented in Table 4. Table 4 1282817 92 Continued table. According to the results of Table 4, the pre- | Lagged products have an activity equal to or comparable to the strains producing and not producing β-lactamase, which indicates good stability with respect to lactammaz. The therapeutic efficacy of the products was determined on a septicemic mouse model. Sepsis was caused by intraperitoneal inoculation of 0.5 ml of the appropriate suspension solution of Escherichia coli SOL 90 strain. The products were administered as a solution in: phosphate buffer at pH 7.0 in a volume of 0.2 ml subcutaneously in batches of 10 mice 1-5 hours after the inoculum microorganism. After four days of observation, during which death was observed, effective doses of 50% (EC were calculated using the Miench and Reed methods). The results are presented in Table. five. Table5 41730 1.4 0.79 ND - not defined. . , According to the table. 5, the products show good therapeutic activity in vivo. In addition, according to the experiments performed on animals, the toxicity of the products offered is insignificant, which allows their use in therapy. Consequently, the products can be used as antibiotics in human medicine or veterinary medicine. They have a wide range of effects on gram 15 0 five positive bacteria and can be used in all bacterial infections with susceptible microbes. Products can be administered in the usual way (parenterally, orally or topically). Pharmaceutical compositions are prepared from Compounds (I) in soluble form, obtained by salt-converting one of the acidic functions of the molecule or one of the amino acid function of chain B. In addition, the pharmaceutical compositions can be solid or liquid and exist, for example, as injectables. , tablets, gelatinous capsules, granules, ointments, creams, gels or suppositories. The dosage can vary widely, particularly depending on the type and severity of the infection to be treated, and depending on the method of administration. Most often when administered to an adult by injection, the dose is 0.250 to 4 grams per day. As an example of a pharmaceutical composition, solutions for injection of sodium salt SR 41973 are prepared. A saturated solution of sodium bicarbonate is added to a solution of 3 g of SR 41973 dichlorohydrate in 25 ml of water. When the pH reaches 3, the solution is removed. The pH is then adjusted to 3.6 by the addition of a few drops of saturated sodium bicarbonate solution. The solution is cooled to 4 ° C and SR 41973 begins to crystallize. 75 ml of acetone are slowly added dropwise. After stirring for 1/2 hour at 4 ° C, the crystals are filtered and washed 2 times with 20 ml of a mixture of (1 i 1) water and acetone, and then 2 times with 20 ml of acetone. The product is dried in a desiccator over. 5 1.9 g of compound SR 41973 is obtained. 1.25 g of SR 41973 thus obtained are suspended in 15 ml water at 4 ° C. A solution of 0.168 g of sodium bicarbonate in 3 ml of water is added dropwise. The resulting liquid solution is frozen and lyophilized, after sterile filtration, to obtain SR 41973 sodium salt, ready for injection. 0 five 0 0
权利要求:
Claims (1) [1] Invention Formula The method of obtaining derivatives of cephalosporin formula mil about -C-C-NH about s oI CH soon 0-C-COOH one the form of syn-isomers, de R and R2 are independently of each other a hydrogen atom or lower alkyl, preferably methyl, or R and R together with the carbon atom to which they are bound form a diclobutyl / X rj ring; oxygen or sulfur atom; one p O or 1; formula group -Z, -NH-R where Zj is a straight or branched C2-C7 alkylene, which can be interrupted by a sulfur atom and substituted by a hydroxyl, methylthio, amino, acetoamido, carbamoyl, phenyl, oxiphenyl or imidazolyl group, or Zj is cyclopentylidene or cyclohexylidene; R is a hydrogen atom or Cj-C, -alkyl; at or R3 is a group of formula -Z, -Alk-NH-R4 de Zj is 1,3-phenylene or 1,4-phenylene, each of which may be substituted with one halogen atom, or with one or two methoxy groups, or with one, two or three methyl groups, or Zg with 1,2-dick-. logexylene or 1,4-cyclohexylene; Alk - right or branched C-C-alkylene; R i, - is as defined above; or Ri is a group of the formula.-Z -N-CO-1-NH-Re, Rf about s where Zg is 1,3-phenylene or 1,4-phenylene, each of which may be substituted by one halogen atom or one or two methyl groups; Rj- and Rg - independently, from each other, g, a, hydrogen atom or methyl; Y-C-Cc-alkylene or Y together with -NH-R forms 4-piperib Dil; or R is a group of the formula where z or , 1,3-cyclohexylene or 1,4-cyclohexylene RJ - group of the formula R7 V YES, S (NHC) p-AlK-NHr, about - hydrogen or methyl atom; O or 1; has the above meaning R3 2-piperidyl, 3-piperidyl or 4-piperidyl, each of which may be substituted at the nitrogen atom by piperidyl-4-carbonyl or by a group of the formula CO-AIk-NHp where Alk has the indicated values or their trifluoro-acetic acid additive salts, which has a compound of the formula Tr-NH 0 0 I - - С-С-Ъ1Н-т -, - 1 Ri o Nx CHsBr 0-t-COO-t-Bu - - RQ, in the form of syn-isomer, where Tr is trityl; t - Bu - tert-butyl; Rj and Rg are as indicated, 0 C-COO-t-Bu R2 where R, Rj, X, N, R, Tr, and t-Bu have the groups, and the target product is given the above values, is removed free form or, in addition, its addictive groups protect the amino and carboxy-Zn salts trifluoroacetic acid. is subjected to interaction with the sodium or potassium salt of the acid form- ly - ™ where X and p are as defined above; R j is given for R, with the proviso that when free amino groups are present, they are protected, in an inert atmosphere at room temperature, in the resulting compound of the formula
类似技术:
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同族专利:
公开号 | 公开日 MA20126A1|1984-12-31| DK255684A|1984-11-28| PT78635A|1984-06-01| ES532805A0|1985-01-16| NO842091L|1984-11-28| PL247843A1|1985-03-26| FI842042A0|1984-05-22| PH20389A|1986-12-10| CS399784A2|1985-07-16| EP0127543A2|1984-12-05| KR910004302B1|1991-06-25| FI842042A|1984-11-28| IL71933D0|1984-09-30| YU90684A|1986-12-31| DD219773A5|1985-03-13| EP0127543B1|1989-09-13| PL144003B1|1988-04-30| HU191658B|1987-03-30| FR2546520B1|1985-08-30| ZA843995B|1984-12-24| KR840009114A|1984-12-24| GR82042B|1984-12-12| IL71933A|1987-11-30| NZ208275A|1986-11-12| US4656166A|1987-04-07| CA1247596A|1988-12-28| JPS59227886A|1984-12-21| FR2546520A1|1984-11-30| HUT34500A|1985-03-28| ES8502706A1|1985-01-16| EP0127543A3|1985-11-27| AU2858284A|1984-11-29| AU570973B2|1988-03-31| PT78635B|1986-06-18| NO163408B|1990-02-12| CS241546B2|1986-03-13| DE3479733D1|1989-10-19| DK255684D0|1984-05-24| NO163408C|1990-05-23| AT46339T|1989-09-15| OA07777A|1985-08-30|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题 US4338438A|1970-06-16|1982-07-06|Merck & Co., Inc.|Cephalosporin antibiotics| BE768844A|1971-06-22|1971-12-22|Fujisawa Pharmaceutical Co|7--3-cephem-4-carboxylic acid derivs - - antibacterials| GB1425933A|1972-03-13|1976-02-25|Astra Laekemedel Ab|Cephalosporins| OA05033A|1974-07-01|1980-12-31|Rhone Poulenc Ind|New cephalosporin derivatives and their preparation.| FR2342733B1|1976-01-14|1978-11-03|Roussel Uclaf| DE2760123C2|1976-01-23|1986-04-30|Roussel-Uclaf, Paris|7-Aminothiazolyl-syn-oxyiminoacetamidocephalosporanic acids, their preparation and pharmaceutical compositions containing them| GR63088B|1976-04-14|1979-08-09|Takeda Chemical Industries Ltd|Preparation process of novel cephalosporins| DE2716677C2|1977-04-15|1985-10-10|Hoechst Ag, 6230 Frankfurt|Cephem derivatives and processes for their preparation| US4341775A|1978-09-11|1982-07-27|Fujisawa Pharmaceutical Co., Ltd.|Cephem compounds| US4409215A|1979-11-19|1983-10-11|Fujisawa Pharmaceutical Co., Ltd.|7-Acylamino-3-substituted cephalosporanic acid derivatives and processes for the preparation thereof| FR2485540B1|1980-06-30|1984-02-24|Sanofi Sa| DE3177090D1|1980-12-31|1989-09-28|Fujisawa Pharmaceutical Co|7-acylaminocephalosporanic acid derivatives and processes for the preparation thereof| FR2501209B1|1981-03-03|1986-07-04|Sanofi Sa|NOVEL CEPHALOSPORIN DERIVATIVES AND ANTIBIOTIC DRUGS CONTAINING THE SAME| FR2506307B1|1981-05-22|1984-03-23|Roussel Uclaf| US4396619A|1981-09-08|1983-08-02|Eli Lilly And Company|Cephalosporin betaines| FR2546520B1|1983-05-27|1985-08-30|Sanofi Sa|NOVEL ANTIBIOTIC COMPOUNDS DERIVED FROM CEPHALOSPORINS|FR2546520B1|1983-05-27|1985-08-30|Sanofi Sa|NOVEL ANTIBIOTIC COMPOUNDS DERIVED FROM CEPHALOSPORINS| FR2570702B1|1984-09-27|1987-01-09|Sanofi Sa|CEPHALOSPORIN DERIVATIVES, PROCESSES FOR OBTAINING THEM AND THEIR APPLICATION AS ANTIBIOTICS| JPS61207822A|1985-03-12|1986-09-16|Toyota Motor Corp|Control of suction control valve of variable suction pipe length type suction apparatus| US4783443A|1986-03-03|1988-11-08|The University Of Chicago|Amino acyl cephalosporin derivatives| US5147871A|1986-07-03|1992-09-15|Hoffmann La-Roche, Inc.|Anti-bacterial cephalosporin compounds| FR2607135B1|1986-11-20|1989-04-28|Sanofi Sa|NOVEL CEPHALOSPORINS DERIVATIVES WITH IMPROVED PHARMACOKINETICS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM| US5189157A|1987-06-16|1993-02-23|Hoffmann La Roche Inc.|Antibacterial cephalosporin compounds| FR2621589B1|1987-10-08|1990-03-02|Sanofi Sa|CEPHALOSPORIN DERIVATIVES WITH IMPROVED PHARMACOKINETICS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM| CS273349B2|1988-03-31|1991-03-12|Hoffmann La Roche|Method of cephalosporin's new derivatives production| US5336768A|1988-05-24|1994-08-09|Hoffmann-La Roche Inc.|Antibacterial cephalosporin compounds| DE10134478B4|2001-07-16|2007-10-31|Priaton Gmbh|Process for the preparation of thiazole-substituted β-lactams| FR2842523A1|2002-07-17|2004-01-23|Sanofi Synthelabo|ACYLAMINOTHIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION|
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申请号 | 申请日 | 专利标题 FR8308862A|FR2546520B1|1983-05-27|1983-05-27|NOVEL ANTIBIOTIC COMPOUNDS DERIVED FROM CEPHALOSPORINS| 相关专利
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