NZ611653A

NZ611653A - Ketolide compounds

Info

Publication number: NZ611653A
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: 2014-04-30

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. 3352/MUM/2010 ﬁled on Dec 09, 2010, the disclosures of which are incorporated herein by reference in its entirety as if fully rewritten .

FIELD OF THE INVENTION The invention relates to ketolide compounds of formula (I) and their pharmaceutically able salts, es, es, rphs and stereoisomers. 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 crobial agents. omycin 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 semisynthetic l4-membered ring macrolide derivatives, characterized by the presence of a keto function at position 3 instead 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 thyl tive of erythromycin i.e. clarithromycin. The patent US 4,349,545 discloses roxithromycin. The azalide omycin is disclosed in US 4,517,359. romycin 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 co-pending PCT publication No. WO 08/023248 discloses several Macrolides and Ketolides.

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 addition of one or more other e, 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, solvate, hydrate, polymorph or stereoisomer f, O NH O HO N N O O H O O 3 a 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 general 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 medicament for the treatment of ion caused by a microorganism.

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

In another general aspect, there is provided a method for ng or preventing microbial infection in a t, comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, e, hydrate, polymorph or stereoisomer thereof.

In r 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 acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In another general aspect, there is provided a method for prophylactic ent of a subject, comprising administering to a subject at risk of infection caused by microorganism, a lactically effective amount of a nd of formula (I) or a pharmaceutically acceptable salt, solvate, e, polymorph or stereoisomer thereof In another general aspect, there is ed a method of 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, polymorph or stereoisomer thereof, optionally with one or more pharmaceutically acceptable ent.

In some other embodiments, there is provided a method for prophylactic treatment of a subject, sing stering to a subject at risk of infection caused by microorganism, a pharmaceutical composition 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 a process for ation of a compound of formula (4-e) N N Br comprising: (i) converting 2-methyl-pyrimidinecarbaldehyde (4-a) to obtain a nd 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 nd of formula (4-d); and 4-d (iv) converting 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 a (19-c).

HO NH 2O O N N O O H O 2-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 19-c (ii) converting a compound of formula (19-c) to a nd of formula (19-d).

In another general aspect, there is provided a process for preparation of a compound of formula (15-f) S O N N S -f comprising; (i) ting 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) converting a nd of formula (15-b) to a compound of formula (15-c); OTBDMS O O -c (iii) converting a compound of formula (15-c) to a compound of formula (15-d) TBDMSO 3 N -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).

In another general aspect, there is ed a process for preparation of a nd of formula (16-d) S O N N S 16-d NO comprising: (i) reacting pyrimidinecarbonylchloride with a compound of formula (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 nd of formula (16-d).

In r general 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 a (17-a) to a compound of formula (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 embodiments of the inventions are set forth in the description below. Other features, aspects and advantages of the inventions will be apparent from the ing description including claims. 2011/050464 DETAILED DESCRIPTION OF THE ION 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 invention is thereby intended. Alterations and further modiﬁcations of the inventive features illustrated herein, and additional applications 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 described.

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 identical chemical composition, but differ with regard to ement of the atoms and the groups in space.

These include enantiomers, diastereomers, geometrical isomers, somer and comformational isomers. Geometric isomers may occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity. An enantiomer is a stereoisomer of a reference molecule that is the nonsuperimposable mirror image of the reference molecule. A diastereomer is a stereoisomer of a nce 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 tory time scale. Conformational s (or conformers or rotational s or rs) 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 indicates that the compounds may be t as either of E- or Z- isomer. Also some of the nds according to this invention may exist as diastereomers. In addition, where the process for the preparation of the nds according to the invention 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 meaning as discussed herewith.

The compounds of invention may exists as ent rphs 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. es), which contains various amounts of water, for instance the hydrate, hemihydrate and sesquihydrate forms. Also the compound can form solvates with common c solvents. Such solvates and hydrates are intended to be included within the scope of this ion.

The term “lower alkyl” refers to C1-C6 alkyl saturated, straight 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 s such as iso-propyl, iso-butyl or tert-butyl.

The term “cycloalkyl” refers to C3-C6 saturated carbocyclic radical containing between three and six carbon atoms. Examples of C3-C6 saturated carbocyclic radical include ropyl, 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 tutions are ﬂuoromethyl, diﬂuoromethyl, romethyl. nitromethyl, aminomethyl, cyanomethyl, hydroxymethyland the like. Examples of C1-C6 alkoxy are methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, pentyloxy, hexyloxy.

The term ”alkylamino” refers to a group having the structure -C6 alkyl) where C1-C6 alkyl is as previously 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 defined. Examples of dialkylamino are, but not limited to, dimethylamino, lamino, 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, nyl, dinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, olyl, thiadiazolyl, oxadiazolyl, thienyl, lyl, triazinyl, furanyl, 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, benzodiazinyl, benzofurazanyl, indazolyl, indolizinyl, benzofuryl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2—b]pyridinyl, furo[2,3- b]pyridinyl), naphthyridinyl, phthalazinyl, pyridopyridyl, quinazolinyl, furyl, thienopyridyl, thienotheinyl, purinyl (such as in-l-yl, 6-amino-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, arbonyl, hio, 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 cological activity of the free base and which are neither biologically nor otherwise undesirable. The salts are suitable for use in contact with the tissues of human and lower animals without undue ty, irritation, ic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For e, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), orated 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 hydrochloric 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, c acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, c acid, cinnamic acid, mandelic acid, esulphonic acid, p-toluene sulphonic acid, clic acid and the like. Also included are the salts with various amino acids such as alanine, arginine, gine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, phan, tyrosine or valine or the optically active isomers thereof or the racemic mixtures thereof or ides, tripeptides and polypeptides derived from the monoaminoacid units thereof.

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

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

Inorganic bases such as KOH, NaOH, 2, 3. The organic base salts from basic amines such as ethylamine, 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 um, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

The term "therapeutically effective amount” means that amount of compound(s) or pharmaceutical 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 ian, which response includes alleviation of the symptoms 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 limited 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 ition or a compound for prophylactic and/or therapeutic es. The term ”prophylactic en ” refers to treating a subject who is not yet infected, but who is tible to, or otherwise at a risk of infection. The term ”therapeutic treatment” refers to administering treatment to a subject already suffering from infection. Thus, in preferred embodiments, treating is the administration to a subject (either for therapeutic or prophylactic purposes) of therapeutically ive amount of compound of formula (I) or a ceutically acceptable salt, solvate, polymorph or stereoisomer f The term ”subject” as used herein refers to rate 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 ia, fungi, protozoa, yeast, mold, and mildew.

The term ”infection” as used herein includes presence of a microorganism in or on a subject, 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 desirable. 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, itis, tonsillitis, and mastoiditis related to infection by ococcus pneumoniae, hilus inﬂuenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clostridium riae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus inﬂuenzae, or Chlamydia pneumoniae, uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever d to infection by Staphylococcus , coagulase-positive staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, ococcus tiae, Streptococcal groups C-F (minute- colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary 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, ema pallidum, Ureaplasma ticum, 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; systemic e syndromes d to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chiamydia trachomatis, ria hoeae, S. aureus, S. pneumoniae, S. es, H. inﬂuenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC) disease related to ion by Mycobacterium avium, or Mycobacterium intracellulare; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic ion related to infection by viridans streptococci; persistent cough related to ion by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae. Bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in animals include the following: bovine respiratory diseases related to infection by P. haem., P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric e related to ion 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., Corynebacterium, or Enterococcus spp.; swine atory e related to infection by A. pleuro., P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by E. coli, Lawsonia intracellularis, ella, or ina hyodyisinteriae; cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by E. coli; cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides 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 infection by E. coli; skin and soft tissue infections in dogs and cats d to ion by Staph. epidermidis, Staph. intermedius, coagulase neg. Staph. or P. multocida; and dental or mouth ions in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella.

In one general , there are provided compounds of formula (I) or a pharmaceutically acceptable salt, e, 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 e, With the provision that when R1 is hydrogen, R3 is ﬂuorine.

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 or 6-membered aryl ring with up to three heteroatoms; Q is unsubstituted 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, 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 ens; and P is attached to Q via carbon-carbon link.

In some embodiments, there are provided compounds of a (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 aryl or ered 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 heteroaryl 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 tuted pyridine or pyrimidine; and P is attached to Q via carbon-carbon link.

In some ments, there are provided compounds of a (I), wherein: T is —C*H(R1)-P-Q; R1 is hydrogen; R3 is ﬂuorine, P is 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 hydrogen; R3 is ﬂuorine, P is isoxazole; Q is tituted 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), n: T is —C*H(R1)-P-Q; R1 is en; R3 is ﬂuorine, P is azole; 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), wherein: 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. 2011/050464 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 pyrimidine; Q is unsubstituted or substituted 5-membered heteroaryl; 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 ole; 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 tuted lower alkyl, cycloalkyls, or aryl; P is heteroaryl ring; Q is unsubstituted or substituted aryl or heteroaryl ring; and P is ed 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 heteroaryl ring; Q is unsubstituted or tuted aryl or heteroaryl ring; and P is attached to Q via carbon-carbon link; and R3 is en 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 e In some embodiments, there are provided compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is unsubstituted or tuted lower alkyl; P is 5-membered aryl 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 ed compounds of formula (I), wherein: T is —C*H(R1)-P-Q; R1 is methyl; P is 5-membered heteroaryl ring with up to three atoms; 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), wherein: T is —C*H(R1)-P-Q; R1 is methyl; P is 5-membered heteroaryl 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 formula (I), wherein: T is 1)-P-Q; R1 is methyl; P is 5-membered heteroaryl ring such as isoxazole or 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 thiadiazole; Q is pyridine or dine; and P is attached to Q via carbon-carbon link; and R3 is en 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 isoxazole; Q is pyridine or dine; 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 ceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, selected from: a compound of formula (I) wherein T is [3-(pyrimidinyl)-isoxazo1yl]- CH2- and R3 is F; a compound of a (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 nd of formula (I) wherein T is [5-(2-amino-pyridinyl)-isoxazol 3- and R3 is F; a compound of a (I) wherein T is [5-(pyridin—2-yl)-isoxazolyl]-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 a (I) wherein T is [2-(pyrimidinyl)-1,3,4-thiadiazol- -yl]—CH2- and R3 is F; a compound of formula (I) wherein T is 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 compound 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 formula (I) wherein T is [2-(2-amino-pyridinyl)-pyridin yl]-CH3- and R3 is F; a compound of formula (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; 2011/050464 a compound of formula (I) wherein T is (R)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(CH3)- and R3 is H; a compound 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) n T is 3-(pyridinyl)-isoxazolyl]- CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (R)-[3-(pyridinyl)-isoxazolyl]- )- and R3 is H; a compound of formula (I) n T is (S)-[3-(pyridinyl)-isoxazolyl]- CH(CH3)- 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 (S)-[5-(pyridinyl)-isoxazolyl]- CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (R)-[5-(pyridinyl)-isoxazolyl]- CH(C3H5)- and R3 is H; a compound of formula (I) wherein T is (S)-[5-(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 nd of formula (I) wherein T is (R)-[2-(pyrimidinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is (S)-[2-(pyrimidinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a nd of formula (I) wherein T is (S)-[2-(2-amino-pyridinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a nd of formula (I) wherein T is (R)-[2-(2-amino-pyridinyl)-l,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; 2011/050464 a compound of formula (I) wherein T is (RS)-[2-(2-amino-pyridinyl)-1,3,4- azol-S-yl]-CH(CH3)- and R3 is H; a nd 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-(pyrazinyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is H; a compound of formula (I) wherein T is -(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) wherein 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- azol-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)-[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) n T is (R)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(CH20H)- 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 a (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- -yl]—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; 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) n 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 -(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 -(pyridinyl)-isoxazolyl]- 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; a compound of a (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)- olyl]—CH(CH3)- and R3 is F.

In some other embodiments, there is provided a compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or isomer thereof, selected from: a compound of formula (I) wherein T is [5-(isoxazolyl)-pyrimidinyl]— CH2- and R3 is F; a compound of a (I) wherein T is [2-(pyrimidinyl)-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 formula (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) n T is (S)-[2-(2-amino-pyridinyl)-1,3,4- azol-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 compound of formula (I) wherein T is (S)-[2-(pyridinyl)-1,3,4-thiadiazol- -yl]—CH(C2H5)- and R3 is H; a nd 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 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-(3-aminophenyl)-1,3,4- thiadiazol-S-yl]-CH(CH3)- and R3 is F; a compound of formula (I) n T is (S)-[5-(isoxazolyl)-pyrimidin (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 formula (I), wherein: Formula | T is —C*H(R1)-P-Q; R1 is hydrogen; 2011/050464 R3 is ﬂuorine, P is 1,3,4-thiadiazole or pyrimidine; Q is pyrimidineyl or isoxazoleyl; and P is attached to Q Via carbon-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- rimidinyl- 1,3 ,4-thiadiazolyl)-methoxy] - carboxamidino]methylene} -erythromycin A; 1R)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 pyrimidinyl; and P is attached to Q Via carbon-carbon link; and R3 is en.

In some other embodiments, there is provided a compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, selected from: 1R)decladinosyl-11,12-dideoxyO-methyloxo-12,11- {oxycarbonyl- [E-N- [ 1 -(5-pyridinyl- 1,3 ,4-thiadiazolyl)-(S)-ethoxy] - amidino]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 ation of a compound of formula (3-e) Br 3i comprising; (i) converting a compound of a (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 compound of formula (3-c) to a nd of formula (3-d) c -_NN N\ 8&OH (iv) converting a compound of formula (3-d) to a compound of formula (3-e).

In other embodiments, there is provided a process for ation of a nd of formula (4-e) ,N _N Br 0WNW comprising: (i) converting ing 2—methyl-pyrimidinecarbaldehyde (4-a) to obtain a compound of a (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) sing: (i) reacting a compound of formula (l9-a) with a compound of formula (l9-b) to obtain a compound of formula (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 nd of formula (19-c) to a compound of formula (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 nd of formula (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 nd of formula (15-c) to a compound of formula (15-d) (iv) converting a compound of formula (15-d) to a compound of a (15-e); and -e (V) converting a compound of formula (15-e) to a compound of formula .

In some embodiments, there is provided a process for preparation of a nd of formula ( l 6-d) comprising: (i) reacting 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 compound of formula (l6-b); OTBDMS SiN/ 16-b (iii) converting a compound of formula (16-b) to a compound of formula (16-c); HBO/k?N ‘N SJS/N/ 16-c (iv) converting a nd 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 formula ( l 7-e) _' J l—QSi \N_ comprising: (i) ting 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) converting a compound of formula (17-d) to a compound of formula (17-e).

In some other embodiments, there is provided a s for preparation of a compound of formula (18-e) comprising, (i) reacting a compound of formula (1 8-a) with a compound formula (l8-b) to a obtain a compound of a (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 Z I n Z/| 18-d (iii) converting a compound of formula (18-d) to a nd 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 formula (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 (ii) converting a compound of a (19-c’) to a compound of a (19-d’).

In some embodiments, there is provided, a process for the preparation of compounds of Formula (I), n the variables have the previously deﬁned meanings, the method comprising the process will be better understood in tion with the following tic Schemes In some ments, there are provided pharmaceutical compositions sing 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.

The term “pharmaceutically acceptable excipient” refers to a substance other than the active ingredient and includes pharmaceutically acceptable carriers, diluents, stabilizers s, coloring agents, buffers, lubricants, disintegrating agents, surfactants, glidants, plasticizers, fillers, extenders, emollients, wetting agents, and so on. The pharmaceutically acceptable excipient often facilitates ry of the active ingredient. The type and amount of any the excipient used depends y 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 example, oral, rectal, vaginal, parenteral (subcutaneous, intramuscular, intravenous), nasal, transdermal, topical and like forms of stration may be employed. Suitable dosage forms include tablets, pills, powders, troches, dispersions, solutions, suspensions, emulsions, capsules, injectable preparations, patches, nts, creams, lotions, shampoos, and the like.

In some embodiments, the pharmaceutical 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 stering to a subject in need thereof a compound of a (I) or a pharmaceutically acceptable salt, solvate, hydrate, rph or stereoisomer thereof In some embodiments, there is ed a method for treating infection caused by a microorganism in a subject, comprising stering to a subject 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 treatment of a subject, sing administering to a subject at risk of infection caused by microorganism, a prophylactically effective amount of a compound of a (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 t in need thereof, a pharmaceutical composition comprising therapeutically effective amount of a compound of a (I) or a pharmaceutically acceptable salt, e, rph or stereoisomer thereof, 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 pharmaceutical composition 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 ent.

The prophylactic or eutic dose of the ketolide compounds of Formula (I) and pharmaceutically acceptable salts thereof, in the acute or chronic management of disease will vary with the severity of condition to be treated, and the route of administration. In addition, the dose, and s the dose frequency, will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose range, for the nds of the invention, for the conditions described 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 ng ian will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient’s response.

General procedures As per scheme-l, heteroaryl aldoxime of formula l-a 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 25°C to 35°C to provide corresponding heteroaryl chloroamidoxime 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 organic base such as triethylamine in a suitable solvent such as toluene or , 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 d with methanesulfonylchloride in the presence of base such as triethylamine in a suitable solvent such as dichloromethane 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 e in a suitable solvent such e; at a temperature ranging from 35°C to 55°C, to provide corresponding bromide ediate 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 reacted with ethylchlorooxamidoacetate in the presence of organic base such as triethylamine, in a suitable solvent such as toluene at a temperature ranging from 80°C to 95°C to provide corresponding ethyl ester derivative of formula 2-b.

The ester derivative 2—b is reacted with reducing agent such as sodium borohydride in a suitable solvent such as methanol or l at a temperature g from 0°C to 35°C to e corresponding methanol derivative of a 2-c, which is reacted with methanesulfonyl de 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 e corresponding methanesulfonic acid ester, which is r reacted with lithium bromide in a suitable solvent such as acetone at a temperature 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 d with hydrazine or hydrazine hydrate in a suitable solvent such as ol or ethanol at a temperature ranging from 25°C to 85°C to provide corresponding ide 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 suitable solvent such as dichloromethane or chloroform or tetrahydrofuran at a temperature ranging from -5°C to 35°C, followed by optionally changing to solvent ed from tetrahydrofuran or 1,4-dioxane and the reaction mixture is d with Lawesson’s reagent at a temperature ranging from 40°C to 70°C to e the requisite Thiadiazole derivative of formula 3-c.

The ester (3-c) is reacted with reducing agent such as sodium borohydride in a suitable solvent ethanol or aqueous l at a temperature g 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 chloroform at a temperature ranging from -5°C to 35°C to provide corresponding mesylate derivative, which is further reacted with lithium bromide in a le t 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 ol 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 le solvent such as methanol or ethanol or water or mixture thereof, at a temperature ranging from 0°C to 35°C, to provide corresponding 2-methyl-pyrimidinecarbalehyde oxime (4-b).

The compound 4-b 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 0° to 35°C to provide corresponding methyl substituted pyrimidinyl chloroamidoxime compound, which is further d with trimethylsilylacetylene in a suitable solvent such as diethyl ether or N,N-dimethylformamide, or mixture thereof, at a ature ranging from -5°C to 35°C to e corresponding nd 4-c.

The compound 4-c is converted to compound 4-d by ng 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 azoisobutyronitrile (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\ c —> 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 temperature ranging from 80°C to 90°C, to provide corresponding tributyltin derivative of pyridine 5-b.

The compound 5-b is coupled with 2—bromo-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 d t 5-c.

The compound 5-c is reacted with a reducing agent such as sodium borohydride in a suitable solvent tetrahydrofuran or ethanol or methanol or aqueous ethanol or mixture thereof, at a temperature g 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 c base such as triethylamine in a suitable solvent such as dichloromethane or chloroform at a ature ranging from 0°C to 25°C to provide corresponding methanesulfonic acid ester of substituted nyl methylalcohol, 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 ponding substituted bispyridinyl methyl bromide compound 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 ium-tetrakis(triphenylphosphine) or iphenylphosphine)palladium(II)dichloride in a suitable t such as toluene, dimethoxyethane or DMF, at a ature ranging from 80°C to 110°C, to provide corresponding tributyltin derivative 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 presence of base such as triethylamine in DMF at a temperature g from 100°C to 110°C to provide a corresponding d product 6-c.

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

The compound 6-d is reacted with methanesulfonylchloride in the presence of c base such as ylamine 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 e in a suitable solvent such as acetone at a temperature ranging from 35°C to 55°C to provide corresponding substituted pyrimidinyl methyl bromide compound 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 scheme-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 d with ethyl propiolate in the presence of organic base such as triethylamine, diisopropylethylamine in a suitable solvent such as e or xylene at a temperature g 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 e thereof, at a temperature ranging from 0°C to 35°C to provide corresponding alcohol of formula 7-d.

The alcohol (7-d) is reacted with oxidizing agent such as Dess-Martin periodinane or pyridiniumchlorochromate (PCC) or niumﬂuorochromate (PFC) in a suitable solvent such as dichloromethane or dichloroethane or chloroform or mixture thereof, at a temperature ranging from 25°C to 35°C to provide corresponding aldehyde derivative of formula 7-e. The aldehyde (7-e) is d 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 ted to corresponding bromomethyl derivative 7-g by reacting either with methanesulfonyl chloride in the presence of base such as triethylamine and isolating corresponding alkyl ate and treating it with lithium bromide in e at reﬂux ature or optionally, by reacting with carbon tetrabromide along with triphenylphosphine 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 As per scheme-8, ethynyl heteroaryl derivative of formula 8-a is reacted with ethylchloro oxamidoacetate in the presence of organic base such as triethylamine in a suitable solvent such as toluene at a ature ranging from 80°C to 110°C to provide corresponding ester (8-b). It is in turn d with methylmagnesiumiodide in a suitable solvent such as dichloromethane or dichloroethane or chloroform or ydrofuran (THF) or mixture thereof, at a temperature ranging from 0°C to 10°C to provide 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 e thereof, at a temperature ranging from 0°C to 35°C to provide ponding alcohol derivative of a 8-d.

The alcohol is converted to the corresponding mesylate derivative 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 g 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 temperature ranging from 45°C to 55°C. <:N>_[<OZ+NHNH Clj\n/<\_=N>_:C;j/£O —> Qefewfw Scheme—9 As per scheme-9, linic acid hydrazide (9-a) is d with pyruvic acid chloride 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 ambient 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 l at a temperature 35°C to provide ne-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 provide corresponding methanesulfonyl ester of pyridinyl-1,3,4- oxadiazolyl-ethanol, which is converted to corresponding pyridine-1,3,4-oxadiazolyl ethyl 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 © Chiral nosylate (lO-f) is synthesized according to scheme 10. R enantiomer of amidine hydrochloride compound lO-a is reacted with vinamidium hlorate salt and aqueous sodium ide in acetonitrile at 25°C to 35°C temperature, to provide corresponding pyrimidine carbaldehyde compound lO-b. The compound lO-b is d with hydroxylamine hydrochloride in presence of sodium carbonate in aqueous methanol at ambient temperature to e corresponding oxime, which is subsequently reacted with N- chlorosuccinamide in DMF at the same temperature to provide corresponding chloroamidate compound lO-c. The compound lO-c is stirred with ylamine and hylsilyl acetylene in DMF and diethyl ether e at -10°C to 25°C to provide corresponding trimethylsilyl protected olyl-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 provide 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, aryl carboxylic acid alkyl ester of formula 11-a. is reacted with hydrazine e in ethanol at a temperature ranging 40°C to 85°C to provide corresponding heteroaryl acid hydrazide (1 1-b). The the hydrazide derivative is then treated with mono ethyl ester of oxalyl chloride in the presence of triethylamine in dichloromethane or tetrahydrofuran at a ature ranging from 5°C to 30°C after which the solvent is optionally changed to tetrahydrofuran and the reaction mixture is treated with Lawesson’s reagent at a temperature ranging from 40°C to 70°C to e corresponding heteroaryl- 1,3,4-thiadiazolyl-carboxylic acid alkyl ester (1 1-c). It is then d with methylmagnesiumiodide in a suitable solvent such as dichloromethane or tetrahydrofuran (THF) or mixture thereof, preferably dichloromethane at a ature g from 0°C to °C to e corresponding heteroaryl-1,3,4-thiadiazolyl-ethanone (1 1-d). The ketone is reduced using sodium borohydride in ethanol or methanol at a ature 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 ethanol, which is converted to corresponding bromide (ll-f) by treating with lithium bromide in acetone, at a reﬂux temperature. _ S o’ﬁ —» \/ N 00 N NO2 Scheme—12 As per scheme-12, 2-bromobutyrate (12-a) is reacted with benzyl alcohol in presence of potassium ide in DMF at 25°C to 35°C up to 3 hr to provide ethyl benzyloxybutyrate (12-b). Compound 12-b is treated with ine 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 dehydrating 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 compound 12-e is stirred with borontribromide in dichloromethane at a temperature g from 0°C to 5°C for 1 hr followed by at 35°C for overnight, to provide corresponding pyridinyl-1,3,4-thadiazolyl ol compound 12-f.

The nd 12-f is treated with p-nitrophenylsulfonyl chloride in the presence triethylamine in a dichloromethane at a temperature g from 0°C to 15°C to provide 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 temperature for overnight to provide ponding acid ide nd 13-b. The compound 13-b is treated 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 Lawesson’s t 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 temperature for 6 hr, to provide corresponding nyl-1,3,4-thiadiazolyl ethanediol compound l3-e. It is then reacted with TBDMS chloride in presence of ylamine and DMAP in dichloromethane 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 te (l4-e) is prepared by ﬁrst reacting racemic alcohol (14-a) with enantiomerically pure (S)-O-acetyl mandelic acid in the presence of ohexylcarbodiimide 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 ved in methanol to provide clear solution and then cooled to 25°C to provide selective crystallization of one diastereomer 14-c as a white solid. The compound 14-c is hydrolyzed by treating it with aqueous sodium hydroxide or potassium hydroxide in methanol at temperature ranging from -15°C to 5°C to provide enantiomerically pure nd l4-d. The alcohol (l4-d) is then d with methanesulfonyl chloride in the presence of triethylamine in dichloromethane at a temperature ranging from -10°C to 5°C to provide enantiomerically pure corresponding esulfonic 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 \ TBDL/ISO OH HC M 15—e 1_'f NO Scheme—1 5 As per scheme-15, commercially ble yl 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 nd 15-b. The compound 15-b is coupled with 2-picolinic acid using dehydrating agent EDC in the ce 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 protected compound 15-d. The TBDMS group in compound 15-d is removed by using 2 N aqueous hydrochloric acid in acetonitrile at temperature 25°C to 35°C to provide a compound 15-e. The compound 15-e is reacted with p-nitrophenylsulfonyl chloride in the ce triethylamine in dichloromethane at a temperature between 10°C to 25°C to e R enantiomer of p-nitrophenylsulfonic 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 ent with thionylchloride in e) is reacted with R enantiomer of TBDMS protected D-lactic acid hydrazide (15-b), 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 ted pyrimidinyl-1,3,4-thiadiazolyl compound l6-b. The TBDMS group is removed by using 2 N aqueous hydrochloric acid in acetonitrile at temperature 25°C to 35°C to provide a compound 16-c. which is reacted with p-nitrophenylsulfonyl de in the presence triethylamine in dichloromethane at a temperature between 0°C to 5°C to provide chirally pure (R)-p-nitrophenylsulfonic acid ester (nosylate) of pyrimidine-1,3,4-thiadiazole as compound 16-d.

Scheme-17 As per scheme-17, (11$,21R)- adinosyl-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. atively, compound l7-b is prepared by reacting amidoxime macrolide l7-a With benzyl e in presence of base such as potassium hydride or potassium ate or potassium xide in presence of phase transfer catalyst such as l8-crownether in a t such as toluene or xylene or acetone or ethyl methyl ketone at a temperature ranging from 200 C to 35°C Compound 17-b is oxidized under standard condition using either NCS and DMS oxidizing species (Kim Corey reagent) or with Dess-Martin periodinane reagent, in a suitable solvent such as romethane 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 ketolide compound 17-d, which is further subjected to hydrogenolysis using 20% palladium hydroxide or 10% palladium on carbon or a e thereof and in the presence of hydrogen source such as hydrogen gas under pressure in solvent 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 d Scheme-18 As per -18, amidoxime compound of formula 18-a, is reacted with racemic or enantiomerically pure appropriate bromide, mesylate, te or nosylate derivative of formula 18-b in the presence of suitable organic base such as potassium hydride or potassium toxide or nic base such as potassium hydroxide with phase transfer catalyst such 2011/050464 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 conditions (made from NCS and DMS) or with Dess-Martin inane reagent, in a suitable solvent such as romethane or dichloroethane or chloroform, at a temperature ranging from -50°C to 10°C to e a 2’- O-triethylsilyl protected ketolide of formula 18-d.

It is in turn reacted with suitable silyl deprotecting agent such as pyridinehydrogenﬂuoride , tetrabutylammonium e, aqueous hloric acid, in a suitable solvent such as acetonitrile or tetrahydrofuran or e 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 pyridine-hydrogenﬂuoride or triﬂuoro acetic acid in acetonitrile to provide corresponding amino derivative.

Optionally, compound 18-e (when ring Q bears 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. 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 As per scheme-19, amidoxime compound 19-a, is d 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 tertbutoxide or inorganic base such as potassium hydroxide with phase transfer catalyst such as l8-crown-6 ether in a suitable solvent 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 d with suitable silyl deprotecting agent such as pyridine- enﬂuoride, tetrabutylammonium 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’. ally, compound l9-d or l9-d’ (when ring Q bear a substituent like Boc-NH or di-Boc-N) is treated with ne-hydrogenﬂuoride or triﬂuoro acetic acid in itrile to provide corresponding amino derivative. ally, compound l9-d or l9-d’ (when ring Q bear 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.

WO 76989 EXPERIMENTAL Pre aration 1: 2- 5-Br0mometh l-isoxazol l - ridine Step- 1: Py_ridinimidoyl chloride To a mixture of ethyl 2-pyridin-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 ld 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 l-isoxazol 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 on 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 liquid.

The compound was characterized by proton NMR.

Hl-NMR (CDC13) 8: 1.39-1.42 (t, 3H), 4.41-4.46 (q, 2H), 7.34-7.37 (m, 1H), 7.55 (s, 1H), 7.78-7.82 (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, s ammonium chloride on was added. The e was extracted with ethyl acetate. Combined organic layers was washed with water and concentrated under vacuum to provide title compound in 7.7 gm quantity. 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), 8.68-8.69 (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 ylamine (6.5 ml) in dichloromethane (40 ml) was added methanesulfonyl chloride (2.8 ml) at 0°C. The on mixture was stirred at 0°C over a period of 1 h. The on 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 ethanesulfonyloxymethyl-isoxazolyl)-pyridine (5.0 gm), lithium 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 suspension. 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- 0meth l-isoxazol-S- l - rimidine: Ste -1: 2- 3-Ethox carbon l-isoxazol l- imidine: To a mixture of 2-ethynyl-pyrimidine (28 gm) and hlorooxamidoacetate (45 gm) in e (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 d 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 n-hexane. The suspension was ﬁltered and the wet cake washed with small quantity of n-hexane to e title nd in 35.1 gm ty (59%) as a cream colored solid.

Mass: m/z: 220.1 (M+1) Ste -2: 2- 3-H drox meth l-isoxazol l- imidine: To a mixture of thoxycarbonyl-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 acetate (4.5 ltr). Combined organic layers was washed with water and concentrated under vacuum to provide crude mass in 23 gm quantity, which was tallized from ethanol to provide the title compound in 15.1 gm ty (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 stirred at 0°C over a period of 0.5 h. The reaction was quenched by addition of water and layers were ted. Organic layer was evaporated under vacuum to provide 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- 3-Bromometh l-isoxazol l- imidine: A mixture of ethanesulfonyloxymethyl-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 reaction 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 ide: 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. t 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 ty 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 ed 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 reagent (208 gm) and the mixture was stirred at 60°C over a period of 4 h.

Solvent was ated 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), 8.26-8.28 (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 e of thoxycarbonyl-1,3,4-thiadiazolyl)-pyridine (8 gm) in ethanol (80 ml), was added sodium borohydride (2.51 gm) in lots at 30°C. It was stirred at 30°C over a period of 2 h. The solvent was evaporated under vacuum to provide a crude mass. To the crude mass, water (100 ml) was added and it was extracted with dichloromethane (200 ml X 2). Combined organic layers was washed with water and trated under vacuum to provide title compound in 6.1 gm quantity (92%). 2011/050464 Hl-NMR(CDC13) 8: 4.87-4.88 (d, 2H), 6.264- 6.26 (bs, 1H), 7.54-7.57 (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 e 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 c layer was washed with aqueous sodium bicarbonate solution followed 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 e (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 stirred with ice-cold water to provide a suspension. The solid was ﬁltered under suction to afford the title compound in 6.5 gm ty (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 actonitrile (2.5 L) at 30°C was added w/v 50% aqueous sodium hydroxide (96.8 gm dissolved in 97 ml water) on 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 e a residue. The residue was d with water (750 ml) and the mixture was extracted with dichloromethane (300 ml X 5). The layers were separated and c layer was evaporated to provide title compound in 52 gm quantity (52%) as a low melting 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 ylformyl-pyrimidine (180 gm) and hydroxylamine hydrochloride (128 gm) in 50% v/v aqueous methanol (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 nd 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 hylsilylacetylene (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 ty which was used as it is for further reaction.

Step-4: 2-Methylisoxazol-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 e was stirred at 40°C up to 1 hr. The reaction mixture was ﬁltered. The solid obtained was washed with ethyl acetate and the ﬁltrate was evaporated under vacuum to provide a residue.

The residue was stirred 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 residue( 133 gm) which upon silica gel column chromatography 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).

Step-5: 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 tetrachloride (1200 ml) was heated to 75°C ature. The reaction mixture was stirred at 75°C for 24 h. The on mixture was ﬁltered under suction at 25°C to 35°C temperature. The solid was washed with carbon hloride (400 ml). The ﬁltrate was washed with ted aqueous sodium bicarbonate on (400 ml X 2) and evaporated under vacuum to provide a crude material (52 gm) which upon silica gel column chromatography afforded desired compound in 14 gm quantity (40%), dibromo compound in 16.8 gm and ng al 6.5 gm quantities.

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 on 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 acetate (150 ml X 3). The ed 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), palladium- 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 through celite. The ﬁltrate was stirred with water (250 ml) and ted with ethyl acetate (100 ml X 2). The ed organic extracts was dried over Na2804, and evaporated under vacuum. The ing crude mass was puriﬁed by using silica gel column chromatography (ethyl acetate / ) to yield title compound 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 starting material, it was concentrated under vacuum.

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

The combined c extract was washed with ted sodium bicarbonate solution (25 ml X 2) followed by brine solution (25 ml). The c layer was dried over NaZSO4, and concentrated under vacuum to e 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 -carbon l-amino 2-methanesulfon 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 dichloromethane (15 ml) was cooled to —50 C and treated with methanesulfonyl chloride (0.395 gm). As TLC showed completion of the on, 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 2-bromometh l- idin l- idine: A suspension of 2-di-(tert-butyloxy-carbonyl)-amino(2-methanesulfonyloxymethyl-pyridinyl )-pyridine (1.6 gm) and lithium bromide (435 mg) in acetone (17 ml) was heated at a reﬂux temperature for 3 hours. As TLC showed completion of on, the reaction mixture was cooled to ambient temperature. The suspension was ﬁltered under suction and trated under vacuum. The obtained residue was stirred with water (25 ml) and extracted with ethyl acetate (30 ml X 2). The combined c 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 ty 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 pyridincarbaldehyde-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 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- x carbon l-isoxazol 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 300 C over a period of 0.5 h. The on 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 (CDC13) 8: 1.39—1.42 (t, 3H), 4.41-4.46 (q, 2H), 7.34-7.37 (m, 1H), 7.55 (s, 1H), 7.78-7.82 (dt, 1H), 80881 (d, 1H), .68 (d, 1H).

Ste -3: 2- 5-H drox meth azol 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 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 provide 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: .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), .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 rtin 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 thiosulfate and sodiumbicarbonate aqueous solution. The layers were separated. Aqueous layer was extracted with dichloromethane. Combined organic layer was ated 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).

WO 76989 To a mixture of 2-(5-formyl-isoxazolyl)-pyridine (3 gm) in THF(30 ml) was added methyl ium 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), 8.66-8.68 (d, 1H).

Ste -6: RS 5- l-Bromoeth l-isoxazol l- ridine To a e of (RS)(5-(1-hydroxy-ethyl)-isoxazolyl)-pyridine (0.9 gm), and triphenylphosphene (1.77 gm) in romethane (20 ml) was added carbontetrabromide (6 gm) at 0° C. The reaction mixture was stirred 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. ed 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 ty (65%).

Hl-NMR (CDC13) 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 - ne Ste -1: 2- 3-Ethox carbon l-isoxazol l- imidine To a mixture of 2-ethynyl-pyrimidine (28 gm) and ethylchlorooxamidoacetate (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. on was allowed to cool at 30° C and water added. Organic layer was separated. Solvent was evaporated under vacuum and the crude mass was ated 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 quantity (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: toluene (6.5 ml: 5 ml) was added triethylamine (16.3 ml) followed by methyl magnesium iodide (28.6 ml, 1.4 M solution in THF) at 0° C. To the reaction mixture, was added 2-(3-ethoxycarbonyl-isoxazolyl)-pyrimidine (2.0 gm) dissolved in toluene (35 ml) in at 0° C over a period of 15 minutes. The on was stirred for 2 h.. It was quenched by addition of 1N aqueous hydrochloric acid (43 ml). It was extracted with toluene. Combined organic layers was washed with saturated sodium bicarbonate solution followed by water. Organic layer was evaporated under vacuum to e 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 ol (20 ml) was added sodium borohydride (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 residue. The residue was stirred with water and extracted with ethyl e (25 ml X3). Combined organic 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 without puriﬁcation for the next reaction.

Ste -4: RS 3- l-Bromoeth l-isoxazol l- ne A e of (RS)(3-(1-hydroxymethyl)-isoxazolyl)-pyrimidine (1.1 gm), in dichloromethane (20 ml) was added carbon romide (7.64 gm) ed 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 e 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. 2011/050464 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 sion 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- x 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 organic layer was washed with aqueous sodiumbicarbonate solution (100 ml). Organic layer was evaporated in vacuum to e crude mass in 110 gm quantity. To a crude mass in tetrahydrofuran (500 ml) was added Lowesson’s reagent (208 gm) and the mixture was stirred at 60° C over a period of 4 h. t 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.

Ste -3: 2- 5- 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 solution in THF) at -40° C over a period of 15 minutes. The on mixture was stirred for 2 h at -40° C. It was quenched by addition of aqueous ammonium chloride solution (20 gm) and stirred at 0° C over a period of 10 s. It was extracted with ethyl acetate (100 ml X 2). ed organic layers was washed with water and ated under vacuum to provide a title compound in 1.5 gm quantity (86%) as off white solid.

Hl-NMR (CDCl3) 8: 2.84(s, 3H), 7.25-7.46(m, 1H), 7.86-7.9 (m, 1H), .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 mixture 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). ed 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 mixture of (RS)(5-(l-hydroxy-ethyl)-l,3,4-thiadiazolyl)-pyridine (1.0 gm), and triethylamine (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 on 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 ated 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 bromide (0.5 gm) in acetone (20 ml) was d 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 combined organic layer was evaporated under vacuum to afford the title compound in 0.8 gm quantity (85%) as oil.

Hl-NMR (CDCl3) 8: 2.2 (d, 2H), 5.51-5.57 (q, 1H), 7.38-7.41 (m, 1H), .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 4-thiadiazol 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 solution of dicyclohexylcarbodimide (11.19 gm) in romethane (25 ml). The reaction mixture was d 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 d by silica gel column chromatography to e 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 methanol (25 ml) to e a clear solution. The reaction mixture was allowed stir at 25° C for 0.5 h to provide itation. 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 d under suction to e a solid. The solid was dried to provide diastereomer-2 in 3.8 gm quantity as a solid. Filtrate was enriched with diastereomer-1.

HPLC ratio of diastereomer-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 dissolved 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 ted with dichloromethane (100 ml X 2). Combined organic layer was washed with saturated sodium bicarbonate solution. Layers were separated 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), 7.45-7.48 (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 ed by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane. Combined organic layer was washed with s sodium bicarbonate solution followed 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 n of R u 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 stirred 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 evaporated 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 2-picolinic acid (258 gm), ert—butyl-dimethylsilyloxy)- propionic acid ide (415 gm) in DMF (1000 ml) was added EDC hydrochloride (546 gm) followed by N—methyl morpholine (418 ml) over a period of 0.5 h at 0° C to 5 ° C. HOBt (29 gm) was added in one lot. Additional DMF (245 ml) was added. The resulting suspension was stirred for 2 hr at 25° C. The reaction e 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 trated in vacuum to e syrup as a title compound in 602 gm quantity 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 ng. 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 extracted with ethyl acetate (2000 ml X 2). The combined organic 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 n of R-l- 5- idin l- 1 3 4 thiadiazol 1 -ethanol To a mixture of R {5-[1-(tert-butyl-dimethylsilyloxy)-ethyl]-1,3,4-thiadiazolyl}- pyridine_(568 gm), in itrile (1800 ml) was added 2N aqueous hydrochloric acid (1800 ml) in one lot under stirring at 32° C. It was d over a period of 19 hr. The reaction mixture was poured in aqueous 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 ted with ethyl acetate (1000 ml X 2). Combined organic layer was dried over sodium e 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- henylsulfonyl chloride (246 gm) dissolved in dichloromethane (500 ml) at 10°C under stirring. 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 d in a mixture of dichloromethane (250 ml) and diethyl ether (500 ml) at 30° C. The suspension was ﬁltered atsuction and washed with a mixture of dichloromethane:diethyl ether mixtire (1:2 ratio, 300 ml). the solid was dried under vacuum to provide title compound in 410 gm quantity 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 e (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, followed by freshly powdered potassium ide (1.57 g) in one lot.

The reaction mixture was stirred for 3.5 h at 30° C. After TLC check the reaction was ﬁltered under n to remove salts. The ﬁltrate was concentrated to complete dryness under vacuum below 45° C to provide a 19 gm . 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 aration of 11S21R decladinos l-11 12-dideox O-meth o-2’-O- trieth lsil l-12 11- ox carbon 1- E- -ben lox -carboxamidino meth lene -e hrom cin To the stirred on of N—chlorosuccinimide (7.5 gm) in dichloromethane (75 ml) was added dimethyl sulﬁde (4.8 ml) at -150 C. The on 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 ing reaction 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 organic layer was concentrated under vacuum to dryness to provide 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 powder. The powder was d in methanol (42 ml) and ﬁltered to provide 11.2 gm (66%) title compound as a white solid (HPLC purity 97.3%).

MS = (m/z) = 874.2 (M+1) Ste -3: Pre aration 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 product (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 mixture was d for 0.5 h at -150 C. To the on 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 ved in ethyl acetate (200 ml) and was washed with 0.5 M aqueous sodium hydroxide solution (50 ml). The c layer separated and evaporated under vacuum to dryness to provide title compound as a solid in 10.3 gm (91.8%) ty (HPLC purity 90.12%).

MS: m/z = 892.2 (M+1) Ste -4: Pre n 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 e of 10% Pd on carbon (1.35 gm) and 20% Pd(OH)2 (1.35 gm). The reaction e 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 dryness to provide 6.7 gm solid, which was stirred with n-pentane (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)- 3-decladinosyl-1 1, 1 2-dideoxyO-methyl-2’-O-triethylsilyl- 12,1 1- rbonyl-[E-(N—hydroxy)-carboxamidino]methylene}-erythromycin A in toluene is d in the presence of base such as potassium hydride or potassium tertbutoxide 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 bromide, or appropriate ester such as mesylate, tosylate or nosylate and R1, P and Q are as bed, at a temperature ranging from ° C to 35° C to provide corresponding 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 s (made from NCS and DMS) in dichloromethane at a temperature g from -50° C to 10° C to provide corresponding 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)- carboxamidino]methylene}-erythromycin-A is reacted with silyl deprotecting agent such as pyridine-hydrogenﬂuoride, or aqueous hydrochloric acid, in acetonitrile at a temperature g from 20° C to 35 ° C to provide the ketolide compound of formula (I) where R3 is H.

For the nds 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) ed as above, where Q bears a tuent such as O-benzyloxy, the benzyl group was ected by stirring it with 10% palladium on carbon under en pressure in ol at 25° C to 35° C followed by puriﬁcation to provide ketolide compound of formula (I).

General rocedure 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 d in the presence of suitable base such as ium hydride or potassium tertbutoxide 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 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 ideoxyﬁuoroO-methyl-3 -oxo-2’-O-triethylsilyl- 12,1 1- {oxycarbonyl-[E-(N— heteroaryl-heteroaryl-(RS) or (R) or (S)-alkoxy)-carboxamidino]methylene}-erythromycin-A.

The compound (11$,21R)- 3-decladinosyl-11,12-dideoxyﬁuoroO-methyl oxo-2’-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 aqueous hydrochloric acid, in acetonitrile at a temperature 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) ed as above, where Q bears a substituent such as t-butoxycarbonylamino, the t-butoxycarbonyl group was deprotected by ng 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 ected by ng 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 embodiments of the invention that are tly best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the ples of the present invention. Numerous modiﬁcations and alternative itions, s, and systems 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 t 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 o-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 12-dideox fluoroO-meth loxo- rieth lsil 1 ox carbon 1- E-N— 5- imidin—2- l-isoxazol l-methox - carboxamidino methylene k -emhromycin A: To the stirred 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 stirred for 5 minutes. To the reaction mixture, 2-(3-bromomethyl-isoxazolyl)- pyrimidine (2.9 gm) was added. The reaction mixture was stirred for 30 minutes. It was quenched by g it in aqueous saturated ammonium chloride on (50 ml) under stirring. The mixture was extracted with ethyl acetate (250 ml X 2). Combined c 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 % e in hexane) to provide title compound as step-1 t 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 ladinos 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- rbonyl- [E-N—(5-pyrimidin—2-yl-isoxazol-3 -yl)-methoxy] - carboxamidino] ene}-erythromycin A (5 gm) ed 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 atmosphere. After completion 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 compound of example-1 in 3.1 gm quantity as a white solid in 71% yield.

MS: m/z: 847.1 (M+1) Following examples were ed 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- 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 -Bromomethyl- 193-194 isoxazol-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 Butyloxycarbonylamino- 202-204 -(5-br0m0methy1—1,3 ,4- thiadiazoly1)-pyridine 2-(5-Br0m0methyl- 1,3 ,4- 207-210 azoly1)-pyridine 2-(3 -Br0m0methy1— 196- 197 isoxazol-S-y1)-pyrazine 2-tert- Butyloxycarbonylamino- 178-180 -(5-br0m0methy1—1,3 ,4- thiadiazol-2—y1)-pyrazine 6-tert-Buty10xy ylamino-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 y1)-amin0(2- 150-152 bromomethyl-pyridin y1)-pyridine. -buty10xy carbonylamino-Z-(3- - 862.1 bromomethyl-isoxazol-5 - yl)-pyrimidine. 2011/050464 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- rbonyl-[E-(N—hydroxy)- amidino]methylene}-erythromycin A (3.5 g) in e (50 ml) was added potassium hydride (0.07 g, 30% suspension in mineral oil), 18-crownether (0.2 g) followed by (R) (5-(1-nosyloxy-ethyl)-1,3,4-thiadiazolyl)-pyridine (1.5 gm) at 00 C temperature. The reaction e was stirred for 4 h. It was quenched by pouring it in aqueous saturated 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 product 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 e 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 quenched with addition of s sodium bicarbonate 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 d under suction. The solid was washed water followed by ether to afford crude nd, which was puriﬁed by recrystalization using ethyl acetate and methanol 2011/050464 (1:4) to provide 2—ﬂuoro-ketolide compound of invention 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 ues of respective side chains: Side chain used for coupling (S)tert— Butyloxycarbonylamino [5-(1- methanesulfonyloxy -ethyl)-1,3 ,4-thiadiazol-2— yl]-pyridine (R)tert- Butyloxycarbonylamino [5-(1- methanesulfonyloxy -ethyl)-1,3 ,4-thiadiazol-2— yl] -pyridine (R)[5-(1- esulfonyloxyethyl 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 -tertbutyloxycarbonylamino [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 tertbutyloxycarbonylamino [3 sy10xy-ethyl)- isoxazol-S-y1]—pyridine (RS)[5-(1-nosy10xy- propyl)-thiadiazol-2—yl] - pyridine Example 31: erythromycin A Ste -1: Pre n of 11S 21R decladinos l-11 12-dideox O-meth l-2’-O- ethoxy -carboxamidino methyleneE-erﬂhromycin A To the stirred solution of (11S,21R)- 3-decladinosyl-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 ium 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 ature. 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). Combined organic layer was dried over NazSO4 ated under vacuum to provide a crude mass which was puriﬁed by using silica gel column chromatography (15 % Acetone:Hexane) to e step-1 product in 1.5 gm quantity (80%) as a off white solid.

MS = (m/z) = 975.3 (MT) Ste -2: Pre aration of 11S 21R decladinos l-11 eox 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 N—chlorosuccinimide (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 on e at -400 C. The ing 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 reaction mixture was poured in aqueous saturated sodium bicarbonate solution (20 ml) and the mixture was extracted with dichloromethane (50 ml X 2). The combined c 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%). 2011/050464 MS = (m/z) = 973.4 (MT) Ste -3: Pre aration of 11S 21R decladinos l-11 12-dideox eth loxo ox carbon 1- E-N— 1- 5- - 1-1 3 4-thiadiazol l - RS -ethox - carboxamidino methylene § -erﬂhromycin A The mixture of step-2 product (1.2 gm) and 70% HF-pyridine solution (0.2 ml) in itrile (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 evaporated under vacuum to obtain crude mass. The crude mass was puriﬁed by using silica gel column tography (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) proportion. M.p. = 135-1370 C, MS = (m/z) = 859.3 (M+) Example 32: 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 - R -ethox -carboxamidin0 ene {-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 eox O-meth loxo-12 11- 0x carbon 1- E-N- 1- 5- ridin 1-1 3 4-thiadiazol l - S -eth0x - carboxamidino |methylene {-erythromycin A : Utilizing the same HPLC ions, 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 ues of respective side chains followed by preparative HPLC separation of diastereomeric mixture.

Example No 1 Side chain used for Mp Mass coupling (°C) (M+1) (RS)[5-(1-bromo- ethyl)-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 ethyl)-isoxazoly1]— pyridine 42 112-114 (RS)[3-(1-br0m0- propyl)-isoxaz01—5 -y1] - 43 6 pyridine 173-175 204-206 (RS)-[5-(1-br0m0-ethy1)- 1,3 adiazoly1] - pyrimidine 170-172 164-166 (RS)tert- butyloxycarbonylamino- 1-br0m0-ethy1)- 170-172 1,3 ,4-thiadiazoly1] - 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 ate 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- amidino methylene § -erﬂhr0mycin A To the stirred solution of (1 IS, 21R)- 3-decladin0syl-11, 12-dide0xyO-methyl-2’- O-triethylsilyl- 12, 1 1- {oxycarbonyl- [E-(N-hydroxy)-carb0xamidin0]methylene} - erythromycin A (35.0 g) in toluene (350 ml) was tially 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 e 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 on (200 ml) as TLC showed complete conversion of starting material. (TLC system: hexane:ethyl e: diethylamine 5:5 :2). The mixture was extracted with ethyl acetate (250 ml X 2). Combined organic layer was washed with brine and dried over NaZSO4, evaporated under vacuum to provide a crude mass as yellow foam in 47 gm ty, which was used as it is, for the next on.

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 dichloromethane (180 ml) was added dimethyl sulﬁde (11.2 ml) at -200 C to -15° C. The reaction 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 mixture at -50° C to -400 C via addition funnel. The resulting reaction e was stirred at -40° C -35° C temperature for 3 hr.

Triethyl amine (15.6 ml) was added at -40° C and stirred until reaction mixture became clear at 30° C. To the reaction mixture was added under stirring ethyl acetate (880 ml) followed by 0.5 N aqueous sodium hydroxide solution (410 ml). The layers were ted after 30 s ng. It was washed successively with water (410 ml) followed by brine solution (410 ml). The organic layer was dried over Na2S04 and ated under vacuum to provide yellow foam in 49 gm quantity, 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 ene § -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 mixture was cooled to 25° C and ted 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) ethanol (84 ml).

The suspension 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 tive 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 adiazoly1] - benzene (R)benzy10xy[5-(1- nosyloxy-ethy1)-1,3 ,4- thiadiazol-Z-yl] -pyridine (R)-3 -[2-(1-nosy10xy- ethyl)-pyrimidin-5 -y1] - isoxazole (R)tertbutyloxycarbonylamino 858.0 6- [3 -( 1 -nOSy10xy- - 172 isoxazol-S-y1]—pyridine (R)benzyloxy[5-(1- nosyloxy-ethyl)-isoxazol- 2-y1]—pyridine (RS)[5-(2- l dimethylsilyloxy nosyloxy-ethyl)-1,3 ,4- thiadiazol-Z-yl]—pyridine (RS)[5-(1-nosyloxypropyl )-thiadiazol-2—yl] - pyridine Biological Protocols & ties 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) ing 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 d with buffered saline (pH 7.2) to the ﬁnal cell density of 5 x 7 , 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 um 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 Visible microbial growth on agar.

The compounds of the invention inhibited the growth of these bacteria with MICs in the range of about 0.007-0.25 mcg/ml (S pneumoniae sensitive 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 ), 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 strain, MIC Telithromycin MIC 16.0 mcg/ml), l- 8 mcg/ml (H zae, Telithromycin MIC 40- 8.0 mcg/ml).

In vivo Evaluation of compounds of the invention The in vivo efficacy of compounds of the invention was evaluated by determining ED50 by oral administration of nds 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 ion. 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 ion showed superior oral efﬁcacy against S. pneumoniae 3773 infection in mice (ED50 6.25 - 50 mg/Kg) compared to Telithromycin (ED50 75 - 100 mg/Kg) The Claims defining the invention are as s: 1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, e, 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 en; P is heteroaryl ring; Q is unsubstituted or substituted aryl or aryl ring; and P is attached to Q via carbon-carbon link; and R3 is fluorine. 2. A compound as d 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; 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; 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 compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; R1 is hydrogen; R3 is fluorine, P is 5-membered aryl ring such as isoxazole or thiadiazole; Q is unsubstituted or substituted aryl or 6-membered heteroaryl ring with up to two nitrogens; and P is attached to Q via carbon-carbon link.

. A compound as claimed in Claim 1, 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 tituted or substituted aryl or 5 or 6-membered heteroaryl ring with up to two heteroatoms; and P is ed to Q via carbon-carbon link. 6. A nd as d in Claim 1, 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 tituted or substituted pyridine or pyrimidine; and P is attached to Q via carbon-carbon link. 7. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; R1 is hydrogen; R3 is fluorine, P is thiadiazole; Q is unsubstituted or substituted pyridine or pyrimidine; and 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; R3 is fluorine, P is isoxazole; Q is unsubstituted or substituted pyridine or pyrimidine; and P is ed to Q via carbon-carbon link. 9. A nd as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; R1 is hydrogen; R3 is fluorine, P is thiadiazole; Q is ne or dine; and P is attached to Q via carbon-carbon link.

. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; R1 is en; 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, 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. 12. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; R1 is hydrogen; R3 is fluorine, P is pyrimidine; Q is isoxazole; and P is attached to Q via carbon-carbon link. 13. A compound as d in Claim 1, ed from: a compound of formula (I) wherein T is [3-(pyrimidinyl)-isoxazolyl]- CH2- and R3 is F; a nd of formula (I) wherein T is [5-(isoxazolyl)-pyrimidinyl]- CH2- and R3 is F; a compound of formula (I) wherein T is [5-(pyrimidinyl)-isoxazolyl]- CH2- and R3 is F; a compound of formula (I) wherein T is [5-(2-amino-pyridinyl)-isoxazol 2- 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 [2-(2-amino-pyridinyl)-1,3,4- thiadiazolyl]-CH2- and R3 is F; a nd 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- thiadiazolyl]-CH2- and R3 is F; a compound of formula (I) wherein T is [2-(pyridinyl)-1,3,4-thiadiazol yl]-CH2- and R3 is F; a compound of formula (I) wherein T is [5-(pyrazinyl)-isoxazolyl]-CH2- and R3 is F; a compound of formula (I) wherein T is [2-(6-amino-pyrimidinyl)-1,3,4- thiadiazolyl]-CH2 and R3 is F; a compound of formula (I) wherein T is [2-(3-amino-phenyl)-1,3,4-thiadiazol- CH2- and R3 is F; a compound of formula (I) wherein T is [2-(2-amino-pyridinyl)-pyridin yl]-CH2- and R3 is F; and a compound of formula (I) wherein T is amino-pyrimidinyl)-isoxazol- 3-yl]-CH2- and R3 is F. 14. A compound as claimed in Claim 1, selected from: a compound of formula (I) wherein T is [5-(isoxazolyl)-pyrimidinyl]- CH2- and R3 is F; and a compound of formula (I) wherein T is [2-(pyrimidinyl)-1,3,4-thiadiazol- CH2- and R3 is F.

. A compound as claimed in Claim 1, wherein: T is ?C*H(R1)-P-Q; 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-carbon link. 16. A compound as d in Claim 1, selected from: 1R)decladinosyl-11,12-dideoxyfluoroO-methyloxo-12,11- {oxycarbonyl-[E-N-[(5-pyrimidinyl-1,3,4-thiadiazolyl)-methoxy]- 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- {oxycarbonyl-[E-N-[(5-isoxazolyl-pyrimidinyl)-methoxy]- carboxamidino]methylene}-erythromycin A O NH O HO N N O O H O O . 17. A process for preparation of a compound of formula (4-e) N N Br 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 a (4-b) to a compound of formula (4-c); X N Si N 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 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 defined 19-a O NH 2 O O N N O O H O 19-c (ii) ting a compound of formula (19-c) to a compound of a (19-d). 19. 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 OTBDMS 3 OTBDMS O O NH -a 15-b (ii) converting a compound of formula (15-b) to a compound of a (15-c); OTBDMS O O -c (iii) converting a compound of formula (15-c) to a nd of formula (15-d) TBDMSO 3 N -d (iv) converting a compound of formula (15-d) to a compound of a (15-e); and 3 N -e (v) converting a nd of formula (15-e) to a compound of formula (15-f).

. A process for preparation of a compound of formula (16-d) S O N N S 16-d 2 comprising: (i) reacting pyrimidinecarbonylchloride with a compound of formula (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 a (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); 3 N 16-c (iv) converting a nd of formula (16-c) to a compound of formula (16-d). 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) ting a compound of formula (17-a) to a compound 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 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). 22. A pharmaceutical ition comprising therapeutically effective amount of a compound of formula (I) as d 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. 24. The use of a compound of formula (I) as claimed in any one of Claims 1 to 16 for the manufacture of a medicament for the treatment of infection caused by a microorganism.

. The use of a compound of formula (I) as claimed in any one of Claims 1 to 16 for the manufacture of a ment for the lactic 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 ed from a bacteria, fungi, protozoa, yeast, mold, or mildew. 27. A compound of any one of Claims 1 to 16, substantially as hereinbefore described. 28. A process of any one of Claims 17 to 21, substantially as hereinbefore described.

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.