NZ611653B

NZ611653B - Ketolide compounds

Info

Publication number: NZ611653B
Application number: NZ611653A
Authority: NZ
Inventors: Sachin Bhagwat; Satish Bhavsar; Deepak Dekhane; Prasad Deshpande; Santosh Diwakar; Sunil Gupta; Mohammad Jafri; Amit Mishra; Mahesh Patel; Vijay Patil
Original assignee: Wockhardt Limited
Priority date: 2010-12-09
Filing date: 2011-02-03
Publication date: 2014-08-01

Abstract

611653 Disclosed are ketolide compounds of Formula (I) and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs and stereoisomers having antimicrobial activity. Also disclosed are pharmaceutical compositions containing the compounds of formula (I) and methods of treating or preventing microbial infections with the compounds of formula (I), wherein, T is -C*H(R1)-P-Q; R1 is hydrogen; P is heteroaryl ring; Q is unsubstituted or substituted aryl or heteroaryl ring; and P is attached to Q via carbon-carbon link; and R3 is fluorine. Examples of compounds of formula (I) are: (11S,21R)-3-decladinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12,11-{oxycarbonyl-[E-N-[(5-pyrimidin-2-yl-1,3,4-thiadiazol-2-yl)-methoxy]-carboxamidino]methylene}-erythromycin A and (11S,21R)-3-decladinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12,11-{oxycarbonyl-[E-N-[(5-isoxazol-3-yl-pyrimidin-2-yl)-methoxy]-carboxamidino]methylene}-erythromycin A. nting microbial infections with the compounds of formula (I), wherein, T is -C*H(R1)-P-Q; R1 is hydrogen; P is heteroaryl ring; Q is unsubstituted or substituted aryl or heteroaryl ring; and P is attached to Q via carbon-carbon link; and R3 is fluorine. Examples of compounds of formula (I) are: (11S,21R)-3-decladinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12,11-{oxycarbonyl-[E-N-[(5-pyrimidin-2-yl-1,3,4-thiadiazol-2-yl)-methoxy]-carboxamidino]methylene}-erythromycin A and (11S,21R)-3-decladinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12,11-{oxycarbonyl-[E-N-[(5-isoxazol-3-yl-pyrimidin-2-yl)-methoxy]-carboxamidino]methylene}-erythromycin A.

Description

KETOLIDE COMPOUNDS RELATED PATENT APPLICATIONS This application claims the beneﬁt of Indian Complete Patent Application No.

UM/2010 ﬁled on Dec 09, 2010, the sures of which are incorporated herein by reference in its entirety as if fully rewritten herein.

FIELD OF THE INVENTION The invention s to ketolide compounds of formula (I) and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs and isomers. The invention also provides pharmaceutical compositions containing these compounds and methods of treating or preventing microbial infections using these compounds.

Formula | BACKGROUND OF THE INVENTION Macrolides are a well-known family of antimicrobial agents. Erythromycin A, a 14- membered macrolide, was isolated in 1952 from Streptomyces erythraeus. Examples of macrolides being used as therapeutic agents are roxithromycin, clarithromycin and azithromycin (azalide). Ketolides are nthetic l4-membered ring macrolide derivatives, characterized by the ce of a keto function at position 3 d of L-cladinose moiety present in the macrolactone ring. Telithromycin and Cethromycin are examples of ketolides.

United States Patent US 4,331,803 discloses the 6-O-methyl derivative of erythromycin i.e. clarithromycin. The patent US 4,349,545 discloses roxithromycin. The azalide omycin is disclosed in US 359. Telithromycin is described in EP 680967 A1 and corresponding US 5,635,485 and Bioorg. Med. Chem. Lett. 1999, 9(21), 3075 -3080.

Another ketolide Cethromycin (ABT 773) is disclosed in WO 98/09978, and J. Med. Chem. 2000, 43, 1045.

The U.S. Patent No. 6,900,183 describes 11,12-g-lactone ketolides having C-21 of the lactone substituted with cyano or amino derivatives. The patent applications such as U.S. 2004/0077557 and PCT publications WO 02/16380, WO 03/42228, WO 03/072588 and WO 34 disclose 11,12-g-lactone ketolides. Our ding PCT ation No. WO 08/023248 discloses several Macrolides and des.

Where the terms ˝comprise˛, ˝comprises˛, ˝comprised˛ or ˝comprising˛ are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or on of one or more other feature, integer, step, component or group thereof.

SUMMARY OF THE INVENTION In one general aspect, there are provided compounds of formula (I) or a pharmaceutically acceptable salt, e, hydrate, polymorph or stereoisomer thereof, O NH O HO N N O O H O O 3 Formula I wherein, T is ?C*H(R1)-P-Q; R1 is H; P is heteroaryl ring; Q is unsubstituted or substituted aryl or heteroaryl ring; and P is attached to Q via carbon-carbon link; and R3 is fluorine.

In another l aspect, there are provided pharmaceutical compositions comprising therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally, with one or more pharmaceutically acceptable excipient.

In another general aspect, there is provided the use of a compound of formula (I) as described herein for the manufacture of a ment for the treatment of infection caused by a microorganism.

In another general aspect, there is ed the use of a compound of formula (I) as described herein for the manufacture of a medicament for the prophylactic treatment of a t at risk of infection caused by a microorganism.

In r l aspect, there is provided a method for treating or preventing microbial infection in a subject, comprising administering to a t in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, rph or stereoisomer thereof.

In another general aspect, there is provided a method for treating infection caused by a microorganism in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically able salt, solvate, hydrate, polymorph or stereoisomer thereof.

In another general , there is provided a method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof In another l aspect, there is provided a method of treating infection caused by a microorganism in a subject, comprising administering to the subject in need f, a pharmaceutical composition sing therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer f, optionally with one or more pharmaceutically acceptable excipient.

In some other embodiments, there is provided a method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a ceutical composition comprising eutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally with one or more pharmaceutically acceptable excipient.

In another general aspect, there is provided a process for preparation of a compound of formula (4-e) N N Br sing: (i) converting 2-methyl-pyrimidinecarbaldehyde (4-a) to obtain a compound of formula (4-b); N HO N N OHC CH 3 CH N N 4-a 4-b (ii) converting a compound of formula (4-b) to a compound of formula (4-c); X N Si N (iii) converting a compound of formula (4-c) to a compound of formula (4-d); and 4-d (iv) ting a compound of formula (4-d) to a compound of formula (4-e).

In another general aspect, there is provided a process for preparation of a compound of formula (19-d) O NH 2 O HO N N O O H O P and Q is as defined ?????????????????? ?????? 19-d comprising: (i) reacting a compound of formula (19-a) with a compound of formula (19-b) to obtain a compound of formula (19-c).

HO NH 2O O N N O O H O Q-P-CH2-Z O 19-b F Z = Br or R-SO2-O- where R= methyl, nosyl ??????????????????P and Q = as d ?????? 19-a O NH 2 O O N N O O H O 19-c (ii) converting a compound of formula (19-c) to a compound of a (19-d).

In another general , there is provided a process for preparation of a compound of formula (15-f) S O N N S -f comprising; (i) converting a compound of formula (15-a) to a compound of formula (15-b); H C H C 3 OTBDMS 3 OTBDMS O O NH -a 15-b (ii) ting a compound of formula (15-b) to a compound of formula (15-c); OTBDMS O O -c (iii) ting a compound of formula (15-c) to a compound of formula (15-d) TBDMSO 3 N -d (iv) ting a compound of formula (15-d) to a compound of formula (15-e); and 3 N 15-e (v) converting a compound of formula (15-e) to a compound of formula (15-f).

In r general aspect, there is ed a process for preparation of a compound of formula (16-d) S O N N S 16-d NO comprising: (i) reacting pyrimidinecarbonylchloride with a compound of a (15-b) to obtain a compound of formula (16-a); H C OTBDMS 3 OTBDMS H C O NH O O NH H 2 N -b 16-a (ii) converting a compound of formula (16-a) to a compound of formula (16-b); OTBDMS H C N 3 N 16-b (iii) converting a compound of formula (16-b) to a compound of formula (16-c); and 3 N 16-c (iv) converting a compound of formula (16-c) to a compound of formula (16-d).

In another l aspect, there is provided a process for preparation of a compound of formula (17-e) HO NH 2 O O N N O O H O 17-e comprising: (i) converting a compound of formula (17-a) to a compound of a (17-b) O NH Si H 2O O N O O NH N 2 O O N O N O O H O O O O H O OH O O OH 17-a 17-b (ii) converting a compound of formula (17-b) to a compound of formula (17-c) O NH 2 O O N N O O H O 17-c (iii) converting a compound of formula (17-c) to a compound of formula (17-d); and O NH 2 O O N N O O H O 17-d (iv) converting a compound of formula (17-d) to a compound of formula (17-e).

The details of one or more ments of the inventions are set forth in the description below. Other features, aspects and advantages of the inventions will be apparent from the following description including claims.

ED DESCRIPTION OF THE INVENTION Reference will now be made to the exemplary embodiments, and speciﬁc language will be used herein to describe the same. It should heless be understood that no limitation of the scope of the ion is thereby intended. Alterations and further modiﬁcations of the inventive es rated herein, and additional ations of the principles of the inventions as illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this speciﬁcation and the appended claims, the singular forms ”a, H H an,” and ”the” include plural referents unless the content clearly dictates otherwise.

In general, the following deﬁnitions are used, unless otherwise bed.

The symbol* indicates chiral center in the formula (I) which is either in the R or in S form or mixture of both forms.

The term ”stereoisomer” refers to compounds, which have cal chemical composition, but differ with regard to arrangement of the atoms and the groups in space.

These include enantiomers, diastereomers, geometrical isomers, atropisomer and comformational isomers. Geometric isomers may occur when a nd contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity. An omer is a stereoisomer of a reference molecule that is the nonsuperimposable mirror image of the reference molecule. A diastereomer is a stereoisomer of a reference molecule that has a shape that is not the mirror image of the reference molecule. An atropisomer is a conformation of a reference compound that converts to the reference compound only slowly on the NMR or laboratory time scale. Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation about 0 bonds, and are often rapidly interconverting at room temperature. Racemic mixtures are also encompassed within the scope of this invention. Some of the compounds of the present invention may have trans and cis isomers and geometric E- and Z- isomers. The wavy bond tes that the compounds may be present as either of E- or Z- isomer. Also some of the compounds ing to this invention may exist as diastereomers. In addition, where the process for the preparation of the compounds according to the ion give rise to mixture of stereoisomers, these isomers, may be separated by conventional techniques such as preparative chromatography and HPLC. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomer.

The term ”polymorphs, solvates and hydrates” has g as discussed herewith.

The compounds of invention may exists as different polymorphs such as crystalline or amorphous forms and as such are intended to be included in the present invention. In addition, some of the compounds may form es with water (i.e. hydrates), which contains various amounts of water, for instance the hydrate, hemihydrate and sesquihydrate forms. Also the compound can form es with common organic solvents. Such solvates and hydrates are intended to be included within the scope of this invention.

The term “lower alkyl” refers to C1-C6 alkyl saturated, ht or branched chain hydrocarbon radicals containing between one and six carbon atoms. Examples of C1-C6 alkyl radicals include but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers such as iso-propyl, iso-butyl or tert-butyl.

The term alkyl” refers to C3-C6 saturated yclic l containing between three and six carbon atoms. es of C3-C6 saturated carbocyclic radical include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term “substituted lower alkyl” refers to substituted C1-C6 alkyl, substituted by independent replacement of one or two or three of the hydrogen atoms thereon with F, Cl, Br, 1, N02, NHZ, CN, OH, C1-C6 alkoxy, alkylamino, dialkylamino, mercapto, formyl, carboxy, alkoxycarbonyl and carboxamide, aryl, heteroaryl, substituted aryl, substituted heteroaryl.

Examples of such substitutions are ﬂuoromethyl, diﬂuoromethyl, triﬂuoromethyl. nitromethyl, aminomethyl, cyanomethyl, hydroxymethyland the like. Examples of C1-C6 alkoxy are methoxy, ethoxy, oxy, isopropyloxy, butyloxy, oxy, hexyloxy.

The term ”alkylamino” refers to a group having the structure -NH(C1-C6 alkyl) where C1-C6 alkyl is as usly deﬁned.

The term ”dialkylamino” refers to a group having the structure -N(C1-C6 alkyl) (C1-C6 alkyl), where C1-C6 alkyl is as previously d. Examples of dialkylamino are, but not d to, dimethylamino, diethylamino, methylethylamino and the like.

The term “aryl” refers to a mono or bicyclic ring system such as phenyl or naphthyl.

The term “heteroaryl” refers to a mono i.e. 5-6 membered or bicyclic i.e. fused aromatic ring system having at least one carbon atom of the aromatic ring replaced by an atom selected from the group of N, O, S. For example pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, zolyl, l, triazolyl, triazinyl, l, N—oxo-pyridyl, and the like. It includes the fused biaryl systems such as indolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzothienyl, N-oxo-quinolyl, idazolyl, benzopyranyl, benzoisothiazolyl, iazinyl, benzofurazanyl, indazolyl, indolizinyl, benzofuryl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2—b]pyridinyl, furo[2,3- dinyl), naphthyridinyl, phthalazinyl, pyridopyridyl, quinazolinyl, thienofuryl, pyridyl, thienotheinyl, purinyl (such as 9H-purin-l-yl, o-9H-purinyl), pyridinyl- lH-pyrazol- l-yl and the like.

The aryl or the heteroaryl group can be optionally substituted by independent replacement of one or more of hydrogen atoms thereon with substituents selected from C1-C6 alkyl, substituted C1-C6 alkyl, cyano, hydroxy, halogen, amino, formyl, carboxy, carboxamide, C1-C6 alkoxy, C1-C6 thioalkoxy, C1-C6 alkylcarbonyl, amino, alkylamino, dialkylamino, mercapto, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylthio, arylthio, heteroarylthio or haloalkyl.

The term “pharmaceutically acceptable salt” as used herein refers to one or more salts of the free base of the invention which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. The salts are suitable for use in contact with the s of human and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable t/risk ratio. ceutically able salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 , incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable acid. These salts may be obtained from inorganic or organic acids. Examples of inorganic acids are hloric acid, nitric acid, perchloric acid, hydrobromic acid, sulphuric acid or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, oxalic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, ic acid, methanesulphonic acid, p-toluene sulphonic acid, salicyclic acid and the like. Also included are the salts with various amino acids such as alanine, arginine, asparagine, aspartic acid, ne, glutamine, glutamic acid, glycine, histidine, cine, e, lysine, methionine, phenylalanine, proline, , threonine, tryptophan, tyrosine or valine or the optically active isomers thereof or the racemic mixtures thereof or dipeptides, tripeptides and polypeptides derived from the monoaminoacid units thereof.

Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, te, bisulfate, borate, butyrate, camphorate, rsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, ate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, sulfate, tartrate, thiocyanate, enesulfonate, undecanoate, valerate salts, and the like.

Salt of an acid moiety in the compound can also be prepared by reacting with a suitable base. These le salts are furthermore those of the inorganic or organic bases.

Inorganic bases such as KOH, NaOH, Ca(OH)2, Al(OH)3. The c base salts from basic amines such as mine, triethylamine, diethanolamine, ethylenediamine, guanidine or heterocyclic amines such as piperidine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, morpholine, piperazine, N—methyl piperazine and the like or basic amino acids such as optically pure and racemic isomers of arginine, lysine, histidine, tryptophan and the like.

Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as , hydroxide, carboxylate, sulfate, ate, nitrate, lower alkyl sulfonate and aryl sulfonate.

The term "therapeutically ive amount” means that amount of compound(s) or ceutical agent(s) that elicit the biological or medicinal response in a tissue system, animal or human sought by a researcher, veterinarian, medical doctor or other clinician, which response includes ation of the ms of the disease or disorder being treated.

The speciﬁc amount of active compound(s) or pharmaceutical agent(s) needed to elicit the biological or medicinal response will depend on a number of factors, including but not d to the disease or disorder being treated, the active compound(s) or pharmaceutical agent(s) being administered, the method of administration, and the condition of the patient.

The term “treat”, “treating” or “treatment” as used herein refers to administering a pharmaceutical composition or a compound for prophylactic and/or therapeutic purposes. The term ”prophylactic treatmen ” refers to treating a subject who is not yet infected, but who is susceptible to, or otherwise at a risk of infection. The term ”therapeutic ent” refers to administering treatment to a subject already suffering from infection. Thus, in red embodiments, ng is the administration to a subject (either for therapeutic or prophylactic purposes) of therapeutically effective amount of compound of a (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof The term ”subject” as used herein refers to vertebrate or invertebrate, including a mammal. The term “subject” includes human, animal, a bird, a fish, or an amphibian.

Typical, miting examples of a ”subject” includes humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.

The term "microorganism" or "microbe" as used herein includes bacteria, fungi, protozoa, yeast, mold, and mildew.

The term ”infection” as used herein includes presence of a microorganism in or on a t, which, if its growth were inhibited, would result in a beneﬁt to the subject. As such, the term ”infection” in addition to referring to the presence of microorganisms also refers to normal ﬂora, which are not ble. The term ”infection” includes infection caused by bacteria, fungi, protozoa, yeast, mold, or mildew.

Typical, non-limiting examples of infections include those such as pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by ococcus pneumoniae, hilus inﬂuenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and ulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clostridium diptheriae, or bacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus inﬂuenzae, or dia pneumoniae, uncomplicated skin and soft tissue ions, abscesses and osteomyelitis, and puerperal fever related to infection by Staphylococcus aureus, coagulase-positive staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (minute- colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute y tract infections related to infection by Staphylococcus saprophyticus or Enterococcus spp.; urethritis and cervicitis; and sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and Toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Helicobacter pylori; ic febrile syndromes d to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chiamydia matis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. inﬂuenzae, or Listeria spp.; disseminated cterium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium ellulare; gastroenteritis d to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection d to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium ngens or Bacteroides spp.; and atherosclerosis d to infection by Helicobacter pylori or dia pneumoniae. Bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in animals e the following: bovine respiratory diseases related to infection by P. haem., P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by E. coli or protozoa (i.e., coccidia, cryptosporidia, etc.); dairy cow mastitis related to infection by Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., bacterium, or Enterococcus spp.; swine respiratory disease related to infection by A. ., P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella, or ina hyodyisinteriae; cow t related to infection by Fusobacterium spp.; cow metritis related to infection by E. coli; cow hairy warts related to infection by cterium horum or oides nodosus; cow pink- eye related to infection by Moraxella bovis; cow premature abortion related to infection by protozoa (i.e. neosporium); urinary tract infection in dogs and cats related to ion by E. coli; skin and soft tissue infections in dogs and cats related to infection by Staph. epidermidis, Staph. intermedius, coagulase neg. Staph. or P. multocida; and dental or mouth infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella.

In one general aspect, there are provided compounds of a (I) or a pharmaceutically acceptable salt, solvate, hydrate, rph or stereoisomer thereof, 2 \ (I? O : HO, N— Formula I wherein, T is —C*H(R1)-P-Q; R1 is hydrogen; unsubstituted or substituted lower alkyl, cycloalkyl or aryl; P is heteroaryl ring; Q is unsubstituted or substituted aryl or heteroaryl ring; and P is attached to Q via carbon-carbon link; and R3 is hydrogen or ﬂuorine, With the provision that when R1 is hydrogen, R3 is ﬂuorine.

In some embodiments, there are provided compounds of formula (I), wherein: T is 1)-P-Q; R1 is hydrogen; R3 is ﬂuorine, P is 5 or ered heteroaryl ring with up to three heteroatoms; Q is tituted or substituted aryl or 5 or 6-membered heteroaryl ring; and P is attached to Q via carbon-carbon link In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is hydrogen; R3 is ﬂuorine, 2011/050464 P is 5 or 6-membered heteroaryl ring with up to three heteroatoms; Q is tituted or substituted aryl or 5 or 6-membered heteroaryl ring with up to two nitrogens; and P is attached to Q via carbon-carbon link.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is hydrogen; R3 is ﬂuorine, P is 5-membered heteroaryl ring such as ole or thiadiazole; Q is tituted or substituted aryl or 6-membered heteroaryl ring with up to two nitrogens; and P is attached to Q via carbon-carbon link.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is hydrogen; R3 is ﬂuorine, P is 6-membered heteroaryl ring such as pyridine or pyrimidine; Q is unsubstituted or substituted aryl or 5 or 6-membered aryl ring with up to two heteroatoms; and P is attached to Q via carbon-carbon link.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is hydrogen; R3 is ﬂuorine, P is 5-membered heteroaryl ring such as isoxazole or thiadiazole; Q is unsubstituted or substituted pyridine or pyrimidine; and P is attached to Q via carbon-carbon link.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is en; R3 is ﬂuorine, P is thiadiazole; Q is unsubstituted or substituted pyridine or pyrimidine; and P is attached to Q via -carbon link.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is hydrogen; R3 is ﬂuorine, P is isoxazole; Q is unsubstituted or substituted pyridine or pyrimidine; and P is attached to Q via carbon-carbon link.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is en; R3 is ﬂuorine, P is thiadiazole; Q is ne or pyrimidine; and P is attached to Q via carbon-carbon link.

In some embodiments, there are provided compounds of formula (I), n: T is —C*H(R1)-P-Q; R1 is hydrogen; R3 is ﬂuorine, P is isoxazole; Q is pyridine or pyrimidine; and P is attached to Q via carbon-carbon link.

In some ments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is hydrogen; R3 is ﬂuorine, P is pyrimidine; Q is unsubstituted or substituted 5-membered heteroaryl; and P is attached to Q via carbon-carbon link.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is en; R3 is ﬂuorine, P is dine; Q is isoxazole; and P is attached to Q via carbon-carbon link.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is unsubstituted or substituted lower alkyl, cycloalkyls, or aryl; P is heteroaryl ring; Q is unsubstituted or tuted aryl or heteroaryl ring; and P is attached to Q via carbon-carbon link; and R3 is hydrogen or e.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is unsubstituted or substituted lower alkyl; P is heteroaryl ring; Q is tituted or substituted aryl or heteroaryl ring; and P is attached to Q via carbon-carbon link; and R3 is hydrogen or ﬂuorine In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is unsubstituted or substituted lower alkyl; P is 5-membered heteroaryl ring with up to three heteroatoms; Q is unsubstituted or substituted aryl or heteroaryl ring; and P is attached to Q via carbon-carbon link; and R3 is hydrogen or ﬂuorine In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is unsubstituted or substituted lower alkyl; P is ered heteroaryl ring with up to three heteroatoms; Q is unsubstituted or substituted aryl or heteroaryl ring with up to two nitrogens; and P is attached to Q via carbon-carbon link; and R3 is hydrogen or ﬂuorine.

In some embodiments, there are provided compounds of formula (I), n: T is —C*H(R1)-P-Q; R1 is ; P is 5-membered heteroaryl ring with up to three heteroatoms; Q is unsubstituted or substituted aryl or heteroaryl ring with up to two nitrogens; and P is attached to Q via -carbon link; and R3 is hydrogen or ﬂuorine.

In some embodiments, there are provided nds of formula (I), wherein: T is 1)-P-Q; R1 is methyl; P is 5-membered aryl ring such as isoxazole or thiadiazole; Q is unsubstituted or substituted aryl or heteroaryl ring with up to two nitrogens; and P is attached to Q via carbon-carbon link; and R3 is hydrogen or ﬂuorine.

In some embodiments, there are provided compounds of a (I), wherein: T is —C*H(R1)-P-Q; R1 is methyl; P is 5-membered heteroaryl ring such as ole or thiadiazole; Q is pyridine or dine; and P is attached to Q via carbon-carbon link; and R3 is hydrogen or ﬂuorine.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is methyl; P is thiadiazole; Q is pyridine or pyrimidine; and P is attached to Q via carbon-carbon link; and R3 is hydrogen or ﬂuorine.

In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is methyl; P is ole; Q is pyridine or pyrimidine; and P is attached to Q via carbon-carbon link; and R3 is hydrogen or ﬂuorine.

In some other embodiments, there is provided a compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, selected from: a nd of a (I) n T is [3-(pyrimidinyl)-isoxazo1yl]- CH2- and R3 is F; a compound of formula (I) wherein T is [5-(isoxazolyl)-pyrimidinyl]— CH2- and R3 is F; a compound of formula (I) wherein T is [5-(pyrimidinyl)-isoxazo1yl]- CH2- and R3 is F; a compound of formula (I) wherein T is [5-(2-amino-pyridinyl)-isoxazol yl]-CH3- and R3 is F; a compound of formula (I) wherein T is ridin—2-yl)-isoxazolyl]-CH2 - and R3 is F; a compound of a (I) wherein T is [2-(2-amino-pyridinyl)-1,3,4- thiadiazol-S-yl]—CH3- and R3 is F; a compound of formula (I) wherein T is [2-(pyrimidinyl)-1,3,4-thiadiazol- -yl]—CH2- and R3 is F; a compound of formula (I) wherein T is [2-(2-amino-pyridinyl)-1,3,4- thiadiazol-S-yl]—CH3- and R3 is F; a compound of formula (I) wherein T is [2-(pyridinyl)-1,3,4-thiadiazol yl]-CH3- and R3 is F; a compound of formula (I) wherein T is [5-(pyrazinyl)-isoxazolyl]-CH3- and R3 is F; a nd of formula (I) wherein T is [2-(6-amino-pyrimidinyl)-1,3,4- thiadiazol-S-yl]—CH2 and R3 is F -; a compound of formula (I) wherein T is [2-(3-amino-phenyl)-1,3,4-thiadiazol- -yl]—CH2- and R3 is F; a compound of a (I) wherein T is [2-(2-amino-pyridinyl)-pyridin yl]-CH3- and R3 is F; a compound of a (I) wherein T is [5-(6-amino-pyrimidinyl)-isoxazol- 3-yl]—CH2- and R3 is F; a compound of formula (I) wherein T is (RS)-[2-(pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; WO 76989 a compound of formula (I) wherein T is (R)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(CH3)- and R3 is H; a nd of formula (I) wherein T is (S)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (RS)-[3-(pyridinyl)-isoxazolyl]- CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (R)-[3-(pyridinyl)-isoxazolyl]- CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[3-(pyridinyl)-isoxazolyl]- )- and R3 is H; a compound of formula (I) wherein T is (RS)-[5-(pyrimidinyl)-isoxazol yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (R)-[5-(pyrimidinyl)-isoxazol yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[5-(pyrimidinyl)-isoxazol yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (R)-[5-(pyridinyl)-isoxazolyl]- CH(CH3)- and R3 is H; a compound of formula (I) wherein T is -(pyridinyl)-isoxazolyl]- CH(CH3)- and R3 is H; a compound of formula (I) wherein T is -(pyridinyl)-isoxazolyl]- CH(C3H5)- and R3 is H; a compound of formula (I) n T is -(pyridin-2—yl)-isoxazolyl]- CH(C2H5)- and R3 is H; a compound of formula (I) wherein T is (RS)-[2-(pyrimidinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (R)-[2-(pyrimidinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of a (I) wherein T is (S)-[2-(pyrimidinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (R)-[2-(2-amino-pyridinyl)-l,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (RS)-[2-(2-amino-pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is -(2-amino-pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (R)-[2-(2-amino-pyridinyl)-l,3,4- azol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (RS)-[2-(pyrazinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a nd of a (I) wherein T is (R)-[2-(pyrazin-2—yl)-l,3,4-thiadiazol- -yl]—CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[2-(pyrazinyl)-1,3,4-thiadiazol- -yl]—CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (RS)-[2-(pyridinyl)-1,3,4- oxadiazol-S-yl]—CH(CH3)- and R3 is H; a compound of formula (I) n T is (S)-[2-(3-aminophenyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and 3 is H; a compound of formula (I) wherein T is (S)-[2-(2-hydroxy-pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is -(isoxazolyl)-pyrimidin yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[5-(2-amino-pyridinyl)- isoxazolyl]—CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[2-(4-hydroxy-pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (R)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(CH20H)- and R3 is H; a compound of a (I) wherein T is (S)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(CH20H)- and R3 is H; a compound of formula (I) wherein T is (RS)-[2-(pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(C3H5)- and R3 is H; a compound of formula (I) wherein T is (S)-[2-(pyridinyl)-1,3,4-thiadiazol- CH(C2H5)- and R3 is H; a compound of formula (I) wherein T is (R)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(C2H5)- and R3 is H; 2011/050464 a compound of formula (I) wherein T is (S)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (R)-[2-(2-amino-pyridinyl)-l,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (S)-[2-(pyrimidinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (S)-[2-(pyrazinyl)-1,3,4-thiadiazol- -yl]—CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (S)-[5-(pyrimidinyl)-isoxazol yl]-CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (S)-[2-(3-aminophenyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (S)-[5-(pyridinyl)-isoxazolyl]- CH(CH3)- and R3 is F; a compound of a (I) wherein T is (S)-[5-(isoxazolyl)-pyrimidin yl]-CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (R)-[5-(isoxazolyl)-pyrimidin yl]-CH(CH3)- and R3 is F; and a compound of formula (I) wherein T is (S)-[5-(2-amino-pyridinyl)- isoxazolyl]—CH(CH3)- and R3 is F.

In some other ments, there is provided a compound or a pharmaceutically acceptable salt, solvate, hydrate, rph or stereoisomer thereof, selected from: a compound of formula (I) wherein T is [5-(isoxazolyl)-pyrimidinyl]— CH2- and R3 is F; a compound of formula (I) wherein T is rimidinyl)-1,3,4-thiadiazol- -yl]—CH2- and R3 is F; a nd of formula (I) wherein T is (S)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(CH3)- and R3 is H; a compound of a (I) wherein T is -(pyrimidinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[5-(isoxazolyl)-pyrimidin yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(CH20H)- and R3 is H; a nd of formula (I) wherein T is -(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(C2H5)- and R3 is H; a compound of formula (I) wherein T is -(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is F; a nd of formula (I) wherein T is (S)-[2-(pyrimidinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (S)-[2-(3-aminophenyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is F; a compound of formula (I) wherein T is (S)-[5-(isoxazolyl)-pyrimidin yl]-CH(CH3)- and R3 is F; and a compound of formula (I) wherein T is (S)-[5-(2-amino-pyridinyl)- isoxazolyl]—CH(CH3)- and R3 is F.

In some embodiments, there are provided compounds of a (I), wherein: T is —C*H(R1)-P-Q; R1 is hydrogen; WO 76989 R3 is ﬂuorine, P is thiadiazole or pyrimidine; Q is pyrimidineyl or isoxazoleyl; and P is attached to Q Via -carbon link.

In some other embodiments, there is provided a compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, selected from: (118,21R)decladinosyl-11,12-dideoxyﬂuoroO-methyloxo-12,11- {oxycarbonyl- [E-N- [(5-pyrimidinyl- 1,3 ,4-thiadiazolyl)-methoxy] - carboxamidino]methylene} -erythromycin A; (118,21R)decladinosyl-11,12-dideoxyﬂuoroO-methyloxo-12,11- {oxycarbonyl- [E-N- [(5-isoxazol-3 -yl-pyrimidinyl)-methoxy] - carboxamidino]methylene} -erythromycin A.

In some embodiments, there are provided compounds of formula (I), wherein: T E \ QNHO=| 0 Formula | T is —C*H(R1)-P-Q; R1 is methyl; P is 1,3,4-thiadiazole; Q is pyridineyl or dinyl; and P is attached to Q Via carbon-carbon link; and R3 is hydrogen.

In some other embodiments, there is provided a compound or a pharmaceutically acceptable salt, e, hydrate, polymorph or stereoisomer thereof, ed from: (118,21R)decladinosyl-11,12-dideoxyO-methyloxo-12,11- {oxycarbonyl- [E-N- [ 1 -(5-pyridinyl- 1,3 ,4-thiadiazolyl)-(S)-ethoxy] - carboxamidino]methylene} -erythromycin A; (118,21R)decladinosyl-11,12-dideoxyO-methyloxo-12,11- {oxycarbonyl-[E-N—[l-(5-pyrimidinyl-1,3 ,4-thiadiazolyl)-(S)-ethoxy] - carboxamidino]methylene} -erythromycin A.

In some other embodiment, there is provided a process for preparation of a compound of formula (3-e) Br 3i comprising; (i) converting a compound of formula (3-a) to a compound of formula (3-b); _N O <\:N/>—/<ﬁ‘NH—N O <\:N/>—/<OCZH 2 3-a 3_'b (ii) converting a compound of formula (3-b) to a compound of formula (3-c); N N\ </ \ / IN _N S/Srocsz (iii) converting a nd of a (3-c) to a compound of formula (3-d) c -_NN N\ 8&OH (iv) converting a compound of formula (3-d) to a nd of formula (3-e).

In other embodiments, there is provided a process for preparation of a compound of a (4-e) ,N _N Br 0WNW comprising: (i) converting ing yl-pyrimidinecarbaldehyde (4-a) to obtain a compound of formula (4-b); (iii) converting a compound of formula (4-c) to a compound of formula (4-d); and ONQ—{lf—CHB—N (iv) converting a compound of formula (4-d) to a compound of formula (4-e); In some embodiments, there is provided a process for preparation of a compound of formula (19-d) comprising: (i) reacting a compound of formula (l9-a) with a compound of formula (l9-b) to obtain a compound of a (19-c).

Q-P-CHZ-Z 19-b Z = Br or R-SOZ-O- where R: methyl, nosyl P and Q = as defined (ii) converting a compound of formula (19-c) to a compound of a (19-d).

In some embodiments, there is provided a process for preparation of a compound of formula (1 5 -f) \ fjfz‘s‘oO I N’ -f comprising; (i) converting a compound of a (15-a) to a compound of formula (lS-b); H30 3 IOTBDMS IOTBDMS o o ['le / NH2 _15-a 15-b (ii) converting a compound of formula (15-b) to a compound of formula (15-c); OTBDMS O N O 1-C \ (iii) converting a compound of formula (15-c) to a compound of formula (15-d) (iv) ting a nd of formula (15-d) to a compound of formula (15-e); and -e (V) converting a compound of formula (15-e) to a compound of formula (lS-f).

In some embodiments, there is provided a process for preparation of a compound of formula ( l 6-d) comprising: (i) ng pyrimidine-2—carbonylchloride with a compound of formula (15-b) to obtain a compound of formula (l6-a); OTBDMS IOTBDMS H30 O NH O O I N NH2 H‘gN -b Q 16-a (ii) converting a compound of formula (l6-a) to a nd of formula (l6-b); OTBDMS SiN/ 16-b (iii) converting a compound of a (16-b) to a compound of formula (16-c); HBO/k?N ‘N SJS/N/ 16-c (iv) converting a compound of formula (16-c) to a compound of formula (16-d); In some embodiments, there is provided a process for preparation of a compound of a ( l 7-e) _' J l—QSi \N_ comprising: (i) converting a compound of formula (l7-a) to a compound of formula (l7-b) (iii) converting a compound of formula (l7-c) to a compound of formula (17- d); and (iv) ting a compound of formula (17-d) to a compound of formula (17-e).

In some other embodiments, there is provided a process for preparation of a compound of formula (18-e) comprising, (i) reacting a compound of a (1 8-a) with a compound formula (l8-b) to a obtain a compound of formula (18-c) Q’PT: 18—b 0 Z = Br or R-SOz-O- where R: methyl, nosyl; 1 -a P and Q is as defined (ii) converting a compound of formula (18-c) to a compound of formula (18-d), and 2011/050464 Z I _|O—<_n Z/| 18-d (iii) converting a compound of formula (18-d) to a compound of formula (18-e).

In some embodiments, there is provided a process for preparation of a compound of formula (1 9-d’) ml / comprising, (i) reacting a compound of formula (19-a) with a compound formula (19-b’) to a obtain a compound of a (19-c’), and Q’P‘S 19-b' Z = Br or R-SOz-O- where R: methyl, nosyl R1 = CH3 — P and Q = as defined 2011/050464 (ii) converting a nd of formula (19-c’) to a compound of formula ).

In some embodiments, there is provided, a process for the preparation of nds of Formula (I), wherein the variables have the previously deﬁned meanings, the method comprising the process will be better understood in connection with the following synthetic Schemes In some embodiments, there are ed pharmaceutical compositions comprising eutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally, with one or more pharmaceutically acceptable excipient.

The term “pharmaceutically acceptable excipient” refers to a substance other than the active ingredient and includes pharmaceutically acceptable carriers, diluents, stabilizers binders, coloring agents, buffers, lubricants, disintegrating agents, tants, glidants, plasticizers, fillers, extenders, emollients, wetting agents, and so on. The pharmaceutically acceptable excipient often facilitates delivery of the active ingredient. The type and amount of any the excipient used s largely on the therapeutic response desired and other factors such as route of administration and so on.

Any suitable route of administration may be employed for providing the patient with an effective dosage of the compounds of the invention. For e, oral, rectal, vaginal, parenteral (subcutaneous, intramuscular, intravenous), nasal, ermal, topical and like forms of administration may be employed. Suitable dosage forms include tablets, pills, powders, troches, dispersions, solutions, suspensions, emulsions, capsules, injectable preparations, patches, ointments, creams, lotions, shampoos, and the like.

In some embodiments, the ceutical compositions according to the invention are administered parenterally or orally.

In some embodiments, there is provided a method for treating or preventing microbial infection in a subject, comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, solvate, e, polymorph or stereoisomer thereof In some embodiments, there is provided a method for treating infection caused by a microorganism in a subject, comprising administering to a t in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In some other embodiments, there is provided a method for prophylactic ent of a subject, comprising administering to a subject at risk of infection caused by microorganism, a prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof In some other embodiments, there is provided a method for treating infection caused by a microorganism in a subject, comprising administering to the subject in need thereof, a pharmaceutical composition comprising therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, rph or stereoisomer thereof, optionally, with one or more pharmaceutically able excipient.

In some other embodiments, there is provided a method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a ceutical composition comprising therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, optionally, with one or more pharmaceutically acceptable excipient.

The prophylactic or therapeutic dose of the ketolide compounds of Formula (I) and pharmaceutically acceptable salts f, in the acute or c management of disease will vary with the severity of condition to be d, and the route of administration. In addition, the dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual t. In general, the total daily dose range, for the compounds of the invention, for the conditions bed herein, is from about 10 mg to about 5000 mg. It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art.

Further, it is noted that the clinician or treating physician will know how and when to interrupt, , or terminate therapy in conjunction with individual patient’s response.

General ures As per scheme-l, heteroaryl aldoxime of formula l-a is reacted with N- chlorosuccinamide or sodium hypochlorite, in a le solvent such as N,N- dimethylformamide or N,N-dimethylacetamide at a temperature ranging from 25°C to 35°C to provide corresponding heteroaryl amidoxime of formula lb _X> {a—X §:N/—X \ 00 H \N,OH —> 2 5 \ N/ \N,OH —> \N’0 —> La R w R 1_c €\:N/_X OH _X —X \ 0‘s 0 \ \ Br \N’0 —> {J \N’0 I, \ —> \ N/ \N’0 R 1 d R L Li R = H or BocNH— X = CH or N Scheme—1 The compound of formula l-b is d with ethyl propiolate in the presence of c base such as triethylamine in a le solvent such as toluene or xylene, at a temperature ranging from 25°C to 50°C to provide corresponding ethyl ester, which in turn was reduced using sodium borohydride in methanol or ethanol at a temperature ranging from 0°C to 35°C to provide corresponding ol derivative of formula 1-d. This intermediate was then reacted with methanesulfonylchloride in the presence of base such as triethylamine in a suitable solvent such as romethane or chloroform at a temperature ranging from - °C to 35°C to provide corresponding methanesulfonic acid ester of formula 1-e, which is further reacted with lithium bromide in a suitable solvent such acetone; at a temperature ranging from 35°C to 55°C, to provide corresponding bromide intermediate of formula l-f.

—X 0 CI \ hf _ + ‘ OH —’ \-X>_NOCZH5/ lN CZHSO N o R 2_a R / OH —> \ / —) , {N_X>_(/\\\/\Br/ N ON ON, R 2;: R R=HorBocNH— X=CH orN Scheme—2 As per scheme-2, ethynyl heteroaryl compound of formula 2-a is d with ethylchlorooxamidoacetate in the presence of organic base such as triethylamine, in a suitable solvent such as toluene at a temperature g from 80°C to 95°C to provide corresponding ethyl ester derivative of formula 2-b.

The ester tive 2—b is reacted with ng agent such as sodium borohydride in a suitable solvent such as methanol or ethanol at a temperature ranging from 0°C to 35°C to provide ponding methanol derivative of formula 2-c, which is reacted with methanesulfonyl chloride in the presence of organic base such as triethylamine, in a suitable solvent such as dichloromethane or chloroform at a temperature ranging from -5°C to 35°C to provide corresponding methanesulfonic acid ester, which is further reacted with lithium bromide in a le solvent such as acetone at a ature ranging from 35°C to 55°C, to provide corresponding methyl bromide derivative of formula 2-d. _x O _x o \ 9—0000sz —> \ H + N N NHNH2 CIJKH/OCZH5 —> La R OCZH5 _X 8%0 S OH \ —X 3 Br \ />_<\ \N —> \ />—<\ ,N _> \ H \N N N’ N N N N’ R a R w R E R = H or Boo—NH— X = CH or N Scheme—3 Compounds of formula 3-e are synthesized according to scheme 3. Thus, ester of of formula 3-a. is reacted with hydrazine or ine hydrate in a suitable solvent such as methanol or ethanol at a temperature ranging from 25°C to 85°C to provide corresponding hydrazide derivative of formula 3-b.

It is then treated with mono ethyl ester of oxalyl chloride in the presence of organic base such as triethylamine in a le solvent such as dichloromethane or chloroform or tetrahydrofuran at a temperature ranging from -5°C to 35°C, followed by optionally ng to t selected from tetrahydrofuran or 1,4-dioxane and the on mixture is treated with Lawesson’s t at a temperature g from 40°C to 70°C to provide the requisite Thiadiazole derivative of formula 3-c.

The ester (3-c) is d with reducing agent such as sodium borohydride in a suitable solvent ethanol or aqueous ethanol at a temperature ranging from -5°C to 35°C to provide corresponding methanol derivative of formula 3-d.

The alcohol (3-d) is reacted with methanesulfonylchloride in the presence of organic base such as triethylamine in a suitable solvent such as dichloromethane or form at a temperature ranging from -5°C to 35°C to provide corresponding mesylate derivative, which is further reacted with lithium e in a suitable solvent such as acetone at a temperature ranging from 35°C to 55°C to provide corresponding bromide of formula 3-e.

Optionally, heteroaryl-l,3,4-thiadiazolyl-methyl bromide derivative of formula 3-e is prepared by reacting methanol intermediate (3-d) with carbontetrabromide along with triphenylphosphine in a suitable solvent such as dichloromethane at a temperature ranging from 0°C to 35°C.

—N HO-N N 0’X ‘N OHC{ /)—CH —> \\_<:— \ \ N’>_ —> \ \ />—CH3 3 \ N \ Sl\ N B Q 4—c ,N _N Br 0 ON _N _, \\ \ /)—CH3 _, \\ \ / N N M 4'—9 Scheme—4 As per scheme-4, 2-methyl-pyrimidinecarbaldehyde (4-a) is reacted with hydroxylamine hydrochloride in the presence of base such as sodium carbonate or sodiumbicarbonate or potassium carbonate in a suitable solvent such as methanol or ethanol or water or mixture thereof, at a temperature ranging from 0°C to 35°C, to provide ponding yl-pyrimidinecarbalehyde oxime (4-b).

The compound 4-b is reacted with N-chlorosuccinamide or sodium hypochlorite, in a suitable solvent such as N,N-dimethylformamide or N,N-dimethylacetamide at a temperature ranging from 0° to 35°C to e ponding methyl substituted pyrimidinyl chloroamidoxime compound, which is further treated with trimethylsilylacetylene in a suitable t such as diethyl ether or N,N-dimethylformamide, or mixture thereof, at a temperature ranging from -5°C to 35°C to provide ponding compound 4-c.

The compound 4-c is converted to compound 4-d by reacting it with base such as sodium carbonate or potassium carbonate or sodiumbicarbonate in a suitable solvent such as methanol or ethanol at a temperature ranging from 0°C to 50°C.

The compound 4-d is reacted with N-bromosuccinamide in the presence of radical initiator such as benzoyl peroxide or butyronitrile (AIBN) in carbon tetrachloride at a temperature ranging from 65°C to 80°C to provide corresponding isoxazolyl-pyrimidinyl methyl bromide compound 4-e.

\ \ I \ / It—Boc _> I / /t—Boc + m Br N N n—Bu3Sn N N Br N/ \t—Boc CHO \t—Boc ‘61 5-b \ t—Boc \ I I I f-BOC N/ |N\ N\t-Boc —> HO / N N —’ OHC N \ \t—Boc / / —c 5-d I EBoc Br / N N N \ \t—Boc Scheme—5 As per scheme-5, 2—bromoN,N-di-t-butyloxycarbonylamino-pyridine (5-a) is reacted with hexabutyldistannane in the presence of palladium catalyst such as Palladium- tetrakis(triphenylphosphine) or bis(triphenylphosphine)palladium(11)dichloride in a suitable solvent such as dimethoxyethane or DMF or toluene, at a ature ranging from 80°C to 90°C, to provide corresponding tributyltin derivative of pyridine 5-b.

The compound 5-b is coupled with o-pyridinecarbaldehyde using catalyst such as palladium-tetrakis(triphenylphosphine) in the presence of lithium chloride and base such as triethylamine in toluene at a temperature ranging from 100°C to 110°C to provide a corresponding coupled product 5-c.

The compound 5-c is reacted with a reducing agent such as sodium borohydride in a suitable solvent tetrahydrofuran or l or methanol or aqueous ethanol or mixture f, at a temperature ranging from 25°C to 35°C to provide corresponding tuted pyridinyl methylalcohol compound 5-d.

The compound 5-d is reacted with methanesulfonylchloride in the presence of organic base such as triethylamine in a le t such as dichloromethane or chloroform at a temperature ranging from 0°C to 25°C to provide corresponding methanesulfonic acid ester of substituted pyridinyl alcohol, which is further reacted with lithium bromide in a suitable solvent such as acetone at a temperature ranging from 35°C to 55°C to provide corresponding substituted bispyridinyl methyl bromide nd 5 -e. i O Br / N N I Buasn N_ N N_ N —> / / \ \ \>—\ O —> , x, N _N 0% N _N OH 6C 6-d N_ N —* \H\H/ N _N Br Scheme—6 Compound 6-e is synthesized according to scheme-6, in which 5-bromo benzoyloxymethyl-pyrimidine (6-a) is reacted with hexabutyldistannane in the presence of palladium catalyst such as Palladium-tetrakis(triphenylphosphine) or bis(triphenylphosphine)palladium(II)dichloride in a suitable solvent such as toluene, dimethoxyethane or DMF, at a temperature ranging from 80°C to 110°C, to e corresponding tributyltin tive of pyrimidine 6-b.

The compound 6-b is coupled with 2—iodo-pyrazine using catalyst such as bis(triphenylphosphine)palladium(11)dichloride or palladium-tetrakis(triphenylphosphine) in the ce of base such as triethylamine in DMF at a temperature ranging from 100°C to 110°C to provide a corresponding coupled product 6-c.

The compound 6-c is saponiﬁed by stirring with a base such as sodium ide in a suitable solvent such as methanol at a temperature ranging from 25°C to 35°C to e corresponding substituted pyrimidinyl methylalcohol compound 6-d.

The compound 6-d is reacted with methanesulfonylchloride in the presence of organic base such as triethylamine in a suitable solvent such as dichloromethane or chloroform at a temperature ranging from 0°C to 25°C to provide corresponding methanesulfonic acid ester of substituted pyrimidinyl methylalcohol, which is further reacted with lithium bromide in a le solvent such as acetone at a temperature g from 35°C to 55°C to provide corresponding substituted dinyl methyl bromide nd 6-e.

QN/HW —>‘X QN/HNDH _» grﬁ—X —X \ OCH 7—a R M R 7-c —> §:N/—X>_(=(\OH —> \_X>—(§(CHO \N’O / \ N N R E R 74° —X X = CH or N \ Br —X \ OH _> \ / \ ’0 R = H or BocNH- or OBn \ N/ \N’0 N N R 7_-f E- As per -7, heteroaryl aldoxime of formula 7-a is reacted with N- chlorosuccinamide or sodium hypochlorite, in a suitable solvent such as N,N- dimethylformamide or N,N-dimethylacetamide or mixture thereof, at a temperature ranging from 25°C to 35°C to provide corresponding heteroaryl chloroamidoxime compound 7-b. It is then treated with ethyl propiolate in the presence of organic base such as triethylamine, diisopropylethylamine in a suitable solvent such as toluene or xylene at a temperature ranging from 25°C to 50°C to provide corresponding ethyl ester of formula 7-c.

The ester intermediate in turn is reacted with reducing agent such as sodium borohydride in a suitable solvent such as methanol or ethanol or tetrahydrofuran (THF) or mixture thereof, at a temperature ranging from 0°C to 35°C to e corresponding alcohol of formula 7-d.

The alcohol (7-d) is reacted with oxidizing agent such as artin inane or pyridiniumchlorochromate (PCC) or pyridiniumﬂuorochromate (PFC) in a suitable solvent such as dichloromethane or dichloroethane or chloroform or e thereof, at a temperature ranging from 25°C to 35°C to e ponding aldehyde derivative of a 7-e. The aldehyde (7-e) is reacted with methylmagnesiumiodide in a suitable solvent such as dichloromethane or dichloroethane or chloroform or tetrahydrofuran (THF) or mixture thereof, at a temperature ranging from 0°C to 10°C to provide corresponding alcohol (7-f).

Which is converted to corresponding bromomethyl derivative 7-g by reacting either with methanesulfonyl chloride in the presence of base such as triethylamine and isolating corresponding alkyl sulfonate and treating it with m bromide in e at reﬂux temperature or optionally, by ng with carbon tetrabromide along with nylphosphine in a suitable solvent such as tetrahydrofuran (THF) at a temperature ranging from 10°C to 35°C. _x 0 CI _ ‘XWOCJ'S —> \ ,OH 2HsO N R ; CH3 CH3 CH3 c—X /\ O —X /\ OH —X>_(/\\88r N ac N N 0’ N 0’ —*\N/ R 8i R E 8—_e X = CH or N R = H or BocNH— or OBn Scheme—8 2011/050464 As per scheme-8, ethynyl heteroaryl derivative of formula 8-a is reacted with hloro oxamidoacetate in the presence of organic base such as triethylamine in a suitable solvent such as toluene at a temperature ranging from 80°C to 110°C to provide corresponding ester (8-b). It is in turn reacted with magnesiumiodide in a suitable solvent such as dichloromethane or dichloroethane or chloroform or tetrahydrofuran (THF) or mixture thereof, at a temperature ranging from 0°C to 10°C to e corresponding ketone derivative (8-c). The ketone is reducued using sodium borohydride in a suitable solvent such as methanol or ethanol or tetrahydrofuran (THF) or mixture thereof, at a temperature ranging from 0°C to 35°C to provide corresponding alcohol derivative of formula 8-d.

The alcohol is converted to the corresponding mesylate tive using methanesulfonylchloride in the presence of organic base such as triethylamine, in a suitable solvent such as dichloromethane or dichloroethane or chloroform or tetrahydrofuran (THF) or mixture thereof, at a temperature ranging from 0°C to 15°C, which is then converted to corresponding heteroaryl-isoxazolyl bromide of formula 8-e by treating it with lithium bromide in a suitable solvent such as acetone; at a ature ranging from 45°C to 55°C. <:N>_[<OZ+NHNH Clj\n/<\_=N>_:C;j/£O —> Qefewfw Scheme—9 As per -9, 2-picolinic acid hydrazide (9-a) is reacted with pyruvic acid de in the presence of organic base such as triethylamine in dichloromethane at a temperature 0°C to 5°C for up to 3 hr. The reaction mixture is further treated with p-toluene sulfonyl chloride and is allowed to stir at t temperature for up to 16 hr to provide pyridine-1,3,4-oxadiazole compound 9-b. The compound 9-b, thus obtained, is d with reducing agent sodium borohydride in methanol or ethanol at a temperature 35°C to provide pyridine-1,3,4-oxadiazole ethanol (9-c). The compound 9-c is reacted with methanesulfonylchloride in the presence of triethylamine in dichloromethane at a temperature ranging from 0°C to 15°C to e corresponding esulfonyl ester of pyridinyl-1,3,4- oxadiazolyl-ethanol, which is converted to corresponding pyridine-1,3,4-oxadiazolyl ethyl 2011/050464 bromide (9-d) by treating sulfonyl ester with lithium bromide in acetone at reﬂux temperature.

OTBDMS TBDMSO N_ NH I 2004 —> H3C 2 .HCI + / '11 \ - H\:/>—CHON | H30 NH /N\ 10-b —a TBDMSO N_ TBDMSO N_ CI _| \ \ \ + ——SI— —> / —> O \ / \ N N‘ OH I HSC H30 N N” 1_—c O’Ii‘ N / CH HO N_ \ \ H\ \ ‘ ' ’ N / \ H30 N N’0 ('3 Ozszo 1 e 1_-f © Scheme—10 Chiral nosylate (lO-f) is synthesized ing to scheme 10. R enantiomer of amidine hydrochloride compound lO-a is reacted with vinamidium diperchlorate salt and s sodium hydroxide in acetonitrile at 25°C to 35°C temperature, to provide corresponding pyrimidine carbaldehyde compound lO-b. The compound lO-b is reacted with hydroxylamine hloride in presence of sodium carbonate in aqueous methanol at ambient ature to provide corresponding oxime, which is subsequently d with N- chlorosuccinamide in DMF at the same ature to provide corresponding amidate compound lO-c. The compound lO-c is stirred with triethylamine and trimethylsilyl acetylene in DMF and diethyl ether mixture at -10°C to 25°C to provide corresponding trimethylsilyl protected isoxazolyl-pyrimidine compound, which upon treatment with sodium carbonate in methanol at ambient temperature provided isoxazolyl-pyrimidinyl compound lO-d. The TBDMS group is removed by reacting lO-d with HF.pyridine reagent in acetonitrile at 25°C to 35°C to e compound lO-e with free hydroxyl function. The hydroxyl group is then protected by reaction of lO-e with p-nitrophenylsulfonylchloride in presence of triethylamine in dichloromethane at 0°C to 5°C temperature to yield corresponding p-nitrophenylsulfonyl ester compound lO-f.

H X = CH or N R = H or Boc—NH— or O—Bn Scheme—11 As per scheme-11, heteroaryl carboxylic acid alkyl ester of formula 11-a. is reacted with hydrazine hydrate in ethanol at a temperature ranging 40°C to 85°C to provide corresponding heteroaryl acid ide (1 1-b). The the hydrazide derivative is then d with mono ethyl ester of oxalyl chloride in the ce of triethylamine in dichloromethane or tetrahydrofuran at a temperature ranging from 5°C to 30°C after which the solvent is optionally changed to tetrahydrofuran and the on mixture is treated with Lawesson’s reagent at a temperature ranging from 40°C to 70°C to provide corresponding heteroaryl- 1,3,4-thiadiazolyl-carboxylic acid alkyl ester (1 1-c). It is then reacted with methylmagnesiumiodide in a suitable solvent such as dichloromethane or tetrahydrofuran (THF) or mixture thereof, preferably romethane at a temperature ranging from 0°C to °C to provide corresponding aryl-1,3,4-thiadiazolyl-ethanone (1 1-d). The ketone is reduced using sodium borohydride in ethanol or methanol at a temperature ranging from 0°C to 35°C to provide corresponding alcohol (ll-e). The alcohol (ll-e) is reacted with methanesulfonylchloride in the presence of triethylamine, in dichloromethane at a temperature ranging from -10°C to 40°C, preferably 0°C to 15°C to provide corresponding methanesulfonic acid ester of heteroaryl-1,3,4-thiadiazolyl l, which is converted to corresponding bromide (ll-f) by treating with lithium e in e, at a reﬂux temperature. _ S o’ﬁ —» \/ N 00 N NO2 Scheme—12 As per scheme-12, ethylbromobutyrate (12-a) is reacted with benzyl alcohol in presence of potassium hydroxide in DMF at 25°C to 35°C up to 3 hr to provide ethyl benzyloxybutyrate (12-b). Compound 12-b is treated with hydrazine hydrate in ethanol at reﬂux temperature to provide corresponding acid hydrazide compound 12—c. The compound 12-c is treated with 2-picolinic acid in the presence of ating agent EDC along With HOBt and N—methyl morpholine in DMF at a temperature 0°C to 30°C for 1 hr to provide uncyclized compound 12—d. The compound 12—d is further treated with Lawesson’s reagent in tetrahydrofuran at a reﬂux temperature for 4 hr to provide corresponding pyridinyl-l,3,4- thiadiazolyl compound 12-e. The nd 12-e is stirred with ribromide in dichloromethane at a temperature ranging from 0°C to 5°C for 1 hr followed by at 35°C for overnight, to provide ponding pyridinyl-1,3,4-thadiazolyl propanol nd 12-f.

The compound 12-f is d with p-nitrophenylsulfonyl chloride in the presence triethylamine in a dichloromethane at a temperature ranging from 0°C to 15°C to e corresponding p-nitrophenyl sulfonic acid ester compound 12—g.

O O O 1 -a 1 -b —13'° /N‘N —> S//.N —> S /N —> S / N / / \ / \ _ — 1-f _ 1 .6 1 -d — OTBDMS N 841 a? _ N’ 0 _q13- Scheme-13 As per scheme-13, O-isopropylidene methyl ester 13-a is reacted with hydrazine hydrate in methanol at 50°C to 55°C ature for overnight to provide corresponding acid hydrazide compound 13-b. The compound 13-b is d with 2-picolinic acid in the presence of dehydrating agent EDC along with HOBt and N—methyl morpholine in DMF at a temperature 0°C to 30°C for 16 hr to provide compound 13-c. It is further treated with on’s reagent in tetrahydrofuran at a 35°C temperature for 36 hr to provide corresponding pyridinyl- 1,3,4-thiadiazolyl compound l3-d.

The protected diol in turn is stirred with aqueous hydrochloric acid in acetone at 40°C ature for 6 hr, to provide corresponding pyridinyl-1,3,4-thiadiazolyl ethanediol compound l3-e. It is then reacted with TBDMS chloride in presence of triethylamine and DMAP in romethane at 0°C to 35°C for 24 hr to afford monoTBDMS protected compound l3-f, which is stirred with p-nitrophenylsulfonyl chloride in the presence triethylamine in a dichloromethane at a temperature ranging from 0°C to 5°C to provide corresponding p-nitrophenyl sulfonate ester compound 13-g.

— S OH S O / \ ,N _ éAc \ / \ —’ \ \ ,N / \ ,N OAc N N N N N N 1 —c 1 — - 1 —b CH3 CH3 ('3' CH3 0 s OH _ _ SW/‘xOﬂpCHS _ S O / \ _ \ N \N’N [\f \N’N \ / \ ,N OAc N N 1 -c 1 —d 14_-e Scheme—14 Enantiomerically pure mesylate (l4-e) is prepared by ﬁrst reacting racemic alcohol (14-a) with enantiomerically pure (S)-O-acetyl mandelic acid in the presence of dicyclohexylcarbodiimide and N,N—dimethylaminopyridine in dichloromethane at a temperature ranging -15°C to 5°C to provide mixture of diastereomers 14-b and 14-c.

This mixture of l4-b and l4-c is dissolved in methanol to provide clear solution and then cooled to 25°C to provide selective crystallization of one reomer 14-c as a white solid. The compound 14-c is hydrolyzed by treating it with aqueous sodium hydroxide or ium hydroxide in methanol at ature ranging from -15°C to 5°C to provide enantiomerically pure compound l4-d. The alcohol (l4-d) is then reacted with methanesulfonyl de in the presence of triethylamine in dichloromethane at a temperature ranging from -10°C to 5°C to e enantiomerically pure corresponding methanesulfonic acid ester compound 14-e.

OTBDMS H30 H3C OTBDMS IOTBDMS O N O N —* —> —> O O H O NH / NH2 N’ \ -a 15-b 15-C \ SO OH HC M 15—e 1_'f NO Scheme—1 5 As per scheme-15, commercially available D-Methyl lactate is ﬁrst protected with TBDMS-Cl, to provide a compound 15-a. and then reacted with hydrazine hydrate at reﬂux temperature in ethanol to provide corresponding acid hydrazide compound 15-b. The nd 15-b is coupled with 2-picolinic acid using dehydrating agent EDC in the presence of N—methyl morpholine and HOBt in a solvent such as DMF at 25°C to 35°C temperature to afford compound 15-c. The cyclization of compound 15-c is effected by reacting it with Lawesson’s reagent in THF at reﬂux temperature to provide pyridinyl-1,3,4-thiadiazole TBDMS ted compound 15-d. The TBDMS group in nd 15-d is removed by using 2 N aqueous hydrochloric acid in acetonitrile at temperature 25°C to 35°C to provide a nd 15-e. The compound 15-e is reacted with p-nitrophenylsulfonyl chloride in the presence triethylamine in dichloromethane at a temperature between 10°C to 25°C to provide R omer of ophenylsulfonic acid ester (nosylate) of pyridine-1,3,4-thiadiazole as compound 15-f.

OTBDMS <\: /_N 0 H30 OTBDMS N O \ o + I N N CI 0 H NH N NH2 NL) b \ 1 _a OTBDMS OH H30 H30 /N.

S ,N H30AFN S 0‘ ’0 —’ /N s —> N \ \N ¢S’ / N\ N I N’ N > N/ \ 16—b - Scheme—16 As per scheme-l6, pyrimidinecarbonylchloride (prepared from 2-cyanopyrimidine by using aqueous sodium hydroxide and subsequent treatment with lchloride in toluene) is reacted with R enantiomer of TBDMS protected ic acid hydrazide , in toluene at a temperature 10°C to 15°C for 1 hr to provide compound 16-a. The compound 16- a is cyclized by reacting with Lawesson’s reagent in THF at reﬂux temperature to provide TBDMS protected pyrimidinyl-1,3,4-thiadiazolyl compound l6-b. The TBDMS group is removed by using 2 N aqueous hydrochloric acid in acetonitrile at ature 25°C to 35°C to e a compound 16-c. which is reacted with p-nitrophenylsulfonyl chloride in the presence triethylamine in dichloromethane at a temperature between 0°C to 5°C to provide ly pure nitrophenylsulfonic acid ester (nosylate) of pyrimidine-1,3,4-thiadiazole as compound 16-d.

Scheme-17 As per -17, (11$,21R)- 3-decladinosyl-11,12-dideoxyO-methyl-2’-O- triethylsilyl- 12, l l- {oxycarbonyl- [E-(N—hydroxy)-carboxamidino]methylene} -erythromycin A (l7-a) is reacted with triethylbenzylammonium bromide (generated in situ by mixing benzyl bromide and triethylamine in tetrahydrofuran) in the presence of powdered potassium hydroxide tetrahydrofuran at a temperature ranging from 20°to 35°C, to provide corresponding benzyl ether amidoxime macrolide compound 17-b.

Alternatively, compound l7-b is prepared by reacting amidoxime macrolide l7-a With benzyl bromide in presence of base such as potassium e or potassium carbonate or potassium t-butoxide in presence of phase transfer catalyst such as l8-crownether in a solvent such as toluene or xylene or acetone or ethyl methyl ketone at a ature g from 200 C to 35°C Compound 17-b is oxidized under standard condition using either NCS and DMS oxidizing species (Kim Corey t) or with artin periodinane reagent, in a suitable solvent such as dichloromethane or dichloroethane or chloroform at a temperature ranging from -50°C to 10°C to provide a benzyl ether amidoxime ketolide compound 17-c. The compound 17-c is ﬂuorinated by reacting it with ﬂuorinating agent such as N- Fluorodibenzenesulfnimide (NFSI) or select-ﬂuor, in the presence of base such as lithium t- butoxide or sodium t-butoxide in a suitable solvent such as N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMAC) or tetrahydrofuran (THF), at a temperature ranging from -40°to 0°C to provide corresponding fluorinated de compound 17-d, which is further subjected to hydrogenolysis using 20% palladium hydroxide or 10% ium on carbon or a mixture f and in the presence of hydrogen source such as hydrogen gas under pressure in t such as methanol or l or ethyl acetate or mixture thereof at a temperature ranging from 20°C to 50°C to provide ﬂuorinated ketolide compound 17-e.

General rocedure for s nthesis of ketolides of invention: 18-b Z = Br or R-SOz-O- where R: methyl, nosyl; P and Q is as defined As per scheme-18, amidoxime compound of formula 18-a, is reacted with racemic or enantiomerically pure appropriate bromide, mesylate, tosylate or nosylate derivative of formula 18-b in the presence of suitable organic base such as potassium e or potassium tertbutoxide or inorganic base such as potassium hydroxide with phase transfer catalyst such as 18-crown-6 ether in a suitable solvent such as toluene at a temperature ranging from - 10°C to 50°C to provide ether derivative of formula 18-c.

It is then oxidized under Corey-Kim oxidizing ions (made from NCS and DMS) or with Dess-Martin periodinane reagent, in a suitable solvent such as dichloromethane or dichloroethane or chloroform, at a temperature ranging from -50°C to 10°C to provide a 2’- thylsilyl protected ketolide of formula 18-d.

It is in turn reacted with le silyl deprotecting agent such as pyridinehydrogenﬂuoride , tetrabutylammonium e, aqueous hydrochloric acid, in a le solvent such as acetonitrile or tetrahydrofuran or dioxane at a temperature ranging from 0°C to 40°C to provide ketolide derivative of Formula (18-e).

Optionally, ketolide of formula 18-e (when ring Q bears a substituent like Boc-NH) is treated with ne-hydrogenﬂuoride or triﬂuoro acetic acid in acetonitrile to e corresponding amino derivative.

Optionally, compound 18-e (when ring Q bears a substituent like OBn) is subjected to enolysis using palladium on carbon under hydrogen pressure in solvent such as methanol to provide corresponding hydroxyl derivative. 19-b 0 Z = Br or R-SOQ-O- where R: methyl, nosyl 19-b= R1: H; 19-b': R1 =CH3 P and Q = as defined Scheme-19 2011/050464 As per -19, amidoxime compound 19-a, is reacted with racemic or enantiomerically pure appropriate bromide, mesylate, tosylate or nosylate derivative of heteroaryl of formula 19-b in the presence of suitable organic base such as potassium hydride or potassium toxide or inorganic base such as potassium hydroxide with phase transfer catalyst such as wn-6 ether in a suitable t such as toluene at a temperature ranging from -10°C to 50°C to provide corresponding ether derivative of formula 19-c.

Which is then reacted with suitable silyl deprotecting agent such as pyridine- hydrogenﬂuoride, utylammonium ﬂuoride, aqueous hydrochloric acid, in a suitable solvent such as acetonitrile or tetrahydrofuran or dioxane at a temperature ranging from 0°C to 40°C to provide the 19-d.

Additionally, compound l9-d’ is prepared in a similar manner reacting l9-a with 19- b’ to provide 19-c’, followed by converting 19-c’ to 19-d’.

Optionally, compound l9-d or l9-d’ (when ring Q bear a substituent like Boc-NH or di-Boc-N) is treated with pyridine-hydrogenﬂuoride or triﬂuoro acetic acid in acetonitrile to provide corresponding amino derivative. ally, compound l9-d or l9-d’ (when ring Q bear a substituent like OBn) is subjected to hydrogenolysis using palladium on carbon under hydrogen pressure in solvent such as methanol to provide corresponding hydroxyl derivative.

EXPERIMENTAL Pre aration 1: 2- 5-Br0mometh l-isoxazol l - ridine Step- 1: Py_ridinimidoyl chloride To a mixture of ethyl din-aldoxime (15 gm) and N-chlorosuccinamide (25 gm) in DMF (30 ml) was stirred at 30°C over a period of 2 h. The reaction mixture was quenched with ice-cold water (150 ml). The suspension was ﬁltered and the wet cake washed with small quantity of water to provide pure title compound in 7 gm quantity (55%) as a white solid.

Mass: m/z: 157 (M+1) Ste -2: 2- 5-Ethox carbon azol l- idine: To a mixture of pyridinimidoyl chloride ( 15 gm), triethylamine (25 ml) in toluene (150 ml) was added ethyl propiolate (10 gm) stirred at 30°C over a period of 0.5 h. The reaction was monitored by TLC. The reaction mixture was quenched with water (100 ml).

The layers were separated. The organic layer was dried over sodium sulfate. It was ated under vacuum to provide a crude mass. Crude mass was puriﬁed by using silica gel column chromatography to provide title compound in 8.2 gm quantity (62%) as a .

The compound was characterized by proton NMR.

Hl-NMR ) 8: 1.39-1.42 (t, 3H), 4.41-4.46 (q, 2H), 7.34-7.37 (m, 1H), 7.55 (s, 1H), .82 (dt, 1H), 808-8.] (d, 1H), 8.67-8.68 (d, 1H).

Ste -3: 2- 5-H drox meth l-isoxazol l- idine: To a mixture of 2-(5-ethoxycarbonyl-isoxazolyl)-pyridine (6.5 gm), in ethanol (80 ml) was added sodium borohydride (2 gm) in lots at 30°C. It was stirred at 30°C over a period of 1.5 h. The reaction was monitored by TLC. Upon consumption of starting material, aqueous ammonium chloride solution was added. The mixture was extracted with ethyl e. Combined organic layers was washed with water and concentrated under vacuum to provide title nd in 7.7 gm ty. It was puriﬁed by using silica gel column chromatography to afford tile compound in 4.5 g (85%) quantity as off-white solid.

Hl-NMR (DMSO) 8: 4.61-4.63 (d, 2H), 5.68-5.71 (t, 1H), 6.86 (s, 1H), 7.46-7.49 (m, 1H), 7.90 —7.94 (m, 1H), 7.98-8.0 (d, 1H), .69 (d, 1H).

Ste -4: 2- 5-Methanesulfon lox eth l-isoxazol l- idine: To a mixture of 2-(5-hydroxymethyl-isoxazolyl)-pyridine (4.0 gm), and triethylamine (6.5 ml) in dichloromethane (40 ml) was added esulfonyl chloride (2.8 ml) at 0°C. The reaction mixture was stirred at 0°C over a period of 1 h. The reaction was quenched by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane (40 ml X 2). Combined organic layer was washed with aqueous sodium bicarbonate solution followed by water and evaporated under vacuum to provide the title compound in 5.1 gm quantity (84%) as a semisolid, which was used without puriﬁcation for the next reaction.

Ste -5: 2- 5-Bromometh l-isoxadiazol l- ridine: A mixture of 2-(5-methanesulfonyloxymethyl-isoxazolyl)-pyridine (5.0 gm), m bromide (3.4 gm) in acetone (50 ml) was stirred at reﬂux temperature over a period of 2 h. The reaction mixture was evaporated under vacuum to provide a crude mass, which was triturated with chilled water (50 ml) to provide a sion. The suspension was ﬁltered at suction to afford the title compound in 3.1 gm quantity (85%).

Mass: m/z: 255.1 (M+2).

Pre aration 2: 2- 3-Br0m0meth l-isoxazol-S- l - ne: Ste -1: 2- 3-Ethox carbon l-isoxazol l- imidine: To a mixture of 2-ethynyl-pyrimidine (28 gm) and hlorooxamidoacetate (45 gm) in toluene (340 ml) was added triethylamine (42 ml) at 90°C, and it was stirred for 0.5 h.

The reaction was monitored by TLC. Reaction was allowed to cool at 30°C and water was added. Organic layers were separated. Organic layer was evaporated under vacuum and the crude mass was triturated with ne. The suspension was ﬁltered and the wet cake washed with small quantity of n-hexane to e title compound in 35.1 gm quantity (59%) as a cream d solid.

Mass: m/z: 220.1 (M+1) Ste -2: 2- 3-H drox meth l-isoxazol l- imidine: To a mixture of 2-(3-ethoxycarbonyl-isoxazolyl)-pyrimidine (35 gm) in 2:1 v/v ethanol :THF mixture (525 ml) was added sodium borohydride (7.5 gm) in lots at 0°C. It was stirred at 30°C temperature over a period of 4 h. The reaction mixture was evaporated under vacuum to provide a residue and to the residue, (150 ml) was added. The suspension was extracted with ethyl e (4.5 ltr). Combined organic layers was washed with water and concentrated under vacuum to provide crude mass in 23 gm quantity, which was recrystallized from ethanol to provide the title compound in 15.1 gm quantity (53%) as pale yellow solid.

Mass: m/z: 178.1 (M+1) Ste -3: 2- 3-Methanesulfon lox eth l-isoxazol l- imidine: To a mixture of 2-(3-hydroxymethyl-isoxazolyl)-pyrimidine (14 gm) and triethylamine (22 ml) in dichloromethane (400 ml), was added methanesulfonyl chloride (7.2 ml) at 0°C. The reaction mixture was d at 0°C over a period of 0.5 h. The reaction was quenched by addition of water and layers were separated. Organic layer was evaporated under vacuum to e title compound in 19.7 gm quantity (97.7%) as a yellow solid. This was used as such for the next reaction.

Ste -4: 2- ometh l-isoxazol l- imidine: A e of 2-(3-methanesulfonyloxymethyl-isoxazolyl)-pyrimidine (19 gm), lithium bromide (13 gm) in acetone (190 ml) was stirred at 30°C temperature over a period of 2 h. The on was monitored by TLC. The reaction mixture was evaporated under vacuum to provide a crude mass which upon stirring with water (150 ml) provided suspension.

Filtration of suspension under suction afforded the title compound in 15.2 gm quantity (75.3%) as a solid.

Mass: m/z: 239.9 and 241.9 (M+1) Pre aration 3: 2- 5-Br0mometh l-1 3 4-thiadiazol l - ridine: Step- 1: Pﬂidincarboxylic acid hydrazide: A mixture of ethyl pyridincarboxylate (90 gm) and ine (60 gm) in ethanol (400 ml) was stirred at 80°C over a period of 4 h. Solvent was evaporated under vacuum to provide a crude mass. The crude mass was stirred with diethyl ether and the suspension was ﬁltered and the wet cake washed with small quantity of ethanol (50 ml) to provide title compound in 76 gm quantity (93%) as a white solid.

Mass: m/z: 138 (M+1).

Ste -2: 2- 5-Ethox carbon l-1 3 4-thiadiazol l - idine: To a mixture of pyridincarboxylic acid hydrazide (76 gm), triethylamine (155 ml) in dichloromethane (600 ml) was added mono ethyl oxalyl chloride (80 gm) over a period of 0.5 h at 0°C. The reaction mixture was d for 2 h. The reaction was quenched by addition of water (100 ml), layers were separated and organic layer was washed with aqueous sodiumbicarbonate solution (100 ml). Organic layer was evaporated in vacuum to provide crude mass in 110 gm quantity. To a crude mass in tetrahydrofurane (500 ml) was added Lowesson’s t (208 gm) and the mixture was stirred at 60°C over a period of 4 h.

Solvent was evaporated and the crude mass was triturated with dicholomethane ether mixture. The suspension was ﬁltered and the wet cake washed with small quantity of methanol (100 ml) to provide title compound in 45 gm quantity (35 % after 2 steps) as off white solid.

Hl-NMR (CDC13) 8: 1.37-1.38 (t, 3H), 4.30-4.38 (q, 2H), 7.51-7.54 (m, 1H), 7.89-7.92 (m, 1H), .28 (d, 1H), 8.59-8.60 (d, 1H). Mass: m/z: 236 (M+1).

Ste -3: 2- 5-H drox meth l-13 4-thiadiazol l- idine: To a mixture of 2-(5-ethoxycarbonyl-1,3,4-thiadiazolyl)-pyridine (8 gm) in ethanol (80 ml), was added sodium dride (2.51 gm) in lots at 30°C. It was stirred at 30°C over a period of 2 h. The solvent was ated under vacuum to e a crude mass. To the crude mass, water (100 ml) was added and it was ted with dichloromethane (200 ml X 2). Combined organic layers was washed with water and concentrated under vacuum to provide title compound in 6.1 gm quantity (92%).

Hl-NMR(CDC13) 8: 4.87-4.88 (d, 2H), 6.264- 6.26 (bs, 1H), .57 (m, 1H), 7.98-8.02 (m, 1H), 8.22-8.24 (d, 1H), 8.67 (d, 1H). Mass: m/z: 194 (M+1).

Ste -4: 2- 5-Methanesulfon lox eth l-13 4-thiadiazol l- idine: To a mixture of 2-(5-hydroxymethyl-1,3,4-thiadiazolyl)-pyridine (6 gm), and triethylamine (13.1 ml) in dichloromethane (150 ml) was added methanesulfonylchloride (5.31 gm) at 0°C. The reaction mixture was stirred at 0°C over a period of 1 h. The reaction was quenched by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane (50 ml X 2). Combined organic layer was washed with aqueous sodium bicarbonate solution ed by water and evaporated under vacuum to provide title compound in 7.5 gm quantity (88%) as oil.

Mass: m/z: 272 (M+1).

Ste -5: 2- 5-Bromometh l-1 3 diazol l - idine: A suspension of ethansulfonuloxymethyl-1,3,4-thiadiazolyl)-pyridine (7.5 gm), lithium bromide (3.84 gm) in acetone (75 ml) was stirred at reﬂux temperature over a period of 1 h. The reaction was monitored by TLC. The on mixture was evaporated under vacuum to provide a crude mass. Crude mass was d with ld water to provide a suspension. The solid was ﬁltered under suction to afford the title compound in 6.5 gm quantity (92%) as a light brownish solid.

Hl-NMR(CDC13) 8: 5.16 (s, 1H), 7.57-7.6 (m, 1H), 8.01-8.04 (m, 1H), 8.24-8.26 (d, 1H), 8.69-8.7 (d, 1H); Mass: m/z: 255 (M-1).

Preparation 4: 2-Bromomethyl-S-isoxazolyl-pyrimidine: Step- 1 : 2-Methylformyl-py_rimidine: To a mixture of vinamidium diperchlorate salt (310 gm, prepared as per procedure described in Collection Czechoslov Chem. Commun. Vol. 30, 1965) and acetamidine hydrochloride (106 gm) in trile (2.5 L) at 30°C was added w/v 50% aqueous sodium hydroxide (96.8 gm dissolved in 97 ml water) solution drop wise over a period of 2 h under stirring. The suspension was stirred for 3 h and pH of the reaction mixture was adjusted to 7 by addition of acetic acid (N 147 ml). The solid was filtered and washed with acetonitrile (750 ml). The ﬁltrate was evaporated under vacuum to provide a residue. The residue was stirred with water (750 ml) and the e was extracted with dichloromethane (300 ml X 5). The layers were separated and organic layer was evaporated to provide title compound in 52 gm quantity (52%) as a low g solid.

HINMR: (DMSO-d6) 8 11.08 (bs, 1H), 10.08 (s, 1H), 9.09 (s, 2H), 2.69 (s, 3H).

Step-2: 2-Methyl-pﬂimidinecarbaldehyde oxime: To a mixture of 2-methylformyl-pyrimidine (180 gm) and hydroxylamine hydrochloride (128 gm) in 50% v/v aqueous ol (3600 ml) was added sodium carbonate (94 gm). The reaction mixture was stirred at 30°C for 0.5 h. The resulting suspension was cooled and ﬁltered at -10°C to provide single isomer of title compound in 113.5 gm quantity (56%) as a solid.

HINMR: (DMSO-d6) 8 11.64 (s, 1H), 8.83 (s, 2H), 8.14 (s, 1H), 2.60 (s, 3H).

Further processing of the ﬁltrate such as evaporation and salt removal, provided a mixture of s in 51 gm quantity which can be used for the next reaction.

Ste -3: 2-Meth l 5-trimeth lsil leth l-isoxazol l- imidine: To a solution of 2-methyl-pyrimidinecarbaldehyde oxime (145 gm) in DMF (435 ml) was added N-chlorosuccinamide (169.6 gm) in portions at 30°C for 0.5 h. As the TLC indicated completion of the reaction, diethyl ether (1450 ml) was added. The reaction mixture was cooled to -5° to 0°C. To a cooled reaction mixture, was added triethylamine (589 ml) followed by trimethylsilylacetylene (450 ml). The mixture was stirred at -5°C for additional 1 h. The solid separated was d at suction. Filtrate was washed with water (300 ml X 4) followed by brine solution (500 ml) and organic layer was concentrated under vacuum to provide a solid in 158 gm quantity which was used as it is for further reaction.

Step-4: ylisoxazol-3 -yl-pﬂimidine: To a mixture of 2-methyl(5-trimethylsilylethynyl-isoxazolyl)-pyrimidine (158 gm) in methanol (1450 ml) was added sodiumbicarbonate (177 gm). The reaction mixture was stirred at 40°C up to 1 hr. The reaction mixture was ﬁltered. The solid obtained was washed with ethyl acetate and the e was ated under vacuum to e a residue.

The residue was d with water (800 ml) and extracted with dichloromethane (500 ml X 3). The layers were separated and the organic layer was evaporated to provide a e( 133 gm) which upon silica gel column tography afforded title compound in 79 gm quantity in 46.4% yield after three steps.

HINMR: (DMSO-d6) 8 9.15 (s, 2H), 9.09 (d, 1H), 7.27 (d, 1H), 2.67 (s, 3H); Mass: m/z: 162 (M+1). : 2-Bromomethylisoxazolyl-pyrimidine: A mixture of 2-methylisoxazolyl-pyrimidine (30 gm), N—bromosuccinamide (49.8 gm), and 98% benzoyl peroxide (13.54 gm) in carbon hloride (1200 ml) was heated to 75°C ature. The reaction mixture was stirred at 75°C for 24 h. The reaction mixture was ﬁltered under suction at 25°C to 35°C temperature. The solid was washed with carbon tetrachloride (400 ml). The ﬁltrate was washed with saturated aqueous sodium bicarbonate solution (400 ml X 2) and evaporated under vacuum to provide a crude material (52 gm) which upon silica gel column chromatography ed desired compound in 14 gm quantity (40%), o compound in 16.8 gm and starting material 6.5 gm ties.

HINMR: (DMSO-d6) 8 9.30 (s, 2H), 9.13 (s, 1H), 7.32 (d, 1H), 4.74 (s, 2H).

Pre aration 5: 2-di- tert-but 10x -carbon l-amino 2-bromometh l- ridin l- pyridine: Ste -1: 2-Di- tert-but lox -carbon l-aminotribut lstann l- idine: A solution of 2-bromoN,N—di-t-butyloxy-carbonyl-amino-pyridine (13 gm) in dimethoxyethane (260 ml) was added hexabutyldistannane (20.21 gm), followed palladium- tetrakis(triphenylphosphine) (2.01 gm) at 250 C, and the resulting mixture was degassed for min. The reaction mixture was heated under stirring at a temperature 800 C for 24 hours.

The reaction mixture was cooled to ambient temperature and ﬁltered through celite. The ﬁltrate was stirred with water (250 ml) and extracted with ethyl e (150 ml X 3). The combined organic extract was washed with water (100 ml X 2), dried over Na2S04. The evaporation of solvents under vacuum afforded titled product as an oil (17.8 gm) in 87 % yield, which was used as such for the next reaction.

Mass: m/z (M+H): 584.1 Ste -2: 2-Di- tert-but lox -carbon l-amino 2-form l- idin-6 1 - ridine: A suspension of 2-di-(tert-butyloxy-carbonyl)-aminotributylstannyl-pyridine (15.3 gm), 2-bromo-pyridinecarbaldehyde (7.0 gm), triethyl amine (10.60 gm), ium- tetrakis(triphenylphosphine) (1.51 gm) and lithium chloride (2.9 gm), in toluene (140 ml), was degassed for 0.5 hr at 25°C. The suspension was heated at reﬂux for 6 hours. The reaction mixture was cooled to ambient temperature and ﬁltered h celite. The ﬁltrate was stirred with water (250 ml) and extracted with ethyl acetate (100 ml X 2). The combined organic extracts was dried over Na2804, and evaporated under vacuum. The ing crude mass was puriﬁed by using silica gel column chromatography (ethyl acetate / hexane) to yield title nd in 2.0 gm quantity in 19.1 % yield.

Mass m/z (M+H): 400.1.

Ste -3:2-Di- tert-but lox -carbon l-amino 2-h drox -meth l- ridin l- idine: A solution of 2-di-(tert-butyloxy-carbonyl)-amino(2-formyl-pyridinyl)-pyridine (1.9 gm) in tetrahydrofuran: methanol mixture (1:1, 20 ml) was treated with sodium borohydride (200 mg) in portions at a temperature between 25°C to 35°C. As the TLC showed the complete consumption of ng material, it was concentrated under vacuum.

The crude mass was stirred with water (25 ml) and ted with ethyl acetate (50 ml X 2).

The combined organic extract was washed with saturated sodium bicarbonate solution (25 ml X 2) followed by brine solution (25 ml). The organic layer was dried over NaZSO4, and concentrated under vacuum to provide a crude mass. It was puriﬁed by using silica gel column chromatography (ethyl acetate / hexane) to afford the tile compound in 1.5 gm quantity in 79% yield.

Mass: m/z: (M+H)+: 402.1.

Ste -4: 2-Di- tert-but lox n l-amino anesulfon lox -meth l- ridin-6 1- pﬂidil’lei A solution of 2-di-(tert-butyloxy-carbonyl)-amino(2-hydroxy-methyl-pyridin yl)-pyridine (1.5 gm) and triethylamine (1.13 gm) in romethane (15 ml) was cooled to —50 C and treated with methanesulfonyl chloride (0.395 gm). As TLC showed completion of the reaction, to it was added water (10 ml) followed by romethane (50 ml). The organic layer was separated and washed with water (25 ml X 2), dried over Na2804, and concentrated under vacuum to provide title compound in 1.6 gm quantity in 90% yield, which was used as such for the next reaction.

Mass: m/z: (M+1): 480.1.

Ste -5: 2-Di- tert-but lox -carbon l-amino ometh l- idin l- idine: A suspension of 2-di-(tert-butyloxy-carbonyl)-amino(2-methanesulfonyloxymethyl-pyridinyl )-pyridine (1.6 gm) and m bromide (435 mg) in acetone (17 ml) was heated at a reﬂux temperature for 3 hours. As TLC showed completion of reaction, the reaction mixture was cooled to ambient temperature. The suspension was ﬁltered under suction and concentrated under vacuum. The obtained residue was stirred with water (25 ml) and extracted with ethyl acetate (30 ml X 2). The combined organic extracts was washed with saturated brine solution (25ml), and dried over NaZSO4. The organic layer was concentrated under vacuum to provide a crude mass, which was puriﬁed by using silica gel column chromatography (ethyl acetate / hexane) to provide title compound in 1.1 gm quantity in 70% yield.

Mass: m/z (M+H) : 465.2.

Pre aration 6: RS 5- l-Bromoeth l -is0xazol l - ridine Step- 1: Pﬂidinimidoyl chloride To a mixture of ncarbaldehyde-oxime (15 gm) and N-chlorosuccinamide (25 gm) in DMF (30 ml) was d at 300 C over a period of 2 h. The reaction e was quenched with ice cold water (150 ml). The sion was ﬁltered and the wet cake washed with small ty of water to provide pure title compound in 7 gm quantity (55%) as a white solid.

Mass: m/z: 157 (M+1) Ste -2: 2- 5-Ethox carbon l-isoxazol l- idine To a mixture of pyridinimidoyl chloride ( 15 gm), triethylamine (25 ml) in toluene (150 ml) was added ethyl late (10 gm) stirred at 300 C over a period of 0.5 h. The reaction was monitored by TLC. The reaction mixture was quenched with water (100 ml).

The layers were separated. The organic layer was dried over sodium sulfate. It was evaporated under vacuum to provide a crude mass. Crude mass was puriﬁed by silica gel column chromatography to provide title compound in 8.2 gm quantity (62%) as a liquid.

Hl-NMR ) 8: 1.39—1.42 (t, 3H), 4.41-4.46 (q, 2H), .37 (m, 1H), 7.55 (s, 1H), 7.78-7.82 (dt, 1H), 80881 (d, 1H), 8.67-8.68 (d, 1H).

Ste -3: 2- 5-H drox meth l-isoxazol l- idine To a mixture of thoxycarbonyl-isoxazolyl)-pyridine (6.5 gm), in ethanol (80 ml) was added sodium borohydride (2 gm) in lots at 30° C. It was stirred at 30° C over a period of 1.5 h. The reaction was monitored by TLC. Upon consumption of ethyl ester, aqueous ammonium chloride on was added. The mixture was extracted with ethyl acetate. Combined organic layers was washed with water and concentrated under vacuum to e title compound in 7.7 gm quantity. It was puriﬁed by silica gel column chromatography to afford tile compound in 4.5 g (85%) quantity as a off-white solid.

Hl-NMR (DMSO) 8: 4.61-4.63 (d, 2H), 5.68-5.71 (t, 1H), 6.86 (s, 1H), 7.46-7.49 (m, 1H), 7.90 —7.94 (m, 1H), 798—80 ((1, 1H), 8.68-8.69 (d, 1H).

Ste -4: 2- 5-form l-isoxazol l- ridine To a mixture of 2-(5-hydroxymethyl-isoxazolyl)-pyridine in dichloromethane (30 ml) was added Des-Martin periodanane reagent (15% solution in DCM, 51 ml) at 30° C. The reaction mixture was stirred at 30° C over a period of 0.5 h. The reaction was monitored by TLC. The reaction was quenched by addition of 1:1 sodiumthiosulfate and sodiumbicarbonate aqueous solution. The layers were ted. Aqueous layer was extracted with romethane. Combined organic layer was evaporated under vacuum to provide title aldehyde in 3 gm quantity (quantitative).

Hl-NMR (CDC13) 8: 7.61 (s, 1H), 7.66-7.7 (t, 1H), 7.98-8.1 (d, 1H), 868-87 ((1, 1H), 10.01 (s, 1H).

To a mixture of 2-(5-formyl-isoxazolyl)-pyridine (3 gm) in THF(30 ml) was added methyl magnesium iodide (19 ml, 1.4 M solution in THF) at 0° C over a period of 15 minutes. The reaction was stirred for 1.5 h and monitored by TLC. The reaction was quenched by addition of aqueous ammonium chloride solution (20 ml) and extracted with ethyl acetate (100 ml X 2). Combined organic layers was washed with water and evaporated under vacuum to provide 1.9 gm crude mass, which was puriﬁed by using silica gel column chromatography to provide a title compound in 1.0 gm quantity (42%) as a solid.

Hl-NMR(CDC13) 8: 1.62-1.64 (d, 3H), 3.14 (s, 1H), 5.04—5.07 (q, 1H), 6.86 (s, 1H), 7.33— 7.36 (m, 1H), 7.77-7.81 (dt, 1H), 8.03-8.05 (d, 1H), .68 (d, 1H).

Ste -6: RS 5- l-Bromoeth l-isoxazol l- ridine To a e of -(5-(1-hydroxy-ethyl)-isoxazolyl)-pyridine (0.9 gm), and nylphosphene (1.77 gm) in dichloromethane (20 ml) was added carbontetrabromide (6 gm) at 0° C. The reaction mixture was d at 30° C over a period of 2.5 h. The reaction was monitored by TLC. The reaction was quenched by addition of water and layers were separated. Combined organic extract was washed with brine and evaporated under vacuum to provide the 1.7 gm crude mass which was puriﬁed by using silica gel column chromatography to provide title compound in 0.8 gm quantity (65%).

Hl-NMR ) 8: 2.09-2.11 (d, 3H), 5.2-5.25 (q, 1H), 6.94 (s, 1H), 7.32-7.36 (m,1H), 7.76-7.81 (m, 1H), 8.05-8.08 (t, 1H), 8.66-8.67 (d, 1H); Mass : M+1 = 254.1.

Pre aration 7: RS 3- l-bromo-eth l -isoxazol l - rimidine Ste -1: 2- x carbon l-isoxazol l- imidine To a mixture of 2-ethynyl-pyrimidine (28 gm) and ethylchlorooxamidoacetate (45 gm) in toluene (340 ml) was added ylamine (42 ml) at 90° C, and it was stirred for 0.5 h. The on was monitored by TLC. Reaction was allowed to cool at 30° C and water added. Organic layer was separated. Solvent was evaporated under vacuum and the crude mass was triturated with n-hexane. The suspension was ﬁltered and the wet cake washed with small quantity of n-hexane to provide title compound in 35.1 gm ty (59%) as a cream colored solid.

Mass: m/z: 220.1 (M+1).

Ste -2: 2- 3- l-Oxo-eth l-isoxazol l- rimidine To a mixture of THF: e (6.5 ml: 5 ml) was added triethylamine (16.3 ml) followed by methyl magnesium iodide (28.6 ml, 1.4 M on in THF) at 0° C. To the reaction mixture, was added thoxycarbonyl-isoxazolyl)-pyrimidine (2.0 gm) dissolved in toluene (35 ml) in at 0° C over a period of 15 minutes. The reaction was stirred for 2 h.. It was quenched by addition of 1N aqueous hydrochloric acid (43 ml). It was extracted with toluene. ed organic layers was washed with saturated sodium bicarbonate solution followed by water. Organic layer was evaporated under vacuum to provide a crude mass which upon puriﬁcation by using silica gel column chromatography provided title compound in 1.2 gm quantity (70%) as solid.

HINMR: (DMSO-d6) 8 9.00 (d, 2H), 7.62 (t, 1H), 7.41 (s, 1H), 2.63 (S, 3H).

Ste -3: RS 3- l-H drox eth l-isoxazol l- imidine To a mixture of 2-(3-(1-oxo-ethyl)-isoxazolyl)-pyrimidine (1.2 gm) in methanol (20 ml) was added sodium dride (0.485 gm) in lots at 0° C. It was stirred at 30° C over a period of 2 h. The reaction mixture was evaporated under vacuum to provide a e. The residue was stirred with water and extracted with ethyl acetate (25 ml X3). Combined c layers was washed with aqueous sodium bicarbonate solution followed by water and concentrated under vacuum to provide title compound in 1.1 gm quantity (91%). It as used as t puriﬁcation for the next reaction.

Ste -4: RS 3- l-Bromoeth l-isoxazol l- rimidine A mixture of (RS)(3-(1-hydroxymethyl)-isoxazolyl)-pyrimidine (1.1 gm), in dichloromethane (20 ml) was added carbon tetrabromide (7.64 gm) followed by triphenylphosphine (1.8 gm) at 0° C. The reaction mixture was stirred at 0° C for 0.5 h and at ° C for 2 h. The reaction mixture evaporated under vacuum to provide a crude mass, which upon silica gel column chromatography afforded the title compound in 0.7 gm quantity (50%) as a solid.

HINMR: (DMSO-d6) 5 8.96 (d, 2H), 7.59 — 7.61 (t, 1H), 7.42 (s, 1H), 5.51 — 5.56 (q, 1H), 2.01 — 2.03 (d, 3H).

Pre aration 8: RS 5- l-Bromoeth l -1 3 4-thiadiazol l - ridine Step- 1: Pﬂidincarboxylic acid hydrazide A mixture of ethyl pyridincarboxylate (90 gm) and hydrazine (60 gm) in ethanol (400 ml) was stirred at 80° C over a period of 4 h. Solvent was evaporated and to provide a crude mass. The mass was stirred with diethyl ether and the suspension was ﬁltered and the wet cake washed with small quantity of ethanol (50 ml) to provide title compound in 76 gm quantity (93%) as a white solid.

Mass: m/z: 138 (M+1).

Ste -2: 2- 5-Ethox carbon l-1 3 4-thiadiazol l - idine To a mixture of pyridincarboxylic acid hydrazide (76 gm), triethylamine (155 ml) in dichloromethane (600 ml) was added mono ethyl oxalyl chloride (80 gm) over a period of 0.5 h at 0° C. The reaction mixture was stirred for 2 h. The reaction was monitored by TLC.

The reaction was quenched by addition of water (100 ml), layers were separated and c layer was washed with aqueous sodiumbicarbonate solution (100 ml). Organic layer was evaporated in vacuum to provide crude mass in 110 gm quantity. To a crude mass in tetrahydrofuran (500 ml) was added Lowesson’s reagent (208 gm) and the e was stirred at 60° C over a period of 4 h. Solvent was evaporated and the crude mass was triturated with omethane ether mixture. The suspension was ﬁltered and the wet cake washed with small ty of methanol (100 ml) to provide title compound in 45 gm quantity (35 % after 2 steps) as off white solid.

Hl-NMR (CDC13) 8: 1.37-1.38 (t, 3H), 4.30-4.38 (q, 2H), 7.51-7.54 (m, 1H), 7.89-7.92 (m, 1H), 8.26-8.28 (d, 1H), 8.59-8.60 (d, 1H). Mass: m/z: 236 (M+1).

Ste -3: 2- 5- l-Oxo-eth l -1 3 4-thiadiazol l - idine To a mixture of 2-(5-ethoxycarbonyl-1,3,4-thiadiazolyl)-pyridine (2 gm) in THF(40 ml) was added methyl magnesium iodide (15 ml, 1.4 M on in THF) at -40° C over a period of 15 s. The on mixture was stirred for 2 h at -40° C. It was WO 76989 ed by addition of aqueous ammonium chloride solution (20 gm) and stirred at 0° C over a period of 10 minutes. It was extracted with ethyl acetate (100 ml X 2). Combined organic layers was washed with water and evaporated under vacuum to provide a title compound in 1.5 gm ty (86%) as off white solid.

Hl-NMR (CDCl3) 8: 2.84(s, 3H), 7.25-7.46(m, 1H), .9 (m, 1H), 8.39-8.41 (d, 1H), 8.67-8.68 (d, 1H); Mass: m/z: 206 (M+1).

Ste -4: RS 5- l-H drox eth l-l 3 4-thiadiazol l- idine To a e of 2-[5-(1-oxo-ethyl)-l,3,4-thiadiazolyl]-pyridine (1.5 gm), in methanol (25 ml) was added sodium borohydride (0.2 gm) in lots at 300 C. It was stirred over a period of 2 h. The reaction was monitored by TLC. Solvent was evaporated under vacuum and water (20 ml) was added. The mixture was extracted with ethyl acetate (100 ml X 2).

Combined organic layers was washed with water and concentrated under vacuum to provide title compound in 1.0 gm quantity (67%). It as used as without puriﬁcation for the next reaction.

Mass: m/z: 208 (M+1).

Ste -5: RS 5- l-Methanesulfon lox -eth l-l 3 4-thiadiazol l- idine To a e of (RS)(5-(l-hydroxy-ethyl)-l,3,4-thiadiazolyl)-pyridine (1.0 gm), and ylamine (2 ml) in dichloromethane (50 ml) was added methanesulfonyl chloride (0.9 gm) at -10°C. The reaction mixture was stirred over a period of l h. The reaction was quenched by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane. Combined organic layer was washed with aqueous sodium bicarbonate followed by water and evaporated under vacuum to provide the title compound in 1.0 gm quantity (73%) as an oil.

Mass: m/z: 286 (M+1).

Ste -6: RS 5- l-Bromoeth l -l 3 4-thiadiazol l - idine A mixture of (RS)[5-(l-methanesulfonyloxy-ethyl)-l,3,4-thiadiazolyl]-pyridine (1.0 gm), lithium e (0.5 gm) in acetone (20 ml) was stirred at reﬂux over a period of l h. The reaction mixture was evaporated under vacuum to provide a crude mass. Crude mass was stirred with ice cold water and extracted with dichloromethane (50 ml X 2). The 2011/050464 combined c layer was evaporated under vacuum to afford the title compound in 0.8 gm quantity (85%) as oil.

Hl-NMR ) 8: 2.2 (d, 2H), 5.51-5.57 (q, 1H), 7.38-7.41 (m, 1H), 7.83-7.87 (m, 1H), 8.32-8.34 (d, 1H), 8.63-8.64 (d, 1H); Mass: m/z: 272 (M+2).

Pre aration 9: R 5- l-Methanesulfon lox -eth l -1 3 diazol l - ridine Ste -1: R 5- l-H drox -eth l-13 4-thiadiazol l- ridine To a mixture of (RS)(5-(1-hydroxy-ethyl)-1,3,4-thiadiazolyl)-pyridine (7.5 gm), and N,N-dimethyl aminopyridine (0.5 gm) and in was added (R)-O-acetyl-mandelic acid (7.1 gm) dichloromethane (150 ml) at -10°C was added a on of dicyclohexylcarbodimide (11.19 gm) in dichloromethane (25 ml). The reaction mixture was stirred over a period of 1 h.

The reaction mixture was ﬁltered under suction and the ﬁltrate was evaporated under vacuum to provide a residue which was puriﬁed by silica gel column chromatography to provide a mixture oftwo diastereomers in 10.0 gm quantity as a semi-solid.

HPLC ratio of diastereomer 2 : diastereomer 1: 42.46:42.11. Mass: m/z: 384 (M+1) The mixture of two diastereomers (10 gm) obtained as above was stirred in ol (25 ml) to provide a clear solution. The reaction mixture was allowed stir at 25° C for 0.5 h to e precipitation. The solid was ﬁltered at suction and the wet cake was washed with methanol (5 ml). The wet solid (5 gm) was suspended in methanol (15 ml). It was stirred for 0.5 h and ﬁltered under suction to provide a solid. The solid was dried to provide diastereomer-2 in 3.8 gm ty as a solid. Filtrate was enriched with diastereomer-1.

HPLC ratio of reomer-2: diastereomer-1 as a solid: 99.5: 0.5 Mass: m/z: 384 (M+1). NMR (CDC13) 8: 1.79-1.81 (d, 3H), 2.23 (s, 3H), 5.96 (s, 1H), 6.29- 6.33 (q, 1H), 7.55-7.58 (m, 1H), 7.76-7.80 (m, 1H), 7.91 — 7.93 (d, 1H), 8.01-8.04 (d, 1H).

HPLC ratio of diastereomer-2: diastereomer-1 (from ﬁltrate): 21.23: 56.35 Mass: m/z: 384 (M+1).

Chirally pure diastereomer-2 was obtained as above (3.8 gm) was ved in methanol (40 ml) and to the reaction mixture was added KOH (1.1 gm dissolved in 4 ml water) at -5° C. The reaction mixture was stirred at -5° C for 2 h. Solvent was evaporated. pH of reaction mixture was adjusted between 4 to 5 using 2N aqueous hydrochloric acid. It was extracted with dichloromethane (100 ml X 2). Combined organic layer was washed with saturated sodium bicarbonate solution. Layers were ted and evaporated under vacuum to provide chirally pure R enantiomer in 2.1 gm with chiral purity 99.11 by HPLC.

NMR(CDC13) 8: 142-16 (d, 3 H), 5.19-5.24 (q, 1H), .48 (m, 1 H), 7.86-7.91 (m, 1 H), 8.13-8.15 (d, 1 H), 8.54 (bs, 1 H), 8.77 - 8.78 (d, 1 H). Mass: m/z: 208 (M+1). [oc]D 25 = +1533O (c 0.5, CHC13).

Ste -2: R 5-Methanesulfon lox eth l-13 4-thiadiazol l- idine To a mixture of (R)[5-(1-hydroxy-ethyl)-1,3,4-thiadiazolyl]-pyridine (2.0 gm), and triethylamine (4.18 ml) in dichloromethane (100 ml) was added methanesulfonylchloride (1.6 gm) at -100 C. The reaction mixture was stirred at -100 C over a period of 1 h. The reaction was quenched by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane. Combined organic layer was washed with aqueous sodium bicarbonate solution ed by water and evaporated under vacuum to provide title compound in 2.4 gm quantity (87%) with chiral purity 98.66% by HPLC.

Mass: m/z: 286 (M+1) Pre aration 10: R 5- 1-n0s 10x -eth l-1 34-thiadiazol l- ridine from methyl-D-lacate Ste -1: Pre aration of R tert-bu l-dimeth lsil lox - ro ionic acidh drazide A mixture of R(tert-butyl-dimethylsilyloxy)-propionic acid methyl ester (417 gm) and hydrazine (144 gm) in ethanol (400 ml) was d at 80° C over a period of 4 h. Solvent was evaporated and to provide a crude mass. The crude mass was stirred with water (150 ml) and extracted with ethyl acetate (800 ml X 2). The organic layer was dried on sodium sulfate and ated under vacuum to provide title compound in 417 gm quantity in quantitative yield as a liquid.

Mass: m/z: (M+1). 219.2, Purity by GC: 76.48% (RT-14.14) Ste -2: Pre aration of R- 2-carbox lic acid N'- 2- tert-bu l-dimeth lsil lox - propionyl -hydrazide To a mixture of linic acid (258 gm), R(tert—butyl-dimethylsilyloxy)- nic acid hydrazide (415 gm) in DMF (1000 ml) was added EDC hydrochloride (546 gm) followed by yl morpholine (418 ml) over a period of 0.5 h at 0° C to 5 ° C. HOBt (29 gm) was added in one lot. onal DMF (245 ml) was added. The resulting suspension was stirred for 2 hr at 25° C. The reaction mixture was poured under stirring in water (7000 ml), and extracted with ethyl acetate (4000 ml X 2). Combined organic layer was dried over sodium sulfate and concentrated in vacuum to provide syrup as a title compound in 602 gm ty in 98% yield.

Mass (m/z) (M+1): 325.2.

Ste -3: Pre aration of R 5- 1- tert-but l-dimeth lsil lox -eth l-1 3 4-thiadiazol l - pﬂidil’le To a mixture of R-pyridinecarboxylic acid N'-[2-(tert—butyl-dimethylsilyloxy)- propionyl]-hydrazide (600 gm) and Lawesson’s reagent (448 gm) in THF (1800 ml) was reﬂuxed for 16 hr under stirring. The reaction mixture was cooled to 25° C and poured in aqueous sodiumbicarbonate solution (prepared from sodiumbicarbonate 366 gm and water 3000 ml) under stirring. The mixture was ted with ethyl acetate (2000 ml X 2). The combined c layer was washed with water (2000 ml) and dried over sodium sulfate.

Organic layer was evaporated under vacuum to provide title compound in 570 gm quantity in 95.3% yield as a syrup.

Mass (m/z) (M+1): 322.2, Purity by GC: 89.68 % (RT 28.80) Ste -4: Pre aration of R-l- 5- idin l- 1 3 4 azol 1 -ethanol To a mixture of R {5-[1-(tert-butyl-dimethylsilyloxy)-ethyl]-1,3,4-thiadiazolyl}- pyridine_(568 gm), in acetonitrile (1800 ml) was added 2N aqueous hydrochloric acid (1800 ml) in one lot under stirring at 32° C. It was stirred over a period of 19 hr. The reaction e was poured in s sodium carbonate solution (prepared by dissolving 560 gm of sodium carbonate in 1800 ml water) under stirring. The organic layer was separated. Aqueous layer was extracted with ethyl acetate (1000 ml X 2). Combined c layer was dried over sodium sulfate and concentrated to afford semisolid in 400 gm quantity, which was puriﬁed by stirring in ethyl acetate (400 ml) and ﬁltering resultant suspension, to provide title compound in 230 gm quantity in 63% yield as a solid.

Mass: m/z: 208 (M+1), Chemical purity: 99.83% (RT 14.82).

Ste -5: Pre aration of R 1-nos lox eth 1-1 3 4-thiadiazol l- idine To a mixture of R(5-pyridin—2-yl-[1,3,4]thiadiazolyl)-ethanol (228 gm), and triethylamine (230 ml) in dichloromethane (2000 ml) was added a solution of p- nitrophenylsulfonyl chloride (246 gm) dissolved in dichloromethane (500 ml) at 10°C under ng. The reaction mixture was stirred over a period of 2 h at 25° C. To the resulting yellow suspension, was added water (2000 ml) and dichloromethane (1000 ml) under stirring.

The layers were ted and dried over sodium sulfate to provide a brown coloured solid in 514 gm quantity. The solid was stirred in a mixture of romethane (250 ml) and diethyl ether (500 ml) at 30° C. The suspension was d atsuction and washed with a mixture of dichloromethane:diethyl ether e (1:2 ratio, 300 ml). the solid was dried under vacuum to provide title compound in 410 gm ty in 95% yield as a pale yellow solid.

Mass: m/z: (M+1) 393.0, Chemical Purity = 97.67%, Chiral Purity = 99.97%, [a]D25= +135.79 (c = 0.5% in acetonitrile) Preparation 11: 12 11- ox carbon 1- E- N-h drox -carboxamidin0 meth lene -er throm cinA: To a solution of triethylamine (4.5 ml) in THF (170 ml) was added benzyl bromide (3.1 ml) via syringe at 30°C. It was stirred for 4 hours to provide a suspension. To the suspension was added (11S,21R)- 3-decladinosyl-11,12-dideoxyO-methyl-2’-O- triethylsilyl- 12, 1 1- {oxycarbonyl-[E-(N-hydroxy)-carboxamidino]methylene} -erythromycin A (17 g) as in one lot, ed by freshly powdered potassium hydroxide (1.57 g) in one lot.

The reaction mixture was d for 3.5 h at 30° C. After TLC check the reaction was ﬁltered under suction to remove salts. The ﬁltrate was concentrated to complete dryness under vacuum below 45° C to provide a 19 gm powder. It was stirred with chilled water (180 ml) for 5 h to provide a suspension. The solid was ﬁltered at suction and air dried to provide title compound in 17.8 gm (93.8%) quantity as a light yellow solid (HPLC purity 96.62%).

MS: m/z = 876.2 (M+1) Ste -2: Pre n of 11S21R decladinos l-11 12-dideox O-meth loxo-2’-O- trieth lsil l-12 11- ox carbon 1- E- -ben lox -carboxamidino meth lene -e hrom cin To the stirred solution of N—chlorosuccinimide (7.5 gm) in dichloromethane (75 ml) was added dimethyl sulﬁde (4.8 ml) at -150 C. The reaction mixture was stirred at -150 C for 1 h. The step-1 product (17 gm) dissolved in dichloromethane (35 ml) was added to the reaction mixture at -400 C. The resulting on mixture was stirred at -40°C temperature for 3 hr. Triethyl amine (6.8 ml) was added and stirred for overnight at 300 C. The reaction mixture diluted with ethyl acetate (220 ml) and washed with 0.5M aqueous sodium hydroxide solution (100 ml). The organic layer was separated and washed with brine solution. The c layer was concentrated under vacuum to s to e a 14 gm powder. The powder was stirred with chilled water (140 ml) for 5 h to provide a suspension. The suspension was ﬁltered and was air dried to provide 14 gm pale yellow . The powder was stirred in methanol (42 ml) and ﬁltered to e 11.2 gm (66%) title compound as a white solid (HPLC purity 97.3%).

MS = (m/z) = 874.2 (M+1) Ste -3: Pre n of 11S 21R decladinos l-11 12-dideox ﬁuoroO-meth loxo- 2’-O-trieth lsil l ox carbon 1- E- -ben lox -carboxamidino meth lene - erﬂhromycin A To a solution of step-2 t (11 gm) in DMF (110 ml) was added lithium tert- butoxide (1.51 gm) as a solid in lots over a period of 30 minutes at -15°C. N- Fluorodibenzenesulﬁiimide (NFSI, 4.19 gm) dissolved in DMF (40 ml) over a period of 30 minutes at -15°C. The reaction e was stirred for 0.5 h at -150 C. To the reaction mixture was added aqueous ammonium chloride solution (13 gm in 750 ml water) under stirring. The suspension was stirred for 0.5 h and was ﬁltered at suction. The solid was dissolved in ethyl acetate (200 ml) and was washed with 0.5 M aqueous sodium hydroxide solution (50 ml). The organic layer separated and evaporated under vacuum to dryness to provide title compound as a solid in 10.3 gm (91.8%) quantity (HPLC purity 90.12%).

MS: m/z = 892.2 (M+1) Ste -4: Pre aration of 11S 21R decladinos l-11 12-dideox fluoroO-meth loxo- 2’-O-trieth lsil l ox carbon 1- E- -h drox -carboxamidino meth lene - erﬂhromycin A To a solution of step-3 product (9 gm) in 1:1 mixture of methanol: ethyl acetate mixture (180 ml) was added a mixture of 10% Pd on carbon (1.35 gm) and 20% Pd(OH)2 (1.35 gm). The reaction mixture was subjected to hydrogenolysis in shaker at 70 psi hydrogen pressure for 48 h. As the TLC showed completion of reaction, it was ﬁltered at suction over a bed of celite. The ﬁltrate was evaporated under vacuum to s to provide 6.7 gm solid, which was stirred with ane (120 ml) and ﬁltered to provide title compound in 5.8 gm quantity (71.6%) as a white solid (HPLC purity 90.39%).

MS: m/z = 802.1 (M+1) General rocedure for the re aration of com ounds of formula I wherein R is H F13 = H; O T is as defined (1 18,21R)- adinosyl-1 1, 1 2-dideoxyO-methyl-2’-O-triethylsilyl- 12,1 1- {oxycarbonyl-[E-(N—hydroxy)-carboxamidino]methylene}-erythromycin A in toluene is reacted in the presence of base such as potassium hydride or potassium toxide and a phase transfer catalyst 18-crown-6 ether, with racemic or enantiomerically pure appropriate side chain of formula Z-C*H(R1)-P-Q where Z is e, or appropriate ester such as te, tosylate or nosylate and R1, P and Q are as described, at a temperature ranging from ° C to 35° C to provide ponding etheriﬁed nd as (11S,21R)- 3-decladinosyl- 1 1,12-dideoxyO-methyl-2’-O-triethylsilyl- 12,1 1- {oxycarbonyl-[E-(N—heteroaryl- heteroaryl-(RS) or (R) or (S)-alkoxy)-carboxamidino]methylene}-erythromycin-A.

The compound (1 18,21R)- 3-decladinosyl-1 1,12-dideoxyO-methyl-2’-O- triethylsilyl-12,11-{oxycarbonyl-[E-(N—heteroaryl-heteroaryl-(RS) or (R) or (S)-alkoxy)- carboxamidino]methylene}-erythromycin-A is oxidized by treating under standard condition using either Corey-Kim oxidizing species (made from NCS and DMS) in dichloromethane at a temperature ranging from -50° C to 10° C to provide ponding oxidized compound as (1 1 S,21R)- 3-decladinosyl-1 1,12-dideoxyO-methyloxo-2’-O-triethylsilyl-12, 1 1- {oxycarbonyl- heteroaryl-heteroaryl-(RS) or (R) or (S)-alkoxy)- carboxamidino]methylene} -erythromycin-A.

The compound (11$,21R)- 3-decladinosyl-11,12-dideoxyO-methyloxo-2’-O- triethylsilyl-12,11-{oxycarbonyl-[E-(N—heteroaryl-heteroaryl-(RS) or (R) or (S)-alkoxy)- amidino]methylene}-erythromycin-A is reacted with silyl deprotecting agent such as pyridine-hydrogenﬂuoride, or aqueous hydrochloric acid, in acetonitrile at a temperature ranging from 20° C to 35 ° C to e the ketolide compound of formula (I) where R3 is H.

For the compounds of formula (I) ed as above, where Q bears a substituent such as t-butoxycarbonylamino, the t-butoxycarbonyl group was deprotected by stirring it with triﬂuoroacetic acid in acetonitrile at 0° C to 35° C for 1 hr followed by puriﬁcation to provide de compound of formula (I).

For the compounds of formula (I) obtained as above, where Q bears a substituent such as O-benzyloxy, the benzyl group was deprotected by stirring it with 10% palladium on carbon under hydrogen pressure in methanol at 25° C to 35° C followed by puriﬁcation to provide ketolide compound of formula (I). l re for the re aration of com ounds of formula I wherein R is F Fl3 = F; O T is as defined (1 IS,2lR)- 3-decladinosyl-1 1,12-dideoxyﬂuoroO-methyloxo-2’-O- triethylsilyl- 12, 1 1- {oxycarbonyl- [E-(N—hydroxy)-carboxamidino]methylene} -erythromycin A in toluene is reacted in the ce of suitable base such as potassium hydride or potassium tertbutoxide and a phase transfer st 18-crown-6 ether, with racemic or enantiomerically pure appropriate side chain of formula Z-C*H(R1)-P-Q where Z is mesylate or nosylate ester and R1, P and Q are as described, at a temperature ranging from ° C to 35° C to provide corresponding etherifled compound as (11$,21R)- 3-decladinosyl- 1 1,12-dideoxyﬁuoroO-methyl-3 -oxo-2’-O-triethylsilyl- 12,1 1- rbonyl-[E-(N— heteroaryl-heteroaryl-(RS) or (R) or (S)-alkoxy)-carboxamidino]methylene}-erythromycin-A.

The compound 1R)- 3-decladinosyl-11,12-dideoxyﬁuoroO-methyl -O-triethylsilyl-12,11-{oxycarbonyl-[E-(N—heteroaryl-heteroaryl-(RS) or (R) or (S)- alkoxy)-carboxamidino]methylene}-erythromycin-A is reacted with silyl deprotecting agent such as pyridine-hydrogenﬂuoride or s hydrochloric acid, in acetonitrile at a ature ranging from 20° C to 35° C to provide the ketolide compound of formula (I) where R3 is F.

For the compounds of formula (I) obtained as above, where Q bears a substituent such as t-butoxycarbonylamino, the t-butoxycarbonyl group was deprotected by stirring it with triﬂuoroacetic acid in acetonitrile at 0° C to 35° C for 1 hr followed by puriﬁcation to provide ketolide compound of formula (I).

For the compounds of Formula (I) obtained as above, where Q bears a substituent such as O-benzyloxy, the benzyl group was deprotected by stirring it with 10% palladium on carbon under hydrogen pressure in methanol at 25° C to 35° C followed by puriﬁcation to provide ketolide compound of formula (I).

EXAMPLES The following examples illustrate the ments of the invention that are presently best known. r, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modiﬁcations and ative compositions, methods, and s may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modiﬁcations and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

Example 1: 118 21R Decladinos l-11 12-dideox fluoroO-meth loxo-12 11- 0x carbon 1- E-N- 5- rimidin l-isoxazol l-methox -carboxamidino methylene {-erythromycin A: Ste -1: Pre aration of 118 21R decladinos 1-11 eox oroO-meth loxo- 2’-O-trieth lsil 1 ox carbon 1- E-N— 5- imidin—2- l-isoxazol l-methox - carboxamidino methylene k -emhromycin A: To the d suspension of potassium hydride (1.46 gm, 30% suspension in mineral oil), followed by 18-crownether (0.660 gm) ) in toluene (300 ml) was added (11$,21R) decladinosyl-l 1,12-dideoxyﬂuoroO-methyloxo-2’ -O-triethylsilyl-12,1 1- {oxycarbonyl-[E-(N—hydroxy)-carboxamidino]methylene}-erythromycin A (8 g) at 30°C. It was d for 5 minutes. To the on mixture, 2-(3-bromomethyl-isoxazolyl)- pyrimidine (2.9 gm) was added. The reaction mixture was d for 30 minutes. It was quenched by pouring it in aqueous saturated ammonium chloride on (50 ml) under stirring. The mixture was extracted with ethyl acetate (250 ml X 2). Combined organic layer was dried over Na2804 and evaporated under vacuum to provide a crude mass, which was puriﬁed by using silica gel column chromatography (12% to 15 % acetone in hexane) to provide title compound as step-1 product in 5 gm quantity in 53% yield as a off white solid.

MS: m/z: 961.4 (M+1) Ste -2: Pre aration of 118 21R decladinos 1-11 12-dideox ﬂuoroO-meth loxo-- 1211- ox carbon 1- E-N— 5- imidin l-isoxazol l-methox -carboxamidino methylene f-emthromycin A: A mixture of (118,21R)decladinosyl-11,12-dideoxyﬂuoroO-methyloxo- 2 ’ -O-triethylsilyl-12,1 1- {oxycarbonyl- [E-N—(5-pyrimidin—2-yl-isoxazol-3 -yl)-methoxy] - amidino] methylene}-erythromycin A (5 gm) obtained as above in step-1, and 70% HF-pyridine solution (0.225 ml) in acetonitrile (50 ml) was stirred at 30°C for 2 hr under N2 here. After tion of reaction, reaction was quenched with addition of aqueous sodium bicarbonate solution (50 ml). The mixture was evaporated under vacuum to half of the volume, and water (20 ml) was added to the residue to provide a suspension which was ﬁltered under suction. The solid was washed with water, followed by ether to afford title nd of example-1 in 3.1 gm quantity as a white solid in 71% yield.

MS: m/z: 847.1 (M+1) ing examples were prepared by using the procedure described in Example-1 as above and utilizing the respective side chains as shown: Formula 1 Side chain used for coupling 2-(5-Bromomethyl- 156-158 isoxazol-3 -yl)-pyrimidine 3 -(2-Bromomethyl- 196- 197 pyrimidinyl)-isoxazole 2-tert- Butyloxycarbonylamino 215-217 6- (3 -bromomethyl- isoxazol-S-yl)-pyridine 2-(3 methyl- 193-194 ol-S-yl)-pyridine 2-tert- butyloxycarbonylamino- 230-232 6-(5-Bromomethyl-1,3 ,4- thiadiazolyl)-pyridine 2-(5-Bromomethyl-1,3 ,4- thiadiazolyl)- 192- 194 pyrimidine 2-(5-Br0m0methyl- 1,3 ,4- 223-225 thiadiazol-2—y1)-pyrazine xycarbonylamino- 202-204 -(5-br0m0methy1—1,3 ,4- thiadiazoly1)-pyridine 2-(5-Br0m0methyl- 1,3 ,4- 207-210 thiadiazoly1)-pyridine 2-(3 -Br0m0methy1— 196- 197 isoxazol-S-y1)-pyrazine 2-tert- Butyloxycarbonylamino- 178-180 -(5-br0m0methy1—1,3 ,4- azol-2—y1)-pyrazine 6-tert-Buty10xy carbonylamino-Z- [5 - bromomethy1-1,3 ,4- 210-214 thiadiazol-Z-yl] - pyrimidine 2-(2-Br0m0methyl- 169-171 pyrimidin-S-y1)-pyrazine 3 -tert-buty10xy carbonylamino(5 - 180-185 bromomethy1-1,3 ,4- thiadiazol-Z-y1)-benzene 2-di-(tert-buty10xy carbony1)-amin0(2- 150-152 bromomethyl-pyridin y1)-pyridine. 6-tert-buty10xy ylamino-Z-(3- - 862.1 ethyl-isoxazol-5 - yl)-pyrimidine.

Example 18: erythromycin A Ste -1: Pre aration of 118 21R decladinos l-11 12-dideox fluoroO-meth loxo- 2’-O-trieth lsil l-12 11- ox carbon 1- E-N— 1- 5- idin l-1 3 4-thiadiazol l - S - ethoxy -carboxamidino methyleneE-erﬂhromycin A To the stirred solution of (118,21R)decladinosyl-11,12-dideoxyﬂuoroO- methyloxo-2’-O-triethylsilyl-12,1 1- {oxycarbonyl-[E-(N—hydroxy)- amidino]methylene}-erythromycin A (3.5 g) in toluene (50 ml) was added potassium hydride (0.07 g, 30% suspension in l oil), wnether (0.2 g) followed by (R) (5-(1-nosyloxy-ethyl)-1,3,4-thiadiazolyl)-pyridine (1.5 gm) at 00 C temperature. The reaction mixture was stirred for 4 h. It was quenched by g it in aqueous ted ammonium chloride solution (50 ml). The mixture was extracted with ethyl acetate (100 ml X 2). Combined organic layer was dried over Na2804 evaporated under vacuum to provide a crude compound to provide step-1 t in 4.0 gm quantity (92%) as a syrup which was used as such for the next reaction.

MS: m/z: 991.3 (M+1) Ste -2: Pre aration of 118 21R decladinos l-11 12-dideox fluoroO-meth loxo- 12 11- ox carbon 1- E-N— 1- 5- idin l-1 3 4-thiadiazol l- S -ethox - carboxamidino methylene f -erﬂhromycin A The mixture of step-1 product (118,21R)decladinosyl-11,12-dideoxyﬂuoroO- methyloxo-2’-O-triethylsilyl-12,1 1- {oxycarbonyl-[E-N-[l-(5-pyridinyl-1,3,4- thiadiazolyl)-(S)-ethoxy]-carboxamidino]methylene}-erythromycin A (4 g), and 70% HF- pyridine solution (0.400 ml) dissolved in acetonitrile (40 ml) was stirred at 300 C for 2 hr under N2 atmosphere. After completion of reaction, reaction was ed with addition of aqueous sodium onate solution (50 ml). The mixture was evaporated under vacuum to half of the volume. Water (20 ml) was added to the crude product to provide a suspension, which was ﬁltered under suction. The solid was washed water followed by ether to afford crude compound, which was puriﬁed by talization using ethyl acetate and methanol 2011/050464 (1:4) to provide 2—ﬂuoro-ketolide compound of ion in 1.3 gm (37%) quantity was a white solid.

Retention time 21.29 (HPLC purity 91.66%), M.p. = 133-1350 C, MS = (m/z) = 877.1 (M+1) Following examples were prepared by using the procedure describes in example 18 and utilizing corresponding p-nitrophenylsulfonyl (nosyl) ester analogues of respective side chains: Side chain used for coupling (S)tert— xycarbonylamino [5-(1- methanesulfonyloxy -ethyl)-1,3 adiazol-2— yl]-pyridine (R)tert- Butyloxycarbonylamino [5-(1- methanesulfonyloxy -ethyl)-1,3 ,4-thiadiazol-2— yl] -pyridine (R)[5-(1- methanesulfonyloxyethyl )-1,3,4-thiadiazol 170 yl]-pyrimidine [\D [\D (R)- [5-(1-nosy10xy-ethyl)- 1,3 ,4-thiadiazolyl] - pyrazine (R)- [3 -(1-nosy10xy-ethyl)- isoxazol-S -y1] -pyrimidine N4; (R)-3 utyloxycarbonylamino [5-(1-nosy10xy-ethyl)- 1,3 ,4-thiadiazolyl] - benzene (R)-2— [3 -(1-nosy10xyethyl )-isoxazol-5 -y1] - pyridine [\D O\ (R)-3 -[2-(1-nosy10xy- ethyl)-pyrimidin-5 -y1] - isoxazole [\D \l (S)[2-(1-nosy10xy- ethyl)-pyrimidin-5 -y1] - isoxazole [\D (R)tertbutyloxycarbonylamino [3 -(1-nosy10xy-ethyl)- ol-S-y1]—pyridine (RS)[5-(1-nosy10xy- propyl)-thiadiazol-2—yl] - pyridine e 31: erythromycin A Ste -1: Pre aration of 11S 21R decladinos l-11 12-dideox eth l-2’-O- ethoxy -carboxamidino eneE-erﬂhromycin A To the d solution of (11S,21R)- adinosyl-11,12-dideoxyO-methyl-2’-O- triethylsilyl- 12, 1 1- {oxycarbonyl-[E-(N-hydroxy)-carboxamidino]methylene} -erythromycin A (1.5 g) in toluene (20 ml) was added potassium hydride (0.3 g, 30% suspension in mineral oil), 18-crownether (0.1 g) followed by (RS)[5-(1-bromo-ethyl)-1,3,4-thiadiazolyl]— pyridine (0.7 gm) at 300 C temperature. The reaction mixture was stirred for 30 minutes. It was quenched by pouring it in aqueous saturated ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (100 ml X 2). ed organic layer was dried over NazSO4 evaporated under vacuum to provide a crude mass which was puriﬁed by using silica gel column chromatography (15 % Acetone:Hexane) to provide step-1 product in 1.5 gm ty (80%) as a off white solid.

MS = (m/z) = 975.3 (MT) Ste -2: Pre aration of 11S 21R decladinos l-11 12-dideox O-meth loxo-2’-O- trieth lsil l-12 11- ox carbon 1- E-N— 1- 5- ridin l-1 3 4-thiadiazol l - RS - ethoxy -carboxamidino methylenef-erﬂhromycin A To the stirred solution of rosuccinimide (1.5 gm) in dichloromethane (75 ml) was added dimethyl sulﬁde (2 ml) at -100 C. The reaction mixture was stirred at -100 C for 30 min. The step-1 product (1.5 gm) dissolved in dichloromethane (25 ml) was added to the reaction mixture at -400 C. The resulting reaction mixture was stirred at -40°C temperature for 3 hr. Triethyl amine (5 ml) was added and stirred for overnight at 30° C. The on mixture was poured in aqueous saturated sodium bicarbonate solution (20 ml) and the e was extracted with dichloromethane (50 ml X 2). The combined organic layer was dried over NazSO4 and evaporated under vacuum to provide crude mass which was puriﬁed by using silica gel column chromatography (12% Acetone:Hexane) to provide step-2 product as a semi solid in 1.2 gm quantity (80%).

MS = (m/z) = 973.4 (MT) Ste -3: Pre aration of 11S 21R decladinos l-11 eox O-meth o ox carbon 1- E-N— 1- 5- idin—2- 1-1 3 4-thiadiazol l - RS -ethox - amidino methylene § -erﬂhromycin A The mixture of step-2 product (1.2 gm) and 70% HF-pyridine solution (0.2 ml) in acetonitrile (20 ml) was stirred at 300 C for 2 hr under N2 atmosphere. Aqueous sodium bicarbonate solution was added (10 ml) and the mixture was extracted with dichloromethane (50 ml X 2). Combined organic layer was dried over sodium sulfate and ated under vacuum to obtain crude mass. The crude mass was puriﬁed by using silica gel column chromatography (3 % MeOH in CHC13) provided the title compound in 0.7 gm (59%) as a off white solid.

HPLC analysis showed mixture was in 44.97 (at 21.42 minutes) and 52.09 (at 25.25 minutes) tion. M.p. = 135-1370 C, MS = (m/z) = 859.3 (M+) Example 32: ion of 118 21R decladinos 1-11 12-dideox O-meth loxo-12 11- 0x carbon 1- E-N- 1- 5- ridin 1-1 3 4-thiadiazol l - R -ethox -carboxamidin0 methylene {-erythromycin A : The 0.5 gm diastereomeric mixture obtained in example 31 was separated on preparative HPLC by using VMC-ODS-A column, 0.05 ammonium acetate buffer: acetonitrile (60:40 ratio) mobile phase adjusted to pH 7 by ammonia and acetic acid and ﬂow rate 18 ml/min at UV detection at 215 nm.

The title compound was obtained with_retention time 21.39 (HPLC purity 93.20%), M.p. = 140-1420 C, MS = (m/z) = 860.1 (M+1) Example 33: Isolation of 118 21R decladinos 1-11 12-dideox O-meth loxo-12 11- 0x carbon 1- E-N- 1- 5- ridin 1-1 3 4-thiadiazol l - S -eth0x - amidino lene {-erythromycin A : 2011/050464 Utilizing the same HPLC conditions, the title compound was obtained with retention time 25.11 (HPLC purity 98.52%), M.p. = 128—1300 C, MS = (m/z) = 860.1 (M+1).

Following examples were prepared by using the procedure describes in example 31 and utilizing corresponding bromo analogues of respective side chains followed by preparative HPLC tion of diastereomeric mixture.

Example No 1 Side chain used for Mp Mass coupling (°C) (M+1) 220-221 (RS)[5-(1-bromo- -isoxazolyl]— 216-21 8 pyridine 118-120 116-1 17 (RS)[3-(1-bromo- ethy )l-isoxazolyl]- 241-243 pyrimidine 121-123 210-212 842.9 (RS)[3-(1-br0m0- 138-140 -isoxazoly1]— pyridine 42 112-114 (RS)[3-(1-br0m0- propyl)-isoxaz01—5 -y1] - 43 174-176 pyridine 173-175 204-206 (RS)-[5-(1-br0m0-ethy1)- 1,3 ,4-thiadiazoly1] - pyrimidine 2 164-166 (RS)tert- butyloxycarbonylamino- -[5-(1-br0m0-ethy1)- 170-172 1,3 adiazoly1] - pyridine 138-140 206-208 (RS)-[5-(1-br0m0-ethy1)- U} )—A 1,3 ,4-thiadiazoly1] - 178-180 pyrazine 206-208 LII U.) (RS)[5-(1-br0m0- ethy1)-1,3 ,4-0xadiazol-2— 120-122 yl]—pyridine Alternate method for preparation of example-33: erythromycin A Ste -1: Pre aration of 118 21R decladin0s 1-11 12-dide0x O-meth l-2’-O- carboxamidino methylene § -erﬂhr0mycin A To the d solution of (1 IS, 21R)- 3-decladin0syl-11, 12-dide0xyO-methyl-2’- O-triethylsilyl- 12, 1 1- rbonyl- [E-(N-hydroxy)-carb0xamidin0]methylene} - erythromycin A (35.0 g) in toluene (350 ml) was sequentially added 18-crownether (1.96 g) followed by potassium t-butoxide (5.6 g) at 30° C. The blue coloured suspension was stirred for 10 minutes to provide a clear solution. To this solution, was added (R)[5-(1- n0syloxy-ethyl)-1,3,4-thiadiazolyl]-pyridine (19.4 gm, prepared from methyl-D-lactate) at ° C temperature as a solid followed by toluene (70 ml). The reaction mixture was stirred for 30 minutes at 30° C. The reaction mixture was quenched with 3% aqueous ammonium chloride solution (200 ml) as TLC showed complete conversion of starting material. (TLC system: hexane:ethyl acetate: lamine 5:5 :2). The mixture was extracted with ethyl acetate (250 ml X 2). ed organic layer was washed with brine and dried over , evaporated under vacuum to provide a crude mass as yellow foam in 47 gm quantity, which was used as it is, for the next reaction.

Mass (M+) = 975.4, HPLC = Chemical purity = 73.7%, diastereomeric purity = 99.42%.

Ste -2: Pre aration of 118 21R decladin0s 1-11 12-dide0x O-meth l0x0-2’-O- trieth lsil 1-12 11- 0x carbon 1- E-N— 1- 5- ridin 1-1 3 4-thiadiazol l- S -eth0x - carboxamidino methylene § -erﬂhr0mycin A To the stirred solution of N-chlorosuccinimide (18.02 gm) in romethane (180 ml) was added dimethyl sulﬁde (11.2 ml) at -200 C to -15° C. The on mixture was stirred at -20° C-150 C for 30 min. The step-1 product (46.7 gm) dissolved in romethane (300 ml) was added to the reaction e at -50° C to -400 C via addition funnel. The resulting reaction mixture was stirred at -40° C -35° C temperature for 3 hr.

Triethyl amine (15.6 ml) was added at -40° C and stirred until on mixture became clear at 30° C. To the reaction mixture was added under stirring ethyl acetate (880 ml) followed by 0.5 N s sodium hydroxide solution (410 ml). The layers were separated after 30 minutes stirring. It was washed sively with water (410 ml) followed by brine solution (410 ml). The organic layer was dried over Na2S04 and evaporated under vacuum to provide yellow foam in 49 gm ty, which was subjected for the next reaction without any puriﬁcation.

Mass (M+) =973.3, HPLC = Chemical purity = 79.35%, Chiral purity = 97.82%, Ste -3: Pre aration of 11S 21R decladinos l-11 12-dideox O-meth loxo ox carbon 1- E-N— 1- 5- idin—2- l-1 3 4-thiadiazol l - S -ethox - carboxamidino methylene § -erﬂhromycin A The mixture of step-2 product (48 gm) and 2N aqueous hydrochloric acid (50 ml) in acetonitrile (125 ml) was stirred at 30° C for 4 hr. To the clear red coloured solution was diluted with water (300 ml) and approximately 125 ml volume of solvents were removed below 55° C under vacuum. The reaction e was cooled to 25° C and extracted with ethyl acetate (150 ml). The aqueous layer was basif1ed using aqueous potassium carbonate (100 ml, 18% w/v). The suspension was extracted with ethyl acetate (250 ml x 2). Organic layer was washed with brine (150 ml) and concentrated under vacuum to provide light brown foam in 42 gm quantity. The crude foam was purified using warm (40° C) l (84 ml).

The sion was ﬁltered at suction at 10° C. The solid cake was washed with chilled ethanol (10 ml X 2). Drying of solid provided light yellow powder in 22.3 gm quantity in 52% yield after three steps.

Mass (M+) = 859.3, HPLC purity 96.48%, M.p. = 135° -137° C.

Following examples were prepared by using the procedure described above for the preparation of example 33, and utilizing corresponding either ophenylsulfonyl (nosyl) ester or methanesulfonyl ester analogues of respective side chains: Side chain used for coupling (R)tert-buty10xy carbonylamin0[5-(1- methanesulfonyloxy- - 1 ,3,4-thiadiazol yl] -pyridine (S)tert—buty10xy carbonylamin0[5-(1- methanesulfonyloxy - ethy1)- 1 ,3,4-thiadiazol yl]-pyridine (R)-3 -tert- butyloxycarbonylamino - [5-(1-nosy10xy-ethy1)- 1,3 ,4-thiadiazoly1] - benzene benzy10xy[5-(1- nosyloxy-ethy1)-1,3 ,4- thiadiazol-Z-yl] -pyridine (R)-3 -[2-(1-nosy10xy- ethyl)-pyrimidin-5 -y1] - (R)tertbutyloxycarbonylamino 858.0 6- [3 -( 1 -nOSy10xy- ethyl)- 172 isoxazol-S-y1]—pyridine (R)benzyloxy[5-(1- xy-ethyl)-isoxazol- 2-y1]—pyridine (RS)[5-(2- l dimethylsilyloxy nosyloxy-ethyl)-1,3 ,4- thiadiazol-Z-yl]—pyridine -[5-(1-nosyloxypropyl )-thiadiazol-2—yl] - pyridine Biological Protocols & activities In vitro Evaluation of com ounds of the invention The antibacterial activity of compounds of the invention was evaluated by determining the minimal inhibitory concentration (MIC) according to standard CLSI agar dilution method. The media used for preculture and main culture were Tryptic Soya broth ( Difco) and Mueller Hinton medium (Difco), respectively. The Mueller Hinton agar was supplemented with 5% sheep blood for streptococci and pneumococci, and with haemoglobin as well as NAD (nicotinamide adenine dinucleotide) for Haemophilus inﬂuenzae, respectively. Overnight cultures were diluted with ed saline (pH 7.2) to the ﬁnal cell density of 5 x 7 CFU/ml, and each bacterial suspension was applied with a replicator (Denley’s multipoint inoculator, UK) onto a series of Mueller-Hinton agar plates containing antibacterial agents at various concentrations. Final inoculum was approximately 104 CFU/spot. The plates were incubated for 18 hrs at 370 C. The MIC was deﬁned as the lowest concentration of an antibacterial agent that inhibits the development of e microbial growth on agar.

The compounds of the ion inhibited the growth of these bacteria with MICs in the range of about 0.007-0.25 mcg/ml (S pneumoniae ive strains, romycin MIC 0.007- 0.015 mcg/ml), 0.007-2.0 mcg/ml (S pneumoniae mef strains, Telithromycin MIC 0.015-1.0 mcg/ml), 0.007-2.0 mcg/ml (S pneumoniae ermb strains, Telithromycin MIC 0.007-0.50 mcg/ml), 0.12—>16 mcg/ml (S pneumoniae 3773 a , high level ermb strain, Telithromycin MIC 4.0 mcg/ml), 0.12->l6 mcg/ml (S pyogene 3530, a high level ermb , MIC Telithromycin MIC 16.0 mcg/ml), l- 8 mcg/ml (H inﬂuenzae, Telithromycin MIC 40- 8.0 mcg/ml).

In vivo Evaluation of compounds of the invention The in vivo cy of compounds of the invention was evaluated by determining ED50 by oral administration of compounds to group of mice (6 mice / dose group) intraperitoneally infected with (5x107- 1x108 CFU/mouse) S pneumoniae 3773. Two doses of compounds of the invention and Telithromycin were administered at 1 hour and 4 hour after infection. On day seven, percentage of animals surviving in various dose groups were employed to determine EDso (Dose protecting 50 % of infected mice) Some of the compounds of the invention showed or oral efﬁcacy against S. niae 3773 infection in mice (ED50 6.25 - 50 mg/Kg) compared to Telithromycin (ED50 75 - 100 mg/Kg)

Claims

The Claims defining the invention are as follows:

1. A compound of a (I) or a pharmaceutically able salt, e, hydrate, polymorph or stereoisomer thereof, O NH O HO N N O O H O O 3 Formula I wherein, T is ?C*H(R1)-P-Q; R1 is hydrogen; 10 P is heteroaryl ring; Q is unsubstituted or substituted aryl or heteroaryl ring; and P is attached to Q via carbon-carbon link; and R3 is ne. 15

2. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; R1 is hydrogen; R3 is fluorine, P is 5 or 6-membered heteroaryl ring with up to three heteroatoms; 20 Q is unsubstituted or substituted aryl or 5 or 6-membered heteroaryl ring; and P is attached to Q via carbon-carbon link.

3. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; 25 R1 is hydrogen; R3 is fluorine, P is 5 or 6-membered heteroaryl ring with up to three heteroatoms; Q is unsubstituted or substituted aryl or 5 or 6-membered heteroaryl ring with up to two nitrogens; and P is attached to Q via carbon-carbon link.

4. A nd as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; 5 R1 is hydrogen; R3 is fluorine, P is 5-membered heteroaryl ring such as isoxazole or thiadiazole; Q is unsubstituted or substituted aryl or 6-membered heteroaryl ring with up to two nitrogens; and 10 P is attached to Q via carbon-carbon link.

5. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; R1 is hydrogen; 15 R3 is fluorine, P is 6-membered heteroaryl ring such as pyridine or pyrimidine; Q is unsubstituted or substituted aryl or 5 or 6-membered heteroaryl ring with up to two heteroatoms; and P is attached to Q via carbon-carbon link.

6. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; R1 is hydrogen; R3 is fluorine, 25 P is 5-membered heteroaryl ring such as isoxazole or azole; Q is unsubstituted or substituted pyridine or pyrimidine; and P is attached to Q via carbon-carbon link.

7. A compound as d in Claim 1, wherein: 30 T is ?C*H(R1)-P-Q; R1 is hydrogen; R3 is fluorine, P is thiadiazole; Q is tituted or substituted pyridine or dine; and 35 P is attached to Q via carbon-carbon link.

8. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; R1 is hydrogen; 5 R3 is fluorine, P is isoxazole; Q is unsubstituted or tuted ne or pyrimidine; and P is attached to Q via carbon-carbon link. 10

9. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; R1 is hydrogen; R3 is fluorine, P is thiadiazole; 15 Q is pyridine or dine; and P is attached to Q via carbon-carbon link.

10. A nd as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; 20 R1 is hydrogen; R3 is fluorine, P is isoxazole; Q is pyridine or pyrimidine; and P is attached to Q via carbon-carbon link.

11. A compound as claimed in Claim 1, n: T is ?C*H(R1)-P-Q; R1 is hydrogen; R3 is fluorine, 30 P is pyrimidine; Q is unsubstituted or substituted 5-membered heteroaryl; and P is attached to Q via carbon-carbon link.

12. A compound as claimed in Claim 1, wherein: 35 T is ?C*H(R1)-P-Q; R1 is hydrogen; R3 is fluorine, P is pyrimidine; Q is isoxazole; and 5 P is attached to Q via carbon-carbon link.

13. A compound as claimed in Claim 1, ed from: a compound of formula (I) wherein T is [3-(pyrimidinyl)-isoxazolyl]- CH2- and R3 is F; 10 a compound of formula (I) wherein T is [5-(isoxazolyl)-pyrimidinyl]- CH2- and R3 is F; a compound of formula (I) n T is [5-(pyrimidinyl)-isoxazolyl]- CH2- and R3 is F; a compound of formula (I) wherein T is [5-(2-amino-pyridinyl)-isoxazol 15 yl]-CH2- and R3 is F; a compound of formula (I) wherein T is [5-(pyridinyl)-isoxazolyl]-CH2 - and R3 is F; a compound of formula (I) wherein T is amino-pyridinyl)-1,3,4- thiadiazolyl]-CH2- and R3 is F; 20 a compound of formula (I) wherein T is [2-(pyrimidinyl)-1,3,4-thiadiazol- 5-yl]-CH2- and R3 is F; a compound of formula (I) wherein T is [2-(2-amino-pyridinyl)-1,3,4- thiadiazolyl]-CH2- and R3 is F; a compound of a (I) wherein T is [2-(pyridinyl)-1,3,4-thiadiazol 25 yl]-CH2- and R3 is F; a compound of formula (I) wherein T is razinyl)-isoxazolyl]-CH2- and R3 is F; a compound of a (I) wherein T is [2-(6-amino-pyrimidinyl)-1,3,4- thiadiazolyl]-CH2 and R3 is F; 30 a compound of formula (I) wherein T is [2-(3-amino-phenyl)-1,3,4-thiadiazol- 5-yl]-CH2- and R3 is F; a compound of formula (I) n T is [2-(2-amino-pyridinyl)-pyridin yl]-CH2- and R3 is F; and a compound of formula (I) wherein T is [5-(6-amino-pyrimidinyl)-isoxazol- 35 3-yl]-CH2- and R3 is F.

14. A compound as claimed in Claim 1, selected from: a nd of formula (I) wherein T is [5-(isoxazolyl)-pyrimidinyl]- CH2- and R3 is F; and 5 a compound of formula (I) wherein T is [2-(pyrimidinyl)-1,3,4-thiadiazol- CH2- and R3 is F.

15. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; 10 R1 is hydrogen; R3 is fluorine, P is 1,3,4-thiadiazole or pyrimidine; Q is pyrimidineyl or isoxazoleyl; and P is attached to Q via -carbon link.

16. A compound as claimed in Claim 1, selected from: (11S,21R)decladinosyl-11,12-dideoxyfluoroO-methyloxo-12,11- {oxycarbonyl-[E-N-[(5-pyrimidinyl-1,3,4-thiadiazolyl)-methoxy]- 20 carboxamidino]methylene}-erythromycin A S N O NH O HO N N O O H O O ; (11S,21R)decladinosyl-11,12-dideoxyfluoroO-methyloxo-12,11- 25 {oxycarbonyl-[E-N-[(5-isoxazolyl-pyrimidinyl)-methoxy]- carboxamidino]methylene}-erythromycin A O NH O HO N N O O H O O .

17. A s for preparation of a compound of formula (4-e) N N Br 5 4-e comprising: (i) converting 2-methyl-pyrimidinecarbaldehyde (4-a) to obtain a compound of formula (4-b); N HO N N OHC CH 3 CH N N 4-a 4-b (ii) converting a compound of formula (4-b) to a compound of formula (4-c); X N Si N 15 4-c (iii) converting a compound of formula (4-c) to a compound of formula (4-d); and (iv) converting a compound of formula (4-d) to a nd of formula (4-e).

18. A process for preparation of a compound of formula (19-d) O NH 2 O HO N N O O H O ????????????????????????????? P and Q is as d 19-d comprising: (i) reacting a compound of a (19-a) with a compound of formula (19-b) 10 to obtain a compound of formula (19-c). HO NH 2O O N N O O H O Q-P-CH2-Z O 19-b F Z = Br or R-SO2-O- where R= methyl, nosyl ?????????????????????????????P and Q = as defined 19-a O NH 2 O O N N O O H O 15 19-c (ii) converting a compound of formula (19-c) to a compound of formula (19-d).

19. A process for preparation of a compound of formula (15-f) S O N N S 15-f comprising; 5 (i) converting a compound of formula (15-a) to a compound of formula (15-b); H C H C OTBDMS 3 OTBDMS O O NH 15-a 15-b 10 (ii) converting a compound of formula (15-b) to a nd of formula (15-c); OTBDMS O O 15-c 15 (iii) converting a nd of formula (15-c) to a compound of formula (15-d) TBDMSO 3 N 15-d (iv) converting a compound of formula (15-d) to a nd of formula (15-e); and 3 N 15-e (v) converting a compound of formula (15-e) to a compound of formula (15-f).

20. A process for preparation of a compound of a (16-d) S O N N S 10 16-d 2 comprising: (i) reacting pyrimidinecarbonylchloride with a compound of formula (15-b) to obtain a nd of formula (16-a); H C OTBDMS 3 OTBDMS H C O NH O O NH H 2 N 15-b 16-a (ii) converting a compound of formula (16-a) to a compound of formula (16-b); OTBDMS H C N 3 N 16-b (iii) converting a nd of formula (16-b) to a compound of formula (16-c); 3 N 16-c (iv) converting a compound of formula (16-c) to a compound of formula (16-d). 10

21. A process for preparation of a compound of formula (17-e) HO NH 2 O O N N O O H O 17-e comprising: (i) converting a compound of formula (17-a) to a nd of formula (17-b) HO NH 2O O N Si N O O NH 2 O O N O N O O H O O O O H O OH O O OH 17-a 17-b (ii) converting a nd of formula (17-b) to a compound of formula (17-c) O NH 2 O O N N O O H O 5 17-c (iii) converting a compound of formula (17-c) to a compound of formula (17- d); and O NH 2 O O N N O O H O 10 17-d (iv) ting a compound of formula (17-d) to a compound of formula (17-e).

22. A pharmaceutical composition comprising therapeutically effective amount of 15 a compound of formula (I) as claimed in any one of Claims 1 to 16, optionally, with one or more pharmaceutically acceptable excipient.

23. A pharmaceutical composition of Claim 22 wherein the composition is formulated for administration. 5

24. The use of a compound of formula (I) as d in any one of Claims 1 to 16 for the manufacture of a medicament for the treatment of infection caused by a microorganism.

25. The use of a compound of formula (I) as claimed in any one of Claims 1 to 16 10 for the cture of a medicament for the prophylactic treatment of a subject at risk of infection caused by a microorganism.

26. The use of Claim 24 or Claim 25, wherein the microorganism is at least one microorganism selected from a bacteria, fungi, protozoa, yeast, mold, or mildew.

27. A compound of any one of Claims 1 to 16, substantially as hereinbefore bed.

28. A process of any one of Claims 17 to 21, substantially as hereinbefore 20 described.