Dihydrochromeno-pyrrole compounds as metallo-beta-lactamase inhibitors and a process for the preparation thereof

Abstract

The invention relates to 1,4-dihydrochromeno[4,3-b]pyrrole derivatives of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions wherein, R1, R2, R3, R4, and 'n' defined herein. The present invention also relates to compositions which comprise a metallo-β-lactamase (MBL) inhibitor compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, optionally in combination with a beta-lactam antibiotic and / or a beta-lactamase inhibitor. The invention further relates to methods for treating a bacterial infection comprising administering to a patient a therapeutically effective amount of a compound of the invention, in combination with a therapeutically effective amount of one or more β-lactam antibiotics. The compounds of the invention are useful in the methods described herein for reducing or overcoming antibiotic resistance.

Description

[0001] DIHYDROCHROMENO-PYRROLE COMPOUNDS AS METALLO-BETA-LACTAMASE INHIBITORS AND A PROCESS FOR THE PREPARATION THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to dihydrochromeno -pyrrole compound of formula (I), stereoisomer or pharmaceutically acceptable salts thereof and pharmaceutical compositions. Particularly, present invention relates to the compound of formula I useful as metallo-P-lactamase (MBL) enzyme inhibitors. The development of such molecules can aid in the fight against antibiotic -resistant microorganisms in combinations with beta-lactam antibiotic / s. More particularly, present invention also relates to a process for the preparation of the compound of formula I.

[0004] Formula I

[0005] BACKGROUND OF THE INVENTION

[0006] Multidrug-resistant (MDR) organisms cause infections and their mortality rate is high as compared to infections caused by susceptible bacteria. Thousands of people are dying due to the infections caused by antibiotic-resistant organisms. Moreover, a recent report predicted that antibiotic resistance might be causing 300 million premature deaths by 2050. Resistance has emerged to all the known antibiotics resulting in increased infections that are untreatable and there is no alternative antibiotic. Despite the numerous successes of the P-lactam antibiotics, bacteria have developed resistance to them and most troubling reason is P-lactamases, the bacterial enzyme. They react with antibiotics and hydrolyse the P -lactam ring, which results in inactivation of beta Lactam antibiotics. Among Gram-negative bacteria, there are four classes of beta-lactamases, the serine P-lactamases (SBLs) of the classes A, C and D, and the MBLs (class B). SBL enzymes uses active serine present in its catalytic site to hydrolyse P-lactam rings in a covalent mechanism whereas MBL enzymes requires Zn metal which helps in coordination and a hydroxide ion to hydrolyse the P-lactam ring. The zinc-dependent class B metallo- p -lactamases are represented mainly by the NDM, VIM, and IMP types. IMP and VIM-producing K. pneumonia were first observed in 1990s in Japan and 2001 in Southern Europe, respectively. IMP- positive strains remain frequent in Japan and have also caused hospital outbreaks in China and Australia. However, dissemination of IMP-producing Enterobacteriaceae in the rest of the word appears to be somewhat limited. VIM producing enterobacteria can be frequently isolated in Mediterranean countries, reaching epidemic proportions in Greece. Isolation of VIM - producing strains remains low in Northern Europe and in the United States. In stark contrast, a characteristic of NDM - producing K. pneumonia isolates has been their rapid dissemination from their epicentre, the Indian subcontinent, to Western Europe, North America, Australia and Far East. Moreover, NDM genes have spread rapidly to various species other than K. pneumonia. To overcome the problem of increasing resistance, the need of the hour is to develop new compounds like inhibitors of P-lactamases which can enhance the efficacy of previously available antibiotics and are potent for both serine as well as MBLs.

[0007] Jurgen Brem et al in ‘Nature Chemistry, (2022), 14, 15-24,’ and W02018215800 discloses indole-2- carboxylates as metallo- P -lactamase inhibitors.

[0008] Mihirbaran Mandal et al in ‘J. Med. Chem, (2022), 65, 16234-16251 and WO2019135920’, discloses sulfonamides as pan-MBL inhibitors.

[0009] WO2022254464A1 disclose the compounds substituted tricyclic compounds related to metallo- P- lactamase inhibitors.

[0010] OBJECTIVE OF THE INVENTION

[0011] The main objective of the present invention is to provide dihydrochromeno-pyrrole compound of formula (I), stereoisomer or pharmaceutically acceptable salts thereof.

[0012] Yet another objective of the present invention is to provide a pharmaceutical composition comprising dihydrochromeno-pyrrole compound of formula (I).

[0013] Another objective of the present invention is to provide compound of formula I useful as metallo- P - lactamase (MBL) enzyme inhibitors.

[0014] Yet another objective of the present invention is to provide a process for the preparation of the compound of formula I.

[0015] SUMMARY OF THE INVENTION

[0016] The present invention provides a dihydrochromeno-pyrrole compound of formula (I), stereoisomer or pharmaceutically acceptable salts thereof, pharmaceutical compositions and a process for the preparation thereof.

[0017] Formula I

[0018] The present invention further relates to the compound of formula I useful as metallo- P -lactamase (MBL) enzyme inhibitors. The development of such molecules can aid in the fight against antibioticresistant microorganisms in combinations with beta-lactam antibiotic / s.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Fig. 1 represents the process steps for the preparation of compound of formula 6.

[0021] Fig. 2 represents the alternative process steps for the preparation of compound of formula 6.

[0022] Fig. 3 represents the process steps for the preparation of compound of formula I

[0023] DETAILED DESCRIPTION OF THE INVENTION

[0024] Accordingly, present invention provides dih drochromeno-pyrrcde compound of formula (I), pharmaceutically acceptable salts thereof.

[0025] Formula I wherein Ri, which may be same or different at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -C(O)ORe, -OC(O)ORe, -O(CRaRb)r- C(O)ORe, -(CRaRb)r-C(O)ORe, -C(O)Rh, NRfRg, -C(O)NRfRg, -NRfC(O)Rh, - NRfS(O)2Rg, -S(0)o-2Re, and-S(O)2NRfRg,

[0026] 'n' is an integer ranging from 0 to 5, both inclusive;

[0027] R2and R3, which may be same or different at each occurrence, are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; R4 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle; wherein preferred substitution is independently selected from the group consisting of halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -C(O)ORe, -OC(O)ORe, -O(CRaRb)r-C(O)ORe, -(CRaRb)r-C(O)ORe, - C(O)Rh, NRfRg, -C(O)NRfRg, -NRfC(O)Rh, - NRfS(O)2Rg, -S(0)o-2Re, and-S(O)2NRfRg;

[0028] Raand Rb, which may be same or different at each occurrence, are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; or Raand Rb together with the carbon atom to which they are attached, may form an unsubstituted or substituted 3 to 7 membered saturated carbocyclic ring;

[0029] Re, which may be same or different at each occurrence, is independently selected from the group consisting of hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted alkyl;

[0030] Rf and Rg, which may be same or different at each occurrence, are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, -(CRaRb)r-C(O)ORe, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or Rf and Rgtogether with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3 to 10 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; at each occurrence, Rh is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;

[0031] 'r' is an integer ranging from 1 to 3, both inclusive

[0032] Rs is selected from the group consisting of

[0033] (i) -OH;

[0034] (ii) -NRiRm, wherein Ri and Rmare independently selected at each occurrence from hydrogen, unsubstituted or substituted alkyl, and unsubstituted or substituted cycloalkyl; methoxy; or Ri and Rmtogether with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;

[0035] (iii) -ORn, wherein Rnis selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl, C1-2 alkyl, aryl, aryl-Ci-2alkyl, heteroaryl, heteroaryl-Ci-2alkyl, heterocyclyl or heterocyclyl-Ci-2alkyl, each of which is optionally substituted by one or more substituent groups; (iv) -Ro, wherein Rois independently selected at each occurrence from thegroup consisting of hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl.

[0036] In yet another embodiment of the present invention, the compound is in free form, salt form or in pharmaceutically acceptable salt form.

[0037] In yet another embodiment, present invention provides a zwitterion of the compound of formula I.

[0038] In yet another embodiment of the present invention, compound of formula I is selected from the group consisting of: i. methyl 3-(3,5-dichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate [1]; ii. 3-(3,5-dichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; iii. 3-phenyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; iv. methyl 3-(5-chloro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; v. methyl 3-(3,4-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; vi. methyl 3-(4-(tert-butyl)phenyl)- 1 ,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; vii. methyl 3-(2-methoxyphenyl)- 1 ,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; viii. methyl 3-(4-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; ix. methyl 3-(3-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; x. methyl 3-(2-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xi. methyl 3-(2-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xii. methyl 3-(3-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xiii. methyl 3-(4-chlorophenyl)- 1 ,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate xiv. methyl 3-(pyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xv. methyl 3-(pyridin-4-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xvi. methyl 3-(3,5-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xvii. methyl 3-(3,5-dimethylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xviii. methyl 3-(2-fluoro-4-methylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xix. methyl 3-(3-chloro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xx. methyl 3-(3-chloro-5-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xxi. methyl 3-(5-fluoro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xxii. methyl 3-(3,5-dimethoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxiii. methyl 3-(3-chloro-5-methylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xxiv. methyl 3-(3-(trifluoromethyl)phenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xxv. methyl 3-(4-(dimethylcarbamoyl)phenyl)- 1 ,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xxvi. methyl 3-(2,3-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxvii. methyl 3-(2,3-dimethoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxviii. methyl 3-(4-fluoro-2-methylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xxix. methyl 3-(4-fluoro-2-methoxyphenyl)- l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xxx. methyl 3-(3-fluoro-4-methoxyphenyl)- l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xxxi. methyl 3-(3-fluoro-5-methoxyphenyl)- l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xxxii. methyl 3-(5-fluoropyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxxiii. methyl 3-(5-chloropyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxxiv. methyl 3-(3,4,5-trifluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxxv. methyl 3-(3,4,5-trichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxxvi. methyl 8-fluoro-3-(3-fluoro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-

[0039] 2-carboxylate; xxxvii. methyl 3-(3-chloro-5-methoxyphenyl)-8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-

[0040] 2-carboxylate; xxxviii. methyl 3-(5-chloro-2-methoxyphenyl)-8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-

[0041] 2-carboxylate; xxxix. methyl 3-(3-chloro-5-methoxyphenyl)-8-methyl-l,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate; xl. methyl 3-(3-chloro-5-methoxyphenyl)-7-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate; xli. methyl 4,4-dimethyl-3-phenyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xlii. 3-(5-chloro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; xliii. 3-(3,4-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; xliv. 3-(4-(tert-butyl)phenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; xlv. 3-(2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; xlvi. 3-(4-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; xlvii. 3-(3-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; xlviii. 3-(2-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; xlix. 3-(2-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0042] 1. 3-(3-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; li. 3-(4-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; lii. 3-(pyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; liii. 3-(pyridin-4-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; liv. 3-(3,5-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0043] Iv. 3-(3,5-dimethylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0044] Ivi. 3-(2-fluoro-4-methylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0045] Ivii. 3-(3-chloro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0046] Iviii. 3-(3-chloro-5-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; lix. 3-(5-fluoro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; lx. 3-(3,5-dimethoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0047] Ixi. 3-(3-chloro-5-methylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0048] Ixii. 3-(3-(trifluoromethyl)phenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0049] Ixiii. 3-(4-(dimethylcarbamoyl)phenyl)- 1 ,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0050] Ixiv. 3-(2,3-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0051] Ixv. 3-(2,3-dimethoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0052] Ixvi. 3-(4-fluoro-2-methylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0053] Ixvii. 3-(4-fluoro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0054] Ixviii. 3-(3-fluoro-4-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0055] Ixix. 3-(3-fluoro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0056] Ixx. 3-(5-fluoropyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0057] Ixxi. 3-(5-chloropyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0058] Ixxii. 3-(3,4,5-trifluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;

[0059] Ixxiii. 3-(3,4,5-trichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; Ixxiv. 8-fluoro-3-(3-fluoro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;

[0060] Ixxv. 3-(3-chloro-5-methoxyphenyl)-8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;

[0061] Ixxvi. 3-(5-chloro-2-methoxyphenyl)-8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;

[0062] Ixxvii. 3-(3-chloro-5-methoxyphenyl)-8-methyl-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;

[0063] Ixxviii. 3-(3-chloro-5-methoxyphenyl)-7-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;

[0064] Ixxix. 4,4-dimethyl-3-phenyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid.

[0065] In yet another embodiment, present invention provides a process for the preparation of compound of formula I as claimed in claim 1 comprising the steps of: i. reducing a tetralone of formula (1) using reducing agents such as sodium borohydride to obtain a compound of formula (2);

[0066] (1) (2) ii. formylation of the compound of formula (2) as obtained in step (i) using in-situ prepared Vilsmeier Haack reagent / adduct to obtain aldehyde of formula (3); iii. treating aldehyde of formula (3) as obtained in step (ii) with an azido ester compound of formula (4) in the presence of a base selected from sodium ethoxide or sodium methoxide to give compound of formula (5); iv. cyclization of compound of formula (5) as obtained in step (iii) in a presence of Lewis acid or in acidic condition to obtain a compound of formula (6); v. converting a compound of formula (8) in the presence of DIPEA, TEA, pyridine etc and pyrrolidine with a ketone of formula (9) to substituted chromanone of formula (10);

[0067] (8) (9) (10) vi. treating ketone of formula (10) as obtained in step (v) with a derivative of hydroxylamine to give a oxime of formula (11); vii. o-alkylation of oxime group of compound (11) with alkyl propionate in presence of trimethylamine to give a compound of formula (13); viii. cyclization of compound of formula (13) in the presence of acidic condition to obtain a compound of formula (6); ix. halogenating the compound of formula (6) as obtained in step (iv) and (viii) using halogenated reagents selected from N-bromo succinimide (NBS) or N-iodosuccinimide (NIS) to give a halogenated compound of formula (7); x. coupling reaction of the halogenated compound of formula (7) with aryl / heteroaryl boronic acids or aryl / heteroaryl boronic esters to obtain a compound of Formula (la); xi. converting compound of Formula (la) as obtained in step (x) to compound of Formula (I) by hydrolysis of corresponding ester using base selected from the group consisting of LiOH, K2CO3, NaOH or KOH.

[0068] In yet another embodiment, present invention provides a pharmaceutical composition comprising: at least one compound of formula (I); and at least one pharmaceutically acceptable excipient. In yet another embodiment of the present invention, pharmaceutically acceptable excipients are selected from the group consisting of water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerytritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.

[0069] In yet another embodiment of the present invention, said composition further comprises an effective amount of a beta-lactam antibiotic / s.

[0070] In yet another embodiment of the present invention, said composition is for use as a beta-lactamase inhibitor, against both serine and metallo-beta-lacatamses or in combination with other betalactamases inhibitors or as a drug.

[0071] In yet another embodiment, present invention provides use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for inhibiting beta-lactamase activity, in the manufacture of a medicament for inhibiting beta-lactamase activity, in combination with a beta-lactam antibiotic for treating a bacterial infection, or in combination with a beta-lactam antibiotic in the manufacture of a medicament for treating a bacterial infection.

[0072] The process for the preparation of compound of formula 6 is depicted in Figure 1 starting from commercially available tetralone of formula (1). Thus, chromanone of formula (1) undergoes reduction using suitable reducing agents such as sodium borohydride to give a compound of formula (2). The compound of formula (2) undergoes formylation using in-situ prepared Vilsmeier Haack reagent / adduct to give compound of formula (3). Further, this aldehyde of formula (3) treated with an azido ester compound of formula (4) in the presence of a base such as sodium ethoxide, sodium methoxide etc. to give compound of formula (5). The compound of formula (5) undergoes cyclization to get the compound of formula (6) in the presence of suitable Lewis acid or in acidic condition.

[0073] The alternative process for the preparation of compound of formula 6 is depicted in Figure 2 starting from commercially available l-(2-hydroxyphenyl)ethan-l-one of formula (8). The compound of formula (8) in the presence of base such as DIPEA, TEA, pyridine etc and pyrrolidine with a ketone of formula (9) converted to substituted chromanone of formula (10). Chromanone of formula (10) treated with a derivative of hydroxylamine to give an oxime of formula (11). Compound (11) undergoes O-alkyation with alkyl propionate in presence of trimethylamine to give compound of formula (13). The compound of formula (13) undergoes cyclization to get the compound of formula (6) in the presence of acidic conditions. The process for the preparation of compound of formula I is depicted in Figure 3 starting from compound of formula 6. The compound of formula (6) undergoes halogenation using halogenated reagents such as NBS, NIS, etc. to give the halogenated compound of the formula (7). This halo compound of formula (7) undergoes coupling reaction with suitable aryl / heteroaryl boronic acids or aryl / heteroaryl boronic esters to give compound of Formula (la). Further, compound of Formula (la) is converted to compound Formula (I) by hydrolysis of corresponding ester using base such as LiOH, K2CO3, NaOH etc. In acid of formula (I) can be converted -COOH into corresponding amide, ester etc.

[0074] The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine. The term "alkyl" refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, for example C1-6 alkyl or C1-6 alkyl, representative groups include e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pcntyl and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched. The term "alkenyl" refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting Examples of alkenyl groups include, for example C2-6 alkenyl, C2-4 alkenyl, ethenyl, 1-propenyl, 2-propenyl (allyl), and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched.

[0075] The term "alkynyl" refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond. Non- limiting Examples of alkynyl groups include, for example C2-6 alkynyl, C2-4 alkynyl, ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched.

[0076] The term "haloalkyl" refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above. For example C 1-6 haloalkyl or C1-4 haloalkyl. Suitably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Suitably, a polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting Examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed herein may be straight chain or branched.

[0077] The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH3 and -OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.

[0078] The term "alkoxyalkyl" refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2-O-CH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3 and the like.

[0079] The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as C3-10 cycloalkyl, C3-6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronaphththyl, adamantyl and norbornyl groups, bridged cyclic groups or Spiro bicyclic groups, e.g., spiro(4,4)non- 2-yl and the like.

[0080] The term "aryl" refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like.

[0081] The term "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl", unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quatemized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond, and one or two carbon atoms / in the heterocyclic ring or heterocyclyl may be interrupted with -CF2-, -C(O)-, -S(O)-, S(O)2 etc. In addition, heterocyclic ring may also be fused with aromatic ring. Non-limiting Examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfoneindoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran and the like. The heterocyclic ring may be attached by any atom of the heterocyclic ring that results in the creation of a stable structure. The term "heteroaryl" unless otherwise specified, refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more heteroatom / s independently selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring may be attached by any atom of the heteroaryl ring that results in the creation of a stable structure. Non-limiting Examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like.

[0082] The term "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the disease, disorder or condition or at least one of its clinical or subclinical symptoms or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0083] The term "inhibitor" refers to a molecule that binds to an enzyme to inhibit the activity of the said enzyme either partially or completely.

[0084] The term “effective amount” refers to the amount of each active agent required to confer the desired effect (e.g., inhibiting MBL) on the subject, either alone or in combination with one or more other active agents. An effective amount varies, as recognized by those skilled in the art, depending on the particular condition being treated, the severity of the condition, the individual patient parameters including age, size, physical condition, weight, and gender, the nature of concurrent therapy (if any), the duration of the treatment, the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0085] A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, disorder or condition, is sufficient to cause the effect in the subject, which is the purpose of the administration. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

[0086] Pharmaceutically Acceptable Salts

[0087] The compounds of the invention may form salts with acid or base. The compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic acid addition salts formed by addition of acids including hydrochloride salts. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases. The compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting sufficiently basic compound such as an amine with a suitable acid.

[0088] Screening of the compounds of invention for MBL inhibitory activity can be achieved by using various in-vitro mentioned herein below or methods known in the art.

[0089] Pharmaceutical Composition

[0090] The invention relates to pharmaceutical compositions containing the compounds of the formula (I), or pharmaceutically acceptable salts thereof disclosed herein. In particular, pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to inhibit MBL to treat the diseases described herein when administered to a subject.

[0091] The subjects contemplated include, for example, a living cell and a mammal, including human. The compound of the invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. The pharmaceutically acceptable excipient includes pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.

[0092] In the formulation if you are using biological material, as mentioned above, provide source and origin of all and file form III for permission from NBA.

[0093] The pharmaceutical compositions described herein may be prepared by conventional techniques known in the art. For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for Example, in a sachet. The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, caplets, orally disintegrating tablets, aerosols, solutions, suspensions or products for topical application.

[0094] The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, oral inhalation, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).

[0095] Solid oral formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatin), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and / or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin and sterile injectable liquids, such as aqueous or non- aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

[0096] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, caplet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0097] For administration to subject patients, the total daily dose of the compounds of the invention depends, of course, on the mode of administration. For example, oral administration may require a higher total daily dose, than an intravenous (direct into blood). The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg by oral administration and 1 pg to 5000 pg by inhalation according to the potency of the active component or mode of administration.

[0098] Those skilled in the relevant art can determine suitable doses of the compounds for use in treating the diseases and disorders described herein. Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient. For example, the daily dosage of the MBL inhibitor can range from about 0.1 to about 30.0 mg / kg by oral administration. Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications envisioned are within the scope of the invention.

[0099] Methods of Treatment

[0100] The invention provides compound of formula (I) and pharmaceutical compositions thereof as MBL inhibitors for treating the diseases, disorders or conditions associated with antimicrobial resistance (AMR). The invention further provides a method of treating diseases, disorders or conditions associated with antimicrobial resistance in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the invention.

[0101] In another aspect, the invention relates to a method of treating diseases, disorders or conditions associated with MBL, AMR, antibacterial. In this method, a subject in need of such treatment is administered a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein.

[0102] Present invention encompasses the compounds of formula (I) or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease or disorder mentioned herein.

[0103] Examples

[0104] Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

[0105] Intermediate 1: Preparation of Methyl 3-iodo-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0106] Step 1: Preparation of chroman-4-ol

[0107] NaBFL (3.88 g, 102.61 mmol) was added to a stirred solution of chroman-4-one (2 g, 13.5 mmol) in methanol (25 mL). The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure. To this reaction mixture, water was added (15 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phase was washed with brine solution (20 mL), dried over Na2S04 and filtered. The organic layer was concentrated to get crude compound. The crude compound was purified by flash column chromatography (Biotage) using eluent (1:9, ethyl acetate: n-hcxanc) to get the titled compound (1.95 g, 97% yield) as a pale yellow oil. LCMS (ESI): m / z = 149.0 (M)“.

[0108] Step 2: Preparation of 2H-chromene-3-carbaldehyde

[0109] To a stirred solution of chroman-4-ol (1.95 g, 13.6 mmol) in DMF (4.87 mL), POCI3 (3.02 mL) was added dropwise at 0 °C and stirred for one hour. The reaction mixture was allowed to rise at room temperature and stirred for another one hour. Further, the stirred solution was heated at 100 °C for overnight. The reaction mixture was quenched at room temperature with water and basified with 3M NaOH. The reaction mixture was extracted with ethyl acetate (3 x 30 mL), washed with brine solution, dried over Na2S04, and concentrated to get the crude compound. The crude compound was purified by flash column chromatography (Biotage) using eluent (1:9, ethyl acetate: n-hexane) to get the 2H- chromene-3-carbaldehyde (0.737g, 35% yield) as a pale yellow oil.

[0110] Step 3: Preparation of methyl (Z)-2-azido-3-(2H-chromen-3-yl)acrylate

[0111] A round bottomed flask purged and maintained with an inert atmosphere was charged with 2H- chromene-3-carbaldehyde (1 g, 4.37mmol), methyl azidoacetate (1.26g g, 10.93 mmol, 1.06 mL) in dry MeOH (15mL) at -15 °C. After 15 minutes to the stirred mixture, a solution of NaOMe (2.2 mL) in MeOH (5.6 mL) was added dropwise over 20 min and stirred at -15 °C for 90 min. Further, slowly warmed to 4 °C and stirred for 12 h. The reaction mixture was then poured into ice-cold saturated aqueous NH4CI (20 mL). The resulting precipitate was isolated on a fritted funnel and washed with deionized water until the filtrate came through clear. The solid was dissolved in DCM and dried over Na2SO4. The organic phase was filtered and evaporated in vacuo to get crude compound. The crude compound was purified by flash column chromatography (Biotage) using eluent (1:9, ethyl acetate: n- hexane) to get the methyl (Z)-2-azido-3-(2H-chromen-3-yl)acrylate as an oil with trace cyclized compound, which was further taken for next reaction.

[0112] Step 4: Preparation of methyl l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0113] To a stirred solution of methyl (Z)-2-azido-3-(2H-chromen-3-yl)acrylate (689 mg, 2.68 mmol) in DCM (4 mL), ZnL (42 mg, 0.134 mmol ) was added slowly and stirred overnight at room temperature. The resulting solution was filtered through a pad of Celite and concentrated under vacuum to get the crude compound. The crude compound was purified by flash column chromatography (Biotage) using eluent (2:8, ethyl acetate: n-hcxanc) to get the methyl l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate (440 mg, 71% yield) as a yellowish solid. LCMS (ESI): m / z = 230.0 (M+H)+.

[0114] Step 5: Preparation of methyl 3-iodo-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0115] To a stirred solution of methyl l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate (420 mg, 1.83 mmol) in DMF (7 mL) was added A odosuccinamide (453.3 mg, 2.02 mmol). The resulting mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The crude mixture was dissolved in DCM and washed with sat. NaHCOs. The organic extracts were dried over Na2S04, filtered and concentrated in vacuo. The crude compound was purified by column chromatography (Biotage) using eluent (2:8, ethyl acetate: n-hexane) to get the methyl 3-iodo-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate (506 mg, 77% yield) as a brown solid. LCMS (ESI)’: m / z = 354.1, 355.1.

[0116] Example 1: Preparation of methyl 3-(3,5-dichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate

[0117] To a solution of methyl 3-iodo-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate (200 mg, 0.57 mmol), 3,5-dichlorophenylboronic acid (130g, 0.68 mmol) in 1,4-dioxane (5.5 mL), aqueous NaiCOs (120.82 mg, 1.14 mmol in 1.5 mL H2O) was added at 25 °C in a sealed tube and nitrogen gas was bubbled through the reaction mixture for 15 minutes. To this [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) was added, packed tightly and the reaction mixture was heated at 80 °C overnight under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25 °C and filtered through celite. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude compound so obtained was purified by column chromatography (Biotage) using eluent (2:8, ethyl acetate: n-hexane) to get the methyl 3-(3,5-dichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate (191 mg, 73% yield) as a solid LCMS (ESI): m / z = 372.0 (M-H)’; ’ H NMR (500 MHz, CDC13) 8 9.37 (s, 1H), 7.34 (td, J = 3.6, 1.5 Hz, 2H), 7.25 (d, J = 1.9 Hz, 2H), 7.20 (td, J = 8.0, 1.5 Hz, 1H), 7.00 (td, J = 7.5, 1.0 Hz, 1H), 6.96 (d, 7 = 8.1 Hz, 1H), 5.21 (s, 2H), 3.80 (s, 3H).

[0118] Example 2: Preparation of 3-(3,5-dichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid

[0119] To a stirred solution of methyl 3-(3,5-dichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate (188 mg, 0.57 mmol) in THF (2.5 mL), MeOH (1.1 mL) and H2O (1.1 mL) was added LiOH.HiO (120 mg, 2.87 mmol). The resultant mixture was stirred at room temperature for 48 h. Reaction mixture was acidified to pH 2 with 2 M HCI and extracted with EtOAc (2 x 25 mL). The organic extracts were dried over NaiSCU, filtered and concentrated in vacuo. The crude compound so obtained was purified by column chromatography (Biotage) using eluent (2:8, ethyl acetate: n-hexane) to get the 3-(3,5-dichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid (65 g, 74.2% yield) as a solid.

[0120] LCMS (ESI): m / z = 358.0 (M-H)’; ’ H NMR (301 MHz, METHANOL-D3) 6 7.64 (dd, J = 7.6, 1.5 Hz, 1H), 7.35 (t, 7 = 1.9 Hz, 1H), 7.30 (d, 7 = 1.9 Hz, 2H), 7.13 (td, J = 7.9, 1.6 Hz, 1H), 6.95 (td, 7 = 7.5, 1.1 Hz, 1H), 6.89 - 6.84 (m, 1H), 5.14 (s, 2H).

[0121] Example 3: Preparation of 3-phenyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0122] Step 1: Preparation of methyl 3-phenyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0123] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with phenylboronic acid.

[0124] LCMS (ESI): m / z = 304.0 (M-H)“; LCMS (ESI): m / z = 304.0 (M-H)“;1H NMR (500 MHz, CDC13) 6 9.28 (s, 1H), 7.43 - 7.39 (m, 2H), 7.37 - 7.33 (m, 4H), 7.18 (td, J = 8.0, 1.6 Hz, 1H), 6.99 (td, J = 7.5, 1.0 Hz, 1H), 6.95 (dd, J = 8.1, 0.8 Hz, 1H), 5.24 (s, 2H), 3.77 (s, 3H).

[0125] Step 2: Preparation of 3-phenyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0126] Prepared by following the similar procedure as described in Example-2

[0127] LCMS (ESI): m / z = 290.1 (M-H)’;XH NMR (500 MHz, MeOD) 5 7.56 (dd, J = 7.6, 1.5 Hz, 1H), 7.26 (d, J = 4.4 Hz, 4H), 7.22 - 7.17 (m, 1H), 7.06-7.00 (m, 1H), 6.89-6.84 (m, 1H), 6.77 (dd, J = 8.1, 0.8 Hz, 1H), 5.05 (s, 2H).

[0128] Example 4: Preparation of methyl 3-(5-chloro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0129] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 5-chloro-2-methoxyphenylboronic acid.

[0130] LCMS (ESI): m / z = 368.0 (M-H)’;1H NMR (500 MHz, CDCI3) 8 9.34 (bs, 1H), 7.33 (dd, J = 7.6, 1.4 Hz, 1H), 7.30 - 7.27 (m, 2H), 7.17 (td, J = 8.0, 1.5 Hz, 1H), 6.98 (td, J = 7.5, 0.9 Hz, 1H), 6.95 - 6.91 (m, 1H), 6.89 - 6.86 (m, 1H), 5.11 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H).

[0131] Example 5: Preparation of methyl 3-(3,4-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate

[0132] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3,4-difluorophenylboronic acid

[0133] LCMS (ESI): m / z = 340.1 (M-H)’; ’ H NMR (500 MHz, CDC13) 8 9.35 (s, 1H), 7.34 (dd, J = 7.6, 1.4 Hz, 1H), 7.20 (td, 7 = 8.0, 1.5 Hz, 1H), 7.00 (td, 7 = 7.6, 0.9 Hz, 1H), 6.96 (d, 7 = 8.1 Hz, 1H), 6.91- 6.86 (m, 2H), 6.83-6.77 (m, 1H), 5.21 (s, 2H), 3.80 (s, 3H).

[0134] Example 6: Preparation of methyl 3-(4-(tert-butyl)phenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0135] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 4-(tert-butyl)phenylboronic acid

[0136] LCMS (ESI): m / z = 360.1 (M-H)’; ’ H NMR (301 MHz, CDCI3) 6 7.41-7.30 (m, 5H), 7.20 - 7.13 (m, 1H), 7.00-6.92 (m, 2H), 5.25 (s, 2H), 3.78 (s, 3H), 1.35 (s, 9H).

[0137] Example 7: Preparation of methyl 3-(2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0138] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 2-methoxyphenylboronic acid

[0139] LCMS (ESI): m / z = 336.1 (M+H)+; ’ H NMR (500 MHz, CDCI3) 6 9.29 (s, 1H), 7.37 - 7.29 (m, 4H), 7.16 (td, 7 = 8.0, 1.6 Hz, 1H), 7.02-6.92 (m, 4H), 5.16 (s, 2H), 3.80 (s, 3H), 3.73 (s, 3H).

[0140] Example 8: Preparation of methyl 3-(4-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0141] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 4-fluorophenylboronic acid

[0142] LCMS (ESI): m / z = 322.1 (M-H)’; ’ H NMR (301 MHz, CDC13) 8 7.36-7.31 (m, 2H), 7.17 (dd, J =

[0143] 7.9, 1.7 Hz, 1H), 7.13 - 7.06 (m, 2H), 7.02-6.93 (m, 3H), 5.21 (s, 2H), 3.77 (s, 3H).

[0144] Example 9: Preparation of methyl 3-(3-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0145] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-fluorophenylboronic acid

[0146] LCMS (ESI): m / z = 322.0 (M-H)’; ’ H NMR (500 MHz, DMSO-d6) 6 12.5 (bs, 1H), 8.06 - 7.81 (m, 1H), 7.55 - 7.36 (m, 1H), 7.28 - 7.13 (m, 4H), 7.08 - 6.96 (m, 1H), 6.96 - 6.87 (m, 1H), 5.19 (s, 2H), 3.71 (s, 3H).

[0147] Example 10: Preparation of methyl 3-(2-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0148] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 2-fluorophenylboronic acid

[0149] LCMS (ESI): m / z = 324.0 (M+H)+; ’ H NMR (500 MHz, CDCI3) 6 9.33 (s, 1H), 7.31 - 7.25 (m, 3H), 7.13 - 7.09 (m, 2H), 7.09 - 7.04 (m, 1H), 6.92 (td, J = 7.5, 1.0 Hz, 1H), 6.88 (dd, J = 8.1, 0.8 Hz, 1H), 5.10 (s, 2H), 3.69 (s, 3H).

[0150] Example 11: Preparation of methyl 3-(2-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0151] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 2-chlorophenylboronic acid

[0152] LCMS (ESI): m / z = 337.9 (M-H)“.

[0153] Example 12: Preparation of methyl 3-(3-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0154] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-chlorophenylboronic acid

[0155] LCMS (ESI): m / z = 337.9 (M-H)’;1H NMR (500 MHz, CDC13) 8 9.36 (s, 1H), 7.37 - 7.32 (m, 4H), 7.24 - 7.17 (m, 2H), 7.02 - 6.94 (m, 2H), 5.22 (s, 2H), 3.78 (s, 3H).

[0156] Example 13: Preparation of methyl 3-(4-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0157] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 4-chlorophenylboronic acid

[0158] LCMS (ESI): m / z = 337.9 (M-H)’; ’ H NMR (500 MHz, CDCI3) 6 9.35 (s, 1H), 7.39 - 7.34 (m, 3H), 7.30 - 7.28 (m, 2H), 7.21 - 7.16 (m, 1H), 7.02 - 6.93 (m, 2H), 5.21 (s, 2H), 3.78 (s, 3H).

[0159] Example 14: Preparation of methyl 3-(pyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0160] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with pyridin-3-ylboronic acid

[0161] LCMS (ESI): m / z = 307.0 (M+H)+; ’ H NMR (500 MHz, DMSO-d6) 5 12.57 (s, 1H), 8.57 - 8.50 (m, 2H), 7.94 (dd, J = 7.7, 1.6 Hz, 1H), 7.82 - 7.76 (m, 1H), 7.45-7.40 (m, 1H), 7.21 - 7.15 (m, 1H), 7.03 - 6.98 m, 1H), 6.92 (dd, J = 8.1, 0.9 Hz, 1H), 5.21 (s, 2H), 3.71 (s, 3H).

[0162] Example 15: Preparation of methyl 3-(pyridin-4-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0163] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with pyridin-4-ylboronic acid

[0164] LCMS (ESI): m / z = 307.0 (M+H)+.

[0165] Example 16: Preparation of methyl 3-(3,5-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate

[0166] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3,5-difluorophenylboronic acid

[0167] LCMS (ESI): m / z = 342.0 (M+H)+;1H NMR (500 MHz, CDC13) 8 9.35 (s, 1H), 7.35 (dd, J = 7.5, 1.5 Hz, 2H), 7.25 - 7.16 (m, 1H), 7.02 - 6.95 (m, 2H), 6.88 (dd, J = 8.3, 2.3 Hz, 1H), 6.82 - 6.78 (m, 1H), 5.21 (s, 2H), 3.80 (s, 3H).

[0168] Example 17: Preparation of methyl 3-(3,5-dimethylphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0169] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3,5-dimethylphenylboronic acid

[0170] LCMS (ESI): m / z = 334.0 (M+H)+;1H NMR (500 MHz, CDCI3) 6 9.28 (s, 1H), 7.34 (dd, J = 7.6, 1.5 Hz, 1H), 7.20 - 7.15 (m, 1H), 7.01 - 6.96 (m, 4H), 6.94 (dd, J = 8.1, 1.0 Hz, 1H), 5.23 (s, 2H), 3.77 (s, 3H), 2.36 (s, 6H).

[0171] Example 18: Preparation of methyl 3-(2-fluoro-4-methylphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0172] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 2-fluoro-4-methylphenylboronic acid

[0173] LCMS (ESI): m / z = 338.0 (M+H)+;1H NMR (500 MHz, CDC13) 8 9.37 (s, 1H), 7.34 (dd, J = 7.6, 1.5 Hz, 2H), 7.20 - 7.14 (m, 1H), 7.01 - 6.93 (m, 4H), 5.16 (s, 2H), 3.76 (s, 3H), 2.40 (s, 3H).

[0174] Example 19: Preparation of methyl 3-(3-chloro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0175] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-chloro-5-methoxyphenylboronic acid

[0176] LCMS (ESI): m / z = 368.0 (M-H)’;1H NMR (500 MHz, CDCI3) 6 9.31 (s, 1H), 7.34 (dd, J = 7.6, 1.5 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.01 - 6.93 (m, 3H), 6.90 - 6.87 (m, 1H), 6.80 (dd, J = 2.3, 1.4 Hz, 1H), 5.22 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H).

[0177] Example 20: Preparation of methyl 3-(3-chloro-5-fluorophenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0178] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-chloro-5-fluorophenylboronic acid

[0179] LCMS (ESI): m / z = 356.0 (M-H)“;1H NMR (500 MHz, CDC13) 6 9.39 (bs, 1H), 7.35 (dd, J = 7.6, 1.5 Hz, 1H), 7.22 - 7.17 (m, 1H), 7.14 (t, J = 1.4 Hz, 1H), 7.10 - 7.06 (m, 1H), 7.02 - 6.98 (m, 2H), 6.96 (dd, J = 8.2, 0.9 Hz, 1H), 5.21 (s, 2H), 3.80 (s, 3H).

[0180] Example 21: Preparation of methyl 3-(5-fluoro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0181] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 5-fluoro-2-methoxyphenylboronic acid

[0182] LCMS (ESI): m / z = 352.0 (M-H)“

[0183] Example 22: Preparation of methyl 3-(3,5-dimethoxyphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0184] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3,5-dimethoxyphenylboronic acid

[0185] LCMS (ESI): m / z = 364.0 (M-H)’;1H NMR (500 MHz, CDCI3) 8 9.39 (s, 1H), 7.36 (dd, J = 7.6, 1.5 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.01 - 6.93 (m, 2H), 6.52 (d, 7 = 2.3 Hz, 2H), 6.46 (t, 7 = 2.3 Hz, 1H), 5.25 (s, 2H), 3.81 (s, 6H), 3.79 (s, 3H).

[0186] Example 23: Preparation of methyl 3-(3-chloro-5-methylphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0187] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-chloro-5-methylphenylboronic acid

[0188] LCMS (ESI): m / z = 352.0 (M-H)’;1H NMR (500 MHz, CDC13) 8 9.32 (bs, 1H), 7.34 (dd, J = 7.6, 1.2 Hz, 1H), 7.22 - 7.13 (m, 3H), 7.04 (s, 1H), 7.01-6.97 (m, 1H), 6.95 (d, J = 8.1 Hz, 1H), 5.21 (s, 2H), 3.78 (s, 3H), 2.41 (s, 3H).

[0189] Example 24: methyl 3-(3-(trifluoromethyl)phenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0190] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-(trifluoromethyl)phenylboronic acid.

[0191] LCMS (ESI): m / z = 374.0 (M-H)’;1H NMR (500 MHz, DMSO) 6 12.55 (s, 1H), 7.95 (dd, J = 7.7, 1.5 Hz, 1H), 7.74 (s, 1H), 7.70 - 7.65 (m, 1H), 7.64 - 7.60 (m, 2H), 7.20 - 7.14 (m, 1H), 6.99 (td, J = 7.6, 1.0 Hz, 1H), 6.92 - 6.88 (m, 1H), 5.20 (s, 2H), 3.70 (s, 3H).

[0192] Example 25: methyl 3-(4-(dimethylcarbamoyl)phenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0193] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 4-(dimethylcarbamoyl)phenylboronic acid.

[0194] LCMS (ESI): m / z = 375.0 (M-H)’;[HNMR (500 MHz, DMSO) 6 12.46 (s, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.44 - 7.36 (m, 4H), 7.16 (t, J = 7.7 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.19 (s, 2H), 3.71 (s, 3H), 2.99 (s, 6H).

[0195] Example 26: methyl 3-(2,3-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0196] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 2,3-difluorophenylboronic acid.

[0197] LCMS (ESI): m / z = 340.0 (M-H)’;1H NMR (500 MHz, CDC13) 8 9.40 (s, 1H), 7.35 (dd, J = 7.6, 1.5 Hz, 1H), 7.21 - 7.07 (m, 4H), 7.02 - 6.93 (m, 2H), 5.16 (s, 2H), 3.77 (s, 3H),

[0198] Example 27: methyl 3-(2,3-dimethoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0199] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 2,3-dimethoxyphenylboronic acid.

[0200] LCMS (ESI): m / z = 364.0 (M-H)’;1H NMR (500 MHz, CDCI3) 6 9.64 (s, 1H), 7.42 (dd, J = 7.6, 1.5 Hz, 1H), 7.18 - 7.14 (m, 1H), 7.10 - 7.05 (m, 1H), 6.98 - 6.91 (m, 4H), 5.26 - 5.00 (m, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 3.57 (s, 3H).

[0201] Example 28: methyl 3-(4-fluoro-2-methylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0202] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 4-fluoro-2-methylphenylboronic acid.

[0203] LCMS (ESI): m / z = 336.0 (M-H)’;1H NMR (500 MHz, CDCI3) 6 10.01 (s, 1H), 7.52 (dd, J = 7.6, 1.5 Hz, 1H), 7.19 - 7.10 (m, 3H), 6.99 - 6.88 (m, 4H), 5.04 (ABq, J =13.0 Hz, 2H), 3.71 (s, 3H), 2.17 (s, 3H).

[0204] Example 29: methyl 3-(4-fluoro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0205] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 4-fluoro-2-methoxyphenylboronic acid.

[0206] LCMS (ESI): m / z = 354.1 (M-H) ’; ’ H NMR (500 MHz, DMSO-d6) 5 12.34 (s, 1H), 7.90 (dd, J = 7.6, 1.2 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.18 - 7.10 (m, 1H), 7.01 - 6.92 (m, 2H), 6.88 (d, J = 7.8 Hz, 1H), 6.77 (td, J = 8.4, 2.4 Hz, 1H), 4.97 (s, 2H), 3.74 (s, 3H), 3.64 (s, 3H).

[0207] Example 30: methyl 3-(3-fluoro-4-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0208] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-fluoro-4-methoxyphenylboronic acid.

[0209] 'H NMR (500 MHz, CDCI3) 6 9.46 (s, 1H), 7.38 (dd, J = 7.6, 1.5 Hz, 1H), 7.20 - 7.16 (m, 1H), 7.13 (dd, J = 12.3, 2.1 Hz, 1H), 7.07 - 7.03 (m, 1H), 7.01 - 6.99 (m, 1H), 6.98 - 6.94 (m, 2H), 5.22 (s, 2H), 3.94 (s, 3H), 3.79 (s, 3H).

[0210] Example 31: methyl 3-(3-fluoro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0211] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-fluoro-5-methoxyphenylboronic acid.

[0212] ECMS (ESI): m / z = 351.9 (M-H)’; ’ H NMR (500 MHz, CDCI3) 6 9.30 (s, 1H), 7.34 (dd, J = 7.6, 1.5 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.01 - 6.94 (m, 2H), 6.71 - 6.65 (m, 2H), 6.61 (dt, J = 10.7, 2.3 Hz, 1H), 5.23 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H).

[0213] Example 32: methyl 3-(5-fluoropyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0214] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 5-fluoropyridin-3-yllboronic acid.

[0215] ’ H NMR (500 MHz, DMSO-d6) 5 12.64 (s, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.42 (t, J = 1.6 Hz, 1H), 7.94 (dd, 7 = 7.7, 1.5 Hz, 1H), 7.81 - 7.75 (m, 1H), 7.17 (td, 7 = 8.0, 1.6 Hz, 1H), 6.99 (td, 7= 7.5, 1.0 Hz, 1H), 6.91 (dd, J = 8.1, 0.7 Hz, 1H), 5.23 (s, 2H), 3.72 (s, 3H).

[0216] Example 33: methyl 3-(5-chloropyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0217] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 5-chloropyridin-3-ylboronic acid.

[0218] LCMS (ESI): m / z = 339.0 (M-H)’; ’ H NMR (500 MHz, DMSO-d6) 5 12.64 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 8.00 -7.88 (m, 2H), 7.17 (t, J = 7.3 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 5.22 (s, 2H), 3.72 (s, 3H).

[0219] Example 34: methyl 3-(3,4,5-trifluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0220] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3,4,5-trifluorophenylboronic acid.

[0221] LCMS (ESI): m / z = 357.9 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.56 (s, 1H), 7.92 (dd, J = 7.6, 1.4 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.16 (td, J = 8.0, 1.5 Hz, 1H), 6.98 (td, 7 = 7.6, 0.8 Hz, 1H), 6.90 (d, 7 = 8.0 Hz, 1H), 5.21 (s, 2H), 3.72 (s, 3H). Example 35: methyl 3-(3,4,5-trichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0222] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3, 4, 5 -trichlorophenyl boronic acid .

[0223] ’ H NMR (500 MHz, DMSO-d6) 5 12.60 (s, 1H), 7.92 (dd, J = 7.7, 1.6 Hz, 1H), 7.64 - 7.61 (m, 2H), 7.21 - 7.13 (m, 1H), 7.03 - 6.96 (m, 1H), 6.90 (dd, J = 8.1, 0.9 Hz, 1H), 5.21 (s, 2H), 3.73 (s, 3H).

[0224] Intermediate 2: Preparation of methyl 3-bromo-8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0225] Step 1: Preparation of 6-fluorochroman-4-ol

[0226] Following a procedure provided for Intermediate 1, Step 1 (99% yield). LCMS (APCI): m / z = 168.3 (M+H)+.

[0227] Step 2: Preparation of 6-fluoro-2H-chromene-3-carbaldehyde

[0228] Following a procedure provided for Intermediate 1, Step 2 (75% yield). LCMS (APCI): m / z = 179.1 (M+H)+.

[0229] Step 3: Preparation of methyl (Z)-2-azido-3-(6-fluoro-2H-chromen-3-yl)acrylate Following a procedure provided for Intermediate 1, Step 3 (91% yield). LCMS (APCI): m / z = 276.3 (M+H)+.

[0230] Step 4: Preparation of methyl 8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0231] Following a procedure provided for Intermediate 1, Step 4 (65% yield). LCMS (ESI): m / z = 246.0 (M- H)’.

[0232] Step 5: Preparation of methyl 3-bromo-8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0233] To a stirred solution of 8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate (760 mg, 3.07 mmol) in DCM (17 mL) was added A-bromo succinamide (547.2 mg, 3.07 mmol). The resulting mixture was stirred at room temperature for 2h. The crude mixture was extracted with DCM and washed with sat. NaHCCh. The organic extracts were dried over Na2S04, filtered and concentrated in vacuo. The crude compound was purified by column chromatography (Biotage) using eluent (2:8, ethyl acetate: n-hexane) to get the methyl 3-bromo-8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate (700 mg, 70% yield) as a yellow solid. LCMS (ESI)’: m / z = 326.0, 324.0.

[0234] Example 36: methyl 8-fluoro-3-(3-fluoro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0235] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-fluoro-5-methoxyphenyl boronic acid.

[0236] LCMS (ESI): m / z = 370.0 (M-H)’;1H NMR (500 MHz, CDC13) 8 9.87 (s, 1H), 7.21 (dd, J = 8.4, 2.7 Hz, 1H), 7.05 - 7.01 (m, 2H), 6.90 - 6.82 (m, 3H), 5.06 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H). Example 37: methyl 3-(3-chloro-5-methoxyphenyl)-8-fluoro-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0237] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-chloro-5-methoxyphenyl boronic acid

[0238] LCMS (ESI): m / z = 385.9 (M-H)’;1H NMR (500 MHz, CDC13) 8 10.23 (s, 1H), 7.33 (dd, J = 8.4,

[0239] 2.8 Hz, 1H), 6.94 - 6.82 (m, 4H), 6.79 - 6.76 (m, 1H), 5.18 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H).

[0240] Example 38: methyl 3-(5-chloro-2-methoxyphenyl)-8-fluoro-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0241] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 5-chloro-2-methoxyphenyl boronic acid

[0242] LCMS (APCI): m / z = 386.3 (M-H)’;[HNMR (500 MHz, DMSO) 6 12.47 (s, 1H), 7.78 (dd, J = 9.4, 3.0 Hz, 1H), 7.36 (dd, J = 8.8, 2.7 Hz, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 6.97 (td, J = 8.7, 3.1 Hz, 1H), 6.90 (dd, J = 8.9, 4.8 Hz, 1H), 4.98 (s, 2H), 3.73 (s, 3H), 3.67 (s, 3H).

[0243] Intermediate 3: methyl 3-bromo-8-methyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0244] Step 1: Preparation of 6-methylchroman-4-ol Following a procedure provided for Intermediate 1, Step 1 (99% yield). LCMS (APCI): m / z = 164.3 (M)+.

[0245] Step 2: Preparation of 6-methyl-2H-chromene-3-carbaldehyde

[0246] Following a procedure provided for Intermediate 1, Step 2 (76% yield). LCMS (APCI): m / z = 175.3 (M)+.

[0247] Step 3: Preparation of methyl (Z)-2-azido-3-(6-methyl-2H-chromen-3-yl)acrylate

[0248] Following a procedure provided for Intermediate 1, Step 3 (95%).

[0249] Step 4: Preparation of methyl 8-methyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0250] Following a procedure provided for Intermediate 1, Step 4 (56% yield). LCMS (ESI): m / z = 241.9 (M- H)\

[0251] Step 5: Preparation of methyl 3-bromo-8-methyl-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0252] Following a procedure provided for Intermediate 2, Step 5 (63%). LCMS (ESI)’: m / z = 319.9, 321.9.

[0253] Example 39: methyl 3-(3-chloro-5-methoxyphenyl)-8-methyl-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-chloro-5-methoxyphenyl boronic acid

[0254] LCMS (ESI): m / z = 381.9 (M-H)’; ’ H NMR (500 MHz, CDC13) 8 9.51 (s, 1H), 7.18 (d, J = 1.4 Hz, 1H), 6.98 (dd, J = 8.3, 1.5 Hz, 1H), 6.94 - 6.92 (m, 1H), 6.89 - 6.84 (m, 2H), 6.80 - 6.78 (m, 1H), 5.17 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 2.32 (s, 3H).

[0255] Intermediate 4: methyl 3-bromo-7-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0256] Step 1: Preparation of 7-fluorochroman-4-ol

[0257] Following a procedure provided for Intermediate 1, Step 1 (99% yield). LCMS (APCI): m / z = 168.3 (M+H)+.

[0258] Step 2: Preparation of 7-fluoro-2H-chromene-3-carbaldehyde

[0259] Following a procedure provided for Intermediate 1, Step 2 (82% yield). LCMS (APCI): m / z = 179.3 (M+H)+.

[0260] Step 3: Preparation of methyl (Z)-2-azido-3-(7-fluoro-2H-chromen-3-yl)acrylate

[0261] Following a procedure provided for Intermediate 1, Step 3 (93% yield). LCMS (APCI): m / z = 276.3 (M+H)+.

[0262] Step 4: Preparation of methyl 7-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate Following a procedure provided for Intermediate 1, Step 4 (30% yield). LCMS (ESI): m / z = 246.0 (M+H)-.

[0263] Step 5: Preparation of methyl 3-bromo-7-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0264] Following a procedure provided for Intermediate 2, Step 5 (63% yield). LCMS (ESI)’: m / z = 323.9, 325.9.

[0265] Example 40: methyl 3-(3-chloro-5-methoxyphenyl)-7-fluoro-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate

[0266] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with 3-chloro-5-methoxyphenyl boronic acid

[0267] LCMS (ESI): m / z = 323.9 (M-H)’;[HNMR (500 MHz, DMSO) 5 12.47 (s, 1H), 7.78 (dd, J = 9.4, 3.0 Hz, 1H), 7.36 (dd, J = 8.8, 2.7 Hz, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 7.00 - 6.94 (m, 1H), 6.92 - 6.87 (m, 1H), 4.98 (s, 2H), 3.73 (s, 3H), 3.67 (s, 3H).

[0268] Intermediate 4: methyl 3-bromo-4,4-dimethyl-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0269] Step 1: Preparation of 2,2-dimethylchroman-4-one

[0270] To a stirred solution of 2-Hydroxyacetophenon (1g, 7.34 mmol) in THF (73 mL) were added DIPEA (1.28 mL, 7.34 mmol), pyrrolidine (0.603 mL, 7.34 mmol), acetone ( 0.598 mL, 8.01 mmol) and heated at 70 °C for 16 h. The reaction mixture was concentrated. 3M solution of NaOH was added and extracted with ethyl acetate (30 mL x 3). The organic layers were collected, dried over NaiSCL and evaporated to afford the desired compound as white solid (0.53 g, 41% yield). ’ H NMR (500 MHz, CDC13) 6 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 - 7.43 (m, 1H), 6.99 - 6.94 (m, 1H), 6.92 (dd, J = 8.2, 0.8 Hz, 1H), 2.72 (s, 2H), 1.46 (s, 6H).

[0271] Step 2: Preparation of 2,2-dimethylchroman-4-one oxime

[0272] To a stirred solution of 2,2-dimethylchroman-4-one (1.3g, 7.43 mmol) in MeOH were added triethylamine (2.06mL, 14.86 mmol) and hydroxylamine hydrochloride (1.03g, 14.86 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated, water was added and extracted with DCM (20 mLx2). The organic layers were collected, dried over NaiSCL and concentrated to get the desired product (79% yield). LCMS (APCI)+: m / z = 192.2; 1H NMR (500 MHz, CDCI3) 8 8.03 - 7.87 (m, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.01 - 6.91 (m, 1H), 6.86 (dd, J = 8.3, 0.9 Hz, 1H), 2.85 (s, 2H), 1.41 (s, 6H).

[0273] Step 3: Preparation of methyl (E)-3-(((2,2-dimethylchroman-4-ylidene)amino)oxy)acrylate

[0274] To a stirred solution of 2,2-dimethylchroman-4-one oxime (300mg, 1.56 mmol) in DCM at 0 °C was added triethylamine ( 0.04mL, 0.314 mmol), methyl propiolate (0.28 mL, 3.12 mmol) and reaction mixture turns orange. The reaction mixture was stirred at room temperature for 1 h. Water was added and extracted with DCM (20 mLx2). The organic layers were collected, dried over NaiSCL and concentrated to get the desired product (80% yield). LCMS (APCI)+: m / z = 276.5; 1H NMR (500 MHz, CDCI3) 6 8.05 (d, J = 12.5 Hz, 1H), 7.88 (dd, J = 7.9, 1.6 Hz, 1H), 7.37 - 7.28 (m, 1H), 6.95 - 6.90 (m, 1H), 6.86 (d, J = 9.2 Hz, 1H), 5.69 (d, J = 12.5 Hz, 1H), 3.74 (s, 3H), 2.90 (s, 2H), 1.40 (s, 6H).

[0275] Step 4: Preparation of methyl 4,4-dimethyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0276] A solution of methyl (E)-3-(((2,2-dimethylchroman-4-ylidene)amino)oxy)acrylate (226 mg, 0.821 mmol) in AcOH was heated at 120 °C in the MW for 4 h. The reaction mixture was evaporated and purified by flash column chromatography (Biotage) using eluent (3:7, ethyl acetate: n-hexane) to get the desired compound. ’ H NMR (500 MHz, CDC13) 8 9.48 (s, 1H), 7.37 (dd, J = 7.5, 1.5 Hz, 1H), 7.19 - 7.13 (m, 1H), 6.96 - 6.90 (m, 2H), 6.72 (d, J = 2.2 Hz, 1H), 3.89 (s, 3H), 1.61 (s, 6H).

[0277] Step 5: Preparation of methyl 3-bromo-4,4-dimethyl-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate

[0278] Following a procedure provided for Intermediate 2, Step 5 (63% yield). LCMS (APCI)’: m / z = 334.0, 336.0.

[0279] Example 41: methyl 3-phenyl-4,4-dimethyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate

[0280] Following a procedure analogous to the one provided for compound of example 1 and replacing 3,5- dichlorophenylboronic acid with phenyl boronic acid.

[0281] LCMS (APCI)+: m / z = 334.1

[0282] The below Examples-42 to 78 were prepared by following the similar procedure as described in

[0283] Example-2

[0284] Example 42: 3-(5-chloro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0285] LCMS (ESI): m / z = 354.0 (M-H)’;[HNMR (500 MHz, MeOD) 5 7.65 (dd, J = 7.6, 1.5 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.17 - 7.07 (m, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.96 (td, 7= 7.5, 1.1 Hz, 1H), 6.86 (dd, J= 8.1, 0.9 Hz, 1H), 5.00 (s, 2H), 3.78 (s, 3H).

[0286] Example 43: 3-(3,4-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0287] LCMS (ESI): m / z = 326.1 (M-H)’;[HNMR (500 MHz, MeOD) 5 7.67 (dd, 7= 7.7, 1.5 Hz, 1H), 7.17

[0288] - 7.12 (m, 1H), 7.00 - 6.95 (m, 3H), 6.92 - 6.85 (m, 2H), 5.18 (s, 2H).

[0289] Example 44: 3-(4-(tert-butyl)phenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0290] LCMS (ESI): m / z = 346.1 (M-H)’; ’H NMR (301 MHz, DMSO-D6) 5 12.21 (s, 1H), 7.91 (dd, 7 =

[0291] 7.6, 1.5 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.32 - 7.24 (m, 2H), 7.13 (td, 7 = 7.8, 1.6 Hz, 1H), 6.95 (td, 7 = 7.5, 1.1 Hz, 1H), 6.87 (dd, 7= 8.1, 0.9 Hz, 1H), 5.15 (s, 2H), 1.30 (s, 9H).

[0292] Example 45: 3-(2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0293] LCMS (ESI): m / z = 322.1 (M+H)+; ’H NMR (500 MHz, MeOD) 5 7.63 (d, 7= 6.1 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.14 - 7.09 (m, 1H), 7.01 (d, 7 = 7.8 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.85 (dd, 7 = 8.1, 0.9 Hz, 1H), 4.99 (s, 2H), 3.78 (s, 3H).

[0294] Example 46: 3-(4-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0295] LCMS (ESI): m / z = 308.0 (M-H)’; ’ H NMR (500 MHz, MeOD) 5 7.66 (dd, J = 7.6, 1.5 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.15 - 7.07 (m, 3H), 6.97 (td, J = 7.5, 1.1 Hz, 1H), 6.87 (dd, J = 8.1, 0.9 Hz, 1H), 5.15 (s, 2H).

[0296] Example 47: 3-(3-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0297] LCMS (ESI): m / z = 308.0 (M-H)’;XH NMR (500 MHz, DMSO) 5 12.45 (s, 1H), 12.35 (s, 1H), 7.97

[0298] - 7.89 (m, 1H), 7.41 (dd, J = 14.4, 7.8 Hz, 1H), 7.25 - 7.10 (m, 4H), 6.97 (t, J = 7.5 Hz, 1H), 6.89 (d, 7 = 8.1 Hz, 1H), 5.17 (s, 2H).

[0299] Example 48: 3-(2-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0300] LCMS (ESI): m / z = 310.0 (M+H)+; ’ H NMR (500 MHz, MeOD) 5 7.66 (dd, J = 7.6, 1.5 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.20 - 7.09 (m, 3H), 6.97 (td, J = 7.5, 1.1 Hz, 1H), 6.87 (dd, J = 8.1, 0.9 Hz, 1H), 5.07 (s, 2H).

[0301] Example 49: 3-(2-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0302] LCMS (ESI): m / z = 324.0 (M-H)’;XH NMR (500 MHz, DMSO) 5 12.40 (s, 1H), 12.28 (s, 1H), 7.91 (dd, 7 = 7.6, 1.5 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.38 - 7.31 (m, 3H), 7.14 (td, J = 8.0, 1.5 Hz, 1H), 6.97 (td, J = 7.5, 0.9 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 5.00 (s, 2H).

[0303] Example 50: 3-(3-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0304] LCMS (ESI): m / z = 324.0 (M-H)’;1H NMR (500 MHz, MeOD) 5 7.66 (dd, J = 7.6, 1.4 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.38 - 7.23 (m, 3H), 7.14 (td, J = 8.0, 1.5 Hz, 1H), 6.97 (td, 7 = 7.6, 1.0 Hz, 1H), 6.88 (d, 7 = 8.1 Hz, 1H), 5.15 (s, 2H).

[0305] Example 51: 3-(4-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0306] LCMS (ESI): m / z = 323.9 (M+H)+; ’H NMR (500 MHz, MeOD) 5 7.66 (dd, 7= 7.6, 1.5 Hz, 1H), 7.38 - 7.33 (m, 4H), 7.14 (td, 7 = 7.9, 1.5 Hz, 1H), 6.97 (td, 7 = 7.5, 0.9 Hz, 1H), 6.88 (d, 7 = 8.1 Hz, 1H), 5.15 (s, 2H).

[0307] Example 52: 3-(pyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0308] LCMS (ESI): m / z = 293.0 (M+H)+;

[0309] Example 53: 3-(pyridin-4-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0310] LCMS (ESI): m / z = 293.0 (M+H)+;1H NMR (500 MHz, DMSO) 5 8.54 (s, 2H), 7.92 (d, 7 = 7.4 Hz, 1H), 7.41 - 7.34(d, 7= 4.1 Hz, 2H), 7.13 (t, 7= 7.9 Hz, 1H), 6.96 (t, 7 = 7.3 Hz, 1H), 6.89 (d, 7 = 8.2 Hz, 1H), 5.21 (s, 2H).

[0311] Example 54: 3-(3,5-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0312] LCMS (ESI): m / z = 328.0 (M+H)+;1H NMR (500 MHz, MeOD) 5 7.65 (dd, J = 7.6, 1.4 Hz, 1H), 7.12 (td, J = 8.0, 1.5 Hz, 1H), 6.99-6.92 (m, 3H), 6.89 - 6.84 (m, 2H), 5.14 (s, 2H).

[0313] Example 55: 3-(3,5-dimethylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0314] LCMS (ESI): m / z = 320.0 (M+H)+;1H NMR (500 MHz, MeOD) 5 7.64 (dd, J = 7.6, 1.5 Hz, 1H), 7.11 (td, 7 = 7.9, 1.5 Hz, 1H), 6.97 - 6.91 (m, 4H), 6.85 (dd, J = 8.1, 0.9 Hz, 1H), 5.11 (s, 2H), 2.30 (s, 6H).

[0315] Example 56: 3-(2-fluoro-4-methylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0316] LCMS (ESI): m / z = 324.0 (M+H)+; ’H NMR (500 MHz, DMSO-d6) 5 12.31 (s, 1H), 12.22 (s, 1H), 7.91 (dd, J = 7.6, 1.2 Hz, 1H), 7.17 - 7.05 (m, 3H), 7.00 -6.94 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 4.96 (ABq, J = 13.0 Hz, 2H), 2.13 (s, 3H).

[0317] Example 57: 3-(3-chloro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0318] LCMS (ESI): m / z = 354.0 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.46 (s, 1H), 12.36 (s, 1H), 7.92 (dd, 7 = 7.7, 1.5 Hz, 1H), 7.14 (td, 7= 8.0, 1.6 Hz, 1H), 7.01 - 6.93 (m, 3H), 6.90 - 6.84 (m, 2H), 5.18 (s, 2H), 3.79 (s, 3H). Example 58: 3-(3-chloro-5-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0319] LCMS (ESI): m / z = 342.0 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.60 (s, 1H), 12.44 (s, 1H), 7.92 (dd, 7 = 7.7, 1.5 Hz, 1H), 7.36 (dt, J = 8.8, 2.1 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.23 - 7.18 (m, 1H), 7.17 - 7.12 (m, 1H), 6.97 (td, 7= 7.5, 1.1 Hz, 1H), 6.89 (dd, 7 = 8.1, 0.9 Hz, 1H), 5.19 (s, 2H).

[0320] Example 59: 3-(5-fluoro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0321] LCMS (ESI): m / z = 338.1 (M-H)’; ’H NMR (500 MHz, DMSO-d6) 5 12.27 (s, 2H), 7.90 (d, 7 = 7.6 Hz, 1H), 7.17 - 6.84 (m, 6H), 4.97 (s, 2H), 3.71 (s, 3H).

[0322] Example 60: 3-(3,5-dimethoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0323] LCMS (ESI): m / z = 350.0 (M-H)’; ’H NMR (500 MHz, DMSO-d6) 5 12.35 (s, 1H), 12.26 (s, 1H), 7.93 (d, 7 = 7.6 Hz, 1H), 7.13 (t, 7 = 7.7 Hz, 1H), 6.96 (t, 7 = 7.5 Hz, 1H), 6.88 (d, 7= 8.1 Hz, 1H), 6.54 - 6.42 (m, 3H), 5.18 (s, 2H), 3.75 (s, 6H).

[0324] Example 61: 3-(3-chloro-5-methylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid LCMS (ESI): m / z = 338.1 (M-H)’; ’ H NMR (500 MHz, DMSO-d6) 5 12.40 (s, 1H), 12.34 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 9.5 Hz, 2H), 7.16 - 7.10 (m, 1H), 7.09 (s, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.88 (d, 7 = 8.1 Hz, 1H), 5.15 (s, 2H), 2.33 (s, 3H).

[0325] Example 62: 3-(3-(trifluoromethyl)phenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid.

[0326] LCMS (ESI): m / z = 357.9 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.52 (s, 1H), 12.43 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.83 - 7.55 (m, 4H), 7.14 (t, J = 7.2 Hz, 1H), 7.03 - 6.82 (m, 2H), 5.19 (s, 2H).

[0327] Example 63: 3-(4-(dimethylcarbamoyl)phenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid

[0328] LCMS (ESI): m / z = 361.2 (M-H)’; ’ H NMR (500 MHz, DMSO-d6) 5 12.43 (s, 1H), 12.34 (s, 1H), 7.93 (dd, 7 = 7.6, 1.0 Hz, 1H), 7.45 - 7.37 (m, 4H), 7.14 (td, J = 8.3, 1.3 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 5.18 (s, 2H), 2.99 (s, 6H).

[0329] Example 64: 3-(2,3-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0330] LCMS (ESI): m / z = 326.0 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.53 (s, 1H), 12.48 (s, 1H), 7.92 (dd, J = 7.6, 1.4 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.24 - 7.12 (m, 3H), 6.97 (td, J = 7.5, 0.9 Hz, 1H), 6.89 (dd, 7 = 8.0, 0.6 Hz, 1H), 5.11 (s, 2H).

[0331] Example 65: 3-(2,3-dimethoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0332] LCMS (ESI): m / z = 350.0 (M-H)’; ’ H NMR (500 MHz, DMSO-d6) 5 12.25 (s, 1H), 12.17 (s, 1H), 7.90 (dd, 7 = 7.6, 1.5 Hz, 1H), 7.12 (td, J = 8.0, 1.6 Hz, 1H), 7.05 - 6.93 (m, 3H), 6.86 (dd, 7 = 8.1, 0.9 Hz, 1H), 6.80 (dd, 7 = 7.4, 1.8 Hz, 1H), 4.97 (s, 2H), 3.82 (s, 3H), 3.48 (s, 3H).

[0333] Example 66: 3-(4-fluoro-2-methylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0334] LCMS (ESI): m / z = 322.0 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.31 (s, 1H), 12.22 (s, 1H), 7.91 (dd, J = 7.6, 1.2 Hz, 1H), 7.17 - 7.05 (m, 3H), 7.00 -6.94 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 4.96 (ABq, J = 13.0 Hz, 2H), 2.13 (s, 3H).

[0335] Example 67 : 3-(4-fluoro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0336] LCMS (ESI): m / z = 337.9 (M-H)’; ‘ H NMR (500 MHz, DMSO-d6) 5 12.21 (s, 2H), 7.90 (dd, J = 7.6, 1.4 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.14 - 7.09 (m, 1H), 6.98 - 6.90 (m, 2H), 6.86 (d, J = 8.1 Hz, 1H), 6.76 (td, J = 8.4, 2.5 Hz, 1H), 4.96 (s, 2H), 3.74 (s, 3H).

[0337] Example 68: 3-(3-fluoro-4-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid LCMS (ESI): m / z = 337.9 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.40 (s, 1H), 12.27 (s, 1H), 7.92 (dd, 7 = 7.5, 1.0 Hz, 1H), 7.24 (dd, J = 12.7, 1.8 Hz, 1H), 7.18 - 7.06 (m, 3H), 6.96 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.17 (s, 2H), 3.87 (s, 3H).

[0338] Example 69: 3-(3-fluoro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0339] LCMS (ESI): m / z = 338.0 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.52 (s, 1H), 12.34 (s, 1H), 7.92 (dd, 7 = 7.6, 1.3 Hz, 1H), 7.14 (t, 7 = 7.7 Hz, 1H), 6.96 (t, 7 = 7.5 Hz, 1H), 6.88 (d, 7 = 8.1 Hz, 1H), 6.80 - 6.70 (m, 3H), 5.18 (s, 2H), 3.78 (s, 3H).

[0340] Example 70: 3-(5-fluoropyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0341] LCMS (ESI): m / z = 309.0 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.62 (s, 1H), 12.52 (s, 1H), 8.50 (d, J = 2.7 Hz, 1H), 8.42 (t, J = 1.6 Hz, 1H), 7.94 (dd, J = 7.7, 1.5 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.15 (td, 7 = 8.0, 1.6 Hz, 1H), 6.97 (td, 7 = 7.5, 1.1 Hz, 1H), 6.90 (dd, 7 = 8.1, 0.9 Hz, 1H), 5.22 (s, 2H).

[0342] Example 71: 3-(5-chloropyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0343] LCMS (ESI): m / z = 324.9 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.64 (s, 1H), 12.53 (s, 1H), 8.58 - 8.46 (m, 2H), 7.98 - 7.91 (m, 2H), 7.15 (td, 7 = 8.0, 1.5 Hz, 1H), 6.97 (td, 7 = 7.5, 0.8 Hz, 1H), 6.89 (d, 7 = 8.0 Hz, 1H), 5.22 (s, 2H).

[0344] Example 72: 3-(3,4,5-trifluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0345] LCMS (ESI): m / z = 343.9 (M-H)’; ’H NMR (500 MHz, DMSO-d6) 5 12.58 (s, 1H), 12.44 (s, 1H), 7.92 (dd, J = 7.5, 0.9 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.18 - 7.11 (m, 1H), 6.96 (t, J = 7.4 Hz, 1H),

[0346] 6.89 (d, J = 8.0 Hz, 1H), 5.21 (d, J = 12.9 Hz, 2H).

[0347] Example 73: 3-(3,4,5-trichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0348] ’H NMR (500 MHz, DMSO-d6) 5 12.50 (s, 2H), 7.92 (dd, J = 7.7, 1.5 Hz, 1H), 7.63 (s, 2H), 7.14 (td, 7 = 8.0, 1.6 Hz, 1H), 6.97 (td, 7= 7.5, 1.0 Hz, 1H), 6.89 (dd, 7 = 8.1, 0.7 Hz, 1H), 5.21 (s, 2H).

[0349] Example 74: 8-fluoro-3-(3-fluoro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid

[0350] LCMS (ESI): m / z = 355.9 (M-H)’; ’H NMR (500 MHz, DMSO-d6) 5 12.41 (s, 1H), 12.34 (s, 1H), 7.79 (dd, 7 = 9.3, 2.8 Hz, 1H), 7.15 - 7.05 (m, 2H), 7.04 - 6.99 (m, 1H), 6.96 - 6.86 (m, 1H), 4.96 (s, 2H), 3.71 (s, 3H).

[0351] Example 75: 3-(3-chloro-5-methoxyphenyl)-8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid LCMS (ESI): m / z = 371.9 (M-H)’; ’ H NMR (500 MHz, DMSO-d6) 5 12.58 (s, 1H), 12.43 (s, 1H), 7.80 (dd, J = 9.4, 3.0 Hz, 1H), 6.99 - 6.93 (m, 3H), 6.92 - 6.88 (m, 1H), 6.86 - 6.83 (m, 1H), 5.17 (s, 2H), 3.79 (s, 3H).

[0352] Example 76: 3-(5-chloro-2-methoxyphenyl)-8-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid

[0353] LCMS (APCI): m / z = 372.1 (M-H)’; ’H NMR (500 MHz, MeOD) 5 7.47 - 7.43 (m, 1H), 7.31 - 7.23 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 7.4, 2.0 Hz, 2H), 4.97 (s, 2H), 3.77 (s, 3H).

[0354] Example 77: 3-(3-chloro-5-methoxyphenyl)-8-methyl-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid

[0355] LCMS (ESI): m / z = 368.0 (M-H)’; ’ H NMR (500 MHz, DMSO-d6) 5 12.45 (s, 1H), 12.31 (s, 1H), 7.79 (d, 7 = 1.6 Hz, 1H), 6.98 - 6.92 (m, 3H), 6.86 - 6.83 (m, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.12 (s, 2H), 3.79 (s, 3H), 2.25 (s, 3H).

[0356] Example 78: 3-(3-chloro-5-methoxyphenyl)-7-fluoro-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid

[0357] LCMS (ESI): m / z = 372.0 (M-H)’;1H NMR (500 MHz, DMSO-d6) 5 12.47 (s, 1H), 12.37 (s, 1H), 7.98 - 7.93 (m, 1H), 6.99 - 6.94 (m, 7H), 6.88 - 6.76 (m, 3H), 5.22 (s, 2H), 3.79 (s, 3H).Example 79: 4,4-dimethyl-3-phenyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid

[0358] LCMS (ESI): m / z = 318.0 (M-H)’; 1H NMR (500 MHz, MeOD) 5 8.01 (d, J = 2.2 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.47 - 7.38 (m, 4H), 7.36 - 7.26 (m, 1H), 7.14 - 7.06 (m, 1H), 6.97 - 6.79 (m, 1H), 1.36 (m, 6H).

[0359] BIOLOGICAL ASSAYS

[0360] Enzyme Activity: Determination of ICso

[0361] The Class B beta-lactamases activities were measured in the presence of the test inhibitors in a fluorescence assay against an in-house synthesized fluorescent cephalosporin substrate FC5 (Berkel, et.al. J. Med. Chem. 2013, 56(17), 6945). The enzyme (NDM-1 or IMP-1 or VIM-1) and the substrate were diluted in 20 mM HEPES, pH 7.4, supplemented with 300 mM NaCl and 10 pM ZnSO4. In the assay, the final concentration of enzyme was 150 pM, and the final concentration of FC5 was 1.5 pM for NDM-1 & VIM-1 and 3 pM for IMP-1. The test inhibitors / compounds were dissolved in dimethylsulfoxide (DMSO) and diluted in the assay with assay buffer (20 mM HEPES, pH 7.4, supplemented with 5% DMSO, 300 mM NaCl, and 10 pM ZnSO4), resulting in a final concentration range of 0.008 pM to 25 pM or 0.064nM to 125 pM. The assays were performed in a 96-well microplate (flat bottom, black). The test inhibitors were incubated with the MBL enzyme for 10 min at room temperature, followed by the addition of the substrate, and the fluorescence was recorded immediately (Zex 380 nm, kern 460 nm) on a microplate reader. Using the initial velocity data was plotted against the inhibitor concentration, the half-maximal inhibitory concentrations were calculated by an IC50 curve-fitting model in GraphPad Prism 9 software. Representative compounds of the present invention exhibit inhibition of Class B P-lactamases in this assay. For example, the compounds of examples 2, 3, 42-78 were tested in this assay and were found to have IC50 values shown in Table 1.

[0362] Table 1: ICso values of dihydrochromeno-pyrrole derivatives against NDM-1 values

[0363] Thus, the above in-vitro assay method shows that the compounds of the invention to have inhibition against MBLs (NDM-1, IMP-1, and VIM-1) in biochemical assay, thereby showing utility for treating diseases, and disorders associated with the modulation of MBL and antibiotic resistance.

[0364] The compound testing results have demonstrated that the dihydrochromeno-pyrrole derivatives of formula (I) are capable of inhibiting clinically important MBLs. The dihydrochromeno-pyrrole derivatives described in this invention can be developed into broad- spectrum high-affinity inhibitors targeting multiple > -lactamases in resistant bacteria, and can be combined with > -lactam antibiotics to treat infections caused by multi-resistant bacteria.

[0365] In the previous patent application (WO2022254464A1) compounds are dihydro-benzo indole derivatives whereas in current application compounds are chromeno-pyrrole derivatives as a MBL inhibitors. In both the cases chemical class is different and hence behaving differently in terms of solubility and ClogP; observed better solubility and ClogP in case of chromeno-pyrrole derivatives. Also made the derivative metabolically stable by introducing oxygen atom at the metabolically soft spot in current patent application.

Claims

AMENDED CLAIMS received by the International Bureau on 19 Nov 2024 (19.11.2024)1. A dihydrochromeno-pyrrole compound of Formula I, stereoisomer or pharmaceutically acceptable salts thereof;Formula I whereinRI may be same or different at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -C(O)ORe, -OC(O)ORe, -O(CRaRb)r-C(O)ORe, - (CRaRb)r-C(O)ORe, -C(O)Rh, NRfRg, -C(O)NRfRg, -NRfC(O)Rh, - NRfS(O)2Rg, -S(0)o-2Re, and-S(O)2NRfRg, 'n' is an integer ranging from 0 to 5, both inclusive;R2and R3, may be same or different at each occurrence, are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;R4is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle; wherein preferred substitution is independently selected from the group consisting of halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -C(O)ORh, -OC(O)ORe, -O(CRaRb)r-C(O)ORe, -(CRaRb)r- C(O)ORe, -C(O)Rh, NRfRg, -C(O)NRfRg, -NRfC(O)Rh, - NRfS(O)2Rg, - S(0)o-2Re, and-S(O)2NRfRg;Raand Rb, may be same or different at each occurrence, are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; or Raand Rbtogether with the carbon atom to which they are attached, may form an unsubstituted or substituted 3 to 7 membered saturated carbocyclic ring;Remay be same or different at each occurrence, is independently selected from the group consisting of hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted alkyl;Rf and Rg, may be same or different at each occurrence, are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, -(CRaRb)r-C(O)ORe, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted oorr unsubstituted heterocyclylalkyl; or Rfand Rgtogether with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3 to 10 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; at each occurrence, Rh is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;'r' is an integer ranging from 1 to 3, both inclusiveR5 is selected from the group consisting of(i) -OH;(ii) -NRiRm, wherein Ri and Rmare independently selected at each occurrence from hydrogen, unsubstituted or substituted alkyl, and unsubstituted or substituted cycloalkyl; methoxy; or Ri and Rmtogether with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;(iii) -ORn, wherein R8is selected from C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl, C1-2alkyl, aryl, aryl-C1-2alkyl, heteroaryl,heteroaryl-Ci-2 alkyl, heterocyclyl or heterocyclyl-Ci-2 alkyl, each of which is optionally substituted by one or more substituent groups;(iv) -Ro, wherein Rois independently selected at each occurrence from thegroup consisting of hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl. The compound as claimed in claim 1, wherein compound of formula I is selected from the group consisting of:

1. methyl 3-(3,5-dichlorophenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylate [1];11. 3-(3,5-dichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid; iii. 3-phenyl-l,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid; iv. methyl 3 -(5-chloro-2-methoxyphenyl)- 1 ,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; v. methyl 3-(3,4-difluorophenyl)-l,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ;VI. methyl 3-(4-(tert-butyl)phenyl)-l,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ; vii. methyl 3-(2-methoxyphenyl)-l,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ;Vlll. methyl 3-(4-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate; ix. methyl 3-(3-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate;X. methyl 3-(2-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate; xi. methyl 3-(2-chlorophenyl)- 1 ,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate;XU. methyl 3-(3-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate;xm. methyl 3-(4-chlorophenyl)- 1 ,4-dihydrochromeno[4,3-b]pyrrole- 2-carboxylate xiv. methyl 3 -(pyridin-3 -yl) - 1 ,4-dihydrochromeno [4,3 -b]pyrrole-2- carboxylate;XV. methyl 3-(pyridin-4-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylate; xvi. methyl 3 -(3 ,5-difluorophenyl)- 1 ,4-dihydrochromeno [4,3 - b] pyrrole-2 -carboxylate ; xvn. methyl 3-(3,5-dimethylphenyl)-l,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ; xviii. methyl 3-(2-fluoro-4-methylphenyl)-l,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ; xix. methyl 3 -(3-chloro-5-methoxyphenyl)- 1 ,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xx. methyl 3 -(3 -chloro-5-fluorophenyl)- 1 ,4-dihydrochromeno [4,3 - b] pyrrole-2 -carboxylate ; xxi. methyl 3-(5-fluoro-2-methoxyphenyl)- 1 ,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxii. methyl 3-(3,5-dimethoxyphenyl)-l,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ; xxin. methyl 3-(3-chloro-5-methylphenyl)-l,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ; xxiv. methyl 3-(3-(trifluoromethyl)phenyl)- 1 ,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ;XXV. methyl 3-(4-(dimethylcarbamoyl)phenyl)- 1 ,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxvi. methyl 3-(2,3-difluorophenyl)-l,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ; xxvii methyl 3 -(2,3 -dimethoxyphenyl)- 1 ,4-dihydrochromeno [4,3 - b] pyrrole-2 -carboxylate ;xxvm. methyl 3-(4-fluoro-2-methylphenyl)- 1 ,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ; xxix. methyl 3-(4-fluoro-2-methoxyphenyl)- 1 ,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxx. methyl 3-(3-fluoro-4-methoxyphenyl)-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxxi. methyl 3-(3-fluoro-5-methoxyphenyl)-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxxn. methyl 3 -(5-fluoropyridin-3 -yl)- 1 ,4-dihydrochromeno [4,3 - b] pyrrole-2 -carboxylate ; xxxiii. methyl 3 -(5-chloropyridin-3 -yl)- 1 ,4-dihydrochromeno [4,3 - b] pyrrole-2 -carboxylate ; xxxi v. methyl 3-(3,4,5-trifluorophenyl)-l,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ; xxxv. methyl 3-(3,4,5-trichlorophenyl)-l,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ; xxxvi. methyl 8-fluoro-3-(3-fluoro-5-methoxyphenyl)-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxxvii. methyl 3-(3-chloro-5-methoxyphenyl)-8-fluoro-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxxvm. methyl 3-(5-chloro-2-methoxyphenyl)-8-fluoro-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xxxix. methyl 3-(3-chloro-5-methoxyphenyl)-8-methyl-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xl. methyl 3-(3-chloro-5-methoxyphenyl)-7-fluoro-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylate; xli. methyl 4,4-dimethyl-3-phenyl- 1 ,4-dihydrochromeno[4,3- b] pyrrole-2 -carboxylate ; xlii. 3-(5-chloro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylic acid;xliii. 3-(3,4-difluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid; xliv. 3-(4-(tert-butyl)phenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid; xlv. 3-(2-methoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid; xlvi. 3-(4-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid; xlvii. 3-(3-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid; xlviii. 3-(2-fluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid; xlix. 3-(2-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;1. 3-(3-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid; li. 3-(4-chlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid; lii. 3 -(pyridin-3 -yl) - 1 ,4-dihydrochromeno [4,3 -b]pyrrole-2- carboxylic acid; liii. 3-(pyridin-4-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid; liv. 3 - (3 , 5 -difluorophenyl) - 1 ,4-dihydrochromeno [4 ,3 -b] pyrrole-2 - carboxylic acid; lv. 3-(3,5-dimethylphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;Ivi. 3-(2-fluoro-4-methylphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylic acid;Ivii. 3-(3-chloro-5-methoxyphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylic acid;Iviii. 3 -(3 -chloro-5-fluorophenyl)- 1 ,4-dihydrochromeno [4,3 - b]pyrrole-2-carboxylic acid; lix. 3 -(5-fluoro-2-methoxyphenyl)- 1 ,4-dihydrochromeno [4,3 - b]pyrrole-2-carboxylic acid; lx. 3-(3,5-dimethoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;Ixi. 3-(3-chloro-5-methylphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylic acid;Ixii. 3 - (3 - (trifluoromethy l)pheny 1) - 1 ,4-dihydrochromeno [4,3- b]pyrrole-2-carboxylic acid;Ixiii. 3-(4-(dimethylcarbamoyl)phenyl)- 1 ,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylic acid;Ixiv. 3 - (2 , 3 -difluorophenyl) - 1 ,4-dihydrochromeno [4 ,3 -b] pyrrole-2 - carboxylic acid;Ixv. 3-(2,3-dimethoxyphenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;Ixvi. 3-(4-fluoro-2-methylphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylic acid;Ixvii. 3-(4-fluoro-2-methoxyphenyl)-l,4-dihydrochromeno[4,3- b]pyrrole-2-carboxylic acid;Ixviii. 3 -(3 -fluoro-4-methoxyphenyl)- 1 ,4-dihydrochromeno [4,3 - b]pyrrole-2-carboxylic acid;Ixix. 3 -(3 -fluoro-5-methoxyphenyl)- 1 ,4-dihydrochromeno [4,3 - b]pyrrole-2-carboxylic acid;Ixx. 3-(5-fluoropyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;Ixxi. 3-(5-chloropyridin-3-yl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;Ixxii. 3-(3,4,5-trifluorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;Ixxiii. 3-(3,4,5-trichlorophenyl)-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid;Ixxiv. 8-fluoro-3-(3-fluoro-5-methoxyphenyl)-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;Ixxv. 3-(3-chloro-5-methoxyphenyl)-8-fluoro-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;Ixxvi. 3-(5-chloro-2-methoxyphenyl)-8-fluoro-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;Ixxvii. 3-(3-chloro-5-methoxyphenyl)-8-methyl-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;Ixxviii. 3-(3-chloro-5-methoxyphenyl)-7-fluoro-l,4- dihydrochromeno[4,3-b]pyrrole-2-carboxylic acid;Ixxix. 4,4-dimethyl-3-phenyl-l,4-dihydrochromeno[4,3-b]pyrrole-2- carboxylic acid.

3. A process for preparation of compound of formula I as claimed in claim 1, comprising the steps of; i. reducing a 4-chormanone of formula (1) using reducing agents such as sodium borohydride to obtain a compound of formula (2);(1) (2) ii. formylation of compound of formula (2) as obtained in step (i) using in-situ prepared Vilsmeier Haack reagent / adduct to obtain a aldehyde of formula (3);in. treating aldehyde of formula (3) as obtained in step (ii) with azido ester compound of formula (4) in the presence of a base selected from sodium ethoxide or sodium methoxide to give compound of formula (5);iv. cyclization of compound of formula (5) as obtained in step (iii) in a presence of Lewis acid or in acidic condition to obtain a compound of formula (6);v. converting a compound of formula (8) in the presence of DIPEA, TEA, pyridine etc and pyrrolidine with a ketone of formula (9) to substituted chromanone of formula (10);vi. treating ketone of formula (10) as obtained in step (v) with a derivative of hydroxylamine to give a oxime of formula (11);vii. o-alkylation of oxime group of compound (11) with alkyl propionate in presence of trimethylamine to give compound of formula (13);viii. cyclization of compound of formula (13) in the presence of acidic condition to obtain a compound of formula (6);ix. halogenating the compound of formula (6) as obtained in step (iv) and (viii) using halogenated reagents selected from N- bromo succinimide (NBS) or iV-iodosuccinimide (NIS) to give the halogenated compound of formula (7);x. coupling reaction of the halogenated compound of formula (7) with aryl / heteroaryl boronic acids or aryl / heteroaryl boronic esters to obtain a compound of Formula (la);xi. converting compound of Formula (la) as obtained in step (x) to compound of Formula (I) by hydrolysis of corresponding ester using base selected from the group consisting of LiOH, K2CO3, NaOH or KOH. A pharmaceutical composition comprising:

1. at least one compound of formula (I) and; ii. at least one pharmaceutically acceptable excipient. The pharmaceutical composition as claimed in claim 4, wherein pharmaceutically acceptable excipients are selected from the group consisting of water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerytritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.The pharmaceutical composition as claimed in claim 4, wherein said composition further comprises an effective amount of a beta-lactam antibio tic / s.The pharmaceutical composition as claimed in claim 4, wherein said composition is for use as a beta-lactamase inhibitor, against both serine and metallo-beta-lacatamses or in combination with other beta-lactamases inhibitors or as a drug. The compound of formula (I) as claimed in claim 1, wherein the compound of formula (I) is used in a composition for inhibiting beta-lactamase activity, or in the manufacture of a medicament for inhibiting beta-lactamase activity, or in combination with a beta-lactam antibiotic for treating a bacterial infection, or in combination with a beta-lactam antibiotic in the manufacture of a medicament for treating a bacterial infection.STATEMENT UNDER ARTICLE 19With reference to the search report and written opinion of ISA / IN, the applicant has amended claims to address clarity objections.

1. The applicant would like to submit that claims 3 and 8 have been amended for more clarity.The Applicant undertakes that no new subject matter has been added in claims and the amended claims do not go beyond disclosure of international application as-filed.

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