SUBSTITUTED PYRIMIDINE COMPOUNDS AND USES THEREOF

FIELD OF THE INVENTION

The present invention relates to substituted pyrimidine compounds (referred to herein as the compounds of formula 1 ), processes for their preparation, pharmaceutical compositions comprising the compounds of formula 1 , and their use in the treatment of diseases or disorders mediated by one or more kinases, particularly proliferative diseases or disorders such as cancer. These compounds can also be used in the treatment of inflammatory disorders.

BACKGROUND OF THE INVENTION

Cancer is an uncontrolled growth and spread of cells that may affect almost any tissue of the body. Cancer can be defined as abnormal growth of tissues characterized by a loss of cellular differentiation. It is caused due to a deregulation of the signaling pathways involved in cell survival, cell proliferation and cell death. It is now well understood that deregulation of oncogenes and tumour-suppressor genes contributes to the formation of malignant tumours, for example, by way of increased cell proliferation or increased cell survival. It is also known that signalling pathways mediated by certain protein kinases have a central role in a number of cell processes including proliferation and survival, and deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases. Cancer therapy currently falls under the following categories that include surgery, radiation therapy, chemotherapy, bone marrow transplantation, stem cell transplantation, hormonal therapy, immunotherapy, antiangiogenic therapy, targeted therapy, gene therapy and others. In the recent times, significant improvements have been observed in the treatment of cancers with identification of small molecules as therapeutic agents acting through different mechanisms.

Protein kinases are enzymes that catalyze the phosphorylation of proteins at the hydroxy groups of tyrosine, serine and threonine residues of proteins. The kinase complement of the human genome contains 518 putative protein kinase genes. The consequences of this activity include effects on cell differentiation, proliferation, transcription, translation, metabolism, cell cycle progression, apoptosis, metabolism, cytoskeletal rearrangement and movement; i.e., protein kinases mediate the majority of signal transduction in eukaryotic cells. Furthermore, abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to cancer. Chromosomal mapping has revealed that over two hundred kinases map to disease loci, including cancer, inflammatory and metabolic disease.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by uncontrolled growth of progenitor cells expressing the tyrosine kinase fusion gene product, Bcr-Abl. Recent reports have shown that ectopic Bcr-Abl expression dramatically increases TGF /Smad-dependent transcriptional activity in Cos1 cells, and that this may be due to enhancement of Smad promoter activity (FEBS Letters, 2007, 581 , 7, 1 329-1 334; Leukemia, 2007, 21 , 494-504). Bcr-Abl expressing TF-1 myeloid cells are more potently growth arrested by TGF compared to the parental TF- 1 cell line. The expression of Bcr-Abl leads to hyper-responsiveness of myeloid cells to TGF , and that this novel cross-regulatory mechanism might play an important role in maintaining the transformed progenitor cell population in CML. A small pocket of haemopoietic stem cells, which are resistant to imatinib mesylate, in part because they are non-cycling, also hinders the complete eradication of CML. Therefore, TGF is a prime candidate for maintaining these CML stem cells in a non-cycling state. An upregulation or prolongation of TGF signaling by Bcr-Abl, suggests that one of the mechanisms by which Bcr-Abl promotes the transformation of haemopoietic progenitor cells, is by influencing the level of TGF signaling activity (FEBS Letters, 2007, 581 , 7, 1 329-1 334). TGF plays a vital role in the preservation of the malignant progenitor population, and is partially responsible for the resistance to treatments targeting Bcr- Abl that is observed in a proportion of CML patients.

The phosphatidylinositol-3 kinase (PI3K) mediated signaling pathway plays a very important role in cancer cell survival, cell proliferation, angiogenesis and metastasis. The PI3K pathway is activated by stimuli such as growth factors, hormones, cytokines, chemokines and hypoxic stress. Activation of PI3K results in the recruitment and activation of protein kinase B / Akt to the membrane, which gets phosphorylated at Serine 473. Thus, phosphorylation of Ser-473 of Akt is a universally approved read-out/detector for the activation of the PI3K-mediated pathway. A cell- based ELISA technique can be used to study such activation.

Two experimental drugs namely nilotinib (AMN-1 07; Novartis) and dasatinib (BMS-354825; Bristol-Myers Squibb) were found to be effective in circumventing some, but not all forms of imatinib mesylate resistance (Expert Reviews, Anticancer Ther., 2008, 8, 9, 1387-1398). The T315I mutant is one of the more predominant mutations seen in imatinib mesylate-resistant patients. This T315I mutation was shown to preserve kinase activity resulting in ineffective binding of imatinib mesylate to Bcr- Abl. Another drug, homoharringtonine (ChemGenex Pharmaceuticals), which is in the Phase I l/l 11 stage study has been found to be useful for patients with imatinib mesylate resistant CML, including those containing the T315I mutation (Expert Reviews, Anticancer Ther., 2008, 8, 9, 1387-1398). Recently, bosutinib (SKI-606; Pfizer), which is a dual tyrosine kinase inhibitor, is being tested in clinical trials. Unlike imatinib, bosutinib inhibits the autophosphorylation of both Abl and Src kinases, resulting in inhibition of cell growth and apoptosis. Because of the dual mechanism of action, this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors (Mol. Cancer Ther., 2008, 7 (5), 1 185-94). However, despite these developments, there still exists a continuing need for agents which are effective against the imatinib mesylate-resistant CML.

US Patent Application publication 20050014753, describes compounds that are substituted pyridinamines and triazinamides to prevent diseases and disorders associated with abnormal or deregulated tyrosine kinase activity, particularly diseases associated with the activity of PDGF-R, c-kit and Bcr-abl.

PCT Application Publication WO2008129080, describes 4,6-disubstituted aminopyrimidine derivatives as inhibitors of protein kinases.

Although, different treatment options are currently available for the treatment of different types of cancers, there still exists a continuing medical need to provide for new drugs for such treatments. The pyrimidine compounds of this invention ("the compounds of formula 1 ") inhibit the activity of one or more protein kinases and are, therefore, found to be useful in the treatment of kinase-associated proliferative diseases or disorders, particularly cancers.

Tumor Necrosis Factor-alpha (TNF-a), a pleiotropic cytokine, is derived from mononuclear cells and macrophages and in turn induces the expression of a variety of genes that contribute to various disorders such as inflammation. TNF-a plays a critical role in innate and acquired immune response and an increase in the production of TNF-a can produce pathological changes resulting in chronic inflammation and tissue damage. TNF-a has been shown to play a crucial role in the pathogenesis of many chronic inflammatory disease such as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non- rheumatoid arthritis, osteoporosis/bone resorption, coronary heart disease, vasculitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, adult respiratory distress syndrome, diabetes, psoriasis, skin delayed type hypersensitivity disorders and Alzheimer's disease.

lnterleukin-6 (IL-6) is a pleiotropic cytokine that regulates immunological reactions involved in host defence, inflammation, haematopoiesis, and oncogenesis. IL-6 is known to be a B-cell differentiation factor, induces T cell growth and cytotoxic T- cell differentiation through effecting IL-2 receptor expression and IL-2 production. This cytokine also acts synergistically with other proteins to affect haematopoiesis, macrophage and osteoclast differentiation and platelet production. It can also work as a cell growth factor inducing proliferation of mesangial cells, epidermal keratinocytes as well as various tumour cells.

IL-6 has been implicated as a mediator in inflammatory disorders, multiple myelomas, plasmacytomas, Castleman's disease, polyclonal B-cell activation, T cell proliferation, autoimmune disease, AIDS, adult respiratory distress syndrome, cancer, diabetes, ischemia-reperfusion injury, multiple sclerosis and rheumatoid arthritis.

The first line of treatment for inflammatory disorders involves the use of nonsteroidal anti-inflammatory drugs (NSAIDs) e.g. ibuprofen, naproxen to alleviate symptoms such as pain. However, despite the widespread use of NSAIDs, many individuals cannot tolerate the doses necessary to treat the disorder over a prolonged period of time as NSAIDs are known to cause gastric erosions. Moreover, NSAIDs merely treat the symptoms of disorder and not the cause. When patients fail to respond to NSAIDs, other drugs such as methotrexate, gold salts, D-penicillamine and corticosteroids are used. These drugs also have significant toxic effects.

Monoclonal antibody drugs such as infliximab, etanercept and adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost, allergy induction, activation of latent tuberculosis, increased risk of cancer and congestive heart disease.

As such, there is a requirement for small molecule inhibitors of pro-inflammatory cytokines such as TNF-a or interleukins ( I L- 1 β , IL-2, IL-6 or IL-8) for the effective treatment of inflammatory or auto-immune disorders implicated by TNF-a and/or interleukins (IL-1 β, IL-2, IL-6 and/or IL-8). SUMMARY OF THE INVENTION

According to one aspect of the present invention, there are provided compounds of formula 1 (as described herein), in all their stereoisomeric, and tautomeric forms and mixtures thereof in all ratios, or pharmaceutically acceptable salts, solvates, prodrugs, polymorphs and N-oxides, thereof.

According to yet another aspect of the present invention, there are provided processes for the preparation of the compounds of formula 1 , or pharmaceutically acceptable salts thereof.

According to another aspect of the present invention, there are provided pharmaceutical compositions comprising one or more compounds of formula 1 , or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof and at least one pharmaceutically acceptable carrier or excipient.

According to a further aspect of the present invention, there is provided a compound of formula 1 , a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, which inhibit one or more kinases as described herein.

According to a further aspect of the present invention, there is provided a compound of formula 1 , or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, for use in the treatment of diseases or disorders mediated by one or more kinases.

According to a further aspect of the present invention, there is provided a method for the treatment of diseases or disorders mediated by one or more kinases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

According to a further aspect of the present invention, there is provided a method for the treatment of a disorder mediated by one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-cc) or interleukins (IL-Ι β, IL-2, IL-6, and/or IL-8), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 .

According to yet another aspect of the present invention, there are provided the compounds of formula 1 , for use in the treatment of a disorder mediated by one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-cc) or interleukins (IL-Ι β, IL-2, IL-6, and/or IL-8). According to another aspect of the present invention there is provided use of a compound of formula 1 for the manufacture of medicaments for use in the treatment of a disorder mediated by one or more cytokines selected from Tumor Necrosis Factor- alpha (TNF-cc) and interleukins such as IL-1 β, IL-2, IL-6, and IL-8.

These and other objectives and advantages of the present invention will be apparent to those skilled in the art from the following description.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 (A) shows effect of the compound of example 4 on Bcr-abl, Phospho- Smad3, Phospho-crkl (Tyr 207), Bcl-2 and β-Actin by western blotting comparative study with imatinib mesylate (standard) and dasatinib (standard) at 48 h, at a concentration: 3 ^χ IC ₅ o-

Figure 1 (B) shows effect of the compound of example 4 on Bcr-abl, Phospho- Smad3 and β-Actin by western blotting comparative study with imatinib mesylate (standard) and dasatinib (standard) at 96 h, at a concentration: 3 ^χ IC ₅ o-

Figure 2(A) shows effect of the compound of example 4 and the compound of example 10 on protein expression by western blotting, comparative study with imatinib mesylate (standard) in K562 cell line and BAF3 cell line at 48 h, at concentrations: IC ₅ o and 3 ^χ IC ₅ o- Figure 2(B) shows effect of the compound of example 4 and the compound of example 10 on protein expression by western blotting comparative study with imatinib mesylate (standard) in T315I cell line and M351 T cell line at 48 h, at concentrations:

Figure 3 shows effect of the compound of example 10 on PI3K/Akt pathway in PC3 cells (which show constitutive activation of this path way).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula 1 ,

wherein,

Ri at each occurrence is independently selected from (Ci-C ₆ )alkyl, -0-(Ci-C ₆ )alkyl, hydroxy, CN, halogen, halo(d-C ₆ )alkyl, NR _a R _b , -0-(Ci-C ₄ )alkyl-0-(C C ₄ )alkyl-0-(Ci- C ₄ )alkyl and -C(0)-R; or two Ri groups present on adjacent carbon atoms of the phenyl ring may optionally form a 5 or 6 membered saturated or unsaturated ring containing 0 to 2 heteroatoms independently selected from O, N and S;

R is hydroxy or -0-(CrC ₆ )alkyl;

n is an integer from 0 to 3;

R ₂ is selected from hydrogen, (C-|-C ₆ )alkyl or halogen;

Yi and Y ₂ are independently selected from hydrogen and -Z-(R ₃ )-W-[R ₄ ] _P ; and atleast one of Yi and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is selected from O, N or S;

R ₃ is hydrogen or (C-|-C ₆ )alkyl; or is absent when Z is O or S;

W is a pyridyl or a phenyl ring;

R ₄ at each occurrence is independently selected from (Ci-C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, halo(Ci-C ₆ )alkyl, ar(C-i-C ₆ )alkyl, halogen, cyano, amino, nitro, hydroxy, -0-(C-i-C ₆ )alkyl, halo(Ci-C ₆ )alkoxy, aryl and heterocyclyl; and

p is an integer from 0 to 5;

R _a and R _b are independently selected from hydrogen, (C-|-C ₆ )alkyl, -C(0)OH, - C(0)0(Ci-C ₆ )alkyl, -C(0)(Ci-C ₆ )alkyl, -S0 ₂ -(Ci-C ₆ )alkyl, -S0 ₂ -aryl, -S0 ₂ -heterocyclyl, ar(CrC ₆ )alkyl, aryl and heterocyclyl;

wherein, each of (Ci-C ₆ )alkyl, -0-(C-i-C ₆ )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (d- C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, hydroxy, -0-(C C ₆ )alkyl, halo(CrC ₆ )alkyl, halo(C C ₆ )alkoxy, halogen, cyano, amino, nitro, -ON0 ₂ , aryl, heterocyclyl, -C(0)OR _a , -C(0)R _a , -SR _a , -NR _a R _b and -C(0)NR _a R _b , wherein R _a and R are as defined above;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof. Definitions

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein and the appended claims. These definitions should not be interpreted in the literal sense as they are not general definitions and are relevant only for this application.

It will be understood that "substitution," "substituted" or "substituted with" means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.

The terms "a", "an" and "the" refers to "one or more" when used in the subject specification, including the claims. Thus, for example, reference to "a compound" may include a plurality of such compounds, or reference to "a disease" or "a condition" includes a plurality of diseases or disorders.

As used herein, the term "alkyi" whether used alone or as part of a substituent group, refers to saturated aliphatic groups, including straight or branched-chain alkyi groups. If the number of carbon atoms is not specified, "alkyi" refers to (C.,-C ₆ )alkyl. Accordingly, a straight-chain or branched chain alkyi has six or fewer carbon atoms in its backbone, for instance, Ci-C ₆ for straight- chain and C ₃ -C ₆ for branched chain. For example, alkyi groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl, 3-hexyl and the like.

Furthermore, unless stated otherwise, the alkyi groups may be unsubstituted or substituted. A substituted alkyi refers to a alkyi substituted with one or more groups independently selected from (Ci-C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, hydroxy, -0-(C-i-C ₆ )alkyl, halo(Ci-C ₆ )alkyl, halo(Ci-C ₆ )alkoxy, halogen, cyano, amino, nitro, -ON0 ₂ , aryl, heterocyclyl, -C(0)OR _a , -C(0)R _a , -SR _a , -NR _a R _b and -C(0)NR _a R _b ; wherein R _a and R _b are independently selected from hydrogen, (CrC ₆ )alkyl, -C(0)OH, -C(0)0(C ₁ -C ₆ )alkyl, -C(0)(C ₁ -C ₆ )alkyl, -S0 ₂ -(C ₁ -C ₆ )alkyl, -S0 ₂ -aryl, -S0 ₂ -heterocyclyl, ar(C ₁ -C ₆ )alkyl, aryl and heterocyclyl. Examples of substituted alkyls include, but are not limited to, trifluoromethyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 -aminoethyl, benzyl, N-morpholino methyl, N-indolomethyl, and N-piperidinylmethyl.

The term "(C ₃ -C ₆ )cycloalkyl" refers to a monocyclic saturated ring system containing 3 to 6 carbon atoms in a ring structure. The cycloalkyl is optionally bridged (i.e., forming a bicyclic moiety), for example a methylene, ethylene or propylene bridge. Examples of cycloalkyl residues are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Furthermore, unless stated otherwise, the term 'cycloalkyl' includes unsubstituted cycloalkyl and cycloalkyl which is substituted with one or more groups independently selected from (Ci-C ₆ )alkyl, halo(Ci-C ₆ )alkyl, 1 -aminoalkyl, (d- C ₆ )alkoxy, amino, halogen, aryl and heterocyclyl.

As used herein, the term "-0-(Ci-C ₆ )alkyl" or "alkoxy" refers to (C-|-C ₆ )alkyl having an oxygen atom attached thereto that is bonded via the oxygen atom. Representative alkoxy groups include, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. A substituted "-0-(Ci-C ₆ )alkyl" or "alkoxy" refers to an alkoxy group in which the (C-|-C ₆ )alkyl is substituted with one or more groups independently selected from (CrC ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, hydroxy, -O- (Ci-C ₆ )alkyl, halo(CrC ₆ )alkyl, halo(Ci-C ₆ )alkoxy, halogen, cyano, amino, nitro, -ON0 ₂ , aryl, heterocyclyl, -C(0)OR _a , -C(0)R _a , -SR _a , -NR _a R _b and -C(0)NR _a R _b ; wherein R _a and R _b are independently selected from hydrogen, (C-|-C ₆ )alkyl, -C(0)OH, -C(0)0(C-|- C ₆ )alkyl, -C(0)(C ₁ -C ₆ )alkyl, -S0 ₂ -(C ₁ -C ₆ )alkyl, -S0 ₂ -aryl, -S0 ₂ -heterocyclyl, ar(C C ₆ )alkyl, aryl and heterocyclyl. Examples of substituted alkoxy include, but are not limited to, trifluoromethoxy, 2-cyanoethoxy or benzyloxy group. A benzyloxy group refers to a benzyl group having an oxygen atom attached thereto.

The term "aryl" as used herein refers to monocyclic or polycyclic hydrocarbon groups having 6 to 14 ring carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system. Examples of (C ₆ -C-i ₄ )aryl residues are phenyl, naphthyl, fluorenyl or anthracenyl. Aryl groups can be unsubstituted or substituted with one or more groups independently selected from (Ci-C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, hydroxy, -0-(C-i-C ₆ )alkyl, halo(C-i-C ₆ )alkyl, halo(C-i-C ₆ )alkoxy, halogen, cyano, amino, nitro, -ON0 ₂ , aryl, heterocyclyl, -C(0)OR _a, -C(0)R _a , -SR _a , -NR _a R _b and -C(0)NR _a R _b ; wherein R _a and R _b are independently selected from hydrogen, (Ci-C ₆ )alkyl, -C(0)OH, - C(0)0(Ci-C ₆ )alkyl, -C(0)(C C ₆ )alkyl, -S0 ₂ -(C C ₆ )alkyl, -S0 ₂ -aryl, -S0 ₂ -hetero cyclyl, ar(CrC ₆ )alkyl, aryl and heterocyclyl. For example, if aryl is phenyl then examples of substituted phenyl groups include, but not limited to, 4-methoxyphenyl, 4- hydroxyphenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4-aminophenyl, 4- cyanophenyl, 3,4-dimethoxyphenyl, 3,4-dihydroxyphenyl, 2,4-dimethoxyphenyl, 2,4- dihydroxyphenyl, 3,5-dimethoxyphenyl, 3,5-dihydroxyphenyl, 2,4-difluorophenyl, 3,5- difluorophenyl, 2,4-dichlorophenyl, 4-methoxy-3-trifluoromethylphenyl, or 4-methyl-3- trifluoromethylphenyl. Any carbon atom of the aryl group with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency. The term "aralkyi" or "ar(Ci-C ₆ )alkyl" refers to an aryl group bonded directly through an (CrC ₆ )alkyl group, such as benzyl (-CH ₂ Ph). The aryl of the aralkyi group may be unsubstituted or substituted as indicated herein above.

The term "heteroatom" as used herein includes nitrogen (N), oxygen (O), and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.

The term "heterocyclyl" includes saturated heterocyclic ring systems, which do not contain any double bonds within the rings, as well as unsaturated heterocyclic ring systems, which contain one or more, for example, 3 double bonds within a ring provided that the resulting mono, bi or tricyclic ring system is stable. The heterocyclyl group may, for example, have 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms and/or 1 to 3 nitrogen atoms in the ring. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S-dioxide. Aromatic heterocyclyl groups may also be referred to by the customary term "heteroaryl" for which all the definitions and explanations relating to heterocyclyl apply. Preferably, heterocyclyl contain 4 to 6 ring atoms forming the ring system. Further, the heterocycle may be fused with an aromatic aryl group such as phenyl. Examples of heterocyclyls include, but are not limited to, oxetane, azetidine, thiophene, thietane, tetrahydrofuran, tetrahydrothiophene, dihydropyran, tetrahydropyran, thio-dihydropyran, thiotetrahydropyran, piperidine, piperazine, morpholine, 1 ,3-oxazinane, 1 ,3-thiazinane, 4,5,6-tetrahydropyrimidine, 2,3-dihydrofuran, dihydrothiene, dihydropyridine, tetrahydropyridine, isoxazolidine, pyrazolidine, pyrrole, pyrrolidine, pyrazole, imidazole, pyrazine, pyridazine, oxazole, triazole, tetrazole, isoxazole, thiazole, isothiazole, furan, thiene, pyridine, pyrimidine, benzothiazole, purine, benzimidazole, benzooxazole, indole, isoindole, isoquinoline, quinoxaline and quinoline. Unless stated otherwise, heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (Ci-C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, hydroxy, -0-(Ci-C ₆ )alkyl, halo(Ci-C ₆ )alkyl, halo(Ci-C ₆ )alkoxy, halogen, cyano, amino, nitro, -ON0 ₂ , aryl, heterocyclyl, -C(0)OR _a, -C(0)R _a , -SR _a , -NR _a R _b or -C(0)NR _a R _b ; wherein R _a and R _b are independently selected from hydrogen, (Ci-C ₆ )alkyl, -C(0)OH, -C(0)0(C ₁ -C ₆ )alkyl, - C(0)(Ci-C ₆ )alkyl, -S0 ₂ -(Ci-C ₆ )alkyl, -S0 ₂ -aryl, -S0 ₂ -hetero cyclyl, ar(CrC ₆ )alkyl, aryl and heterocyclyl. The substituents may be present on either the ring carbon or the ring nitrogen atom. The substituents can be present at one or more positions provided that a stable molecule results. The term "halogen" or "halo" refers to a fluorine, chlorine, bromine, or iodine atom.

Within the context of the present application and as used herein, the term "halo(Ci-C ₆ )alkyl" or "haloalkyl" refers to radicals wherein one or more of the hydrogen atoms of the alkyl group are substituted with one or more halogens. Examples of halo(Ci-C ₆ )alkyl or haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoro methyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl and difluoropropyl.

Within the context of the present application and as used herein, the term

"halo(CrC ₆ )alkoxy" or "haloalkoxy" refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens. Representative examples of haloalkoxy groups include but not limited to difluoromethoxy (OCHF ₂ ), trifluoromethoxy (OCF ₃ ) or trifluorethoxy (OCH ₂ CF ₃ ).

The term "amino" refers to the group "NH ₂ " which may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but not limited to, (CrC ₄ )alkyl, aryl or the like groups.

Within the context of the present invention and as used herein interchangeably throughout this application, the terms "compound of formula 1 ", "compounds of formula 1 ", and "compounds of the present invention" include all the stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable polymorphs and N-oxides thereof.

The term "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human.

The term "mammal" used herein refers to warm-blooded vertebrate animals of the class Mammalia, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young. The term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig as well as human.

The term, "therapeutically effective amount" as used herein means an amount of the compound of formula 1 or a composition comprising a compound of formula 1 , sufficient to significantly induce a positive modification in the condition (a disease or a disorder) to be treated, but low enough to avoid undue or severe side effects within the scope of sound medical judgment. The therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the patient (subject in need of the treatment), the severity of the condition being treated/prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized.

As used herein, the terms "treatment" "treat" and "therapy" refer to alleviate, slow the progression, attenuation or cure of existing disease or condition (e.g., cancer). Treatment also includes treating the symptoms of the disease or condition. "Prevent or "Prevention", as used herein, refers to delaying, slowing, inhibiting, reducing or ameliorating the onset of cancer.

Within the context of the present invention and as used herein, the term "stereoisomer" is a general term used for all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).

Within the context of the present invention and as used herein, the term "tautomer" refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.

As used herein, the term "pharmaceutically acceptable" means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation or composition, and not deleterious to the recipient thereof.

The term "pharmaceutically acceptable salt" refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base.

As used herein, the term "solvate" or "pharmaceutically acceptable solvate" describes a complex wherein the compound is coordinated with a proportional amount of a solvent molecule. Specific solvates, wherein the solvent is water, are referred to as hydrates.

Within the context of the present invention, the term "prodrugs" or "pharmaceutically acceptable prodrugs" includes simple prodrugs of the compounds of formula 1 , for example esters, amides and other simple derivatives. The term "prodrug" refers to compounds that are drug precursors, which following administration, release the drug in vivo via a chemical or physiological process e.g., a prodrug on being brought to the physiological pH or through an enzyme action is converted to the desired drug form.

The compounds can be crystallized in different forms. The term "polymorph" or "pharmaceutically acceptable polymorph" refers to a specific crystalline form of a compound which differs only in the arrangement and/or conformation of the molecule in the crystal lattice. Polymorphs of a compound have different physical and chemical properties.

The term "N-oxide" as used herein refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N-oxide can be formed in presence of an oxidizing agent for example peroxide such as m-chloro-perbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N->0 bond.

Embodiments

In one embodiment, the present invention provides a compound of formula 1 ,

formula 1

wherein,

Ri at each occurrence is independently selected from (CrC ₆ )alkyl, -0-(Ci-C ₆ )alkyl, hydroxy, CN, halogen, halo(C C ₆ )alkyl, NR _a R _b , -0-(Ci-C ₄ )alkyl-0-(C C ₄ )alkyl-0-(Ci- C ₄ )alkyl and -C(0)-R; or two Ri groups present on adjacent carbon atoms of the phenyl ring may optionally form a 5 or 6 membered saturated or unsaturated ring containing 0 to 2 heteroatoms independently selected from O, N and S;

R is hydroxy or -0-(CrC ₆ )alkyl;

n is an integer from 0 to 3;

R ₂ is selected from hydrogen, (C-|-C ₆ )alkyl or halogen; Yi and Y ₂ are independently selected from hydrogen and -Z-(R ₃ )-W-[R ₄ ] _P ; and atleast one of Yi and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is selected from O, N or S;

R ₃ is hydrogen or (C-|-C ₆ ) alkyl; or is absent when Z is O or S;

W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),

or a phenyl ring of formula (iv),

^* is a point of attachment to Z;

R ₄ at each occurrence is independently selected from (Ci-C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, halo(Ci-C ₆ )alkyl, ar(Ci-C ₆ )alkyl, halogen, cyano, amino, nitro, hydroxy, -0-(Ci-C ₆ )alkyl, halo(Ci-C ₆ )alkoxy, aryl and heterocyclyl; and

p is an integer from 0 to 5;

R _a and R _b are independently selected from hydrogen, (C-|-C ₆ )alkyl, -C(0)OH, - C(0)0(C ₁ -C ₆ )alkyl, -C(0)(CrC ₆ )alkyl, -S0 ₂ -(C ₁ -C ₆ )alkyl, -S0 ₂ -aryl, -S0 ₂ -heterocyclyl, ar(CrC ₆ )alkyl, aryl and heterocyclyl;

wherein, each of (Ci-C ₆ )alkyl, -0-(Ci-C ₆ )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (d- C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, halo(C-i-C ₆ )alkyl, halogen, cyano, amino, nitro, -ON0 ₂ , hydroxy, -0-(CrC ₆ )alkyl, halo(CrC ₆ )alkoxy, aryl, heterocyclyl, -C(0)OR _a , -C(0)R _a , - SR _a , -NR _a R _b and -C(0)NR _a R _b , wherein R _a and R _b are as defined above;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In another embodiment, the present invention provides a compound of formula

1 ,

wherein,

Ri at each occurrence is independently selected from (Ci-C ₆ )alkyl, -0-(C-i-C ₆ )alkyl, hydroxy, CN, halogen, halo(C ₁ -C ₆ )alkyl, NR _a R _b , -O-td-C^alkyl-O-td-C^alkyl-O-td- C ₄ )alkyl and -C(0)-R; or two Ri groups present on adjacent carbon atoms of the phenyl ring may optionally form a 5 or 6 membered saturated or unsaturated ring containing 0 to 2 heteroatoms independently selected from O, N and S;

R is hydroxy or -0-(CrC ₆ )alkyl;

n is an integer from 0 to 3;

R ₂ is selected from hydrogen, halogen or (C-|-C ₆ )alkyl;

Yi is hydrogen and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is selected from O, N or S;

R ₃ is hydrogen or (C-|-C ₆ ) alkyl; or is absent when Z is O or S;

W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),

or a phenyl ring of formula (iv),

^* is a point of attachment to Z;

R ₄ at each occurrence is independently selected from (Ci-C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, halo(Ci-C ₆ )alkyl, ar(C-i-C ₆ )alkyl, halogen, cyano, amino, nitro, hydroxy, -0-(C-i- C ₆ )alkyl, halo(C-i-C ₆ )alkoxy, aryl and heterocyclyl; and

p is an integer from 0 to 5;

R _a and Rb are independently selected from hydrogen, (CrC ₆ )alkyl, -C(0)OH, - C(0)0(C ₁ -C ₆ )alkyl, -C(0)(CrC ₆ )alkyl, -S0 ₂ -(C ₁ -C ₆ )alkyl, -S0 ₂ -aryl, -S0 ₂ -heterocyclyl, ar(CrC ₆ )alkyl, aryl and heterocyclyl;

wherein, each of (Ci-C ₆ )alkyl, -0-(Ci-C ₆ )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (d- C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, halo(C-i-C ₆ )alkyl, halogen, cyano, amino, nitro, -ON0 ₂ , hydroxy, -0-(C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkoxy, aryl, heterocyclyl, -C(0)OR _a, -C(0)R _a , - SR _a , -NR _a R _b and -C(0)NR _a R _b , wherein R _a and R _b are as defined above;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In another embodiment, the present invention provides a compound of formula

1 ,

wherein,

Ri is hydroxy or -0-(CrC ₆ )alkyl; n is an integer from 0 to 3;

R ₂ is hydrogen or halogen;

Yi is hydrogen and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is N;

R ₃ is hydrogen or (Ci-C ₆ )alkyl;

W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii), or a phenyl ring of formula (iv),

^* is a point of attachment to Z;

R ₄ at each occurrence is independently selected from halogen, halo(CrC ₆ )alkyl, (d- C ₆ )alkyl, and -0-(CrC ₆ )alkyl; and

p is an integer from 0 to 5;

wherein, (CrC ₆ )alkyl and -0-(CrC ₆ )alkyl may be unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, nitro and -O- (d-C ₆ )alkyl;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In another embodiment, the present invention provides a compound of formula

1 ,

wherein,

Ri is hydroxy or -OCH ₃ ;

n is 2;

Ri groups are present on adjacent carbon atoms C-3 and C-4 of the phenyl ring;

R ₂ is hydrogen;

Yi is hydrogen and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is N;

R ₃ is hydrogen;

W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),

(i) or a phenyl ring of formula (iv) ,

^* is a point of attachment to Z;

R ₄ at each occurrence is independently selected from bromine, fluorine and trifluoromethyl; and

p is an integer from 0 to 5;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In yet another embodiment, the present invention provides a compound of formula 1 ,

wherein,

Ri is hydroxy;

n is 2;

Ri groups are present on adjacent carbon atoms C-3 and C-4 of the phenyl ring;

R ₂ is hydrogen;

Yi is hydrogen and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is N;

R ₃ is hydrogen;

W is a pyridyl rin selected from the roups of formula (i), (ii) or (iii),

(i) or a phenyl ring of formula (iv) ,

^* is a point of attachment to Z;

R ₄ at each occurrence is independently selected from bromine, fluorine and trifluoromethyl; and

p is an integer from 0 to 5; or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In yet another embodiment, the present invention provides a compound of formula 1 ,

wherein,

n is 2;

Ri groups are present on adjacent carbon atoms C-3 and C-4 of the phenyl ring;

R ₂ is hydrogen;

Yi is hydrogen and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is N;

R ₃ is hydrogen;

W is a pyridyl rin selected from the groups of formula (i), (ii) or (iii),

(i) or a phenyl ring of formula (iv) ,

^* is a point of attachment to Z;

R at each occurrence is independently selected from bromine, fluorine or trifluoromethyl; and

p is an integer from 0 to 5;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In yet another embodiment, the present invention provides a compound of formula 1 ,

wherein,

Ri is hydroxy or -OCH ₃ ;

n is 2;

Ri groups are present on carbon atoms C-2 and C-4 of the phenyl ring;

R ₂ is hydrogen;

Yi is hydrogen and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is N; R ₃ is hydrogen or (C-|-C ₆ )alkyl;

W is a pyridyl rin selected from the roups of formula (i), (ii) or (iii), or a phenyl ring of formula (iv) ,

IV

^* is a point of attachment to Z;

R at each occurrence is independently selected from bromine, fluorine or trifluoromethyl; and

p is an integer from 0 to 5;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In yet another embodiment, the present invention provides a compound of formula 1 ,

wherein,

Ri is hydroxy or -OCH ₃ ;

n is 2;

Ri groups are present on carbon atoms C-3 and C-5 of the phenyl ring;

R ₂ is hydrogen;

Yi is hydrogen and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is N;

R ₃ is hydrogen or (CrC ₆ )alkyl;

W is a pyridyl ring selected from the roups of formula (i (ii) or (iii),

(i) a phenyl ring of formula (iv) ,

IV

^* is a point of attachment to Z;

R at each occurrence is independently selected from bromine, fluorine or trifluoromethyl; and p is an integer from 0 to 5;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In yet another embodiment, the present invention provides a compound of formula 1 ,

wherein,

Ri at each occurrence is independently selected from NR _a R _b , halogen, halo(d- C ₆ )alkyl, CN, -C(0)R and (C ₁ -C ₆ )alkyl;

R is hydroxy or -0-(C-i-C ₆ )alkyl;

n is an integer from 0 to 3;

R ₂ is hydrogen or halogen;

Y is hydrogen and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is N;

R ₃ is hydrogen or (Ci-C ₆ )alkyl;

W is a pyrid or (iii),

(i) (ii) (iii) a phenyl ring of formula (iv),

^* is a point of attachment to Z;

R ₄ at each occurrence is independently selected from halogen, halo(CrC ₆ )alkyl, (d- C ₆ )alkyl and -0-(CrC ₆ )alkyl; and

p is an integer from 0 to 5;

R _a and R _b are independently selected from hydrogen, (C-|-C ₆ )alkyl, -C(0)OH, - C(0)0(C ₁ -C ₆ )alkyl, -C(0)(Ci-C ₆ )alkyl, -S0 ₂ -(C ₁ -C ₆ )alkyl, -S0 ₂ -aryl, -S0 ₂ -hetero cyclyl, ar(CrC ₆ )alkyl, aryl and heterocyclyl;

wherein, each of (Ci-C ₆ )alkyl, -0-(Ci-C ₆ )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from halogen, halo(Ci-C ₆ )alkyl, hydroxy, cyano, nitro, aryl, -ON0 ₂ and -0-(C-i-C ₆ )alkyl; or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In one embodiment, the present invention provides a compound of formula 1 , wherein,

Two Ri groups present on carbon atoms C-3 and C-4 of the phenyl ring, form a 5 or 6 membered saturated or unsaturated ring containing 1 to 2 heteroatoms independently selected from O and N ;

R ₂ is selected from hydrogen, (C-|-C ₆ )alkyl or halogen;

Yi is hydrogen and Y ₂ is -Z-(R ₃ )-W-[R ₄ ] _P ;

Z is selected from O, N or S;

R ₃ is hydrogen or (C-|-C ₆ ) alkyl; or is absent when Z is O or S;

W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),

or a phenyl ring of formula (iv),

^* is a point of attachment to Z;

R ₄ at each occurrence is independently selected from (Ci-C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, halo(Ci-C ₆ )alkyl, ar(C-i-C ₆ )alkyl, halogen, cyano, amino, nitro, hydroxy, -0-(C-i- C ₆ )alkyl, halo(C-i-C ₆ )alkoxy, aryl and heterocyclyl; and

p is an integer from 0 to 5;

R _a and Rb are independently selected from hydrogen, (CrC ₆ )alkyl, -C(0)OH, - C(0)0(C ₁ -C ₆ )alkyl, -C(0)(CrC ₆ )alkyl, -S0 ₂ -(C ₁ -C ₆ )alkyl, -S0 ₂ -aryl, -S0 ₂ -heterocyclyl, ar(CrC ₆ )alkyl, aryl and heterocyclyl;

wherein, each of (Ci-C ₆ )alkyl, -0-(Ci-C ₆ )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (d- C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, halo(C-i-C ₆ )alkyl, halogen, cyano, amino, nitro, -ON0 ₂ , hydroxy, -0-(C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkoxy, aryl, heterocyclyl, -C(0)OR _a, -C(0)R _a , - SR _a , -NR _a R _b and -C(0)NR _a R _b , wherein R _a and R _b are as defined above;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In an embodiment, the present invention provides a compound of formula 1 , wherein,

Ri at each occurrence is independently selected from (Ci-C ₆ )alkyl, -0-(Ci-C ₆ )alkyl, hydroxy, CN, halogen, halo(CrC ₆ )alkyl, NR _a R _b , -0-(Ci-C ₄ )alkyl-0-(C C ₄ )alkyl-0-(Ci- C ₄ )alkyl and -C(0)-R; or when two Ri groups are present on adjacent carbon atoms of the phenyl ring, they may optionally form a 5 or 6 membered saturated or unsaturated ring containing 0 to 2 heteroatoms selected from O, N and S;

R is hydroxy or -0-(C-i-C ₆ )alkyl;

n is an integer from 0 to 3;

R ₂ is selected from hydrogen, (CrC ₆ )alkyl or halogen;

Yi is -Z-(R ₃ )-W-[R ₄ ] _P and Y ₂ is hydrogen;

Z is selected from O, N or S;

R ₃ is hydrogen or (C-|-C ₆ ) alkyl; or is absent when Z is O or S;

W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),

or a phenyl ring

^* is a point of attachment to Z;

R ₄ at each occurrence is independently selected from (Ci-C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, halo(Ci-C ₆ )alkyl, ar(C-i-C ₆ )alkyl, halogen, cyano, amino, nitro, hydroxy, -0-(C-i- C ₆ )alkyl, halo(Ci-C ₆ )alkoxy, aryl and heterocyclyl; and

p is an integer from 0 to 5;

R _a and R _b are independently selected from hydrogen, (C-|-C ₆ )alkyl, -C(0)OH, - C(0)0(C ₁ -C ₆ )alkyl, -C(0)(CrC ₆ )alkyl, -S0 ₂ -(C ₁ -C ₆ )alkyl, -S0 ₂ -aryl, -S0 ₂ -heterocyclyl, ar(CrC ₆ )alkyl, aryl and heterocyclyl;

wherein, each of (Ci-C ₆ )alkyl, -0-(Ci-C ₆ )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (C C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, halo(C-i-C ₆ )alkyl, halogen, cyano, amino, nitro, -ON0 ₂ , hydroxy, -0-(C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkoxy, aryl, heterocyclyl, -C(0)OR _a, -C(0)R _a , - SR _a , -NR _a R _b and -C(0)NR _a R _b , wherein R _a and R _b are as defined above;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In another embodiment, the present invention provides a compound of formula

1 ,

wherein, Ri at each occurrence is independently selected from (Ci-C ₆ )alkyl, -C(0)R, -0-(C _r C ₆ )alkyl and hydroxy;

n is 2;

R is hydroxy or -0-(C-i-C ₆ )alkyl;

R ₂ is hydrogen or halogen;

Yi is -Z-(R ₃ )-W-[R ₄ ] _P and Y ₂ is hydrogen;

Z is N;

R ₃ is hydrogen or (Ci-C ₆ )-alkyl;

iii),

(i) ⁽ ϋ ⁾ or a phenyl ring of formula (iv), ,

(iv)

* is a point of attachment to Z;

R ₄ at each occurrence is independently selected from halogen, halo(Ci-C ₆ )alkyl, (d- C ₆ )alkyl and -0-(C ₁ -C ₆ )alkyl; and

p is an integer from 0 to 5 ;

wherein, (CrC ₆ )alkyl and -0-(CrC ₆ )alkyl is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, nitro and 0-(Ci- C ₆ )alkyl;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In another embodiment, the present invention provides a compound of formula

1 ,

wherein,

Ri at each occurrence is independently selected from hydroxy, -OCH ₃ and -C(0)R; n is 2;

R is hydroxy or -0-(C C ₆ )alkyl;

Ri groups are present on adjacent carbon atoms C-3 and C-4 of the phenyl ring;

R ₂ is hydrogen;

Yi is -Z-(R ₃ )-W-[R ₄ ] _P and Y ₂ is hydrogen;

Z is N; R ₃ is hydrogen;

W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),

(ii)

or a phenyl ring of formula (iv)

(iv)

^* is a point of attachment to Z;

R at each occurrence is independently selected from bromine, fluorine or trifluoromethyl; and

p is an integer from 0 to 5;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In yet another embodiment, the present invention provides a compound of formula 1 ,

wherein,

Ri at each occurrence is independently selected from hydroxy and -OCH ₃ ;

n is 2;

Ri groups are present on carbon atoms C-2 and C-4 of the phenyl ring;

R ₂ is hydrogen;

Yi is -Z-(R ₃ )-W-[R ₄ ] _P and Y ₂ is hydrogen;

Z is N;

R ₃ is hydrogen;

W is a pyridyl rin selected from the groups of formula (i), (ii) or (iii),

(i) or a phenyl ring of formula (iv) ,

^* is a point of attachment to Z;

R ₄ is bromine or trifluoromethyl; and

p is an integer from 0 or 1 ; or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In yet another embodiment, the present invention provides a compound of formula 1 ,

wherein,

Two Ri groups present on adjacent carbon atoms C-3 and C-4 of the phenyl ring form a 5 or 6 membered saturated ring containing 2 oxygen atoms;

R ₂ is hydrogen;

Yi is -Z-(R ₃ )-W-[R ₄ ] _P and Y ₂ is hydrogen;

Z is N;

R ₃ is hydrogen;

W is a pyridyl rin selected from the roups of formula (i), (ii) or (iii),

(i) or a phenyl ring of formula (iv)

i

^* is a point of attachment to Z;

R is bromine or trifluoromethyl; and

p is an integer 0 or 1 ;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In yet another embodiment, the present invention provides a compound of formula 1 ,

wherein,

Ri at each occurrence is independently selected from (Ci-C ₆ )alkyl, -0-(C-i-C ₆ )alkyl and hydroxy;

n is 2;

R ₂ is halogen;

Yi is -Z-(R ₃ )-W-[R ₄ ] _P and Y ₂ is hydrogen;

Z is N;

R ₃ is hydrogen or (CrC ₆ )-alkyl;

W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),

^* is a point of attachment to Z;

R ₄ at each occurrence is independently selected selected from halogen, halo(C-i- C ₆ )alkyl, (C ₁ -C ₆ )-alkyl, and -0-(CrC ₆ )-alkyl; and

p is an integer from 0 to 5 ;

wherein, (Ci-C ₆ )alkyl and -0-(CrC ₆ )alkyl is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, nitro and 0-(C C ₆ )alkyl;

or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In an embodiment, representative compounds of the present invention are:

(5-Bromo-pyridin-2-yl)-[6-(3,4-dimethoxy-phenyl)-pyrimidi n-4-yl]-amine;

4-[6-(5-Bromo-pyridin-2-ylamino)-pyrimidin-4-yl]-benzene-1 ,2-diol;

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-(4-trifluoromethyl -pyridin-2-yl)-amine;

4-[6-(4-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl ]-benzene-1 ,2-diol;

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-(5-trifluoromethyl -pyridin-2-yl)-amine;

4-[6-(5-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol;

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-(6-trifluoromethyl -pyridin-2-yl)-amine;

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol;

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl ]-benzene-1 ,2-diol

hydrochloride;

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol

methanesulfonate;

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol

4-methylbenzenesulfonate;

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol

benzenesulfonate;

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol

hydrobromide; 4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol sulfate;

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-pyridin-2-yl-am ine;

4-[6-(Pyridin-2-ylamino)pyrimidin-4-yl]-benzene-1 ,2-diol;

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-(6-trifluoromet hyl-pyridin-3-yl)-am 4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol;

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-pyridin-3-yl-am ine;

4-[6-(Pyridin-3-ylamino)pyrimidin-4-yl]-benzene-1 ,2-diol;

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-(3-trifluoromet hyl-pyridin-4-yl)-ami 4-[6-(3-Trifluoromethyl-pyridin-4-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol;

6-(3, 4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-4- amine;

4-(6-((3-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)ben zene-1 ,2-diol;

6-(3,4-Dimethoxyphenyl)-N-(2-(trifluoromethyl)phenyl)pyri midin-4-amine;

4-(6-((2-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)ben zene-1 ,2-diol;

6-(3,4-Dimethoxyphenyl)-N-(4-(trifluoromethyl)phenyl)pyri midin-4-amine;

4-(6-((4-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)ben zene-1 ,2-diol;

6-(3,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)pyridin-2-y l)pyrimidin-4-amine; 4-(6-((3-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol;

6-(3,4-Dimethoxyphenyl)-N-(3,5,6-trifluoropyridin-2-yl)py rimidin-4-amine;'

4-(6-((3,5,6-Trifluoropyridin-2-yl)amino)pyrimidin-4-yl)b enzene-1 ,2-diol;

6-(3,4-Dimethoxyphenyl)-N-(perfluorophenyl)pyrimidin-4-am ine;

4-(6-((Perfluorophenyl)amino)pyrimidin-4-yl)benzene-1 ,2-diol;

6-(2,4-Dimethoxyphenyl)-N-(6-(trifluoromethyl)pyridin-2-y l)pyrimidin-4-amine;

4- (6-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl)be nzene-1 ,3-diol;

6-(3,5-Dimethoxyphenyl)-N-(6-(trifluoromethyl)pyridin-2-y l)pyrimidin-4-amine;

5- (6-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl)be nzene-1 ,3-diol;

6- (4-Methoxyphenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimid in-4-amine;

4-(6-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4- yl)phenol;

6-(Benzo[d][1 ,3]dioxol-5-yl)-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin -4-amine; 4-(3,4-Dimethoxyphenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)p yrimidin-2-amine; 4-(2-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol;

4-(3,4-Dimethoxyphenyl)-N-(6-(trifluoromethyl)pyridin-3-y l)pyrimidin-2-amine; 4-(2-((6-(Trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol;

4-(3,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)pyridin-2-y l)pyrimidin-2-amine; 4-(2-((3-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol; 4-(3,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)pyridin-4-yl)p yrimidin-2-am 4-(2-((3-(Trifluoromethyl)pyridin-4-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol;

N-(5-Bromopyridin-2-yl)-4-(3,4-dimethoxyphenyl)pyrimidin- 2-amine;

4-(2-((5-Bromopyridin-2-yl)amino)pyrimidin-4-yl)benzene-1 ,2-diol;

4-(3,4-Dimethoxyphenyl)-N-(2-(trifluoromethyl)phenyl)pyri midin-2-amine;

4-(2-((2-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)ben zene-1 ,2-diol;

4-(3,4-Dimethoxyphenyl)-N-(4-(trifluoromethyl)phenyl)pyri midin-2-amine;

4-(2-((4-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)ben zene-1 ,2-diol;

4-(3,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)phenyl)pyri midin-2-amine;

4-(2-((3-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)ben zene-1 ,2-diol;

4-(3,4-Dimethoxyphenyl)-N-(4-(trifluoromethyl)pyridin-2-y l)pyrimidin-2-amine;

4-(2-((4-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4- yl)benzene-1 ,2-diol;

4-(3,4-Dimethoxyphenyl)-N-(perfluorophenyl)pyrimidin-2-am ine;

4-(2-((Perfluorophenyl)amino)pyrimidin-4-yl)benzene-1 ,2-diol;

4-(4-(3,4-Dimethoxyphenyl)-N-(3,5,6-trifluoropyridin-2-yl )pyrimidin-2-amine;

4-(2-((3,5,6-Trifluoropyridin-2-yl)amino)pyrimidin-4-yl)b enzene-1 ,2-diol;

4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(3-(trifluoromethyl)pyridin-4-yl)pyrimidin -2-amine; 4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-ami ne;

4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin -2-amine; 4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin -2-amine; 4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrimidin -2-amine; 4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(3-(trifluoromethyl)pyridin-2-yl)pyrimidin -2-amine; 4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(5-(trifluoromethyl)pyrid in-2-yl)pyrimidin-2-ami 4-(5-Fluoro-2-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrimi din-4-yl)benzene-1 ,2-diol; N-(5-Bromopyridin-2-yl)-4-(3,4-dimethoxyphenyl)-5-fluoropyri midin-2-amine;

4-(2-((5-Bromopyridin-2-yl)amino)-5-fluoropyrimidin-4-yl) benzene-1 ,2-diol;

4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(3-(trifluoromethyl)py ridin-2-yl)pyrimidin-2-ami 4-(5-Fluoro-2-((3-(trifluoromethyl)pyridin-2-yl)amino)pyrimi din-4-yl)benzene-1 ,2-diol; 4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(2-(trifluoromethyl)pyrid in-4-yl)pyrimidin-2-am 4-(5-Fluoro-2-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrimi din-4-yl)benzene-1 ,2-diol; 4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(3,5,6-trifluoropyridin-2 -yl)pyrimidin-2-amine; 4-(5-Fluoro-2-((3,5,6-trifluoropyridin-2-yl)amino)pyrimidin- 4-yl)benzene-1 ,2-diol; 4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(4-(trifluoromethyl)pyrid in-2-yl)pyrimidin-2-am 4-(5-Fluoro-2-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrimi din-4-yl)benzene-1 ,2-diol; 4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(2-(trifluoromethyl)pheny l)pyrimid

4-(5-Fluoro-2-((2-(trifluoromethyl)phenyl)amino)pyrimidin -4-yl)benzene-1 ,2-diol ;

4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(3-(trifluoromethyl)ph enyl)pyrimidin-2

4-(5-Fluoro-2-((3-(trifluoromethyl)phenyl)amino)pyrimidin -4-yl)benzene-1 ,2-diol ;

6-Phenyl-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4-a mine;

6-(2,4-Difluorophenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)py rimidin-4-amin

6-(4-(Trifluoromethyl)phenyl)-N-(6-(trifluoromethyl)pyridin- 2-yl)pyrimi

(2,6-Dichloro-4-(6-((6-(trifluoromethyl)pyridin-2^

methanol ;

Ethyl 3-(6-((6-(trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzoate;

4-(6-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4- yl)benzonitrile;

6-(2,3-Dihydrobenzo[b][1 ,4]dioxin-6-yl)-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin -4- amine;

4-(3,4-Dimethoxyphenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)p yrimidin-2-amine;

4-(2-((5-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4- yl)benzene-1 ,2-diol ;

6-(2,4-Dimethoxyphenyl)-N-(3,5,6-trifluoropyridin-2-yl)pyrim idin-4-amine;

4-(2,4-Dimethoxyphenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)p yrimidin-2-amine;

4-(2,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)phenyl)pyrimid in-2-amine;

4-(2,4-Dimethoxyphenyl)-N-(4-(trifluoromethyl)pyridin-2-yl)p yrimidin-2-amine;

N-(4-(6-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin -4-yl)phenyl)acetamide;

6-(4-Aminophenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimid in-4-amine;

Methyl-2-methoxy-5-(6-((6-(trifluoromethyl)pyridin-2-yl)amin o)pyrimidin-4-yl)benzoate;

Methyl-2-hydroxy-5-(6-((6-(trifluoromethyl)pyridin-2-yl)a mino)pyrimidin-4-yl)benzoate; or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

Individual compounds can also be found in the examples set out below.

The compounds of the present invention also include all stereoisomeric and tautomeric forms and mixtures thereof in all ratios and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable polymorphs and N-oxides.

According to another aspect of the present invention, the compound of formula

1 can be prepared in a number of different ways including using methods well known to a person skilled in the art. Examples of methods to prepare the present compounds are described below, and are particularly illustrated in Schemes 1 and 2, but are not limited thereto. It will be appreciated by persons skilled in the art that within certain of the processes described herein, the order of the reaction steps employed may be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate (starting compound or an intermediate) and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent to be used in the synthetic steps.

One or more of the reagents, reactants and intermediates used in the following processes are either commercially available or can be prepared according to standard procedures known in the art. The starting compounds and the intermediates used for the synthesis of compounds of the present invention are referred to by the symbols A, B, C, D, E, F and G.

Throughout the process description, the corresponding substituent groups in the various formulae representing starting compounds and/or intermediates have the same meaning as that of the compound of formula 1 as described in one or more embodiments of the invention, unless stated otherwise.

Processes for the preparation of the compounds of formula 1 of the present invention are depicted in schemes 1 and 2 presented below. For ease of reference, the reaction steps shown in the Schemes 1 and 2, are referred to by using general symbols namely 1a, 1 b, 1 c, 1d, 2a, 2b, 2c, 2d and 2e.

Scheme 1 : Preparation of the compound of formula 1 [referred to in Scheme 1 as compound of formula D (wherein R-i, n, R ₂ , Yi and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) and compound of formula E (wherein R is a hydroxy, and n, R ₂ , Yi and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein)].

D E

(Corresponding to (Corresponding to compound of compound of formula 1 ) formula 1 , wherein is hydroxy)

Step 1

Compound of formula A (wherein R and n are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with bis- pinacolatodiborane in the presence of chloro(1 ,5-cycloo ctadiene)iridium (I) dimer and bipyridyl in the presence of a solvent such as n-heptane and dioxane, at a temperature ranging from 25 °C to 30 °C. The resulting reaction mixture is warmed to 70 °C to 95 °C, for 12 - 20 h, which results in the formation of a boron complex represented by the compound of formula B (wherein R and n are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 1a).

Step 2

The boron complex i.e. the compound of formula B (as obtained in step 1 ; wherein R and n are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with a compound of formula G, which is a dihalopyrimidine compound (wherein, Xi is halogen, R _x and R _y are selected from hydrogen or halogen such that at least one of R _x and R _y is hydrogen and the other is halogen; and R ₂ is as defined in any one of the embodiments of the compound of formula 1 described herein), in the presence of reagents such as potassium carbonate, triphenyl phosphine and palladium acetate, in a mixture of solvents; such as dimethoxy ethane-water or dioxane-water, at a temperature ranging from 25 °C to 30 °C. The reaction mixture is warmed to 70 °C to 90 °C, for 12 - 20 h, which results in the formation of the compound of formula C (wherein, X is halogen, R _x and R _y are selected from hydrogen or halogen such that at least one of R _x and R _y is hydrogen and the other is halogen; and R-i, n and R ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 1 b).

Step 3

The compound of formula C (as obtained in step 2; wherein, Xi is halogen, R _x and R _y are selected from hydrogen or halogen such that at least one of R _x and R _y is hydrogen and the other is halogen; and R-i, n and R ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with an amine represented by the formula, R ₃ -NH-W-[R ₄ ] _P (wherein R ₃ , R ₄ , W and p are as defined in any one of the embodiments of the compound of formula 1 described herein) in the presence of a base selected from sodium hydride, potassium carbonate or sodium carbonate and a solvent such as Ν,Ν-Dimethylformamide (DMF) and dimethylsulfoxide (DMSO), at a temperature ranging from 25 °C to 30 °C, for 12 - 20 h, which results in the formation of a compound of formula D (wherein R-i , n, R ₂ , Yi and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 1 c).

Step 4

The compound of formula D (as obtained in step 3; wherein R _; n, R ₂ , Y and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with boron tribromide in a solvent selected from dichloromethane, chloroform or carbon tetrachloride, at a temperature ranging from -40 °C to -10 °C, for 10 - 55 min. The reaction mixture is warmed to 20 °C to 30 °C, for 2 - 5 h, which results in the formation of a compound of formula E (wherein R is a hydroxy, and R-i , n, R ₂ , Yi and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 1d).

Scheme 2: Preparation of the compound of formula 1 [referred in Scheme 2 as the compound of formula D (wherein R-i , n, R ₂ , Y and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) and the compound of formula E (wherein Ri is a hydroxy and R-i , n, R ₂ , Yi and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein)].

Scheme 2

D E

(Corresponding to (Corresponding to

compound of formula 1 ) compound of formula 1 ,

wherein is hydroxy)

Step 1

A compound of formula F (wherein R and n are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with a compound of formula G, which is a dihalopyrimidine compound (wherein, X is halogen, R _x and R _y are selected from hydrogen or halogen such that at least one of R _x and R _y is hydrogen and the other is halogen; and R ₂ is as defined in any one of the embodiments of the compound of formula 1 described herein), in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium and a base selected from potassium carbonate, sodium carbonate or cesium carbonate, in the presence of a mixture of solvents such as dimethoxy ethane-water or dioxane-water. The reaction mixture is warmed to 70 °C to 95 °C, for 15 - 25 h which results in the formation of a compound of formula C (wherein, X is halogen, R _x and R _y are selected from hydrogen or halogen such that at least one of R _x and R _y is hydrogen and the other is halogen; and R-i , n and R ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 2a).

Step 2

The compound of formula C (as obtained in step 1 ; wherein, X is halogen, R _x and R _y are selected from hydrogen or halogen such that at least one of R _x and R _y is hydrogen and the other is halogen; and R-i , n, R ₂ , are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with an amine represented by formula, R ₃ -NH-W-[R ₄ ] _P (wherein R ₃ , R ₄ , W and p are as defined in any one of the embodiments of the compound of formula 1 described herein) in the presence of a base selected from sodium hydride, potassium carbonate or sodium carbonate and an inert solvent such as DMF and DMSO, at a temperature ranging from 25 °C to 30 °C, for 12 - 20 h which results in the formation of compound of formula D (wherein R _; n, R ₂ , Yi and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 2b).

Alternatively, compound of formula C (as obtained in step 1 ; wherein, Xi is halogen, R _x and R _y are selected from hydrogen or halogen such that at least one of R _x and R _y is hydrogen and the other is halogen; and R-i , n, R ₂ , are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with an amine represented by the formula, R ₃ -NH-W-[R ₄ ] _P (wherein R ₃ , R ₄ , W and p are as defined in any one of the embodiments of the compound of formula 1 described herein) in the presence of an inert solvent such as dioxane, at a temperature ranging from 80 °C to 90 °C, for 12 - 20 h which results in the formation of compound of formula D (wherein R-i, n, R ₂ , Y and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 2b).

Step 3

The compound of formula D (as obtained in step 2; wherein R-i , n, R ₂ , Yi and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with 40 % hydrobromic acid in water at a temperature ranging from 120 °C to 140 °C, for 12 - 20 h which results in the formation of compound of formula E (wherein R is a hydroxy, n, R ₂ , Y and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 2c). Alternatively, the compound of formula D (as obtained in step 2; wherein R _; n, R ₂ , Yi and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) and methane sulphonic acid is reacted with L-methionine at a temperature ranging from 25 °C to 30 °C, for 20 - 50 min. The reaction mixture is warmed to 70 °C to 1 10 °C, for the period of 12 - 20 h which results in the formation of compound of formula E (wherein Ri is a hydroxy, n, R ₂ , Yi and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 2d).

In yet another alternative method, the compound of formula D (as obtained in step 2; wherein R-i , n, R ₂ , Yi and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with boron tribromide in the presence of a solvent selected from dichloromethane, chloroform or carbon tetrachloride at a temperature -78 °C, for 10 - 55 min. The reaction mixture is warmed to 20 °C to 30 °C, for 2 - 5 h, and was stirred for 20 - 30 h which results in formation of a compound of formula E (wherein R is a hydroxy, n, R ₂ , Y and Y ₂ are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 2e).

The compounds of formula 1 (designated as compound D and E in the above schemes), as obtained in Scheme 1 or Scheme 2 may be optionally converted into their corresponding pharmaceutically acceptable salts.

The phrase "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds of the formula 1 that are safe for use in mammals. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds of the invention (the compounds of formula 1 ). Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate salts. Certain compounds of the invention (compounds of formula 1 ) can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc, salts.

The pharmaceutically acceptable salts of the present invention can be synthesized from the compound of formula 1 , which contains a basic or an acidic group, by using conventional chemical methods. Generally, the salts are prepared by treating the compound of formula 1 which may be a free base or an acid with a suitable salt-forming inorganic or organic acid or a base in a suitable solvent or dispersant or from another salt by cation or anion exchange. Suitable solvents are, for example, ethyl acetate, diethyl ether, methanol, ethanol, acetone, tetrahydrofuran, dioxane or mixtures of these solvents.

The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Various polymorphs of compound of formula 1 can be prepared by crystallization of the compound under different conditions. The different conditions are, for example, using different solvents or their mixtures for carrying out crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallization or by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs can be determined by IR (Infra-red) spectroscopy, solid probe NMR (Nuclear Magnetic Resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

The present invention also encompasses within its scope prodrugs of the compound of formula 1 . The prodrugs of the compounds of the present invention are derivatives of the said compounds which upon administration to a subject in need thereof undergoes conversion by metabolic or chemical processes to release the parent drug in vivo from which the prodrug is derived. The preferred prodrugs are pharmaceutically acceptable ester derivatives e.g., alkyl esters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- or di-substituted alkyl esters that are convertible by solvolysis under physiological conditions to the parent carboxylic acid (e.g. the compound of Formula I containing the carboxylic acid group), and those conventionally used in the art.

The present invention furthermore relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt thereof in addition to a customary pharmaceutically acceptable carrier or excipient, and to a process for the production of a pharmaceutical compositions, which includes bringing at least one compound of formula 1 , into a suitable administration form using a pharmaceutically acceptable excipient and, if appropriate, further suitable additives or auxiliaries.

Accordingly, in an aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In an aspect, the present invention relates to a method for the treatment of a disease or a disorder mediated by one or more kinases comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 , or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In another aspect, the present invention relates to use of a compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N- oxide thereof, for the treatment of a disease or a disorder mediated by one or more kinases.

In another aspect, the present invention provides use of the compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N- oxide thereof, for the manufacture of a medicament, for treating a disease or a disorder mediated by one or more kinases.

According to further aspect of the present invention, there is provided a method of inhibiting one or more kinases, comprising treating a subject in need thereof, an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof capable of inhibiting said kinases.

The kinases which can be inhibited by the compounds of formula 1 are selected from, but not limited to, Abelson murine leukemia viral oncogene homolog 1 T315I (ABL1 T315I), Abelson murine leukemia viral oncogene homolog 1 wt (ABL1 wt), activin receptor-like kinase 1 RL-1 (ACV-RL1 ), v-raf murine sarcoma viral oncogene homolog B1 600E (B-RAF V600E), v-raf murine sarcoma viral oncogene homolog B1 wt (B-RAF wt), Cyclin- dependent kinase 1 / cyclin A (CDK1 /CycA), Cyclin- dependent kinase 1 / cyclin B1 (CDK1 /CycB1 ), Cyclin- dependent kinase 1 / cyclin E1 (CDK1 /CycE1 ), Cyclin- dependent kinase 21 cyclin A (CDK2/CycA), Cyclin- dependent kinase 21 cyclin E1 (CDK2/CycE1 ), Cyclin- dependent kinase 3/ cyclin E1 (CDK3/CycE1 ), Cyclin- dependent kinase 4/ cyclin D1 (CDK4/CycD1 ), Cyclin- dependent kinase 4/ cyclin D3 (CDK4/CycD3), Cyclin- dependent kinase 5/ p25NCK (CDK5/p25NCK), Cyclin- dependent kinase 5/ p35NCK (CDK5/p35NCK), Cyclin- dependent kinase 6/ cyclin D1 (CDK6/CycD1 ), Cyclin- dependent kinase 8/ cyclin C (CDK8/CycC), Cyclin- dependent kinase 9/ cyclin K (CDK9/CycK), Cyclin- dependent kinase 9/ cyclin T (CDK9/CycT), CDC-like kinase 1 (CLK1 ), CDC-like kinase 4 (CLK4), fms-related tyrosine kinase 3 D835Y (FLT3 D835Y), fms-related tyrosine kinase 3 ITD (FLT3 ITD), fms-related tyrosine kinase 3 wt (FLT3 wt), Glycogen synthase kinase 3 alfa (GSK3-alpha), Glycogen synthase kinase 3 beta (GSK3-beta), Homeodomain- interacting protein kinase 1 (HI PK1 ), Homeodomain-interacting protein kinase 4 (HI PK4), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog wt (KIT wt), LIM domain kinase 1 (LIMK1 ), mitogen-activated protein kinase kinase kinase 7 (MAP3K7/MAP3K7I P1 ), mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), Dual specificity mitogen-activated protein kinase kinase 2 (MEK2), Myosin light chain kinase 2 (MYLK2), platelet-derived growth factor receptor, alpha polypeptide V561 D (PDGFR-alpha V561 D), platelet-derived growth factor receptor, alpha wt polypeptide (PDGFR-alpha wt), platelet-derived growth factor receptor, beta polypeptide (PDGFR-beta), Receptor-interacting serine/threonine-protein kinase 2 (RI PK2), c-Src tyrosine kinase [SRC (GST-HIS-tag)] or Transforming growth factor, beta receptor2 (TGFB-R2).

In an embodiment of the invention, the kinase(s) that mediate the disease or disorder, particularly a proliferative disorder e.g. cancer, that is capable of being treated by the compounds of the present invention include one or more kinases selected from, ABL1 T31 5I, ABL1 wt, ACV-RL1 , B-RAF V600E, B-RAF wt, CDK1 /CycA, CDK1 /CycB1 , CDK1 /CycE1 , CDK2/CycA, CDK2/CycE1 , CDK3/CycE1 , CDK4/CycD1 , CDK4/CycD3, CDK5/p25NCK, CDK5/p35NCK, CDK6/CycD1 , CDK8/CycC, CDK9/CycK, CDK9/CycT, CLK1 , CLK4, FLT3 D835Y, FLT3 ITD, FLT3 wt, GSK3-alpha, GSK3-beta, HI PK1 , HI PK4, KIT wt, LIMK1 , MAP3K7/MAP3K7I P1 , MAP4K4, MEK2, MYLK2, PDGFR-alpha V561 D, PDGFR-alpha wt, PDGFR-beta, RI PK2, SRC (GST-HIS-tag) or TGFB-R2. In an embodiment, the disease or the disorder mediated by one or more kinases is a proliferative disorder.

In an embodiment, the proliferative disorder is cancer.

Accordingly, in an embodiment, the present invention relates to a method for the treatment of cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 , or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.

In another embodiment, the present invention relates to use of a compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, for the treatment of cancer.

In another embodiment, the present invention provides use of the compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, for the manufacture of a medicament for treating cancer.

In an embodiment of the present invention, the cancer is selected from: leukemia, lung cancer, brain tumors, non-Hodgkin's lymphoma, Hodgkin's disease, liver cancer, kidney cancer, bladder cancer, cancer of urinary tract, breast cancer, head and neck cancer, endometrial cancer, lymphoma, melanoma, cervical cancer, thyroid cancer, gastric cancer, germ cell tumor, cholangiocarcinoma, extracranial cancer, sarcoma, mesothelioma, malignant fibrous histiocytoma of bone, retinoblastoma, esophageal cancer, multiple myeloma, pancreatic cancer, ependymoma, neuroblastoma, skin cancer, ovarian cancer, recurrent ovarian cancer, prostate cancer, testicular cancer, colorectal cancer, lymphoproliferative disease, refractory multiple myeloma, resistant multiple myeloma or myeloproliferative disorder.

According to an embodiment of the present invention, the cancer is selected from: acute lymphocytic leukemia, acute myeloid leukemia, adult acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia resistant to treatment with imatinib mesylate, hairy cell leukemia, non-small-cell lung cancer, small-cell lung cancer, brain stem glioma, glioblastoma, astrocytoma including cerebellar astrocytoma and cerebral astrocytoma, visual pathway glioma, hypothalamic glioma, supratentorial primitive neuroectodermal, pineal tumors, medulloblastoma, primary central nervous system lymphoma, mantle cell lymphoma, Hodgkin's disease, hepatocellular carcinoma, renal cell carcinoma, Wilms' tumor, bladder cancer, cancer of urinary tract, Ewing's sarcoma family of tumors, osteosarcoma, rhabdomyosarcoma, soft tissue sarcomas, mesothelioma, breast cancer, endometrial cancer, oral cancer, melanoma, cervical cancer, thyroid cancer, gastric cancer, germ cell tumor, cholangiocarcinoma, extracranial cancer, malignant fibrous histiocytoma of bone, retinoblastoma, esophageal cancer, multiple myeloma, pancreatic cancer, ependymoma, neuroblastoma, skin cancer, ovarian cancer, recurrent ovarian cancer, prostate cancer, testicular cancer, colorectal cancer, lymphoproliferative disease, refractory multiple myeloma, resistant multiple myeloma or myeloproliferative disorder.

According to further embodiment of the present invention, the cancer is selected from: acute lymphocytic leukemia, acute myeloid leukemia, adult acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia resistant to treatment with imatinib mesylate, hairy cell leukemia, non-small-cell lung cancer, small-cell lung cancer, brain stem glioma, glioblastoma, astrocytoma including cerebellar astrocytoma and cerebral astrocytoma, medulloblastoma, renal cell carcinoma, bladder cancer, cancer of urinary tract, breast cancer, oral cancer, melanoma, cervical cancer, thyroid cancer, gastric cancer, pancreatic cancer, skin cancer, frovarian cancer, recurrent ovarian cancer, prostate cancer or colorectal cancer.

In an embodiment, the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, adult acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, imatinib resistant chronic myeloid leukemia, or hairy cell leukemia.

In an embodiment, the cancer is chronic myeloid leukemia.

In an embodiment, the cancer is chronic myeloid leukemia that is resistant to treatment with imatinib mesylate.

In an embodiment, the compounds of the present invention are used in a method for reducing the population of imatinib mesylate sensitive (e.g., K-562 , KU 812 or Ba/F3 Bcr-AbI/ WT) and imatinib mesylate resistant (Ba/F3 Bcr-AbI/ T315I, Ba/F3 Bcr-AbI/ E255K, Ba/F3 Bcr-AbI/ M351 T, Ba/F3 Bcr-AbI/ F359V, Ba/F3 Bcr-AbI/ E255V, Ba/F3 Bcr-AbI/ F317V, Ba/F3 Bcr-AbI/ H396R, Ba/F3 Bcr-AbI/ H396P, Ba/F3 Bcr-AbI/ M244V, Ba/F3 Bcr-AbI/ Q252H, Ba/F3 Bcr-AbI/ Y253F and Ba/F3 Bcr-AbI/ Y253H), chronic myeloid leukemia (CML) cells and HL 60-Bcr-abl negative cell lines in vitro.

In an embodiment, the compounds of the present invention can be used to reduce proliferation of the human cell lines that comprise: H460 (lung carcinoma), HCT-1 16 (colon carcinoma), A2780 (ovarian carcinoma), Miapaca-2 (pancreatic carcinoma), PC-3 (prostate carcinoma), MCF-7, MDA-MB-231 , MDA-MB-468 and BT- 549 (human breast cell lines), Miapaca-2, Panc-1 , Capan-1 and BxPC-3 (human pancreatic cell lines).

The in vivo efficacy of the compounds of the present invention in imatinib mesylate-sensitive and imatinib mesylate-resistant tumor models can be evaluated by using cell lines such as Ba/F3 transfectants expressing full-length wild type Bcr-Abl (Ba/F3 Bcr-Abl/ WT) or mutated Bcr-Abl (Ba/F3 Bcr-Abl/T315l) in xenograft models of SCID (Severely Combined Immune-Deficient) mice.

In an embodiment, a compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof can be used to reduce, inhibit, or diminish the proliferation of tumor cells, and thereby asist in reducing the size of a tumor.

In an embodiment, the present invention provides use of the compound of formula 1 , or a stereoisomer, tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, for reduction in the proliferation of CML stem cells.

The present invention also relates to use of a compound of formula 1 or a pharmaceutically acceptable salt thereof; in combination with at least one further therapeutically active compound or other therapies such as radiation. The compounds of the present invention can be administered alone or in combination with other therapies suitable for the disease or disorder e.g. cancer to be treated. Where separate dosage formulations are used, the compound and the other therapeutic agent can be administered at essentially the same time (concurrently) or at separately staggered times (sequentially). The pharmaceutical combination is understood to include all these regimens. Administration in these various ways are suitable for the present invention as long as the beneficial therapeutic effect of the compound and the other therapeutic agent are realized by the patient at substantially the same time. In an embodiment, such beneficial effect is achieved when the target blood level concentrations of each active drug are maintained at substantially the same time.

Accordingly, the compound of formula 1 or a pharmaceutically acceptable salt thereof can be combined with one or more therapeutic agents, particularly anti-cancer agents. For example, the compounds of the present invention can be used in combination with one or more known anti-cancer agents or an investigational drug that could be approved by regulatory agencies for use in the treatment of cancers. For instance, a pharmaceutical composition containing a compound of formula 1 or a pharmaceutically acceptable salt can be administered to a subject in need thereof, particularly a mammal e.g. a human, with one or more anti-cancer compound, in combination. Therefore, the present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of the compound of the present invention and a pharmaceutically acceptable carrier and a further therapeutic active agent, such as an anti-cancer agent. A person of ordinary skill in the art would be able to discern which combinations of the therapeutic agents including the compounds of the present invention would be useful based on the particular characteristics of the drugs (therapeutic agents) and the cancer to be treated. Such anti-cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents, agents that interfere with cell cycle checkpoints, agents that interfere with receptor tyrosine kinases (RTKs) and cancer vaccines. Examples of such anticancer agents are, but not limited to, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, epirubicin, etoposide, fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, streptozocin, tamoxifen, thioguanine, vinblastine, vincristine, vindesine, aminoglutethimide, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2', 2'- difluorodeoxycytidine, docetaxel, erythro-9-(2-hydroxy-3-nonyl) adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine, alsterpaullone, butyrolactone I, 2-(2-hydroxyethylamino)-6-(3-chloroanilino)-9-isopropyl purine, indirubin-3'-monoxime, kenpaullone, olomoucine, iso-olomoucine, N ⁹ -isopropyl- olomoucine, purvalanol A, roscovitine, (S)-isomer roscovitine and WHI-P180 [4-(3'- hydroxyphenyl)amino-6,7-dimethoxyquinazoline]. According to another aspect, the present invention relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder mediated by one or more pro-inflmmatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a), and interleukins (IL-1 β, IL-2, IL-6 and/or IL-8).

According to another aspect of the present invention, there are provided pharmaceutical compositions including a therapeutically effective amount of one compound of formula 1 or a pharmaceutically acceptable salt thereof, as an active ingredient and pharmaceutically acceptable carrier, for use in the treatment of a disorder mediated by one or more pro-inflmmatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a), and interleukins (IL-1 β, IL-2, IL-6 and/or IL-8).

According to another aspect of present invention, there is provided a method of treatment of a disorder mediated by one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a), and interleukins (IL-1 β, IL-2, IL-6 and/or IL-8), comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides use of the compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, for the manufacture of a medicament, for treating a disorder mediated by one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a), and interleukins (IL-1 β, IL-2, IL-6 and/or IL-8).

According to further aspect of the present invention, there is provided a method of inhibiting one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a), and interleukins (IL-1 β, IL-2, IL-6 and/or IL-8), comprising treating a subject in need thereof, an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof capable of inhibiting said pro-inflammatory cytokines.

According to an embodiment, the disorder mediated by the pro-inflammatory cytokine is selected from: inflammatory bowel disease, inflammation, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non- rheumatoid arthritis, osteoporosis/bone resorption, Crohn's disease, septic shock, endotoxic shock, atherosclerosis, ischemia-reperfusion injury, coronary heart disease, vasculitis, amyloidosis, multiple sclerosis, sepsis, chronic recurrent uveitis, hepatitis C virus infection, malaria, ulcerative colitis, cachexia, psoriasis, plasmocytoma, endometriosis, Behcet's disease, Wegener's granulomatosis, meningitis, AIDS (Acquired immune deficiency syndrome), HIV infection, autoimmune disease, immune deficiency, common variable immunodeficiency (CVID), chronic graft-versus-host disease, trauma and transplant rejection, adult respiratory distress syndrome, pulmonary fibrosis, recurrent ovarian cancer, lymphoproliferative disease, refractory multiple myeloma, myeloproliferative disorder, diabetes, juvenile diabetes, ankylosing spondylitis, skin delayed-type hypersensitivity disorders, Alzheimer's disease, systemic lupus erythematosus, and allergic asthma. .

According to another embodiment, the disease or disorder mediated by proinflammatory cytokine, interleukins (I L- 1 β, IL-2, IL-6 and/or IL-8) is selected from: rheumatoid arthritis, osteoarthritis and other autoimmune conditions.

Pharmaceutical Compositions and Methods

The methods of treatment and the uses as described herein as well as the methods of inhibiting one or more kinases or TNF-a or the interleukins (I L- 1 β, IL-2, IL- 6 and/or IL-8) described herein, involve use of the pharmaceutical compositions described above that can be administered by the following routes or modes of administration.

The pharmaceutical compositions of the present invention can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.

The pharmaceutical compositions according to the invention are prepared in a manner known and familiar to one skilled in the art. Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compound of formula 1 , or a pharmaceutically acceptable salt for the production of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, gum arabica, magnesia or glucose, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc. Suitable carriers for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.

The pharmaceutical preparations normally contain about 1 to 99 %, for example, about 5 to 70 %, or from about 10 to 30 % by weight of the compound of the formula 1 or a pharmaceutically acceptable salt thereof. The amount of the compound of the formula 1 or its salt in the pharmaceutical compositions can normally range from about 5 to 500 mg. Typically, the dose of the compounds of the present invention, which is to be administered, can cover a wide range. The dose to be administered daily is to be selected to suit the desired therapeutic effect. A suitable dose can range from about 0.01 to 100 mg/kg/day of the compound of formula 1 or a pharmaceutically acceptable salt, for example, about 0.1 to 50 mg/kg/day of a compound of formula 1 or a pharmaceutically acceptable salt of the compound. If required, higher or lower daily doses can also be administered.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compounds employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and factors well known in the medical arts.

In addition to the compound of the formula 1 or a pharmaceutically acceptable salt and carrier substances, the pharmaceutical preparations can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain two or more compounds of formula 1 or their salts.

It is understood that modifications that do not substantially affect the activity of the various aspects of this invention are included. Accordingly, the following examples are intended to illustrate but not to limit the present invention. EXAMPLES

The following abbreviations or terms are used herein:

L : Liter min : Minutes

mL : Milliliter RT : Room temperature (25 ± 5 °C)

: Microliter CD ₃ OD : Deuteriated methanol

g : Gram CDCI3 Deuteriated chloroform

mg : Milligram DMF : N,N-Dimethylformamide

μ9 : Microgram DMSO : Dimethylsulfoxide

mmol : Milimolar DMSO-de : Deuteriated dimethyl sulfoxide h : Hours HCI : Hydrochloric acid

°C : Degree Celsius N : Normal

Example 1

2-(3,4-Dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolane

Bis(pinacolato)diborone (19.68 g, 77.5 mmol), chloro(1 ,5-cyclooctadiene)iridium (I) dimer (0.33 g, 0.492 mmol) and bipiridyl (0.237 g, 1 .5 mmol) were added to the mixture of veratrol (10.0 g, 72.4 mmol) and n-heptane (60 mL) at 25 °C. The reaction mixture was warmed to 90 °C to 95 °C and was stirred for 16 -18 h.

The reaction mixture was cooled to temperature 25 - 30 °C and ethyl acetate

(50 mL) was added and mixture was stirred for 5 - 10 min. 1 N HCI solution (60 mL) was added to the reaction mixture and was stirred for 15 - 20 min. The reaction mixture was cooled to 25 °C and the organic layer was separated and was washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated to obtain the title compound.

Yield: 20 g (98 %); ¹ H NMR (300 MHz, CDCI ₃ ): δ 7.4 (dd, 1 H, 1 .2 & 8.1 Hz), 7.3 (d, 1 H, 1 .2 Hz), 6.9 (d, 1 H, 8.1 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 1 .36 (s, 12H); MS (ES+): 264 (M+1 ). Example 2

4-Chloro-6-(3,4-dimethoxy-phenyl)-pyrimidine

Method A

Compound of example 1 (5.0 g, 27.4 mmol), 4,6-dichloropyrimidine (4.29 g, 28.4 mmol), potassium carbonate (7.58 g, 54.9 mmol), triphenylphosphine (1 .74 g, 6.4 mmol) and palladium acetate (0.308 g, 1 .37 mmol) were added in a mixture of solvents dimethoxyethane (40 mL) and water (1 2.5 mL) at 25 °C to 30 °C. The reaction mixture was warmed to 80 - 85 °C, for 1 6 - 1 8 h. The reaction mixture was cooled to 25 °C and ethyl acetate (25 mL) was added and was stirred for 5 - 10 min. 1 N HCI (60 mL) was added to the reaction mixture and stirred for 1 5 - 20 min. The reaction mixture was filtered through celite. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated to obtain the crude product (5.6 g). The crude product was suspended in methanol (25 mL) at 50 °C and slowly cooled to 25 - 30 °C. The precipitated product was filtered and washed with chilled methanol (5 mL) and dried to obtain the title compound.

Yield: 2.5 g (49 %) ; ¹ H NMR (300 MHz, CDCI ₃ ) : δ 8.9 (s, 1 H), 7.7 (d, 1 H, 0.6Hz), 7.68 (d, 1 H, 0.6 Hz), 7.63 (dd, 1 H, 1 .8 & 8.4 Hz), 6.9 (d, 1 H, 8.4 Hz), 4.0 (s, 3H), 3.9 (s, 3H) ; MS (ES+) : 251 (M+1 ).

Method B

To 4,6-dichloropyrimidine (0.350 g, 2.36 mmol) in 1 ,4-dioxane (1 0 mL) was added 3,4-dimethoxyphenylboronic acid (0.3 g, 1 .64 mmol) and tetrakis (triphenyl phosphine) palladium (0.06 g, 0.06 mmol). Potassium carbonate (0.44 g, 3.2 mmol) was dissolved in water (5 mL) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 1 0 mL) and water (1 0 mL). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound.

Yield: 0.4 g (97.56 %); ¹ H NMR (300 MHz, CDCI ₃ ) : δ 8.9 (s, 1 H, 2.1 Hz), 7.65 (d, 1 H, 0.9 Hz), 7.60 (dd, 1 H, 2.1 & 8.4 Hz), 6.94 (d, 1 H, 8.4Hz), 3.97 (s, 3H), 3.93 (s, 3H); MS (ES+): 251 (M+1 ).

Example 3

(5-Bromo-pyridin-2-yl)-[6-(3,4-dimethoxy-phenyl)-pyrimidin-4 -yl]-amine

5-Bromo-pyridin-2ylamine (0.6 g, 3.46 mmol) was added at 25 - 30 °C to a mixture of sodium hydride (0.96 g, 40 mmol) and N,N-dimethylformamide (8 mL) under nitrogen gas and the reaction mixture was stirred for 1 5 - 20 min. Compound of example 2 (1 .0 g, 4.0 mmol) was added to the reaction mixture and was stirred for 16 - 18 h.

The reaction mixture was cooled to 10 °C and to it methanol (2 mL) was added. A chilled solution of 20 % ammonium chloride solution (100 mL) was added drop-wise to the reaction mixture at 10 - 15 °C and was stirred for 25 - 30 min. The precipitated product was filtered and was washed with water followed by petroleum ether. The product was dried at 45 - 50 °C for 20 - 22 h.

Yield: 1 .2 g (78 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.3 (s, 1 H), 8.7 (s, 1 H), 8.4 (d, 1 H, 2.4 Hz), 8.0 (s, 1 H), 7.9 (dd, 1 H, 2.4 & 8.6 Hz), 7.8 (d, 1 H, 9 Hz), 7.66 (d, 1 H, 1 .8 Hz), 7.60 (dd, 1 H, 1 .8 & 1 .8 Hz), 7.1 (d, 1 H, 8.7z), 3.83 (s, 3H), 3.82 (s, 3H); MS (ES-): 385 (M-1 ).

Example 4

4-[6-(5-Bromo-pyridin-2-ylamino)-pyrimidin-4-yl]-benzene-1 ,2-diol

Method A

Solution of boron tribromide (0.37 mL, 3.88 mmol) in dichloromethane (5 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min. Compound of example 3 (0.5 g, 1 .29 mmol) dissolved in dichloromethane (2.5 mL), was added to the reaction mixture at -40 °C to -35 °C over a period of 5 - 10 min. The reaction mixture was stirred for 30 - 35 min. The reaction mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h. The reaction mixture was quenched into chilled 5 % sodium bicarbonate (20 mL) solution at 15 - 20 °C (pH 8-9). The product was extracted with ethyl acetate (25 mL). The organic layer was washed with brine and was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product (0.25 g). The crude product was purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.

Yield: 0.1 15 g (25 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.3 (s, 1 H), 9.4 (s, 1 H), 9.2 (s, 1 H), 8.6 (s, 1 H), 8.4 (d, 1 H, 2.1 Hz), 7.95 (dd, 1 H, 2.4 & 9.0 Hz), 7.8 (d, 1 H, 8.7), 7.5 (s, 1 H), 7.5 (d, 1 H, 2.1 Hz), 7.3 (d, 1 H, 6.9 Hz), 6.8 (d, 1 H, 8.4 Hz); MS (ES+): 360 (M+1 ).

Method B

Compound of example 3 (1 .0 g, 2.58 mmol) and 40 % hydrobromic acid in water (5 mL) were mixed. The reaction mixture was warmed to 130 - 135 °C and was stirred for 16 - 18 h. The reaction mixture was cooled to 25 - 30 °C, chilled water (10 mL) was added and was stirred for 10 - 15 min. The reaction mixture was reacted with sodium carbonate till pH of the solution was 10. The product was extracted ethyl acetate (2 x 25 mL). The combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product (0.67 g). The crude product was purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.

Yield: 0.2 g (20 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.3 (s, 1 H), 9.4 (s, 1 H), 9.2 (s, 1 H), 8.6 (s, 1 H), 8.4 (d, 1 H, 2.4 Hz), 7.95 (dd, 1 H, 2.4 & 9.0 Hz), 7.92 (s, 1 H,), 7.8 (d, 1 H, 9.0 Hz), 7.5 (d, 1 H, 2.1 Hz), 7.3 (dd, 1 H, 1 .8 & 8.4 Hz), 6.8 (d, 1 H, 8.1 Hz); MS (ES+): 360 (M+1 ).

Example 5

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-(4-trifluoromethyl -pyridin-2-yl)-amine

4-(Trifluoromethyl)-pyridine-2ylamine (0.27 g, 1 .72 mmol) was added to a mixture of sodium hydride (0.48 g, 19.9 mmol) and N,N-dimethylformamide (4.32 mL) at 25 - 30 °C under nitrogen gas and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (0.5 g, 1 .99 mmol) was added to the reaction mixture and was stirred for 16 - 18 h.

The reaction mixture was cooled to 10 °C and to it methanol (1 mL) was added.

A chilled solution of 20 % ammonium chloride solution (50 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The precipitated product was filtered and the crude product was purified by column chromatography (silica gel, 0.3 % methanol in chloroform) to obtain the title compound.

Yield: 0.3 g (40 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.5 (s, 1 H), 8.8 (s, 1 H),

8.6 (d, 1 H, 5.1 Hz), 8.3 (s, 1 H), 8.0 (s, 1 H), 7.7 (d, 1 H, 1 .5 Hz), 7.64 (dd, 1 H, 1 .5 & 8.4 Hz), 7.3 (d, 1 H, 5.1 Hz), 7.12 (d, 1 H, 8.4 Hz), 3.86 (s, 3H), 3.84 (s, 3H); MS (ES): 377 (M+1 ). Example 6

4-[6-(4-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol

Solution of boron tribromide (0.15 mL, 1 .59 mmol) in dichloromethane (2 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min. Compound of example 5 (0.2 g, 0.532 mmol) was dissolved in dichloromethane (1 .0 ml_) and was added drop- wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and the mixture was stirred for 30 - 35 min. the reaction mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and stirred for 2 - 3 h. The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (8 ml_) till pH was 9, at 15 - 20 °C. The product was extracted with ethyl acetate (10 ml_), was washed with brine and was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product (0.096 g) and was purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.

Yield: 0.04 g (22 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.5 (s, 1 H), 9.5 (s, 1 H),

9.3 (s, 1 H), 8.7 (s, 1 H), 8.6 (d, 1 H, 5.1 Hz), 8.29 (s, 1 H), 7.9 (s, 1 H), 7.5 (d, 1 H, 1 .8 Hz), 7.4 (dd, 1 H, 1 .8 & 8.1 Hz), 7.3 (d, 1 H, 5.1 Hz), 6.88 (d, 1 H, 8.1 Hz); MS (HRMS+): 349 (M+1 ). Example 7

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-(5-trifluoromethyl -pyridin-2-yl)-amine

5-(Trifluoromethyl)-pyridine-2ylamine (0.47 g, 2.92 mmol) was added to a mixture of sodium hydride (0. 81 g, 33.9 mmol) and N,N-dimethylformamide (6.8 ml_) under nitrogen gas at 25 - 30 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (0.85 g, 3.39 mmol) was added to the reaction mixture and was stirred for 16 - 18 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (85 ml_) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The precipitated product was filtered, washed with water followed petroleum ether. The resulting product was dried at 45 - 50 °C for 20 - 22 h.

Yield: 0.75 g (59 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.6 (s, 1 H), 8.8 (s, 1 H), 8.7 (s, 1 H), 8.2 (s, 1 H), 8.1 (d, 1 H, 9Hz), 8.0 (d, 1 H, 8.7 Hz), 7.7 (s, 1 H), 7.65 (d, 1 H, 8.7 Hz), 7.1 (d, 1 H, 8.4 Hz), 3.86 (s, 3H), 3.84 (s, 3H); MS (ES+): 377 (M+1 ). Example 8

4-[6-(5-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol

Solution of boron tribromide (0.105 ml_, 1 .12 mmol) in dichloromethane (1 .4 ml_) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 7 (0.14 g, 0.372 mmol) dissolved in dichloromethane (0.7 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product (0.1 g) which was further purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.

Yield: 0.03 g (23 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.6 (s, 1 H), 9.5 (s, 1 H), 9.29 (s, 1 H), 8.77 (d, 1 H, 0.3 Hz), 8.71 (s, 1 H), 8.14 (d, 1 H, 2.1 Hz), 8.10 (d, 1 H, 0.6 Hz), 8.0 (d, 1 H, 9.0 Hz), 7.5 (d, 1 H, 1 .8 Hz), 7.4 (dd, 1 H, 2.1 & 8.4), 6.8 (d, 1 H, 4.5 Hz); MS (HRMS+): 349 (M+1 ).

Example 9

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-(6-trifluoromethyl -pyridin-2-yl)-amine

6-(Trifluoromethyl)-pyridin-2ylamine (0.7 g, 4.27 mmol) was added to a mixture of sodium hydride (1 .2 g, 49.7 mmol) and N,N-dimethylformamide (9.96 mL) under nitrogen gas at 25 - 30 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (1 .245 g, 4.97 mmol) was added to the reaction mixture and was stirred for 16 -18 h.

The reaction mixture was cooled to 10 °C and methanol (2.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (125 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The precipitated product was filtered, and was washed with water followed by petroleum ether. The resulting product was dried at 45 - 50 °C for 20 - 22 h.

Yield: 1 .45 g (78 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.6 (s, 1 H), 8.8 (s, 1 H), 8.4 (s, 1 H), 8.0 (t, 1 H, 7.5 Hz), 7.9 (s, 1 H,), 7.6 (d, 2H, 7.2 Hz), 7.5 (d, 1 H, 7.5 Hz), 7.1 (d, 1 H, 8.7 Hz), 3.86 (s, 3H), 3.84 (s, 3H); MS (ES+): 377 (M+1 ).

Example 10

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol Method A

Solution of boron tribromide (0.6 mL, 6.38 mmol) in dichloromethane (8 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 9 (0.8 g, 2.12 mmol) was dissolved in dichloromethane (4 mL) and was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5

- 10 min. The reaction mixture was stirred for 30 - 35 min and was allowed to attain 25

- 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h. The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (32 mL) at 15 - 20 °C (pH was 9). The product was extracted with ethyl acetate (40 mL), the organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product (0.7 g). The crude product was purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.

Yield: 0.5 g (67 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.6 (s, 1 H), 9.5 (s, 1 H), 9.2 (s, 1 H), 8.7 (s, 1 H), 8.1 (t, 1 H, 8.4 Hz), 8.0 (d, 2H, 8.1 Hz), 7.55 (d, 1 H, 1 .8 Hz), 7.4 (d, 1 H, 9.0 Hz), 7.37 (dd, 1 H, 1 .8 & 8.1 Hz), 6.8(d, 1 H, 8.4 Hz); MS (ES+): 349 (M+1 ). Method B

Compound of example 9 (0.5 g, 1 .33 mmol) and methane sulphonic acid (10.0 mL) were stirred at 25 - 30 °C for 30 - 35 min. L-Methionine (0.6 g, 3.99 mmol) was added to the reaction mixture, stirred for 10 - 15 min. The reaction mixture was warmed to 98 - 100 °C and stirred for 16 - 18 h. At the end of the reaction, the reaction mixture was cooled to 25 - 30 °C. Chilled water (50 mL) was added and stirred for 30 - 35 min. The precipitated product was filtered, washed with water followed by petroleum ether. The crude product (0.56 g) was purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.

Yield: 0.28 g (61 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.6 (s, 1 H), 9.5 (s, 1 H), 9.2 (s, 1 H), 8.7 (s, 1 H), 8.1 (t, 1 H, 8.4 Hz), 8.0 (d, 2H, 8.1 Hz), 7.55 (d, 1 H, 1 .8 Hz), 7.4 (d, 1 H, 9.0 Hz), 7.37 (dd, 1 H, 1 .8 & 8.1 Hz), 6.8 (d, 1 H, 8.4 Hz); MS (ES+): 349 (M+1 ). Example 10 A

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol

hydrochloride To a suspension of compound of example 10 (1.1 g, 3.1 mmol) in methanol (10 mL) at 40-45 °C, 5-8 % diethyl ether hydrochloride (8 mL) was added. The reaction mixture was maintained at 40-45 °C for 30-45 min and the solvent was distilled. Isopropyl ether (10 mL) was added. The reaction mixture was allowed to attain room temperature, and precipitated solid was filtered to obtain the title compound.

Yield: 1 g (82 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 11.40 (s, 1H), 9.8 (s, 2H),

8.94 (s, 1H), 8.25 (s, 1H), 8.09 (m, 2H), 7.63 (d, 1H),7.46 (d, 1H), 7.37 (dd, 1H), 6.96 (d, 2H); MS (ES+): 349 (M+1).

Example 10 B

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diolmethane sulfonate

To a solution of compound of example 10 (0.2 g, 0.57 mmol) in tetrahydrofuran (1.5 mL) maintained at 50-55 °C, a solution of methanesulfonic acid (60 mg, 0.63 mmol) in tetrahydrofuran (0.5 mL) was added. The reaction mixtrure was maintained at 50-55 °C for 30-45 min. The reaction mixture was stirred at room temperature for 30- 45 min. The precipitated solid was filtered to obtain the title comound.

Yield:190 mg (76 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 11.37 (s, 1H), 8.93 (s, 1H), 8.25 (s, 1H,), 8.12 (t, 1H), 8.02 (d, 1H), 7.63 (d, 1H), 7.42 (d, 1H), 7.32 (dd, 1H),

6.95 (d,1H); MS (ES+): 349 (M+1).

Example 10 C

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol-4-methyl benzenesulfonate

To a solution of compound of example 10 (0.25 g, 0.71 mol) in isopropyl alcohol

(6.25 mL) maintained at 60-65 °C, a solution of p-toluenesulfonic acid (150 mg, 0.79 mol) in isopropyl alcohol (1.5 mL) was added. The reaction mixture was maintained at 60-65 °C for 30-45 min. The reaction mixture was stirred at room temperature for 30- 45 min. The precipitated solid was filtered to obtain the title compound.

Yield: 310 mg (80 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 11.35 (s, 1H), 8.92 (s,

1H), 8.24 (s, 1H), 8.12 (t, 1H), 8.03 (d, 1H), 7.62 (d, 1H), 7.46 (m, 3H), 7.32 (dd, 1H), 7.11 (d, 1 H), 6.94 (d, 1 H), 2.28 (s,3H); MS (ES+): 349 (M+1 ). Example 10 D

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol

benzenesulfonate

To a solution of compound of example 10 (0.25 g, 0.71 mmol) in tetrahydrofuran (2.5 ml_) maintained at 50-55 °C, a solution of benzenesulfonic acid (124 mg, 0.79 mmol) diluted with tetrahydrofuran (1 .0 ml_) was added. The reaction mixture was maintained at 50-55 °C for 30-45 min. The reaction mixture was stirred at room temperature for 30-45 min. The precipitated solid was filtered to obtain the title compound.

Yield: 260 mg (72 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1 1 .33 (s, 1 H), 8.92 (s,

1 H), 8.24 (s, 1 H), 8.12 (t, 1 H), 8.03 (d, 1 H), 7.61 (m, 3H), 7.43 (s, 1 H), 7.31 (m, 4H), 6.94 (d, 1 H); MS (ES+): 349 (M+1 ).

Example 10 E

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl ]-benzene-1 ,2-diol

hydrobromide

Compound of example 10 (0.1 g, 0.28 mmol) was dissolved in isopropyl alcohol (3.5 ml_) at 50-55 °C. The reaction mixture was cooled to 0-5 °C and ~ 49 % hydrobromic acid solution (0.096 ml_, 0.57 mmol) was added through an addition funnel over a period of 5 min. The reaction mixture was maintained at 0-5 °C for 4-6 h and the precipitated solid was filtered to obtain the title compound.

Yield: 90 mg (73 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1 1 .40 (s, 1 H), 9.8 (s, 2H), 8.94 (s,1 H), 8.25 (s, 1 H), 8.12 (t, 1 H), 8.02 (d, 1 H), 7.63 (d, 1 H), 7.41 (d, 1 H), 7.32 (dd, 1 H), 6.95 (d, 2H); MS (ES+): 349 (M+1 ).

Example 10 F

4-[6-(6-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol sulfate

Compound of example 10 (0.1 g, 0.28 mmol) was dissolved in isopropyl alcohol (3.5 ml_) at 50-55 °C. The reaction mixture was cooled to 25-30 °C and an aqueous solution of sulfuric acid (31 mg, 0.31 mmol) diluted with 0.2 ml_ chilled water was added through an addition funnel over a period of 5 min. The reaction mass was maintained at 25-30 °C for 2-3 h and the precipitated solid was filtered to obtain the title compound. Yield: 100 mg (78 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1 1 .04 (s, 1 H), 9.54 (s, 2H), 8.85 (s, 1 H), 8.19 (s, 1 H), 8.08 (m, 2H), 7.56 (d, 1 H), 7.48 (d, 1 H), 7.34 (dd, 1 H), 6.91 (d, 1 H); MS (ES+): 349 (M+1 ). Example 1 1

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-pyridin-2-yl-amine

Compound of example 2 (0.100 g, 0.39 mmole) and pyridine-2-ylamine (0.47 mmole) were dissolved in dioxane (5 mL). The reaction mixture was heated at 85 °C under nitrogen for 15 h. The solvent was evaporated and residue was dissolved in dichloromethane (10 mL) followed by treatment with aqueous sodium bicarbonate till pH is 9 and mixture was stirred for 30 min. The organic layer was separated and dried over sodium sulphate. The solvent was evaporated to obtain the title compound.

Yield: 0.095 g (77.24 %); ¹ H NMR (300 MHz, CDCI ₃ ): δ 8.82 (s, 1 H), 8.35 (m, 1 H), 7.98 (s, 1 H), 7.75 (s, 1 H), 7.72 (d, 1 H, 0.9 Hz), 7.69 (m, 1 H), 7.66 (dd, 1 H, 2.1 & 8.4 Hz), 7.61 (m, 1 H), 6.96-6.99 (m, 1 H), 4.01 (s, 3H), 3.96 (s, 3H); MS (ES+): 309 (M+1 ).

Example 12

4-[6-(Pyridin-2-ylamino)pyrimidin-4-yl]-benzene-1 ,2-diol

Compound of example 1 1 (0.080 g, 0.259 mmol) was dissolved in dichloromethane (4 mL) under nitrogen gas and the reaction mixture cooled to -78 °C and stirred for 10 - 15 min. Boron tribromide (0.148 mL, 1 .55 mmol) in dichloromethane (8 mL) was added drop-wise to the reaction mixture at -78 °C over a period of 5 - 10 min. The reaction mixture was stirred for 30 - 35 min and was allowed to attain 25 - 30 °C over a period of 55 - 60 min and was stirred for 24 h. The reaction mass was cooled to 5 °C and methanol was added slowly. The reaction mass was allowed to warm to room temprature and treated with solid sodium carbonate till pH was 9. The solvent was evaporated and the crude was purified by column chromatography (silica gel, 10 % methanol in chloroform) to obtain the title compound.

Yield: 0.020 g (27.77 %); ¹ H NMR (300 MHz, CDCI ₃ ): δ 10.12 (s, 1 H), 9.43 (s,

1 H), 9.24 (s, 1 H), 8.67 (s, 1 H), 8.31 (m, 1 H), 8.06 (s, 1 H), 7.74 (m, 2H), 7.52 (d, 1 H, 1 .5 Hz), 7.37 (dd, 1 H, 2.1 & 8.4 Hz), 6.98 (t, 1 H, 5.4 Hz), 6.84 (d, 1 H, 8.4 Hz); MS (ES+): 281 (M+1 ). Example 13

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-(6-trifluoromethyl -pyridin

6-trifluoromethyl-pyridin-3-ylamine (0.25 g, 1 .54 mmol) was added to a mixture of sodium hydride (0.22 g, 9.16 mmol) and N,N-dimethylformamide (2 mL) at 25 - 30 °C under nitrogen gas and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (0.44 g, 1 .7 mmol) was added to the reaction mixture and was stirred for 6 - 8 h.

The reaction mixture was cooled to 10 °C and methanol (1 .2 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (10 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The precipitated product was filtered, and was washed with water followed by petroleum ether. The resulting product was dried at 45 - 50 °C for 20 - 22 h.

Yield: 0.4 g (68.96 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.28 (s, 1 H), 8.9 (s, 1 H), 8.8 (s, 1 H), 8.58 (d, 1 H, 8.7 Hz), 7.87 (d, 1 H, 8.7 Hz), 7.66 (d, 1 H, 9 Hz), 7.32 (s, 1 H), 7.1 (d, 1 H, 8.4 Hz), 3.86 (s, 6H, 6.3 Hz); MS (ES+): 377 (M+1 ).

Example 14

4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-4-yl)-b enzene-1 ,2-diol

Solution of boron tribromide (0.075 mL, 0.79 mmol) in dichloromethane (8 mL) was cooled to -60 °C to -50 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 13 (0.1 g, 0.27 mmol) was dissolved in dichloromethane (4.0 mL) and was added drop-wise to the reaction mixture at -60 °C to -50 °C over a period of 5 - 10 min. The reaction mixture was stirred for 30 - 35 min and was allowed to attain 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h. The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (8 mL) at 15 - 20 °C (pH was 9). The product was extracted with ethyl acetate (15 mL), the organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product (0.085 g). The crude product was purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.

Yield: 0.01 1 g (12 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.9 (s, 1 H), 8.7 (s, 1 H), 8.6 (d, 1 H, 8.7Hz), 7.7 (s, 1 H, 8.7Hz), 7.49 (s, 1 H, ), 7.4 (d, 2H, 8.1 Hz), 7.1 (s, 1 H), 6.9 (d, 1 H, 8.4 Hz); MS (ES+): 349 (M+1 ). Example 15

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-pyridin-3-yl-amine

Compound of example 2 (0.100 g, 0.39 mmole) and pyridine-3-ylamine (0.47 mmole) were dissolved in dioxane (5 mL). The reaction mixture was heated at 85 °C under nitrogen for 15 h. The solvent was evaporated and residue was dissolved in dichloromethane (10 mL) followed by treatment with aqueous sodium bicarbonate till pH is 9 and mixture was stirred for 30 min. The organic layer was separated and dried over sodium sulphate. The solvent was evaporated to obtain the title compound.

Yield: 0.069 g (56.09 %); ¹ H NMR (300 MHz, CDCI ₃ ): δ 8.78 (s, 1 H), 8.66 (d, 1 H, 2.4 Hz), 8.41 (dd, 1 H, 1 .2 & 4.8 Hz), 8.06 (m, 1 H), 7.66 (d, 1 H, 1 .8 Hz), 7.50 (dd, 1 H, 2.1 & 8.4 Hz), 7.35 (m, 1 H), 7.01 (s, 1 H), 6.92-6.96 (m, 2H), 3.98 (s, 3H), 3.94 (s,3H); MS (ES+): 309 (M+1 ).

Example 16

4-[6-(Pyridin-3-ylamino)pyrimidin-4-yl]-benzene-1 ,2-diol

Compound of example 15 (0.080 g, 0.259 mmole) was dissolved in dichloromethane (4 mL) under nitrogen gas and the reaction mixture cooled to -78 °C and stirred for 10 - 15 min. Boron tribromide (0.148 mL, 1 .55 mmole) in dichloromethane (8 mL) was added drop-wise to the reaction mixture at -78 °C over a period of 5 - 10 min. The reaction mixture was stirred for 30 - 35 min and was allowed to attain 25 - 30 °C over a period of 55 - 60 min and was stirred for 24 h. The reaction mass was cooled to 5 °C and methanol was added slowly. The reaction mass was allowed to warm to room temperature and treated with solid sodium carbonate till pH was 9. The solvent was evaporated and the crude was purified by column chromatography (silica gel, 10 % methanol in chloroform) to obtain the title compound.

Yield: 0.008 g (17.60 %); ¹ H NMR (300 MHz, CDCI ₃ ): δ 10.12 (s, 1 H), 9.43 (s, 1 H), 9.24 (s, 1 H), 8.67 (s, 1 H), 8.32 (m, 1 H), 8.06 (s, 1 H), 7.73 (m, 2H), 7.52 (d, 1 H, 1 .5 Hz), 7.37 (dd, 1 H, 2.1 & 8.4 Hz), 7.00 (t, 1 H, 6.6 Hz), 6.84 (d, 1 H, 8.4 Hz); MS (ES+): 281 (M+1 ).

Example 17

[6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-yl]-(3-trifluoromethyl -pyridin-4-yl)-amine 3-Trifluoromethyl-pyridin-4-ylamine (0.25 g, 1 .54 mmol) was added to a mixture of sodium hydride (0.22 g, 9.16 mmol) and N,N-dimethylformamide (2 mL) under nitrogen gas at 25 - 30 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (0.44 g, 1 .7 mmol) was added to the reaction mixture and was stirred for 6 - 8 h.

The reaction mixture was cooled to 10 °C and methanol (1 .2 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (10 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The precipitated product was filtered, and was washed with water followed by petroleum ether. The resulting product was dried at 45 - 50 °C for 20 - 22 h.

Yield: 0.32 g (55.17 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.0 (s, 1 H), 8.83 (s, 1 H), 8.76 (s, 1 H), 8.7 (d, 1 H, 5.4Hz), 8.2 (d, 1 H, 5.4Hz), 7.7 (s, 1 H), 7.6 (d, 2H, 7.5Hz), 7.2 (d, 1 H, 7.8 Hz), 3.8 (s, 6H); MS (ES+): 377 (M+1 ). Example 18

4-[6-(3-Trifluoromethyl-pyridin-4-ylamino)-pyrimidin-4-yl]-b enzene-1 ,2-diol

Solution of boron tribromide (0.075 mL, 0.79 mmol) in dichloromethane (8 mL) was cooled to -60 °C to -50 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 17 (0.1 g, 0.27 mmol) was dissolved in dichloromethane (4 mL) and was added drop-wise to the reaction mixture at -60 °C to -50 °C over a period of 5

- 10 min. The reaction mixture was stirred for 30 - 35 min and was allowed to attain 25

- 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h. The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (8 mL) at 15 - 20 °C (pH was 9). The product was extracted with ethyl acetate (15 mL), the organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product (0.06 g). The crude product was purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.

Yield: 0.01 1 g (12 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): 5 9.5 (s,1 H), 9.26 (s,1 H), 9.0 (s, 1 H), 8.8 (s, 1 H), 8.7 (d, 1 H, 6.9Hz), 8.2 (d, 1 H, 6Hz), 7.6 (s, 1 H), 7.5 (d, 1 H, 1 .8Hz), 7.4 (dd, 1 H, 8.4Hz & 1 .4Hz), 6.8 (d, 1 H, 8.1 Hz); MS (ES+): 349 (M+1 ). Example 19

6-(3,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)phenyl)pyrimid in-4-amin

3-(Trifluoromethyl)aniline (0.248 g, 1 .73 mmol) was added to a mixture of sodium hydride (0.5 g, 20.8 mmol) and N,N-dimethylformamide (5 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (0.5 g, 2.0 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.85 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (7.5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (20 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.133 g (21 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.99 (s, 1 H), 8.76(s, 1 H), 8.31 (s, 1 H), 7.93 (d, 1 H), 7.62 (m, 3H), 7.36 (d, 1 H), 7.23 (s, 1 H), 7.1 1 (d, 1 H), 3.86 (s, 6H) _: MS (ES+): 376 (M+1 ).

Example 20

4-(6-((3-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzen e-1 ,2-diol

Solution of boron tribromide (0.199g, 0.796 mmol) in dichloromethane (2 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 19 (0.100 g, 0.266 mmol) dissolved in dichloromethane (0.7 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.07 g (76 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.16 (s, 1 H), 8.69 (s,

1 H), 8.31 (s, 1 H), 7.96 (d, 1 H), 7.55 (m, 2H), 7.35 (m, 2H), 7.22 (s, 1 H), 6.85 (d, 1 Hz); MS (HRMS+): 348 (M+1 ). Example 21

6-(3,4-Dimethoxyphenyl)-N-(2-(trifluoromethyl)phenyl)pyrimid in-4-amin

2-(Trifluoromethyl)aniline (0.56 g, 3.47 mmol) was added to a mixture of sodium hydride (0. 5 g, 20.8 mmol) and N,N-dimethylformamide (12 ml_) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (1 .0 g, 4.0 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .9 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (17.5 ml_) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (46 L) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.2 g (17 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.92 (s, 1 H), 9.03(s, 1 H), 8.51 (s, 1 H), 7.69 (m, 5H), 7.22 (s, 1 H), 7.10 (d, 1 H), 3.82 (s, 6H); MS (ES+): 376.3 (M+1 ).

Example 22

4-(6-((2-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzen e-1 ,2-diol

Solution of boron tribromide (1 .2 g, 4.8 mmol) in dichloromethane (4 ml_) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 21 (0.3 g, 0.8 mmol) dissolved in dichloromethane (2.2 ml_) was added drop- wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (16 ml_) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (21 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.05 g (18 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.39 (s, 1 H), 9.19 (s, 1 H),

8.98 (s, 1 H), 8.46 (s, 1 H), 7.76 (m, 3H), 7.45 (m, 2H), 7.33 (d, 1 H), 7.02 (s, 1 H), 6.83 (d, 1 Hz); MS (HRMS+): 348.3 (M+1 ). Example 23

6-(3,4-Dimethoxyphenyl)-N-(4-(trifluoromethyl)phenyl)pyrimid in-4-amin

4-(Trifluoromethyl)aniline (0.56 g, 3.47 mmol) was added to a mixture of sodium hydride (0. 5 g, 20.8 mmol) and N,N-dimethylformamide (12 ml_) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (1 .0 g, 4.0 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .9 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (17.5 ml_) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (46 L) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.15 g (12 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): ¹ H NMR (300 MHz, DMSO-de): δ 10.03 (s, 1 H), 8.76(s, 1 H), 7.98 (m, 2H), 7.66 (m, 2H), 7.27 (s, 1 H), 7.13 (d, 1 H), 3.83 (s, 6H); MS (ES+): 376.3 (M+1 ).

Example 24

4-(6-((4-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzen e-1 ,2-diol

Solution of boron tribromide (0.435 g, 1 .74 mmol) in dichloromethane (1 .3 ml_) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 23 (0.1 g, 0.29 mmol) dissolved in dichloromethane (0.7 ml_) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 ml_) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.03 g (32 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): ¹ H NMR (300 MHz,

DMSO-de): δ 9.97 (s, 1 H), 9.46 (s, 1 H), 9.25 (s, 1 H), 8.70 (s, 1 H), 7.96 (m, 2H), 7.69 (m, 2H), 7.51 (s, 1 H), 7.36 (d, 1 H), 7.15 (s, 1 H), 6.84 (d, 1 Hz); MS (HRMS+): 348.3 (M+1 ). Example 25

6-(3,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)pyrid^

3-(Trifluoromethyl)pyridin-2-amine (0.56 g, 3.47 mmol) was added to a mixture of sodium hydride (0. 5 g, 20.8 mmol) and N,N-dimethylformamide (12 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (1 .0 g, 4.0 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .9 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (17.5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (46 L) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound.

Yield: 0.32 g (26 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.00(s, 1 H), 8.69(m, 2H), 8.24 (d, 1 H), 7.89 (s, 1 H), 7.65 (m, 2H), 7.41 (m, 1 H), 7.08 (d, 1 H), 3.82 (s, 6H); MS (ES+): 377.2 (M+1 ).

Example 26

4-(6-((3-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol

Solution of boron tribromide (0.39 g, 1 .56 mmol) in dichloromethane (1 .3 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 25 (0.1 g, 0.26 mmol) dissolved in dichloromethane (0.7 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.04 g (43 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (s, 1 H), 9.26 (s, 1 H), 8.96 (s, 1 H), 8.71 (m, 2H), 8.25 (d, 1 H), 7.79 (s, 1 H), 7.52 (s, 1 H), 7.40 (d, 2H), 6.83 (d, 1 Hz); MS (HRMS+): 349.3 (M+1 ). Example 27

6-(3,4-Dimethoxyphenyl)-N-(3,5,6-trifluoropyridin-2-yl)pyrim idin-4-amin

3,5,6-Trifluoropyridin-2-amine (0.51 g, 3.44 mmol) was added to a mixture of sodium hydride (0. 495 g, 20.6 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (1 .0 g, 3.99 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound.

Yield: 0.35 g (29 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.14 (s, 1 H), 8.73 (s, 1 H), 8.35 (m, 1 H), 7.84 (s, 1 H), 7.64 (m, 2H), 7.10 (d, 1 H), 3.83 (s, 6H); MS (ES+): 363.2 (M+1 ).

Example 28

4-(6-((3,5,6-Trifluoropyridin-2-yl)amino)pyrimidin-4-yl)benz ene-1 ,2-diol

Solution of boron tribromide (0.414 g, 1 .65 mmol) in dichloromethane (1 .3 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 27 (0.1 g, 0.276 mmol) dissolved in dichloromethane (0.7 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.03 g (32 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.96 (s, 1 H), 9.76 (s, 1 H), 8.80 (s, 1 H), 8.46 (m, 1 H), 7.68 (s, 1 H), 7.36 (s, 1 H), 7.33 (d, 1 H), 6.91 (d, 1 H); MS (HRMS+): 335.2 (M+1 ). Example 29

6-(3,4-Dimethoxyphenyl)-N-(perfluorophenyl)pyrimidin-4-amine

2,3,4,5,6-Pentafluoroaniline (0.63 g, 3.47 mmol) was added to a mixture of sodium hydride (0. 5 g, 20.8 mmol) and N,N-dimethylformamide (12 ml_) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (1 .0g, 4.02 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (2.1 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (18 ml_) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (48 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.3 g (22 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.60 (s, 1 H), 8.60 (s, 1 H), 7.67 (m, 2H), 7.24 (s, 1 H), 7.08 (d, 1 H), 3.83 (s, 6H); MS (ES+): 398.4 (M+1 ).

Example 30

4-(6-((Perfluorophenyl)amino)pyrimidin-4-yl)benzene-1 ,2-diol

Solution of boron tribromide (1 .510 g, 6.042 mmol) in dichloromethane (5.2 ml_) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 29 (0.4 g, 1 .007 mmol) dissolved in dichloromethane (2.8 ml_) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (22 ml_) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (28 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.05 g (13 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.52 (s, 1 H), 9.44 (s, 1 H),

9.20 (s, 1 H), 8.54 (s, 1 H), 7.52 (s, 1 H), 7.40 (d, 1 H), 7.08 (s, 1 H), 6.82 (d, 1 H); MS (HRMS+): 370.3 (M+1 ). Example 31

4-Chloro-6-(2,4-dimethoxyphenyl)pyrimidine

To a 100 mL flask containing 4,6-dichloropyrimidine (4.9 g, 32.9 mmol) in isopropyl alcohol (40 mL) was added 2,4-dimethoxyphenylboronic acid (5 g, 27.4 mmol), palladium acetate (0.31 g, 1 .3 mmol) and triphenyl phosphine (1 .74 g, 6.6 mmol). Potassium carbonate (5.69 g, 3.2 mmol) was dissolved in water (12.5 mL) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 25 mL) and water (20 mL). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.

Yield: 3.5 g (43 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 9.01 (s, 1 H), 8.10 (m, 2H), 6.73 (m, 2H), 3.93 (s, 3H), 3.85 (s, 3H); MS (ES+): 251 .4 (M+1 ).

Example 32

6-(2,4-Dimethoxyphenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)p yrimidin-4-amine

6-(Trifluoromethyl)pyridin-2-amine (0.146 g, 0.90 mmol) was added to a mixture of sodium hydride (0.129 g, 5.4 mmol) and N,N-dimethylformamide (3.0 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 31 (0.26 g, 1 .04 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (4 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound.

Yield: 0.1 g (29 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.57 (s, 1 H), 8.77(s, 1 H), 8.34 (s, 1 H), 8.19 (d 1 H), 7.99(m, 2H), 7.46 (d, 1 H), 6.69 (m, 2H), 3.84 (s, 6H); MS (ES+): 377.2 (M+1 ). Example 33

4-(6-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzene-1 ,3-diol

Solution of boron tribromide (0.39 g, 1 .56 mmol) in dichloromethane (1 .3 ml_) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 32 (0.10 g, 0.26 mmol) dissolved in dichloromethane (0.7 ml_) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 ml_) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.03 g (32 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 13.83 (s, 1 H), 10.78 (s, 1 H), 10.1 1 (s, 1 H), 8.77 (s, 1 H), 8.36 (s, 1 H), 8.01 (m, 2H), 7.61 (d, 1 H), 7.53 (d, 1 H),

6.42 (d, 1 H), 6.30 (s, 1 H); MS (HRMS+): 349.3 (M+1 ).

Example 34

4-Chloro-6-(3,5-dimethoxyphenyl)pyrimidine

To a 100 ml_ flask containing 4,6-dichloropyrimidine (4.9 g, 32.9 mmol) in isopropyl alcohol (40 ml_) was added 3,5-dimethoxyphenylboronic acid (5 g, 27.4 mmol), palladium acetate (0.31 g, 1 .3 mmol) and triphenyl phosphine (1 .74 g, 6.6 mmol). Potassium carbonate (5.69 g, 3.2 mmol) was dissolved in water (12.5 ml_) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 25 ml_) and water (20 ml_). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.

Yield: 3.5 g (43 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 9.08 (s, 1 H), 8.37 (s, 1 H),

7.41 (s, 2H), 6.75 (s, 1 H), 3.83 (s, 3H), 3.79 (s, 3H); MS (ES+): 251 .4 (M+1 ). Example 35

6-(3,5-Dimethoxyphenyl)-N-(6-(trifluoromethyl)pyrid^

6-(Trifluoromethyl)pyridin-2-amine (0.19 g, 1 .17 mmol) was added to a mixture of sodium hydride (0.168 g, 7.02 mmol) and N,N-dimethylformamide (3.8 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 34 (0.339 g, 1 .35 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.6 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (15 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.1 g (22 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.74 (s, 1 H), 8.85 (s, 1 H), 8.50 (s, 1 H), 8.03 (m, 1 H), 7.91 (d, 1 H), 7.51 (d, 1 H), 7.22 (s, 2H), 6.68 (s, 1 H), 3.83 (s, 6H); MS (ES+): 377.2 (M+1 ).

Example 36

5-(6-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzene-1 ,3-diol

Solution of boron tribromide (0.39 mL, 1 .56 mmol) in dichloromethane (1 .3 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 35 (0.1 g, 0.26 mmol) dissolved in dichloromethane (0.7 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (21 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.69 (s, 1 H), 9.52 (s, 2H), 8.80 (s, 1 H), 8.08 (m, 3H), 7.50 (d, 1 H), 6.93 (s, 2H), 6.38 (s, 1 H); MS (HRMS+): 349.3 (M+1 ). Example 37

4-Chloro-6-(4-methoxyphenyl)pyrimidine

To a 100 mL flask containing 4,6-dichloropyrimidine (1 .7 g, 1 1 .6 mmol) in isopropyl alcohol (20 mL) was added 4-methoxyphenylboronic acid (2 g, 1 1 .04 mmol), palladium acetate (0.12 g, 0.55 mmol) and triphenyl phosphine (0.7 g, 2.67 mmol). Potassium carbonate (2.28 g, 16.5 mmol) was dissolved in water (5 mL) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 15 mL) and water (10 mL). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.

Yield: 1 .0 g (40.0 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 9.00 (s, 1 H), 8.23 (m, 3H), 7.1 1 (d, 2H, 3.85 (s, 3H); MS (ES+): 221 .4 (M+1 ).

Example 38

6-(4-Methoxyphenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)pyrim idin-4-amine

6-(Trifluoromethyl)pyridin-2-amine (0.31 g, 1 .91 mmol) was added to a mixture of sodium hydride (0.275 g, 1 1 .4 mmol) and N,N-dimethylformamide (6.2 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 37 (0.48 g, 2.21 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .0 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (9 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (25 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound

Yield: 0.3 g (45 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.66 (s, 1 H), 8.8 (s, 1 H), 8.30 (s, 1 H), 8.03 (m, 4H), 7.48 (m, 1 H), 7.12 (d, 2H), 3.77 (s, 3H); MS (ES+): 347.4 (M+1 ). Example 39

4-(6-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) phenol

Solution of boron tribromide (0.645 g, 2.58 mmol) in dichloromethane (2.0 ml_) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 38 (0.15 g, 0.43 mmol) dissolved in dichloromethane (1 .0 ml_) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (8.4 ml_) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (10 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.04 g (29 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.62 (s, 1 H), 10.03 (s, 1 H), 8.77 (s, 1 H), 8.23 (s, 1 H), 8.01 (m, 2H), 7.93 (d, 2H), 7.49 (d, 1 H), 6.92 (d, 1 H);

MS (HRMS+): 332.4 (M+1 ).

Example 40

4-(Benzo[d][1 ,3]dioxol-5-yl)-6-chloropyrimidine

To a 100 ml_ flask containing 4,6-dichloropyrimidine (0.94 g, 6.0 mmol) in dimethoxyethane (8 ml_) was added benzo[d][1 ,3]dioxol-5-ylboronic acid (1 g, 6.32 mmol), palladium acetate (0.067 g, 0.30 mmol) and triphenyl phosphine (0.7 g, 2.67 mmol). Potassium carbonate (1 .24 g, 9.0 mmol) was dissolved in water (2.5 ml_) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 15 ml_) and water (10 ml_). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.

Yield: 0.4 g (27 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 9.01 (s, 1 H), 8.24 (s, 1 H),

7.91 (d, 1 H), 7.81 (s, 1 H), 7.1 1 (d, 1 H), 6.15 (s, 2H); MS (ES+): 235.4 (M+1 ). Example 41

6-(Benzo[d][1 ,3]dioxol-5-yl)-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin -4-amine

6-(Trifluoromethyl)pyridin-2-amine (0.15 g, 0.92 mmol) was added to a mixture of sodium hydride (0. 13 g, 5.5 mmol) and N,N-dimethylformamide (3.0 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 40 (0.24 g, 1 .06 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (4.5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound.

Yield: 0.04 g (12 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.68 (s, 1 H), 8.8 (s, 1 H), 8.29 (s, 1 H), 8.01 (m, 2H), 7.64 (d, 1 H), 7.53 (m, 3H), 7.1 1 (d, 1 H), 6.13 (s, 2H); MS (ES+): 361 .4 (M+1 ).

Example 42

2-Chloro-4-(3,4-dimethoxyphenyl)pyrimidine

To a 100 mL flask containing 2,4-dichloropyrimidine (1 1 .8 g, 79.5 mmol) in dimethoxyethane (100 mL) was added 2-(3,4-dimethoxyphenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (20 g, 79.53 mmol), palladium acetate (0.85 g, 3.7 mmol) and triphenyl phosphine (4.8 g, 18.3 mmol). Potassium carbonate (15.67 g, 1 13.5 mmol) was dissolved in water (25 mL) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 100 mL) and water (50 mL). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.

Yield: 12 g (61 %); ¹ H NMR (300 MHz, CDCI ₃ ):5 8.58 (d, 1 H), 7.73 (s, 1 H), 7.68 (d, 1 H), 7.58 (d, 1 H), 6.96 (d, 1 H), 4.01 (s, 3H), 3.97 (s, 3H); MS (ES+): 251 .4 (M+1 ). Example 43

4-(3,4-Dimethoxyphenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)p yrimidin-2-a

6-(Trifluoromethyl)pyridin-2-amine (0.56 g, 3.45 mmol) was added to a mixture of sodium hydride (0.25 g, 10.4 mmol) and N,N-dimethylformamide (1 1 .2 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (1 .0 g, 4.0 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .9 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.2 g (17 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.34 (s, 1 H), 8.66(d 1 H), 8.60 (d 1 H), 8.06 (m, 1 H), 7.87 (s, 1 H), 7.84 (d, 1 H), 7.60 (d, 1 H), 7.47 (d, 1 H), 7.13 (d, 1 H), 3.89 (s, 3H), 3.85 (s, 3H); MS (ES+): 377.2 (M+1 ).

Example 44

4-(2-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol

Solution of boron tribromide (0.159 g, 0.638 mmol) in dichloromethane (1 .0 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 43 (0.08 g, 0.212 mmol) dissolved in dichloromethane (0.6 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (4.5 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.03 g (34 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.23(s, 1 H), 9.63 (s, 1 H), 9.27 (s, 1 H), 8.64 (d, 1 H), 8.53 (d, 1 H), 8.06 (m, 1 H), 7.63 (s, 1 H), 7.47(m, 3H), 6.89 (d, 1 H); MS (HRMS+): 349.3 (M+1 ). Example 45

4-(3,4-Dimethoxyphenyl)-N-(6-(trifluoromethyl)pyridin-3-yl)p yrimidin-2-a

6-(Trifluoromethyl)pyridin-3-amine (0.169 g, 1 .043 mmol) was added to a mixture of sodium hydride (0.075 g, 3.125 mmol) and N,N-dimethylformamide (3.38 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (0.3 g, 1 .209 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (14 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.08 g (20 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.30 (s, 1 H), 9.12 (s, 1 H), 8.59 (m, 2H), 7.83 (m, 3H), 7.59 (d, 1 H), 7.16 (d, 1 H), 3.89 (s, 3H), 3.85 (s, 3H); MS (ES+): 377.2 (M+1 ).

Example 46

4-(2-((6-(Trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol

Solution of boron tribromide (0.39 g, 1 .56 mmol) in dichloromethane (1 .3 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 45 (0.1 g, 0.26 mmol) dissolved in dichloromethane (0.7 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.03 g (32 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.21 (s, 1 H), 9.62 (s, 1 H), 9.30 (s, 1 H), 9.13 (s, 1 H), 8.53 (m, 2H), 7.86 (d, 1 H), 7.62 (s, 1 H), 7.51 (d, 1 H), 7.36 (d, 1 H), 6.87 (d, 1 H); MS (HRMS+): 349.3 (M+1 ). Example 47

4-(3,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)pyridin-2-yl)p yrimidin-2-a

3-(Trifluoromethyl)pyridin-2-amine (0.28 g, 1 .7 mmol) was added to a mixture of sodium hydride (0. 245 g, 10.2 mmol) and N,N-dimethylformamide (5.6 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (0.49 g, 1 .97 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.95 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (8.5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (22 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.08 g (13 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.03 (s, 1 H), 8.71 (m, 2H), 8.26 (d, 1 H), 7.89 (s, 1 H), 7.66 (m, 2H), 7.42 (m, 1 H), 7.1 1 (d, 1 H), 3.85 (s, 3H), 3.83 (s, 3H); MS (ES+): 377.2 (M+1 ).

Example 48

4-(2-((3-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol

Solution of boron tribromide (0.159 g, 0.638 mmol) in dichloromethane (1 .0 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 47 (0.08 g, 0.212 mmol) dissolved in dichloromethane (0.6 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (4.5 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (27 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.71 (m, 2H), 8.25 (d, 1 H), 7.81 (s, 1 H), 7.54 (s, 1 H), 7.41 (m, 2H), 6.85 (d, 1 H); MS (HRMS+): 349.3 (M+1 ). Example 49

4-(3,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)pyrid^

3-(Trifluoromethyl)pyridin-4-amine (0.169 g, 1 .04 mmol) was added to a mixture of sodium hydride (0.149 g, 6.2 mmol) and N,N-dimethylformamide (4 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (0.3 g, 1 .21 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (9 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (14 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound

Yield: 0.1 g (25 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.82 (s, 1 H), 8.76 (d, 1 H), 8.59 (m, 2H), 8.42 (d, 1 H), 7.79 (m, 2H), 7.68 (d, 1 H), 7.10 (d, 1 H), 3.86 (s, 6H); MS (ES+): 377 (M+1 ).

Example 50

4-(2-((3-(Trifluoromethyl)pyridin-4-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol

Solution of boron tribromide (0.315 g, 1 .26 mmol) in dichloromethane (1 .0 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 49 (0.08 g, 0.21 mmol) dissolved in dichloromethane (0.6 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate.

Yield: 0.02 g (27 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.79 (s, 1 H), 8.73 (d, 1 H), 8.54 (d, 1 H), 8.46 (d, 1 H), 7.61 (s, 1 H), 7.49 (m, 2H), 6.84 (d, 1 H); MS (HRMS+): 349.3 (M+1 ). Example 51

N-(5-Bromopyridin-2-yl)-4-(3,4-dimethoxyphenyl)pyrimidin-2-a mine

5-Bromopyridin-2-amine (0.5 g, 2.89 mmol) was added to a mixture of sodium hydride (0. 41 g, 17.3 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (0.83 g, 3.35 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.15 g (13 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.08 (s, 1 H), 8.57 (d, 1 H), 8.40 (m, 2H), 8.03 (d, 1 H), 7.82 (m, 2H), 7.56 (d, 1 H), 7.13 (d, 1 H), 3.89 (s, 3H), 3.85 (s, 3H); MS (ES+): 388.4 (M+1 ).

Example 52

4-(2-((5-Bromopyridin-2-yl)amino)pyrimidin-4-yl)benzene-1 ,2-diol

Solution of boron tribromide (0.213 g, 0.85 mmol) in dichloromethane (1 .4 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 51 (0.1 1 g, 0.284 mmol) dissolved in dichloromethane (0.8 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (6.1 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (8 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (19 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.77 (d, 1 H), 8.37 (m, 2H), 8.03 (d, 1 H), 7.31 (m, 3H), 6.44 (d, 1 H); MS (HRMS+): 360.1 (M+1 ). Example 53

4-(3,4-Dimethoxyphenyl)-N-(2-(trifluoromethyl)phenyl)pyrimid in-2-amine

2-(Trifluoromethyl)aniline (0.52 g, 3.22 mmol) was added to a mixture of sodium hydride (0. 46 g, 19.3 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (0.93 g, 3.73 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound.

Yield: 0.15 g (12 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.70 (s, 1 H), 8.39 (s, 1 H), 7.27 (m, 5H), 7.39 (m, 2H), 7.12 (d, 1 H), 3.81 (s, 3H), 3.79 (s, 3H); MS (ES+): 376.2 (M+1 ).

Example 54

4-(2-((2-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzen e-1 ,2-diol

Solution of boron tribromide (0.360 g, 1 .44 mmol) in dichloromethane (1 .2 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 53 (0.09 g, 0.24 mmol) dissolved in dichloromethane (0.7 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.03 g (36.%); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.53 (s, 1 H), 9.18 (s, 1 H), 8.50 (s, 1 H), 8.32 (d, 1 H), 7.87 (d, 1 H), 7.72 (m, 2H), 7.50 (s, 1 H), 7.42 (m, 2H), 7.21 (d, 1 H), 6.82 (d, 1 H); MS (HRMS+): 348.4 (M+1 ). Example 55

4-(3,4-Dimethoxyphenyl)-N-(4-(trifluoromethyl)phenyl)pyrimid in-2-amin

4-(Trifluoromethyl)aniline (0.52 g, 3.22 mmol) was added to a mixture of sodium hydride (0. 46 g, 19.3 mmol) and N,N-dimethylformamide (10 ml_) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (0.93 g, 3.73 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 ml_) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound.

Yield: 0.3 g (25 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.06 (s, 1 H), 8.56 (d, 1 H), 8.08 (d, 2H), 7.81 (m, 2H), 7.61 (d, 2H), 7.51 (d, 1 H), 7.13 (d, 1 H), 3.89 (s, 3H), 3.84 (s, 3H); MS (ES+): 376.2 (M+1 ).

Example 56

4-(2-((4-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzen e-1 ,2-diol

Solution of boron tribromide (0.360 g, 1 .44 mmol) in dichloromethane (1 .2 ml_) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 55 (0.09 g, 0.24 mmol) dissolved in dichloromethane (0.7 ml_) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 ml_) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.05 g (60 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.00 (s, 1 H), 9.58 (s, 1 H), 9.29 (s, 1 H), 8.49 (d, 1 H), 8.08 (d, 2H), 7.67 (m, 3H), 7.53 (d, 1 H), 7.32 (d, 1 H), 6.88 (d, 1 H); MS (HRMS+): 348.4 (M+1 ). Example 57

4-(3,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)phenyl)pyrimid in-2-amine

3-(Trifluoromethyl)aniline (0.24 g, 1 .49 mmol) was added to a mixture of sodium hydride (0.214 g, 8.94 mmol) and N,N-dimethylformamide (4.8 ml_) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (0.43 g, 3.73 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.8 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (7.2 ml_) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (20 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.07g (13 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.99 (s, 1 H), 8.56 (d, 1 H), 8.43 (s, 1 H), 8.03 (d, 1 H), 7.78 (m, 2H), 7.54 (m, 2H), 7.30 (d, 1 H), 7.13 (d, 1 H), 3.87 (s, 3H), 3.85 (s, 3H); MS (ES+): 376.2 (M+1 ).

Example 58

4-(2-((3-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzen e-1 ,2-diol

Solution of boron tribromide (0.12 g, 0.48 mmol) in dichloromethane (0.8 ml_) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 57 (0.06 g, 0.16 mmol) dissolved in dichloromethane (0.5 ml_) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution 3.4 ml_) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (5 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.03 g (54 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.91 (s, 1 H), 9.61 1 (s, 1 H), 9.16 (s, 1 H), 8.50 (d, 1 H), 8.40 (s, 1 H), 8.06 (d, 1 H), 7.54 (m, 3H), 7.29 (m, 2H), 6.88 (d, 1 H); MS (HRMS+): 348.4 (M+1 ). Example 59

4-(3,4-Dimethoxyphenyl)-N-(4-(trifluoromethyl)pyridin-2-yl)p yrimidin

4-(Trifluoromethyl)pyridin-2-amine (0.28 g, 1 .73 mmol) was added to a mixture of sodium hydride (0. 25 g, 10.38 mmol) and N,N-dimethylformamide (5.6 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (0.5 g, 2.0 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .0 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (8.4 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (22 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.1 g (15 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.42 (s, 1 H), 8.78 (s, 1 H), 8.63 (d, 1 H), 8.57 (d, 1 H), 7.82 (m, 2H), 7.61 (d, 1 H), 7.34 (d, 1 H), 7.13 (d, 1 H), 3.87 (s, 3H), 3.85 (s, 3H); MS (ES+): 377.2 (M+1 ).

Example 60

4-(2-((4-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzene-1 ,2-diol

Solution of boron tribromide (0.159 g, 0.63 mmol) in dichloromethane (1 .04 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 59 (0.08g, 0.212 mmol) dissolved in dichloromethane (0.6 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.0 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (27 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.30 (s, 1 H), 9.72 (s, 1 H), 9.1 1 (s, 1 H), 8.82 (s, 1 H), 8.56 (d, 1 H), 7.56 (m, 2H), 7.38 (dd, 2H), 6.88 (d, 1 H); MS (HRMS+): 349.3 (M+1 ). Example 61

4-(3,4-Dimethoxyphenyl)-N-(perfluorophenyl)pyrimidin-2-amine

2,3,4,5,6-Pentafluoroaniline (0.63 g, 3.47 mmol) was added to a mixture of sodium hydride (0.5 g, 20.8 mmol) and N,N-dimethylformamide (12 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (1 .0 g, 4.02 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (2.0 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (18 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (48 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.6 g (40 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.57 (s, 1 H), 8.44(d, 1 H), 7.69 (m, 2H), 7.46 (d, 1 H), 7.08 (d, 1 H), 3.82 (s, 3H), 3.80 (s, 3H); MS (ES+): 398.4 (M+1 ).

Example 62

4-(2-((Perfluorophenyl)amino)pyrimidin-4-yl)benzene-1 ,2-diol

Solution of boron tribromide (0.755 g, 3.01 mmol) in dichloromethane (2.6 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 61 (0.2 g, 0.503 mmol) dissolved in dichloromethane (1 .4 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (1 1 .2 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (14 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.09 g (51 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (s, 1 H), 9.41 (s, 1 H),

9.17 (s, 1 H), 8.35 (m, 1 H), 7.42 (m, 2H), 7.27 (d, 1 H), 6.83 (d, 1 H); MS (HRMS+): 370.4 (M+1 ). Example 63

4-(4-(3,4-Dimethoxyphenyl)-N-(3,5,6-trifluoropyridin-2-yl)py rimidin-2-amm

3,5,6-Trifluoropyridin-2-amine (0.51 g, 3.47 mmol) was added to a mixture of sodium hydride (0. 5 g, 20.8 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (1 .0 g, 4.02 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.3 g (24 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.62 (s, 1 H), 8.43 (d, 1 H), 8.02 (m, 1 H), 7.69 (m, 2H), 7.42 (d, 1 H), 7.07 (d, 1 H), 3.81 (s, 3H), 3.79 (s, 3H); MS (ES+): 363.1 (M+1 ).

Example 64

4-(2-((3,5,6-Trifluoropyridin-2-yl)amino)pyrimidin-4-yl)benz ene-1 ,2-diol

Solution of boron tribromide (0.825 mL, 3.3 mmol) in dichloromethane (2.6 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 63 (0.2 g, 0.55 mmol) dissolved in dichloromethane (1 .4 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (1 1 .2 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (14 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.05 g (27 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.51 (s, 2H), 9.17 (s, 1 H), 8.36 (d, 1 H), 8.01 (m, 1 H), 7.41 (m, 2H), 7.23 (d, 1 H), 6.82 (d, 1 H); MS (HRMS+): 334.4 (M+1 ). Example 65

4-(Benzo[d][1 ,3]dioxol-5-yl)-2-chloropyrimidine

To a 100 ml_ flask containing 2,4-dichloropyrimidine (9.4 g, 63.2 mmol) in dimethoxyethane (100 ml_) was added benzo[d][1 ,3]dioxol-5-ylboronic acid (10 g, 60.2 mmol), palladium acetate (0.67 g, 3.0 mmol) and triphenyl phosphine (3.8 g, 14 mmol). Potassium carbonate (12.4 g, 90.3 mmol) was dissolved in water (25 ml_) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 100 ml_) and water (50 ml_). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.

Yield: 7.0 g (47 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 8.75 (d, 1 H), 8.08 (d, 1 H), 7.84 (d, 1 H), 7.24 (s, 1 H), 7.12 (d, 1 H), 6.16 (s, 2H); MS (ES+): 235.8 (M+1 ).

Example 66

4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(3-(trifluoromethyl)pyridin-4-yl)pyrimidin -2-amine

3-(Trifluoromethyl)pyridin-4-amine (0.15 g, 0.92 mmol) was added to a mixture of sodium hydride (0. 13 g, 5.5 mmol) and N,N-dimethylformamide (3.0 ml_) nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 65 (0.25 g, 1 .06 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (4.5 ml_) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.07 g (21 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.9 (s, 1 H), 8.74 (d, 1 H), 8.56 (m, 2H), 8.4 (d, 1 H), 7.81 (m, 2H), 7.64 (d, 1 H), 7.12 (d, 1 H), 6.05 (s, 2H); MS (ES+): 361 .4 (M+1 ). Example 67

4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-ami ne

3-(Trifluoromethyl)-aniline (0.142 g, 0.88 mmol) was added to a mixture of sodium hydride (0. 126 g, 5.28 mmol) and N,N-dimethylformamide (2.8 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 65 (0.238 g, 1 .02 mmol) was added to the reaction mixture at 5

- 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (4.5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.04 g (12 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 100 (s, 1 H), 8.56 (d, 1 H), 8.49 (s, 1 H), 7.95 (d, 1 H), 7.77(m, 2H), 7.54 (m, 1 H), 7.45 (d, 1 H), 7.30 (d, 1 H), 7.09 (d, 1 H), 6.14 (s, 2H); MS (ES+): 360.2 (M+1 ).

Example 68

4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin -2-amine

6-(Trifluoromethyl)pyridin-2-amine (0.108g, 0.66 mmol) was added to a mixture of sodium hydride (0. 095 g, 3.96 mmol) and N,N-dimethylformamide (2.1 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 65 (0.238 g, 0.77 mmol) was added to the reaction mixture at 5

- 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.4 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (3.1 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (9 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.03 g (12 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.34 (s, 1 H), 8.58 (m, 2H), 8.06 (m, 1 H), 7.83 (m, 2H), 7.55 (d, 1 H), 7.47 (d, 1 H), 7.10 (d, 1 H), 7.10 (d, 1 H), 6.41 (s, 2H); MS (ES+): 361 .4 (M+1 ). Example 69

4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin -2-amine

4-(Trifluoromethyl)pyridin-2-amine (0.15 g, 0.92 mmol) was added to a mixture of sodium hydride (0.14 g, 5.5 mmol) and N,N-dimethylformamide (3.0 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 65 (0.248 g, 1 .06 mmol) was added to the reaction mixture at 5

- 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (4.5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.04 g (12 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.44(s, 1 H), 8.81 (s, 1 H), 8.61 (m, 2H), 7.79 (m, 2H), 7.57(d, 1 H), 7.34 (d, 1 H), 7.10 (d, 1 H), 6.15 (s, 2H); MS (ES+): 361 .4 (M+1 ).

Example 70

4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrimidin -2-amine

5-(Trifluoromethyl)pyridin-2-amine (0.15 g, 0.92 mmol) was added to a mixture of sodium hydride (0.14 g, 5.5 mmol) and N,N-dimethylformamide (3.0 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 65 (0.248 g, 1 .06 mmol) was added to the reaction mixture at 5

- 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (4.5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.05 g (15 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.45 (s, 1 H), 8.66 (s, 1 H), 8.63 (d, 1 H), 8.54 (d, 1 H), 8.19 (d, 1 H), 7.81 (m, 2H), 7.58 (d, 1 H), 7.1 1 (d, 1 H), 6.15 (s, 2H; MS (ES+): 361 .4 (M+1 ). Example 71

4-(Benzo[d][1 ,3]dioxol-5-yl)-N-(3-(trifluoromethyl)pyridin-2-yl)pyrimidin -2-amine

3-(trifluoromethyl)pyridin-2-amine (0.15 g, 0.92 mmol) was added to a mixture of sodium hydride (0.14 g, 5.5 mmol) and N,N-dimethylformamide (3.0 ml_) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 65 (0.248 g, 1 .06 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (4.5 ml_) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.07 g (21 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.0 (s, 1 H), 8.74 (m, 2H), 8.36 (d, 1 H), 7.80 (s, 1 H), 7.61 (m, 2H), 7.42 (m, 1 H), 7.10 (d, 1 H), 6.1 (s, 2H); MS (ES+): 361 .4 (M+1 ).

Example 72

2-Chloro-4-(3,4-dimethoxyphenyl)-5-fluoropyrimidine

To a 100 ml_ flask containing 2,4-dichloro-5-flouoropyrimidine (7.3 g, 43.7 mmol) in isopropyl alcohol (100 ml_) was added 3,4-dimethoxy-phenylboronic acid (1 1 g, 41 .6 mmol), palladium acetate (0.467 g, 20.8 mmol) and triphenyl phosphine (2.64 g, 10 mmol). Potassium carbonate (8.62 g, 62.4 mmol) was dissolved in water (25 ml_) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 100 ml_) and water (50 ml_). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.

Yield: 8.0 g (68 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 8.87 (d, 1 H), 7.72 (d, 1 H),

7.61 (s, 1 H), 7.15 (d, 1 H), 3.86 (s, 3H), 3.84 (s, 3H); MS (ES+): 269.4 (M+1 ). Example 73

4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(5-(trifluoromethyl)pyrid in-2-yl)pyrimid

5-(Trifluoromethyl)pyridin-2-amine (0.15 g, 0.925 mmol) was added to a mixture of sodium hydride (0.133 g, 5.55 mmol) and N,N-dimethylformamide (3 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 72 (0.287 g, 1 .07 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (4.5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound.

Yield: 0.06 g (16 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.65 (s, 1 H), 8.71 (m 2H), 8.47 (d, 1 H), 8.18 (d, 1 H), 7.76 (m, 2H), 7.18 (d, 1 H), 3.87 (s, 6H); MS (ES+): 395.4 (M+1 ).

Example 74

4-(5-Fluoro-2-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrimi din-4-yl)benzene-1 ,2-diol Solution of boron tribromide (0.19 g, 0.76 mmol) in dichloromethane (0.7 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 73 (0.05 g, 0.126 mmol) dissolved in dichloromethane (0.4 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (3.0 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (4 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (43 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.51 (s, 1 H), 9.72 (s, 1 H), 9.39 (s, 1 H), 8.65 (s, 2H), 8.46 (d, 1 H), 8.16 (d, 1 H), 7.62 (s, 1 H), 7.51 (d, 1 H), 6.93 (d, 1 H); MS (HRMS+): 367.4 (M+1 ). Example 75

N-(5-Bromopyridin-2-yl)-4-(3,4-dimethoxyphenyl)-5-fluoropyri midin-2-amin

5-Bromo-pyridin-2-amine (0.59 g, 3.41 mmol) was added to a mixture of sodium hydride (0.49 g, 20.4 mmol) and N,N-dimethylformamide (1 1 .8 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 72 (1 .06 g, 3.95 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (2.0 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (18 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (48 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.2 g (14 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.26 (s, 1 H), 8.66(d 1 H), 8.38 (s, 1 H), 8.27 (d, 1 H), 8.00 (d, 1 H), 7.73 (m, 2H), 7.13 (d, 1 H), 3.86 (s, 6H); MS (ES+): 406.1 (M+1 ).

Example 76

4-(2-((5-Bromopyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)ben zene-1 ,2-diol

Solution of boron tribromide (0.369 g, 1 .47 mmol) in dichloromethane (1 .3 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 75 (0.1 g, 0.246 mmol) dissolved in dichloromethane (0.7 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (3.0 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (8 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (21 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.12 (s, 1 H), 9.69 (s, 1 H), 9.37 (s, 1 H), 8.59 (d, 1 H), 8.37 (s, 1 H), 8.25 (d, 1 H), 7.99 (d, 1 H), 7.59 (s, 1 H), 7.48 (d, 1 H), 6.91 (d, 1 H); MS (HRMS+): 378 (M+1 ). Example 77

4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(3-(trifluoromethyl)pyrid in-2-yl)pyrimid

3-(Trifluoromethyl)pyridin-2-amine (0.157 g, 0.96 mmol) was added to a mixture of sodium hydride (0.25 g, 5.76 mmol) and N,N-dimethylformamide (3.2 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 72 (0.298 g, 1 .1 1 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.08 g (21 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.57 (s, 1 H), 8.73 (d 1 H), 8.51 (d, 1 H), 8.25 (d, 1 H), 7.61 (d, 1 H), 7.50 (m, 2H), 7.1 1 (d, 1 H), 3.83 (s, 3H), 3.74 (s, 3H); MS (ES+): 395.4 (M+1 ).

Example 78

4-(5-Fluoro-2-((3-(trifluoromethyl)pyridin-2-yl)amino)pyrimi din-4-yl)benzene-1 ,2-diol Solution of boron tribromide (0.180 g, 0.72 mmol) in dichloromethane (0.7 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 77 (0.05 g, 0.12 mmol) dissolved in dichloromethane (0.4 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (3.0 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (4 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (43 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.53(s, 2H), 8.70 (s, 1 H), 8.44 (s, 1 H), 8.25 (d, 1 H), 7.46 (m, 2H), 7.37 (d, 1 H), 6.83 (d, 1 H); MS (HRMS+): 367.4 (M+1 ). Example 79

4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(2-(trifluoromethyl)pyrid in-4-yl)pyrimi^

2-(Trifluoromethyl)pyridin-4-amine (0.26 g, 1 .6 mmol) was added to a mixture of sodium hydride (0.23 g, 9.6 mmol) and N,N-dimethylformamide (5.2 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 72 (0.498 g, 1 .86 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.9 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (8 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (20 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.1 g (15 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): 5 8.82 (s, 2H), 8.71 (m 2H), 8.28 (d, 1 H), 7.69 (m, 2H), 7.14 (d, 1 H), 3.86 (s, 3H), 3.83 (s, 3H); MS (ES+): 395.4 (M+1 ).

Example 80

4-(5-Fluoro-2-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrimi din-4-yl)benzene-1 ,2-diol Solution of boron tribromide (0.304 g, 1 .21 mmol) in dichloromethane (1 .0 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 79 (0.08 g, 0.203 mmol) dissolved in dichloromethane (0.6 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (4.5 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.03 g (41 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.75(s, 1 H), 9.42 (s, 1 H), 8.80 (s, 1 H), 8.71 (d, 1 H), 8.63 (s, 2H), 8.29 (d, 1 H), 7.58 (s, 1 H), 7.49(s, 1 H), 6.91 (d, 1 H); MS (HRMS+): 367.4 (M+1 ). Example 81

4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(3,5,6-trifluoropyridin-2 -yl)pyrimidin-

3,5,6-Trifluoropyridin-2-amine (0.48 g, 3.24 mmol) was added to a mixture of sodium hydride (0.46 g, 19.4 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 72 (1 .0 g, 3.76 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .6 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.2 g (16 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.74 (s, 1 H), 8.52(d, 1 H), 8.03 (m, 1 H), 7.61 (m, 2H), 7.09 (d, 1 H), 3.83 (s, 3H), 3.77 (s, 3H); MS (ES+): 381 .1 (M+1 ).

Example 82

4-(5-Fluoro-2-((3,5,6-trifluoropyridin-2-yl)amino)pyrimidin- 4-yl)benzene-1 ,2-diol

Solution of boron tribromide (0.71 g, 2.84 mmol) in dichloromethane (2.4 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 81 (0.18 g, 0.47 mmol) dissolved in dichloromethane (1 .2 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (10 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (13 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.05 g (30 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.62(s, 2H), 9.25 (s, 1 H), 8.45 (d, 1 H), 7.98 (m, 1 H), 7.48 (s, 1 H), 7.37 (d, 1 H), 6.86 (d, 1 H); MS (HRMS+): 353.4 (M+1 ). Example 83

4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(4-(trifluoromethyl)pyrid in-2-yl)pyrimid

4-(Trifluoromethyl)pyridin-2-amine (0.15 g, 0.92 mmol) was added to a mixture of sodium hydride (0.132 g, 5.5 mmol) and N,N-dimethylformamide (3.0 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 72 (0.28 g, 1 .06 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (4.5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.08 g (22 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.40 (s, 1 H), 9.06(s 1 H), 8.70 (d, 1 H), 8.49 (d, 1 H), 7.85 (d, 1 H), 7.73 (m, 1 H), 7.17 (s, 1 H), 3.86 (s, 6H); MS (ES+): 395.4 (M+1 ).

Example 84

4-(5-Fluoro-2-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrimi din-4-yl)benzene-1 ,2-diol Solution of boron tribromide (0.375 g, 1 .5 mmol) in dichloromethane (1 .3 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 83 (0.10 g, 0.25 mmol) dissolved in dichloromethane (0.7 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.5 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (21 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.31 (s, 1 H), 9.69 (s, 1 H), 9.38 (s, 1 H), 9.08 (s, 1 H), 8.63 (s, 1 H), 8.50 (d, 1 H), 7.83 (d, 1 H), 7.60 (s, 1 H), 7.48 (d, 1 H), 6.91 (d, 1 H); MS (HRMS+): 367.4 (M+1 ). Example 85

4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(2-(trifluoromethyl)pheny l)pyrimidin-2-^

2-(Trifluoromethyl)-aniline (0.52 g, 3.22 mmol) was added to a mixture of sodium hydride (0.46 g, 19.3 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 72 (1 .0 g, 3.73 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (41 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.2 g (15 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.80 (s, 1 H), 8.47(d 1 H), 7.75 (m, 3H), 7.59 (m, 2H), 7.40 (m, 1 H), 7.08 (d, 1 H), 3.82 (s, 3H), 3.74 (s, 3H); MS (ES+): 394.1 (M+1 ).

Example 86

4-(5-Fluoro-2-((2-(trifluoromethyl)phenyl)amino)pyrimidin-4- yl)benzene-1 ,2-diol

Solution of boron tribromide (0.375 g, 1 .5 mmol) in dichloromethane (1 .3 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 85 (0.1 g, 0.25 mmol) dissolved in dichloromethane (0.7 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (21 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.63(s, 1 H), 9.28 (s, 1 H), 8.74 (s, 1 H), 8.41 (d, 1 H), 7.69 (m, 3H), 7.38 (m, 3H), 6.82 (d, 1 H); MS (HRMS+): 366.2 (M+1 ). Example 87

4-(3,4-Dimethoxyphenyl)-5-fluoro-N-(3-(trifluoromethyl)pheny l)pyrimidin-2-^

3-(Trifluoromethyl)-aniline (0.52 g, 3.22 mmol) was added to a mixture of sodium hydride (0.46 g, 19.3 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 72 (1 .0 g, 3.73 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (41 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.2 g (15 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.09 (s, 1 H), 8.65(d 1 H), 8.31 (s, 1 H), 7.99 (d, 1 H), 7.68 (m, 2H), 7.53 (m, 1 H), 7.27 (d, 1 H), 7.13 (d, 1 H), 3.85 (s, 6H); MS (ES+): 394.1 (M+1 ).

Example 88

4-(5-Fluoro-2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4- yl)benzene-1 ,2-diol

Solution of boron tribromide (0.151 g, 0.606 mmol) in dichloromethane (0.7 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas. Compound of example 87 (0.04 g, 0.101 mmol) dissolved in dichloromethane (0.3 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (2.2 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (4 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.01 g (27 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.02 (s, 1 H), 8.58 (d, 1 H), 8.33 (s, 1 H), 7.95 (d, 1 H), 7.52 (m, 3H), 7.26 (d, 1 H), 6.88 (d, 1 H); MS (HRMS+): 366.2 (M+1 ). Example 89

6-Chloro-N-(6-(trifluoromethyl) pyridin-2-yl) pyrimidin-4-amine

6-(Trifluoromethyl)pyridin-2-amine (10 g, 61 .72 mmol) was added to a mixture of sodium hydride (4.44 g, 185.18 mmol) and N,N-dimethylformamide (100 ml_) under nitrogen gas at 0-5 °C and the reaction mixture was stirred for 15 - 20 min. Compound of 4,6-dichloropyrimidine (10.1 1 g, 67.90 mmol) was added to the reaction mixture at 0-5 °C, then allow the temperature to 25-30 °C and stirred for 14-16 h. The reaction mixture was cooled to 0 -5 °C and methanol (10 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (20 ml_) was added drop-wise to the reaction mixture at 0-5 °C and was stirred for 10-15 min. Further 100 ml_ of water was added drop wise, raise the temperature to 25-30 °C and added ethyl acetate (100 ml_). The reaction mixture is stirred for 15-20 min and separated the layers. The aqueous layer was extracted with ethyl acetate (50 ml_). Combined both the organic layers and washed with 40% brine solution. The organic layer was dried over sodium sulphate and distilled out the solvent completely under vacuum at 40-45 °C to get crude. It was further purified by column chromatography to obtain the title compound

Yield: 8 g (80 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.96 (s, 1 H), 8.64(s, 1 H), 8.07 (t, 1 H), 7.97 (d, 1 H), 7.86(s, 1 H), 7.54 (d, 1 H); MS (ES+): 275.4 (M+1 ). Example 90

6-Phenyl-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4-amin e

To a 250 ml_ flask containing compound of example 89 (0.5 g, 1 .81 mmol) in dimethylformamide (10 ml_) was added phenylboronic acid (0.44 g, 3.63 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.12 g, 0.18 mmol). Sodium carbonate (0.57 g, 5.54 mmol) was dissolved in water (3 ml_) and was added to the reaction mixture. The reaction mixture was stirred at 1 10°C for 16-18 h. The reaction mixture was cooled to room temperature, filter through celite bed, washed the bed with DMF and filtrate was concentrated. The residue was dissolved in ethyl acetate (20 ml_) and washed with water (10 ml_). Organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude. It was further purified by column chromatography to obtain the title compound.

Yield: 0.1 g (17%); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 7.51 (m, 1 H), 7.60 (m, 3H), 8.06 (m, 4H), 8.36 (s, 1 H), 8.86 (s, 1 H), 10.75 (s, 1 H); MS (ES+): 317.3 (M+1 ). Example 91

6-(2,4-Difluorophenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)py rimidin

To a 25 ml_ flask containing compound of example 89 (0.2 g, 0.72 mmol) in dimethylformamide (10 ml_) was added 2,4-difluorophenylboronic acid (0.22 g, 1 .45 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.051 g, 0.072 mmol). Sodium carbonate (0.23 g, 2.18 mmol) was dissolved in water (2 ml_) and was added to the reaction mixture. The reaction mixture was stirred at 1 10°C for 16-18 h. The reaction mixture was cooled to room temperature, filter through celite bed, washed with DMF and filtrate was concentrated. The residue was dissolved in ethyl acetate (20 ml_) and washed with water (10 ml_). Organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude. It was further purified by column chromatography to obtain the title compound.

Yield: 0.1 g (39 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 7.31 (t, 1 H), 7.50 (m, 2H), 8.04 (d, 2H), 8.20 (d, 1 H), 8.35 (s, 1 H), 8.88 (s, 1 H), 10.82 (s, 1 H); MS (ES+): 353.1 (M+1 ).

Example 92

6-(4-(Trifluoromethyl)phenyl)-N-(6-(trifluoromethyl)pyridin- 2-yl)pyrimidin-4-amine

To a 25 ml_ flask containing compound of example 89 (0.2 g, 0.72 mmol) in dimethylformamide (10 ml_) was added 4-(trifluoromethyl)phenylboronic acid (0.2 g, 1 .09 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.051 g, 0.072 mmol). Sodium carbonate (0.23 g, 2.18 mmol) was dissolved in water (2 ml_) and was added to the reaction mixture. The reaction mixture was stirred at 1 10°C for 16-18 h. The reaction mixture was cooled to room temperature, filter through celite bed, washed with DMF and filtrate was concentrated. The residue was dissolved in ethyl acetate (20 ml_) and washed with water (10 ml_). Organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude. It was further purified by column chromatography to obtain the title compound

Yield: 0.12 g (44 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 7.54 (d, 1 H), 7.96 (d, 2H), 8.09 (m, 2H), 8.24 (d, 2H), 8.36 (s, 1 H), 8.92 (s, 1 H), 10.86 (s, 1 H); MS (ES+): 385.2 (M+1 ). Example 93

(2,6-Dichloro-4-(6-((6-(trifluorom

methanol

To a 250 ml_ flask containing compound of example 89 (0.5 g, 1 .81 mmol) in dimethylformamide (15 ml_) was added (2,6-dichloro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)methanol pinnacol ester (0.94 g, 2.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.13 g, 0.182 mmol). Sodium carbonate (0.58 g, 5.46 mmol) was dissolved in water (3.0 ml_) and was added to the reaction mixture. The reaction mixture was stirred at 1 10 °C for 16-18 h. The reaction mixture was cooled to room temperature, filter through celite bed, washed with DMF and filtrate was concentrated. The residue was dissolved in ethyl acetate (20 ml_) and washed with water (10 ml_). Organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain crude. It was further purified by column chromatography to obtain the title compound.

Yield: 0.1 g (30 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 4.74 (d, 2H), 5.34 (m, 1 H),

7.53 (d, 1 H), 7.93 (d, 1 H), 8.07 (m, 3H), 8.50 (s,1 H), 8.88 (s,1 H), 10.83 (s,1 H); MS (ES+): 416.0 (M+1 ).

Example 94

Ethyl 3-(6-((6-(trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzoate

To a 250 ml_ flask containing compound of example 89 (0.5 g, 1 .81 mmol) in dimethylformamide (15 ml_) was added 3-(ethoxycabonyl)phenylboronic acid (0.52 g, 2.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.13 g, 0.182 mmol). Sodium carbonate (0.58 g, 5.46 mmol) was dissolved in water (3.0 ml_) and was added to the reaction mixture. The reaction mixture was stirred at 1 10 °C for 16-18 h. The reaction mixture was cooled to room temperature, filter through celite bed, washed with DMF and filtrate was concentrated. The residue was dissolved in ethyl acetate (20 ml_) and washed with water (10 ml_). Organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude. It was further purified by column chromatography to obtain the title compound.

Yield: 0.16 g (20 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 1 .39 (t, 3H), 4.42 (q, 2H), 7.53 (d, 1 H), 7.76 (t, 1 H), 8.05 (m, 2H), 8.14 (d,1 H), 8.34 (d,1 H), 8.49 (s,1 H), 8.67 (s, 1 H), 8.90 (s,1 H), 10.83 (s,1 H); MS (ES+): 389.2 (M+1 ). Example 95

4-(6-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-yl) benzoni^

To a 250 mL flask containing compound of example 89 (0.1 g, 0.36 mmol) in dimethylformamide (5 mL) was added 4-cyanophenylboronic acid (0.08 g, 0.54 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.025 g, 0.036 mmol). Sodium carbonate (0.1 1 g, 1 .09 mmol) was dissolved in water (1 mL) and was added to the reaction mixture. The reaction mixture was stirred at 1 10 °C for 16-18 h. The reaction mixture was cooled to room temperature, filter through celite bed, washed with DMF and filtrate was concentrated. The residue was dissolved in ethyl acetate (10 mL) and washed with water (5 mL). Organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude. It was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (16 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 7.54 (d, 1 H), 8.08 (m, 4H), 8.20 (d, 2H), 8.34 (s, 1 H), 8.92 (s, 1 H), 10.88 (s, 1 H); MS (ES+): 342.1 (M+1 ).

Example 96

6-(2,3-Dihydrobenzo[b][1 ,4]dioxin-6-yl)-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin -4- amine

To a 250 mL flask containing compound of example 10 (0.5 g, 1 .43 mmol) in ethyl methyl ketone (10 mL) was added powdered potassium carbonate (0.49 g, 3.59 mmol) and 1 ,2-dibromo ethane (0.13 g, 0.71 mmol). The reaction mixture was stirred at 80-85 °C for 16-18 h. The reaction mixture was cooled to room temperature, added 10 mL of ethyl acetate and 10 mL of water. The reaction mass was stirred for 10 min, separated the organic layer and dried over sodium sulphate. The solvent was evaporated to obtain the crude. It was further purified by column chromatography to obtain the title compound.

Yield: 0.3 g (44 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 4.31 (s, 4H), 7.04 (d, 1 H), 7.49 (d, 2H), 7.57 (d, 2H), 8.02 (m,2H), 8.29 (s,1 H) 8.79 (s, 1 H), 10.67 (s 1 H); MS (ES+): 375.2 (M+1 ).

Example 97

4-(3,4-Dimethoxyphenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)p yrimidin-2-amine

5-(Trifluoromethyl)pyridin-2-amine (0.175 g, 1 .08 mmol) was added to a mixture of sodium hydride (0.155 g, 6.48 mmol) and N,N-dimethylformamide (5 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (0.31 g, 1 .25 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.6 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (14 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound.

Yield: 0.08 g (20 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.45 (s, 1 H), 8.62(m,

2H), 8.18 (m, 1 H), 7.83 (m, 2H), 7.62 (d, 1 H), 7.10 (d, 1 H), 6.72 (s, 1 H), 3.89 (s, 3H), 3.84 (s, 3H); MS (ES+): 377.2 (M+1 ).

Example 98

4-(2-((5-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4- yl)benzene-1 ,2-diol

Solution of boron tribromide (0.159 g, 0.638 mmol) in dichloromethane (1 .0 mL) was cooled to -40 °C to -35 °C and stirred for 10 - 15 min under nitrogen gas.

Compound of example 97(0.08 g, 0.212 mmol) dissolved in dichloromethane (0.6 mL) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -10 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (4.5 mL) till pH was 9, at 15 - 20 °C The product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.03 g (34 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.44(s, 1 H), 9.66 (s,

1 H), 9.31 (s, 1 H), 8.65 (s, 1 H), 8.54 (d, 2H), 8.14 (d, 1 H), 7.54 (m, 3H), 6.87(d, 1 H);

MS (HRMS+): 349.3 (M+1 ).

Example 99

6-(2,4-Dimethoxyphenyl)-N-(3,5,6-trifluoropyridin-2-yl)pyrim idin-4-amine 3,5,6-Trifluoropyridin-2-amine (0.5 g, 3.37 mmol) was added to a mixture of sodium hydride (0.48 g, 20.2 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 31 (0.98 g, 3.9 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound.

Yield: 0.45 g (36 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.02 (s, 1 H), 8.70(s, 1 H), 8.32 (m, 2H), 8.06 (d, 1 H), 6.65(m, 2H), 3.92 (s, 3H), 3.843(s, 3H); MS (ES+): 363.2 (M+1 ).

Example 100

2-Chloro-4-(2,4-dimethoxyphenyl)pyrimidine

To a 100 mL flask containing 2,4-dichloropyrimidine (9.8 g, 65.7 mmol) in isopropyl alcohol (80 mL) was added 2,4-dimethoxyphenylboronic acid (10 g, 54.9 mmol), palladium acetate (0.62 g, 2.7 mmol) and triphenyl phosphine (3.48 g, 13.2 mmol). Potassium carbonate (1 1 .38 g, 82.4 mmol) was dissolved in water (25 mL) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 100 mL) and water (50 mL). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.

Yield: 10 g (61 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 8.68 (d, 1 H), 8.04 (m, 2H), 6.74 (m, 2H), 3.92 (s, 3H), 3.88 (s, 3H); MS (ES+): 251 (M+1 ).

Example 101

4-(2,4-Dimethoxyphenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)p yrimidin-2-amine

6-(Trifluoromethyl)pyridin-2-amine (0.56 g, 3.46 mmol) was added to a mixture of sodium hydride (0.49 g, 20.7 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 1 5 - 20 °C and the reaction mixture was stirred for 1 5 - 20 min. Compound of example 1 00 (1 .0 g, 4.01 mmol) was added to the reaction mixture at 5 - 1 0 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 1 0 °C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (1 5 mL) was added drop-wise to the reaction mixture at 1 0 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.3 g (23 %) ; ¹ H NMR (300 MHz, DMSO-d ₆ ) : δ 1 0.22 (s, 1 H), 8.55(m, 2H),

8.04 (m, 2H), 7.55 (d, 1 H), 7.44(d, 1 H), 6.70 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H) ; MS (ES+) : 377.2 (M+1 ).

Example 1 02

4-(2,4-Dimethoxyphenyl)-N-(3-(trifluoromethyl)phenyl)pyrimid in-2-amine

3- (Trifluoromethyl)-aniline (0.5 g, 3.1 mmol) was added to a mixture of sodium hydride (0.44 g, 18.6 mmol) and N,N-dimethylformamide (1 0 mL) under nitrogen gas at 1 5 - 20 °C and the reaction mixture was stirred for 1 5 - 20 min. Compound of example 1 00 (0.9 g, 3.59 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 1 0 °C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (1 5 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.1 g (8.6 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.90 (s, 1 H), 8.48(m, 2H), 8.00 (m, 2H), 7.48 (m, 2H), 7.26(d, 1 H), 6.70 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H); MS (ES+) : 376.2 (M+1 ). Example 1 03

4-(2,4-Dimethoxyphenyl)-N-(4-(trifluoromethyl)pyridin-2-yl)p yrimidin-2-amine

4- (Trifluoromethyl)pyridin-2-amine (0.56 g, 3.46 mmol) was added to a mixture of sodium hydride (0.49 g, 20.7 mmol) and N,N-dimethylformamide (1 0 mL) under nitrogen gas at 1 5 - 20 °C and the reaction mixture was stirred for 1 5 - 20 min. Compound of example 100 (1 .0 g, 4.01 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.37 g (28 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.33 (s, 1 H), 8.81 (s, 1 H), 8.55 (m, 2H), 8.02 (d, 1 H), 7.56(d, 1 H), 7.30 (d, 1 H), 6.69 (m, 2H), 3.90 (s, 3H), 3.86 (s, 3H); MS (ES+): 377.2 (M+1 ).

Example 104

N-(4-(6-Chloropyrimidin-4-yl)phenyl)acetamide

To a 100 mL flask containing 4,6-dichloropyrimidine (3.37 g, 20.09 mmol) in isopropyl alcohol (30 mL) was added (4-acetamidophenyl)boronic acid (3 g, 16.7 mmol), palladium acetate (0.188 g, 0.83 mmol) and triphenyl phosphine (1 .06 g, 4.0 mmol). Potassium carbonate (3.46 g, 25.1 mmol) was dissolved in water (7.5 mL) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 25 mL) and water (20 mL). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.

Yield: 3.2 g (64 %); ¹ H NMR (300 MHz, DMSO-d ₆ ):5 10.26 (s, 1 H), 9.02 (s, 1 H), 8.23 (m, 3H), 7.77 (d, 2H), 2.05 (s, 3H); MS (ES+): 248.8 (M+1 ).

Example 105

N-(4-(6-((6-(Trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4- yl)phenyl)acetamide

6-(Trifluoromethyl)pyridin-2-amine (2.25 g, 13.9 mmol) was added to a mixture of sodium hydride (1 .74 g, 72.6 mmol) and N,N-dimethylformamide (22 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min. Compound of example 104 (3.0 g, 12.1 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (7.6 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (67 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (2 x 22 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 2.2 g (43 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.70 (s, 1 H), 10.21 (s, 1 H), 8.81 (s, 1 H), 8.29 (s, 1 H), 7.98 (m, 3H), 7.70(d, 3H), 7.49 (d, 1 H), 2.10 (s, 3H); MS (ES+): 374.1 (M+1 ).

Example 106

6-(4-Aminophenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimid in-4-amine

10% Methanolic hydrochloride (5 mL) was added to a mixture of Compound of example 105(1 g) and methanol (10 mL) and the mass was stirred for 5 - 10 min at 25- 30 °C. The reaction mixture was heated to 40-45 °C and maintained for 6 h. After completion of the reaction, evaporated the solvent completely and quenched the mass in to 10 mL of water. A solution of chilled 5 % sodium bicarbonate solution (12 mL) was added drop-wise to the reaction mixture at 10 °C until the pH is basic and stirred for 25 - 30 min. The product precipitated was filtered and dried to obtain the title compound.

Yield: 0.5 g (56 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.53 (s, 1 H), 8.70(s, 1 H), 8.17 (s, 1 H), 7.99 (d, 2H), 7.77(d, 2H), 7.47 (t, 1 H), 6.66 9d, 2H), 5.73 (s, 2H); MS (ES+): 332.1 (M+1 ). Example 107

Methyl 5-(6-chloropyrimidin-4-yl)-2-methoxybenzoate

To a 100 mL flask containing 4,6-dichloropyrimidine (8.03 g, 53.9 mmol) in dimethoxyethane (120 mL) was added methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoate (15 g, 51 .3 mmol), palladium acetate (0.507 g, 2.2 mmol) and triphenyl phosphine (3.25 g, 12.4 mmol). Potassium carbonate (10.6 g, 76 mmol) was dissolved in water (37.5 mL) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 °C for 20 h. The reaction mixture was cooled to room temperature and was concentrated under vacuum below 45 °C. The residue was partitioned between ethyl acetate (2 x 50 mL) and water (20 mL). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.

Yield: 5 g (33 %); ¹ H NMR (300 MHz, DMSO-d ₆ ) : δ 9.05 (s, 1 H), 8.57(s, 1 H), 8.47 (d, 1 H), 8.33 (s, 1 H), 7.35(d, 1 H), 3.92 (s, 3H), 3.83 (s, 3H); MS (ES+): 279.4 (M+1 ).

Example 1 08

Methyl-2-methoxy-5-(6-((6-(trifluoromethyl)pyridin-2-yl)amin o)pyrimidin-4-yl)benzoate

6-(Trifluoromethyl)pyridin-2-amine (1 .0 g, 6.1 7 mmol) was added to a mixture of sodium hydride (0.88 g, 37.0 mmol) and N,N-dimethylformamide (20 ml_) under nitrogen gas at 1 5 - 20 °C and the reaction mixture was stirred for 1 5 - 20 min. Compound of example 1 07 (2.0 g, 7.1 mmol) was added to the reaction mixture at 5 - 1 0 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 1 0 °C and methanol (3.4 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (30 ml_) was added drop-wise to the reaction mixture at 1 0 °C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (2 x 40 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound.

Yield: 0.4 g (1 6 %) ; ¹ H NMR (300 MHz, DMSO-d ₆ ) : δ 1 0.96 (s, 1 H), 8.85(s, 1 H), 8.53 (s, 2H), 8.38 (d, 1 H), 8.1 6(t, 1 H), 7.68 (d, 1 H), 7.51 (s, 1 H), 7.35 (d, 1 H), 3.99 (s, 3H); MS (ES+): 405.6 (M+1 ). Example 1 09

Methyl-2-hydroxy-5-(6-((6-(trifluoromethyl)pyridin-2-yl)amin o)pyrimidin-4-yl) benzoate Solution of boron tribromide (0.285 g, 1 .14 mmol) in dichloromethane (1 .3 ml_) was cooled to -40 °C to -35 °C and stirred for 1 0 - 1 5 min under nitrogen gas.

Compound of example 1 08 (0.08 g, 0.1 9 mmol) dissolved in dichloromethane (0.7 ml_) was added drop-wise to the reaction mixture at -40 °C to -35 °C over a period of 5 -1 0 min and was stirred for 30 - 35 min. The mixture was allowed to warm to 25 - 30 °C over a period of 55 - 60 min and was stirred for 2 - 3 h.

The reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (4.5 ml_) till pH was 9, at 1 5 - 20 °C The product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

Yield: 0.02 g (26 %); ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 12.29 (s, 1 H), 1 1 .25 (s, 1 H), 8.84 (s, 2H), 8.56 (d, 1 H), 8.30 (d, 1 H), 8.17 (t, 1 H), 7.70 (d, 1 H), 7.47 (s, 1 H), 7.16 (d, 1 H), 3.98 (s, 3H); MS (HRMS+): 391 .3 (M+1 ).

Biological evaluation

The pharmacological activity of the representative compounds of formula 1 can be evaluated by using a number of pharmocological assays known to persons skilled in the art. The exemplified pharmacological assay, given below, has been carried out using representative compounds of the present invention.

The following abbreviations are used herein:

mM : Millimolar H ₃ PO ₄ : Phosporic acid

μΜ : Micromolar NaCI : Sodium chloride

nM : Nanomolar NaOH : Sodium hydroxide

w/v : Weight per volume CaCI ₂ Calcium chloride

+ve : Positive MgCI ₂ : Magnesium chloride

- ve : Negative MnCI ₂ Manganese(ll) chloride rpm : Revolutions per minutes PI : Propidium Iodide

p.o. : Oral adminstration o.i.d. : Once a day

i.p. :lntra-peritoneal administration b.i.d : Twice a day

IC50 : 50 % Inhibitory concentration FCS : Fetal Calf Serum

DTT : Dithiothreitol FBS : Fetal Bovine Serum

PKC : Protein kinase C PBS : Phosphate Buffered Saline

GMP : Guanine Mono Phosphate CO ₂ : Carbon dioxide

TGF :TransformingGrowth Factor-β

ATCC : American Type Culture Collection

OHSU : Oregon Health and Science University, Oregon, USA

RPMI : Roswell Park Memorial Institute

IMDM : Iscove's Modified Dulbecco's Medium

EDTA : Ethylenediaminetetraacetic acid

PTEN (gene) : Phosphatase and tensin homolog protein DNA-PKcs : DNA-dependent protein kinase, catalytic subunit

MEM EBS : Minimum Essential Medium with Earle's Balanced Salts

RPMI 1640 : Roswell Park Memorial Institute 1640 medium

MEBM : Mammary epithelium basal medium

MEGM : Mammary epithelium cell growth medium

DMEM : Dulbecco's Modified Eagles Medium

MTS : (3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2- (4- sulfonyl)- 2H-tetrazolium)

Representative compounds of the present invention are tested for their antiproliferative activity against the imatinib mesylate sensitive cell line K-562 and KU812 and Ba/F3 Bcr-AbI/ WT and imatinib mesylate resistant cell lines, Ba/F3 Bcr-AbI/ T315I, Ba/F3 Bcr-AbI/ E255K, Ba/F3 Bcr-AbI/ H396P, Ba/F3 Bcr-AbI/ M351 T, Ba/F3 Bcr-AbI/ F359V, Ba/F3 Bcr-AbI/ E255V, Ba/F3 Bcr-AbI/ F317L, Ba/F3 Bcr-AbI/ H396R, Ba/F3 Bcr-AbI/ M244V, Ba/F3 Bcr-AbI/ Q252H, Ba/F3 Bcr-AbI/ Y253F, Ba/F3 Bcr-AbI/ Y253H, and HL 60 Bcr-abl negative using various pharmacological assays as described below. The exemplified pharmacological assays, which follow, have been carried out with imatinib mesylate, and representative compounds of the present invention or their pharmaceutically acceptable salts.

Several imatinib-resistant cell lines were procured from Dr. Brian Druker's laboratory, Howard Hughes Medical Institute, Oregon Health and Science University (OHSU) Cancer Institute, Portland, Oregon, USA, the details of which are provided in the following Table 1 . K562 cell line and HL 60 cell line were procured from ATCC, USA. These cell lines were maintained under optimum conditions of growth as suggested by the respective suppliers. Description of imatinib sensitive and imatinib resistant cell lines which are used for in vitro studies is presented in Table 1 .

Table 1 : Description of imatinib sensitive and imatinib resistant cell lines

Sr. Medium of propagation

Cell line Source Ph status

No (FBS %)

Ba/F3 Bcr-AbI/

1 OHSU + ve wild type RPMI-1640 (10 %)

WT

Ba/F3 Bcr-AbI/

2 OHSU + ve mutated RPMI-1640 (10 %)

T315I Ba/F3 Bcr-Abl/

3 OHSU + ve mutated RPMI-1640 (10 %)

E255K

Ba/F3 Bcr-Abl/

4 OHSU + ve mutated RPMI-1640 (10 %)

H396P

Ba/F3 Bcr-Abl/

5 OHSU + ve mutated RPMI-1640 (10 %)

M351 T

Ba/F3 Bcr-Abl/

6 OHSU + ve mutated RPMI-1640 (10 %)

F359V

Ba/F3 Bcr-Abl/

7 OHSU + ve mutated RPMI-1640 (10 %)

E255V

Ba/F3 Bcr-Abl/

8 OHSU + ve mutated RPMI-1640 (10 %)

F317L

Ba/F3 Bcr-Abl/

9 OHSU + ve mutated RPMI-1640 (10 %)

H396R

Ba/F3 Bcr-Abl/

10 OHSU + ve mutated RPMI-1640 (10 %)

M244V

Ba/F3 Bcr-Abl/

1 1 OHSU + ve mutated RPMI-1640 (10 %)

Q252H

Ba/F3 Bcr-Abl/

12 OHSU + ve mutated RPMI-1640 (10 %)

Y253F

Ba/F3 Bcr-Abl/

13 OHSU + ve mutated RPMI-1640 (10 %)

Y253H

14 K562[S] ATCC +ve wild type RPMI-1640 (10 %)

Ph -ve myeloid IMDM + 20% FCS

15 HL 60 ATCC

leukemia cell line

Ph +ve

chromosome

RPMI-1640

16 KU812 ATCC (at least 1 Ph

+ 10 % FCS

chromosome is

present)

Representative compounds of the present invention are tested for their antiproliferative activity on human cancer cell lines such as H460 (lung carcinoma), HCT- 1 16 (colon carcinoma), A2780 (ovarian carcinoma), Miapaca-2 (pancreatic carcinoma), PC-3 (prostate carcinoma), MCF-7, MDA-MB-231 , MDA-MB-468 and BT-549 (human breast cell lines), Miapaca-2, Panc-1 , Capan-1 and BxPC-3 (human pancreatic cell lines), WI-38 and MCF-10A (normal human cell lines), and A-375 (melanoma). Human cancer cell lines were procured from ATCC, USA.

Example 1 10

In vitro assay

Cell proliferation and cytotoxicity CCK-8 assay

The assay was carried out as described in reference, Biological and Pharmaceutical Bulletin, 1996, 19, 1518, which is incorporated herein for the teaching of the method.

Cell Counting Kit-8 (CCK-8) assay is a sensitive colorimetric assay for the determination of number of viable cells in cell proliferation and cytotoxicity assays. Cell Counting Kit-8 (CCK-8) utilizes Dojindo's highly water-soluble tetrazolium salt. The amount of the formazan dye generated by dehydrogenases in cells is directly proportional to the number of living cells.

Source of cell lines and sample preparation

Imatinib mesylate was purchased from Natco Pharma, India. For the representative compounds of the present invention and standard imatinib mesylate, 10 mM stock was prepared in DMSO.

The cell lines described in Table 1 were used to test the antiproliferative activity of the representative compounds of the present invention.

Method

Cells were seeded at a density of ~ 5 x 10 ³ per well (0.09 ml_) in a transparent 96-well tissue culture plate (NUNC, USA) and allowed to incubate at 37 °C, 5 % C0 ₂ incubator for 2 - 6 h. Representative compounds of the present invention of different concentrations were added to the wells of the culture plate in triplicate. Imatinib mesylate was used as a standard. Plates were further incubated in an incubator at 37 °C in presence of 5 % C0 ₂ for 72 h. 10 μΙ_ of the CCK-8 solution was added to each well and plate was incubated for 1 - 4 h in the incubator. The absorbance was measured at 450 nm using a microplate reader. The percent inhibition and IC ₅ o were calculated in comparison with the control values.

Anti-proliferative activity of the representative compounds of the present invention, expressed as IC ₅ o values in μΜ, in imatinib mesylate sensitive (Ba/F3 Bcr- Abl/ Wild Type, K562 cell line) and resistant (Ba/F3 Bcr-AbI/ T315I) cell lines are presented in Table 2.

Anti-proliferative activity of the representative compounds of the present invention expressed as IC ₅₀ values in μΜ for different cell lines with imatinib mesylate resistant mutations (Ba/F3 Bcr-AbI/ E255K, Ba/F3 Bcr-AbI/ E255V, Ba/F3 Bcr-AbI/ F317L, Ba/F3 Bcr-AbI/ F359V, Ba/F3 Bcr-AbI/ H396R, Ba/F3 Bcr-AbI/ H396P, Ba/F3 Bcr-AbI/ M244V, Ba/F3 Bcr-AbI/ Q252H, Ba/F3 Bcr-AbI/ Y253F, Ba/F3 Bcr-AbI/ Y253H, and Bcr-abl/ M351 T, HL 60 and KU 812) are presented in Table 3.

IC ₅₀ values for inhibition of cell proliferation on human cell lines H460 (lung carcinoma), HCT-1 16 (colon carcinoma) A2780 (ovarian carcinoma), Miapaca-2 (pancreatic carcinoma) PC-3 (prostate carcinoma) and A-375 (melanoma) are presented in Table 4.

IC ₅₀ values for inhibition of cell proliferation on human breast cell lines MCF-7, MDA-MB-231 , MDA-MB-468 and BT-549 are presented in Table 5.

IC ₅₀ values for inhibition of cell proliferation on human pancreatic cell lines

Miapaca-2, Panc-1 , Capan-1 and BxPC-3 are presented in Table 6.

IC ₅₀ values for inhibition of cell proliferation on normal human cell lines WI-38 and MCF-10A are presented in Table 7. Table 2: Inhibitory concentrations (IC ₅ o) for representative compounds of the present invention in imatinib mesylate sensitive and resistant cell lines.

Cell lines (IC ₅₀ in μΜ)

Sr. Compound Imatinib sensitive Imatinib resistant No Ba/F3 Bcr-AbI/ Ba/F3 Bcr-AbI/

K562

WT T315I

1 Imatinib mesylate 0.5 0.7 Inactive

2 Compound of example 4 1 .85 ± 0.05 1 .3 ± 0.1 1 .9

3 Compound of example 6 3.6 8 3.6

4 Compound of example 10 0.4 0.8 0.2

5 Compound of example 14 1 .9 1 .05 ± 0.353 1 .55 ± 0.919

6 Compound of example 18 1 .7 ± 0.282 1 .65 ± 0.212 1 .2 ± 0.282 Table 3: IC ₅₀ values for inhibition of cell proliferation in various mutated CML cell lines Time point: 72 h.

- : Not tested

Table 4: IC ₅₀ values for inhibition of cell proliferation on human cancer cell lines; Time point: 48 h.

- : Not tested

Table 5: IC ₅ o values for inhibition of cell proliferation (human breast cell lines); Time point: 48 h.

Compound Cell lines (IC ₅₀ in μΜ)

MCF-7 MDA-MB-231 MDA-MB-468 BT-549

Table 6: IC ₅ o values for inhibition of cell proliferation (human pancreatic cancer cell lines); Time point: 48 h.

- : Not tested

Table 7: IC ₅₀ values for inhibition of cell proliferation on normal human cancer cell lines; Time point: 48 h.

Conclusion: Representative compounds of the present invention exhibited significant inhibitory activity against Bcr-Abl mutated imatinib mesylate resistant cells.

The representative compounds of the present invention also exhibited inhibition of cell proliferation on human cancer cell lines.

Example 1 1 1

Flow cytometric analysis

Effect of the representative compounds of present invention in Bcr-Abl mutated imatinib mesylate-resistant cell lines on cell cycle and apoptosis using flow cytometry.

The assay was carried out as described in reference, FEBS Letters, 2007, 581 , 7, 1329-1334.

Flow cytometry was used to study the effect of representative compounds of the present invention to induce apoptosis in Bcr-abI mutated imatinib mesylate resistant cell lines. Cells were seeded at a density of 10 X 10 ⁴ cells/mL and incubated in an incubator with 3 x IC ₅ o concentration of a representative compound of the present invention (as determined in example 1 10) and vehicle control (untreated) for 48 h and 96 h at 37 °C in the presence of 5 % C0 ₂ . The experiment was repeated with 5 x IC ₅ o concentration of representative compound of the present invention (as determined in example 1 10) and vehicle control (untreated) for 48 h and 96 h at 37 °C in the presence of 5 % C0 ₂ . At the end of incubation, cells were harvested by centrifugation at 1000 rpm for 10 min, washed with phosphate buffered saline (PBS) and gradually resuspended in 70 % ice-cold ethanol (to facilitate the permeablisation of stains). Cell suspension was stored for a minimum period of 4 h before staining with propidium iodide (PI). Fixed cells were stained with PI (80 μg/mL) in presence of RNase A (50 μ9/ιηΙ_), and read on Becton Dickinson FACS Calibur (USA) for cell cycle analysis. The results of this study are presented in Table 8.

Table 8: Screening in imatinib mesylate resistant cell lines.

(i) Time point: 48 h, concentration: 3χ IC ₅ o

^* vehicle control (untreated)

(ii) Time point: 48 h, concentration: 5χ IC ₅ o

^* vehicle control (untreated)

(iii) Time point: 96 h, concentration: 3χ IC ₅ o

^* vehicle control (untreated)

(iv) Time point: 96 h, concentration: 5χ IC ₅ o

^* vehicle control (untreated) (v) Time point: 48 h, concentration : 3 ^χ IC ₅ o

*vehicle control (untreated)

(vi) Time point: 48 h, concentration : 5 ^χ IC ₅ o

*vehicle control (untreated)

(vii) Time point: 96 h, concentration : 3 ^χ IC ₅ o

*vehicle control (untreated)

(viii) Time point: 96 h, concentration : 5 ^χ IC ₅ o

*vehicle control (untreated)

Conclusion : Induction of apoptosis by the representative compounds of the present invention in imatinib mesylate-resistant cell lines is significant.

Example 1 1 2

hPBMNC cytotoxicity assay

The assay was carried out as described in reference, Cancer Research, 1 991 , 51 , 1 81 -189. Blood was collected from healthy donors into Potassium EDTA vacutainer tubes (BD vacutainer). The human peripheral blood mononuclear cells (hPBMNCs) were isolated using gradient centrifugation in Histopaque-1077 solution. Isolated PBMNCs were suspended in RPMI-1640 culture medium containing 10 % FBS, 100 U/mL penicillin and 100 μg/mL streptomycin. The cell concentration was adjusted to 1 χ 10 ⁶ cells/mL. The viability as determined by trypan blue dye exclusion was uniformly >_98 %. The cell suspension (100 μΙ_) was added to the wells of a 96-well culture plate. Concavalin A (EMD Chemicals) adjusted to a concentration of (400 μg/mL) was added to the plate. This was the stimulated plate. Complete medium was added to the unstimulated plate and both the plates were kept in the incubator for 16 - 18 h. After incubation and stimulation, test compound (representative compound of the present invention) was added to both the plates in the same template and the plates were kept for further incubation for 24 - 48 h. After incubation CellTiter 96® AQueous MTS Reagent was overlaid in each of the wells and the reading was taken on Spectramax microplate reader (Molecular devices, USA) at 490 nM and the IC ₅ o values were evaluated. Results are depicted in Table 9.

Table 9: IC ₅₀ values for inhibition of cell proliferation in normal human peripheral blood mononuclear cells; Time point: 72 h, Method: MTS assay n= 3.

inhibited proliferation of hPBMNCs.

Example 1 13

TGF3 assay

TGF is a prime candidate for maintaining the CML stem cells in a non-cycling state. An upregulation or prolongation of TGF signaling by Bcr-AbI suggests that one of the mechanisms by which Bcr-AbI promotes the transformation of haemopoietic progenitor cells, is by influencing the level of TGF signaling activity (FEBS Letters, 2007, 581 , 7, 1329-1334). TGF plays a vital role in the preservation of the malignant progenitor population, and is known to be partially responsible for the resistance to treatments targeting Bcr-Abl observed in a proportion of CML patients.

Inhibition of TGF by the representative compounds of the present invention was demonstrated using Western Blot Analysis.

Western Blot Analysis

The Western Blot assay was carried out as described in reference, Analytical Biochemistry, 1981 , 1 12, 2, 195-203.

Western blot analysis was performed to decipher the mechanism of action of representative compounds of the present invention. Ba/F3 Bcr-Abl/T315l (imatinib mesylate resistant) cells were seeded in tissue culture grade 75 mm ² flasks at a density of 2 to 4 x 10 ⁶ cells per flask. The cells were incubated in a humidified incubator for 2 - 4 h at 37 °C. Subsequently, cells were treated with IC ₅ o concentration of the representative compound of the present invention and 3 x IC ₅ o concentration of the representative compound of the present invention (as determined in example 1 10) or standard molecule (imatinib mesylate or dasatinib). Cells were then incubated for 48 h and 96 h. Following the incubation, cells were harvested, washed with ice-cold phosphate buffered saline (PBS) and lysed with cold Cell Lytic buffer (Sigma Aldrich) supplemented with complete protease inhibitor cocktail (Roche, Germany). The protein extracts were obtained after centrifugation at 14,000 g at 4 °C (30 min). Aliquots of the resulting extracts were analyzed for their protein content using Bradford Reagent (Sigma) as per the manufacturer's instructions. In all the experiments, equivalent amounts of protein (70 μg) were loaded on 7.5 % -10 % Tris-glycine gels and resolved at 100 V for 2 h in a buffered solution (24.9 mM Tris base, 250 mM glycine, 0.1 % SDS (sodium dodecyl sulfate)). After electrophoresis, the proteins were transferred from the gel to a polyvinylidene difluoride membrane (Sigma-Aldrich) at 25 V for 45 min. in transfer buffer (47.9 mM Tris base, 38.6 mM glycine, 0.037 % SDS, 20 % methanol; pH 9.2-9.4). Blots were blocked in Tris-buffered saline (TBS) (20 mM Tris base, 0.9 % NaCI; pH 7.4) containing 5 % nonfat dry milk (Santa Cruz Biotechnology, USA) for 2 h at room temperature, and incubated with gentle rocking after addition of the primary antibody which was prepared in TBS at 4 °C for a time ranging from 16 - 18 h. Primary antibodies included antibodies against TGF , Smad2/3, phospho-Smad2/3 (Cell Signaling) and β-Actin (Cell Signaling). Following the incubation, membranes were washed and then probed with horse-radish peroxidase (HRP)-conjugated secondary antibody. Bands were visualized using chemiluminescent peroxidase substrate (Pierce, IL) and a Kodak Imaging station. Blots were stripped with stripping buffer (50 mM Tris-HCI pH 6.8, 1 % SDS and 100 mM β-mercaptoethanol) for 30 min at 55 °C, washed and re-probed with a primary antibody to the housekeeping protein, β-actin was used as a loading control.

The results are depicted in Figure 1 (A) and Figure 1 (B).

Effect of the compound of example 4 and the compound of example 10 on protein expression by western blotting comparative study with imatinib mesylate (standard) is depicted in Figure 2(A) and Figure 2(B).

Conclusion: Compound of example 4 and compound of example 10 downregulated p-Smad2 and p-Smad3, effector target molecules of TGF signaling, indicating their role in inhibiting the TGF pathway in imatinib mesylate and dasatinib resistant cell lines. Example 1 14

PI3K assay

The PI3K assay was carried out as described in reference, Cancer Research, 2007, 67 (12), 5840-5850.

PC-3 (Prostate carcinoma) cells were used for this study as they are PTEN mutated and thus exhibit constitutively active PI3K/Akt pathway. PC-3 cells were seeded into T-25 flasks at a density of 0.7 ^χ 10 ⁶ cells/flask. Cells were left to adhere and the next day were serum starved in RPMI-1640 medium containing 0.1 % FCS. After overnight serum starvation, test compound (representative compound of the present invention) was added at desired concentration (3 μΜ and 5 μΜ) followed by serum stimulation (with RPMI-1640 + 10 % FCS) for 30 min. Then lysates were prepared, protein was estimated and separated on 10 % SDS-polyacrylamide gel. Western blotting was carried out using phospho-AktSer473, total Akt and phospho-4E- BP1 antibodies. Results are depicted in Figure 3.

Conclusion: The representative compounds of the present invention were found to inhibit phosphorylation of Akt and its downstream effect on phospo-4E-BP1

Example 1 15

Protein Kinase Assay The kinase inhibition profile was carried out by: ProQinase GmbH, (USA) (@ProQinase).

The kinase inhibition profile of the test compound (compound of example 10) was determined by measuring residual activity values at two concentrations in singlicate in 333 protein kinase assays.

The compound of example 10A was dissolved in 100% DMSO. The final DMSO concentration in all reaction cocktails (including high and low controls) was 1 %.

A radiometric protein kinase assay (33PanQinase® Activity Assay) was used for measuring the kinase activity protein kinases. All kinase assays were performed in 96- well Flash PlatesTM from Perkin Elmer (Boston, MA, USA) in a 50 μΙ_ reaction volume. The reaction cocktail was pipetted in 4 steps in the following order:

1 . 10 μΙ_ of non-radioactive ATP solution (in water);

2. 25 μΙ_ of assay buffer/ [γ-33Ρ]-ΑΤΡ mixture;

3. 5 μΙ_ of test sample in 10 % DMSO;

4. 10 μΙ_ of enzyme/substrate mixture.

The assay for all protein kinases contained 70 mM HEPES-NaOH, pH 7.5, 3 mM MgCI ₂ , 3 mM MnCI ₂ , 3 μΜ Na-orthovanadate, 1 .2 mM DTT, ΑΤΡ/[γ-33Ρ]-ΑΤΡ. All PKC assays (except the PKC-mu and the PKC-nu assay) additionally contained 1 mM CaCI ₂ , 4 mM EDTA, 5 μg/mL Phosphatidylserine and 1 μg/mL 1 ,2-Dioleyl-glycerol. The CAMK1 D, CAMK2A, CAMK2B, CAMK2D, CAMK4, CAMKK1 , CAMKK2, DAPK2, EEF2K, MYLK, MYLK2 and MYLK3 assays additionally contained 1 g/ml Calmodulin and 0.5 mM CaCI ₂ .

The PRKG1 and PRKG2 assays additionally contained 1 μΜ cGMP.

The DNA-PK assay additionally contained 2.5 μg/mL DNA.

The protein kinase reaction cocktails were incubated at 30 °C for 60 min. The reaction was stopped with 50 μΙ_ of 2 % (v/v) H ₃ PO ₄ , plates were aspirated and washed two times with 200 μΙ_ 0.9 % (w/v) NaCI.

All protein kinase assays were performed with a BeckmanCoulter Biomek 2000/SL robotic system. Incorporation of 33Pi (counting of "cpm") was determined with a microplate scintillation counter (Microbeta, Wallac).

The results of this study are presented in Table 10. Table 10: IC ₅ o (μΜ) values for compound of example 10A for inhibition of protein kinases

Conclusion: Compound of example 10A inhibits protein kinases. Example 1 16

In vivo assay

All experiments were carried out in accordance with the guidelines of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) and with the approval of Institutional Animal Ethics Committee (IAEC) in Piramal Enterprises Limited (formerly known as Piramal Healthcare Limited), Goregoan, Mumbai, India.

Representative compounds of the present invention were tested in vivo for their anti-proliferative activity in imatinib-resistant tumor models by using cell line such as Ba/F3 transfectants expressing mutated Bcr-Abl (Ba/F3 Bcr-Abl/T315I).

The assay was carried out as described in reference, Cancer Research, 2006, 66 (23), 1 1314-1 1322 which is incorporated herein for the teaching of the method. Objective

To test representative compounds of the present invention in vivo for their activity in imatinib resistant tumor models.

Cell Line

Cell lines Ba/F3 transfectants expressing mutated imatinib resistant (Ba/F3 Bcr-

Abl/T3151) was used in this study. This recombinant cell line was licensed from Dr.

Brian Druker's laboratory, Howard Hughes Medical Institute, Oregon Health and Science University Cancer Institute, Portland, Oregon, USA (Cancer Research, 2002,

62, 7149-7153), which is incorporated herein for the teaching of the method.

Conditions for storage of the compounds

All the test compounds including the standard (Imatinib mesylate) were stored at

4 °C to 8 °C in an amber colored bottle. The compounds in solutions were also maintained at 4 °C to 8 °C in a refrigerator. Sample for animal injection was made fresh everyday, residual volume were pooled and discarded as per standard operating procedure (SOP) for chemical disposals.

Dose preparation

Representative compound of the present invention was weighed and admixed with 0.5 % (w/v) carboxymethylcellulose (CMC) and triturated with Tween-20 {secundum artum) with gradual addition of water to make up the final concentration. Imatinib mesylate was used as a standard. Efficacy study in SCID mice

A group of Severely Combined Immune-Deficient (SCID strain-CBySmn.CB17- Prkdc ^scid /J, The Jackson Laboratory, Stock # 001803) male mice, 5-6 weeks old, weighing -20 g, were used.

Ba/F3 Bcr-Abl/T315l cells were grown in RPMI1640 medium containing 10 % fetal calf serum in 5 % CO ₂ incubator at 37 °C. Cells were pelleted by centrifugation at 1000-rpm for 10 min. Cells were resuspended in saline to get a count of 80 - 100 X 10 ⁶ cells per mL, 0.2 mL of this cell suspension was injected by subcutaneous (s.c.) route in SCID mice. Mice were observed alternate days for palpable tumor mass. Once the tumor size reached a size of 5 - 7 mm in diameter, animals were randomized into respective treatment groups. Dose of control or test compound was administered every day. Tumor size was recorded at 2 - 5 day intervals.

Tumor measurement

a) Tumor weight in milligram was calculated using the formula for a prolate ellipsoid:

Tumor weight (mg) = Length (mm) x [Breadth (mm) ² ] x 0.5 b) Treated to control ratio (T/C %) for group on a given day X was calculated using the formula:

Ax - Ao

T/C % on day X = x 100

Cx - Co

wherein:

Ax is the tumor size of group (treatment with test compound) on day X;

Ao is the tumor size of group (treatment with test compound) on day 0;

Cx is the tumor size of group (treatment with control) on day X; and

Co is the tumor size of group (treatment with control) on day 0.

c) Growth inhibition (Gl) was calculated as

Gl on day X = 100 - T/C % on day X

Results with

Gl % = 50 % drug is considered as active;

Gl % > 75 % drug is considered as very active; and

Gl % < 50 % drug is considered as inactive.

Respective treatment groups are presented in Table 1 1 and Table 13. Results are presented in Table 12 and Table 14. Table 1 1 : Treatment groups in the xenograft models (SET I)

Designation: Ba/F3 Bcr-Abl/T315l

Table 12: Tumor growth inhibition percent (% Gl) for representative compounds of the present invention in imatinib resistant cell lines (Ba/F3 Bcr-Abl/T315l).

Table 13: Treatment groups in the xenograft models (SET II)

Designation: Ba/F3 Bcr-Abl/T315l

Number of

Groups Sample Dose Route n

treatments

Control

I Vehicle p.o. oid 15 5

(untreated)

Control

II Vehicle i.p. oid 15 5

(untreated)

Compound of 50

III p.o. oid 15 5 example 9 mg/kg

Compound of 50

IV i.p. oid 15 5 example 9 mg/kg Compound of 100

V i.p. oid 15 5 example 10 mg/kg

Table 14: Tumor growth inhibition percent (% Gl) for representative compounds of the present invention in imatinib resistant cell lines (Ba/F3 Bcr-Abl/T315l).

Conclusion: The data presented in Table 14 demonstrates that the compounds of example 9 and example 10 of the present invention exhibited significantly greater in vivo efficacy than imatinib mesylate in inhibiting the most predominant mutated form of Bcr-Abl i.e. Ba/F3 Bcr-Abl/T315l.

Example 1 17

Cell growth inhibition assay

Propidium Iodide (PI) assay:

A modified Propidium Iodide assay was used to assess the effect of the representative compounds of the present invention on the growth of the human tumor cell lines. The assay was designed as given in the reference, Anti-cancer Drugs, 1995, 6, 522-532, the disclosure of which is incorporated by reference for the teaching of the assay.

Cells were plated in 96-well flat-bottom microtiter plates at a cell density of

3000-3500 cells/well. After a 24 h recovery period to allow the cells to resume exponential growth, the representative compounds (20 mM stock concentration in DMSO) were treated at eight concentrations in triplicates (10, 3, 1 , 0.3, 0.1 , 0.03, 0.01 and 0.003 μΜ) for a period of 48 h, after which the medium was removed from the wells and 200 μΙ_ of Propidium Iodide (PI) working solution (7 μg/mL in sterile 1 X PBS) was added per well. A 1 .5 mM (5 mg of PI in 5ml_ of sterile water) stock solution of PI stored at 4 °C was used. The plate was frozen at -80 °C for 24 h. After 24 h incubation, the plate was thawed. The plate was again frozen and thawed for a second time and was then read on the fluorimeter, using 540 nonometer (nm) excitation and 640 nm emission wavelength. The percentage (%) cytotoxicty and cell growth was calculated as follows:

reading of control - reading of treated cells

% Cytotoxicity = X 100 reading of control

Cell growth= 100 - % Cytotoxicity

The IC ₅ o values were calculated on Graph Pad Prism 5. Alternatively, where the Graph Pad Prism could not calculate reliable IC50 values by non-linear regression, the IC50 value was estimated by visual inspection of the concentration-effect curve.

The cell lines described in Table 15, were used to test the cell growth inhibition activity of the representative compounds of the present invention. Cell lines are adherent in nature and were obtained from ATCC, USA,

IC50 values for representative compounds of the present invention are indicated in Table 16.

Table 15: Description of the cell lines

Sr.

Cell line Origin Growth Medium

No.

Renal cell MEM EBS + 10% FBS

1 ACHN adenocarcinoma + 1 % Antimycotic

Pancreatic MEM EBS + 10% FBS

2 PANC-1

carcinoma + 1 % Antimycotic

Lung; epidermoid MEM EBS + 10% FBS

3 Calu-1

carcinoma + 1 % Antimycotic

Large cell lung RPMI 1640 + 10% FBS

4 H460

cancer + 1 % Antimycotic

Colorectal MEM EBS + 10% FBS

5 HCT-1 16

carcinoma + 1 % Antimycotic

Normal breast; MEBM+ MEGM single quots

6 MCF-10A epithelial cells + 10% FBS + 1 % Antibiotic

+ Growth hormones

Breast; melanoma RPMI 1640 + 10% FBS

7 MDAMB-435S

+ 1 % Antimycotic

Skin; malignant McCoy's 5A Medium

8 G-361

melanoma + 10% FBS + 1 % Antimycotic

Skin; malignant DMEM + 10% FBS

9 A-375

melanoma + 1 % Antimycotic Table 16: IC ₅ o values for the representative compounds of the present invention for their inhibitory effect on different cancer cell lines

Not tested

Cell lines: 1 ^* - ACHN; 2 ^* - PANC-1 ; 3 ^* - Calu-1 ; 4 ^* - H460; 5 ^* - HCT-1 16;

6 ^* -MCF-10A; 7 ^* - AMDAMB-435S; 8 ^* - G-361 ; 9 ^* - A-375

Conclusion: The representative compounds of the present invention were found to inhibit the growth of the selected human tumor cell lines. Example 1 18

Human peripheral blood mononuclear cells (hPBMC) assay

Representative compounds of the present invention were evaluated for their anti-inflammatory activity in the hPBMC assay. The effect of the representative compounds of the present invention on lipopolysaccharides (LPS)-induced cytokine production from hPBMC was ascertained by the method as described in Physiol. Res.,

2003, 52, 593-598, the disclosure of which is incorporated by reference for the teaching of the assay. Regular peripheral blood was collected from healthy donors into potassium EDTA vacutainer tubes (BD Biosciences). Peripheral blood mononuclear cells were isolated using density gradient centrifugation using Histopaque-1 077 solution (Sigma Aldrich ; St. Louis, MO). Isolated hPBMC were resuspended to 1 x1 0 ⁶ cells/mL in Rosewell Park Memorial Institute (RPMI) 1 640 culture medium (Sigma Aldrich) containing 1 0 % heat inactivated fetal bovine serum (FBS; JRH), 1 00 U/mL penicillin (Sigma Chemical Co. ; St. Louis, MO) and 1 00 μg/mL streptomycin (Sigma Chemical Co.). The viability of hPBMCs was determined by trypan blue dye exclusion and was uniformly found to be >98%. 1 00 μί. of the cell suspension was added to wells of a 96- well culture plate. Following cell plating, 79 μί. of the culture medium and 1 μί. of various concentrations of the representative compounds of the present invention(final concentration 0.03, 0.1 , 0.3, 1 , 3, 1 0, 30 and 1 00 μΜ) dissolved in dimethylsulfoxide (DMSO; Sigma Aldrich) were added to the cells. The final concentration of DMSO was adjusted to 0.5%. The vehicle (0.5 % DMSO) was used as negative control. Rolipram (300 μΜ) was used as a standard TNF-cc inhibitor, Dexamethasone (1 0 μΜ) was used a standard interleukin-6 (IL-6) inhibitor. The cells were incubated with test compounds or DMSO for 30 min at 37°C, 5% CO ₂ . Subsequently, 20 μί of 1 0 μg/mL LPS {Escherchia coli 01 27:B8, Sigma Chemical Co., St. Louis, MO) was added per well to achieve a final concentration of 1 μg/mL LPS. The cells were then incubated for 5 h at 37°C, 5% CO ₂ following which supernatants were collected, stored at -70 °C and assayed later for TNF-cc and IL-6 by ELISA (OptiEIA ELISA sets, BD Biosciences, Pharmingen). The 50% inhibitory concentration (IC ₅ o) values were calculated by a nonlinear regression method using GraphPad software (Prism 3.03). In all experiments, a parallel plate was run to ascertain the toxicity of test compounds. The toxicity was determined using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfonyl)-2H-tetrazolium) reagent.

The results of the testing using representative compounds of the present invention are summarized in Table 1 7.

Table 17: IC ₅ o (μΜ) values in human peripheral blood mononuclear cells (hPBMCs) assay

IC50 (μΜ)

Example no.

TNF-α IL-6

32 1 1 .8 33 0.2 0.2

36 1 .5 0.5

38 3.3 3.9

46 1 .32 0.7

50 4.5 4.5

56 0.6 0.4

57 0.1 0.85

60 0.4 1 .8

76 3.5 4.5

77 0.7 77

77 1 .8 1 .5

80 2.1 33

82 3 3

84 0.1 0.1

88 0.1 0.1

90 1 0.5

91 2.34 2

94 0.04 1 .2

95 0.04 0.8

96 0.6 2

106 0.4 1 .4 Conclusion: Representative compounds of the present invention are found to be active in human peripheral blood mononuclear cells (hPBMCs) assay.