SA99191151A - 3-descladinose 6-o-substituted erythe - Google Patents

Abstract

This invention relates to new erythromycin multi-ring compounds and pharmaceutically acceptable salts and esters that have an antibacterial efficacy and have a formula chosen from the class that consists of a combination of combinations containing a therapeutically effective amount of the compound of the invention in combination with a pharmaceutically acceptable carrier, as well as a method for treating bacterial infections by giving two breasts a pharmaceutical composition It contains a therapeutically effective amount of a compound formulas (1) to (5).

Description

. Derivatives of “-des-cladinose erythromycin with a Sy at the oxygen atom in situ + FULL DESCRIPTION BACKGROUND: This invention relates to novel semi-synthetic macrolides with antibacterial activity, pharmaceutical compositions containing these compounds and a medicinal method for their treatment. Specifically, it relates to derivatives of “-des-cladinose-erythromycin, which carries a substituent at the oxygen atom at the +0 position, methods for their preparation, compositions containing these compounds, and a method for treating bacterial infections with these structures. Erythromycins from A to D are represented by the formula (e): CH, Nie, OA HO.,, CHy,, CH Erythromycin RY R& HOw, + ; oh. 0". : -CH, -OH fe 7 Hy HG H H .. CH; H = 3 CH, ON CH, k0 0 H “OH J cH CH, Lai on l on 0 d -H -H with 2 (=) A which are well known pretty effective antibacterial agents widely used for the treatment and prevention of bacterial |lay. For antibacterial agents cs a1 adsorbed; On which bacterial strains Wa has insufficient resistance or susceptibility to erythromycin.Erythromycin A also has only weak activity against Gram-negative bacteria.Therefore, the need continues to characterize Wa compounds.

0 . New erythromycin derivatives that have improved activity against bacteria, have less ability to cause resistance, or have a targeted activity against Gram-negative bacteria, or have unexpected selectivity against target microorganisms. As a result; Several researchers have prepared chemical derivatives of erythromycin in an effort to obtain analogues with improved no-modified profiles of antibiotic activity. Morimoto et al. describe the preparation of 1-0-methylerythromycin A in the Journal of Antibiotics; FY vol. p. VAY (1191484). Morimoto also describes 0-7-alkyl erythromycin A derivatives in the Journal of Antibiotics; June 1948. The European patent application "ro, Yoo" issued in YA March 19897 describes compounds 0-7-low alkyl erythromycin ye as stimulants AS jad contraction of the gastrointestinal tract US patent describes 5,444,151 Derivatives of “-oxoerythromycin A carry a substituent at the oxygen atom 76, where the substituents are selected from alkyl, -CONH, alkyl-(0011712)0-, and alkyl--.CONHSO, and describes the international patent application according to PCT No. 97/007011 Issued March 01 VAY Derivatives 0-1-Methyl Ga Adenose vo Erythromycin International Patent Application Bulletin Lady PCT 17 Issued 19397 gle 11 describes derivatives Guam Cladinose erythromycin deoxygenated at position 7. IPO 97/095114 pursuant to the PCT issued on June 11, 1997 describes 0-7-methylerythromycin A tricyclic derivatives. Certain osmotic compounds related to this invention are listed in the US patent application with serial number 1 FVHM. EP 0114867 of 11 May 1996 describes bicyclic derivatives of 0-7-methyl-7-oxoerythromycin A. US Patent 5,577,211 issued in £June 1937 describes derivatives of 0-7-methyl-Guam-cladinose 0-7-carbamoyl erythromycin.

The present invention introduces a new class of *-descladinose erythromycin derivatives bearing Sp at 1 oxygen atom having antibacterial activity. : One of the aspects of the present invention is to present compounds or their salts and esters that are acceptable 00 pharmaceutically in a formula that chooses from the category consisting of: RP N Me: 8 1 ~~ for 1 6 Ou, n,, > HO, = oy wo 0 - 1" for 0 0 )0 RP NM 1 i I 82 0 "8 . 771 love. for Y 00 : (v) 9 B 0 N 0 8 fe NMe, > 1 NO; Ng 77 LEN AY Malaz hy. ) 0 + this ST ONL I 7 v ) SPX ( 1

:: o.

J 0 RP Hide : O,,. . 8 0 a = O,, py a z . 5 0 8 PNM 8 L 8 SE 0 A 0 : ' 0p Tolan NR z od < wr Ve u 2 OS 0 (°) or its salt or ester or His accepted prodrug asa 5Y ve 2 bua form group X X chooses from the class consisting of: ( 3 ) 0=««=N-OH (V) > (?) = N-O-R' where RT chooses from the class consisting of: (a) alkyl Ja (OV Ye) substituents; (b) alkyl (VY) bearing Sha of aryl; (c) alkyl k VY Ya) ( has a aryl substituent 3(d) alkyl (k1-k11) has a aryl substituent laa ve (e) alkyl (VY) has a mixed aryl substituent ;

Y

(17k-7k) (and) cycloalkyl (Yee) separately from the alkyl 18” GRE (7)8p)0827-:5 where selects 12, (J) and aryl; and each separately from RC on its previous meaning and choose p and RY for 8-0-87)89-0-8-0-0 where (4) denotes the class consisting of: 0 hydrogen; 0 of the substituents; gla (VY El) (b) an aryl alkyl; Sy bearing (VY) (c) an alkyl (d) alkyl (k1-k?1) substituting aryl substituents; lie; (e) an alkyl (C1-C71) bearing an aryl substituent; (f) an alkyl (C1-C1) bearing a mixed aryl substituent; or ()11K-+ “k) and 85 form with the atom to which they are attached a cyclo-alkyl ring RS or 7, one of which represents a hydrogen atom, and the other chooses from the category consisting of: 7 vo hydrogen; (V) hydroxy; ) 7) sterile hydroxy; and (7) separately of a hydrogen and an alkyl (C1-C1); or JSRY selects 87 and dus 11878” (?) with a nitrogen atom to which it is attached to a triple- to hept-ring Constituent members of R® HRT > © form the ring; when the ring is five to seven it may contain a heterofunctional group -1k) and (alkyl-1-k181)1- (aryl): and (alkyl) NH- is chosen from the category consisting of -0- and -1k(Jal) and (mixed aryl)”+ and NS and (alkyl (k1-k1) aryl bearing Nd k1)” Aryl mixed with substituents) 80- and- 5- and (8)0- where (ld a mixed aryl) for 8- and (kil (1a or ? e; 1 equals

7 may not exist or choose from the set of -0-, -NH-CO-, N=CH- and -NH- RY choose from the set of: (1) hydrogen; (7) an alkyl (C1-C1) Shay may bear one or more of them, each choosing from the class consisting of: Jah (0) (b) a substituent aryl; (c) a lie aryl ( d) aryl substituent; (4) hydroxy; 0 (f) alkoxy (C1-C1); (g) 01828 where RY and p as previously defined (h) -CH,-M-R® Where 14 chooses from the category consisting of: -C(0)-NH- (1) (Y) vo -Rm "-NH- (¥) N= (£) "-N (CH3)- (©) «-NH-C(0)-0- (1) -NHC(O)-NH- (VY) | 0 «-0-C(0)-NH - (A) “-0-C(0)-0- (1) (V+) -0- (VY) -(500-) where « equals zero, 1, or ?; -C(0)-0- (VY) vo | ,

: -0-C(0)- (VY) -C(0)- (V1) RO choose from the category composed of: (1) Alkyl (K (Td) may By Jang choose from the category consisting of: (i) : aryl; b” (bb) aryl with substituents (c c) remove-substituted a (dd d) aryl with substituents; (1) ryl 0 0 (©) aryl with substituents; ea (0) aryl with substituents” and 2 (1) cycloalkyl las (1) cycloalkyl (Yaya) ve (4) aryl ) 2) a substituent aryl; () a mixed aryl” and (VY) a substituent aryl; “1” represents a hydrogen or hydroxy protective group; © © © Select from the class consisting of: (1) Sd bearing From a moiety choose from !of the class composed of: (a) to 2 F (=) CORY (2) where Gia RY tel (Parl) alkyl (C1-C7) carries a 2-aryl substituent or Ankil Soy Gang (Fs) dl by Ariel Mukhallat;

: (d) S(O)R" where " is equal to zero, 1, or 7 and LER is a priori defined (e)". 1111(0(8)". NHC(O)NR''RY selects O and "!18 separately from hydrogen, an alkyl (C1-K) and an alkyl (C1-K9) bearing Sa from an aryl, aryl substituted, aryl ° and aryl substituent 0 (J) aryl; (h) aryl substituent; (La) aryl lie (j) aryl substituent;) 11 0 alkyl (C7-C10) bearing one or more substituents Choose from the category consisting of: (a) halogen; (b) hydroxyl (c) alkoxy (C1-C3); (d) alkoxy (C1-C3)-alkoxy (C1-K); vo 2 ( exo ¢ Nj (J) “-CHO (J) z (h) (alkyl (C1-C1) substituent) -,0-50; (i) 21878 where RP selects and 1284 each separately from the class consisting of: (1) 0 hydrogen” (Y) alkyl (VY el) (7) alkyl (C1-H11) substituents (2) alkynyl (C1-C71); dali (0) (k1k?1) has Cia Yo (1) alkynyl (VY)

1 has substituted (VY) alkynyl (v) “Jad (A)

Adv (9) Substituted Ad-YE Cycloalkyl (0 4) Substituted Aryl; (0)° Mixed Cycloalkyl; (VY) Substituted Cycloalkyl; (VY) K1-K71 alkyl carries an aryl substituent; (1) (dis) K1-K71 alkyl carries an aryl substituent with (10) a mixed cycloalkyl; Say carries a YY dE alkyl ( 11) 1 K1-K71 alkyl carries a cycloalkyl substituent with it; (VY)

AGT from Cycloalkyl Shay Alk1-K11 carries (VA) (ily From Cycloalkyl K7*-K+ in it Shay carries VY GE Alkyl (V9) hla Aryl (01) Substituted aryl; (TY)vo is substituent of aryl; V Yd alkyl (YY) of aryl is substituent; Say is VY alkyl (YY) or 01 They form, with the atom to which they are attached, a cycloalkyl ring with which it is mixed from © to RY Lg and one or more, each of which is selected separately from the category Shas. (1) 0-hydroxy(Y) ?k-1k-alkoxy (©)

Fare iscola-7k-1k (;) alkoxy ©

VY

Exo (0)

Fev alkyl (1); k-1k halo-alkyl (7) ا-1k lykla-7k-1k alkoxy (A) © “lg as previously known dua -CORY (Z) (K) 8 for 0 (118)©- where cua and “Lg as previously defined . as previously defined RY Cua 0-87 (J) “-C=N (m) or ? and “for 8 As previously known, 1 equals zero or Cua 0-S(O)RY (n) (o) aryl; p) aryl substituents; (s) cycloalkyl (C7-K8);

Jil has (Adve) (t) a cycloalkyl vo carrying a mixed aryl substituent VY a (u) a mixed cycloalkyl Jif (v) (s) a cycloalkyl substituent » Where "L is as previously known NHC(O)R" (x) (y) 0100712 where "L" and "L are as previously known 7 As previously known RY | and RP where =N-NR "R" (Ua) where "8 as previously known =N-R° (i) where" as previously known =N-NHC(O)RY (b b) (lane (cg) 2l 1-112(0(118) where aa and “laa as they are known) carry a substitute from a moiety chosen from the category consisting of: (Ye) alkynyl (© +) ve

\Y halogen" 0 "-CHO (b) WSR predefined where -CORY (c) WER' predefined where -C(0)-R' (d ) | (lps define LER? and RY where -C(ONRVR) (e). -C=N (3) (g) aryl; (h) aryl with substituents; (i ) a mixed aryl (z) a mixed aryl with substituents; 0 (k) cycloalkyl (k7-k7”); 4 Jail (£) or more to choose from the category consisting of: Tasty alkynyl (k-10) bearing a substitute (0) (om sta (a) vo; (7k-1k) (b) alkoxy (c) exo; “-CHO (>) as a priori RY where -CORY (2 a priori LER?”) and Cua -CONR'R™ (f) 2 a priori LER (g) “208.78 where “L and a priori WSR where =N-0-R” (h) -C=N (i) Define a priori WER and Y or 1 equals zero or « Cua 0-S(0).RY (j) (k) aryl; Yo

VE

Substituted aryl; (J) (M) aryl-substituted; (N) aryl-substituted; (O) cycloalkyl (K7-K7); from aryl-substituted; Shay bearing VY (P) Alkyl ° as previously known RY where NHC(O)R" (V) and "L as previously known R" where NHC(O)NR''R? thief) lous and “la” as defined by RP where =N-NRPRY (s) | As defined by the predecessors of R®, where =N-RY (R) as defined by the predecessors of RY, where =N-NHC(O)R™ (si) Ve, where “L” and “L” were also known. Presets =N-NHC(O)NR''R" (V) (Vr dvd) Alkynyl (6) choose from category consisting of: one SST or Say Carry (Vv eT ) alkynyl (v) (a) tri-alkyl silyl; (b) aryl; f) Substituent aryl; choose from the class consisting of: [17 hydrogens; (1) hydroxyl (Y) buffered hydroxy; (V) not present or choose from the class consisting of: ‎ 7 Cus 4-0-7 (4)

C0) (I) |»

vo “-C(0)-0 (b) “CH (c)” C(S)-S- (9) (1k-1k) ; represents hydrogen or alkyl RE where -C(O)NR Y)- (4) or ";1 where « equals zero or SO) (f) 0 or 7;1 where « equals zero or -§(0 ),-0- (J) (Ved) and 8 represents alkyl Y or 1 where « is equal to zero or -PO)OR) (h) as previously defined; and RY where -S0,-N(RY)- (i) | From the category consisting of: Jl RY is selected from the category consisting of: Sn alkyl K1-K1 may carry () 0 aryl; (1) Aryl with substituents; (Y)

Lalas Aryl (1): Substituted aryl; (2) Substituted cycloalkyl; (1)0-substituted cycloalkyl; (1) Hydroxy; (VY); K-1K Alkoxy (A) as previously defined RY and R7 wherein NR'R® (9) may carry a substituent chosen from the class consisting of: YE (b) alkynyl | © Ariel; (1) aryl substituent; (Y) alia aryl (1) aryl substituent; (¢) lis cycloalkyl (0) vs

(1) Substituent cycloalkyl; (VY) hydroxy; (A) alkoxy ard (9) 11878 where RT and RY as previously defined 0 (c) cycloalkyl (YY) may carry a substituent selecting from the category consisting of: “dt (1) (Y) a substituent aryl; (©) an aryl (laa (8) a substituent aryl; 0 (©) mixed cycloalkyl; Z(1) substituted cycloalkyl; (VY) hydroxy; (A) alkoxy Add (4) 11828 where R7 and R® are as previously defined 0 (d) aryl; (e) substituent aryl; (f) alia aryl (g) ally substituent aryl; (h) cycloalkyl substituent “0” or in compounds of formulas (1) and (7) A with UT forms a double bond between the two carbons to which it is bonded; and "N is a hydrogen or in compounds of formulas (7) and (©)" with A forms a double bond between the two carbons to which it is bonded.

,| Z | This invention also provides pharmaceutical formulations comprising an effective amount, Ladle, of a compound as defined, in combination with a pharmaceutically acceptable carrier. The invention also relates to a method for treating bacterial infections in the breasts of a host in need of this treatment, which includes giving the breasts that need such treatment an effective Thais Ladle of M-compound, as previously known. - In another aspect of this invention; Processes for passing macrolide derivatives of formulas from (V) to (0) above bearing a substituent at the oxygen atom in the sell are presented. Detailed description: In a first embodiment of the invention, a compound of formula (1) is presented as described above. The embodiment is 0 - “The preferred in a compound of formula (1) where it forms 9 and 2 with the group X is 0= and the typical compounds of the invention with formula (1) are those compounds selected from the class consisting of: a compound of the formula: (1) 8 represents the allele; “1 represents U” 0 diag X H represents 011; compound of the form: (1) © represents the “8 represents benzoyl” allele; X represents 0” U has $ OH - compound with formula R:1(representing (7-quinolinyl)-.011-011-,011-” R® represents XH represents Jia UO 'OH is a compound of formula R:1(representing Jia UO Jig X H Jig RP CH CH=CH (sid iS) 0-Khalil; compound with the formula R:1(representing (7-quino linel)-,011-011-. 11©- XH Jing R® mates © diag U ©-(-methoxy) benzoyl z compound with the formula:(1)© represents (<-quinolinyl)-.11©-011-. .11©-» 1 UO Jig XH Jing represents 0-methanesulfonyl; compound with the formula (1) 8: (7-quinolinyl)-,011-011-011-; 17 Jing XH 0; U stands for (7-nitrophenyl)-0-00 -014.

VA

In a second embodiment of the invention; A compound of formula (7) is presented as described above. The embodiment

H represents RY not present and W dua (7) is preferred in a compound of formula and the typical compounds of the invention with formula (7) are those selected from the class consisting of:

RY does not exist; WH represents (-CH,-CH=CH, (Js) 55) Jia R HY) a compound of the formula ¢OH na represents H represents | 0

RY not present; WH stands for (7-quinolinyl)-.011-011-.011; 87 represents 1:8) a compound with the formula 0-Khalil; Jia 11; Na dia 1” does not exist WH represents (7-quinolinyl)-:011-011-.17©-; 8 R:(7) represents a compound with the formula 0-(;-nitrobenzoyl); .11©-; 8 represents R:7() a compound with the formula 0-benzoyl; Jing represents 11; Na

RY not found; WH (7-quinolinyl)-.011-011-,11©-; 0 represents Jig R :)( a compound of the formula represents 0-(5,7-Diphenylpyridine carboxyl); U 11;diay

RY not found; WH stands for (7-quinolinyl)-:H:©-011-,11©-; 1 represents R:7( a compound with the formula 0-(7-nitrobenzoyl); U cH represents ve

RY not present WH Compound with formula (7): © represents (7-quinolinyl)-:011-011-.011-; A represents 0-(4:7;#-trimethoxybenzoyl);diay U H Jing

RY not present WH stands for R® stands for (7-quinolinyl)-,011-011-,11©-; R:7(compound with formula stands for 0-(7-thiophene carboxylate); U cH represents RY not found; WH represents (7-quinolinyl)-011-011-,11©-.011-011-; 1 represents RY). Compound with formula © 0-(1- methylbutanoyl); diag U oH represents | RY not found WH Jig R” (-Cly-CH=CHy-(Jgi 525-7) dias R):7(compound with the formula .-bromo-bezoyl); 4(-0 Jia na oH RY represents not present; WH represents RP (7-quinolinyl)-.011-0!1-,11©-; Jia 1 compound with the formula (?): 0-(? -pyridine carboxylate); jig na oH diag vo

1 3 Compound with formula (7): R is (7-quinolinyl)-,011-011-.011; RP is WH not found; RY stands for 14 Na stands for 0-(methoxycarbonyl); Compound with formula (7): R stands for (7-quinolinyl)-:011-011-.011-”; 10 is WH not found; RY stands for UH stands for 0-(1010-Dimethylethoxycarbonyl); 0 - Compound with formula (7): R is (7-quinolinyl)-011-011-.11©-; RP is WH not found; RY stands for (H Na stands for 0-(7-bromobenzoyl); compound with formula (7): R stands for (7-quinolinyl)-,011-011-.11©-; 18 WH dia Not present RY represents oH Na represents 0-(;-methoxybenzoyl); compound with formula (7): 8 represents (70-quinolinyl)-011-012-,11©-; “8 represents WH does not exist RY © _represents U WH represents 0-(7-carboxylate furan); compound with formula (7): R represents (7-quinolinyl)-,011-011-.11©-; RP stands for WH other than RY gage stands for H stands for NA stands for 0-butanyl; compound with formula (7): 8 stands for (7-quinolinyl)-,011-011-,11©-; 12 stands for WH Other than 33290 RY Jing 11; Na Jig 0-methane sulfonyl; - compound with the formula WH Jig RP ¢-CHyCH=CH,-(Jsi 51S Y) dig R:1)(none) RY (H Jig na is 0-(7-methylpropynyl)); compound with formula (7): © represents (7-quinolinyl)-,011-011-.011-; 10 represents X H represents WO non Present; RY stands for U (H stands for phenyl-0-20-1111; compound of formula (7): R stands for (7-quinolinyl)-011-011-,11©-.011; R® X represents H represents 0 W is not »© | present; RY represents U H representing the -0-260-111 allele; compound of formula ©:(1) represents (7-quinolinyl)-.011 011-,11©-; 107 stands for XH stands for 0< W unavailable; RY is 11; U represents (011)611-(11)2)0(0011--0-00-11; compound of formula (7): © represents (7-quinolinyl)-:011-011-.11©-; WO Jim X (H Jia R® n/a; RY stands for 11; ¢0-CO-NH-CH(CH;), diay U

Ye is 77 0 Jig X 11 representing R? Represents (7-quinolinyl)-.011-011-.11©-;R:7) Compound with formula Represents 11; does not represent hexyl-0-00-11; RY present; 0 represents ;77 other than X H compound with formula (7): © represents (7-quinolinyl)-.011-011-.011- 87 represents NA (;-fluorophenyl)-0-00-11; (H represents RY present; not W represents 0; X H represents RP represents (7-quinolinyl)-.011-011-,11©-; R:(7) Compound with formula - 0 (7-nitrophenyl)-0-00-11; diay U (H represents RY present; non WO represents XH represents (7-quinolinyl)-:011 -011-:11©-;18 represents R:7(compound with the formula Na represents (-methyl-7-nitrophenyl)0-00-171; (H represents R present; | other than WO represents X H represents R? represents (7-quinolinyl)-,011-011-,11©-;R:7(compound with the formula represents (;-nitrophenyl) )-0-00-011; UH represents RY present; 0 non WO represents XH represents (7-quinolinyl)-.11-011-011©-; 87 represents R :) 7 (compound of formula phenyl)-0-00-11; oS sie) represents 11; does not represent RY present; does not exist; WH Jig R® Compounds of formula (7): © represents (7-quinolinyl)-011-011-.11©-; 011.-011-011 -(Linelonic-07) Compounds of the formula (7): © represents vo represents ,(:11)011-:011-:0-5(0)2-011?U represents 11; RY Not present WH represents RP represents (7-quinolinyl)-,011-011-,11©-; R:7( compounds with the formula represents phenyl-5-:011-,011-(0) -5)0?U ¢H Jing RY N/A WH Jia R® Represents (7-quinolinyl)-,011-011-,011-;R:7) Compounds with the formula º Represents © -Allele; UH represents 8' ©

RY not present WH stands for RP stands for (7-quinolinyl)-.011-011-.011; R:7(compound with the formula -morpholine carbonyl; 4(-0 Jig) 11;

RY not present; WH represents RP represents (7-quinolinyl)-,011-017-.11©-”R:7) compound with formula 0-pyrrolidinyl carbonyl; Jig U 11 ding

AR!

Compound with formula (7): R is (7-quinolinyl)-,011-011-.11©-; R? is WH not present; RY : represents 11; Na represents 0-(7-tetrahydropyranyl); Compound with formula (7): 1 represents (7-quinolinyl)-,011-011-.011©-; 87 represents 11; 77 does not exist RY has U (H represents .5011-(5-)0-0; © is a compound of the form R: (Y¥) represents RY ¢-CH,-CH=CH,- represents 11; U and "Na together form a double bond; W does not exist; RY represents tH compound of formula (7): R represents (7”-quinolinyl)-.011-011 -.11©-; RP represents 11; Na and UY form a bas double bond; 7 does not exist; RY represents 1]; compound of formula (1): R represents (1-nitro -?-quinolinyl)-,01-01-R1T- RP stands for Al-Na and U'

Ve forms with a double bond; 7 not found; RY is 11; Compound with formula (7): R is H diay R® -CH-CH=CH,-(Jii= Y= aS gi) Na and U' form bea double bond; W does not exist; RY is fH a compound of formula (1): 8 represents (7-(*-(7-ylyl isoxase)-7"-Fur (CH CH=CH (J 108) represents U cH and " They do not form a bee double bond; W is not present; RY is fH

ve is a compound of the formula (7): R stands for RY (NH diag WH diag RP “-CH,-CH=CH, stands for U oH kills” OH is a compound of the formula R:1( represents (7-quinolinyl)-,011-011-,11©-; R? represents WH does not exist RY represents 11; Na represents H 'l 1 represents tH compound of formula ( 7): W does not exist; RY stands for RH stands for RP -CH,CH(O) stands for U “Jada

OH stands for < RP < -CH,CHNHCH,-J Jag RH diag RY Not found; W:7( compound of formula 011; Jia U Khalil » RP ¢- CH,CH,-NHCH,CH, represents phenyl RH represents RY does not exist; W i(Y) compound with the formula 'OH Na' represents 'Jia' represents

YY

-CH,CH,-NHCH,CH,CH, represents phenyl R H represents RY Not present; W:7) Compound with the formula ¢OH Jia U «dda Jig RP ~CH,CH, less Neil R 11 says RY does not exist; W:7) is a compound in the formula representing 011; U represents Khalil” 2” <(NHCH,CH,CH,CH, representing (-7) quinolinyl):011:011-- RH represents RY not present; WV) compound with formula 0 ¢OH Jia U represents K; RP <(NHCH,CH,CH,- ~CH,CHy ( Ji) 53S) denotes 11 # denotes RY not present; Wi(Y) is a compound of the form 'OH denotes U' Jia denotes R' <NHCH,-

RP -CH,CH=NO-(J8) represents R H represents RY not present; 1:177 is a compound with the formula 'OH Jia U Khalil' Jia. -CH,CH=NOCH, ~(J1#8) represents 11 © represents R” does not exist; W is a compound of the form (?): ¢OH represents U KH; Jig RP represents (4-:110-phenyl) - R 11 is RY, a compound with the formula (1): 7, not not present; RY represents a compound of formula (1): 107 is not present; ¢OH Jia is K; Na RP “CH,CH=NOCH,- represents (7-quinolyl)-© H represents RY is not Existing; W:(71) a compound of formula ¢OH representing chloride “NA” representing RP “CH,CH=NOCH,- representing (?-quinolyl)- RH representing RY compound of formula (1) : 17 not found;

OH stands for U stands for KH.” R® “CH,CH=NOCH,~ - >.” In a third embodiment of the invention; A compound of formula (7) is presented as described above. The typical compounds of the invention of formula (3) include those to be selected from the class consisting of: | ¢H has 1 «OH Na representing (H Jing 1 -CH,-CH=CH, representing R:7) a compound with the formula

YY

17" «OH Na stands for H stands for RP stands for (?-quinolinyl)-:011-011-.011-;R:7(compound with the formula ¢H stands for R? -CH,CH(O) for RH for RY is not present; W is a compound with the formula (?): 'OH for U H -CH,CH,NHCH;-Js#8 for RH RY is not present; WF) is a compound with the formula 0m: ¢OH is U 11 is RP -CH,CH=NO is (phenyl) R H is RY is not present; W is a compound of formula (?): .OH representing U H Jiu RP and in a fourth embodiment of the invention a compound of formula (8) is presented as described above. Typical compounds of the invention of formula (4) include those which are selected from the class 0 is composed of: ¢OH (representing Khalil) Na representing RP -CH,;-CH=CH, (representing R:4) a compound of formula 011; Jia U Khal; Jig RP (7-quinolinyl)-.011-011-,11©-; R:4 (compound with the formula Ta imql) represents (?-quinolinyl)-.011-011-.011-; L(R)(4) is a compound with the formula: phospho-(0-0)0; yo represents (7-nitro U(7-quinolinyl)-,011-011-,011-; L Al Jig represents 4:)(a compound of the formula phenyl)-(0-3)0; | ©” -CH;CH(0) represents R (H represents RY Not present; (4)(W) is a compound with the formula: “OH represents U H represents (Phenyl)- R 41 representing RY is not present; Wi(E) is compounded with the formula © ¢OH Jia U 11 representing RP? “CH,CH,NHCH,- -CH,CH=NO(J=i8) RH is represented by RY Not present; W:4( Compound with the formula .OH Na is H Jig RP In a fifth embodiment of the invention, a compound of the formula (0) is presented as described above

Exemplary compounds of the invention of formula (2) include those selected from the class consisting of: a compound of formula (2): R representing .011©-011-.11©-; 8 represents WH Na represents 011; A compound of the form (©): R stands for :011-611-.11©-; RY represents oH does not represent 0-alpha; d - Compound with formula (5): 8 Jia .011-011-.11©-; “8 represents oH na represents oH” tH is a compound of formula (2): 11 does not exist; RY represents RH representing Jia ©! -CH.CH(O) UH represents the 'OH' compound with the formula W (0) not present; RY kills 1 » represents (phenyl)- (CH.CH,NHCHs-” M Na represents OH | : 0 compound of formula (©2): 17 not present; RY represents 1 Jia R (phenyl)11:011-10-; UH Jiu RP represents OH The compounds of this invention include those classes where the group at position Vo is the natural isomer (pV) and those where the group at position 7 is the unnatural isomer (37). One aspect of the invention is a process for preparing a compound with the formula dua (1) 7 and 1 2 together form a group X representing = 0 with the form HN) Os : 8 Ar Ntdey i, 0 On HO, : pel wt 4 (h) 0 where “©” and “la” were defined (Gaus). The method includes: (a) Treatment of a compound with the following formula: hydrolytic treatment with acid:

: 0HNMe; 8 : 0 A : 7 A 0 Or ~~

HO, ns PY

HO 0 9 0 oH “OMe predefined WSR H: To produce a compound with the formula 0 8 1 H NM 83 . 2 7 0 Os,

HO, = :

HO Mo

Oh

0 . Hydroxy; Jin and not H possess R and it is a compound of formula (10) where > (b) treatment of the compound resulting from step (1) is permitted by a hydroxy buffer reactor to produce a compound: of formula 8 RP NM 0 Low 8 2 R Ou,

HO,, :

HO Be

Oh

0 0 hydroxy then diay a protective group for the hydroxy and la Jing RY where (IV) which is a compound with the formula converting a compound with natural isomerism (7p) permissibly into a compound with isomerism other than 0

(37) selectively oxidizes the 7-hydroxyl group 3 J Rad is 7-oxo group to produce the unnatural isomer (7s); It does not represent a hydroxy group (compound produced from step (b)) by an excess of 011)8 in an 8-aprotic solvent followed by the reaction of the intermediate anion with :25 and 1,611, to form an intermediate compound of xanthes, which is subsequently treated with BusSnH in an inert atmosphere. And in the presence of a catalytic amount of initiator radical suitable for the production of the deoxygenated compound at the desired © location with the formula: 0 A NMs, .', 0 0, returned = S

HO ge or 0 kk 0 0 : it is a compound of formula (1a) where Jia U is hydrogen; (3) Treating the compound with formula (i) as a gasa where “© represents a hydroxy protective group and U 0 represents a hydroxy group (compound produced from step b with a hydroxy buffer reactor to produce a compound of formula i) 1 where Ja RP The ic and ad group of the hydroxy group and Jia U is a buffered hydroxyl group; (e) Treating the compound with the formula (1) passport | RY aoa representing a hydroxy protective group and la 7 where (LTR is a hydroxy group ( The compound obtained from step b) with a base and a reactant of dia defined earlier in this statement and representing an eliminable reactant group suitable for the production of LER and yo compound with the formula:

: AP NM; 0 1 00

Sd

Ou Ol

HO TOTS and wt < 0-7-8 for 0 (f) remove the protective group and isolate the desired compound of formula (1a) permissibly. In the process of preparing compounds of formula (1); Select reactor 1-1-8 in step (e) of consisting of: adsl: L8-(0)0-halogen; (1-H): (E-0C5-(0) 0)-0; !18-halogen; (072) ¢0=C=N-R' (1--H) 0

INRHH-R' (E<NO)dicarbonyldiimidazole followed by {C1-5(0),-O-R' {CI-P(0)(OR),-R' {C1-5(0),-O-R' {CI-P(0)(OR),-R' (V+ = a) In the process of preparing compounds of the formula (\) ' in step e, replace the SY of the Ya yo reactor 1-7-8 in the presence of a 507-dihydro-117 base -pyran in the presence of an acid catalyst

HY) Another aspect of the invention is a process for preparing a compound of the formula 0 RP NMe, : 2 2 " 0 : 8 A Sw J Re; Qu,

SM, = o=__"Ne) 0 "

PL

(7) 3

Where the symbols GRY and Nar Ar Alama refer to their meanings mentioned in this statement. The method includes: (a) treatment of a compound with the following formula (V8) hydrolysis with a gawaza acid: 1 8 RP NM RY Cx 0 ! 82 fo, MB | LN N “a, . ,4 o=x a Ke) 0 - b 111" AN : © , hl 0 (0) where WSR defined Woe and "8 represents a hydroxy protective group to produce a compound of formula 8: RP NMe 8 i " | 3 0 2 0 7 HO,,, = i HO HoT u A (A) IL v 00 where U is a hydroxy group and not a hydrogen; (b) treat the compound obtained from step 0 permissibility with an excess of sodium hexamethyldisilazide or the hydride base in the presence of carbonyldiimidazole in a aprotic solvent to produce a compound of the formula: :

May Tq RP PE 0 NTN ho 0. PS Co : Lg LL | ~~ ! MN = ~ LT \ . NE 0 0 ~ AN | a o | > : 0 hig 3 1 ! How 0 . Where La and La (La) form a double bond: ) =( treatment of the resulting compound from step 3) = ( gas az | with a manic ammonia solution to produce the desired compound with the formula (); where La and La together form a double bond and 17 is not present and RY represents tH ° (d 1) treatment of a compound produced from step 3 ([b] adjacent to the capsid amine PRE Jang of the formula “H,N-W-R¥” where W is not present and RY does not represent H, otherwise it may denote its aforementioned meaning to produce the desired compound with the formula (7) where U or bee forms a double bond and 7 does not exist and RY does not Jia tH ) =(treatment of a compound produced from step 8 ([b (permissibly with a hydroxylamine compound ~H-N-W dx pally RY 0 where WwW represents -0- and RY as defined by the value of the desired compound by the formula) Y (' where U and La together form a double bond and Jig W -0- and '8' as previously defined; (f) treatment of a compound resulting from step (b) with an unsubstituted hydrazine to produce aS pall desired by formula (1) where U and Z together form a double bond and 17 represents -NH- and RY represents 1]; (g) Treatment of a compound produced from step (b) with a substituent hydrazine In the form CHoN-NH-RY 03 where RY is not yum Like H, otherwise it may carry its aforementioned meaning Una to produce the desired compound in the formula (7) where La and La together form a double bond Wo representing -NH-RY and p is incomplete O; (h) Treatment of a compound with the formula (VE) as defined by name: facultative treatment with a strong 3 base selected from the class consisting of (1) sodium hexamethyldisilazide and () Y base an alkali metal anhydride in the presence of carbonyldiimidazole in a solvent A protonated to produce a compound with the formula:

I EE Basm Aw

On Tr 5 B No 2 AM TT 0 A N 2 NN ; 1 © 2 rl Tees o A fo, 0. A a mr_-0 ap 3 6 mo | J 0 Wa "5 8. Yara A 2 .. 1: 7 OMe R (i) Treatment of a compound resulting from step (h) selective treatment with an aqueous ammonia solution to produce a compound (: 1 V1) with the formula 3 8 Ma:

R oo 3 : 8 8 : N 2 \ Ox 1 | 7 :

Mu i Oo. De

BSE

( | 1 ) 0 5 where W is not present, RY is !1, and U is cladinose containing a hydroxy buffer at position 6; (J) Treating the compound resulting from step z A atmosphere ol Bl where b is not present and RY represents 0 Jia cladenose containing a hydroxy buffer at site TE with factor A selected from the category that 1 It consists of RY a sila to produce z compound 1 1) dually 1 where W is not present and 0a represents the cladinose hydroxy site at position 4” and RY as it is defined as a path ¢ (k) treatment The compound resulting from the mixture (h) is permissible “an amine compound carrying substituents of the formula HN W-RY where WwW does not exist and RY as previously known with the exception of hydrogen c to produce a compound with the formula Cua 1 01 b not found. And 0 Sieg cladenose hydroxy site at p site and BY Vo as previously known except for tH º

(J) Treating the compound produced from step (h) permissively with a hydroxylamine compound of formula HN “7-8” where W represents -0- and “8” as previously known to produce a compound of formula (11a); where 17 -0- and Jig U represent the cladinose hydroxy site at gall 4 and 18' as previously defined; (m) Treating the compound obtained from step (h) with a free-substituted hydrazine to produce compound 0 with formula (11a) where W is NH, U is the cladinose hydroxy site at position 4, and Jig RY 1]; (n) Processing of the resulting compound from step (m) JA; Where W represents NH-, U represents cladinose hydroxy site at position 4, and RY represents!! with an acidifying agent chosen from the class consisting of: Halogen-(0)©-”-2 or (R™-C(0))-0 to produce a compound of formula (1171) Wena representing SNH 60-0 and Na represents cladinose hydroxy site at site; and “8 as previously defined; (o) treatment of the compound produced from step (m) is a part where W represents -NH and Na represents cladinose hydroxy site at position 578 H Jig RY Aldehyde treatment of formula 0110-”8 where RY was defined as las to produce a compound of formula (N17) where N=CH- Jia W and U representing the cladinose hydroxy site at position 4” and RY As previously known; ve (p) treated the compound produced from step (h) ss with a hydrazine compound bearing substituents of the formula “RY Cua 1:11” as defined by Gras to produce a compound of the formula (171) where W -1011- and Na represent cladinose hydroxy site at position 578 “*” as previously defined except for hydrogen; d (l) d (m) d (n) d (o) and (p) to produce the desired compound of formula (7) where U imql OH may be followed by the conversion of the compound in the natural isomeric form (BY) into a compound In the Zamiri body is not natural (BY) selectively oxidizes the 7-hydroxyl group and reduces the ?-exo group to produce the unnatural isomer (?s); )=( treatment of a compound of formula ( ) permissive where © represents a hydroxy protective group and U vo represents a hydroxy group (compound produced from step (q)) with an excess amount of NaH in solvent ry to form an intermediate of xanthes CHIL aproton followed by the reaction of the intermediate anion with :05 and with 85011 in an inert atmosphere. In the presence of a catalytic amount of suitable initiating radical Ga which reacts as hydrogen; U to produce the desired compound of formula (7) where Hydroxy protective group and Jia 8" (s) does not represent a treatment compound with formula (1) as a passport where

R' d hydroxy group (compound resulting from step (q)) with a base and a reactant of L-1-8-], where 1 and the removal is a suitable reactant to produce the desired compound dle ude gana represents Lg as previously defined it represents '0 -7-8; and U in the form (7), where

AY) (t) Removing the protective group permissibly and isolating the desired compound by the formula

CASH In the process of preparing compounds with formula (7) in step (s), 1-7-8 is extracted from, consisting of: 0L8-(0)-halogen; (1-H) and N-0 )-0; aR (e<-) alkali metal hydride followed by ,65 then ae t0=C=N-R' (1)

IN(RPH-R' carbonyl diimidazole followed by (V2) (E-) Yes . throw; -e(+ Alternatively; in the process of preparing compounds of formula (1); in step s replace the reactant with 1-1-8 in the presence of a 07-dihydro-117-pyran base in the presence of an acid catalyst. 0 HV) of the invention in a process for preparing a compound of the formula AT whose face is y a arn 0 1 : No, 2 5 : o=x Sd i oh o for “0 3 0

Where the symbols RP, SR, LA, and "LA" denote their meanings mentioned in this statement; the method includes: M (a) treatment of a compound with formula (V8) following hydrolytic treatment with acid: PNM: 82 A i A : 0 a On.

RP 0 'OMe (V4) WSR Cus 0 is already known and 88 is a hydroxy protective group to produce a compound of formula PA RP NMe, 8 vo | 7 0 JO Ou. HO, 7 08 eg : HO | ow 1 8 0 0 0 73 0 (A) 5 where Jing U is a hydroxy group and "is not hydrogen, which may be followed by the conversion of the compound in the natural isomeric form (7p) to the compound in the unnatural isomer form (BV) by oxidation of the 0-hydroxyl group and selective reduction of the 7-oxo group (JS) to produce an isomer other than the natural (HAY):

vi U where (A) and compound (1 (b) represent the treatment of a compound selected from the class composed of the compound consisting of hydrogen hexmethyldisilazide A with a base chosen from hydroxy diag and “la Sodium and a base of a metal hydride in the presence of carbonyldiimidazole in a protonated solvent respectively (dod 11151 nS all) to produce a compound chosen from the class of 8 i 8 A? NMa,

G On. <0. xN = 7)

Ve I

Q \ | L 0 3 L 0 SH “-Khalil-cladinose and I represents 4 -0- Jia U ua do double bond; ba and “L U where V0 forms 5 For step (b) diethylene diamine to produce a ve sve compound (c) treatment of a compound selected from the class - where Na represents 0-4-helix dT) bicyclic carbamates selected from the class constituent of the compound, respectively; Aa where A and A form a (TV) bond with cladenose and the compound 0 8 RP NM 0 : i 82 0 = A L X N 2 ip

VE 0 6 the “0 u 0 3 7 0 0-;”- Khalil Cladino Jia U dua (IV)

AES forming a U bond and U Cua cal 1 a|aan (z ) 8 b for step 1 treatment of an anesthetic compound from the class of compounds consisting of nhf, (3) and 77b, respectively; IVY Diluted to produce a compound selected from the class of two compounds vo v2

H NMe; : R 4 "SN 1 m : 60 7, 6 m" > bl te, 1g ke 0 0 sa > < } 0 ä APN oO 0 mitl 4-0 ”- Khalil Cladinone U ua (YY where Nau 0 forms a double bond TET from step (3) by acid treatment; re-(ivr) hydrolytic cleavage of cladinose from compound al (=>) protecting the 77-hydroxyl group by treating with a buffer reactor to hydroxy, followed by the conversion of compound 5 by oxidation (G1) in the natural isomeric form (£7) and then to the compound in the unnatural isomer form selectively to produce the non-PURSE isomer of the 7-hydroxyl group and the reduction of the natural group (7s) to produce A compound with the formula (7?p); U represents 11 and RY which is a compound of formula (7) where 0. is hydrogen; Jia is hydroxy and "la" Jia represents 11 and "la" RP and "Boas" where © is also known: previously known to produce a compound WSR that represents an easy-to-remove group and 7 and L where (L-T-R' and a hydrogen reactor; Jia Rz "L -O0-T-R dia U and H RP Cua (7) is represented by the formula 1

(i) Treatment of the A'-hydroxy group of the compound produced from step (e) with the formula (7) having previously defined WSR dua and “8 representing 5H non-hydroxy and “non-hydrogen” sequentially by the amount of a pill of NaH and CS; and 611:1 to form an intermediate compound of 0-7-xanthate that is treated with BusSaH in the presence of an initiator to produce the desired compound of formula 7 (where RP and a and d" do not represent hydrogen; ) J) Permissibly removing the protective group and isolating the desired compound with formula (3). : (e-1)l8-(0)©-halogen; 1,00 (e-0) jarim)-0; (e-?) and na -0-(0)0)-0? (e-e)l-8-.011-halogen?; (0-0) alkali metal hydride followed by ,065 and then 8-halogen: (1-2) l ahmmah; ve (e<la) carbonyl di Imidazole followed by '85711-8)l: ¢C1-S(0),-0-R" (A—-a) (E-A) ¢Cl-P(0)(OR"),-R (HH-10) -CI-SO-NRY-R' Alternatively; in the process of preparing compounds of formula (7); in step f replace 0 - reactor LTR in the presence of base B SUEY hydro-?1]-pyane in the presence of an acid catalyst.Another aspect of the invention is a process for preparing A compound of the form Hf) o ; 8 RP NMe, Ore. 9 ,, o=x_ gh 0 u + : 0 ou ()

Cua The symbols RP and “a” denote their meanings mentioned 8 in this statement, and the method includes: (a) the treatment of the following Taal (8 (0) compound: p NMe2 : 0, 8 “ 0 0 1" 0 color HO, hy HO oo Ou... 0 0 : 4

(V£) 0 “OMe - 0 where R is previously defined and # represents a hydroxy protective group; with carbonyldiimidazole and sodium hexamethyldisilazide for a short period of time at about 0? dm under

zero to produce a compound of formula IY RP NMe; _0O ) : 5 A 1 “OMe (Y4) 6 ( (b) Treating a compound of formula (VE) passively as indicated in step of) with an alkali metal hydride and a carbonylating agent chosen from the class consisting of phosgene 2nd Phosgene and 3rd Phosgene in anhydrous conditions with the amount of base present being carefully controlled to prevent base-catalyzed decarboxylation to produce the compound with formula (V9) as shown in step (a);

Ya

U represents for the production of a compound of formula (1) where (V1) (c) acid hydrolytic treatment of a compound with the formula hydroxy and “8 represents a protective hydroxy group followed by conversion of the compound in the isomeric form by oxidation of the group ?*- (BY ) the natural (7p) permissive to the compound with the unnatural isomer form (BY) 7-exo_ selectively to produce the unnatural isomer de gana hydroxyl and reductase representing RP (d) treatment of a compound with the formula (;) permissive; Where the hydroxy group and © does not represent a protective group for the hydroxy (compound resulting from step (h)) in an excess of 14011 in a solvent to form an intermediate compound of unprotonated CHI and then the reaction of the intermediate anion with .65 and in an atmosphere Inert in the presence of a catalytic amount of the BusSnH conjugated initiator radical xanthate, which is subsequently treated with hydrogen and 8 representing a protective group U to produce the desired compound of formula (4); where for hydroxy; 0 is a protective group dig 8 "hydroxy and dia U (e) treatment of a compound of formula (4) permissibility where the hydroxy (compound produced from step c) with a base and reactor 1-7-8 where ? and © as they know (4) represent an easy group The removal is a suitable reactant to produce the desired compound with the formula Ly MS Remaining a hydroxy protective group; Jig RP represents 0-1-8 and U where . (4) (f) Permissibly removing the protective group and isolating the desired compound with formula 1 The process of preparing the compounds with the formula (;); selects the 1-7-8 reactor in step (e) A of the category consisting of: 8-(0)©-halogen; (1-h)-m)-e; (e-); Diimidazole is followed by '83(11-8); Am.Rmqa; (A=) >

(e-e) tCI-P(O)(OR),-R' (m-10) 8-rt) to enable. Alternatively, in the process of preparing compounds of the formula (¢) ¢ in step A, the reactant L-T-R is replaced in the presence of base-a-dihydro-7a-pyran in the presence of an acid catalyst. > Another aspect of selection |2 is the process To prepare a compound of formula 2 (: H 8 Re NMe: RP, R, and uU have their meanings given herein; the method includes: (a) treatment of a compound with the following formula (1) 8: RP NMe, 8 : 7 a then 0 o Ou .RN ,,14 HO,,, ' _ 1 ry : HO © 0 a _O .© .' 0 tosen "~~ 0 'OM (V6)) Where LER is already defined and RP represents a hydroxyprotective group with a reactant selected from the class consisting of: (1) formaldehyde in the presence of an acid and (1) chloriodoethane in the presence of a base to produce a compound of formula (YY) .

H AP NMes ol < Or fit BR 0 0 (YT) 0 J, RY To produce a compound of formula (VV) (b) Hydrolytic treatment of a compound produced from step (1) of formula

Co represents a protective hydroxy group that may be followed by the conversion of RP where the hydroxy and (0) (BV) compound in the natural isomeric form (27) does not represent the compound in the unnatural isomeric form 0 selectively to produce an isomer other than SIT By oxidizing the 7-hydroxyl group and reducing the group

The natural HAT RP (c) treatment of a compound with the formula (©) is permissible, where Na is a hydroxy group and in the solvent NaH a protective hydroxy group (compound from step (b)) with an excess of And 1,011 to form an intermediate compound of aprotic CS xanthate followed by the reaction of the intermediate anion with 0 catalysts from a suitable initiating moiety lade in an inert atmosphere in the presence of BusSnH with GaY which reacts to produce the desired compound with the formula (0) where does not represent hydrogen and 8 represents a hydroxy protective group; RP represents a hydroxy protective group and dia (d) treatment of a compound of formula (4;) is a gaseous; where no hydroxy (compound produced from Step b) with a 1-7-8 base and reactor where 7 and 8, as they are known, vo (0) are an easy-to-remove reactant group suitable for producing the desired compound with the formula Jig L in advance and a protective group for the hydroxychloroquine; Jig 8" and O-T-R ding Where not (0) (e) Permissibly remove the protective group and isolate the desired compound with the formula In the process of preparing the compounds with the formula 2) the reactor for 1-1-8 in step (d) is selected from 1 of the category consisting of : > 0 tO Sa-C(O)-R ! )1-e(£0-(C(0)-RY), (E-7)

al (e-0) with -0-rm)-0; (e-;) '11.5©-halogen; (0a) alkali metal hydride followed by ,65 and then '18-halogen; (obviously) blasphemous and unbridled; 0 | (H-No) carbonyl diimidazole followed by IN(RI)H-R' (HMD) ¢C1-5(0),-0-R' (H-) ¢CI-P(O )(OR),-R' (E-10) .CI-SO.-N(R®)-R' instead; In the process of preparing compounds of formula (#); In step d, replace 0 - reactant 1-1-8 in the presence of a base with 7: ;-dihydro-117-pyran in the presence of an acid catalyst. WS Definitions Use throughout this description and appended claims; The following terms indicate their indicated meanings. The term alkyl va “alkyl K1-K+” or “alkyl YEE when used herein refers to straight or branched chain saturated hydrocarbon radicals derived from a hydrocarbon radical containing between 1 and ? or 1 and 1 or 1 and 1 carbon atom respectively by removing one hydrogen atom Examples of alkyl moieties JEL IE include methyl, ethyl, propyl, and isopropyl Examples of alkyl moieties K1-K1 include but are not limited to mel, ethyl, propyl, isopropyl, p-butyl, and th- butyl, neopentyl, p-hexyl, and examples of alkyl moieties K1-YA include all of the above examples, p-heptyl, p-octyl, p-nonyl, p-decyl, p-indecyl and p-dodecyl for example. Also used in this statement to the K1-K1 alkyl group, as defined previously; the primary molecular Gall is bound by an oxygen atom.Examples of the K1-K1 alkoxy include but are not limited to methoxy, ethoxy, propoxyve, isopropoxy and p Botox, botoxy, neopentoxy, and p-hexoxy.

L and the term "alkenyl C1-C10" refers to a monovalent group derived from a hydrocarbon moiety containing of ? to VY carbon atom and contains at least one carbon-carbon double bond with one hydrogen atom removed. Examples of alkynyl groups include e.g. ethynyl, propenyl, butynyl, 1-methyl-7-butenyl (1) and the like. The term “alkynyle” LEY Ye vel used in this statement refers to a monovalent group derived from a hydrocarbon containing VY carbon atom and contains at least one carbon-carbon triple bond with one hydrogen atom removed.Examples include alkynyl ethanyl groups, 7-propynyl (Propargyl), 1-propynyl, etc. The term 'alkylene' refers to a divalent group derived from a saturated hydrocarbon 0 > straight or branched chain removal of two hydrogen atoms e.g. methylene, 07-ethylene, OBEY, Gulag YO, 717-dimethylpropylene, Abd, and the term JS denotes as 1-K7-amino"; As used in this statement to a k,-k alkyl group, or two groups; as already known; the basic molecular Ball is bound by a nitrogen atom. Examples of a k1-k alkyl group include but are not limited to JU 1-amino, dimethylamino, ethylamino, diethylamino, propylamino The term “exo” refers to a group where two hydrogen atoms have been replaced by a single carbon atom in the alkyl group As previously known, one oxygen atom (i.e. a carbonyl group). judy The term "aprotic solvent" as used in this statement refers to a solvent that is inert © Gand of proton activity ie does not act as a proton donor. Examples of this solvent include but are not limited to hydrocarbons such as hexane, toluene, eg halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, etc., mixed cyclic compounds such as tetrahydrofuran (JEN) pyrrolidinone, and ethers such as diethyl ash and di-methoxymethyl ether. These compounds are well known to the tech savvy and it is clear to the tech savvy that vo prefers to use single solvents or combinations thereof for particular Jeli compounds and conditions; depending on factors

Such as the solubility of the reactants, the reactivity of the reactors, and the preferred temperature ranges, for example, JU. Other details about nonprotonated solvents can be found in the Textbook of Organic Chemistry or in special studies; For example, a study entitled Physical properties of organic solvents and methods of purification; Class dag) Hl issued in the name of A. John Reddick and those with him; the number? in string 0 | Chemistry Technologies » John Wiley & NIA (ma Giga) The term “aryl” as used herein refers to a monocyclic or dicyclic carbon system containing one or two aromatic rings including but not limited to phenyl, naphthyl and tetrahydronaphthyl Indanyl, Indenel, and the like. Aryl groups (including dicyclic aryl groups) may be devoid of substituents or contain one or more substituents or three 0 individually selected substituents of reduced alkyl, substituent low alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, diaclkylamino, acidamino and cyano And hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, and carboxamide. In addition; Aryl groups bearing substituents include tetrafluorophenyl and pentafluorophenyl. Vo and the term “cycloalkyl k?-k” 11 denotes a monovalent group derived from a monocyclic or dicyclic saturated carbon cyclic compound by removing one hydrogen atom. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heptyl [YF OY] dicyclic and octyl SEY oY oY]cyclic. The terms “halo” and “halogen” as used herein refer to an atom chosen from © - fluorine, chlorine, bromine and iodine. The term 'alkyl amino' refers to a group with the structural formula ANH Cua RY #representing JS as previously defined. Examples of alkyl amino moieties include methylamino, ethylamino, isopropylamino and the like. The second term 'alkylamino' refers to a group With the structural formula "1088" where ve selects JSR SR separately from the alkyl as previously defined. In addition it may constitute

es RY RY -(011)-where k is an integer ranging from_? to 1 Examples of dialkylamino groups include dimethylamino, diethylaminocarbonyl, methylethylamino, piperidino and the like. The term "halo alkyl" refers to an alkyl group; As previously known, it contains one, two, or three halogen atoms attached to it. Examples of these groups include Jha, chloromethyl0, bromoethyl, trifluoromethyl, and the like. Jig The term "alkoxycarbonyl" is an esterification group i.e. an alkoxy group attached to the primary molecular moiety via a carbonyl group such as methoxycarbonyl, ethoxycarbonyl and the like. The term "thioalkoxy" refers to an alkyl group as previously defined attached to the Z0 moiety. The primary molecule is made up of a sulfur atom. The term “carboxaldehyde” as used in this statement refers to a group of the formula –CHO. The term “carboxy” as used in this statement refers to a group of the formula -CO,H vo The statement indicates a set of the form -CONHR'R where RY and “8 each separately select a halogen or alkyl or RJ and © Cea may permit the notch load) – where k is an integer ranging from ? to 6. The term “mixed aryl” as used in this statement refers to A cyclic aromatic moiety containing from © to 10 atoms in the ring and choosing one cyclic atom from 8 and 0 Ny or being a © atom | one or two additional hetero-atoms selected separately from [8, 0, and 1] and the remaining cyclic atoms are carbon atoms; The moiety is attached to the rest of the molecule by any of the Fie ring atoms pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, xazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl and the like.

The term “mixed cycloalkyl” as used herein refers to a non-aromatic ring system that is unsaturated or wholly saturated with Wie from © to 01 ring-forming members; Contains single rings with “©” to “A” atoms and dicyclic or tricyclic systems that may include lila aryl or mixed six-membered aryl aromatic. These mixed cycloalkyl rings include those with 0 containing from 1 to Cl AY individually selected hetero-oxygen, sulfur, and nitrogen; Where it is permissible to oxidize the heterotrophic nitrogen and sulfur atoms, and it is permissible to make the heterotrophic nitrogen atom in a quaternary form. Examples of mixed rings include but are not limited to pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 0-xazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothia, lindinyl and tetrahydrofuryl. Particular mixed cycloalkyl rings that are useful for the preparation of the compounds of the invention include: 7-methyl-;-(7-methylphenyl)piperazine, JAY piperidine, 5-(di-(;-fluorophenyl)methyl)piperazine and JE) Phenyl (die) piperazine and;-(ethoxycarbonyl)piperazine and;- (ethoxycarbonyl methyl) piperazine and 4-(phenylmethyl) piperazine and;-(1-phenylethyl)piperazine and (dite gnath-01(- ve ethoxycarbonyl)piperazine and ;-(7-di-(7-propenyl)amino)ethyl)piperazine and 4;-(7-(diethylamino)ethyl)piperazine and ;-(7-chlorophenyl)piperazine f=f (7-cyanophenyl)piperazine, 4-(7-ethoxyphenyl)piperazine, 4-(7-ethylphenyl)piperazine, 4-(7-fluorophenyl)piperazine and ; -(7-hydroxyethyl)piperazine and ;-(7-methoxyethyl)piperazine and ;-(7-methoxyphenyl)piperazine and; -(7-methylphenyl)piperazine and 4-(7-methylthio(dv.)piperazine and ;-(7-nitrophenyl)piperazine; 5-(7-phenylethyl)piperazine and 4-(7-pyridyl)piperazine and 4-(7-pyrimidinyl)piperazine and 4-(7,7-dimethylphenyl)piperazine and 4-(407-difluorophenyl)piperazine and 4-JSG)methoxy (did piperazine) and (AU EY ) mE methylphenyl)piperazine and 4-(©,7-dimethylphenyl)piperazine and (AUTON) mE methylphenyl)piperazine and 4-(7-chlorophenyl)piperazine and ;-(7-methylphenyl) piperazine and 4-(7-trifluoromethylphenyl) ve piperazine and ;-(7;-dichlorophenyl) piperazine and ; GU EV) methoxyphenyl) piperazine f

JUS EF)methylphenyl)piperazine and ;-(;-methyldioxyphenyl)piperazine and Gallo cE = methoxyphenyl)piperazine and ;-(7,*-dichlorophenyl)piperazine and ON) Dimethoxyphenyl) piperazine and 4-(;-(phenylmethoxy)phenyl) piperazine and SEV) mMethyl ethyl)phenylmethyl) piperazine and 4-(;-chloro-?-difluoromethylphenyl) piperazine and ;- 0 (;-chlorophenyl)-”-methylpiperazine and; -(4-chlorophenyl)piperazine and 4-(;?-chlorophenylmethyl)piperazine and ?-(4,-fluorophenyl)piperazine and 4-(;-methoxyphenyl)piperazine and 4-(;1-methyl phenyl) piperazine and ;-(?-nitrophenyl) piperazine and = CAE)fluoromethylphenyl) piperazine and ;-cyclohexylpiperazine and ; -ethyl piperazine and; -hydroxy-4-(4-chlorophenyl)methylpiperidine 5-hydroxy-?; -phenylpiperidine and; -Hydroxypyrrolidine and 0-methylpiperazine and ?-phenylpiperazine and 4-piperidinylpiperazine and ? -((7-furanyl)carbonyl)piperazine and ;-(70-dioxolanyl(*))_methyl)piperazine and 7-fluoro-70701;;-tetrahydro-7-methylquinoline (GE) azacycloheptane and 7,7-Dihydrindolyl and GUYOT Methylpiperidine and 4?-ethylenedioxypiperidine and ml EVO hydroisoquinoline and am EN hydroquinoline and azacycloctane and dexhydroquinoline and piperazine and piperidine and pyrrolidine ve and thiomorpholine and triazole .

The term “aryl-methylated alkyl” as used in this statement refers to a chelated aryl group as defined above attached to the primary molecular moiety via an alkylene group where

The alkylene group contains from 1 to ; carbon atoms. The term “hydroxy protective group” as used herein refers to a vo-removable group known in the technique to protect a hydroxyl group against an unintended reaction during synthesis procedures and to be selectively removable. The use of hydroxy-protective groups is well known in the technique to protect groups against unintended reactions during a synthesis procedure and many such protective groups are known; Consider, for example, the research of T. Atmish Green and P. J. M. Watts in the book Protective Groups in Organic Synthesis; All ed. John ve Wiley aif Sunny New York”; 1931 Examples of hydroxyprotective groups include eg

Ly, to name a few, methyl thiomethyl, th-dimethylsilyl, th-butyl diphenylsilyl and ethers such as methoxymethyl esters including acyl benzoyl and the like. Easy to remove Known in technology to protect ketone groups against unintended reactions during synthesis procedures and to be selectively removable. The use of ketone protective groups is well known in technology to protect groups against undesired reactions during a synthesis procedure and many such protective groups are known; Consider, for example, the research of T. H. Green and John All PJM Watts in the book Protective Groups in Organic Synthesis; Ed., Wiley & Sons, New York; 1991. Examples of ketone protective groups include but are not limited to ketals, oximes, and oximes with an oxygen substituent of 0-benzyyl y. oxime, 0-phenylthiomethyl oxime, 1-isopropoxyhexylcycloaxime, and the like. The term “hydroxy with a protective group” refers to a hydroxy group shielded by a hydroxy protective group; As defined above; The groups include benzoyl, acyl, trimethylsilyl, triethylsilyl and methoxymethyl for example. The term “protonogenic organic solvent” as used herein refers to a solvent that tends to provide protons such as alcohols such as methanol, ethanol, propanol and isopropanol For those familiar with the technique, fam, butanol, th-butanol, and the like will become clear. Such solvents are known to the tech savvy that it is preferable to use single solvents or mixtures thereof for particular compounds and reaction conditions; Depending on factors such as solubility of reactants, reactivity of reactants, and temperature ranges of proton generating solvents in opal preferred for example. Details can be found in organic chemistry text books or in special studies such as a study titled Physical Properties issued in the name of A. John Reddick and those with him; diol I for organic solvents and methods of purification; Edition

NAAT Sunny New York; al John Wiley ce lial in Technologies Series (Yaad) The term “substituted aryl” as used herein refers to an aryl group as defined herein bearing substituents independent of an atom one or two hydrogens vo

L or three in group B!©, +8, ©, 1, 011, cyano, K1-k alkyl?, er alkoxy, or K1-K1 alkoxy bearing an aryl, haloalkyl, or thioalkoxy substituent Amino, Alkyl Amino, Diakyl Amino, Mercapto, Nitro, Carboxaldehyde, Carboxy, Alkoxycarbonyl, or Carboxamide. In addition; Substitutes may choose from aryl, para-aryl, or 0-alkyl cycloalkyl. as well; Aryl groups bearing substituents include tetrafluorophenyl and pentafluorophenyl. z and the term “substituted aryl” as used herein refers to a scrambled aryl group as defined herein that bears substituents by independent substitution of one, two, or three hydrogen atoms in group B©, Br, ©, 1, 011, or ON, alkyl K1-K?, alkoxy K1-K1, or alkoxy K1-K1 bearing an aryl, haloalkyl, thioalkoxy, amino, alkylamino, diaclkylamino, mercapto, nitro, carboxaldehyde, carboxy, or alkoxy carbonyl or carboxamide. In addition; The substituents may choose from an aryl group, a scrambled aryl, or a scrambled cycloalkyl group. The term “substituted mixed cycloalkyl” as used herein refers to a vo-substituted cycloalkyl group; As I know, ode carries substituents independently of one, two, or three hydrogen atoms in group b) 1, Br, “a, 1, 011, cyano, alkyl C1-k?, alkoxy C1-C1, or Alkoxy K1-K1 carries an aryl, haloalkyl, thioalkoxy, amino, alkylamino, diaclkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, or carboxamide substituents. Mixed aryl ah mixed cycloankyl. There may be many asymmetric centers in the compounds of the present invention. The present invention includes the various stereoisomers and mixtures thereof unless otherwise stated. Accordingly, when a bond is imitated with a wavy line, it is meant by the possibility of a mixture - of stereoscopic or chimeric directions Single for a definite or indefinite direction.

The term “pharmaceutically acceptable salt” when used in this statement refers to those salts that are “fit for use” within the realm of sound medical judgment; In contact with tissues of humans and lower animals without toxic, irritating, harmful allergic response, etc. and its validity can be measured by a reasonable benefit/risk ratio. Pharmacologically acceptable salts are well known in the 0 technique. For example, SM Borg and those with him described pharmaceutically acceptable salts in detail in the Journal of Pharmaceutical Sciences. Volume 17 p. 13397013-1 which are mentioned in this statement for reference. The salts can be prepared in situ during the last two steps of separation and purification of the compounds of this invention or separately by the reaction of the functionalized base group with a suitable organic acid. Examples of non-toxic and pharmaceutically acceptable acid plus salts include de penal salts

0 amino formed with inorganic acids Jie hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or by using methods Others used in technology such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, and benzene salts 10 | sulfates, benzoates, bisulfates, borates, butyrates, camphors, camphor sulfates, citrates, pentanecyclopropionate, digluconate, dodecyl sulfate, ethansulfate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, half sulfate, heptanoate, hexanoate, hydroiodide, 7-hydroxy-ethane sulfate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfate, ? © sulfates, tecotines, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3?-phenylpropionates, phosphates, pirates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, para-toluene sulfates, indicanoates, valerates and the like. Examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium

And the like. Other pharmaceutically acceptable salts include; as appropriate; Non-toxic ammonium and quaternary ve ammonium and amine AS Se cations using neutralizing ions such as halide and hydroxide

carboxylates, sulfates, phosphates, nitrates, low molecular weight alkyl sulfons, and aryl sulfons. The term "pharmaceutically acceptable ester" when used in this statement refers to all-body hydrolyzed esters and includes those esters that hydrolyze immediately in the human body to leave base compound 0 or its salt. The ester groups include: For example, those groups that are derived from pharmacologically acceptable aliphatic carboxylic acids, in particular alkanoic, alkenoic, cycloalkanoic and dioic alkanes, where it is desirable that the alkyl or alkynyl moiety not contain more than 1 carbon atom. Examples of special esters include formates, acetates, propiones, butyrates, acrylates, and ethyl succinate. ve the term “pharmaceutically acceptable prodrugs” as used herein refers to such prodrugs of the compounds of this invention; that within the correct medical decision; are suitable for use in contact with tissues of humans and inferior animals with adverse toxic, irritative or anaphylactic response, etc., their suitability can be measured at a reasonable ratio of benefit and risk, and they are effective for their intended use in addition to their diionized forms” as applicable; One of the compounds of this invention is Vo. The term “prodrug” refers to compounds that are rapidly converted in vivo to produce the parent compound of the above formula; For example, by hydrolysis. A fuller explanation can be found in the reference of T. Higuchi, Gy Stella, in a paper titled Drugs as New Discharge Systems; VE volume for the American Chemical Society Symposium Series and in Edward P. Roque vs. Reference ALE Carriers for Reflection in Drug Design; American Pharmaceutical-Association Pergamon Pr.19897 Both are incorporated into this statement for reference. Antibacterial activity Typical compounds of the present invention were titrated in test tubes to determine their antibacterial activity as follows: Twelve Petri dishes containing successive aqueous dilutions of the test compound mixed with 10 mL of sterile agar for infusion were prepared by

=)

Heart and Brain (BHD) (from DEFCO 0418-01-35) and inoculated each plate with 100% dilutions (or 1:0 for slow growing strains Jia Micrococcus and Streptococcus) of 77 Ln WES different flours on “SY” using the anti-propagation inhibitor Steers.The inoculated plates were incubated at a temperature ranging from 7-77 µm for a period ranging from 11-700 hours.In addition, 0 control plates were prepared using BHT agar. It was devoid of the test compound and incubated at the beginning and end of each test. An additional plate containing a compound with known susceptibility patterns for the tested organisms and belonging to the same class of antibiotics as a test compound was also prepared and incubated as an additional control so that a comparison could be made between each other test. Erythromycin was used ( a) for this

Forgiveness. a

(MIC) and after incubation; Visually inspect each dish. The lowest inhibitory concentration 1 was defined as the lowest concentration of the drug that produced isolated, non-growing colonies that were slightly dusty or scattered on a spot below; Efficacy (Y) of the vaccine compared to a growth control. The results of this calibration shown in the table show the antibacterial properties of the compounds of this invention

Table 1 Antibacterial Activity (MIC Values) for Selected Compounds Microorganism Organism Code Erythromycin A Staphylococcus aureus Gis 6538P Culture Collection Y AA © American Standard (ATCC) 5.1 BB 85177 Staphylococcus aureus 011 > 00 A-5278 Staphylococcus aureus

JA nD CMX 642 A Staphylococcus aureus +, ¥A EE NCTC 10649M Staphylococcus aureus

Va FF CMX 553 Staphylococcus aureus 011 > GG 1775 Staphylococcus aureus

Va 1111 3519 Staphylococcus epidermidis 5d" I ATCC 8043 Enterococcus vacumum dv ¥ 1) A-5169 Lud gr Streptococcus m. KK CMX 508 Streptococcus agalactia "00 LL EES 61 Streptococcus pyogenes 011 > MM 930 Streptococcus pyogenes 1,¥ NN PIU 2548 Streptococcus pyogenes «00 00 ATCC 9341 Micrococcus luteis 0, PP ATCC 4698 Micrococcus luteis 001 > QQ JUHL E. coli E. ‎ RR SS Escherichia coli

Yeo > SS DC-2 Escherichia coli

Yeu > Tr CCH 442 Candida albicans Mycobacterium smigmatis 114 ATCC Nl n ov Organismal code Organismal code Erythromycin A 0,1 VV ATCC 9970 Nocardia steroids ¢ WAY DILL AMP R Haemophilus influenzae for you » ATCC 6303 Streptococcus phimonia Li YY GYR 1171 Li gash Streptococcus YYA > 22 3979 Streptococcus phimonia Streptococcus phimonia 5649 77 L “-” Missing data is marked with * (1). Z Followed table for selected compounds (MIC) Antibacterial activity (values NA © M | A ) 1 I | Basically, we have died

I'm on the net | Add a na a ol oy (1) (A) (v) 0 (°) 8 9 neighbourhood en fer |v and if we bow d« | for | Haha Naa Ala Ala I Aa Aman ar en | Ar Na Je A I did not enact that of | ae

Missing data is indicated with a “-” sign.

Table (1) Antibacterial activity (MIC values for selected compounds) Object code 1 Example Example | 1 JE Example Example Vo 14 | (Ov) | OY 11 Ye 1 11

7 aa | In order for him to return Aya Ahlab ov | oo | disappointed vee qaat

Xo se heehee [ves] 66

VA | a wn [| vk[vA| 0010

SITES IRL EEA TI

TE p oe ey Tan oo eee

EE A Fi 7 7

Oe[Xe| ee[avs|e| ove [ov | xx

FE er aaa Missing data is indicated by “-”.

(1) Follow table | for selected compounds (MIC ad) antibacterial activity

Y¢ Yy YY 1 4 for VY J © YA

EE ETE LA BET ETE HA ETE | © [ Vet | vA[ver| ova Lakr | coming | vel | pp [vo ajna ya en [voc na ve | 66

VA[VA[ven| va [ven [ova [vet | mm

EEL CP rt vt [0 [ew] [ox vn [oa oe [kk

CY[oes[ov|ov| ve oY [oe [yn | of oa | Um [ov | 00 «m | boredom | Snack | Kidd Qar Qar | ee | a

YY 01 VYA< eo 0X.”-” Missing data is marked

Follow Table (1) Antibacterial activity (theme (MIC) for selected compounds Yo 913 TA YV Y1 Yo | 7 ova | ox | = | solution | read | #1 | 38 cd It would have come except va | hala tak | ova | pp ova | an | hala | R | read | am | BE

LYS oy ex ex ex pews [eva ey | No

EEE Liter Instruments re st i es TH

EEN ERT EE ETE EEN ER A | 6 l 0 l | Anh 0 oo [ee [ey per [ee | I became fey | lL[Ye[ave| ev Jove [ave | oxo | 0.01 | They oy [eee boon Joey | qi [pe fee | 00

Ys | [eva | read | cr | open | even | “Fr al | to leave | Tbah | RR.”-” Missing data is marked

>A (1) Follow table of selected compounds (MIC antibacterial activity) Rate my | ro

YA 7 177 Yo Y¢ YY YY

BARN

- - |e [ov] | BB vy uy pews Ak | read | ova | ova | 00 vo wy | Lam leva [eva | rah | 8#

Vee | | on | Yo [hee to | ey | A | 01 A LAB BLR L ALC LLD . load qn | oY | 00 A 001 0.0. > A 0. | 00 ad l l vo) [ve | REA | A | >

Eeeee | 01 AH 9 Bi

EET | Tal | EV | A A for 80| »#[ As |v Leave | Mi a a EE.”-” Missing data is indicated by a sign

(V) mG table } for selected compounds (MIC) Antibacterial activity (values io | io £1 3 7 31 1 12 Ya

Na bees | > | oe |» | ce]

Ba vt | Jelly ey bey [ey poy | Except | Ha am ey Jee | good fee [yer | deh a en en | er [eee | l | at | KK

Yo | xe | ev eo | no | 1 | 00 7t | cr | cr | R | by | Qa [ver | ope 0. no | 0. RITES EEO | Md EE 00 9 001 < | 0>

NA vo | vo | The | axe | ove | a

EH Lihd: H D L D L D Missing data is indicated by a “-”.

0 Antibacterial activity (MIC values) for selected compounds

Hama ETE Aam |e oT Jenr | oc 1 LA EET EN at the | La A A A A A A Secret || About | God bless Ha | ven tat | a vv | evs | 00 ‎fee thief | ro bees | Q @ | Na | ‎vee Jove lee | No ETE ETE DV IRE ovo fw a oo | ove Missing data is indicated with a “-” sign.

Sh Pharmaceutical compositions

Pharmaceutical compositions according to the present invention include an effective amount (Ladle) of the compound of the present invention formed with one or more acceptable carriers (Wana). The term “lana” when used in this statement refers to a filler, diluent, coating material, or molding agent of any kind that is non-toxic, inert, semi-solid, or liquid. Some examples of materials that may Serve as pharmaceutically acceptable carriers Sugars such as lactose, glucose, and sucrose Starches such as corn starch, potato starch, cellulose and its derivatives such as carboxy-die cellulose sodium, ethyl cellulose, cellulose acetate, tragacanth powder, malt, gelatin, talc, excipients such as cocoa butter, supporting waxes, and oils such as peanut oil and cottonseed oil 0 safflower oil, sesame oil, olive oil, corn oil, soybean oil, glycols such as propylene glycol, esters such as ethyl oleate, diethyl laurate, agar, pH-regulating agents such as magnesium hydroxide, aluminum hydroxide, alginic acid, water without pyrogens, normalized saline, Ringer's solution, ethyl alcohol, and phosphate solutions of temperature-regulating acidity plus other compatible non-toxic lubricants such as sodium lauryl sulfate 1e and magnesium stearate plus coloring agents and release agents Coating agents, sweetening agents, flavoring agents, and scenting agents. Preservatives and anti-oxidants may also be present in the composition, according to the decision of the person preparing the composition. La Pharmaceutical Compositions of this can be administered to humans and other animals orally, rectally, parenterally, intravaginally, intravaginally, intraperitoneally, topically (in the form of powders, ointments, or drops) or

© Via the cheek or spray in the mouth or nose. Oral liquid dosage forms include lozenges, microemulsions, solutions, suspensions, and pharmaceutically available syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the Jie technique, water or other solvents, dissolving agents, and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, glycol

Oli mY), dimethyl formamide, oils (in particular oils of cottonseed, peanut, maize, seed, olive, castor and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, sorbtan fatty acid esters and mixtures thereof. In addition to inactive diluents, oral formulations may also contain auxiliary additives such as wetting agents, emulsifiers, suspensions, sweetening agents, flavoring agents and aromatizing agents. injectable formulations may be formed; such as sterile aqueous or oily suspensions given by injection; Gig to the known technology using Jal go suitable dispersing or wetting and suspension-forming agents. The all-enabled eal may also be a sterile parenteral solution, suspension, or emulsion in a diluent or non-toxic solvent suitable for parenteral administration such as a solution of 0,7-butanediol. Among the acceptable excipients and solvents that may be used are water, Ringer's solution, USP., and normal sodium chloride solution. In addition, fixed sterile oils (sale) are used as solvents or suspension mediums. For this purpose, any stable, non-stimulant oil can be used, including synthetic mono- and diglycerides. In addition, 6 fatty acids, Jie oleic acid, are used in the preparation of parenteral formulations. Injectable formulations may be sterilized, for example, by filtering through a bacteria-trapping filter or by incorporation of sterilizing agents in the form of sterile solid formulations that may be dissolved or dispersed in sterile water or another sterile injectable medium immediately prior to use. In order to prolong the effect of “lie,” it is often desired to slow down the absorption of the drug when injected subcutaneously or intramuscularly. Gilad can do this by using a liquid suspension of a crystalline or amorphous material that has poor solubility in water. Hence, the rate of absorption of the drug depends on the rate of its dissolution, which in turn depends on the crystal size and crystal shape. Alternatively, absorption of an injectable drug can be delayed by dissolving or suspending the drug in an oily slurry. The injectable buffer forms are made by forming micro-encapsulated blocks of the drug in Jie Gilead polylactide-vo-polyglycolide hydrolyzed polymers. Depending on the drug-to-polymer ratio and the nature of the particular polymer used;

+1 The rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly(ortho-esters) and poly(anhydride). Stocked injectable formulations can also be prepared by retaining the drug in lipid particles or micro-emulsions that are compatible with body tissues. It is preferred that the compositions administered rectally or vaginally be in the form of suppositories that can be prepared by mixing the compounds of this invention with appropriate non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or wick wax that is solid at ambient temperature but liquid at ambient temperature. Body heat thus melts in the anal or vaginal cavity and releases the active compound. Oral solid dosage forms include capsules, tablets, 0-pills, powders, and granules. In such solid dosage forms the active compound shall be mixed with at least one pharmaceutically acceptable inert excipient or dala such as sodium citrate or dicalcium phosphate and/or (a) fillers or extensors Jie starch, lactose, sucrose, glucose, mannitol and silicic acid ; (b) binders such as carboxymethylcellulose, alginate compounds, gelatin, PVP, sucrose, agave, and (c) vo-moisture absorbents such as glycerol; (d) dispersing agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicate compounds, and sodium carbonate; (e) solution-blocking agents such as paraffin; (f) Jie adsorption accelerators quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol stearate; (h) sorbents such as kaolin clay and bentonite; and (i) lubricants such as talc and calcium stearate Magnesium stearate, solid polyethylene glycolate, sodium lauryl sulfate and mixtures thereof. Als the use of capsules, tablets and pills the dosage formulation may also contain pH-regulating agents. Solid compositions of a similar type can also be used as fillers in capsules filled with soft and hard gelatin using such excipients as lactose or milk sugar in addition to polyethylene glycols of high molecular weight and the like.

(b) Solid dosage forms may be prepared from tablets, intoxicating pills, capsules, pills and granules with outer layers and coatings such as enteric and other outer layers known as Tas in pharmaceutical composition technology. These forms may contain bloating agents and may also be of such a composition as to release Active ingredient(s) dad 6 or preferably in a specific part of the gastrointestinal tract and may be delayed formulation Examples of encapsulated formulations that may be used include polymeric and waxy materials Silas type solid formulations may also be used as fillers in capsules filled with Soft and hard gelatin using such excipients as lactose or milk sugar as well as polyethylene glycols of high molecular weight, etc. The active compounds may also be in microencapsulated form with one or more of the above-mentioned excipients.Dosage forms may be prepared Solid tablets, sweetened pills, capsules, pills and granules with outer layers and coatings such as enteric outer layers, controlled-release outer layers and other outer layers are well known in the technique of forming pharmaceutical compositions. High in these solid dosage forms with at least one inert diluent ae die sucrose, SU, or starch. These dosage forms may also include; As usual; Substances other than inert Jie diluents Tablet-forming lubricants and other tablet-forming auxiliaries Jie Magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may also include pH-regulating agents. These forms may contain bloating agents and may also be of such a formulation that they release the active ingredient(s) only or preferably into a specific part of the intestinal tract and may be delayed. Examples of embedded compositions that may be used include polymeric and waxy materials. Dosage forms intended for administering a compound according to this invention for topical or dermal administration include ointments, pastes, creams, lotions, gels, powders and solutions »| Sprays, inhalation materials, and smears. The active ingredient is mixed in aseptic conditions with

> A pharmaceutically acceptable carrier and any preservatives or pH-regulating agents needed as needed. The invention also includes in scope an eye composition, ear drops, ointments, powders and ophthalmic solutions. Ointments, pastes, creams and gels may contain, in addition to the active compound of this 0 - the invention, excipients Jie animal and vegetable fats, oils, waxes, paraffins, THA, gum tragacanth, cellulosic derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, or mixtures thereof. Powders and sprays may also contain; In addition to the compounds of this invention on excipients such as lactose, talc, silicic acid, aluminum hydroxide and silicate compounds. Calcium polyamide powder or mixtures of these substances. The aerosols may also contain common propellant gases Jie CFCs. The patches given through the skin have the advantage of a controlled release of the compound into the body. These dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the rate at which the compound flows through the skin. The rate can be controlled by providing a rate control film or by dispersing the compound in a polymeric template or gel. Gi for treatment methods with this invention” A patient such as a human or a lower animal is treated or protected from bacterial infections by giving him a therapeutically effective amount of a compound according to this invention in specific amounts and for a period of time that guarantees obtaining the desired result. The term “therapeutic effective amount” of a compound according to this invention denotes an amount of the compound sufficient to treat bacterial infections with a reasonable benefit/risk ratio that can be used in any medical treatment. However, we have to realize that the total daily dose of the compounds and compositions, Gy of this invention, is determined by the attending physician, Gig, for a correct medical decision. The specific effective Ladle dose level for any given patient depends on several factors, including the disorder being treated and its severity, the efficacy of the particular compound used, the particular formulation used, the patient's age, weight, general health, gender, diet, time and method of administration, rate of elimination of the particular compound used, treatment period, and drugs.

Used in combination with the special compound used and similar agents are well known in medical technologies. The total daily dose of the compounds of this invention given to humans or other mammals in uniform or divided doses may range, for example, from 0.00 to 00 mg/kg of body weight 0, and the most usual from 1.1 to © 7 mg/kg of body weight. body weight. Standardized dosage formulations may contain such amounts or Integer Portions (Late) to form the daily dose. As (dale) the treatment systems according to this invention include giving a patient who needs this treatment from about 01 mg to about 0001 mg of the compound(s) of this invention daily in the form of standardized or double doses. Abbreviations The following abbreviations were used to describe the diagrams and examples: 9-BBN denotes ?-bora [00707] noonan dicyclic AIBN Jags denotes azo diisobutyronitrile 1 denotes tributyltin hydride and ODI denotes carbonyl Diepimidazole, and DBU denotes HUA aza[5;;;0] indesine-7 dicyclic, DEAD denotes diethyl dicarboxylate azo, DMAP denotes ;-dimethylaminopyridine, and DMF denotes Dimethyl formamide, DPPA, Diphenylphosphoryl azide, Jus 8:02, on ethyl acetate, Le MeOH, Methanol, Jags 140118105, Sodium hexamethyldisilazane, indicating NaN(TMS), on binary (trimethyl Sodium silylamide, NMMO denotes L<1-oxide -]-methylmorpholine, TEA denotes triethylamine, The Jas denotes tetrahydrofuran, and TPP© denotes -triphenylphosphine. AY) The selection compounds are prepared Current Lady of the representative methods described in diagrams (0-1) below. The groups U, Na, 1, 11, eX 7, 7, #, “©, and RP” for the compounds shown in the diagrams indicate their meanings given to compounds with formulas (1) to (0) unless ve states otherwise below.

Tv

Scheme (1) shows the preparation of compounds (1) that are useful as starting materials for the preparation of compounds of formulas (1) to (0) according to the invention. The preparation of buffered erythromycin A is described in the following US patents (333.43107) and (AT) (£77) 5 (FTR 4.14) and (5,1975,5854) which are incorporated in this statement for reference. The European patent © (760,1748) are also incorporated for reference. In general; The 4 carbon atom of compound (1) is in an axiom form (where V is 4-0-8 ! 51 =N-0-CR)R)-O-R' where WER!lie is defined and select 8 and 85 separately from A consisting of (a) hydrogen, (b) an alkyl (C1-C1) without substituents, (c) an alkyl (C1-C1) bearing an aryl substituent, and (D) ) an alkyl (K1-H1) bearing a substituent aryl or forming RY and RY with the carbon atom to which β is attached to the K7-K?1 cycloalkyl ring. The protective group of the carbonyl is particularly preferred

AV 0-(1-isopropoxyhexyl (Als) oxime. The two (V) hydroxyl groups at positions ? and 4 are buffered by reaction with a suitable hydroxy buffer reactor; such as those described by T.W-Green and B.G. M. Watts in a book titled Protective Groups in Organic Synthesis; 2nd Edition; John Wiley adh Sunl AA Cll ve mentioned in this statement as a reference Protective groups for hydroxy include Se acetic anhydride or benzoic anhydride or benzyl chloroformate or Hexmethyldisilazane or Trialkylsilyl chloride in a protonated solvent Examples of aprotic solvents include dichloromethane, chloroform, DMF, tetrahydrofuran (THF), !1-methylpyrrolidinone, dimethyl sulfoxide, diethyl sulfoxide, or GB-NN methylfouramide or GENO methylclaamide © > or triamide hexafrican Jie phosphoric or a mixture thereof or a mixture of one of these solvents with an acer, tetrahydrofuran, 017-dimethoxyethane, klonitrile, ethyl acetate, acetone, and the like. Aprotic solvents adversely affect reaction and it is preferable to use dichloromethane, chloroform, DMF, tetrahydrofuran or 1-methyl Pyrrolidinone or a combination thereof. Protection of the 7- and TE-hydroxy groups of compound (7) can be done sequentially or simultaneously.

TA

It represents a hydroxyprotective group. It is considered the third methyl silyl RY, where (V7) to produce the preferred protective compound. RP group, then the alkylation step of group 7-hydroS all (3) is carried out by its reaction with an alkylation agent in the presence of a base to produce compound (;). Alkylating agents include alkyl chlorides, m-alkyl bromides, alkyl iodides or alkyl sulfones. Specific examples of alkylating agents include allyl bromide, propargyl bromide, benzyl bromide, 7-fluoroethyl bromide, 4-nitrobenzyl bromide and ;-chlorobenzyl bromide; -methoxybenzyl, alpha-bromo-para-toluentrile, cinnamyl bromide, gag yt, methyl crotonate, crotyl bromide, 1-bromo-?-pentene, 7-bromo-1-propenylphenyl sulfone, 7-bromo-1-trimethylsilyl-1 -propene, 7-bromo-7-actene, 1-,0-bromo-7-butene, 7-picolyl chloride, ?-picolyl chloride, 4-picolyl chloride, ;-bromomethylquinoline, bromokhonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, bromo Methyl acetate, methoxymethyl chloride, bromochloramide, 7-bromoacetophenone, 1-bromo-7-butanone, bromochloromethane, bromomethylphenylsulfone, 017-dibromo-1-propene and the like. Examples of alkyl sulfones include: allyl-0©-tosylate, EY propyl- + -©-trifluoromethane sulfones, p-butyl-0-methane sulfones, and the like. Examples of solvents used include aprotic solvents such as dimethyl sulfoxide, diethyl sulfoxide, 0[7-dimethylformamide (AUN) methyl helamide, 8-methyl-7-pyrrolidone, hexamethylphosphoric triamide, and mixtures thereof, or a mixture of one of these solvents with ether and tetrahydrofuran SEY) methoxyethane, chloronitrile, ethyl acetate, acetone, and the like. Examples of © bases that can be used include potassium hydroxide, cesium hydroxide, tetraalkyl ammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium heth-butoxide, potassium isobutoxide, and the like. Schematics V, A, and below describe the post-notch detailing procedures at the + location of the compounds of the invention. Then, a step is taken to remove the protective group from the two groups? - and 4-hydroxyl ve according to methods described in the publications, for example, QUIS Green and Watts, referred to previously. and usually lead

Gig, bal used to remove the protective group from groups TY and ; -hydroxylation to convert X to =N-OH (for example, the use of acetic acid in klonitrile and water removes the protective group of the 7- and 4-hydroxyl groups and converts X from =N-O-R' or '-1-0-0087089-0 where R', ©, and RS are already defined as 8-011-). If this condition is not available 0; The transformation takes place in a separate step.

The deoxication reaction can be performed according to methods described in the literature such as those described by Green (in op. cit.) et al. Examples of deoxicants include inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium persulfate, sodium thiosulfate, sodium sulfite, sodium sulfite, sodium hydrosulfite 0, sodium metabisulfite, sodium dithionate, potassium thiosulfate, potassium metabisulfite and the like, and inorganic nitrite salts such as sodium nitrite or nitrite potassium. Examples of solvents used include protonated solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol, or a combination of one or more of the mentioned solvents, and the like. The deoxication reaction most commonly takes place in the presence of 1 organic acid such as formic acid, acetic acid, and trifluoroacetic acid. The amount of acid used ranges from about 1 to about 10 guesses as to the amount of compound (0) used. In a preferred embodiment, the Jel is deoxicated using an organic acid Jie formic acid

in ethanol and water to produce the desired compound (1). Scheme (1) shows the conversion of the intermediate compound (1) into compounds of the formula Lady (1) © of the invention. Where the cladinose moiety is removed from the macrolide (1) by mild hydrolysis with aqueous acid or by enzymatic hydrolysis to produce the compound (7).Examples of acids include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid, or trifluoroacetic acid.Suitable solvents for the reaction include methanol, ethanol, isopropanol, butanol, and the like.The time range is usually The reaction ranges from 0.0 to YE hours.It is preferable that the temperature of Yo reacts from minus 01 dm (degree Celsius) to V dm, and compound (7) is converted to v. Convenient protection from Jolie which is protected at the 7-hydroxy site by treatment with (A) a hydroxy compound such as acetic anhydride, benzoic anhydride, benzyl chloroformate or tri-alkyl silyl chloride in an aprotic solvent; as defined above; preferably a second chloromethane, chloroform, pyrrolidinone, or a combination thereof Protective groups include die N, tetrahydrofuran, or DMF (1) Compounds of formula (A) and (V) preferred It is trimethylsilyl, acyl and benzoyl. The two compounds are considered to be 0-hydroxy Y and it is possible to reverse the order of steps to remove cyanodinose and protect the group without affecting the rate of production of the process. At a temperature of about zero Celsius Nall with an excess of (A) Then the compound (68, dm below zero) is treated in an inert atmosphere in a protonic solvent, then by the interaction of the intermediate anion with (V) dm to form the intermediate xanthate compound (3) which is 01 and night at about © dm below zero to vs equivalent of 1120:5011 in an inert atmosphere and in the presence of 0.7 to 0.1 g using about Gal treated shot cracks such as benzene, Jeli al, or other suitable crack starter In an AIBN catalytic solvent of toluene, under reflux conditions, for example, to produce the desired deoxygenated compound in hydrogen. Jia 11 where (1) is a compound of formula (01) position 7 1. glue, where 7 and 8 as they are known (LTR), is thickened in the reactor (A) and by treating the compound vo (11). The base produces the compound aga halogens; These interactions are well known to those savvy in the technique, for example with (A) where 7 represents -(0))- in the form '0-0)01 -8; Compound (11) reacts to prepare the appropriate acidic halide compounds of the formula 18-(0)-halogen or acidic anhydride with the formula, in an aprotic solvent and in the presence of a ternary organic amine base, such as triethyl O(C(O) (R), | © morpholine and “-methylpyrrolidine and the like or JN amine and dimethylaminopyridine and or the like at Lil, KH and Nall inorganic bases like 800 : 00, 00.a, and dm Vor a temperature ranging from about zero dm to about represents -0-(0)). As '0-8-(0-0)0'. T reacts where (11) and for the preparation of compounds

Ailes with the appropriate carbonate compound of the formula '0-0)0-0-8- 8 in conditions of (A) compound Yo

Except for the preparation of compounds (11) where T is Cl with the formula 0-0112-8; the compound (/); reacts with a strong base Jie hydride or the alkali metal hexamate disilazide; for example, followed by a reaction with lla A suitable alkyl of the formula '18-:11©-halogen. For the preparation of compounds (11) where 7 represents -C(8)-S of the formula '0-C(S)-S-R' the compound 6 reacts (A) with a strong base hydride Jie or an alkali metal hexamyldisilazide; Sle followed by a reaction with CS; then with a suitable organic halide of the formula Op aR! and for the preparation of compounds (11) where die T ‏ -(03)87)©-؛ where RS is 11 or an alkyl (C1-C76); of the formula '8-(0-0)0(4)80; Compound (A) reacts with a strong base NaH Jie or LiH or NaN(TMS), or the like and then with a cr-pamoyl radical addition reactor or compound (A) reacts with the appropriate -isocyanate of the formula ' 0-0-8-8 in the presence of a ternary amine base. Instead; Compound (A) may react with a carbonyl compound such as carbonyl diimidazole or a dicarbonyl (benzotriazole) followed by the reaction of the intermediate compound formed in this way with an amine of the formula (11) E11 to prepare the desired compound. For the preparation of compounds (11) where T represents S(O) where “represents zero, 1, or ?; ve of the formula -R!(0-8(0<), (0-8(0)) reacts with the appropriate acid anhydride of the formula RY ),(0-6560 in an aprotic solvent and in the presence of a ternary organic amine base; such as triethylamine, dimethylaminopyridine, JBN morpholine, L8-methylpyrrolidine and the like, or inorganic bases such as ,210.00, 0,3, and NaH, KH, LiH, etc. at a temperature ranging from about 0 dC to about 156 dC and for the preparation of compounds (11); Gua 7 is (S(O) ) where « equals zero, 1, or ?; of the formula '0-5(0(,8); compound (A) reacts with the appropriate acid-chloride compound of formula SC S(0),-O-R in similar conditions, and for the preparation of compounds (11), where 7 represents -,0)0((-08), where « equals zero or 1 or “ and “© represents an alkyl (C1-C1); in the form 0-14 -1)0(0187); Compound (A) reacts with M-acid Yo chloride Fits with the formula 18-,1-0)0)017) in similar circumstances.

vy as previously known RY (where SSONRY)-represents T and for the preparation of compounds (11); where with the appropriate acid chloride of formula (A) of formula L-8-(0-50,14)82.; The compound reacts under similar conditions. CI-SON(RY)-R! and to prepare compounds (11); where 7 represents a 7-tetra mixed cycloalkyl group in the aprotic solvent of Olu HY sa JUTE with (A) hydropyranyl; The compound reacts 0 Presence of an acid catalyst. By methods (11) and (01), it is permissible to remove the protective group of ?-hydroxy ester compounds such as acetate or Jia 8" and when (1) standard compounds are produced. Not signed in the format

RY benzoate; The protective group can be removed from the compound by treating it with methanol or ethanol. And when it represents a third alkyl silyl group; The protective group can be removed from the compound by treating it with fluoride © or chloronitrile. THF or by reaction with (VV) hydrochloride and (01) 1-oxime of the two lide compounds. Hydroxylamine may be prepared in the presence of a base or hydroxylamine in the presence of an acid as described in the patent =N-0 or =N-OH Jia X to form compounds of formula (1); where (0,YVE, + AG) US

NH,OR', and the reaction with hydroxylamine, which carries substituents of the formula [1 Big p], where p 1 or 19-0-8 p (1011-0-0)857) leads to the formation of compounds where a represents a moiety other than hydrogen . instead; compounds can be prepared; where Jia has a non-hydrogen moiety with the initial formation of the unsubstituted oxime as described above followed by the reaction with RIN! 9 It is permissible to prepare 1-amino derivatives of compounds (01) and (11) by preparing a 1-oxime compound and reducing the 4-oxime compound to 1-amino by treating it with a reducing agent of borohydride or hydrogen gas in the presence of a catalyst of a precious metal and then treating the amine Aldehyde or di-aldehyde is suitable for the preparation of the intermediate imine and the reduction of the imine by treating it with a reducing agent of borohydride or hydrogen gas in the presence of a catalyst of a precious metal to prepare the desired compound where the substituent at Yo position 1 is an amino group of the formula “11808718 where 87 and RY are knew in advance.

(1) The comb: H Money: H NMe, 0 | 0 H 0 5

Ny, OH LO 2 0 0 0 1 6 HO, 8

XT} No

HO © 0 HO SL

RE b hip

AM 1 . Q,, 0 a, o 0 0 0 2 ~~ “ry 0 2 -n H 9) 4 o— H : “OMe 2 1 1 1 8 NMs, } 8 : NMes 7 AR v v

I RPO, 1 Reo, a > - ’ 0”. 0. 3 Ho, and for !

HO 1] OQ. a HO 2 OO o wo tha ow

On. 0 ©, _0O 0 . 0 * 0 3 and ORP 0 - 0 M06 “OMe OMe 3 r 8 H NMe

TH 8 Ie}: 8 | 2

H "R H NMe, 1} 5 : N b { 0 8 te, 1 0 8: wo, yay lo y| HO, 2 4 HO le 0 : HO OE o n 1 nb o, o \ yy ! 5 !©. 1

No Lo ) APRN NN 7 1 Me 0 1 A 3 NMa, Cu, 1 1 2 |" co, 7 <2 “IN > ard! a ey J . a, : lson a b class 9 Os NNT hy | A 1 ! “omy g a . : f0 . Y | 1 fe) 1 3 a” NMa, 3 a 8 a AP NMa, ) & .| > or) NE 1D Ve 0 Na gh A Ho, for HO we HQ Ne oN PY QL wr ! ON C(S)-8-Cty << © 8 : 1 3 | | 1 li 8 oS : 3 NMe, 8 wo, NN yee 5 , ) for 3 HO, S [ i' 1 - ,0 . : HO “am - , HO “a b” we & Nes © a 5 1 0 1 Ye. Scheme (7) shows the methods used to confuse compounds of formula (a) according to the invention. Converting compound (1) that carries a substituent at the oxygen atom (1) into a buffered compound with a hydroxy group and treating it with acid to lyse the cleavage of cladinose to produce compound (MN) as described in Scheme (1). (Y) and compound (A) can be processed (8) oxidized the ylider group s asyl to a group of ic exo at ve site SY by selective reduction at site ? to produce compound (A) where the group

The hydroxyl is in the unnatural BV form. Instead; Compound (A) can be processed by oxidizing the de sens hydroxyl to an exo group at the ? Then by non-selective reduction to produce the compound that contains a hydroxyl group at the Y site? and 4 and then by selective re-oxidation of the OH group at position 9 to an exo group; to produce compound (A) where 0 is the hydroxyl group in the unnatural 37 form. In these cases; It may be necessary to separate the different groups by chromatography »; As is well known in technology. The isomerization procedures can be added in any of the schemes shown below to produce the desired compound containing the unnatural hydroxyl group of form 7s at position 3. Z Yay than that; Compound (1) can be converted to a hydroxyl group buffer (VE). Using a suitable hydroxy buffer group with the aforementioned procedures. Then compounds (A) and (VE) can be treated with an excess of hexamethyldisilazide Sodium or a base of hydride in the presence of carbonyl diimidazole in a protonated solvent for a period ranging from YE MA dela at a temperature ranging from about Ve dm below zero to room temperature to produce compounds 11b and die on Arrangement The hydride base may for example be 6 sodium hydride or potassium hydride or lithium hydride and the aprotic solvent may be a solvent chosen from predefined solvents The reaction may require a cooling or heating procedure of about 01 dm below zero to about Ve dm, depending on the conditions used preferably from about 0°C to about room temperature The reaction requires a time period from about half an hour to about 10 days and preferably from about 1 to 2 days to complete. ‎ov, some of the sequential steps of this reaction and the procedures described by Becker and others in the Journal of Organic Chemistry; M Leather OF p. 774: 0 19848 that was mentioned in this section for reference. Instead; by treating compound (A) with a sulfonylating agent; such as methanesulfonyl anhydride, methanesulfuronyl chloride, ethanesulfuronyl chloride or para-toluene sulfonyl; in the aprotic solvent ve with stirring at a temperature ranging from about zero degrees Celsius to temperature

Ambient atmosphere for a period of time ranging from about one hour to about YE an hour to selectively produce Spall containing a sulfonate group at the oxygen atom at position 7 (not shown) and then by treating this sulfonate compound with a hydride base in the presence of carbonyl diimidazole in An aprotic solvent that produces the desired unsaturated compound at the y-site? And ? (VO).

° and perform compound processing (11a); ‎diay U ua ‎Shaq ©-; acylcladinose in an aqueous solution of ammonia to form cyclocarbamate (111) where U is the -0 moiety; -Acetal cladinose Wy is not present RY is hydrogen. Treating compound (210) where 5U forms 1 with a dil bond in an aqueous ammonia solution leads to the formation of cyclocarbamate (QV) where U and “bee form a double bond 1.” Similarly, The interaction of the two compounds (10) or (210) where U represents the 0-4-acylcladinose moiety or Na and Na form a double bond, respectively, with an amine bearing a substituent of the formula W Cua (HLN-W-RY) Existing and RY does not represent 11! But it may carry its aforementioned meaning (ls) to the carbamate cycloformation bearing Shy at the nitrogen atom (11) or (71b); where Jia is a slit 0 -;”-Khalil Kladinos or Na and “! together form a Jil bond respectively and

Vo 57 not found.

For schema (©) H NMe 8 o : 1 ) 2 ey, 22 > HO,,, py “1 EN y ow for Or. 0 : o—H | "7 0 08 1 A AP NM : RP MMe 8 A 82 0 : 8 | 2 : 0 xX { o 0 1 Re 7 4, 0 t,, ,4' HOY, = HO, b HO 0 HOW Ww sab —_— Rk wr na OQ, bo: . 0 ‘hy, 0 0 0-8 0 2 0 OMe A SR that represents SL OH w 8 RP NMe N 8 RP NMe, R 0 : R | 2 0 0 i Noo Ke “OL ~~ 0 On ~~ Oh No, - N 0 ver N cr * 1 0 fas 0 ' 5 wo / b 8 0 lnbssshh 8 1 : 0 a 0 a gr ur ra 0 f 0 0 1° riz yml 0 aX Eli va yl 0 -”_Khalil_Claditos. yey wal Waly oy ay they form a double bond; In the form 7 Hb Ue Bb 7 1 + In the form EAR y - In the form 2? ; > Na represents OH a1 —_— : + Na eadha- 0-7 vA moiety 0-4 - Khalil Jia U or (10) where (Ie) leads to the reaction of the two compounds “lS, Cladinose or Na and “do not form a double bond together. Respectively; with a non-existent hydroxylamine compound or representing -0- and “8” as previously known; to formation 17 of the formula “1120-1578 where moiety 4- 0 - Khalil Jia U where (V1) or (D1) the cyclic carbamates that carry substituents as defined by RY represent -0- and 17 respectively; and Gls and “not together” Cladinose U bond or forms 0 moiety 0-4-Acetylcladinose or Jia U dua (B11) or (De) Jeli compounds and performs a double bond, respectively, with hydrazine free of Substituents” to the formation of β forms UT Na and moiety 0-;

H represents RY and -NH- represents Wo, respectively; dpi bond ba 'a Ve represents a -0 crack; - Khalil Kladinos or U or (11b); where (he) and the interaction of the two compounds leads to a double bond; Respectively; With a hydrazine compound bearing substituents of the formula be (SGU) NA and its aforementioned meaning to form Jang that does not represent hydrogen but may RY where 1,1111187” is a 0© moiety -;- acylcladinose or forms Bley Cua (B17) or (D1) the cyclic carbamate compound does not represent hydrogen RY and -NH-RY represents W where ca ill is a double bond;. on aa U ta and vo, but it may have the aforementioned meaning. For example, by L(V) treatment, alternative or additional procedures may be used to prepare compounds of the formula 0-; dia U where (Yo) or (Ire) the alkylating compound with the formula HO represents non-existent RY and 17 double bonds, respectively, where it does not represent hydrogen but may carry The aforementioned meaning RY produces halogen-*8, where -

Loe moiety 0-;”-chloridenose or Na and “do not form a dia U where (V1) the compound (191) or does not represent a hydro and gene. RY is not present and 17 double bonds; respectively; and where the 4-0 moiety does not represent -Khalil (ne) or (ho), similarly, the treatment of compound 11 leads to RY and -NH- representing Wg, respectively. Bil (cladinose or Na) and “do not form a bond together does not represent hydrogen but may carry its aforementioned meaning RY with an alkylating agent of the formula halogen-1”; where ve

pre; leads to the production of compound (101) or (1) where U occupies a -© moiety; -alkyl-cladinose or forms a “na” and “ka” dil bonds, respectively; and 17 dig -8011- and “8 no represents hydrogen. © is represented by 11 with an acidity factor 0 chosen from the class consisting of an acid halide of the formula halogen-(0)©-*” or an acid anhydride of the formula ((R™-C(0)),-0 where RY is not Represents 11, but it may carry its aforementioned meaning. Compound produces (117) or (V1) where Jia U is a 0© radical; It possesses -NH-CO and SRY previously known. By treating compound (112) or (010) where U represents the 0-4 acylcladinose moiety or Na and -" does not form a Gilli bond. Respectively, 17 Jig -8011- and RY represent oH in an aldehyde of the formula (R™-CHO, where RY as previously known yields compound (!11) or (71b); where La Jia-0-, or K-cladinose moiety forms a La and La Ga double bond, respectively; and W represents N=CH- and RY as previously defined. Ladenose from compound (11a) by hydrolysis with an acid as described by Gis produces 1 - compound (VY) which is a compound of formula (7) where Jig is a hydroxy and “is not H” and then the compound can be treated (VY) by the previously described procedure for converting compound (A) to compound (01) to produce the desired compound (MA) of formula (YF) where U and 'do not form a hydrogen atom and a gene. Compound (VY) may also be pretreated with the apa gall procedure to convert compound (A)© into compound (11) to produce the desired compound (V4) with the formula oT) where U is ' 0-1-8- and U is a hydrogen atom. By removing the protective group, is it permissible for a group? -hydroxy compounds (11b), (VY), (VA) and (VA) by previously described methods; The corresponding unsubscribed compounds denoted by the formula AY are produced

As describes the scheme; Preparation of compounds with formula (7) where compound (110) or on AE is treated with the ©- moiety; DMF aqueous chloronitrile or die in suitable solvent (V0) polyethylene diamine cag il represents the 0-4-helix U moiety for the production of dicyclic carbamates (1?a) or (17b); where (A?1) Together they form a double bond, respectively. Then a ring of the compound UT, cladinose or Na0 is formed in a suitable organic solvent such as 1101 acetic acid or Jie by treating it with a dilute acid; (VY ) or (YY) or (YY) ethanol or propanol to produce the compound, radical 0 -;

Jing represents a hydroxy group and Na U and it is a compound of formula (©) where (YF) to produce the compound by the procedures described in (Yo) and (VE) to the two compounds (YY) hydrogen. Then convert the component to -0 respectively. and compounds (13) and (VA) to compounds (VY) The scheme for the conversion of the compound and can (VY) are embodiments of compounds of the formula (Yo), (VE), and (YY) and (YY) Perform the permissive removal of the protective assembly by the previously described methods.

A

(4) Chart H 88 NMe

Op ~_ 1 2 : =~ 0 06 She _ 5 Squirt Nr 0 Mo

Ww 0 1 : 0 : NH, 0 0 [ Y - 0 NH = Clad 1 Lis s- 0, bas Ue [le : . aus “a 7 . a 0 feu

NH, : RP NM 0 #0 1 52 ly, Lech Nites and A o=—=x 5: 1 0 8 8 NMe, 5 LY / B 5 HO,,, p 0 3 l 5 : 7 l oy 0 o=_ 0 0 | Cladinose 1 £0 ashe ] | . And no 7 i 71 7 8 0 8 0 and al 8 8 aa " N. yell 0 khalil kladitos "7 ~~ o HO, latsklan_metastatic bond Uo tn = melah a “vy oa o or 7 U : W 0 : 1 . full!! Ue 2 ? ; in the form) 0

OH _represents + YY t 0-T-Rba U Y as + Yo

AY

And in a capacity. 1 4) B Nac Cyclic in the formula al Preparation of compounds ai a (2) The diagram illustrates

GF) 7; The preparation is as shown in the pal diagram at pall (1?) especially when the compound is converted to dim under Yo in a controlled reaction at a temperature and agitation (about (Ya) cyclic carbonate min) using carbonyl Diimidazole and hexamethane 70 0) for a short time (approximately reacts cautiously with (V ) 1?) of the compound (GS gall) sodium silazide. Alternatively, sodium hydride or lithium hydride and phosgene or diferrsegne or triphosgene are prepared in atmosphere d to call for catalytic carboxylation of sall sac all by the amount of aqueous Saal with control bY conditions that may be repeated The arrangement of its atoms (isomerized) to (YY) to produce the compound (YT) with a base. And the compound, as described above, is formed if it so desires. (GY) The chime, by the procedures described in (Y 3 ) 0 ( >< A), to the compound (AY) and then transforms the compound 3 and ) 03) in order. The two compounds (0A) and (VV) represent Scheme (7) for the conversion of an optional compound of these compounds in mode 3 described above. (*) Scheme H 8 RP NMa : 8 AP NMe, o : i 1 2 0 - Ke Ou, i 22 fh,

H.O.: Oz On. on

HO oO “0 0 b —— wt > 0 0 b fe, 0 0 0 > o y yr o— funnel 0 and 4 2 0 mo vb 1 1 “OMe 1 OMe 1

OH; In the format p a l represents yy

OH represents U «Gysslab » + 2 º 0-T-R® Jar No + Vsslab vq

AY

(1) Compound 283, (2 ase ail) is treated with the compounds preparation method (hs) and the scheme is described with formaldehyde in the presence of acid or chloriodoethane in: d base (according to the procedure for the production of (YAIAA) YEE = 0 methylated antibiotic volume (d_xa described by Hunt and Moqe and is 8 = a compound with the formula) [¢] (where 0 0 Si-methylene di YY) the compound is a hydroxyprotective group. Then The ligand can be removed from this compound in the form of RP representing an optional 5-dioxyli YOY at position 7 by the methods described above to produce compound (71) hydrogen atoms. Compound (7) is hydrolyzed to produce compound RY with the formula (©) where it represents the procedures described in (v7) a 0 Y) to the compound (AIR) and then converts the compound (03) and (03) in order. The two compounds (0A) represent the two compounds ( 1) Scheme (©) for the protective compound conversion of these aS luminous embodiments of compounds of the formula 2 { .5 ner 2 Mg (YY) and (YY ) Ve. compounds optionally by the methods described above. (1) Scheme o i ;

HO, = 2 Q, ~ S 7” “ey << fr. 5 vey

HO om 0 0 8 0 ww b ht 1 7 . G,, 0 0 re 0 . , ( T 7 0 > " o—RP 0 > 8m08 “uh” OMe 10 | Y- , OH stands for Ue; in the form M21

Hie yg + 0 in the form vy 2 i - 0-1-8 ml Ul pasalbe py . _—!

Scheme (V) describes typical examples of further elaboration of the moiety at position (1) for the compounds of this invention. The desired compound bearing a substituent at the oxygen atom at position (1) may be prepared directly as described above, or it may be obtained from chemical modification of a compound bearing Sy at the oxygen atom at position (1) prepared elementary. For example, another 6 derivative can be formed for the compound (YE), where R: 6-0-011,011-011 and 1” represents a massive ring system. Perform the following on the di-bond of the allyl compound (a) catalytically reduce it to produce 0-7-propyl (FO) (b) treat it with osmium tetroxide to produce 717-dihydroxypropyl (VT) to which a group can be added A successor to it, for example, by pasteurizing it with an acidic acidic halide or acidic anhydride at every oxygen atom to produce compound (77); (c) oxidizing it with chloropyroxybenzoic acid in an aprotic solvent to produce an epoxymethyl compound (YA) whose ring can be opened using Nucleophilic compounds such as JE amines or mixed aryl compounds containing a nitrogen atom.To produce compounds with side chains containing an atom nitrogen (79); (d) their oxidation under Wacker conditions as described by Henry in the book Catalytic Oxidation of Hydrocarbons Cp ddl Riedel Publishing Co. vo Dordrecht; VTA dail ga to produce the compound 6-0-CH-C(0)-CH; (+£(¢ )=) its azozone to produce an aldehyde (£3) that can be converted to oximenes (£7) and (£7) by reacting with SHNOR? In the presence of a reducing agent of borohydride or with the formation of an imine and subsequent catalytic reduction to produce the amine (??).It results from the reaction of oxime (£7) with diabsopropyl carbodiimide in the aprotic solvent © and in the presence of CuCl nitrile (£0) and results in nitrile (£0). Reaction of compound (VE) with an aryl halide under Heck conditions in the presence of palladium(7) or palladium(0), phosphine, and an amine or inorganic base (see Journal of Organic Reactions; TY vol. 30-7545 (VAAY). Compound (47) results in, for example, the reduction of the double bond in compound (67) using

Hydrogen and palladium on the compound carbon (EY).

: N 1 < 7 b 8 i] pe 088

M—0O OH

YY for Q qs

M he N cH 7 7 ra

HO

, a mr wad a dd on YA v 1 0 mhr 7 1 i.e. 0 M'—0 and 04 0 grit and | with re yd | Ce

Q 0 pve Ar 0 NHA N D EY N N D L SI 1 - 193 te . Sim OH / — C=N 1 83 Sir A Ye Haha M 5

M—0 Ly

Scheme (A) shows an alternative method for the preparation of compounds with formula (7) where R represents an alkynyl carrying a substituent. Compound 0-7-aryl erythromycin (01) where R represents an allyl is converted to compound (48) by removing cladinose and protecting the free hydroxyl group at position TY as described in the preceding schematics.The subsequent reaction of compound (EA) with a compound of formula 0-halogen-**8 results, where **8 is an aryl, a substituent aryl, or a mixed aryl or a mixed aryl substituent” under Heck conditions and in the presence of (Y) Pd or Pd (zero), phosphine, an amine, or an inorganic base; the compound of interest (£3) where R is a substituent alkynyl. (11a); where R represents an aryl; to a compound (alkenyl that carries substituents) at the oxygen atom (1) of formula (4) in its reaction with aryl alls or aryl halide bearing © -substituted or mixed aryl halide or aryl halide Mixed bearing substituents under heck conditions using (Y) Pd or Pd (zero) and phosphine and an amine or an inorganic base as previously described. Then compound (04) can be converted to the desired compound (£3) where R jig is an alkynyl It carries alternatives by removing the cladinose and the protective group may be removed as previously described in A to previous schemes. These procedures can be used when any further modification of the substituent at the oxygen atom Sha (1) | is made by making the modifications described in Scheme (7) or (3) and Scheme (9) shows typical examples of another subsequent elaboration of site (1). The compound can be prepared The desired one that carries a substituent at the oxygen atom (1) by chemical modification of the compound 0-7-Propargyl prepared initially.For example, another derivative of the compound ‎(©1) can be formed which illustrates a compound according to this invention where R represents Propargyl and represents 17 Lala Lalli © in bulk The triple bond of compound (00) can be treated with an aryl halide or aryl halide bearing substituents or mixed aryl halide or mixed aryl halide bearing substituents in the presence of: A©: (triphenylphosphine) 1M 5 Cul in the presence of an organic amine such as triethylamine to produce the compound (27).The compound (oY) can subsequently be selectively reduced to the corresponding o-olefin (OF) by catalytically hydrogenating in ethanol at atmospheric pressure in the presence of 8050/1 70% and quinoline (see what came on the authority of Rad and those with him vo in the Journal of Organic Chemistry.; volume 0) p. 1163-4158 ((VIAT) and it can also be treated

AY

Compound (01) with a boronic acid derivative (118)087 where RY represents a hydrogen atom or an alkyl K1-K0 in an aprotic solvent at a temperature ranging from zero Celsius to ambient temperature to produce compounds (4 2) that are subsequently treated b, (Triphenylphosphine) 80 and aryl halide or aryl halide bearing substituents or mixed aryl halide or mixed aryl halide carrying substituents under 0 conditions Suzuki reaction to produce compound (00) and compound (51) can also be treated with SAN succinimide in acetic acid to produce the compound (521). Compound (0) can also be treated with an alkynyl halide substituent Jie-halogen-1a©-8-011, where Ar is an aryl, aryl substituent, mixed aryl, or mixed aryl Substituents in the presence of O(triphenylphosphine)00 and Cul in the presence of an organic amine such as triethylamine to produce suitably substituent compounds (BV)

AA in graph A NMe- m8 8 1 RW : | - 0 0 \ wbl 88 2 W 0 te, \ 0 ire, = \ 7 0 0 \ a 7 RY i.e. 1 ohm Nm. , Yalla : te... 0 . 4 . 0 0 and forever 0 0 = Q Ww a i oo esa ~ AP 0 0-2 >” 0 0 y A . Q 1 A A of 58 7 1 \ : Il Khalil Yanur .e 8 LJ 8 p NMe; 3 RY : 0 0 0 \ Asan 80 3 . 8 except | A" On, \ In, 5 3 0 \ m Om Mo OPN 5 1" 5 WNi,, “ey ; 0 O=_ Te, 0 0 " mn > OO 0 wo 1 8 0 02 0 0 0 £9 0 7 2 mm J

Scheme 1 Aryl 7 TT Aryl : km #9 M—Q CTT 2 8 > 1m sq SN RZ ~~ - : M—0 M=0 ol ~~ af | : 1 _— =o | 0 M'=O : ol - Acyl H BS Aryl M—0 = 00 and P to oY 1 The above can be best ped by referring to the following examples presented for the purpose of Explanation and not to limit the scope of the innovative concept of the invention. In NMR spectra (Ran M) the following notations will be used: delta to be 0 7 over the difference; stand single spectrum 3 Bi = dual spectrum; w: le three; = quadrupole spectrum p specific spectrum ¢ = z unit = a (Js) Hz Examples: The procedures described above for the preparation of compounds according to the present invention will be better understood by referring to the following ARNT; Scope: Yo Invention Those familiar with Aly will see the options of 5 ic alia modifications to the tagged embodiments.

Such changes and modifications including but not limited to JU relating to chemical compositions, substitutes, derivatives, intermediates, synthetic methods, compositions and/or methods of using the invention may be made without derogating from Principle and scope. | Example (1) © A compound of the form X H Jig 1" “ll Jig R:1) has 0 OH din U in step 1(a): Compound (;) of Scheme (1); V methyl 1-0-(1-isopropoxycyclohexyl); 0 g (0,0, mmol) of 7,4-di-0-trimethylsilylerythromycin A 4-ve[0-(1-isopropoxycyclohexyl)oxime at zero seminiferous temperature; Lily prepared for the method described in US Patent No. 130,107, in © 08080 ml and © 7 ml. After approximately 7 minutes a solution of 10.7 mL of potassium 3-butoxide of 1 molecular concentration was added © ml of DMSO and © ml of THF drop by drop during four hours The reaction mixture was dissolved in ethyl acetate and washed with water and brine The organic phase was concentrated in a vacuum yielding 1,117 ve | g of the desired compound in the form of foam white. 1a) in VY ml of chloronitrile and A0 ml of water at a temperature of A to the ocean atmosphere. after several hours; The reaction mixture was diluted with Yoo mL of toluene and concentrated under a vacuum. It turns out that yy the resulting ore contains the unreacted feedstock; To this Vo ml of chloronitrile, 1 ml of water and 7 ml of 11080 was added additionally. After two hours, an additional portion of 1 ml of M108 was added]. After about another three hours, the reaction mixture was refrigerated overnight. The reaction mixture, Bal, was left to ambient temperature; and diluted with Yoo ml of toluene and concentrated in a vacuum. The ore was treated twice with toluene and dried to a constant weight of 4 1.87 g. »| Step 1(c): Component (1) of the diagram: (1) # represents A

mL of a mixture of 11 g of the compound obtained from step (1b) in 0.175 μL of 11 mg of acid from 801150, 701 and 801 were treated with a 1:1 enanol and water ratio D.M for two and a half hours. The reaction mixture was left to cool to atmospheric temperature AT formic at 1 ambient NaOH concentration; and diluted with water in the amount of ©-1 ml; It was made alkaline using and extracted with ethyl acetate. 01 gauge until the pH ranged from 1 to 0. The organic extracts were washed after mixing them with brine water; It was dried over 04850, filtered at 71 by age chromatography with methanol concentration A, and concentrated in a vacuum. The material was purified from the compound TAT (Vintage J) methylene chloride containing ammonium hydrate and oxide, its concentration (Ze) labeled with the title (production rate 0.11 (meckah) 1 mm (Vm) salt (A) =) 70.7 Lh (CPCL) 0 k" rang m < 0 (Yl) relay ((W=d) YALA (od) YAY (Vd) 42.4 (Vm) 010.1 (VAY) Rm (11a) let (ema) TAY (Md) tel (Yd) YY E (VY) VED

YY, ((N(CHy)))) VY (A=) dp (Y=) mv (CHOY) £4, (Yd): k- (CH= Y=) under 0) YALE (Y=) YET (Ved) 71 (Ed) (K-?- 01.1 RAAD (CIA) VAY (T=) VAY (VEE) YO A (CH= D (CH= Ed) AY 01 (CH Y =e) 1 (CH= “CH

F(Rtg) AVY (HEE) YVE (Fast Atomic Bombardment Mass Spectrum) k/l (FAB) Tc OH equals U represents ©; X 1 represents Rp allele.” diag R:1(d): the compound with the formula 1 (step mVou) molesine to a suspension of 7.77 gm 1 mani concentration HOT ml of VA was added ml of water During Vo ml of ethanol and Yo c) in 1 (mol) of the compound produced from the inert Ye reaction for nine hours at ambient temperature; Then leave my je for a few minutes. And stir 0 aqueous concentration of ? NaOH (mmol) of VA) to settle in the refrigerator overnight. 4 ml particle was added, resulting in the formation of a white precipitate. The mixture was diluted with water and filtered. The solid, gm of des-cladinosyl compound (compound (7) of 11.7) was washed with water and dried in a vintage vacuum (7).

Example (1) Compound with formula R:1: “J” represents 1 benzoyl; X represents 0 U represents OH VET was added (gm TEA) (Use of benzoic anhydride of concentration 744 and 1.1 mL TL EA (mmol) of triethylamine to a solution of 7.11 g (00 mmol) of M of the compound produced in example (1) in Yo ml of dichloromethane, the white suspension was stirred for 71 dela at ambient temperature, aqueous sodium carbonate, concentration 70, was added, the mixture was stirred for 10 minutes, then extracted with dichloromethane, and Jud the organic phase using aqueous sodium bicarbonate Its concentration was Zo and brine water, it was dried over sodium sulfate and concentrated in a vacuum, resulting in a white foam.By chromatography on silica gel with a mixture of acetone and ve-hexanes, the concentration of which was 7700, YET resulted in grams of the compound labeled with title A in the form of a white solid. (EST) & da (mass spectrum according to the electron spray ionization method) k/u 0 (c+0)+. Example 7 is a compound with the formula:(1)p representing (7-quinolinyl)-:11©-11)-:!1©; RY represents 11 represents 0 U represents OH 1s Step (¥ a): Compound (A) of the diagram R:1() has 505-7 RP (CHy-CH= CH,-(Jaid represents 1.11 ml (£2 mmol) of 7-bromoquinoline and 0.17 mg (;5 mmol) of palladium acetate and ; 7.7 mg (0, mmol) of tri-(ortho-tolyl) phosphine and ALT 10 ml (mmol) of triethylamine to a sample of 71.57 g (mmol) of © - The compound resulting from example is 001 (YT) mL of chloronitrile. The gases were removed from the mixture by forcing bubbles of nitrogen through it for 70 minutes. Seal it tightly in a tube in nitrogen atmosphere; Then heat at 1 00 dL for 1 hour and at 1 00 dL for 1 hour. The mixture was cooled to ambient temperature and diluted with 1-ethyl acetate. organic gall separation; It was washed with NaHCO; From the compound named with the title (production rate

CH) AY GES (EST) Tk AEY,EVY (high-differentiation mass spectrum) calculated for the formula R0-olamine: (HRMS) tk Practical analysis: 4 8591,447. for "0

XH represents (7-Kino Linel)-:1-2011©-:611; * represents R:1(step)¥b: the compound in the form

OH being U «0 representing mmol) of the compound produced from step (?b) +, V VA) stir a solution of 700 mg in ¾ mL of methanol at reflux for six hours. The reaction mixture was concentrated in a vacuum and the ore was quenched by chromatography on silica gel using a mixture of dichloromethane and methanol © mg of the named compound in the title in the form of foam 171 and ammonia in a ratio of 0:0:90, 4 white. AYLY OYE

YALE Kat AAT Tech YT AYA YAY Arlik (YE, as a whole ALY Kat £07) Ark File TeV ATELY YY Balls VEY YLT ae

Aa, aaY,e Ae, HE YAY ALY YT, Arakhalat ALYY | * (Hg) VEY tac k/u (6) Example Jia U 0 diag XH represents 8" cCHL-CH=CH- (Jai 528-1) represents R:1) A Compound of the form 0-Khalil.benzoyl; Jia RP (?-quino linel)-:1-611©-ya©; Jig R (1):(step)£ a): Compound of the form represents 0-Khalil. U0 Jia X oF (mmol) of the compound produced from example +VVA) 001 mg A sample of 560 µl (©,795 mmol) of acetic anhydride was treated; and YA using (FF) in step vo it “NN mmol) of +00 VTE (mmol) triethylamine and ?mg (Y +, 90) µl mL of dichloromethane at room temperature for three 1secimethylaminopyridine days. X 11 represents R® (CHp-CH=CHE-) Ji represents (7-kyno R:1)(E : step (b): the compound with formula 0 1 represents 0-alkyl.© and heated oi £) + mL of methanol was subsequently added to the reaction mixture produced from the -benzoyl step. 1 at 1 °C Rewind heat for five hours to remove the protective group of ge all and upon completion of the reaction; the solvents were removed by evaporation; the ore was purified by flash chromatography on silica gel by chromatography using a mixture of dichloromethane n, methanol and ammonium hydroxide in a ratio of mg of the compound named with the title in the form of VAT to 2:11:70 produced 0 0 7783 white foam (production rate (c + 11)'. YAe k/ U (EST) i.k

NAS EAN computed for the formula R0ROLAMAM: (HRMS) cc

YAe, 45437 Practical Analysis: ( °) Example vo represents U 0 represents XH represents R” cCHCHECH (Jai) 608-1) represents R:1( the compound of the form 0-(;-methoxy) benzoyl. represents benzoyl; RP (7-quinyl)-.11-411©-011; Jig R1(:1) Step (0a): compound of formula 0-(;-methoxy)benzoyl. Jin U «0 dig X fF (mmol) of the compound produced from example + VEY (071 mg a) sample of (mmol) of para- anhydride was treated methoxybenzoyl and TVA) in step (©a) using 850 mg ml of aqueous toluene 1 methylaminopyridine in SENN mmol) of 0, VTE) mg Yo dm for Four days. 0-(; -mtoxy) Jig U 0 represents ve

Add 1 ml of JS to the reaction mixture obtained from step 0 of and heat the mixture

At a temperature of five hours rewind to remove the protective group l? -Penzoyl. And at

completion of the reaction; Solvents were removed by evaporation; The ore was purified by flash chromatography on silica gel

By elution using a mixture of dichloromethane, mechanol and ammonium hydroxide in the ratio of 10 EY eens mg of the title compound in the form of foam

White (production rate (VAS pi k (BST) k/m AVY (C+11)').

The HRMS computed for the formula,

Practical Analysis: AVY, EAE | z

1 1 ) Example Ve has U 0 represents XH represents 00" (7-quinolinyl)-:1a©-11-.11); Jia R:1) the compound with the formula 0-Methane sulfonyl.

A sample of 5.14 mg ©,A (mmol) of CS pall obtained from example oF) was treated in step (7) with 7.76 g (1.3?mmol) M#:anhydride captonyl methane and 7.0 ml (©4,Y) vo mmol) of triethylamine in ON ml of anhydrous dichloromethane at 0°C to room temperature for 10 hours. the mixture was further diluted with dichloromethane; and washed with cada go Sa NaHCO; concentrated and yielded by flash chromatography on silica gel by chromatography with a mixture of hexane and acetone in a ratio of 17:7

4 g of product and 0.60 00 g of unreacted starting material.

7 A sample of 0 #2 mg of the above mixture was heated in ¾ mL of methanol at reflux temperature for three hours to remove the protective group of ? -Penzoyl. And when the interaction is completed; The solvents were removed by evaporation and the concentrate was purified by flash chromatography on silica gel by chromatography with a mixture of dichloromethane, methanol, hydrate and ammonium oxide in a ratio of 8:1 0,0 to von iY yielding 05 mg of the title compound in the form of a white foam (production rate 7488) .

ve TK (881) AYY cash (J+1)'.

i k (HRMS) calculated for the formula 05Rlay] M: E Trav Practical Analysis: 71.4728 (Vv) Jud

Compound with formula R” CH-CHECH- (Jd 0ST) diag R:1)(represents X cH represents 0” U represents 0 | (7-nitro 0-CO-NH-(Jy)

Step 7a: Compound with formula 8(1):(7-quinolinyl)-,011-0112671; “8 Jie benzoyl”

U 0 Jia X represents (7-nitrophenyl)-0-30-1

A sample of 111 mg (8 V0 0.0 mmol) of the compound obtained from example (7) was treated;

In step (#a) using TA +, mg TTY + mmol) of an-ortho-nitrophenyl isocyanate and 0 140 mg (1997"; mmol) of JENN methylaminopyridine in ? ml of anhydrous toluene

At 001 dm for four hours.

Step B)V): Compound with formula:(1)”©” represents (7?- Kino Linell)-:011-211-.1; Jey RY 1 for X

1 stands for (7-nitrophenyl)-0-00-11 U ©; Jiay

A mL of methanol was subsequently added to the reaction mixture obtained from step (7a)” and heated

(Bas iY) the mixture was kept at refrigeration temperature for five hours to remove the protective group of Vo

ie reaction completed; Solvents were removed by evaporation; The ore was purified by flash chromatography on a gel

Silica by denaturation with a mixture of dichloromethane, methylthiol and ammonium hydroxide at a ratio of

1, to v0 Ye yielding 171 mg of the title compound in foam form

(737 yellow (production rate) 0007 YS (EST) 0007 YS (EST) vy.

iK (HRMS) calculated for the formula Rsalmal: 33/321334

Practical analysis: +097,413 3.

(A) Example

Compound with formula (): R stands for (“-quinolinyl)-,1a6©-1!©-.!11)”; A stands for WH not found; RY

OH stands for UH stands for vo

Step A: Compound (?1) of the schema (©): #1 Bag allele; RY represents Khalil. £0 mL (£00 mmol) of maleic anhydride was added to a solution of Avg 01)

mM (Use of compound from example (1) and 0 g TTY mmol) of DMAP in

0 mL of dichloromethane. The solution was stirred for five hours at ambient temperature; The mixture was diluted with 8080 mL a dichloromethane. and washing the organic phase using

Na,CO; its concentration is 75 and NaHCO, saturated clay brine: ching over MgSO, and the solvent was removed in

void The ore is dried. And crystallized in klonitrile produced 10.00 g of the compound named title.

t k (01 t 2) k/st AeA (c + 1) .

Step A) b): Component 0 (a) of the scheme (©); 8 represents an allele; © represents Khalil; It does not represent.”- Ve Khalil Kladinos

16.0 mL (10.0 mmol) of SUE (trimethylsilyl) sodium amide was added

(concentration 1 momol in 1118) to a solution of 7.85 g 1 (5 mmol) of the resulting compound

of step (1A) in You mL of The cooled to -560 dF in a dry ice bath

and nitrile free within 00 minutes. after £0 minutes; A solution of 77.47 g (001 mmol) + .carbonyldiimidazole in 0901 ml of THF and 100 ml of DMF was added and the mixture was stirred for

Two and a half hours at minus 46 dm and 18 hours at room temperature. and watering mix

The reaction was carried out by adding a solution of 80,000 mL of 8:11:00, concentration of 5 molecules. and isolate the product

The reaction mixture was extracted using ethyl acetate. Sada ll was skimmed over MgSO, and the yield was concentrated

raw product which was purified by flash chromatography using a mixture of acetone and hexanes with a concentration of 715-406 ©, yielding £1 g of the compound named with the title (production rate 7/08).

APCI (mass spectrum using a chemical ionization source at atmospheric pressure) K/S 174

(C+11).

Step A) c): Compound (111) of the plot (?); R represents the allele. “© Jig Khalil” 0 represents =f

Khalil Kladinos; 7 not found; RY is .1!

F.A

74-770 mL of concentrated ammonium hydroxide with a concentration of 111 0001 in (QA) was added to a solution of 50.60 g (7.3 mmol) of the compound obtained from the step and the mixture was stirred at room temperature for seven THF ml of 100 ml of klonitrile and days; Then the solvents were removed in a vacuum and the ore was dissolved in acetate. The organic layers were washed with brackish water. It was dried over 0.81050 and concentrated in broilers. The ore was impregnated on silica gel (0 vintage veo) by flocculation with a mixture of dichloromethane, methanol and ammonium hydroxide in a gm ratio of the compound named with the title. YY,

ANY at k/u T(HYz) iAK calculated for China: 0Yayyyyyyyyyyyyyyyyyyy: 37LKa (HRMS) 4 i AAT, 0 Practical analysis: 0

RP represents (7-quinolinyl)-:11©-11-bit R(T) d): compound (107) of diagram A) step HJR RY not found; 1 represents -4 Khalil cladinose; U Khalil diag mM EY) 0.10 g quinoline; and ses mY (mmol) of TY) added 1.47 ml (mmol)_of tertiary-(ortho-tolyl)phosphine and (VAY mol) of palladium acetate and 7.17 g ml (10.0 mmol) of triethylamine to a solution of 70.8 g (77.7 mmol) 3.17 v6 ml of klonitrile. Gases were removed from the mixture 100 c) in A) of the resulting compound from step min; Seal it tightly in a tube in an atmosphere of TL by forcing bubbles of nitrogen through it for a period of dm. and cooled 100 hours at VE dm for one hour and for 10 minutes in nitrogen and heated at saturated and brine water; NaHCO: the organic layer was separated and washed with (JY) the mixture and diluted with acetate and the solvents were removed The crude product was purified by chromatography on silica gel MSO, then dried over © 11.1 gm by lysing with a mixture of acetone and hexane with a concentration ranging from 10-710 to produce the compound called the title. Khalil represents RY » ©11:-611-©1 (7-keno-linel)-(RY) represents H: the compound of formula A) step .1! It represents RY sage other than WOH Jig Na

The compound labeled with the title was produced by treating the resulting compound from Step A) d) hydrolytic treatment with iy acid of the procedures described in Example (1); in Step 1(d).

Sg) 01 JS (APC) tak step A) f): compound of the form (?); b represents 7-kyno (CHy-CH=CH-(Jid) b represents all no o represents WOH not present; RY represents H sakhn 001 mg (1174 mmol) ) of the compound obtained from step A) e) in ¥ ml of heated methanol with reflux for three hours to remove the protective group of L?-alkyl. Chloromethane, methanol, and hydroxy:a-nabome in a ratio of: 08:1 to 0.04, resulting in 0 mg of the compound called the title (production rate of 4.8 71).

HY) Av Haza 0, Haj 5a) ALYY Delta 4,1 (5<chh,0 ham) (CDCL)'H n HY) YAY (Ga AEs Zn Jalarf, 0 SHY) 12 (Ga 1.0 Hz) 0.2 A = z jd HY) 51 Hz TV TL 1.71 Ga Ye dma 211 g s 8 (Ja 0, 0 Y =2 55d) 000A (EH) 131 hm 1.1 Vo, 4=p

HY) 17 (HY) fa kla db) Tech (HY ce) 13 (Sa V,Y=g HD) vo co HY) 17 hamza 1,1 clea G5 dD) TOY E dD) blood (3a n Jahla = pz) no (for 5 AY = m 1.1 hamza HD) 31 on HY) YEA p) dH) Y, Ye F (VL VE Emp 55d) 1 hamza HY) VAN a 0.7 (a 01 (HY) VEY DA LK 01 (a 001 VE Zn Jah HY) Yo A shake 03 (AV=z HY) 01" (Ga 1,1 = z HY) Ye HY) 0 0 1,1 GH (T= WHT) 01 here HY) A Net Jahl Haz). WH represents not present; RY ve represents UH represents 0-Khalil.

ve. mmol) of the compound obtained from the example (TY) +0 mg © 0 Stir a mixture of a solution of 0.01 mL of pyridine, 0.0 mL of 01 in DMAP, and a catalytic amount of (aA) (/); In the step (Jeli ambient). Upon completion of onl hours at a temperature ued acetic anhydride for a period of time, the solvents were removed by evaporation in a vacuum. The concentrate was re-dissolved in 5 ml of methanol and heated at the temperature of the protective group of ?-Khalil Selective removal and evaporation of AY by heat reflux for three hours 0 mg of compound TO solvent; and purify the crude product by flash chromatography on silica gel with the label title. (C+1). U (APC) t k q to 1 calculated for the mikha: N0 RLLAAB: (HRMS) t k .800,490849 Practical analysis: Ve (+) Example RY does not exist; 17 1! represents RY CHL-CH=CH- (Jd 50ST) represents RY) the compound with the formula 0-(?-nitrobenzoyl).dia Na H diay g 0.01 e) and A) In step (A) heat a solution of the compound obtained from example (mmol) of -;-nitrobenzoic anhydride; and 017 g (+00 mmol) of TV) mmol) of tri-butylamine in © ml of VEY + g (00 ml #1 and DMAP) ml of ethyl acetate; 40 dM for four hours. Draw up solution B 001 toluene at and the organic layer was washed with sodium carbonate; water and brine; and dried Above 0, it was filtered and concentrated in a vacuum. The crude product was purified by flash chromatography with a mixture of acetone and hexane in a ratio of 3:7, yielding 076 g of yellow foam (production rate Yo). The product was dissolved in ¾ ml of methanol and heated at reflux temperature for three (78 hours). The solvent was removed In a vacuum, the crude product was purified by flash electrophoresis by electrophoresis with a mixture of 5/107 g of dichloromethane, methanol, hydrate and ammonium oxide in a ratio of 14:2, resulting in (714). C+11).

01 (12) to (11) of iY) following the procedures described in example (10); Except for the use of the acidification reactor described in the preparation of (V0) compounds of anhydride-; -nitrobenzoic used in the example Yay the table below z oll is shown in the table LSU using the moiety (Yo) to (11) examples of non-existent WH compounds in the formula (7) : “1 represents (7-quinolinyl)-:1!©-11)-:11); © represents 0 as shown. UH Jig RY

Hog) MY cash (ES ak | si (eS nS) pyridine carboxylpyridine (Hg) $Y d (651) cash <1 (so) 0 methoxybenzoic methoxybenzoyl) (gbho )* AVA k/u (BSI) chloride-7-thiophene ©-(7-thiophene MacV calculated for the formula (HRMS) carboxylate carboxylate) that

AYA, 717: AVAEYY A | For Practical Explanation: K/U ADE (C+1)* (ESI) & bs Chloride-7-Methyl Propanoyl | ©0-(7-instance "1 calculated for formula (HRMS) K I Pro Banuel) No. 001: Luab Practical Analysis: L. Damer 0 CA/S 1560 (C+ 1) (ESI) ak (L sos i) 0 | e-bromobenzoic anhydride calculated of the formula (HRMS) benzoyl) | mak

01 404, YAY : ) and LAS 56,7877 EXPERIMENTAL ANALYSIS: (C+YR)* AVY k/u (ESI) chloride-; -pyridine 0 (: -pyridine ak YA calculated for the formula (HRMS) carboxylate carboxylate) ak

AVY, £104 : Loal © 897747531 Practical Analysis: k/st 11m (c+1)* (ESI) Mac | S51) 0

B carbonyl)

H(Htg) ATA Di-Th-Butyl-Diac (001) K/U Enoxycarbonyl Carbonate)” (Htz) 90% K/U (ESI) 7-Bromobenzoic Anhydride | 0-(7-bzomed mac benzoyl) for cache 07 (c+1)* (BSI) (-(-methoxy|ac-benzoic A (c+11) ANY k/m (ESI) ak DAY) 0 |chloride-7-furan (Cr-Boxyl) (Cr-Boxyl) (Hg) AVA BS (851) butanoyl anhydride ©-butanoyl AT K Y¢

H(Htg) AE Cash (BST) Methane Sulfonyl Chloride 0 Methane Sulfonyl Chloride | Mac Yo Calculated for Format (HRMS) Z 5 KB

ALLEY Carmelmen: 855,477 6 Practical Analysis: (Hg) AY k/m (BSI) 0-(7-Methylpropene 1 kC Carboxyl) (1) Jed

011 other than W 0 represents XH represents R? (7-quinolinyl)-:611©-011-,011; R:1) The compound with the formula represents Phenyl-0-00-1.U present; ) of the compound obtained from Example (8); and 1,111) from step (4e); and 1.4 mg pyridine in 7 mL of anhydrous toluene at methyl sid GEN (174; mmol) from 6 dM to The analysis by thin layer chromatography showed complete consumption of the starting material. The mixture was cooled to room temperature, then 4 ml of methanol was added. The mixture was heated at reflux temperature for hours to remove the #-Khalil group. The solvents were removed by evaporation; The ore was purified by flash chromatography on silica gel by liquefaction first with dichloromethane and then mg 006 Vantage 1,05:1:100 with a mixture of dichloromethane, methanol and ammonium hydroxide in a ratio of - (ZY +r) from the compound named with the title ( production rate

AAV EAT i.e. the computed higher differentiation of formula 9, have:

ANY EAT PRACTICAL ANALYSIS: Compounds of the formula (YU) to (YA) 7:) in the form of vo except using a YY isocyanate reactor following the procedures described in the example shown in the table below Instead of phenyl isocyanate in example (77), the examples shown in the table below were prepared. (7): © represents (3-quinolinyl)-,011©-01©-:11©; Na as shown. ) (PCI) dL] 0-CO-NH-JA Lyle isocyanate YA calculated for formula (HRMS) y k

Ao, EAT (CHNL On

Neo ] "(Htg) AVY Cache (APCI) 1 phenyl0-4 jit ;-nitrophenyl | Yo Calculated for Formula E | 1771787 and 0 maltamam: | :

IVY, £11): lead) Analysis (Hig) 010 Cash (APCI) 1 tc-4 4;-1 methoxyphenyl Calculated for formula (HRMS) phenyl isocyanate-0- 00-1411 | i k

VY, and 0ptukami: 17 h

FIYRICT Practical Analysis: (ry) The proverb does not exist WH represents RP «CH-CH=CH,~(Jiid 585 V) represents R:7() compounds of the formula 0-8( 0),-CH=CH, Jia; U 11 represents ©“natha-1-roulic-”?-dirulec mmol) from 1.37 edn +, YY) added 77,” g

JU g (1.100 mmol) of the resulting compound of 1,57 sulfonyl to a stirred solution of 0 mL of pyridine cooled to 0°C. and warm the mixture to 117 AH); In V) step (VY) is the temperature of the ambient atmosphere and an overnight stir. The mixture was diluted with 0 lb of ethyl acetate; the organic layer was washed with saturated sodium bicarbonate; water and brine, dried over 148:50, filtered and concentrated in a vacuum. The raw material was purified by chromatography © with a mixture of dichloromethane, methanol and ammonium hydroxide in a ratio of 14:9:. The product was dissolved in -0 mL methanol and heated with regurgitation for three hours. The solvent was removed in chicks; The material was purified by chromatography by chromatography with a mixture of dichloromethane, methanol, and ammonium hydroxide (VY g) from the compound called the title (production rate 01.0971, with a ratio of 1:90:14, yielding (c + 0).” AeA Cash (EST) tak (YA) example yo

0 Compounds of formula (7): R is (7-quinolinyl)-.61©-011-,11; RP has W eH other than 990( “2 represents 0-5(0),-CH,-CH,-N(CH3), Jia U ¢H 1.004 mL of dimethylamine added Its concentration is 7 moles in 1117 to a solution of 7 g (YF) + 00 mmol) of the compound obtained from example (VV) in ? mL of klonitrile; 0 and stirred the solution for 11 hours. The solvent was removed in a vacuum; The material was purified by chromatography by chromatography with a mixture of acetone, hexane and triethylamine at a ratio of 1:70:76, resulting in 1001 g of the compound called the title in the form of white foam (production rate 4 77). (BST) dL k/u 107 Fare) for “a example (¥4). Compounds of formula (7): R is (7-quinolinyl)-,11©-11©-:011;” 8 WH Jia is not present; RY stands for U H stands for Phenyl-5-,011-,011-:(0-8)0 Prepare ,010+g of the compound labeled with the title following the procedure described in example (YA ) except for the substitution of dimethylamine by thiophenol (production rate 7778). Compounds with the formula (?): R stands for (CHp-CH=CH,-(Jiid 86 Y) © W stands for cH not found; RY stands for Jig UH allyl-0. Added 1, Use 07 g (0.90 mM) of NaH 7710 in mineral oil to a stirred solution of 6.08 g (00083 mmol) of compound obtained from Example (A) Step A) ve (e)YYY 0 g vu YW) fill 194 mM (Use) of cdl bromide in ¥ mL of THF cooled to 0°C. The mixture was stirred overnight; then diluted with Yo ml of ethyl acetate, washed with water and brine, dried over 14:50, filtered and concentrated in vacuum.The raw material was purified by chromatography by chromatography with a mixture of dichloromethane, methanol and ammonium hydroxide in a ratio of 0:0:14, and the product was dissolved in ½ ml of The methanol was heated by reflux for three hours, the solvent was removed under vacuum, and the material was purified by chromatography with a mixture of

10 g of the mixture of 1,014 chloromethane, methanol and ammonium hydroxide in a ratio of 1:2:14; Production (718) labeled as white foam. oH stands for RP stands for (7-quinolinyl)-,11©-011-,011;R:1(compound of formula 0 (;-morpholine carbonyl)-0.Jig U cH stands for mmol) of sodium di(trimethylsilyl)amide +, YO) mL 0, YYO (A) was added dropwise to a sample of 15 mg (,1197; mmol) of the compound obtained from Example dm below zero and fe dry cleaner cooled to THF e) in ?ml of step A) min. 8.5 mg 01 nitrogen was added; the mixture was stirred at 50 d. C below zero for mmol) of chloride-; zero to thin film chromatography with some starting material remaining The reaction mixture was cooled to -56 dm and both reactors were added in the same manner as described above; the reaction was left to continue for a further two hours with the temperature slowly raised to chamber and dilute ae mixture with ethyl acetate; washing with sodium bicarbonate 70 and brine water; Jeli was dried over B50E11 and concentrated to produce the crude product. The material was treated with b + ml of methanol at the reflux temperature for four hours to remove the 7-chloride group of the compound called the title.

J(H+g) AMY k/m (BST) tk . AA 0.117 (CyHuN,0); Calculated for formula (HRMS) & 2d 881.54177. Empirical analysis: (metal L8” not found; W represents Al, RP represents (7-quinolinyl)-,60© -011-,011;R:7) The compound with the formula is 0.0 U H Jig

01 | Prepare the compound named with the title by following the procedure described in Example (£1) except for the substitution of -; '.Jud.(£7) Compound of formula (7): R stands for (7-quinolinyl)-,11©-011-.011; R® stands for WH not present; R' representing Ji U cH (7-tetrahydropyranyl)-0.00 mg (+001 mmol) of the compound produced from example (A) step (4e); in ?mL of dichloromethane was treated with 0.01 mL (.01 mmol) of 0;-dihydro-117-pyran and a catalytic volume of p-toluene sulfonic acid at room temperature for 2 h. The reaction mixture was washed with aqueous NaHCO; and dried. The group 7-alkyl was removed by normal treatment with hot methanol, resulting in YA mg of the named compound after purification by chromatography with a mixture of dichloromethane, methanol, and ammonium hydroxide in a ratio of 0:85:14 (production rate VY, ae TK ( 881) AoY GES (C+1). 1) represents (7-keno Linell)-.11©-011-,011; RP is WH not found; RY © stands for U H stands for 31-5801---0. An excess of NaH was slowly added to a solution of the compound produced from example (A) step (4e) in THF at -01 dM in an inert atmosphere over a time period of 6 minutes; Then I add CS, after a few minutes. Methyl iodide was added after a few minutes; The reaction mixture, Bag, was left to 10 dl gradually. After one hour, the reaction mixture was irrigated with vo-ethyl acetate and the organic layer was washed with saturated aqueous NaHCO and brine; It was dried over MgSO and concentrated

Ved We produced the raw product. Purification by chromatography with a mixture of silica, acetone and hexane resulted in a range and the 7-acyl (TF) group was removed to 1:; The xanthate compound at a carbon atom of 0:1 ranges from overnight treatment with hot methanol, resulting in the compound called the title.

AeA Cash (BST) AOA EV Calculated for Formula 0:Multiple: (HRMS) 00

AoA Evo: Leal) analysis (¢°) Example Al dha) be and do not form UH representing 8” “CH,-CH=CH, representing R:1( the compound in the formula

H stands for RY not found; W

U stands for benzryl Na and RP stands for “CH-CH=CH, stands for R:1(step)0£a): compound of formula 11.0 stands for RY not present; 17 together form double bond; mL (10.0 mmol) of sodium dis(trimethylsilyl)amide 1.00 g (13 mmol) of compound of 001 was added to a solution of THE molecules in 1 concentration and 0 ml of THF (ml of 001 in CDI g (19.0 mmol) of #11 Example (7) and min. 01 d. below zero in a dry bath of ice and klonitrile during 500 dmf cooled to VO 1 hour at 18 degrees and stirred for two and a half hours at minus 46 dm for 0.8 ml of ,14:11: 00 concentration is 0010 room temperature. And quenching the reaction mixture by adding a solution of two molecules. The product was isolated by extracting the reaction mixture using ethyl acetate. The extract was dried over 16 ml of Chlonitrile and 17618 and concentrated to produce the crude product. This substance was dissolved in MgSO, ml of concentrated ammonium hydroxide with a concentration of 78-7970 without purification. YY of 2211# and © and the mixture was stirred at room temperature for three weeks. solvents were removed in a vacuum; MgSO, the ore was dissolved and concentrated in ethyl acetate. The organic layers were washed with brackish water; and dried up in a vacuum. The ore was impregnated on silica gel by liquefaction with a mixture of dichloromethane and methanol, producing the compound called the title 0.05:1:01 and ammonium hydroxide in a ratio of

00

U 5 UH represents RP «CH,-CH=CH, level R: 17 (Step (0£b): Compound of the form

H represents RY is not present; WAG and bee bond form A sample of the resulting compound from step (45a) was treated with methanol at the reflux temperature for three hours, resulting in the compound called the title. C+0) WY YS (BSH) Tk 0 (£1) Jud represents Al Na and “Na forms RY represents (*-quinolinyl)-,11©-011-,11©; R : (1) The compound in the formula

H Jia RY not present” W with double bond ;

Ca A) mg YY 137 mL (534+ mmol) of 7-bromoquinoline was added; f mmol) of tri-(ortho-tolyl)phosphine (VEY) mmol) of palladium acetate and £0 mg © mg (£3 mm Yoo mmol) of triethylamine to solution of V,YY) 1.171 mL and mol) of the compound produced from Example (45); step (©;b); in ; ml of klonitrile. a minute was removed; Seal it in a tube in 700 gases from the mixture by forcing bubbles of nitrogen through it for any ped Av hour at VE dm for one hour for 10 atmospheres of nitrogen; And heated up

God is saturated with brine water; Then NaHCO was dried; Mix and dilute with ethyl acetate. Where separated and washed b. The solvents were removed and the crude product was purified by chromatography on silica gel by chromatography with a mixture of MgSO, of acetone and hexane, with a concentration of 6;-7710, yielding 160 mg of the product (production rate 8 (c + 1)). Yoo isd kh 7n Ola 71 Calculated for Worllamine formula: (HRMS) & i 7 6,47 117 Practical analysis: (£4) Examples from (7?) to are shown in the table below; WSR Attended Example compounds (97;) to (£3) where by following the procedures described in Example (49); except for the use of an aryl halide shown in £7) table below instead of the reactant 7-bromo-quinoline in example vo

VA a wera | «| sw aw]. , db J A £A k/u 074 (c+11) naphthalene (HRMS) & ka calculated for the formula 0 RLOLABNA: 567 for experimental analysis: 45417 YVA, (form name furanyl) isoxazole example } 0 ¢) Compound of formula (4): “CH,-CH=CH, Jia R” 8 represents K; U possesses OH Step (04a): Compound of formula (?): R ® “CH-CH=CH, Jia R is an acyl; Na represents 4;>- 0 acylcladinose 17.8 mL VY,A (mmol) of disodium (trimethylsilane)amide was added concentration of 1 mole in THF to a solution of 0.1 g (11.1 m) (se) of the compound produced from step (TA) in 151 mL of THE cooled to minus 56 dm in a dry bath of snow and klonitrile during yo min and after 11 min a solution of TA g (£.9 mmol) of 0 |carbonyldiimidazole was added in 080 mL of THF and the mixture was stirred for 2½ hours at -560 dC and warmed to room temperature for 1V min.The reaction mixture was quenched by adding a solution of 0 0 ml of 14011.00, concentration of 10 + molecular. product isolation by extraction of the reaction mixture with ethyl acetate; The extract was dried over MgSO, and concentrated to yield the crude product; which is pure

VAY

710-460 by flash chromatography using a mixture of acetone and hexanes with a concentration of ZY (g) of the titled compound (production rate 1.41 ph. (c+1) AME k/v (BST) ) dL .011 represents U methylated chloride “RP” CH,-CH=CH, Step (04b): The compound with the formula (#): 1 slowly converts to a solution of ZEA mol) of hydrobromic acid its concentration AA) was added; ml o ml of VE (100 mmol) of the compound obtained from step VIIA) from 1.75 g ml of water until the solution becomes clear. And when the reaction is completed as determined by VE ethanol and its concentration? Standard for quenching NaOH by 17.8 ml thin film chromatography; Add ml of ethyl acetate. You washed the reaction mix. The ethanol was removed in a vacuum. and dissolve the ore in water and brine; And dried over (ida +,0 concentration of NaOH) ethyl acetate solution using

CHCl, and concentrate and purify the crude product by chromatography on silica gel by chromatography with a mixture of MgSO, yielding 7.77 g of the named compound in the form of 0:90:10 and methanol and 141,011 in a ratio of 7975.8 (white foam). Production rate (Hg) 184 iS (EST) tk (0)) Example vo

OH Jia U represents the Khalil; R® «CH-CH=CH-(J3id 50S—Y) Jia)R4() compound with the formula

Va YY) mg OF mmol) of 0-bromoquinoline; and (Y, £71) g 011 mmol) of tri-(ortho-tolyl) phosphine (YY (00 mg) 71 mmol) of palladium acetate and g( 7) were added; .7 mmol (1.1 mmol) of triethylamine to a solution of (£,TA) 1.11 g and 1 ml of klonitrile. The gases were removed from the mixture 01 (00). of the resulting compound © by bubbling nitrogen through it for 90 minutes; And tighten it in a tube in an atmosphere of d.m. and cooled 100 hours at VE dm for one hour and for Te nitrogen and heated at saturated and brackish water; NaHCO; The mixture was diluted with ethyl acetate, the organic layer was separated, washed with B, solvents were removed, and the crude product was purified by chromatography on silica gel MgSO, then dried over

WY

So, the compound named T = Ee was produced by denaturation with a mixture of acetone and hexane, the concentration of which ranged from in the title. (C+1) MY GES (BST) vol. (57) Jud

H stands for 1 «OH Jia U stands for ]]; R? “CHy-CH=CH, R:7) has a compound of the form 0 representing a chloride. ©” J dig ©7:) from the diagram (ivy (step (0%)a): the compound 7.17 mL (79.1 mmol) of ethylenediamine was added to a solution of 7.15 g in 0 mL of (A) step (A) mmol) of the compound produced from (Example 91), and the solution was stirred in a nitrogen atmosphere overnight at “The Chlonitrile” and ml of dm for three hours. The solvents were removed by evaporation; Av was dissolved at room temperature; then heated at > and brine, dried and concentrated. NaHCO; the ore in ethyl acetate. and washing the solution with 11 ally; From ethanol to 400 The compound obtained from step (7©a) was re-dissolved in a mixture of ;, ml of acetic acid and the mixture was heated at reflux temperature for five hours. The ethanol was evaporated and the ore was dissolved in dichloromethane; then washed ve aqueous sodium bicarbonate; brine and dried the concentrate. Khalil represents. RP Jill represents R:©( from diagram (YY) Step (7 5c): Compound B) in 00 mL of a second (0X) solution of the crude product obtained from step mL was treated of triethylamine at 7,500 chloromethane using 7.4 ml of acetic anhydride and 1 h. Solvents and unreacted reactants are evaporated; The crude product YE was purified at room temperature for > © 7.76 Vintage 0.0 0:1:0 by chromatography with a mixture of .011:01, methanol and 101.011 in a g ratio of the compound called the title (production rate 745.7 in the three steps). (c+1) 16 k/m (BSI) tk allyl. Jig ©”:©( from diagram (YY) d): compound 2X) step

00 mM YY) g 7.01 ml of 1101 aqueous, its concentration? My gauge to a comment of 01 minutes added. And stir 10 ml of ethanol through 10 c) (oY) mol) of the compound obtained from the hour step. At this moment, analysis 11 of the reaction mixture at ambient temperature for ml of acetate #50 by chromatography in the form of a thin layer showed the completion of the reaction. Add a portion equivalent to its aqueous concentration? standard. and dilute the mixture NaOH mL of ethyl yo to the reaction mixture followed by 0 saturate; The layers were separated and the organic phase was washed with a NaCl solution using ethyl acetate and saturated Gay, dried and concentrated in a vacuum, yielding 1.71 g of the dis-cladinosyl compound named NaCl from (AYALA) with the title (production rate z | F(Htg) 718 Cash (BST) TK NAA EEY0 Calculated for the formula R0rlam: (HRMS) TK 0

RAY REAR PRACTICAL ANALYSIS: “OH chelates, O, Na, methylates RP” CHp-CH=CH, 1: (7): the compound with the formula oY) step 11. represents U A sample of the compound obtained from step (0d) was heated with reflux in methanol for four hours, producing the compound labeled with the title. JAY hours to remove the group - .' (c+1) 117 iS (BST) tk (oY) Example 1: (OH stands for (7-quinolinyl)-:011-017-:11; © ! © 1:) Compound of the formula Khalil Jie 8” (7-quinolinyl)-,11©-011-,11©;diay R 7:(Step 0a): Compound of the formula © 11. U «OH represents Na (£7) Prepare the compound labeled with the title by following the procedures described in the example (£7) of the feedstock in Example Yay d); 0X)shall ((0F ) except for using the example compound (c+1). ave k/u (ESI) dk

11 11 represents (7-quinolinyl)-:011-011-.11.” A represents R:(compound with formula 1 oF) step H represents U OH represents U in methanol For four (1 ov) hours a sample of the compound produced from the example was heated with rewind to remove the 7-alyl group and produce the compound labeled with the title.

SH) YAY GS (BS tc 0 (° ¢ ) Example Namctl cH of compound of formula (4): © imql(7-quinoliyl)-.11©-011-.011; Phenyl-(0-6)0. The compound named with the title was prepared in two steps by following the procedures of acidification at the ©-km site and removal of the alkyl group at carbon atom (7) described in Example (10); except for 1. Using benzoic anhydride instead of acetic anhydride. ‎(C+0)'. -(dsid 53S V) Jig R:4:(the compound with the formula phenyl)-(0-2)0.1 The compound named with the title was prepared in two steps by following acidification procedures at the 0-km site and removing the Hebron group at Carbon atom (7) described in example (10); except that 1-nitrobenzoic anhydride is used instead of acetic anhydride. Y.

Jia UH represents RY (NH Jia WH represents RP (CH,-CH=CH, represents R):7) the compound with the formula -OH ="¢ is U Khalil; Jia 8” From Scheme (7): © represents an allele” (i V1) Step (1©): compound

JH Jia RY NH Jia 17 Khalil Cladinos;

Add 1.77 mL (11.7 mM) (Use) of anhydrous hydrazine to a solution of 7.10 g (¥ 90 mmol) of the compound produced from step (A) in Vo mL Who is Chlontril and? ml from 8 . The solution was stirred under nitrogen atmosphere at room temperature for 1 hour. The pally solvents were removed and the ore was purified by chromatography on silica gel by chromatography with a mixture of 0:10 to 0:40 acetone and 0:80 acetone, yielding LEA g of the labeled compound. tk (EST) k/u AA (c+1) . step (01b): compound with formula (7): 8 diag allele; 8 represents Khalil; U represents WOH, RY represents NH, represents JH, and Ve. The compound was treated with the formula: (1) where R represents RP «CH-CH=CH, WH represents Rs (NH represents 1 L and Na represents 4-(Acetylcladinose) obtained from step (1 07) using 1 M HCI in ethanol following the procedures described in example (1); step (1d); Discladinose compound Step (01c): Compound with formula (7): 8 represents (CH-CH=CH, ' represents (NH Jia WH RY vo represents 11 Na OH Jia heated with reflux A sample of the resulting compound from step (0b) was soaked in methanol for five hours to remove the JAY group, resulting in the titled compound. IK (ESI) K/U206(C+0)". Example ov) © - Compound with the form (©): R represents (1a©-11©-.11; R” mitl 1]; U is OH .m below zero for about 30 minutes using carbonyldiimidazole and sodium hexmethyl disilazide.The intermediate product was treated with ethanolic HCI, producing an intermediate discladinose compound, where © represents Khalil. This compound was heated with

17 Rewind with methanol overnight. The crude product was purified by chromatography on silica gel, resulting in the compound named with the title. in the formula

o A sample of the intermediate compound D-cladinose, where 18 represents Khalil obtained from example (0), was treated with acetic anhydride, to produce the intermediate compound, where 8 represents Khalil and U represents Khalil-0. This compound was heated with methanol reflux overnight. The product was purified Crude by flash chromatography on silica gel to produce the compound called the title.

| Example (2) Ve compound with the formula (©) R represents (UH Jia UH Jia) 8” “CHp-CH=CH, represents H A sample of the compound was treated with D-cladinose intermediate, where 8 represents the product of Example (oY) using tertiary (p-butyl)tin hydride in a nitrogen atmosphere and a catalytic amount of AIBN in toluene at the reflux temperature, resulting in an intermediate compound containing a “7-alyl” group, and the 7-alkyl group was removed by overnight treatment with Hot methanol produced ve the compound named with the title. Compound with formula (7): © (CHy-CH=CHy (sid 5iS7Y) 8 represents WH not present; RY represents H na represents UH A sample of the intermediate xanthate compound where “8” represents the acyl product of the example (£8) > was treated with tri(p-butyl) tin hydride in a nitrogen atmosphere and a catalytic amount of AIBN in toluene at a temperature The reflux produced an intermediate compound containing a 1-alkyl group, and the 7-alkyl group was removed by an overnight treatment with hot methanol, producing the compound labeled with the title.: Example 1(0

Ghala compound with formula (7): 17 does not exist; RY represents 11 © represents “CH,CH(O) !1 represents U H represents .OH The resulting compound from (A)JE was treated (step A) b); Using ozone in a nitrogen atmosphere followed by treatment with diphenyl sulphide and triphenyl phosphine. The intermediate compound M was treated with ethanolic HOE and the product was heated with methanol reflux overnight. The crude product was purified by chromatography on silica gel, producing the compound called the title. Example 0)(Y) compound with the form 1:17( does not exist; RY stands for RH stands for “CH,CH;NHCH,~d—i8 !1 stands for U H stands for 011. , fix The resulting compound from example (11) using benzylamine in dichloromethane Gila in the presence of molecular sieves Lege hE; The intermediate compound using ethanolic HOE, this product was heated with methanol reflux overnight. R eH represents “CH,CH,NHCH,CH,~ di q represents 11; TA represents 011. The compound from example (TV) was treated with phenethylamine in dry dichloromethane in the presence of molecular sieves RE eyes; angstroms; the resulting imine was treated with pH catalyst of palladium on carbon with a concentration of 701 at one atmosphere of hydrogen. The intermediate compound was treated with ethanolic HCH; this product was heated with methanol reflux overnight. The crude product was purified chromatographic On silica gel, we produce the compound called the title. Example (4) Compound in the form (): 17 does not exist; RY represents !l R represents <CH,CH,NHCH,CH,CH,— Ji vo #8 represents U H represents Oh

Via using ?*-phenyl-1-propylamine in the second (13) JU. The resulting compound of dry chloromethane was treated in the presence of molecular sieves with eyes of 1 Å in diameter; the resulting imine was treated under one atmospheric pressure of 701 By using a catalytic amount of palladium on carbon of ethanolic concentration, this product was heated with hydrogen HOE reflux, the intermediate compound was treated with methanol overnight, and the crude product was purified by chromatography on silica gel, resulting in the compound named title 0 Te ( Ex. 2 Nissl- J GR HJ Sag RY not found; 1:11) the compound in the form

OH represents U H Jia “OH” CH,CH,NHCH,CH,CH,CH, The resulting compound from example (11) was treated with 4-phenyl-1-butylamine in 1-dichloromethane dry in the presence of Molecular sieves angstrom eyes diameter The resulting imine was treated at 1 atm of 701 using a palladium-on-carbon catalyst of ethanolic concentration This product was heated with hydrogen HCL reflux The intermediate compound was treated with methanol for a while The crude product was purified by chromatography on silica gel, and the compound named with the title was produced. ,

OH represents U represents O R “CH,CH,NHCH,CH,CH, amine in Gary pr Vm (ASW) The resulting compound from example (1) was treated using a molecular diameter of its eyes; Angstrom. The imine was treated with "Jule" dry dichloromethane in the presence of © under one atmospheric pressure, 7901, using a catalyst of palladium on carbon of ethanolic concentration, and this product was heated with HCL of hydrogen. in methanol overnight, and the crude product was purified by chromatography on silica gel, producing the compound named with the title (ly) for example Yo

0 : compound of the form (): 17 does not exist; R represents R 41 represents (CHCHNHCH; = dl pS w8 represents UH represents OH The compound from example (1) was treated with 7-(aminomethyl)quinoline in dry dichloromethane in the presence of screens Molecular eye diameter: angstroms The resulting imine was treated with a catalyst of palladium on carbon with a concentration of 701 under one atmosphere of hydrogen The intermediate compound was treated with ethanolic HOI This product was heated with methanol reflux overnight The crude product was purified by chromatography on silica gel, resulting in the compound named Co. Did: (1 : - the compound with the formula WHY) not present; RY represents RH mates xenyl) RP “CH,CH=NO mates U H represents OH The resulting compound from example (1) was treated with hydrochloride-0-phenylhydroxylamine in dry dichloromethane in the presence of 3 Ethylamine. The intermediate compound was treated with “ethanolic HCH.” This product was heated with methanol reflux overnight. The crude product was purified by chromatography on silica gel, resulting in the compound called the title. Nothing but an abstract; RY has R 11 amethyl (phenyl) R® (CH,CH=NOCH, representing OH Jia U H) The compound named with the title is prepared from example compound (1) and -0-benzyl hydrochloride © - Hydroxylamine in dry dichloromethane in the presence of triethylamine.The intermediate compound was treated with ethanolic HCI;this product was heated with methanol reflux overnight.The crude product was purified by chromatography on silica gel, resulting in the compound named with the title.(v2)gad compound with the formula ( 7): W is unabsorbed; RY represents RH represents CH,CH=NOCH, (phenyl-U!h-RP »)4 Yo represents ILNA represents OH

171 and hydrochloride-0-; -Nitro (11) The compound named with the title was prepared from the example compound, phenylhydroxylamine, in dry dichloromethane in the presence of triethylamine. The intermediate compound was treated with ethanolic [16]; this product was heated with methanol reflux overnight. The crude product by chromatography on silica gel, resulting in the compound named with the title. The compound named with the title was prepared from example compound (11) using 0-(;-quinolyl) methylhydroxylamine in dry dichloromethane in the presence of triethylamine. The compound was treated the intermediate using 116 ethanol; this product was heated with methanol reflux overnight. and purified © the crude product by chromatography on silica gel producing the compound named title. (VY) Example SCH,CH=NOCH,~ (Jal siS= Y) represents R oH represents RY does not exist; 7-quinolyl) vo hydroxylamine in dry dichloromethane in the presence of triethylamine. Install the medium and heat this product with reflux with methanol overnight. The crude product, oil 1101, was purified using chromatography on silica gel, resulting in the compound named with the title. (Vr) Example “CH,CH=NOCH,~ (Jd 5iS~Y) represents 11 8 RY represents the compound By formula (7): 7 does not exist; Ye .OH represents U H Jig R? And 0-(7”-quinolyl)methyl (TV) The compound called with the title was prepared from the example compound hydroxylamine in dry dichloromethane in the presence of triethylamine. The intermediate compound was treated with ethanol, and this product was heated with methanol reflux overnight. The crude product, HCL, was purified using chromatography on silica gel, producing the compound called the title.

Composite example (Yi) of the form (7): 17 does not exist; RY represents 11 R less than (CH,CH(0) “© means UH represents 011. The resulting compound from Example (07) was treated with ozone in a nitrogen atmosphere and then treated with Jie dioxide sulfide and triphenylphosphine, the intermediate compound was treated with ethanolic HCI, and this product was heated with methanol reflux overnight. No Not present; R represents RH represents R CHCHNHCH, Us represents OH Jig UH 0 The compound from example (VE) was treated with benzylamine in dry dichloromethane in the presence of angstrom-eye diameter molecular sieves The resulting imine was treated with a catalytic amount of palladium on carbon with a concentration of 70 under 1 atm of hydrogen The intermediate compound was treated with ethanol HOT, and this product was heated with methanol reflux overnight.ae The crude product was cured by chromatography on silica gel So we produce the compound named with the title. Example (V1) Compound with the formula (?): 177 does not exist; RY represents RH represents “CH,CH=NO (Jai) ' represents U H represents OH treated compound obtained from a For example (VE) using -0-phenylhydroxyl©-amine hydrochloride in dry dichloromethane in the presence of triethylamine. The intermediate was treated with ethanolic HCI, and this product was heated with methanol reflux overnight. The crude product was purified by chromatography on silica gel, producing the compound called the title. Composite example (VY) of the form (4): W does not exist; RY stands for (CH,CH(O) dias R olf "© stands for UH vo stands for OH

The resulting compound of JUL (00) was treated with ozone in nitrogen atmosphere and then treated with dimethyl sulfide and triphenylphosphine. The intermediate was treated with ethanolic HCl; this product was heated with methanol reflux overnight. The crude product was purified by chromatography on AGL gel produced the compound labeled with the title. > Example (YA) compound with formula (4): 7 is not present; RY represents RH represents RP (CH,CH,NHCH,— did represents U H Representing OH The resulting compound of example (VY) was treated with benzylamine in dry dichloromethane in the presence of 1 ang diameter line molecular sieves The resulting imine was treated with >0 catalytic volume of palladium on carbon of concentration 701 under one atmospheric pressure of hydrogen. The intermediate compound was treated with “ethanolic HOT” and this product was heated with methanol reflux overnight. The crude product was purified by chromatography on silica gel, resulting in the compound called the title. Not present RY represents ROH represents (phenyl) RP “CH,CH=NO represents UH | 10 represents OH The resulting compound from example (VV) was treated with 0-phenylhydroxyl hydrochloride My mom n in dry dichloromethane in the presence of triethylamine. The intermediate compound was treated with ethanolic HCL. This product was heated with methanol reflux overnight. The crude product was purified by chromatography on ciaica gel to produce the compound named title. A) Example B Compound in the form (©): OV) using ozone in a nitrogen atmosphere and then treated with dimethyl sulfide and triphenylphosphine. The intermediate was treated with HCI

14 ethanolic” and heat this product with methanol reflux overnight. The crude product was purified by chromatography on silica gel, producing the compound named with the title. A AN) Example: RP represents phenyl-:11:011:1110]1” RH represents RY Not found; 17:©( compound in the form

OH stands for UH | 0

Gila with benzylamine dichloromethane (A+) The resulting compound from the example was treated in the presence of molecular sieves with a diameter of their eyes; angstrom. The resulting imine was treated with one atmosphere of hydrogen. 701 palladium catalysts were treated with ethanolic carbon; This product was heated with methanol reflux overnight. HOT the intermediate compound using Certification of the crude product by chromatography on silica gel resulting in the compound labeled with the title. (Ar) Example RP represents (phenyl) 01:011-40 R oH RY represents the compound with the formula (©): /l1 not found; Dry dichloromethane in the presence of triethylamine. The intermediate compound was treated with 1 ethanol and this product was heated with methanol reflux overnight. The crude product, HCI, was purified by chromatography on silica gel, producing the compound called the title.

Claims (1)

Chord 1-1 is a compound selected from the class consisting of: Jaabel Al 06 7 Al YATRA | Q on. 3 0 “7 HO,,, p S Y cel > 0 MN ey HO 0” TY wl na 0 2 0 0 IM l 3 oy 1 LI Ou, > “8: Sell 3 Sw A Return” Qo 7 7 Milk. 0 ~y \ J : 0 hE 0 7 N : 8 ia NMe, t CN No on A i. 5) Ramla rd EL 0 0 l 8 a 0 l z 0 : 17 8 mg NM, 0 ~~ 7 A 0 Or. On, S 3 JA BY 0 Ww u LK 8 0 8 3 8 88 NMaoq 0 To 7 0 On. ~~ Qu, = 0 1 < on. oe ° or 0 > no 2 0 (°) no, its salt, its ester, or its primary drug that is acceptable in pharmacies, where A . X set ba Lao 27 form 3 where Ve chooses from the category consisting of: X 1 “=0 ( 1 ) VY “=N-OH (Y) VY from the category consisting of: RY where =N-O-R' (7) chooses VE : (a) alkyl (k,-k,,) unsubstituted Vo (b) alkyl (k,-k”,), bearing an aryl substituent; 1 1 carries a substituent aryl” (1 yd dl) alkyl (z) VY d VA (d) alkyl (k,-k”,) Sas bears an aryl alae Va (2) alkyl (k,-k,,;) bears a mixed aryl substituent » " 5 )( cycloalkyl (how-k?); (J) A (5-82)8()8- where 1 and GR 87 are selected separately from alkyl (=i) (bed A and aryl; =N-O-C(R*IRY)-O-R' (£) vy where RY stands for its former meaning and selects 185 and SSR 7 apart from the class consisting of: vo (a) hydrogen; 1 (b) alkyl (k,-k,) unsubstituted; 1 rv (c) alkyl (reir) substituent of aryl; YA (9) alkyl (seedy) substituent aryl substituents; (a) “(vie)alkyl substituent aryyl” and 9 (f) alkyl OE ENE substituent aryl 71 or ry C and RE They form with the atom to which they are attached an alkyl ring (revel) Gila YY or Y Ye and 7 one of them represents a hydrogen atom and chooses the other from the category consisting of: (V) Yo hydrogen » (Y) 791 hydroxyl 9(7) buffered hydroxy; vA(?) 11878 where 17 and JSRY separately selects from a hydrogen and an alkyl (k,-7 ke) or forms an “8” and RY with the nitrogen atom to which it bonds Triple to Seven Ring 3 members form a ring; and when The ring is five to seven and may contain 3 heterofunctional groups chosen from the category consisting of -0-, -NH-, (Ned alkyl, ty -(aryl)0<, (ND alkyl) ( dma) and (alkyl (k,-k,.) aryl substituents)- and (aryl AYA f (alkyl (k,-k) aryl scrambled) and (alkyl (k,-k) aryl scrambled) 1--N(dabis ey XV f) 80 where « equals -S - and tt - and -N=CH- and -NH-CO- do not exist or choose from the -0- component group and SW to ¢ {NH- £1 choose from the component category of: RY Lv hydrogen; (V) tA one or more each selected from the constituent class Shay alkyl (k,-k.) may carry (Y) £4 of: 8 - aryl) (b) substituent aryl; oY substituent aryl; (2) 1 (d) substituent aryl; ot (e) hydroxy; 00 (rd) uss (f ) on (g) 018787 where t and 8 * 7 as previously defined and ov -CH-M-R' (7) oA is chosen from the category consisting of: M where 4 ° "-C(0 )-NH- (1) 1 "-NH-C(0)- (Y) 1 "-NH- )( 17 "-N= (4) (17 -mt)l (°) 1 "-NH- C(0)-0- (1) 10 "-NHC(0)-NH- (V) 11 "-O-C(0)-NH- (A) bin 18 «-0-C(0)-0- (4) TA -0- (1+) 14 or ?: 1 equals zero or n where -560(,- (VY) 5 -C (0)-0- (VY) al and 0 «-0-C(0)- (VY) vy and +C(0)- (14) al of the class composed of: HU, R® ve is selected from the category consisting of: Sn alkyl (k,-k,); may carry (0) ve - Cdyn (bb) aryl substituted vy (cc) mixed aryl; f vA (dd d) va aryl substituted aryl; (Y) A substituted aryl; (Y) AY aryl substituted (4) AY aryl substituted” and 0 AY Mixed Cycloalkyl (7) At (vere) Cycloalkyl (Y) Ae ; (?) Aryl; A Aryl Substituents; (°) AY Mixed Aryl” and (7) AA Substituted aryl; (VY)Ad b C representing a hydrogen or hydroxy protective group; Select from the class consisting of: a Substituent-carrying moiety of a moiety Select from the class consisting of: (1) A VY. “eN (1) av F (b) ag where “a represents an alkyl(k,-km) or alkyl(k,-km) bearing a -CORY (2) 10 aryl or alkyl (k,) substituent -km) carries a mixed aryl substitute; 1 LER a priori ? or ? and 1 equals zero or n where S(O)RY (3) ay a priori WS RY where NHC(O)R' (e) AA separately from hydrogen JSR?HRY where NHC(O)NR'R™ (f) selects 14 and alkyl (k,-km) and alkyl (k ,-km) carries a substituent of aryl and aryl with substituents Ves and aryl with substituents and aryl with substituents; a z 011 aryl; (0) 01 dia (h) aryl with VY (i) scrambled aryl; and Vet (J) aryl mixed with substituents; Veo (K+-K,) alkyl (K+-K) bearing one or more substituents to choose from the category consisting of: (Y) Vel (A) halogen; Vey (Som) (b) 0118 (rein) (c) alkoxy 04 (reid) (d) alkoxy (k,-km)-alkoxy “” (e) exo; 111 the (J) VAY “ -CHO (J) WY (h) (alkyl (k,-k;) substituent)-0-50,2; -NRPR™ (i) Vie hydrogen; (V) < 1 alkyl (k,-k,); (Y) ny a (1) alkyl (k,-k,,) substituents” (hve) Jaf (%) Via 1” 0 alkynyl (k,-k”,,) substituents (ved) dash (1 ) “1 (v)” 1 alkynyl (k,-k,,) in (Jil (A) yyy aryl; VY (9) cycloalkyl (km-km); (01) (1 “Cycloalkyl (K+-KM) has substitutes” 11) 71 Aryl has substitutes | a d (VY) alkyl ila scrambled; (VF) YEA alkyl ila mixed with substituents; 11 (€ 0) Alkyl (k,-k”,,) Shay is from aryl» (V0) we Alkyl (k,-k”,,) Say from aryl has substituents 101 (11) Alkyl (k,-k”,) Shy carries a 7-substituted cycloalkyl (197) Alkyl (rye) carries a 7-substituted cycloalkyl; (VA)” 7 alkyl (k) ,-k”,) Say of cycloalkyl (fred) Ve (09) alkyl (k,-k”,) bearing a cycloalkyl (dred) substituent; (01) Amylated aryl (YY) 71 Amylated aryl with substituents » (YY) Vey alkyl (k,-k,) Say bears from methylated aryl; and (YY)VPA alkyl (k,-k) ,,) Say carries a scrambled aryl with its substituents; 799 or RE Ve and RM form with the atom to which they are attached a scrambled cycloalkyl ring of 1-01” VE) ring-forming members may Hold a Tandy Say or more, each of which to choose from a VEY category consisting of: (V) VEY halogen; Vet (7) hydroxychloroquine; ee (©) kirxi (k,-km); VET (?) alkoxy(k,-km) -alkoxy(k,-km); VEY (0) exo ¢ VEA (7) alkyl (k,-km); i= ga (Vv) 124 (k,-km); and (A) Vo. alkoxy (k, -km)- alkyl (k,-km); vor(j)" 00,:8- where RY is already defined; a yor (k) -COINRR where RY and LS RY? is an a priori definition; =N-0-R" (J) Vor where RY is also an a priori defined by Vos (m) "-C=N 0-S(0)RY (0) Veo where “is equal to zero or 1 or Y and LER is a priori Vel (o) aryl.” voy (p) aryl has ila VoA (q) aryl scrambled ( Ua) 14 aryl substituent; Ve (s)alkyl (dred) Sila Vi (t) cycloalkyl (k,-km); substituent; “+ (u)alkyl ose) Sar carries a scrambled aryl; Vay (v) a dali cycloalkyl; Vie (w) a scalated cycloalkyl substituent; 0 z Ve (x) NHC(O)RY where " 28 As previously defined 1< (y) NHC(O)NR''R' where sR" ag as previously defined =N-NR"R" (ua) 7 Where l and RM as known Advance =N-R° 0 1 where WER? a priori defined 4 (bb) =N-NHC(O)R™ where “l as defined as las and We (cc) =N- NHC(ONR''R" where O and "L as previously defined no (©) alkynyl (ved) carries a substituent from a moiety chosen from the class consisting of: L0 halogen A(2)"-CHO RY dua -CORY (2) VV as a priori defined -C(O)-R' (3) 70 where 87 is a priori defined as Na (ha, left-handedness)- where RY and VSR? are a priori defined as “.C=N (5) VY VA (0) aryl; k) a cycloalkyl (vere) and (J) VAY alkyl (k,-k,,;) bearing a methylated aryl substituent (4) alkynyl (rd) VA (©) alkynyl ( K:-K.,) carries one or more substituents, selecting each separately from: VAT (1) halogen VAY (b) alkoxy (red) HA (c) oxo + “CHO (2) ) VA4 -CORY (2) 1a. where LS R™ is a priori defined) 14 (f) -C(O)NR''R™ where RY and RP? are a priori defined Vay (g) -NRPR™ where RP and WSR are predefined AR where m as previously defined 0-0 (2) Vat “-C=N (i) Yao” for 8 as previously defined 5Y or 1 equals zero or n where 0-S (0)RY (j) 1a lag (k) aryl; substituent aryl (J) ha alia aryl (a) co-substituted aryl; (0) Ye. (o) cycloalkyl (k-k,); (R' (q) 77 (lua defined LER? (p) 10126011882 where A and Yt are previously defined as RM and RP where =N-NR”R™ (3) Yeo Where 17 as previously known =N-R' (R) 1 "l as previously known and dua =N-NHC(O)R" (u) Y.v as previously known LE R™ where No, =N-NHC(O)NR''R" (2) 7 alkynyl (K+-K); and (1) Yes, one or more separately selected from Class Shay Alkenyl (K+-K,) carries (2) (7) consisting of: 11 (a) tri-alkyl silyl; 77 (b) aryl; ny (c) aryl substituents.” ne alae aryl (9) Tyo halogen” (2) 171 : |, (and) aryl mixed with substitutes; hy na choose from the category consisting of: 1 Hydrogen; (V) OH-hydroxy; (Y) YY. sufficient hydroxychloroquine; (7) 9 not found or choose from the category consisting of: T Gua 30-7 (¢) YYY “-C(0)- (1) yy “-C(0)-0 ( b) Yre “CH (zg) - oo “C(S)-S- (9) 771 is hydrogen or alkyl (k,-k)); RE Gua C(O) d (e p) or 7;1 where « equals zero or S(O).(f) YYA XV (g) -0-,(5)0- where « equals zero or YY or 7 and 8 represents alkyl(k,-k); and 1(h)-.8)0()087- where “ is equal to zero or Yr. As previously known; and 8* Cua -SO,-N(RY- (i) 701 Choose from the category consisting of: »' 7 Choose from the category consisting of: Say may (rey) a) Alkyl “Jat (1) Yre (dita aryl in (Y) Yveo P (7) aryl scrambled; (ily aryl scluted with (£) Yry) cycloalkyl scrambled (0) YYA (1) hydroxy Tv; (V) Yi. (1d) alkoxy (A) YE as previously defined by R® and R7 where NR'R® (1 ) 7" is selected from the category consisting of: Sn (b) alkynyl (k+-k); may carry vey ny (0 Yet Yeo (7) substituent aryl” Ye (¥) substituent aryl; vey (8) substituent aryl” z YEA 0 alkyl substituent Yea (1) cycloalkyl substituents; (V) Yo hydroxy; (A) rey alkoxy (k,-k); NR'R? (1) voy where R? and LER? are customary. precursors of Yor (c) cycloalkyl (k+-k”,); Soy may be of the category consisting of: Yot (1) Aryl (Y) Yoo Aryl with edily You (7) aryl-substituted; rev (4) aryl-substituted; YoA (0) aryl-substituted You (1) aryl-substituted; (VY)Yi.hydroxy; ( A) +11 alkoxy (red) YY (1) 5 where “8” and 2 “as previously defined z Yr (3) aryl; AY: (e) aryl with substituents (4) aryl scrambled; (J) 711 aryl scrambled with substituents; and Y1v (h) scalar alkyl. 51 U with A forms a double bond between the two carbon atoms to which it bonds in AR compounds of formulas (Y) and (7). 1 no and TU Jig is hydrogen or U with U forms a double bond between the two carbon atoms to which TY is attached in compounds of formulas (7) and (7) — Y 1 Pharmaceutical compound for the treatment of bacterial infections that includes Ladle effective amount of compound Ly Y of claim of protection (1) or its pharmaceutically acceptable salt or ester in combination with a pharmaceutically acceptable carrier. . Jad is a combination treatment, Gana Y, which contains a therapeutically effective amount of the Giy compound of (1) lal or its salt or its pharmacologically acceptable ester. 1 - Compound (ad for protection) 1 {In the form (1): NMe, 88 and next Ze !) | Ou, 0 73[ HO, : HO "0 0 Y 8 ~ 0 0 (") r = 0 is a compound X according to claim (4) where 7 and 2 together form a group — 0 1 0 composite according to claim (;) where it is chosen from the category consisting of: - + 0 represents 011; U represents 0; X H Jing©” represents the allele; R:1) of a compound of the formula Ca compound with formula 1:(JigR) allyl; “8-methylbenzoyl; X represents 0” OH diay U : Compound with formula 1:(R)(7-quinolinyl)-011-011. -:011- XH Jim R® methylation UO 'OH Jia ° A compound with formula R:1(methyl(7-quinolinyl)-.011-011-.011- R® XH methyl 0" U Jia v 0-AlH;4 compound with formula R:1(representing (7-quinolinyl)-:011-011-.011-R® represents XH stands for 0 U Jia \ 0-(4-methoxy)benzoyl;ve compound with the formula Jiggy©(1):(7-quinolinyl)-:011-011-,11-R® X represents oH represents 0" U Jia 1 0-methane sulfonyl; f-VY is a compound of formula 8(1):(7-quinolinyl)-:011-011-:011- XH Jia RP has UO © Jia VY (7-nitro .0-CO-NH-(Jaid) 1 7- Process for preparing a compound of formula (1) where it forms 7 and Lan Z The set X is Y 0 = in the form (1a): m 8 1 Or, 0 “HO, TL Y HO 5 0 0 (i) I : where Jig RP 1 hydrogen or hydroxy protective group; 7c choose from class consisting of: (1) 4 methylated Sad of moiety choose from class consisting of: a (a) “N where Ve (b) F 1 (c) -COR” where RY is the alkyl (k,-km); or an alkyl (k,-km) bearing a substituent VY from an aryl or an alkyl (k,-km) bearing a Shy from a scrambled aryl; wv (3) "860.8" where « equals zero, 1, or ? and "8 as defined by NHC(O)R's predecessors" (2) VE where RY is defined by Gaus Ve (f) NHC(O)NR''R" where P and JSR? select separately from hydrogen 8 and an alkyl (k,-km) and an alkyl (k,-km) bearing an aryl substituent and an aryl with a VY substituent a mixed aryl and a substituted aryl; “dal (3) VA 4 (2) a substituted aryl; Y. (i) a scrambled aryl” and 71 (j) a scrambled aryl with substituents; (Y) YY alkyl (k+-K,) Shay bearing one or more select from the class consisting of: YY (1) halogens; vi (b) (mS sa 2 (c) ) alkoxy (om) v1 (3) alkoxy (k,-km)-alkoxy (reid) l (2) exo ¢ (J) YA lilac “-CHO (J) Ya a(h)(alkyl (d=)substituted)-,0-80; 791(i) dus-NRPRM selects RP and “H separately from the category of: (1) YY hydrogen” ry (¥) alkyl (redi=ydl) (Y) re alkyl (reel) has substituents; 06 (remy) Jail (€) vo (Jia has (remy) alkynyl (0) 5 (rede) alkynyl (1) rv alkynyl (k,-k',) has substitutes (v ) YA “Jal (A) Ya Ce) cycloalkyl (-) 3 (ily) cycloalkyl (km-km) having (3) (01) aryl substituents; (1) 0) mixed cycloalkyl (VY) ex substituent cycloalkyl; (V1) 2 carrying an aryl substituent; (vrei) alkyl (1) to (dil) aryl with Say alkyl (k,-k,, ) carries (V0) 3 mixed cycloalkyl Sy carries (ved) alkyl (V1) 3 mixed cycloalkyl substituted Say alkyl (k,-k”,) carries (VY ) £A alkyl (k,-k,,) bearing a cycloalkyl (k+-km) substitution; -k”,) carries (19) 2 alia aryl (01) - city aryl mixed with (YY) oY and lie alkyl (k,-k”,) carries an aryl substituent (YY ) ov an alkyl (k,-k”,) bearing a scrambled aryl substituent; (YY) ot or oo 01 form with the atom to which they are attached a 9-stamped cycloalkyl ring to RY and RY on Ring forming members may carry one or more substituents, each selected separately from the category ov consisting of: oA halogen”; (V) oq AA (Y) 1: hydroxychloroquine; 1+ (©) alkoxy (rely) 27 (;) alkoxy(k,-km)-alkoxy(k,-km); 217 0 exo ¢ Jf (7) 1 (k,-km); (V) 10 halo-alkyl (k,-km); and (A) 11 alkoxy (k,-km)-alkyl (k,-km); 17 (j) '08©- where RY as predefined dua -C(O)NR''R" (<) TA C and "L as predefined =N-0-R" (J) 14 where "c as je 2 priors la (m) «-C=N 0 1l (n) 0-S(0)R" where n equals zero or 1 or ? WER? was defined as pas for (x) aryl; vr (p) ariel by will ve (q) ariel mixed; ° (r) aryl mixed with substituents; v1 (s) cycloalkyl (k+-km); vy (t) alkyl Gila (km-km) has substituents; z VA (u) alkyl (k,-k”;) bearing an aryl substituent (alae va (v) a cycloalkyl A (w) substituent cycloalkyl; AN (x) NHC(O)RY where “y as predefined NHC(O)NR''R™ (3) AY where RY and WSR? are predefined AY (z) = N-NR"R™ where Al and RM as defined (pe = N-R° (1) At where 87 as previously known VEY and Buus as defined by RY where =N-NHC(O)R" b) 4) Ao predefined LER? where O and =N-NHC(O)NR'" 'R' (cc) AT bearing a moiety substituent chosen from the class consisting of: (red) alkynyl (©) AY halogen; (1) AA "-CHO (b) Ad As predefined RY where CORY (7) A. predefined; WSR” where -C(0)-R (3) a lps define LER? and R” where - C(O)NR''R? (j) Substituent aryl; 97. (k,-kb) and Sila (k) alkyl aA alia alkyl (k,-k,,) substituent of aryl (J) 14 Alkenyl (K:-K,) (4) Ves one or more separately selected from constituent class Shay carrying (ved) Alkenyl 0 011 of: 11 (a) halogens; Ver z (remy) (b) alkoxy (c) oxo; oo “-CHO (d) 1 predefined LER and (e) 08©- where and “to ez as Prior definitions R" (and) "0 (1188)- where 01 is also defined prior to RY p and ua 21878" (g) Ved VEY as predefined RY where =N-O-R" (H 0 "-C=N (i) 11 predefined SRY or 7 and 1 equals zero or Cus 0-S (0)RY (j) VY Jal (<) VAY Aryl substituent; (J)" 1 (m) aryl scrambled; No (o) a cycloalkyl Chl carries a substituent of aryl (vee) (p) alkyl 1 ius as defined by RY where NHC(O)R' (q) Via and “l As they were previously known as RY, where NHC(O)NR''R" (R) VY. They were also previously known as RM, where "p and =N-NR"R" (33) YY was also known R® Prefix where =N-R' (R)" 7 and Gaus defined LER where =N-NHC(O)R" (U)1» predefined LER? where O and =N-NHC(O)NR''R" (v) VY alkynyl (k+-k); and (1) ", or more each chosen from Constituent class Tandy alkynyl (k,-k.,) carries a (7) VY substituent of: (a) tri-alkylsilyl; 1 “Jul (<) <4 (c) aryl substituent “7 aryl scrambled (2) 11(e) halogens; 7(f) aryl scrambled substituents; and VY na choose from class consisting of: 7 Vet hydrogen; (1) re hydroxyl (Y) AR hydroxy buffer; (V) b Not present or choose from the category consisting of: 7 Cus O-T-R' (;) VTA “ -C(0)- (1) 174 «-C(0)-0 (b) VE «-CHy- (c) 1 «C(S)-S- (d) VEY REE SNE ) represents the alkyl hydrogen hydrogen SCR CO(NR)- (e) Vey XA nl (f)-(5)0- where « is zero or or 7; 1 is equal to zero or » ua -S(0),-0- (g) Veo and ofr) and 8 is the alkyl (YS) equals zero or n where -POYOR),- (h)Ve foreknowledge WER WHERE SO, NRY- (i) vey is chosen from the category consisting of: R VEA (a) alkyl (k,+-k.) may carry a substitute selected from the category consisting of: 4 aryl; (1) Vo. aryl substituent; (Y) 111 aryl substituent; (7) Voy aryl substituent; (£) Voy cycloalkyl; (0) ) vot substituent cycloalkyl; (1) vee hydroxy; (VY) you alkoxy (k,-k); (A) voy as previously defined RY where T and NRR® (1) 01 (b) Alkenyl (K,-K.) may carry a substitute to choose from the category consisting of: Ved Vio | p (1) aryl” (Y) 11 substituent aryl; 1 (7) aryl substituted; and naid (2) aryl substituted; Vig 0 cycloalkyl kl.b)1 (substituted cycloalkyl; (Y)am hydroxy; Vy 0 alkoxy (red) NR'R® (4) VIA where 87 and RY as previously defined) 11a (c ) a cycloalkyl (k+-k”,) may carry a substituent of the category consisting of: “Jat (1) We (Y) WA aryl with 7 (¥) mixed aryl substituents; and 7 (?) aryl Wi (0) alkyl ila scrambled; Vo (1) cycloalkyl scrambled (diy (V) 17 hydroxyl A 0 alkoxy (1d) VA (9) ) 11878 where R7 and “2 as defined by Gaus va (d) ariel; VA. (e) a VA-substituted aryl; (f) a aryl lie VAY; (g) a val-substituted aryl; and VAY (h) cycloalkyl hla ke and the method includes: ve treatment of a compound with the following formula acid hydrolysis: (1) VAS 0 : A H NM 82 7 0 Qu, HO,,, ge - A HO 00 P VAT d A Or ° A H NM 08 0 It was previously known as R Cua VAY to produce a compound of the formula: VAA 0 : 8 H NMe, l Yt, 0 Ou., HO, Rn : VA HO 0 VS N OH AS 0 representing hydroxy; U is 11 and RP is a compound of formula (1a) where Va. H (b) Treating the compound obtained from step 0 permissively with a hydroxy buffer reactor to produce compound A with the formula: 8 85 N Mes 1 8 0 ~~: - 7, . Re Ou, VAY HO,,, = S “or ~~ HO re a> b” : CH 0 : And Tkha, which is a compound with the formula (1), where RY paralyzes a hydroxy protective group, and Vie does not follow a hydroxy; then converting the compound with the natural isomerase (7p) permissibly into a compound with the unnatural isomeric form 'As' (GF) by selectively oxidizing the dimou Ye penal and reducing the group =T not as] to produce the unnatural isomer HAT) This (c) treatment of the compound with formula (1a) is permissible; where 8 Jig is a hydroxy protective group and U Vad represents a hydroxy group (the compound from step (b)) with an excess amount of NaH in Te aprotic solvent following the reaction of the intermediate anion with Csy and 611: 1 to form an intermediate compound 0,711 from xanthate, which is subsequently treated with Bu;SaH in an inert atmosphere in the presence of a catalyst amount of initiator radical 77 suitable for the production of the deoxygenated compound at the desired location (7) with the formula: LEED 8 . o On, Yor: 0 Walk: HO, Has HO "ro . 8" 71 Q a) It is a compound of formula (10) where U diag is hydrogen; the compound produced from step (b)) in the b-hydroxy als reactor to produce a compound of formula (1a) where 8 ding is a hydroxy protective group and La Jin is a 1 buffered hydroxyl group; VIA represents a protective group for the hydroxy and RY (e) treatment of the compound with formula (10) passports, where Yo LT is a hydroxy group (compound produced from step (b)) with a base and a reactant of Jing Na YA. An easy-removing reactant assembly suitable for the production of L, 8 as previously defined, and 7 Sua RR TH geal compound THY c : 0 8 NMe “Ke On, SNLS or” (UN 0 f; 706 (f) Removing the protective group; and isolating the compound of interest of formula (1a) permissibly. Te in step (e) of class LTR where reactor (V) selects a process in accordance with the protection requirement A=1 constituent from: Y 8-(0)©-halogen; rm0)-0;°l-,11©-8-halogen; (£2) 1 then '8-halogen;z CS, alkali metal hydride followed by (0-22) (e-a) 0-0-14-80; A NROH-R carbonyldiimidazole followed by (Y=) \ z 0 {C1-8(0),-0-R*(HD) 1 ¢CL -P(O)(OR),-R* (e-e) 1 Vid. Leuc (1 + —-a) VY rot in the presence of a base in L-T-R' reactor Cua (Vv) for protection requirement Ga process —-9 1 Step (e) b ?-second Hydro-317-pyran in the presence of an acid catalyst. 7:1(with formula (1) of protection claim Gy compound 1-01 8 AP NMe 1 8 2 8 0 L | i i” W 4, Re in * t rubl 0 l : 1 dd 0 : b BN 6 «(Y) 3 05 Sia RY does not exist and Ww where 1 A ) of protection claim Gd, composite 11-1 Where he chooses from the category consisting of: (A) for the protection claim (By compound 1-1 other than WH representing RP representing (7-quinolinyl)-.011-0-,01 - R:7) a compound of formula 1 ¢OH representing U (H representing RY (23a 5a) and 1 non-WH representing RP a compound of formula (71): 1 representing (7- quinolinyl)-.011-011-.011- ¢ Na represents M-Al; (H is RY present; ° not WH represents RP -CHp-CH=CHp- (Jit) 51S 7) represents R:(7) (compound of formula 1 represents 0-(; -nitro bezoyl); U cH Jig RY present; (-.011-011-,011-) Jia R : (7) compound of formula A representing 0-benzoyl; UH representing RY present; 4 ve. non-WH representing RP Represents (7-quinolinyl)-:011-011-.011-;R:7 ( compound of formula Ve representing 0-(7;*-diphenylpyridinecarboxylate); UH representing RY present; 11 non-WH representing RP compound of formula (1): 8 representing ( *-quinolinyl)-.011-01-,01-;" -- represents 0-(*-nitrobenzyryl); UH represents RY present; 3 not WH represents RY CHCH =CH-{(Umsi 45) Compound with formula (1): 8 represents ve represents 0-(3;*-trimethoxybenzoyl); U 1 represents RY; not present; not WH It represents R® ¢-CH,-CH=CH,-{ sil 518"). Jie R:7(compound with formula 51 mL 0-[1-thiophene carboxylate); U cH present; 8 represents 1 other than WH represents (-CH,-CH=CH-{ Ji 55 ¥) represents: (Y) except a compound of the formula 0-(7-methylbutanoyl); Jia UH represents RY present; 8 is not WH represents RP A compound of formula (7):8-methyl(7-quinolinyl)-.011-011-,011-4 representing 0-40-bromo benzoyl); not representing 0-7-pyridine carboxylate); In the form YY does not represent 0-(methoxycarbonyl); 11 Jing RY is present; Ye is not W eH represents RP imitate (7-quinolinyl)-:01-01-,01-R : (1) A compound with the formula Yo -dimethyl ethoxycarbonyl)? 011-01-.011-R compound with formula (?): 1 7-bromobenzoyl); (-© dim UH represents RY present; YA not WH represents R (- CHy-CH=CH,~(J—sid 5151) ©:1(compound with the formula YA represents 1)=0 -methoxybenzoyl); JH represents RY present; 2 not WH is RP -CH,-CH=CHy- (Joi 5357) which is the R:(1) compound In formula 9 represents 2-(1-furancarboxylate); UGH represents RY present © 177 I is a compound with the formula Jig©:(1):((7-quinolinyl)-.011-011-,011-; WH does not represent Yo, but RY is (H does not represent -0). Butanoyl a is a compound with formula (7): R stands for (7-quinolinyl)-011-011-,011- RP stands for WH not present RY stands for U oH stands for -0 Methane sulfonyl YA is a compound with the formula (1): 8 RP -CHy-CH=CH,-(Jsiad 561) Jing has WH not 1 present; RY represents 11 U represents 0 -(1 -methylpropynyl); Not present; RY is U (H is phenyl-0-020-1111; £Y is a compound of formula (7): R is RP “-CH,-CH=CH,-(J1isl 5uS) —V) represents X H represents m Ww l does not exist; R¥ represents UH represents the -0-60-1117 allele; £4 is a compound of the form ©:(1) represents -7 quinolinyl)-011-0117-.011-; Ta represents X sH containing 0” W go not present; RY represents H na represents ¢0-CO-NH-CH(C) 0)OCH;)-CH(CHs), 3 is a compound of formula (7): R stands for RP -CH,-CH=CH,-( Jai 5S Y) stands for X H stands for 0 W ty does not exist; RY stands for U (FH stands for t0-CO-NH-CH(CH;), £A is a compound of the formula (7): Jiu X 11 Jig RP -CH,- CH=CH,-(Jsid 51:5) Jia R m W £4 not found; RY is U (H methylhexyl $0-CO-NH-_ ila on compound with formula (7): R methyl(7-quinolinyl)-.011-011-,011- ;l X represents H represents 0” W 2 does not exist; RY represents U H represents (; -fluorophenyl)-0-00-71; oY is a compound of formula R:1((7) -quinolinyl)-.011-011-,11©-; “2 W “0 Jia X H diag oY not found; U H Jig RY represents (7-niterphenyl)0-00-1111 ot Compound with formula (7): R methyl(7-quinolinyl)-,011-01-,011-; RP stands for T; X stands for 0”; W oo does not exist; RY stands for H 1 represents (4-methyl- "-nitr 5¢0-CO-NH-(Jid 2) compound with formula (7): R represents (7-quinolinyl)-:011-011-:011 - "a represents Jie X (H m W ov not found; H Jig RY NA represents (?-nitrophenyl)-0-00-411; oA D014 Compound with formula (7): © represents (7-quinolinyl)-011-0112-,011-; RP represents 11 X represents 0; W : 1 does not exist; RY stands for H NA stands for (4-methoxyphenyl)-0-00-17; 211 Compound with formula (7): 8 represents (0-quinolinyl).,+011-07-,11©-» RP represents XH represents 0 W 27 not found; U H Jig RY stands for {0-5(0),-CH=CH, 17 compounds with the formula ( "): R stands for (7-quinolinyl)-.011-011-.011-; RP WH represents non-existent 1; RY represents Diay U H (:11)011-:011-011-:(0-5)0? Compounds of formula (1): RP;”-011:- 011-01,-(linelonic-0) Jia R stands for WH Not 11 present; R" stands for U H stands for ¢0-S(0),-CH,-CH,-S-J13 1 Compounds of formula (1): R stands for (©-quinolinyl)-,01-01-,01- R stands for WH not 0 present; RY stands for U(H stands for 0-alle 14 Compound with formula (7): R undenatured (?-quinolinyl)-:011-011-,011-; R? represents WH not present; RY represents H not representing -0 (?-morpholine carbonyl; 2) is a compound with formula (7): R stands for (7-quinolinyl)-011-012-,011-; “p1 stands for 11 77 not found; RY stands for UH stands for © 0-pyrrolidinyl carbonyl; VY is a compound with formula (7): © represents (7-quinolinyl)-.011-011-.011- RP represents WH ve not present; UH Jig RY represents 0 -(7-tetrahydropyrenyl); vo compound with formula (7): R is reduced (7-quinoenyl)-:011-011-,011-; R? represents WH not va present RY stands for U H stands for ¢0-C(=S)-SCH; for a compound of formula R:1( stands for (7-quinolinyl)-.011 -011-m011- L does not have both U' VA forming a bea double bond; W does not exist; RY is tH va a compound of formula (7): R denotes 55-7 -CH-CH=CHp-(J—sid of UH Ja and U' Ae They form a non-existent W dill bond; RY represents 11; A compound of formula (7): R represents ji (5-7-quinolinyl)-011-011-,11©. -; RP stands for UH and UF AY together form a double bond; W does not exist; JingRY 1; AY 017 and UH represents (7-methoxy-7-typhyl)-,011-011-.011-th8 represents R:1) a compound of the formula At tH represents RY not present; W double bond; laa m "la form CHy 1 compound with formula (7): © imql (7-(*-(7-isoxazolyl)-"-ferranyl) nar At (H represents RY Not found W is a double bond; bee represents 11 la and “does not form R% AV Na H represents RY NH represents WH represents RP -CH,-CH=CH, represents R (¥) Compound of the formula AA (OH (OH) for Ad other than WH for -CH-CH=CH-{— 51ST) for R:(7) Compound of the formula A. tH Represents UH Represents H Represents RY 252 30 91 Jas Jig RP -CH,CH(O) Represents RH Represents RY Does not exist W :)( Compound with the form AY OH Represents Represents ay RP -CH,CH,NHCH-J#8 Represents RH Represents R” Not found; W:1) Compound with the formula At’OH Represents U Represents Khalil; 10 » -CH,CH,NHCH,CH, represents phenyl © (H is not present; 8” represents W:7) a compound of the formula a 'OH Kl; Na represents Jig RP 4 —-CH,CH , compound with formula (7): 77 does not exist; H represents phenyl; RY is not present; W:7) is a compound of formula 1 011e; dia Na “Jia represents RP <(NHCH,CH,CH,CH, AY represents 11 © represents (7-quinolinyl)- RY not present; W is a compound of formula (?): ay ¢OH stands for Khalil; na stands for R? “CH,CH,-NHCH,CH,CH,- at represents (7-quinolinyl)- RH represents RY not present; W:7(b) compound with the formula “OH Jia U represents K RP “CH,CH,-NHCH,- an (phenyl)-RH Jay RY does not exist; CH,CH=NO-AA Vel is (phenyl)-RH is RY is not present; W(Y) is a compound of the formula be ¢OH is U is Khalil” R? “CH,CH=NOCH,-011 represents (:-:10<-phenyl)- RH represents RY not present; 7:17(compound with formula 01” 'OH constituting U' Jia Jie R® «CH,CH=NOCH,- Vey represents (4-quinolyl)- RH represents RY compound with the formula (?): 7 does not exist; Vt ¢OH represents U «Jaa represents RP? «CH,CH=NOCH,- Veo (SY) represents RH represents RY Compound (?): 17 does not exist; ,CH=NOCH,- 017 chelates (”-quinolyl)- RH represents RY compound of formula (7): 17 does not exist; ,- 011 7:) Process for preparing a compound of formula 1 - 1 2 o i i v NMe, A Kel den “ ing “OL (Y) oo A 1 7 0 , where: hydrogen or a hydroxy protective group; Jia RP ° is selected from the class consisting of: © 1 of the moiety is selected from the class consisting of: Sd methyl bearing (1) v «CN 0 A F (<2) 4 yoo representing an alkyl (k,-km ) or an alkyl (k,-km) bearing an R™ substituent where CORY (c) 5 is from a mixed aryl; Shas is an aryl or an alkyl (k,-km) bearing 1 Baa or 7 and “!8 as defined by 1 equals zero or” Cus S(O)R™ (d) VY as previously defined by RY where NHC(O)RY b (e) separately of Hydrogen JSR?SRY Where NHC(OINR'R (f) selects an alkyl (k,-km) and an alkyl (k,-km) bearing an aryl substituent, an aryl substituent (Jia, a mixed aryl, and a mixed aryl 8 “dal d (g) (h) aryl with substituents; M VA and habia (i) aryl 4 (y) aryl with substituents; 1 (a) halogen; YY (b) hydroxy; YY (c) alkoxy (k,-km); ve (rm) alkoxy (k,-km) -alkoxy (3) vo : ¢ Exo(2) 71a(7“-CHO (J) YA (h) (alkyl (k,-k) substituent)-0-802; Ya : separately from constituent class From: JSRM and RP where -NRPRY (i) 7 corso (1) chooses 9. an alkyl (k, al?,); () yy has substituents; (yd a) Alkyl (©) vv m (2) alkynyl (k,-k?,); Yel alkynyl (k,-k”,;) has substituents; (0) Yo alkynyl (k,-k); (1) a alkynyl (k,-k,;) has substituents; (v) aryl” (A) YA cycloalkyl (qm-qm); (9) ra cycloalkyl (qm-qm) with substituents; (0 4) 13 cdi aryl with (VY) 3 mixed cycloalkyl (VY) £Y substituent cycloalkyl; (17) ey alkyl (k,-k”,,) bearing an aryl substituent; (0 €) £1 alkyl (k (V0) to alkyl (k,-k”,),) carries a cycloalkyl substituent; (V1)£1 carries a cycloalkyl substituent (vey) alkyl (Vv) 3 adr) Gils of alkyl Shay (k,-k,,) carrying JS (1A) 2 of cycloalkyl (km-km) substituted Say alkyl (k,-k,;) carries (149) 4 alia aryl (01) 9 (ily aryl chelated with (YY) 3) an alkyl (k,-k”,) carries a methylated aryl substituent” and (YY) oY bearing a scrambled aryl substituent; (veld) alkyl (YY) ov or of 01 HV forming with the atom to which they are attached a scrambled cycloalkyl ring of RY HRY 00 Ring-forming members may carry one or more substituents, each selected separately from or : the class consisting of: oy halogens; (1) hydroxy oA; (Y) °4 001 (k,-km); aS S(T) 1: (?) alkoxy (k,-km)-alkoxy (k,-km); 11 exo 0 17 alkyl (k, -km); (1) 1 halo-alkyl (k,-km); and (V) 1 alkoxy (k,-km)-alkyl (k,-km); (A) 1 as predefined RY Cua -COR" (J) 1 predefined LER? Where O and -C(O)NR''R" (4) 19 as previously defined R where =N-0-R" (J) 14 -C=N (m) 15 Define a priori LER or ? and 1 where “ is zero or 0-S0)RY (n) v. (x) aryl; vy (y) aryl with substituents; VY (q ) aryal scrambled vy (r) aryl substituents; vi (s) cycloalkyl (km-km); vo substituted; (hdr) (t) cycloalkyl v1 of aryl scrambled Sha (u) alkyl (k,-k”,;) carries vy li (v) cyclokyl VA (w) cyclokyl mixed with substituents; va © predefined WS RY where NHC(ORY (x) Ae) as previously defined by R™ and R" where NHC(O)NR''R (3) is as previously defined by RM where 3 is for and where =N-NR"R" (U2) AY predefined WSR? where =N-R° (fl) AY where "ar as predefined and =N-NHC(O)R" (bb) At 01 WER? A and dys =N-NHC(O)NR'R" (CC) Ae from a moiety selected from the class consisting of: Shy alkynyl (km) carrying (Y) 81 (a) halogen AY “-CHO (<2) AA as previously defined RY where -CORY (i) 4m as previously defined 87 Cua -C(O)-R' (d) a Where C and “L as previously known -C(O)NR''R" (E) a) «-C=N (J) 9 ' dil 0) ay Aryl has substituents; (2) At (i) Scattered aryl; 10 (j) Scrattled aryl with substituents a1 and (vr) cycloalkyl (9) ay from scrambled aryls bearing (sree) alkyl (J ) Wn (?) alkynyl (k:-k); a4 carries one or more substituents selected separately from: (ded) alkynyl (0) Ves (a) halogen; Ve ( b) Alkoxy (K,-Km); Vey Akso; (2) Vey “-CHO (>) Vet where “Vet as previously known” -CORY (e) Veo where O and “L as Prior custom - C(O)NR''R™ (F) 1 (g) 20828 “Where L as known prior 011 (H)” 1-0-8 “L as known Advance 01 “-C=N (i) 01 1001 predefined WER or f 1(j) 0-50(.8 where “equals zero or 0” (k) aryl; 111 aryl has substituents; (J) ny (m ) aryl scrambled; nr (n) aryl scalded with substituents 111 (o) cycloalkyl (km-km); Vio from aryl sclute; Shay alkyl (k,-k,) carrying ( 5) 11 laa As defined by RY where NHC(O)R' (q) VAY lips are defined as R™ and R" where NHC(O)NR''R™ (02 ) VA as defined a priori by RY and RP where =N-NRVR™ (s) Via where “8 as defined a priori =N-R’ (t) VY. Where “L As previously defined and =N-NHC(O)R" (U) VY where "N and “N as previously defined =N-NHC(O)NR''R" (V) 7" Alkynyl (K+-K..); and (3) " or more each choose from constituent class Tandy Shay Alkynyl (Km-K.,) Carrying (V) YE of: 17H d (a) trialkyl silyl; (b) aryl; 7 (c) aryl with substituents; 178 alia (d) aryl Ya halogen, (2) Ve (f) Substituted aryl; 71 Na select from class consisting of: 7 hydrogens; (1) 7 hydroxy; (Y)7" d (TV) buffered hydroxychloroquine; 74 (?) '0-1-8-; where 7 does not exist or is selected from the category consisting of: 171 (a) «-C(0)- 7 (b) «-C(0)-0 74 (c) “-CH; - “€@©)s- (3) - -CO)NRY)- (2) Ve) where “8 represents hydrogen or an alkyl (k,-k); Vey (f) -.(5)0- where « is zero, 1, or ?; (J) Ver -0-,(8(0-) where “ equals zero, 1, or 9 a Vit (h) -.8)0(087-) where “ equals zero, 1, or 9 a RY stands for alkyl sored (Veo(i) -SO,NRY)- where RY is defined above; and RY 1 choose from class consisting of: VEY (1) alkyl (k-k) may carry Shy select from class consisting of: EA (0) aryl; (Y) 14 Aryl substituents (V) Vo. Aryl alae and 111 (£) aryl substituents; Voy (0) cycloalkyl alia yor (7) cycloalkyl ally (VY) vot hydroxy;m(A)alkoxy (k,-k); vo (9) 118285 where p and R® as previously defined Voy (b)alkenyl (k) +-k.) may carry a substitute chosen from the category consisting of: (1) 1 aryl; vod (7) aryl with substitutes; (£) 11 bli cycloalkyl 0 VY substituent cycloalkyl; (7) 17' hydroxy; (VY) 6 ( dd) crixy (4) es, where ta and *8 were previously known, 11878 (4) vit (c) cycloalkyl (k, +-k”,) may carry a substitute from the category consisting of: Vy Aryl” (0 VIA Substituent 7) 04 Aryl Substituted; F (7) We Substituted Aryl; (8) WA L (0) Mixed Cycloalkyl; has alternatives; (7) 7 cS gun (VY) for alkoxy (k,-k.); (A) 76 “where 87 and 18” as previously defined 10808 (9) 1171 “da (d) 1 al (e) aryl substituent 1 alae (f) aryl 74 (g) aryl substituent “VA cycloalkyl substituent” | z (2) A double bond between The two carbons it bonds with; UY with U or VAY forms a bond between the two carbons it bonds with; U represents hydrogen or forms with UP VAY K 77 may not exist or choose from the category of -0- and -NH-CO- and 11-011 and -mh ¢NH- and m RY choose from the category of: (1) VAY HY (Y) alkyl (vem) may bear one or more substituents, each of which shall be selected from its constituent category of: Va. (a) “dat 01 (b) an aryl with substituents; Z 0" (C) Removed 1 A Vay (D) Aryl Substituent; Vat (E) Hydroxy; M (F) Alkoxy (K,-K); (J) a “0878 where 87 and *8 are previously defined and -CH-M-R' (7) Vay ha where M is selected from the category consisting of: “-C(0)-NH- (1) 144 “-NH-C(0)- (Y) Ye. “-NH- (¥) Yo “N= (4) oy “-N(CHy)- (°) 7 “-NH-C(0)-0- (1) Yet “-NHC(0)-NH- (V) Y.o ¢-0-C(0)-NH- (A) Ye No (1) «-0-C(0)-0- A. (V+) -0- VY or ?;1 where « equals zero or -5(0(,- (1) Ye -C(0)-0- (1Y) Yh. f -0-C(0)- ) 1) 11 and -000(- (£) ny of the category consisting of: HUA, RO YY alkyl (k,-k,); may carry a substitute chosen from the category consisting of: (0) vit “dat (1) Yio (bb) aryl with substituents; 7 (cc) aryl scrambled and ny aryl aryl with substituents” (23) YA aryl (7) 5 “diay aryl with (7) Yv. mixed aryl (¢) YY aryl substituents; and (0) YYY α (7) mixed cycloalkyl cycloalkyl (cm-kb); (V) 7 » Jat (4) 7, ily aryl with (©) 771 mixed aryl; and (7) 7 aryl mixed with substitutes; (V) YYA The method includes: 7719 hydrolytic acid treatment Passport: 14 (a) Treatment of a compound with formula YY kNMe, and 8 i 0 Te Ho, . 5 . A ;5 3 a, 0 V¢ LK 1 YYY Tg 0n b 3 0 “OMe ARE where WSR is defined above and !8 Jia is a hydroxy protective group to produce a compound In the form (A (Io) shelf: 8 h 0 NM CF] y 9 0 7 HO, : HO hn ar . ARI b: wr 1 8 b A Nr “a Q yd where Jig has no hydroxy group and “tonne <i (773) does not represent the treatment of a compound produced from step a ( gas | with an excess amount of sodium hexamethyldioxide silazide or hydride base in the presence of a carbonyl diimidazole in Gada 51 aprotonal anta 3 compound with the formula: o 8 8 RP NMe, § radi 0 RY tn, . == a KL ty 2 n’a re o we u © 3 0 na 0 Cua 77 a and aa ke form a double bond: Vie treatment of a compound resulting from step (b) with an aqueous ammonia solution to produce the compound (2) res RY non-existent and Wo and “not together U” where they form oF) of the formula Yeo fH Jia 71 HON of the form Sy (d) Treatment of a compound resulting from step (b) is permissible with an amine compound bearing Tey, otherwise it may imply its aforementioned meaning H not representing RY not present and W where (W-R Y where A and "N together form a double bond and 7 is not (YF) to produce the desired compound with the formula Yea is not 1]; Z RY is present and Yo. Treatment of a compound resulting from step (b ) a conjugate with a hydroxylamine compound with the formula (2) Yo) as previously known to produce the desired compound with the formula RY representing -0- and W where (HN-W-RY YoY was previously known; LSRY representing -0 - and W is a double bond, ba and “Na U where (oY) ror (f) treatment of a compound produced from step (b) forms a pass with unsubstituted hydrazine to produce vot and -NH- W represents a double bond and be UT and U the desired compound of formula (7) where Yoo 'H Jig RY Yo HN (g) is the treatment of a compound produced from step (b) with a hydrazine having a substituent of formula Yov To produce the desired compound Grae and S D carries its aforementioned meaning H does not represent RY where (NH-R" Yo 'H represents YR' and -NH-RY represents W together a double bond and UT and U In formula (7) where Yod (h) constitutes a compound treatment of formula £ 1 as defined as an optional treatment with a strong base chosen from 7" and (7) alkali metal hydride base ag pall hexmethyldisilazide (1) The substrate formed from YN in the presence of carbonyldiimidazole in a protonated solvent to produce a compound with the formula: 5 : 0 1 NMe; - 0 “os No or MOT ° 0 | M 0 M "Bard 0 : 0 3 7" Mo OMe Ha Tie (i) treatment of a compound resulting from step (h) optionally treatment with an aqueous ammonia solution to produce a Yio compound of formula (11a): w 8 : RP NMae o : 0 | 2 the a ol ~ d 0 “go ~ Yau 5 == u ) (h1) 0 8 Yay]1 8 0 YA where W is nonexistent and RY is 11 and U stands for cladinose containing 74 hydroxy ions at position (78) TV. (j) Treatment of the compound produced from step (i) flea where W is not present, RY is H 71, and U is cladinose containing a buffered hydroxy at position (78) An alkylating agent chooses YVvY from the category consisting of RY Gua sila to produce a compound of formula (11a) where W is not 77 present and U represents the hydroxy site cladinose at position (78) and RY as previously defined No (k) treatment of a compound resulting from step (h) is permissible with an amine compound bearing substituents of the formula (H,N-W-RY Yve where W is not present and “8” as defined by rue except for hydrogen to produce 174 compounds of the formula (111) (where W is not present and Jia is not the hydroxy site cladinose at A AY site 0) and RY is as defined in the context except for tH (J) YVA treatment of a compound resulting from step (2) ha with a hydroxylamine compound with the formula “H,N-W-R” 7174, where N represents -0- and RY was also known (sia) to produce a compound with the formula 1 124 YA, where W represents -0- and U represents Cladinose hydroxy site at position (4) and RY as YAN previously defined; 1 ~~ 0 And YAY (m) treated a compound resulting from step (h) with hydrazine (JA) from the alternatives to produce a compound VAY with the formula (11) where W represents NH and U mates with cladinose-hydroxy moiety at site n ( 4) and RY represents the H-(n) treatment of the compound produced from step (m) bypass, where 7 represents NH- and 1 represents YAY the hydroxy site cladinose at position (4) and RY H is represented by an acidity agent chosen from YAY class consisting of: halogen-(0)©-”8 or 0-:((0)©-”8) to produce a compound of the formula (171) TAA where W represents -NH-CO- and U represent the cladinose hydroxy site at position (4) and RY 7 as previously defined; Ya. (o) Treatment of the resulting compound from step (m) is positive, where W represents NH, U represents YA, the hydroxy site cladenose at position (78), and RY represents H, an aldehyde treatment with formula 18 “CHO ray where LS RY is previously defined to produce a compound of formula (111) where W represents N=CH- and U Yay represents the hydroxy site cladinose at site (Tf) and RY As previously known; Ya (p) treated a compound resulting from step (2) with a hydrazine compound carrying substituents of the formula “¢HN-NH-R” Yao, where RY was previously known to produce a compound with the formula (1171) where W represents -NH- 1 and U represents cladinose hydroxy site at position (8) and RY is previously known as Yay with the exception of hydrogen; Ha (q) hydrolytic treatment with acid of a compound selected from the class of Gl compounds shall (i) and (j) va and (9) d (l) d (m) d (n) d (o) and (p) to produce the desired compound of formula (1) where na ve has “OH may be followed by the conversion of the compound with the natural isomer form (7p) to the compound ye with the unnatural isomer form (37) by oxidizing the 7-hydroxyl group and selectively reducing the group YoY suSY to produce the unnatural isomer (BY) Yer (p) Treatment of a compound of formula (V) as Jing RP is a hydroxy protective group and U Yet is a hydroxy group (compound produced from step (q)) with an excess of NaH reo in an aprotic solvent followed by anion intermediate reaction with :68 and CH to form an intermediate ve compound of xanthate which subsequently reacts with BusSnH in an inert atmosphere in the presence of VIA represents a catalytic U of a seed moiety suitable for the production of the desired compound of formula (¥) where vey is hydrogen; -1-8 Resultant from step (q)) base and reactor of GS all) hydroxy group Jia Q suitable for producing elite easy to remove group Jig L 5 predefined WSR and 7 Cua FA stands for 0-1-8; And U is the desired compound of formula (7) where YAY (t) remove the protective group and isolate the desired compound of formula (7) permissibly. AY in step (s) of the category LTR! Where the VF reactor selects a process according to protection requirement 14-1 consisting of: 1 18-(0)>-halogen; (1-e) ¥ (0-(C(0)-) RY), (Y—-2) ¢ £0-(C(0)-0-RY, )0-e) > (e-;) !8-.011-halogen; 1 then '8 -halogen?; S(0),-O-R' (A—-a) 0" ¢CI-P(O)(OR),-R') 4 The presence of a base with ALT-R, where the reactor (VF) of the protection requirement is replaced by a Gig process - 1'-dihydro-117-pyran in the presence of an acid catalyst. (7 Y:7) for the requirement Protection (1) in the form Gay Compound - 1 AA Ne A A NMe, b 1 ) 0 0 27 r Y > 2 ms o=_ "" vy oh . 0 0 > > u > 0 7 0 7 a ) 7 1 '-117 1 Compound Ty of the claim (VY) where it is selected from the class consisting of: Y Compound of formula (7): R representing RP “-CHy-CH=CH, representing 11; Na represents “OH” L represents `tH Y compound with the formula (7): R represents (5287 RP -CH,-CH=CH.-{ Jil represents 11 “OH Jiay U) U ¢ represents tH ° compound of formula (7): 17 does not exist; RY represents RH kills -CH,CH(O) with H Jia 1 na' OH Jia L A compound of the formula 0: /aa other than RY saga represents 1 “© methylphenyl-R” “CH,CH,NHCH,- A represents 1 Na represents 011H; 3 is a compound of the formula 0) : Ww does not exist « RY means 1 [R] represents (phenyl) “CH,CH=NO 01 L” H Jig Na represents OH HV) is a process for preparing a compound of formula 8 -1 SNE 2 Ke No, > Y o==x Ou "0 0 L : 1 0 (7); A 0 0 where : 1 RP > represents a hydrogen or hydroxy protective group; R 1 is selected from the class consisting of: (1) v an instance carrying a substituent of a notch that is selected from the class consisting of: “CN 0 A oF (<) 3 Ve (c) CORY where RY is an alkyl (k,-km) or an alkyl (k,-km) carries a 1-aryl substituent or an alkyl (k,-km) carries a scrambled aryl substituent; VY (d) "' 5(0)8 where n equals zero or 1 or ? and “for 8 as defined by the precursors of VY (e) NHC(O)RY where” as defined by the precursors of Ve (and) NHC (O)NR'RY where O and RP select separately from hydrogen vo, an alkyl (k,-km) and an alkyl (k,-km) bearing an aryl substituent, aryl with V1 substituents, aryl scrambled, aryl s 1 (J) aryl substituent; (Y) 711 alkyl (k+-k,) Shay bearing one or more select from the class consisting of: YY (a) Osha YY (b) hydroxy; Ye (c) alkoxy(k,-km); r (d) alkoxy (k,-k,)-alkoxy (k:-km); 7 (e) exo ¢ (J) Yv wa “-CHO (J) YA 2 (h) (v=) Jl) has substituents)-,0-50; 2 (i) “0828 Cua selects !8 and RY separately from the class consisting of: (1) 91 hydrogen; (veda) Ji (Y) 2 YY (7) alkyl (wed) has substituents; re (?) alkynyl (vey) Yo (*) alkynyl (k,-k”,) has substituents; 4 (1) alkynyl (k,-k ?,) ; (1) aryl substituent (VY) £Y cycloalkyl substituent (VY) 33 aryl substituent (0) 0 alkyl (veda) substituent from edit to ) 10) an alkyl (vein) bearing Shar of an aryl with substituents; £1 (11) alkyl (k,-k, ;) bearing a cycloalkyl substituent; (VY) 9 alkyl (heey) bearing a cycloalkyl substituent; (VA) £A alkyl (vrei) carrying a cycloalkyl (k-km); 23 (19) alkyl (k,-k”;) carrying a cycloalkyl (k,+-k”) having a substituent; (01) 9 Aryl alia (YY) 2 aryl-substituted; (YY) oY alkyl (k,-k” ,”) substituent of aryl” and (vv)ov alkyl (1rd) Carrying an aryl substituent mixed with substituents of” or b) RP and RY forming with the atom to which they are attached a mixed cycloalkyl ring of 01 GUY 2 members of the ring formation Shay may carry one or more Each selects separately from the category ov consisting of: oA (1) 24-hydroxy (Y) halogen; (Y) 1.alkoxy (k,-km); 11 (;) alkoxy (k) ,-km)-alkoxy(k,-km); 17(0) exo; , 17(1) alkyl(k,-km); (v)1 halo-alkyl(k,-km); and (A) 10 alkoxy (k,-km)-alkyl (k,-km); 41 (j) -COR™ where RY as previously defined 47 (k) 82 0(118)- where the and WSR” defined lous (J) TA 1-0-8 where “l as previously defined 14 (m)”-C=N n Cua 0-S(0)RY (0) v . is equal to zero or 1 or Y and " 8 as previously known aa la (o) ariel; VY (p) aryl has substituents; 7 (P) Aryl Mukhallat; l(r)aryl mixed with substituents; vo (s)alkyl (atv) Sila l (t)cyclakyl (ppd) has substituents vy (u)alkyl (k,-k”,”) carries a mixed aryl substituent” VA (v) mixed cycloalkyl Ya (w) mixed cycloalkyl (Jia 0 As (x) NHC(O)R" where LER" is predefined as NHC(O)NR'' R (3) AN where A and LER” are predefined =N-NRPRY (Ua) AY where RY and RY are predefined =N-R° (I) AY where WSR? a priori defined At (core b) =N-NHC(O)R" where RY is as a priori defined; and Ao(cc) =N-NHC(O)NR'R" where R" and R™ as previously defined (Y) AY alkynyl (km) bearing a moiety substitute select from the class consisting of: AY (1) halogen; AA (b) “-CHO AY (c) CORY where RY is predefined -C(0)-R (3) 4 where LER? is predefined a (e)R" Cua -C( O)NR''R? mixed; VV (j) aryl-substituted; 1(k)cyclakyl (km-km); av alkyl (k-k”); (rod) Alkenyl (2) 14 or more, each selected separately from the constituent category Shay carries (1. d=) Alkenyl (0) Veo from: 011 Oa sla (0 Vey For (b) Alkoxy (k,-km); ? and RY where -C(ONR''R"™ (f) Vey and “p as previously defined RP where -NRPR™ (g) 01 as previously known RY (h) “1-0-8 where 4 “-C=N (i) 0 and “8” as predefined by Y or 1 (z) 0-5008 where “ is zero or 11 “Jal (4) 1” ila aryl By (J) VY laa (m) aryl Vt aryl substituent; (0) Wo (vere) (o) cyclokyl Na substituent From mixed aryls; (yey) (p) alkyl ny as previously known RY where NHC(O)RY a (q)p and “p” as previously known dus NHC(O)NR ''R' (r) Via as previously defined RM where f =N-NRPR™ (s) VY. =N-R° 0) YY where WSR? is predefined VYY (u) =N-NHC(O)R” where “as predefined; and” (v) =N-NHC (O)NR''RY where O and LER? are predefined YE (1) alkynyles (k+-k); and 9 (7) rd alkynyls). or more each chosen from the category YY composed of: VYV (a) tri-alkylsilyl; VYA (b) aryl; a (c) aryl substituents' | z VY (d) aryl scrambled; VE (e) halogen; 7(f) aryl scrambled with substituents; U 77 selected from the class consisting of: (1) 74 hydrogen; (Y): hydroxy VYo; d (? ) hydroxy (Bsa YY (?) O-T-R' where 7 does not exist or choose from the category consisting of: VFA (a) “-C(0)- Va (b ) “-C(0)-0 “-CH,- (z) VE “C(S)-S- (2) VEN VEY (e) “C(0)-N (RY)- where RY is a hydrogen or an alkyl (k,-k;); Vey (f) Cus S(O) « equals zero, 1, or 7; z (J) Vit -0-.(5- where n equals zero or 1 or 7 Veo (h) -P(O)OR). where n equals zero or 1 or ? and 8 represents an alkyl (k,-k); +7 VET (i) -SO, -NRY)- where *8 is already defined; And and R select from the category consisting of: 4 (a) alkyl (k,-k;) may carry a substitute choose from the category consisting of: Vea 0 aryl» Vo. and Voy (4) an aryl mixed with substituents; vor (0) scrambled cycloalkyl; yo (1) scrambled cycloalkyl substituent; (V) hydroxy cycloalkyl; ey (8) alkoxy fd) not (1) NR'R® where s and RY as previously defined 01 (b) alkynyl (k,-k;) may carry a substituent of choice From the class consisting of: (1) vod aryl; (Y) Vie aryl substituent Vi (7) aryl scrambled; and 17” (£) aryl aryl substituted Jif (0) Vir cyclo-substituted Vig (1) alkyl cycloadylated (ily (V) RE hydroxy; (A) Vin alkoxy (k,-k); NR'R® (4) VY where R7 and SRY prior custom VIA (c) cycloalkyl (k,+-k”,) may carry a substituent of the category consisting of: (1) via aryl; (Y) We aryl in it alternatives; f(?) aryl mixed with substituents; wr (0) ila alkyl scrambled VV iE (1) cyclo-substituted ila alkyl; oo (VY) ve hydroxy; (A) Ya alkoxy IRENE) NR'R ? ( 4 ) \VYY where R' and RY are previously defined. . 7(3) Ariel; 73(e) Ariel has alternatives; YA.(1) unsubstituted aryl. (J)YAN unsubstituted aryl; YAY (h-unsubstituted cycloalkyl VAY or forms a U with 0 double bond between the two Ose oS atoms which are bonded lags and VAL "La Jia hydrogen or forms with U a double bond between the two carbon atoms that are attached to the YA ® hama. The method includes: VAT (a) treatment of a compound with formula 14 acid hydrolysis passport: AP NMe 8 oe AL 9 1 1 o Ou Ou HO, 4 HAS HO OTN ot 3 AY aw © 0 AR] 0 << o—RP VAA 'OMe YA, where 8 is as defined above and 88 represents a protective hydroxy group to produce a compound with the formula A Ya. VVYA 8 RP NM, H 1 1 o Ou, or M0 S 01 HO 0 A u 0 - A for VAY - Q represents hydrogen; Followed by the conversion of the compound in the form UT hydroxy group and Jia U, where the natural isomeric Var (7 p) is permissible to a compound in the unnatural isomer form (?s) by oxidizing the Vat group 7-hydroxyl and reducing the group 7-oxo selectively to produce isomer Yio HAY) the natural Van U where 0 (A) and the compound (Vy ¢ ) formed from the compound dll (b) treatment of a compound chosen from Vay representing hydrogen with a base chosen from the van formed from Hexmethyl U hydroxy and Jie the sodium silazide and a base of metal hydride in the presence of carbonyldiimidazole in J 04 and 010 on 11 aprotic solvent to produce a compound to choose from the class of the two compounds Yeo cas all Yo NH, o 8 8 0 NMae, 7776 A P H M Arad 0 o= "Mo bsn 0 y YoY 0 3 1 ' 0 y -and- 4 “-Khalil-Kladenos ». R dia U Gua Yo is a double bond; a N1 and U where B10 forms Y.4 A disamine to produce Ol and <1b for step (b) Vo m (c) treatment of a compound to choose from class Fa U where IY) composed of LAH compounds a bicyclic carbonate to choose from 75 ci ill b 0-;”-Khalil Cladinos and 17b; where a and " do not form a double bond on 8 RP NMe,; has 1 o Ou = BD N i \ 72 M l. Cel “a 0 YA o 1 0 7 : 0 represents 0-;”-Khalil Cladinon (U Cua IY) 7.4 where 10 form a double bond cal 1 700 (z) for step WY) and hi 1 Compounds consisting of as treatment of a compound chosen from (2) Yi: B on Y and Ivy a compound chosen from the channel consisting of the two compounds z (WEY diluted aan 711 ca pill YAY: NMe, ING > 00 2 = Nia. cy 6 == 0 0 TE om a uU 0 8 7 0 : Cladinose 6 and Jala represent 0 - U where Jy Y Yye form a double bond; UT where NO and oY YA MB (a) removal of the hydrolytic cladinose moiety from compound IVY from step (d) by acid treatment; MA and reprotection of the 7-hydroxyl group by treatment with a hydroxy buffer reactor followed by the conversion of compound 714 in the natural isomeric form (27) to the compound in the non-AR isomeric form (GF) by oxidation of the 7-hydroxyl group and reduction of the “-oxo” group in the form of 9 Selective for the production of an unnatural isomer (7 s) to produce a compound with the formula (VY z RPO, lL 1 y 'b 6 . 3 Nin oy SO YYY : 0 his hand 777 y | a naab 0 ,7 which is a compound in formula (7) where “8 Jia 1] and U is hydroxy and Yye is not hydrogen; a 771 (f) treatment of the 7-hydroxy group of the resulting compound from step (e) in formula (7); 777 where WSR is already known and RP represents 1] and does not represent hydroxy and "Never represents hydrogen. YYA is a base-carboxylate and a 1-7-8 reactant; where Jia L is an easy-to-remove group and 7 and WSR is customary 9." in advance to produce a compound of formula (7) where "8" represents 11 and U represents 5-0-T-R "1 has Yr. hydrogen; ry (1) treatment of the 7-hydroxy group of the compound produced from step (e) with formula (3) 77 where WSR is already defined, 80 represents 1!, U represents hydroxy, and “1 represents hydrogen ry is permissible in form Sequentially an excess of NaH, 65, and CHE to form an intermediate complex of Tre <-0-transgressions treated with BusSnH in the presence of a suitable starting cleft to produce the eluted compound 79 with formula oY) where 8# and no and "They do not represent Heder and When; (J) Removing the protective group and isolating the desired compound with the formula (©) permissibly. 0 aga 1 4- process according to protection requirement dua (VA) selects reactor 1-7-8 in step (f) of class \ consisting of: 1(e-1)l8-(0)©-halogen; (Y—-a) 1 ram))-0; ° (e-") £0-(C(0)-0-RY), 1 (e-8 ( Cea olla-CH,-R ¢ v (e-0) metal hydride Alkaline followed by ,05 and then L-8-halogen?; Ve {C1-S(0),-0-R' tC1-P(0)(OR),-R' (122) 11 VY (H-10) to be —Y 1 Gig process for protection requirement (VA) where the reactant 1-7-8 in the presence of a base is replaced by 1-dihydro = Glow HY in the presence of an acid catalyst. Gy of protection claim (1) in form (4): NMe, © M 0 8 : Ke Ou, 7 Pos == 0 U of 8 0 : lu v (¢)" 0 YAY where it is selected from the class consisting of: (V0) a compound according to the claim – “77 1 'OH is represented by U representing Khalil; 8” -CH-CH=CH, representing R is a compound of the formula (?): Y is condensed; U is an alkyl; RP stands for (7-quinolinyl)-.011-011-.011-; R:4(compound with the formula >canyl-(0-0)0;1=V) stands for UH stands for R? represents (7-quinolinyl)-:011-611-,011-; R(4):(compound with formula 1-nitrophenyl)-0-0)0; A : RP “-CH, CH(0) is less than R ¢ H Mia RY Unabridged 07 Compound with the formula (;): 3 'OH Na for H b for (phenyl)-RH for RY Not present; Wid) compound of formula 11 Na stands for 011; and 11 Jia 8” “CH,CH,NHCH.-vy methylated (phenyl)-RH stands for RY Not found; WE) A compound of formula 1.OH represents U «H represents 2 «CH,CH=NO Ve:4( Process to prepare a compound of formula -* E 1 o 8 1 AP NMe, 2 Ke = x or 2 “OL 1 o button z (8) I ; where 4 VAY represents a hydrogen or a hydroxy protective group; RP° is selected from the class consisting of: R 1 substituent-carrying moiety chosen from the class consisting of: (1) “CN (a) A F (b) 1 represents an alkyl (k,-k") or alkyl (k,-km) bearing a substituent RY where CORY (c) 1 is from a mixed aryl; San carries (r=) from 1 aryl or alkyl (laa or 7 and “l8 as defined by 1 where “ is zero or S(0)RY(d)VY) as predefined by RY where NHC(OR® ( 4) Vy separately from hydrogen RZ selects the p and Cus NHC(O)NR''R™ (5) from an aryl and arbel with substituents Say carrying (rey) and an alkyl (k,- km) and alkyl, aryl-substituted and aryl-substituted; 1 (g) aryl; VY aryl-substituted; (2) VA (i) aryl-substituted; and 4a(j) aryl-substituted Substituents; or more to choose from the class consisting of: Tandy Shay alkyl (k+-k,) bearing (7) Y/halogen; (1) YY (b) hydroxy; YY (rr ) (c) alkoxy re alkoxy(k,-km)-alkoxy(k,-km); (2) Yo (e) exo; 71 blk (J) YY “-CHO (J ) YA (h) (alkyl (k,-k,) substituents) -,0-50; 3 As Gua NRPRM (5) 7 selects RP and “!8” separately from the class of: (1) 9 hydrogen; (Y) YY alkyl (ied) (7) alkyl (k,-k”,;) has substituents (rv) Jans (4) Ye (e) Yo alkynyl (k,-k”;) has substituents das (1) a (k, -k,); the (v)alkenyl (k,-k”,),) has substituents; (VY) 3-substituted cycloalkyl (VY) 31-substituted cycloalkyl (VY) 2 (£1) Alkyl (k,-k”,) carries Sa from dil (V0) to alkyl (k,-k”,;) carries an aryl substituent; (V1)£1 alkyl (k ,-k”,) bearing a cycloalkyl substituent [VY] 3 alkyl (k,-k”,) bearing a cycloalkyl substituent; (VA) 2 alkyl (k,-k »,) carries a cycloalkyl substitute (adv) 4 (09) alkyl (k,-k,,) Shay carries a cycloalkyl (adored) with (diy (01) o. Aryl alia (VY) 2 is a scrambled aryl; (YY)oY alkyl (k,-k”), substituent of a scalar aryl” and (YY)oy alkyl (k,-k) »,,) carries an aryl substituent mixed with it; ot or M °° Tlj and “L” form with the atom to which they are attached a cycloalkyl ring mixed with who? To 2 01 ring-forming members may carry one or more substituents each Leia selecting separately from the class ov consisting of: (1) oA” (Y) 4-hydroxy halogen; ( alkoxy (k,-km); 2 (4) alkoxy (k,-km)-alkoxy (rds) z 0 TY (©) exo ¢ oo 1 (1) alkyl (k,- k); ' (v) 1 halo-alkyl(k,-km); f : (A) +6 alkoxy(k,-km)-alkyl(k,-km); 11(j) -CORY where RY as previously defined: 2 (K) -C(ONR'RY where R” and “8 as previously defined (J) A” 8-0-8 where “L as a priori 11 (m) “-C=N z 2 (n) 0-S(0)RY where n is zero or 1 or ? and WER? a priori 1l (x ) aryl; : l (p) da) substituents; ow (q) aryl scrambled vie (y) aryl scalded; ve (3) alkyl(km-km); vi (t) cycloalkyl (k,-km) has a butylate; VY (u) alkyl (k,-k”,) carries a scrambled aryl substituent; : VA (v) scalar cycloalkyl va ( d) a substituent cycloalkyl; YA is predefined LER where NHC(O)R" (x) | predefined; LER ? and RY where NHC(O)NR''R" (3) A As previously defined RY and R ® where =N-NR "RY (rt) AY where 87 as previously defined 4-85 (ff) AY previously defined; and WER where = N-NHC(O)R" (BB) At LER? and R! where =N-NHC(O)NR'R" (cc) Ae an alkynyl (how much) bearing a moiety is selected from the class consisting of: (©) AT halogen; |) AY "- CHO (b) AA as a priori defined by RY where COR” (c) Ad as a priori defined by LER” where -C(O)-R (3) a as a priori defined by R ® where O and -C(O)NR''RY (2) an "-C=N (J) ay "ily At (2) 10(j) chelated aryl with substituents; and av alkyl (k,-k”,,) bearing a methylated aryl substituent (J) AA (1d) alkynyl (2) 3 alkynyl (k;-k,,) bearing one or more substituents choose Each separately from: (0) Ve halogen; (1) Ve (rey) (b) alkoxy vy ¢ oxo (=) Voy «CHO (3) Vet VAY as predefined RY where -CORY (e) 010 predefined LER? A and Cus -©)0(1882 (f) Ve awe as defined by R™ and RP where -NRPR™ (g) 01 where “V awe as previously known = N-O-R" (h) 01 -C=N (i) Ved Predefined LER and Y or 1 where " is zero or 0-S(0)R" (j) ne (k)aryl; (p) an alkyl (k,-k’,) bearing a mixed aryl substituent; VA as predefined RY where NHC(O)R’ (q) VAY predefined LER? where O and NHC(O)NR''R? =N-R? (O)NR''R" (v)1 and ofr. dred) alkynyl (1) YY an alkynyl (k,-k,) carries one or more substituents each selected from the constituent class (V) “7 of: 0 d (a) trialkylsilyl; “Jol (b) VY (c) substituent aryl; 17 alia (d) 14 aryl Ha VY. (e) halogen” 171 (f) aryl with mixed substituents; 77 NA choose from the class consisting of: (VY) IAA hydrogen; (Y) vi hydroxy; bd (V) buffered hydroxychloroquine; 7 (?) *-0-7-; where 7 does not exist or is selected from the category consisting of: YY (a) «-c(0)- «-C(0)-0 (<3) 7 ed (c) -ittn-; Ve (d) “C(S)-S- C(O)N(R)- (=) Ve) where RY is hydrogen or alkyl (rede) S(O) (5) VEY where n is zero or 1 or ; (J) Vey -0-,(5)0- where n equals zero YSIS Vit (h) -.8)0()087- where « equals zero, 1, or ? and RT is the alkyl (rere) Veo (i) -SO,-N(RY)- where RY is defined above; And R VET chooses from the category consisting of: VEY (a) alkyl (k,-k) may carry a substitute chooses from the category consisting of: “Jat (1) VEA (Y) Vea aryl have alternatives vo. (¥) aryl dala and Vo (2) substituent aryl Voy (0) cycloalkyl substituent; Vor (1) substituent cycloalkyl; (VY) Vot hydroxy m" ree (8) krxi fom) NR'R® (4) vou where 87 and RY as previously defined 011 (b) alkynyl (k+-k.) may carry a substitute Select from the category consisting of: “Jt (1) VoA (Y) Ved substituent aryl; sad) 0 51 (£) substituent aryl; VY (0) cycloalkyl substituent; var (1) Substituent cycloalkyl; | ) (VY) Vig hydroxy; (A) Vie alkoxy (1d) Vin (9) 11878 where R7 and LS RY are a priori custom (z) Vv a cycloalkyl (k-k?.) may carry a substituent from the category consisting of: “VIA” 0( aryl “(Y) 14 aryl substituents” We (7) mixed aryl; and WA(2)substituted aryl; L(°)substituted cycloalkyl 77(7)substituted cycloalkyl; L(V)hydroxy;(A)76alkoxy (k,-k. ); BET "(g) aryl mixed with substituents. lie (H alkyl found YAN). The method includes: VAY: 08 (a) treatment of a compound with the formula ay : 8 id NM 89 0 i o Ou, . n, o Je : wg HO © VAS Ww On, 9 p. In the form z (Lanta Dual) Dm under Yo for a short period of time 8 3 at around YAY Z RP NMe, 0 : i iN From: R i 0 Ou, . == o "0 0 VAA 1 Q,, 00 AR © VAR : 0 3 7 Mon “OMe alkali metal hydride of) (b) treatment of a compound of formula 1 permissibly as indicated in step 0 H and a carbonylating agent chosen from the class consisting of phosgene 2-phosgene and 3-phosgene in anhydrous conditions while controlling the amount of base present in a careful way to prevent decarboxylation 7: ¢(1) as shown in step YS catalyzed with a base to produce the compound with the formula Var U compound with the formula (¢) where z Lay 1 normally GS yal gel treatment (z ) 16 hydroxy edly acidifies and 88 represents a protective hydroxy group followed by the conversion of the compound Jia Vie Ha 1 natural isomer (7p) permissive to the compound in the unnatural isomer form (BV) by oxidizing if the 7-hydroxyl group and selectively reducing de pana 7-oxo to produce an isomer other than natural (ON) 04 (d) treating a compound of formula (4) permissively; Jig U dua hydroxy group and RP Ye represents a hydroxy protective group (compound produced from step (h)) by an excess of NaH in Ye aprotic solvent and then the reaction of the intermediate compound anion with CS; and CHIL to form a Toy intermediate compound of xanthates that treats Gay with 80.5011 in an inert atmosphere in the presence of a catalytic amount of an initiator radical suitable for the production of the desired compound with formula (2) where diag is no hydrogen and R® Jin Yet is a hydroxy protective group; a Yeo (2) treatment of a compound of formula (£) is permissible, where U is a hydroxy and RP is a hydroxy protective Yeu group (compound produced from step c) with a base and a 1-1 reactant 8- Where T and R' are as previously defined and L represents an easily removed reactant group suitable for producing the desired compound 1 with the formula (£) where U represents 0-7-8 ! and 8 represents Hydroxy protective group; Yed (f) Remove the protective group and isolate the desired compound with formula (4) permissively—Yo 1 Gig process for protection requirement dus (YE) selects the L-T-R reactor in step (e) of class/component of: 1 (E-1) tC sla-C(O)-R* £ (E-)¢0-(C(0)-RY), ° (E-¢0 -(C(0)-0-RY), 1 ) 1 (e-;) for©,11-8-h face l(0-2) alkali metal hydride followed by CS, then '8-halogen; -R' 1 (e-)l'-0.rm5n; 4 1 4 Af ¢CI-P(O)OR)-R' (1-2) 1 CI-SO”-N(R)-R* (01-H) VY ALT-R base exists Replace the reactant dua (YE) of claim Gig lee-7 with 1-dihydro-711-pyran in the presence of an acid catalyst. Y (0) of claim (1) with formula Gig Compound-77 1 1 : .88 am b 0 py Y rg < . 0 + N 1 N “(°) 0. 1 and 0 HES where he chooses from the constituent class (1 A) of the protection claim (ad 4 -YA \ tOH compound possesses U <H (fia R® -CH,-CH=CH, R:)*( A compound of the form Y has 0-alkyl; U H stands for R® -CH-CH=CH; R:(0) represents a compound of the form r 11 "does not represent [; UH Jia R” “-CH-CH=CH, R:5) represents a compound of the form ¢ RP “-CH , CH(O) Ji R 11 represents RY not present; We ( ° ) is a compound of the form 0 'OH Jia na H has 1 equal to RY non-existent W: ( o) L compound Ba 1 sinekha NA is 011; Not found Ww : ( =o] ) Compound of formula 3 AA OH consisting of U yen Jia R® “CH,CH=NO v : ( 5 ) Process for preparing a compound of formula 2 -Yi 1 VAY 8 RP NMes Luo FT o On. 0 > = f 776 oy < om ww not 0 1 ) 7 : 0 where t 0 is a hydrogen or a hydroxy protective group; RP > is chosen from the category composed of: R 1 An instance carrying a substituent of a moiety chosen from the class consisting of: (1) “CN (1) A F (<) 4 Say representing an alkyl (k) or an alkyl (k) bearing RY (c) “-0,8© where 01 of an aryl or alkyl (k,-km) carries a mixed aryl substituent; (d) bY is a priori defined LS RY where NHC(O)R' (e) VY separately from hydrogen RP selects the p and dua NHC(O)NR''R™ (f) VE and alkyl (k,-km) and alkyl (k,-km) carry an aryl substituent, aryl with substituents ve 3 Ji, aryl scrambled and aryl scrambled vi «Jal (J) VY (h aryl It has substituents; VA chelated aryl and (5) ALY) (Jala (j) aryl 7) Choose from the category consisting of: ESE alkyl (k+-k,) bearing one substituent or (Y) 711 14 halogens (1) YY (b) hydroxy; vw {rde) (c) acoxy (d) alkoxy (k,-km)-alkoxy(k,-km); Yo (e ) exo; 7 (f) sans YY “-CHO (J) YA” 0-80, (Ji (alkyl (k,-k)) in it (2) Ya where he chooses z and “all Separately of the class consisting of: NRPRM (L) Ye hydrogen; (1) 791 (remy) alkyl (0) ry substituents (yyy) alkyl (7) YY (veel) alkynyl (4) ve has substituents; (remy) alkenyl (0) Yo (remy) alkynyl (1) = has substituents; (hed) alkynyl (7) vv “Jul (A) YA (dred) cycloalkyl (1) ' substituent; (plored) cycloalkyl (14) '. Aryl substituent; (1) 3 (lia cycloalkyl (VY) x (VY) alkyl (k,-k”,) aryl-substituted (0) 2 aryl-substituted (vem) alkyl (10) 2 of mixed cycloalkyl; Sa alkyl (k,-k,,) bearing (17) 5 Vio alkyl (k,-k,,) bearing a cycloalkyl substituent (VY) 3 from a cycloalkyl (k+-km); Shay bearing (vem, dl) JH (VA) 3 Carries a cycloalkyl (k+-km) substituent; (vrei) alkyl (09) 2 Lalas aryl (01) 0. Substituted aryl; (YY) 51 carries a substituent of A scrambled aryl; and (ye dl) alkyl (YY) oY alkyl (k,-k”;) bearing a scrambled aryl substituent; (YY) oy or of 01 forms with the atom they bond It has a cycloalkyl ring mixed with it from © to RY and 2 members of the ring formation may carry one or more substituents, each chosen separately from 2 of the category consisting of: ov halogens; (V) oA (Y) ed alkoxy (k,-km); (YY) 1. (red) nS SU (rtm (?) alkoxy 11 oxo(0) +11 alkyl (k) ,-km); (1) 1 and (rd) halo-alkyl (7) +1 alkoxy (k,-km)-alkyl (k,-km); (A) 10 as a priori definition RY where -CORY (j) 13 (laws a priori LER? where "C and -C(O)NR''R (k) +17 a priori definition LER where =N-0-R" (J) TA “CoN (m) 1 predefined LER or ? and 1 equals zero or n where 0-S(0)R" ( 0 for “Jal(s) 1 Van diy aryl with (2) 7 (p) aryl scrambled; vr aryl scalded with substituents; (0a) no (pte) (s) cycloalkyl ve . (t) cycloalkyl (k+-km) substituent; v1 (u) alkyl (k,-k”,) bearing a scrambled aryl substituent of 2% (v) scrambled cycloalkyl vA (w ) a mixed cycloalkyl with substituents; va preconvention LS RY where “NHC(O)R(x)A preconvention WSR” and R” Cus NHC(O)NR''R (3) AN and “RA as previously defined RP dus =N-NRVRY (Ua) AY as previously defined by R® where =N-R° (AA) AY where “!8 as previously defined; f =N-NHC(ORY (<2 3) At a priori LER? C and Cus =N-NHC(O)NR''R" (cc) Ao alkynyl (how much) carries Substitute from a moiety chosen from the class consisting of: (Y) A halogen; Predefined WSR' where -C(0)-R' (9) q. They also predefined RY and RY prefixes where -C(O)NR''R' (2) 1) « -C=N (3) 7 “Jal (g) ay (h aril has substitutes 4 (i) mixed aril 40 city (j) aril mixed with 1 Vay (km-k”); and ils (k) alkyl av alkyl (k,-k”,),) bears a chelated aryl substituent (J) AA TAREE) alkynyl 8 a4 alkynyl (k,-k,,) bears one substituent or more, each separately selected from category (0) Veo consisting of: 011 Halogen 0 Vey (b) Alkoxy (k,-km); Voy Exo; (2) Vet ; «-CHO (2) Veo lia where “L as defined by COR” (e) Vel as previously defined by R™ and RY where -C(O)NR''R' and ( f) As previously defined RM where “C and -NRPR™ (g) 01 (h)” 8-0-8 where “L as previously defined Vea”-C=N i) 10 or ? and “.8 as previously known 1 equals zero or “Cus 0-5008” (J) 111 (k) aryl; WY aryl substituent; (J) VY mixed aryl (a ) Wt aryl-substituted; (0) Vio(s)cyclakyl (km-kb); 1 aryl-substituted (sve)(p)alkyl AY as previously known RY Where NHC(O)RY(P)VIA is a prior definition of WSR? where !m and NHC(O)NR''R (a) 14 and "l as previously defined R" where =N-NR"R™ (s) VY. Define priors WSR” where =N-RY (R) 11 AQA VY (U) 010208 where LS RY is previously defined; and YY (v) =N-NHC(O)NR''R" where O and LER? are already defined; VY (1) alkynyl(k+-k..); and ( V)"0 alkynyl (K+-K,) Shay bears one or more each selected from a class composed of: 11 (a) tri-alkylsilyl; (b) aryl; VTA; 19 (2) Substituent aryl; VY (d) aryl; VY (e) halogen; and YY (f) substituent aryl; U 77 choose from the category consisting of: (1) 7hydrogen; -C(0)- (1) VA «-C(0)-0 (<3) 174 + (c) «-CHz-VEN (d) «C(S)-S - VEY (e) -C(0)-N(RY)- where RE is hydrogen or an alkyl (red) VEY (f) -5000- where n is zero or 1 or OY (J) Vig -0-,)5(0- where n is zero or 1 or 7; Veo (h) -POYOR) where “ equals zero, 1, or ?and 8 represents alkyl (reel) VET (i) -SO,-N(R)- where RY is defined previously; and VEY does not choose from the category consisting of: 08 (a) alkyl (K,-K,) may carry a substitute choose from the category consisting of: “did (1) Vea (Y) Veo aryl in it Substituents; Vo! (7) aryl-substituted; Vox (2) aryl-substituted; Voy (0) aryl-substituted; vot (1) aryl-substituted; (V) ) Veo hydroxy; g0 (A) vou alkoxy (1d) Vo (1) 11878 where R7 and RY as previously defined Vo (b) alkynyl (k,-k.) may carry a substituent selecting from the category consisting of: 1 (0) aryl; (Y) Vie substituent aryl; Vi (7) mixed aryl” and dy Jf (2) VY substituent aryl; Vy (0) a mixed cycloalkyl; Vig (7) a mixed cycloalkyl substituted (gS sa (VY) Vio am (4) alkoxy fd) Viv (1) 11878 where R7 and “8 as previously defined VIA (c) cycloalkyl (1rd) may carry a substituent of the class consisting of: Via (0) aryl (Y) VY. Substituent aryl; WA (7) Ariel Mukhallat and Yoo 77 (3) aryl mixed with NSH “except (°) cycloalkyl ANE Justi (1) 74 cyclomixed with (Jil) (VY) Ve hydroxy; (A) a alkoxy (k,-k); for la (1) “10878 where 87 and RY are previously known: a (3) eal Count (e) Ariel with “Jil BG (and) Ariel Lila b Agha (J) aryl mixed with substituents VAY (h) mixed cycloalkyl VAY The method includes: Cr (a) treatment of a compound of formula E ) 1 : ’ 0 : 8 fl NMe, , 0 Ou HO, for : TL ~ HO OTN wt ©, _O f 0 . A CJ. VAT 0 >” 0-8 ‘OMe all represents a hydroxy protective group with a reactant chosen from R? As defined above and R Cua VAY sacl 3 chloriodiomethane in the presence of 1 Y) and A formaldehyde in the presence of (1) consisting of: YAA VAR to produce a compound of formula TY n 11 : 8 RP NMes z ° Loo x <0 g PS BY > 0 ©, 00 0 Yr 0 A 88 Ya) OMe d (b) hydrolytic treatment of a compound produced from step (1) in the formula (TV) To produce a compound that represents a hydroxy protective group, RY may be hydroxy and iy U with the formula (0) where VAY is followed by the conversion of the compound with the natural isomeric form (7p) to the compound with the unnatural isomeric form at 1 ( BT) oxidizes the 7-hydroxyl group and selectively reduces the ?-1-oxo group to produce the unnatural isomer (?s); (0) Permissibility where Vay VAA is a protective group for the hydroxy (compound produced from step (b)) with an excess amount of NaH in a 4 aprotic solvent following the reaction of the intermediate anion with .65 and CHL to form an intermediate compound .7 of xanthate which subsequently reacts with BusSnH in an inert atmosphere in the presence of a catalyst of 88 being hydrogen and U a suitable initiating moiety to produce the compound of interest with formula 0) where Ye Jing Ye is a hydroxy protective group; Yor (3) treatment of a compound of the formula (1) a passport where U represents a hydroxy and 188 represents a © group where 7 and L-T-R are protective for the hydroxy (the compound from step B) with the base and reactor of Yet Yeo as previously known Sa Lg is an easy to remove group suitable reactant to produce the compound of interest with formula (©) where U is 0-1-8 and 88 is the hydroxy protective group; (Passport. 9.1 dl) In step (e) of the LTR, the reactant Cua (Y9) of the protection claim selects a process Gy -©0 1 consisting of: L8-(0)-halogen; ) 10-e( ¥ t0-(C(0)-RY), )0-e(£ ¢0-(C(0)-0-RY), )1 (e-° (e- ;) 11-.1©-halogen; 1 b (e-e) alkali metal hydride followed by ,05 and then 18-halogen; ¢0O=C=N-R' (=) A z EN(ROH-R ' (E-7) carbonyl diimidazole followed by 4 0 {C1-S(0),-OR* (e-d) ve {CI-P(O)(OR),-R (peep) 1 for water droplet. (01-e) VY where the reactor 1-7-8 in step (e) is replaced in (V1) for protection requirement Gy-71 process 1 in the presence of an acid catalyst. Narib-1117-pink SUEY with base b