DESC:RELATED APPLICATION
This application is related to and takes priority from the provisional application 202241071962 filed 11/3/2023 and is incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to a novel synthetic flavonoid compound that are active against severe acute respiratory syndrome-2 (SARS-CoV-2), Human respiratory syncytial virus, influenza A & B types, Chikungunya virus, Zika virus and Rabies. Furthermore, the invention relates to the compounds, their preparation methods, pharmaceutical compositions containing the compounds, and their broad spectrum anti-viral activity.
BACKGROUND OF THE INVENTION

Coronaviruses (CoVs) belonging to the order Nidovirales, and family Coronaviridae, are enveloped and genetically diverse viruses, consisting of four genera such as alpha, beta, gamma, and delta. Multiple animal species are susceptible to CoVs infections with several cross species transmission incidences (1). Further, zoonotic transmission is thought to be the source of all human CoV infections (2–4). However, only alpha and beta CoVs are known to infect humans with varying pathology (5). In the past two decades, two novel coronaviruses outbreaks of zoonotic origin have been witnessed, such as severe acute respiratory syndrome (SARS) caused by SARS-CoV in 2002, and Middle East respiratory syndrome (MERS) in 2012, caused by MERS-CoV. SARS-CoV reported 8,098 confirmed cases with a fatality rate of around 10% (774 deaths), while 2,502 confirmed cases with a case fatality rate higher than 30% has been reported with MERS-CoV (5,6). The ongoing pandemic known as coronavirus disease 2019 (COVID-19), caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belonging to Beta coronaviruses was reported in the early December 2019, in Wuhan, China (7,8). The rapid spread of COVID-19 throughout the world in a very short time prompted the World Health Organization (WHO) to declare COVID-19 as pandemic, on 11 March 2020. Mutations in the spike protein of SARS-CoV-2 has led to the emergence multiple variants such as B.1.1.7 (Alpha), B.1.351 (beta), B.1.1.28.1/P.1 (gamma), B.1.617.2 (Delta), B.1.617.1 (kappa) and Omicron (B.1.1.529) are circulating around the world in the ongoing COVID-19 pandemic (9). Severe acute respiratory syndrome (SARS) is a viral respiratory disease, and the etiological agent is SARS-associated coronavirus. It was emerged in China at the end of 2003 and spread to 4 other countries. While Middle East respiratory syndrome (MERS) caused by a novel coronavirus (Middle East respiratory syndrome coronavirus, or MERS-CoV) was first identified in Saudi Arabia in 2012 (10).
Influenza virus belonging to Orthomyxoviridae family are negative sense, segmented RNA viruses that presents a substantial burden to human health. Influenza viruses are of four types such as A, B, C and D, however, seasonal epidemics of disease (known as flu season) are caused by human influenza A and B viruses. Based on the surface proteins (hemagglutinin (H) and neuraminidase (N)) Influenza A viruses are divided into subtypes. Current subtypes of influenza A viruses that routinely circulate in people include A(H1N1) and A(H3N2). While influenza B viruses are classified into two lineages such as Victoria and Yamagata.
Respiratory syncytial virus (RSV) belonging to Pneumoviridae family cause of acute lower respiratory tract infection in infants, children, immunocompromised adults, and the elderly. (11). RSV is a non-segmented virus with negative sense single stranded RNA genome encoding 11 proteins. Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) belonging to the genus Flavivirus and the family Flaviviridae with single-stranded RNA. In tropical and subtropical regions, ZIKV is transmitted primarily by the bite of an infected mosquito Aedes aegypti. Further, ZIKV is also transmitted from mother to fetus during pregnancy, through sexual contact, transfusion of blood and blood products, and organ transplantation. Currently, no vaccine is available for the prevention or treatment of Zika virus infection (12).
Chikungunya virus (CHIKV) belonging to genus Alphavirus, and family Togaviridae. is a re-emerging mosquito-borne virus (13). CHIKV is an enveloped, positive single-stranded-RNA viruses and infections in humans, is of rapid onset and is typically cleared in 5–7 days. The clinical symptoms of CHIKV infection include high fever, headache, rigors, a petechial rash or maculopapular rash and photophobia. In addition, most infected individuals complain of severe joint pain that is often incapacitating.

STATEMENT OF THE INVENTION
The present invention provides a compound of formula (I):

FORMULA (I)

Wherein,
X is independently selected from a group consisting of Oxygen, NH, and NR3
where R3 is C1-C6 alkyl.
R1 is independently selected from a group consisting of Hydrogen, Halogens, OH, OCH3, CF3, OCF3, COOH, CONHR where R = C1-C6 alkyl and optionally substituted C6-C18 aryl.
R2 is independently selected from the group consisting of Hydrogen, Halogens, OH, OCH3, CF3, OCF3, COOH , -(CH2)n-OR, -(CH2)n-COOH and -(CH2)n-CONHR, where n=0, 1, 2, 3, 4 and R= Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C6-C18 aryl, optionally substituted C1-C18 heteroaryl, and acyl.
The invention also relates to pharmaceutical compositions including a compound of the invention and pharmaceutically acceptable carrier, diluent, or excipients.

DETAILED DESCRIPTION OF THE INVENTION
In this specification several terms are used which are well known to a skilled person in the art. Nevertheless, for the purposes of clarity several terms will be defined.
The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted or fused (to form a condensed polycyclic system), with one or more non-hydrogen substituent groups. In certain embodiments the substituent groups are one or more groups independently selected from the group consisting of H, Halogen, =0, =S, -CN, -N02, -CF3, -OCF3, alkyl, cycloalkyl, heterocycloalkyl, aryl , heteroaryl, and Acyl.
"Acyl" means an R-C(=O)- group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. Compounds of acyl include acetyl and benzoyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the carbonyl carbon.
"Alkyl" refers to a group of an aliphatic hydrocarbons which may be straight or branched chains preferably having from C1-C12 carbon atoms, more preferably C1-C10carbon atoms, most preferably C1-C6 carbon atoms in the normal or branched chain. Exemplary structures include but are not limited to Methyl, Ethyl, and propyl. The group may be a terminal group or a bridging group.
"Aryl" as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle. (Ring structure having ring atoms that are all carbon) preferably having from C5-C12atoms per ring. Compounds of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C5-7 cycloalkyl or C5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydro naphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group: Typically, an aryl group is a C6-C18 aryl group.
"Cycloalkyl" refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. A cycloalkyl group typically is a C3-C12 alkyl group. The group may be a terminal group or a bridging group.
"Halogen" represents chlorine, fluorine, bromine, or iodine.
"Heteroaryl" either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen, and Sulphur. The group may be a monocyclic or bicyclic heteroaryl group. Compounds of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho(2,3- b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pytidazine, tetrazole, . indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, . carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1-, 3-, 4-, or 5- isoquinolinyl 1-, 2-, or 3- indolyl, and 2-, or 3-thienyl. A heteroaryl group is typically a C1-C18 heteroaryl group. The group may be a terminal group or a bridging group.
"Heterocyclic" refers to saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom. Compounds of heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.
Additionally, Formula (I) is intended to cover, where applicable, solvated as well as un solvated forms of the compounds. Thus, the formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Compounds of such inorganic acids are hydrochloric, sulfuric. and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic. aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, Compounds of which are formic, acetic, propanoic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, aryl sulfonic. In a similar vein base addition salt may be prepared by ways well known in the art using organic or inorganic bases. Compound of suitable organic bases include simple amines such as methylamine, ethylamine, triethylamine, and the like. Compounds of suitable inorganic bases include NaOH, KOH, and the like. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents, and salts may exist in different crystalline or polymorphic forms. all of which are intended to be within the scope of the present invention and specified formulae.
The term “therapeutically effective amount” or “effective amount” is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations.
An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
The invention also relates to pharmaceutical compositions including a compound of the invention and a pharmaceutically acceptable carrier diluents, excipients, and prodrug thereof.
Specific compounds of the invention include the following:

Compound 1
Compound 2
Compound 3

Compound 4

Compound 5

Compound 6

Compound 7
Compound 8
Compound 9

Compound 10

Compound 11
Compound 12

Compound 13

Compound 14

Compound 15

Compound 16
Compound 17 Compound 18

Compound 19
Compound 20

Compound 21

Compound 22
Compound 23

Compound 24
Compound 25

Compound 26 Compound 27

Compound 28
Compound 29
Compound 30

Compound 31
Compound 32
Compound 33

Compound 34 Compound 35

Compound 36
Compound 37
Compound 38

Compound 39

Compound 40
Compound 41

Compound 42
Compound 43
Compound 44
Compound 45

Compound 46
Compound 47
Compound 48
Compound 49
Compound 50

Compound 51
Compound 52

Compound 53
Compound 54

Compound 55
Compound 56
Compound 57

Compound 58
Compound 59 Compound 60

Compound 61
Compound 62

Compound 63

Compound 64
Compound 65
Compound 66

Compound 67

Compound 68

(1) 6-methoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one
(2) 6-methoxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (3) 7-methoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (4) 7-methoxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (5) 5,7-dimethoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (6) 4-oxo-2-(3-phenoxyphenyl)-4H-chromene-6-carboxylic acid (7) 4-oxo-2-(4-phenoxyphenyl)-4H-chromene-6-carboxylic acid (8) 2-(3-phenoxyphenyl) quinolin-4(1H)-one (9) 2-(4-(4-fluorophenoxy) phenyl)-6-methoxy-4H-chromen-4-one (10) 2-(4-(3,4-difluorophenoxy) phenyl)-6-methoxy-4H-chromen-4-one (11) 4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy) benzonitrile (12) 2-(4-(2-fluorophenoxy) phenyl)-6-methoxy-4H-chromen-4-one (13) 6-methoxy-2-(4-(4-methoxyphenoxy) phenyl)-4H-chromen-4-one (14) 2-(4-(4-hydroxyphenoxy) phenyl)-6-methoxy-4H-chromen-4-one (15) 6-methoxy-2-(4-(phenylamino) phenyl)-4H-chromen-4-one (16) 6,7-dimethoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (17) 6-methoxy-2-(4-(pyridin-2-yloxy) phenyl)-4H-chromen-4-one (18) 6-methoxy-2-(4-(4-(trifluoromethyl) phenoxy) phenyl)-4H-chromen-4-one (19) 2-(4-(3,5-dimethylphenoxy) phenyl)-6-methoxy-4H-chromen-4-one (20) 6-methoxy-2-(3-methoxy-4-phenoxyphenyl)-4H-chromen-4-one (21) 2-(4-cyclohexylphenyl)-7-methyl-4-oxo-4H-chromene-6-carboxylic acid (22) 2-(4-cyclohexylphenyl)-8-methyl-4-oxo-4H-chromene-6-carboxylic acid (23) 2-(4-cyclohexylphenyl)-8-fluoro-4-oxo-4H-chromene-6-carboxylic acid (24) 6-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (25) 6-hydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (26) 7-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (27) 5,7-dihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (28) 5,6,7-trihydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (29) 5,6,7-trihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (30) 2-(4-(4-fluorophenoxy) phenyl)-6-hydroxy-4H-chromen-4-one (31) 2-(4-(2-fluorophenoxy) phenyl)-6-hydroxy-4H-chromen-4-one (32) 2-(4-(3,4-difluorophenoxy) phenyl)-6-hydroxy-4H-chromen-4-one (33) 6-hydroxy-2-(4-(4-methoxyphenoxy) phenyl)-4H-chromen-4-one (34) 6-hydroxy-2-(4-(phenylamino) phenyl)-4H-chromen-4-one (35) 2-([1,1'-biphenyl]-4-yl)-6-hydroxy-4H-chromen-4-one (36) 6-hydroxy-2-(4-(pyridin-4-yl) phenyl)-4H-chromen-4-one (37) 6,7-dihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (38) 4-oxo-2-(4-phenoxyphenyl)-4H-chromene-6-carboxylic acid (39) 6-hydroxy-2-(4-(pyridin-3-yl) phenyl)-4H-chromen-4-one (40) 6-hydroxy-2-(4-(pyridin-2-yl) phenyl)-4H-chromen-4-one (41) 6-hydroxy-2-(6-phenylpyridin-3-yl)-4H-chromen-4-one (42) 6-hydroxy-2-(4-(pyridin-2-yloxy) phenyl)-4H-chromen-4-one (43) 4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl) phenoxy) benzonitrile (44) 6-hydroxy-2-(4-(4-isopropylphenoxy) phenyl)-4H-chromen-4-one (45) 2-(4-(3,5-dimethylphenoxy) phenyl)-6-hydroxy-4H-chromen-4-one (46) 6,7-dihydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (47) 6-hydroxy-2-(4-(6-methylpyridin-3-yl) phenyl)-4H-chromen-4-one (48) 6-hydroxy-2-(4-(pyrimidin-5-yl) phenyl)-4H-chromen-4-one (49) 6-hydroxy-2-(3-methyl-4-phenoxyphenyl)-4H-chromen-4-one (50) 6-hydroxy-2-(3-hydroxy-4-phenoxyphenyl)-4H-chromen-4-one (51) 6-methoxy-2-(4-(pyridin-3-yloxy)phenyl)-4H-chromen-4-one (52) 6-(2-aminoethoxy)-2-(4-phenoxyphenyl)-4H-chromen-4-one (53) 6-(2-(dimethyl amino) ethoxy)-2-(4-phenoxyphenyl)-4H-chromen-4-one (54) 6-(2-hydroxyethoxy)-2-(4-phenoxyphenyl)-4H-chromen-4-one (55) 2-(4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy)phenyl)acetamide (56) 2-(4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy)phenyl)acetamide (57) 3-(4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy)phenyl)propanamide (58) 3-(4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy)phenyl)propanamide (59) : 4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy)benzaldehyde (60) 2-(4-(4-(hydroxymethyl)phenoxy)phenyl)-6-methoxy-4H-chromen-4-one (61) 6-hydroxy-2-(4-(4-(hydroxymethyl)phenoxy)phenyl)-4H-chromen-4-one
(62) 4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy)benzoic acid (63) : 6-methoxy-2-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4H-chromen-4-one (64) : 6-methoxy-2-(4-((tetrahydrofuran-3-yl) oxy)phenyl)-4H-chromen-4-one (65) 6-methoxy-2-(4-((4-methylcyclohexyl)oxy)phenyl)-4H-chromen-4-one (66) 2-(4-(((1S,4R)-bicyclo[2.2.1]heptan-2-yl)oxy)phenyl)-6-methoxy-4H-chromen-4-one (67) 2-(4-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)-6-methoxy-4H-chromen-4-one (68) 2-(4-((4-fluorophenoxy) methyl) phenyl)-6-methoxy-4H-chromen-4-one
SYNTHESIS OF COMPOUNDS OF THE INVENTION

The agents of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available. The preparation of compounds of the embodiments is described in- detail in the following Compounds, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare several other agents of the various embodiments. For Compound, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T.W. Greene's Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1991. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments.

Reagents useful for synthesizing compounds may be obtained or prepared according
to techniques known in the art.
The symbols, abbreviations, and conventions in the processes, schemes, and Compounds are consistent with those used in the contemporary scientific literature. Specifically, but not meant as limiting, the following abbreviations may be used in the Compounds and throughout the specification.
g (grams)
L (liters)
Hz (Hertz)
mol (moles)
RT (room temperature)
min (minutes)
MeOH (methanol)
CHCI3 (chloroform)
DCM (dichloromethane)
DMSO (dimethyl sulfoxide)
EtOAc (ethyl acetate)
mg (milligrams)
ml (milliliters)
psi (pounds per square inch)
mM (millimolar)
MHz (megahertz)
hr (hours)
TLC (thin layer chromatography)
EtOH (ethanol)
CDCI3 (deuterated chloroform)
HCI (hydrochloric acid)
DMF (N, N-dimethylformamide)
THF (tetrahydro furan)
RM (Reaction Mixture)
Unless otherwise indicated, all temperatures are expressed in °C (degree centigrade)
All reactions were conducted at room temperature unless otherwise mentioned.
All the solvents and reagents used are commercially available and purchased from Sigma Aldrich, Avra, BLD pharma, Rankem and Chempure.
NMR spectra were recorded on a Bruker AV 400. Chemical shifts are expressed in parts per million (ppm, d units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiple), or br (broad).
Mass spectra were obtained on UPLC-MS/MS TQD system from waters incorporation, using Electrospray ionization (ESI) either in positive or negative mode.

SCHEMES
Scheme I:

Reagents and conditions: (a) Potassium Hydroxide, Ethanol, RT, 16 h; (b) Iodine, DMSO, 100 °C, 16 h; (c) Aluminium chloride, Toluene, 100 °C, 4 h.
Experimental Protocol:
Preparation of Intermediate-1 (a):
To a stirred solution of 2'-Hydroxy-5'-methoxyacetophenone (1 eq) in Ethanol, followed by Potassium hydroxide (5.0 eq) into the reaction mixture and Phenoxy benzaldehyde (1.0eq) was added to the reaction mixture at room temperature. The Reaction mixture was stirred for 16h at room temperature. The reaction mixture was concentrated and redissolved in water and acidified with 10% HCL solution and extracted with Ethyl acetate. The combined organic layer was back washed with water, saturated brine solution, dried over anhydrous sodium sulphate and evaporated on rotavapor to get the desired crude compound. The obtained crude was purified by column chromatography to get title compound as light-yellow solid product.
Preparation of Intermediate 2 (b):
To a stirred solution of Int-1 (1 eq) in DMSO, added Iodine (0.1 – 0.3 eq) and stirred at 100 0C for 16h. The reaction was cooled to room temperature and poured into ice cold water. The aqueous mixture was extracted with Ethyl acetate and the organic layer was back washed with sodium thiosulphate solution, water, and brine solution. Then the organic layer was dried over anhydrous Sodium sulphate and evaporated on rotavapor to get the crude which was purified by column chromatography to get title compound as yellow solid product.
Preparation of compounds ( c )
To a stirred solution of compound (1.0 eq) in Toluene, aluminium chloride (3.0 eq) was added and stirred for 4h at 100 0C. The reaction mixture was cooled to room temperature, quenched with 10% HCl solution and extracted with Ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulted crude was purified by silica column chromatography.
Compounds provided herein are for better understanding of the invention and cannot be construed as limiting the invention in any way.
Compound 1: 6-methoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (11122)

Compound 1 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 3.87(s, 3H), 6.98(s, 1H), 7.12-7.13(t, 3H), 7.22-7.27 (t, 2H), 7.43-7.50(q, 4H), 7.73-7.76(d, 2H), 8.11-8.14(d, 1H).
LC/MS (ESI-MS) m/z 345.37 (M+1).
Compound 2: 6-methoxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (11123)

Compound 2 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 3-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 3.87(s, 3H), 6.94(s, 1H), 7.06-7.11 (t, 2H), 7.17-7.19(d, 2H), 7.42-7.46(t, 4H), 7.75-7.61(t, 1H), 7.74-7.80(t, 2H), 7.88-7.91(d, 1H).
LC/MS (ESI-MS) m/z 345.63 (M+1).
Compound 3: 7-methoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (11152)

Compound 3 was synthesized from 1-(2-hydroxy-4-methoxyphenyl) ethan-1-one and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 3.93(s, 3H), 6.70(s, 1H), 6.96-7.01(m, 2H), 7.08-7.11(d, 4H), 7.18-7.23(t, 1H), 7.38-7.43(t, 2H), 7.86-7.89(d, 2H), 8.12-8.15(d, 1H).
LC/MS (ESI-MS) m/z 345.56 (M+1).
Compound 4: 7-methoxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (11063)

Compound 4 was synthesized from 1-(2-hydroxy-4-methoxyphenyl) ethan-1-one and 3-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 3.93(s, 3H) , 6.71(s, 1H), 6.95-7.01(m, 2H), 7.05-7.08(d, 2H), 7.15-7.20(t, 2H), 7.37-7.42(t, 2H), 7.44-7.50(t, 2H), 7.65-7.55(s, 1H), 8.11-8.14(d, 1H).
LC/MS (ESI-MS) m/z 345.46 (M+1).
Compound 5: 5, 7-dimethoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (11151)

Compound 5 was synthesized from 1-(2-hydroxy-4, 6-dimethoxyphenyl) ethan-1-one and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 3.91(s, 3H), 3.96(s, 3H), 6.37-6.38(d, 1H), 6.55-6.56(d, 1H), 6.61(s, 1H), 7.06-7, 09(t, 4H), 7.17-7.22(t, 1H), 7.37-7.43(t, 2H), 7.82-7.85(d, 2H).
LC/MS (ESI-MS) m/z 375.68 (M+1).
Compound 6: 4-oxo-2-(3-phenoxyphenyl)-4H-chromene-6-carboxylic acid (11085)

Compound 6 was synthesized from 3-acetyl-4-hydroxybenzoic acid and 3-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 7.08-7.13(t, 3H), 7.17-7.22(t, 2H), 7.42-7.47(t, 2H), 7.57-7.63(t, 1H), 7.83(s, 2H), 7.91-7.94(d, 1H), 8.28-8.31(d, 1H), 8.57(s, 1H).
LC/MS (ESI-MS) m/z 359.6(M+1).
Compound 7: 4-oxo-2-(4-phenoxyphenyl)-4H-chromene-6-carboxylic acid (11086)

Compound 7 was synthesized from 3-acetyl-4-hydroxybenzoic acid and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 7.04(s, 1H), 7.13-7.16(d, 4H), 7.23-7.28(t, 1H), 7.45-7.50(t, 2H), 7.81-7.84(d, 1H), 8.14-8.17(d, 2H), 8.28-8.31(d, 1H), 8.57(s, 1H).
LC/MS (ESI-MS) m/z 359.47(M+1).
Compound 8: 2-(3-phenoxyphenyl) quinolin-4(1H)-one (11075)

Compound 8 was synthesized 1-(2-aminophenyl) ethan-1-one and 3-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): ?? 6.32(s, 1H), 7.10-7.12(d, 2H), 7.16-7.22(m, 2H), 7.31-7.36(t, 2H), 7.42-7.47(t, 2H), 7.51(s, 1H), 7.58-7.60(d, 2H), 7.67-7.69(d, 1H), 7.74-7.77(2, 1H), 8.07-8.10(d, 1H).
LC/MS (ESI-MS) m/z 314.5 (M+1).
Compound 9: 2-(4-(4-fluorophenoxy) phenyl)-6-methoxy-4H-chromen-4-one (11288)

Compound 9 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(4-fluorophenoxy) benzaldehyde by following the similar procedure described in Scheme I. 1H NMR(DMSO, 400MHz): d 3.94(s, 3H), 6.77(s, 1H), 7.07-7.12(m, 6H), 7.28-7.32(m, 1H), 7.50-7.52(d, 1H), 7.62-7.63(d, 1H), 7.89-7.92(m, 2H).
LC/MS (ESI-MS) m/z 363.39 (M+1).
Compound 10: 2-(4-(3, 4-difluorophenoxy) phenyl)-6-methoxy-4H-chromen-4-one (11292)
Compound 10 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(3, 4-difluorophenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 3.92(s, 3H), 6.76(s, 1H), 6.81-6.84(m, 1H), 6.9-6.96(m, 1H), 7.08-7.11(m, 2H), 7.15-7.22(q, 1H), 7.27-7.31(q, 1H), 7.48-7.51(d, 1H), 7.60-7.61(d, 1H), 7.89-7.92(m, 2H).
LC/MS (ESI-MS) m/z 381.44 (M+1).
Compound 11: 4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy) benzonitrile (11293)

Compound 11 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(4-formylphenoxy) benzonitrile by following the similar procedure described in Scheme I.
1H NMR (CDCl3, 400MHz): d 3.92(s, 3H), 6.79(s, 1H), 7.10-7.12(m, 2H), 7.18-7.2(m, 2H), 7.29-7.32(q, 1H), 7.49-7.52(d, 1H), 7.60-7.61(d, 1H), 7.66-7.68(m, 2H), 7.95-7.98(m, 2H).
LC/MS (ESI-MS) m/z 370.92 (M+1).
Compound 12: 2-(4-(2-fluorophenoxy) phenyl)-6-methoxy-4H-chromen-4-one (11294)

Compound 12 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(2-fluorophenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR (CDCl3, 400MHz): d 3.92(s, 3H), 6.75(s, 1H), 7.06-7.08(d, 2H), 7.17-7.19(m, 2H), 7.20-7.21(m, 2H), 7.47-7.50(d, 2H), 7.59-7.60(d, 1H), 7.87-7.90(m, 2H).
LC/MS (ESI-MS) m/z 363.33 (M+1).
Compound 13: 6-methoxy-2-(4-(4-methoxyphenoxy) phenyl)-4H-chromen-4-one (11307)

Compound 13 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(4-methoxyphenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR (CDCl3, 400MHz): d 3.83(s, 3H), 3.91(s, 3H), 6.74(s, 1H), 6.92-6.94(m, 2H), 7.02-7.05(m, 4H), 7.47-7.49(d, 2H), 7.59-7.60(d, 1H), 7.84-7.87(q, 2H).
LC/MS (ESI-MS) m/z 375.49 (M+1).
Compound 14: 2-(4-(4-hydroxyphenoxy) phenyl)-6-methoxy-4H-chromen-4-one (11309)

Compound 14 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(4-methoxyphenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 3.78(s, 3H), 6.86(s, 2H), 7.01-7.03(d, 2H), 7.06(s, 1H), 7.10-7.12(m, 2H), 7.22-7.25(m, 1H), 7.31-7.32(d, 1H), 7.61-7.63(d, 1H), 8.05-8.07(d, 2H), 9.99(s, 1H).
LC/MS (ESI-MS) m/z 359.36 (M+1).
Compound 15: 6-methoxy-2-(4-(phenylamino) phenyl)-4H-chromen-4-one (11312)

Compound 15 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(phenylamino) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR (CDCl3, 400MHz): d 3.91(s, 3H), 6.05(s, 1H), 6.72(s, 1H), 7.06-7.11(m, 3H), 7.18-7.20(m, 1H), 7.25-7.26(d, 1H), 7.33-7.37(m, 2H), 7.46-7.49(d, 1H), 7.601-7.609(d, 1H), 7.80-7.83(q, 2H).
LC/MS (ESI-MS) m/z 344.86 (M+1).
Compound 16: 6, 7-dimethoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (11332)

Compound 16 was synthesized from 1-(2-hydroxy-4, 5-dimethoxyphenyl) ethan-1-one and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I. 1H NMR (CDCl3, 400MHz): d 3.99-4.01(s, 6H), 6.72(s, 1H), 6.98(s, 1H), 7.08-7.10(d, 4H), 7.18-7.22(t, 1H), 7.38-7.42(m, 2H), 7.57(s, 1H), 7.86-7.88(d, 2H).
LC/MS (ESI-MS) m/z 375.45(M+1).
Compound 17: 6-methoxy-2-(4-(pyridin-2-yloxy) phenyl)-4H-chromen-4-one (11354)

Compound 17 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(pyridin-2-yloxy) benzaldehyde by following the similar procedure described in Scheme I.
LC/MS (ESI-MS) m/z 346.48(M+1).
Compound 18: 6-methoxy-2-(4-(4-(trifluoromethyl) phenoxy) phenyl)-4H-chromen-4-one (11306)

Compound 18 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(4-(trifluoromethyl) phenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR (CDCl3, 400MHz): d 3.92(s, 3H), 6.79(s, 1H), 7.14-7.17(m, 4H), 7.26-7.31(q, 1H), 7.49-7.51(d, 1H), 7.60-7.66(q, 3H), 7.93-7.79(d, 2H).
LC/MS (ESI-MS) m/z 413.37(M+1).
Compound 19: 2-(4-(3, 5-dimethylphenoxy) phenyl)-6-methoxy-4H-chromen-4-one (11316)

Compound 19 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(3, 5-dimethylphenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR (CDCl3, 400MHz): d 2.32-2.32(s, 6H), 3.91(s, 3H), 6.71-6.71(t, 2H), 6.75(s, 1H), 6.83-6.84(s, 1H), 7.07-7.09(d, 2H), 7.26-7.29(q, 1H), 7.47-7.56(d, 1H), 7.59-7.60(d, 1H), 7.86-7.89(d, 2H).
LC/MS (ESI-MS) m/z 373.66(M+1).
Compound 20: 6-methoxy-2-(3-methoxy-4-phenoxyphenyl)-4H-chromen-4-one (11342)

Compound 20 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 3-methoxy-4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR (CDCl3, 400MHz): d 3.92(s, 3H), 3.98(s, 3H), 6.78(s, 1H), 6.98-7(d, 1H), 7.02-7.05(q, 2H), 7.14(t, 1H), 7.28-7.31(q, 1H), 7.34-7.38(q, 2H), 7.48-7.52(m, 3H), 7.60-7.61(d, 1H).
LC/MS (ESI-MS) m/z 375 (M+1).
Compound 21: 2-(4-cyclohexylphenyl)-7-methyl-4-oxo-4H-chromene-6-carboxylic acid (11134)

Compound 21 was synthesized from 5-acetyl-4-hydroxy-2-methylbenzoic acid and 4-cyclohexylbenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 1.32-1.52(m, 5H), 1.71-1.83(d, 6H), 2.69(s, 3H), 7.02(s, 1H), 7.44-7.46(d, 2H), 7.75(s, 1H), 8.02-8.04(d, 2H), 8.51(s, 1H),13.18(s, 1H).
LC/MS (ESI-MS) m/z 363.52(M+1).
Compound 22: 2-(4-cyclohexylphenyl)-8-methyl-4-oxo-4H-chromene-6-carboxylic acid (11135)

Compound 22 was synthesized from 5-acetyl-4-hydroxy-3-methylbenzoic acid and 4-cyclohexylbenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 1.32-1.52(m, 5H), 1.70-1.83(m, 6H), 7.07(s, 1H), 7.45-7.48(d, 2H), 8.03-8.06(d, 2H), 8.19(s, 1H), 8.44(s, 1H), 13.277(s, 1H).
LC/MS (ESI-MS) m/z 363.52(M+1).
Compound 23: 2-(4-cyclohexylphenyl)-8-fluoro-4-oxo-4H-chromene-6-carboxylic acid (11136)

Compound 23 was synthesized from 5-acetyl-4-hydroxy-3-Fluoro benzoic acid and 4-cyclohexylbenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 1.23-1.29(m, 5H), 1.29-1.47(m, 5H), 1.70-1.83(m, 1H), 7.15(s, 1H), 7.46-7.48(d, 2H), 8.00-8.02(d, 2H), 8.15-8.18(d, 1H), 8.37(s, 1H).
LC/MS (ESI-MS) m/z 367.53(M+1).
Compound 24: 6-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (11124)

Compound 24 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1HNMR(DMSO, 400MHz): ?? 6.96(s, 1H), 7.11-7.15(t, 4H), 7.23-7.27(t, 2H), 7.31(s, 1H), 7.44-7.49 (t, 2H), 7.62-7.65(d, 1H), 8.09-8.12(d, 2H).
LC/MS (ESI-MS) m/z 331.65 (M+1).
Compound 25: 6-hydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (11125)

Compound 25 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 3-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1HNMR(DMSO, 400MHz): ?? 6.98(s, 1H), 7.07-7.10(t, 2H), 7.14-7.19(t, 3H), 7.30(s, 1H), 7.41-7.46(t, 2H), 7.55-7.60(t, 1H), 7.63-7.66(d, 1H), 7.76(s, 1H), 7.86-7.89(d, 1H).
LC/MS (ESI-MS) m/z 331.55 (M+1).
Compound 26: 7-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (11153)

Compound 26 was synthesized from 1-(2-hydroxy-4-methoxyphenyl) ethan-1-one and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1HNMR(DMSO, 400MHz): ?? 6.84(s, 1H), 6.91-6.99(m, 2H), 7.11-7.15(t, 4H), 7.22-7.26(t, 1H), 7.45-7.49(t, 2H), 7.87-7.89(d, 1H), 8.07-8.09(d, 2H).
LC/MS (ESI-MS) m/z 331.53 (M+1).
Compound 27: 5, 7-dihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (11154)

Compound 27 was synthesized from 1-(2-hydroxy-4, 6-dimethoxyphenyl) ethan-1-one and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1HNMR(DMSO, 400MHz): ?? 6.21-622(d, 1H), 6.50-6.51(d, 1H), 6.91(s, 1H), 7.11-7.16(t, 4H), 7.23-7.28(t, 1H), 7.44-7.50(t, 2H), 8.80-8.11(d, 2H), 10.91(s, 1H), 12.86(s, 1H).
LC/MS (ESI-MS) m/z 347.48 (M+1).
Compound 28: 5, 6, 7-trihydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (11077)

Compound 28 was synthesized from 1-(6-hydroxy-2, 3, 4-trimethoxyphenyl) ethan-1-one and 3-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1HNMR(DMSO, 400MHz): ?? 6.59(s, 1H), 6.96(s, 1H), 7.07-7.10(d, 2H), 7.17-7.22(t, 2H), 7.41-7.46(t, 2H), 7.54-7.59(t, 1H), 7.73(s, 1H), 7.83-7.86(d, 1H), 8.83(s, 1H), 10.59(s, 1H), 12.60(s, 1H).
LC/MS (ESI-MS) m/z 363.7(M+1).
Compound 29: 5, 6, 7-trihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (11079)

Compound 29 was synthesized from 1-(6-hydroxy-2, 3, 4-trimethoxyphenyl) ethan-1-one and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1HNMR(DMSO, 400MHz): ?? 6.87(s, 1H), 6.94(s, 1H), 7.10-7.15(m, 3H), 7.22-7.27(t, 1H), 7.44-7.49 (t, 2H), 8.07-8.16(t, 2H), 8.80(S, 1H), 10.56(s, 1H), 12.69(s, 1H).
LC/MS (ESI-MS) m/z 363.4 (M+1).
Compound 30: 2-(4-(4-fluorophenoxy) phenyl)-6-hydroxy-4H-chromen-4-one (11289)

Compound 30 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(4-fluorophenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 6.89(s, 1H), 7.10-7.12(m, 2H), 7.18-7.22(m, 2H), 7.23-7.28(m, 2H), 7.30-7.32(m, 2H), 7.62-7.64(d, 1H), 8.08-8.10(m, 2H), 10(s, 1H).
LC/MS (ESI-MS) m/z 349.77 (M+1).
Compound 31: 2-(4-(2-fluorophenoxy) phenyl)-6-hydroxy-4H-chromen-4-one (11295)

Compound 31 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(2-fluorophenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 6.89(s, 1H), 7.10-7.12(d, 2H), 7.23-7.26(m, 1H), 7.29-7.36(m, 4H), 7.43-7.48(m, 1H), 7.61-7.64(d, 1H), 8.07-8.11(m, 2H).
LC/MS (ESI-MS) m/z 349.21 (M+1).
Compound 32: 2-(4-(3, 4-difluorophenoxy) phenyl)-6-hydroxy-4H-chromen-4-one (11296)

Compound 32 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(3, 4-difluorophenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 6.91(s, 1H), 6.98-7.03(m, 1H), 7.16-7.19(m, 2H), 7.23-7.26(m, 1H), 7.31-7.32(d, 1H), 7.35-7.40(m, 1H), 7.49-7.56(q, 1H), 7.62-7.65(d, 1H), 8.09-8.12(q, 2H).
LC/MS (ESI-MS) m/z 367.22 (M+1).
Compound 33: 6-hydroxy-2-(4-(4-methoxyphenoxy) phenyl)-4H-chromen-4-one (11308)

Compound 33 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(4-methoxyphenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 3.87(s, 3H), 6.82-6.84(q, 2H), 6.93(s, 1H), 6.97-6.99(m, 1H), 7.02-7.04(d, 3H), 7.40-7.43(m, 2H), 7.72-7.74(q, 1H), 8.06-8.08(d, 2H).
LC/MS (ESI-MS) m/z 361.93 (M+1).
Compound 34: 6-hydroxy-2-(4-(phenylamino) phenyl)-4H-chromen-4-one (11315)

Compound 34 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(phenylamino) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR (CDCl3, 400MHz): d 6.76(S, 1H), 6.96-7(t, 1H), 7.14-7.23(m, 4H), 7.3-7.35(m, 3H), 7.58-7.60(d, 1H), 7.92-7.94(d, 2H), 8.79(s, 1H).
LC/MS (ESI-MS) m/z 330.47 (M+1).
Compound 35: 2-([1, 1'-biphenyl]-4-yl)-6-hydroxy-4H-chromen-4-one (11320)

Compound 35 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and [1, 1'-biphenyl]-4-carbaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 7.025(s, 1H) , 7.26-7.29 (q, 1H), 7.33-7.34 (d, 1H), 7.45-7.46(d, 1H), 7.50-7.54(t, 2H), 7.68-7.70(d, 1H), 7.77-7.79(d, 2H), 7.87-7.90(d, 2H), 8.17-8.19(d, 2H).
LC/MS (ESI-MS) m/z 314.1(M+1).
Compound 36: 6-hydroxy-2-(4-(pyridin-4-yl) phenyl)-4H-chromen-4-one (11321)

Compound 36 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(pyridin-4-yl) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 7.08(s, 1H), 7.27-7.30(q, 1H), 7.34-7.35(d, 1H), 7.7(d, 1H), 7.85-7.87(d, 2H), 8.03-8.05(d, 2H), 8.24-8.26(d, 2H), 8.71-8.72(d, 2H).
LC/MS (ESI-MS) m/z 316.8(M+1).
Compound 37: 6, 7-dihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (11333)

Compound 37 was synthesized from 1-(2-hydroxy-4, 5-dimethoxyphenyl) ethan-1-one and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 6.77(s, 1H), 7.0(s, 1H), 7.10-7.14(t, 4H), 7.24-7.25(t, 1H), 7.28(S, 1H), 7.44-7.48(t, 2H), 8.04-8.06(d, 2H), 10.04(s, 1H).
LC/MS (ESI-MS) m/z 347.31(M+1).
Compound 38: 4-oxo-2-(4-phenoxyphenyl)-4H-chromene-6-carboxylic acid (11335)

Compound 38 was synthesized from 3-acetyl-4-hydroxybenzoic acid and 4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 7.06(s, 1H), 7.14-7.17(d, 4H), 7.24-7.27(t, 1H), 7.45-7.50(t, 2H), 7.86-7.89(d, 1H), 8.15-8.17(d, 2H), 8.30-8.32(q, 1H), 8.59(d, 1H).
LC/MS (ESI-MS) m/z 358.3(M+1).
Compound 39: 6-hydroxy-2-(4-(pyridin-3-yl) phenyl)-4H-chromen-4-one (11340)

Compound 39 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(pyridin-3-yl) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 7.05(s, 1H), 7.26-7.29(m, 1H), 7.33-7.34(s, 1H), 7.57-7.60(m, 1H), 7.69-7.71(d, 1H), 7.96-7.98(d, 2H), 8.21-8.28(m, 3H) 8.65-8.66(d, 1H), 9.04(s, 1H), 10.03(s, 1H). LC/MS (ESI-MS) m/z 316.38(M+1).
Compound 40: 6-hydroxy-2-(4-(pyridin-2-yl) phenyl)-4H-chromen-4-one (11344)

Compound 40 was synthesized from 1-(2-hydroxy-5-me9thoxyphenyl) ethan-1-one and 4-(pyridin-2-yl) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 7.04(s, 1H), 7.26-7.29(m, 1H), 7.33-7.34(d, 1H), 7.41-7.44(m, 1H), 7.69-7.71(d, 1H), 7.92-7.96(t, 1H), 8.10-8.12(d, 1H), 8.20-8.22(d, 2H), 8.28-8.31(d, 2H), 8.72-8.73(m, 1H).
LC/MS (ESI-MS) m/z 316 (M+1).
Compound 41: 6-hydroxy-2-(6-phenylpyridin-3-yl)-4H-chromen-4-one (11345)

Compound 41 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 6-phenylnicotinaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 7.14(s, 1H), 7.27-7.34(m, 2H), 7.51-7.57(s, 3H), 7.70-7.72(d, 1H), 8.18-8.22(t, 3H), 8.53-8.55(d, 1H), 9.36-9.37(s, 1H), 10.05(s, 1H).
LC/MS (ESI-MS) m/z 316 (M+1).
Compound 42: 6-hydroxy-2-(4-(pyridin-2-yloxy) phenyl)-4H-chromen-4-one (11355)

Compound 42 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(pyridin-2-yloxy) benzaldehyde by following the similar procedure described in Scheme I.
LC/MS (ESI-MS) m/z 332.42(M+1).
Compound 43: 4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl) phenoxy) benzonitrile (11297)

Compound 43 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(4-formylphenoxy) benzonitrile by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 6.95(s, 1H), 7.23-7.33(m, 6H), 7.64-7.66(d, 1H), 7.89-7.91(d, 2H), 8.16-8.18(d, 2H), 10.02(s, 1H).
LC/MS (ESI-MS) m/z 356.24(M+1).
Compound 44: 6-hydroxy-2-(4-(4-isopropylphenoxy) phenyl)-4H-chromen-4-one (11314)

Compound 44 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(4-isopropylphenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR (CDCl3, 400MHz): d 1.21-1.23(d, 6H), 2.91-2.94(m, 1H), 6.87(s, 1H), 7.05-7.11(m, 4H), 7.23-7.26(q, 1H), 7.31-7.34(m, 3H), 7.61-7.63(d, 1H), 8.07-8.09(q, 2H), 10(s, 1H).
LC/MS (ESI-MS) m/z 373.66(M+1).
Compound 45: 2-(4-(3, 5-dimethylphenoxy) phenyl)-6-hydroxy-4H-chromen-4-one (11317)

Compound 45 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(3, 5-dimethylphenoxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 2.27-2.28(s, 6H), 6.74(s, 2H), 6.87-6.88(q, 2H), 7.09-7.12(d, 2H), 7.23-7.26(q, 1H), 7.31-7.32(d, 1H), 7.61-7.64(d, 1H), 8.07-8.09(m, 2H).
LC/MS (ESI-MS) m/z 359.62(M+1).
Compound 46: 6, 7-dihydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (11334)

Compound 46 was synthesized from 1-(2-hydroxy-4, 5-dimethoxyphenyl) ethan-1-one and 3-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 6.84(s, 1H), 6.98(s, 1H), 7.08-7.10(d, 2H), 7.14-7.17(m, 1H), 7.19-7.21(d, 1H), 7.28(s, 1H), 7.42-7.46(t, 2H), 7.53-7.57(t, 1H), 7.68-7.69(t, 1H), 7.80-7.82(d, 1H).
LC/MS (ESI-MS) m/z 347.45 (M+1).
Compound 47: 6-hydroxy-2-(4-(6-methylpyridin-3-yl) phenyl)-4H-chromen-4-one (11338)

Compound 47 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(6-methylpyridin-3-yl) benzaldehyde by following the similar procedure described in Scheme I.
LC/MS (ESI-MS) m/z 330.41 (M+1).
Compound 48: 6-hydroxy-2-(4-(pyrimidin-5-yl) phenyl)-4H-chromen-4-one (11339)

Compound 48 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(pyrimidin-5-yl) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 7.089(s, 1H), 7.26-7.29(q, 1H), 7.33-7.34(d, 1H), 7.69-7.72(d, 1H), 8.04-8.06(d, 2H), 8.24-8.26(d, 2H), 9.24(s, 1H), 9.268(s, 2H), 10.036(s, 1H).
LC/MS (ESI-MS) m/z 317.46(M+1).
Compound 49: 6-hydroxy-2-(3-methyl-4-phenoxyphenyl)-4H-chromen-4-one (11341)

Compound 49 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(o-tolyloxy) benzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 2.33(s, 3H), 6.90(s, 1H), 6.92-6.95(d, 1H), 7.02-7.04(d, 2H), 7.18-7.20(t, 1H), 7.23-7.26(q, 1H), 7.31-7.32(d, 1H), 7.40-7.44(t, 2H), 7.63-7.65(d, 1H), 7.89-7.92(m, 1H), 8.07-8.08(d, 1H), 9.99(s, 1H).
LC/MS (ESI-MS) m/z 345.66(M+1).
Compound 50: 6-hydroxy-2-(3-hydroxy-4-phenoxyphenyl)-4H-chromen-4-one
(11343)

Compound 50 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 3-hydroxy-4-phenoxybenzaldehyde by following the similar procedure described in Scheme I.
1H NMR(DMSO, 400MHz): d 6.79(s, 1H), 6.96-6.98(t, 2H), 7.03-7.05(d, 1H), 7.09-7.12(t, 1H), 7.24-7.27(q, 1H), 7.32-7.39(m, 3H), 7.52-7.55(q, 1H), 7.59-7.62(t, 2H), 10.01(s, 2H).
LC/MS (ESI-MS) m/z 347 (M+1).
Compound 51: 6-methoxy-2-(4-(pyridin-3-yloxy)phenyl)-4H-chromen-4-one
(11359)

Compound 51 was synthesized from 1-(2-hydroxy-5-methoxyphenyl) ethan-1-one and 4-(pyridin-3-yloxy) benzaldehyde by following the similar procedure described in Scheme I.
LC/MS (ESI-MS) m/z 346.1 (M+1).

Scheme II

Reagents and conditions: (a) Potassium carbonate, DMF, 120 0C, 10 h (b) TFA, DCM, 0-RT.
Preparation of Intermediate 3 (a) :
To the stirred solution of compound 24(1 eq) in DMF, K2CO3 (2.5eq), tert-butyl (2-bromoethyl) carbamate (1.2eq) were added and stirred for 10 hour at 120 0C. The progress of the reaction mixture was monitored by TLC. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was back washed with water, brine solution, dried over sodium sulphate and concentrated on rotavapor. The crude was purified by silica column chromatography to get the desired product.
Preparation of compound 52 (b):
To the stirred solution of Int-1 (1eq) in DCM and 2, 2, 2-trifluoroacetic acid (2eq) was added into the reaction mixture and stirred for overnight at room temperature. The reaction progress was monitored by TLC. The reaction mixture was concentrated.
Compound 52: 6-(2-aminoethoxy)-2-(4-phenoxyphenyl)-4H-chromen-4-one (11310)

Compound 52 was synthesised from 6-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one and tert-butyl (2-bromoethyl) carbamate by following the similar procedure described in Scheme II.
1H NMR(DMSO, 400MHz): d 3.27-3.29(d, 2H), 4.28-4.30(t, 2H), 6.98(s, 1H), 7.12-7.16(t, 4H), 7.23-7.27(t, 1H), 7.45-7.51(m, 4H), 7.78-7.80(d, 1H), 8.01(s, 2H), 8.11-8.14(t, 2H).
LC/MS (ESI-MS) m/z 373.97(M+1).
Compound 53: 6-(2-(dimethyl amino) ethoxy)-2-(4-phenoxyphenyl)-4H-chromen-4-one (11287)

Compound 53 was synthesised from 6-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one and 2-bromo-N, N-dimethylethan-1-amine hydrobromide by following the similar procedure described in Scheme II.
1H NMR (CDCl3, 400MHz): d 2.38(s, 6H), 2.80-2.82(t, 2H), 4.18-4.21(t, 2H), 6.75(s, 1H), 7.08-7.10(m, 4H), 7.20(t, 3H), 7.32-7.35(q, 1H), 7.38-7.42(m, 2H), 7.87-7.89(m, 2H).
LC/MS (ESI-MS) m/z 402.50(M+1).
Compound 54: 6-(2-hydroxyethoxy)-2-(4-phenoxyphenyl)-4H-chromen-4-one (11291)

Compound 54 was synthesised from 6-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one and 2-bromoethan-1-ol by following the similar procedure described in Scheme II.
1H NMR (CDCl3, 400MHz): d 4.01-4.02(t, 2H), 4.19-4.22(t, 2H), 6.76(s, 1H), 7.06-7.11(m, 4H), 7.18-7.22(t, 1H), 7.29-7.34(m, 1H), 7.39-7.43(m, 2H), 7.49-7.52(d, 1H), 7.61-7.62(d, 1H), 7.86-7.90(d, 2H).
LC/MS (ESI-MS) m/z 375.41(M+1).

Scheme-III

Reagents and conditions: (a) K2CO3, DMF, 80 0C, 2 – 4 h; (b) Potassium Hydroxide, Ethanol, RT, 16 h; (c) Iodine, DMSO, 100 °C, 8 h; (d) BBr3, DCM, 0 0C -RT.
Preparation of intermediate 4:
To the stirred solution of 2-(4-hydroxyphenyl)acetamide (1 eq) in DMF, K2CO3 (2.5eq), 4- fluoro benzaldehyde (1eq) were added and stirred for 10 hour at 120 0C. The progress of the reaction mixture was monitored by TLC. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was back washed with water, brine solution, dried over sodium sulphate and concentrated on rotavapor. The crude was purified by silica column chromatography to get the desired product.
Preparation of compound 55:
After synthesising int-4, Scheme I procedure was followed to get compound 55 and compound 56.
Compound 55: 2-(4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy)phenyl)acetamide (11379)

Compound 55 was synthesised by 1-(2-hydroxy-5-methoxyphenyl)ethan-1-one and 2-(4-(4-formylphenoxy)phenyl)acetamide by following similar procedure described in Scheme III.
1H NMR(DMSO, 400MHz): d 3.40(s, 2H) 3.87(s, 3H) 7.07-7.13(m, 4H) 7.32-7.48(m, 5H) 7.72-7.74(q, 1H) 8.09-8.12(d, 2H).
LC/MS (ESI-MS) m/z 401.4 (M+1).
Compound 56: 2-(4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl) phenoxy) phenyl) acetamide (11380)

Compound 56 was synthesised from 2-(4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy)phenyl)acetamide by following similar procedure described in Scheme III.
LC/MS (ESI-MS) m/z 386.06 (M+1).
Compound 57: 3-(4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy) phenyl) propanamide (11381)

Compound 57 was synthesised from 1-(2-hydroxy-5-methoxyphenyl)ethan-1-one and 3-(4-(4-formylphenoxy)phenyl)propanamide by following similar procedure described in Scheme III (till cyclisation).
LC/MS (ESI-MS) m/z 416 (M+1).
Compound 58 : 3-(4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl) phenoxy) phenyl) propanamide (11382)

Compound 58 was synthesised from 3-(4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy) phenyl) propanamide by following similar procedure described in Scheme III.
1H NMR(DMSO, 400MHz): d 2.36-2.40(t, 2H), 2.81-2.85(t, 3H), 6.78(s, 1H), 6.88(s, 1H), 7.00-7.10(m, 4H), 7.23-7.26(q, 1H), 7.28-7.32(t, 4H), 7.62-7.64(d, 1H), 8.07-8.09(d, 2H).
LC/MS (ESI-MS) m/z 402 (M+1).
Compound 59: 4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy)benzaldehyde (11384)

Compound 59 was synthesised from 1-(2-hydroxy-5-methoxyphenyl)ethan-1-one and 4,4'-oxydibenzaldehydeby following a similar procedure described in Scheme III.
1H NMR(DMSO, 400MHz): d 3.88(s, 3H), 7.01-7.03(s, 1H), 7.25-7.33(m, 4H), 7.42-7.46(m, 2H), 7.75-7.77(t, 1H), 7.97-7.99(d, 2H), 8.18-8.21(d, 2H), 9.97(s, 1H).
LC/MS (ESI-MS) m/z 373 (M+1).
Compound 60: 2-(4-(4-(hydroxymethyl)phenoxy)phenyl)-6-methoxy-4H-chromen-4-one (11385)

Compound 60 was synthesised from 1-(2-hydroxy-5-methoxyphenyl)ethan-1-one and 4-(4-(hydroxymethyl)phenoxy)benzaldehyde by following a similar procedure described in Scheme III.
1H NMR(DMSO, 400MHz): d 3.87(s, 3H), 4.51-4.52(d, 2H), 5.21-5.24(t, 1H), 6.96(s, 1H), 7.09-7.12(q, 4H), 7.39-7.43(m, 4H), 7.73-7.75(q, 1H) 8.10-8.12(d, 2H).
LC/MS (ESI-MS) m/z 375 (M+1).
Compound 61: 6-hydroxy-2-(4-(4-(hydroxymethyl)phenoxy)phenyl)-4H-chromen-4-one

Compound 61 was synthesised from 1-(2-hydroxy-5-methoxyphenyl)ethan-1-one and 4-(4-(hydroxymethyl)phenoxy)benzaldehyde by following a similar procedure described in Scheme III.
LC/MS (ESI-MS) m/z 361.3 (M+1).
Compound 62: 4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy)benzoic acid (11353)

Compound 62 was synthesised from 4-fluorobenzaldehyde and methyl 4-hydroxybenzoate by following a similar procedure described in Scheme III.
1H NMR(DMSO, 400MHz): d 6.94(s, 1H), 7.16-7.23(d, 2H), 7.24-7.28(m, 3H), 7.32-7.23(d, 1H), 7.64-7.66(d, 1H), 7.99-8.01(d, 2H), 8.14-8.16(d, 2H), 10.02(s, 1H), 12.89(s, 1H).
LC/MS (ESI-MS) m/z 375.33 (M+1).
Scheme-IV

Reagents and conditions: (a) Potassium Hydroxide, Ethanol, RT, 16 h; (b) Iodine, DMSO, 100 °C, 8 h; (c) Aliphatic bromo compound, K2CO3, DMF, 80 0C, 2h.
Preparation of intermediate 7:
To a stirred solution of 2'-Hydroxy-5'-methoxyacetophenone (1 eq) in Ethanol, followed by Potassium hydroxide (5.0 eq) into the reaction mixture and 4-hydroxy benzaldehyde (1.0eq) was added to the reaction mixture at room temperature. The Reaction mixture was stirred for 16h at room temperature. The reaction mixture was concentrated and redissolved in water and acidified with 10% HCL solution and extracted with Ethyl acetate. The combined organic layer was back washed with water, saturated brine solution, dried over anhydrous sodium sulphate and evaporated on rotavapor to get the desired crude compound. The obtained crude was purified by column chromatography.
Preparation of intermediate 8:
To a stirred solution of Int-7 (1 eq) in DMSO, added Iodine (0.1 – 0.3 eq) and stirred at 100 0C for 8h. The reaction was cooled to room temperature and poured into ice cold water. The aqueous mixture was extracted with Ethyl acetate and the organic layer was back washed with sodium thiosulphate solution, water, and brine solution. Then the organic layer was dried over anhydrous Sodium sulphate and evaporated on rotavapor to get the crude which was purified by column chromatography.
Preparation of Compound 63: 6-methoxy-2-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4H-chromen-4-one (11369)
To the stirred solution of int-8 (1 eq) in DMF added K2CO3 (3-5 eq) and 4-bromotetrahydro-2H-pyran(1 eq) were added and stirred at 100 0C for 6 hours. The reaction was cooled to room temperature and poured into water. The aqueous mixture was extracted with Ethyl acetate and the organic layer was back washed with sodium thiosulphate solution, water, and brine solution. Then the organic layer was dried over anhydrous Sodium sulphate and evaporated on rotavapor.

1H NMR(DMSO, 400MHz): d 1.83-2.12(m, 4H), 3.65-3.75(m, 4H), 3.75(m, 1H), 3.87(s, 3H), 6.94(s, 1H), 7.10-7.12(d, 2H), 7.40-7.43(s, 1H), 7.73-7.75(d, 1H), 7.95(s, 1H), 8.04-8.06(d, 2H).
LC/MS (ESI-MS) m/z 353 (M+1).
Compound 64: 6-methoxy-2-(4-((tetrahydrofuran-3-yl) oxy)phenyl)-4H-chromen-4-one (11368)

Compound 64 was synthesised from 2-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-one and 3-bromotetrahydrofuran by following a procedure similar to that outlined in Scheme IV.
1H NMR(DMSO, 400MHz): d 2.01(m, 1H), 2.35(m, 1H), 3.75-3.95 (m, 5H), 3.89(s, 3H), 6.94(s, 1H), 7.10-7.12(d, 2H), 7.40-7.43(s, 1H), 7.73-7.75(d, 1H), 7.95(s, 1H), 8.04-8.06(d, 2H).
LC/MS (ESI-MS) m/z 339.1 (M+1).
Compound 65 : 6-methoxy-2-(4-((4-methylcyclohexyl)oxy)phenyl)-4H-chromen-4-one (11371)

Compound 64 was synthesised from 2-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-one and 1-bromo-4-methylcyclohexane by following a procedure similar to that outlined in Scheme IV.
1H NMR (DMSO, 400MHz): d 0.91(m, 3H), 1.43-2.16 (m, 9H), 3.84(s, 3H), 4.21(m, 1H), 6.92-6.96(m, 2H), 6.97(s, 1H), 7.22(d, 1H), 7.40-7.43(dd, 1H), 7.52-7.53(d, 1H), 7.72-7.79(dd, 2H).
LC/MS (ESI-MS) m/z 365.4 (M+1).
Compound 66: 2-(4-(((1S, 4R)-bicyclo[2.2.1]heptan-2-yl)oxy)phenyl)-6-methoxy-4H-chromen-4-one (11372)

Compound 66 was synthesised from 2-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-one and (1R, 2R, 4S)-2-bromobicyclo[2.2.1]heptane by following a procedure similar to that outlined in Scheme IV.
1H NMR (DMSO, 400MHz): d 1.26-1.63(m, 8H), 2.35(m, 1H), 2.63(m, 1H), 3.91(s, 3H), 4.25(m, 1H), 6.74(s, 1H), 6.94-6.99(t, 2H), 7.18-7.28(d, 1H), 7.47-7.49(d, 1H), 7.59-7.60(d, 1H), 7.83-7.85(d, 2H).
LC/MS (ESI-MS) m/z 363.3 (M+1).
Compound 67: 2-(4-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)-6-methoxy-4H-chromen-4-one (11373)

Compound 66 was synthesised from 2-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-one and 6-bromo-2-oxaspiro [3.3]heptane by following a procedure similar to that outlined in Scheme IV.
LC/MS (ESI-MS) m/z 365 (M+1).
Scheme V:

Reagents and conditions: (a) Potassium Hydroxide, Ethanol, RT, 16 h; (b) Iodine, DMSO, 100 °C, 8 h; (c) PPh3, CBr4, DCM, RT, 4 h; (d) 4-fluorobenzaldehyde, K2CO3, DMF, 80 0C, 2h.

Preparation of intermediate-9:
To a stirred solution of 2'-Hydroxy-5'-methoxyacetophenone (1 eq) in Ethanol, followed by Potassium hydroxide (5.0 eq) into the reaction mixture and 4-hydroxymethylbenzaldehyde (1.0eq) was added to the reaction mixture at room temperature. The Reaction mixture was stirred for 16h at room temperature. The reaction mixture was concentrated and redissolved in water and acidified with 10% HCL solution and extracted with Ethyl acetate. The combined organic layer was back washed with water, saturated brine solution, dried over anhydrous sodium sulphate and evaporated on rotavapor to get the desired crude compound. The obtained crude was purified by column chromatography.
Preparation of intermediate-10:
To a stirred solution of Int-9 (1 eq) in DMSO, added Iodine (0.1 – 0.3 eq) and stirred at 100 0C for 8h. The reaction was cooled to room temperature and poured into ice cold water. The aqueous mixture was extracted with Ethyl acetate and the organic layer was back washed with sodium thiosulphate solution, water, and brine solution. Then the organic layer was dried over anhydrous Sodium sulphate and evaporated on rotavapor to get the crude which was purified by column chromatography.
Preparation of intermediate-11:
To the stirred solution of Int-10(1 eq) in DCM, added PPh3 (2 eq) followed by CBr4 (1 eq) and stirred at room temperature for 4 hours. The reaction mixture was redissolved in water and extracted with ethyl acetate. The combined organic layer was back washed with water, saturated brine solution, dried over anhydrous sodium sulphate and evaporated on rotavapor to get the desired crude compound.
Preparation of Compound 68: 2-(4-((4-fluorophenoxy) methyl)phenyl)-6-methoxy-4H-chromen-4-one (11393)

To the stirred solution of int-11 (1 eq) in DMF added K2CO3 (3-5 eq) and 4-fluorobenzaldehyde (1 eq) were added and stirred at 80 0C for 2 hours. The reaction was cooled to room temperature and poured into water. The aqueous mixture was extracted with Ethyl acetate and the organic layer was back washed with sodium thiosulphate solution, water, and brine solution. Then the organic layer was dried over anhydrous Sodium sulphate and evaporated on rotavapor
1H NMR (CDCl3, 400MHz): d 3.91(s, 3H), 5.11(s, 2H), 6.76-6.99(m, 8H), 7.51-7.61(m, 3H), 7.93-7.95(d, 1H).
LC/MS (ESI-MS) m/z 377 (M+1).
BIOLOICAL ACTIVITY

Antiviral Screening:
The compounds were tested for in-vitro antiviral activity against a panel of viruses: SARS-CoV-2, influenza (A and B), zika virus, chikungunya virus (CHIKV), Enterovirus, hRSV and Junin virus. SARS-CoV-2 testing was performed in Vero-E6 cell lines using test media DMEM (high glucose) supplemented with 2% FBS and antibiotic and antimycotic solutions. Influenza testing was performed in MDCK cells using test media of MEM with 10 U/mL trypsin, 1 µg/mL EDTA, and 50 µg/mL gentamicin. Zika and CHIKV were tested in Vero-76 cells with test media of MEM supplemented with 2% FBS and gentamicin. Junin virus was tested in Vero E6 cells in MEM with 2% FBS and gentamicin.
Compounds were solubilized in DMSO to prepare a 20 mg/mL or 10 mM stock solution. The antiviral activity of compounds against SARS-CoV-2 was determined by standard plaque assay. For antiviral evaluating the compounds were serially diluted (two-fold) with a top concentration of 25 µM. Each dilution was added to 2 wells of a 96-well plate with 80-100% confluent cells and infected with virus at MOI of 0.01. The cells were incubated for 3-5 days before processing the plates for plaque scoring. The controls such as cell only control and virus only controls were maintained through out to determine the antiviral activity. The cytotoxicity of compound 24 was determined in Vero-E6 cells by measuring LDH assay using Cytoquant LDH assay kit.
Upon completion of incubation, the plates were fixed using 4% paraformaldehyde for 30 minutes and stained with crystal violet for 10-15 minutes. The plaques were scored in each well and % reduction in the virus load was calculated in comparison to virus only control wells. The IC50 of compounds were then determined using Graph Pad Prism (version-9.0).
The results of compounds of the invention provided in the following Table-1.
Compound number IC 50 in µM
SARS-CoV-2 Influenza A Rabies
1 ND 6.25 >25
2 ND >25 >25
3 >25 ND ND
4 >25 >25 >25
5 9.1 ND ND
6 >25 >25 >25
7 >25 >25 >25
8 >25 >25 6
9 ND >25 ND
10 ND >25 ND
11 ND >25 ND
12 ND >25 ND
13 >25 3.13 ND
14 ND 3.13 >25
15 ND >25 ND
16 >25 >25 >25
17 >25 >25 >25
18 ND >25 ND
19 >25 >25 >25
20 ND ND >25
21 >25 >25 ND
22 12.5 >12.5 ND
23 >25 ND ND
24 0.9 1.3 >25
25 25 >25 ND
26 2.5 6.53 >25
27 ND >25 ND
28 >25 >25 >25
29 >25 >25 >25
30 >25 >25 ND
31 ND 2.5 ND
32 ND >25 ND
33 25 6.25 ND
34 4.9 12.5 >25
35 >25 >25 ND
36 >25 >25 >25
37 >25 25 >25
38 25 25 >25
39 >25 ND >25
40 ND 25 >25
41 ND ND >25
42 >25 >25 >25
43 ND >25 ND
44 1.56 3.13 >25
45 25 >25 >25
46 12.5 1.56 >25
47 >25 ND >25
48 >25 ND >25
49 25 >25 >25
50 ND ND >25
51 ND >25 >25
52 >25 >25 ND
53 ND >25 ND
54 ND >25 ND
55 ND >25 >25
56 >25 >25 2
57 >25 >25 >25
58 >25 >25 >25
59 >25 >25 >25
60 >25 1.0 >25
61 ND 1.0 ND
62 ND >25 >25
63 ND >25 >25
64 ND >25 >25
65 ND >25 >25
66 ND 25 >25
67 ND >25 >25
68 ND >25 >25

ND: Not done
In-vitro ADME
Mouse Liver Microsomal Stability:
Mouse microsomal stability of the compound was determined. A homogenate of MLM/HLM (Mouse/Human Liver Matrix)- 0.625 mg/ml was prepared. Compounds at a concentration of 10 µm were spiked into the homogenate to get the final concentration of 1µm and kept in water bath at 370 C for 5min. Sample was collected in triplicates at 0 min and the reaction was quenched using 250 ng/ml acetonitrile containing Internal standard. nicotinamide adenine dinucleotide phosphate (NADPH), 10 mM was added to the above remaining sample to get the final concentration of 1mM and kept in water bath at 370C for different time points (0, 30 and 60min for microsomal stability and 0, 5, 15, 30, 45 and 60min for microsomal intrinsic clearance). At each time point 30µL of reaction mix was aliquoted and quenched using 90µL of acetonitrile containing Internal standard. The samples were centrifuged for 10 minutes at 13000 RPM, supernatant was collected and submitted for analysis. The results are summarized in Table-2 and the compounds had wide range of metabolic profile.
Table-2:
S. No Compound Number % Of compound Remaining
30 min 60 min
1 Compound 4 40.75 20.12
2 Compound 21 83.42 80.48
3 Compound 22 79.45 38.36
4 Compound 23 79.68 62.44
5 Compound 24 95.42 93.18

CYP Inhibition :
CYP inhibition is performed using various CYP isoforms to understand the potential of a compound to inhibit a specific cytochrome P450 enzyme which is important as the co-administration of compounds may result in one or both inhibiting the other’s metabolism. This may affect plasma levels in vivo and potentially lead to adverse drug reactions or toxicity.
For Compound 24, CYP inhibition was determined using 3 isoforms such as CYP3A4, CYP2B6, and CYP2C9. The proposed protocol remains similar for all 3 isoforms. However, the substrate and positive control inhibitors are varied based on the requirement.
Assay Protocol:
Preparation of Reagents:
1) 100mM Phosphate Buffer Solution (PBS): Weighed 0.607 g of K2HPO4 and 0.212 g of KH2PO4 in milli-Q water and made up the solution to 50mL. pH was adjusted to ~ 7.38-7.42, using 0.1M HCL or NaOH.
2) Stock of Substrate/Test compound/Positive control: 10mM stock conc. of the test compound/Positive Control was prepared using DMSO as a diluent.
3) 10mM NADPH: Weighed the required quantity of NADPH and diluted the same using phosphate buffer to achieve 10mM NADPH.
4) Preparations of Serial concentrations of Test/ Positive control (200 X): Prepared 200 X of intermediate serial concentrations ranging from 0.2, 2, 20, 100, 200, 1000, 2000, and 5000 µM using PBS buffer.
5) Microsomal Mixture: Transferred 80 µL of 20mg/mL Human Liver Microsomes (HLM) to 3104 µL of PBS to achieve 0.5mg/mL as final conc. To this, 16 µL of 10mM Substrate was added to achieve 50µM of substrate conc. The total volume of the microsomal mixture is 3200 µL.
Procedure:
Aliquoted 200 µL of the microsomal mixture to the labelled tubes and added 1µL of 200X conc. of Test/Positive control to the microsomal mixture to get final conc. of 0.001, 0.05, 0.1, 1, 5, 10, 10, 25 µM. Aliquoted 100 µL of eight conc. of both test/positive control in labelled tubes in duplicate and 100 µL of the microsomal mixture in separate tubes in duplicate added 1 µL of DMSO that is considered as control. Preincubated the tubes in a water bath with a shaker at 30 rpm for 10 min at 37oC. Collected 10 µL from each tube into other tubes and quenched with acetonitrile containing internal standard and labelled as zero hours.
To the preincubated tubes, 10µL of 10mM NADPH was added to achieve 1mM NADPH. The tubes were incubated at 37oC in a water batch with shaking at 30rpm. Collected 50 µL in duplicate from each substrate solution and quenched using 50 µL of acetonitrile containing internal standard at desired time interval i.e., 20 min. Centrifuged the quenched samples at 13000rpm for 10min at 4oC and transferred the supernatant into the autosampler vials and loaded for analysis, by LC-MS/MS. The results were summarised in Table-3.
Table-3:
Test Compound CYP Isoforms IC50
(uM)
Compound 24 CYP3A4 10.1
CYP2B6 41.75
CYP2C9 25.88

Plasma Protein Binding:
The depth of binding to plasma influences the way in which a drug distributes into body tissues. Extensive plasma protein binding also limits the amount of free compound available to access sites of action in the cell, and metabolism and elimination may be slower. Equilibrium dialysis is the most widely accepted method for assessing plasma protein binding as non-specific binding
Protocol:
10mM stock solution of the compound was prepared using DMSO as a diluent. Prepared intermediate conc. of 500µM by spiking 15µl of stock in 285µl of acetonitrile. Prepared sample by spiking 5µl of intermediate stock in 295µl of blank plasma to achieve the final concentration at 5µM. Aliquoted 200 µL of the sample into the sample chamber (red ring of the insert). Added 350 µL of dialysis buffer (1X PBS pH 7.4) to the buffer chamber. Covered the unit with sealing tape and incubated at 37oC on an orbital shaker at 100rpm for 4.0 hrs. Aliquoted 100 µL from both the buffer and the plasma chambers and transferred into the different tubes. Added 100 µL of plasma to the buffer samples, and 100 µl of 1X PBS pH 7.4 to the collected plasma samples. Added 400 µL of acetonitrile containing internal standard to precipitate protein and release the compound. Vortexed and centrifuged at 13,000rpm for 10 minutes at 4oC. Transferred the supernatant into the autosampler vials and loaded for analysis, by LC-MS/MS.
Calculation:
% Free = (Concentration buffer chamber/Concentration plasma chamber) x 100%
% Bound = 100% - % Free
The compound 24 displayed 99% of plasma protein binding affinity.
In-vivo Pharmacokinetics:
Determination of Pharmacokinetic and Pharmacodynamic of Compound 24 in Mice Plasma and Lungs:
The infected and healthy mice animals were used for dosing compound 24 via the IP and oral route of administration. The dosing formulation was prepared by suspending the compound in 5% DMA, 10% Solutol, and 85% NS. The pharmacokinetic and pharmacodynamic analysis was done in infected animals, including male and female groups. The animals infected with Influenza A were dosed with compound 24 through the intra-peritoneal route and the healthy animals were dosed with the 100 mg/kg through the oral route.
For each group, 6 animals were used for dosing. n=2 plasma samples were collected at desired time points i.e., 0.5, 1, 2, 4, 6, and 24hrs from the infected and non-infected male groups, and n=1 from the infected female groups. A sparse sampling method was followed for collecting the plasma samples. The lung samples were collected from two animals (n=2) from healthy animals administered through the oral route at 6- and 24-hours’ time points. The samples were stored at -80°C until analysis.
An LC-MS/MS analytical method was developed to determine compound 24 following a simple protein precipitation processing technique. The method found linear from 100 to 5000 ng/mL in plasma and 100 to 5000 ng/gm in lung matrices. The regression (r2) was found fit at > 0.99. The plasma and lung samples were analyzed individually along with calibration curve standards prepared with the respective matrices. All the batches met the acceptance criteria.
The PK parameters obtained from plasma samples for 100 mg/kg IP and oral dose groups were shown in Table 4.
Table -4: Compound 24: Plasma Pharmacokinetic Parameters for 100 mg/kg Dose Groups
Parameter IP_100 mg/kg (male) IP_100 mg/kg (female) Oral_100 mg/kg
t1/2 (h) 13.45 20.86 2.28
Tmax (h) 0.5 0.5 1
Cmax 2460 1931 780
(ng/mL)
AUC 0-t 23390 22272 2521
(ng/ml*h)
MRT 17.8 30.92 3.6
(ng/ml*h)
Cl/F_obs (mg/kg)/ 0.003 0.002 0.032
(ng/ml)/h

The lung concentration obtained from non-infected animals, oral route, was as per Table 5.
Table-5: Lung Concentration Data from 100 mg/kg Oral Route from Non-Infected Animals
Subject ID Individual Conc. (ng/gm) Average Conc. (ng/gm)
Sub-1_6H_Compound 24_ Oral 100 mpk 242 199
Sub-2_6H_ Compound 24_ Oral 100 mpk 155
Sub-1_24H_ Compound 24_ Oral 100 mpk 0 0
Sub-2_24H_ Compound 24_ Oral 100 mpk 0
The compound of the present invention, particularly, compound 24 have shown a decent PK profile and were orally bioavailable.
In an embodiment, the present invention provides pharmaceutical compositions that include any administrable form including solid (tablets, pills, capsules, granules, and the like) liquid (solutions, suspensions, emulsions, and the like) for oral, topical, or parenteral administration.
,CLAIMS:CLAIMS

We claim:

1. A compound of formula (I):

FORMULA (I)

Wherein,
X is independently selected from a group consisting of Oxygen, NH and NR3,
where R3 is C1-C6 alkyl;
R1 is independently selected from a group consisting of hydrogen, halogens, OH, OCH3, CF3, OCF3, COOH and CONHR, where R = C1-C6 alkyl and optionally substituted C6-C18 aryl.
R2 is independently selected from the group consisting of hydrogen, halogens, OH, OCH3, CF3, OCF3, COOH , -(CH2)n-OR, -(CH2)n-COOH and -(CH2)n-CONHR, where n=0, 1, 2, 3, 4 and R= hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C6-C18 aryl, optionally substituted C1-C18 heteroaryl, and acyl.
2. The compound of Formula (I) as claimed in claim 1, wherein the said compound is selected from the group consisting of:
(1) 6-methoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one;
(2) 6-methoxy-2-(3-phenoxyphenyl)-4H-chromen-4-one; (3) 7-methoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one; (4) 7-methoxy-2-(3-phenoxyphenyl)-4H-chromen-4-one; (5) 5,7-dimethoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one; (6) 4-oxo-2-(3-phenoxyphenyl)-4H-chromene-6-carboxylic acid; (7) 4-oxo-2-(4-phenoxyphenyl)-4H-chromene-6-carboxylic acid; (8) 2-(3-phenoxyphenyl) quinolin-4(1H)-one; (9) 2-(4-(4-fluorophenoxy) phenyl)-6-methoxy-4H-chromen-4-one; (10) 2-(4-(3,4-difluorophenoxy) phenyl)-6-methoxy-4H-chromen-4-one; (11) 4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy) benzonitrile; (12) 2-(4-(2-fluorophenoxy) phenyl)-6-methoxy-4H-chromen-4-one; (13) 6-methoxy-2-(4-(4-methoxyphenoxy) phenyl)-4H-chromen-4-one; (14) 2-(4-(4-hydroxyphenoxy) phenyl)-6-methoxy-4H-chromen-4-one; (15) 6-methoxy-2-(4-(phenylamino) phenyl)-4H-chromen-4-one; (16) 6,7-dimethoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one; (17) 6-methoxy-2-(4-(pyridin-2-yloxy) phenyl)-4H-chromen-4-one; (18) 6-methoxy-2-(4-(4-(trifluoromethyl) phenoxy) phenyl)-4H-chromen-4-one; (19) 2-(4-(3,5-dimethylphenoxy) phenyl)-6-methoxy-4H-chromen-4-one; (20) 6-methoxy-2-(3-methoxy-4-phenoxyphenyl)-4H-chromen-4-one; (21) 2-(4-cyclohexylphenyl)-7-methyl-4-oxo-4H-chromene-6-carboxylic acid; (22) 2-(4-cyclohexylphenyl)-8-methyl-4-oxo-4H-chromene-6-carboxylic acid; (23) 2-(4-cyclohexylphenyl)-8-fluoro-4-oxo-4H-chromene-6-carboxylic acid; (24) 6-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one; (25) 6-hydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one; (26) 7-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one; (27) 5,7-dihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one; (28) 5,6,7-trihydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one; (29) 5,6,7-trihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one; (30) 2-(4-(4-fluorophenoxy) phenyl)-6-hydroxy-4H-chromen-4-one; (31) 2-(4-(2-fluorophenoxy) phenyl)-6-hydroxy-4H-chromen-4-one; (32) 2-(4-(3,4-difluorophenoxy) phenyl)-6-hydroxy-4H-chromen-4-one; (33) 6-hydroxy-2-(4-(4-methoxyphenoxy) phenyl)-4H-chromen-4-one; (34) 6-hydroxy-2-(4-(phenylamino) phenyl)-4H-chromen-4-one; (35) 2-([1,1'-biphenyl]-4-yl)-6-hydroxy-4H-chromen-4-one; (36) 6-hydroxy-2-(4-(pyridin-4-yl) phenyl)-4H-chromen-4-one; (37) 6,7-dihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one; (38) 4-oxo-2-(4-phenoxyphenyl)-4H-chromene-6-carboxylic acid; (39) 6-hydroxy-2-(4-(pyridin-3-yl) phenyl)-4H-chromen-4-one; (40) 6-hydroxy-2-(4-(pyridin-2-yl) phenyl)-4H-chromen-4-one; (41) 6-hydroxy-2-(6-phenylpyridin-3-yl)-4H-chromen-4-one; (42) 6-hydroxy-2-(4-(pyridin-2-yloxy) phenyl)-4H-chromen-4-one; (43) 4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl) phenoxy) benzonitrile; (44) 6-hydroxy-2-(4-(4-isopropylphenoxy) phenyl)-4H-chromen-4-one; (45) 2-(4-(3,5-dimethylphenoxy) phenyl)-6-hydroxy-4H-chromen-4-one; (46) 6,7-dihydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one; (47) 6-hydroxy-2-(4-(6-methylpyridin-3-yl) phenyl)-4H-chromen-4-one; (48) 6-hydroxy-2-(4-(pyrimidin-5-yl) phenyl)-4H-chromen-4-one; (49) 6-hydroxy-2-(3-methyl-4-phenoxyphenyl)-4H-chromen-4-one; (50) 6-hydroxy-2-(3-hydroxy-4-phenoxyphenyl)-4H-chromen-4-one; (51) 6-methoxy-2-(4-(pyridin-3-yloxy)phenyl)-4H-chromen-4-one; (52) 6-(2-aminoethoxy)-2-(4-phenoxyphenyl)-4H-chromen-4-one; (53) 6-(2-(dimethyl amino) ethoxy)-2-(4-phenoxyphenyl)-4H-chromen-4-one; (54) 6-(2-hydroxyethoxy)-2-(4-phenoxyphenyl)-4H-chromen-4-one; (55) 2-(4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy)phenyl)acetamide; (56) 2-(4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy)phenyl)acetamide; (57) 3-(4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy)phenyl)propenamide; (58) 3-(4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy)phenyl)propenamide; (59) : 4-(4-(6-methoxy-4-oxo-4H-chromen-2-yl) phenoxy)benzaldehyde; (60) 2-(4-(4-(hydroxymethyl)phenoxy)phenyl)-6-methoxy-4H-chromen-4-one; (61) 6-hydroxy-2-(4-(4-(hydroxymethyl)phenoxy)phenyl)-4H-chromen-4-one; (62) 4-(4-(6-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy)benzoic acid; (63) : 6-methoxy-2-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4H-chromen-4-one; (64) : 6-methoxy-2-(4-((tetrahydrofuran-3-yl) oxy)phenyl)-4H-chromen-4-one; (65) 6-methoxy-2-(4-((4-methylcyclohexyl)oxy)phenyl)-4H-chromen-4-one; (66) 2-(4-(((1S,4R)-bicyclo[2.2.1]heptan-2-yl)oxy)phenyl)-6-methoxy-4H-chromen-4-one; (67) 2-(4-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)-6-methoxy-4H-chromen-4-one; and (68) 2-(4-((4-fluorophenoxy) methyl) phenyl)-6-methoxy-4H-chromen-4-one.
3. A pharmaceutical composition comprising the compound as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or a diluent.
4. A pharmaceutical composition comprising the compound as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof, for use in the treatment of viral infections caused bySARS-CoV-2, Human respiratory syncytial virus, influenza A & B types, Chikungunya virus, Zika virus, and Rabies virus.
5. A method of treating viral infections comprising administering to a subject in need thereof a therapeutically effective amount of a compound as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof.