FOR THE TREATMENT OF CANCER

1

SULFONE DERIVATIVES

Field of the Invention

The present invention is related to novel compound of the general formula (I) ,

its tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its N- oxides, its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates, its co-crystals, its combinations with suitable medicament, its pharmaceutical compositions, its methods of preparation, and its use as PKM2 modulator, which includes use as PKM2 activator and therapeutic utility thereof in various pathological conditions.

Background of the invention

Tumor cells, unlike normal cells, use aerobic glycolysis for glucose metabolism (referred to as the Warburg effect) and this step is essential for tumorigenesis. Additionally, cancer cells show preferential utilization of glucose (aerobic glycolysis) and reduced oxidative phosphorylation (mitochondrial ETC). Cancer cells utilize a very small fraction of glucose for oxidative phosphorylation (and the subsequent generation of CO2). The majority goes towards macromolecular synthesis, a property seen in fetal cells as well. Cancer cells thus show a distinct reprogramming of metabolic pathways as compared to normal cells (Mazurek et al., Semin. Cancer Biol., 2005, 15, p. 300).

A key enzyme in the metabolism of glucose is pyruvate kinase. It catalyzes the conversion of phosphoenol pyruvate (PEP) to pyruvate and in the process generates energy in the form of adenosine triphosphate (ATP). Humans possess four isoforms of PK (L: Liver; R: RBC; Ml : adult tissues; M2: fetal tissues). PKM1 and PKM2 are splice variants and differ in one exon. PKM2 is present in fetal tissues as well as adult tissues (Bluemlein et al., Oncotarget, 2011 , 2(5), p. 393-400). Cancer cells are known to harbour both dimeric as well as the tetrameric forms of PKM2 (Mazurek et al., Semin. Cancer Biol., 2005, 15, p. 300). Dimeric (less active) form allows synthesis of amino acids, macromolecules, etc. Accumulation of fructose- 1 ,6-bisphosphate (FBP) leads to tetramerization which in turn leads to enhanced formation of pyruvate and lactate. Phosphorylation of PKM2 by tyrosine kinases (e.g. Bcr-Abl, FGFR1) leads to retention of PKM2 in dimeric form and subsequent lack of pyruvate kinase activity (Christofk et al., Nature, 2008, 452(7184), p. 181- 186; Hitosugi et al., Sci Signal, 2009, 2(97), ra73). The tetrameric PKM2 is allosterically activated by fructose- 1 ,6-bis-phosphate (FBP) through binding at the flexible loop region near the dimer-dimer interface of the tetramer. PKM1 although has high affinity for PEP, is not bound by FBP. The glycolytic intermediates are channelized towards macromolecular synthesis by the two activity states of PKM2. In the low activity state, PKM2 cannot efficiently catalyze the conversion of PEP to pyruvate and this leads to the accumulation of glycolytic intermediates. These are then utilized for synthesis of amino acids, nucleic acids, etc. Once the concentration of FBP in the cell reaches a certain level, the dimeric low activity PKM2 is converted to a tetrameric high activity state. In this conformation, PKM2 rapidly converts PEP to pyruvate and generates energy in the form of ATP. In cancer cells, PKM2 is phosphorylated (by tyrosine kinases) and is maintained in its dimeric low activity state. It can oscillate between the low and high activity state depending upon the phosphorylation status and the intracellular concentration of FBP. The function of PKM2 is thought to be critical for cancer cell survival and for the sustenance of the Warburg effect. (Vander Heiden et al., Science, 2009, 324, p. 1029; Ferguson and Rathmell, Trends Biochem. Sci., 2008, 33, p. 359). Activating PKM2 would starve cancer cells of building blocks essential for survival. In human lung cancer cells, accumulation of reactive oxygen species (ROS) was shown to lead to inhibition of PKM2 activity by oxidation of Cys358 (Anastasiou et al., Science, 201 1 , 334(6060), p. 1278-83). The tumor suppressor protein DAPK (Death Associated Protein Kinase) has been shown to bind to and activate PKM2 function. Binding of DAPK to PKM2 stabilizes the later in the active tetrameric form. Inactivation of DAPK in most cancers allows cancer cells to retain PKM2 in the inactive dimeric form (Mor et al., Oncogene, 2012, 31 (6), p. 683-93; Erol Cell Cycle, 2012, 1 1 (8)).

Nuclear dimeric PKM2 has been shown to regulate the activity of transcription factors such as HIF- la (Luo et al., Cell, 2011 , 145(5), p. 732-44), b-catenin (Yang et al., Nature, 201 1 , 480(7375), p. 118- 122) and STAT3 (Gao et al., Mol. Cell, 2012, 45(5), p. 598-609). This is an additional mechanism by which dimeric PKM2 can promote tumorigenesis.

PKM2 modulators can be used for treatment of diseases including but not limited to cancer and other diseases occurring as a result of cell proliferation and/or deregulation of PKM2 activity.

Summary of the Invention

According to one aspect of the present invention there is provided a novel compound of the general formula (I), its tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its N-oxides, its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates, or its co-crystals,

wherein, and (R ² ) _m are 'n' and 'm' times repetition of 'R ¹ ' and 'R ² ' groups respectively, wherein each 'R ¹ ' and 'R ² ' are independently selected at each repetition from the group consisting of halogen, nitro, cyano, substituted or unsubstituted alkyl, perhaloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, (OH)2B- , R ³ (0) _q S-, R ³ 0-, R ³ C(=0)-, R ⁴ C(=0)(R ³ )N-, R4(R3)N-, R ³ 0C(=0)-, R ³ C(=0)0-, R ⁴ (R ³ )NS0 ₂ -, and two R ^: s or two R ² s and the carbon atoms to which they are attached together form a substituted or unsubstituted 5 to 6 member saturated or unsaturated cyclic system which optionally contains 1 to 3 heteroatoms/groups selected from -NH-, - S-, -0-, -C(=0)-, -C(=S)-; or two R ^! s or two R s and the carbon atoms to which they are attached together form a substituted or unsubstituted 5 to 6 member aromatic system which optionally contains 1 to 2 heteroatoms selected from N, S, or O;

'n' and 'm' are the integers independently selected from 0, 1 , 2 and 3, 'q' is an integer selected from 0, 1 and 2; ring 'A' is selected from

( ^a > ( ^b ) ( ^c ) (d) wherein,

D and E are independently selected from CR ⁵ , S, O and NR ^5a ; G and G' are independently selected from N and CH, such that when either of G or G' is selected as CH, being a part of ring, hydrogen of CH may be substituted with Re or R ⁷ ;

R ⁵ is selected from hydrogen, substituted or unsubstituted alkyl, halogen, and hydroxy;

R ^5a is selected from hydrogen, and substituted or unsubstituted alkyl;

R ⁶ is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, R ⁴ (R ³ )N-, R ⁴ (R ³ )NC(=0)-, R ³ OC(=0)-, and R ³ C(=0)(R ⁴ )N-;

R ⁷ is selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted alkyl, R ⁴ (R ³ )NC(=0)-, and R ³ 0C(=0)-;

R ³ and R ⁴ are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; such that when they are the part of groups selected from R ⁴ C(=0)(R ³ )N-, R ⁴ (R ³ )N-, R ⁴ (R ³ )NC(=0)-, together with the atom(s) to which they are attached may form a 3 to 10 membered substituted or unsubstituted saturated/unsaturated monocyclic/bicyclic or optionally bridged heterocyclic ring system; with a proviso that when ring 'A' is selected as (a) with E being C or N, (i) both of 'n' and 'm' are not selected as 0 at the same time;

(ii) if 'n' = 1 and 'm' = 0, R ¹ is not selected as halogen;

(iii) if 'n' = 0 and 'm' = 1 , R ² is not selected as halogen;

(iv) if 'n' = 1 and 'm' = 1 , R ¹ and R ² both are not selected as halogen at the same time; when ring 'A' is selected as (d), G≠ G'; when ring 'A' is selected as (d) with G being N and G' being CH, and one of R ⁶ and R ⁷ is hydrogen the other is not selected as -CN when it takes alpha position from fusion.

In another aspect, the present invention provides a pharmaceutical composition containing the compound of the general formula (I) as defined herein, its tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its N- oxides, its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates, or its co-crystals in combination with the usual pharmaceutically employed carriers, diluents and the like are useful for the treatment of a disease responsive to activation of human PKM2.

Yet in another aspect, the present invention provides the compound of general formula (I) for use in treating a disease responsive to activation of human PKM2.

Detailed Description of the invention

According to one aspect of the present invention there is provided a novel compound of the general formula (I), its tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its N-oxides, its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates, or its co-crystals thereof,

wherein,

(R ^! jn and (R ² ) _m are 'n' and 'm' times repetition of 'R ¹ ' and 'R ² ' groups respectively, wherein each 'R ¹ ' and 'R ² ' are independently selected at each repetition from the group consisting of halogen, nitro, cyano, substituted or unsubstituted alkyl, perhaloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, (OH) ₂ B-, R ³ (0) _q S-, R ³ 0-, R ³ C(=0)-, R ⁴ C(=0)(R ³ )N-, R*(R ³ )N-, R ³ OC(=0)-, R ³ C(=0)0-, R ⁴ (R ³ )NS0 ₂ -, and two R ^! s or two R ² s and the carbon atoms to which they are attached together form a substituted or unsubstituted 5 to 6 member saturated or unsaturated cyclic system which optionally contains 1 to 3 heteroatoms/groups selected from -NH-, - S-, -0-, -C(=0)-, -C(=S)-; or two R ^: s or two R ² s and the carbon atoms to which they are attached together form a substituted or unsubstituted 5 to 6 member aromatic system which optionally contains 1 to 2 heteroatoms selected from N, S, or O;

'n' and 'm' are the integers independently selected from 0, 1 , 2 and 3, 'q' is an integer selected from 0, 1 and 2; ring 'A' is selected from

(a) (b) (c) (d) wherein,

D and E are independently selected from CR ⁵ , S, O and NR ^5a ; G and G' are independently selected from N and CH, such that when either of G or G' is selected as CH, being a part of ring, hydrogen of CH may be substituted with R ⁶ or R ⁷ ; R ⁵ is selected from hydrogen, substituted or unsubstituted alkyl, halogen, and hydroxy;

R ^5a is selected from hydrogen, and substituted or unsubstituted alkyl;

R ⁶ is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, R ⁴ (R ³ )N-, R ⁴ (R ³ )NC(=0)-, R ³ OC(=0)-, and R ³ C(=0)(R ⁴ )N-;

R ⁷ is selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted alkyl, R ⁴ (R ³ )NC(=0)-, and R ³ 0C(=0)-; R ³ and R ⁴ are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; such that when they are the part of groups selected from R ⁴ C(=0)(R ³ )N-, R ⁴ (R ³ )N-, R ⁴ (R ³ )NC(=0)-, together with the atom(s) to which they are attached may form a 3 to 10 membered substituted or unsubstituted saturated/unsaturated monocyclic/bicyclic or optionally bridged heterocyclic ring system; with a proviso that when ring 'A' is selected as (a) with E being C or N,

(i) both of 'n' and 'm' are not selected as 0 at the same time;

(ii) if 'n' = 1 and 'm' = 0, R ¹ is not selected as halogen;

(iii) if 'n' = 0 and 'm' = 1 , R ² is not selected as halogen; (iv) if 'n' = 1 and 'm' = 1 , R ¹ and R ² both are not selected as halogen at the same time; when ring 'A' is selected as (d), G≠ G'; when ring Ά is selected as (d) with G being N and G' being CH, and one of R ⁶ and R ⁷ is hydrogen the other is not selected as -CN when it takes alpha position from fusion; the substituents on 'alkyl', 'alkenyl', and 'alkynyl' are selected from the group consisting of oxo, halogen, nitro, cyano, aryl, cycloalkyl, heteroaryl, R ^S A ¹ -, R ^8a S0 ₂ -, R ^8a OC(=0)-, R ^8a C(=0)0-, R ⁸ (H)NC(=0)-, R ⁸ (alkyl)NC(=0)-, R ^8a C(=0)(H)N-, R ⁸ (H)N-, R ⁸ (alkyl)N-, R ⁸ (H)NC(=A ⁱ )(H)N-, and R ⁸ (alkyl)NC(=A ⁱ )(H)N-; the substituents on 'cycloalkyl', 'cycloalkenyl' and '5-6 membered cyclic system' are selected from the group consisting of oxo, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, R ⁸ A ⁱ -, R ^8a S0 ₂ -, R ^8a OC(=0)-, R ^8a C(=0)0-, R ⁸ (H)NC(=0)-, R ⁸ (alkyl)NC(=0)-, R ^8a C(=0)(H)N-, R ⁸ (H)N-, R ⁸ (alkyl)N-, R ⁸ (H)NC(=A ⁱ )(H)N-, and R ⁸ (alkyl)NC(=A ⁱ )(H)N-; the substituents on 'aryl' and '5-6 membered aromatic system' are selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, perhaloalkyl, cycloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl(H)N-, alkyl(alkyl)N-, H ₂ N-, alkyl-SC -, perhaloalkyl-S0 ₂ -, alkyl-C(=0)(H)N-, alkyl-C(=0)(alkyl)N-, alkyl(H)NC(=0)-, alkyl(alkyl)NC(=0)-, H ₂ NC(=0)-, alkyl(H)NS0 ₂ - , alkyl (alkyl) NS0 ₂ -, H ₂ NS0 ₂ -, 3 to 6 membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein the said 3 to 6 membered heterocycle is substituted or unsubstituted with alkyl, alkenyl, alkynyl, or alkyl-C(=0)-; or the said substituted or unsubstituted aryl ring optionally fused with cycloalkane ring or heterocycle ring containing 1 to 3 heteroatoms selected from S, O, N, across a bond, wherein the said cycloalkane ring or heterocycle ring is optionally substituted with oxo, alkyl, alkenyl, alkynyl or alkyl-C(=0)-; the substituents on 'heteroaryl' are selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, perhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-S0 ₂ -, perhaloalkyl-S0 ₂ -, H ₂ N-, alkyl(H)N-, alkyl(alkyl)N-, alkyl-C(=0)(H)N-, alkyl-C(=0)(alkyl)N-, NH ₂ C(=0)-, alkyl(H)NC(=0)-, alkyl(alkyl)NC(=0)-, NH ₂ S0 ₂ -, alkyl(H)NS0 ₂ -, alkyl(alkyl)NS0 ₂ - and 3 to 6 membered heterocycle containing 1 to 2 heteroatoms selected from N, O and S, wherein the heterocycle is substituted or unsubstituted with one to four substituents selected from the group consisting of alkyl, alkenyl, alkynyl or alkyl-

C(=0)-; the substituents on ring carbon(s) of 'heterocycle' and '3- 10 membered heterocyclic ring system' are selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, aryl, heteroaryl, R ⁸ A ⁱ -, R ^8a OC(=0)-, R ^8a C(=0)0-,

R ⁸ (H)NC(=A ⁱ ) (H)N-, and R ⁸ (alkyl)NC(=A ⁱ ) (H)N-; the substituents on ring nitrogen(s) of 'heterocycle' and '3- 10 membered heterocyclic ring system' are selected from the group consisting of alkyl, alkenyl, alkynyl, heteroaryl, R ^8a S02-, R ^8a C(=0)-, R ^8a OC(=0)-, R ⁸ (H)NC(=0)-, R ⁸ (alkyl)NC(=0)- and aryl substituted or unsubstituted with 1 to 3 substituents selected independently from halogen, alkyl, alkenyl, alkynyl, cyano or nitro;

R ⁸ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R ^8a is selected from alkyl, alkenyl, alkynyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; and

A ¹ is selected from the group consisting of O and S.

In one of the embodiments of the present invention of compound of formula (I) as described above, ring Ά is selected from

wherein R ⁵ , R ^5a , R ⁶ , and R ⁷ are as defined above.

In another embodiment of the present invention of compound of formula (I) as described above, R ¹ is selected from R ³ 0-, halogen, substituted or unsubstituted alkyl, perhaloalkyl, and R ³ C(=0)(R ⁴ )N-, wherein R ³ and R ⁴ are as defined above; and n is selected from 1 and 2.

Yet in another embodiment of the present invention of compound of formula (I) as described above, R ² is selected from R ³ 0-, halogen, substituted or unsubstituted alkyl, perhaloalkyl, R ³ C(=0)(R ⁴ )N-, and two R ² s combining to form six membered ring containing two oxygen atom, wherein R ³ and R ⁴ are as defined above; and m is selected from 1 and 2.

In any of the embodiment of the present invention of compound of formula (I) as described above, ring 'A' is selected from

wherein R ⁵ , R ^5a , R ⁶ , and R ⁷ are as defined above;

R ¹ is selected from R ³ 0-, halogen, substituted or unsubstituted alkyl, perhaloalkyl, and R ³ C(=0)(R ⁴ )N-; R ² is selected from R ³ 0-, halogen, substituted or unsubstituted alkyl, perhaloalkyl, R ³ C(=0)(R ⁴ )N-, and two R ² s combining to form six membered ring containing two oxygen atom, wherein R ³ and R ⁴ are as defined above; n is selected from 1 and 2; and m is selected from 1 and 2.

General terms used hereinabove can be defined as follows; however, the meaning stated should not be interpreted as limiting the scope of the term per se.

The term 'alkyl' as used herein, means a straight chain or branched hydrocarbon containing from 1 to 20 carbon atoms. Preferably the alkyl chain may contain 1 to 10 carbon atoms. More preferably alkyl chain may contain up to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, and n-hexyl.

The term 'alkenyl' as used herein, means an alkyl group as defined hereinabove containing 2 to 20 carbon atoms and containing at least one double bond. Representative examples of alkenyl include, but are not limited to, ethylene, propenyl, isopropenyl, n-butenyl, sec-butenyl, isobutenyl, tert-butenyl, pentenyl, isopentenyl, hexenyl, and the like. The term 'alkynyl' as used herein, means an alkyl group as defined hereinabove containing 2 to 20 carbon atoms and containing at least one triple bond. Representative examples of alkynyl include, but are not limited to propynyl, isopropynyl, n-butynyl, sec-butynyl, isobutynyl, tert-butynyl, pentynyl, isopentynyl, hexynyl, and the like.

'Alkyl', 'alkenyl' or 'alkynyl' as defined hereinabove may be substituted or unsubstituted with one or more substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, cycloalkyl, hereroaryl, R ⁸ A ^! -, R ^8a S0 ₂ -, R ^8a OC(=0)-, R ^8a C(=0)0-, R ⁸ (H)NC(=0)-, R ⁸ (alkyl)NC(=0)-, R ^8a C(=0)(H)N-, R ⁸ (H)N-, R ⁸ (alkyl)N-, R ⁸ (H)NC(=A ^! )(H)N-, and R ⁸ (alkyl)NC(=A ¹ )(H)N-; wherein R ⁸ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R ^8a is selected from alkyl, alkenyl, alkynyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; and A ¹ is selected from the group consisting of O and S. The term 'perhaloalkyl' used herein means an alkyl group as defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen. The perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl and the like.

The term 'cycloalkyl' as used herein, means a monocyclic, bicyclic, or tricyclic non- aromatic ring system containing from 3 to 14 carbon atoms, preferably monocyclic cycloalkyl ring containing 3 to 6 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[3.1.0]hexane, bicyclo[410]heptane, bicyclo[3.2.0]heptanes, and octahydro- lH-indene. Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non- adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0 ^{3 7} ]nonane and tricyclo[3.3.1.1 ^{3 7} ]decane (adamantane) . The term cycloalkyl also include spiro systems wherein one of the ring is annulated on a single carbon atom such ring systems are exemplified by spiro [2.5] octane, spiro[4.5]decane, spiro[bicyclo[4.1.0]heptane-2, 1 '-cyclopentane] , hexahydro-2'H- spiro [cyclopropane- 1 , 1 '-pentalene] .

The term 'cycloalkenyl' as used herein, means cycloalkyl group as defined hereinabove containing 3 to 20 carbon atoms and containing at least one double bond. Representative examples of cycloalkenyl include, but are not limited to cyclopentenyl and cyclohexenyl.

'Cycloalkyl' and 'cycloalkenyl' as defined hereinabove may be substituted with one or more substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, R ^S A ¹ -, R ^8a S0 ₂ -, R ^8a OC(=0)-, R ^8a C(=0)0-, R ⁸ (H)NC(=0)-, R ⁸ (alkyl)NC(=0)-, R ^8a C(=0)(H)N-, R ⁸ (H)N-, R ⁸ (alkyl)N-, Rs(H)NC(=A ⁱ )(H)N-, and R ⁸ (alkyl)NC(=A ⁱ )(H)N-; wherein Rs is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R ^8a is selected from alkyl, alkenyl, alkynyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; and A ¹ is selected from the group consisting of O and S.

The term 'aryl' refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Aryl group also include partially saturated bicyclic and tricyclic aromatic hydrocarbons such as tetrahydro-naphthalene. The said aryl group also includes aryl rings fused with heteroaryl or heterocyclic rings such as 2,3-dihydro-benzo[l ,4]dioxin-6-yl, 2,3- dihydro-benzo[ 1 ,4]dioxin-5-yl, 2,3-dihydro-benzofuran-5-yl, 2,3-dihydro- benzofuran-4-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-benzofuran-6-yl, 2,3- dihydro- lH-indol-5-yl, 2,3-dihydro- lH-indol-4-yl, 2,3-dihydro- lH-indol-6-yl, 2,3- dihydro- lH-indol-7-yl, benzo[l ,3]dioxol-4-yl, benzo[l ,3]dioxol-5-yl, 1 ,2,3,4- tetrahydroquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydrobenzothien-4-yl, 2-oxoindolin-5-yl.

'Aryl' as defined hereinabove may be substituted or unsubstituted with one or more substituents selected independently from the group comprising of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, perhaloalkyl, cycloalkyl, alkyl-O-, alkenyl- 0-, alkynyl-O-, perhaloalkyl-O-, alkyl(H)N-, alkyl(alkyl)N-, H ₂ N-, alkyl-S0 ₂ -, perhaloalkyl-S0 ₂ -, alkyl-C(=0)(H)N-, alkyl-C(=0)(alkyl)N-, alkyl(H)NC(=0)-, alkyl(alkyl)NC(=0)-, H ₂ NC(=0)-, alkyl(H)NS0 ₂ -, alkyl(alkyl)NS0 ₂ -, H ₂ NS0 ₂ -, 3 to 6 membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein the said 3 to 6 membered heterocycle is substituted or unsubstituted with alkyl, alkenyl, alkynyl, or alkyl-C(=0)-

The term 'heteroaryF refers to a 5- 14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic. Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1. 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, 1 -oxo- pyridyl, furanyl, thienyl, pyrro!yl, oxazolyl, oxadiazolyl, imidazolyl, fhiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, beiizimidazolyl, benzothiazolyl, benzothiadiazolvl. benzoxadiazolyl, indolyl, azaindolvl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2 ,31 pyri midinyl , pyrazolo[3,4jpyrimidinyl, and benzo(b) thienyl, 2,3- thiadiazolyl, lH-pyrazolo[5, l-c]- l ,2,4-triazolyl, pyrrolo 3,4-d]- l,2,3-triazolyl, cyclopentatriazolyl, 311 - py ro 1 o [ 3 , 4 - c ] i soxazoly 1 and the like.

'Heteroaryl' as defined hereinabove may be substituted or unsubstituted with one or more substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, perhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-S0 ₂ -, perhaloalkyl-S0 ₂ -, H ₂ N-, alkyl(H)N-, alkyl(alkyl)N-, alkyl-C(=0)(H)N-, alkyl-C(=0) (alkyl)N-, NH ₂ C(=0)-, alkyl(H)NC(=0)-, alkyl(alkyl)NC(=0)-, NH ₂ S0 ₂ -, alkyl(H)NS0 ₂ -, alkyl(alkyl)NS0 ₂ -, and 3 to 6 membered heterocycle containing 1 to 2 heteroatoms selected from N, O and S, wherein the heterocycle is substituted or unsubstituted with one to four substituents selected from the group consisting of alkyl, alkenyl, alkynyl or alkyl- C(=0)-.

The term 'heterocycle' or 'heterocyclic' as used herein, means a cycloalkyl group wherein one or more of the carbon atoms replaced by -0-, -S-, -S(0 ₂ )-, -S(O)-, - N(R ^m )-, -Si(R ^m )R ⁿ -, wherein, R ^m and R ⁿ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl. The heterocycle may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl; azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, 1 ,3-dithiolanyl, 1 ,3- dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1 , 1 -dioxidothiomorpholinyl(thiomorpholinesulfone) , thiopyranyl, and trithianyl. Representative examples of bicyclic heterocycle include, but are not limited to 1 ,3-benzodioxolyl, 1 ,3-benzodithiolyl, 2,3-dihydro- l ,4- benzodioxinyl, 2,3-dihydro- l -benzofuranyl, 2,3-dihydro- l -benzothienyl, 2,3- dihydro- lH-indolyl and 1 ,2,3,4-tetrahydroquinolinyl. The term heterocycle also include bridged heterocyclic systems such as azabicyclo[3.2. 1 ]octane, azabicyclo[3.3. 1 ]nonane and the like.

'Heterocyclyl' group may be substituted or unsubstituted on ring carbons with one or more substituents selected independently from the group consisting halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, aryl, heteroaryl, R ⁸ A ^! -, R ^8a OC(=0)-, R ^8a C(=0)0-, R ⁸ (H)NC(=0)-, R ⁸ (alkyl)NC(=0)-, R ⁸ (H)N-, R ⁸ (alkyl)N-, R ^8a C(=0) (H)N-, R ⁸ (H)NC(=A ⁱ ) (H)N-, and R ⁸ (alkyl)NC(=A ⁱ ) (H)N-; the substituents on ring nitrogen(s) of 'heterocycle' and '3- 10 membered heterocyclic ring system' are selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, R ^8a S02-, R ^8a C(=0)-, R ^8a OC(=0)-, R ⁸ (H)NC(=0)-, R ⁸ (alkyl)NC(=0)- and aryl substituted or unsubstituted with 1 to 3 substituents selected independently from halogen, alkyl, alkenyl, alkynyl, cyano or nitro; wherein R ⁸ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R ^8a is selected from alkyl, alkenyl, alkynyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; and A ¹ is selected from the group consisting of O and S.

The term 'oxo' means a divalent oxygen (=0) attached to the parent group. For example oxo attached to carbon forms a carbonyl, oxo substituted on cyclohexane forms a cyclohexanone, and the like.

The term 'halo' or 'halogen', as used herein, means a substituent selected from Group VIIA, such as, for example, fluorine, bromine, chlorine, and iodine.

The phrase 'pharmaceutically acceptable salt' is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.

Whenever a range of the number of atoms in a structure is indicated (e.g., a C i to C20 alkyl, C2 to C20 alkenyl, C3 to C20 alkynyl etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1- 6 carbon atoms (e.g., C i to Ce) , 2-6 carbon atoms (e.g. , C2 to Ce), 3-6 carbon atoms (e.g. , Ca to Ce) , as used with respect to any chemical group (e.g., alkyl, alkenyl, etc.) referenced herein encompasses and specifically describes 1 , 2, 3, 4, 5, and/ or 6 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms as appropriate). A compound its stereoisomers, racemates, and pharmaceutically acceptable salt thereof as described hereinabove wherein the compound of general formula (I) is selected from:

1. 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-benzo[d]imidazole.

2. 4,7-bis((4-methoxyphenyl)sulfonyl)- 1-methyl- lH-benzo[d] imidazole.

3. 4-((2,3-dihydrobenzo[b] [ 1 ,4]dioxin-5-yl)sulfonyl)-7-((4-methoxyphenyl)sulfonyl) benzo [c] [1,2, 5] thiadiazole.

4. 4,7-bis((4-methoxyphenyl)sulfonyl)benzo[c][l,2,5]thiadiazole .

5. 4, 7-bis( (4-fluorophenyl)sulfonyl)benzo [cj [1 ,2, 5 j thiadiazole .

6. 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-benzo[d][l ,2,3]triazole.

7. 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-indazole.

8. 4, 7-bis((4-methoxyphenyl)sulfonyl)- 1-methyl- lH-indazole.

9. 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-indole.

10. 4,7-bis((4-methoxyphenyl)sulfonyl)- 1-methyl- lH-indole.

1 1. 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-benzo[d]imidazol-2(3H)-one.

12. 5, 8-bis( (4-methoxyphenyl) sulfonyl) quinoline .

13. 5,8-bis((4-methoxyphenyl)sulfonyl)isoquinoline.

14. 5 , 8-bis ( (4-fluorophenyl) sulfonyl) isoquinoline .

15. 5,8-bis((4-(trifluoromethoxy)phenyl)sulfonyl)isoquinoline.

16. 5,8-bis((5-fluoro-2-methoxyphenyl)sulfonyl)isoquinoline.

17. 5,8-ditosylisoquinoline.

18. 5,8-bis((3-methoxyphenyl)sulfonyl)isoquinoline. 19. 5,8-bis((4-isopropoxyphenyl)sulfonyl)isoquinoline.

20. N,N'-((isoquinoline-5,8-disulfonyl)bis(4, l-phenylene))diacetamide.

21. 5,8-bis((4-methoxyphenyl)sulfonyl)quinoxaline.

22. 5 , 8-bis ( (4-iluorophenyl) sulfonyl) quinoxaline .

23. 5 , 8-bis ( (4-methoxyphenyl) sulfonyl) -2,3- dimethylquinoxaline .

24. 5, 8-bis( (4-methoxyphenyl) sulfonyl) -2-methylquinoxaline .

25. 2-methoxy- 5 , 8-bis ( (4-methoxyphenyl) sulfonyl) quinoxaline .

26. 5,8-bis((4-methoxyphenyl)sulfonyl)-N-methylquinoxalin-2-amin e.

27. 5,8-bis((4-methoxyphenyl)sulfonyl)isoquinolin- 1 (2H)-one.

28. 5,8-bis((4-fluorophenyl)sulfonyl)isoquinolin- 1 (2H)-one.

29. l-methoxy-5,8-bis((4-methoxyphenyl)sulfonyl)isoquinoline.

30. 5,8-bis((4-methoxyphenyl)sulfonyl)quinazolin-4(3H)-one.

31. 5,8-bis((4-methoxyphenyl)sulfonyl)quinoxalin-2( lH)-one.

32. 2-(cyclopropylamino)-5,8-bis((4-methoxyphenyl)sulfonyl)quina zolin-4(3H)-one.

33. 5, 8-bis( (4-methoxyphenyl) sulfonyl)phthalazine .

34. 5,8-bis((4-methoxyphenyl)sulfonyl)phthalazin- 1 (2H)-one.

According to a feature of the present invention, the compound of general formula (I) where all the symbols are as defined earlier, can be prepared by method given in Scheme 1 or examples. Representative procedures are shown below, however; the disclosure should not be construed to limit the scope of the invention arriving at compound of formula (I) as disclosed hereinabove.

Scheme-

The present invention provides a method of preparation of compound of formula (I) by coupling the compound of formula (III), wherein meaning of R ¹ , R ² , n, m and ring 'A' are as defined above and L represents a suitable leaving group such as chloro, bromo, iodo, methanesulfonyloxy and trifluoromethanesulfonyloxy group, with compound of formula (II) and (V) followed by subsequent oxidation of compound of formula (VI).

A compound of formula (III) can be conveniently coupled under standard C(aryl)-S bond formation conditions with an appropriate benzenethiol of formula (II) in presence of suitable base, for example, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, potassium tert-butoxide or sodium tert- butoxide, Ν,Ν-diisopropylethylamine in an appropriate solvent, for example, toluene, 1 ,2-dimethoxyethane, 1 ,4-dioxane and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C in presence of suitable metal catalyst, e.g. a mixture of an appropriate palladium source such as palladium acetate, £rfe(dibenzylideneacetone)dipalladium(0) and appropriate ligand such as bis(2-diphenylphosphinophenyl)ether, l-dicyclohexylphosphino-2-di-tert-butyl phosphino ethylferrocene, l , l'-bis(di-tert-butylphosphino)ferrocene, 9,9-dimethyl- 4,5-bis(diphenylphosphino)xanthene to afford compound of formula (IV).

Coupling of compound (IV) with an appropriate benzenethiol (V) under the above described conditions afford compound of formula (VI). Oxidation of sulfur atoms in the compound of formula (VI) can be readily accomplished employing well known procedures. Considerations such as solubility and reactivity of the compound of formula (VI) and the ease of the product recovery can dictate the choice of the most appropriate oxidizing agent and the conditions to be employed for the oxidation. Oxidizing agents such as hydrogen peroxide /glacial acetic acid, hydrogen peroxide/trifluoroacetic acid, hydrogen peroxide/potassium permanganate, hydrogen peroxide/p-toulenesulfonylimidazole, urea.hydrogen peroxide/trifluoroacetic acid, magnesium monoperoxyphthalate, potassium monopersulfate, m-chloroperbenzoic acid and other organic peracids and the like can be employed for the oxidation. The intermediates and the compounds of the present invention are obtained in pure form in a manner known per se, for example by distilling off the solvent under vacuum and re- crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichloro me thane, ethyl acetate, acetone or their combinations or subjecting it to one of the purification methods, such as column chromatography (e.g. flash chromatography) on a suitable support material such as alumina or silica gel using eluent such as dichlorome thane, ethyl acetate, hexane, methanol, acetone and their combinations. Preparative LC-MS method is also used for the purification of molecules described herein.

Salts of compound of formula (I) are obtained by dissolving the compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which was then treated with the desired acid or base as described in Berge S.M. et al. "Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences, volume 66, page 1- 19 (1977)" and in handbook of pharmaceutical salts properties, selection, and use by P.H. Einrich Stahland Camille G. wermuth, Wiley- VCH (2002).

In another aspect the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, their tautomeric forms, their stereoisomers, their analogs, their prodrugs, their isotopes, their N-oxides, their metabolites, their pharmaceutically acceptable salts, polymorphs, solvates, optical isomers, clathrates, or co-crystals in combination with the usual pharmaceutically employed carriers, diluents and the like are useful for the treatment of a disease responsive to activation of human PKM2. Yet in another aspect, the present invention provides the Modulators of PKM2 described herein can be used for treatment of various cancers. These include but are not limited to acute myelpoid leukemia, chronic myelogenous leukemia, prostate cancer (Hitosugi et al., Sci Signal, 2009, 2(97), ra73), breast cancer (Iqbal and Bamezai, PLoS One, 2012, 7(5), e36764; Chiavarina et al., Cancer Biology and Therapy, 201 1 , 12(12), p. 1 101-1 1 13), non-small cell lung cancer (Dong et al., Molecular Cell, 201 1 , 42, p. 719-730; Goldberg and Sharp, J. Exp. Med., 2012, 209 (2), p. 217-24), cervical carcinoma, hepatocellular carcinoma (Iqbal and Bamezai PLoS One, 2012, 7(5), e36764), glioblastoma (Yang et al., Nature, 201 1 , 480(7375), p. 118-22), squamous cell carcinoma (Wong et al., Int. J. Cancer, 2008, 123, p. 251-257), renal cell carcinoma (Ashrafian et al., Cancer Res., 2010, 70(22) p. 9153-65), colon cancer, ovarian cancer, multiple myeloma, melanoma (Goldberg and Sharp, J. Exp. Med., 2012, 209(2), p. 217-24).

In addition, the compound of present invention will be useful in the treatment of all types of leukemias, lymphomas, solid tumors such as sarcoma and carcinoma (liposarcoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, mesothelioma, rhabdomyosarcoma, pancreatic cancer, cervical cancer, uterine cancer, bladder cancer, glioma, medulloblastoma, astrocytoma, and retinoblastoma). PKM2 is known to be expressed in adipose tissue. PKM2 modulators could be used for the treatment of type II diabetes.

Autoimmune disorders that could be treated with PKM2 modulators include but are not limited to Crohn's disease, ulcerative colitis, multiple sclerosis, rheumatoid arthritis, systemic lupun erythematosus, autoimmune liver diseases, autoimmune diabetes, autoimmune neutropenia, pernicious anemia, and Sjorgen's syndrome.

Proliferative diseases include but are not limited to cancer, benign prostatic hyperplasia, lymphoproliferative disorders, and psoriasis

Following examples demonstrate preparation of few representative compound embodied in formula (I); however, the same should not be construed as limiting the scope of the invention.

Example 1: Preparation of 4,7-bis((4-methoxyphenyl)sulfonyl)-lH-benzo[d] imidazole

Step 1: 3,6-dibromobenzene- l ,2-diamine (lb) 4,7-dibromobenzo[c]- l ,2,5-thiadiazole (la) was dissolved (2 g, 6.8 mmol) in tetrahydrofuran (20 ml) and ethanol (45 ml) under stirring. C0CI2 (10 mg, 0.07 mmol) was added followed by portion wise addition of sodium borohydride (708 mg, 18.73 mmol), during an interval of 30 min. The reaction was continued at reflux temperature till the consumption of starting material. The reaction mixture was cooled at room temperature and quenched with water (50 ml). The resulting mass was stirred vigorously for 10 min and the gummy precipitate was filtered off using Celite. Organic layer so obtained was concentrated and the residual product was extracted with dichloro me thane. The resulting organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residual product so obtained was purified by flash column chromatography to afford 3,6-dibromobenzene- l ,2-diamine ( lb) which was immediately used for the next step.

Step 2: 4,7-dibromo- lH-benzo[d]imidazole (lc) Diamine ( lb) (1 g, 3.76 mmol) was dissolved in methanol (20 ml) under stirring. To the resulting solution triethyl orthoformate (0.748 ml, 4.5 mmol) and sulfamic acid ( 18 mg, 0.18 mmol) was added. The resulting reaction mixture was stirred overnight. Solvent was evaporated from the reaction mass to obtain the residue which was rinsed with ether, dried under air to afford (950 mg, 50% yield for 2 steps) 4,7-dibromo- lH-benzo[d]imidazole ( lc) as a yellow solid.

MS (EI) m/z: 276.9 (M+l). NMR (400 MHz, DMSO-d ₆ ): 5 13.2 (bs, 1H), 8.36 (s, 1H), 7.35 (s, 2H).

Step 3: 4,7-bis((4-methoxyphenyl)thio)- lH-benzo[d]imidazole ( Id)

4,7-dibromo- lH-benzo[d]imidazole ( lc) (150 mg, 0.54 mmol) was dissolved in dry 1 ,4-dioxane (5 ml) under stirring to which diisopropylethyl amine (281 mg, 1.63 mmol) was added. The reaction mixture was evacuated and backfilled with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (Pd ₂ (dba) ₃ ) (24.88 mg, 0.027 mmol), xantphos (31.41 mg, 0.054 mmol) and 4-methoxybenzenethiol (0.2 ml, 1.63 mmol) were added and the reaction mixture was again degassed twice more. The reaction mixture was heated to reflux for 18 hour. After the completion of reaction, the reaction mixture allowed to reach ambient temperature, filtered and concentrated. The crude product so obtained was purified by flash column chromatography to afford 4,7-bis((4-methox ^r phenyl)thio)- lH-benzo[d]imidazole ( Id) (50 mg, 23% ) as an oil.

MS (EI) m/z: 395. 1 (M+l ). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 12.85 (s, 1H), 8.24 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.03-7.09 (m, 4H), 6.89 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 8.8 Hz, 1H), 3.79 (s, 3H), 3.70 (s, 3H).

Step 4: 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-benzo[d]imidazole (1)

4,7-bis((4-methoxj. ⁷ phenyl)thio)- lH~benzo[djimidazole ( Id) (30 mg, 0.076 mmol) was dissolved in 2 ml of acetic acid under stirring. 3 ml of 30% hydrogen peroxide was added drop-wise to the resulting solution which was then heated at 70°C under inert atmosphere for 3 hours. The reaction was quenched with saturated NaHCOa and diluted with dichlorome thane (15 ml). The resulting mixture was basified with IN NaOH and allowed to stir for an additional 30 min. The resulting organic layer was separated, washed with water, dried over anhydrous Na SC>4 and concentrated under vacuum to afford 4,7-bis((4-methoxyphenyl)sulfonyl)- l H-benzo[d]imidazole ( 1) (20 mg, 57.35 %) as a solid.

MS (El m/z: 459. 1 (M+ l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 13.37 (s, 1H), 8.51 (s, 1H), 8.06 (d, J = 8.8 Hz, 4H), 7.99 (s, 2H), 7.08 (d, J = 9.2 Hz, 4H), 3.77 (s, 6H).

Example 2: Preparation of 4, 7-bis((4-methoxyphenyl)sulfonyl)-l -methyl- 1H- benzo[d]imidazole

Step 1: 4,7-dibromo- l-methyl- lH-benzo[d]imidazole (2a)

4,7-dibromo- lH-benzo[d]imidazole ( lc) (300 mg, 1.08 mmol) was dissolved in dry ethanol ( 10 ml) under stirring. K2CO3 (414 mg, 3.24 mmol) was added to the resulting solution. The reaction mixture was heated at reflux to which iodomethane (0. 13 ml, 2.17 mmol) was added dropwise and the mixture was maintained at reflux for 1 hour. The reaction mixture was cooled at room temperature to which water (20 ml) was added. From the said mixture ethanol was evaporated and the so formed precipitate was collected by filtration. The resulting solid cake was washed with water, hexane/ diethyl ether ( 1 / 1), and dried to afford (250 mg, 79% yield) 4,7- dibromo- l-methyl- lH-benzo[d]imidazole (2a) as a solid.

MS (EI) m/z: 290.9 (M+l).

Ή NMR (400 MHz, DMSG-d ₆ ): 8 8.32 (s, 1H), 7.34 (s, 2H), 4.05 (s, 3H). Step 2: 4,7-bis((4-methoxyphenyl)thio)- l-methyl- lH-benzo[d]imidazole (2b)

The title compound 4,7-bis((4-methoxyphenyl)thio)- l-methyl- lH-benzo[d]imidazole (2b) was prepared by using the procedure as described for (Id).

MS (EI) m/z: 409. 1 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 7.99 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7. 10 (d, J = 1 1.2 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.0 Hz, 1H), 3.83 (s, 3H), 4.02 (s, 3H), 3.74 (s, 3H).

Step 3: 4,7-bis((4-methoxyphenyl)sulfonyl)- l-methyl- lH-benzo[d]imidazole (2)

Title compound 4, 7-bis((4-methoxyphenyl)sulfonyl)- l -methyl- lH-benzo[d]imidazole (2) was prepared by fallowing the procedure as described for ( 1).

MS (EI) m/z: 473. 1 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 8.17 (s, 1H), 7.96-7.99 (m, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.16 (s, 3H), 3.92 (s, 3H), 3.82 (s, 3H).

Example 3: Preparation of 4-((2,3-dihydrobenzo[b][l ,4]dioxin-5-yl)sulfonyl)-7- ((4-methoxyphenyl)sulfonyl)benzo[c][l,2,5]thiadiazole

Step 1: 4-bromo-7-((4-methoxyphenyl)thio)benzo[c] [ l ,2,5]thiadiazole (3a)

Title compound 4-bromo-7-((4-methoxyphenyl)thio)benzo[c][ l ,2,5]thiadiazole (3a) was prepared from 4,7-dibromobenzo[cj[ l ,2,5]thiadiazole and 4- methoxybenzenethiol by fallowing the coupling conditions as described for ( id). MS (EI) m/z: 354.4 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 7.48 (d, J = 6.8 Hz, 2H), 7.03 (d, J = 6.8 Hz, 2H), 6.80 (s, 2H), 3.78 (s, 3H).

Step 2: 4-((2,3-dihydrobenzo[b][ l ,4]dioxln-5-yl)thio)-7-((4- methoxyphenyl)thio)benzo[c] [ l ,2,5]thiadiazole (3b)

Title compound 4-((2,3-dihydrobenzo[b] [ 1 ,4]dioxin-5-yl)thio)-7-((4- methoxyphenyl)thio) benzo[c][ l ,2,5]thiadiazole (3b) was prepared from intermediate (3a) and 2,3-dihydrobenzo[b][ l ,4]dioxine-6-thiol by fallowing the coupling conditions as described for ( Id). MS (EI) m/z: 441. 1 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 7.5 (d, J = 7.6 Hz, 2H), 6.88-7.07 (m, 6H), 6.79 (d, J = 7.6 Hz, IH), 4.23-4.27 (m, 4H), 3.79 (s, 3H).

Step 3: 4-((2,3-dihydrobenzo[b] [ l ,4]dioxin-5-yl)sulfonyl)-7-((4- methoxyphenyl)sulfonyl) benzo[c][ l ,2,5]thiadiazole (3) Title compound 4-((2,3-dihydrobenzo[b][ l ,4]dioxin-5-yl)sulfonyl)-7-((4- methoxyphenyl) sulfonyl)benzo[c] [l ,2,5]thiadiazole (3) was prepared by fallowing the oxidation of intermediate (3b) as described for (1).

MS (EI) m/z: 505. 1 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 8.60 (s, 2H), 8.07 (d, J = 8.8 Hz, 2H), 7.57-7.62 (m, 2H), 7.1 1 (d, J = 9.2 Hz, 2H), 7.05 (d, J = 8.8 Hz, IH), 4.24-4.28 (m, 4H), 3.79 (s, 3H).

Example 4: Compounds (4) and (5) were prepared in analogous manner as that of example 3 from appropriate intermediates.

(4) 4,7-bis((4-methoxyphenyl)sulfonyl)benzo[c][ l ,2,5]thiadiazole. MS (EI) m/z: 477. 1 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 8.61 (s, 2H), 8.07 (d, J = 8.8 Hz, 4H), 7.11 (d, J = 9.2 Hz, 4H), 3.78 (s, 6H).

( 5) 4 , 7-bis ( (4- fluorophenyl) sulfonyl)benzo [c] [ 1 , 2 , 5] thiadiazole .

MS (EI) m/z: 453.1 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 8.68 (s, 2H), 8.20-8.23 (m, 4H), 7.43-7.48 (m, 4H).

Example 6: Preparation of 4,7-bis((4-methoxyphenyl)sulfonyl)-lH- benzo[d][l,2,3] triazole

Step 1: 4,7-dibromo- lH-benzo[d][l ,2,3]triazole (6a)

3,6-dibromobenzene- l,2-diamine (2) (1.0 g, 3.76 mmol) was dissolved in 12 ml of acetic acid, to which a solution of NaN02 (290 mg, 4.21 mmol) in 10 ml of ¾0 was added. After 20 minutes of stirring at room temperature, the precipitate so obtained was collected by filtration and washed with water to afford 4,7-dibromo- lH-benzo[d] [l ,2,3]triazole (6a) ( 360 mg, 25 %) as a solid.

MS (EI) m/z: 277.9 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 7.62 (s, 2H). Step 2: 4,7-bis((4-methoxyphenyl)thio)- lH-benzo[d][ l ,2,3]triazole (6b)

Title compound 4,7-bis((4-methoxyphenyl)thio)- lH-benzo[d][ l ,2,3]triazole (6b) was prepared from intermediate (6a) and 4-methoxybenzenethiol by fallowing the coupling conditions as described for ( Id). MS (EI) m/z: 396.5 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 16.94 (s, 1H), 7.53 (bs, 2H), 7.34 (d, J = 8.2 Hz, 4H ), 6.93 (d, J = 8.2 Hz, 4H ), 3.72-3.80 (m, 6H).

Step 3: 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-benzo[d][ l ,2,3]triazole (6)

4,7-bis((4-methoxyphenyl)thio)- lH-benzo[d] [l ,2,3]triazole (6b) ( 150 mg, 0.37 mmol), 1-tosyl- lH-imidazole (269 mg, 1.21 mmol) and H ₂ 0 ₂ (30%) (0.073 ml, 0.64 mmol) in methanol (10 ml) were mixted together under stirring to which 0.5 ml 2N NaOH was added slowly. After completion of the reaction, the reaction mixture was concentrated under vacuum. The residue so obtained was suspended in water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated to obtain product which was purified by column chromatography to afford (50 mg, 29%) 4,7-bis((4-methoxyphenyl)sulfonyl)- lH- benzo[d][ l ,2,3]triazole (6) as a solid.

MS (EI) m/z: 460.3 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 16.22 (s, 1H), 8.24 (bs, 2H), 8.10 (d, J = 8.8 Hz, 4H), 7.12 (d, J = 8.8 Hz, 4H), 3.79 (s, 6H).

Example 7: Preparation of 4,7-bis((4-methoxyphenyl)sulfonyl)-lH-indazole

Step 1: 4,7-dibromo- lH-indazole (7b)

3,6-dibromo-2-fluorobenzaldehyde (7a) ( 1 g, 3.54 mmol) was dissolved in dimethylsulfoxide (DMSO) ( 10 ml), to which hydrazine hydrate (0.68 ml, 14.16 mmol) was added dropwise over 15 min under stirring. The resulting yellow slurry was heated at 120°C for 24 hours. The reaction mixture was allowed to cool at room temperature before quenching with ice cold ¾0 (25 ml) and the resulting mixture was stirred for 30 min. The precipitate so obtained was collected by suction filtration, washed thoroughly with ¾0 and dried in air to afford 4,7- dibromo- lH-indazole (7b) (900 mg, 92 %) as a solid.

MS (EI) m/z: 276.9 (M+l ).

Ή NMR (400 MHz, DMSO-d ₆ ): δ 14.0 (s, IH), 8.19 (s, IH), 7.51 (d, J = 7.6 Hz, IH), 7.27 (d, J = 7.6 Hz, IH). Step 2: 4,7-bis((4-methoxyphenyl)thio)- lH-indazole (7c)

Title compound 4,7-bis((4-methoxyphenyl)thio)- lH-indazole (7c) was prepared from intermediate (7b) and 4-methoxybenzenethiol by fallowing the coupling conditions as described for ( I d). MS (EI) rn/z: 395, 1 (M+ l) . ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 13.77 (s, 1H), 8.10 (s, 1H), 7.45-7.49 (m, 2H), 7.05-7.27 (m, 4H), 6.63-6.96 (m, 4H), 3.78 (s, 6H).

Step 3: 4,7-bis((4-methox} Dheiiyl)sulfonyl)- lH-mdazole (7) Title compound 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-indazole (7) was prepared by fallowing the oxidation of intermediate (7c) as described for (1).

MS (EI) m/z: 459. 1 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 14.06 (s, 1H), 8.60 (s, 1H), 8.13-8.19 (m, 2H), 7.95-8.02 (m, 4H), 7.05-7.12 (m, 4H), 3.78 (s, 6H). Example 8: Compound (8) was prepared in analogous manner of example 7 from appropriate intermediates

(8) 4,7-bis((4-methoxyphenyl)sulfonyl)- 1 -methyl- lH-indazole. MS (EI) m/z: 473. 1 (M+l).

Example 9: Preparation of 4,7-bis((4-methoxyphenyl)sulfonyl)-lH-indole

Step 1: (2-nitro- 1 ,4-phenylene)bis((4-methoxyphenyl)sulfane) (9b)

Title compound (2-nltro- l,4-phenylene)bls((4-methoxyphenyl)sulfane) (9b) was prepared as described for (Id) starting from l,4-dibromo-2~nitrobenzene (9a) and 4-methoxybenzenethiol. MS (El m/z: 400.1 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): δ 7.96 (s, 1H), 7.39-7.46 (m, 4H), 7.03 (d, J = 10.4 Hz, 1H), 6.95-6.98 (m, 2H), 6.89-6.92 (m, 2H), 6.66 (d, J = 6.66 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H).

Step 2: 4,4'-(2-nitro- l,4-phenylenedisulfonyl)bis(methox3^benzene) (9c) Urea.hydrogen peroxide (280 mg, 0.30 mmol), trifluoroacetic anhydride (0.3 ml) and acetonitrile (5 ml) were mixted together under stirring. The solution of (2-nitro- l ,4-phenylene)bis((4-methoxyphenyl)sulfane) (9b) (100 mg, 0.25 mmol) in acetonitrile (5 ml) was added and the reaction mixture was allowed to stir at room temperature for 3 hours. After completion of oxidation, water (10 ml) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (20 ml). The resulting organic layer was washed with water, dried over anhydrous Na2S04, concentrated under reduced pressure and purified by column chromatography to afford (1 10 mg, 86%) 4, 4'- (2-nitro- 1 ,4- phenylenedisulfonyl)bis(methoxybenzene) (9c) as a solid. MS (EI) m/z: 464.4 (M+l). ⁱ H NMR (DMSO-de): δ 8.39 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 7.87-7.91 (m, 4H), 7.02-7.04 (m, 4H), 3.89 (s, 6H).

Step 3: 4,7-bis((4-methoxyphenyl)sulfonyl)-lH-indole (9)

1 M vinyl magnesium bromide (1.29 ml, 1.29 mmol) in anhydrous tetrahydrofuran (10 ml) and 4,4 ^, -(2-nitro- l ,4-phenylenedisulfonyl)bis(methox ^r benzene) (9c) (200 mg, 0.43 mmol) were mixed together at -70°C under nitrogen atmosphere. The resulting mixture was stirred for additional 20 min at -50°C, and then poured into saturated NH4CI. Thereafter the crude product was extracted with ethyl acetate. Organic layer so obtained was dried over anhydrous Na2S04 and evaporated under reduced pressure. The resulting crude product was purified by column chromatography to afford (20 mg, 10 %) 4,7-bis((4-methoxyphenyl)sulfonyl)- lH- indole (9) as a solid.

MS (EI) rn/z: 458.04 (M+ l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 11.89 (s, 1H), 8.07 (d, J = 2.6 Hz, 2H), 7.92 (m, 4H), 7.66-7.67 (m, 1H), 7.04-7.10 (m, 4H), 6.94-6.95 (m, 1H), 3.79 (s, 6H).

Example 10: Compound (10) was prepared in analogous manner of example (9) from appropriate intermediates

(10) 4, 7-bis((4-methoxyphenyl)sulfonyl)- l -methyl- lH-indole. MS (EI) m/z: 472.04(M+1).

Example 11: Preparation of 4,7-bis((4-methoxyphenyl)sulfonyl)-lH-benzo[d] imidazol-2(3H)-one

Step 1: 3,6-bis((4-methoxyphenyl)sulfonyl)benzene- l ,2-diamine (11a)

Sodium borohydride (NaBH4) (278.9 mg, 7.34 mmol) was added portion wise to a suspension of 4,7-bis((4-methoxyphenyl)sulfonyl)benzo[c][l ,2,5]thiadiazole (4) (350 mg, 0.734 mmol) in ethanol (15 ml), under nitrogen atmosphere at a temperature below 15°C. The resulting reaction mixture was allowed to warm to 30°C and was stirred for 1 hour. Thereafter, the reaction mixture was cooled at 5°C, quenched by addition of ¾0 (25 ml) and concentrated under reduced pressure. The residue was diluted with diethyl ether /H2O and extracted with diethyl ether (2 x 15 ml). The resulting organic layer was washed with H2O and brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to obtain 3,6-bis((4- methoxyphenyl)sulfonyl) benzene- 1 ,2-diamine ( 1 1a) which was used immediately for the next step.

Step 2: 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-benzo[d]imidazol-2(3H)-one ( 1 1)

3, 6-bis((4-methoxyphenyl)sulfonyl)benzene- 1 ,2-diamine ( 1 1a) (250 mg, 0.55 mmol) was dissolved in tetrahydrofuran (6 ml), to which carbonyldiimidazole ( 107.09 mg, 0.66 mmol) was added. The resulting reaction mixture was heated to reflux for 24 hours and thereafter allowed to cool at ambient temperature. Solvent was removed from the reaction mixture under vacuum and the residue was purified by flash column chromatography to afford 4,7-bis((4-methoxyphenyl)sulfonyl)- lH- benzo[d]imidazol-2 (3H)-one ( 1 1) (25 mg, 7%) as a solid.

MS (EI) m/z: 475.5 (M+l). iH NMR (400 MHz, DMSO-d ₆ ): 8 1 1.42 (s, 2H), 8.14 (d, J = 9.2 Hz, 4H), 7.59 (s, 2H), 7.10 (d, J = 8.8 Hz, 4H),3.80 (s, 6H).

Example 12: Preparation ©f 5,8~bis((4-meth©xypheeyl}sulf©riyl}quie©liiie

Step 1: 5,8-bis((4-methoxyphenyl)thio)quinoline (12b) Title compound 5,8-bis((4-methoxyphenyI)thio)quinomie (12b) was prepared as described for (I d) starting from 5,8-dibromoquinoline ( 12a) and 4- methoxybenzenethiol.

MS (EI) m/z: 406.4 (M+l). Ή NMR (400 MHz, DMSO-d ₆ ): 8 8.99 (s, 1H), 8.69 (dd, J = 1.6 Hz, J = 1.6 Hz, 1H), 7.58-7.61 (m, 2H), 7.49-7.52 (m, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.17-7.22 (m, 2H), 7.0-7.03 (m, 1H), 6.78-6.82 (m, 3H), 3.88 (s, 3H), 3.77 (s, 3H).

Step 2: 5,8-bis((4-methoxyphenyl)sulfonyl)quinoline ( 12)

Title compound 5,8-bis((4-methoxyphenyl)sulfonyl)quinoline (12) was prepared by fallowing the oxidation of intermediate (12b) as described for (6).

MS (EI) m/z: 470.5 (M+l). ⁱ H NMR (400 MHz, CDC1 ₃ ): 8 8.89 ( 1H, s), 8.74 (d, J = 8 Hz, 1H), 8.46 (d, J = 8 Hz, 2H), 8.1 1-8.15 (m, 2H), 7.82-7.86 (m, 2H), 7.47-7.50 (m, IH), 6.88-6.95 (m, 4H), 3.80 (s, 6H).

Example 13: Preparation ©f 5,8-¾is((4-metlioxypheoyl}siilfonyl}is©qtiisioliiae

Step 1: 5,8-dibromoisoquinoline (13b)

Isoquinoline ( 13a) (1.83 ml, 15.50 mmol) was added slowly to concentrated H2SO4 ( 17 ml) at 0°C under stirring. The mixture was cooled at -25°C and sodium borohydride (6.34 g, 35.65 mmol) was added at a rate such that the reaction temperature was maintained between -25°C to -20°C. The resulting reaction was continued for 1 hour at the said temperature and then allowed to reach at room temperature. The reaction mixture was poured into crushed ice and the pH was adjusted to 7.0 using concentrated aqueous N¾. The resulting slurry was stirred for 1 hour at 0°C after which it was filtered and washed with ice-cold water. The crude product so obtained was air dried and purified by column chromatography to afford (2.5 g, 56%) 5,8-dibromoisoquinoline (13b).

MS (EI) rn/z: 286 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 9.48 (s, 1H), 8.78 (d, J = 6 Hz, 1H), 8.06 (d, J = 8 Hz, 1H), 7.98 (dd, J = 6 Hz, J = 8 Hz, 2H).

Step 2: 5,8-bis((4-methoxyphenyl)thio)isoquinoline ( 13c)

Title compound 5,8-bis((4-methoxyphenyl)thio)isoquinoline ( 13c) was prepared as described for ( I d) starting from 5,8-dibromoisoquinoline ( 13b) and 4- methoxybenze ethiol , MS (El) m/z: 406.4 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 9.65 (s, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.09 (d, J = 6.4 Hz, 1H), 7.36-7.45 (m, 5H), 7.23 (d, J = 8 Hz, 1H), 7.02-6.97(m, 4H), 3.75 (s, 6H).

Step 3: 5,8-bis((4-methoxyphenyl)sulfonyl)isoquinolme ( 13) 3% KM11O4 (5 ml) solution was added dropwise to a solution of 5,8-bis((4- methoxyphenyl)thio)isoquinoline ( 13c) ( 150 nig, 0.37 mmol) in acetic acid (5 ml) until the purple color of permanganate persisted. The resulting reaction mixture was made alkaline with 20% NaHSOs (25 ml) and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under vacuum. The crude product so obtained was purified by flash column chromatography to afford 5,8-bis((4-methoxyphenyl)sulfonyl)isoquinoline ( 13) (75 mg, 43%) as a solid. MS (EI) rn/z: 470,4 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 10.01 (s, IH), 8.78-8.80 (m, 2H), 8.63 (d, J = 8 Hz, IH), 8.50 (d, J = 5.6 Hz, IH), 8.20-7.98 (m, 4H), 7.10-6.16 (m, 4H), 3.80 (s, 6H).

Example 14: Compounds (14) to (20) were prepared in analogous manner as that of example 13 from appropriate intermediates

(14) 5,8-bis((4-iluorophenyl)sulfonyl)isoquinoline. MS (EI) m/z: 446.4 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 9.98 (s, IH), 8.86 (d, J = 7.6 Hz, IH), 8.78 (d, J = 6.4 Hz, IH), 8.70 (d, J = 7.6 Hz, IH), 8.48 (d, J = 6 Hz, IH), 8.68-8.15-8.21 (m, 4H), 7.46-7.52 (m, 4H).

(15) 5 , 8-bis ( (4- (triiluoromethoxy) phenyl) sulfonyl)iso quinoline . MS (EI) m/z: 578.0 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 9.98 (s, IH), 8.90 (d, J = 8 Hz, IH), 8.79 (d, J = 6 Hz, IH), 8.75 (d, J = 7.6 Hz, IH), 8.47 (d, J = 6 Hz, IH), 8.22-8.27 (m, 4H), 7.61- 7.65 (m, 4H).

(16) 5,8-bis((5-iluoro-2-methoxyphenyl)sulfonyl)isoquinoline. MS (EI) m/z: 505.69 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 9.81 (s, IH), 8.91 (d, J = 8 Hz, IH), 8.77 (d, J = 8 Hz, IH), 8.68 (d, J = 6 Hz, IH), 8.27 (d, J = 6 Hz, IH), 8.12-8.21 (m, 2H), 7.59-7.66 (m, 2H), 7.14-7.19 (m, 2H), 3.59 (s, 6H).

(17) 5,8-ditosylisoquinoline. MS (EI) m/z: 438.08 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 9.96 (s, IH), 8.84 (d, J = 7.6 Hz, IH), 8.75 (d, J = 6 Hz, IH), 8.69 (d, J = 8 Hz, IH), 8.45 (d, J = 6 Hz, IH), 7.93-7.96 (m, 4H), 7.42-7.46 (m, 4H), 2.34 (m, 6H).

(18) 5,8-bis((3-methoxyphenyl)sulfonyl)isoquinoline. MS (EI) m/z: 470.07 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 9.97 (s, IH), 8.86 (d, J = 8 Hz, IH), 8.77 (d, J = 8 Hz, IH), 8.70 (d, J = 8 Hz, IH), 8.48 (d, J = 6 Hz, IH), 7.50-7.65 (m, 6H), 7.27-7.32 (m, 2H), 3.81 (s, 6H).

(19) 5,8-bis((4-isopropoxyphenyl)sulfonyl)isoquinoline. MS (EI) m/z: 526.13 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 10.01 (s, IH), 8.87 (d, J = 8 Hz, 2H), 8.62 (d, J = 8 Hz, IH), 8.51 (d, J = 6 Hz, IH), 7.94-7.98 (m, 4H), 7.08-7.1 1 (m, 4H), 4.69-4.75 (m, 2H), 1.15- 1.25 (m, 12H).

(20) N,N'-((isoquinoline-5,8-disulfonyl)bis(4, l-phenylene))diacetamide. MS (EI) m/z: 524.01 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 10.43 (d, J = 8 Hz, 2H), 9.98 (s, IH), 8.75-8.79 (m, 2H), 8.63 (d, J = 8 Hz, IH), 8.46 (d, J = 7.2 Hz, IH), 7.97-8.02 (m, 4H), 7.77-7.81 (m, 4H), 2.05 (s, 6H).

Example 21: Preparation of 5,8-¾isi(4-metli©x pl eoyl)stilf©oyl)quiooxaline

Step 1 : 5,8-dibromoquinoxaline (21a)

3,6-dibromobenzene- l ,2-diamine ( lb) (250 mg, 0.94 mmol) in ethanol (6 ml), and 40% aqueous solution of glyoxal (0. 17 ml, 1.2 mmol) were mixed together under stirring. The resulting reaction mixture was heated to reflux for 3 hours and thereafter allowed to stir for 18 hours at room temperature. Filtered the said reaction mixture under vacuum to afford (60 mg, 22%) 5,8-dibromoquinoxaline (21a) as a solid.

MS (EI) m/z: 288.9 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 9. 13 (s, 2H), 8.18 (s, 2H). Step 2: 5,8-bis((4-methoxyphenyl)thio)quinoxaline (21b)

Title compound 5,8-bis((4-methoxyphenyl)thio)quinoxaline (21b) was prepared as described for (Id) starting from 5,8-dibromoisoquinoline (21a) and 4- methoxybenzenethiol.

MS (EI) m/z: 407.4 (M+l ). ⁱ H NMR (400 MHz, CDC1 ₃ ): 8 9.05 (s, 2H), 7.48 (d, J = 8.8 Hz, 4H), 7.05 (d, J = 8.8 Hz, 4H), 6.74 (s, 2H), 3.78 (s, 6H).

Step 3: 5,8-bis((4-rnethoxyphenyl)sulfonyI)quinoxalme (21)

Title compound 5,8-bis((4-methoxyphenyl)sulfonyl)quinoxaline (21) was prepared by fallowing the oxidation of intermediate (21b) as described for (13). MS (EI) m/z: 471.4 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 8.94 (s, 2H), 8.83 (s, 2H), 8.14 (d, J = 8.8 Hz, 4H), 6.96 (d, J = 8.8 Hz, 4H), 3.81 (s, 6H).

Example 22: Compound (22) was prepared in analogous manner as that of example 21 from appropriate intermediates (22) 5,8-bis((4-iluorophenyl)sulfonyl)quinoxaline. MS (EI) m/z: 447.45 (M+ l) . ⁱ H NMR (400 MHz, DMSO-d ₆ ) : 8 9.01 (s, 2H) , 8.89 (s, 2H) , 8. 16-8.20 (m, 4H) , 7.39- 7.44 (m, 4H). Example 23: Preparation of 5,8-bis((4-methoxyphenyl)sulfonyl)-2,3- dimethylquinoxaline

Step 1 : 5,8-dibromo-2,3-dimethylquinoxaline (23a) 3,6-dibromobenzene- l ,2-diamine ( lb) (0.95 g, 3.57 mmol) in ethanol (6 ml) and butanedione (0.49 ml, 5.71 mmol) were mixed together and heated to reflux for 2 hours. The resulting reaction mixture was allowed to cool at room temperature and filtered under vacuum to obtain 5,8-dibromo-2,3-dimethylquinoxaline (23a) (0.7 g, 62 %) as a solid. MS (EI) m/z: 316.8 (M+ l) . ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 8.01 (s, 2H) , 2.76 (s, 6H) .

Step 2: 5,8-bis((4-methoxyphenyl)thio)-2,3-dimethylquinoxaline (23b) Title compound 5,8-bis((4-methoxyphenyl)thio)-2,3-dimethylquinoxaline (23b) was prepared as described for ( Id) starting from 5,8-dibromo-2,3-dimethylquinoxaline (23a) and 4-methoxybenzenethiol.

MS (EI) m/z: 435.57 (M+ l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 7.46 (d, J = 9.6 Hz, 4H), 7.03 (d, J = 9.6 Hz, 4H), 6.80 (s, 2H), 3.78 (s, 6H), 2.76 (s, 6H).

Step 3: 5,8-bis((4-methoxyphenyl) sulfonyl)-2,3-dimethylquinoxaline (23)

Title compound 5,8-bis((4-methoxyphenyl)sulfonyl)-2,3-dimethylquinoxaline was prepared by fallowing the oxidation of intermediate (23b) as described for (13).

MS (EI) m/z: 499.02 (M+ l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 8.69 (s, 2H), 8.05 (d, J = 8.8 Hz, 4H), 7.07 (d, J = 9.2 Hz, 4H), 3.78 (s, 6H), 2.64 (s, 6H).

Example 24: Preparation of 5,8-bis((4-methoxyphenyl)sulfonyl)-2- methylquinoxaline

Methylglyoxal

( ^ib >

Step 1: 5,8-dibromo-2-methylquinoxaline (24a)

3,6-dibromobenzene- l ,2-diamine ( lb) (0.8 g, 3.01 mmol) in ethanol (6 ml) and methylglyoxal (0.29 ml, 4.81 mmol) were mixed together and heated to reflux for 2 hours. The resulting reaction mixture was allowed to cool at room temperature and filtered under vacuum to afford (0.6 g, 66 %) 5,8-dibromo-2-methylquinoxaline (24a) as a solid.

MS (EI) m/z: 303.15 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 89.01 (s, 1H), 8.09 (d, 2H), 2.80 (s, 3H).

Step 2: 5,8-bis((4-methoxyphenyl)thio)-2-methylquinoxaline (24b)

Title compound 5,8-bis((4-methoxyphenyl)thio)-2-methylquinoxaline was prepared as described for (Id) starting from 5,8-dibromo-2-methylquinoxaline (24a) and 4- methoxybenzenethiol.

MS (EI) m/z: 421.1 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 88.94 (s, IH), 7.45-7.49 (m, 4H), 7.02-7.06 (m, 4H), 6.67 (s, 2H), 3.78 (s, 6H), 2.80 (s, 3H).

Step 3: 5,8-bis((4-methoxyphenyl)sulfonyl)-2-methylquinoxaline (24)

Title compound 5,8-bis((4-methoxyphenyl)sulfonyl)-2-methylquinoxaline was prepared by fallowing the oxidation of intermediate (24b) as described for (13).

MS (EI) m/z: 485.54 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 88.90 (s, IH), 8.78 (d, J = 8.0 Hz, IH), 8.72 (d, J = 8.0 Hz, IH), 8.06 (d, J = 9.2 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.04-7.10 (m, 4H), 3.78 (s, 6H), 2.68 (s, 3H).

Example 25: Preparation of 2-methoxy-5,8-bis((4-methoxyphenyl)sulfonyl) quinoxaline

Step 1: 5,8-dibromoquinoxalin-2( lH)-one (25a)

3,6-dibromobenzene- l ,2-diamine ( lb) (0.8 g, 3.01 mmol) in ethanol (6 ml) and glyoxylic acid monohydrate (0.41 g, 4.51 mmol) were mixed together and heated to reflux for 15 min. The resulting reaction mixture was allowed to cool at room temperature and filtered under vacuum to afford (0.7 g, 77%) of 5,8- dibromoquinoxalin-2(lH)-one (25a) as a solid.

MS (EI) m/z: 304.7 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 1 1.80 (s, 1H), 8.28 (s, 1H), 7.78 (d, J = 10.4 Hz, 2H).

Step 2: 5,8-dibromo-2-chloroquinoxaline (25b)

5,8-dibromoquinoxalin-2(lH)-one (25a) (0.6 g, 1.97 mmol) and POCl ₃ (3 ml, 32.2 mmol) were mixed together at 1 10°C under an inert atmosphere for 3 hours. The resulting reaction mixture was allowed to cool at room temperature and concentrated. The residue was diluted with dichlorome thane /NaHCC»3 saturated aqueous solution and extracted with dichloromethane (2 x 25 ml). The combined organic layer was washed with water, dried over anhydrous Na2S04 and concentrated. The crude product was purified by flash column chromatography to afford (0.5 g, 24 %) 5,8-dibromo-2-chloroquinoxaline (25b) as a solid. MS (EI) m/z: 323.37 (M+ l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 9. 15 (s, 1H), 8.18 (d, J = 10.4 Hz, 2H).

Step 3: 5,8-dibromo-2-methoxyquinoxaline (25c)

5,8-dibromo-2-chloroquinoxaline (25b) (0.3 g, 0.93 mmol) was dissolved in 5 ml of dimethylformamide to which sodium methoxide (0.12 g, 2.23 mmol) was added under stirring. The reaction mixture was heated at 45°C for 4 hours. After completion of the reaction, the reaction mixture was allowed to cool at room temperature and quenched dropwlse into water (50 ml). The resulting mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with brine and water, dried over Na2S04 and concentrated under vacuum. The crude product so obtained was purified by flash column chromatography to afford (0. 15 g, 50.7 %) 5,8-dibromo-2-methoxyquinoxaline (25c) as a solid.

MS (EI) m/z: = 318.9 (M+ l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 8.29 (s, 1H), 7.80 (d, J = 10.4 Hz, 2H), 4.01 (s, 3H). Step 4: 2-methoxy-5,8-bis((4-methoxyphenyl)thio)quinoxaline (25d)

Title compound 2-methoxy-5,8-bis((4-methoxyphenyl)thio)quinoxaline (25d) was prepared as described for (Id) starting from 5,8-dibromo-2-methoxyquinoxaline (25c) and 4-methoxybenzenethiol.

MS (EI) m/z: 437 (M+ l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 8.55 (s, IH), 7.46-7.53 (m, 4H), 6.91-6.96 (m, 4H), 6.76 (d, J = 12 Hz, IH), 6.61 (d, J = 12 Hz, IH), 4.01 (s, 3H), 3.84 (s, 6H). Step 5: 2-methoxy-5,8-bis((4-methoxyphenyl)sulfonyl)quinoxaline (25)

Title compound 2-methoxy-5,8-bis((4-methoxyphenyl)sulfonyl)quinoxaline was prepared by fallowing the oxidation of intermediate (25d) as described for ( 13) .

MS (EI) m/z: 501.01 (M+ l) . ⁱ H NMR (400 MHz, DMSO-d ₆ ) : 8 8.78 (d, J = 8.4 Hz, 1H) , 8.66 (s, 1H) , 8.58 (d, J = 8.4 Hz, 1H) , 7.96-8.01 (m, 4H) , 7.05-7. 10 (m, 4H) , 3.97 (s, 3H) , 3.78 (s, 6H).

Example 26: Preparation of 5,8-bis((4-methoxyphenyl)sulfonyl)-N- methylquinoxalin-2-amine

Step 1 : 5,8-dibromo-N-methylquinoxalin-2-amine (26a)

5,8-dibromo-2-chloroquinoxaline (25b) (0.20 g, 0.62 mmol) was dissolved in tetrahydrofuran (6 ml) to which a solution of methyl amine in tetrahydrofuran (3 ml) was added at room temperature. The resulting reaction mixture was refluxed for 2 hours. After completion of the reaction, the volatiles were removed under vacuum and water (20 ml) was added to the reaction mixture. The resulting aqueous layer was extracted with ethyl acetate (3 x 15 ml). The combined organic layer so obtained was washed with water (20 ml) and brine (20 ml) , dried over Na ₂ S0 ₄ and concentrated under vacuum. The crude product so obtained was purified by flash column chromatography to afford (0. 18 g, 92%) 5,8-dibromo-N- methylquinoxalin-2-amine (26a) .

MS (EI) m/z: = 317.9 (M+ l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8.35 (s, 1H), 8. 16 (bs, 1H), 7.81 (d, J = 8 Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 2.99 (s, 3H).

Step 2: 5,8-bis((4-methoxyphenyl)thio)-N-methylquinoxalin-2-amine (26b)

Title compound 5,8-bis((4-methoxyphenyl)thio)-N-methylquinoxalin-2-amine (26b) was prepared as described for (Id) starting from 5,8-dibromo-N-methylquinoxalin- 2-amine (26a) and 4-methoxybenzenethiol.

MS (EI) m/z: 436.5 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 8.27 (s, 1H), 7.48-7.52 (m, 4H), 6.92 (d, J = 1 1.2 Hz, 4H), 6.65 (d, J = 8 Hz, IH), 6.45 (d, J = 8 Hz, IH), 5.07 (s, IH), 3.83 (s, 6H), 3.19 (s, 3H).

Step 3: 5,8-bis((4-methoxyphenyl)sulfonyl)-N-methylquinoxalin-2-amin e (26)

5,8-bis((4-methoxyphenyl)thio)-N-methylquinoxalin-2-amine (26b) (100 mg, 0.23 mmol), ethyl acetate (5 ml), sodium tungstate dehydrate ( 1.36 mg, 4.13 mmol) and tetrabutylammonium hydrogen sulfate (5.96 mg, 17.55 mmol) were mixed together at 0°C to which 30% hydrogen peroxide (0.065 ml, 0.58 mmol) was added dropwise and the reaction was continued at room temperature. After the completion of reaction, the reaction mixture was diluted with ethyl acetate (30 ml) and washed with dilute aqueous sodium thiosulfate and brine. The resulting organic layer was dried over Na2S04 and concentrated under vacuum. The crude product so obtained was purified using combiflash chromatography (petroleum ether: ethyl acetate 6:4) to afford (50 mg, 43.6%) 5,8-bis((4-methoxyphenyl)sulfonyl)-N-methylquinoxalin-2- amine (26).

MS (EI) m/z: 499.8 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): δ 8.55 (d, J = 8 Hz, IH), 8.25 (s, IH), 8.19 (d, J = 8 Hz, IH), 7.92-7.98 (m, 4H), 7.60 (d, J = 8.8 Hz, 4H), 5.76 (s, IH), 3.78 (s, 6H), 2.87 (s, 3H). Example 27: Preparation of 5,8-bis((4-methoxyphenyl)sulfonyl)isoquinolin- l(2H)-one

Step 1: 5,8-bis((4-methoxyphenyl)sulfonyl)isoquinoline-2-oxide (27a)

5,8-bis((4-methoxyphenyl)sulfonyl)isoquinobne (13) (0.9 g, 1.92 mmol) was dissolved in acetic acid (5 ml) to which 30% aqueous hydrogen peroxide solution ( 1.8 ml) was added and the resulting reaction mixture was heated at 75°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum and the residue was partitioned between aqueous sodium carbonate solution and dichloromethane. The combined organic layer was separated, dried over Na2S04, filtered, and concentrated under vacuum to afford 5,8-bis((4- methoxyphenyl) sulfonyl)isoquinoline-2-oxide (27a) which was directly used in the next step without further purification. MS (EI) m/z: 486 (M+ l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 9.26 (s, 1H), 8.60 (d, J=8 Hz, 2H), 8.49 (d, J= 8 Hz, 1H), 8.36-8.38 (m, 1H), 7.93-7.99 (m, 4H), 7. 13-7.18 (m, 4H), 3.82 (s, 6H).

Step 2: 5,8-bis((4-methoxyphenyl)sulfonyl)isoquinolin- l (2H)-one (27)

5,8-bis((4-methoxyphenyl)sulfonyl)isoquinolin- l (2H)-one (27a) (950 mg, 1.95 mmol) was dissolved in acetic anhydride (5 ml) and the mixture was heated under reflux for 3 hours. The resulting reaction mixture was concentrated under reduced pressure, and the residue so obtained was heated in aqueous sodium hydroxide (2 M, 10 ml) for 1 hour. The resulting mixture was acidified to pH 6 with citric acid (5% in water) and extracted with dichloromethane (2 x 20 ml). The combined organic layer was dried over anhydrous Na2S04 and concentrated to afford 5,8- bis((4-methoxyphenyl)sulfonyl) isoquinolin- l (2H)-one (27) as a solid (600 mg, 63 %).

MS (EI) m/z: 485.9 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 1 1.73 (s, 1H), 8.68-8.74 (m, 2H), 7.91 (d, J = 12 Hz, 2H), 7.74 (d, J = 12 Hz, 2H), 7.40 (bs, IH), 7. 1 1-7.16 (m, 3H), 7.04 (d, J = 2.8 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H).

Example 28: Compound (28) was prepared in analogous manner as that of example 27 from appropriate intermediates

(28) 5,8-bis((4-fluorophenyl)sulfonyl)isoquinolin- 1 (2H)-one.

MS (EI) m/z: 461.9 (M+l). Ή NMR (400 MHz, DMSO-d ₆ ): 8 1 1.81 (s, IH), 8.80 (d, J = 8.4 Hz, IH), 8.73 (d, J = 8.4 Hz, IH), 8.06-8.097 (m, 2H), 7.83-7.86 (m, 2H), 7.46-7.52 (m, 2H), 7.34-7.44 (m, 3H), 7.05 (d, J = 7.6 Hz, IH).

Example 29: Preparation of l-methoxy-5,8-bis((4-methoxyphenyl)sulfonyl) isoquinoline

(29)

5,8-bis((4-methoxyphenyl)sulfonyl)isoquinolin- l (2H)-one (27) ( 100 mg, 0.21 mmol) was dissolved in chloroform (5 ml), to which silver carbonate (1 17 mg, 0.43 mmol) was added followed by dropwlse addition of iodomethane (0.026 ml, 0.43 mmol) and the reaction was continued at room temperature for 20 hours. The resulting reaction mixture was quenched by addition of triethylamine (0.5 ml) and the inorganic solids were filtered over a pad of celite. The resulting filtrate was concentrated and the crude residue was purified by flash column chromatography to afford l-methoxy-5,8-bis((4-methoxyphenyl)sulfonyl)isoquinoline (29) (40 mg, 37 %).

MS (EI) m/z: 500.0 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 8.83 (m, 2H), 8.22 (d, J = 6 Hz, 1H), 8.03 (d, J = 6 Hz, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 9.2 Hz, 2H), 7.1 1-7.15 (m, 4H), 3.82 (s, 6H), 3.69 (s, 3H).

Example 30: Preparation of 5,8-bis((4-methoxyphenyl)sulfonyl)quinazolin- 4(3H)-one

Step 1: 3,6-dibromo-2-nitrobenzaldehyde (30b) H2SO4 (6.87 ml, 129 mmol) and KNO3 (1.64 g, 16.26 mmol) were mixed together under cooling to which 2,5-dibromobenzaldehyde (30a) (1.5 g, 5.68 mmol) was added slowly, while maintaining the temperature below 30°C. The reaction mixture was further stirred at 23°C for 16 hours. The reaction mixture was quenched by careful addition of H ₂ 0 (100 ml) and extracted with CH ₂ C1 ₂ (3 x 80 ml). The combined organic layer was washed with saturated aqueous NaHCOa (50 ml), dried over anhydrous Na ₂ SC>4 and concentrated under vacuum to obtain the crude residue which was purified by flash column chromatography to afford 3,6-dibromo- 2-nitrobenzaldehyde (30b) (1.5 g, 42.7%) as a solid. MS (EI) m/z: 309.8 (M+l).

Ή NMR (400 MHz, DMSO-d ₆ ): 10.07 (s, 1H), 8.1 1 (d, J = 8.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H).

Step 2: 2-amino-3,6-dibromobenzaldehyde (30c)

Fe powder (2.71 g, 48.0 mmol) in H ₂ 0 (5 ml) and concentrated HCL (18 ml) were added to a solution of 3,6-dibromo-2-nitrobenzaldehyde (30b) (1 g, 3.24 mmol) in ethanol (15 ml) under stirring. The resulting reaction mixture was heated to reflux and stirred vigorously for 90 min. The reaction mixture was cooled at room temperature and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water, dried over anhydrous Na ₂ S04, filtered, and concentrated under vacuum to afford 2-amino-3,6-dibromobenzaldehyde (30c) (430 mg, 47.6%) as a solid which was directly used in the next step without further purification.

MS (EI) m/z: 279.9 (M+l).

Step 3: 5,8-dibromoquinazolin-4(3H)-one (30d) 2-amino-3,6-dibromobenzaldehyde (30c) (0.65 g, 2.33 mmol) and urea (1.95 g, 32.6 mmol) were fused at 160°C under inert atmosphere. After 6 hours, the mixture was allowed to cool at room temperature and 5 ml of water was added under stirring in 5 min. The precipitated solid was filtered off and washed with water. The solid residue so obtained was suspended in a solution of 0.5 N NaOH in water. The resulting suspension was heated to boil for 5 min and then cooled at room temperature. The pH of resulting mixture was adjusted to 2 with concentrated HCL, and the solid so obtained was filtered, washed with water: methanol ( 1 : 1), and dried under vacuum to afford (270 mg, 28. 1%) of 5,8-dibromoquinazolin- 4(3H)-one (30d).

MS (EI) m/z: 304.9 (M+ l) . ⁱ H NMR (400 MHz, DMSO-d ₆ ) : 7.38 (d, J = 8.4 Hz, 1H), 7. 17 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H) , 6.0 (s, 1H) . Step 4: 5,8-bis((4-methoxyphenyl)thio)quinazolin-4(3H)-one (30e)

Title compound 5,8-bis((4-methoxyphenyl)thio)quinazolin-4(3H)-one (30e) was prepared as described for ( Id) starting from 5,8-dibromoquinazolin-4(3H)-one (30d) and 4-methoxybenzenethiol.

MS (EI) m/z: 423.2 (M+ l) . Ή NMR (400 MHz, DMSO-d ₆ ) : 8 8. 18 (s, 1H), 12 (s, 1H) , 7.82 (d, J = 8.4 Hz, 2H) , 7.49 (d, J = 8.8 Hz, 4H) , 7. 1 1 (d, J = 8.8 Hz, 4H) , 3.83 (s, 6H).

Step 5: 5,8-bis((4-methoxyphenyl)sulfonyl)quinazolin-4(3H)-one (30)

Title compound 5,8-bis((4-methoxyphenyl)sulfonyl)quinazolin-4(3H)-one (30) was prepared by fallowing the oxidation of intermediate (30e) as described for ( 13) . MS (EI) m/z: 487. 17 (M+ l) . ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 12.66 (s, 1H) , 8.89 (d, J = 8.4 Hz, 1H) , 8.64 (d, J = 8.4 Hz, IH), 8. 18 (m, IH), 8.0 (d, J = 9.2 Hz, 2H) , 7.77 (d, J = 8.8 Hz, 2H ) , 7.03- 7.09 (m, 4H), 3.82 (s, 6H).

Example 31 : Preparation of 5,8-bis((4-methoxyphenyl)sulfonyl)quinoxalin- 2(lH)-one

Step 1: 5,8-bis((4-methoxyphenyl)thio)quinoxalin-2(lH)-one (31a)

Title compound 5,8-bis((4-methoxyphenyl)thio)quinoxalin-2(lH)-one (31a) was prepared as described for (Id) starting from 5,8-dibromoquinoxalin-2(lH)-one (25a) and 4-methoxybenzenethiol.

MS (EI) m/z: 423.2 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 9.55 (s, 1H), 8.29 (s, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 9.6 Hz, 2H), 7.03 (d, J = 9.6 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 6.47 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 3H).

Step 2: 5,8-bis((4-methoxyphenyl)sulfonyl)quinoxalin-2( lH)-one (31)

Title compound 5,8-bis((4-methoxyphenyl)sulfonyl)quinoxalin-2(lH)-one (31) was prepared by fallowing the oxidation of intermediate (31 a) as described for (13).

MS (EI) m/z: 487 (M+ l).

Ή NMR (400 MHz, DMSO-d ₆ ): 8 12.03 (s, 1H), 10.55 (s, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 9.2 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 9.2 Hz, 2H ), 7.08 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H).

Example 32: Preparation of 2-(cyclopropylamino)-5,8-bis((4-methoxy phenyl) sulfonyl)quinazolin-4(3H)-one

Step 1: 2,5-bis((4-methoxyphenyl)thio)aniline (32a)

(2-nitro- l ,4-phenylene)bis((4-methoxyphenyl)sulfane) (9b) (300 mg, 0.75 mmol) was dissolved in ethanol (10 ml) to which concentrated HCL (0.09 ml, 0.75 mmol) was added followed by portion wise addition of iron dust (189 mg, 3.38 mmol). The resulting reaction mixture was heated under reflux for 2 hours, cooled at room temperature and made alkaline using a 1M NaOH solution in 50% aqueous ethanol. The mixture so obtained was filtered, washed with brine (50 ml) and extracted with CH2CI2 (2 x 50 ml). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated under vacuum to afford 2,5-bis((4- methoxyphenyl)thio) aniline (32a) (250 mg, 90%) as a solid.

MS (EI) m/z: 370.20 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 7.43 (d, J = 10Hz, 2H), 7.09-7.15 (m, 3H), 7.01 (d, J = 10 Hz, 2H), 6.87 (d, J = 10 Hz, 2H), 6.48-6.49 (m, 1H), 6.24-6.27 (m, 1H), 5.43 (s, 2H), 3.78 (s, 3H), 3.77 (s, 3H).

Step 2 : (E) - ( ( (2 , 5-bis ( (4-methoxyphenyl) thio) phenyl) amino) (cyclopropylamino) methylene)ethylcarbamate (32b)

2,5-bis((4-methoxyphenyl)thio)aniline (32a) (200 mg, 0.54 mmol) was dissolved in dichloromethane (10 ml) at 0°C to which O-ethyl carbonisothiocyanatidate (0.085 g, 0.650 mmol) was added under stirring and reaction was continued for 1 hour at the said temperature. Triethylamine (0.23 ml, 1.624 mmol), and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (100 mg, 0.65 mmol) were added to the said reaction mixture and the reaction was continued at room temperature for 12 hours. The resulting mixture was concentrated, diluted with water, and extracted with CH2CI2. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under vacuum. The crude product so obtained was purified by flash column chromatography to afford (E)-(((2,5-bis((4- methoxyphenyl)thio)phenyl)amino) (cyclopropylamino)methylene)ethylcarbamate (32b) as a solid ( 190 mg, 67.2 %).

MS (EI) m/z: 524. 1 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 1 1.60 (s, 1H), 1 1.35 (s, 1H), 7.6 (s, 1H ), 7.43 (d, J = 10 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.99-7.07 (m, 3H), 6.92-6.96 (m, 3H), 4. 18 (t, 2H), 3.77 (s, 6H ), 1.22- 1.26 (m, 3H), 0.83 (bs, IH), 0.73 (bs, 2H), 0.54 (bs, 2H).

Step 3: 2-(cyclopropylamino)-5,8-bis((4-methoxyphenyl)thio)quinazoli n-4(3H)-one (32c)

(E)-(((2,5-bis((4-methoxyphenyl)thio)phenyl)amino)(cyclop ropylamino)methylene) ethylcarbamate (32b) (200 mg, 0.38 mmol) was dissolved in anhydrous dimethylformamide (5 ml) to which chlorotrimethylsilane (0.49 ml, 3.83 mmol) was added and the resulting mixture was heated at 85°C for 12 hours in a sealed tube. The reaction mixture was allowed to cool and quenched with water (2 ml). The reaction mixture was concentrated under reduced pressure and the pH of the resulting mixture was adjusted to 7 using aqueous NH4OH to obtain a solid precipitate. The precipitate so obtained was triturated well and collected by vacuum filtration. The resulting crude product was purified by flash column chromatography to afford 2-(cyclopropylamino)-5,8-bis((4- methoxyphenyl)thio)quinazolin-4(3H)-one (32c) ( 150 mg, 82 %) as a solid.

MS (EI) m/z: 478.59 (M+ l) . ⁱ H NMR (400 MHz, DMSO-d ₆ ) : 8 10.95 (s, 1H) , 7.35-7.41 (m, 4H) , 6.88-7.03 (m, 4H), 6.41 (d, J = 8.4 Hz, 1H) , 5.88 (d, J = 8.4 Hz, 1H) , 3.78 (s, 6H), 1.90 (s, 1H ) , 0.85 (bs, 1H) , 0.75 ( bs, 2H) , 0.56 (bs, 2H) .

Step 4: 2-(cyclopropylamino)-5,8-bis((4-methoxyphenyl)sulfonyl)quina zolin-4(3H)- one (32)

Title compound 2-(cyclopropylamino)-5,8-bis((4- methoxyphenyl)sulfonyl)quinazolin-4(3H)-one (32) was prepared by fallowing the oxidation of intermediate (32c) as described for (9c) .

MS (EI) m/z: 542.60 (M+ l) .

Ή NMR (400 MHz, DMSO-d ₆ ): 8 1 1.0 (bs, 1H) , 8.64 (d, J = 8.4 Hz, 1H) , 8. 15 (d, J = 8.4 Hz, 1H) , 8.05 (d, J = 8 Hz, 2H), 7.70-7.77 (m, 2H) , 7.01 -7.07 (m, 4H) , 3.77 (s, 6H), 1.90 (s, 1H) , 0.83 (bs, 2H) , 0.60 (bs, 2H) . Example 33: Preparation of 5,8-bis((4-methoxyphenyl)sulfonyl)phthalazine

Step 1: (lE,2E)- l ,2-bis(2,5-dibromobeiizylideiie)hydrazine (33a)

Hydrazine hydrate (0.14 ml, 2.84 mmol) was added dropwise to a solution of 2,5- dibromobenzaldehyde (27a) (1.5 g, 5.68 mmol) in methanol (50 ml) at room temperature under stirring. The resulting reaction mixture was refluxed for 2 hours and the precipitate so obtained was filtered and washed with methanol to afford (1.4 g, 47%) (lE,2E)- l,2-bis(2,5-dibromobenzylidene)hydrazine (33a) as a solid.

MS (EI) rn/z: 524.4 (M+l). Step 2: 5,8-dibromophthalazine (33b)

(lE,2E)- l ,2-bis(2,5-dibromobenzylidene)hydrazine (33a) (1.40 g, 2.69 mmol), aluminium (III) chloride (5.38 g, 40.93 mmol), and aluminium (III) bromide (5.31 g, 19.93 mmol) were mixed together and heated at 185-200°C for 1 hour under stirring. The dark gummy residue was cooled in an ice bath and slowly treated with 100 ml of water. The resulting precipitate was filtered and washed with 5% HCL. The solution so obtained was made basic with 15% potassium hydroxide and extracted with ethyl acetate. The organic layer were dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. The crude product so obtained was purified by flash column chromatography to afford ( 175 mg, 23%) 5,8- dibromophthalazine (33b) as a solid.

MS (EI) m/z: 288.94 (M+ l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 9.75 (s, 2H), 8.28 (s, 2H).

Step 3: 5,8-bis((4~mefhox henyl)thio)phthalazi e (33c) Title compound 5,8-bis((4-methoxyphenyl)thio)phthalazine (33c) was prepared as described for ( I d) starting from 5,8-dibromophthalazine (33b) and 4- methoxybenzenethiol.

MS (EI) m/z: 407.4 (M+l). ⁱ H NMR (400 MHz, DMSO-d ₆ ): 8 9.91 (s, 2H), 7.51 (s, 2H), 7.46 (d, J = 10 Hz, 4H), 7.02 (d, J = 8 Hz, 4H), 3.77 (s, 6H).

Step 4: 5,8-bis((4~mefhox henyl)sulfonyl)phthalazi e (33)

Title compound 5,8-bis((4-methoxyphenyl)sulfonyl)phthalazine (33) was prepared by fallowing the oxidation of intermediate (33c) as described for ( 13).

MS (EI) m/z: 471.4 (M+l). Ή NMR (400 MHz, CDC1 ₃ ): 510.3 (s, 2H), 8.89 (s, 2H), 8.07 (d, J = 8.8 Hz, 4H), 7.16 (d, J = 8.8 Hz, 4H), 3.81 (s, 6H).

Example 34: Preparation of 5,8-bis((4-methoxyphenyl)sulfonyl)phthalazin- l(2H)-one

Step 1: 3,6-dibromo-2-(carboxycarbonyl)benzoic acid (34b)

1 ,4-dibromonaphthalene (34a) (15 g, 52.45 mmol) was dissolved in 0.5 N NaOH (240 ml) under reflux to which 700 ml of boiling aqueous potassium permanganate (49.72 g, 314.64 mmol) was added dropwise during an interval of 1.5 hours under stirring. The reaction was continued to reflux for another 45 min to complete the oxidation. The reaction mixture was quenched by addition of 100 ml of ethanol, allowed to cool at room temperature and filtered. The resulting filtrate was acidified with 30% HCL and extracted with ethyl acetate (3 x 75 ml). The combined organic layer was dried over anhydrous Na2S04, and concentrated under vacuum to afford (3.75 g, 20.31%) 3,6-dibromo-2-(carboxycarbonyl)benzoic acid (34b) as a solid. MS (EI) m/z: 352.9 (M+ l). ⁱ H NMR (400 MHz, DMSO): 8 13.95 (s, 1H), 13.50 (s, 1H), 7.75 (s, 2H). Step 2: 3,6-dibromophthalic acid (34c)

3.6- dibromo-2-(carboxycarbonyl)benzoic acid (34b) (3.75 g, 10.65 mmol) was dissolved in 5% aqueous KOH (75 ml) at 0°C, to which a 30% solution of H ₂ 0 ₂

(41.25 ml) was added dropwise and the reaction was continued at the said temperature for 30 min, followed by room temperature for 2 hours. The pH of the solution was adjusted to 3-4 by adding a 5% solution of sulfuric acid. The resulting mixture was extracted with ethyl acetate (2 x 50 ml). The organic layer so obtained was dried over anhydrous Na2S04, filtered and concentrated under vacuum to afford (2.5 g, 72 %) of 3,6-dibromophthalic acid (34c).

MS (EI) m/z: 322.9 (M- l). ⁱ H NMR (400 MHz, DMSO): 8 13.9 (s, 1H), 13. 13 (s, 1H), 7.69 (s, 2H).

Step 3: 4,7-dibromoisobenzofuran- l ,3-dione (34d) 3,6-dibromophthalic acid (34c) (2.5 g, 7.71 mmol) was refluxed for 1 hour with acetic anhydride (8.33 ml, 81.5 mmol). The reaction mixture was cooled in an ice bath and the resulting precipitate was filtered, washed with cold ether and dried under reduced pressure to afford 4,7-dibromoisobenzofuran- l ,3-dione (34d) (1.6 g , 69 %) as a solid. MS (EI) m/z: 306.9 (M+ l).

Ή NMR (400 MHz, DMSO): 8 8.05 (s, 2H).

Step 4: 4,7-dibromoisoindoline- l ,3-dione (34e)

4.7- dibromoisobenzofuran- l ,3-dione (34d) (1.6 g, 5.23 mmol), urea (0.47 g, 7.86 mmol) and xylene (15 ml) were mixed together and heated in a microwave for 30 min at 150°C. The resulting reaction mixture was cooled at room temperature and the precipitate so obtained was filtered, washed with water and dried under reduced pressure to afford 4,7-dibromoisoindoline- l ,3-dione (34e) ( 1 g, 62.5%) as a solid.

MS (EI) m/z: 305.9 (M+ l). Ή NMR (400 MHz, DMSO): 8 1 1.69 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H).. Step 5: 4,7-dibromo-3-hydroxyisoindolin- l-one (34f)

4,7-dibromoisoindoline- l ,3-dione (34e) (800 mg, 2.62 mmol) was added to a suspension of zinc powder (206 mg, 3.15 mmol) and copper(II) sulfate pentahydrate (3.34 mg, 0.0135 mmol) in aqueous sodium hydroxide (2M, 3.34 ml) at 0°C (ice- bath) in six portions over 30 min. The resulting mixture was stirred at 0°C for an additional 30 min, followed by room temperature for 2.5 hours to complete the reaction. After filtration, the reaction mixture was neutralized to pH 7 with 20% hydrochloric acid, diluted with 5 ml of ethanol, and then extracted with ethyl acetate (2 x 35 ml). The combined organic layer was washed with brine, dried over Na2S04 and concentrated under vacuum to afford (600 mg, 75%) 4,7-dibromo-3- hydroxyisoindolin- 1 -one (34f) as a yellow solid.

MS (EI) m/z: 307.9 (M+l). ⁱ H NMR (400 MHz, DMSO): 8 9.26 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H), 5.74 (d, J = 10.6 Hz, 1H). Step 6: 5,8-dibromophthalazin- l (2H)-one (34g)

4,7-dibromo-3-hydroxyisoindolin- l-one (34f) (600 mg, 1.95 mmol) was suspended in isopropyl alcohol (10 ml) and heated at 90°C for 1.5 hours. Hydrazine mono hydrate (0.12 ml, 3.91 mmol) was added in 4 increments and the resulting suspension was filtered and washed with isopropyl alcohol to afford 5,8- dibromophthalazin- l (2H)-one (34g) (225 mg, 27.9%) as a solid.

MS (EI) m/z: 304.9 (M+l). ⁱ H NMR (400 MHz, DMSO) : 8 12.94 (s, IH) , 8.43 (s, IH), 7.96 (d, J = 8.4 Hz, IH), 7.79 (d, J = 8.4 Hz, IH) .

Step 7: 5,8-bis((4-methoxyphenyl)thio)phthalazin- l (2H)-one (34h)

Title compound 5,8-bis((4-methoxyphenyl)thio)phthalazin- l (2H)-one (34h) was prepared as described for ( I d) starting from 5,8-dibromophthalazin- l (2H)-one (34g) and 4-methoxybenzenethiol.

MS (EI) m/z: 423.04 (M+ l) . ⁱ H NMR (400 MHz, DMSO): 8 12.81 (s, IH), 8.52 (s, IH), 7.43-7.40 (m, 3H), 7.30 (d, J = 8.8 Hz, 2H) , 7. 10 (d, J= 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.4 Hz, IH) , 3.84 (s, 3H), 3.73 (s, 3H).

Step 8: 5,8-bis((4-methoxyphenyl)sulfonyl)phthalazin- l (2H)-one (34)

Title compound 5,8-bis((4-methoxyphenyl)sulfonyl)phthalazin- l (2H)-one (34) was prepared by fallowing the oxidation of intermediate (34h) as described for ( 13).

MS (EI) m/z: 486.9 (M+ l) . ⁱ H NMR (400 MHz, DMSO) : 8 13.08 (s, IH) , 8.95 (d, J = 8.2 Hz, IH), 8.84 (d, J = 8.4 Hz, IH) , 8.00 (d, J = 9.2 Hz, 2H) , 7.79 (d, J = 8.8 Hz, 2H), 7. 17 (d, J = 9.2 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 3.84 (s, 6H).

Example 15: Pharmacological screening

0.5 - 5 ng of human recombinant PKM2 was incubated with PEP and ADP in the presence and absence of various concentrations of FBP or the test compounds. The reactions were incubated at 25°C for 30 - 45 min. The ATP generated was detected by using KinaseGlo (Promega) following the manufacturer's instructions. The luminescence obtained with the "minus FBP" control was used as the basal level to calculate percentage activation with respect to FBP. These percentages were used for the calculation of the EC50 values using GraphPad Prism 5.0. Biological Activity

AC50 (nM) Group: Compounds with ACsoinM) between 1 - 100 are grouped as A, the compound with ACsoinM) between 101-500 are grouped as B, and the compound with ACsoinM) above 501 are grouped as C. Following table 1 provides AC5o(nM) of the compounds of the present invention.

All references, including publications, patent applications , and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

The use of the terms 'a' and 'an' and 'the' and similar referents in the context of describing the invention (especially in the context of the following claims) are to be contrued to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms 'having ^* , 'including', and 'containing' are to be contrued as open-ended terms (i.e. meaing 'including, but not limited to') unless otherwise noted. Recitation of ranges of values herein are m erely intended to served as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separated value is incorporated into the specification as if it were individually recited herein. All methods described herein can be perfomred in any suitable order unless otherewise indicated herein or otherwise clearly contradicted by context. The used of any and all examples, or exemplary language (e.g., 'such as') provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the sepcification should be contrrued as indicating any non-claimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisan to employ such variations as appropriate, and the inventors intent for the inventino to be practiced otherwise than as specificaly described herein. Accoringly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as premitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.