WO2014072930A2

WO2014072930A2 - Fused pyridine derivatives as antibacterial agents

Info

Publication number: WO2014072930A2
Application number: PCT/IB2013/059972
Authority: WO
Inventors: Takhi Mohamed; Subramanya Hosahalli; Sunil Kumar Panigrahi
Original assignee: Aurigene Discovery Technologies Limited; Um Pharmauji Sdn. Bhd
Priority date: 2012-11-09
Filing date: 2013-11-07
Publication date: 2014-05-15
Also published as: WO2014072930A3

Abstract

The present invention relates to fused pyridine derivatives of formula (1) which may be therapeutically useful as as anti-bacterial agents, more particulalrly FabI inhibitors, in which P, Q, R₁, R₂, R₃ and "n" have the same meanings given in the specification, and pharmaceutically acceptable salts and 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

"FUSED PYRIDINE DERIVATIVES AS ANTI-BACTERIAL AGENTS"

This application claims the benefit of Indian provisional application number 4705/CHE/2012 filed on 09^th November 2012 and 2431/CHE/2013 filed on 03^rd June 2013 which hereby incorporated by reference.

FIELD OF INVENTION

The present invention relates to fused pyridine 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.

FabI (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 FabI by palmitoyl- ACP (Heath, et al, (1996), J. Biol. Chem. 271 , 1833-1836).

Thus, FabI is among one of the major biosynthetic enzyme 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 target. Grassberger, et al in J. Med Chem 27, 947-953 (1984) reported derivative of 2bl 8 (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, 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 problem in recent years. Of particular concern has been the increasing incidence of methiciUin-resistant Staphylococcus spp., vancomycin-resistant Enterococcus spp., and penicillin-resistant Streptococcus pneumoniae.

Despite various disclosures on Fabl 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 fused pyridine derivatives of formula (1) useful as anti-bacterial agents.

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

wherein;

P-Q is a linker selected from -C-, -C-C-, -C-N-, -N-C-, -C-C-C-, -N-C-C-, -C-N-C-, -C-C-N-, -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 4-12 membered monocyclic or bicyclic ring containing 0-3 heteroatoms independently selected from N, S and O; wherein the optional substituent is independently selected from one or more R4;

R₃ is selected from hydrogen and alkyl;

each R4 is independently selected from halogen, nitro, carboxy, cyano, hydroxy, thio, oxo, amino, alkyl, alkoxy, aryl, cycloalkyl and heterocyclyl;

each R5 is independently selected from hydrogen, halogen, nitro, alkyl, amino, cyano, hydroxy, oxo, -C(0)OR₇, -C(0)R₇, -(CH₂)_PR₇ and -C(0)NR₇R₇; or two of the R5 groups on the same atom or on the adjacent atoms combined together to form an optionally substituted 3-8 membered spiro/ fused ring containing 0-3 hetero atoms/heterogroups independently selected form N, O, S, C(O), NH, S(O) and S(0)2, wherein the optional substituent is independently selected from one or more R6;

each R₆ is independently selected from hydrogen, halogen, hydroxyl, alkyl, -

(CH₂)_PR₇, -C(0)OR₇, -C(0)R₇, -C(0)CH₂OH, -C(0)CH(OH)CH₂OH and - C(0)CH₂NHC(0)R₇;

each R₇ is independently selected from hydrogen, hydroxyl, alkyl and optionally substituted heterocyclyl, wherein the optional substitutent is selected from alkyl and nitro;

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

at each occurance 'p' is an integer selected from 0, 1, 2 and 3;

or pharmaceutically acceptable salts thereof or pharmaceutically acceptable stereoisomers thereof.

In a further aspect of the present invention, it relates to the pharmaceutical composition comprising fused pyridine 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 fused pyridine derivatives of formula (1), its salts and 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- FabI or FabK or both.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present application provides novel fused pyridine derivatives of formula (1) useful as anti-bacterial agents.

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

wherein; P-Q is a linker selected from -C-, -C-C-, -C-N-, -N-C-, -C-C-C-, -N-C-C-, -C-N-C-, -C-C-N-, -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;

each R5 is independently selected from hydrogen, halogen, nitro, alkyl, amino, cyano, hydroxy, oxo, -C(0)OR₇, -C(0)R₇, -(CH₂)_PR₇ and -C(0)NR₇R₇;

or two of the R5 groups on the same atom or on the adjacent atoms combined together to form an optionally substituted 3-8 membered spiro/ fused ring containing 0-3 hetero atoms/heterogroups independently selected form N, O, S, C(O), NH, S(O) and S(0)₂, wherein the optional substituent is independently selected from one or more Re;

each R6 is independently selected from hydrogen, halogen, hydroxyl, alkyl, - (CH₂)_PR₇, -C(0)OR₇, -C(0)R₇, -C(0)CH₂OH, -C(0)CH(OH)CH₂OH and - C(0)CH₂NHC(0)R₇;

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

at each occurance 'p' is an integer selected from 0, 1, 2 and 3;

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, specifically provided are compounds of formula (1), in which Ri and R₃ are selected from hydrogen. According to another embodiment, specifically provided are compounds of formula

(1), in which R₂ is

wherein ring A is 5-9 membered monocyclic or bicyclic ring containing 0-3 heteroatoms independently selected from N, S and O and p is 0.

According to yet another embodiment, s ecifically provided are compounds of

formula (1), in which R₂

wherein ring A is 5-6 membered ring containing 0-3 heteroatoms independently selected from N, S and O and p is 0.

According to yet another embodiment, specifically provided are compounds of

formula (1), in which R₂ is

, wherein ring A is independently selected from

According to yet another embodiment, specifically provided are compounds of formula (1), in which R4 is selected from hydrogen, alkoxy or alkyl; and q is 0 or 1.

According to yet another embodiment, specifically provided are compounds of formula (1), in which R4 is independently selected from hydrogen, methoxy or methyl.

According to yet another embodiment, specifically provided are compounds of formula (1), in which R5 is selected from hydrogen, alkyl, -C(0)OR₇ or -(CH₂)_PR₇.

According to yet another embodiment, specifically provided are compounds of formula (1), in which R5 is independently selected from hydrogen, methyl,

According to yet another embodiment, specifically provided are compounds of formula (1), in which two of the R5 groups on the same atom or adjacent atom combined together to form an optionally substituted 3-8 membered spiro/fused ring containing 0-3 hetero atoms or heterogroups independently selected form N, O, S, C(O), NH, S(O) and S(0)₂, wherein the optional substituent is independently selected from one or more !¾.

According to yet another embodiment, specifically provided are compounds of formula (1), in which two of the R5 groups on the same atom combined together to form an optionally substituted 3-7 membered sipro ring containing 0-3 heteroatoms or heterogroups selected from O, N and C(O); wherein the optional substituent is independently selected from one or more !¾_.

According to yet another embodiment, specifically provided are compounds in

According to yet another embodiment, specifically provided are compounds of formula (1), in which R6 is selected from hydrogen, alkyl, halogen, -(CH2)_P 7, -C(0)OR₇, - C(0)R₇, -C(0)CH₂OH, -C(0)CH(OH)CH₂OH or -C(0)CH₂NHC(0)R₇.

According to yet another embodiment, specifically provided are compounds of

According to yet another embodiment specifically provided are compounds formula (1), in which p is 0, 1, 2 or 3. According to yet another embodiment, specifically provided are compounds of formula (1), in which n is 1 or 2.

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

wherein, Ri, R₂, R₃, R5 and 'n' are same as defined in formula (1) and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof.

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

According to yet another embodiment, specifically provided are compounds of formula (lb), in which Ri and R₃ are selected from hydrogen; and n is 1 or 2.

According to yet another embodiment, s ecifically provided are compounds of

formula (lb), in which R₂ i

, wherein ring A is 5-6 membered ring containing 0-3 heteroatoms independently selected from N, S and O and p is 0.

According to yet anoth fically provided are compounds of

formula (lb), in which R₂

, wherein ring A is independently selected from

According to yet another embodiment, specifically provided are compounds of formula (lb), in which R5 is alkyl for example methyl.

According to yet another embodiment, specifically provided are compounds of formula (lb), in which two of the R5 groups on the same atom or adjacent atom combined together to form an optionally substituted 3-8 membered spiro/fused ring containing 0-3 hetero atoms or heterogroups independently selected form N, O, S, C(O), NH, S(O) and S(0)2, wherein the optional substituent is independently selected from one or more !¾.

According to yet another embodiment, specifically provided are compounds of formula (lb), in which two of the R5 groups on the same atom combined together to form an optionally substituted 3-8 membered spiro ring containing 0-3 hetero atoms or is selected

According to yet another embodiment, specifically provided are compounds of formula (lb), in which R6 is selected from hydrogen, alkyl, halogen, -C(0)CH₂OH or - C(0)R₇.

According to yet another embodiment, specifically provided are compounds of formula (lb), hydrogen, methyl, fluorine, -

C(0)CH₂OH,

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

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

According to yet another embodiment specifically provided are compounds of formula (Id), in which Ri_, R3 and R5 are selected from hydrogen; and n is 1.

According to another embodiment, specifically provided are compounds of formula

(Id), in which R₂

, wherein ring A is 5-9 membered monocyclic or bicyclic ring containing 0-3 heteroatoms independently selected from N, S and O and p is 0.

According to yet another embodiment, s ecifically provided are compounds of

formula (Id), in which R₂ i

According to yet another embodiment, specifically provided are compounds of

formula (Id), in which R₂ is ring A is selected from

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

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

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

wherein, Ri, R₂, R₃, R5 and 'n' are same as defined in formula (1) and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof. According to yet another embodiment, specifically provided are compounds of formula (lg), in which Ri_, R₃ and R5 are selected from hydrogen; and n is 1.

According to yet another embodiment, specifically provided are compounds

formula (lg), in which R₂ is

s 5 membered ring containing 1-3 heteroatoms independently selected from N, S and O and p is 0.

According to yet another embodiment, specifically provided are compounds of

formula (lg), in which R₂ is

and q is 0.

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

wherein, Ri, R₂, R3, R5 and 'n' are same as defined in formula (1) and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof.

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

wherein, Ri, R₂, R3 and 'n' are same as defined in formula (1) and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof.

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

wherein, Ri, R₂, 3 and 'n' are same as defined in formula (1) and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof.

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

Comp

IUPAC Name

No.

1 (E)-3,3-dimethyl-5-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l- en- 1 -yl)-l H-pyrrolo [2,3-b]pyridin-2(3H)-one;

2 (E)-3,3-dimethyl-5-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin-l-yl)prop-l- en- 1 -yl)-l H-pyrrolo [2,3-b] pyridin-2(3H)-one;

3 (E)-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)spiro [cyclobutane- 1 ,3 '-pyrrolo [2,3 -b Jpyridin] -2'(1 'H)-one ;

4 (E)-5'-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin- 1 -yl)prop-l -en-1 -yl)spiro [cyclobutane- 1 ,3 '-pyrrolo [2,3 -b Jpyridin] -2'(1 'H)-one ;

5 (E)-6-(3-(4-(4-methoxybenzylidene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)-3,4- dihydro- 1 , 8 -naph thyridin-2( 1 H) -one ;

6 (E)-6-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-3,4- dihydro- 1 ,8-naphthyridin-2(l H)-one;

7 (E)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-3,4- dihydro- 1 ,8-naphthyridin-2(l H)-one;

8 (E)-6-(3-oxo-3-(4-(thiazol-5-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-3,4- dihydro- 1 ,8-naphthyridin-2(l H)-one;

9 (E)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-3,4- dihydro- 1 ,8-naphthyridin-2(l H)-one;

10 (E)-6-(3-(4-((5-methylthiazol-2-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-3,4-dihydro-l ,8-naphthyridin-2(lH)-one;

11 (E)-3,3-dimethyl-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l- en-l-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one; (E)-3 -dimethyl-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l- en-l-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one;

(E)-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)-l 'H- spiro [cyclopropane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)-l 'H- spiro [cyclobutane-l,3'-[l ,8]naphthyridin]-2'(4'H)-one;

(E)-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)-l 'H- spiro[cyclobutane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-tert-butyl 2-oxo-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l- en-l-yl)-2,4-dihydro-lH-spiro[[l ,8]naphthyridine-3,4'-piperidine]-l'- carboxylate;

(E)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop-l -en- 1-yl)- 2 3',5',6'-tetrahydro-lH-spiro[[l ,8]naphthyridine-3,4'-pyran]-2(4H)-one;

(E)-3-(2-moφholinoethyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(lH)-one;

(E)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)-l 'H- spiro[azepane-4,3'-[l,8]naphthyridine]-2',7(4'H)-dione;

(E)-3-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-3-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-3-(3-oxo-3-(4-(thiazol-5-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-3-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-3-(3-(4-((5-methylthiazol-2-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-3-(3-(4-(oxazol-2-ylmethylene)piperidin-l -yl)-3-oxoprop-l-en-l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-3-(3-(4-((l,3,4-thiadiazol-2-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-8-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]diazepin-4(5H)-one; (E)-7-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-3,5- dihydropyrido [2,3 -e] [1 ,4]oxazepin-2(lH)-one;

(E)-7-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-3,5- dihydropyrido [2,3-e] [1 ,4]oxazepin-2(lH)-one;

(S,E)-3-(3 -oxo-3-(4-(thiophen-2-ylmethylene)piperidin- 1 -yl)prop-l -en- 1 -yl)- 7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[l ,2-a][l,4]diazepin-10(l lH)-one;

(S,E)-3-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)- 7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[l ,2-a][l,4]diazepin-10(l lH)-one;

(S,E)-3-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)- 7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[l ,2-a][l,4]diazepin-10(l lH)-one;

(E)-6'-(3-(4-((2-methylthiazol-4-yl)methylene)piperidin- l-yl)-3-oxoprop- 1-en- 1 - yl)-l'H-spiro[cyclopropane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-3-(3-(4-((2-methylthiazol-4-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)- 1 -methyl-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop- 1 -en- 1 - yl)-l'H-spiro[azepane-4,3'-[l ,8]naphthyridine]-2',7(4'H)-dione;

(E)-4,4-difluoro-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l-en- l-yl)-l'H-spiro[cyclohexane-l,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-3,3-difluoro-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l-en- l-yl)-l'H-spiro[cyclobutane-l ,3'-[l ,8]naphthyridin]-2'(4'H)-one;

(E)- 1 -acetyl-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop- 1 -en- 1 - yl)-l'H-spiro[azetidine-3,3'-[l ,8]naphthyridin]-2'(4'H)-one;

(E)-5'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)- 2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

(E)-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)- 2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

(E)-6-(3-(4-((l,3,4-thiadiazol-2-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-3,3-dimethyl-3,4-dihydro-l ,8-naphthyridin-2(lH)-one;

3,3-dimethyl-6-((E)-3-oxo-3-(4-(thiazol-4-ylmethylene)azepan-l-yl)prop-l-en- l-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one;

(E)- 1 -acetyl- 5 '-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop- 1 -en- 1 - yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one;

(E)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)-l 'H- spiro [cyclopropane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-tert-butyl 2'-oxo-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop- l-en-l-yl)-2 4'-dihydro-l 'H-spiro[azetidine-3,3'-[l,8]naphthyridine]-l- carboxylate;

(E)-tert-butyl 2-oxo-6-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin-l-yl)prop- l-en-l-yl)-2,4-dihydro-lH-spiro[[l,8]naphthyridine-3,4'-piperidine]-l'- carboxylate;

(E)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)-l'H- spiro[cyclohexane-l,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- 1-yl)- 2 3',5',6'-tetrahydro-lH-spiro[[l ,8]naphthyridine-3,4'-pyran]-2(4H)-one;

(E)-2-oxo-6-(3-oxo-3-(4-(tMophen-2-ylmethylene)piperidin-l-yl)prop-l-en-l- yl)-2,4-dihydro- 1 H-spiro [[1 ,8]naphthyridine-3 ,4'-piperidine]- 1 '-carbaldehyde;

(E)- 1 '-acetyl-6-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin- 1 -yl)prop- 1 -en- 1 - yl)-lH-spiro[[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one;

(E)-l'-butyryl-6-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin-l -yl)prop-l-en- l-yl)-lH-spko[[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one;

(E)-l'-(2-hydroxyacetyl)-6-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)-lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one;

(E)-3-(2-moφholinoethyl)-6-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(lH)-one;

(E)-7-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-4,5- dihydro-lH-pyrido[2,3-e][l,4]diazepin-2(3H)-one;

(E)-tert-butyl 2-oxo-7-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l- en-l-yl)-2,3-dihydro-lH-pyrido[2,3-e] [l ,4]diazepine-4(5H)-carboxylate;

(E)-7'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)-4',5'- dihydrospiro[cyclopropane- 1 ,3 '-pyrido [2 ,3 -e] [ 1 ,4] diazepin] -2'( 1 'H)-one;

(E)-tert-butyl 2-oxo-7-(3-oxo-3-(4-(thiophen-3-ylmethylene)piperidin-l-yl)prop- l-en-l-yl)-2,3-di ydro-lH-pyrido[2,3-e][l ,4]diazepine-4(5H)-carboxylate;

(E)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)-l'H- spiro [azetidine- 3 , 3 ' - [ 1 , 8 ] naphthyridin] -2' (4Ή) -o ne hydrochloride;

(E)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop-l -en- 1-yl)- 1H- spiro[[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one 2,2,2-trifluoroacetate; (E)-l'-(2-hydroxyacetyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)-lH-spko[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one;

(E)- 1 '-(furan-2-carbonyl)-6-(3-oxo-3 -(4-(thiazol-4-ylmethylene)piperidin- 1 - yl)prop-l-en-l-yl)-lH-spko[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one;

(E)- -(5-methylfuran-2-carbonyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene) piperidin- l-yl)prop-l-en- 1 -yl)- lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]- 2(4H)-one;

(E)- -(5-nitroluran-2-carbonyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop- 1 -en- 1 -yl)- 1 H-spiro [[1 ,8 ]naphthyridine-3,4'-piperidin]-2(4H)-one;

(E)- 1 '-(3-hydroxypropyl)-6-(3-oxo-3 -(4-(thiophen-2-ylmethylene)piperidin- 1 - yl)prop-l-en-l-yl)-lH-spko[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one;

(E)-N-(2-oxo-2-(2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l- yl)prop- 1-en- 1 -yl)-2,4-dihydro-l H-spiro [[1 ,8]naphthyridine-3 ,4 '-piperidin]- 1 '- yl)ethyl)pivalamide;

(E)-l'-(2-hydroxyacetyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)-lH-spko[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one;

(E)-l'-(2,3-dihydroxypropanoyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene) piperidin- l-yl)prop-l-en- 1 -yl)- lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]- 2(4H)-one;

(E)- 1 '-(furan-2-carbonyl)-6-(3-oxo-3 -(4-(thiazol-2-ylmethylene)piperidin- 1 - yl)prop-l-en-l-yl)-lH-spko[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one;

(E)-7-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-4,5- dihydro-lH-pyrido[2,3-e][l,4]diazepin-2(3H)-one 2,2,2-trifluoroacetate;

(E)-6-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin- 1 -yl)prop-l -en- 1 -yl)- 1 H- spiro[[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one 2,2,2-trifluoroacetate;

(E)-7-(3-oxo-3-(4-(thiophen-3-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-4,5- dihydro-lH-pyrido[2,3-e][l,4]diazepin-2(3H)-one 2,2,2-trifluoroacetate;

(E)-6-(3-(4-benzylidenepiperidin- 1 -yl)-3 -oxoprop-1 -en- 1 -yl)-3,4-dihydro- 1 ,8 - naphthyridin-2(lH)-one;

(E)-3-(3-(4-(benzo[d]thiazol-2-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-6-(3-oxo-3-(4-(pyridin-3-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)-3,4- dihydro- 1 ,8-naphthyridin-2(l H)-one;

(E)-6-(3-(4-(fluoro(thiazol-2-yl)methylene)piperidin- 1 -yl)-3-oxoprop- 1 -en- 1 - yl)-3,4-dihydro-l ,8-naphthyridin-2(lH)-one;

(E)-3-(3-(4-(fluoro(thiazol-2-yl)methylene)piperidin- 1 -yl)-3-oxoprop- 1 -en- 1 - yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)spiro [piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one;

(E)-6-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-3,3-dimethyl-3,4-dihydro-l ,8-naphthyridin-2(lH)-one;

(E)-3-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-l-(2-hydroxyacetyl)-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)-l'H-spiro[azetidine-3,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop-l -en- 1-yl)- 1H- spiro [[1,8] naphthyridine- 3 ,3 '-oxetan] -2(4H) -one ;

(E)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- 1-yl)- 1H- spiro [[1,8] naphthyridine- 3 ,3 '-oxetan] -2(4H) -one ;

(E)-6-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-lH-spiro[[l,8]naphthyridine-3,3'-oxetan]-2(4H)-one;

(E)-6-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)-lH- spiro [[1,8] naphthyridine- 3 ,3 '-oxetan] -2(4H) -one ;

(E)-6-(3-(4-(oxazol-2-ylrnethylene)piperidin-l -yl)-3-oxoprop-l-en-l-yl)-lH- spiro [[1,8] naphthyridine- 3 ,3 '-oxetan] -2(4H) -one ;

(E)-6'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-3,3-difluoro-l 'H-spiro[cyclobutane-l ,3'-[l ,8]naphthyridin]-2'(4'H)-one;

(E)-3,3-dilluoro-6'-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l- en-l-yl)-l 'H-spiro[cyclobutane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-3,3-dilluoro-6'-(3-(4-(oxazol-2-ylmethylene)piperidin-l -yl)-3-oxoprop-l-en- l-yl)-l'H-spiro[cyclobutane-l ,3'-[l ,8]naphthyridin]-2'(4'H)-one;

(E)-6,6-dilluoro-3-(3-oxo-3 -(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop- 1 -en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-3-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-6,6-difluoro-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-6,6-dilluoro-3-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l- en-l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one; (E)-6,6-dilluoro-3-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-6,6-dilluoro-3-(3-oxo-3 -(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop- 1 -en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-l-(2-hydroxyacetyl)-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)spko[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one;

(E)-l-acetyl-6'-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en- l-yl)-l'H-spiro[azetidine-3,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-6'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-l -acetyl- l'H-spiro[azetidine-3,3'-[l ,8]naphthyridin]-2'(4'H)-one;

(E)-6'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-l-(2-hydroxyacetyl)-l H-spko[azetidine-3,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-l-(2-hydroxyacetyl)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)-l'H-spiro[azetidine-3,3'-[l,8]naphthyridin]-2'(4'H)-one;

(E)-l-(2-hydroxyacetyl)-6'-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3- oxoprop-1 -en- 1 -yl)- 1 Ή-spiro [azetidine-3,3'- [1 ,8 ]naphthyridin]-2'(4'H)-one;

(E)-7,7-dilluoro-3-(3-oxo-3 -(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop- 1 -en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-7,7-dilluoro-3-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-3-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-7,7-difluoro-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-5'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)spiro[oxetane-3,3'-pyrrolo[2,3-b]pyridin]-2'(l 'H)-one;

(E)-5'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)spiro [oxetane-3,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

(E)-5'-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)spiro [oxetane-3,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

(E)-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)spiro [oxetane-3,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

(E)- 1 -acetyl- 5 '-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop- 1 -en- 1 - yl)spiro [piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

(E)-l-(2-hydroxyacetyl)-5'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)spko[piperidme-4 '^yrrolo[2 -b]pyridin]-2 l'H)-one;

109 (E)-6'-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)-l'H- spiro [cyclobutane-l,3'-[l ,8]naphthyridin]-2'(4'H)-onel;

110 (E)-l'-(2-hydroxyacetyl)-6-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3- oxoprop-l-en-l-yl)-lH-spiro[[l,8]naphthyridine-3,4'^iperidin]-2(4H)-one;

111 (E)-6'-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)-l'H- spiro[cyclopropane-l,3'-[l ,8]naphthyridin]-2'(4'H)-one;

112 (E)-6-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)-3,3- dimethyl-3 ,4-dihydro- 1 ,8 -naphthyridin-2( 1 H)-one ;

113 (E)-6-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)- 2 3 5 6'-tetrahydro-lH-spko[[l ,8]naphthyridine-3,4'^yran]-2(4H)-one;

114 (E)-3-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

115 (E)-6-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)-3,4- dihydro- 1 ,8-naphthyridin-2(l H)-one;

116 (E)-6'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-lH-spiro[cyclobutane-l,3'-[l,8]naphthyridin]-2'(4'H)-one;

117 (E)-5'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-l-acetylspiro[piperidine-4 '^yn"olo[2 -b]pyridiii]-2'( H)-one;

118 (E)-6'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-lH-spiro[cyclopropane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one;

119 (E)-5'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-l-(2-hydroxyacetyl)spko[piperidine-4 '^yrrolo[2 -b]pyridin]-2 l'H)-one and

120 (E)-l-(2-hydroxyacetyl)-5'-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3- oxoprop- 1 -en- 1 -yl)spiro [piperidine-4,3 '-pyrrolo [2,3 -b]pyridin]-2'( 1 'H)-one.

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

(E)-3,3-dimethyl-6-(3-oxo-3-(4-(thiazol-2-yl-methylene)piperidin-l-yl)prop-l-en-l- yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one,

(E)-3,3-dimethyl-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l-en-l- yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one, (E)-6'-(3-oxo-3-(4-(tMazol-2-ylmethylene)piperidin-l -yl)prop-l-en-l-yl)-l'H-spiro [cyclopro pane-l ,3'-[l,8] naphthyridin]-2'(4'H)-one,

(E)-6'-(3-oxo-3-(4-(tMazol-4-ylmethylene)piperidin-l -yl)prop-l-en-l-yl)-l'H-spiro [cyclopro pane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one,

(E)-6-(3-oxo-3-(4-(thiazol-2-yrmethylene)piperidin-l-yl)prop-l-en-l-yl)-2',3',5',6'- tetrahydro-lH-spiro[[l ,8]naphthyridi ne-3,4'-pyran]-2(4H)-one,

(E)-6-(3-oxo-3-(4-(thiazole-4-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-2',3',5',6'- tetrahydro-lH-spiro[[l ,8]naphthyridine-3,4'-pyran]-2(4H)-one,

(E)-l'-(2-hydroxyacetyl)-6-(3-oxo-3-(4-(tMazol-2-ylmethylene)piperidiri-l -yl)prop- l-en-l-yl)-lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one,

(E)-l'-(2-hydroxyacetyl)-6-(3-oxo-3-(4-(tMazol-4-ylmethylene)piperidiri-l -yl)prop- 1 -en- l-yl)-l H-spiro [[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one,

(E)- -(furan-2-carbonyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop- l-en-l-yl)-lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one,

(E)-6'-(3-oxo-3-(4-(tMazol-2-ylmethylene)piperidrn-l -yl)prop-l-en-l-yl)- H- spiro[azepane-4,3'-[l,8]naphthyridine]-2',7(4'H)-dione,

(E)- 1 -methyl-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop- 1 -en- 1 -yl)- l'H-spiro[azepane-4,3'-[l,8]naphthyridine]-2',7(4'H)-dione,

(E)-3-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one,

(E)-3-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8 (9H)-one,

(E)-7-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-4,5- dihydro- 1 H-pyrido [2,3 -e] [ 1 ,4] diazepin-2(3 H)-one,

(E)-3-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one,

(E)-4,4-difluoro-6'-(3-oxo-3-(4-(thiazol-4-ylrnethylene)piperidin-l-yl)prop-l-en-l - yl)- H-spiro[cyclohexane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one,

(E)- -(fliran-2-carbonyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop- l-en-l-yl)-lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one,

(E)-l'-(5-methylfuran-2-carbonyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- l-yl)prop-l -en-l-yl)-lH-spiro[[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one and

(E)-l'-(5-nitrofuran-2-carbonyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l - yl)prop-l-en- 1 -yl)- lH-spiro[[l ,8]naphthyridine-3 ,4'-piperidin]-2(4H)-one. 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 freeof (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 and 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 and 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 fused pyridine 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 FabI inhibitor, so that the combinations of the present invention in certain instances will include one agent that is a FabI 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.

"Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a Ci-Oo alkyl group may have from 1 to 10 (inclusive) carbon atoms in it. Similary C1-C4 alkyl group may have from 1 to 4 (inclusive) carbon atoms. Examples of Ci-Cioalkyl 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, /so-propoxy, «-butoxy and i-butoxy. An alkoxy group can be unsubstituted or substituted with one or more suitable groups. "Amino" refers to an -N- group, the nitrogen atom of said group being attached to a hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or any suitable groups. Representative examples of an amino group include, but are not limited to -NHCH₃, -NHC]¾-phenyl, and - NH-cyclopropyl. An amino group can be unsubstituted or substituted with one or more of the 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.

"Oxo" refers to =0 group.

"Thio" refers to an -S- group, the sulphur atom of said group being attached to a hydrogen, alkyl, cycloalkyl, aryl, amino, oxo or any suitable groups. Representative examples of an thiogroup include, but are not limited to -SH (thiol), -SCH₃, -SOCH₃, - SO₂CH₃ and -SO₂NHCH₃. Thio group can be unsubstituted or substituted with one or more of the suitable groups.

"Carboxyl or Carboxy" refers to an -COO- group, the carboxy group being attached to any suitable groups. Representative examples of carboxy include, but are not limited to - COOH, -COOCH₃, -COO-aryl, the carboxy group can be unsubstituted or substituted with one or more of the suitable groups.

"Aryl" refers to an optionally substituted monocylic,bicyclic or polycyclic aromatic hydrocarbonring system of about 6 to 14 carbon atoms. Examples of a Ce-Cwaryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. Aryl group can be unsubstituted or substituted with one or more suitable groups;

"Cycloalkyl" refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a cycloalkyl include, but are not limited to eye lo propyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-l-yl, octahydro-lH-inden-2-yl and decahydro-lH-benzo[7] annulen-2-yl. 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 a saturated, monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatomsselected fromoxygen, sulfur 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.

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

"Heterogroup" refers to -C(O)-, -S(O), -NH and S(0)₂.

"4-12 membered monocyclic or bicyclic ring containing 0-3 heteroatoms" refers to a saturated, partially saturated or unsaturated monocyclic or bicyclic ring, in which 1 to 4 of the ring carbon atoms have been independently replaced with a heteroatom/heterogroups such as N, O, S,-C(0)-, -S(O), -NH and S(0)2- Representative examples of a 4 to 12 membered ring include, but are not limited to morpholine, pyrrole, cyclobytyl, pyrrole, phenyl, pyridine, pyridnone, tetrahydroisoquinoline.

"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 fused pyridine 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 substituted fused pyridine 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.

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

°C (degree Celsius); δ (delta); % (percentage); AcOH (Acetic acid); ACN (Acetonitrile); Ac₂0 (Acetic anhydride); brine (NaCl solution); Br or Br₂ (Bromine); NBS (N-bromo succinimide); n-BuLi (n-Butyl lithium); BF₃.Et₂0 (Boron trifluoride diethyletherate); t-BuOH (tert-Butanol); (Boc)₂0 (Di tert-butyl dicarbonate); bs or brs (Broad singlet); CAN (Ceric ammonium nitrate); CDI (Carbonyl diimidazole); CDCI₃ (Deuteriated chloroform); CH₂C1₂/DCM (Dichloro methane); Cs₂CC>3 (Cesium carbonate); mCPBA (m-Chloroperbenzoicacid); DAST (Diethylaminosulfer trifluoride); DMF (Dimethyl formamide); DMSO (Dimethyl sulphoxide); DIPEA/DIEA (N, N- Diisopropyl ethylamine); DMAP (Dimethyl amino pyridine); DMSO-d₆ (Deuteriated DMSO); d (Doublet); dd (Doublet of doublet); dt (Doublet of triplet); EDC.HC1 (l-(3- Dimethylaminopropyl)-3-carbodiimide hydrochloride); EtOH (Ethanol); Et₂0 (Diethyl ether); EtOAc (Ethyl acetate); g (gram); H or H₂ (Hydrogen); H₂0(Water); HCHO (Formaldehyde); HOBt (1-Hydroxy benzotriazole); H₂S0₄ (Sulphuric acid); HBr (Hydrobromic acid); HC1 (Hydrochloric acid); h or hr (Hours); HATU (2-(lH-7- Azabenzotriazol-l-yl)— 1,1,3,3-tetramethyl uranium hexafluoro phosphatemethanaminium); Hz (Hertz); J (Coupling constant); K₂CO₃ (Potassium carbonate); K₃PO₄ (Potassium phosphate); KOAc (Potassium acetate); KOBu' (Potassium tert-butoxide); KSCN (Potassium thiocyanate); LDA (Lithium diisopropylamide); LAH (Lithium aluminium hydride); LiOH.H₂0 (Lithium hydroxide monohydrate); LiHMDS (Lithium bis(trimethylsilyl)amide); MeOH/CH₃OH (Methanol); mmol (Millimol); M (Molar); μΐ (Microlitre); ml (Millilitre); mg (Milligram); m (Multiplet); MHz (Megahertz); MS (ES) (Mass spectroscopy-electro spray); min (Minutes); MTBE (Methyl tert-butyl ether); NaHMDS (Sodium bis(trimethylsilyl)amide); NaOBu' (Sodium tert-butoxide); NaOCH₃ (Sodium methoxide); NaOAc (Sodium acetate); NaOH (Sodium hydroxide); NaBFL (Sodium borohydride); NaCNBH₃ (Sodiumcyanoborohydride); NaH (Sodium hydride); Na₂SC>4 (Sodium sulphate); N₂(Nitrogen); NMR (Nuclear magnetic resonance spectroscopy); NH₄C1 (Ammonium chloride); Na₂C0₃ (Sodium carbonate); NH₂OH.HCl (Hydro xylamine hydrochloride); Pd (OAc)₂ (Palladium diacetate); Pd(dppf)₂Cl₂ (1,1'- Bis(diphenylphosphino)ferrocene) palladium(II) dichloride); Pd₂ (dba)₃ (Trisdibenzylideneacetone) dipalladium; PPh₃(Triphenyl phosphine); P(OEt)₃(Triethyl phosphine); P (o-tolyl)₃ (Tri-o-tolyl phosphine); P(OMe₃)₃(Trimethylphosphite); PhMe (Toluene); PBr₃ (Phosphorous tribromide); PTS-C1 (p-Toluene sulfonyl chloride); SEM-C1 (2-(Trimethylsilyl)ethoxymethyl chloride); SOCI₂ (Thionyl chloride); S (Singlet); TEA (Triethyl amine); TFA/CF₃COOH (Trifluoroaceticacid); TLC (Thin Layer Chromatography); THF (Tetrahydrofuran); Ti(Opr)4 (Titanium tetra isopropoxide); TMDA (Tetramethylethylenediamine); t (Triplet); Xantphos (4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene); Zn (Zinc) 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:

As shown in the above scheme, the novel compounds of the present invention of formula (1) can be synthesized from formula 1.4 and 1.7 through acid-amine coupling, alternatively from formula- 1.5 and 1.6 through Pd catalyzed C-C bond formation. The reactions progresses can be monitored by conventional methods such as TLC/NMR/LC-MS/ES-MS.

The formula 1.0 can undergo Arbuzov reaction with trimethyl phosphite or triethyl phosphite to provide formula 1.1 at a temperature of about 120°C to 150°C for about 16-48 h to provide 1.1. The formula 2.0 can be synthesized by treating formula 1.0 with triphenyl phosphine in presence of suitable solvents such as DCM, Toluene, ACN and the like, at a temperature of about 20-35°C to 100°C for about 16-48 h. The formula 1.2 undergoes Horner-Wadsworth-Emmons (HWE) reaction with formula 1.1 to provide formula 1.3. This coupling 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 20-35°C to 85°C for about 2-16 h. The formula 1.2 undergo Wittig reaction with formula 2.0 to provide formula 1.3. This coupling 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 the like and their molar solutions, at a temperature of about -30°C to 20-35°C for about 16-48 h. The deprotection of formula 1.3 can be carried out by using the suitable deprotecting agents such as TFA, HC1 in diethyl ether molar solutions to provide formula 1.4. The deprotection reaction can be carried out in suitable solvents such as DCM, THF, DCM/THF (1 :5) and the like at a temperature of about 20-35°C for about 2-6 h. The formula 1.5 can be synthesized by treating formula 1.4 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 1.4 with formula 1.7 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 -hydro xybenzotriazole (HOBt), benzotriazole-l-yloxytris (dimethylamino)phosphoniumhexafluorophosphate and 2-(lH- benzotriazol-l-yl)-l,l ,3,3-tetra methyluronium hexafluorophosphate and an azabenzotriazole-containing reagent such as 0-(7-azabenzotriazole-l-yl)-N 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/or DMAP and the like at a temperature of about 20-35°C for about 12-48 h to provide formula-l.The reaction progress can be monitored by conventional methods such as TLC/NMR/LC-MS/ES-MS.

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

The formula- 1 can be synthesized by treating formula 1.5 with formula 1.6 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 organic bases such as TEA, DIPEA and the like by using catalysts such as Pd(OAc)₂, Pd(PPh₃)₂Cl₂ or Pd₂(dba)₃ and the like, in the presence of ligands P(o-tolyl)₃, P(m-tolyl)₃ or 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 thereby; 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:

^-NMR: Varian 400 MHz. The microwave chemistry was performed on a CEM Explorer.

The procedure for the compounds of Formula (1) are detailed herein below stepwise including the general synthesis of various intermediates involved in process of manufacture of the compounds according to the present invention.

(j_c) Intermediate-1

(i) SOCl₂, DCM, 20°C, 0.5 h; (ii) P(OEt)₃, 125°C, 16 h; (iii) NaH, THF, 85°C, 16 h;

(iv) 2M HCl in diethyl Ether, DCM, 20-35°C, 3 h;

(Ref. for step-(i): US2009/082403)

Step-(ii): Synthesis of diethyl (thiazol-2-ylmethyl)phosphonate (lb).

A stirred solution of 2-(chloromethyl)thiazole (l a) (5 g, 37.30 mmol) in triethyl phosphite (25 mL) was heated at 125°C for 16 h. Then the reaction mixture was quenched with ice water (5 mL) at 20-35°C, diluted with ethyl acetate (100 mL), water (100 mL) and partitioned into layers. The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SC>4 and filtered. The filtrate was rotary evaporated to get the desired compound as a brown liquid (6 g, 68%); LC-MS: 236.1 (M+l)⁺.

Step-(iii): Synthesis of tert-butyl 4-(thiazol-2-ylmethylene)piperidine-l-carboxylate (lc). To a stirred solution of tert-butyl 4-oxopiperidine-l-carboxylate (lb) (4 g, 20.42 mmol) and diethyl(thiazol-2-ylmethyl)phosphonate (lb) (6 g, 25.53 mmol) in dry THF ( 60 mL) was added NaH (0.92 g, 38.29 mmol, 60 wt% in oil dispersion) at 20-35°C under nitrogen atmosphere and the reaction mixture was heated at 85 °C for 16 h. Then the reaction mixture was quenched with water (5 mL) at 20-35°C, diluted with ethyl acetate (100 mL), water (100 mL) and partitioned into layers. The organic layer was washed with brine (50 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 20% ethyl acetate/he xane as an eluent to get the desired compound as an off-white solid (5 g, 83%); H NMR (400MHz, DMSO-de) δ 7.81 (d, J=3.5 Hz, 1H), 7.65 (d, J=3.4 Hz, 1H), 6.59 (s, 1H), 3.48- 3.38 (m, 4H), 2.90-2.86 (m, 2H), 2.36-2.30 (m, 2H), 1.42 (s, 9H); LC-MS: 281.1 (M+l)⁺.

Step-(iv): Synthesis of 2-(piperidin-4-ylidenemethyl)thiazole HCl (1). To a stirred solution of tert-butyl 4-(thiazol-2-ylmethylene)piperidine- l -carboxylate(lc) (4 g, 14.28 mmol) in diethyl ether (10 mL) was added 2M HC1 in diethyl ether (20 mL) drop wise at 0°C and the reaction mixture was allowed to stir at 20-35°C for 3 h. Then diethyl ether was rotary evaporated to get the desired compound as a pale brown solid (3.65 g, Quantitative). ^XH NMR (400MHz, DMSO-d₆) δ 9.48 (bs, 2H), 7.88 (d, J=2.9 Hz, IH), 7.74 (d, J=2.9 Hz, IH), 6.67 (s, IH), 3.24-3.12 (m, 6H), 2.64-2.58 (m, 2H); LC-MS: 181.1 (M+l )⁺. Alternatively this reaction can be carried out in presence of TFA/DCM.

The below Intermediates-2 to 8 were prepared according to the above protocol (Intermediate- 1).

Intermediate-9: Synthesis of 2-(piperidin-4-ylidenemethyl)-l,3,4-thiadiazole HC1.

9c Intermediate-9

(i) PBr₃, DCM, 50°C, 4 h; (ii) PPh₃, DCM, 40°C, 3 h; (iii) Potassium tert-butoxide; DCM, 20-35°C, 16 h; (iv) 2M HC1 in Diethyl Ether, DCM, 20-35°C, 3 h.

(Ref.for steps-(i-ii): WO2010/030810)

Step-(iii): Synthesis of tert-butyl 4-((l,3,4-thiadiazol-2-yl)methylene)piperidine-l- carboxylate (9c).

To a stirred solution of ((l ,3,4-thiadiazol-2-yl)methyl)triphenyl phosphonium bromide (9b) (0.98 g, 2.71 mmol) in DCM (10 mL) was added potassium tert-but oxide (0.38 g, 3.39 mmol) at 20-35°C. After 15 minutes, tert-butyl 4-oxopiperidine-l-carboxylate (0.45 g, 2.26 mmol) was added and continued stirring at 20-35°C for 16 h.Then the reaction mixture was diluted with ethyl acetate (50 mL), water (50 mL) and partitioned into layers. The organic layer was washed with brine (30 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 60% ethyl acetate/hexane as an eluent to get the desired compound as an off-white solid (0.31 g, 49%); H NMR (400MHz, DMSO-d₆) δ 9.54 (s, 1H), 6.78 (s, 1H), 3.50-3.42 (m, 4H), 2.77 (t, J=5.9 Hz, 2H), 2.41 (t, J=5.9 Hz, 2H), 1.42 (s, 9H); LC-MS: 282.2 (M+l)⁺. Alternatively this reaction can be carried out in presence of bases such as LiHMDS, NaHMDS and n-BuLi in THF.

Step-(iv): Synthesis of 2-(piperidin-4-ylidenemethyl)-l ,3,4-thiadiazole hydrochloride^). The process of this step was adopted from step-(iv) of intermediate- 1. The desired compound obtained as a brown solid (230 mg, Quantitative); ^XH NMR (400MHz, DMSO- d₆) δ 9.58 (s, 1H), 9.28 (bs, 2H), 6.84 (s, 1H), 3.26-3.16 (m, 4H), 3.08 (t, J=5.8 Hz, 2H), 2.8-2.65 (m, 2H).

The below Intermediate- 10 was prepared according to the above protocol (Intermediate-9).

Intermediate- 11 : Synthesis of l-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-2-en-l-one.

Intermediate- 1 In termed iate- 11

(i) Acryloyl chloride, triethyl amine, CH₂C1₂, 20-35°C, 16 h.

Step-(i): Synthesis of l-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-2-en-l-one(l l).

To a stirred suspension of 2-(piperidin-4-ylidenemethyl)thiazole hydrochloride (Intermediate- 1) (2 g, 7.87 mmol) in DCM (20 mL) was added triethylamine (5.46 mL, 39.37 mmol) followed by acryloyl chloride (0.96 mL, 11.81 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 (2x50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 20% ethyl acetate/pet ether as an eluent to get the desired compound as light brown liquid (320 mg, 26%); H NMR (400MHz, DMSO-ife) δ 7.83 (d, J=3.5 Hz, 1H), 7.67 (d, J=2.9 Hz, 1H), 6.90-6.81 (m, 1H), 6.62 (s, 1H), 6.13 (dd, J=2.0 Hz, 17.1 Hz, 1H), 5.69 (dd, J=2.0 Hz, 10.7 Hz, 1H), 3.72-3.26 (m, 4H), 3.00-2.88 (m, 2H), 2.46-2.36 (m, 2H).

The below Intermediates- 12 and 13 were prepared according to the above protocol (Intermediate- 11). Int Starting Characterization data

Intermediate formed

No. compound (^lU NMR/LC-MS/ES-MS)

lU NMR (400MHz, DMSO-d₆) δ: 7.46 (d, J=4.4 Hz, 1 H), 7.04 (d, J=3.9 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.89-6.80

12 HCl (m, 1H), 6.52 (s, 1H), 6.12 (dd, J= 2.0

Intermediate-2

Hz, 16.6 Hz, 1H), 5.68 (dd, J= 2.0 Hz, 10.7 Hz, 1H), 3.66-3.54 (m, 4H), 2.64- 2.54 (m, 2H), 2.40-2.32 (m, 2H).

^XH NMR (400MHz, DMSO-d₆) δ:7.57 (dd, J=5.0 Hz, 2.9 Hz, 1 H), 7.40 (s, 1H), 7.15 (d, J=4.4 Hz, 1H), 6.89 (dd,

13 J=10.3 Hz, 16.6 Hz, 1H), 6.38 (s, 1H),

^{¾ v} HCl

6.18 (dd, J=2.0 Hz, 16.6 Hz, 1 H), 5.74 Intermediate-3

(dd, J=2.4 Hz, 10.3 Hz, 1H), 3.69-3.60 (m, 4H), 2.40-2.36 (m, 4H). ate.

(i) Bromomethyl triphenyl phosphonium bromide; LiHMDS, THF, -15°C to 20-35°C, 16 h;

(ii) 3PO4, Pd(dppf)₂Cl₂, Acetonitrile:H₂0 (9: 1), 90°C, 2 h; (iii) CF3COOH, DCM, 20-35°C, 3 h. (Ref. for step-(i): WO2011/029633)

Step-(ii): Synthesis of tert-butyl 4-(4-methoxybenzylidene)piperidine- l-carboxylate (14b). A stirred solution of 4-methoxyphenyl boronic acid (198 mg, 1.30 mmol), tert-butyl 4- (bromo methylene) piperidine- l -carboxylate(14a) (300 mg, 1.09 mmol) and K₃PO₄ (700 mg, 3.27 mmol) in acetonitrile/water (4 mL/1 mL)) was degassed with nitrogen for 10 minutes. After 10 minutes Pd(dppf)2Ci2 (89 mg, 0.11 mmol) was added, again degassed with nitrogen for 10 minutes and the reaction mixture was allowed to stir at 90°C for 2 h. Then the reaction mixture was cooled to 20-35°C, filtered through celite and filtrate was rotary evaporated. The resultant residue was diluted with water (50 mL) and extracted with ethyl acetate (2x50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 10% ethyl acetate/pet-ether as an eluent to get the desired compound as an oily liquid (180 mg, 54%); H NMR (400 MHz, DMSO-d₆) δ 7.14 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 6.30 (s, 1H), 3.74 (s, 3H), 3.40 (t, J=5.9 Hz, 2H), 3.36-3.34 (m, 2H), 2.37 (t, J=5.9 Hz, 2H), 2.28-2.24 (m, 2H), 1.41 (s, 9H).

Step-(iii): Synthesis of 4-(4-methoxybenzylidene)piperidine 2,2,2-trifluoroacetate(14). The process of this step was adopted from step-(iv) of intermediate- 1. The desired compound obtained as a brown liquid (250 mg, Quantitative). ^XH NMR (400MHz, DMSO- de) δ 8.70-8.60 (m, 2H), 7.17 (d, J=8.3 Hz, 2H), 6.91 (dt, J=2.9 Hz, 4.9 Hz, 2H), 6.39 (s, 1H), 3.76 (s, 3H), 3.22-3.04 (m, 4H), 2.59 (t, J=5.9 Hz, 2H), 2.50-2.47 (m, 2H).

Intermediate- 15 : Synthesis of 5'-bromospiro[cyclobutane-l,3'-pyrrolo[2,3-b]pyridin]- 2'(l 'H)-on

15a Intermediate-15

(i) 1,3-dibromo propane, n-BuLi, TMEDA, dry THF, -78°C to 20-35°C, 15 h;

(ii) NBS. DMF, 0°C to 20-35°C, 4 h; (Ref .for steps-(i-ii): WO2013/042035).

Intermediate- 16 : Synthesis of tert-butyl 5'-bromo-2'-oxo-l'-((2-(tri methyl silyl)ethoxy) methyl)- 1 ',2'-di ydrospiro [piperidine-4,3'-pyrrolo [2,3-b]pyridine]- 1 -carboxylate.

l^t,d Intermediate-16

(i) SEM-C1, NaH, DMF, 0°C, 1 h then <10°C, 1 h; (ii) pyridinium bromide perbromide, 1,4-dioxan, 20-35°C, 1 h; (iii) Sat. aq. NH₄C1 solution, Zn, THF, 20-35°C, 3 h; (iv) iert-butyl bis(2-chlorocthyl)carbamatc, Cs₂C0₃, DMF, 20-35°C, 48 h; (v) NBS, DMF, 20-35X, 48 h. (Ref.for steps-(i-m): WO2007/016087)

Step-(iv): Synthesis of tert-butyl 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)- ,2'-dihydro spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-l-carboxylate (16d). To a stirred solution of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin- 2(3H)-one (16c) (3 g, 11.36 mmol) in dimethyl formamide (30 mL) were added dried CS₂CO₃ (9.26 g, 28.40 mmol), followed by tert-butyl bis(2-chloroethyl)carbamate (3.3 g, 13.63 mmol) at 20-35°C and the reaction mixture was allowed to stir at 20-35°C for 48 h. Then the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 30% ethyl acetate/hexane as an eluent to get the desired compound as a brown solid (2.34 g, 48%); H NMR (400MHz, DMSO-d₆) δ 8.23 (dd, J=1.5 Hz, 4.9 Hz, 1H), 7.56 (dd, J=1.5 Hz, 7.3 Hz, 1H), 6.99 (dd, J=5.4 Hz, 7.3 Hz, 1H), 5.25 (s, 2H), 3.93-3.85 (m, 2H), 3.74-3.69 (m, 2H), 3.69-3.62 (m, 2H), 1.92-1.88 (m, 2H), 1.80-1.12 (m, 2H), 1.50 (s, 9H), 0.99-0.93 (m, 2H), -0.03 (s, 9H).

Step-(v): Synthesis of tert-butyl 5'-bromo-2'-oxo-l '-((2-(trimethylsilyl)ethoxy)methyl)- ,2'- dmydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-l-carboxylate(16).

To a stirred solution of tert-butyl 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)- ,2'-dihydro spiro [piper- idine-4,3'-pyrrolo[2,3-b]pyridine]-l-carboxylate (16d) (2.34 g, 5.40 mmol) in dimethyl formamide (25 mL) was added N-bromo succinimide (1.60 g, 8.10 mmol) at 20- 35°C and the reaction mixture was allowed to stir at 20-35°C for 48 h. The progress of the reaction was monitored by TLC. After 48 h, the reaction mixture was diluted with water (100 mL) 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 to get residue which was purified by column chromatography using a mixture of 20% ethyl acetate/hexane as an eluent to get the desired compound as a brown liquid (1.5 g, 54%); ^XH NMR (400MHz, DMSO-d₆)8: 8.28 (d, J=1.9 Hz, 1H), 7.66 (s, 1H), 5.21 (s, 2H), 3.93-3.83 (m, 2H), 3.76-3.60 (m, 4H), 1.92-1.88 (m, 2H), 1.80-1.72 (m, 2H), 1.49 (s, 9H), 0.98-0.92 (m, 2H), 0.03 (s, 9H).

Intermediate- 17 : Synthesis of tert-butyl 6-bromo-2-oxo-2,4-dihydro-lH-spiro[[l ,8] naphthyridine-3 '-piperidine]-l '-carboxylate.

Intermediate-17

(i) Ethyl l-boc-piperidine-4-carboxylate, LDA (1M in THF), dry THF, -78°C to 20-35°C, 16 h. (Ref . for step-(i): WO2007/067416A2) The below Intermediates- 18 to 23 were prepared according to the above protocol (Intermediate- 17).

Intermediates-24: Synthesis of 6-bromo-lH-spiro[[l,8]naphthyridine-3,4'-piperidin]- 2(4H)-one.2,2,2-trifiuoroacetic acid.

Intermediate- 17 Intermediate-24

The process of this step was adopted from step-(iv) of intermediate- 1. The desired compound obtained as a light brown solid (700 mg, 68%); ^XH NMR (400MHz, DMSO-d₆) δ 10.85 (bs, IH), 8.70-8.48 (m, 2H), 8.25 (d, J=2.0 Hz, IH), 7.89 (d, J=2.0 Hz, IH), 3.26- 3.06 (m, 4H), 2.99 (s, 2H), 2.04-1.92 (m, 2H), 1.60-1.50 (m, 2H).

The below Intermediates 25 to 28 were the analogs of Intermediate-24, which were prepared by using various conditions given in the table.

Intermediate-24

Intermediate-29 : Synthesis of 6-bromo-l'-methyl-lH-spiro[[l,8]naphthy- ridine-3,4'- piperidin]-2(4 -one.

Intermediate-24 Tntermediate-29 (i) 37% HCHO solution, triethylamine, NaBH₄, MeOH, 20-35°C, 16 h.

To a stirred solution of 6-bromo-lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one 2,2,2-trifluoroacetic acid (Intermediate-24) (0.5 g, 1.22 mmol) in methanol (10 mL) was added 37% HCHO solution (0.11 g, 3.67 mmol), followed by triethylamine (0.51 mL, 3.66 mmol) at 20-35°C and the mixture was continued stirring at 20-35°C for 30 minutes. Then NaB¾ (0.07 g, 1.83 mmol) was added slowly portion wise at 0°C and the reaction mixture was allowed to stir at 20-35°C for 16 h. Then the reaction mixture was rotary evaporated, resultant residue diluted with water (30 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using mixture a of 60% ethyl acetate/he xane as an eluent to get the desired compound as an off-white solid (0.5 g, 40%); H NMR (400MHz, DMSO-d₆) δ 10.64 (bs, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 3.20 (s, 3H), 2.91 (s, 2H), 2.76-2.60 (m, 4H), 1.86-1.76 (m, 2H), 1.36-1.26 (m, 2H).

Intermediate-30 : Synthesis of 6-bromo-3-(2-mo holinoethyl)-3,4-dihydropyrido[2,3-d] pyrimidin-2(lH)-one.

Intermediate-30

(i) Br₂, AcOH, 20-35°C, 3 h; (ii) Triethyl amine, MeOH, 4-(2-Aminoethyl)morpholine , 20-35°C, 16 h then NaBH₄, 20-35°C, 16 h; (iii) CD1, Dioxane, 80°C, 14 h; (Ref . for Steps-(i-iii): WO2004/052890)

Intermediate-31 : Synthesis of 6'-bromo-l'H-spiro[azepane-4,3'-[l,8]naphthyridine]-

2',7(4' -dione.

(i) Ethane- 1,2-dithiol, BF₃.Et₂0, DCM, 20-35°C, 2 h; (ii) LDA (2M in THF), dry THF, -78°C, 2h then 20-35^uC, 16 h; (iii) Ceric ammonium nitrate, acetonitrile:H₂0, 20-35^uC, 2 h; (iv) Hydroxylamine hydrochloride, Na₂C0₃, ethanol:H₂0, 20-35°C, 4 h; (v) PTS-C1, triethylamine, DCM, 20-35°C, 4 h;

Step-(i): Synthesis of ethyl l,4-dithiaspiro[4.5]decane-8-carboxylate (31a).

To a stirred solution of ethyl 4-oxocyclohexanecarboxylate (5 g, 29.41 mmol) and ethane-1 , 2-dithiol (4.14 g, 44.11 mmol) in DCM (25 mL) was added BF₃.Et₂0 (4.17 g, 29.41 mmol) at 0°C and the reaction mixture was allowed to stir at 20-35°C for 2 h. Then the reaction mixture was rotary evaporated to get residue which was purified by column chromatography using a mixture of 5% ethyl acetate/hexane as an eluent to get the desired compound as a yellow liquid (5.4 g, 75%); ¾ NMR (400MHz, DMSO-d₆) δ 4.05 (q, J=7.4 Hz, 2H), 3.34-3.26 (m, 4H), 2.42-2.34 (m, 1H), 2.10-2.02 (m, 2H), 1.96-1.84 (m, 4H), 1.66- 1.54 (m, 2H), 1.17 (t, J=7.3 Hz, 3H).

Step-(ii):Synthesis of Intermediate (31b).

The process of this step was adopted from step-(i) of intermediate- 17. The desired compound obtained as an off-white solid (0.85 g, 30%); H NMR (400MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.92 (d, J=1.9 Hz, 1H), 3.30-3.26 (m, 4H), 2.93 (s, 2H), 2.12-2.04 (m, 4H), 1.92-1.82 (m, 2H), 1.46-1.38 (m, 2H).

Step-(hT): Synthesis of 6'-bromo-l'H-spiro[cyclohexane-l,3'-[l ,8]naphthyridine]-2',4(4'H)- dione (31c).

To a stirred solution of Intermediate-31b (0.85 g, 2.21 mmol) in acetonitrile/water (15 mL/5 mL) was added eerie ammonium nitrite (9.7 g, 17.68 mmol) at 0°C and the reaction mixture was allowed to stir at 20-35°C for 2 h. Then the reaction mixture was diluted with ethyl acetate (50 mL), washed with NaHCC solution (50 mL), water (30 mL), brine (30 mL), dried over on anhydrous Na₂SC>4 and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 40% ethyl acetate/hexane as an eluent to get the desired compound as an off-white solid (0.35 g, 51 %); ^lU NMR (400MHz, DMSO-d₆) δ 10.78 (s, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 3.07 (s, 2H), 2.42-2.32 (m, 4H), 2.08-1.96 (m, 2H), 1.74-1.64 (m, 2H).

Step-(iv): Synthesis of 6'-bromo-4-(hydroxyimino)-l'H-spiro[cyclohexane-l ,3'-[l ,8]naph- thyridin]-2'(4'H)-one (31d).

To a stirred solution of 6'-bromo- H-spiro[cyclohexane-l ,3'-[l ,8]naphthyridine]-2',4(4'H)- dione (31c) (0.35 g, 1.13 mmol) in ethanol/water (18 mL/2 mL) were added Na₂C0₃ (0.6 g, 5.68 mmol) and hydroxylamine hydrochloride (0.39 g, 5.68 mmol) at 20-35°C and the reaction mixture was allowed to stir at 20-35°C for 4 h. Then the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed brine (20 mL), dried over on anhydrous Na₂SC>4 and filtered. The filtrate was rotary evaporated to get the desired compound as an off-white solid (200 mg, 95%); ^XH NMR (400MHz, DMSO-d₆) δ 10.69 (s, 1H), 10.28 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 2.99 (s, 2H), 2.30-2.16 (m, 4H), 1.84-1.66 (m, 2H), 1.50-1.38 (m, 2H).

Step-(v): Synthesis of 6'-bromo- H-spiro[azepane-4,3'-[l,8]naphthyridine]-2',7(4'H)-dione (31).

To a stirred solution of 6'-bromo-4-(hydroxyimino)-l'H-spiro[cyclohexane-l ,3'-[l ,8]naph- thyridin]-2'(4'H)-one(31d) (200 mg, 0.62 mmol) in DCM (10 mL) were added triethylamine (0.26 mL, 1.86 mmol) and pTS-Cl (0.35 g, 1.86 mmol) 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, resultant residue was dissolved in DCM and absorbed on silica gel to form lactum. The crude lactum was purified by column chromatography using a mixture of 10% methanol/dichloromethane as an eluent to get the desired compound as a white solid (180 mg, 90%); ^XH NMR (400MHz, DMSO-d₆) δ 10.71 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.48 (t, J=5.4 Hz, 1H), 3.22-3.14 (m, 2H), 2.98 (dd, J=16.7 Hz, 19.6 Hz, 2H), 2.48-2.38 (m, 1H), 2.37-2.30 (m, 1H), 1.84-1.72 (m, 2H), 1.48-1.40 (m, 2H).

Intermediate-32 : Synthesis of 6'-bromo-l-methyl-l'H-spiro[azepane-4,3'-[l ,8]naphtha yridine]- ',7(4'H)-dione.

Intermediate-32

(i) SEM-C1, NaH, DMF, 20-35°C, 2 h; (ii) Dimethyl sulphate, Potassium tert-butoxide, THF, 20- 35°C, 16 h; (lii) TFA, DCM, 20-35°C, 3 h then Ethylene diamine, DCM, 20-35°C, 1 h.

Step-(i): Synthesis of 6'-bromo- -((2-(trimethylsilyl)ethoxy)methyl)- H-spiro[azepane- 4,3'-[l,8]naphthyridine]-2',7(4'H)-dione (32a).

To a stirred solution of 6'-bromo- H-spiro[azepane-4,3'-[l,8]naphthyridine]-2',7(4'H)-dione (Intermediate-31) (2 g, 6.20 mmol) in DMF (15 mL) were added 60% NaH (270 mg, 6.81 mmol) and SEM-C1 (1.1 g, 6.81 mmol) at 20-35°C and the reaction mixture was allowed to stir at 20-35°C for 2 h. Then the reaction mixture was diluted with water, obtained solid was filtered and dried under vacuum to get the desired compound as an off-white solid (2.1 g, 74%); ^XH NMR (400MHz, DMSO-d₆) δ 8.36 (d, J=1.9 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.49 (t, J=5.2 Hz, 1H), 5.42 (s, 2H), 3.20-3.14 (m, 2H), 3.08-2.98 (m, 2H), 2.46-2.41 (m, 1H), 2.38-2.28 (m, 1H), 1.84-1.72 (m, 2H), 1.52-1.44 (m, 2H), 1.28-1.20 (m, 2H), 0.88-0.76 (m, 2H), -0.08 (s, 9H).

Step-(ii): Synthesis of 6'-bromo-l -methyl- -((2-(trimethylsilyl)ethoxy)methyl)-l'H-spiro [azepane-4,3'-[l,8]naphthyridine]-2',7(4'H)-dione (32b).

To a stirred solution of 6'-bromo- -((2-(trimethylsilyl)ethoxy)methyl)-l'H-spiro[azepane- 4,3'-[l,8]naphthyridine]-2',7(4'H)-dione (32a) (2 g, 4.40 mmol) in THF (20 mL) were added potassium tert-butoxide (1.23 g, 6.60 mmol) and dimethyl sulphate (1.27 g, 5.70 mmol) at 20-35°C and the reaction mixture was allowed to stir at 20-35°C for 16 h. Then the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed brine (50 mL), dried over on anhydrous Na₂S04 and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 2% methanol/ dichloromethane as an eluent to get the desired compound as a pale yellow liquid (1.5 g, 75%); H NMR (400MHz, CDC1₃) δ 8.33 (d, J=2.4 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 5.60-5.50 (m, 2H), 4.02-3.94 (m, 1H), 3.68-3.60 (m, 2H), 3.28-3.20 (m, 1 H), 2.97 (s, 3H), 2.92-2.70 (m, 3H), 2.48-2.40 (m, 1 H), 2.14-2.08 (m, 1H), 2.07-1.97 (m, 1H), 1.52-1.46 (m, 2H), 0.96-0.90 (m, 2H), -0.04 (s, 9H).

Step-(iii): Synthesis of 6'-bromo-l -methyl-l'H-spiro[azepane-4,3'-[l ,8]naphthyridine]- 2',7(4'H)-dione (32).

To a stirred solution of 6'-bromo-l -methyl- -((2-(trimethylsilyl)ethoxy)methyl)-l'H-spiro [azepane-4,3'-[l ,8]naphthyridine]-2',7(4'H)-dione (32b) (1.5 g, 3.20 mmol) in DCM (10 mL) was added trifluoro acetic acid (8 mL) and the reaction mixture was allowed to stir at 20-35°C for 3 h. Thenthe reaction mixture was rotary evaporated to get residue which was diluted with DCM (20 mL) and treated with ethylene diamine (8 mL) at 20-35°C for 1 h. Then the reaction mixture was diluted with NaHCC>3 solution (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed brine (50 mL), dried over on anhydrous Na₂S04 and filtered to get the desired compound as an off-white solid (650 mg, 65%). H NMR (400MHz, DMSO-d₆) δ 10.72 (bs, 1H), 8.23 (d, J=2.4 Hz, 1H), 7.82 (d, 3=1.9 Hz, 1H), 3.50-3.46 (m, 2H), 2.97 (s, 2H), 2.83 (m, 3H), 2.56-2.46 (m, 2H), 1.88-1.72 (m, 2H), 1.50-1.42 (m, 2H).

-one.

Intermediate-33

(i) LDA (2M in THF), Isoamylnitrite, MTBE, -15°C, 2 h; (ii) ^-Toluenesulfonyl chloride,

triethylamine, DCM, 20-35°C, 16 h; (iii) KOAc, Ethanol/H₂0, 110°C, 16 h; (iv) Br₂, DCM, 20-35°C, 16 h; ( ef. for step-(i): Synthetic communications, 33, 20, 3497, 2003) (Ref . for step-(ii-iv):

WO2007/067416).

Intermediate-34 : Synthesis of 8-bromo-2,3-dihydro-lH-pyrido[2,3-b] [l ,4]diazepin-4(5H)- one

34a Intermediate-34

(i) Azetidin-2-one, Pd₂(dba)₃, Xantphos, Cs₂C0₃, Toluene, 1 10°C, 16 h; (ii) TifOPr^, Toluene, 1 10°C, 16 h; (Ref. for steps-(i-ii): WO2007067416) Intermediate-35 and 36: Synthesis of 7-bromo-4,5-dihydro-lH-pyrido[2,3- e][l ,4]diazepin-2(3H)-one and tert-butyl 7-bromo-2-oxo-2,3-dihydro-lH-pyrido[2,3-e][l ,4] diaze

Intcrmcdiatc-36

(i) Glycine ethyl ester hydrochloride, triethylamine, DMF, 20-35°C, 5 h; (ii) NaH, DMSO, 20-35°C, 5 h; (iii) (Boc)₂0, triethylamine; DCM, 20-35°C, 16 h. (Reference for Stcp-(i): US2005009970) (Reference for Step-(i-iii): J. Med. Chem. 2003, 46, 1627-1635).

one.

Intermediate-38 : Synthesis of 7'-bromo-4\5'-d ydrospiro[cyclopropane-l ,3'-pyrido[2,3- e]

(i) Triethyl amine, MeOH, 0°C to 20-35°C, 16 h then NaBH₃CN, 0°C to 20-35°C, 16 h; (ii) NaH, DMSO, 0°C to 20-35°C, 3 h.

Step-(i): Synthesis of ethyl l-(((2-amino-5-bromopyridin-3 yl)methyl)amino) cyclopropane carboxylate (38a).

To a stirred solution of ethyl- 1-aminocyclopropanecarboxylate hydrochloride (30a) (9.77 g, 59.21 mmol) in methanol (100 mL) were added triethylamine (15.46 mL, 111.18 mmol), followed by 2-amino-5-bromonicotinaldehyde hydro bromide (30a) (10.3 g, 36.78 mmol) at 0°C and the reaction mixture was allowed to stir at 20-35°C for 16 h. Then sodium cyano borohydride (7 g, 111.39 mmol) was added at 0°C and the reaction mixture was again continued stirring at 20-35 °C for 16 h. Then the reaction mixture was rotary evaporated to get residue which was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over on anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 4% methanol/dichloromethane as an eluent to get the desired compound as a brown waxy solid (5.6 g, 48%); H NMR (400MHz, DMSO-d₆) δ 7.89 (d, 3=2.4 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 6.16 (brs, 2H), 4.13-4.03 (m, 2H), 3.59 (d, J=4.4 Hz, 2H), 2.92-2.84 (m, 1H), 1.24-1.14 (m, 5H), 1.04-0.98 (m, 2H); LC-MS: 314 (M+H)⁺.

Step-(ii): Synthesis of 7'-bromo-4',5'-dihydrospiro[cyclopropane-l ,3'-pyrido[2,3-e][l ,4] diazepin]-2'(l'H)-one (38).

To a stirred solution of ethyl l-(((2-amino-5-bromopyridin-3-yl)methyl)amino)cyclo- propane carboxylate (38a) (0.81 g, 2.59 mmol) in DMSO (3 mL) was added NaH (123 mg, 3.10 mmol) at 0°C and the reaction mixture was allowed to stir at 20-35°C for 3 h. Then the reaction mixture was diluted with ice-water (30 mL), obtained solid was filtered, washed with water and dried under vacuum to get the desired compound as an off-white solid (0.47 g, 68%); H NMR (400MHz, DMSO-d₆) δ 9.95 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 3.85 (d, J= 6.3 Hz, 2H), 3.51 (t, J=6.4 Hz, 1H), 1.28 (dd, J=3.4 Hz, 6.9 Hz, 2H), 0.89 (dd, J=3.4 Hz, 6.9 Hz, 2H).

Intermediate-39: Synthesis of (S,E)-3-(10-oxo-7,8,9,9a,10,l l-hexahydro-5H-pyrido[2,3- e]pyrro

(i) L-Mcthyl pyrrolidinc-2-carboxylatc, tricthylaminc, DMF, 20-35°C, 16 h; (ii) NaH, DMSO, 20-35°C, 4 h;(Ref. for step-(i-ii): WO2004/052890).

Intermediate-40 : Synthesis of (E)-3-(3,3-dimethyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]

(i) tert-butyl acrylate, Pd(OAc)₂, P(o-tolyl)₃, DIPEA, DMF:Propionitrile (1 :4), 110-125°C, 16 h;

(ii) TFA, CH₂C1₂, 20-35 °C, 3 h.

Step-(i): Synthesis of (E)-tert-butyl 3-(3,3-dimethyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)acrylate (40a). To a stirred solution of 5-bromo-3,3-dimethyl-lH-pyrrolo[2,3-b]pyridin-2(3H)-one(2.5 g, 10.33 mmol) in dimethyl formamide/propionitrile (8mL /32mL) were added tert-butyl acrylate (6 mL, 41.32 mmol) ), DIPEA (5.4 mL, 30.99 mmol) and the mixture was degassed with N₂ for 10 minutes. Then Pd(OAc)₂ (0.70 g, 3.09 mmol), P(o-tolyl)₃ (0.63 g, 20.70 mmol) were added, again degassed with N₂ for 10 minutes and then heated at 110- 125°Cfor 16 h. Then the reaction mixture was cooled to 20-35°C and filtered through Celite. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 50% ethyl acetate/he xane as an eluent to get the desired compound as a pale yellow solid (2.3 g, 79%); H NMR (400MHz, DMSO-i¾) δ 11.21 (bs, 1H), 8.28 (d, J=1.9 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H), 6.53 (d, J=16.1 Hz, 1H), 1.48 (s, 9H), 1.30 (s, 6H).

Step-(ii): Synthesis of (E)-3-(3,3-dimethyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)acrylic acid (40).

To a stirred solution of (E)-tert-butyl 3-(3,3-dimethyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)acrylate (40a) (2 g, 6.94 mmol) in DCM (10 mL) was added trifluoro acetic acid (8 mL, 69.44) at 0°C and the reaction mixture was allowed to stir at 20-35°C for 3 h. Then the reaction mixture was rotary evaporated to get residue which was triturated with diethyl ether get the desired compound as a white solid (1.6 g, 81 %).^ NMR (400MHz, DMSO-d₆) δ 12.30 (bs, 1H), 11.22 (s, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.57 (d, J=16.1 Hz, 1H), 6.53 (d, J=16.21 Hz, 1H), 1.31 (s, 6H).

The below Intermediates-41 to 53 were prepared according to the above protocol

(Intermediate-40).

Characterization data

Int Starting Intermediate

H NMR 400MHz, DMSO-d₆/LC-MS/ ES- No. compound formed

MS

δ 12.32 (bs, 1H), 11.12 (s, 1H), 8.41 (d, J=1.9 Hz, 1H), 8.27 (d, J=1.9 Hz, 1H), 7.59

41

(d, J=15.7 Hz, 1H), 6.63 (d, J=16.1 Hz,

H H

1H), 2.44-2.40 (m, 4H), 2.40-2.28 (m, 2H). δ 12.36 (bs, 1H), 10.70 (s, 1H), 8.35 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.54 (d,

42

H H J=16.2 Hz, 1H), 6.51 (d, J=16.1 Hz, 1H),

2.91 (t, J=7.8 Hz, 2H), 2.56-2.50 (m, 2H). δ 10.66 (s, IH), 8.37 (d, J=2.0 Hz, IH), 8.01 (s, IH), 7.55 (d, J= 16.1 Hz, IH), 6.51 (d, J=15.6 Hz, IH), 2.80 (s, 2H), 1.08 (s, 6H).

δ 10.76 (s, IH), 8.38 (d, J=1.4 Hz, IH), 7.94 (s, IH), 7.55 (d, J= 16.1 Hz, IH), 6.49 (d, J=15.7 Hz, IH), 2.88 (s, 2H), 1.14-1.09 (m, 2H), 0.81-0.77 (m, 2H).

δ 10.63 (s, IH), 8.35 (d, J=2.4 Hz, IH), 8.05 (d, J= 1.5 Hz, IH), 7.54 (d, J=16.1 Hz, IH), 6.50 (d, J= 16.1 Hz, IH), 3.06 (s, 2H), 2.34 (dd, J= 9.3 Hz, 18.6 Hz, 2H), 2.06- 1.92 (m, IH), 1.91-1.84 (m, IH), 1.82-1.72 (m, 2H).

δ 12.38 (bs, IH), 10.75 (s, IH), 8.37 (d, J=1.4 Hz, IH), 8.05 (s, IH), 7.54 (d, J=16.2 Hz, IH), 6.49 (d, J=15.6 Hz, IH), 3.74-3.65 (m, 2H), 3.63-3.56 (m, 2H), 2.99 (s, 2H), 1.84-1.74 (m, 2H), 1.36-1.26 (m, 2H).

δ 12.42 (bs, IH), 10.77 (s, IH), 8.38 (d, J=1.9 Hz, IH), 7.99 (d, J=1.9 Hz, IH), 7.55 (d, J=16.1 Hz, IH), 7.48 (t, J= 5.6 Hz, IH), 6.47 (d, J=16.1 Hz, IH), 3.24-3.16 (m, 2H), 3.02-2.96 (m, 2H), 2.44-2.32 (m, 2H), 1.84-1.72 (m, 2H), 1.50-1.42 (m, 2H). ES-MS= 330.2 (M+l)⁺

δ 12.22 (bs, IH), 10.10 (s, IH), 8.50 (d, J=2.0 Hz, IH), 8.10 (d, J=1.9 Hz, IH), 7.58

Intermediate-54 : Synthesis of (E)-3-(l'-(tert-butoxycarbonyl)-2-oxo-2,4-dihydro-lH-spiro [[1 ,8]naphthyridine-3,4'-piperidin]-6-yl)acrylic acid.

Intermediate-54

The below Intermediate 55 was prepared according to the above protocol (Intermediate-54).

Int Characterization data

Starting compound Intermediate formed

No. (^lU NMR/LC-MS/ES-MS)

Intermediate-56: Synthesis of (E)-3-(4,4-difluoro-2'-oxo-2',4'-dihyd] spiro[cyclohexane- 1 ,3'-[l ,8]naphthyridin]-6'-yl)acrylic acid.

(i) DAST, DCM, -40°C to 20-35°C, 16 h; (ii) tert-butyl

(iii) acrylate, Pd(OAc)₂, P(o-tolyl)₃, DIE A, DMF:Propionitrile,

110°C, 16 h; (iii) TFA, DCM, 0°C to 20-35°C, 2 h.

Intermediate-56

Step-(i): Synthesis of 6'-bromo-4,4-difluoro- H-spiro[cyclohexane-l ,3'-[l ,8]naphtha yridin] -2'(4'H)-one (56a).

To a stirred solution of 6'-bromo- H-spiro[cyclohexane-l ,3'-[l ,8]naphthyridine]-2',4(4'H)- dione (31c) (1.6 g, 6.72 mmol) in DCM (20 mL) was added DAST (2.67 mL, 13.44 mmol) at -40°C and the reaction mixture was allowed to stir at 20-35°C for 16 h. Then the reaction mixture was quenched in a mixture of Na₂C0₃ and ice, and allowed to stir 10 minutes. The reaction mixture was extracted with DCM (100 mL) and washed with brine (50 mL), dried over on anhydrous Na₂SC>4 and filtered. The filtrate was rotary evaporated to get the desired compound as a brown waxy solid (650 mg, 29%); H NMR (400MHz, DMSO-d₆) δ 10.75 (s, 1H), 8.23 (d, J=2.5 Hz, 1H), 7.87 (d, J=1.9 Hz, 1H), 2.96 (s, 2H), 2.14-1.92 (m, 4H), 1.90-1.80 (m, 2H), 1.52-1.44 (m, 2H).

Step-(ii): Synthesis of (E)-tert-butyl 3-(4,4-difluoro-2'-oxo-2',4'-dihydro-l'H-spiro [cyclohexane-1 ,3'-[l ,8]naphthyridin]-6'-yl)acrylate (56b).

The process of this step was adopted from step-(i) of intermediate-40. The desired compound obtained as a brown solid (180 mg, 24%). ^lU NMR (400MHz, DMSO-d₆) δ 10.82 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.06 (s, 1H), 7.51 (d, J=16.1 Hz, 1H), 6.47 (d, J=16.2 Hz, 1H), 2.94 (s, 2H), 2.13-1.89 (m, 4H), 1.88-1.78 (m, 2H), 1.50-1.42 (m, 2H), 1.48 (s, 9H); LC-MS: 379.2 (M+l)⁺.

Step-(iii): Synthesis of (E)-3-(4,4-difluoro-2'-oxo-2',4'-dihydro- H-spiro[cyclohexane-l,3'- [l,8]naphthyridin]-6'-yl)acrylic acid (56). The process of this step was adopted from step-(ii) of intermediate-40. The desired compound obtained as an off-white solid (90 mg, 59%). H NMR (400MHz, DMSO-d₆) δ 12.34 (bs, 1H), 10.82 (s, 1H), 8.38 (d, J=1.9 Hz, 1H), 8.04 (s, 1H), 7.55 (d, J=15.6 Hz, 1H), 6.47 (d, J=16.1 Hz, 1H), 2.96 (s, 2H), 2.14-1.94 (m, 4H), 1.91-1.82 (m, 2H), 1.56-1.44 (m, 2H); LC-MS: 323.2 (M+l)⁺.

Intermediate-57 : Synthesis of (E)-3-(3,3-difluoro-2'-oxo-2',4'-dihydro-l'H-spiro [cyclobutane-l,3'-[l,8]naphthyridin]-6'-yl)acrylic acid.

s'' Intermediate-57

(l) Tnethyl ortho acetate, Toluene, 110°C, 5 h; (n) Ethane- 1,2-dithiol, BF₃.Et₂0, 0°C to 20-35°C, 3 h;

(iii) LDA (2M), -78°C to 20-35°C, 16 h; (iv) 37% HCL DMSO: 1,4-dioxan, 20-35°C, 48 h; (v)

DAST, DCM, -5°C to 20-35°C, 16 h; (v) tert-butyl acrylate, Pd(OAc)₂, P(o-tolyl)₃, DIEA,

DMF:Propionitrile, 120°C, 16 h; (vi) TFA, DCM, 0°C to 20-35°C, 3 h.

(Ref. for step-(i): WO2011/035900)

Step-(ii): Synthesis of ethyl 5,8-dithiaspiro[3.4]octane-2-carboxylate (57b).

The process of this step was adopted from step-(i) of intermediate-31. The desired compound obtained as an oily liquid (10.5 g, 68%); ^XH NMR (400MHz, DMSO-d₆) δ 4.07 (q, J=6.9 Hz, 2H), 3.26 (s, 4H), 3.18-3.10 (m, 1H), 2.82-2.66 (m, 4H), 1.78 (t, J=6.9 Hz, 3H).

Step-(iii): Synthesis of Intermediate (57c).

The process of this step was adopted from step-(i) of intermediate- 17. The desired compound obtained as a yellow solid (2.6 g, 12%); ^lU NMR (400MHz, DMSO-d₆) δ 10.74 (s, 1H), 8.22 (d, J=2.4 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 3.29 (d, J=5.4 Hz, 2H), 3.24 (d, J=5.8 Hz, 2H), 3.21 (s, 2H), 3.06 (d, J=14.2 Hz, 2H), 2.42 (d, J=14.2 Hz, 2H).

Step-(iv): Synthesis of 6'-bromo-l 'H-spiro[cyclobutane-l,3'-[l ,8]naphthyridine]-2',3(4'H)- dione (57d).

To a stirred solution of Intermediate-57c (2.6 g, 7.41 mmol) in 1,4-dioxan (37 mL) were added 3.6M aqueous HC1 solution (16 mL) and DMSO (5.3 mL) at 20-35°C and the reaction mixture was allowed to stir at 20-35°C for 48 h. Then the reaction mixture was poured into aqueous NaHCC>3 (100 mL) solution and obtained solid was filtered, washed with water and dried to get the desired compound as a yellow solid (1.8 g, 90%); H NMR (400MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.26 (d, J=1.9 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H), 3.28- 3.22 (m, 4H) , 3.06-2.96 (m, 2H) .

Step-(v): Synthesis of 6'-bromo-3,3-difiuoro- H-spiro[cyclobutane-l,3'-[l ,8] naphthyridin]-2'(4'H)-one (57e).

The process of this step was adopted from step-(i) of intermediate-56. The desired compound obtained as a brown solid (910 mg, 46%); H NMR (400MHz, DMSO-d₆ & D₂0) δ 8.26 (d, J=2.0 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 3.14 (s, 2H), 3.08-2.92 (m, 2H), 2.52-2.46 (m, 2H).

Step-(vi): Synthesis of (E)-tert-butyl 3-(3,3-difiuoro-2'-oxo-2',4'-dihydro-l'H- spiro[cyclobutane-l,3'-[l,8]naphthyridin]-6'-yl)acrylate (57f).

The process of this step was adopted from step-(i) of intermediate-40. The desired compound obtained as a black solid (150 mg, 19%). H NMR (400MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.13 (s, 1H), 7.51 (d, J=15.7 Hz, 1H), 6.53 (d, J=15.7 Hz, 1H), 3.12 (s, 2H), 3.08-2.92 (m, 2H), 2.52-2.42 (m, 2H), 1.48 (s, 9H); LC-MS: 351.2 (M+l)⁺.

Step-(vii): Synthesis of (E)-3-(3,3-difluoro-2'-oxo-2',4'-dihydro-l'H-spiro[cyclobutane-l,3'- [l,8]naphthyridin]-6'-yl)acrylic acid (57).

The process of this step was adopted from step-(ii) of intermediate-40. The desired compound obtained as a black solid (120 mg, 95%). ^XH NMR (400MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.12 (s, 1H), 7.55 (d, J=15.6 Hz, 1H), 6.53 (d, J=15.7 Hz, 1H), 3.14 (s, 2H), 3.06-2.92 (m, 2H), 2.52-2.42 (m, 2H) (-COOH proton was unrevealed by H NMR instrument); LC-MS: 295.1 (M+l)⁺.

Intermediate-58 : Synthesis of (E)-3-(l-acetyl-2'-oxo-2',4'-dihydro-l'H-spiro[azetidine-3,3'- [1 ,8]naphthyridin]-6'-yl)acrylic acid.

(58c) (Interitiediate-58)

(i) TFA, CH₂C1₂, 20-35°C, 3 h; (ii) Ac₂0, Pyridine, 0°C to 20-35°C, 6 h; (iii) tert-butyl acrylate, Pd(OAc)_:

P(o-tolyl)₃, DIPEA, DMF:Propionitrile (1:4), 1 10°C, 16 h; (iv) TFA, CH₂C1₂, 20-35°C, 3 h.

Step-(i): Synthesis of 6'-bromo-l'H-spiro[azetidine-3,3'-[l ,8]naphthyridin]-2'(4'H)-one 2,2,2-trifluoroacetate (58a).

The process of this step was adopted from step-(iv) of intermediate- 1. The desired compound obtained as an off-white solid (900 mg, 89%). H NMR (400MHz, DMSO-d₆) δ 11.10 (s, 1H), 9.12-8.94 (m, 2H), 8.8.27 (d, J=2.4 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 4.26- 4.16 (m, 2H), 3.86-3.76 (m, 2H), 3.34 (s, 2H); LC-MS: 268.0 (M+l)⁺.

Step-(ii): Synthesis of l-acetyl-6'-bromo-l'H-spiro[azetidine-3,3'-[l,8]naphthyridin]- 2'(4'H)-one (58b).

The process of this step was adopted from preparation of intermediate-26. The desired compound obtained as a pale yellow solid (800 mg, 51%). ^XH NMR (400MHz, DMSO-d₆) δ 10.93 (s, 1H), 8.25 (d, J=1.9 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 4.27 (d, J=8.3 Hz, 1H), 4.03 (d, J=9.2 Hz, 1H), 3.91 (d, J=8.3 Hz, 1H), 3.61 (d, J=9.3 Hz, 1H), 3.26 (s, 2H), 1.75 (s, 3H); LC-MS: 312.1 (M+2)⁺.

Step-(iii): Synthesis of (E)-tert-butyl 3-(l-acetyl-2'-oxo-2',4'-dihydro-l'H-spiro[azetidine- 3,3'-[l,8]naphthyridin]-6'-yl)acrylate (58c).

The process of this step was adopted from step-(i) of intermediate-40. The desired compound obtained as an off-white solid (300 mg, 25%). ^XH NMR (400MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.41 (d, J=1.4 Hz, 1H), 8.07 (s, 1H), 7.51 (d, J=16.2 Hz, 1H), 6.52 (d, J=16.1 Hz, 1H), 4.29 (d, J=8.3 Hz, 1H), 4.03 (d, J=9.3 Hz, 1H), 3.91 (d, J=8.3 Hz, 1H), 3.61 (d, J=9.3 Hz, 1H), 3.25 (s, 2H), 1.76 (s, 3H), 1.48 (s, 9H); LC-MS: 358.2 (M+l)⁺.

Step-(iv): Synthesis of (E)-3-(l-acetyl-2'-oxo-2',4'-dihydro-l 'H-spiro[azetidine-3,3'-[l ,8] naphthyridin]-6'-yl)acrylic acid (58).

The process of this step was adopted from step-(ii) of intermediate-40. The desired compound obtained as a pale brown solid (200 mg, 80%). H NMR (400MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.40 (s, 1H), 8.06 (s, 1H), 7.55 (d, J=15.7 Hz, 1H), 6.52 (d, J=16.1 Hz, 1H), 4.28 (d, J=8.3 Hz, 1H), 4.04 (d, J=9.3 Hz, 1H), 3.92 (d, J=8.3 Hz, 1H), 3.62 (d, J=9.3 Hz, 1H), 3.26 (s, 2H), 1.76 (s, 3H); LC-MS: 302.1 (M+l)⁺.

Intermediate-59 : Synthesis of (E)-3-(2'-oxo-l',2,2',3,5,6-hexahydrospiro[pyran-4,3'- pyr -b]pyridin]-5'-yl)acrylic acid.

(i) l-chloro-2-(2-chloroethoxy)ethane, Cs₂C0₃, DMF, 20-35°C, 48 h; (ii) NBS, DMF, 20-35°C, 48 h; (iii) TFA, DCM, 20-35°C, 3 h then ethylene diamine, DCM, 20-35°C, 2 h; (iv) tert-butyl acrylate, Pd(OAc)₂, P(o-tolyl)₃, DIE A, DMF:Propionitrile, 120°C, 16 h; (v) TFA, DCM, 20-35°C, 3 h.

Step-(i): Synthesis of -((2-(trimethylsilyl)ethoxy)methyl)-2,3,5,6-tetrahydrospiro[pyran- 4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one (59a).

To a stirred solution of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin- 2(3H)-one (16c) (1.3 g, 4.92 mmol) in dimethyl formamide (10 mL) were added dried Cs₂C0₃ (6.42 g, 19.69 mmol), followed by l-chloro-2-(2-chloroethoxy)ethane (0.85 g, 5.90 mmol) at 20-35°C and the reaction mixture was allowed to stir at 20-35°C for 48 h. Then the reaction mixture was diluted with water (100 mL) 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 to get residue which was purified by column chromatography using a mixture of 60% ethyl acetate/hexane as an eluent to get the desired compound as a brown liquid (1 g, 61 %); ^XH NMR (400MHz, DMSO-d₆) δ 8.24 (dd, J=1.5 Hz, 5.3 Hz, 1H), 7.65 (dd, J=1.5 Hz, 7.3 Hz, 1H), 7.01 (dd, J=5.4 Hz, 7.3 Hz, 1H), 5.26 (s, 2H), 4.28-4.18 (m, 2H), 3.92-3.86 (m, 2H), 3.70-3.62 (m, 2H), 1.98-1.92 (m, 2H), 1.88-1.78 (m, 2H), 1.00-0.92 (m, 2H), -0.03 (m, 9H); LC-MS: 335.2 (M+l)⁺.

Step-(ii): Synthesis of 5'-bromo-l'-((2-(trimethylsilyl)ethoxy)methyl)-2,3,5,6- tetrahydrospiro [pyran-4,3'-pyrrolo[2,3-b]pyridin]-2'(l'Hi-one (59b).

To a stirred solution of l'-((2-(trimethylsilyl)ethoxy)methyl)-2,3,5,6-tetrahydrospiro[pyran- 4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one (59a) (1 g, 2.99 mmol) in dimethyl formamide (10 mL) was added N-bromo succinimide (0.8 g, 4.49 mmol) at 20-35°C and the reaction mixture was allowed to stir at 20-35 °C for 48 h. Then the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 50% ethyl acetate/hexane as an eluent to get the desired compound as a brown liquid (750 mg, 61%). H NMR (400MHz, DMSO-d₆) δ 8.33 (d, J=2.0 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 5.08 (s, 2H), 4.08-3.96 (m, 2H), 3.88-3.78 (m, 2H), 3.57 (t, J=7.8 Hz, 2H), 1.90-1.72 (m, 4H), 0.88-0.76 (m, 2H), -0.07 (s, 9H); MS (ES) m/e 413.3 (M+l)⁺.

Step-(iii): Synthesis of 5'-bromo-2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[2,3-b]pyridin]- 2'(l 'H)-one (59c).

To a stirred solution of 5'-bromo-l'-((2-(trimethylsilyl)ethoxy)methyl)-2,3,5,6- tetrahydrospiro [pyran-4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one (59b) (0.75 g, 1.82 mmol) in DCM (10 mL) was added trifluoro acetic acid (3 mL) and the reaction mixture was allowed to stir at 20-35 °C for 3 h. Then the reaction mixture was rotary evaporated to get residue which was diluted with DCM (20 mL) and treated with ethylene diamine (3 mL) at 20-35 °C for 2 h. Then the reaction mixture was diluted with NaHCC>3 solution (50 mL) and extracted with dichloromethane (50 mL). The organic layer was washed brine (50 mL), dried over on anhydrous Na₂SC>4 and filtered. The filtrate was rotary evaporated to get the desired compound as an off-white solid (500 mg, 97%); ¾ NMR (400MHz, DMSO-d₆) δ 9.80 (bs, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.15 (d, J=2.5 Hz, 1H), 4.04-3.94 (m, 2H), 3.84-3.72 (m, 2H), 1.84-1.72 (m, 4H); LC-MS: 283.0 (M+l)⁺.

Step-(iv): Synthesis of (E)-tert-butyl 3-(2'-oxo-l',2,2',3,5,6-hexahydrospiro[pyran-4,3'- pyrrolo[2,3-b]pyridin]-5'-yl)acrylate (59d).

The process of this step was adopted from step-(i) of intermediate-40. The desired compound obtained as a white solid (430 mg, 73%). H NMR (400MHz, DMSO-d₆) δ 11.30 (s, 1H), 8.39 (d, J=1.9 Hz, 1H), 8.33 (d, J=1.4 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H), 6.70 (d, J=16.1 Hz, 1H), 4.02-3.86 (m, 4H), 1.88-1.70 (m, 4H), 1.48 (s, 9H); LC-MS: 331.2 (M+l)⁺.

Step-(v): Synthesis of (E)-3-(2'-oxo- ,2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[2,3- b]pyridin]-5'-yl)acrylic acid (59).

The process of this step was adopted from step-(ii) of intermediate-40. The desired compound obtained as a white solid (320 mg, 90%); ^XH NMR (400MHz, DMSO-d₆) 812.30 (bs, 1H), 11.29 (s, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.5 Hz, 1H), 7.58 (d, J=16.1 Hz, 1H), 6.69 (d, J=16.1 Hz, 1H), 4.02-3.94 (m, 4H), 1.84-1.72 (m, 4H); LC-MS: 275.1 (M+l)⁺.

Intermediate-60 : Synthesis of (E)-3-(l-acetyl-2'-oxo-l\2'-dihydrospko[piperidine-4,3'- pyrrolo[2,3-b]pyridin]-5'-yl)acrylic acid.

(60c) (Intermediate-60)

(i) TFA, DCM, 20-35°C, 16 h then Ethylene diamine, DCM, 20-35°C, 3 h; (ii) Acetic anhydride, Pyridine,

20-35°C, 16 h; (iii) tert-butyl acrylate, Pd(OAc)₂, P(o-tolyl)₃, DIEA, DMF:Propionitrile, 120°C, 16 h;

(iv) TFA, DCM, 20-35°C, 3 h.

Step-(i): Synthesis of 5'-bromospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one (60a).

The process of this step was adopted from step-(iii) of intermediate-59. The desired compound obtained as a brown solid (600 mg, 70%). H NMR (400MHz, DMSO-d₆) δ 11.22 (bs, 1H), 8.22 (d, J=2.5 Hz, 1H), 8.05 (d, 3=1.9 Hz, 1H), 3.22-3.12 (m, 2H), 3.10-2.96 (m, 2H), 1.86-1.78 (m, 2H), 1.72-1.66 (m, 2H); LC-MS: 284.0 (M+2) ⁺.

Step-(ii): Synthesis of l-acetyl-5'-bromospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]- 2'(l 'H)-one (60b).

The process of this step was adopted from preparation of intermediate-26. The desired compound obtained as an off-white solid (530 mg, 77%). ^lU NMR (400MHz, DMSO-d₆) δ 11.26 (s, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.15 (d, J=1.9 Hz, 1H), 3.84-3.64 (m, 4H), 2.05 (s, 3H), 1.84-1.78 (m, 2H), 1.76-1.68 (m, 2H); LC-MS: 326.1 (M+3) ⁺.

Step-(iii): Synthesis of (E) -tert-butyl 3-(l-acetyl-2'-oxo-l\2'-dihydrospko[piperidine-4,3'- pyrrolo[2,3-b]pyridin]-5'-yl)acrylate (60c).

The process of this step was adopted from step-(i) of intermediate-40. The desired compound obtained as an off-white solid (150 mg, 25%). H NMR (400MHz, DMSO-d₆) δ 11.33 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.32 (d, J=1.9 Hz, 1H), 7.52 (d, J=16.1 Hz, 1H), 6.67 (d, J=16.1 Hz, 1H), 3.82-3.65 (m, 4H), 2.08 (s, 3H), 1.82-1.78 (m, 2H), 1.76-1.64 (m, 2H), 1.47 (s, 9H); LC-MS: 370.2 (M-l).

Step-(iv): Synthesis of (E)-3-(l-acetyl-2'-oxo- ,2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3- b]pyridin]-5'-yl)acrylic acid (60): The process of this step was adopted from step-(ii) of intermediate-40. The desired compound obtained as an off-white solid (90 mg, 71 %). ^lU NMR (400MHz, DMSO-d₆) δ 11.33 (s, 1H), 8.36 (s, 1H), 8.32 (d, J=1.5 Hz, 1H), 7.57 (d, J=15.2 Hz, 1H), 6.67 (d, J=16.1 Hz, 1H), 3.84-3.74 (m, 4H), 2.07 (s, 3H), 1.81 (dd, J=11.2 Hz, 4.9 Hz, 2H), 1.71 (t, J=5.9 Hz, 2H); LC-MS: 316.2 (M+l) ⁺.

The present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds according to the invention.

Example-I: Synthesis of (E)-3,3-dimethyl-5-(3-oxo-3-(4-(tMazol-2-ylmethylene)piperidin- l-

(i) HOBt, EDC.HCl, DIPEA, DMF, 20-35°C, 16 h.

DIPEA (0.66 mL, 3.77 mmol) was added to a stirred solution of 2-(piperidin- ylidenemethyl)thiazole hydrochloride (Intermediate-l) (195 mg, 0.90 mmol), (E)-3-(3,3- dimethyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)acrylic acid (Intermediate-40) (175 mg, 0.75 mmol), HOBt (122 mg, 0.90 mmol), EDC.HCl (287 mg, 1.50 mmol) in dry DMF (5 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 and stirred for 15 minutes. The obtained solid was filtered, washed with water and dried to get the desired compound as a pale yellow solid (100 mg, 34%); ^lU NMR (400MHz, DMSO-d₆) δ 11.19 (s, 1H), 8.29 (d, J=1.9 Hz, 1H), 8.24 (s, 1H), 7.84 (d, J=3.4 Hz, 1H), 7.68 (d, J=2.9 Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.30 (d, J=15.1 Hz, 1H), 6.65 (s, 1H), 3.88-3.78 (m, 2H), 3.74-3.64 (m, 2H), 3.08- 2.92 (m, 2H), 2.52-2.42 (m, 2H), 1.33 (s, 6H); LC-MS: 395.1 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example-I with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Co Characterization data

Int Int

m. Compound structure U NMR (400MHz, DMSO-i¾) in δ /

No. No.

No LC-MS (M+1)7ES-MS 11.18 (s, IH), 8.29 (s, IH), 8.25 (s,

IH), 7.51 (d, J=15.2 Hz, IH), 7.48- 7.44 (m, IH), 7.36-7.26 (m, IH), 7.08-

2 40 7.02 (m, 2H), 6.55 (s, IH), 3.84-3.74

H

(m, 2H), 3.70-3.60 (m, 2H), 2.70-2.56 (m, 2H), 2.46-2.36 (m, 2H), 1.33 (s, 6H); LC-MS: 394.1 (M+l) ⁺.

10.08 (s, IH), 8.45 (s, IH), 8.28 (s, IH), 7.84 (d, J=1.9 Hz, IH), 7.68 (d, J=3.4 Hz, I H), 7.54 (d, J=15.1 Hz,

1 41 IH), 7.38 (d, J=15.1 Hz, IH), 6.66 (s,

IH), 3.96-3.64 (m, 4H), 3.08-2.94 (m, 4H), 2.44-2.22 (m, 6H); LC-MS: 405.5 (M-l).

11.08 (s, IH), 8.45 (d, J=1.5 Hz, IH), 8.28 (d, 3=1.9 Hz, IH), 7.53 (d, J=15.2 Hz, I H), 7.48 (dd, J=4.8 Hz , 1.4 Hz, l H), 7.41-7.36 (m, I H), 7.06-7.04 (m,

2 41

2H), 6.56 (s, IH), 3.84-3.78 (m, 2H), 3.78-3.62 (m, 2H), 2.72-2.62 (m, 4H), 2.46-2.20 (m, 6H); LC-MS: 404.4 (M- i).

10.64 (s, IH), 8.35 (s, I H), 8.10 (d, J=7.3 Hz, I H), 7.47 (d, J=15.2 Hz, IH), 7.32-7.30 (m, IH), 7.17 (d, J=8.8 o Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.40-

14 42 ^^s^— N N^O 6.33 (m, IH), 3.75 (s, 3H), 3.70-3.67

H

(m, 2H), 3.66-3.62 (m, 2H), 2.91 (t, J=7.4Hz, 2H), 2.67-2.55 (m, 4H), 2.40-2.32 (m, 2H); MS (ES) m/e 404.2 (M+l) ⁺.

10.64 (s, IH), 8.36 (d, J=2.0 Hz, IH),

2 42 8.11 (s, IH), 7.50-7.46 (m, 2H), 7.33-

H 7.27 (m, IH), 7.05 (dd, J=3.9 Hz, 8.8 Hz, 2H), 6.56-6.53 (m, 1H), 3.80-3.76

(m, 2H), 3.66-3.62 (m, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.67-2.59 (m, 4H), 2.40-2.36 (m, 2H); MS (ES) m/e 380.2 (M+l) ⁺.

10.65 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.11 (s, 1H), 7.84 (d, J=2.9 Hz, 1H), 7.67 (d, J=3.4 Hz, 1H), 7.48 (d, J=15.2 Hz, 1H), 7.33-7.28 (m, 1H), 6.65-6.63

1 42

(m, 1H), 3.81-3.79 (m, 2H), 3.68-3.66 (m, 2H), 3.00-2.94 (m, 2H), 2.92 (t, J=7.4 Hz, 2H), 2.56-2.52 (m, 4H); MS (ES) m/e 381.2 (M+l) ⁺.

10.64 (s, 1H), 9.02 (s, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.47 (d, J=5.7 Hz, 1H),7.31 (m,

5 42 1H), 6.60 (s, 1H), 3.78 (brs, 2H), 3.65

(brs, 2H), 2.93-2.89 (m, 2H), 2.58- 2.54 (m, 4H), 2.44-2.40 (m, 2H); LC- MS: 381.20 (M +l) ⁺.

10.62 (s, 1H), 9.08 (d, J=1.5 Hz, 1H), 8.34 (d, J=1.4 Hz, 1H), 8.08 (s, 1H), 7.52 (s, 1H), 7.45 (d, J=15.2 Hz, 1H), o

7.29 (d, J=15.2 Hz, 1H), 6.40 (s, 1H),

4 42

*^**^· 3.80-374 (m, 2H), 3.62 (d, J=17.1 Hz,

2H), 2.95-2.88 (m, 4H), 2.65-2.52 (m, 2H), 2.38-2.31 (m, 2H); LC-MS: 381.1 (M +l) ⁺.

10.64 (s, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 7.52-7.46 (m, 2H), 7.30

0

(d, J=15.2 Hz, 1H), 6.52 (s, 1H), 3.81-

7 42

3.79 (m, 2H), 3.66-3.64 (m, 2H), 2.92 (t, J=7.4 Hz, 4H), 2.56-2.52 (m, 2H), 2.43-2.32 (m, 5H); MS (ES) m/e 395.4

Example-II: Synthesis of (E)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene) piper- idin-l-yl)prop- -en- 1 -yl)- 1 'H-spiro[cyclopropane- 1 ,3'-[l ,8 ]naphthyridin]-2'(4'H)-one (Compound-44).

Intermediate-!! Intermediate-! 9 Compound-44

(i) Pd(OAc)₂, P(0-tolyl)₃, DIPEA, Propionitrile:DMF (4:1), 110°C, 16 h.

To a stirred solution of l-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-2-en-l- one(Intermediate-l l) (286 mg, 1.22 mmol) and 6'-bromo-l'H-spiro[cyclopropane-l,3'- [l,8]naphthyridin]-2'(4'H)-one (Intermediate- 19) (280 mg, 1.11 mmol) in dimethyl formamide/propionitrile (2 mL /8 mL) was added DIPEA (0.58 mL, 3.33 mmol) at 20- 35°C and the mixture was degassed with N2 for 10 minutes. Then Pd(OAc)2 (25 mg, 0.11 mmol) and P(o-tolyl)₃ (67 mg, 0.22 mmol) were added, again degassed with N2 for 10 minutes and then heated at 110°C for 16 h. Then the reaction mixture was cooled to 20- 35°C and filtered through Celite. The filtrate was rotary evaporated to get residue which was diluted with water (30 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 5 % methanol/dichloromethane as an eluent to get the desired compound as a yellow solid (70 mg, 16%); ^XH NMR (400MHz, DMSO-d₆) δ 10.72 (bs, 1H), 8.40 (s, 1H), 7.84 (d, J= 3.4 Hz, 1H), 7.68 (d, J= 2.9 Hz, 2H), 7.49 (d, J= 15.2 Hz, 1H), 7.30 (d, J= 15.7 Hz, 1 H), 6.64 (s, 1H), 3.82-3.62 (m, 4H), 3.02-2.94 (m, 2H), 2.88 (s, 2H), 2.56-2.52 (m, 2H), 1.12 (d, J= 2.4 Hz, 2H), 0.81 (d, J= 2.4 Hz, 2H); LC-MS: 407.1 (M+l) ⁺.

The below compounds were prepared by procedure similar to the one described in Example-II with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below Table.

Co Characterization data

Int Int

m. Compound structure (^lU NMR (400MHz, DMSO-i¾) in δ / No. No.

No LC-MS (M+1)7ES-MS (M+l)⁺

10.91 (s, 1 H), 8.41 (d, J=2.5 Hz, 1H), 8.13 (s, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.67 (d, J=3.4 Hz, 1H), 7.49 (d, J=15.1 Hz, 1 H), 7.33 (d, J=15.2 Hz, 1 H), 6.64

45 11 23

(s, 1H), 4.04 (d, J=6.8 Hz, 2H), 3.81 (bs, 2H), 3.66 (brs, 4H), 3.25 (s, 2H), 2.97 (d, J=19.5 Hz, 2H), 2.44 (brs, 2H), 1.38 (s, 9H); LC-MS: 522.2 (M+l) ⁺.

10.74 (bs, 1 H), 8.38 (s, 1 H), 8.1 1 (s, 1H), 7.50-7.44 (m, 2H), 7.36-7.24 (m, 1H), 7.06-7.02 (m, 2H), 6.55 (s, 1H),

46 12 17 3.82-3.76 (m, 3H), 3.66-3.62 (m, 3H),

3.60-3.44 (m, 4H), 2.95 (s, 2H), 2.78- 2.66 (m, 3H), 1.39 (s, 9H), 1.40-1.24 (m, 3H); MS (ES) m/e 547 (M-l).

10.59 (bs, 1 H), 8.35 (s, 1 H), 8.16 (s, 1H), 7.84 (d, J=2.9 Hz, 1H), 7.68 (d,

47 11 21

J=2.9 Hz, 1H), 7.48 (d, J=15.7 Hz, 1H), 7.29 (d, J=15.1 Hz, 1H), 6.65 (s, 1H), 3.86-3.76 (m, 2H), 3.74-3.66 (m, 2H),

3.08-2.94 (m, 2H), 2.91 (s, 2H), 2.56-

2.42 (m, 2H), 1.72-1.54 (m, 4H), 1.53-

1.38 (m, 2H), 1.37-1.24 (m, 4H); MS

(ES) m/e 447 (M-l).

10.71 (bs, 1H), 8.38 (d, J=2.0 Hz, 1H),

8.15 (s, 1H), 7.84 (d, J=3.4 Hz, 1H),

7.68 (d, J=3.4 Hz, 1H), 7.48 (d, J=15.1

Hz, 1H), 7.30 (d, J=14.7 Hz, 1H), 6.65

11 22

(s, 1H), 3.86-3.78 (m, 2H), 3.77-3.61 (m, 6H), 3.04-2.92 (m, 2H), 2.99 (s, 2H), 2.49-2.40 (m, 2H), 1.86-1.77 (m, 2H), 1.36-1.28 (m, 2H).

10.77 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H),

7.99 (s, 1H), 7.48 (d, J=14.7 Hz, 1H),

7.47 (s, 1H), 7.33-7.25 (m, 1H), 7.04 (d,

J=4.9 Hz, 2H), 6.55 (s, 1H), 3.84-3.78

12 29 (m, 2H), 3.76-3.60 (m, 2H), 3.58-3.42

(m, 2H), 3.36-3.26 (m, 2H), 2.99 (s, 2H), 2.76-2.56 (m, 2H), 2.50-2.30 (m, 2H), 1.84-1.62 (m, 2H), 1.48-1.28 (m, 2H); MS (ES) m/e 477 (M+l) ⁺.

10.76 (brs, 1H), 8.39 (s, 1H), 8.12 (s,

1H), 7.50-7.45 (m, 2H), 7.36-7.26 (m,

1H), 7.08-7.02 (m, 2H), 6.55 (s, 1H),

3.82-3.74 (m, 2H), 3.72-3.58 (m, 4H),

12 26 2.97 (s, 2H), 3.66-3.54 (m, 2H), 2.42- 2.32 (m, 2H), 1.99 (s, 3H), 1.96-1.76 (m, 1H), 1.75-1.64 (m, 1H), 1.44-1.25 (m, 2H), 1.24-1.20 (m, 2H); MS (ES) m e 489 (M-l).

10.76 (brs, 1H), 8.39 (s, 1H), 8.12 (s,

12 27 1H), 7.50-7.44 (m, 2H), 7.38-7.24 (m,

1H), 7.04 (d, J=4.9 Hz, 2H), 6.55 (s, 1H), 3.82-3.72 (m, 4H), 3.70-3.60 (m,

2H), 3.44-3.40 (m, 2H), 2.97 (s, 2H), 2.68-2.56 (m, 2H), 2.42-2.36 (m, 2H), 2.27 (t, J=6.8 Hz, 2H), 1.84-1.64 (m, 2H), 1.50 (q, J=7.4 Hz, 2H), 1.42-1.26 (m, 2H), 0.88 (t, J=7.4 Hz, 3H); MS (ES) m/e 519 (M+l) ⁺.

10.77 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.12 (s, 1H), 7.51 -7.46 (m, 2H), 7.36- 7.20 (m, 1H), 7.06-7.02 (m, 2H), 6.65 (s, 1H), 4.52 (t, J=5.4 Hz, 1H), 4.08- 4.02 (m, 2H), 3.82-3.76 (m, 2H), 3.76-

12 28

3.68 (m, 2H), 3.66-3.60 (m, 2H), 3.52- 3.42 (m, 2H), 2.97 (s, 2H), 2.68-2.56 (m, 2H), 2.44-2.32 (m, 2H), 1.84-1.66 (m, 2H), 1.44-1.32 (m, 2H); MS (ES) m e 505 (M-l).

9.89 (s, 1H), 8.35 (s, 1H), 8.00 (s, 1H), 7.49-7.43 (_m, m), 7.45 (d, J=10.3 Hz, 1H), 7.30-7.21 (m, 1H), 7.05 (t, J=3.4 Hz, 1H), 7.04 (s, 1H), 6.54 (s, 1H), 4.55

12 30

N (s, 2H), 3.84-3.74 (m, 2H), 3.72-3.62

(m, 2H), 3.60-3.49 (m, 5H), 3.48-3.40 (m, 2H), 2.70-2.56 (m, 3H), 2.48-2.30 (m, 6H); MS (ES) m/e 494 (M+l) ⁺.

10.05 (bs, 1H), 8.44 (d, J= 2.0 Hz, 1H), 8.04 (s, 1H), 7.50-7.47 (m, 2H), 7.36- 7.30 (m, 1H), 7.06-7.04 (m, 2H), 6.55

12 35 (s, 1H), 3.92 (s, 2H), 3.82-3.72 (m, 2H),

~^0

3.71-3.53 (m, 4H), 3.12-3.04 (m, 1H), 2.67-2.58 (m, 2H), 2.46-2.32 (m, 2H); MS (ES) m/e 395.2 (M+l) ⁺. 10.38 & 10.30 (s & rotamer, 1H), 8.50

(d, J=11.7 Hz, 1H), 8.24-8.16 (m, 1H), 7.83 (d, J=2.9 Hz, 1H), 7.67 (d, J=3.4

° Y. Hz, 1H), 7.51 (d, J=15.7 Hz, 1H), 7.38

55 11 36 I (d, J=15.2 Hz, 1H), 6.65 (s, 1H), 4.62- 4.50 (m, 2H), 4.40-4.30 (m, 2H), 3.88- 3.76 (m, 2H), 3.74-3.66 (m, 2H), 3.08- 2.94 (m, 2H), 2.52-2.40 (m, 2H), 1.24 (s, 9H); LC-MS: 496 (M+H) ⁺.

9.97 (bs, 1H), 8.41 (s, 1H), 8.02 (s, 1H),

7.84 (d, J=3.4 Hz, 1H), 7.68 (d, J=2.9 Hz, 1H), 7.49 (d, J=15.7 Hz, 1H), 7.32 (d, J=15.7 Hz, 1H), 6.65 (s, 1H), 3.98-

56 11 38 3.85 (m, 2H), 3.83-3.78 (m, 2H),3.70- 3.62 (m, 2H), 3.57-3.50 (m, 1H), 3.00- 2.90 (m, 2H), 2.45-2.40 (m, 2H), 1.30 (d, J=3.4 Hz, 2H), 0.93 (d, J=3.5 Hz, 2H); LC-MS: 422.2 (M+l) ⁺.

(at 90°C) 9.83 (bs, 1H), 8.46 (d, J=1.4 Hz, 1H), 8.05 (s, 1H), 7.48-7.42 (m, 2H), 7.29-7.23 (m, 2H), 7.08 (d, J=4.9 VL

Hz, 1H), 6.33 (s, 1H), 4.54 (s, 2H), 4.32

57 13 36

(s, 2H), 3.71-3.63 (m, 4H), 2.54 (t, J=5.7 Hz, 2H), 2.38 (t, J=5.7 Hz, 2H), 1.32 (s, 9H); LC-MS: 495.2 (M+l)⁺.

Example-Ill: Synthesis of (E)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop- 1 -en-1 -yl)- 1 'H-spiro[azetidine-3 ,3'-[l,8]naphthyridin]-2'(4'H)-one hydrochloric acid (

To a stirred solution of (E)-tert-butyl 2'-oxo-6'-(3-oxo-3-(4-(thiazol-2- ylmethylene)piperidin- 1 -yl)prop-l -en- 1 -yl)-2',4'-dihydro-l Ή-spiro [azetidine-3 ,3'- [l,8]naphthyridine]-l-carboxylate (Compound-45) (0.12 g, 0.23 mmol) in DCM/MeOH (5 mL/0.5 mL) was added 2M HC1 in diethyl ether (12 mL) drop wise at 0°C and the reaction mixture was allowed to stir at 20-35°C for 4 h. Then the reaction mixture was rotary evaporated to get the desired compound as a yellow solid (150 mg, Quantitative). ^ιΐΙ NMR (400MHz, DMSO-d₆) δ 11.11 (s, 1H), 10.04 (brs, 1H), 9.19 (bs, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.21 (s, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.50 (d, J=15.2 Hz, 1H), 7.44-7.36 (m, 1H), 6.67 (s, 1H), 4.26-4.20 (m, 2H), 3.83 (brs, 2H), 3.77-3.73 (m, 2H), 3.68 (brs, 2H), 3.42-3.36 (m, 2H), 2.96 (d, J=9.5 Hz, 2H), 2.44 (d, J=3.5 Hz, 2H); LC-MS: 422.2 (M+l) ⁺.

Example-IV: Synthesis of (E)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l -yl) prop- l-en-l-yl)-lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one 2,2,2-trifluoroacetate and (E)-l '-(2-hydroxyacetyl)-6-(3-oxo-3 -(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop- 1 -en- 1 - yl)- -spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one (Compounds-59 and 60).

Step-(i): Synthesis of (E)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l-en-l- yl)-lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Compound-59).

To a stirred solution of (E)-tert-butyl 2-oxo-6-(3-oxo-3-(4-(tliiazol-4-ylmethylene)piperidin- l-yl)prop-l -en-l-yl)-2,4-dihydro-lH-spiro[[l ,8]naphthyridine-3,4'-piperidine]-l'- carboxylate (Compound-16) (0.17 g, 0.31 mmol) in DCM (3 mL) was added trifluoro acetic acid (3 mL) drop wise at 20-35°C and the reaction mixture was allowed to stir at 20- 35°C for 3 h. Then the reaction mixture was rotary evaporated to get the residue which was triturated with diethyl ether twice to get the desired compound as an off-white solid (150 mg, 86%). ^XH NMR (400MHz, DMSO-d₆) δ 10.88 (s, 1H), 9.10 (s, 1H), 8.60-8.44 (s, 2H), 8.43 (d, J=2.0 Hz, 1H), 8.11 (s, 1H), 7.55 (s, 1H), 7.49 (d, J=15.7 Hz, 1H), 7.29 (d, J=15.1 Hz, 1H), 6.43 (s, 1H), 3.82-3.60 (m, 4H), 3.26-3.10 (m, 4H), 2.98 (s, 2H), 2.94-2.88 (m, 2H), 2.48-2.34 (m, 2H), 2.04-1.92 (m, 2H), 1.62-1.54 (m, 2H); LC-MS: 450.2 (M+l) ⁺.

Step-(ii): Synthesis of (E)-l '-(2-hydroxyacetyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene) piperidin- 1 -yl)prop- 1 -en- 1 -yl)-l H-spiro[[l ,8]naphthyridine-3 ,4'-piperidin]-2(4H)-one (Compound-60).

DIPEA ( 0.22 mL, 1.28 mmol) was added to a solution of (E)-6-(3-oxo-3-(4-(thiazol-4-yl methylene)piperidin- 1 -yl)prop- 1 -en- 1 -yl)- 1 H-spiro [[1 , 8]naphthyridine-3 ,4'-piperidin] - 2(4H)-one 2,2,2-trifluoroacetate (Compound-59)(140 mg, 0.25 mmol), glycolic acid (38 mg, 0.51 mmol), HOBt (67 mg, 0.51 mmol), EDC.HC1 (95 mg, 0.51 mmol) in dry DMF (2 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 and stirred for 15 minutes. The obtained solid was filtered, washed with water and dried to get the desired compound as a yellow solid (16 mg, 13%); H NMR (400MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.10 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.54 (s, 1H), 7.48 (d, J=15.2 Hz, 1H), 7.29 (d, J=15.6 Hz, 1H), 6.42 (s, 1H), 4.51 (s, 1H), 4.08 (s, 2H), 3.82-3.62 (m, 6H), 3.56-3.38 (m, 2H), 2.97 (s, 2H), 2.96-2.86 (m, 2H), 2.46-2.32 (m, 2H), 1.86-1.66 (m, 2H), 1.46-1.32 (m, 2H); LC-MS: 508.2 (M+l) ⁺.

The below compounds were prepared by procedure similar to the one described in Example-IV step-(ii) with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below Table.

Characterization data

Co Start

U NMR (400MHz, DMSO-i¾) m. Com Reactant Compound structure

in δ / LC-MS (M+1)7ES-MS No P

(M+l)⁺

10.78 (bs, 1H), 9.10 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 7.54 (s, 1H), 7.48 (d, J=15.1 Hz, 1H), 7.30 (d, J=15.2 Hz, 1H),

61 59 6.98 (s, 1H), 6.61 (s, 1H), 6.42 (s,

1H), 3.92-3.56 (m, 8H), 3.04-2.88 (m, 2H), 3.00 (s, 2H), 2.46-2.28 (m, 2H), 1.90-1.76 (m, 2H), 1.52- 1.42 (m, 2H); LC: 544.3 (M+l) ⁺.

Example-V: Synthesis of (E)-l'-(3-hydroxypropyl)-6-(3-oxo-3-(4-(thiophen-2-yl methylene)piperidin- 1 -yl)prop- 1 -en- 1 -yl)- 1 H-spiro [[1 , 8]naphthyridine-3 ,4'-piperidin] - 2

Step-(i): Synthesis of (E)-6-(3-oxo-3-(4-(thiophen-2-ylmethylene)piperidin-l -yl)prop-l-en- 1 -yl)- 1 '-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)- 1 H-spiro [[1 ,8]naphthyridine-3 ,4'- piperidin]-2(4H)-one (Compound-64a). The process of this step was adopted from preparation of compound-44. The desired compound obtained as an off-white solid (140 mg, 41%); ^lU NMR (400MHz, DMSO-d₆) δ 10.92 (brs, 1H), 9.12 (bs, 1H), 8.50-8.42 (m, 1H), 8.20-8.10 (m, 1H), 7.56-7.48 (m, 1H), 7.36-7.24 (m, 1H), 7.08-7.02 (m, 2H), 6.55 (s, 1H), 4.56 (s, 1H), 3.84-3.64 (m, 5H), 3.54- 3.42 (m, 4H), 3.24-3.08 (m, 4H), 3.00-2.90 (m, 2H), 2.70-2.56 (m, 2H), 2.48-2.30 (m, 2H), 2.28-2.06 (m, 2H), 2.05-1.88 (m, 3H), 1.78-1.58 (m, 4H), 1.54-1.40 (m, 4H); MS (ES) m/e 591 (M+H)⁺.

Step-(ii): Synthesis of (E)-l'-(3-hydroxypropyl)-6-(3-oxo-3-(4-(thiophen-2-ylmethylene) piperidin- 1 -yl)prop- 1 -en- 1 -yl)-l H-spiro[[l ,8]naphthyridine-3 ,4'-piperidin]-2(4H)-one (Compound-64).

The process of this step was adopted from preparation of compound-58. The desired compound obtained as an off-white solid (60 mg, 50%); H NMR (400MHz, DMSO-d₆) δ 10.66 (s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 7.52-7.44 (m, 2H), 7.36-7.24 (m, 1H), 7.08-7.02 (m, 2H), 6.55 (s, 1H), 4.50-4.40 (m, 1H), 3.82-3.74 (m, 2H), 3.72-3.60 (m, 2H), 3.46-3.40 (m, 2H), 2.92 (s, 2H), 2.68-2.50 (m, 4H), 2.42-2.32 (4H), 2.30-2.16 (m, 2H), 1.84 (t, J=10.3 Hz, 2H), 1.57 (t, J=6.9 Hz, 2H), 1.42-1.32 (m, 2H); MS (ES) m e 507 (M+H)⁺.

Example-VI: Synthesis of (E)-N-(2-oxo-2-(2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethylene) piperidin- 1 -yl)prop- 1 -en- 1 -yl)-2,4-dihydro- lH-spiro[[l ,8 ]naphthyridine-3,4'-piperidin]- 1 '- yl)

(i) Inteimediate-1, HOBt, EDC.HC1, DIPEA, DMF, 20-35^cC, 16 h; (ii) TFA, DCM, 20-35°C, 3 h;

(iii) 2-pivalamidoacetic acid, HOBt EDC.HC1, DIPEA, DMF, 20-35°C, 16 h

Step-(i): Synthesis of (E)-tert-butyl 2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- l-yl)prop-l -en-l-yl)-2,4-dihydro-lH-spiro[[l ,8]naphthyridine-3,4'-piperidine]-l'- carboxylate (Compound-65a).

The process of this step was adopted from preparation of compound-1. The desired compound obtained as a yellow solid (600 mg, 50%); H NMR (400MHz, DMSO-d₆) δ 10.74 (s, 1H), 8.39 (d, J=2.0Hz, 1H), 8.11 (s, 1H), 7.83(d, J=3.4Hz, 1H), 7.67 (d, J=3.4Hz, IH), 7.48 (d, J=15.6 Hz, I H), 7.29 (d, J=14.7Hz, IH), 6.65 (s, IH), 3.82-3.78 (m, 2H), 3.69- 3.66 (m, 2H), 3.58-3.56 (m, 2H), 3.28-3.26 (m, 2H), 3.00-2.98 (m, 2H), 2.95 (s, 2H), 2.44- 2.42 (m, 2H), 1.73-1.70 (m, 2H), 1.40 (s, 9H), 1.36-1.31 (m, 2H).

Step-(ii): Synthesis of (E)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l -yl)prop-l-en- l -yl)- lH-spiro[[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one (Compound-65b).

The process of this step was adopted from preparation of compound-59. The desired compound obtained as an off-white solid (205 mg, Quantitative). ^XH NMR (400MHz, DMSO-de) δ 10.89 (s, IH), 8.56-8.40 (m, 2H), 8.44 (d, J=1.4 Hz, IH), 8.10 (s, IH), 7.84 (d, J=3.4 Hz, IH), 7.68 (d, J=3.4 Hz, IH), 7.50 (d, J=15.1 Hz, I H), 7.30 (dd, J=6.6 Hz, 15.4 Hz, I H), 6.65 (s, IH), 3.88-3.77 (m, 2H), 3.70-3.64 (m, 2H), 3.28-3.08 (m, 4H), 3.07-2.92 (m, 2H), 2.98 (s, 2H), 2.50-2.40 (m, 2H), 2.06-1.92 (m, 2H), 1.62-1.52 (m, 2H).

Step-(iii): Synthesis of (E)-N-(2-oxo-2-(2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piper- idin- 1 -yl)prop- 1 -en- 1 -yl)-2,4-dihydro-l H-spiro [[1 ,8]naphthyridine-3 ,4'-piperidin]- 1 '- yl)ethyl)pivalamide (Compound-65).

The process of this step was adopted from preparation of compound-60. The desired compound obtained as an off-white solid (40 mg, 19%); H NMR (400MHz, DMSO-d₆) δ 10.77 (bs, IH), 8.40 (s, IH), 8.12 (s, I H), 7.84 (d, J=2.4 Hz, IH), 7.68 (s, I H), 7.51-7.45 (m, 2H), 7.30 (d, J= 15.7 Hz, IH), 6.65 (s, IH), 3.90-3.85 (m, 2H), 3.85-3.78 (m, 2H), 3.78- 3.58 (m, 4H), 3.45-3.37 (m, 2H), 3.02-2.90 (m, 4H), 2.45-2.40 (m, 2H), 1.87-1.65 (m, 2H), 1.44-1.25 (m, 2H), 1.11 (s, 9 H); LC-MS: 591.3 (M+l) ⁺.

The below compounds were prepared by procedure similar to the one described in

Example- VI with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below Table.

Example-VII: Synthesis of (E)-7-(3-oxo-3-(4-(thiazol-2-ylmethylene)piper- idin-l-yl)prop- l-en-l-yl)-4,5-dihydro-l H-pyrido [2,3-e][l,4]diazepin-2(3H)-one. 2,2 ,2-trifluoro acetate

The process of this step was adopted from preparation of compound-59. The desired compound obtained as a brown solid (100 mg, 83%). H NMR (400MHz, DMSO-d₆) δ 9.89 (s, IH), 8.42 (d, J=2.4 Hz, IH), 8.01 (d, J=1.5 Hz, IH), 7.82 (d, J=3.4 Hz, IH), 7.65 (d, J=2.9 Hz, IH), 7.49 (d, J=15.7 Hz, IH), 7.30 (d, J=15.6 Hz, IH), 6.63 (s, IH), 3.92 (s, 2H), 3.86-3.76 (m, 2H), 3.68-3.61 (m, 2H), 3.63 (s, 2H), 3.06 (bs, IH), 3.03-2.92 (m, 2H), 2.48- 2.42 (m, 2H); LC-MS: 396.1 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example VII with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below Table.

Example-VIII: Synthesis of (E)-6-(3-(4-benzylidenepiperidin-l-yl)-3-oxoprop-l-en-l-yl)- 3,4-dihydro-l ,8-naphthyridin-2(lH)-one (Compound -72).

(i) P(OMe)₃, 140°C, 8 h; (ii) tert-butyl 4-oxopiperidine-l-carboxylate, NaH, THF, 85°C, 4 h; (iii) CF₃COOH, DCM,

20-35°C, 1 h then Iiitermediate-42; HOBt, EDC.HC1, DIEA, DMF, 20-35°C, 16 h. (Ref.for step-(i): J.Med.Chem, 25 (10), 1231-1235, 1982)

Step-(ii): Synthesis of tert-butyl 4-benzylidenepiperidine-l-carboxylate (72b).

To a stirred solution of tert-butyl 4-oxopiperidine-l-carboxylate (0.8 g, 4.0 mmol) and dimethyl benzylphosponate (72a) (1 g, 5.0 mmol) in dry THF (10 mL) was added NaH (0.144 mg, 6.0 mmol, 60 wt% in oil dispersion) at 20-35°C under nitrogen atmosphere and the reaction mixture was heated at 85°C for 4 h. Then the reaction mixture was quenched with N¾C1 solution at 20-35°C and diluted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na₂S0₄ and evaporated to get the desired compound as a colorless oily liquid (1.05 g, 90%); H NMR (400MHz, DMSO-d₆) δ 7.36-7.30 (m, 2H), 7.24-7.18 (m, 3H), 6.37 (s, 1H), 3.41 (t, J=5.9 Hz, 2H), 3.34 (d, J=5.8 Hz, 2H), 2.39 (t, J=5.8 Hz, 2H), 2.28 (t, J=5.9 Hz, 2H), 1.41 (s, 9H).

Step-(iii): Synthesis of (E)-6-(3-(4-benzylidenepiperidin-l-yl)-3-oxoprop-l-en-l -yl)-3,4-di hydro-1 ,8-naphthyridin-2(lH)-one (Compound -72).

To a stirred solution of tert-butyl 4-benzylidenepiperidine-l-carboxylate (72b) (250 mg, 0.91 mmol) in THF (10 mL) was added trifluoro acetic acid (0.5 mL) and the reaction mixture was allowed to stir at 20-35°C for 1 h. Then the reaction mixture was rotary evaporated to get the desired compound as brown liquid (150 mg, Quantitative) which was added to a stirred solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)acrylic acid (Intermediate-42)(98 mg, 0.45 mmol) in dry DMF (3 mL) at 20-35°C, followed by HOBt (121 mg, 0.90 mmol), EDC.HC1 (170 mg, 0.90 mmol) and DIPEA (0.23 mL, 1.35 mmol) were added 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 and stirred for 15 minutes. The obtained solid was filtered, washed with water and dried to get the desired compound as a pale yellow solid (30 mg, 13%); H NMR (400MHz, DMSO-d₆) δ 10.64 (s, 1H), 8.36 (s, 1H), 8.10 (d, J=11.8 Hz, 1H), 7.47 (d, J=15.1 Hz, 1H), 7.39-7.20 (m, 6H), 6.43 (s, 1H), 3.84-3.76 (m, 1H), 3.75-3.64 (m, 2H), 3.62-3.58 (m, 1H), 2.92 (t, J=7.3Hz, 2H), 2.57-2.53 (m, 2H), 2.44-2.30 (m, 4H); MS (ES) m/e 374.2 (M+l)⁺. Example-IX: Synthesis of (E)-3-(3-(4-(berizo[d]thiazol-2-ylrnethylene)piperidin-l-yl)-3- oxopr -l-en-l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound-73).

(i) P(OEt)₃, 165°C, 5 h; (li) tert-butyl 4-oxopiperidine-l-carboxylate, NaH, THF, 85°C, 5 h;

(iii) CF3COOH, DCM, 20-35°C, 2 h then Intermediate-50; HOBt, EDC.HC1, DIEA, DMF,

20-35°C, 16 h; (Ref. for step-(i): US2009/082403)

Step-(ii): Synthesis of tert-butyl 4-(benzo[d]thiazol-2-ylmethylene)piperidine-l-carboxylate (73b).

The process of this step was adopted from step-(ii) of compound-72. The desired compound obtained as a colorless oily liquid (310 mg, 64%); LC-MS: 331.2 (M+l)⁺.

Step-(iii): Synthesis of (E)-3-(3-(4-(benzo[d]thiazol-2-ylmethylene)piperidin-l -yl)-3-oxo prop-l-en-l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound-73).

The process of this step was adopted from step-(iii) of compound-72. The desired compound obtained as a light yellow solid (15 mg, 4%); ^lU NMR (400MHz, DMSO-d₆) δ 10.05 (brs, 1H), 8.48 (d, J=5.3 Hz, 1H), 8.15 (d, J=1.9 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.94 (d, J=7.4 Hz, 1H), 7.52-7.46 (m, 2H), 7.42-7.38 (m, 1H), 7.38-7.24 (m, 1H), 5.79 (s, 1H), 4.30-4.26 (m, 1H), 4.10-4.06 (m, 1H), 3.90-3.86 (m, 2H), 3.82-3.78 (m, 1H), 3.68-3.64 (m, 1H), 2.74-2.68 (m, 2H), 2.28-2.10 (m, 6H).

Example-X: Synthesis of (E)-6-(3-oxo-3-(4-(pyridin-3-ylmethylene)piperidin-l-yl)prop-l- en-l-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one (Compound-74).

(i) 3-Bromopyridine, Pd(OAc)₂, P(0-tolyl)₃, DIPEA, Propionitrile:DMF (4:1), 110°C, 16 h; (ii) CF₃COOH, DCM, 20-35°C, 3 t en Intermeiliate-42; HOBt, EDC.HC1, DIEA, DMF, 20-35°C, 16 .

Step-(i): Synthesis of tert-butyl 4-(pyridin-3-ylmethylene)piperidine-l -carboxylate (74a). DIPEA (0.78 mL, 4.56 mmol) was added to a solution of 3-bromo pyridine (306 mg, 1.95 mmol), tert-butyl 4-methylenepiperidine-l-carboxylate (300 mg, 1.52 mmol), Pd(OAc)2 (33 mg, 0.15 mmol), P(o-tolyl)3 (91 mg, 0.31 mmol) in propionitrile/DMF (4 mL/1 mL) was degassed with Nitrogen for 15 minutes and then heated at 110°C for 16 h. Then the reaction mixture was cooled to 20-35°C and filtered on celite. The filtrate was concentrated, resultant residue was diluted with water (30 mL) and extracted with ethyl acetate (2x30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SC>4 and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 50% ethyl acetate/pet-ether as an eluent to get the desired compound as a yellow waxy solid (130 mg, 31 %); ¾ NMR (400MHz, DMSO-d₆) δ 8.46-8.41 (m, 2H), 7.65 (dd, J=1.9 Hz, 7.9 Hz, 1H), 7.38-7.34 (m, 1H), 6.37 (s, 1H), 3.42 (t, J=5.9 Hz, 2H), 3.38-3.35 (m, 2H), 2.39-2.35 (m, 2H), 2.34-2.30 (m, 2H), 1.41 (s, 9H).

Step-(ii): Synthesis of (E)-6-(3-oxo-3-(4-(pyridin-3-ylmethylene)piperidin-l -yl)prop-l-en- l-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one (Compound -74).

The process of this step was adopted from step-(iii) of compound-72. The desired compound obtained as a yellow waxy solid (130 mg, 31 %); H NMR (400MHz, DMSO-d₆) δ 8.46-8.41 (m, 2H), 7.65 (dd, J=1.9 Hz, 7.7.9 Hz, 1H), 7.38-7.34 (m, 1H), 6.37 (s, 1H), 3.42 (t, J=5.9 Hz, 2H), 3.38-3.35 (m, 2H), 2.39-2.35 (m, 2H), 2.34-2.30 (m, 2H), 1.41 (s, 9H).

Example-XI: Synthesis of (E)-6-(3-(4-(fluoro(thiazol-2-yl)methylene)piperidin-l-yl)-3- oxoprop-l-en-l-yl)-3,4-dihydro-l ,8-naphthyridin-2(lH)-one and (E)-3-(3-(4-(fluoro (thiazole-2-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l -yl)-6,7-dihydro-5H-pyrido[2,3- b]a

Step-(i): Synthesis of 2-((thiazol-2-ylmethyl)thio)benzo[d]thiazole (75a).

To a stirred solution of benzo[d]thiazole-2-thiol (10 g, 59.88 mmol) in THF (200 mL) was added sodium hydride (2.87 g, 119.58 mmol) at 0°C and continued stirring at 0°C for 10 minutes. After 10 minutes, 2-(chloromethyl)thiazole (7.96 g, 59.88 mmol) was added and the reaction mixture was allowed to stir at 20-35°C for 5 h. Then the reaction mixture was quenched with ice water (200 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with brine (200 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 20% ethyl acetate/hexane as an eluent to get the desired compound as a brown oily liquid (8.4 g, 53%); LC-MS: 265.1 (M+l)⁺.

Step-(ii): Synthesis of 2-((thiazol-2-ylmethyl)sulfonyl)benzo[d]thiazole (75b).

To a stirred solution of 2-((thiazol-2-ylmethyl)thio)benzo[d]thiazole (75a) (0.5 g, 1.89 mmol) in chloroform (20 mL) was added raCPBA (0.97 g, 5.68 mmol) at 0°C and reaction mixture was allowed to stir at 20-35°C for 16 h. Then the reaction mixture was quenched with aq.NY Cl (5 mL), then diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get the desired compound as a brown liquid (0.31 g, Quantitative); ^lU NMR (400MHz, DMSO-d₆) δ 8.61 -8.09 (m, 1H), 7.72-7.66 (m, 4H), 7.62-7.54 (m, 1H), 7.48-7.36 (m, 2H).

Step-(iii): Synthesis of 2-((fluoro(thiazol-2-yl)methyl)sulfonyl)benzo[d]thiazole (75c).

To a stirred solution of 2-((thiazol-2-ylmethyl)sulfonyl)benzo[d]thiazole (75b) (1 g, 3.37 mmol) in toluene (30 mL) was added LDA (1.8 mL, 3.71 mmol; 2M in Toluene) drop wise at -85°C and continued stirring at -85°C for 10 minutes. After 10 minutes, N- fluorobenzenesulfonimide (1.06 g, 3.37 mmol) was added drop wise, continued stirring at - 85°C for 1 h, then slowly warmed to 20-35 °C and continued stirring at 20-35°C for 1 h. Then the reaction mixture was quenched with aq.NELCl (5 mL), then diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get the desired compound as a pale yellow solid (0.53 g, 50%); H NMR (400MHz, DMSO-d₆) δ 10.05 (s, 1H), 8.62 (s, 1H), 8.24-8.21 (m, 1H), 7.72-7.64 (m, 4H).

Step-(iv): Synthesis of tert-butyl 4-(fluoro(thiazol-2-yl)methylene)piperidine-l-carboxylate (75d).

To a stirred solution of tert-butyl 4-methylenepiperidine-l-carboxylate (0.2 g, 1.02 mmol) in dry THF (30 mL) was added LiHMDS (3.2 mL, 3.17 mmol; 1M in THF) at 0°C and continued stirring at 0°C for 1 h. After 1 h, 2-((fluoro(thiazol-2-yl)methyl) sulfonyl) benzo [d]thiazole (75c) (0.4 g, 1.27 mmol) was added and the reaction mixture was allowed to stir at 20-35°C for 1 h. Then the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 70% ethyl acetate/hexane as an eluent to get the desired compound as a brown waxy solid (0.28 g, 72%); LC-MS: 243.1 (M-57).

Step-(v): Synthesis of (E)-6-(3-(4-(fluoro(thiazol-2-yl)methylene)piperidin-l-yl)-3- oxoprop-l-en-l-yl)-3,4-dihydro-l ,8-naphthyridin-2(lH)-one (Compound-75).

The process of this step was adopted from step-(iii) of compound-72. The desired compound obtained as an off-white solid (20 mg, 4%); ^lU NMR (400MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.36 (d, J=1.5 Hz, 1H), 8.10 (s, 1H), 8.00 (t, J=3.4 Hz, 1H), 7.89 (d, J=3.4 Hz, 1H), 7.48 (d, J=15.6 Hz, 1H), 7.30 (d, J=15.1 Hz, 1H), 3.88-3.78 (m, 2H), 3.74-3.64 (m, 2H), 3.12-3.00 (m, 2H), 2.92 (t, J=7.3 Hz, 2H), 2.58-2.52 (m, 4H).

Step-(vi): Synthesis of (E)-3-(3-(4-(fluoro(thiazol-2-yl)methylene)piperidin-l-yl)-3- oxoprop-l-en-l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound-76).

The process of this step was adopted from step-(iii) of compound-72. The desired compound obtained as a brown solid (10 mg, 4%); ^lU NMR (400MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.18 (s, 1H), 7.99 (d, J=3.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.37 (d, J=15.2 Hz, 1H), 3.88-3.82 (m, 2H), 3.74-3.66 (m, 2H), 3.20 (s, 2H), 3.16-3.02 (m, 2H), 2.76-2.72 (m, 2H), 2.30-2.22 (m, 2H), 2.21-2.12 (m, 2H).

Example-XII: Synthesis of (E)-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene) piperidin-l-yl) pr -l-en-l-yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one (Compound-77).

(i) Intermediate-11, Pd(OAc)₂, P(0-tolyl)₃, DIPEA, Propionmile:DMF, 110°C, 16 h; (ii) TFA, DCM, 20-35°C, 3 h then etliylene diamine, DCM, 20-35°C, 6 h.

Step-(i): Synthesis of (E)-tert-butyl 2'-oxo-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- 1 -yl)-l '-((2-(trimethylsilyl)ethoxy)methyl)- 1 ',2'-dihydrospiro [piperidine- 4,3'-pyrrolo[2,3-b]pyridine]-l-carboxylate (77a).

The process of this step was adopted from preparation of compound-44. The desired compound obtained as a pale brown solid (500 mg, 64%). H NMR (400MHz, DMSO-d₆) δ 8.35 (d, J=1.9 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.68 (d, J=15.7 Hz, 1H), 7.27 (d, J=2.9 Hz, 1H), 6.88 (d, J=15.2 Hz, 1H), 6.57 (s, 1H), 5.25 (s, 2H), 3.90-3.72 (m, 8H), 3.68-3.63 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.48 (m, 2H), 1.92-1.86 (m, 2H), 1.85-1.76 (m, 2H), 1.51 (s, 9H), 0.98-0.92 (m, 2H), -0.03 (s, 9H); LC-MS: 666.3 (M+l)⁺. Step-(ii): Synthesis of (E)-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l -yl)prop-l-en- l-yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one (Compound-77).

To a stirred solution of (E)-tert-butyl 2'-oxo-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene) piperidin- 1 -yl)prop- 1 -en- 1 -yl)-l '-((2-(trimethylsilyl)ethoxy)methyl)- 1 ',2'-dihydrospiro

[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-l-carboxylate (77a) (0.5 g, 0.75 mmol) in DCM (5 mL) was added trifluoro acetic acid (5 mL) and the reaction mixture was allowed to stir at 20-35°C for 3 h. The reaction mixture was rotary evaporated to get residue which was diluted with DCM (20 mL) and treated with ethylene diamine (5 mL) at 20-35°C for 6 h. Then the reaction mixture was diluted with NaHCC>3 solution (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed brine (50 mL), dried over on anhydrous Na₂S0₄ and filtered to get the desired compound as a pale brown solid (100 mg, 24%). ^lU NMR (400MHz, DMSO-d₆) δ 8.42 (d, J=9.8 Hz, 1H), 8.31 (d, J=8.8 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.68 (d, J=2.9 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H), 7.35 (d, J=15.7 Hz, 1H), 6.65 (s, 1H), 3.90-3.76 (m, 2H), 3.72-3.64 (m, 2H), 3.14-3.08 (m, 2H), 3.07-2.90 (m, 5H), 2.50-2.40 (m, 2H), 1.82-1.70 (m, 2H), 1.66-1.54 (m, 2H); LC-MS: 436.2 (M+l)⁺. Example-XIII: Synthesis of (E)-6-(3-(4-((l ,2,4-thiadiazol-3-yl)methylene)piperidin-l -yl)- 3-oxoprop-l-en-l-yl)-3,3-dimethyl-3,4-dihydro-l ,8-naphthyridin-2(lH)-one (Compound- 78) and (E)-3-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)- 6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound-79).

DMF, 20-35°C, 16 h. (Ref.fur step-(i): WO2009/015193 Al)

Step-(ii): Synthesis of 3-(chloro methyl)- 1 ,2,4-thiadiazole (78b).

To a stirred solution of 3-(chloromethyl)-l ,2,4-thiadiazol-5-amine (78a) (5 g, 33.55 mmol) in DMF (25 mL) was added isoamyl nitrate (39.26 g, 335.52 mmol) at 20-35°C and the reaction mixture was allowed to stir at 70°C for 16 h.Then the reaction mixture was diluted with ethyl acetate (200 mL), water (200 mL) and partitioned into layers. The organic layer was washed with brine (100 mL), dried over anhydrous Na₂S0₄ and filtered. The filtrate was rotary evaporated to get residue which was triturated with diethyl ether to get the desired compound as an off-white solid (3.41 g, 76%);¹U NMR (400MHz, DMSO-d₆) 810.33 (s, 1H), 4.71 (s, 2H).

Step-(iii): Synthesis of diethyl((l ,2,4-thiadiazol-3-yl)methyl)phosphonate (78c).

The process of this step was adopted from step-(ii) of Intermediate- 1. The desired compound obtained as a pale brown liquid (420 mg, 24%); LC-MS: 237.1 (M+l )⁺.

Step-(iv): Synthesis of tert-butyl4-((l ,2,4-thiadiazol-3-yl)methylene)piperidine-l - carboxylate (78d).

The process of this step was adopted from step-(iii) of Intermediate- 1. The desired compound obtainedas an oily liquid (120 mg, 24%); ^XH NMR (400MHz, DMSO-d₆) δ 10.24 (s, 1H), 6.58 (s, 1H), 3.48-3.36 (m, 4H), 3.02 (t, J=5.9 Hz, 2H), 2.37 (t, J=5.9 Hz, 2H), 1.42 (s, 9H).

Step-(v): Synthesis of (E)-6-(3-(4-((l ,2,4-thiadiazol-3-yl)methylene)piperidin-l -yl)-3- oxoprop-l -en- l-yl)-3,3-dimethyl-3,4-dihydro-l ,8-naphthyridin-2(lH)-one (Compound-78). The process of this step was adopted from step-(iii) of compound-72. The desired compound obtained as a pale brown solid (35 mg, 21 %); ^XH NMR (400MHz, DMSO-d₆) δ 10.62 (s, 1H), 10.26 (s, 1 H), 8.38 (s, 1H), 8.10 (s, 1H), 7.49 (d, J=15.7 Hz, 1 H), 7.32 (d, J=15.2 Hz, 1 H), 6.64 (s, 1 H), 3.86-3.66 (m, 4H), 3.16-3.06 (m, 2H), 2.81 (s, 2H), 2.58-2.48 (m, 2H), 1.09 (s, 6H); LC-MS: 410.2 (M+l)⁺.

Step-(vi): Synthesis of (E)-3-(3-(4-((l ,2,4-thiadiazol-3-yl)methylene)piperidin-l -yl)-3- oxoprop-l -en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound-79).

The process of this step was adopted from step-(iii) of compound-72. The desired compound obtained a brown solid (3 mg, Quantitative); LC-MS: 396.0 (M+l)⁺.

Example-XIV: Synthesis of (E)- l-(2-hydroxyacetyl)-6'-(3-oxo-3-(4-(thiazol-4- ylmethylene)piperidin- 1 -yl)prop-l -en- 1 -yl)-l Ή-spiro [azetidine-3 ,3'- [1 ,8]naphthyridin]- 2'(4'H)-one (Compound-80).

(i) Inteimediate-4, HOBt, EDC.HCL, DIPEA, DMF, 20-35°C, 16 h; (ii) TFA, DCM, 20- 35°C, 1 h; (iii) Glycolic acid, HOBt, EDC.HCL, DIPEA, DMF, 20-35°C, 16 h.

Step-(i): Synthesis of (E)-tert-butyl 2'-oxo-6'-(3-oxo-3-(4-(tMazol-4-ylrnethylene)piperidin- 1 -yl)prop-l -en-1 -yl)-2',4'-dihydro-l 'H-spiro[azetidine-3,3'-[l ,8]naphthyridine]- 1 - carboxylate (80a).

The process of this step was adopted from preparation of compound-1. The desired compound obtained as an off-white solid (120 mg, 25%). H NMR (400MHz, DMSO-d₆) δ 10.91 (s, IH), 9.10 (d, J=1.9 Hz, IH), 8.42 (s, IH), 8.40 (d, J=1.9 Hz, IH), 7.54 (d, J=1.5 Hz, IH), 7.47 (d, J=15.2 Hz, IH), 7.31 (d, J=15.7 Hz, IH), 6.43 (s, IH), 4.08-4.00 (m, 2H), 3.84-3.70 (m, 2H), 3.69-3.58 (m, 3H), 3.30-3.20 (m, 2H), 3.00-2.88 (m, 2H), 2.46-2.36 (m, 3H), 1.38 (s, 9H); LC-MS: 522.3 (M+l) ⁺.

Step-(ii): Synthesis of (E)-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l -yl)prop-l-en- l-yl)-l'H-spiro[azetidine-3,3'-[l ,8]naphthyridin]-2'(4'H)-one 2,2,2-trifluoroacetate (80b). The process of this step was adopted from step-(i) of compound-69. The desired compound obtained as a brown solid (85 mg, 89%); LC-MS: 422.2 (M+l) ⁺.

Step-(iii): Synthesis of (E)-l -(2-hydroxyacetyl)-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene) piperidin- 1 -yl)prop- 1 -en- 1 -yl)- 1 'H-spiro[azetidine-3,3'- [1 ,8]naphthyridin]-2'(4'H)-one (Compound-80).

The process of this step was adopted from step-(ii) of compound-60. The desired compound obtained as an off-white solid (25 mg, 26%). H NMR (400MHz, DMSO-d₆) δ 10.95 (s, IH), 9.10 (d, J=2.0 Hz, IH), 8.42 (d, J=1.4 Hz, IH), 8.14 (s, IH), 7.54 (d, J=1.5 Hz, IH), 7.48 (d, J=15.6 Hz, IH), 7.32 (d, J=15.6 Hz, IH), 6.43 (s, IH), 4.98 (t, J=5.9 Hz, IH), 4.36 (d, J=8.8 Hz, IH), 4.12 (d, J=9.3 Hz, IH), 4.00 (d, J=9.3 Hz, IH), 3.91 (d, J=5.9 Hz, 2H), 3.84-3.58 (m, 5H), 3.30-3.20 (m, 2H), 3.02-2.86 (m, 2H), 2.44-2.32 (m, 2H); LC-MS: 480.1 (M+l)⁺.

Although the present application has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present application encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof. For example, the following compounds are also included in the scope of the present application

90

PHARMACOLOGICAL ACTIVITY:

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

The biological screening of the various fused pyridine 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 PROTO COL:

Compounds were evaluated for their potency to inhibit Staphylococcus aureus FabI in a spectropho to metric assay adapted from the reported protocol used by Kaplan et al., with some modifications [Kaplan N, Albert M, Awrey D, Bardouniotis E, Berman J, Clarke T, Dorsey M, Hafkin B, Ramnauth J, Romanov V, Schmid M.B, Thalakada R, Yethon J, 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 S. 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 <0.2 μΜ were grouped as 'a' , compounds exhibiting IC5₀ value in the range 0.21 μΜ to 0.4 μΜ were grouped as 'b' and the compounds exhibiting IC5₀ value >0.41 μΜ were grouped as 'c'.

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

MIC BY BROTH MICRODILUTION METHOD:

The in vitro antibacterial activity of compounds 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:

MSSA MRSA MRSE

6 0.06 0.06 0.12

50 0.015 0.015 0.015

66 0.12 0.12 0.12

21 0.12 0.12 0.25

13 0.5 0.5 1.0

23 0.25 0.25 0.25

62 0.06 0.06 0.12

63 0.06 0.06 0.06

25 0.25 0.25 0.5

14 0.12 0.12 0.12

51 0.03 0.03 0.06

12 0.25 0.25 0.5

35 0.12 0.12 0.25

In Vitro METABOLIC STABILITY IN MOUSE LIVER MICROSOMES:

In vitro metabolism of Compound-21 was studied in mouse liver microsomes to assess the metabolic stability at 1 μΜ concentration. The typical reaction mixture consists of incubation buffer (KH₂P04, pH 7.4), protein (liver microsomes, assay concentration: 0.3 mg/ml), NADPH (assay concentration: 1 mM) and test compound. Reaction was initiated by the addition of 20 μΐ of NADPH. Reaction mixture was incubated at 37 °C in a water bath. Reactions were terminated at designated time points (0, 15 and 60 min) by adding 100 μΐ_^ of acetonitrile containing internal standard (carbamazapine - 0.50 μg/ml) and contents were extracted by cyclomixing for 2 min. This mixture was centrifuged for 5 min at 13000 rpm and 180 μΐ of the clear supernatant was separated. An aliquot of 20 μΐ of the sample was injected onto LC-MS/MS for analysis. The percentage of parent remaining at the termination of reaction was quantified (Table-C).

In Vitro PROTEIN BINDING STUDIES: In vitro protein binding studies were conducted using the rapid equilibrium dialysis method. Compound-21 was prepared and spiked into blank mice plasma at 10 μΜ concentration. These spiked plasma samples were aliquoted (200 μΐ_^) in red chamber and blank buffer (350 μΐ_^) was taken in white chamber of RED inserts.

Equilibrium dialysis inserts were kept in a RED base plate and incubated on an orbital shaker at 37 °C for approximately 6 h at 200 rpm. Upon completion of the incubation, 50 μΕ of plasma samples was mixed with 50 μΕ of blank buffer and vice versa. These samples were analyzed for analyte area using LC-MS/MS. (Table-C).

Table-C: Summary of In vitro ADME studies of selected compounds

Pharmacokinetics of Compound-21 in male Swiss albino mice (CD-I):

To determine the pharmacokinetic parameters of test compounds in mice, male Swiss albino mice (CD-I) (n=8-9), weighing between 25 to 35 g were used in the study. The oral pharmacokinetics study was conducted under fasted condition (~4 h) and animals had free access to water. Test compound was administered by oral gavage at dose of 10 mg/Kg as a suspension. The excipients used for the formulation was 0.25 % Tween 80 and 0.225 % of sodium carboxy methyl cellulose. To determine the intravenous (i.v) pharmacokinetics, Compound-21 was administered to mice (n=9) under fed state as i.v injection via tail vein at 3 mg/Kg dose. The excepients used for the formulation was 5% DMSO and 20 % HPBCD in purified water.

Blood samples (0.25 ml) were collected from retro-orbital plexus at designated time points (sparse sampling, n=3 per time point) into micro centrifuge tubes containing 10 μΐ of EDTA and centrifuged at 13000 rpm for 4 min. The supernatant plasma was stored at -20 °C until analysis. The samples were analysed for test compound concentration using a suitable LC-MS/MS method. The pharmacokinetic parameters of test compound were calculated by non-compartmental analysis using WinNonlin Professional Version 5.2 and the results of the study were given in Table-D.

Table-D: Pharmacokinetics parameters of compound-21 in male Swiss albino (CD-I) mice

IN VIVO SYSTEMIC INFECTION MODEL:

The in vivo efficacy of compounds was evaluated following a literature procedure (Kaplan N, Albert M, Awrey D, Bardouniotis E, Berman J, Clarke T, Dorsey M, Hafkin B, Ramnauth J, Romanov V, Schmid MB, Thalakada R, Yethon J and Pauls HW. Mode of Action, In Vitro Activity, and In Vivo Efficacy of AFN-1252, a Selective Antistaphylococcal Fabl Inhibitor. Antimicrobial Agents and Chemotherapy 56 (11) p.5865-5874).

Female and male Swiss Albino mice, 4 - 6 weeks old, weighing 20 ± 2 g. were used in the study. Organisms were sub-cultured on Columbia blood agar (CBA) media and incubated at 35±2°Cfor 18-24 hours. Inoculum was prepared in NS and optical density (OD) adjusted at 560nm which corresponds to 1 - 2 x 10⁸ CFU/ mL with final mucin concentration of 5% (wt/vol) and 0.5 ml of inoculum was injected intra-peritoneally in to each mice. Two groups of mice left untreated, serve as control (UTC). NCEs (New chemical entities) / standard antibiotics were formulated in Tween 80 + 0.25 % CMC or specified formulations for oral administration.NCEs/ antibiotics were administered as bid. at 0 to 5h post infection. End pointwas determined by survival / death in each treated and untreated groups, animals were monitored for 5 days and the ED50's were calculated by Probit analysis.

Some of the compounds of the invention/examples display good in vivo efficacy properties and protected mice from infection as measured by percentage survival.

Claims

We claim:

1. A compound of formula ( 1) :

wherein;

P-Q is a linker selected from -C-, -C-C-, -C-N-, -N-C-, -C-C-C-, -N-C-C-, -C-N-C-,

-C-C-N-, -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;

or two of the R5 groups on the same atom or on the adjacent atoms combined together to form an optionally substituted 3-8 membered spiro/ fused ring containing 0-3 hetero atoms/heterogroups independently selected form N, O, S, C(O), NH, S(O) and S(0)2, wherein the optional substituent is independently selected from one or more R₆;

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

at each occurance 'p' is an integer selected from 0, 1, 2 and 3; or pharmaceutically acceptable salts thereof or pharmaceutically acceptable stereoisomers thereof.

2. The compound of claim 1 wherein the compound of formula (1) is a compound of formula (la) to (lj):

wherein, independently for each occurrence Ri, R₂, R3, R5 and 'n' are same as defined in claim 1.

wherein, 'q' is an integer selected from 0, 1 and 2; and R4 independently for each occurrence is same as described in claim 1.

4. The compound of claim 1 , wherein R4 is alkoxy and alkyl.

5. The compound of claim 1 , wherein Ri, R₃ and R4 are hydrogen. pound of claim 1, wherein R5 is hydrogen, alkyl,

and

7. The compound of claim 1 , wherein two of the R5 groups on the same atom combined together to form an optionally substituted 3-7 membered sipro ring containing 0-3 heteroatoms or heterogroups selected from O, N and C(O); wherein the optional substituent is independently selected from one or more R6.

10. A compound according to claim 1 is compound of Formula (lb)

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

11. The compound of claim 10, wherein Ri is hydrogen.

12. The compound of claim 10, wherein R₂ is

in which Ring A is thiazole and 'p' is 0.

13. The compound of claim 10, wherein each R5 is alkyl preferably methyl.

14. The compound of claim 10, wherein both the R5 groups together with the carbon to which they are attached to form a 3-7-membered spiro ring optionally containing heteroatoms or groups selected from CO, NH or O.

15. A compound selected from the group consisting of

Comp

IUPAC Name

No.

10 (E)-6-(3-(4-((5-methylthiazol-2-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-3 ,4-di ydro- 1 ,8-naphthyridin-2(l H)-one;

11 (E)-3,3-dimethyl-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l- en-l-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one;

12 (E)-3,3-dimethyl-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l- en-l-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one;

(E)-8-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]diazepin-4(5H)-one;

(E)-7-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- l-yl)-3,5- dihydropyrido [2,3 -e] [1 ,4]oxazepin-2(lH)-one;

(E)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)-l'H- spiro [cyclopropane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one; (E)-tert-butyl 2'-oxo-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop- l-en-l-yl)-2 4'-dihydro-l 'H-spiro[azetidine-3,3'-[l,8]naphthyridine]-l- carboxylate;

(E)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop-l -en- 1-yl)- 1H- spiro[[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one 2,2,2-trifluoroacetate;

(E)-l'-(2-hydroxyacetyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)-lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one; (E)- 1 '-(furan-2-carbonyl)-6-(3-oxo-3 -(4-(thiazol-4-ylmethylene)piperidin- 1 - yl)prop-l-en-l-yl)-lH-spko[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one;

(E)-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)spiro

77

[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one;

(E)-6-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l-

78

yl)-3,3-dimethyl-3,4-dihydro-l ,8-naphthyridin-2(lH)-one;

(E)-3-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l-

79

yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

(E)-l-(2-hydroxyacetyl)-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-

80

yl)prop-l-en-l-yl)-l'H-spiro[azetidine-3,3'-[l,8]naphthyridin]-2'(4'H)-one;

81 (E)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop-l -en- 1-yl)- 1H- spiro [[1,8] naphthyridine- 3 ,3 '-oxetan] -2(4H) -one ;

82 (E)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop-l -en- 1-yl)- 1H- spiro [[1,8] naphthyridine- 3 ,3 '-oxetan] -2(4H) -one ;

83 (E)-6-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-lH-spiro[[l,8]naphthyridine-3,3'-oxetan]-2(4H)-one;

84 (E)-6-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)-lH- spiro [[1,8] naphthyridine- 3 ,3 '-oxetan] -2(4H) -one ;

85 (E)-6-(3-(4-(oxazol-2-ylrnethylene)piperidin-l -yl)-3-oxoprop-l-en-l-yl)-lH- spiro [[1,8] naphthyridine- 3 ,3 '-oxetan] -2(4H) -one ;

86 (E)-6'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-3,3-difluoro-l 'H-spiro[cyclobutane-l ,3'-[l ,8]naphthyridin]-2'(4'H)-one;

87 (E)-3,3-dilluoro-6'-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l- en-l-yl)-l 'H-spiro[cyclobutane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one;

88 (E)-3,3-dilluoro-6'-(3-(4-(oxazol-2-ylmethylene)piperidin-l -yl)-3-oxoprop-l-en- l-yl)-l'H-spiro[cyclobutane-l ,3'-[l ,8]naphthyridin]-2'(4'H)-one;

89 (E)-6,6-dilluoro-3-(3-oxo-3 -(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop- 1 -en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

90 (E)-3-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-6,6-difluoro-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

91 (E)-6,6-dilluoro-3-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l- en-l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

92 (E)-6,6-dilluoro-3-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one; 93 (E)-6,6-dilluoro-3-(3-oxo-3 -(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop- 1 -en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

94 (E)-l-(2-hydroxyacetyl)-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)spko[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one;

95 (E)-l-acetyl-6'-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en- l-yl)-l'H-spiro[azetidine-3,3'-[l,8]naphthyridin]-2'(4'H)-one;

96 (E)-6'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-l -acetyl- l'H-spiro[azetidine-3,3'-[l ,8]naphthyridin]-2'(4'H)-one;

97 (E)-6'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-l-(2-hydroxyacetyl)-l H-spko[azetidine-3,3'-[l,8]naphthyridin]-2'(4'H)-one;

98 (E)-l-(2-hydroxyacetyl)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)-l'H-spiro[azetidine-3,3'-[l,8]naphthyridin]-2'(4'H)-one;

99 (E)-l-(2-hydroxyacetyl)-6'-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3- oxoprop-1 -en- 1 -yl)- 1 Ή-spiro [azetidine-3,3'- [1 ,8 ]naphthyridin]-2'(4'H)-one;

100 (E)-7,7-dilluoro-3-(3-oxo-3 -(4-(thiazol-4-ylmethylene)piperidin- 1 -yl)prop- 1 -en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

101 (E)-7,7-dilluoro-3-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en- l-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

102 (E)-3-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-7,7-difluoro-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one;

103 (E)-5'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)spiro[oxetane-3,3'-pyrrolo[2,3-b]pyridin]-2'(l 'H)-one;

104 (E)-5'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)spiro [oxetane-3,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

105 (E)-5'-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)spiro [oxetane-3,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

106 (E)-5'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l -en-l-yl)spiro [oxetane-3,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

107 (E)- 1 -acetyl- 5 '-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin- 1 -yl)prop- 1 -en- 1 - yl)spiro [piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

108 (E)-l-(2-hydroxyacetyl)-5'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l- yl)prop-l-en-l-yl)spko[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one;

109 (E)-6'-(3-(4-(isothiazol-3-ylmethylene)piperidin- 1 -yl)-3-oxoprop- 1 -en- 1 -yl)- 1 Ή- spiro [cyclobutane-l,3'-[l ,8]naphthyridin]-2'(4'H)-onel;

110 (E)-l'-(2-hydroxyacetyl)-6-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3- oxoprop-l-en-l-yl)-lH-spiro[[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one;

111 (E)-6'-(3-(4-(isothiazol-3-ylmethylene)piperidin- 1 -yl)-3-oxoprop- 1 -en- 1 -yl)- 1 Ή- spiro[cyclopropane-l,3'-[l ,8]naphthyridin]-2'(4'H)-one;

113 (E)-6-(3-(4-(isothiazol-3-ylmethylene)piperidin-l-yl)-3-oxoprop-l-en-l-yl)- 2',3',5',6'-tetrahydro-lH-spiro[[l ,8]naphthyridine-3,4'-pyran]-2(4H)-one;

116 (E)-6'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-l'H-spiro[cyclobutane-l,3'-[l,8]naphthyridin]-2'(4'H)-one;

117 (E)-5'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-l-acetylspiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one;

118 (E)-6'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-l'H-spiro[cyclopropane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one;

119 (E)-5'-(3-(4-((l,2,4-thiadiazol-3-yl)methylene)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-l-(2-hydroxyacetyl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(l 'H)-one and

120 (E)-l-(2-hydroxyacetyl)-5'-(3-(4-(oxazol-2-ylmethylene)piperidin-l-yl)-3- oxoprop-l-en-l-yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'( H)-one; or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.

16. A compound selected from the group consisting of

(E)-3,3-dimethyl-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l-en-l- yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one,

(E)-6'-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-l'H-spiro [cyclopro pane-l ,3'-[l,8] naphthyridin]-2'(4'H)-one, (E)-6'-(3-oxo-3-(4-(tMazol-4-ylmethylene)piperidin-l -yl)prop-l-en-l-yl)-l'H-spiro [cyclopro pane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one,

(E)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-2',3',5',6'- tetrahydro-lH-spiro[[l ,8]naphthyridine-3,4'-pyran]-2(4H)-one,

(E)- -(2-hydroxyacetyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l -yl)prop- l-en-l-yl)-lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one,

(E)- -(2-hydroxyacetyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l -yl)prop- 1 -en- l-yl)-l H-spiro [[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one,

(E)- -(furan-2-carbonyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethylene)piperidin-l-yl) prop-l-en-l-yl)-lH-spko[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one,

(E)-6'-(3-oxo-3-(4-(tMazol-2-ylmethylene)piperidrn-l -yl)prop-l-en-l-yl)-l'H- spiro[azepane-4,3'-[l,8]naphthyridine]-2',7(4'H)-dione,

(E)-3-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l-en-l-yl)-6,7- dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one,

(E)-4,4-difluoro-6'-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop-l-en-l - yl)-l'H-spiro[cyclohexane-l ,3'-[l,8]naphthyridin]-2'(4'H)-one,

(E)- -(iuran-2-carbonyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin-l-yl)prop- l-en-l-yl)-lH-spiro[[l ,8]naphthyridine-3,4'-piperidin]-2(4H)-one,

(E)-l'-(5-methylfuran-2-carbonyl)-6-(3-oxo-3-(4-(thiazol-4-ylmethylene)piperidin- l-yl)prop-l -en-l-yl)-lH-spiro[[l,8]naphthyridine-3,4'-piperidin]-2(4H)-one

(E)-l'-(5-nitrofuran-2-carbonyl)-6-(3-oxo-3-(4-(tMazol-4-ylmethylene)piperidin-l - yl)prop-l-en- 1 -yl)- lH-spiro[[l ,8]naphthyridine-3 ,4'-piperidin]-2(4H)-one; and

pharmaceutically acceptable salts thereof or pharmaceutically acceptable stereoisomers thereof.

17. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (1) according to any of claim 1 to 16, their pharmaceutically acceptable salts and stereoisomers, in admixture with at least one pharmaceutically acceptable carrier or excipient including mixtures thereof in all ratios, for use as a medicament.

18. A method of treating bacterial infections which comprises administering to a subject in need thereof an effective amount of a compound according to any of claim 1 to 16.

19. A method for inhibiting FabI which comprises administering to a subject in need thereof an effective amount of a compound according to any of claim 1 to 16.

20. A compound according to any of claim 1 to 16, for use in the treatment of bacterial infections in animals including humans.

21. Use of a compound according to any of claim 1 to 16, in the manufacture of a medicament for use in the treatment of bacterial infections in animals including humans.