FIELD OF THE INVENTION

The present invention relates to pharmaceuticals. Specifically, the present invention relates to novel compounds of Formula I, their pharmaceutically acceptable tautomers, isomers and salts thereof, exhibiting therapeutic activity and acting as anti-neoplastic agents. The present invention further relates to process for preparation of compounds of Formula I.

BACKGROUND OF THE INVENTION

Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Gastric cancer with gastric adenocarcinoma is the fifth most common cancer and the third leading cause of cancer-related deaths. According to WHO report, an estimated 1.0 million new gastric cancer cases and 723,100 deaths occurred in 2012 themselves, which levy a considerable global health burden. Most of the cases were recorded in Asian countries included Japan, China, Korea, and Mongolia with few incidences in North America and Africa. Gastric cancer is solid tumor, which develops in the stomach. This cancer often diagnosed at very advanced stage with lot of complications and non-treatable conditions. The average survival rate for the late stage gastric cancer is about 6–10 months. Segmentectomy is the preferred way of therapy with total or partial recovery depending on the size and location of the primary tumor.
[0004] The primary treatment options in chemotherapeutic interventions are neoadjuvant or adjuvant. Recent reports confirm that the incidence of metastatic patients was actually increased from 24% in 1990 to 44% in 2011. Patients in advanced cancer stage initially respond to chemotherapy, but eventually sicken and fail due to chemotherapeutic resistance. Therefore, drug resistance becomes a major obstacle to achieve effective therapeutic treatment. Reports suggest that intravenous therapy is effective for gastric cancer, also the systematic treatment and proper care can improve the quality of life to some extent. Only a small number of chemotherapeutic agents provide active palliation in this disease.
[0005] The identification of new candidate molecules is thus a major aim for the development of specific biotherapies. In addition, need is there for the invention of the compounds that are effective against several types of cancers such as Bowel, Bladder, Breast, and Cervical cancer indicating that these molecules may be active in all type of cancers.
[0006] The present invention addresses the cancer related to stomach and others. Gastric cancer remains a considerable health burden throughout the world. Single agent therapies proved to be much more effective as compare to chemo-combination. The results achieve from the combination therapies is very unsatisfactory in terms of survival.
[0007] There is, therefore, a need to develop novel compounds acting as anti-neoplastic agents that can overcome deficiencies associated with the known arts and act as anti-cancer compounds against a variety of cancers.

OBJECTS OF THE INVENTION
[0008] An object of the present invention is to provide novel fused heterocyclic compounds acting as anti-neoplastic agents.
[0009] An object of the present invention is to provide novel compounds useful for the treatment of variety of cancers.
[0010] Yet another object of the present invention is to develop anti-neoplastic compounds which can overcome deficiencies associated with the known arts.
[0011] Another object of the present invention is to provide novel compounds acting as anti-neoplastic agents, with improved efficacy and better safety profile.
[0012] Another object of the present invention is to provide novel compounds with high therapeutic activity and less toxic effects.
[0013] The other objects and preferred embodiments and advantages of the present invention will become more apparent from the following description of the present invention when read in conjunction with the accompanying examples and figures, which are not intended to limit scope of the present invention in any manner.

SUMMARY OF THE INVENTION
[0014] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0015] The present invention relates to pharmaceuticals. Specifically, the present invention relates to novel compounds of Formula I, acting as anti-neoplastic agents.
[0016] In one aspect, the present invention relates to novel compounds of Formula I, useful for the treatment of variety of cancers.
[0017] In one aspect, the present invention relates to novel compounds acting as anti-neoplastic agents, with improved efficacy and better safety profile.
[0018] In another aspect, the present invention relates to novel compounds with high therapeutic activity and less toxic effects.
[0019] In yet another aspect, the present invention relates to a compound of Formula I, its pharmaceutically acceptable tautomers, isomers and salts thereof,

Formula I
wherein:
ring A represents aryl or heteroaryl ring, which may further be fused to other aryl, heteroaryl or cyclic rings; Ring A can be optionally substituted with one to four substituents selected from alkyl, aryl, F, Cl, Br, I, ORa, -CONH2, -NH2, -CHO, -CN, -COORa, CSORa, alkylaryl, -NO2, -COOH;
Ring A can be attached to its neighboring 5 membered heteroaryl ring either at 4 or 5 position;
X represents H, N or B;
R1 represents hydrogen, alkyl, aryl, heteroaryl or alkyl-aryl;
R2 represents CH2, CHRa, CRaRb, SO2, C=O, C=S;
Ra and Rb represent alkyl, aryl, F, Cl, Br, I, ORa, -CONH2, -NH2, -CHO, -CN, -COORa, CSORa, alkylaryl, -NO2, -COOH;
R3 represents alkyl, aryl or heteroaryl ring; which can be optionally substituted with one to four substituents selected from alkyl, aryl, F, Cl, Br, I, ORa, -CONH2, -NH2, -CHO, -CN, -COORa, CSORa, alkylaryl, -NO2, -COOH;
W represents S or SO2; and
Z represents N, O or S.
[0020] In another aspect, the present invention relates to the process for the synthesis of novel compounds of Formula I their pharmaceutically acceptable tautomers, isomers and salts thereof.
[0021] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION
[0022] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0023] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0024] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0025] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0026] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[0027] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0028] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0029] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
[0030] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0031] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
[0032] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0033] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0034] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
Definitions
[0035] Relative to the above description of the compounds of the present invention, the following definitions apply.
[0036] The term “alkyl” as used herein alone or as part of another group refers to a straight or branched chain aliphatic hydrocarbon chain, having from 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, t-butyl and the like. Alkyl groups may further be substituted with one or more suitable substituents.
[0037] The term “aryl” herein refers to six to ten membered monocyclic aromatic group, for example phenyl or naphthyl ring and the like optionally substituted with one or more suitable substituents. The aryl group may optionally be fused with one or two cycloalkyl group(s) or other aryl group(s) resulting in polycyclic ring system. The fused group may be further substituted with one or more suitable substituents.
[0038] The term “heteroaryl” unless and otherwise specified refers to a five to ten membered aromatic monocyclic ring structure, containing one to five heteroatoms independently selected from N, O, S or B. “Heteroaryl” also includes, but is not limited to, bicyclic or tricyclic rings, wherein the above defined heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a heterocyclyl ring and another monocyclic heteroaryl ring. Examples of heteroaryl groups include, but are not limited to, oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, imidazo[1,2-a]pyrimidine, imidazo[1,2-a]pyrazine, tetrahydroquinoline and the like. The heteroaryl group may be further substituted at any available position with one or more suitable substituents. Point of attachment of heteroaryl group to another group may be through carbon or heteroatom.
[0039] A “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. A “pharmaceutically acceptable salt” also encompasses any compound according to the present invention that is utilized in the form of a salt thereof, especially where the salt confers on a compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound.
[0040] In all the above definitions, nitrogen, sulphur and phosphorus heteroatom can optionally be quaternerized or oxidized wherever permissible.
[0041] The present invention relates to pharmaceuticals. Specifically, the present invention relates to novel compounds of Formula I, acting as anti-neoplastic agents.
[0042] In one embodiment, the present invention relates to a compound of Formula I, its pharmaceutically acceptable tautomers, isomers and salts thereof,

Formula I
wherein:
ring A represents aryl or heteroaryl ring, which may further be fused to other aryl, heteroaryl or cyclic rings; Ring A can be optionally substituted with one to four substituents selected from alkyl, aryl, F, Cl, Br, I, ORa, -CONH2, -NH2, -CHO, -CN, -COORa, CSORa, alkylaryl, -NO2, -COOH;
Ring A can be attached to its neighboring 5 membered heteroaryl ring either at 4 or 5 position;
X represents H, N or B;
R1 represents hydrogen, alkyl, aryl, heteroaryl or alkyl-aryl;
R2 represents CH2, CHRa, CRaRb, SO2, C=O, C=S;
Ra and Rb represent alkyl, aryl, F, Cl, Br, I, ORa, -CONH2, -NH2, -CHO, -CN, -COORa, CSORa, alkylaryl, -NO2, -COOH;
R3 represents alkyl, aryl or heteroaryl ring; which can be optionally substituted with one to four substituents selected from alkyl, aryl, F, Cl, Br, I, ORa, -CONH2, -NH2, -CHO, -CN, -COORa, CSORa, alkylaryl, -NO2, -COOH;
W represents S or SO2; and
Z represents N, O or S.
[0043] In a preferred embodiment, the present invention relates to a compound of Formula I, wherein ring A represents aryl or heteroaryl selected from phenyl, pyridyl or pyrimidyl; optionally substituted with one or two substituents selected from alkyl, ORa, Cl, F, Br, I or NO2.
[0044] In another preferred embodiment, the present invention relates to a compound of Formula I, wherein X is H or N.
[0045] In another preferred embodiment, the present invention relates to a compound of Formula I, wherein Z is N.
[0046] In another preferred embodiment, the present invention relates to a compound of Formula I, wherein W is S or SO2.
[0047] In another preferred embodiment, the present invention relates to a compound of Formula I, wherein R1 is H, or heteroaryl selected from pyridyl or pyrimidyl.
[0048] In another preferred embodiment, the present invention relates to a compound of Formula I, wherein R2 is SO2, C=O or C=S.
[0049] In another preferred embodiment, the present invention relates to a compound of Formula I, wherein R3 is alkyl or aryl; optionally substituted with one to two substituents selected from alkyl, F, Cl, Br, I, ORa, or -NO2.
[0050] In yet another embodiment, particularly useful examples of the present invention include but are not limited to the compounds selected from the group consisting of:
[0051] N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1a);
[0052] N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-methylbenzenesulfonamide (1b);
[0053] N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-methoxybenzenesulfonamide (1c);
[0054] 4-Fluoro-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1d);
[0055] 4-Chloro-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1e);
[0056] 4-Bromo-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1f);
[0057] N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-nitrobenzenesulfonamide (1g);
[0058] N-(5-phenylthiazol-2-yl)-N-(pyrimidin-2-ylmethyl)benzamide (1h);
[0059] N-(5-phenylthiazol-2-yl)-N-(pyrimidin-2-ylmethyl)acetamide (1i);
[0060] N-(1,1-dioxido-5-phenylthiazol-2-yl)pyridine-2-sulfonamide (1j);
[0061] N-benzyl-5-phenyl-N-(pyridin-2-ylmethyl)thiazol-2-amine (1k);
[0062] N-methyl-5-phenyl-N-(pyridin-2-ylmethyl)thiazol-2-amine (1l);
[0063] N-(5-phenylthiazol-2-yl)-N-(pyridin-2-ylmethyl)benzamide (1m);
[0064] N-(1,1-dioxido-5-phenylthiazol-2-yl)-N-(pyridin-2-ylmethyl)benzamide (1n);
[0065] N-(1,1-dioxido-5-phenylthiazol-2-yl)pyridine-2-sulphotoluamide (1o);
[0066] N-(1,1-dioxido-5-phenylthiazol-2-yl)pyrimidine-2-sulphotoluamide (1p);
[0067] N-(1,1-dioxido-5-phenylthiazol-2-yl)-N-methylpyridine-2-sulfonamide (1q);
[0068] N-(1,1-dioxido-5-phenylthiazol-2-yl)-N-(pyridin-2-ylsulfonyl)acetamide (1r);
[0069] N-(1,1-dioxido-5-phenylthiazol-2-yl)-N-(pyrimidin-2-ylsulfonyl)acetamide (1s);
[0070] N-(Pyridin-2-ylmethyl)-N-(4-(pyrimidin-2-yl)thiazol-2-yl)acetamide (1t);
[0071] N-(4-(pyrimidin-2-yl)thiazol-2-yl)-N-(pyrimidin-2-ylmethyl)acetamide (1u); and
[0072] N-benzyl-N-(4-(pyrimidin-2-yl)thiazol-2-yl) ethanethioamide (1v).
[0073] Certain compounds according to Formula I, can also exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. These tautomers, either separately or as mixtures, are also considered to be within the scope of the invention.
[0074] The present invention also encompasses geometrical isomers of compounds of Formula I and the mixtures thereof. The geometrical isomers may exist in E or Z; Syn or anti configurations. These geometrical isomers, either separately or as mixtures, are also considered to be within the scope of the invention.
[0075] In another embodiment, the present invention relates to the process for the synthesis of novel compounds of Formula I their pharmaceutically acceptable tautomers, isomers and salts thereof.
[0076] The compounds of the present invention may be prepared by the following reaction sequences as depicted in Scheme No 1. The compounds disclosed may also be prepared by techniques known in the art and familiar to the skilled organic chemist. All of the starting materials are either commercially available or can be prepared by procedures that would be well known to one of ordinary skill in organic chemistry.

Scheme 1
[0077] In one embodiment, the process for synthesis of compounds of Formula I comprise the steps of :
a) reacting acetophenone derivatives of Formula II with thiourea of Formula III to obtain compounds of Formula IV; and
b) reacting compounds of Formula IV with compounds of Formula V in the presence of base in a suitable solvent to obtain compounds of Formula I.
[0078] In a preferred embodiment, the present invention relates to the process for synthesis of compounds of Formula I, wherein the base can be chosen from but not limited to K2CO3, KOtBu, Et3N, Diisopropylethylamine and the like.
[0079] In a preferred embodiment, the present invention relates to the process for synthesis of compounds of Formula I, wherein the solvent can be selected from a group consisting of Acetone, Dichloromethane, DMF, THF and the like.

[0080] In a preferred embodiment, the present invention relates to the process for synthesis of compounds of Formula I, wherein compounds of Formula II react with compounds of Formula III, in the presence of iodine and alcoholic solvent.
[0081] In another embodiment, the compounds of Formula I exhibit pharmacological properties.
[0082] In yet another embodiment, the present invention relates to novel compounds of Formula I useful against cancers of all types.
[0083] In one embodiment, the present invention relates to novel compounds of Formula I, useful for the treatment of variety of cancers.
[0084] In one embodiment, the present invention relates to novel compounds acting as anti-neoplastic agents, with improved efficacy and better safety profile.
[0085] In another embodiment, the present invention relates to novel compounds with high therapeutic activity and less toxic effects.
[0086] In still another embodiment, the compounds of Formula I demonstrate more therapeutic efficacy as compared to 5-fluorouracil.
[0087] The compounds of the present invention are associated with high therapeutic activity with less toxic effects.
[0088] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
[0089] The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.
[0090] Example 1: General procedure for synthesis of phenylthiazole derivatives of compounds of Formula I:
[0091] Step 1: Synthesis of Phenylthiazole amine derivatives of Formula IV
[0092] Appropriate acetophenone derivative (Formula II), (1.0 equiv) was treated with iodine (1.1 equiv) and thiourea derivative (Formula III), (3.0 equiv) in alcoholic solvent under reflux condition for 12.0–16.0 h. Then, the reaction mixture was cooled and quenched with NaOH(aq) solution (2.0 equiv) and the ethanol was removed under reduced pressure. The residue was extracted with ethyl acetate and the combined organic layer were washed the brine and dried over MgSO4(s). After being filtered and condensed under reduced pressure, the crude product was purified by column chromatography on silica gel in different ratios of ethyl acetate and hexane as eluent to give compound of Formula IV.
[0093] Step 2: Synthesis of compounds of Formula I
[0094] To a solution containing phenylthiazole amine derivative ((Formula IV), 1.0 equiv) in anhydrous ethereal solvent (2.0–3.0 mL) was added potassium carbonate (1.3 equiv) and a halide (Formula V), (1.1 equiv). After the reaction mixture was stirred at 25 oC for 2.0–3.0 h, it was diluted with dichloromethane (5.0 mL). Inorganic solids were filtered off and the filtrate was concentrated under reduced pressure to afford the residue. It was then purified by use of column chromatography on silica gel (various ratio of methanol to dichloromethane) to give the desired conjugates (Formula I).
[0095] The following compounds were synthesized following the procedure as described in Example 1:
[0096] N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1a): Yield 80%, green solid product. IR (film): 3569.1, 2811.2, 1560.1, 1481.2, 1374.2, 1131.6, 853.4
cm-1. 1HNMR (CDCl3, 400 MHz): 7.58–7.55 (m, 2 H, 2 × ArH), 7.53–7.51 (m, 1 H, H-6), 7.43–7.33 (m, 3 H, 3 × ArH), 6.84 (d, J = 2.0 Hz, 1 H, H-3), 6.79–6.77 (m, 1 H, H-5), 6.55 (s, 1 H, SCH), 3.75 (s, 3 H, OMe) ppm. 13CNMR (CDCl3, 100 MHz): 166.8, 163.9, 158.3, 147.2, 143.7, 131.5, 125.9, 121.1, 113.6, 113.2, 108.8, 106.2, 55.6 (OMe) ppm; HRMS (ESI+) m/z [M + H]+ calculated for C16H14N2O4S2, 363.0395, found 363.0396.
[0097] N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-methylbenzenesulfonamide (1b): Yield 84%, off-white solid product. IR (film): 3579.1, 2921.2, 1580.1, 1491.2, 1384.1, 1141.6, 843.4 cm-1. 1HNMR (CDCl3, 400 MHz): 7.44 (d, J = 8.8 Hz, 1 H, H-6), 7.39 (d, J = 8.2 Hz, 2 H, 2 × ArH), 7.06 (d, J = 8.2 Hz, 2 H, 2 × ArH), 6.81 (d, J = 2.4 Hz, 1 H, H-3), 6.74 (dd, J = 8.8, 2.4 Hz, 1 H, H-5) 6.52 (s, 1 H, SCH), 3.72 (s, 3 H, OMe), 2.29 (s, 3 H, CH3) ppm. 13CNMR (CDCl3, 100 MHz): 167.8, 159.3, 147.0, 145.3, 144.4, 132.1, 130.5, 129.1, 128.2, 120.9, 113.1, 108.7, 105.9, 55.4 (OMe), 21.4 (CH3) ppm; HRMS (ESI+) m/z [M + H]+ calculated for C17H16N2O4S2, 377.0551, found 377.0551.

[0098] N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-methoxybenzenesulfonamide (1c): Yield 83%, off-white solid product. IR (film): 3672.1, 2931.1, 1560.6, 1473.2, 1388.1, 1142.7, 817.4 cm-1. 1HNMR (CDCl3, 400 MHz): 7.46–7.42 (m, 3 H, H-6 + 2 × ArH), 6.86 (d, J = 2.8 Hz, 1 H, H-3), 6.76–6.72 (m, 3 H, H-5 + 2 × ArH), 6.57 (s, 1 H, SCH), 3.75 (s, 3 H, OMe), 3.74 (s, 3 H, OMe) ppm. 13CNMR (CDCl3, 100 MHz): 166.8, 163.9, 159.4, 147.1, 144.7, 130.5, 125.9, 121.0, 113.7, 113.2, 108.8, 106.2, 55.6 (OMe), 55.5 (OMe) ppm; HRMS (ESI+) m/z [M + H]+ calculated for C17H16N2O5S2, 393.0501, found 393.0498.
[0099] 4-Fluoro-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1d): Yield 81%, white solid product. IR (film): 3695.5, 2943.3, 1589.7, 1493.9, 1378.3, 1157.7, 837.7 cm-1. 1HNMR (CDCl3, 400 MHz): 7.51–7.48 (m, 2 H, 2 × ArH), 7.41 (d, J = 8.8 Hz, 1 H, H-6), 6.95–6.91 (m, 2 H, 2 × ArH), 6.86 (d, J = 2.6 Hz, 1 H, H-3), 6.75 (dd, J = 8.8, 2.6 Hz, 1 H, H-5), 6.46 (s, 1 H, SCH), 3.74 (s, 3 H, OMe) ppm. 13C NMR (CDCl3, 100 MHz): 167.3, 167.1, 164.5, 159.4, 146.8, 144.5, 131.2, 130.6, 120.9, 115.9, 115.6, 113.3, 108.9, 105.8, 55.5 (OMe) ppm; HRMS (ESI+) m/z [M + H]+ calculated for C16H13FN2O4S2, 381.0301, found 381.0302.
[00100] 4-Chloro-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1e): Yield 81%, white solid product. IR (film): 3708.8, 2796.7, 1566.74, 1459.55, 1314.15, 1256.54, 984.95 cm-1. 1HNMR (CDCl3, 400 MHz): 7.53 (d, J = 8.8 Hz, 1 H, H-6), 7.48–7.46 (m, 2 H, 2 × ArH), 7.29–7.27 (m, 2 H, 2 × ArH), 6.94 (d, J = 2.4 Hz, 1 H, H-3), 6.82 (dd, J = 8.8, 2.4 Hz, 1 H, H-5), 6.56 (s, 1 H, SCH), 3.81 (s, 3 H, OMe) ppm. 13CNMR (CDCl3, 100 MHz): 167.2, 159.5, 146.8, 144.7, 140.7, 133.2, 130.7, 129.6, 128.7, 120.9, 113.5, 109.1, 106.0, 55.6 (OMe) ppm; HRMS (ESI+) m/z [M + H]+ calculated for C16H13ClN2O4S2, 397.0005, found 397.0006.
[00101] 4-Bromo-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1f): Yield 83%, white solid product. IR (film): 3691.2, 2838.7, 1591.3, 1479.1, 1362.1, 1143.7, 821.7 cm-1. 1HNMR (CDCl3, 400 MHz): 7.36–7.33 (m, 3 H, H-5 + 2 × ArH), 7.28–7.26 (m, 2 H, 2 × ArH), 6.80 (d, J = 1.6 Hz, 1 H, H-3), 6.71 (dd, J = 8.8, 1.6 Hz, 1 H, H-5), 6.35 (s, 1 H, SCH), 3.69 (s, 3 H, OMe) ppm. 13CNMR (CDCl3, 100 MHz): 167.2, 164.3, 158.4, 145.7, 143.6, 132.3, 121.2, 115.6, 113.2, 108.7, 105.2, 56.4 (OMe) ppm; HRMS (ESI+) m/z [M + H]+ calculated for C16H13BrN2O4S2, 440.9500, found 440.9502.
[00102] N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-nitrobenzenesulfonamide (1g): Yield 84%, orange solid product. IR (film): 3607.7, 2685.6, 1554.65, 1360.65, 1325.25, 1267.54, 964.95 cm-1. 1HNMR (CDCl3, 400MHz): 8.06 (d,J=8.0Hz, 2H, 2 × ArH), 7.59(d, J=8.0Hz, 2H, 2 × ArH),7.29 (d, J = 8.6 Hz, 1 H, H-6), 6.90 (s, 1 H, H-3), 6.77 (d, J = 8.6 Hz, 1 H, H-5), 6.32 (s, 1 H, SCH), 3.76 (s, 3 H, OMe) ppm. 13CNMR (CDCl3, 100 MHz): 167.2, 162.0, 156.2, 151.1, 147.8, 145.9, 132.9, 128.2, 124.2, 112.8, 107.4, 105.0, 104.2, 55.8 (OMe) ppm; HRMS (ESI+) m/z [M + H]+ calculated for C16H13N3O6S2, 408.0246, found 408.0247.
[00103] N-(5-phenylthiazol-2-yl)-N-(pyrimidin-2-ylmethyl)benzamide (1h): Yield 68%, white solid product. IR (film): 2543.2, 1716.1, 1369.3, 1317.4, 1289.5, 776.9 cm-1. 1HNMR (CDCl3, 400MHz): 8.12 (d, J=8.0 Hz, 2H, 2 × ArH), 7.65 (d, J=8.0 Hz, 2H, 2 × ArH), 7.53 (br, 2H, ArH), 7.34-7.31 (m, 2H, 2 × ArH), 7.25-7.21 (m, 2H, 2 × ArH), 7.20-7.16 (m, 2H, ArH), 5.82 (s, 1H, H-4), 4.98 (s, 2 H, CH2) ppm.
[00104] N-(5-phenylthiazol-2-yl)-N-(pyrimidin-2-ylmethyl)acetamide (1i): Yield 71%, white solid product. 13CNMR (CDCl3, 100MHz): 176.2, 161.9, 154.4, 147.4, 145.1, 139.8, 134.8, 130.2, 127.0, 123.7, 118.5, 110.2, 46.0, 34.5.
[00105] N-(1,1-dioxido-5-phenylthiazol-2-yl)pyridine-2-sulfonamide (1j): Yield 54%, yellow solid product. 1HNMR (CDCl3, 400MHz): 8.01 (d, J=8.0 Hz, 2H, 2 × ArH), 7.63 (t, J=8.0 Hz, 1H, ArH), 7.51 (m, 3H, 3 × ArH), 7.34 (m, 2H, 2 × ArH), 7.20 (s, 1H), 7.20 (m, 1H, ArH), 7.08 (t, J=8.0 Hz, 1H).
[00106] N-benzyl-5-phenyl-N-(pyridin-2-ylmethyl)thiazol-2-amine (1k): Yield 74%, off-white solid product. 1HNMR (DMSO-d6, 400MHz): 8.47 (d, J=8.0 Hz, 1H, ArH), 8.16-8.03 (m, 3H, 3 × ArH), 7.88 (d, J=8.0 Hz, 1H, ArH), 7.82 (t, J=8.0 Hz, 1H, ArH), 7.68-7.62 (m, 3H, 3 × ArH), 7.52 (t, J=8.0 Hz, 1H, ArH), 7.23-7.21 (m, 1H), 7.13 (s, 1H, ArH), 7.06-7.02 (m, 2H), 6.37 (s, 1H), 5.47 (s, 2H), 4.58 (s, 2H).
[00107] N-methyl-5-phenyl-N-(pyridin-2-ylmethyl)thiazol-2-amine (1l): Yield 74%, off-white solid product. 1HNMR (CDCl3, 400MHz): 8.22 (d, J=8.0 Hz, 1H, ArH), 7.76-7.74 (m, 3H, 3 × ArH), 7.73 (d, J=8.0 Hz, 1H, ArH), 7.71-7.64 (m, 3H, 3 × ArH), 7.41 (t, J=8.0 Hz, 1H, ArH), 7.37-7.31 (m, 3H), 7.16 (d, J=8.0 Hz, 1H, ArH), 6.81 (s, 1H), 6.63 (s, 1H), 4.43 (s, 2H), 2.41 (s, 3H).
[00108] Example 2: Biological assays
[00109] Cell Culture: Different cell lines, including human gastric adenocarcinoma (AGS), human cervix adenocarcinoma (HeLa), human pancreas adenocarcinoma (PaTu8988t), human colorectal adenocarcinoma (HT-29), and mouse colon carcinoma (CT26.WT) cells were purchased from Bioresource Collection and Research Center (BCRC, Taiwan) to evaluate anticancer activity of phenylthiazole-amine derivatives. Cell lines were cultured in their respective media purchased from Gibco (Life Technologies, Grand Island, NY, USA) and Hyclone (GE Healthcare Life Science). Cells were cultured in 90% medium mixed with 10% serum at 37 ?C in humidified atmosphere with 5% CO2 and grown in T-75 flask with a feeding cycle of two to three days. The composition and procedures of preparing culture media for different cell lines were followed by instruction manual of suppliers.
[00110] Cell Viability Assay: The different cell lines were seeded into 96-well tissue culture plates at a concentration of 5 x 103 cells/100 µL/well overnight. Phenylthiazol-amine derivatives of various concentrations were added to the cell culture followed by 48 h of incubation. After the incubation, MTT assay was used to determine the cell viability. Briefly, 100 µL of 2 mg/mL MTT reagent (Sigma-Aldrich, St. Louis, MO, USA) was added to each well and incubated for 4 h at 37 ?C. Later, the medium was aspirated and 100 µL of dimethyl sulphoxide (DMSO) added to each well; finally, the OD595 of each well was measured by ELISA reader (TECAN, Wien, Austria).
[00111] The anticancer activity of the newly synthesized compounds against AGS, HeLa, PaTu8988t, HT-29, and CT26.WT was evaluated as described in Table 1.

Table 1: Anticancer activity of compounds against various cell lines

Compounds IC50 (?M)
AGS HeLa PaTu8988t HT-29 CT26.WT
1a >50 >50 31.1 20.7 >50
1b 22.0 27.4 38.7 14.1 >50
1c 4.0 5.8 15.8 4.4 10.0
1d 7.2 13.8 31.4 11.2 >50
1e >50 >50 >50 13.4 >50
1f >50 16.4 22.8 11.0 >50
1g >50 >50 >50 47.8 30.0
1h >50 21.4 16.3 6.3 12.4
1i 31.2 5.4 19.5 7.5 >50
1j >50 8.7 12.9 6.5 27.5
1k 27.3 7.3 29.4 9.7 25.3
1l 23.6 5.3 32.1 5.9 13.5
5-FU 43.8 2.2 12.5 7.2 9.2

[00112] The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

ADVANTAGES OF THE PRESENT INVENTION

[00113] The present invention provides novel compounds acting as anti-neoplastic agents.
[00114] The present invention provides novel compounds useful for the treatment of variety of cancers.
[00115] The present invention provides anti-neoplastic compounds, which can overcome deficiencies associated with the known arts.
[00116] The present invention provides novel compounds acting as anti-neoplastic agents, with improved efficacy and better safety profile.
[00117] The present invention provides novel compounds with high therapeutic activity and less toxic effects.

We Claim:

1. A compound of Formula I, its pharmaceutically acceptable tautomers, isomers and salts thereof,

Formula I
wherein:
ring A represents aryl or heteroaryl ring, which may further be fused to other aryl, heteroaryl or cyclic rings; Ring A can be optionally substituted with one to four substituents selected from alkyl, aryl, F, Cl, Br, I, ORa, -CONH2, -NH2, -CHO, -CN, -COORa, CSORa, alkylaryl, -NO2, -COOH;
Ring A can be attached to its neighboring 5 membered heteroaryl ring either at 4 or 5 position;
X represents H, N or B;
R1 represents hydrogen, alkyl, aryl, heteroaryl or alkyl-aryl;
R2 represents CH2, CHRa, CRaRb, SO2, C=O, C=S;
Ra and Rb represent alkyl, aryl, F, Cl, Br, I, ORa, -CONH2, -NH2, -CHO, -CN, -COORa, CSORa, alkylaryl, -NO2, -COOH;
R3 represents alkyl, aryl or heteroaryl ring; which can be optionally substituted with one to four substituents selected from alkyl, aryl, F, Cl, Br, I, ORa, -CONH2, -NH2, -CHO, -CN, -COORa, CSORa, alkylaryl, -NO2, -COOH;
W represents S or SO2; and
Z represents N, O or S.
2. The compound as claimed in claim 1, wherein ring A represents aryl or heteroaryl selected from phenyl, pyridyl or pyrimidyl; optionally substituted with one or two substituents selected from alkyl, ORa, Cl, F, Br, I or NO2.
3. The compound as claimed in claim 1, wherein X is H or N.
4. The compound as claimed in claim 1, wherein Z is N.

5. The compound as claimed in claim 1, wherein W is S or SO2.
6. The compound as claimed in claim 1, wherein R1 is H, or heteroaryl selected from pyridyl or pyrimidyl.
7. The compound as claimed in claim 1, wherein R2 is SO2, C=O or C=S.
8. The compound as claimed in claim 1, wherein R3 is alkyl or aryl; optionally substituted with one to two substituents selected from alkyl, F, Cl, Br, I, ORa, or -NO2.
9. A compound selected from the group consisting of:
N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1a);
N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-methylbenzenesulfonamide (1b);
N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-methoxybenzenesulfonamide (1c);
4-Fluoro-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1d);
4-Chloro-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1e);
4-Bromo-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (1f);
N-[4-(2-Hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-nitrobenzenesulfonamide (1g);
N-(5-phenylthiazol-2-yl)-N-(pyrimidin-2-ylmethyl)benzamide (1h);
N-(5-phenylthiazol-2-yl)-N-(pyrimidin-2-ylmethyl)acetamide (1i);
N-(1,1-dioxido-5-phenylthiazol-2-yl)pyridine-2-sulfonamide (1j);
N-benzyl-5-phenyl-N-(pyridin-2-ylmethyl)thiazol-2-amine (1k);
N-methyl-5-phenyl-N-(pyridin-2-ylmethyl)thiazol-2-amine (1l);
N-(5-phenylthiazol-2-yl)-N-(pyridin-2-ylmethyl)benzamide (1m);
N-(1,1-dioxido-5-phenylthiazol-2-yl)-N-(pyridin-2-ylmethyl)benzamide (1n);
N-(1,1-dioxido-5-phenylthiazol-2-yl)pyridine-2-sulphotoluamide (1o);
N-(1,1-dioxido-5-phenylthiazol-2-yl)pyrimidine-2-sulphotoluamide (1p);
N-(1,1-dioxido-5-phenylthiazol-2-yl)-N-methylpyridine-2-sulfonamide (1q);
N-(1,1-dioxido-5-phenylthiazol-2-yl)-N-(pyridin-2-ylsulfonyl)acetamide (1r);
N-(1,1-dioxido-5-phenylthiazol-2-yl)-N-(pyrimidin-2-ylsulfonyl)acetamide (1s);
N-(Pyridin-2-ylmethyl)-N-(4-(pyrimidin-2-yl)thiazol-2-yl)acetamide (1t);
N-(4-(pyrimidin-2-yl)thiazol-2-yl)-N-(pyrimidin-2-ylmethyl)acetamide (1u); and
N-benzyl-N-(4-(pyrimidin-2-yl)thiazol-2-yl)ethanethioamide (1v).
10. A process for the preparation of compounds of Formula I as claimed in claims 1-9, comprising the steps of:
a) reacting acetophenone derivatives of Formula II with thiourea of Formula III to obtain compounds of Formula IV; and
b) reacting compounds of Formula IV with compounds of Formula V in the presence of base in a suitable solvent to obtain compounds of Formula I.
11. The process as claimed in claim 10 wherein the base is selected from K2CO3, KOtBu, Et3N, and Diisopropylethylamine.
12. The process as claimed in claim 10 wherein the solvent is selected from Acetone, Dichloromethane, DMF and THF.
13. The process as claimed in claim 10 wherein compounds of Formula II react with compounds of Formula III, in the presence of iodine and alcoholic solvent.