WO2015071780A1

WO2015071780A1 - Alkylidine substituted heterocyclyl derivatives as anti-bacterial agents

Info

Publication number: WO2015071780A1
Application number: PCT/IB2014/061104
Authority: WO
Inventors: Takhi Mohamed; Subramanya Hosahalli; Sunil Kumar Panigrahi
Original assignee: Aurigene Discovery Technologies Limited; Um Pharmauji Sdn. Bhd
Priority date: 2013-11-12
Filing date: 2014-04-30
Publication date: 2015-05-21

Abstract

The present invention relates to alkylidine substituted heterocyclyl derivatives of formula (1) which may be therapeutically useful as as anti-bacterial agents, more particulalrly FabI inhibitors; I in which P, Q, Ri, R2, R3 and "n" have the same meanings given in the specification, and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting Enoyl-ACP reductase enzyme (FABI) activity. The present invention also provides methods for synthesizing and administering the FabI inhibitory compounds. The present invention also provides pharmaceutical formulations comprising at least one of the FabI inhibitory compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

Description

ALKYLIDINE SUBSTITUTED HETEROCYCLYL DERIVATIVES AS ANTIBACTERIAL AGENTS

This application claims the benefit of Indian provisional application number 5133/CHE/2013 filed on 12^th November 2013, which hereby incorporated by reference. FIELD OF INVENTION

The present invention relates to alkylidine substituted heterocyclyl derivatives of formula (1) which are useful as anti-bacterial agents. The present invention also relates to the preparation of compounds of formula (1) and their use for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder associated where there is an advantage in inhibiting Enoyl-ACP reductase enzyme (FABI) activity.

BACKGROUND AND PRIOR ART

Fatty acid biosynthesis (or Fab) is an essential metabolic process for all living organisms. It is used to synthesize the metabolic precursors for membrane phospholipids in the cell wall. Fatty acids are synthesized by mammals (using enzyme FAS I) and bacteria (using enzyme FAS II) via substantially different biosynthetic mechanisms, thus providing the possibility of bacteria-specific drug targeting. Indeed, inhibitors targeting the various stages of the fatty acid biosynthetic pathway have been investigated as novel anti-bacterial agents. Broadly, the pathway of saturated fatty acid biosynthesis (FAB) is more or less similar in all organisms, however, the fatty acid synthase (FAS) enzymatic biosynthesis systems vary considerably with respect to their structural organization. Mammalian fatty acid synthesis (FAS-I) employs a multifunctional enzyme complex in which all enzymatic activities reside on a single polypeptide. In contrast, bacterial fatty acid synthesis (FAS-II) elongation cycle utilizes several distinct monofunctional enzymes with activity pertaining to respective enzyme peptides effecting fatty acid chain elongation and ultimately cell membrane production. Enoyl acyl carrier protein reductase (Fabl) is the component of FAS- II that catalyzes the final reaction in the enzymatic sequence. Hence, there appears to be considerable scope for the selective inhibition of the bacterial FAS system enzymes by exploring newer anti-bacterial agents.

Fabl (a protein enzyme encoded by EnVM gene) acts as an enoyl-ACP reductase (Bergler, et al, (1994), J. Biol. Chem. 269, 5493-5496) in the final step of the reactions involved in each cycle of bacterial fatty acid biosynthesis. Further rounds of this cycle, adding two carbon atoms per cycle, eventually lead to palmitoyl-ACP (16- Carbon), and subsequently the cycle is blocked largely due to feedback inhibition of Fabl by palmitoyl- ACP (Heath, et al, (1996), J. Biol. Chem. 271 , 1833-1836).

Thus, FabI is among one of the major biosynthetic enzymes and appears to be a key moderator in the overall bacterial fatty acid biosynthetic pathway. Therefore, FabI may be one of the meaningful target for acquiring anti-bacterial role.

Though there is plethora of literature on FabI, which provides different inhibitors, however, among promising literature, it reveals that diazaborine (an antibiotics) inhibit fatty acid, phospholipid and lipopolysaccharide (LPS) biosynthesis via FabI as one of the antibacterial targets. Grassberger, et al in /. Med Chem 27, 947-953 (1984) reported derivative of 2b 18 (a peptide) possessing non-competitive inhibitory activity of FabI (Bergler, et al, (1994) J. Biol. Chem. 269, 5493-5496). Bergler et al in J. Biol. Chem. 269, 5493- 5496(1994) reported that inhibition of FabI either by diazaborine or by raising the temperature in a FabI temperature sensitive mutant is lethal. These results demonstrate that FabI appears to be essential for the survival of the organism. McMurry et al in Nature 394, 531 -532 (1998) have shown that FabI is also the target for the well known broad spectrum anti-bacterial agent triclosan. Recent literature including US7790716, US7741339, US7557125, US7524843, US7250424, US7049310, US6846819, US6765005, US6762201 , US6730684 and US6503903 also reveals that diverse compounds are known to possess FabI inhibitory activity and have anti-bacterial role, and, therefore, may be useful for the treatment of bacterial infections in mammals, particularly in man.

International patent applications WO2013021054A1 , WO2013021052A1,

WO2013021051A1 , WO2013080222A1, WO2011061214A1 and WO2008009122A1 also disclosed the compounds possesing FabI inhibitory activity and are used as anti-bacterial agents.

Further various antimicrobial resistances among clinical isolates have been observed as one of the major problems in recent years. Of particular concern has been the increasing incidence of methicillin-resistant Staphylococcus spp., vancomycin-resistant Enterococcus spp., and penicillin-resistant Streptococcus pneumoniae.

Despite various disclosures on FabI inhibitors, however, with the rise in number of patients affected by diverse bacterial and related microbial diseases and drug resistance, there appears to be unmet need for newer drugs that can treat such diseases more effectively. There is still need for newer anti-bacterial agents, which may be further useful in a wide variety of bacterial infections and possessing broader spectrum. SUMMARY OF THE INVENTION

The present invention relates to alkylidine substituted heterocyclyl derivatives of formula (1) useful as anti-bacterial agents.

In one aspect of the present invention, it relates to compound of formula (1):

or pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, wherein,

P-Q is a linker selected from -C-, -C-C-, -C-0-, -C-C-C-, -C-N-C-, -C-0-C-; wherein P-Q linker is optionally substituted with one or more R5 to meet the desired valency requirements;

Ri is se logen, nitro, cyano, hydroxyl and alkyl;

R₂ is

wherein, Ring A is optionally substituted 4-6 membered monocyclic ring containing 0-2 heteroatoms independently selected from N and S; wherein the optional substituent at each occurrence is independently selected from one or more R4;

R3 is selected from hydrogen and alkyl;

R4 is selected from halogen, alkyl and alkoxy;

each R5 is independently selected from halogen, alkyl, cyano and -C(0)Oalkyl; alternatively, two of the R5 groups on the same carbon atom can be taken together to form a 3-6 membered spiro ring optionally containing a heteroatom, wherein the heteroatom is Ό' ;

'n' is an integer selected from 1 and 2; and

'p' is an integer selected from 0 and 1.

In a further aspect of the present invention, it relates to the pharmaceutical composition comprising alkylidine substituted heterocyclyl derivatives of formula (1) and processes for preparing thereof.

In yet further another aspect of the present invention, it relates to the use of novel alkylidine substituted heterocyclyl derivatives of formula (1), its pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, including mixtures thereof in all suitable ratios wherever applicable as a medicament for the treatment and prevention of disorder or diseases by inhibitory action on enzymes- Fabl or FabK or both.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present application provides novel alkylidine substituted heterocyclyl derivatives of formula (1) useful as anti-bacterial agents.

One of the embodiment of the present invention provides compound of formula (1):

P-Q is a linker selected from -C-, -C-C-, -C-0-, -C-C-C-, -C-N-C-, -C-0-C-; wherein P-Q linker is optionally substituted with one or more R₅ to meet the desired valency requirements;

Ri is se logen, nitro, cyano, hydroxyl and alkyl;

R₂ is

R3 is selected from hydrogen and alkyl;

R4 is selected from halogen, alkyl and alkoxy;

'n' is an integer selected from 1 and 2; and

'p' is an integer selected from 0 and 1.

The embodiment below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. According to one embodiment of the present invention, specifically provided are compounds of formula (1), in which Ri and R₃ are hydrogen.

According to another embodiment of the present invention, specifically provided are compounds of formula (1), in which R₂ is

According to preceding embodiment, specifically provided are compounds of formula (1), in which Ring A is selected from thiophene, thiazole and optionally substituted phenyl.

According to preceding embodiment, specifically provided are compounds of formula (1), wherein the optional substituents are selected from halogen, alkyl and alkoxy; in particular halogen is fluoro, alkyl is methyl and alkoxy is methoxy.

According to yet another embodiment of the present invention, the compound of formula (1) is a compound of formula l a):

wherein, Ri, R2, R3, R5 and 'n' are same as defined in formula (1).

According to preceding embodiment, specifically provided are compounds of formula (l a), in which R₂ is selected from thiazole and phenyl.

According to one of the preceding embodiments, specifically provided are compounds of formula (l a), in which R₅ at each occurrence is alkyl; in particular alkyl is methyl.

According to further yet another embodiment of the present invention, the compound of formula (1) is a compound of formula (lb)

wherein,

Ri, R₂, R₃, R5 and 'n' are same as defined in formula (1); and

X is selected from C and O.

According to preceding embodiment, specifically provided are compounds of formula (lb), in which R₅ at each occurrence is selected from hydrogen and alkyl; in particular alkyl is methyl and ethyl.

According to an embodiment of one of the preceding embodiments, specifically provided are compounds of formula (lb), in which two of the R5 groups on the same carbon atom can be taken together to form a 3-6 membered spiro ring optionally containing a heteroatom, wherein the heteroatom is Ό'.

According to preceding embodiment, specifically provided are compounds of formula (lb), wherein the spiro ring is cyclopropyl and pyran.

Accoording to further yet another embodiment of the present invention, the compound of formula (1) is a compound of formula (lc)

wherein,

X is selected from C, O and NR₅; and

Ri, R₂, R3, R5 and 'n' are same as defined in claim 1.

According to preceding embodiment, specifically provided are compounds of formula (lc), in which R₅ is hydrogen and -C(0)Oalkyl; in particular alkyl is tert-butyl.

In yet another particular embodiment of the present invention, the compound of formula (1) is selected from the group consisting of

(£)-6-(3-(3-benzylideneazetidin-l-yl)-3-oxoprop-l-en-l-yl)-3,4-dihydro-l,8- naphthyridin-2( 1 H)-one (Compound- 1 ) ;

(£)-6-(3-oxo-3-(3-(thiazol-2-ylmethylene)azetidin- l-yl)prop-l-en-l-yl)-3,4-dihydro- 1 ,8-naphthyridin-2(l H)-one (Compound-2) ;

(£)-3-(3-(3-benzylideneazetidin-l-yl)-3-oxoprop-l-en-l-yl)-6,7-dihydro-5H- pyrido[2,3-b]azepin-8(9H)-one (Compound-3);

(£)-3-(3-(3-(4-fluorobenzylidene)azetidin-l -yl)-3-oxoprop-l-en-l-yl)-6,7-dihydro- 5 H-pyrido [2, 3 -b ] azepin- 8 (9H) -one (Compound-4) ; (£)-3-(3-(3-(4-methoxybenzylidene)azetidin-l-yl)-3-oxoprop-l-en-l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound-5);

(£)-3-(3-oxo-3-(3-(thiazol-2-ylmethylene)azetidin- l-yl)prop-l-en-l-yl)-6,7-dihydro- 5 H-pyrido [2, 3 -b ] azepin- 8 (9H) -one (Compound-6) ;

(£)-7-(3-(3-benzylideneazetidin-l-yl)-3-oxoprop-l-en-l-yl)-3,5-dihydropyrido[2,3- e][l ,4]oxazepin-2(lH)-one (Compound-7);

(£)-7-(3-oxo-3-(3-(thiazol-2-ylmethylene)azetidin- l-yl)prop-l-en-l-yl)-3,5- dihydropyrido[2,3-e][l ,4]oxazepin-2(lH)-one (Compound-8);

(£)-5-(3-(3-benzylideneazetidin-l-yl)-3-oxoprop-l-en-l-yl)-3,3-dimethyl-lH- pyrrolo[2,3-b]pyridin-2(3H)-one (Compound-9);

(£)-3,3-dimethyl-5-(3-oxo-3-(3-(thiazol-2-ylmethylene)azetidin-l-yl)prop-l-en-l- yl)- 1 H-pyrrolo [2,3 -b]pyridin-2(3H)-one (Compound- 10) ;

(Z?)-6-(3-oxo-3-(3-(2-phenylethylidene)azetidin- 1 -yl)prop-l -en- 1 -yl)-3 ,4-dihydro- 1 , 8 -naphthyr idin-2 ( 1 H)-one (Compou nd- 11);

(Z?)-3-(3-oxo-3-(3-(2-phenylethylidene)azetidin- 1 -yl)prop-l -en- 1 -yl)-6 ,7-dihydro- 5 H-pyrido [2, 3 -b ] azepin- 8 (9H) -one (Compound- 12) ;

(£)-3-(3-oxo-3-(3-(2-(thiophen-2-yl)ethylidene)azetidin-l-yl)prop-l-en-l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound- 13);

(£)-3,3-dimethyl-6-(3-oxo-3-(3-(2-phenylethylidene)azetidin- 1 -yl)prop- 1 -en- 1 -yl)- 3,4-dihydro-l ,8-naphthyridin-2(lH)-one (Compound- 14);

(£)-6-(3-(3-(2-(4-fluorophenyl)ethylidene)azetidin-l-yl)-3-oxoprop-l-en-l -yl)-3,3- dimethyl-3 ,4-dihydro- 1 ,8 -naphthyridin-2( 1 H)-one (Compound- 15);

(£)-3,3-dimethyl-6-(3-oxo-3-(3-(2-(m-tolyl)ethylidene)azetidin-l-yl)prop-l-en-l- yl)-3 ,4-dihydro- 1 , 8-naphthyridin-2( 1 H)-one (Compound- 16) ;

(£)-3,3-dimethyl-6-(3-oxo-3-(3-(2-(thiophen-2-yl)ethylidene)azetidin-l-yl)prop-l- en- 1 -yl)-3 ,4-dihydro- 1 ,8 -naphthyridin-2( 1 H)-one (Compound- 17) ;

(£)-3,3-diethyl-6-(3-oxo-3-(3-(2-(thiophen-2-yl)ethylidene)azetidin-l-yl)prop-l-en- 1 -yl)-3,4-dihydro- 1 ,8-naphthyridin-2(lH)-one (Compound- 18);

(£)-2,2-dimethyl-7-(3-oxo-3-(3-(2-(thiophen-2-yl)ethylidene)azetidin-l-yl)prop-l- en-l-yl)-2H-pyrido[3,2-b][l ,4]oxazin-3(4H)-one (Compound-19);

(£)-6-(3-oxo-3-(3-(2-phenylethylidene)azetidin-l-yl)prop-l-en-l-yl)-2',3',5',6'- tetrahydro-lH-spiro[[l ,8]naphthyridine-3,4'-pyran]-2(4H)-one (Compound-20);

(£)-6-(3-oxo-3-(3-(2-(thiophen-2-yl)ethylidene)azetidin-l-yl)prop-l-en-l-yl)- 2\3',5',6'-tetrahydro-lH-spiro[[l ,8]naphthyridine-3,4'-pyran]-2(4H)-one (Compound-21); (Z?)-tert-butyl 2-oxo-7-(3 -oxo-3-(3-(thiazol-2-ylmethylene)azetidin- 1 -yl)prop- 1 -en- l-yl)-2,3-dihydro-lH-pyrido[2,3-e][l,4]diazepine-4(5H)-carboxylate (Compound-22);

(£)-6'-(3-oxo-3-(3-(thiazol-2-ylmethylene)azetidin- l-yl)prop-l -en- 1-yl)- 1 Ή- spiro[cyclopropane-l,3'-[l ,8]naphthyridin]-2'(4'H)-one (Compound-23);

(£)-6-(3-oxo-3-(3-(thiazol-2-ylmethylene)azetidin- l-yl)prop-l-en-l-yl)-2',3',5',6'- tetrahydro-lH-spiro[[l ,8]naphthyridine-3,4'-pyran]-2(4H)-one (Compound-24);

(Z?)-7-(3-oxo-3-(3-(miazol-2-ylmethylene)azetidin- 1 -yl)prop- 1 -en- 1 -yl)-4,5-dihydro- lH-pyrido[2,3-e][l,4]diazepin-2(3H)-one hydrochloride (Compound -25);

33-dimethyl-6-((£T)-3-oxo-3-((£ )-3-(thiazol-4-ylmethylene)pyrrolidin-l-yl)prop-l - en-l-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one (Compound-26); and

33-dimethyl-6-((^-3-oxo-3-((Z)-3-(thiazol-4-ylmethylene)pyrrolidin-l-yl)prop-l - en-l-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one (Compound-27),

or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof.

In further yet another particular embodiment, the definition of "compounds of formula (1)" inherently includes all stereoisomers of the compound of formula (1) either as pure stereoisomer or as amixture of two or more stereomers. The word stereoisomers includes enantiomers, diasteroisomers, racemates, cis isomers, trans isomers and mixture thereof.

The absolute configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. When a specific stereisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1 % of the other isomers. Thus when a compound of formula (1) is for instance specified as (R), this means that the compound is substantially free of (S) isomer; when the compound of formula (1) is for instance specified as E, this mens that the compound is free of the Z isomer; when the compound of formula (1) is for istance specified as cis isomer, this means that the compound is free of the trans isomer.

Use of compounds as above and pharmaceutically acceptable salts or stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and prevention in diseases or disorder, where there is an advantage in inhibiting enzymes- Fabl.

Use of compounds as above and pharmaceutically acceptable salts or stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and prevention of bacterial diseases, where there is an advantage in inhibiting enzymes- Fabl.

Use of compounds as above wherein there is an advantage in inhibiting enzymes- Fabl for anti bacterial or antimicrobial diseases.

Use of the compounds as above for the preparation of a medicament for the treatment and prophylaxis of cancer diseases, inflammatory bowel disease or rheumatoid arthritis.

The invention further provides the use of alkylidine substituted heterocyclyl derivatives of formula (1) in combination with anti-bacterial agents such as cephalosporins, quinolones and fluoroquinolones, penicillins, penicillins and beta lactamase inhibitors, carbepenems, monobactams, macrolides and lincosamines, glycopeptides, rifampin, oxazolidonones, tetracyclines, aminoglycosides, streptogramins, sulfonamides, and the like. Other general categories of antibiotic agents which may be part of a subject composition include those agents known to those of skill in the art as antibiotics and that qualify as (with defined terms being in quotation marks): "drug articles" recognized in the official United States Pharmacopoeia or official National Formulary (or any supplement thereto); "new drug" and "new animal drug" approved by the FDA of the U.S. as those terms are used in Title 21 of the United States Code; any drug that requires approval of a government entity, in the U.S. or abroad ("approved drug"); any drug that it is necessary to obtain regulatory approval so as to comply with 21 U.S.C. [section]355(a) ("regulatory approved drug"); any agent that is or was subject to a human drug application under 21 U.S.C. [section]379(g) ("human drug"). (All references to statutory code for this definition refer to such code as of the original filing date of this provisional application). Other antibiotic agents are disclosed herein, and are known to those of skilled in the art. In certain embodiments, the term "antibiotic agent" does not include an agent that is a Fabl inhibitor, so that the combinations of the present invention in certain instances will include one agent that is a Fabl inhibitor and another agent that is not other anti-bacterial compounds. A preferred composition is comprising a compound of formula (1) and Cyclosporin A, FK506, rapamycin, 40-(2- hydroxy)ethyl-rapamycin. Another preferred composition may comprise a compound of formula (1) and a rheumatoid arthritis active agent selected from leflunomide, etanercept (Enbrel), infliximab (Remicade), anakinra (Kineret), adalimumab (Humira), rituximab (Rituxan), and abatacept (Orencia). Without limiting the scope of present invention, the following definitions are provided in order to aid those skilled in the art in understanding the detailed description of the present invention.

The term "Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; in particular alkyl is Ci- Qo alkyl group which may have 1 to 10 (inclusive) carbon atoms in it; in more particular alkyl is Ci-Ce alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is C1-C4 alkyl group which may have 1 to 4 (inclusive) carbon atoms in it. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkyl group can be unsubstituted or substituted with one or more suitable groups.

"Alkoxy" refers to the group alkyl-O- or -O-alkyl, where alkyl group is as defined above. Exemplary Ci-Cioalkyl group containing alkoxy groups include but are not limited to methoxy, ethoxy, «-propoxy, wo-propoxy, «-butoxy and i-butoxy. An alkoxy group can be unsubstituted or substituted with one or more suitable groups.

"Halogen" or "halo" includes fluorine, chlorine, bromine or iodine.

"Cyano" refers to -CN group.

"Hydroxy" or "Hydroxyl" refers to -OH group.

"Nitro" refers to -N0₂ group.

The term "Cycloalkyl" refers to a non-aromatic, saturated or unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl and the like. A cycloalkyl can be unsubstituted or substituted with one or more suitable groups.

The term "Heterocyclyl" includes the definitions of "heterocycloalkyl" and "heteroaryl". The term "Heterocycloalkyl" refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(0)₂, NH and C(O). Exemplary heterocycloalkyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1 ,3- dioxolanyl, 1,4-dioxanyl and the like. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups.

"Heteroaryl" refers to monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatom selected from oxygen, sulphur and nitrogen. Examples of C5-C10 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1 ,2,4- triazole, 1 -methyl- 1 ,2,4-triazole, lH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. A heteroaryl group can be unsubstituted or substituted with one or more suitable groups.

"Hetero atom" refers to a sulfur, nitrogen or oxygen atom.

The term "fused" as used herein with respect to two polyatomic, cyclic rings means that such rings have two adjacent atoms thereof common to both rings. The two adjacent atoms can be C or N. The fused ring can be 4-6 membered ring inclusive of the fused bond.

The term "membered ring" can embrace any cyclic structure. The term"membered" is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5 -membered rings.

"Optionally substituted or substituted" as used herein means that at least one or two hydrogen atoms of the optionally substituted group has been substituted with suitable groups as exemplified but not limited to alkyl, alkenyl, alkoxy, alkynyl, aryl, amido, amino, carboxy, cyano, cycloalkyl, guanidine, halogen, imidamide, hydroxy, nitro, haloalkyl, haloalkoxy, heterocyclyl, oxo(=0), thio(=S), -P(0)₃H, -P(0)₂NH₂, -P(0)₂NH(alkyl), - P(0)₂NH(cycloalkyl),-P(0)₂NH(heterocyclyl), -P(0)₂NH(aryl), -C(0)(alkyl), -C(0)(aryl), - C(0)(cycloalkyl), -C(0)(heterocyclyl), or two substituents on the same carbon atom combined together to form an optionally substituted 3-8 member ring containing 0-3 heteroatoms independently selected form N, O and S in any stable combination;

"Comprise" or "Comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable derivatives" is taken to mean an active ingredient, which comprises a compound of the formula (1) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.

The use of the term "including" as well as other forms, such as "include", "includes" and "included" is not limiting.

As used herein, the terms "treat", "treating" or "treatment" encompass either or both responsive and prophylaxis measures, e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms. The terms "treat," "treating" or "treatment", include, but are not limited to, prophylactic and/or therapeutic treatments.

As used herein the terms "subject" or "patient" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other embodiments, the subject can be a normal subject. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.

As used herein the term "therapeutically effective amount" refers to a sufficient amount of a compound or a composition being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.

"Pharmaceutically acceptable" means that, which is useful in preparing a pharmaceutical composition that is generally safe, non- toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).

Novel alkylidine substituted heterocyclyl derivatives of formula (1), its pharmaceutically acceptable salts and stereoisomers thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from suitable lipids or phospholipids or both, such as, for example, cholesterol, stearylamine or phosphatidylcholines or the like.

A therapeutically effective amount of a compound of the formula (1) and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to lOmg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.

In a further aspect, the present invention relates to a process for preparing alkylidine substituted heterocyclyl derivatives of formula (1).

An embodiment of the present invention provides the FABI inhibitor compounds according to formula (1) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted. In a further aspect, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as ²H ("D"), ¾ ^UC, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I and ¹²⁵I. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.

Another embodiment of the present invention provides methods useful for making the compounds of formula (1) are set forth in the examples below and generalized in below scheme. One of skill in the art will recognize that the below scheme can be adapted to produce the compounds of formula (1) and their pharmaceutically acceptable salts and stereoisomers thereof.

The abbreviations used in the entire specification may be summarized hereinbelow with their particular meaning.

°C (Degree Celsius); % (Percentage); AcOH/CH₃COOH (Acetic acid); brine (NaCl solution); Br/Br₂ (Bromine); n-BuLi (n-Butyl lithium); brs/bs (Broad singlet); J (Coupling constant); DMF (N,N-Dimethylformamide); DMSO (Dimethylsulphoxide); DMSO-d₆ (Deuterated Dimethylsulphoxide); DIPEA/DIEA (Ν,Ν-Diisopropylethylamine); (BOC)₂0 (Di tert-butyl dicarbonate), CH₂C1₂ DCM (Dichloromethane); d (Doublet); dd (Doublet of doublet); dt (Doublet of triplet); EDC.HC1 (l -(3-Dimethylaminopropyl)-3-carbodiimide hydrochloride); EtOH (Ethanol); H/H₂ (Hydrogen), HOBt (1-Hydroxy benzotriazole); HBr (Hydro bromic acid); HC1 (Hydrochloric acid); h(Hours); LAH (Lithium aluminiumhydride); LDA (Lithium diisopropylamide); LiHMDS (lithium hexamethyldisilazide); CH₃OH/MeOH (Methanol); MTBE (Methyl tert-butyl ether); mmol (Millimol); M (Molar); mL (Milliliter); mg (Milligram); m (Multiple t); MHz (Megahertz); ES-MS (Electro Spray-Mass Spectrometry); min (Minutes); LC-MS (Liquid Chromatography-Mass Spectrometry); N₂ (Nitrogen); NMR (Nuclear magnetic resonance spectroscopy); K₂CO₃ (Potassium carbonate); KOAc (Potassium acetate); Pd(OAc)₂ (Palladium diacetate); Na₂CC>3 (Sodium carbonate); NaH (Sodium hydride); NaOH (Sodium hydroxide); NaOCH₃ (Sodium methoxide); Na₂SC>4 (Sodium sulphate); s (Singlet); THF (Tetrahydrofuran); P(o-tolyl)₃ (tri-o-tolylphosphine); PTS-C1 (p-Toluene sulfonyl chloride); TEA (Triethylamine); TFA/CF₃COOH (Trifluoro acetic acid); t (Triplet); H₂0 (Water), NADPH (nicotinamide adenine dinucleotide phosphate), NADH (Nicotinamide adenine dinucleotide) and etc.

Another embodiment of the present invention provides methods useful for making the compounds of formula (1) are set forth in the examples below and generalized in below scheme. One of skill in the art will recognize that the below schemecan be adapted to produce the compounds of formula (1) and pharmaceutically accepted salts of compounds of formula (1) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented herein by below scheme. General Scheme:

procedure for the reparation of i

The formula 1.0 can undergo Arbuzov reaction with triethyl phosphite at a temperature of about 120°C to 150°C for about 16-48 h to provide 2.0. The compound-A (ieri-butyl 4-oxoazetidine-l-carboxylate or tert-butyl 3-oxopyrrolidine-l -carboxylate) can undergo Wittig reaction with formula 1.1 to provide formula 1.2. This reaction can be carried out in suitable solvents such as DCM, toluene, THF, diethyl ether, and the like, in the presence of suitable base such as NaOBu', KOBu', NaHMDS, LiHMDS, BuLi and their molar solutions and the like, at a temperature of about -30°C to 20-35°C for about 16-48 h. Alternatively compound-A (teri-butyl 4-oxoazetidine-l-carboxylate or tert-butyl 3- oxopyrrolidine-l-carboxylate) can undergo Wittig horner reaction with formula 2.0 to provide formula 1.2. This reaction can be carried out in suitable solvents such as THF, toluene, benzene and the like, in the presence of suitable base such as NaH, NaOBu', KOBu' and the like, at a temperature of about 20-35X! to 85°C for about 2-16 h. The Boc- deprotection of formula 1.2 can be carried out by using the suitable deprotecting agents such as TFA, HC1 in ether solutions and the like, in suitable solvents such as DCM, diethyl ether, THF and the like, at a temperature of about 0°C to 20-35°C for about 2-6 h to provide formula 1.3.

Gene

As shown in the above scheme, the compounds of the present invention of formula- 1 can be synthesized from formula 1.3 and 1.6 through acid-amine coupling, alternatively from formula- 1.4 and 1.5 through Pd catalyzed C-C bond formation. The reactions progresses can be monitored by conventional methods such as TLC/NMR7LC-MS/ES-MS.

The formula 1.4 can be synthesized by treating formula 1.3 with acryloyl chloride in presence of suitable solvents such as DCM, THF, diethyl ether and the like, in the presence of suitable base such as Triethylamine, pyridine and the like, at a temperature of about 0°C to 20-35°C for about 3-16 h.

Method-I: (Acid- Amine Coupling)

The acid-amine coupling of formula 1.3 with formula 1.6 can be carried out by a conventional amide bond formation method by using a suitable coupling reagents such as benzotriazole-containing coupling reagents such as 1 -hydroxybenzotriazole (HOBt), benzotriazole-l-yloxytris (dimethylamino)phosphoniumhexafluorophosphate and 2-(lH- benzotriazol-l-yl)-l,l ,3,3-tetra methyluroniumhexafluorophosphate and also the dicarboimides containing reagent such as l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodi imide, HATU and the like, in a suitable solvent such as DMF, THF, DMSO or DCM and the like, in the presence of suitable bases such as TEA, DIPEA and the like, at a temperature of about 20-35°C for about 12-48 h to provide formula- 1.

Method-II: (Pd-Catalyzed C-C Bond formation)

Alternatively, the compound of formula-1 can be synthesized by treating formula 1.4 with formula 1.5 through Pd-catalyzed C-C coupling reaction. The Pd-catalyzed C-C coupling reaction can be carried out in suitable polar solvents such as DMF, propionitrile, ACN, THF or DMSO and the like, in a suitable bases such as TEA, DIPEA and the like, by using catalysts such as Pd(OAc)2, Ρά(ΡΡ1¾)2θ2, Pd2(dba)3 and the like, in the presence of ligands P(o-tolyl)3, P(m-tolyl)3, P(p-tolyl)3 and the like, at a temperature of about 100-130°C for about 12-48 h.

EXAMPLES

Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited there by; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

The MS data provided in the examples described below were obtained as follows:

Mass spectrum: LC/MS Agilent 6120 Quadrapole LC/MS

The NMR data provided in the examples described below were obtained as follows:

lU NMR: Varian 400 MHz.

The microwave chemistry was performed on a CEM Explorer.

Step-(i): Synthesis of benzyltriphenylphosphonium bromide (1.1)

To a stirred solution of triphenyl phosphine (30 g, 114.23 mmol) in toluene (300 mL) was added benzyl bromide (29.3 g, 171.34 mmol) at 20-35°C and the reaction mixture was allowed to stir at 110°C for 24h. The reaction mixture was cooled to 20-35 °C, obtained solid was filtered and washed with toluene to get the desired compound as a white solid (30 g, 60%); ^lU NMR (400MHz, DMSO-<¾) δ 7.91 (t, J=7.4 Hz, 3H), 7.80-7.73 (m, 6H), 7.72- 7.64 (m, 6H), 7.32 (d, J=1.0 Hz, 1H), 7.31-7.22 (m, 2H), 6.98 (dd, J=1.5 Hz, 7.4 Hz, 2H), 5.19 (s, 1H), 5.15 (s, 1H). Step-(ii): Synthesis of tert-butyl 3-benzylideneazetidine-l-carboxylate (1.2)

To a stirred solution of benzyltriphenylphosphonium bromide (1.1) (11.14 g, 25.73 mmol) in dry THF (100 mL) was added LiHMDS (25.7 mL, 1M in THF, 25.73 mmol) at 0°C and continued stirring at same temperature for 30 min. After 30 min, a solution of tert- butyl 3-oxoazetidine-l-carboxylate (A) (4 g, 23.39 mmol) in dry THF (40 mL) was added dropwise at 0°C, then allowed to 20-35°C and continued stirring at 20-35°C for 4 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SC>4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using a mixture of 10% ethyl acetate/hexane as an eluent to get the desired compound as an oily liquid (3.0 g, 52%); ^lU NMR (400MHz, DMSO-<¾) δ 7.35 (t, J=7.9 Hz, 2H), 7.24 (d, /=7.1 Hz, 1H), 7.16 (d, /=7.9 Hz, 2H), 6.35 (s, 1H), 4.86-4.76 (m, 2H), 4.64-4.54 (m, 2H), 1.42 (s, 9H).

Alternatively, this reaction can be conducted in presence of Potassium teri-butoxide or n-Butyllithium instead of LiHMDS in presence of suitable solvents such as toluene or diethylether.

Step-(iii): Synthesis of 3-benzylideneazetidine 2,2,2-trifluoroacetate (Inetrmedaite-1)

To a stirred solution of tert-butyl 3-benzylideneazetidine-l-carboxylate (1.2) (250 mg, 1.02 mmol) in DCM (5 mL) was added trifluoroacetic acid (1.16 g, 10.2 mmol) dropwise at 20-35°C and the reaction mixture was allowed to stir at 20-35°C for 2 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was triturated with diethyl ether to get the desired compound as a brown solid (300 mg, quantitative); ^lU NMR (400MHz, DMSO-<¾) δ 9.51 (bs, 2H), 7.40-7.36 (m, 2H), 7.30-7.28 (m, 1H), 7.20-7.11 (m, 2H), 6.41 (t, J=2.5 Ηζ,ΙΗ), 4.95 (d, J=2A Hz,2H), 4.80-4.72 (m, 2H).

Alternatively, the above reaction (Boc deprotection) was conducted in presence of 2M HC1 in presence of diethylether, hence some of the intermediates in the below table were prepared as HC1 salts.

The below Intermediates-2 to 8 were prepared according to the above protocol (intermediate- 1) by using appropriate reactants, reagents at suitable conditions. The physiochemical characteristics of the intermediates are summarized herein.

δ

Intermediate-9: Synthesis of l-(3-(thiazol-2-ylmethylene^')azetidin-l-yl^')prop-2-en-l-one.

(Intennediate-4) (Intermediate-9)

To a stirred suspension of 2-(azetidin-3-ylidenemethyl)thiazole 2,2,2-trifluoroacetate (Intermediate-4) (2.5 g, 9.34 mmol) in DCM (30 mL) was added triethylamine (3.89 mL, 28.02 mmol) followed by acryloyl chloride (1.0 g, 11.21 mmol) at 0°C and the reaction mixture was allowed to stir at 20-35 °C for 16 h. Then the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (2 x 50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂S0₄ and filtered.The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 2 methanol/dichloromethane as an eluent to get the desired compound as a light brown liquid (1.2 g, 62%); ^lU NMR (400MHz, DMSO-<¾) δ 7.87-7.86 (m, IH), 7.75 (d, J=2.9 Hz, IH), 6.83 (dd, J=5A Hz, 3.0 Hz, IH), 6.47-6.34 (m, IH), 6.15 (d, /=16.7 Hz, IH), 5.74-5.69 (m, IH), 5.13 (dd, /=6.8 Hz, 3.4 Hz, IH), 5.00 (d, J=\ .9 Hz, IH), 4.80-4.76 (m, IH), 4.67-4.66 (m, IH).

Intermediate- 10: Synthesis of 6-bromo-3,4-dihvdro-l,8-naphthyridin-2(lH)-one

10.4 (Intermediate- 10)

Reference for Step-(i): WO 2005/095391

Ref . for Step-(n-v): J. Med. Chem. 2003, 46, 1627-1635

Intermediate- 11 : nthesis of -bromo- 7-dih dro- - rido 2 -b aze in- H -one

(Intermediate- 1 1)

Intermediate- 12: Synthesis of tert-butyl 7-bromo-2-oxo-2,3-dihydro-lH-pyridor2,3-eiri ,41

Reference for Step-(i): US2005009970

Reference for Step-(i-iii): J. Med. Chem. 2003, 46, 1627-1635

Intermediate- 13: Synthesis of 7-bromo-3,5-dihydropyridor2,3-eiri,41oxazepin-2(lH)-one

10.3 13.1 (Intermediate-13)

Reference for Step-(i-ii): WO2007/067416

Intermediate- 14: Synthesis of 6-bromo-3 -dimethyl-3,4-dmydro-l,8-naphthyridin-2(lH)- one

10.3 (Intermediate- 14)

To a stirred suspension of (2-amino-5-bromopyridin-3-yl)methanol hydrobromide

(10.3) (5 g, 14.53 mmol) in dry THF (50 mL), LDA (7.21 mL, 2M in THF, 14.53 mmol) was added dropwise under N₂ at -78°C and the mixture was stirred at same temperature for 30 min. In a separate flask, LDA (21.6 mL, 2M in THF, 43.18 mmol) was added dropwise to a stirred solution of ethyl isobutyrate (5.01 g, 43.18 mmol) in dry THF (50 mL) under N₂ at -78°C and the mixture was stirred at same temperature for 30 min. via canula, the lithium salt of ethyl isobutyrate was added dropwise over 30 min and the reaction mixture was allowed to stir at -78°C for 2 h, then allowed to 20-35°C and continued stirring at 20-35°C for 16 h. The reaction mixture was quenched with NH₄CI solution (50 mL), diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated under vacuum to get residue which was triturated with methanol to get the desired compound as a white solid (1.5 g, 41%); ^lU NMR (400MHz, DMSO-<¾) δ 10.59 (bs, 1H), 8.21 (d, J=2.5 Hz, 1H), 7.85 (d, J=2A Hz, 1H), 2.79 (s, 2H), 1.06 (s, 6H).

The below Intermediates- 15 to 17 were prepared according to the above protocol (intermediate- 14) by using appropriate reactants, reagents at suitable conditions. The physiochemical characteristics of the intermediates are summarized herein.

¾ NMR (400MHz, DMSO-<¾) δ 10.69 (bs,

⁰ 1 T 1H), 8.2 J

16 ^B'X (d,

Ht 3 =2A Hz, 1H), 7.77 (d, /= 1.5 Hz, 1H), 2.87 (s, 2H), 1.13-1.10 (m, 2H), 0.80-0.76 (m, 2H).

lU NMR (400MHz, DMSO-<¾) δ 10.68 (bs, lH), 8.22 (d, J=1.9 Hz, 1H), 7.88 (d, /=1.5

17 Hz, 1H), 3.71-3.66 (m, 2H), 3.62 (dd, J=2.9

H

Hz, 8.3 Hz, 2H), 2.99 (s, 2H), 1.82-1.76 (m, 2H), 1.31-1.27 (m, 2H).

Intermediate- 18: Synthesis of 7-bromo-2,2-dimethyl-2H-pyridor3,2-biri,41oxazin-3(4H)- one

18.1 (Intermediate- 18)

Step-(i): Synthesis of 2,2-dimethyl-2H-pyridor3,2-biri,41oxazin-3(4H)-one (18.1)

To a stirred solution of 2-aminopyridin-3-ol (5 g, 45.45 mmol) in acetone (50 mL) was added K₂CO₃ (25.09 g, 181.81 mmol) followed by ethyl 2-bromo-2-methylpropanoate (13.29 g, 68.18 mmol) at 20-35°C and the reaction mixture was allowed to stir at 70°C for 16 h. Then the reaction mixture was cooled to 20-35°C and diluted with ice water. The obtained solid was filtered and washed with water to get the desired compound as a white solid (5 g, 97%); H NMR (400MHz, DMSO-<¾) δ 11.17 (s, 1H), 7.91 (d, /=4.4 Hz, 1H), 7.34 (d, /=7.8 Hz, 1H), 6.98 (dd, /=4.9 Hz, 7.9 Hz, 1H), 1.41 (s, 6H); LC-MS: 179.3 (M+l)⁺.

Step-(ii): Synthesis of 7-bromo-2.2-dimethyl-2H-pyridor3.2-biri.41oxazin-3(4H)-one (Intermediate- 18)

To a stirred solution of 2,2-dimethyl-2H-pyrido[3,2-b][l ,4]oxazin-3(4H)-one (18.1) (2 g, 11.23 mmol) in DCM (20 mL) was added Na₂C0₃ (3.57 g, 33.70 mmol) followed by bromine (0.92 mL, 17.97 mmol) at 0°C and the reaction mixture was allowed to stir at 20- 35°C for 16 h. Then the reaction mixture was diluted with ice water, obtained solid was filtered and washed with water to get the desired compound as a white solid (1.8 g, 86%); ^lU NMR (400MHz, DMSO-<¾) δ 11.39 (s, 1H), 8.04 (d, J=\.9 Hz, 1H), 7.66 (d, /=1.4 Hz, 1H), 1.43 (s, 6H); LC-MS: 257.0 (M+l)⁺. Intermediate- 19: Synthesis of (£T)-3-(7-oxo-5,6 ,7,8-tetrahvdro-l ,8-naphthyridin-3-yl)acrylic acid

Ref. for Step-(i-ii): J. Med. Chem. 2003, 46, 1627-1635

The below Intermediates-20 to 27 were prepared according to the procedure described in above reference (intermediate- 19) by using appropriate reactants, reagents at suitable conditions. The physiochemical charecteristics of the intermediates are summarized herein.

Example-I: Synthesis of (£T)-6-(3-(3-benzylideneazetidin- l-yl^')-3-oxoprop-l-en-l -yl^')-3 ,4- dihydro- 1 ,8-naphthyridin-2( 1 H)-one (Compound- 1 ).

(Intermediate- 1 ) (Tntermediate-19) Compound-1

DIPEA (0.96 mL, 5.50 mmol) was added to a stirred solution of 3-benzylidene azetidine 2,2,2-trifluoroacetate (Intermediate- 1) (300 mg, 1.19 mmol), (£T)-3-(7-oxo-5,6,7,8- tetrahydro-l ,8-naphthyridin-3-yl)acrylic acid (Intermediate- 19) (200 mg, 0.92 mmol), HOBt (180 mg, 1.37 mmol) and EDC.HC1 (350 mg, 1.83 mmol) in dry DMF (3 mL) at 20- 35°C and the reaction mixture was allowed to stir at 20-35 °C for 16 h. Then the reaction mixture was poured into ice water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (30 mL), dried over on anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 3% methanol/dichloromethane as an eluent to get the desired compound as an off-white solid (40 mg, 12%); H NMR (400 MHz, DMSO- d₆) δ 10.67 (s, 1H), 8.37 (s, 1H), 8.07-8.04 (m, 1H), 7.45 (d, /=16.1 Hz, 1H), 7.42-7.36 (m, 2H), 7.30-7.20 (m, 3H), 6.88-6.76 (m, 1H), 6.45 (s, 1H), 5.28-5.26 (m, 1 H), 5.08-5.02 (m, 1H), 4.94-4.90 (m, 1 H), 4.72-4.68 (m, 1H), 2.93 (t, /=7.8 Hz, 2H), 2.56-2.50 (m, 2H); ES- MS: 344.2 (M-l)⁺. The below compounds were prepared by procedure similar to the one described in Example- 1 with appropriate intermediate A and intermediate B, appropriate quantities of reagents at suitable recation conditions. The physicochemical characteristics of the compounds are summarized herein below table.

11.21 (s, IH), 8.31 (d, J=2.0 Hz, IH), 8.19 (d, /=4.4 Hz, IH), 7.48 (d, /=15.6 Hz, IH), 7.42-7.34 (m, 2H), 7.30-7.20 (m, 3H), 6.88-6.78 (m, IH),

1 22

6.45 (s, IH), 5.30-5.26 (m, IH), 5.08- 5.02 (m, I H), 4.92-4.88 (m, IH), 4.72- 4.68 (m, IH), 1.34 (s, 6H); ES-MS: 360.1 (M+l )⁺.

11.20 (s, IH), 8.31 (s, IH), 8.26 (s, IH), 7.88 (d, J=2.9 Hz, IH), 7.76 (d,

0 J=3A Hz, 1H),7.48 (d, /= 15.6 Hz,

4 22 IH), 6.92-6.78 (m, 2H), 5.26-5.18 (m,

H IH), 5.12-5.06 (m, IH), 4.86-4.80 (m, IH), 4.76-4.70 (m, IH), 1.34 (s, 6H); ES-MS: 367.8 (M+l)⁺.

10.66 (s, IH), 8.35 (s, IH), 8.01 (s, IH), 7.42 (d, /=15.2 Hz, I H), 7.38-

0 7.30 (m, 2H), 7.28-7.16 (m, 3H), 6.75

(t, /=16.2 Hz, IH), 5.61 (s, IH), 4.94

5 19

(s, IH), 4.83 (s, IH), 4.54-4.48 (s, 2H), 3.30-3.22 (m, 2H), 2.91 (t, /=7.3 Hz, 2H), 2.56-2.52 (m, 2H); ES-MS: 360.3 (M+l )⁺.

10.07 (s, IH), 8.49 (s, IH), 8.10 (d, J=2.9 Hz, IH), 7.45 (dd, J=2A Hz, 16.1 Hz, IH), 7.34-7.28 (m, 2H), 7.27-7.18 (m, 3H), 6.88-6.78 (m, IH),

5 20 5.62 (t, J=1A Hz, IH), 4.98-4.92 (m,

IH), 4.88-4.84 (m, IH), 4.54-4.48 (m, 2H), 3.30-3.22 (m, 2H), 2.72 (t, /=6.9 Hz, 2H), 2.28-2.22 (m, 2H), 2.20- 2.10 (m, 2H); ES-MS: 374.4 (M+l)⁺. 10.07 (s, 1H), 8.49 (d, /=2.0 Hz, 1H), 8.09 (d, /=1.9 Hz, 1H), 7.45 (d, /=15.6 Hz, 1H), 7.35(dd, /=1.4 Hz, 5.3 Hz, IH), 6.96 (dd, /=3.4 Hz, 5.4 Hz, IH), 6.90 (d, /=2.9 Hz, IH), 6.88-

8 20

6.78 (m, IH), 5.64 (d, /=1.9 Hz, IH), 4.94-4.90 (m, IH), 4.88-4.86 (m, IH), 4.51 (d, /=6.8 Hz, 2H), 3.52-3.46 (m, 2H), 2.72 (t, /=7.3 Hz, 2H), 2.28-2.20 (m, 2H), 2.18-2.10 (m, 2H).

10.63 (s, IH), 8.36 (s, IH), 8.00 (s, IH), 7.42 (d, /=15.7 Hz, IH), 7.34-

0 7.28 (m, 2H), 7.26-7.18 (m, 3H), 6.75

(t, /=16.2 Hz, IH), 5.60 (d, /=7.4 Hz,

5 23

IH), 4.98-4.90 (m, IH), 4.86-4.80 (m, IH), 4.54-4.48 (m, 2H), 3.27 (t, /=8.8 Hz, 2H),2.80 (s, 2H), 1.08 (s, 6H); LC-MS: 388.2 (M+l)⁺.

10.63 (s, IH), 8.36 (s, IH), 8.00 (s,lH), 7.42 (d, /=15.7 Hz, IH), 7.30- 7.24 (m, 2H), 7.16-7.08 (m, 2H), 6.75 (t, /=15.2 Hz, IH), 5.60 (d, /=9.8 Hz,

6 23

XX IH), 4.96-4.90 (m, IH), 4.88-4.80 (m,

IH), 4.54-4.46 (m, 2H), 3.26 (t, /=8.8 Hz, 2H), 2.80 (s, 2H), 1.08 (s, 6H); LC-MS: 406.2 (M+l)⁺.

11.63 (s, IH), 8.36 (s, IH), 8.00 (s, IH), 7.42 (d, /=15.7 Hz, IH), 7.18 (t, /=7.4 Hz, IH), 7.08-6.98 (m, 3H), 6.82-6.72 (m, IH), 5.59 (s, IH), 4.98-

7 23

4.92 (m, IH), 4.86-4.80 (m, IH), 4.54- 4.48 (m, 2H), 3.23 (t, /=8.3 Hz, 2H), 2.80 (s, 2H), 2.28 (s, 3H), 1.08 (s, 6H); LC-MS: 402.4 (M+l)⁺. 11.63 (s, IH), 8.36 (s, IH), 8.00 (s,lH), 7.42 (d, 7=15.7 Hz, IH), 7.38- 7.34 (m, IH), 6.98-6.94 (m, IH), 6.90 (d, /=2.9 Hz, IH), 6.80-6.68 (m, IH),

8 23

5.64 (s, IH), 4.94-4.90 (m, IH), 4.88- 4.84 (m, IH), 4.56-4.48 (m, 2H), 3.52- 3.44 (m, 2H), 2.80 (s, 2H), 1.08 (s, 6H); LC-MS: 394.1 (M+l)⁺.

10.62 (s,lH), 8.33 (s,lH), 8.03 (s,lH), 7.41 (d, 7=15.7 Hz, IH), 7.35 (d, J= A Hz, IH), 6.98-6.93 (m, IH), o 6.90 (s, IH), 6.80-6.70 (m, IH), 5.64

8 24 (s, IH), 4.92-4.88 (m, IH), 4.86-4.82

(m, IH), 4.54-4.48 (m, 2H), 3.52-3.44 (m, 2H), 2.82 (s, 2H), 1.58-1.40 (m, 4H), 1.86-1.76 (m, 6H); ES-MS:422.1 (M+l)⁺.

11.41 (s, IH), 8.18 (s, IH), 7.85 (s, IH), 7.41 (d, 7=15.7 Hz, IH), 7.35 (d, /=4.4 Hz, IH), 6.95 (d, J=4.9 Hz, IH), 6.90 (s, IH), 6.86-6.76 (m, IH), 5.64

8 27

(s,lH), 4.92-4.88 (m, IH), 4.86-4.82 (m, IH), 4.56-4.46 (m, 2H), 3.52-3.42 (m, 2H), 1.44 (s, 6H); LC-MS: 396.5 (M+l)⁺.

10.73 (s,lH), 8.36 (s, IH), 8.06 (d, /=4.9 Hz, IH), 7.42 (d, 7=16.1 Hz, IH), 7.34-7.28 (m, 2H), 7.27-7.18 (m, 3H), 6.80-6.68 (m, IH), 5.62 (s,lH),

5 26 4.98-4.92 (m, IH), 4.88-4.82 (m, IH),

4.54-4.46 (m, 2H), 3.76-3.69 (m, 2H), 3.68-3.56 (m, 2H), 3.36-3.26 (m, 2H), 2.99 (s, 2H), 1.86-1.76 (m, 2H), 1.38- 1.28 (m, 2H); LC-MS: 430.3 (M+l)⁺.

Example-II: Synthesis of (£T)-tert-butyl 2-oxo-7-(3-oxo-3-(3-(thiazol-2-ylmethyl ene azetidin-l-yl prop-l -en-l-yl -2,3-dmydro-lH-pyridor2,3-eiri,41diazepine-4(5H^')-

(Intermediate-9) (Intermediate- 12) Compound-22

To a stirred solution of l-(3-(thiazol-2-ylmethylene)azetidin-l-yl)prop-2-en-l-one (Intermediate-9) (266 mg, 1.29 mmol) and tert-butyl 7-bromo-2-oxo-2,3-dihydro-lH- pyrido[2,3-e] [l ,4]diazepine-4(5H)-carboxylate (Intermediate- 12) (400 mg, 1.18 mmol) in DMF/propionitrile (4 mL/16 mL) was added DIPEA (0.61 mL, 3.53 mmol) at 20-35°C and the mixture was degassed with N2 for 10 minutes. Then Pd(OAc)2 (26 mg, 0.11 mmol), P(o- tolyl)₃ (71 mg, 0.23 mmol) were added, again degassed with N₂ for another 10 rnin and heated at 110°C for 16 h. The reaction mixture was cooled to 20-35 °C and filtered through celite. The filtrate was rotary evaporated under vacuum to get residue which was washed with mixture of 10% methanol/hexane to get the desired compound as anoff-white solid (23 mg, 42%);¹H NMR (400MHz, DMSO-<¾) δ 9.80 (s, 1H), 8.47 (d, /=1.9 Hz, 1H), 8.03 (s, 1H), 7.84 (d, /=2.9 Hz, 1H), 7.67 (d, /=2.9 Hz, 1H), 7.47 (d, /= 15.6 Hz, 1H), 6.84-6.78 (m, 1H), 6.81 (s, 1H), 5.20-4.96 (m, 2H), 4.96-4.70 (m, 2H), 4.55 (s, 2H), 4.33 (s, 2H), 1.32 (s, 9H); LC-MS: 468.2 (M+l) ⁺.

The below compounds were prepared by procedure similar to the one described in Example-2 with appropriate intermediate A and intermediate B, appropriate quantities of reagents at suitable recation conditions. The physicochemical characteristics compounds are summarized herein below table.

Example-Ill: Synthesis of (£ )-7-(3-oxo-3-(3-(thiazol-2-ylmethylene^')azetidin-l-yl^')prop-l- -l-yl)-4,5-dihydro-lH-pyridor2,3-eiri ,41diazepin-2(3H)-one hydrochloride (Compound-

To a stirred solution of (£T)-tert-butyl 2-oxo-7-(3-oxo-3-(3-(thiazol-2-ylmethylene) azetidin- 1 -yl)prop- 1 -en- 1 -yl)-2,3-dihydro-l H-pyrido [2,3-e] [1 ,4]diazepine-4(5H) carboxylate (Compound-22) (150 mg, 0.32 mmol) in 1 ,4-dioxane(5 mL) was added 2M HCl in dioxane (8 mL) at 20-35°C and the reaction mixture was allowed to stir at 20-35°C for 4 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was purified by preparative HPLC to get the desired compound as an off-white solid (30 mg, 25%); H NMR (400MHz, DMSO-<¾) δ 11.10 (s, 1H), 9.70 (bs, 2H), 8.75(s, 1H), 8.31 (s, 1H), 7.86 (d, 7=2.4 Hz, 1H), 7.75 (d, J=2.9 Hz, 1H), 7.52 (d, 7=15.7 Hz, 1H), 6.96 (d, /=16.2 Hz, 1H), 6.84 (s, 1H), 5.24-5.14 (m, 1H), 5.10-5.00 (m, 1H), 4.86-4.78 (m, 1H), 4.76-4.68 (m, 1H), 4.28(s, 2H), 3.86 (s, 2H); LC-MS: 368.1 (M+l)⁺.

Preparative HPLC condintions: Column- Phenomenex Luna CI 8 (2) (250x21. lmm, 5μ), Mobile Phase: (A) 0.1 % TFA(Aq); (B) ACN; Flow rate: 15ml/min.

Example-IV: Synthesis of 3,3-dimethyl-6-((£T)-3-oxo-3-((£ )-3-(thiazol-4-ylmethylene^') pyrrolidin- 1 -yDprop- 1 -en- 1-ylV 3,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one (Compound-26) &

3.3- dimethyl-6-((£)-3-oxo-3-((Z)-3-(thiazol-4-ylmethylene)pyrrolidin-l-yl)prop-l-en-l-yl)-

3.4- dihydro-l .8-naphthyridin-2(lH)-one (Compound-27).

Step-(i): Synthesis of diethyl (thiazol-4-ylmethyl)phosphonate (26a).

Triethyl phosphite (15 mL) was added to 4-(chloromethyl)thiazole (2.1 g, 15.79 mmol) at 20-35°C and the reaction mixture was allowed to stir at 140°C for 24 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 10% methanol/dichloromethane as an eluent to get the desired compound as an oily liquid (3.5 g, 93%); LC-MS: 236.1 (M+l)⁺.

Step-(ii): Synthesis of (E)-tert-butyl 3-(thiazol-4-ylmethylene)pyrrolidine-l-carboxylate & (Z)-tert-butyl 3-(thiazol-4-ylmethylene)pyrrolidine-l-carboxylate (26b) (Mixture of E & Z).

To a stirred solution of diethyl(thiazol-4-ylmethyl)phosphonate (26a) (1.24 g, 5.27 mmol) in dry THF (5 mL) were added NaH (250 mg, 10.51 mmol, 60 wt% in oil dispersion), followed by dry THF(5 mL) solution of tert-butyl 3-oxopyrrolidine-l- carboxylate (650 mg, 3.51 mmol) at 0°C and the reaction mixture was allowed to stir at 20-35 °C for 1 h. Then the reaction mixture was quenched with water (50 mL) at 20-35 °C and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SC>₄ and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 15% ethyl acetate/hexane as an eluent to get the desired compound as an oilyliquid (450 mg, 48%); LC-MS: 267.2 (M+l)⁺.

Step-(iii): Synthesis of (E)-4-(pyrrolidin-3-ylidenemethyl)thiazole hydrochloride &(Z)-4- (pyrrolidin-3-ylidenemethyl)thiazole hydrochloride (26b) (Mixture of E & Z).

The process of this step was adopted from preparation of compound-25. The desired compound obtained as a brown waxy solid (320 mg,93%); LC-MS: 167.1 (M+l)⁺.

Step-(iv): Synthesis of 3,3-dimethyl-6-((£ )-3-oxo-3-((£ )-3-(thiazol-4-ylmethylene) pyrrolidin- 1 - yl)prop- 1 -en- 1- yl)-3,4-dihvdro- 1 ,8-naphthyridin-2( 1 H)-one (Compound-27) & 3,3-dimethyl-6-((£)-3-oxo-3-((Z)-3-(thiazol-4-ylmethylene)pyiTolidin-l-yl)prop-l-en-l-y 3.4-dihydro-l .8-naphthyridin-2(lH)-one (Compound-28).

The process of this step was adopted from preparation of compound- 1. The Έ' isomer obtained as an off-white solid (50 mg, %); ^lU NMR (400MHz, DMSO-<¾) δ 10.62 (s,lH), 9.12 (d, /=1.5 Hz, IH), 8.38 (s, IH), 8.07 (s, IH), 7.66-7.56 (m, IH), 7.48 (d, /=15.7 Hz, IH), 7.10-6.98 (m, IH), 6.62 (d, /=14.2 Hz, IH), 4.57 (s, IH), 4.28 (s, IH), 3.92 (t, /=7.3 Hz, IH), 3.67 (t, /=7.3 Hz, IH), 3.18-3.12 (m, IH), 3.08-3.02 (m, IH), 2.81 (d, /=4.4 Hz, 2H), 1.09 (s, 3H), 1.08 (s, 3H);LC-MS: 395.1 (M+l)⁺. The 'Z' isomer obtained as an off-white solid (60 mg, %); ^lU NMR (400MHz, DMSO-<¾) δ 10.62 (s, IH), 9.16 (t, /=2.0 Hz, IH), 8.39 (dd, /=2.0 Hz, 8.4 Hz, IH), 8.06 (d, /=4.4 Hz, IH), 7.56 (d, /=1.5 Hz, IH), 7.50 (dd, /=5.4 Hz, 15.7 Hz, IH), 7.10-7.02 (m, IH), 6.61 (d, /=25.9 Hz, IH), 4.70 (s, IH), 4.48 (s, IH), 3.85 (t, /=7.3 Hz, IH), 3.59 (t, /=7.3 Hz, IH), 2.89 (t, /=6.8 Hz, IH), 2.86- 2.78 (m, IH), 2.81 (s, 2H), 1.10 (s, 3H), 1.09 (s, 3H); LC-MS: 395.2 (M+l)⁺.

PHARMACOLOGICAL ACTIVITY:

Biological screening of the compounds of formula (1) of the present invention

The biological screening of the various alkylidine substituted heterocyclyl derivatives of formula (1) was carried out using FabI protocol designed for evaluating enzymatic assay for FabI. Following protocol was used for the evaluation purpose and the results are summarized below.

FabI ASSAY PROTOCOL: Compounds were evaluated for their potency to inhibit Staphylococcus aureus FabI in a spectrophotometric assay adapted from the reported protocol used by Kaplan et al., with some modifications [Kaplan N, Albert M, Awrey D, Bardouniotis E, Berman /, Clarke T, Dorsey M, Hafkin B, Ramnauth /, Romanov V, Schmid M.B, Thalakada R, Yethon /, Pauls H.W 2012. Mode of Action, In Vitro Activity, and In Vivo Efficacy of AFN-1252, a selective antistaphylococcal FabI Inhibitor. Antimicrobial Agents and Chemotherapy 56 (l l) p.5865-5874)].

The enzymatic assay is based on the decrease in absorbance at 340 nm resulting from the oxidation of NADPH accompanying the reduction of enoyl - ACP, catalyzed by 5. aureus FabI enzyme. The assay buffer was 100 mM Sodium ADA (N-[2-Acetamido] iminodiacetic acid) buffer, pH 6.5. 20μ1 of FabI enzyme (2400ng/assay) and ΙΟμΙ of NADH (375μΜ) were pre-incubated with test compounds for 30 minutes and the reaction was started by adding 10 μΕ of Crotonoyl CoA (250 μΜ). The reaction volume was made upto to ΙΟΟμΙ with Sodium ADA buffer and the plate was incubated for 2 hrs at room temperature. The reduction of NADH was monitored by following the decrease in absorbance at 340 nm. IC₅₀ values were estimated by fitting the dose-response data to sigmoidal dose response (variable slope), curve fitting program using Graphpad Prism software V5.

IC₅₀ values of the selected compounds of present invention were provided in table A, Compounds exhibiting IC50 values <0.3 μΜ were grouped as 'a' , and compounds exhibiting IC50 value in the range IC50 value >0.31 μΜ were grouped as 'b' .

Table A: FABI inhibition activity of the selected compounds (IC₅₀).

MIC BY BROTH MICRODILUTION METHOD:

The in vitro antibacterial activity of selected compounds of present invention was evaluated following the reported literature procedure (Clinical and Laboratory Standards Institute (CLSI) guidelines. M7-A7, Volume 26, Number 2, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved standard - Seventh edition, January 2006).

Required quantity of the test compound was weighed and dissolved in suitable solvent to yield lmg/ml stock solution.The stock solution was diluted in MHB / CAMHB (Mueller Hinton Broth/Cation adjusted Mueller Hinton Broth) by serial two fold dilutions of the compounds in 96 well microtitre trays. Organisms were grown in MHA overnight at 35±2°C and the inoculum was prepared by directly suspending colonies from an overnight grown culture in 0.9% saline or MHB and the optical density(OD) adjusted at 625nm which corresponds to 0.5 Mc Farland (1-2 x 10⁸ cfu/ml) and cultures were further diluted 1 :1000 times. To each of the wells of the microtitre tray, 50μΙ. of the above diluted organism is inoculated to obtain a final in oculum density of (5+0.5) x 10⁴cfu/well. Broth, compound and organism controls were set up. Microdilution trays were incubated at 35+2 °C for 16-20 hours in an ambient air incubator. After the incubation period, growth of organism in the wells was detected by unaided eye facilitated by a viewing device. The amount of growth in the wells containing the antibiotic is compared with the amount of growth in organism control wells (no antibiotic) to help in determining the end point. The lowest concentration of antimicrobial agent that completely inhibits growth of the organism as detected by the unaided eye was taken as MIC. MIC values for selected compounds were provided in Table-B.

Table-B: MIC ^g/mL) values for selected compounds of the present invention:

Claims

We claim:

1. A compound of formula ( 1) :

logen, nitro, cyano, hydroxyl and alkyl;

R₃ is selected from hydrogen and alkyl;

R4 is selected from halogen, alkyl and alkoxy;

each R5 is independently selected from halogen, alkyl, cyano and -C(0)Oalkyl; alternatively, two of the R5 groups on the same carbon atom can be taken together to form a 3-6 membered spiro ring optionally containing oxygen atom;

'n' is an integer selected from 1 and 2; and

'p' is an integer selected from 0 and 1.

2. The compound according to claim 1 , wherein Ri and R₃ are hydrogen.

3. The compound according to claim 1 , wherein Ring A is selected from thiophene, thiazole and optionally substituted phenyl.

4. The compound of claim 3, wherein the optional substituents are halogen, alkyl and alkoxy.

5. The compound according to claim 1 , wherein the compound of formula (1) is a compound of formula (la)

wherein,

Ri, R₂, R₃, R5 and 'n' are same as defined in claim 1.

6. The compound of claim 5, wherein R5 is alkyl.

7. The compound according to claim 1 , wherein the compound of formula (1) is a compound of formula (lb)

wherein,

Ri, R₂, R₃ and 'n' are same as defined in claim 1 ;

X is selected from C and O; and

each R5 is independently selected from hydrogen and alkyl;

alternatively, two of the R5 groups on the same carbon atom can be taken together to form a 3-6 membered spiro ring optionally containing a heteroatom, wherein the heteroatom is Ό' .

8. The compound of claim 7, wherein two of the R₅ groups on the same carbon atom can be taken together to form a 3 or 6 membered spiro ring.

9. The compound of claim 7, wherein R5 is is methyl or ethyl.

10. The compound according to claim 1 , wherein the compound of formula (1) is a compound of formu

wherein,

X is selected from C, O and NR₅; and

Ri, R₂, R₃, R5 and 'n' are same as defined in claim 1.

11. The compound of claim 10, wherein R₅ is hydrogen and -C(0)Oalkyl.

12. A compound selected from the group consisting of

(£)-6-(3-oxo-3-(3-(thiazol-2-ylmethylene)azetidin- l-yl)prop-l-en-l-yl)-3,4-dihydr( 1 ,8-naphthyridin-2(l H)-one (Compound-2) ;

(£)-3-(3-(3-(4-fluorobenzylidene)azetidin-l -yl)-3-oxoprop-l-en-l-yl)-6,7-dihydro- 5 H-pyrido [2, 3 -b ] azepin- 8 (9H) -one (Compound-4) ;

(£)-3-(3-(3-(4-methoxybenzylidene)azetidin-l-yl)-3-oxoprop-l-en-l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound-5);

(£)-3-(3-oxo-3-(3-(thiazol-2-ylmethylene)azetidin- l-yl)prop-l-en-l-yl)-6,7-dihydr( 5 H-pyrido [2, 3 -b ] azepin- 8 (9H) -one (Compound-6) ;

(£)-7-(3-(3-benzylideneazetidin-l-yl)-3-oxoprop-l-en-l-yl)-3,5-dihydropyrido[2,3 e][l ,4]oxazepin-2(lH)-one (Compound-7);

(£)-6-(3-(3-(2-(4-fluorophenyl)ethylidene)azetidin-l-yl)-3-oxoprop-l-en-l -yl)-3,3 dimethyl-3 ,4-dihydro- 1 ,8 -naphthyridin-2( 1 H)-one (Compound- 15);

(£)-3,3-dimethyl-6-(3-oxo-3-(3-(2-(m-tolyl)ethylidene)azetidin-l-yl)prop-l-en-l- yl)-3 ,4-dihydro- 1 , 8-naphthyridin-2( 1 H)-one (Compound- 16) ; (£)-3 -dimethyl-6-(3-oxo-3-(3-(2-(miophen-2-yl)ethylidene)azetidin-l-yl)prop-l- en- 1 -yl)-3 ,4-dihydro- 1 ,8 -naphthyridin-2( 1 H)-one (Compound- 17) ;

(£)-3 -diethyl-6-(3-oxo-3-(3-(2-(tMophen-2-yl)ethylidene)azetidin-l-yl)prop-l-en- 1 -yl)-3,4-dihydro- 1 ,8-naphthyridin-2(lH)-one (Compound- 18);

(£)-2,2-dimethyl-7-(3-oxo-3-(3-(2-(miophen-2-yl)ethylidene)azetidin-l-yl)prop-l- en-l-yl)-2H-pyrido[3,2-b][l ,4]oxazin-3(4H)-one (Compound-19);

(£)-6-(3-oxo-3-(3-(2-(thiophen-2-yl)ethylidene)azetidin-l-yl)prop-l-en-l-yl)- 2\3^5 6'-tetrahydro-lH-spko[[l ,8]naphthyridine-3,4'-pyran]-2(4H)-one (Compound-21);

(Z?)-tert-butyl 2-oxo-7-(3 -oxo-3-(3-(thiazol-2-ylmethylene)azetidin- 1 -yl)prop- 1 -en- l-yl)-2,3-dihydro-lH-pyrido[2,3-e][l,4]diazepine-4(5H)-carboxylate (Compound-22);

(£)-7-(3-oxo-3-(3-(thiazol-2-ylmethylene)azetidin- l-yl)prop-l-en-l-yl)-4,5-dihydro- lH-pyrido[2,3-e][l,4]diazepin-2(3H)-one hydrochloride (Compound -25);

33-dimethyl-6-((£ -3-oxo-3-((£T)-3-(thiazol-4-ylmethylene)pyrrolidin-l-yl)prop-l - en-l-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one (Compound-26); and

33-dimethyl-6-((^-3-oxo-3-((Z)-3-(thiazol-4-ylmemylene)pyrrolidin-l-yl)prop-l - en- 1 -yl)-3,4-dihydro-l ,8 -naphthyridin-2(l H)-one (Compound-27) ;

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of the claims 1-12, their pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, in admixture with atleast one pharmaceutically acceptable carriers, diluents or excipients, including mixtures thereof in all ratios, for use as a medicament.

14. A pharmaceutical combination comprising a compound according to any of the claims 1-12, their pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, and atleast one or more additional therapeutically active ingredient.

15. A compound according to any of the claims 1 -12, their pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, for use in therapy.

16. A compound according to any of the claims 1 -12, their pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, for use in treatment of diseases or conditions for which Fabl inhibitor is indicated.

17. A compound according to claim 16, wherein the disease or condition is bacterial infection.

18. Use of a compound according to any of the claims 1-12, their pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, in the manufacture of medicament for the treatment of diseases or conditions for which Fabl is indicated.

19. A method of treating of diseases or conditions for which Fabl is indicated in a subject in need thereof which comprises administering a therapeutically effective amount of a compound according to any of the claims 1-12, their pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof.

20. The method of treating according to claim 19, wherein the disease or condition is bacterial infection.

21. The method of treating according to claim 19 and 20, wherein the subject is an animal including human.