TWI229677B - 2-halo-6-O-substituted ketolide derivatives - Google Patents

Abstract

Novel 2-halo-6-O-substituted ketolide derivatives and pharmaceutically acceptable salts and esters thereof having antibacterial activity having a formula compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier, a method for treating bacterial infections by administering to a mammal a pharmaceutical composition containing a therapeutically-effective amount of a compound of the invention, and processes for their preparation.

Description

1229677 V. Description of the invention (1) Technical scope The present invention relates to novel semi-synthetic macrolides with antibacterial activity, pharmaceutical ingredients containing the compound, and medical methods of treatment. More specifically, the present invention relates to a novel 2--6-0-substituted ketoglycoside derivative, a method for preparing the same, and a method containing the compound to form an infectious disease. Background of the invention Erythromycins A to D, represented by formula (E), and the use of this ingredient to treat bacteria

(E)

Erythromycin: Rb A -OH -CH; B -Η -CH C -OH -H D -Η -H is a known and potent antibacterial agent, widely used to treat and prevent bacterial infections. However, like other antibacterial agents, strains have been identified that are resistant or less susceptible to erythromycin. At the same time, erythromycin A has only weak activity against Gram's bacterium. Therefore, there is a need to seek for neoerythromycin derivatives, which have improved antibacterial activity, low potential for resistance development, ideal activity against Gram-negative bacteria, or unanticipated selective resistance

Page 7 D: \ 1234 \ 55395.ptd 1229677 V. Description of the invention (3) The stereochemical structure of the atom. Summary of the Invention The present invention provides a novel type of 2-halo-6-0-substituted ketoglycoside derivatives which have antibacterial activity. One of the characteristics of the present invention is a compound, or a pharmaceutically acceptable salt and ester thereof, having a molecular formula selected from

D: \ 1234 \ 55395.ptd Page 9 1229677 V. Description of the invention (4) (1) D-heart-alkyl optionally substituted with one or more substituents, the substituents being selected from (a) Aryl, (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) -NR3R4, wherein R3 and R4 are each selected from hydrogen and -alkyl, or R3 and R4 can be combined through atoms to form a 3-7 member ring. The ring contains: -0-, -NH-, -n (Ci-c6-alkyl-)-, N (aryl_Ci --C6-alkyl _)-, -N (substituted aryl-(^-06-alkyl-N (heteroaryl-C6-alkyl-)-)-, and -N (substituted heteroaryl (2) -CH2-CH-di-CH-Y, where Υ is selected from (a) H, (b) aryl, (c) substituted aryl, (d) heteroaryl Group, (e) substituted heteroaryl; (f) -CH: H2, (g) -CH = CH-aryl, (h) -CH = CH-substituted aryl, (i) -CH = CH-heteroaryl, and (j) -CH = CH- substituted heteroaryl, (k) (aryl) fluorenyl, (1) (substituted aryl) fluorenyl,

D: \ 1234 \ 55395.ptd Page 10 1229677 V. Description of the invention (7) '------ ~ ---- Carbonized compounds that have been burnt and methylbenzene, such as: methylene 2 emulsified t-Ethyl chloride, chloroform, and the like, heteroaryl compounds, such as tetracefuran and n-methylpyrrolidinedione, and ethers, such as: ether, methoxyfluorenyl ether. Such compounds are known to those skilled in the art, and can choose a better solvent or its / tD combination according to the specific compound and reaction conditions (such as the solubility of the reagent, the reactivity of the reagent, and the preferred temperature range). Thing. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specific books, such as: Organic Solvents Physical Properties And Methods of Purification, 4th ed., Edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. The n-aryl group n herein refers to a mono- or bi-carbocyclic ring functional group formed by a hydrocarbon compound containing one or two aromatic rings, respectively, after removing one hydrogen atom. This aryl functional group includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, hydroindenyl, indenyl, and the like. In this context, π (aryl) and fluorenyl π refer to a molecule in which an aryl group (as defined above) is linked to the bulk via a carbonyl group. Herein, n c3-c7-cycloalkyl " refers to a monovalent group formed from a monocyclic or bicyclic saturated carbocyclic compound by removing a hydrogen atom. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo [2 · 2 · 1] heptyl. Herein, "pi halogen" and "f halogen" refer to an atom selected from fluorine, chlorine, bromine and iodine.

D: \ 1234 \ 55395.ptd Page 13 1229677 V. Description of the invention (8) "Alkylamino group π" herein refers to a functional group with NHR 'structure, where R' is an alkyl group (as defined above), and an alkylamine Examples of radicals include amido, ethylamino, isopropylamino, and the like. The "dialkylamino group" herein refers to a functional group having a structure of NR 'Rn, wherein R' and R ^ are each selected from an alkyl group (as defined above). In addition, R 'and Rn can be optionally combined into-(CH2) k-, where k is an integer of 2 to 6. Examples of the dialkylamino group include: dimethylamino, diethylaminocarbonyl, methylethylamino,? -Hexahydropyridyl, and the like. “Haloalkylπ” herein refers to an alkyl group (as defined above), which is connected to one, two, or three halogen atoms. Examples are: chloromethyl, bromoethyl, trifluorofluorenyl, and the like. Herein, πalkoxycarbonylπ refers to an ester group; that is, an alkoxy group is connected to the molecular part of the body via a carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, etc.). Herein, “πthioalkoxy” is The alkyl group as defined above is connected to the molecular part of the body via a sulfur atom. In the text " formamyl " refers to a group of formula -CHO. Herein, π carboxyπ refers to a group of formula -C02H. Herein, "πamido" refers to a group of the formula -CONHR 'R ", wherein R' and Rn are each selected from hydrogen or alkyl, or R 'and R" can be optionally combined to form-(CH2) k- , And k is an integer from 2 to 6. In this context, πheteroarylπ refers to a cyclic aryl group, and the aromatic ring of the aryl group has five to ten atoms, and the atomic system on one ring is selected from: S , 0, and N; there are zero, one, or two additional heteroatoms on the ring, each selected from S, 0, and

D: \ 1234 \ 55395.ptd Page 14 1229677 V. Description of the invention (10) Selective removal. The use of hydroxy-protecting groups is a known technique. Synthetic methods can prevent unnecessary reactions in synthetic methods. Many such protective groups can be found in ‘for example: T.H. Greene and P.G.M, Wuts,

Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons (1991). Examples of hydroxy-protecting groups include, but are not limited to, methylthio, tertiary-dimethylsilyl, tertiary-butyldiphenylsilyl, ether, such as ethoxymethyl, and esters Class, including ethenyl, exoyl, etc. The "π ketone protecting group" herein refers to a group that can be easily removed. This group is known to protect the ketone group from unnecessary reactions in the synthetic method and can be selectively removed. Using a keto-protecting group Protective groups are a known technique in synthetic methods to avoid unnecessary reactions. Many such protective groups can be found in, for example, ······· Greene and PGM · ffuts, Protective

Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York (1991). Examples of keto-protecting groups include, but are not limited to, ketals, oximes, and 0-substituted oximes, such as' ... 〇-yl oxime, 0-phenylthiosulfonyl oxime, 1-isopropoxy Cyclohexyl and so on. "Keto" as used herein refers to a group in which two hydrogen atoms of one carbon atom on an alkyl group (as defined above) are replaced by one oxygen atom (ie, a carbonyl group). As used herein, "N-protecting group" or "N-protected" refers to a group that protects an amine group from unnecessary reactions in a synthetic method. The N-protecting group includes: Aminofuric acid. L includes: Heteroaryl , N-alkyl derivative, amino condensation: Derivative, N-5 based derivative, imine derivative, enamine derivative and heteroatom derivative. The preferred protecting groups are: fluorenyl, Ethyl, Henry

1229677 V. Description of the invention (11) group, tert-pentamyl, phenylsulfonyl, phenyl, triphenylmethyl (tribenzyl), third butoxycarbonyl (Boc), gasoxycarbonyl ( Cbz). Common N-protecting groups are disclosed in T.H. Greene and P.G.M.

Wuts, Protective Groups in Organic Synthesis. 2nd Edition, John Wiley & Sons, New York (1991), which is hereby incorporated by reference in its entirety. Herein, "π-protected amine group" refers to an amine group protected by an N-protecting group (as defined above), which includes: alkanoyl, acetate, trimethylsilyl, triethylsilyl, and methoxy曱 基 et al.

“Π protected hydroxy group” herein refers to a hydroxy group protected by a hydroxy protecting group (as defined above), including: methylamyl, ethylamyl, fluorenyl, tert-pentamyl, phenylsulfonyl, fluorenyl, Triphenylmethyl (triphenylfluorenyl), tert-butoxycarbonyl (Boc), and 4-oxycarbonyl (Cbz).

Herein, "proton-producing organic solvent" refers to a solvent such as "ferment" that has a tendency to provide protons, such as methanol, ethanol, propanol, isopropanol, butanol, tertiary-butanol, and the like. Such compounds It is well known to those skilled in the art, and can select a better individual solvent or a mixture thereof according to specific compounds and reaction conditions (for example, the solubility of the reagent, the reactivity of the reagent and a preferred temperature range). Further discussion on the generation of protic solvents See also organic chemistry textbooks or specific books, such as: Organic Solvents Physical Properties and Methods of Purification, 4th ed., Edited by John A. Riddick et al., V.l. II, in the Techniques of Chemistry Series, John Wiley & amp Sons, NY, 1986.

Page 17 1229677

Herein, the substituted aryl π refers to a group in which one,% or three hydrogen atoms of the aryl group (as defined above) are each substituted, and the substituents are: ΐ, _, cyano, Ci- Cf alkyl, c! -C6-alkoxy, aryl-substituted & Ci-Ce-alkoxy, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, fluorene Amine, sulfhydryl, nitro, fluorenyl, carboxyl, alkoxycarbonyl and fluorenylamino. In addition, any substituent may be aryl, heteroaryl, or heterocycloalkyl. Meanwhile, substituted aryl groups include: tetrafluorophenyl and pentafluorophenyl. The "substituted heteroaryl group" herein refers to a group in which one, two, or three hydrogen atoms on the heteroaryl (as defined above) are each substituted, and the substituents are: -C 1, -Br, -F, -1, -0H, -CN, Ci-C3-alkyl, q-Cs-alkoxy, QQ-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amine, and amine Diamine, sulfhydryl, sulfhydryl, methyl, methyl, sulfanyl, oxycarbonyl and amido, N-protected amine, -CH (= N-〇H), -CH (= n-NH2), and -CH (= NN = C (CH3) 2). In addition, any substituent may be aryl, heteroaryl, or heterocycloalkyl. As used herein, "substituted (aryl) fluorenyl" refers to a group in which one, two, or three hydrogen atoms on the (aryl) fluorenyl (defined above) are each substituted. The substituents are: -Cl, -Br, -F, -I, -0H, -CN, Ci-Q-alkyl, Ci alkyl, aryl substituted ^-^-alkoxy, haloalkyl, thioalkoxy, amine Base, amine, diamine, sulfhydryl, nitro, formate, oxyalkyl and amine, N-Polyazine,

-ch (= N-㈣, _CH (= N_NH2), and _CH (=: (except for L, any substituent may be an aryl group * cc ^) This is a doped% alkyl group.

Page 1229677 V. Explanation of the invention (13) "Substituted (heteroaryl) has the same meaning as above) The previous one, two or three u-groups 72 =) fluorenyl (this substituent is defined as: -C 1 , -Br, -F, -membrane, disubstituted group, group, Cfc6-alkyloxy, aryl, substituted -H: CN, Cl-C3-thiosulfanyloxyamine, amine, Alkyl λ generation of ^ @ ~ alkoxy, oxyalkyl, formyl, methyl, alkoxy, carboxyl and amino, -ch (= n-0H), -CH (= N, 2) , * _CH (winter, = amino group, in addition, any substituent may be aryl, heteroaryl, or heteroC = 3 ^). This compound of the present invention has many asymmetric centers.: 1 The invention includes various stereo Isomers and their mixtures. G When σ is also shown on this line, it means that there is an individual isomer in which the orientation is specified in a wave shape. The body-oriented exhibit is either specified or not specified here. "Medically acceptable salts" in Chinese refers to a kind of salt, which can be in proper contact with human and lower animal tissues within the claimed medical scope without causing undue toxicity and inflammation. , Allergic reactions, etc., and are commensurate Reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, s. M. Berge, et al. ^ Describe the pharmaceutically acceptable salts in J. pha rmaceut i ca1

Sciences · 6 6: 1-1 9 (1 9 77), the entire text of which is incorporated herein by reference. Such salts can be prepared in situ during the final isolation and purification of the compound of the present invention, or can be obtained by reacting the free base of the compound with an appropriate organic acid alone. Examples of pharmaceutically acceptable, non-toxic acidic addition salts are salts formed by amine groups with inorganic or organic acids or salts formed by other methods (e.g., ion exchange). Inorganic acids, such as: hydrochloric acid, hydrogen acid,

Page 19 1229677 V. Description of the invention (14) Acid, sulfuric acid and perchloric acid. Organic acids, such as: acetic acid, oxalic acid, tartaric acid, tartaric acid, citric acid, succinic acid, or malonic acid. Other pharmaceutically acceptable salts include adipic acid, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, Camphor salt, camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptane Sugar acid, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lactate, lactate, laurate, lauryl sulfate Salt, malate, dehydrated malate, malonic acid, pinane sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, hydrazone Scopolamine, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, tert-valerate, propionate, stearyl, succinate, sulfuric acid Salt, tartrate, thiocyanide, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include: sodium, lithium, potassium, calcium, magnesium and the like. Other suitable pharmaceutically acceptable salts include: non-toxic ammonium, quaternary ammonium, and amine cations formed with counter ions, such as: halides, hydroxides, metaborates, sulfates, Phosphates, nitrates, low-carbon alkyl sulfonates and aryl sulfonates. Herein, π pharmaceutically acceptable vinegar π refers to esters which can be hydrolyzed in a living body, including esters of compounds or salts thereof which are rapidly decomposed in the human body. Suitable esters include, for example, esters from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanecarboxylic acids, olefinic acids, naphthenic acids, and alkanedicarboxylic acids, each of which is an alkyl or alkenyl group The part does not exceed 6 carbon atoms.

苐 Page 20 1229677

Examples of specific esters include: phosphonate, acetate, propionate, butyrate, acrylate, and ethyl acetate. In this context, π medically acceptable drug precursors refers to the drug precursors of the compounds of the present invention. The precursors can be in proper contact with humans and lower animal tissues within the claimed medical scope without causing inconvenience. With appropriate toxicity, inflammation, allergic reactions, etc., and a reasonable and reasonable benefit / risk ratio, the compounds of the invention and their possible zwitterionic forms can be effectively used. As used herein, "drug precursor" refers to a compound that can be rapidly transformed in a living body to produce a bulk compound of the above formula, such as hydrolysis in blood. For a detailed discussion, see T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vo 1. 14 of the A. C. S.

Symposium Series, and Edward B. Roche, ed., Bi orevers i b 1 e Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. Preferred Specific Embodiments The first specific embodiment of the present invention is a compound of formula (I). In a preferred embodiment of formula (I), X is F. A second embodiment of the present invention is a compound of formula (I I). In a preferred embodiment of formula (I I), X is F. The third embodiment of the present invention is a compound of formula (I I) b

Page 21 1229677 V. Description of the invention (16)

(H) b where Y and RP are defined as follows. Representative compounds of the present invention are selected from the group consisting of: compounds of formula (I), RP is fluorene, R1 is fluorenyl, and X is F; compounds of formula (I), RP is fluorene, R1 is methyl, and X is C 1; A compound of formula (I), RP is} 1, R1 is fluorenyl, and X is Br; a compound of formula (II) b, Rp is R, R1 is -CH2-CH = CH_Y, Y is hydrogen, and X is F, the formula ( II) b compound, Rp is Η, R1 is -CH2-CH = CH_Y, Y is (3-quinolinyl), X is F; 'Compound of formula (II) b, RP is Η, R1 is -CH2-CH Di-CH-fluorene, fluorene is 6-nitro-3-quinolinyl-, and X is F; a compound of formula (II) b, Rp is fluorene, R1 is -CH2-CH = CH-Y, Y is phenyl- , X is F; compound of formula (II) b, RP is} 1, R1 is -CH2-CH di CH-Y, Y. is 6-fourth-butoxyweilylamino-3 -quinolinyl- , X is F;

D: \ 1234 \ 55395.ptd Page 22 1229677 V. Description of the invention (17) Compound of formula (II) b, RPgH 'R1 is -CH2-CHdiCH-Y, Y is 6-amino-3-quinoline -, X is F; compounds of formula (II) b, Rp is H'R1 is -CH2-CH = CH-Y, fluorene is 6-quinolinyl-, and X is F; compounds of formula (II) b, Rp H is -CH2-CH = CH-Y, Υ is 3- (1,8-Caiyi)-, and X is F; compound of formula (II) b, # is 11 'R1 is -CH2-CH = CH -Y, Y are 6-quinazolinyl-, and X is F; a compound of formula (II) b, RP is H'R1 is -CH2-CH = CH-fluorene, and fluorene is 6- (dimethylamino)- 3-quinolinyl-, X is F; compound of formula (II) b, 1 ^ is} 1 'R1 is -CH2-CH diCH-Y, Y is 6- (aminosulfonylfluorenyl) -3 -Quinolinyl-, X is F; compounds of formula (II) b, Rp is Η, R1 is -CH2-CH = CH-Y, Υ is 6- (aminocarbonyl) -3-quinolinyl-, X Is F; a compound of formula (II) b, Rp is fluorene, R1 is -CH2-CH = CH-Y, Y is 6- (n-fluorenylamino) -3-quinolinyl-, and X is F; Formula ( II) b compound, Rp is Η, R1 is -CH2-CH = CH-Y, Y is 6- (methylamino) -3-quinolinyl-, and X is F; compound of formula (II) b, 1 ^ 11 'R1 is -CH2-C H = CH-Y, Y is 6-[(hydroxyimino) fluorenyl] -3-quinolinyl-, and X is F; compounds of formula (II) b, RP is H is -CH2-CH = CH- Y and Y are 6- [aminoimino (fluorenyl)]-3 -pyrenyl-, and X is F; compound of formula (II) b, RP is H'R1 is -CH2-CH = CH-Y Υ is 6-[[(1-fluorenylethylene) aminoimino] fluorenyl] -3 -quinolinyl-, X is

D: \ 1234 \ 55395.ptd Page 23 1229677 V. Description of the invention (19) 0418 01-5) ° Each culture plate was inoculated on a steers repiicator block 1 ·· ι 〇〇 × (or 1:10 slow-growing strains, such as spherococcus and streptococcus) diluted up to 32 different microorganisms. The inoculated plate was incubated at 35-37 ° C for 20 to 24 hours. In addition, control group culture plates were prepared from BH I agar containing no test compound, and cultured before and after each test. In addition, a culture dish containing a compound having known potency to the organism and a compound of the same type as the antibiotic to be tested is prepared and tested as a genus group 'as a compatibility test. Erythromycin A was therefore used. Visually inspect each plate after incubation. The minimum inhibitory concentration (M 丨 c) is determined as the lowest concentration of the drug in a non-growth condition (compared to the growth control group, the inoculation point has only a slight _ paste or sparse colonies). The results of the activity of the compounds of the present invention are shown in Table 1B. A few fine

The abbreviation of microorganisms in Table 1A and Table 1B. Microorganism code S. aureus ATCC 6538P AA S. aureus A5177 BB S. aureus A-5278 CC S. aureus CMX 642A DD S. aureus NCTC10649M EE S. aureus CMX 553 FF Staphylococcus aureus 1775 GG Staphylococcus epidermidis 3519 HH Enterococcus faecalis ATCC 8043 II Streptococcus bovis A-5169 JJ

1229677 V. Description of Invention (20)

Streptococcus agalactiae CMX 508 KK Streptococcus pyogenes EES61 LL Streptococcus pyogenes 930 MM Streptococcus pyogenes PIU 2548 NN S. luteus ATCC 9341 00 S. luteus ATCC 4698 PP E. coli JUHL QQ E. coli SS E.coli DC-2 SS Candida albicans CCH 442 TT Streptococcus pneumoniae 5979 ZZ Streptococcus pneumoniae 5649 ZZA Table 1 Antibacterial activity of selected compounds

ιιιιιι · ιι Page 26 1229677 V. Description of the invention (21) Table 1B Examples of antibacterial active microorganisms of selected compounds Examples Examples Examples Erythromycin A; Code 1 2 3 4 Standard AA 0.1 25 0.39 0.78 0.2 BB 0.1 25 0. 39 0. 78 3.1 CC > 100 > 100 > 100 > 100 > 100 DD 0.1 50 0.39 0. 78 0.39 EE 0.2 25. 0.39 0. 78 0. 39 FF 0.1 25 0.39 0 .78 0.39 GG > 100 > 100 > 100 > 100 > 100 HH 0.2 25 0.39 0. 78 0.39 II 0. 05 12.5 0.1 0.2 0. 05 JJ 0.01 1.56 0.2 0.2 0.02 KK 0. 02 3.1 0.2 0.2 0.05 LL 0.01 3.1 0.05 0.2 0.05 MM > 100 > 100 > 100 > 100 > 100 NN 0.2 6.2 0.39 0.39 6.2 00 0.02 3.1 0.05 0.39 0.05 PP 0.2 6.2 0.39 0. 78 0.2 QQ > 50 > 100 > 100 > 100 > 100 RR 0.2 0.78 0.39 0.78 0.78 SS 25 > 100 > 100 > 100 > 100 Tintin > 100 > 100 > 100 > 100 > 100 UU 0.2 > 100 1.56 6.2 3.1 VV 0.05 50 0.39 0.39 0.1 WW 2 32 8 8 4 XX 0. 03 4 0.125 0.06 0.06 YY 0.03 4 0.125 0.03 0.06 ZZ > 128 > 128 128 & g t; 128 > 128 ZZA 0.5 4 2 0.25 16 mmm \ D: \ 1234 \ 55395.ptd Page 27 1229677 V. Description of the invention (22) Table 1B (continued) Microbial coding Example 5 Example 6 Example 7 Implementation Example 8 Erythromycin A Standard AA 0. 05 0.05 0.05 0.39 0.2 BB 0.05 0.05 0.05 0.39 6.2 CC > 100 100 100 > 100 > 100 DD 0.05 0.05 0.05 0.39 0.39 EE 0.05 0.1 0.05 0.39 0.39 FF 0.05 0. 05 0.05 0.39 0.39 GG > 100 100 100 > 100 > 100 HH 0.05 0. 05 0.05 0.39 0.2 II 0.02 0.05 0.02 0.2 0. 05 JJ 0.005 0.01 ^ 0. 005 0.05 0.05 KK 0.01 0.02 SO. 005 0.05 0.05 LL 0.01 S0. 005 SO. 005 0.05 0.02 MM 0.2 0.39 25 12.5 > 100 NN 0.05 0.05. 0.05 0.05 0.39 12.5 00 0.01 0.01 € 0 · 005 0.05 0.02 PP 0.1 0.05 0.02 0.39 0.39 QQ 25 25 50 > 100 50 RR 0.2 0.05 0 · 1 6.2 0.39 SS 25 25 25 > 100 > 100 TT 12.5 100 > 100 > 100 > 100 UU 0.2 0.1 0.05 0.78 6.2 VV 0.005 0.02 SO · 005 0.78 0.05 WW 1 2 2 16 4 XX 0.03 $ 0 · 004 SO · 004 0. 06 0.125 YY 0. 03 ^ 0. 004 SO · 004 0.06 0.06 ZZ 1 1 64 16 > 128 ZZA 0.25 0 .125 0.25 1 16 umw \ Page 28 D: \ 1234 \ 55395.ptd 1229677 V. Description of the invention (23) Table 1B (continued) Microbial coding Example 9 Example 10 Example 11 Example 12 Erythromycin A Standard Product AA 0.02 0.1 0. 05 0. 05 0.2 BB 0.02 0.1 0.05 0.05 6.2 CC > 100 > 100 > 100 > 100 > 100 DD 0.02 0.1 0.05 0.05 0.39 EE 0.05 0.1 0.05 0.05 0.39 FF 0.02 0.1 0. 05 0.05 0.39 GG > 100 > 100 100 > 100 > 100 HH 0.02 0.2 0.05 0. 05 0.2 II 0.01 0.05 0. 05 0.01 0. 05 JJ ^ 0.005 0.01 0.01 ^ 0. 005 0.05 KK ^ 0.005 0.05 0.01 0.01 0.05 LL ^ 0.005 0.02 0.39 0.01 0.02 MM 0.2 0.39 0.1 0.2 > 100 NN 0.1 0.1 0.01 0. 05 12.5 00 ^ 0. 005 0. 02 0.01 flat. 005 0. 02 PP 0. 02 0.1 0.05 0. 05 0.39 QQ 25 100 25 12.5 50 RR 0.2 0.1 0.2 0.1 0.39 SS 25 100 12.5 12.5 > 100 TT > 100 > 100 > 100 > 100 > 100 UU 0. 75 0.1 0.78 0.2 6.2 VV $ 0.005 0.01 0.01 ^ 0.005 0.05 WW 2 2 2 2 4 XX 0.015 0.015 $ 0.004 $ 0.004 0.125 YY 0.015 0.015 ^ 0.004 S0. 004 0. 06 ZZ 0.25 0.25 0.125 1 > 128 ZZA 1 0.25 0.25 0. 125 16 Drawing__1 Page 29 D: \ 1234 \ 55395.ptd 1229677 V. Description of the invention (24) Table 1B (continued) Microbial coding Example 13 Example 14 Example 15 Example 16 Erythromycin A Standard ΑΑ 0.2 0. 05 0.05 0.05 0.2 Β 0.2 0.1 0.05 0.05 6.2 CC > 100 > 100 > 100 > 100 > 100 DD 0.2 0.1 0.05 0.05 0.39 Ε 0.2 0.2 0.05 0.05 0.39 FF 0.2 0.1 0.05 0.05 0. 39 GG > 100 > 100 > 100 > 100 > 100 ΗΗ 0.2 0.1 0.05 0. 05 0.2 II 0.1 0.1 0.05 0.05 0.05 JJ 0. 02 $ 0.005 0.01 $ 0.005 0.05 KK 0.02 0.01 0.01 0.01 0.05 LL 0.05 0.01 0.01 0.01 0.02 MM 0.78-0.1 0.39 > 100 Ν0.2 0.2 0.2 0.1 0.05 12.5 00 0.02 0.01 0.01 0.01 0.02 PP 0.2 0.2 0. 05 0. 05 0.39 QQ 50 50 25 50 50 RR 0.78 0.1 0.2 0.2 0.39 SS 100 100 12.5 50 > 100 ΤΤ > 100 > 100 > 100 > 100 > 100 UU 0.78 3.1 0.39 0.39 6.2 VV 0.05 0.1 0.05 0.01 0.05 WW 8 2 4 2 4 XX 0.06 $ 0 · 004 ^ 0.004 0.03 0.125 ΥΥ 0.06 $ 0.004 $ 0.004 0.03 0.06 11 1 2 0.5 1 > 128 ZOZ 0.5 0.5 0.25 0.25 0.25 16 ηκηιιιι Page 30 D: \ 1234 \ 55395.ptd 1229677 V. Description of the invention (25) Table 1B (continued) Microbial coding Example 17 Example 18 Example 19 Example 20 Erythromycin A Standard AA 0.05 0.02 0.1 0.1 0.2 BB 0 · 1 0.05 0.2 0.1 6.2 CC > 100 50 > 100 > 100 > 100 DD 0.1 0. 05 0.2 0.1 0.39 EE 0.2 0. 05 0.2 0.2 0.39 FF 0.1 0.05 0.2 0.1 0.39 GG > 100 50 > 100 > 100 > 100 HH 0 · 1 0.05 0.2 0.2 0.2 II 0.05 0. 02 0.05 0.1 0. 05 JJ 0.01 ^ 0.005 ^ 0.005 0.01 0.05 KK 0.02 0.01 0.02 0.02 0. 05 LL 0. 02 $ 0.005 0.02 0.02 0. 02 MM 0.78 0.2 1.56 1.56 > 100 NN 0.2 0.02 0.2 0.2 12.5 00 0.02 0.01 0.02 0.02 0.02 PP 0.05 0.02 0.1 0.1.1 0.39 QQ 100 25 100 > 100 50 RR 0.78 0.2 0.78 0.78 0.39 SS 100 50 100 > 100 > 100 TT > 100 > 100 > 100 > 100 > 100 UU 0.39 0.78 0.78 0.78 6.2 VV 0.02 0.01 0.02 0.02 0.05 WW 2 2 2 4 4 XX 0.03 0.015 0.06 0.125 0.125 YY 0.015 0.015 0.06 0.06 0.06 ZZ 1 0.25 1 2 > 128 ZZA 0.5 0.25 0.5 1 16 mmmu Page 31 D: \ 1234 \ 55395.ptd 1229677 V. Hair Explanation (26) Table 1B (continued) Microbial coding Example 23 Example 24 Example 25 Example 26 Erythromycin A Standard AA 1.56 1.56 0.39 0.05 0.2 BB 0.78 1.56 0.39 0.05 6.2 CC > 100 > 100 > 100 > 100 > 100 DD 1.56 1.56 0.39 0. 05 0.39 EE L56 1.56 0.78 0.1 0.39 FF 0.78 1.56 0. 39 0. 05 0.39 GG > 100 > 100 > 100 > 100 > 100 HH 1.56 1.56 0.39 0.05 0.2 II 0.78 0.39 0.2 0.02 0.05 JJ 0.1 0.2 0.1 0.01 0.05 KK 0.39 0.39 0.1 0.02 0.05 LL 0.39 0.39 0.1 0.02 0.02 MM > 100 100 6.2 0.1 > 100 NN 1.56 3.1 0.39 0.05 12.5 00 0.2 0.2 0.2 0.02 0.02 PP 1.56 0.78 0.39 0.05 0. 39 QQ > 100 100 > 100 25 50 RR 3.1 3.1 3.1 0.2 0.39 SS > 100 > 100 > 100 25 > 100 TT > 100 > 100 > 100 > 100 > 100 UU 3.1 3.1 0.78 0.2 6.2 VV 0.78 0.78 0.2 0.01 0.05 WW 8 16 2 2 4 XX 0.03 0.06 $ 0.004 $ 0.004 0.125 YY 0. 03 0. 03 ^ 0.004 ^ 0. 004 0.06 ZZ > 128 > 64 0.06 16 > 128 ZZA 2 1 0.06 0.25 16 mmni Page 32 D: \ 1234 \ 55395.ptd 1229677 V. Description of the invention (27) Table 1B (continued) Microbiological Examples Example Erythromycin A Code 27 28 Standard AA 0.1 0.05 0.2 BB 0.1 0.1 6.2 CC 50 > 100 > 100 DD 0.1 0.1 0.39 EE 0.1 0.2 0.39 FF 0.1 0.1 0.39 GG 25 > 100 > 100 HH 0.1 0.1 0.2 II 0.02 0.05 0.05 JJ ^ 0. 005 0.01 0.05 KK 0.01 0.02 0.05 LL 0.01 0.02 0.02 MM 0.78 0.78 > 100 NN 0.1 0.2 12.5 00 ^ 0.005 0. 02 0.02 PP 0.1 0.05 0.39 QQ 100 100 50 RR 0.2 0.78 0.39 SS > 100 100 > 100 TT > 100 > 100 > 100 UU 0.2 0.39 6.2 VV 0.02 0.02 0.05 WW 4 2 4 XX 0.015 ^ 0.004 0.125 YY 0.015 ^ 0.004 0.06 ZZ 0.5 16 > 128 ZZA 0.125 0.25 16 1_ · _ΙΙ D: \ 1234 \ 55395.ptd Page 33 1229677 V. Description of the invention (28)

Table 1C Antibacterial activity of selected 2-halo substituted compounds of formula (I) (Rp is Η, R1 is methyl) in vitro_ (MIC's) effect microorganism standard Example 1 Example 2 Example 3 (X is F) (X is F) (X is C1) (X is Br) AA 0.2 0.1 25 0.78 BB 0.2 0.1 25 0.78 CC > 100 > 100 > 100 > 100 LL 0.02 0.03 4 < 0.125 MM > 100 > 128 128 128 NN 0.39 0.5 16 4/32 WW 4 2 32 8 XX 0.06 0.03 4 0.25 ZZ > 128 > 128 > 128 > 128 ZZA 0.5 0.5 4 1 As shown in Table 1C, Introducing fluorine at position 2 of the ketolides, compared with compounds in which X is hydrogen, Br, or C1, the compounds of formula I can produce improved inhibitory activity.

Page 34 D: \ 1234 \ 55395.ptd 1229677

Table 1D V. Explanation of the invention (29) Effect of 2-H of the selected compound of formula (lib) on the antibacterial activity (MIC's) in vitro compared to the 2-F substituent Microorganism Standard A Example 5 Standard Β Example 7 Standard C Example 12 (X is Η) (X is Η) (X is Η) (X is F) (X is Η) (X is Η) LL 0.03 0.03 0.03 $ 0.04 0.03 $ 0.04 ΜΜ. 1 0.25 64 16 1 0.5 ΝΝ0.25 0.25 0.25 0.25 0.25 0.25 0.125 WW 2 1 4 2 2 2 XX 0.03 0.03 0.03 $ 0.04 0.015 $ 0.004 ZOZ 16 1 128 64 64 1 ZOZ 0.25 0.25 0.25 0.25 1 0.5 0.125 As shown in Table 1D, The compound (ketoHdes) has fluorine at position 2 and can be modified in activity compared with compounds in which X is hydrogen (standard A, β, or g). In-vitro testing In-vitro testing of the antibacterial activity of representative compounds of the present invention, such as mouse protection testing • Use of milk to evaluate bicyclic ketones for acute bacterial infections. The female CF-1 was removed from the qi & 9 η ο 〇 Shi, & ^ ^ spores 丨 Jin, lnn old (weight, force 20-28 grams) intraperitoneal inoculation of 50% dare tablets 1 mile (5G) loo Staphylococcus aureus NCT dead bacteria AC63 03 for 24 hours L 1 064 9 or pneumococcal log dilution of bacterial inoculation, confirming a group of ten mice of ld50 females, a total of five logarithmic assimilation, untreated, untreated The old-fashioned group (ten mice diluted each log) was inoculated with 5 pairs: dilute :,

Page 35 1229677 V. Description of the invention (30) Bacteria. The mortality of untreated mice after 100 × L D5G treatment was 100%. The test compound was formulated in 2% ethanol in PBS, and the drug was administered at 1 hour and 5 hours after infection for oral treatment or subcutaneous injection. The death test was performed for 7 days, and the average effective dose to protect 50% old oxygen (ED5G) was calculated from a modified logit analysis of cumulative mortality. Haemophilus influenzae infection of the lungs Haemophilus influenzae was used to evaluate the effects of tricyclic ketones on acute bacterial infections of the lungs. Haemophilus influenzae 1 435 was grown overnight at ^ 1. Normally non-immunosuppressed female CF-1 mice (20-26 g) were nasally inoculated (100 # culture broth containing approximately 4.0 x 106 c haemophilus influenzae). Drugs were infused at 1, 12, 24, and 36 hours after infection for oral treatment or subcutaneous injection of a chemical therapy. At 4 § hours after infection, the lung tissue secretion was diluted and smeared on a chocolate plate, and the content of bacteria was measured. The therapeutic amount was established as the dose of logarithmic bacterial content reduction in -70% of mice (compared to the untreated control group). The test results are shown in Table 1E. Table 1E The 2-F substituents of the compound of formula (1) (Rp is 11, R1 is a fluorenyl group) are: F Staphylococcus aureus 13 9. 4 Haemophilus influenza 10 7.2 Streptococcus pneumoniae > 60 35.9

1229677 V. Description of the invention (31) Table 1F Compound of formula (lib) (Rp is η,! ^ Is 6_quinolinyl) 2 -F takes the effect of antibacterial activity (MIC, s) in # body Substitute microorganism X is Η '2 < 6. 5 5. 5 25. 9 S. aureus pneumococcus is shown in Tables 1E and 1F. The position of the ketone compound (ketOHdes):' and X are hydrogen Compared with the compounds, the living ingredients can be improved and inhibited in vivo. The pharmaceutical ingredients of the present invention include an effective therapeutic amount of the compounds of the present invention and one or more pharmaceutically acceptable carriers. The "medicine-acceptable carrier" herein refers to a non-toxic, inert solid, semi-solid or liquid, diluent, sealant substance, or any form of adjuvant. Examples of pharmaceutically acceptable carrier substances are sugars, such as dilactose, glucose, and sucrose; starches, such as corn starch and horse bell μ; powder; cellulose and its derivatives, such as ... Carboxymethylcellulose sodium, 7 ^ cellulose and cellulose acetate; powdered Tragarcons gum trees, malt; gels; talc; excipients such as cocoa butter and Suppositories are bad; ,, such as 彳 彳 raw oil, cottonseed oil, red oil, sesame oil; contempt oil; corn oil and soybean oil; ethylene glycol; for example, propylene glycol; ^, such as : Ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; Alcohol, and phosphate buffered solution,

Page 37 D: \ 1234 \ 55395.ptd 1229677 V. Description of the invention (32) Other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium octadecanoate, and coloring agents, thinners, coating agents , Sweeteners, flavors and fragrances, preservatives and antioxidants can also add pharmaceutical ingredients according to the judgment of the adjuster. The pharmaceutical ingredients of the present invention can be administered orally, rectally, parenterally, intracranially, intravaginally, intraperitoneally, topically (powder, salve, or drip), buccal, or oral or nasal spray Sprinkle paths to treat humans and other animals. Liquid dosage forms for oral treatment include: pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and liquors. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in general techniques, such as water or other solvents, solubilizers, and emulsifiers, such as alcohol, isopropanol, ethyl carbonate, ethyl acetate, and fluorenyl. Alcohols, gas benzoates, propylene glycol, 1,3-buteneglycol, diamidamine, oils (especially cottonseed, groundnut, corn, germ, olive, castor bean, and Sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid sorbitol esters, and mixtures thereof. In addition to inert diluents, oral ingredients may include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and fragrances. Injectables, such as sterile injectable aqueous solutions or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a non-toxic parenterally acceptable diluent or solvent of a sterile injectable solution, suspension or emulsifier, for example, a 1,3-butanediol solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Also sterilizes fixed oils

D: \ 1234 \ 55395.ptd Page 38 1229677 V. Description of the invention (33) Traditionally, solvents or suspension media can be used. For this purpose any non-irritating fixed oils can be used, including ... synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables. Sterilization methods for injection formulations, such as filtering with bacteria-blocking membranes or adding sterilization reagents in the form of sterilized solid ingredients (which can be dissolved or dispersed sterilized water or other sterilized injection media) before use. In order to prolong the effect of the drug, it is often necessary to reduce the absorption of the drug subcutaneously or intramuscularly. It is therefore possible to use liquid suspensions of poorly soluble crystalline or amorphous materials. The absorption rate of a drug depends on the rate of dissolution, that is, on the size and form of the total η,, one by one, · ^. In addition, a form of drug treatment that delays parenteral absorption can be achieved by dissolving or suspending in an oily carrier. Injectable solutions can be stored in the form of biodegradable polymers in the microencapsulated matrix of the drug, such as polylactic acid-polyglycolic acid. Depending on the ratio of drug to polymer and the characteristics of the polymer used, drug release can be controlled. Examples of degraded polymers include poly (n-esters) and poly (anhydrides). Nazizhuang's formulations can also be prepared with the drug's microlipids or micro-tissue compatibility). Dagger, better rectal or vaginal household, hemp + eight & ~ w ^ The invention compound and a suitable non-knife is a suppository, which is prepared by mixing this oil, polyethylene glycol or Π = or a carrier, : Solids that can be treated orally: "active compounds: active compounds. Powders, and fine particles. On this solid =: =, tablets, pills,-a kind of inert, scientific; in the formula: the active compound and at least Another adjuvant or carrier mix, for example:

1229677

V. Description of the invention (34) sodium citrate or dicalcium phosphate and / or a) filler or extender, for example: splash powder, lactose, sucrose, glucose, mannitol, and acetic acid, b) Binders such as ... such as carboxyfluorenyl cellulose, alginate, gels, polyvinyl glutamidine dione, sucrose, and acacia, c) wetting agents such as glycerol, d) disintegrants such as: Agar-agar, calcium carbonate, horse bell or cassava meal, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption enhancers such as: quaternary ammonium Compounds, wetting agents such as cetyl alcohol and glyceryl monooctadecanoate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate , Solid polyethylene glycol, sodium lauryl sulfate, and compound. Dosage forms for capsules, tablets and pills also include buffering agents. / 'This σ-like solid component can be used as soft and hard filling gelatin or nougat and high molecular weight polyethylene glycol as the heart capsule (using solid sugar dosage form tablets, sugar-coated pills, gums ^ 二 — It can be filled with a shell and a coating (for example: a coating of the intestine, a pill and a known coating made of fine particles). It can optionally contain opaque: Ingredients that can release the active ingredient, or a better choice of reagents can also contain only delayed release. It can be used as an embedding ingredient in certain intestinal tracts and waxes. Dagger: polymeric substances, Yidan it ^ The excipients such as pills, capsules, coatings of drugs and intestines, and similar solid ingredients can be used as active compounds such as soft and hard fillings or nougat and high molecular weight polyethylene glycols. They can also contain one or more Form. Tablets and sugar-coated granules in solid dosage form can be prepared with a coating and shell, such as

D: \ 1234 \ 55395.ptd Page 40 1229677 V. Description of the invention (35) _____ Known coatings on pharmaceutical formulas. This solid shot = ~~ At least one inert diluent is mixed. For example, the active compound in the form of π can be used in the same way. This dosage form can also be sucrose, lactose or starch. Straighteners and adjuvants for other tablets, such as = diluent (other than the lubricating substance of tablets. Capsules, tablets, sedatives and microcrystalline cellulose). The dosage form which can optionally include ^ = Le Pills can include ingredients of buffering ingredients, or preferably, Qin's reagent and can also contain only release active. It can be used as an embedding ingredient = selective delayed release in some intestinal parts. The compound of the present invention is local or: 2: 2, including: polymeric substances and soil. Dosage forms of ointments, ointments, creams, lotions, curatives, including: medicinal products or patches. The active ingredients are sterilized in 2 doses of the solution, sprayed, inhaled carrier and necessary preservatives or: under the pieces and pharmaceutically acceptable eye =, powders and solutions are all included in this; by preparations, eye drops, containing ingredients Formulations, such as: Animals and rhenium compounds can be powdered in addition to the active compounds of the present invention, Tragacons Gum II; Derived from: Types: waxes, paraffin waxes, yakisoba, bentonite, oxalic acid, slippery ί In addition to the compounds of the present invention, biological, polyethylene glycol, and polylithium oxide are also compounds. For example: lactose 'talc, oxalic acid, ^: Radix may contain excipients, examples, or mixtures thereof. Lice calcium silicate and polyamine powder fluorocarbons. $ Spray can contain conventional propellant sprays, such as: gas, didermal patches, which have the advantage of controlling the form of the compound and can dissolve or disperse the compound. Dosage Dosage Increased Compounds by Guild II? : Shelley. Absorption enhancer can be used to flow through the skin. Its rate can be determined by

1229677 V. Description of the invention (36) Disperse the compound in: Subtract the compound matrix or gel and add u ^ According to the treatment method of the present invention, for fine control.?, Or lower mammals) for treatment or prevention Patients with τ syndrome (for example: The compound of the present invention for treatment 1 at this dosage. Λ & can give the patient effective results. The compound of the present invention " effective treatment. t: a period of time to achieve necessary, sufficient to treat bacteria Infectious diseases and reasonable, V: The amount of any medical treatment compound. The medical scope of each risky proportion of the compounds of the present invention is determined. Any specific disease = I depends on the doctor's claim, including the disease treated and its severity The effective amount of treatment depends on various activities, specific ingredients used, age, body, specific compounds used, patient's diet, treatment time, treatment status, general health, sexual secretion rate, treatment period, use of Medicine: two: the specific compound used, and other known medical technology reasons & or the simultaneous use of special treatment of humans or other mammals, the present invention combined dose The total dose can be, for example: 〇 〇 〇 5 〇 early or even the usual 0.425 mg / kg of body weight. A single 228 grams of body weight or more or divided into multiple doses to achieve the daily dose. Generally and In other words, the treatment process of the preparation includes two or more rounds of the compound of the present invention with a dose of about 1 shot per day and about 2 mg of the compound of the present invention to prepare formulae (I) and (II). ) Compound mm Page 42 D: \ 1234 \ 55395.ptd 1229677 V. Description of the invention (37)

D: \ 1234 \ 55395.ptd Page 43 1229677 V. Explanation of the invention (39) The limitation is that if R1 of the compound of formula (II) is selected from option (1), then q-C6 • The alkyl group must be substituted The method includes: (a) reacting a compound selected from the group consisting of (I) and (II) with a halogenating agent, and selectively performing a deprotection reaction.

(D 〇 = <

, and

(Π) In the above preferred method, the halogenating agent is selected from the group consisting of: N-fluorobenzenesulfonimide in the presence of a base, osmic acid containing 10% F2, 3, 5-dichloro-1-fluoropyridine Fluoroborate, 3,5-Digas-1-fluoropyridine trifluoromethanesulfonate, (CF3S02) 2NF, N-fluoro-N-fluorenyl-P-toluenesulfonamide in the presence of a base, N- Flupirtine

D: \ 1234 \ 55395.ptd Page 45 1229677

2 0 Aprotic solvents will not affect the reaction. Imitation, DMF, and irq air-drying are dilute methane and gas. Protect THF (THF), N_ " fluorenyl D, biloxedione or its mixed acetamidine, diammonium hydrazone: A '2 of matter': and 4: _ hydroxyl groups to obtain compound 3, And the two dagger storms protect the base. Preferred hydrazone protecting groups include: and dimethyl sulfanyl. Next, the 6-hydroxy group of compound 3 is subjected to an alkylation reaction with an alkylating agent in the presence of a base to obtain compound 4. Alkylating agents include: alkyl gas, bromide, iodide or alkyl sulfonate. Specific examples of the alkylating agent include: dilute propyl bromide, propargyl bromide, fluorenyl bromide, 2-fluoroethyl bromide, 4-nitro 4-bromo bromide, chloroethynyl bromide, 4 -Methoxybenzyl > smell, > sm-p-methylbenzyl, cinnamyl desert, 4-bromocrotonate, crotonyl bromide, 1-bromo-2 -pentene, 3- 1-propenyl bromide bromide, 3-bromo-1-trimethylsilyl-1-propyne, 3-bromo-2-octyne, 1-bromo-2-butyne, 2-picoline Picolyl chloride, 3-picoyl (pic ο 1 y 1) gaseous compounds, 4-picoyl (Pic 0 1 y 1) chloride, 4-bromomethylquinoline, bromoacetonitrile, 3-Chloro-1,2-bromoepoxide, bromofluoromethane, bromonitromethane, methyl bromoacetate, ethoxyfluorenyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo -2-methyl ethyl ketone, bromochloromethane, bromomethyl phenyl maple, 1,3-dibromo-1-propylene, and the like. Examples of alkyl sulfonate are: 0-methylbenzite allyl ester, 3-phenylpropyltrifluoromethane fluorite, n-butyl-0-pyrenate lutein and the like. Examples of the use of aprotic solvents, such as: dimethylimine, diethylimine, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2 -11 to 17 each of ketones, hexamethyltrimethylamine, mixtures thereof or one such solvent with ether, tetrahydrofuran, 1,2-dimethoxyethyl

D: \ 1234 \ 55395.ptd Page 48 1229677 V. Description of the invention (43) A mixture of sintered, acetonitrile, ethyl acetate, acetone, etc. Examples of the bases include potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydroxide, potassium isopropoxide, tertiary-butoxide, potassium isobutoxide, and the like. 2'- and 4Π- the basis of deprotection is based on methods such as Greene and PGM Wuts in Protective Groups in Organic Synthesis, 2nd ed ·, John Wiley & Son, Inc ·, 1991, which is incorporated herein in its entirety references. The reaction conditions for the deprotection of 2,-, and 4 "hydroxyl groups pass X to 0H. (For example, deprotection of 2,-and 4'1-hydroxyl groups using acetonitrile of acetic acid and water, X is removed from or = C ( Rb) (Rc) -〇-Ra (where the definition of 驴, donkey, and as above) is converted to = N-0H). Otherwise, it can be converted in another step. The reaction to remove oxime can be performed according to the method described in the literature For example: Greene (as mentioned above) and other literatures. Examples of deoxime agents are inorganic sulfur oxide compounds. For example: sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrogen sulfite, partial weight Sulfur, sodium disulfonate, potassium thiosulfate, partial potassium sulfite, etc. Examples of solvents are protic solvents, such as: water, methanol, ethanol, propanol, isopropanol, dimethylsilanol or Mixtures of one or more of the above solvents, etc. The reaction for removing the buffs is more easily performed in the presence of organic acids (for example, formic acid, acetic acid and trifluoroacetic acid). The amount of acid used is between about 1 to about 10 equivalents of compound Dosage. In a preferred embodiment, the anti-false effect Organic acids (e.g., ethanol and formic acid in water) are used to obtain the required 6-0-substituted erythromycin compound 6. In a preferred method of the present invention, R1 in compound 6 is dilute propyl.

1229677 V. Description of the invention (56) ---- y difluorophenylarsenimine (1.02 g, Li equivalent), the mixture was washed in 0t concentrated brine '(ν,), dried, dried, and concentrated. The oxidized stone oxide layer was dissolved and dissolved with 10-20% propane to obtain the title compound Ms (DCI / NH3) m / z 6 9 9 (M + H) +; 13C _ (75MΗζ, CDCl3 ) 5217.3, d (2033 and 2030),., D 165.6 and 165.3), 1 57.4, 1 35 4, 1 1 8 R Rl " 3 and 96.6), 8 3.6, 79 '', 78.7, 78.5,., .2, 64 · 6, 63.2, 57.6, 44.2, 40.6, 40.5, 9,, '30.6, d (25.U 24.9), 22 2 1 20.9, 20.7, 17.8, 14. 9, 13.7, 13 3 106. Step 4b: Compound of formula ii) b; RP is hydrogen, _.ch = c is hydrogen. The solution of the compound of step 4aA (40 mg, 0572 mmol) in methanol (00 ml) is stirred at room temperature. After 24 hours, remove 2, methanol was removed under vacuum. The crude product was purified by chromatographic analysis of dichloromethane and eluted with 3% methanol in dichloromethane to obtain 36.0 mg of the title compound.

13C NMRdOOMHz, CDC13) 5 217.4, d (20.3.6 and 20.3.4), d (165.6 and 165.4), 157.4, 135.4, 117.9, 103.9, d (98.7 and 96.7), 83.6, 79.8, 79.1, 78.4, 70.3, 69 · 6, 65.8, 64.6, 57.5, 44.2, 40.5, 40.2, 3 8.7, 37.4, 28.2, d (25.3 and 25 · 1), 22 · 2, 21.1, 20.7, 17.7, 15 · 4, 13.8, 13.3, 10.6;

Page 1229677 V. Description of the invention (58) 130.1, 129.5, 129.1, 129.0, 128.1, 128.0, 126.7, 104 · 〇, d (99.3 and 96 · 6), 83.4, 79.5, 79.3, 79 · 0, 70.3, 69.9, 65 · 8, 64.2, 58 · 0, 44.1, 40.7, 40 · 2, 39 · 〇, 37.4, 28.1, d (25.4 and 25.1) 22.3, 21.1, 20.8, 17.6, 15. 4,13 · 7,13 · 2,1 0 · 6; QHmFNA. HRMS ιη / ζ (Μ + Η) + estimated value: 784. 41 84. Measured value: 784 · 4196 〇

General experimental method A: using the Heck reaction to prepare a compound of formula (ll) b 'wherein Y is not hydrogen, RP is not hydrogen, and X is F Step a: compound of formula (II) b; γ is not hydrogen, rp is —c (〇) CH or — C (〇) C6H5, χ is f

A compound containing formula 11 (b) (where γ is hydrogen, χ is! ^, And RP is -c (〇) CK, -c (o) c6h5) (i equivalent), Pd (〇c (〇) CH3) Degas the acetonitrile mixture with 2 (〇2 when "= phosphine ^ equivalent), fill with nitrogen, and react with the 2: small: base product (2 equivalents), add by-pass at 9 ° C, # μ 文B. Dilution, sequential analysis with NaHC03 aqueous solution and concentrated saline gel color = 4) 遽 ', and concentrated. The residue was subjected to silica step b: formula (Lb 生 2, protected title) Compounds.

弋 TT f dagger, Y is not hydrogen, Rp is hydrogen, X is F -c (〇) m5 into the formula 11 (b) reflux or methanol overnight at room temperature to convert the oxidized stone Winning tube; wherein γ is not hydrogen, RP is hydrogen, and X is π, and the title compound is obtained after chromatographic analysis of Example 6.

1229677 V. Explanation of the invention (59) • Compound of formula (II) b; Rp is 11, R1 is -CH.f-CH = CH-Y, Y is 6 —Yenyl-3-quinolinyl-, X is f In step a and step b of method A of the general experiment, the title compound was prepared using the compound of Example 4 (step 4a). 13C NMR (100 MHz, CDCl3) (5218.0, d (204.4 and 20 4.1), d (166 · 0 and 16 5 · 8), 157 · 1,153 · 0,149 · 3,145 · 8, 133.9 , 131.4, 131.3, 131.0, 128 · 9, 127.0, 124.7, 122 · 4, 104 · 0, d (99.0 and 96 · 9), 83.4, 79.5, 79 · 4, 79 · 0, 70 · 3, 69.7, 65.8, 64.0, 58.0, 44 · 1, 40.8, 40.2, 38.9, 37.4, 28.2, d (25.4 and 25.2), 22.3, 21.1, 20. 8, 17.6, 15.4, 13.7, 13.2 , 10.7; HRMS m / z (M + Η / Estimated value: 829.4035. C42H58N4012F. Found: 829 · 4044. Example 7

Compound of formula (II) b; Rp is fluorene, R1 is -CH2-CH: CH-Y, Y is phenyl-, and X is F. According to step a and step b of method A of the general experiment, Example 4 (Step Compound of 4a) The title compound was prepared. MS (DCI / NH3) m / z 73 3 (M + H) +; 13C NMR (100MHz, C DC 13) 5 2 1 7. 7, d (2 0 4. 0 and 2 0 3 · 8), d (165.7 and 165.5), 156.9, 136.4, 133.7, 128 · 7, 127.8, 126.5, 126.1, 104.0, d (98.9 and 96.8), 83.4, 79.7, 79.2, 79.0, 70.3, 69.6, 65.8, 64.2, 58.1, 44 · 2, 40 · 6, 40.2, 38.9, 37 · 4, 28.1, d (25.4 and 25 · 2),

Page 65 1229677 V. Description of the invention (60) 22.3, 21.1, 20.8, 17.7, 15.4, 13.8, 13.3, 10.8. Example 8

A compound of formula (II) b 4; Rp is Η, R1 is -CH2-CH = CH-Y, Y is 6- third -butoxycarbonylamino-3-quinolinyl-, and X is F In step a and step b of method A of the general experiment, the title compound was prepared using the compound of Example 4 (step 4a). 13C NMR (100MHz, CDC13) 5217.7, d (2 0 4 · 2 and 2 0 3 · 9), d (165.8 and 165.2), 157.1, 152.6, 148.0, 144.4, 1 36. 7, 1 32. 0, 1 3 0.1, 1 29.9, 1 2 9.8, 1 29.1, 1 2 8.6, 122.2, 114.1, 104.0, d (98.9 and 96.9), 83.4, 80.7, 79. 6, 7 9. 3, 78. 9, 70. 3 , 6 9. 6, 65. 8, 64. 3, 58. 1, 44.1, 40 · 7, 40 · 2, 39 · 0, 37.4, 28.3, 28.2, d (25.3 and 25.1), 22.3, 2 1.1, 2 0.7, 1 7.6, 1 5.4, 1 3.8, 1 3.2, 10.6; HRMS m / z (M + Η) + estimated value of C47H68N401GF: 8 99.48 1 2. Measured value: 899 · 4816. Example 9

Compounds of formula (II) b; Rp is Η, R1 is -CH2-CH = CH-Y, Y is 6-amino-3_pyrinyl-, and X is F. According to step a and step of method A of general experiment b. The title compound was prepared from the compound of Example 4 (step 4a). 13C NMRClOOmHz, C DC 13) 5 2 1 7. 7, d (2 0 4.1 and 20 3 · 9), d (165.7 and 165.5), 157.1, 145.9, 144.9, 142.7, 1 30.5, 1 30.5, 1 3 0, 1 2 9.6, 1 2 9.4, 1 28.4, 1 2 1.2,

1229677 on page 66 5. Description of the invention (61) 107 · 7, 104.0, d (98.7 and 97.1), 83.4, 79.5, 79.2, 79 · 〇, 70.3, 69.6, 65.7, 64 · 2, 58.0, 44 · 1,40.7, 40 · 1, 38 · 9, 37.3, 28 · 2, d (25.2 and 25.0), 22.2, 21.0, 20.7, 17.5, 15.3, 13.7, 13.1, 10.6 .; HRMS m / z (M + Η) + estimate of C42H6GN4〇1GF: 799. 4288. Found: 799 · 4274. Example 1 0

Compound of formula (Π) b; Rp is Η, R1 is -CH2-CH = CH-Y, Υ is 6-quinolinyl-, and X is F

The title compound was prepared from the compound of Example 4 (Step 4a) according to step a and step b of General Experiment Method A. 13C NMR (100MHz, CDC13) (5 1 27. 8, d (204. 2, 20 3.9), d (165.7 and 165.5), 156.9, 149.9, 148.0, 136.1, 134.7, 132.8, 129.6 , 128.4, 127.9, 127.4, 126.1, 121 · 2, 103.9, d (98.8 and 96 · 8), 83.3, 79.4, 79.1, 79.0, 70.3, 69.5, 65.7, 64.1, 58.0, 44.1, 40.6, 40 · 1, 38 · 9, 37 · 3, 28 · 2, d (25.3 and 25.1), 22.2, 21.0, 20. 7, 17. 5, 15.4, 13. 7, 13.2, 10.6;

〇421159 仏 01 (^ HRMS m / z (Μ + Η) + Estimated value: 784.4 4 84. Found: 784.417. Example 11

Compound of formula (II) b; Rp is H, R1 is -CH2-CH = CH-Y, Υ is 3- (1,8-naphthalenyl), and X is F according to steps a and Step b, using Example 4 (step

Page 67 1229677 V. Description of the compound of (62) 4a) The title compound was prepared. 13C NMR (125MHz, CDC13) (5218.0, d (20 4.3 and 2 04.0), d (165.9 and 165.6), 157.2, 152.9, 137.4, 133.3, 1 31.5, 1 30.6, 1 3 0.4, 1 29.2, 1 25.4, 1 22.7, 1 2 2.4, 104 · 0, d (99.3 and 96.5), 83.5, 79.4, 79.4, 78.9, 70.3, 69.6, 65 · 7, 64.0, 58.0, 44.1, 40 · 7, 40.2, 38.9, 37.3, 28.2, d (25.4 and 25.1), 22.2, 21.1, 20.8, 17. 5, 15. 4, 13.7, 13.1, 10.6;

C41H58N401QF HRMS m / z (Μ + Η) + estimated value · 785 · 4132. Measured value: 785.4132. Example 1 2

A compound of formula (II) b; Rp is Η, R1 is -CH2-CH = CH-Y, Υ is 6-quinolinolyl-, and X is F. According to step a and step b of method A of the general experiment, use Example 4 (Step 4a) Compound The title compound was prepared. 13C NMR (125MHz, CDC13) 5217.8, d (204.1 and 2 0 3.9), d (165.9 and 165.7), 156.9, 145.1, 144.3, 143.4, 1 42.8, 1 38.5, 1 3 2.0, 1 29.9, 1 2 9.7, 1 27.8, 1 2 7.3,

104.1, d (98.7 and 9 7.0), 83.3, 79.6, 79.5, 7 8.9, 70.3, 69.6, 65.8, 64.0, 58.0, 44.2, 40.7, 40.1, 38.9, 37.4, 28.1, d (25.3 and 25 · 2), 22.3, 21 · 1, 20 · 8, 17. 6, 15. 4, 13.7, 13.2, 10.7; HRMS m / z (Μ + Η) + C41H58N401 () F + Estimated value: 785. 4 1 31. Measured value: 785.4133.

Page 68 1229677 V. Description of the invention (63) Example 1 3

Compound of formula (II) b; RP is H'R1 is -CH2-CH diCH-Y, Y is 6- (diamidoamino) -3-quinazolinyl-, and χ is F according to the general experimental method In step a and step b of A, the title compound was prepared using the compound of Example 4 (step 4a). 13C NMR (125MHz, CDC13) (5217.8, d (204.2 and 20 3.9), d (165.7 and 165.6), 157.2, 148.8, 145.6, 141.9, 130 · 8, 130.6, 129.6, 129.5, 129.5, 128.2 , 119.2, 105.6, 104.0, d (98.8 and 97.1), 83.4, 79.6, 79.3, 79.0, 70 · 4, 69.6, 65.8, 64.4, 58 · 1, 44.2, 40.7, 40.7, 40.2, 39.0, 37 · 4, 28.2, d (25.3, 25.2), 22.3, 21.1, 20.8, 17.6, 15.4, 13.8, 13.2, 10.7; HRMS m / z (M + HV estimated value of C44H64N401QF: 827.460 1. Measured value: 827.4605. Example 1 4

Compound of formula (II) b; Rp is H'R1 is -CH2-CH diCH-Y, Y is 6- (aminosulfonylfluorenyl) -3-quinolinyl-, and X is F. According to the general experiment In step a and step b of method A, the title compound was prepared from the compound of Example 4 (step 4a). 13 CNMR (125 MHz, CDC13) (5217.6, d (204.3 and 204.1), d (165.8 and 165.6), 157.8, 148.7, 144.9, 135.7, 1 32.8, 1 3 0.7, 1 3 0.4, 1 30.1, 1 28.8, 1 28.6, 1 2 3.2, 116 · 1, 104.0, d (98.8 and 97.2), 83.8, 79.3, 79.3, 79.1, 70.4, 69.7, 6 5.8, 64.2, 5 8.4, 44.0 , 40.8,

1229677 on page 69 5. Description of the invention (64) 40.2, 39.2, 38.9, 37.4, 28.2, d (25.5 and 25.3), 22.4, 21 · 2, 20 · 9, 17 · 6, 15 · 4, 13 · 8,13 · 3,10 · 8; HRMS m / z (M + H) + of C43H62N4012SF: Estimated value: 87 7.406 3. Measured value: 877.4065. Example 1 5

Compound of formula (II) b; Rp is Η, R1 is -CH2-CH = CH-Y, Y is 6- (aminocarbonyl) -3-quinolinyl-, and X is F. Follow the steps of method A of general experiment. a and step b. The title compound was prepared from the compound from Example 4 (step 4 a). 13C NMR (125MHz, CDC13) (5218 · 2, (1 (204 · 3 and 20 4.1), 168 · 9, d (165.5 and 165.3)), 157.5, 151.8, 148.8, 1 32. 9, 1 3 1.6, 1 3 0.5, 1 29. 6, 1 29.6, 1 29. 6, 1 2 8.2, 1 27. 7, 1 27. 1, 104 · 1, (1 (98 · 7 and 97 · 1), 83. 8, 79. 5, 79.3, 79.2, 70.4, 69.7, 65.8, 6 3.8, 58.4, 44.1, 40. 7, 40.2, 39.0, 3 7. 4, 28. 2, d (2 5 · 4 and 2 5 · 2), 22.3, 21.1, 21.0, 17.7, 15.5, 13.9, 13.2, 10.6; HRMS m / z (M + 之) + estimated value of C43H6QN40uF: 827.4237. Found: 827.4236. Example 1 6

Compound of formula (II) b; Rp is fluorene, R1 is -CH2-CH-di-CH-Y, Y is 6 ~ methylamino group) -3-lindenyl _, X is F according to step a of method A of general experiment And step b, the title compound was prepared from the compound of Example 4 (step 4a). 13C NMR (125MHz, CDC13) 5127.8, d (20 4.2 and 2 04 · 〇)

1229677 V. Description of the invention (65) d (165.8 and 165.6), 157.2, 147.4, 145.4, 142.7, 1 30.6, 1 3 0.6, 1 2 9.9, 1 2 9.8, 1 2 9.7, 128.3, 121.0, 104 · 1, 103.0, d (98.8 and 97.1), 83.5, 79.7, 79.3, 79.0, 70 · 4, 69.7, 65 · 9, 64.4, 58.1, 44.2, 40.8, 40.2, 39.0 , 37 · 4, 30 · 7, 28 · 2, d (25.3 and 25 · 2), 22.3, 21 · 1, 20 · 9, 17 · 7, 15. 4, 13 · 8, 13 · 3, 10 · 7 ·; HRMS m / z (Μ + Η) + estimate of C43H62N401QF: 8 1 3.4445. Measured value: 81 3 · 443 6. Example 1 7

Compound of formula (II) b; Rp is H'R1 is -CH2-CH = CH-Y, Y is 6- (fluorenyl) -3-quinolinyl-, and X is F according to the procedure of general experimental method A a and step b. The title compound was prepared from the compound from Example 4 (Step 4 a). 13C NMR (125MHz, CDC13) 5218.1, d (20 4, 4 and 2 04.2), 191.6, d (165.9 and 165, 7), 157.2, 152.3, 150.1, 134.6, 134.3, 133.7, 130.7, 130.5, 130.4 , 129.5, 127.6, 126.1, 104 · 1, d (98.8 and 97.2), 83.5, 79.5, 79.4, 79.0, 70.4, 69.7, 65.8, 6 4.1, 58.1, 44.2,

40 · 8, 40.2, 39 · 〇, 37 · 4, 28.2, d (25.4 and 25.2), 22.3, 21.2, 20.8, 17.6, 15.4, 13.8, 13.2, 10.7 .; HRMS m / z (Μ of QUOuF) + Η) + Estimates · 812 · 4134. Measured value: 81 2 · 4128. Example 1 8 Compound of formula (I I) b; RP is Η, R1 is -CH2-CH = CH-Y, Υ is 6-[(hydroxyl

Page 71 1229677 V. Description of the invention (66) Imine) methyl) -3 -quinolinyl-, X is F · Example 17 A methanol solution of the sample 7 was reacted with hydrazine at room temperature, concentrated, and The title compound was obtained by oxidative analysis. 13C NMR (125MHz, CDC13) (5218 · 〇, d (204.4 and 204.1), d (165 · 9 and 165.7), 157.4, 150.0, 149.2, ΐ48 ·, 1 32.9, 1 3 1.3, 1 3 0.2, 1 29.8, 1 29.6, 1 29.6, 1 28.1, 128.0, 126.3, 104.0, d (98.8 and 97.2), 83.6, 79.5, 79.4, 79.1, 70.4, 69.6, 65.8, 6 4.2, 58.2, 44.2, 40 · 8, 40 · 2, 39 · 0, 37 · 4, 28 · 3, d (25.4 and 25.2), 22.3, 21.1, 20.8, 17.6, 15.4, 13.8, 13 2 10 7;

CisHsoKOnF HRMS m / z (Μ + Η) + estimate: 827.4237. Measured value: 827 · 4228. Example 1 9

Compound of formula (II) b; Rp is H is -CH2-CH = CH-Y, Y is 6- [aminoimine (fluorenyl-3-quinolinyl-, X is F) The alcohol solution was reacted with hydrazine at room temperature, concentrated, and analyzed by silica gel chromatography to obtain the title compound. 13CNMR (125MHz, CDC13) 5217.9, d (2 0043 and 2041), d (165.8 and 165.6), 157.2, 149.7 147 9 142 2 133.8, 132.6, 13 0.0, 130 · 〇, 129.6, 129.3, 128.0, 1 26.4, 1 26.2, 1 0 4.1, d (9 8.8, 97.2), 83.5, 79.6, 79.4 , 79.0, 70.4, 6 9.7, 65.8, 6 4.3, 58.1, 44.2, 40 · 8, 40.2, 39.0, 37.4, 28,2, d (25.4 and 25.2), 22.3, 21.1, 20.8, 17.6, 15.4, 13.8, 13 2 10 7;

1229677 V. Description of the invention (67) HRMS m / z (M + H) + of C43H61N501QF Estimated value: 8 26. 43 97. Measured value: 826 · 4395. Example 2 0

Compound of formula (II) b; Rp is fluorene, R1 is -CH2-CHdiCH-Y, Y is 6-[[(1-fluorenylethylene) aminoimine] fluorenyl] -3 -quinoline The radical-and X are F. Example 19 A methanol solution of a sample of 9 was reacted with hydrazine at room temperature, concentrated, and analyzed by silica gel chromatography to obtain the title compound. MS (DCI / NH3) m / z 8 6 6 (M + H) +;

13C NMR (125MHz, CDC13) 5 2 17 · 9, d (20 4 · 3 and 2 04. 1), 167.9, d (165. 9 and 165.7), 157.1, 156.8, 150.5, 148.8, 133.3, 132.9, 130.2 , 129.9, 129.8, 129.7, 129.6, 127.9, 127.1, 104.0, d (98.8 and 97.2), 83.4, 79.5, 79.4, 79.0, 70.4, 69.7, 65.8, 64.3, 58.1, 44. 2, 40. 8, 40.2, 39.0, 37. 4, 2 8. 2, 25.4, d (25.4 and 2 5.2), 2 2.3, 2 1.1, 2 0.8, 1 8.7, 1 7.6, 1 5.4, 1 3.8, 13. 2, 10.7. Example 2 1

Compound of formula (II) b; Rp is H'R1 is -CH2-CH diCH-Y, Y is 3- (5-cyano) pyridyl-, and X is F according to step a and step of method A of general experiment b. The title compound was prepared from the compound of Example 4 (step 4a). 13C NMR (125MHz, CDC13) 5218.1, d (2 〇 4. 4 and 2 〇 4 · 2), d (166.1 and 165.9), 157.2, 151.2, 150.8, 135.9, 132 · 6, 132 · 1, 127 · 4, 116 · 5, 110 · 1, 104. 0,

Page 73 1229677 V. Description of the invention (74) Benzyl group is more than cyclyl-, χ is F Example 3 3 Compound of formula (11) 1); 1 ^ is hydrogen, 1? 1 is-(:) 12- (: } 1 two (:) 1-yah, yah is 5- (2-pyridyl) -2-D ratio σ each group-, X is F Example 3 4 Compound of formula (II) b; RP is hydrogen, R1 Is -CH2-CH = CH-Y, Y is 2-quinazolinyl-, and X is F. Example 3 5 Compound of formula (II) b; RP is hydrogen, and R1 is -CH2-CH = CH-Y, Y Is 5-〇-fluorenyl-2-pyridyl) -2-pyrrolyl-, and X is F. Example 3 6 Formula (II) b 4 d; RP is hydrogen, R1 is a CH2-CH = CH- Y and Y are 5- (1-methyl-2-Q specific alkyl) -2-D and biloyl- and X is F. Example 3 7 Compound of formula (II) b; RP is hydrogen and R1 is -CH2 -CH = CH-Y, Y is 5- (2 -pyridin) -2-furyl-, and X is F Example 3 8 Compound of formula (II) b; RP is hydrogen and R1 is -CH2-CH = CH -Y, Y is 5- (3-pyridyl) -2-furylfluorenyl-, and X is F Example 3 9 Compound of formula (II) b; RP is hydrogen, and R1 is -CH2-CH = CH-Y Y5- (2-pyridyl) -2-furylfluorenyl-, X is F Example 40 Compound of formula (II) b; RP is hydrogen, R1 is -CH2-CH di-CH-Y, Y7-[( Krypton

D: \ 1234 \ 55395.ptd Page 80 1229677 V. Description of the invention (75) imino) methyl] -7-quinazolinyl-, X is F Example 4 1 Compound of formula (11) 1) ; 1 ^ is hydrogen, 1 ~ 1 is-(: 112-(:) 1 = (: [1-y, y is 5- (3-pyridyl) -2-thienyl-, and X is F Example 4 2 Compound of formula (II) b; RP is hydrogen, R1 is -CH2-CH = CH-Y, Y is 5- (2-pyridyl) -2-hexeno-, and X is F Example 4 3 Formula (11) 13 compounds; 1 ^ is hydrogen, 1? Is-(: [12-(:) ^ 11-yah, yah is 5- (4-pyridyl) -2-thienyl-, and X is F Example 4 4 Compound of formula (II) b; RP is hydrogen, R1 is -CH2-CHdiCH_Y, Y is 5- [5- (aminocarbonyl) -3 -pyridyl] -2 -thienyl-, X is F Example 4 5 Compound of formula (II) b; RP is hydrogen, R1 is -CH2-CHdiCH-Y, Y is 5- (2-_azolyl) -2-thienyl-, and X is F Example 4 6 Compound of formula (II) b; RP is hydrogen, R1 is -CH2-CHdiCH-Y, Y is-(5-thiazolyl) -2-thienyl-, and X is F Example 4 7 Formula (II ) b compound; RP is hydrogen, R1 is -CH2-CH = CH-Y, Y is 5- [2- (fluorenyl) -5-thiazolyl]-2-thienyl-, and X is F Example 4 8

D: \ 1234 \ 55395.ptd Page 81 1229677 V. Description of the invention (76) imino) methyl] -7-quinazolinyl-, X is F Example 4 9 Compound of formula (II) b; Rp is hydrogen, R1 is -CH2-CH = CH-Y, Y is 5- (5-pyrimidinyl) -2-thienyl-, and X is F Example 50 0 Compound of formula (II) b; RP is hydrogen, R1 is -CH2-CH = CH-Y, Y is 5- (2-pyrimidinyl) -2-thienyl-, and X is F Example 5 1 Compound of formula (II) b; RP is hydrogen and R1 is -CH2 -CH = CH-Y, Y is 5-[5- (methoxycarbonyl)-3-pyridyl] -2-thienyl-, and X is F Example 5 2 Compound of formula (II) b; RP is hydrogen , R1 is -CH2-CH = CH-Υ, Υ is 5-thiophene [2, 3-b] pyridyl-, and X is F Example 5 3 Compound of formula (II) b; RP is hydrogen, and R1 is -CH2 -CH = CH-Y, Y is 1H-pyrrole [2 3-b] pyridyl-, and X is F Example 5 4 Formula (II) b4 dagger compound; / is hydrogen, 1? 1 is one (^ 2 -(:) 1 = (: 11- ¥, ¥ is 3 []-3-methylimidazole [4 5-b] pyridyl-, and X is F Example 5 5 Compound of formula (II) b; RP is hydrogen R1 is -CH2-CH = CH-Y, Y is 6-carboxy-3-quinolinyl-, and X is F. Example 5 6 Compound of formula (II) b; RP is hydrogen, and R1 is -CH2 -CH = CH-Y, Y is 5- (2-thio

D: \ 1234 \ 5539o.ptd Page 82

Claims (1)

1229677 O: \ 55 \ 55395-931102.ptc Page 91 1229677 _Case No. 87117980_Amendment _ Sixth, the scope of application for patent 8-naphthyridinyl)-, χ is F; Compound of formula (II), Rm, R1 Is -CH2-CH diCH-Y, y is 6-quinazolinyl-, and X is F; a compound of formula (II), Rp, R1 is -CH2-CH = CH-Y, and y is 6- (dimethylamine Group) -3-quinolinyl-, X is F; compound of formula (II), Rp is Η, R1 is -CH2-CH = CH-Y, and y is 6- (aminocarbonyl) -3-quinolinyl -, X is F; compound of formula (II), Rm, R1 is -CH2-CH = CH-Y, ¥ is 6- (1 methylamino) -3-quinolinyl-, and X is F; formula (11 ) 4 compound, 1 ^ is 11, 1 ~ 1 is one (: 112- (: 11 = (: 11- ¥, ¥ is 6- (fluorenyl) -3 -quinolinyl-, X is F A compound of formula (II), Rp is Η, R1 is -CH2-CH = CH-Y, Y is 6-[(hydroxyimino) methyl] -3 -quinolinyl-, and X is F; II) Compound, RP is fluorene, R1 is -CH2-CH = CH-Y, y is 6- [aminoimino (fluorenyl)]-3 -quinolinyl-, and X is F; Formula (II) Compound, RP is Η, R1 is -CH2-CH diCH-Υ, y is 6-[[(1-fluorenylethylene) aminoimino]] ]-3 -quinolinyl-, X is F; compounds of formula (II), Rp is fluorene, R1 is -CH2-CH = CH-Y 1 is 3- (5-cyano) pyridyl-, X is F A compound of formula (11) 4, Rp is hydrogen, R1 is a CH2-C triCY, Y is hydrogen, X is F, a compound of formula (II), Rp is hydrogen, R1 is -CH2-CtriC_Y, Υ is phenylweiyl-'X is F; O: \ 55 \ 55395-931102.ptc Page 92 1229677 _Case No. 87117980_Year_Month__ VI. Patent application scope Formula (11) 4 dagger compound, Rp is hydrogen, R1 is a CH2-C three CY , Y is 2-thienylcarbonyl-, and X is F; the compound of formula (11) 4, Rp is hydrogen, R1 is a CH2-C = CY, and y is (6-chloro-3 -sulfonyl). -, X is F; a compound of formula (11), Rp is hydrogen, R1 is a CH2-C triCY, y is 3-quinolinyl-, and X is F; a compound of formula (11) 4 , Rp is hydrogen, R1 is a CH2-C EC-Y, y is (2,2'-bisthiophene) -5-yl-, and 1 is? And a compound of formula (11) 4, Rp is hydrogen, R1 is a CH2-C-Y, y is [5- (2-pyridyl) -2-thienyl]-, and X is F. 3. A pharmaceutical composition for treating a bacterial infection, comprising a therapeutically effective amount of a compound according to item 1 of the scope of patent application, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 4 · The compound according to item 1 of the scope of patent application, wherein X is F. 5. The compound according to item 1 of the scope of patent application, which has the formula (I I) b, O: \ 55 \ 55395-931102.ptc Page 93 1229677 Case No. 87117980 Amendment VI. Application for Patent Scope 6. — A method for preparing compounds having the formula and their pharmaceutically acceptable salts, (II ) Wherein Rp is nitrogen or a protecting group; X is F, C1 or Br; and R1 is selected from the group consisting of: (1) -CH2-CH = CH-Y, where Y is selected from the group consisting of Group consisting of (a) H, (b) phenyl, (c) quinolinyl, (d) naphthyridinyl, (e) pyridyl; (f) quinolinolyl, (g) thiophene Group, where (c)-(f) is selected from a group consisting of nitro, amine, and alkylamine II O: \ 55 \ 55395-931102.ptc Page 94 1229677 _Case No 87117980_Year_Fi_ 6. Application for patent scope, dialkylamino, carboxyamido, cyano, thienyl, -CH (= N-NH2), -CH (= NN DiC (CH3) 2) and N- protected amine group (where the protecting group is the third butoxycarbonyl group), ( h) (phenyl) acid, (i) (thienyl) fluorenyl, and (j) (substituted heteroaryl) fluorenyl, wherein the substituted heteroaryl is pyridyl substituted with dentyl; And (2)-CH2-C eC-Y, where Y is as defined above, the method includes (a) treating a compound of the following formula with a halogenating agent and deprotecting it if necessary, 7. The method according to item 6 of the scope of patent application, wherein the halogenating agent is selected from the group consisting of N-fluorobenzenesulfonimide in the presence of a base, containing 10% iF2 / formic acid, and 3, 5-dichloro-1 -fluoropyridine. Tetrafluoroborate, 3,5-digas-1 -fluoropyridine triflate, (CF3S02) 2NF, N-fluoro-N-methyl-p-toluenesulfonamide in the presence of a base , N-fluoropyridine triflate, N-fluoroperfluorohexadecane in the presence of a base O: \ 55 \ 55395-931102.ptc Page 95 1229677 Case No. 87117980 Amendment VI. Patent application scope Hydropyridine, six gas ethane in the presence of alkali, CF3CF2CH2CIC12, S02C12, S0C12, CF3S02C1 in the presence of alkali C12, NaOCl in the presence of acetic acid, Br2 · D ratio bite · ΗΒγ, Br2 / acetic acid, N-bromobolan sub-monthly in the presence of 5 LDA / BrCH2CH2Br 5 LDA / CB r4, in the presence of Nanjin N_ iodosuccinimide and group of 12. 8. The method according to item 6 of the scope of patent application, wherein X is thallium and the halogenating agent is N-fluorobenzenesulfonimide in the presence of sodium hydride. 9. The method of claim 8 in the scope of patent application, wherein R1 is -CH2 -CH = CH-Y, and Y is selected from (3-quinolinyl), 6-nitro-3-quinolinyl-, benzene N-, 6-tert-butoxycarbonylamino-3 -quinolinyl, 6-amino-3 -quinolinyl-, 6-quinolinyl-, 3- (1,8-naphthyridinyl)- , 6-quinolinyl-, 6- (dimethylamino) -3_quinolinyl-, 6_ (N-methylamino)-3-quinolinyl-, 6- (formamyl) -3 _Quinolinyl-, 6-[(hydroxyimino) methyl] -3 -quinolinyl-, 6-[aminoimino (methyl)]-3 -quinolinyl-, 6- [ [(1-methylethylene) aminoimino] methyl] -3 -quinolinyl-, and 35-cyano) pyridyl-. O: \ 55 \ 55395-931102.ptc Page 96