WO2012059932A1 - 2, 4 -diaminopyrimidine derivatives as protein kinase inhibitors - Google Patents

Abstract

The present invention relates to novel pyrimide derivatives of formula (I): that are useful as kinase inhibitors. More particularly, the present invention relates to novel pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders.

Description

2 , 4 -DIAMINOPYRIMIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS

FIELD OF INVENTION

This invention relates to compounds useful as inhibitors of protein kinases.

This invention particularly relates to the compounds, processes for preparing the compounds of this invention, the isoforms of these compounds, and pharmaceutical compositions comprising the same as active ingredients.

The present invention further relates to the prodrugs, tautomeric forms, derivatives, analogues, stereo isomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing compounds as described herein and their use in the treatment of various disorders.

BACKGROUND AND PRIOR ART

Cancer is a group of varied diseases characterized by uncontrolled growth and spread of abnormal cells: Generally, all types of cancers involve some abnormality in the control of cell growth and division. The pathways regulating cell division and or cellular

communication become altered in cancer cells such that the effects of these regulatory mechanisms in controlling and limiting cell growth fails or is bypassed. Through successive rounds of mutation and natural selection, a group of abnormal cells, generally originating from a single mutant cell, accumulates additional mutations that provide selective growth advantage over other cells, and thus evolves into a cell type that predominates in the cell mass. This process of mutation and natural selection is enhanced by genetic instability displayed by many types of cancer cells, an instability which is gained either from somatic mutations or by inheritance from the germ line. The enhanced mutability of cancerous cells increases the probability of their progression towards formation of malignant cells. As the cancer cells further evolve, some become locally invasive and then metastasize to colonize tissues other than the cancer cell's tissue of origin. This property along with the heterogeneity of the tumor cell population makes cancer a particularly difficult disease to treat and eradicate. Traditional cancer treatments take advantage of the higher proliferative capacity of cancer cells and their increased sensitivity to DNA damage: Ionizing radiation, including γ- rays and x-rays, and cytotoxic agents, such as bleomycin, cis-platin, vinblastine,

cyclophosphamide, 5'- fluorouracil, and methotrexate rely upon a generalized damage to DNA and destabilization of chromosomal structure which eventually leads to destruction of cancer cells. These treatments are particularly effective for those types of cancers that have defects in cell cycle checkpoint, which limits the ability of these cells to repair damaged DNA before undergoing cell division. The non-selective nature of these treatments, however, often results in severe and debilitating side effects. The systemic use of these drugs may result in damage to normally healthy organs and tissues, and compromise the long-term health of the patient. Consequently, identification of other chemotherapeutic agents is critical for establishing therapies effective for attacking the heterogeneous nature of proliferative disease and for overcoming any resistance that may develop over the course of therapy with other compounds. Moreover, use of combinations of chemotherapeutic agents which may have differing properties and cellular targets, increases the effectiveness of chemotherapy and limits the generation of drug resistance.

Due to better understanding of the structure of enzymes and other biomolecules associated with diseases the search for new therapeutic agents in recent years has become much more focused than before. One important class of enzymes that has been the subject of extensive study are the protein kinases.

Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell.

(Hardie,G . and Hanks, S., The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995) .

Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250- 300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g. protein- tyrosine, protein- serine/ threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (for example Hanks, S .K-, Hunter, T., FASEB J . 1995, 9 , 576-596; Knighton et al., Science 1991, 253, 407-414; Hiles et al ., Cell 1992, 70, 419-429; Kunz et al ., Cell 1993, 73, 585-596; Garcia- Bustos et al., EMBO J . 1994, 13, 2352-2361).

Based on the substrates, the protein kinases may be broadly divided into two groups; those that phosphorylate serine or threonine residues (serine /threonine kinases, STK) which are inclusive of but not limited to the likes of AKT, P70 S6, J K, AURORA, P38, ERK, IKK, AMPK, CHK, CDKs, GSK, PKC, Raf, PLK,

and those that phosphorylate tyrosine residues (protein tyrosine kinases, PTK) which are inclusive of but not limited to the receptor types such as EGFR, PDGFR, JAK, C-Kit, and the non -receptor types which include C-SRC, FLT3, Abl, FGFR1 , KDR/ (VEGFR2), Ret, c-MET, JAK2, Syk ,FAK and dual Kinase inhibitors such as MEK.

Several therapeutic strategies are being targeted at protein kinases since they are critical components in signal transduction pathways. There is a much better precedent for selectively targeting the enzymatic activity of kinases with small molecules that can occupy the catalytic ATP (Adenosine Tri Phosphate site). Kinase inhibitors also known to allow other therapeutic agents additional time to become effective and act synergistically with current treatments in certain cases.

Although some anticancer compounds described above have made a significant contribution to the art, there is a continuing need in this field of art to improve anticancer pharmaceuticals with better selectivity or potency, reduced toxicity, or fewer side effects.

Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

It is well known that biological consequences of multi -kinase activity are poorly defined, and an important step toward in the direction of finding a therapy for diseases would be to understand the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. A detailed and comprehensive study has been reported by Mazen W Karaman, Sanna Herrgard, et al in Nat Biotech; 08 Feb in an article titled "A quantitative analysis of kinase inhibitor selectivity". This study discusses binding affinities for known targets of the compounds which were in line with published results from conventional assays. The new data represent a comprehensive view of kinase inhibitor selectivity available to date, and reveal a diversity of interaction patterns of small molecules with the human kinome.

It is therefore desirable to target multiple kinases such as those selected from the likes of Aurora, CDK2, EGFR, C-SRC, FGFR, VEGFR, C-MET, JAK and FAK while retaining a sufficient therapeutic window.

Aurora kinase is involved in mitosis, and has been demonstrated to be a putative oncoprotein overexpressed in several cancer cells of breast, colon, pancreas and ovarian cancer (Carvajal RD et al., Clin. Cancer Res., 12(23), 6869-75, 2006). Several Aurora kinase inhibitors have been reported so far and some of them have been discussed previously in this document.

Cycline-dependent kinase (CDK) is known to play a prominent role in Gl/S transition and G2 M transition in cell cycle (Kim Nasmyth, Science, 21 A, 1643-1677, 1996) to regulate cell growth. In particular, there have been found mutations of genes encoding CDK or CDK regulator in cancer cells in the exponential growth phase (Webster, Exp. Opin. Invest. Drugs, 1 , 865-887, 1998).

From the tyrosine kinase family, the epidermal growth factor receptor (EGFR) family comprises four closely related receptors (HERl/EGFR, HER2, HER3 and HER4) involved in cellular responses such as differentiation and proliferation. Over-expression of the EGFR kinase, or its ligand TGF-alpha, is frequently associated with many cancers, including breast, lung, colorectal, ovarian, renal cell, bladder, head and neck cancers, glioblastomas and astrocytomas, and is believed to contribute to the malignant growth of these tumors. Recent reports have shown that the sensitivity of cell lines to growth inhibition by EGFR inhibitors is dependent on the down-regulation of the PI3K-PDK1-Akt pathway. There can be extensive overlap in signaling where an EGFR signaling pathway can also be regulated by several other receptor tyrosine kinases. This potential for multiple inputs in EGFR signaling pathways suggests that inhibiting EGFR alone may not allow for growth inhibition of all tumor cells and highlights the potential for multi-point intervention utilizing combinations of receptor tyrosine kinase inhibitors. Non-receptor tyrosine kinases belonging to the Src family are key effectors of signal transduction. C-src was initially discovered as the oncogenic protein of the retrovirus Rous sarcoma virus, and it is now well established that the family of src kinases play an important role in cell cycle control, cell adhesion, proliferation and differentiation, as well as lymphokine-mediated cell survival and angiogenesis (Schlessinger, Cell, 2000, 100, 293- 296). The kinase activity of several members of the Src family, including c-src, fyn, and lyk is negatively regulated by phosphorylation by c-src tyrosine kinase. C-src tyrosine kinase phosphorylates c-src on tyrosine 527 which induces intramolecular interactions between phosphotyrosine sites that leads to a conformational change which maintains c-src in a catalytically inactive conformation. Through this action, c-src tyrosine kinase holds a pivotal role in many signal transduction pathways that regulate the cell cycle (Latour and Veillette, Curr. Opin. Immunol, 2001, 13, 299306).

The Janus kinases (JAK) are a family of non receptor tyrosine kinases consisting of JAK1, JAK2, JAK3 and TYK2. The JA s play a critical role in cytokine signaling. The downstream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis as well as in solid and hematological malignancies such as leukemias and lymphomas. The pharmaceutical intervention in the JAK/STAT pathway has been reviewed ( Frank Molt Med. 5: 432-456 1999 & Seidel, et al, Oncogene 19: 2645- 2656).

Still another member of the tyrosine kinase growth factor receptor family is MET, often referred to as c-Met. c-Met is also known as hepatocyte growth factor receptor or scatter factor receptor. c-Met is thought to play a role in primary tumor growth and metastasis and compounds modulating this target have been discussed in US7250417.

Given the involvement of pathogenic angiogenesis in such a wide variety of disorders and diseases, inhibition of angiogenesis, and particularly of VEGF signaling, is a desirable therapeutic goal. VEGF acts through two high affinity tyrosine kinase receptors, VEGFRl or Fms-related tyrosine kinase, Flt-1), and VEGFR2 (also known as kinase domain receptor or kinase insert domain-containing receptor, KDR). Although VEGFR1 binds VEGF with a 50- fold higher affinity than KDR, KDR appears to be the major transducer of VEGF angiogenic effects, i.e. mitogenicity, chemotaxis and induction of tube formation (Binetruy-Tourniere et al., supra). Inhibition of KDR mediated signal transduction by VEGF therefore represents an excellent approach for anti-angiogenic intervention. In this regard, inhibition of

angiogenesis and tumor inhibition has been achieved by using agents that either interrupt VEGF/KI)R interaction and/or block the KDR signal transduction pathway,

FGFR binds the angiogenic growth factors aFGF and bFGF and mediates subsequent intracellular signal transduction. It has been suggested that growth factors such as bFGF may play a critical role in inducing angiogenesis in solid tumors that have reached a certain size; Yoshiji et al., Cancer Research, 57, 3924-3928 (1997). Unlike VEGF-R2 however, FGF-R is expressed in a number of different cell types throughout the body and may or may not play important roles in other normal physiological processes in the adult, Nonetheless, systemic administration of a small molecule inhibitor of the kinase activity of FGF-R has been reported to block bFGF-induced angiogenesis in mice without apparent toxicity; Mohammad et al, EMBO Journal, 17, 5996-5904 (1998).

Focal Adhesion Kinase (FAK) is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes. Focal adhesion kinase (FAK) is a 125 kDa, highly conserved, non-receptor tyrosine kinase originally identified as a substrate for the oncogene protein tyrosine kinase v-src (Guan, 1992 9 /id;Kanner, 1990 8 /id). This cytosolic kinase has been implicated in diverse cellular roles including cell locomotion, mitogen response and cell survival.

Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases. In particular it would be desirable to develop compounds that are useful as inhibitors of Aurora, CDK2, EGFR, C-SRC, FGFR, VEGFR, C-MET, JAK family and FAK particularly given the inadequate treatments currently available for the majority of disorders implicated in their activation.

More than 800 compounds which are inhibitors of various kinases (glycogen synthase kinase 3 [GSK-3], Aurora- A, cyclin-dependent kinase 2 [CDK2], Src and others) have been disclosed in clusters of highly similar patent applications WO2002/022601, WO2002/022602, WO2002/022603, WO2002/022604, WO2002/022605, WO2002022606, WO2002022607, WO2002022608, WO2002/50066, WO2002/0591 12, WO2002/50065 ,WO2002/62789 , WO2002/05911 1, WO2002/057259, WO05118544, WO06091737, WO06010915, WO06136442, WO20070731 17, WO 2004000833,

Acronyms and abbreviations:

The following acronyms, abbreviations, terms and definitions have been used throughout this disclosure, including the experimental section.

THF (tetrahydrofuran), K₂C0₃ (potassium carbonate), Na₂C0₃ (sodium carbonate), Cbz (carbobenzoxy), Fmoc (9-Fluorenylmethyl carbamate), EDC or EDCI (N-ethyl-N'-(3- dimethylaminopropyl)carbodiimide hydrochloride), HOBt (1-hydroxyl benzotriazole), DMAP (Ν,Ν-dimethylaminopyridine), Pd/C (palladium carbon), Pt/C (platinum Carbon), Ni/C (nickel carbon), TFA (trifluoroacetic acid) DMF (N,N-dimethylformamide, i-PrOH or IPA (iso-propanol), NaCl (sodium chloride), NaH (sodium hydride), EtOAc (ethyl acetate), MeOH (methanol), CDI (N, N'-carbonyl-diimidazole), EtOH (ethanol), Pd₂(dba)₃ (tris- dibenzylidene acetone di-palladium (0)), DPPA (diphenyphosphorylazide), DIPEA (N-ethyl- diisopropylamine), Na₂S0₄ (sodium sulfate), DMA (Ν,Ν-dimethylacetamide), DCM

(dichloromethane), TEA (triethylamine), KI (potassium iodide), NH₄C1 (ammonium chloride), CHC1₃ (chloroform), NaOH (sodium hydroxide), NaHC0₃ (sodium bicarbonate), TBAF (tetra-n-Butyl ammonium fluoride), NaBH₄ (sodium borohydride), L1AIH4 (lithium aluminium hydride), Cul (copper (I) iodide), Cs₂C0₃ (cesium carbonate), CH₃CN

(acetonitrile), mCPBA (meta-chloro-perbenzoic acid), NMM (N-methyl-morpholine), Et₃N (triethylamine), Pd(OAc)₂ (palladium acetate), BINAP (2,2'-bis(diphenylphosphino)-l,T- binaphthyl), Xantphos ( 9,9-dimethyl-4,5-bis (diphenylphosphino)xanthene), TLC (Thin layer chromatography), (g, gm, gms (grams), mg (milli grams), mL (milliliters), mp (melting point), rt or RT (room temperature), RM (reaction mixture), RB, rbf(round bottom flask); TFAA (trifluoro acetic anahydride), DMSO-d⁶ (deuterated dimethylsulfoxide), aq (aqueous), min (minute), h or hr (hour), atm (atmosphere), cone, (concentrated), MS or mass spec (mass spectroscopy/spectrometry), NMR (nuclear magnetic resonance). NMR abbreviations: br (broad), apt (apparent), s (singlet), d (doublet), t (triplet), q (quartet), dq (doublet of quartets), dd (doublet of doublets), dt (doublet of triplets), m (multiplet), bs (broad singlet). SUMMARY OF THE INVENTION

It has been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of protein kinases such as including but not limited to kinase inhibitors which belongs to the class of serine /threonine kinases and/ or protein tyrosine kinases (PTK) or dual kinase inhibitors such as kinases selected from the likes of Aurora, CDK2, EGFR, C-SRC, FGFR, VEGFR, C-MET, JAK and FAK.

In one aspect of the present invention, there are provided compounds of

Formula 1

or a salt, solvate, or physiologically functional derivative thereof:

wherein R , A, and R are as described below.

The invention further includes the compounds as described herein, their tautomeric forms, their derivatives, their analogues, their stereo isomers, prodrugs, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them for the treatment of tumors or for the treatment of cancers.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 or a salt, solvate, or a physiologically functional derivative thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

In another aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by at least one of inappropriate Aurora, CDK2, EGFR, C-SRC, FGFR, VEGFR, C-MET , JAK and FAK activity, comprising administering to said mammal a therapeutically effective amount of a compound of formula 1 or a salt, solvate or a physiologically functional derivative thereof. Said method may include preliminary testing to establish the need for such treatment and/or subsequent monitoring to determine the effect of such treatment, optionally by measurement of one or more biomarkers, optionally chemical biomarkers.

In another aspect of the present invention, there is provided a compound of formula 1 , or a salt, solvate, or a physiologically functional derivative thereof for use in therapy.

In a another aspect of the present invention, there is provided the use of a compound of formula 1, or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by at least one of inappropriate Aurora, CDK2, EGFR, C-SRC, FGFR, VEGFR, C-MET , JAK and FAK activity.

In a further aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by at least one such inappropriate activity, comprising administering to said mammal therapeutically effective amounts of (i) a compound of formula 1 , or a salt, solvate or physiologically functional derivative thereof and (ii) an agent to inhibit growth factor receptor function.

In another aspect of the present invention, there is provided a method of treating proliferative disorders

In a yet another aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being characterized by inappropriate angiogenesis, comprising administering to said mammal a therapeutically effective amount of a compound of formula 1 , or a salt, solvate or physiologically functional derivative thereof. An aspect of the present invention is also to provide a method of treating by enhancing immune response towards cancer, e.g. c-src and Jak, through inhibition of Stat3.

The compounds of formula 1 and pharmaceutically acceptable compositions thereof are useful for treating or preventing a variety of diseases, disorders or conditions in which proliferation, angiogenesis or immune response need to be modulated for therapeutic efficacy. These diseases, disorders or conditions include, but are not limited to, proliferative disorders such as cancer, defective wound healing, heart disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, infectious diseases,

immunologically-mediated diseases, neurodegenerative or neurological disorders, or viral diseases. The compositions are also useful in inhibiting cell death and hyperplasia and due to which these compounds may be used to treat or prevent reperfusion/ischemia in stroke, heart attacks, and organ hypoxia.

The compounds provided by this invention are also useful for the evaluation of kinases in various biological processes including their role in intracellular signal transduction pathways. These compounds will also be useful as reference compounds in evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

To describe the present invention, certain terms are defined herein as follows.

The term "compound" is used to denote a molecular moiety of unique, identifiable chemical structure. A molecular moiety ("compound") may exist in a free species form, in which it is not associated with other molecules. A compound may also exist as part of a larger aggregate, in which it is associated with other molecule(s), but nevertheless retains its chemical identity. A solvate, in which the molecular moiety of defined chemical structure ("compound") is associated with a molecule(s) of a solvent, is an example of such an associated form. A hydrate is a solvate in which the associated solvent is water. The recitation of a "compound" refers to the molecular moiety itself (of the recited structure), regardless whether it exists in a free form or and an associated forms. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients such as the said compound, their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, esters, ethers, metablolites, mixtures of isomers, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions in specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient (s), and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention are meant to encompass any composition made by admixing compounds of the present invention and their pharmaceutically acceptable carriers.

The term "pharmaceutically acceptable" as used herein means that the carrier, diluents or excipients are meant to be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Unless otherwise specified, the following terms have the indicated meanings when used in this specification.

"Antiproliferative compound" refers to a compound that inhibits the proliferation of a cell as compared to an untreated control cell of a similar type. The inhibition can be brought about by any mechanism or combination of mechanisms, and may operate to inhibit proliferation cytostatically or cytotoxically. As a specific example, inhibition as used herein includes, but is not limited to, arrest of cell division, a reduction in the rate of cell division, proliferation and/or growth, and/or induction of cell death, by any mechanism of action, including, for example apoptosis.

The terms "treatment," "treating," "treat," and the like are used herein to refer generally to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. "Treatment" as used herein covers any treatment of a disease in a subject, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom, but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e. arresting its development; or (c) relieving the disease symptom, i.e. causing regression of the disease or symptom.

The term "therapeutically effective amount" refers to the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or patient that is being sought.

In describing the compounds, certain nomenclature and terminology is used throughout to refer to various groups and substituents. These terms apply regardless of whether a term is used by itself or in combination with other terms. For example, the definition of "alkyl" applies to "alkyl" as well as to the "alkyl" portions of "alkoxy" etc. The description "C_x-C_y" refers to a chain of carbon atoms or a carbocyclic skeleton containing from x to y atoms, inclusive. The designated range of carbon atoms may refer independently to the number of carbon atoms in the chain or the cyclic skeleton, or to the portion of a larger substituent in which the chain or the skeleton is included. For example, the recitation "Ci-C₈ alkyl" refers to an alkyl group having a carbon chain of 1 to 8 carbon atoms, inclusive of 1 and 8. The chains of carbon atoms of the groups and substituents described and claimed herein may be saturated or unsaturated, straight chain or branched, substituted or

unsubstituted.

As used herein, the term "alkyl," employed alone or in combination with other terms means both branched and straight-chain saturated or unsaturated aliphatic hydrocarbon group having a specified number of carbon atoms. Preferably the alkyl groups of the invention are saturated. Preferably, they have from 1 to 10 carbon atoms, e.g. 1-6 carbon atoms or 1-3 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl. The term "monoalkylamino" is intended to include an amino group substituted one time with the above-defined "alkyl" group. In a non-limiting example, mono Ci-C₈ alkylamino group include methylamino, ethylamino, propylamino, and the like.

The term "dialkylamino" is intended to include an amino group substituted two times with the above-defined "alkyl" groups. In a non- limiting example, di Q-Q alkylamino groups include dimethylamino, diethylamino, methylethylamino, and the like.

The term "cycloalkyl" employed alone or in combination with other terms means a cyclic saturated akyl group having 3 to 15 carbon atoms, e.g. 3-8 carbon atoms, e.g. 3-6, especially 5 or 6 carbon atoms. In a non-limiting example, C₃-C₈ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, substituted adamantyl and the like.

The term "cycloalkylalkyl" is intended to include above defined "cycloalkyl" groups substituted with an above defined "alkyl" group. In a non-limiting example, C₃-C₈ cycloalkyl Ci-C₈ alkyl groups are cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like.

As used herein, the term "alkoxy," is intended to mean a chain of carbon atoms and is defined as 'alkyl-O-', wherein alkyl group is as defined above. The chains of carbon atoms of the alkoxy groups described and claimed herein are saturated or unsaturated (preferably saturated), and may be straight chain or branched. In a non-limiting example, "Ci-C₈ alkoxy" denotes an alkoxy group having carbon chain with from 1 to 8 carbon atoms, inclusive, straight chain or branched, substituted or unsubstituted. Exemplary Ci-C₈ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and the like.

"Aryl" employed alone or in combination with other terms means an aromatic monocyclic or polycyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

As used herein, the term "aryloxy," is intended to mean 'aryl-O-', wherein aryl group is as defined above. Examples of the aryloxy include phenoxy, 1-naphthyloxy, and the like. The term "aralkyl" herein used means the above mentioned "alkyl" substituted with the above mentioned "aryl" at any possible position. Examples of the aralkyl are benzyl, phenethyl (e.g., 2-phenethyl), phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (e.g., 1- naphthylmethyl and 2-naphthylmethyl) and the like.

The term "heteroaryl" employed alone or in combination with other terms means an aromatic monocyclic or polycylic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryl groups include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, benzooxazolyl, benzothiazolyl and the like.

The term "heteroaralkyl" is intended to include the group wherein the above- mentioned "alkyl" group is substituted with the above-mentioned "heteroaryl". Examples of the heteroarylalkyl are thienylmethyl (e.g., 2-thienylmethyl), thienylethyl (e.g., 2-(thiophen- 2-yl)ethyl), furylmethyl (e.g., 2-furylmethyl), furylethyl (e.g., 2-(furan-2-yl)ethyl), pyrrolylmethyl (e.g., 2-pyrrolylmethyl), pyrrolylethyl (e.g., 2-(pyrrol-2-yl)ethyl),

imidazolylmethyl (e.g., 2-imidazolylmethyl, 4-imidazolylmethyl), imidazolylethyl (e.g., 2- (imidazol-2-yl)ethyl), pyrazolylmethyl (e.g., 3-pyrazolylmethyl), pyrazolylethyl (e.g., 2- (pyrazol-3-yl)ethyl), thiazolylmethyl (e.g., 2-thiazolylmethyl), thiazolylethyl (e.g., 2-(thiazol- 2-yl)ethyl), isothiazolylmethyl (e.g., 3 -thiazolylmethyl), isoxazolylmethyl (e.g., 3- isoxazolylmethyl), oxazolylmethyl (e.g., 2-oxazolylmethyl), oxazolylethyl (e.g., 2-(oxazol-2- yl)ethyl), pyridylmethyl (e.g., 2-pyridylmethyl , 3-pyridylmethyl, 4-pyridylmethyl), pyridylethyl (e.g., 2-pyridylethyl) and the like.

The term "heterocyclyl" employed alone or in combination with other terms means an aromatic or non-aromatic monocyclic or polycylic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. The prefix aza, oxa, or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heterocyclyl can be optionally oxidized to the corresponding N-oxide. Non- limiting examples of suitable heterocylic groups include pyrrolidinyl (e.g., 1-pyrrolidinyl, 2- pyrrolidinyl), pyrrolinyl (e.g., 3-pyrrolinyl), imidazolidinyl (e.g., 2-imidazolidinyl), imidazolinyl (e.g., imidazolinyl), pyrazolidinyl (e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g., pyrazolinyl), piperidinyl (e.g., piperidino, 2-piperidinyl), piperazinyl (e.g., 1 -piperazinyl), indolynyl (e.g., 1-indolynyl), isoindolinyl (e.g., isoindolinyl), morpholinyl (e.g., morpholino, 3 -morpholinyl), tetrahydrofuranyl, tetrahydropyranyl, and the like.

The term "heterocyclylalkyl" is intended to include a group wherein the above- mentioned "alkyl" is substituted with the above-mentioned "heterocyclyl". Examples of the heterocyclylalkyl are pyrrolidinylmethyl (e.g., 1-pyrrolidinylmethyl), pyrrolinylethyl (e.g., 3- pyrrolinylethyl), imidazolidinylmethyl (e.g., 2-imidazolidinylmethyl), pyrazolidinylethyl (e.g., 1 -pyrazolidinylethyl), piperidinylethyl (e.g., 2-piperidinylethyl), piperazinylmethyl (e.g., 1 -piperazinylmethyl), indolynylmethyl (e.g., 1 -indolynylmethyl), and the like.

The term "acyl" employed alone or in combination with other terms means alkylcarbonyl in which alkyl group is as defined above, and arylcarbonyl in which aryl group is as defined above. Examples of the acyl are acetyl, propionyl, benzoyl, and the like.

The term "acylamino" employed alone or in combination with other terms means amino group substituted with the above-mentioned "acyl" group. Examples of the acylamino include acetylamino, propionylamino, benzoylamino, and the like.

The term "acyloxy" is intended to include a group acyl-O, wherein acyl group is as defined above. Examples of the acyloxy group include acetyloxy, propionyloxy,

benzoyloxy, and the like.

The term "haloalkyl" is intended to mean an above-defined "alkyl" group is substituted with the above defined "halogen" group at any one or more of the 1 to 8 carbon atoms of the alkyl group. Examples of the haloalkyl group are trifluoromethyl,

trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl, and the like. The term "perhaloalkyl" refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

The term "substituted", as used herein, means that one or more hydrogens on the designated atom are replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.

Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds .that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

The term "inhibitor" is intended to indicate a molecule that exhibits inhibition of the enzymatic activity of the indicated enzyme, such as from 1-100% inhibition. In the present context an "inhibitor" is also intended to comprise active metabolites and prodrugs. In the present context "inhibitors" are also referred to as modulators or "effectors" that decrease or prevent a chemical reaction (e.g they prevent or decrease phosphorylation in the context of kinase inhibitors).

By the term "treatment" is understood the management and care of a patient for the purpose of combating the disease condition or disorder and cancer in the present context.

As used herein the term "halogen", including when represented by "X", means F, CI, Br, or I.

The letters C, N, O, P and S where the context so permits and unless otherwise specified refer to carbon , nitrogen, oxygen, phosphorous and sulphur atoms respectively throughout this document

"Optical isomer", "stereoisomer", "diastereomer" as referred to herein have the standard art recognized meanings (Cf., Hawley's Condensed Chemical Dictionary 11th Ed.).

In accordance with one aspect, the present invention provides kinase inhibitors having Formula 1 HN

R

R Formula 1 wherein,

R² is -OH, -NH₂, -O-alkyl or -O-cycloalkyl, -S-alkyl or -S-cycloalkyl, -CH₂OH, -C¾0alkyl or -CH₂0-cycloalkyl, -NHCO-alkyl or -NHCO-cycloalkyl, -NHCO-aryl, -CONH-alkyl or - CONH-cycloalkyl, -CONH-aryl, or -0-CO-NH₂ ; 'A' is H, C]-C₆ straight or branched alkyl, d-C₆ alkenyl or C_\-C₆ alkynyl, C₅-C₈ cyclic, C₅- C₈ heterocyclic, or halogen;

R¹ is a group represented by the following general formula 2;

Formula 2 wherein:

Q is nitrogen or carbon and Q¹ independently is nitrogen or optionally substituted carbon; with a proviso that not both of Q and Q¹ are nitrogen; either T is R⁴ and the other T is -L-R³ where 'L' is a bond or a linker selected from -CO-, - CO-NH-, -0-(CH₂) 1.2 -, - (CH₂) _1-2 -0-, -S0₂-, -S0₂-NH-, -NH-S0₂-, -N(R⁹)-S0₂-, -CO- N(R⁹)-, -C 1 -C3 alkylene-, -NHCO-, and combinations thereof, where R⁹ is as defined above; R³ is selected from -H, -OH , -NH₂, Ci- C straight or branched alkyl, Ci- Ci₂ straight or branched alkanol, Ci-C₃ alkylamide, C₅- C _& aryl hydroxyl, Ci- C₁₂ straight or branched haloalkyl, phosphonic acid ester, C₃- C₈ substituted or unsubstituted cycloalkyl (including bicycloalkyl), or heterocyclic (including heterobicyclic) with at least one hereoatom, aryl, heteroaryl with at least one heteroatom; each optionally substituted by one or more groups R⁸ or wherein L is a bond and R³ together with R⁴ constitute a saturated or unsaturated, optionally heteroatom containing fused ring, optionally substituted by up to n groups R⁸; where R⁸ is selected from =0, -OH, straight or branched Ci-C₆ alkyl, C]-C₆ alkanol, Ci-C₆ alkoxy, Ci-C₆ alkoxy alkyl, -S0₂-alkyl, halogen , Ci-C₆ haloalkyl, amide, ester, saturated, unsaturated or aromatic carbocyclic or heterocyclic, or -N (R⁵ R⁶), wherein, R⁵ and R⁶ are independently selected from H, C C₆ alkyl , Ci-C₆ alkanol, Ci-C₆ alkanediol, C|-C₆ alkoxy; with the proviso that R⁵ and R⁶ are not both H; or R³ is a group of the formula 3

Formula 3 wherein 'B' is a ring which is an optionally heteroatomic ring wherein R¹⁰ is H, -CX₃ or -C,-C₆ alkyl;

R⁴ is selected from H, C C₆ straight or branched alkyl , CrC₆ straight or branched alkanol, Ci-C₆ alkoxy, C,-C₆ haloalkyl,- CX₃, CN, C₂ alkynyl, halogen; C|-C₆ alkyl amide, - NR⁹- CO-alkyl/ cycloalkyl, -S0₂-alkyl/ cycloalkyl, -NH-(C,_-8)-heterocyclic, -NH-alkyl, cycloalkyl, -NR⁹-S0₂-alkyl/ cycloalkyl, -CH₂)_m-P-(0-alkyl/ cycloalkyl)₂ , -(CH₂)_m- CO(NR⁹-0-alkyl/ cycloalkyl)₂ , -(CH₂)_m-S0₂- alkyl/ cycloalkyl , -(CH₂)_m-CO-NR⁹-0- alkyl/ cycloalkyl , -(CH₂)_m-S0₂-NR⁹-0 alkyl/ cycloalkyl, -(CH₂)_m-CO-N R⁹-CH_nl- (alkyl/ cycloalkyl)_m , -(CH₂)_m- (C]-C₈) heterocyclic or carbocyclic groups optionally containing one or more carbonyl group in the ring and further substituted with up to m R⁸ groups or - (S0₂)-N(R⁹ )₂ , wherein ;

R⁹ is H, or a Ci-C₆ alkyl,

m = 0, 1, 2, 3, or 4

n = 0, 1, or 2

X is halogen

or a salt, solvate, or physiologically functional derivative thereof.

The present disclosure relates to compounds described in formula 1 their

pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, prodrugs thereof or mixtures thereof.

The disclosure also relates to compounds of interest in formula 1 , their polymorphs, and suitable formulations for oral dosage.

In a first subsidiary aspect of the invention are compounds as represented by Formula 1 where R¹ is represented by Formula 2 below;

Formula 2

wherein:

Q is nitrogen or carbon and Q¹ independently is nitrogen or optionally substituted carbon; with a proviso that not both of Q and Q¹ are nitrogen; either T is R⁴ and the other T is -L-R³ where 'L' is a bond and R³ is as defined above or more preferably is an amide of the formula -CO-NH-R', or -NH-CO-R' wherein R' is selected from C,-C₆ alkyl, Ci-C₆ alkanol, C C₆ alkanediol C_rC₆ alkoxy, and N-(R⁵ R⁶) , wherein, R⁵ and R⁶ are independently selected from H, C_!-C alkyl , straight or branched Ci-C₆ alkanol, C_rC₆ alkanediol, Ci-C₆ alkoxy with the proviso that R⁵ and R⁶ are not both H;

R⁴ is as defined above or more preferably is H, Ci-C₆ alkyl , C]-C haloalkyl , C₂ alkynyl, or CX₃ (e.g. CF₃).

Q may preferably be carbon and Q¹ may preferably then be nitrogen or may be optionally substituted carbon. Q may be carbon and Q¹ may be optionally substituted carbon.

Representative compounds of this subsidiary aspect of the invention include but are not limited to those illustrated below in table -I below; TABLE -I

In accordance with a second subsidiary aspect of the invention are compounds of Formula 1 containing as R¹ the moiety Formula 2a represented below;

Formula 2a

Where Q¹ and R⁴ are as defined above or more preferably R⁴ is H, (Ci-C₆) alkyl (e.g. CH₃), CX₃ (e.g. CF₃), CN, or C₂ alkynyl,

'L' is a bond or a linker as defined above, preferably selected from the likes of CO, - CO-NH-, -, -O- (CH₂)_m, -(CH₂)_m-0-, -CH₂)_m- and -S0₂; and

R is a heterocyclic or heteroaryl ring exemplified by the following non limiting representative groups;

R is as defined above, but may preferably be selected from H, straight or branched C,-C₆ alkyl, C C₆ alkanol, d-Q alkoxy, -S0₂-R', halogen , C_rC₆ haloalkyl, C_rC₆ alkyl, Ci-C₆ hydroxy alkyl, CO-NH-R', alkoxy, ester, cycloalkyl or heteroaryl

R' is H or lower alkyl such as methyl; Representative compounds of the second subsidiary aspect of the invention include not limited to those exemplified in table -II below;

TABLE -II

Compounds where L is a bond:-

-30 2-(4-{4-[5-Bromo-4-(5-methoxy-adamantan-2- ylamino)-pyrimidin-2-ylamino]-phenyl } - piperazin- 1 -yl)-ethanol

-3 1 4-(5-Chloro-2-{4-[4-(2-hydroxy-ethyl)- piperazin- 1 -yl] -3 -methyl -phenylamino } - pyrimidin-4-ylamino)-adamantan- 1 -ol

-32 2-(4-{4-[5-Chloro-4-(5-methoxy-adamantan-2- ylamino)-pyrimidin-2-ylamino]-phenyl } - piperazin- 1 -yl)-ethanol

OH

xempary compoun s w eren s - - CH_{2 m};

Exemplary compounds wherein' L' is -CO- ;

Exemplary compounds wherein 'L ' is -CO-NH ;

Exemplary compounds wherein 'L' is (CH₂ )_m are represented below;

S.NO STRUCTURE IUPAC NAME

11-50 4- { 5-Chloro-2- [4-(4-methyl-piperazin- 1 -

ΗΛ NH ylmethyl)-phenylamino]-pyrimidin-4- ylamino } -adamantan- 1 -ol

Exemplary compounds wherein, 'L' is S0₂

Exemplary compounds where R2 = - 0-CO-NH2 (Carbamates)

STRUCTURE IUPAC NAME

11-54 XX' Carbamic acid 4-(5-chloro-2-{4-[4-(2- hydroxy-ethyl)-piperazin- 1 -yl] -3 -methyl- phenylamino } -pyrimidin-4-ylamino)- adamantan-l-yl ester Trifluoro-acetic acid F

A third subsidiary aspect of the present invention provides compounds of formula 1 containing as R¹ the moiety as represented by the formula 2a, but wherein R⁴ is H,

Q¹ is as described for formula 1,

'L' is a bond;

3 8

R is a N- bicyclic bridgehead group optionally substituted by R , and further exemplified by the following representative groups;

wherein;

R is as defined above but is preferably selected from H, Cj-C alkyl, OH, Ci-C₆ alkanol, C|-C₆ alkoxy ;

Representative compounds of the third subsidiary aspect of the invention include but are not limited to those illustrated below in table -III ;

TABLE -III

A fourth subsidiary aspect of the present invention provides compounds of Formula 1 containing the moiety represented by the followin formula 2b;

Formula- 2b wherein ;

R⁴ is as defined above but is preferably H, or halogen;

R⁸ is as defined above but is preferably selected from H, hydroxyl, Ci-C₆ alkyl, OH, Ci-C<5 alkanol, C C₆ alkoxy ; amide;

Q¹ is as described for formula I.

Representative compounds of formula 2b are including but not limited to those illustrated in table -IV below;

TABLE -IV

A fifth subsidiary aspect of the present invention provides compounds of formula 1

comprising the moiety represented by the formula 2c ;

Formula 2c

wherein R³ is H; and Q¹ is as described for Formula 1; and

R⁴ is represented by the following fragments;

C_rC₆ alkyl amide,

wherein,

R⁹isH,Xor ad-C₆alkyl.

Representative compounds of the fifth subsidiary aspect of the invention include but are not limited to those illustrated below in table -V below; TABLE -V

In a sixth subsidiary aspect of the present invention there are provided compounds of formula 1 comprising the moiety of Fo

Formula 2d

wherein

R³ is H;

'L' is a bond or a linker selected from -(CH₂)-_m, -O- , -(CH₂)_m-NH-CO- , -(CH₂)_m- CO-NH-, S0₂ ;

Q¹ is as described for formula 1 ; and

R⁴ is group selected from the groups selected from; Ci-C₆ alkyl; Ci-C₈ cycloalkyl,

R is selected from H, one or more Ci-C₆ straight or branched alkyl; Ci-C₆ straight branched alkanol, Ci-C₆ alkoxy; and

wherein

R⁹ is H, X or a Q-Q alkyl;

Representative compounds of the sixth subsidiary aspect of the invention include but are not limited to those illustrated below in table -VI below;

TABLE -VI

In a seventh subsidiary aspect of the present invention are compounds of formula 1 wherein R of formula 1 is represented by the following group;

Formula 3

wherein;

R is selected from H, CF₃, one or more Q-Q straight or branched alky 1; Ci-C straight or branched alkanol, Ci-C₆ alkoxy;

R¹⁰ is H or C,-C₆ alkyl;

R⁴ is selected from H, C₃-C₆ alkyl, X, CN, -C₂alkynyl;

Ring 'B' is selected from a carbocyclic, heterocyclic, aryl, heteroaryl ring wherein the heterocyclic or heteroaryl rings contain one or more heteroatoms; and is optionally substituted, e.g. with -CF₃;

Q is as described for formula 1 ;

Representative compounds of the seventh subsidiary aspect of the invention include not limited to those illustrated below in VII below; TABLE -VII

According to an eighth subsidiary aspect of the present invention compounds are provided of formula 1 wherein R¹ of formula 1 is re re ented by the following group;

wherein;

R⁸ is selected from H , one or more C[-C₆ straight or branched alkyl; Ci-C straight or branched alkanol, Ci-C₆ alkoxy, cycloalkyl, or heterocycloalkyl;

R¹⁰ is H or Ci-C₆ alkyl;

Ύ' when present is one or more of N, O, or combinations thereof;

each n independently = 0, 1, or 2.

It may be observed that here the groups R³ and R⁴ of Formula 1 form a saturated or unsaturated optionally heteroatom containing fused ring C of from 3 to 6, preferably 5 or 6 atoms. Representative compounds according to the eighth subsidiary aspect of the invention include but are not limited to those illustrated below in table VIII below;

TABLE- VIII

In another embodiment, the compounds of the present invention encompass stereoisomers.

Thus, some of the described compounds have optical centers. If the optical configuration at a given optical center is not defined with specificity, the recitation of chemical structure covers all optical isomers produced by possible configurations at the optical center and should be taken as a disclosure of each isomer as if each were recited separately. The term "optical isomer" defines a compound having a defined optical configuration at least one optical center. This principle applies for each structural genus described herein, as well as for each subgenus and for individual structures.

The compounds of the invention will exist as cis- and trans- isomers with respect to the adamantyl group. In our tests we have found that typically trans- isomers show better activity in terms of IC50 values, but cis- isomers show better activity in terms of EC50 values.

Where applicable the present invention also relates to useful forms of compounds such as disclosed herein, such as freebase forms and pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" and the term 'veterinarily acceptable salts' as used herein include those obtained by reacting the main compound functioning as a base with an inorganic or organic acid to form a salt for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric, and methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, acetic acid, succinic acid, tartaric acid, para-toluene sulfonic acid, citric acid, benzoic acid, salicylic acid, mandelic acid and carbonic acid

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U. S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methylcellulose, hydroxy-propylmethyl cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;

dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or acetyl alcohol.

Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative and flavoring and coloring agent. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc. containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)

In the treatment or prevention of disease or disorder conditions which require inhibition of protein kinase activity an appropriate dosage level will generally be about 0.01 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.

The precise dosage of the agents of the invention to be employed for treating conditions mediated by inhibition of protein kinase depends upon several factors, including the host, the nature and the severity of the condition being treated, the mode of

administration and the particular compound employed. However, in general, conditions mediated by inhibition of protein kinases are effectively treated when an agent of the invention is administered enterally, e.g. orally, or parenterally, e.g. intravenously, preferably orally, at a daily dosage of from about 0.002 mg/kg to about 10 mg/kg, preferably of from about 0.02 mg/kg to about 2.5 mg/kg body weight or, for most larger primates, a daily dosage of from about 0.1 mg to about 250 mg, preferably from about 1 mg to about 100 mg. A typical oral dosage unit is from about 0.01 mg/kg to about 0.75 mg/kg, one to three times a day. Usually, a small dose is administered initially and the dosage is gradually increased until the optimal dosage for the host under treatment is determined. The upper limit of dosage is that imposed by side effects and can be determined by trial for the host being treated.

The agents of the invention may be formulated into enteral and parenteral

pharmaceutical compositions containing an amount of the active substance that is effective for treating or preventing disease or disorder conditions mediated by inhibition of protein kinases, such compositions in unit dosage form and such compositions comprising a pharmaceutically acceptable carrier.

Agents of the invention may be administered in enantiomerically pure forms or as racemic mixtures. The above dosage ranges are based on the compounds of formula 1.

This dosage regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of

administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of Formula 1 or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug (s) may be administered, by a route and in an amount commonly used thereof, contemporaneously or sequentially with a compound of Formula 1. When a compound of Formula 1 is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula 1 is preferred. However, the combination therapy may also include therapies in which the compound of Formula 1 and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula 1.

An embodiment of the present invention provides preparation of the novel compounds of formula 1 according to the procedure of the following schemes, using appropriate materials. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein.

The pharmaceutical compositions of the present invention comprising compounds of Formula 1 or pharmaceutically acceptable salt, solvate or pro-drug thereof, may be manufactured in a manner that is known in the art, e.g. by means of conventional mixing,^' encapsulating, dissolving, granulating, emulsifying, entrapping, dragee-making, or lyophilizing processes. These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, steric acid or its salts can be used as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules include vegetable oils, waxes and fats. Depending on the nature of the active substance, no carriers are generally required in the case of soft gelatin capsules. In such cases, pharmaceutically acceptable carriers are considered to include soft gelatin capsules. Suitable carriers for the manufacture of solutions and syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection are water, alcohols, polyols, glycerine, vegetable oils, phospholipids and surfactants. Suitable carriers for suppositories are natural or hardened oils, waxes, fats and semi-liquid polyols. GENERAL SCHEMES:

The following reaction schemes describe processes for the preparation of compounds of Formula 1 in which R² has the following values.

Series I: R² = - OH

Series II: R² = - 0-CH₃

Series III: R² = - CH₂- OH

Series IV: R² = - CO- NH- R /Ar

Series V: R² = - NH- CO- R

Series VI: R² = - 0-CO-NH₂

All temperatures are in degrees Celsius unless otherwise noted.

SERIES I STEP-1

Synthesis of 4-Aminoadamantan-l-ol:

Step-IA: 5 -Hydroxy adamantan-2-one : Suitable mineral acid such as fuming nitric acid is added to 2-adamantanone and the mixture is optionally heated. Excess acid is then distilled under reduced pressure and the resultant residual mass is treated with water along with mineral acid such as conc.H₂S0₄. The resultant is heated, cooled and neutralized with inorganic bases such as dil. NaOH, KOH, K₂C0₃ and the like. The aqueous layer is extracted with a suitable organic solvent such as DCM, CHC1₃ and the like and the combined organic layer is concentrated under reduced pressure. The residue is then dissolved in a minimum amount of solvent such as DCM, CHC1₃ and the like and the required product is precipitated with solvents selected from hexane, petroleum ether etc. Step-1 B:

Synthesis of 4-Aminoadamantan-l-ol

Method- 1

Ammonium formate is added to 5-hydroxyadamantan-2-one in an organic solvent such methanol and the like. Reducing agent such as 10% Pd-C (2.5g) is then added and the resultant is allowed to react at about 60° for about 15mins to 3hrs. Susequenly the reaction mixture is cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue is dissolved in a minimum amount of water, basified with a base such as NaOH and extracted with an organic solvent such as ethylacetate. The organic layer is concentrated under reduced pressure and the product obtained is washed with a suitable organic solvent such as hexane to yield a mixture of cis/trans isomers of the 4-Aminoadamantan-l-ol.

Method-2:

5-hydro yadamantan-2-one is added to ammonia in methanol and molecular sieves.

After stirring at ambient temperature overnight a suitable reducing agent such as NaBH₄ is added in portions. The resultant reaction mixture is concentrated. This is followed by the addition of a basic solution such as NaOH solution, extraction with a suitable solvent such as ethyl acetate and concentration, to yield the required compounds as a mixture of cis / trans isomers of the 4-Aminoadamantan-l-ol.

STEP-2

Step -2A

'A' is selected from atoms or groups such as H, C_!-C₆ straight or branched alkyl, alkenyl or alkynyl, C₅-C₈ cyclic, heterocyclic,halogen;

Synthesis of Cis and trans pyrimidino-adamantan-l-ol

4-Aminoadamantan-l-ol is added to a solution of a suitable amino pyrimidine such as for example, 5-bromo-2,4-dichloropyrimidine in a solvent such as n-butanol, or ethanol followed by Ν,Ν-diisopropyl ethyl amine, TEA, and the like. The reaction mixture is heated. The solvent is then distilled under reduced pressure. Solvent such as DCM is added to the residual mass, washed with brine. The organic layer is dried and concentrated under reduced pressure to afford crude cis and trans 4-(5-Bromo-2-chloropyrimidin-4-ylamino)adamantan- 1 -ol as the required product.

Procedure for resolution of the Cis and trans 4-(5-bromo-2-chIoropyrimidin-4-ylamino) adamantan-l-ol:

The cis and trans isomers are separated by methods such as preparative HPLC to afford the cis- and trans-isomers of 4-(5-bromo-2-chloropyrimidin-4-ylamino) adamantan-l- ol.

Separation of the cis and trans 4-(5-Bromo-2-chloropyrimidin-4-ylamino) adamantan- l-ol:

The cis and trans isomers are separated by methods such as preparative HPLC or silcagel column chromatography to afford the cis- and trans-isomers of 4-(5-Bromo-2- chloropyrimidin-4-ylamino) adamantan-l-ol in about 95-99% pure form.

STEP-3 : General procedure for the preparation of the final compounds

Purified c/s / Trans / Racemic Mixture

3a 3b 3c (Final compounds)

Step-3A:

Synthesis of the various R¹ -NH₂ groups may be by the various procedures which are described in the specific examples below.

Step-3B: Synthesis of the final adamantanol compounds

Trans isomers:

To a mixture of R¹ -NH₂ and trans isomer of 3b in a solvent such as n-Butanol, NMP and the like is added an acid such as cone. HCl , TFA and the like and the resultant is heated overnight. The reaction mixture is concentrated; the crude product is triturated with a hot solvent such as methanol, ether, ethyl acetate and the like and filtered. The residue is purified by a method such as preparative HPLC, silica gel column chromatography etc. to give the product in about 93-99% purity.

Cis isomers:

The same procedure as above is followed using the cis isomer of 3 b with R¹ -NH₂ to yield a cis product of 93-99% purity.

Series II

STEP: 1

4-Aminoadamantantyl methyl ether:

Step-1 A: 5-Methoxyadamantan-2-one Suitable base such as sodium hydride, potassium carbonate, or potassium hydride is added to solvents such as THF, DMSO or DMF at 0°C and the resultant is stirred for 15min at 0°C. To this is added 5-hydroxyadamantan-2-one, followed by the addition of methyl iodide dropwise over a period of 5-10mins and stirring is continued for further lhr at 0°C. To the resulting reaction mixture is added ice cold water and the mixture is extracted with solvents such as ethylacetate, ether, DCM, chloroform etc. The organic layers are combined, dried and concentrated to afford the 5-methoxyadamantan-2-one as the required product.

Step-IB: 4-Aminoadamantyl methyl ether

Ammonium formate is added to a solution of 5-methoxyadamantan-2-one in solvent such as methanol or ethanol and the resultant is stirred for 15 mins at the ambient temperature. To this residual mass is added a suitable catalyst such as Pd/C and the reaction mixture is heated to about 40-60°C for 2hrs. The resulting reaction mixture is cooled to ambient temperature, filtered through a celite bed and concentrated under reduced pressure to afford 4-aminoadamantyl methyl ether.

Steps 2( 2A) and 3 are the same as for Series I

SERIES III STEP: 1

-Aminoadamantan-l-yl) methanol:

Step- 1 A : 4-Oxoadamantan- 1 -carboxylic acid

5-Hydroxyadamantan-2-one dissolved in formic acid is added drop wise to oleum at about 60°C over a period of 3hrs. After the addition is complete, additional formic acid is added and the reaction is maintained at about 50-60°C for 2hrs. The reaction mass is then poured into crushed ice and extracted with solvent such as DCM, chloroform, ethyl acetate etc. The combined organic layers are extracted with 10% aqueous solution of a base such as NaOH or KOH and the like; the aqueous layer obtained is acidified with cone. HCl and extracted with DCM and concentrated under reduced pressure to afford 4-oxoadamantan-l- cafboxylic acid as the required product. Step-IB: 4-Aminoadamantan-l-carboxylic acid

4-Oxoadamantane-l-carboxylic acid is added to a solution of ammonium formate in solvent such as methanol or ethanol and the reaction mixture is stirred at ambient temperature for 15min. Suitable catalyst such as Pd/C is then added and the reaction mixture is heated to reflux for about lh. The resulting reaction mixture is cooled to ambient temperature, filtered through celite and concentrated to give 4-aminoadamantan-l-carboxylic acid as the pure product (as a mixture of cis/trans isomers).

Step-lC: (4-Aminoadamantan-l-yl) methanol

4-Aminoadamantane-l-carboxylic acid is added to a solution of LiAlH₄ in THF or ether at about 0°C and the resulting reaction mixture is gradually heated to reflux for about 3hrs. The residual reaction mixture was again cooled to about 0°C and quenched by careful addition of about 20% aqueous solution of a base such as NaOH or KOH solution. After stirring at the ambient temperature for about lh, the reaction mixture is filtered and the clear filtrate is concentrated to give the pure product (as a mixture of cis/trans isomers).

Steps 2 (2A) and 3 are the same as for Series I

SERIES IV STEP: 1

Step 1 A is the same as for Series III

Step-B: Synthesis of 4-Oxo-adamantane-l-carboxylic acid cyclopropylamide.

Cyclopropyl amine, HOBt, 4-DMAP and ED AC are added to a stirred solution of 4- oxo-adamantane-l-carboxylic acid dissolved in solvents such as DCM or THF about 0°C and the resultant is stirred at the ambient temperature overnight. The reaction is monitored by TLC. The resulting reaction mixture is diluted with solvents such as DCM, chloroform or THF washed with water, about 10% HC1, saturated NaHC0₃ solution and brine solution. The organic layer is dried over anhydrous sodium sulphate and concentrated affording the crude product which is purified by silica gel column chromatography using solvents such as about 40% ethyl acetate in hexane as eluant to give 4-oxo-adamantane-l-carboxylic acid cyclopropylamide as the required product.

Step-C: Synthesis of 4-Amino-adamantane-l-carboxylic acid cyclopropylamide.

4-oxo-adamantane-l-carboxylic acid cyclopropylamide is added to a solution of ammonium formate in methanol and is stirred at the ambient temperature for about 1 Omin. A suitable catalyst such as Pd/C is added to the residual reaction mass and is heated to about 40-60°C for about 2hrs. The reaction is monitored by TLC. The resulting reaction mixture is cooled to ambient temperature, filtered through celite bed and concentrated to afford 4- amino-adamantane-l-carboxylic acid cyclopropylamide as the required product.

Steps 2 and 3 are the same as for Series I

SERIES V

Step 1A is the same as for Series III

Step-IB: Synthesis of (4-Oxo-adamantan-l-yI)-carbamic acid tert-butyl ester.

DPPA and bases such as N-ethyldiisopropylamine or TEA are added to a solution of 4-oxo-adamantane-l-carboxylic acid in tert-butanol and the resultant is heated to reflux for about 18hrs. The reaction is monitored by TLC. The residual mass is cooled to ambient temperature, followed by the addition of saturated solution of bases such as NaHC0₃ or Na₂C0₃ or ₂C0₃ and the resulting reaction mixture is extracted with suitable solvents such as DCM or ethylacetate and the like. The combined organic layer is concentrated to afford the crude compound which is purified by silica gel column chromatography using an eluant such as about 20% ethylacetate in hexane to afford (4-oxo-adamantan-l-yl)-carbamic acid tert-butyl ester as the required product.

Step-lC: Synthesis of 5-Amino-adamantan-2-one hydrochloride.

HC1 in 1,4-dioxane is added to a solution of (4-oxo-adamantan-l-yl)-carbamic acid tert-butyl ester at about 0°C and the temperature of the residual mixture is gradually raised to ambient temperature. The reaction is monitored by TLC. The resulting reaction mixture is concentrated under reduced pressure, followed by the addition of ether and filtered to afford the title compound. Step-ID: Synthesis of Cyclopropanecarboxylic acid (4-oxo-adamantan-l-yI)-amide.

Cyclopropane carbonyl chloride is added dropwise over a period of 5-10mins to a stirred solution of 5-amino-adamantan-2-one hydrochloride and DIPEA in solvents such as DCM or THF at about 0-5°C. The resulting reaction mixture is stirred at about 0-5°C for 2hrs. The reaction is monitored by TLC. The residual reaction mixture is quenched with ice cold water and the organic layer obtained is washed with dil. HC1, saturated NaHC0₃ and brine solution. The resultant is concentrated and the crude product obtained is purified by silica gel column chromatography using a suitably polar solvent such as ethylacetate in hexane as eluant to afford cyclopropane carboxylic acid (4-oxo-adamantan-l-yl)-amide as the required product.

Step-IE: Synthesis of Cyclopropanecarboxylic acid (4-amino-adamantan-l-yl)-amide.

Cyclopropanecarboxylic acid (4-oxo-adamantan-l-yl)-amide is added to a solution of ammonium formate in solvent such as methanol or ethanol and is stirred at the ambient temperature for about lOmin. A suitable catalyst such as Pd/C is added to the residual reaction mass and is heated to about 40-60°C for 2hrs. The reaction is monitored by TLC. The resulting reaction mixture is cooled to ambient temperature, filtered through celite bed and concentrated to afford cyclopropane carboxylic acid (4-amino-adamantan-l-yl)-amide as the required product.

Steps 2 and 3 are the same as for Series I

SERIES VI

Steps 1 and 2A are the same as for Series I

STEP: 2B

Synthesis of Carbamic acid 4-(2,5-dichloro-pyrimidin-4-ylamino)-adamantan-l-yl ester.

Trichloroacetylisocyanate is added to a solution of 5-substituted 4-(2-chloro- pyrimidin-4-ylamino)-adamantan-l-ol in a suitable solvents such as dichloromethane or THF at -about 0°C and the resultant is stirred for about 20mins to 2h at about 0°C. Then the temperature of the reaction mixture is gradually increased to ambient temperature and stirring is continued for about another 2hrs. The reaction is monitored by TLC. The solvent is removed by distillation and suitable solvents such as ethanol or methanol are added, followed by the addition of a saturated solution of a suitable base such as K₂C0₃ or Na₂C0₃ and the like. The residual reaction mixture is heated to about 40-50°C and maintained for 4-6h. The reaction is again monitored by TLC. Solvent is distilled out. Water is added to the residual mixture, the resultant is filtered, washed with water and dried to afford 5-substituted 4-(2- chloro-pyrimidin-4-ylamino)-adamantan-l-yl ester as the required product.

The procedure for Step 3 is the same as for series I

EXAMPLES:

General Synthetic Procedures:

Room temperature is defined as an ambient temperature range, typically from about 20°C to about 35°C, specifically it can in each instance be 25 °C. An ice bath (crushed ice and water) temperature is defined as a range, typically from about -5°C to about 0 °C.

Temperature at reflux is defined as ±15°C of the boiling point of the primary reaction solvent. Overnight is defined as a time range of from about 8 to about 16 hours and can specifically be 12 hours. Vacuum filtration (water aspirator) is defined as occurring over a range of pressures, typically from about 5 mm Hg to about 15 mm Hg. Dried under vacuum is defined as using a high vacuum pump at a range of pressures, typically from about 0.1 mm Hg to about 5 mm Hg. Neutralization is defined as a typical acid-based neutralization method and measured to a pH range of from about pH 6 to about pH 8, using pH-indicating paper. Brine is defined as a saturated aqueous sodium chloride. Nitrogen atmosphere is defined as positive static pressure of nitrogen gas passed through a Drierite™ column with an oil bubbler system. Concentrated ammonium hydroxide is defined as an approximately 15 M solution. Melting points were measured against a mercury thermometer and are not corrected.

All eluents for column or thin layer chromatography were prepared and reported as volume: volume (v:v) solutions. The solvents, reagents, and the quantities of solvents and/or reagents used for reaction work-up or product isolation can be those that typically would be used by one of ordinary skill in organic chemical synthesis, as would be determined for the specific reaction or product to be isolated. For example: 1) crushed ice quantity typically ranged from about 10 g to about 1000 g depending on reaction scale; 2) silica gel quantity used in column chromatography depended on material quantity, complexity of mixture, and size of chromatography column employed and typically ranged from about 5 g to about 1000 g; 3) extraction solvent volume typically ranged from about 10 mL to about 500 mL, depending upon the reaction size; 4) washes employed in compound isolation ranged from about 10 mL to about 100 mL of solvent or aqueous reagent, depending on scale of reaction; and 5) drying reagents (potassium carbonate, sodium carbonate, sodium sulphate or magnesium sulfate) ranged from about 5 g to about 100 g depending on the amount of solvent to be dried and its water content determined for the specific reaction or product to be isolated.

Spectroscopic and other Instrumental Procedures

NMR. The Ή spectra described herein were obtained using Varian 3 OOmHz system

(Model-Mercury Plus) using a 300 Auto SW PFG probe. Spectrometer field strength and NMR solvent used for a particular sample are indicated in the examples. Typically, Ή NMR chemical shifts are reported as δ values in parts per million (ppm) downfield from

tetramethylsilane (TMS) (δ = 0 ppm) as an internal standard. Solid or liquid samples were dissolved in an appropriate NMR solvent (typically CDCI3 or DMSO-d₆), placed in a NMR sample tube, and data were collected according to the spectrometer instructional manuals. Most samples were analyzed in Variable Temperature mode, typically at about 55 °C, though some data for some samples were collected with the probe at ambient probe temperature. NMR data were processed using the software provided by Varian, VNMR 6.1 C version.

SPECIFIC EXAMPLES

The following examples are provided so that invention might be more fully understood. The manner in which the compounds of this invention can be prepared is illustrated in the following examples, which demonstrate the preparation of typical species of the invention. In these examples, the identities of compounds, intermediates and final, were confirmed by mass spectrometry, nuclear magnetic spectral analyses as necessary. The examples are for the purpose of illustration only and should not be regarded as limiting the invention in any way.

SERIES I

SYNTHESIS OF HYDROXYL ADAMANTYL DERIVATIVES

EXAMPLE -1 : Synthesis of_4-(5-Bromo-2-{4-[4-(2-hydroxy-ethyl)-piperazin-l-yl]- phenylamino } -pyrimidin-4-ylamino)adamantan- 1 -ol

STEP-1

Synthesis of 4-Aminoadamantan-l-ol:

SCHEME-I

Step-IA: 5-Hydroxyadamantan-2-one :

Fuming nitric acid (900 ml) was added to 2-adamantanone (lOOg, 0.66mole) and the mixture heated at 60° for 16h. Excess nitric acid was distilled under reduced pressure at 60° and the residual mass was treated with water (350ml) and conc.H₂S0₄ (120 ml), heated at 95- 100° for 2h, cooled to ambient temperature and neutralized with 10% NaOH. The resultant was partitioned using water and CHC1₃ and the combined organic layer was concentrated under reduced pressure. The residual mass was dissolved in a minimum amount of CHC1₃ and precipitated using hexane. The precipitate was collected to yield 56g (51%) of 5- Hydroxyadamantan-2-one as the required compound.

Ή NMR (DMSO-D₆): δ 1.88-1.95 (m,l 1H), 2.2 (m,lH), 2.4 (m,2H), 4.75 (s,lH).

Step-1 B:

Synthesis of 4-Aminoadamantan-l-ol

Ammonium formate (65g, 1.03mole) was added to 5-hydroxyadamantan-2-one (55g,

0.33 lmole) in MeOH (250 ml).10% Pd-C (2.5g) was then added and the mixture heated to 60° for lh. It was cooled to ambient temperature, filtered through celite and the clear filtrate was concentrated under reduced pressure. The residue was dissolved in a minimum amount of water and basified with NaOH pellets (pH 9). It was extracted with EtOAc and the combined organic layer concentrated under reduced pressure. The solid obtained was washed with hexane to give the pure product (as a mixture of cis/trans isomers).

Yield: 50g (90%) Ή NMR (DMSO-D ): δ 1.2-1.3 (m,2H), 1.5-1.6 (m,6H), 1.7-1.8 (m,2H), 1.9-2.0 (m.2H), 2.7 (s, 0.36H), 2.8 (s, 0.48H), 4.2-4.35 (s, 1H).

LC-MS: 168 (M + 1)

STEP-2

-II

Synthesis of Cis and trans 4-(5-bromo-2-chloropyrimidin-4-yIamino) adamantan-l-ol

4-Aniinoadamantan-l-ol (2.2g, 13.2mmoles) was added to a solution of 5-bromo-2,4- dichloropyrimidine (3g, 13.2mmoles) in n-butanol (30ml) followed by Ν,Ν-diisopropyl ethyl amine (3.4g, 26.5mmoles). The reaction mixture was heated at 80° overnight, n-butanol was removed by distillation under reduced pressure. DCM was added to the residual mass which was then was washed with brine. The organic layer was concentrated under reduced pressure to afford the crude product which was purified by preparative HPLC to afford the cis- and trans-isomers.

Yield of Cw-4-(5-Bromo-2-chloropyrimidin-4-ylamino)adamantan-l-ol was l .Og, 21% 1H NMR (DMSO-D₆) δ 8.1(s,lH), 5.8(d,lH), 4.18(d,lH), 2.3-2.35(br,2H), 2.2(br,lH), 1.75- 1.9(m,7H),1.6-1.7(m,2H), 1.45-1.5(Br,lH)

¹³C NMR (DMSO-d6) δ 28.97, 33.17, 35.14, 44.95, 53.67, 65.29, 103.29, 156.77, 158.23, 158.41 LC-MS: 358 (M + 1) Yield of rara-4-(5-Bromo-2-chloropyrimidin-4-ylamino)adamantan-l-ol (1.7g, 36%) Ή NMR (DMSO-D₆) 6 8.1(s,lH), 5.8(d,lH), 4.2(d,lH), 2.2-2.3(m,2H), 1.9-2.0(m,2H), 1.8- 1.9(m,4H), 1,7-1.8(br, 2H), 1.6-1.65(br,2H),

C NMR (DMSO-D₆) δ 28.88, 30.09, 32.3, 40.3, 44.0, 44.98, 54.28, 65.3, 103.29, 156.69, 158.23, 158.57 LC-MS: 358 (M + 1)

STEP-3

Step-3A: Synthesis of amine intermediate R¹-NH₂ for coupling with pyrido-adamantyl compound in the last step ( 3B) .

Synthesis of 4-amino-N-(2-dimethylamino-ethyl)-benzamide.

SCHEME- III

Step3A-l: Synthesis of N-(2-Dimethylamino-ethyl)-4-nitro-benzamide.

EDCI.HCI (2.29g, 0.01 196mmol), followed by HOBt.H₂0 (161mg, 0.00119mol), DIPEA (3.12ml, 0.0179mol) and N,N-dimethyl-ethane-l,2-diamine (0.65ml, 0.00598mol) were added to a solution of 4-nitro-benzoic acid (lg, 0.00598mmol) in DMF (10ml) at 0°C. The resultant was stirred overnight at RT. The reaction was monitored by the TLC (10% methanol: chloroform).

The reaction mixture was quenched with crushed ice, stirred for lOmins, extracted with ethyl acetate and washed with water. The organic phase was washed with 10 % dil. HCl and extracted. The aqueous layer obtained was basified with 20% NaOH solution, and the resultant was partitioned with ethyl acetate, washed with brine solution, dried over Na₂S0₄ and concentrated with ethyl acetate to afford lg (71.4% yield) of N-(2-dimethylamino-ethyl)- 4-nitro-benzamide. Step3A-2: Synthesis of 4-Amino-N-(2-dimethylamino-ethyl)-benzamide

To a solution of N-(2-dimethylamino-ethyl)-4-nitro-benzamide (lg, 0.4219mmol) in MeOH was added Pd-c and hydrogenated for overnight. The reaction was monitored by the TLC (20% MeOH: CHC1₃). The resultant was filtered through celite, concentrated and the crude product so obtained was purified by preparative HPLC to afford 850mg (97.7% yield) of 4-amino-N-(2-dimethylamino-ethyl)-benzamide.

Step-3B: Synthesis of 4-[5-bromo-4-(5-hydroxy-adamantan-2-ylamino)-pyrimidin-2- yIamino]-N-(2-dimethylamino-ethyl)-benzamide

SCHEME-IV

(Final compound)

Step-3B:

Synthesis of 4-[5-Bromo-4-(5-hydroxy-adamantan-2-ylamino)-pyrimidin-2-yIamino]-N- (2-dimethylamino-ethyl)-benzamide

Procedure:

Cone. HC1 (0.3mL) was added to a mixture of 4-(5-bromo-2-chloro-pyrimidin-4- ylamino)-adamantan-l-ol (60mg, 0.167mmoles) and 4-amino-N-(2-dimethylamino-ethyl)- benzamide (45mg, 0.217mmoles) in n-butanol and the resultant was heated to 1 10°C for 16hrs. The reaction was monitored by the TLC (8:2, chloroform: methanol). The resulting reaction mixture was cooled to 80°C diluted with 5ml of n-butanol and filtered. The residue was washed with ether to afford 42mg (47% yield) of 4-(5-Bromo-2-{4-[4-(2-hydroxy- ethyl)-piperazin-l-yl]-phenylamino}-pyrimidin-4-ylamino)adamantan-l-ol as the required product.

Ή NMR (DMS 0-D₆) 6 9.8 (s, 1H), 9.7-9.6 (m, 1H), 8.7-8.6 (t, 1H), 8.17 (s, 1H), 8.0-7.0 (m, 4H), 6.0 (d, 1H), 3.2 (m, 2H), 2.9 (2s, 6H), 2.3-1.5 (m, 12H)

LCMS: 78.2%; m/z= 529.18 (M+l)

HPLC: 92.7%

Representative compounds for series -I

The following non limiting examples were synthesized in the same manner as described for Example 1.

EXAMPLE TABLE NO: 1

EXAMPLE 2

SERIES II SYNTHESIS OF METHOXY ADAMANTYL COMPOUNDS STEP-1

Synthesis of 4-Aminoadamantantyl methyl ether SCHEME-

Step-1 A: 5-Methoxyadamantan-2-one

Sodium hydride (0.577g, 24mmoles) was added to DMSO (20ml) at 0°C with stirring at 0°C. To this was added 5-hydroxyadamantan-2-one (2g, 12.04mmoles), followed by dropwise addition of methyl iodide (1.88g, 13.24mmoles) over a period of lOmins with continued stirring for a further lhr at 0°C. The resulting reaction mixture was partitioned between water and ethylacetate. The organic layers were combined, dried and concentrated to afford 2.1g (97% yield) of 5-methoxyadamantan-2-one as the required product.

Step-1 B: 4-Aminoadamantyl methyl ether

10% Pd/C (400mg) was added to a stirred solution (15 min) of ammonium formate (3.5g, 55.5mmoles) in 5-methoxyadamantan-2-one (2g, 1 l .Ommoles) in MeOH (30ml) at ambient temperature. The reaction mixture was heated to 60°C for 2hrs. The resulting reaction mixture was cooled to ambient temperature, filtered through a celite bed and concentrated under reduced pressure to afford 78g (89% yield) of 4-aminoadamantyl methyl ether as the required product.

Ή NMR (DMSO-D₆): δ 1.3-1.5 (m, 2H), 1.6-1.75 (m, 6H), 1.9-2.2 (m, 6H), 3.1 (d, 3H), 3.15-3.2 (m, 1H).

Steps 2 and 3 were carried out in a manner similar to those for series I

EXAMPLE TABLE NO: 2

Representative compounds of series II are as illustrated below:

EXAMPLE 3

SERIES III

SYNTHESIS OF ALKYL HYDROXY DERIVATIVES OF ADAMANTLY

COMPOUNDS

STEP-1

Synthesis of (4-Aminoadamantan-l-yl) methanol

SCHEME- VI

Step-IA: 4-Oxoadaniantan-l-carboxylic acid

5-Hydroxyadamantan-2-one (5g, 30mmoles) dissolved in formic acid (13ml) was added drop wise to oleum (400ml) at 60°C over a period of 3hrs. After the addition was complete, additional formic acid (13ml) was added and the reaction was maintained at 60°C for 2hrs. The reaction mass was then poured into crushed ice and extracted with CH₂C1₂. The combined organic layers were extracted with 10% NaOH; the aqueous layer obtained was acidified with cone. HCl and extracted with CH₂C1₂ and concentrated under reduced pressure to afford 3.2g (55% yield) of 4-oxoadamantan-l-carboxylic acid as the required product. Ή NMR (DMSO-D₆): δ 12.4 (s, 1H), 2.4 (br, 2H), 1.8-2.15 (m, 11H). Step-IB: 4-Aminoadamantan-l-carboxylic acid

4-Oxoadamantane-l-carboxylic acid (2.75g, 14.17mmoles) was added to a-solution of ammonium formate (4.46g, 70.87mmoles) in methanol (50ml) and the reaction mixture was stirred at ambient temperature for 15min. 10% Pd-c (0.55g) was then added and the reaction mixture was heated under reflux for lhr. The resulting reaction mixture was cooled to ambient temperature, filtered through celite and the filterate was concentrated to afford 2.7g (98%o) of 4-aminoadamantan-l-carboxylic acid as a mixture of cis/trans isomers.

'H NMR (D₂0): δ 3.5 (m, 1H), 2.1-2.2 (m, 2H), 1.6-2.0 (m, 1 1H).

Step-lC: (4-Aminoadamantan-l-yl) methanol

4-Aminoadamantane-l-carboxylic acid (2.77g, 14.19mmol) was added to a solution of L1AIH4 (1.037g, 28.39mmoles) in THF (25 ml) at 0°C and the resulting reaction mixture was gradually heated to reflux for 3hrs. The residual reaction mixture was again cooled to 0°C and quenched by careful addition of 20% NaOH solution (7ml). After stirring at the ambient temperature for lh, the reaction mixture was filtered and the clear filtrate was concentrated to give 2.3g ( 90%) of (4-Aminoadamantan-l-yl) methanol as a product which is a mixture of cis/trans isomers).

'H NMR (CDCI₃): δ 3.2 (d, 2H), 2.9-3.0 (m, H), 1.2-2.0 (m, 16H)

LC-MS: M+l at 182

Steps 2 and 3 were carried out in a manner similar to those for series I

EXAMPLE TABLE NO: 3

Representative compounds of series III are as illustrated below:

EXAMPLE 4

SERIES IV

SYNTHESIS OF ADAMANTYL -CO-NH-R / AR DERIVATIVES

STEP-1

Synthesis of 4-Aminoadamantane-l-carboxylic acid cyclopropylamide -VII

Step 1-A : Was carried out in the same manner as for as for series III Step-l-B: Synthesis of 4-Oxo-adamantane-l-carboxylic acid cyclopropylamide.

Cyclopropyl amine (0.412g, 7.23mmoles), HOBt (lg, 7.74 mmoles), 4-DMAP (1.5g, 12.2mmoles) and ED AC (2.37g, 12.36mmoles) were added to a stirred solution of 4-oxo- adamantane-l-carboxylic acid (1.2g, 6.18mmole) dissolved in DCM at 0°C and the resultant was stirred at the ambient temperature overnight. The reaction was monitored by the TLC. The resulting reaction mixture was diluted with DCM, washed with water, 10% HC1, sat.NaHC0₃ solution and brine solution. The organic layer was dried over anhyd.sodium sulphate and concentrated affording the crude product which was purified by silica gel column chromatography using 40% ethyl acetate in hexane as eluant to give 1.1 g (77% yield) of 4-oxo-adamantane-l-carboxylic acid cyclopropylamide as the required product.

Ή NMR (DMSO-D₆): δ 7.5 (d, 1H), 2.6 (m, 1H), 2.4 (br s, 2H), 1.8-2.1 (m, 12H), 0.55-0.6 (m, 2.24), 0.4 (m, 2H)

Step-lC: Synthesis of 4-Amino-adamantane-l-carboxylic acid cyclopropylamide.

4-oxo-adamantane-l-carboxylic acid cyclopropylamide (lg, 4.28mmoles) was added to a solution of ammonium formate (1.35g, 21.4mmoles) in methanol and the resultant was stirred at the ambient temperature for lOmin. This was followed by the addition of 10% Pd/C (200mg) and the resultant was heated to 60°C for 2hrs, filtered through celite bed and the filterate was concentrated to afford 800mg (62% yield) of 4-amino-adamantane-l-carboxylic acid cyclopropylamide as the required product. 'H NMR (DMSO-D₆) 6 7.2 (s, 1H), 2.75-2.85 (br s, 1H), 2.5-2.6 (m, 1H), 2.0 (d, 2H), 1.2-1.9 (m, 13H), 0.5-0.6 (m, 2H), 0.35-0.45 (m, 2H)

Steps 2 and 3 were carried out in the same manner as for series-1

Representative compounds of series IV are illustrated below:

EXAMPLE TABLE NO: 4

4.0 (m, 1 H), 3.9-3.7

(m, 2 H), 3.6-3.5 (m, 2 H), 3.2-2.9 (m, 4 H),

• 2.1 (s, 3 H), 2.0-1.9 (m,

5 H), 1.9-1.6 (m, 7 H), 1.5 (d, 1 H), 0.6-0.5 (m, 2 H), 0.5-0.4 (m, 2 H)

The following compounds may be prepared similarly:

EXAMPLE 5

SERIES V

SYNTHESIS OF ADAMANTYL-NH-CO-R TYPE OF DERIVATIVES STEP-1

Synthesis of Cyclopropanecarboxylic acid (4-amino-adamantan-l-yl)-amide

Step-1 E step-1 D Step 1A : Performed in a manner similar to what has been described previously for series HI

Step-IB: Synthesis of (4-Oxo-adamantan-l-yl)-carbamic acid tert-butyl ester.

DPPA (720mg, 2.57mmol) and N-ethyldiisopropylamine (332mg, 2.57mmol) were added to a solution of 4-oxo-adamantane-l-carboxylic acid in tert-butanol (500mg,

2.57mmol) and the resultant was heated to reflux for 18hrs. The reaction was monitored by the TLC (7: 3, hexane: ethylacetate). The residual mass was cooled to ambient temperature, saturated solution of NaHC0₃ was added and the resulting reaction mixture was extracted with DCM. The combined organic layer was concentrated to afford the crude compound which was purified by silica gel column chromatography using 20% ethylacetate in hexane as eluant to afford 393mg (57.6% yield) of (4-oxo-adamantan-l-yl)-carbamic acid tert-butyl ester as the required product.

'H NMR (CDC1₃) δ 4.4 (s, 1H), 2.6 (s, 2H), 2.4-1.9 (m, 11H), 1.4 (s, 9H) Step-lC: Synthesis of 5-Amino-adamantan-2-one hydrochloride.

HCl in 1,4-dioxane (3ml) was added to a solution of (4-oxo-adamantan-l-yl)- carbamic acid tert-butyl ester (350mg) in Dioxane (7ml)at 0°C . The temperature of the residual mixture was gradually raised to ambient temperature. The reaction was monitored by the TLC (5:5, hexane: ethylacetate). The resulting reaction mixture was concentrated under reduced pressure and filtered. The residue was collected to afford 230mg (86% yield) 5- Amino-adamantan-2-one hydrochlocoride as the required product.

Step-ID: Synthesis of Cyclopropanecarboxylic acid (4-oxo-adamantan-l-yl)-amide.

Cyclopropane carbonyl chloride (1 16.5mg, 1.1 1 15mmol) was added dropwise over a period of 5-10mins to a stirred solution of 5-amino-adamantan-2-one hydrochloride (225mg, 1.115mmol) and DIPEA (0.432g, 3.345mmol) in DCM at 0-5°C. The resulting reaction mixture was stirred at 0-5°C for 2hrs. The reaction was monitored by the TLC (20% methanol in chloroform). The residual reaction mixture was quenched with ice cold water and the organic layer obtained was washed with dil. HCl, aq.NaHC0₃ and brine solution. The resultant was concentrated and the crude product obtained was purified by silica gel column chromatography using ethylacetate in hexane as eluant to afford 162mg (62% yield) of cyclopropanecarboxylic acid (4-oxo-adamantan-l-yl)-amide as the required product.

Ή NMR (CDC1₃) δ 5.4 (s, 1H), 2.6 (s, 2H), 2.3-2.0 (m, 12H), 1.2 (m, 2H), 1.0-0.8 (m, 4H)

Step-IE: Synthesis of Cyclopropanecarboxylic acid (4-amino-adamantan-l-yl)-amide.

Cyclopropanecarboxylic acid (4-oxo-adamantan-l-yl)-amide (158mg, 0.678mmol) was added to a solution of ammonium formate (171mg, 2.7mmol) in methanol (4ml) and was stirred at the ambient temperature for lOmin. 5% Pd/c (35mg) was added to the residual reaction mass and was heated to 60°C for 2hrs. The reaction was monitored by the TLC (100% ethylacetate). The resulting reaction mixture was cooled to ambient temperature, filtered through celite bed and the filterare was concentrated to afford 140mg (88.6% yield) of cyclopropanecarboxylic acid (4-amino-adamantan-l-yl)-amide as the required product. 'H NMR (DMSO-D₆) δ 8.4 (m, 1H), 7.6 (d, 2H), 2.1-1.3 (m, 15H), 0.5 (m, 4H) LCMS: 235.1 (M+l)

Steps 2 and 3 are performed in a manner similar to what has been described previously in this document for series I

Representative compounds of series V

EXAMPLE TABLE NO: 5

Compo Structure Yeild, Mass and NMR Values IC50 EC50 und

No.

76 Yield (8mg, 15.3%), MS m/z 0.586

? 551.27 (M+H⁺), 1H NMR (300 μηι

Q MHz, CDC13) δ 7.8 (d, 1 H), 7.6- 7.5 (m, 1 H), 7.3 (m, 1 H), 7.0 (d,

1 H), 5.8 (d, 1 H), 5.4 (d, 1 H),

5.2-5.0 (m, 1 H), 3.4 (t, 4 H), 3.2

(t, 4 H), 2.3 (s, 3 H), 2.3-2.2 (m, 4

H), 2.1-2.0 (m, 6 H), 1.8 (d, 3 H),

1.0-0.8 (m, 2 H), 0.8-0.6 (m, 2 H)

(Checked)

77 Yield (lOmg, 21.7%), MS m/z

? 551.27 (M+H⁺), 1H NMR (300

0 MHz, CDC13) δ 10.1 (s, 1 H), 7.7- 7.5 (m, 2 H), 7.4-7.3 (m, 1 H), 7.0

(d, 1 H), 6.1-6.0 (m, 1 H), 5.4 (s, 1

H), 4.2-4.0 (m, 1 H), 3.4-3.3 (m, 4

H), 3.3-3.2 (m, 4 H), 2.7-2.6 (m, 1

H), 2.3 (s, 3 H), 2.3-2.2 (m, 3 H),

1.9-1.4 (m, 10 H), 0.9-0.8 (m, 2

H), 0.8-0.6 (m, 2 H) (Checked) EXAMPLE 6

SERIES VI

For - Adamantyl -O-CO-NH2 (Carbamates) series

Synthesis of Carbamic acid 4-(2,5-dichloro-pyrimidin-4-ylamino)-adamantan-l-yl ester Steps 1 and 2A are same as for series I

STEP: 2B

SCHEME IX

Synthesis of Carbamic acid 4-(2,5-dichloro-pyrimidin-4-ylamino)-adamantan-l-yl ester.

Trichloroacetylisocyanate (0.091ml, 0.7638mmol) was added to a solution of 4-(2,5- dichloro-pyrimidin-4-ylamino)-adamantan-l-ol (200mg, 0.7638mmol) in DCM (7ml) at 0°C and the resultant was stirred for 30mins at 0°C. Then the temperature of the reaction mixture was gradually increased to ambient temperature and with stirring being continued for a further 2hrs. The reaction was monitored by the TLC (10% methanol in chloroform). The solvent was removed by distillation and the residual mass was diluted with methanol and this was followed by the addition of a saturated solution of K₂C0₃ (10ml). The reaction mixture was heated at 50°C for lhr. Solvent was removed by distillation, The residual mass was diluted, filtered .The residue was washed with water and dried to afford 180mg (79.29% yield) of 4-(2,5-dichloro-pyrimidin-4-ylamino)-adamantan-l-yl ester as the required product. LCMS: 87.94%; m/z= 357 (M+l) Remaining steps were performed in a manner similar to what has been described for series I.

Representative compounds of series VI are as illustrated below:

EXAMPLE TABLE NO: 6

The following examples illustrate the synthesis of various R'-NH₂ groups apart from those represented for steps 3a to 3b for the various series above. The steps to arrive at the amine which is used for synthesizing the final compounds after step 3b have been described in various steps such as 3A-1 , 3A-2, 3A-3 etc.depending on the number of steps performed before arriving at the starting material to be coupled with the pyrido adamantyl derivative in the final step EXAMPLE 7

Step: 3A-1

Synthesis of 4-(4-Nitro-phenyl)-thiomorpholine.

Procedure:

K₂C0₃ (2.15g, 0.0155mol) followed by 1 -Fluoro-4-nitro-benzene (2g, 0.0141mol) was added to a solution of thiomorpholine (1.46g, 0.0141mol) in DMF (10ml) and stirred for 2- 3hrs at 80°C. The reaction was monitored by the TLC (30% EtOAc: hexane). The resultant was cooled to RT and precipitated using ice. The precipitate was collected, dried under reduced pressure to afford 2.3g (72.3% yield) of 4-(4-Nitro-phenyl)-thiomoipholine.

Step: 3A-2

Synthesis of 4-(4-Nitro-phenyl)-thiomorpholine 1,1-dioxide.

Procedure:

mCPBA (924.23mg, 5.35mmol) was added to a stirred solution of 4-(4-Nitro-phenyl)- thiomorpholine (600mg, 2.67mmol)in CHC1₃ at 10-15°C. The reaction was monitored by the TLC (10% MeOH: CHC1₃). CHC1₃ was distilled from the reaction mixture. The residue and washed with saturated NaHC0₃ solution and extracted with EtOAc, washed with, dried over a₂S04 and concentrated. The residual crude product was purified by column chromatography (silica gel of mesh size of 60-120, 5% MeOH in CHC1₃ as eluant) to afford 600mg (87% yield) of 4-(4-Nitro-phenyl)-thiomo holine 1,1 -dioxide.

Step: 3A-3

Synthesis of 4-(l,l-Dioxo- ⁶-thiomorpholin-4-yl)-phenylamine.

Procedure:

10% Pd-C was added to a solution of 4-(4-Nitro-phenyl)-thiomorpholine 1,1 -dioxide (350mg, 1.3671mmol) in MeOH while bubbling of ¾ gas. The reaction was monitored by the TLC ( 10% MeOH: CHC1₃). The resultant was filtered through celite, filterate was evaporated to afford 150mg (49% yield) of 4-(l,l-Dioxo-l ⁶-thiomorpholin-4-yl)- phenylamine.

Compounds 2, 42, 43 etc. were prepared following the aboye procedure.

EXAMPLES 8, 9, 10

SCHEME XI

The following non limiting examples 8, 9 and 10 are representative of the above schemes wherein E is represented by (a), (b), (c), and (d) ,(e) and (f) can be synthesized by the procedures described for any of these examples.

EXAMPLE 8

Step: 3A-l

Synthesis of l-Methyl-4-(2-methyl-4-nitro-phenyl)-piperazine.

Procedure:

K₂C0₃ (1.77g, 0.0128mol), 1-Methyl-piperazine (0.85ml, 0.0077mol) were added to a stirred solution of l-Fluoro-2-methyl-4-nitro-benzene (lg, 0.0064mol) in DMF and stirred at RT overnight. The reaction was monitored by the TLC (20% EtOAc: hexane). The resultant was quenched with crushed ice to get a solid precipitate. The precipitate was collected and dried to afford 660mg (45% yield) of l-Methyl-4-(2-methyl-4-nitro-phenyl)- piperazine.

Step: 3A-2

Synthesis of 3-Methyl-4-(4-methyl-piperazin-l-yl)-phenylamine.

Procedure:

Pd-C (130mg) was added to a stirred solution of l-Methyl-4-(2-methyl-4-nitro- phenyl)-piperazine (650mg, 0.0027mol) in MeOH (10-15ml) in N2 atmosphere. Following this it was hydrogenated for 4-5hrs by maintaining the reation flask in an atmosphere of H2 gas (under pressure). The reaction was monitored by the TLC (10% MeOH: CHC1₃). The resultant was filtered through celite plate and concentrated to afford 520mg (94% yield) of 3- Methylr4-(4-methyl-piperazin- 1 -yl)-phenylamine. EXAMPLE 9

Step: 3A-1

Synthesis of l-(4-Nitro-phen -piperidin-4-ol.

Procedure:

K₂C0₃ (2.44g, 0.0177mol) followed by l-Fluoro-4-nitro-benzene (lg, 0.00708mol) was added to a stirred solution of Piperidin-4-ol (0.86g, 0.00850mol) in DMF (5ml) and stirred at RT. The resulting reaction mixture was heated at 60°C. The reaction was monitored by the TLC (50% EtOAc: hexane). The reaction mixture was cooled to RT, and ice was added into it to precipitate a solid which was collected to afford 1.45g (92% yield) of l-(4- Nitro-phenyl)-piperidin-4-ol.

Step: 3A-2

Synthesis of l-(4-Amino-ph

Procedure:

Pd-C (150mg) was added to a stirred solution of l-(4-Nitro-phenyl)-piperidin-4-ol (1.4g, 0.00630mol) in MeOH (5ml) under nitrogen atmosphere and then hydrogen gas was passed. The reaction was monitored by the TLC (10% MeOH: CHC1₃). The resultant was filtered and concentrated to afford 1.15g (96% yield) of l-(4-Amino-phenyl)-piperidin-4-ol.

EXAMPLE 10

Step: 3A-l

Synthesis of 2-[4-(4-Nitro-phenyI)-piperazin-l-yl]-ethanol.

Procedure:

K₂C0₃ (3.912g, 0.02834mol) followed by 1 -Fluoro-4-nitro-benzene (2g, 0.01417mol) was added to a solution of 2-Piperazin-l-yl-ethanol (5.21ml, 0.0425 lmol) in DMF (10ml) and the reaction flask was maintained at 80°C for 5hrs. The reaction was monitored by the TLC (10% MeOH: CHC1₃). The resultant was quenched with ice to afford 3g (86% yield) of 2-[4-(4-Nitro-phenyl)-piperazin-l-yl]-ethanol as a yellow solid.

Step: 3A-2

Synthesis of 2-[4-(4-Amino-phenyl)-piperazin-l-yl]-ethanol.

Procedure:

Pd-C (0.3g) was added to a solution of 2-[4-(4-Nitro-phenyl)-piperazin-l-yl]-ethanol (3g, 0.01195mol) in MeOH (20ml) and hydrogenated for 2hrs. The reaction was monitored by the TLC (20% MeOH: CHC1₃). The resultant was filtered, washed with MeOH and concentrated to afford 1.8g (69% yield) of 2-[4-(4-Amino-phenyl)-piperazin-l-yl]-ethanol as a pink solid.

The following compounds were prepared by the procedure as described by any of the procedures described for examples 8, 9 and 10 where E and F are represented by the following variants;

Where the product of step 3 A-2 is

EXAMPLE TABLE NO: 7

or

wherein;

SCHEME XII

EXAMPLE 11

Step: 3A-1

Synthesis of l-(4-Nitro-phenyl)-piperidine-4-carboxylic acid.

Procedure:

K₂C0₃ (3.5g, 0.0255mol), 1 -Fluoro-4-nitro-benzene (1.2g, 0.00805mol) were added to a solution of Piperidine-4-carboxylic acid (lg, 0.00805mol) in DMF (10ml) and heated at 80°C for 4hrs. The reaction was monitored by the TLC (10% MeOH: CHC1₃). The reaction mixture was cooled to RT precipitated using ice and filtered. The filtrate obtained was acidified to a pH of 2 to 3 using citric acid to afford a solid precipitate. The precipitate was collected, dried under reduced pressure to afford lg (47% yield) of l-(4-Nitro-phenyl)- piperidine-4-carboxylic acid.

Step: 3A-2

Synthesis of l-(4-Nitro-phenyl)-piperidine-4-carboxylic acid amide.

Procedure:

NMM (262mg, 2.6mmol), l-Chloro-3 -methyl -butane (355mg, 2.6mmol) was added to a stirred solution of l-(4-Nitro-phenyl)-piperidine-4-carboxylic acid (500mg, 2.0mmol) in THF at -70°C and stirred for 2hrs. Ammonia gas was passed for about 10-15mins. The reaction was monitored by the TLC (5% MeOH: CHC1₃). The reaction mixture was concentrated, and the residue was dissolved in water, extracted with EtOAc . The organic layer was washed with brine solution and dried over Na₂S0₄ and concentrated to afford 400mg (80% yield) of 1 -(4-Nitro-phenyl)-piperidine-4-carboxylic acid amide.

Step: 3A-3

Synthesis of l-(4-Amino-phenyl)-piperidine-4-carboxylic acid amide.

Procedure:

10% Pd-C (lOOmg) was added to a solution of l-(4-Nitro-phenyl)-piperidine-4- carboxylic acid amide (400mg, 1.6mmol) in MeOH while H₂ gas was bubbled at RT. The reaction was monitored by the TLC (5% MeOH: CHC1₃). The resultant was filtered through celite, concentrated to afford 340mg (97% yield) of l-(4-Amino-phenyl)-piperidine-4- carboxylic acid amide.

SCHEME: XIII

EXAMPLE 12

Step: 5a

Synthesis of 4-(4-Nitro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester.

Procedure:

K₂C0₃ (2.7g, 0.0194mol) was added to 1 -Fluoro-4-nitro-benzene (2.5g, 0.0177mol) and Piperazine-1 -carboxylic acid tert-butyl ester (3.2g, 0.0177mol) in DMF (10ml) at 80°C. The reaction was monitored by the TLC (30% EtOAc: hexane). The resultant was cooled to RT and precipitated by the addition of ice. The precipitate was collected and dried at reduced pressure to afford 2.6g (48% yield) of 4-(4-Nitro-phenyl)-piperazine-l- carboxylic acid tert- buyl ester. Step: 5b

Synthesis of l-(4-Nitro-phenyl)-piperazine.

Procedure:

TFA (6ml) and was added to a solution of 4-(4-Nitro-phenyl)-piperazine-l -carboxylic acid tert-butyl ester (2g, 0.07166mol) in DCM (20ml) and stirred for lhr at RT. The reaction was monitored by TLC (10% MeOH: CHC1₃). The reaction mixture was concentrated and the residue was washed with water and and dried at reduced pressure to afford a 2.2g (90% yield) of solid l-(4-Nitro-phenyl)-piperazine.

Step: 5c

Synthesis of l-Methanesu!fonyl-4-(4-nitro-phenyl)-piperazine.

Procedure:

Et₃N (244mg, 2.41mmol) was added to a solution of l-(4-Nitro-phenyl)-piperazine

(500mg, 2.41mmol) in DCM at 0-5°C. Methanesulfonyl chloride (276mg, 2.41mmol) was added to the above and the resultant was stirred for about 1 hour. The reaction was monitored by the TLC (5% MeOH: CHC1₃). The reaction flask was concentrated and the residual mixture was extracted with EtOAc, washed with brine solution, dried over Na₂S0₄ and concentrated to afford 550mg (80% yield) of l-Methanesulfonyl-4-(4-nitro-phenyl)- piperazine.

Step: 5d

Synthesis of 4-(4-Methanesulfonyl-piperazin-l-yl)-phenylamine.

Procedure:

10% Pd-C (lOOmg) was added to a solution of l-(4-Nitro-phenyl)-piperidine-4- carboxylic acid amide (350mg, 0.0035mol) in MeOH) and H₂ gas was passed through the reaction flask at RT . The reaction was monitored by the TLC (5% MeOH: CHC1₃). The resultant was filtered through celite and concentrated to afford 270mg (86% yield) of 4-(4- Methanesulfonyl-piperazin- 1 -yl)-phenylamine.

EXAMPLE 13

SCHEME

Step: 3A-l

Synthesis of 4-[2-(2-Fluoro-4-nitro-phenoxy)-ethyl]-morpholine.

Procedure:

NaH (0.6g, 0.025mol) was added to a solution of 2-Morpholin-4-yl-ethanol ( 1.649g,

0.0125mol) in DMF and stirred for 30mins at 0°C. 1 ,2-Difluoro-4-nitro-benzene (2g, 0.0125mol) was then added with continued stirring for a further 2hrs. The reaction was monitored by the TLC (50% ethylacetate: hexane). The reaction mixture was quenched with ice cold water and extracted with ethylacetate. The organic layer was washed with water, concentrated, dried over Na₂S0₄ to afford the crude product which was purified by column chromatography to afford 1.6g (47% yield) of 4-[2-(2-Fluoro-4-nitro-phenoxy)-ethyl]- morpholine. Step: 3A-2

Synthesis of 3-Fluoro-4-(2-morpholin-4-yl-ethoxy)-phenylamine.

Procedure:

To a solution of 4-[2-(2-Fluoro-4-nitro-phenoxy)-ethyl]-morpholine (1.6g,

0.5925mmol) in MeOH was added Pd-C (320mg) in nitrogen atmosphere and stirred for 5hrs in hydrogen atmosphere. The reaction was monitored by the TLC (20% MeOH: CHC1₃). The resultant was filtered through celite bed and concentrated to afford 1.4g (100% yield) of 3- Fluoro-4-(2-mo holin-4-yl-ethoxy)-phenylamine.

EXAMPLE 14

SCHEME: XV

Step: 3A-l

Synthesis of (4-Methyl-piperazin-l-yl)-(4-nitro-phenyl)-methanone.

Procedure:

To a solution of 4-Nitro-benzoic acid (500mg, 2.9918mmol) in THF was added EDCI (856mg, 4.4865mmol), followed by HOBt (200mg, 2.9918mmol), DIPEA (1.5ml,

8.9754mmol) and 1 -Methyl -piperazine (329mg, 3.291mmol) at 0°C. The resultant was stirred overnight. The reaction was monitored by the TLC (10% methanol: chloroform).

The reaction mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated and dried over Na₂S0₄ to afford 440mg (59% yield) of (4- Methy 1-piperazin- 1 -yl)-(4-nitro-phenyl)-methanone. Step: 3A-2

Synthesis of (4- Amino-phenyl)-(4-methy 1-piperazin-l - l)-methanone.

Procedure:

Pd-C (150mg) was added to a solution of (4-Methyl-piperazin-l-yl)-(4-nitro-phenyl)- methanone (440mg, 1.7670mmol) in MeOH and stirred for 2hrs in a hydrogen atmosphere. The reaction was monitored by the TLC (10% MeOH: CHC1₃). The resultant was filtered through celite bed and concentrated to afford 380mg (98% yield) of (4-Amino-phenyl)-(4- methyl-piperazin- 1 -y l)-methanone.

Following the above procedure, the following compounds were prepared; wherein J is represented by the following variants;

EXAMPLE TABLE NO: 8

SCHEME: XVI

(k) (I)

EXAMPLE 15

Step: 3A-1

Synthesis of 2-(4-Nitro-phenyl)-2-aza-bicyclo [2.2.1] heptan-5-ol.

Procedure:

K₂C0₃ (2.8g, 0.0204mol) and l-Fluoro-4-nitro-benzene (0.65ml, 0.0061mol) were added to a solution of 2-Aza-bicyclo[2.2.1]heptan-5-ol (770mg, 0.0068mol) in DMF at 0°C. The reaction mixture was heated at 80°C for lhr and 30mins. The reaction was monitored by the TLC (50% EtOAc: hexane). The reaction mixture was cooled to RT and quenched with crushed ice to get a solid precipitate. The precipitate was collected and dried under reduced pressure to afford 1.2g of the crude of 2-(4-Nitro-phenyl)-2-aza-bicyclo[2.2.1]heptan-5-ol which was taken as such for the next step without purification. Step: 3A-2

Synthesis of 2-(4-Amino-phenyl)-2-aza-bicyclo[2.2.1]heptan-5-ol.

Procedure:

Pd-C (0.3g) was added to a solution of 2-(4-Nitro-phenyl)-2-aza- bicyclo[2.2.1]heptan-5-ol (1.2g, 0.5128mmol) in MeOH and THF and hydrogenated in a parrshaker at 25-30 psi for 2hrs. The reaction was monitored by the TLC (10% MeOH:

CHC1₃). The reaction mixture was filtered through celite and concentrated. The crude product obtained was washed with hexane and ether to afford 1.0g (95%yield) of 2-(4-Amino- phenyl)-2-aza-bicyclo[2.2.1 ]heptan-5-ol.

Following the above procedure, the following compounds were prepared; wherein K is represented by the following variants;

EXAMPLE TABLE NO: 9

EXAMPLE 16

Synthesis of l-(4-Amino-2-fluoro-phenyl)-lH-pyrazole-4-carboxyIic acid amide.

Procedure:

1 -(4-Amino-2-fluoro-phenyl)- 1 H-pyrazole-4-carboxylic acid methyl ester (0.2g,

0.8510mmol) was taken in methanolic ammonia in a steel bomb reactor and heated for 48hrs at 80°C. The reaction mixture was cooled to RT. The reaction was monitored by TLC (50% ether: ethyl acetate). The resultant was concentrated and crystallized using diethyl ether and hexane to afford l-(4-Amino-2-fluoro-phenyl)-lH-pyrazole-4-carboxylic acid amide as a colorless solid.

EXAMPLE 17

Step: 3A-1

Synthesis of Cyclopropanecarboxylic acid (3-nitro-phenyl)-amide.

Procedure:

Et₃N (1.759g, 0.01738mol) and Cyclopropanecarbonyl chloride (1.66g, 0.01593mol) in DCM were added to a stirred solution of 3-Nitro-phenylaniline (2g, 0.01448mol) in DCM (10ml) at 0°C. The resultant was stirred for 2hrs at RT. The reaction was monitored by the TLC (3:7 EtOAc: hexane). The reaction mixture was concentrated and the crude product was partitioned between ethyl acetate and water. The organic phase was washed with brine solution, dried over Na₂S0₄ and concentrated to afford 2.71 g (90.6% yield) of

Cyclopropanecarboxylic acid (3-nitro-phenyl)-amide.

Step: 3A-2

Synthesis of Cyclopropanecarboxylic ac ino-phenyl)-amide.

Procedure:

10% Pd-c (1.2g) was added to a solution of Cyclopropanecarboxylic acid (3-nitro- phenyl)-amide (2.71g, 1.315mmol) in MeOH (15ml) and DCM (12ml) under nitrogen atmosphere and stirred overnight under H₂ pressure. The reaction was monitored by the TLC (1 : 1 EtOAc: hexane). The reaction mixture was diluted with MeOH, filtered through celite bed and the filtrate was concentrated to dryness. The resultant was stirred in hexane for 15mins, filtered and dried under reduced pressure to afford 2.2 lg (95.3% yield) of

Cyclopropanecarboxylic acid (3-amino-phenyl)-amide.

Compounds 29, 30, 41 etc. were prepared following the above procedure.

TABLE- VI

EXAMPLE 18

STEP 3A-1:

Synthesis of l-Methyl-4-(3-nitro-phenyl)-piperazine.

Procedure:

Cs₂0₃ (1 1.285g, 0.0346mol), Pd(OAc)₂ (0.277g, 0.0012mol), BINAP (576mg, 0.9243mmol) were added to dry DMF (60ml) with stirring under N₂ atmosphere and the flask was stirred for 15mins. l-Bromo-3-nitro-benzene (5g, 0.0247mol), 1 -Methyl -piperazine (3.297ml, 0.0296mol) were added to the reaction mixture and the flask was heated at 90°C overnight. The reaction was monitored by the TLC (10% methanol: chloroform). The reaction mixture was heated for a further 4hrs, diluted with ethylacetate, filtered through celite and the filterate was concentrated under reduced pressure. The residue was partitioned between Ethyl acetate and water and the organic phase was washed with water, brine solution and concentrated under reduced pressure to get the crude product, which was purified by column chromatography (using silica gel of mesh size of 60-120, 100% ethylacetate as eluant) to afford 2g (36% yield) of l-Methyl-4-(3-nitro-phenyl)-piperazine.

Step: 3A-2

Synthesis of 3-(4-Methyl-piperazin-l-yl)-phenylamine.

Procedure:

Pd-C was added to a solution of l-methyl-4-(3-nitro-phenyl)-piperazine (2g,

0.904mmol) in MeOH and stirred for 3hrs under H₂ pressure. The reaction was monitored by the TLC (10% MeOH: CHC1₃). The reaction mixture was filtered through celite, washed with methanol and the filterate was concentrated. The crude product obtained was purified by column chromatography (using silica gel of mesh size of 60-120, 2% methanol in chloroform as eluant) to afford l . lg (64.7% yield) of 3-(4-methyl-piperazin-l-yl)-phenylamine.

EXAMPLE 19

SCHEME: XX

Step: 3A-l

Synthesis of 4-(3-Nitro-phenyl)-thiomorpholine.

Procedure:

Pd₂(dba)₃ (0.362g, 0.0003mol), Xantphos (343mg, 0.0005mol), K₂C0₃ (1.91g, 0.0138mol) were added to a flask containing dioxane flushed previously with nitrogen gas for about 20mins. Nitrogen gas was flushed for a further lOmins and this was followed by the addition of l-Bromo-3-nitro-benzene (2g, 0.0098mol), thiomorpholine (1.2g, 0.0118mol) and the flask was refluxed overnight. The reaction was monitored by the TLC (20% EtOAc: hexane). The reaction mixture was then filtered through celite, the filterate was concentrated and the crude product was purified through column chromatography (using silica gel of mesh size of 60- 120, 10% ethylacetate in hexane as eluant) to afford 1.8g (81 % yield) of 4-(3- nitro-phenyl)-thiomorpholine.

Step: 3A-2

Synthesis of 4-(3-Nitro-phenyl)-thiomorpholine 1,1 -dioxide.

Procedure:

mCPBA (3.4g, 0.020mol) was added to a solution of 4-(3-Nitro-phenyl)- thiomorpholine (1.8g, 0.0080mol) in DCM (25ml) maintained at 10-15°C and stirred for 30mins at 10-15°C. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by the TLC (5% methanol: chloroform). The reaction flask was concentrated, washed with saturated NaHC0₃. The residual mixture was extracted with ethylacetate, the extract was washed with brine solution, dried over Na₂S0₄ and concentrated to get the crude product which was purified by column chromatography (using silica gel of mesh size of 60-120, 5% methanol in chloroform as eluant) to afford 1.5g (75% yield) of 4- (3-Nitro-phenyl)-thiomorpholine 1,1 -dioxide. Step: 3A-3

Synthesis of 3-(l,l-Dioxo-lλ⁶-thiomorpho yl)-phen Iamine.

Procedure:

10% Pd-C (200mg) was added to a solution of 4-(3-Nitro-phenyl)-thiomo holine 1,1 -dioxide (1.5g, 0.0058mol) in MeOH in an atmosphere of N₂ gas and the reaction was carried out under ¾ gas pressure. The reaction was monitored by the TLC (10% MeOH: CHC1₃). The reaction mixture was filtered through celite and concented to afford lg (77% yield) of 3-(l,l-Dioxo-l ⁶-thiomorpholin-4-yl)-phenylamine.

Example 20

Synthesis where R'- I^ is 2-[4-(4-aminophenyl)piperazin-l-yl]ethanol

Step 3 B (synthesis of final compounds): Synthesis of //O#is-4-(5-Bromo-2-{4-[4-(2- hydroxy-ethyl)-piperazin-l-yl]-phenylamino}-pyrimidin-4-ylamino)adamantan-l-ol:

Conc.HCl (20mL) was added to a mixture of tra«s-4-(5-bromo-2-chloropyrirnidin-4- ylamino)adamantan-l-ol (50mg, 139 mmoles) and 2-[4-(4-aminophenyl)piperazin-l- yl]ethanol (37mg, 0.167mmoles) in n-butanol (3ml) was and the mixture was heated at 1 10- 120° overnight. The reaction mixture was cooled to 80°, n-butanol (5 ml) was added and filtered. The residue was triturated with hot MeOH, purified by preparative HPLC to afford lOmg of trara-4-(5-Bromo-2-{4-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-phenylamino}- pyrimidin-4-ylamino)adamantan-l-ol inl3% yield.

'H NMR (DMSO-d₆) δ 10.2-10.35 (br s, H), 9.2-9.3 (br s,lH), 8.1-8.2 (s,lH), 7.5 (d,2H), 7.0 (d,2H)„6.2(s,lH), 3.0-4.0 (m,12H), 2.2-2.3 (s,2H), 2.0-2.1 (s,lH), 1.6-1.8 (m,7H), 1.3-1.5 (m,4H) LC-MS: 543 (M + l) Synthesis of c s-4-(5-Bromo-2-{4-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-phenylamino}- pyrimidin-4-ylamino)adamantan-l-ol: (synthesis of final compounds):

Coupling cz,s-4-(5-bromo-2-chloropyrimidin-4-ylamino)adaniantan-l-ol with 2-[4-(4- aminophenyl)piperazin-l-yl]ethanol was carried out in a manner similar to what has been decribed previously for the trans example (above) to afford the corresponding cz^'s-product which was purified by prepartive HPLC to afford the enantiomerically pure c/s-isomer. Ή NMR (DMSO-d₆) δ 9.3-9.6(m,2H), 8.1(s,lH), 7.5-7.6(d,2H), 6.9-7.0(d,2H), 3.9- 4.0(m,lH), 3.7-3.8(t,4H), 3.1-3.3(m,4H), 2.9-3.15(t,2H), 2.25-2.3(br,2H), 2.0-2. l(br,lH), 1.5-1.8(m,9H) LC-MS: 543 (M + 1)

Example: 21

Scheme: XXI

Step: 3A-1

Synthesis of 2-[(2-Hydroxy-ethyl)-(4-nit -phenyl)-amino]-ethanol.

Procedure:

A solution of l-Fluoro-4-nitro-benzene (lg, 0.00708mol) and 2-(2-Hydroxy- ethylamino)-ethanol (0.744g, 0.00708mol) in DMSO and was heated at 140°C for 2hrs. The reaction was monitored by the TLC (1 :9 methanol: chloroform). The resulting reaction mixture was quenched with water and partitioned with ethylacetate. The organic layer was washed with water, concentrated and was dried over Na₂S0₄ to afford 500mg (31.25% yield) of 2-[(2-Hydroxy-ethyl)-(4-nitro-phenyl)-amino]-ethanol. Step: 3A-2

Synthesis of 2- [(4- Amino-phenyl)-(2-hydroxy-ethyl)-amino] -ethanol.

Procedure:

Pd-C (150mg) was added to a solution of 2-[(2-Hydroxy-ethyl)-(4-nitro-phenyl)- amino] -ethanol (500mg, 2.21mmol) in methanol under nitrogen atmosphere and was stirred for 2hrs under hydrogen pressure. The reaction was monitored by the TLC (10% methanol: chloroform). The resulting reaction mixture was filtered through celite bed and was concentrated to afford 400mg (92% yield) of 2-[(4-Amino-phenyl)-(2-hydroxy-ethyl)- amino]-ethanol.

The following representative compound was prepared using the above intermediate;

Example: 22 Scheme: XXII

Step: 3A-1

Synthesis of N-(2-Hydroxy-ethyI)-4-nitr -benzamide.

Procedure:

EDCI.HCI (2.29g, 0.01 196mol), followed by HOBt.H₂0 (161mg, 0.001 19mol), DIPEA (3.12ml, 0.0179mol), 2-Amino-ethanol (0.36ml, 0.00598mol) was added to a solution of 4-Nitro-benzoic acid (lg, 0.00598mol) in DMF (10ml) at 0°C, was added. The reaction mixture was stirred overnight at RT. The reaction was monitored by the TLC (10% methanol: chloroform). The reaction mixture was quenched with crushed ice, and extracted with ethylacetate and the organic layer was washed with 10% HCl, brine solution, dried over Na₂S0₄ and concentrated to get the crude product. The crude product was purified by column chromatography (using silica gel of mesh size of 60-120, 50% EtOAc in hexane as eluant) to afford 600mg (48% yield) of N-(2-Hydroxy-ethyl)-4-nitro-benzamide.

Step: 3A-2

Synthesis of 4-Amino-N-(2-hydroxy-ethyl)-benzamide.

Procedure:

Pd-C (80mg) was added to a solution of N-(2-Hydroxy-ethyl)-4-nitro-benzamide (700mg, 3.333mmol) in MeOH and was hydrogenated overnight. The reaction was monitored by the TLC (20% methanol: chloroform). The resulting reaction mixture was filtered through celite.The filterate was concentrated to afford 600mg (100% yield) of 4- Amino-N-(2-hydroxy-ethyl)-benzamide.

The following representative compound was prepared using the above intermediate;

Example: 23

Scheme: III

Step: 3A-l

Synthesis of {l-[2-(4-Nitro-phenoxy)-ethyl]-piperidin-4-yl}-methanol.

Procedure:

A solution of l-(2-Chloro-ethoxy)-4-nitro-benzene (lg, 0.0049mol) and Piperidin-4- yl-methanol (2.86g, 0.024mol) was taken in DMA(7ml) and was heated to 60°C overnight. The reaction was monitored by the TLC (5% methanol: chloroform). The resulting reaction mixture was cooled to RT, concentrated and extracted with ethylacetate. This was washed with brine, dried over Na₂S0₄ and concentrated to afford 1.2g (86% yield) of { l-[2-(4-Nitro- phenoxy)-ethyl]-piperidin-4-yl}-methanol.

Step: 3A-2

Synthesis of {l-[2-(4-Amino-phenoxy)-ethyl]-piperidin-4-yI}-methanoI.

Procedure:

10% Pd-C (250mg) was added to a solution of { l-[2-(4-Nitro-phenoxy)-ethyl]- piperidin-4-yl} -methanol (lg, 0.0035mol) in MeOH (15ml), which was then maintained in hydrogen atmosphere at RT for completion of the reaction. The reaction was monitored by the TLC (5% methanol: chloroform). The resulting reaction mixture was filtered through celite, and the filterate was concentrated, washed with ether to afford 850mg (95.5% yield) of { 1 -[2-(4-Amino-phenoxy)-ethyl]-piperidin-4-yl}-methanol.

The following representative compound was prepared using the above intermediate;

EXAMPLE: 24

SCHEM - XXIV

Step: 3A-1

Synthesis of 4-[3-(4-Nitro-phenoxy)-propyl]-morpholine.

Procedure:

K₂C0₃ (lg, 0.00718mol), 4-(3-Chloro-propyl)-mo holine (1.6g, 0.00897mol), followed by KI (50mg) was added to a solution of 4-Nitro-phenol (0.5g, 0.00359mol) in dry DMF (6ml) and heated at 90°C. The reaction was monitored by the TLC (30% ethylacetate in hexane). The reaction mixture was quenched with water, partitioned with ethylacetate and concentrated under reduced pressure. The liquid concentrate was washed with hexane to afford 0.3g (31% yield) of 4-[3-(4-Nitro-phenoxy)-propyl]-morpholine as a yellow solid. Step: 3A-2

Synthesis of 4-(3-Morpholin-4-yI-propoxy)-phenylamine.

Procedure:

Pd-C (50mg) was added under N₂ atmosphere to a solution of 4-[3-(4-Nitro- phenoxy)-propyl]-morpholine (0.3g, 0.00112mol) in methanol (5ml) and the reaction was carried out under H₂ pressure. The reaction was monitored by the TLC (5% methanol in chloroform). The reaction mixture was filtered, the filterate was concentrated to afford 0.2g (75% yield) of 4-(3-Moφholin-4-yl-propoxy)-phenylamine. The following representative compound was prepared using the above intermediate;

EXAMPLE 25

SC ME-XXV

Step: 3A-1

Synthesis of l-Methyl-piperidin-4-yIamine

Procedure:

Ammonium formate (2.226g, 0.035348mol) was added to a solution of 1 -Methyl- piperidin-4-one (lg, 0.008837mol) in MeOH and stirred for lOmins. 20% Pd-C was added to this and the reaction mixture was heated at 60°C for 2hrs. The reaction was monitored by the TLC (10% methanol in chloroform). The reaction mixture was filtered through celite bed, concentrated to afford lg (100% yield) of l-Methyl-piperidin-4-ylamine.

Step: 3 A -2

Synthesis of N-(l-Methyl-piperidin-4-yl)- -nitro-benzamide.

Procedure:

EDCI (2.508g, 0.01313mol), HOBt (1.1822g, 0.008757mol), 1 -Methyl-piperidin-4- ylamine (lg, 0.00875mol), DIPEA (4.8ml, 0.026272mol) was added to a solution of 4-Nitro- benzoic acid (1.462g, 0.00875mol) in THF at 0°C and then overnight at RT. The reaction was monitored by the TLC (10% methanol in chloroform). The resulting reaction mixture was concentrated, the residual mixture was partitioned using ethyl acetate and water. The organic layer was concentrated and was dried over Na₂S0₄ to afford 400mg (17.39% yield) of N-(l- Methyl-piperidin-4-yl)-4-nitro-benzamide.

Step: 3A-3

Synthesis of 4-Amino-N-(l-methyl-piperidin-4-yl)-benzamide.

Procedure:

Zn (99.3mg, 1.51923mmol) was added portionwise into a stirred mixture ( 10 mins) of NH₄C1 (81mg, 1.51923mmol), 0.5mL water , N-(l-Methyl-piperidin-4-yl)-4-nitro- benzamide (lOOmg, 0.37980mmol) in THF and stirred overnight at RT. The reaction was monitored by the TLC (20% methanol in chloroform). The resulting reaction mixture was filtered through celite.The filtrate obtained was concentrated and the residue was partitioned between ethylacetate and water. The organic layer was concentrated and was dried over

Na₂S0₄ to afford 50mg (56.49% yield) of 4-Amino-N-(l-methyl-piperidin-4-yl)-benzamide. The following representative compound was prepared using the above intermediate;

EXAMPLE: 26

SCHE -XXVI

Step: 3A-1

Synthesis of l-Methyl-4-(3-nitro-benzyl)-piperazine.

Procedure:

K₂C0₃ (638mg, 4.6286mmol) was added to a solution of 1-Methyl-piperazine

(254mg, 2.5458mmol) in DMF, and stirred for lOmins. This was followed by the addition of l-Bromomethyl-3-nitro-benzene (500mg, 2.3143mmol) and the reaction flask was heated at 80°C for 2hr The reaction was monitored by the TLC (50% EtOAc in hexane). The reaction mixture was taken partitioned between ethylacetate and with water and the organic layer was concentrated, dried over Na₂S0₄ to afford 380mg (69.86% yield) of 1 -Methyl-4-(3-nitro- benzyl)-piperazine.

Step: 3A-2

Synthesis of 3-(4-Methyl-piperazin-l-ylmethyl)-phenylamine.

Procedure:

NH4CI (345mg, 6.468mmol), water (1 ml)was added to a solution of l-Methyl-4-(3- nitro-benzyl)-piperazine (380mg, 1.61702mmol) in THF. This was followed by addition of Zn powder (422mg, 6.468mmol) and the reaction mass was stirred for 2hrs at RT. The reaction was monitored by the TLC (10% CHCI3 in MeOH). The reaction mixture was filtered through celite bed and concentrated. The residue was extracted with ethylacetate, dried over Na₂S0₄ to afford 150mg (45.3% yield) of 3-(4-Methyl-piperazin-l-ylmethyl)- phenylamine. The following representative compound was prepared using the above intermediate;

EXAMPLE: 27

SCHEME- XXVII

be

Step: 3A-1

Synthesis of 4-(4-Nitro-benzenesulfonyl)-morpholine.

Procedure:

TEA (0.7 ml, 4.5122 moles) was added to a solution of Morpholine (216mg, 2.48 lmmol) in DCM, This was followed by the addition of 4-Nitro-benzenesulfonyl chloride (50Omg, 2.256 lmmol) and the flask was stirred for 2hrs at RT. The reaction was monitored by the TLC (5% CHC1₃ in MeOH). The resulting reaction mixture was taken partitioned with DCM and water .The organic layer was concentrated, dried over Na₂S0₄ to afford 500mg (81.3% yield) of 4-(4-Nitro-benzenesulfonyl)-morpholine.

Step: 3A-2

Synthesis of 4-(Morpholine-4-sulfonyl)-phenyIamine.

Procedure:

Pd-C (150mg) was added under nitrogen atmosphere to a solution of 4-(4-Nitro- benzenesulfonyl)-morpholine (400mg, 1.469mmol) in MeOH and the reaction flask was stirred for 4hrs under hydrogen pressure. The reaction was monitored by the TLC (10% CHCI3 in MeOH). The reaction mixture was filtered through celite bed and concentrated to afford 255g (71.8% yield) of 4-(Μο ^Ηη6-4-5υ1ίο^1)-ρη6^ΐ3τηΐηε.

The following representative compound was prepared using the above intermediate;

EXAMPLE 28

SCHEME-XXVIII

Step: 3A-1

Synthesis of 2-Methyl-5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane.

Procedure:

TEA (0.214g, 2.112mmol) was added to a stirred solution of 2-(4-Nitro-phenyl)-2,5- diaza-bicyclo[2.2.1]heptane Hydrochloride (0.45g, 1.76mmol) in EDC (10ml) and stirring was continued for lOmins. This was followed by the addition of formaldehyde (0.265g, 8.8mmol) with stirring being continued for the next 3hrs followed by the addition of Sodium triacetoxy-borohydride (0.56g, 2.64mmol) with continued stirring at RT for the next 2 days. The reaction was monitored by the TLC (1 :9 MeOH: CHCI3) The reaction mixture was basified with NaOH solution and extracted with DCM. The organic layer was washed with water, brine solution, dried over Na₂S04 and concentrated to afford 400mg (97.56% yield) of 2-Methyl-5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1 Jheptane.

Step: 3A-2

Synthesis of 4-(5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yI)-phenylamine.

Procedure:

10% Pd-c (0.2g) was added to a solution of 2-Methyl-5-(4-nitro-phenyl)-2,5-diaza- bicyclo[2.2.1]heptane (0.38g, 1.629mmol) in Methanol (40ml) under nitrogen atmosphere. Hydrogenation was carried out in a Parr hydrogenator at 40 PSI for 2hrs. The reaction was monitored by the TLC (2:8 MeOH: CHCl₃).The reaction mixture was diluted with excess of methanol and was filtered through celite bed. The filtrate was concentrated to afford 320mg (96.96% yield) of 4-(5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-yl)-phenylamine.

The following representative compound was prepared using the above intermediate;

EXAMPLE 29

SCHEME-XXIX

Step: 3A-1

Synthesis of 5-(4-Nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert- butyl ester.

Procedure

K₂C0₃ (1.2g, 8.64mmol) was added to a stirred solution of l-Fluoro-4-nitro-benzene (0.6g, 4.32mmol) and 2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.95g, 4.79mmol) in DMF (10 + 5ml) and the reaction was allowed to be carried out at 80°C for 6hrs. The reaction was monitored by the TLC (5:5 EtOAc: hexane). Crushed ice was added to the reaction flask, the contents were filtered. The residue was collected to afford l.lg (80.88% yield) of 5-(4-Nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester.

N

Step: 3 A -2

Synthesis of 2-(4-Nitro-phenyl)- -diaza-bicyclo[2.2.1]heptane Hydrochloride.

Procedure:

HC1 in Dioxane (3ml) was added to a solution of 5-(4-Nitro-phenyl)-2,5-diaza- bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (l.lg, 0.00344mol) in 1,4-Dioxane at 0-5°C and the reaction flask was allowed to stirr for 2hrs at 0-5°C. The reaction was monitored by the TLC (9: 1 chloroform: methanol). The resulting reaction mixture was concentrated and ether was added to the solid formed. The resultant precipitate obtained was collected to afford 0.8g (91 % yield) of 2-(4-Nitro-phenyl)-2,5-diaza-bicyclo[2.2.1 ]heptane Hydrochloride.

Step: 3A - 3

Synthesis of 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyll-5-(4-nitro-phenyl)-2,5^diaza- bicyclo [2.2.1] heptane.

Procedure:

K₂C0₃ (810mg, 5.86mmol), followed by (2-Bromo-ethoxy)-tert-butyl-dimethyl- silane (560mg, 2.34mmol) was added to a solution of 2-(4-Nitro-pheny)-2,5-diaza- bicyclo[2.2.1]heptane Hydrochloride (500mg, 1.95mmol) in DMF (8ml) and the contents were allowed to stir for 16hrs at RT. The reaction was monitored by the TLC (9: 1 chloroform: methanol). Crushed ice was added to the reaction mixture. This was followed by extraction with ethylacetate. The ethylacetate layer was washed with brine solution, concentrated to afford 738mg, (100% yield) of 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]- 5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane.

Step: 3A - 4

Synthesis of 2-[5-(4-Nitro-phenyl)-2,5-diaza-bicycIo[2.2.1]hept-2-yl]-ethanol.

Procedure:

TBAF (1.5g, 5.8mmol) was added to a mixture of 2-[2-(tert-Butyl-dimethyl- silanyloxy)-ethyl]-5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane (730mg, 1.933mmol) in THF (8ml) at 0-5°C and the temperature and stirred for 1.30hrs at RT. The reaction was monitored by the TLC (1 :9 MeOH: CHC1₃). The reaction mixture was concentrated and partitioned with water and DCM. The DCM layer was dried over anhydrous Na₂S0₄ , concentrated to afford lOOmg (19.64% yield) of 2-[5-(4-Nitro-phenyl)-2,5-diaza- bicyclo[2.2.1]hept-2-yl]-ethanol.

Step: 3A -5

Synthesis of 2- [5-(4- Amino-pheny l)-2,5-diaza-bicyc!o [2.2.1] hept-2-yl] -ethanol.

Procedure:

10% Pd-C (150mg) was added to a solution of 2-[5-(4-Nitro-phenyl)-2,5-diaza- bicyclo[2.2.1]hept-2-yl]-ethanol (95mg, 0.3609mmol) in MeOH and was subjected to hydrogenation in a Parr shaker at 30-35°C for 3hrs. The reaction was monitored by the TLC (2:8 MeOH: CHC1₃). The reaction mixture was filtered through celite bed, concentrated to afford 80mg (90% yield) of 2-[5-(4-Amino-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]- ethanol.

The following representative compound was prepared using the above intermediate;

EXAMPLE: 30

SCHEME-XXX

Step: 3A-1

Synthesis of 8-(4-Nitro-phenyI)-8-aza-bicycIo [3.2.1 ] octan-3-one.

Procedure:

K₂C0₃ (5.133g, 0.0372mmol) was added to a solution of 8-Aza-bicyclo[3.2.1]octan- 3-one (2g, 0.0124mol) and l-Fluoro-4-nitro-benzene (1.76g, 0.0124mmol) in DMF and the reaction flask was heated at 80°C overnight. The reaction was monitored by the TLC (50% EtOAc: hexane). The resulting reaction mixture was quenched with water, extracted with ethylacetate and was washed with water. The organic layer was concentrated , dried over

Na₂S0₄ to get the crude product which was purified by column chromatography (using silica gel of mesh size of 60-120, 50% EtOAc in hexane as eluant) to afford 1.3g (43% yield) of 8- (4-Nitro-phenyl)-8-aza-bicyclo[3.2.1]octan-3-one.

Step: 3A-2

Synthesis of 8-(4-Nitro-phenyl)-8-aza-bicyclo[3.2.1]octan-3-ol.

Procedure:

NaBH₄ was added to a solution of 8-(4-Nitro-phenyl)-8-aza-bicyclo[3.2.1]octan-3- one (1.3g, 0.00527mol) in MeOH at 0°C and the flask was stirred for lhr. The reaction was monitored by the TLC (80% EtOAc: hexane). Crude exo and endo isomers obtained were separated by column chromatography (using silica gel of mesh size of 230-400, 80% EtOAc in hexane as eluant) to afford 740mg (exo) (56% yield) and 300mg (endo) (23% yield) of 8- (4-Nitro-pheny l)-8 -aza-bicyclo [3.2.1] octan-3 -ol . Step: 3A-3

Synthesis of 8-(4-Amino-phenyl)-8-aza-bicyclo[3.2.1]octan-3-ol.

^HC D^N-^<G^^NH*

Procedure:

Pd-C (180mg) was added to a solution of 8-(4-Nitro-phenyl)-8-aza- bicyclo[3.2.1]octan-3-ol (exo) (740mg, 2.980mmol) in MeOH under nitrogen atmosphere and was hydrogenated with stirring for 2hrs. The reaction was monitored by the TLC (10% MeOH: CHC1₃). The resulting reaction mixture was filtered through celite bed and was concentrated to afford 580mg (exo) (89% yield) of 8-(4-Amino-phenyl)-8-aza- bicyclo[3.2.1]octan-3-ol. The endo compound from the previous step 3A-2 above was also reduced by the same procedure to afford the corresponding product.

The following representative compound was prepared using the above intermediate;

EXAMPLE 31

SC -XXXI

Step: 3A - 1

Synthesis of N-(3-Nitro-phenyl)-methanesulfonamide.

Procedure:

Pyridine (0.7ml, 0.0086mol), followed by dropwise addition of Methanesulfonyl chloride (0.56ml, 0:0072mol) was made to a solution of 3-Nitro-phenylamine (lg,

0.0072mol) in DCM at 0°C. The reaction flask was stirred for 2hrs at 0°C. The reaction was monitored by the TLC (50% EtOAc: hexane). The resulting reaction mixture was diluted with DCM, washed with water, dil. HCl, brine solution , dried over Na₂S0₄ and concentrated to afford 900mg (57.69% yield) of N-(3-Nitro-phenyl)-methanesulfonamide. Step: 3A - 2

Synthesis of N-(3-Amino-phenyl)-methanesulfonamide.

Procedure:

Pd-C was added to a solution of N-(3-Nitro-phenyl)-methanesulfonamide (900mg, 6.5217mmol) in MeOH(10 ml) and THF (10 ml) and the reaction mixture was subjected to hydrogenation overnight. The reaction was monitored by the TLC (50% EtOAc: hexane). The resulting reaction mixture was filtered through celite, concentrated to afford 800mg (65.95% yield) of N-(3-Amino-phenyl)-methanesulfonamide.

The following representative compound was prepared using the above intermediate;

EXAMPLE 32

-XXXII

Synthesis of l-MethylsuIfanylmethyl-3-nitro-benzene.

Procedure:

Sodium thiomethoxide (0.456g, 0.00694mol) was added to a stirred solution of 1- Bromomethyl-3-nitro-benzene (lg, 0.00462mol) in MeOH (20ml) at 0°C, and the flask was stirred for 2hrs at RT. The reaction was monitored by the TLC. The reaction mass was concentrated and the residue was dissolved in Na₂S0₃ solution, extracted with ethylacetate. The extract was washed with brine solution, and was concentrated to afford lg of 1- Methylsulfanylmethyl-3-nitro-benzene.

Step: 3 A-2

Synthesis of l-Methanesulfonylmethyl- -nitro-benzene.

Procedure:

Oxone (8.3g, 0.0136mol) was added to a solution of l-Methylsulfanylmethyl-3-nitro- benzene (lg, 0.00545) in DMF (10ml) at 0°C and the reaction flask was stirred at T for 2hrs. The reaction was monitored by the TLC (9: 1 CHC1₃: MeOH). The resulting reaction mixture was quenched with crushed ice and the precipitate was collected, washed with ice cold water and dried to afford 0.8g (68.37% yield) of l-Methanesulfonylmethyl-3 -nitrobenzene.

Step: 3 A- 3

Synthesis of 3-Methanesulfonylmethyl-phenylamine.

Procedure:

Zn (0.486g, 0.00744mol), NH₄C1 (0.398g, 0.00744mol), water (1ml) were added to a stirred solution of 1 -Methanesulfonylmethyl-3-nitro-benzene (0.4g, 0.00186mol) in THF

(5ml), and the reaction flask was heated at 50°C for 2hrs. This was followed by the addition of 4 equivalents of Zn/NH₄C1 and the flask was heated at 60°C for 3hrs The reaction was monitored by the TLC (50% EtOAc: hexane) The resulting reaction mixture was filtered and concentrated, The concentrate was extracted with ethylacetate and water, dried and was concentrated to get the crude product. The crude product so obtained was purified by recrystallization with ether and ethylacetate to afford 0.215g (62.5% yield) of 3- Methanesulfonylmethyl-phenylamine.

The following representative compound was prepared using the above intermediate;

EXAMPLE 33

SCHEM -XXXIII

H

Step: 3A - l

Synthesis of l-(3-Nitro-benzyl)-lH-[l,2,4]triazole.

Procedure:

K₂C0₃ (0.958g, 0.00693mol), followed by lH-[l ,2,4]Triazole (0.3g, 0.00462mol) was added to a solution of l -Bromomethyl-3-nitro-benzene (lg, 0.00462mol) in dry DMF, and the flask was maintained at RT overnight. The reaction was monitored by the TLC (5% MeOH: CHC1₃). The reaction mixture was quenched with water and extracted with ethylacetate. The EtOAc layer was concentrated to afford the crude material which was purified by column chromatography (using silica gel of mesh size of 60-120, chloroform as eluant) to afford 600mg (63.55% yield) of l-(3-Nitro-benzyl)-lH-[l,2,4]triazole.

Step: 3 A-2

Synthesis of 3-[l,2,4]Triazol-l-yImethyI-phenylamine.

Procedure:

Addition of saturated NH₄C1 (2.5g, 0.0468mol) followed by portion wise addition of

Zn powder (1.5g, 0.0234mol) was made to a solution of l-(3-Nitro-benzyl)-lH- [l,2,4]triazolo (0.6g, 0.00293mol) in THF (3ml) and the reaction was stirred at RT for lhr. The reaction was monitored by the TLC (10% MeOH: CHC1₃). The resulting reaction mixture was quenched with water, extracted with ethylacetate and concentrated to afford 400mg (80% yield) of 3-[l,2,4]Triazol-l-ylmethyl-phenylamine.

Compounds 107-109 were also prepared following the above procedure.

pyrimidine-2,4-diamine

EXAMPLE 34

SCHEME- XXXIV

Step: 17a

Synthesis of [l-(3-Nitro-benzyl)-lH-[l,2,3]triazol-4-yl]-methanol.

Procedure:

DIPEA (8.5ml, 0.0491mol), Cul (5.61g, 0.0294mol), prop-2-yn-l-ol (1.25ml,

0.0216mol) were added to a solution of l-Azidomethyl-3-nitro-benzene (3.5g, 0.0196mol) in acetonitrile at 0°C and the flask was stirred for 3hrs at RT. The reaction was monitored by the TLC (10% MeOH: CHC1₃). To the resulting reaction mixture was added cold saturated NH₄CI solution. This was followed by extraction with ethylacetate, washing with brine solution, and drying over Na₂S0₄, concentration to afford 3.2 g ( 69.5% yield) of [l-(3-Nitro- benzyl)- 1 H-[ 1 ,2,3]triazol-4-yl]-methanol.

Step: 17b

Synthesis of [l-(3-Amino-benzyl)-lH-[l,2,3]triazol-4-yl]-methanol.

Procedure:

Zn (3.45g, 0.0528 mol), followed by NH4C1 (2.82 g, 0.0528 mol), water (l-2ml) were added to a solution of [l-(3-Nitro-benzyl)-lH-[l,2,3]triazol-4-yl]-methanol (3.1g, 0.0132 mol) in THF at 0°C and the reaction flask was stirred at 60°C for 4hrs. The reaction was monitored by TLC (10% MeOH: CHCI3). The reaction mixture was filtered through celite and the filtrate was extracted with ethylacetate. The ethylacetate layer was washed with water, brine solution, dried over Na₂S0₄ and concentrated to afford 2.5g (92.5 % yield) of [1- (3-Amino-benzyl)-lH-[l,2,3]triazol-4-yl]-methanol. The following representative compound was prepared using the above intermediate;

SCHEME- XXXV

Step: 18a

Synthesis of l-(3-Nitro-benzyl)-pyrrolidi -2-one.

Procedure:

NaH (0.22g, 0.00924mol) was added to strirred, cooled (ice bath, 0 °C degree) solution of Pyrrolidin-2-one (0.228ml, 0.0030mol) in DMF (10ml). After 10 mins of stirring, this was followed by the addition of l-Bromomethyl-3-nitro-benzene (0.5g, 0.0023 lmol) and the reaction flask was stirred at RT for 1.30hrs. The reaction was monitored by the TLC (10% MeOH: CHC1₃). DMF was distilled from the reaction mixture, ice was added into the residue and the contents were then extracted with ethylacetate. The ethylacetate layer was concentrated and the concentrate was purified by column chromatography (using silica gel of mesh size of 60-120, 50% EtOAc in hexane as eluant) to afford 120mg (24% yield) of l-(3- Nitro-benzyl)-pyrrolidin-2-one.

Step: 18b

Synthesis of l-(3-Amino-benzyl)-pyrroIidin-2-one.

Procedure:

Zn powder (0.142g, 0.001 18mol), NH₄C1 solution (0.1 16g, 0.001 18mol) was added to a solution of l-(3-Nitro-benzyl)-pyrrolidin-2-one (0.12g, 0.000545mol) in THF and the reaction flask was heated to 55°C for 2.30hrs. The reaction was monitored by the TLC (10% MeOH: CHC1₃). The resulting reaction mixture was filtered through celite, concentrated and the concentrate was partitioned between ethylacetate and water. The ethylacetate layer was concentrated to afford 50mg (50% yield) of l-(3-Amino-benzyl)-pyrrolidin-2-one.

The following representative compound was prepared using the above intermediate;

EXAMPLE 36

SCHEME- XXXVI

Step: 19a

Synthesis of 2-(3-Nitro-phenoxy)-pyrimidine.

Procedure:

CsC0₃ (5.6g, 0.0171 mol) was added to solution of 3-Nitro-phenol (l g, 0.007mol) and 2-Chloro-pyrimidine (1.2g, 0.0104 mol) in DMF, and the flask was heated at 100°C overnight. The reaction was monitored by the TLC (10% MeOH: CHC1₃). The resulting reaction mixture was quenched with ice cold water and filtered to afford 500mg (32% yield) of 2-(3 -Nitro-phenoxy)-pyrimidine.

Step: 19b

Synthesis of 3-(Py rimidin-2-yIoxy)-phenylamine.

Procedure:

Pd-C (150mg) was added to a solution of 2-(3-Nitro-phenoxy)-pyrimidine (500mg, 2.3mmol) in MeOH under nitrogen atmosphere and was stirred for 2hrs under H₂ pressure. The reaction was monitored by the TLC (10% MeOH: CHCI3). The resulting reaction mixture was filtered ttirough celite bed, column chromatography (using silica gel of mesh size of 60-120, gradient of ethylacetate in hexane as eluant) to afford 400mg (92.8 % yield) of 3-(Pyrimidin-2-yloxy)-phenylamine.

The following representative compound was prepared using the above intermediate;

EXAMPLE 37

- XXXVII

Step: 20a

Synthesis of 7-(4-Nitro-phenyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- ajpyrazine.

Procedure:

K₂C0₃ (4.4g, 0.053mol), followed by l-Fluoro-4-nitro-benzene (1.5g, 0.0177mol) was added to a solution of 3-Trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyrazine (3.2g, 0.0230mol) in DMF (15ml), and the flask was stirred for 6hrs at 80°C. The reaction was monitored by the TLC (20% ethylacetate in hexane). From the resulting reaction mixture DMF was distilled, the residue was purified by column chromatography (using silica gel of mesh size of 60-120, 20% ethylacetate in hexane as eluant) to afford 1.2g (36.36% yield) of 7-(4-Nitro-phenyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-[l ,2,4]triazolo[4,3- ajpyrazine.

Step: 20b

Synthesis of 4-(3-Trifluoromethyl-5,6-dihydro-8H-[l,2,4]triazolo[4,3-a]pyrazin-7-yI)- phenylamine.

Procedure:

10% Pd-c (lOOmg) was added to a solution of 7-(4-Nitro-phenyl)-3-trifluoromethyl- 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine (270mg, mol) in methanol and

hydrogenation was carried out for lhr. The reaction was monitored by the TLC (10% methanol in chloroform). The reaction mixture was filtered through celite, concentrated, to afford 190mg (77.86% yield) of 4-(3-Trifluoromethyl-5,6-dihydro-8H-[l,2,4]triazolo[4,3- a]pyrazin-7-yl)-phenylamine.

The following representative compound was prepared using the above intermediate;

EXAMPLE 38

SCHEME- XXXVIII

Step: 21a

Synthesis of 5-Nitro-l,3-dihydro-benzoimidazol-2-one.

Procedure:

CDI (6.35 g, 0.039 mol) was added to a solution of 4-Nitro-benzene- 1 ,2-diamine (2g, 0.013mol) in DMF and the flask was stirred for lhr at RT. The reaction was monitored by the TLC (10% methanol in chloroform). The resulting reaction mixture was quenched with crushed ice, stirred for lOmins, filtered and the filterate was dried under reduced pressure to afford 1.7 g ( 73.9 % yield) of 5-Nitro-l ,3-dihydro-benzoimidazol-2-one.

Step: 21b

Synthesis of 5-Amino-l,3-dihydro-benzoimidazol-2-one.

Procedure:

Pd-C(140 mg) was added to a solution of 5-Nitro-l,3-dihydro-benzoimidazol-2-one (1.4g, 0.0078mol) in MeOH and EtOAc, and was hydrogenated for 6hrs. The reaction was monitored by the TLC (10% methanol in chloroform). The resulting reaction mixture was filtered through celite bed and was concentrated to afford lg (86 % yield) of 5-Amino-l,3- dihydro-benzoimidazol-2-one.

The following representative compound was prepared using the above intermediate;

EXAMPLE 39

SCHEME - XXXIX

Step: 22a

Synthesis of (2,4-Dinitro-phenyl)-methyl-amine.

Procedure:

To a solution of l-Chloro-2,4-dinitro-benzene (3g, 0.0148mol) in ethanol (30ml) at 0°C, was added Methylamine (8.22ml) and was stirred at RT for 15hrs. The reaction was monitored by the TLC (20% EtOAc in hexane). The reaction flask was concentrated, hot water was added and the solid precipitate obtained was filtered, washed with hexane to afford 2.7g (93% yield) of (2,4-Dinitro-phenyl)-methyl-amine. Step: 22b

Synthesis of N'-Methyl-^nitro-benzene- -diamine.

Procedure:

TEA (5.64g, 0.0404mol) and Pd-C (0.108g) was added to a solution of 1 -Chloro-2,4- dinitro-benzene (2g, O.OlOlmol) in CH₃CN. The flask was chilled to -15 °C , formic acid (2.07ml, 0.0505mol) was added and was maintained at -15 °C for 5mins. The flask was stirred at RT for 4.5 hrs followed by heating at 80°C for lOmins. The reaction was monitored by the TLC (50% EtOAc in hexane). The resulting reaction mixture was filtered, the residue was washed with MeOH and the filtrate was concentrated, purified by column

chromatography (using silica gel of mesh size of 60-120, 12% EtOAc in hexane as eluant) to afford lg (59% yield) of N¹ -Methyl -4-nitro-benzene-l,2-diamine.

Step: 22c

Synthesis of l-Methyl-5-nitro-l,3-dihydr -benzoimidazol-2-one.

Procedure:

Di-imidazol-l-yl-methanone (2.91g, 0.0179mol) was added to a cooled solution of N¹-Methyl-4-nitro-benzene-l,2-diamine (lg, 0.00598mol) in DMF (7ml) and the flask was stirred at RT for 2hrs. The reaction was monitored by the TLC (50% EtOAc in hexane). The resulting reaction mixture was quenched with ice and filtered to afford lg (66.6% yield) of 1- Methyl 5-nitro- 1 ,3-dihydro-benzoimidazol-2-one. Step: 22d

Synthesis of 5-Amino-l-methyI-l,3-dihydro-benzoimidazol-2-

Procedure:

Pd-C (lOOmg) was added to a solution of l-Methyl-5-nitro-l,3-dihydro- benzoimidazol-2-one (lg, 0.00518mol) in MeOH (20ml) and hydrogenation was carried out in a Parr shaker for 1.30hrs. The reaction was monitored by the TLC (10% MeOH in CHC1₃). The resulting reaction mixture was filtered, concentrated to afford 800mg (94.67% yield) of 5-Amino-l-methyl-l,3-dihydro-benzoimidazol-2-one.

The following representative compound was prepared using the above intermediate;

EXAMPLE 40

SCHEME-

Step: 23a

Synthesis of 5-Nitro-3H-benzooxazol-2-

Procedure:

CDI (3.932g, 0.02425mol) was added to a stirred mixture of 2-Amino-4-nitro- phenol (1.245g, 0.00808mol) dissolved in DMF (12.45ml) and cooled to 0°C and the flask was stirred for lhr at T. The reaction was monitored by the TLC (10% CHC1₃: MeOH). To the resulting reaction mixture was added ice cold water, filtered. The residue was washed with water and dried under reduced pressure to afford 1.11 lg (76.30% yield) of 5-Nitro-3H- benzooxazol-2-one.

Step: 23b

Synthesis of 5-Amino-3H-benzooxazol-2-

Procedure:

Pd-c (1 1 lmg) was added to a stirred solution of 5-Nitro-3H-benzooxazol-2-one (1.1 1 lg, 6.168mmol) was dissolved in Methanol (20ml) and THF (10ml). The contents were hydrogenated with stirring for 6 hrs. The reaction was monitored by the TLC (10% CHC1₃: MeOH). The resulting reaction mixture was filtered through celite, concentrated and washed with hexane. The solid obtained was dried under reduced pressure to afford 930mg (100% yield) of 5-Amino-3H-benzooxazol-2-one.

The following representative compound was prepared using the above intermediate;

Compound FINAL COMPOUND IUPAC NAME IC50 EC50

No. (HCT1 16)

EXAMPLE 41

SCHEME-XLI

CDI, DMF, RT

Step 24c

Step: 24a

Synthesis of (2,4-Dinitro-phenyI)-(2-methoxy-ethyl)-amine.

Procedure:

K₂C0₃ (4.45g, 0.03224mol), followed by 2-Methoxy-ethylamine (1.2ml,

0.01612mol) was added to a chilled solution of l-Fluoro-2,4-dinitro-benzene (3g,

0.01612mol) in DMF. The reaction flask was stirred at RT for 1.30hrs. The reaction was monitored by the TLC (50% EtOAc in hexane). DMF distilled from the reaction flask, and the contents were precipitated using ice cold water and the precipitate was collected and dried by conventional means to afford 3.4g (87.6% yield) of (2,4-Dinitro-phenyl)-(2- methoxy-ethyl)-amine as yellow solid.

Step: 24b

Synthesis of N¹-(2-Methoxy-ethyI)-4-nitr -benzene-l,2-diamine.

Procedure:

TEA (7.85ml, 0.0504mol) and Pd-c (0.183g) were added to a solution of (2,4-Dinitro- phenyl)-(2-methoxy-ethyl)-amine (3.4g, 0.0141mol) in CH₃CN (20ml). At -15°C was added formic acid (2.07ml, 0.0505mol) and was maintained at RT for 2hrs. The reaction was monitored by the TLC (50% EtOAc in hexane). The resulting reaction mixture was filtered, washed the ethylacetate and partitioned between water and ethylacetate. The ethylacetate layer was concentrated and the concentrate was purified by column chromatography (using silica gel of mesh size of 60-120, 27% EtOAc in hexane as eluant) to afford lg (33.67% yield) of N ¹ -(2-Methoxy-ethyl)-4-nitro-benzene- 1 ,2-diamine.

Step: 24c

Synthesis of l-(2-Methoxy-ethyI)-5-nitro- -dihydro-benzoimidazol-2-one.

Procedure:

CDI (1.152g, 0.00708mol) was added to stirred, chilled solution of ( ) of N'-(2- Methoxy-ethyl)-4-nitro-benzene-l,2-diamine (0.5g, 0.00236mol) in DMF and the reaction flask was stirred for 2hrs. The reaction was monitored by the TLC (10% MeOH in CHC1₃). The reaction mixture was quenched with ice, filtered to afford 600mg of 1 -(2-Methoxy- ethyl)-5-nitro-l ,3-dihydro-benzoimidazol-2-one as a crude product which was used without further purification for the next step. Step: 24d

Synthesis of 5-Amino-l-(2-methoxy-eth ihydro-benzoimidazol-2-one.

Procedure:

Pd-C (lOOmg) was added to a solution of l-(2-Methoxy-ethyl)-5-nitro-l,3-dihydro- benzoimidazol-2-one (0.6g, 0.0025mol) in methanol and ethylacetate (20ml) under an atmosphere of nitrogen and the flask was hydrogenated with stirring at RT for the next 2.30hrs.. The reaction was monitored by the TLC (10% MeOH in CHC1₃). The resulting reaction mixture was filtered, concentrated and was washed with ether to afford 300mg (57.6 % yield) of 5-Amino-l-(2-methoxy-ethyl)-l,3-dihydro-benzoimidazol-2-one.

The following representative compound was prepared using the above intermediate;

IN VITRO AND IN VIVO INHIBITION MEASUREMENTS:

Many of the compounds compounds described herein were tested against aurora and kinases selected from Abl(h); CDK2/cyclinA(h); CHKl(h); CHKl(h); CHKl(h); EGFR(h); FGFRl(h); Flt3(h); IGF-lR(h); JA 2(h); JNK2a2(h); JNK2a2(h); KDR(h); Lck(h);

mTOR(h); PDGFRa(h); Plkl(h); Ret(h); Tie2(h) cells for their ability to inhibit proliferation assays.

1. The main cell line at which the XTT assays were done is HCT116 (primary cell line) 2. Once the compounds were found to be potent in the HCTl 16 were evaluated in HT29 and A549.

3. Compounds that were found potent in all the three cell lines were taken for evaluating the selectivity by doing an HTT in primary hepatocytes.

IC 50 studies:

Cell cycle analysis by Flow Cytometry

Procedure:

> MCF7 cells seeded at a density of 1 X 10⁵cells/well in a 6 well plate. Incubated in 37° C0₂ incubators overnight.

. Cells treated with compounds at desired concentrations or DMSO (vehicle) for 48 hours. DMSO concentration not exceeding 0.2%.

> Trypsinized cells after 48hours, wash cells once to remove trypsin.

> Cells resuspended in 600uL of lx Phosphate Buffered Saline (PBS).

> Fixed cells by adding 1.4ml of 100% ice cold ethanol, drop wise to the cells with constant vortexing. Cells left in ethanol for 1 hour or overnight at 4°C.

> Fetal bovine serum (FBS) added to a final concentration of 2%.

Cells spun down at 1300 rpm for 5 minutes. Washed cells once with IX PBS.

> Resuspended in 1ml of IX PBS. treated with RNase (lOOug/ml) for 1 hour at 37°C. > Labeled cells with Propidium iodide (20ug/ml) for at least 15 minutes at room temperature.

> DNA profiles of the compound treated and control cells analyzed by Flow Cytometry and CellQuestPro software. References: 1. Crissman HA, Steinkamp JA. Rapid simultaneous measurement of DNA, protein and cell volume in single cells from large mammalian cell populations. J. Cell Biol., 59:766, 1973.

2. Krishan A. Rapid flow cytofluorometric analysis of cell cycle by propidium iodide staining. J. Cell Biol., 66:188, 1975. Aurora, c-Src and c-Met kinase glo assay protocol:

Screening of compounds for inhibition of Aurora kinase activity Compounds were screened for Aurora A inhibition using Kinase Glo ATP depletion assay. Aurora A enzyme expressed and purified in-house was used for the assay. Test compounds were incubated with enzyme in 40 mM Tris-HCl pH 7.5, 20 mM MgCl₂, 0.1% BSA in a Greiner 384-well white plate. Control reactions had DMSO instead of test compounds. Final DMSO concentration was 2.5%. Total reaction volume was

10/20 μ 1. After 2h incubation at room temperature, ATP, MgCl₂ and the peptide substrate - kemptide were added to all the wells. The final concentrations were as follows: 10 μΜ ATP, 10' μΜ Kemptide (SIGMA K-l 127) and 7.5 mM MgCl₂. The kinase reaction was allowed to run for 30 minutes at room temperature. Kinase Glo® reagent (Promega), equal in volume to that of the reaction mixture, was added to all the wells. Plate was kept on the shaker for 10 min, and the luminescence was measured. All the luminescence measurements were carried out on a Tecan Ultra fluorescence/luminescence reader. VX680 was used as a reference inhibitor for the assay. The compounds were initially screened at 100 nM and 1 μ M. IC₅o values were determined for compounds that inhibited Aurora A more than 50% at 100 nM. For IC5o determination, serial l/3^rd dilutions of compound were made in DMSO containing buffer. IC₅o values were obtained by fitting the dose-response data to sigmoidal equation using GraphPad Prism software.

Screening compounds for inhibition of c-Src/c-Met kinase activity Procedure is similar to that for Aurora kinase assay with the following modifications:

Protein and compound were allowed to incubate for lhr at room temperature.

MgCl₂ and substrates were added to all wells so that their final concentrations were as follows: 2μΜ ATP,

poly (Glu-Ala-Tyr) and 7.5mM MgCl₂. Staurosporine was used as a reference inhibitor for the assay. Comparison of 2-5 and 1-3 adamantyl substitution patterns

Compounds according to the invention and similar compounds having 3 -substituted 1- adamanyl substituent's were compared in their Aurora A IC50 values, with the following results:

Cis

* Comparative It can be seen that the activity of the compounds according to the invention is far superior to that of the comparative compounds.

Applicants reserve the right to proviso out or to restrict from any claim currently presented, or from any claim that may be presented in this or any further application based upon this disclosure, including claims drawn any genus or subgenus disclosed herein, any compound or group of compounds disclosed in any reference, including any reference provided herein. In this specification, unless expressly otherwise indicated, the word Or' is used in the sense of an operator that returns a true value when either or both of the stated conditions is met, as opposed to the operator 'exclusive or' which requires that only one of the conditions is met. The word 'comprising' is used in the sense of 'including' rather than in to mean 'consisting of . All prior teachings acknowledged above are hereby incorporated by reference.

Claims

A compound of formula (I)

wherein. R² is -OH, -NH₂, -O-alkyi or -O-cycloalkyl, -S-alkyl or -S-cycloalkyl, -CH₂OH, -CH₂0- a!kyl or -CH₂0-cyc!o?lkyl, -NKCO-alkyl or -NHCO-cycloalkyl, -NHCO-aryl, -CONH¾lkyl or -CONH-cycloalkyi, -CONH-aryl, or -0-CO-NH₂ ; i

'A' is H, Ci-Q straiglit.or branched alkyi, aikenyl cr lkyriyl, C₅-Cg cyclic, heterocyclic, or halogen;

R¹ is a group represented by the following general formula 2;

O 2012/059932

175

wherein:

Q is nitrogen or carbon and Q¹ independently is nitrogen or optionally substituted carbon; with a proviso that not both of Q and Q¹ are nitrogen;

either T is R⁴ and the other T is -L-R³ where 'L' is a bond or a linker selected from -CO-, - CO-NH-, -0-(CH₂) 1.2 -, - (CH₂) _1-2 -0-, -S0₂-, -S0₂-NH-, -NH-S0₂-, -N(R⁹)-S0₂-, -CO- N(R⁹)-, -C₁ -C3 alkylene-, -NHCO-, and combinations thereof;

R is selected from -H, -OH , -NH₂, C_r C₆ straight or branched alkyl, Ci- Ci₂ straight or branched alkanol, Ci-C₃ alkylamide, C - C ₈ aryl hydroxyl, C_r C₁₂ straight or branched haloalkyl, phosphonic acid ester, C₃- C₈ substituted or unsubstituted cycloalkyl (including bicycloalkyl), or heterocyclic (including heterobicyclic) with at least one hereoatom, aryl, heteroaryl with at least one heteroatom; each optionally substituted by one or more groups R⁸

or wherein L is a bond and R³ together with R⁴ constitute a saturated or unsaturated, optionally heteroatom containing fused ring, optionally substituted by up to n groups R ; or R is a group of the formula 3

Formula 3 wherein 'B' is a ring which is an optionally heteroatomic ring,

R⁴ is selected from H, Ci-C₆ straight or branched alkyl , Ci-C₆ straight or branched alkanol, C₁ -C6 alkoxy, Ci-C₆ haloalkyl,- CX₃, CN, C₂ alkynyl, halogen ; Ci-C₆ alkyl amide, - NR⁹- CO-alkyl/ cycloalkyl, -S0₂-alkyl/ cycloalkyl, -NH-(Ci_-8)-heterocyclic, ? -NH-alkyl, cycloalkyl, -NR⁹-S0₂-alkyl/ cycloalkyl, -CH₂)_m-P-(0-alkyl/ cycloalkyl)₂ , -(CH₂)_m- CO(NR⁹-0-alkyl/ cycloalkyl)₂ , -(CH₂)_m-S0₂- alkyl/ cycloalkyl , -(CH₂)_m-CO-NR⁹-0- alkyl/ cycloalkyl , -(CH₂)_m-S0₂-NR⁹-0 alkyl/ cycloalkyl, -(CH₂)_m-CO-N R⁹-CH_m- (alkyl/ cycloalkyl)_m , -(CH₂)_m- (Ci-C₈) heterocyclic or carbocyclic groups optionally containing one or more carbonyl group in the ring and further substituted with up to m R⁸ groups or - (S0₂)-N(R⁹ )₂ , wherein R is selected from =0, -OH, straight or branched C_\-C alkyl, Ci-C₆ alkanol, Ci-C₆ alkoxy, Ci-C₆ alkoxyalkyl, -S0₂-alkyl, halogen , Ci-C haloalkyl, amide, ester, saturated, unsaturated or aromatic carbocyclic or heterocyclic, or -N (R⁵ R⁶), wherein, R⁵ and R⁶ are independently selected from H, Ci-C₆ alkyl , Ci-C₆ alkanol, Ci-Ce alkanediol, Q-C6 alkoxy; with the proviso that R⁵ and R⁶ are not both H;

R⁹ is H, or a Ci-C₆ alkyl,

R¹⁰ is H, -CX₃ or -C,-C₆ alkyl; m = 0, 1 ,2, 3 or 4

n = 0,1 or 2

X is halogen;

or a salt, solvate, or physiologically functional derivative thereof.

2. A compound as claimed in claim 1, wherein R¹ is represented by formula 2 below;

Formula 2

wherein,

"Q" is nitrogen or carbon and "Q¹ independently is nitrogen or optionally substituted carbon; with a proviso that not both of Q and Q¹ are nitrogen; either T is R⁴ and the other T is -L-R³ where 'L' is a bond and R³ is as defined in claim 1 or more preferably is an amide of the formula- CO -NH-R', or -NH- CO-R' wherein RVis selected from C,-C₆ alkyl, Q-C₆ alkanol, C,-C₆ alkanediol d-C₆ alkoxy, N (R⁵ R⁶) , k wherein, R³ and R⁶ are independently selected from H, C(-C₆ alkyl , straight or branched C i-C₆ alkanol, C I -C₆ alkanediol, C]-C₆ alkoxy with the proviso that R⁵ and R⁶ are net bcfh H; and R⁴ is as defined in claim 1.

3. A compound as claimed in claim 2, wherein R⁴ is H, Ci-C₆ alkyl , Ci-C₆ haloalkyl , acetylene, or CX₃.

4. A compound as claimed in claim 1 or claim 2, wherein Q is carbon and Q¹ is nitrogen.

5. A compound as claimed in claim 1 or claim 2, wherein Q is carbon and Q¹ is optionally substituted carbon.

6. A compound according to claim 1, wherein R¹ is of Formula 2a below; O 2012/059932

178

Formula 2a

where Q¹ and R⁴ are as defined in claim 1,

'L' is a bond or a linker as defined in claim 1, preferably selected from the likes of CO, -CO-NH-, -, -O- (CH₂)_m, -(CH₂)_m-0-, -CH₂)_m- and -S0₂; and

R³ is a heterocyclic or heteroaryl ring and R is as defined in claim 1.

7. A compound as claimed in claim 6, wherein R⁸ is selected from H, straight or branched C\-C₆ alkyl, Ci-C₆ alkanol, C C₆ alkoxy, -S0₂-R', halogen , C)-C₆ haloalkyl, d- C₆ alkyl, Ci-C₆ hydroxy alkyl, CO-NH-R', alkoxy, ester, cycloalkyl or heteroaryl, wherein R" is H or lower alkyl.

8. A compound as claimed in claim 6 or claim 7, wherein R³ is one of the following groups:

9. A compound as claimed in any one of claims 6 to 8, wherein R⁴ is H, (Ci-C₆) alkyl (e.g. CH₃), CX₃ (e.g. CF₃), CN, or C₂ alkynyl.

10. A compound as claimed in claim 1, wherein R¹ is as represented by Formula 2a of claim 6, but wherein

R⁴ is H,

Q¹ is as defined in claim 1,

'L' is a bond; and

R is a N- bicyclic bridgehead group optionally substituted by R .

11. A compound as c f the following groups

wherein;

R⁸ is as defined in claim 1.

12. A compound as claimed in claim 11, wherein R⁸ is H, C C₆ alkyl, OH, Ci-C₆ alkanol, or C]-C alkoxy.

13. A compound as claimed in claim 1, wherein R¹ is represented by the following Formula 2b;

Formula- 2b

wherein ;

R⁴ is as defined in claim 1 , but is preferably H, or halogen;

R⁸ is as defined in claim 1, but is preferably selected from H, hydroxyl, Ci-C₆ alkyl, OH, Ci-C₆ alkanol, Q-C6 alkoxy ; amide;

Q¹ is as defined in Claim 1.

A compound as claimed in claim 1 , wherein R is represented by the Formula 2c

Formula 2c

wherein R³ is H; Q¹ are as defined for Formula 1; and

R is represented by any one of the following fragments:

Ci-C₆ alkyl amide,

wherein,

R⁹ is H, X or C_rC₆ alkyl.

15. A compound as claimed in clai is of Formula 2d below:

Formula 2d wherein;

R³ is H;

' L' is a bond or a linker selected from -(CH₂)-_m, -O- , -(CH₂)_m -NH-CO- , -(CH₂)_n

CO-NH-, SO 2 ;

Q¹ is as defined in claim 1; and

R⁴ is rou selected from Ci-C₆ alk l Q-Q c cloalk l,

wherein;

R⁸ is selected from H, one or more Ci-C₆ straight or branched alkyl; Ci-C₆ straight or branched alkanol, Ci-C₆ alkoxy;

and

R⁹ is H, X or C,-C₆ alkyl.

16. A compounds as claimed in claim 1 , wherein R^l of formula 1 is represented by a group of the Formula 2e

wherein;

R is selected from H , one or more Ci-C₆ straight or branched alkyl; Ci-C₆ straight or branched alkanol, C]-C₆ alkoxy, cycloalkyl, or heterocycloalkyl;

R¹⁰ is H or C,-C₆ alkyl

'Υ' when present is one or more of N, O, or combinations thereof;

each n independently = 0, 1 or 2;

'C is a saturated or unsaturated optionally heteroatom containing fused ring of from 3 to 6 atoms.

17. A compound as claimed in claim 16, wherein 'C is a saturated or unsaturated optionally heteroatom containing fused ring of 5 or 6 atoms.

18. A compound as claimed in claim 1, wherein R³ of formula 1 is a group of the Formula 3 below:

Formula 3

wherein;

R is selected from H, CF₃, one or more Cj-C₆ straight or branched alky 1; Ci-C₆ straight or branched alkanol, and C]-C alkoxy;

R⁴ is selected from H, C₃-C₆ alkyl, X, CN, and -C₂alkynyl;

ring 'B' is selected from a carbocyclic, heterocyclic, aryl, or heteroaryl ring wherein the heterocyclic or heteroaryl rings contain one or more heteroatoms; and is optionally substituted with one or more groups R¹⁰ where R¹⁰ is as defined in claim 1.

19. A compound as claimed in any preceding claim for use as a medicament.

A compound as claimed in any one of claims 1 to 18 for use in treating a proliferative rder, an angiogenesis disorder or an immune response disorder.