WO2015128698A1

WO2015128698A1 - Substituted heterocyclic amine derivatives as multikinase inhibitors for the treatment of cancer

Info

Publication number: WO2015128698A1
Application number: PCT/IB2014/059325
Authority: WO
Inventors: Abhijit Roychowdhury; Rajiv Sharma; Pradip Keshavrao GADEKAR; Ganesh Devidas URUNKAR; Balapadmasree SEELABOYINA; Nabajyoti Deka; Mahesh Balasaheb DAWANGE; Chandrika B-RAO; Smriti KHANNA
Original assignee: Piramal Enterprises Limited
Priority date: 2014-02-28
Filing date: 2014-02-28
Publication date: 2015-09-03

Abstract

The present invention relates to compounds of formula (I), their isotopic forms, stereoisomeric forms, tautomeric forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, polymorphs or N-oxides thereof. The present invention also relates to processes for the preparation of compounds of formula (I) and pharmaceutical compositions comprising the compounds of formula (I). The compounds and their pharmaceutical compositions are multikinase inhibitors and are useful in the treatment of proliferative disorders, such as cancers.

Description

SUBSTITUTED HETEROCYCLIC AMINE DERIVATIVES AS MULTIKINASE

INHIBITORS FOR THE TREATMENT OF CANCER

Technical Field of the Invention

The present invention relates to heterocyclic compounds of formula (I), processes for their preparation, pharmaceutical compositions containing them, their use as multikinase inhibitors and methods of using these compounds in the treatment or prevention of diseases or disorders associated with abnormal protein kinase activity such as proliferative diseases.

Background of the Invention

Cancer can be defined as an abnormal growth of tissues characterized by a loss of cellular differentiation. Cancer is caused due to deregulation of the signalling pathways involved in cell survival, cell proliferation and cell death. Current treatments for cancer include surgery, radiation therapy, chemotherapy, bone marrow transplantation, stem cell transplantation, hormonal therapy, immunotherapy, antiangiogenic therapy, targeted therapy and gene therapy.

Protein kinases are a family of enzymes that play crucial roles in all major cellular processes, such as signal transduction, cell differentiation, cell proliferation and cell cycle progression (Biol. Cell., 2005, 97, 113-118). The best-characterized protein kinases phosphorylate proteins on the hydroxyl moiety of serine, threonine and/or tyrosine residues. The phosphorylation of proteins represents a major post-translational signaling mechanism and regulatory pathway that controls a diverse set of cellular processes (Cell Mol. Life Sci. 2009, 66, 63-77). Based upon the nature of the phosphorylated-hydroxyl group, these enzymes are classified as protein-serine/threonine kinases and protein-tyrosine kinases (Biochemical and Biophysical Research Communications 2005, 331, 1-14). Protein Tyrosine Kinases (PTKs) primarily act as growth factor receptors. Growth factor receptors associated with PTK activity are known as Receptor Tyrosine Kinases (RTKs). The receptor tyrosine kinases (RTK) are cell- surface receptors with an extracellular domain that selectively binds to and is activated by various growth factors, such as epidermal growth factor (EGF), insulin-like growth factor (IGF), or vascular endothelial growth factor (VEGF). Upon binding of these growth factor ligands, the RTK dimerizes and activates the intracellular protein kinase domain, resulting in the further activation of signal transduction pathways (Cell Mol. Life Sci. 2009, 66, 63-77). The Platelet- derived growth factor (PDGF) subfamily of tyrosine kinase receptors includes PDGF-alpha and PDGF-beta receptors. The Fetal liver kinase (FLK) subfamily comprises of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms- like tyrosine kinase-1 (Flt-1).

The insulin-like growth factor I receptor (IGF-IR) pathway plays a major role in cancer growth, tumour cell survival and resistance to therapy (Current Drug Targets 2009, 10(10), 1- 13). The insulin-like growth factor (IGF) system is composed of the circulating ligands, insulinlike growth factor-I (IGF-I), IGF-II, and insulin; multiple receptors; and binding proteins. The type I IGF receptor (IGF-IR) is a RTK closely related to the insulin receptor (IR). In normal physiology, ligand activation of IGF-IR plays a role in fetal growth and linear growth of the skeleton and other organs, whereas insulin acts via IR to regulate glucose homeostasis (Mol. Cancer Ther. 2007, 6, 1-12). IGF-IR is composed of two covalently linked polypeptide chains, each with an extracellular a-subunit and a transmembrane β-subunit, which possesses tyrosine kinase activity. IGFs are implicated in several different cancers including breast cancer, prostate cancer, colon cancer, liver cancer, pancreatic cancer, melanoma, multiple myeloma, mesothelioma and glioblastoma (Embo J. 1986, 5(10), 2503-2512; Mol. Cancer Ther. 2007, 6, 1- 12).

The human epidermal growth factor receptor (HER) family members belongs to the ErbB (gene symbol derived from the name of a viral oncogene, Erythroblastic Leukemia Viral Oncogene) family of RTKs and include epidermal growth factor receptor (EGFR; erbB l), i IhR. /;,·<··» (erbB2), HERS (erbBS), and HER4 (erbB4) that are structurally related, and all except HERS contain intracellular tyrosine kinase domain. EGFR and ER2/neu are over expressed or abnormally activated in several epithelial malignancies (CA Cancer J Clin. 2009, 59, 111-137; Clin. Cancer Res. 2006, 12(18), 5268-5272; The Journal of Biological Chemistry 1990, 265(14), 7709-7712).

The non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including but not limited to, intracellular Signalling Kinases selected from Src, PI3K, Frk, Tec, Csk, Abl, Syk/Zap70, Fak, Jak, Ack and lymphocyte-specific protein tyrosine kinase (Lck) (Frontiers in Bioscience, 2003, 8, s595-635). Dysregulated Src and Lck activities have been implicated in the development and progression of several human cancers, including breast, colorectal, lung, ovarian, and haematologicai malignancies (CA Cancer J Clin. 2009, 59, 111- 137). The family of serine-threonine kinases includes, but is not limited to, AGC, Ca 7calmodulin-dependent protein kinase (CaMK) and Casein kinase 1 (CK1). Aurora kinases identified in mammalian ceils and being implicated as mitotic regulators have generated significant interest in cancer therapy due to their elevated expression in human cancers (Clin. Cancer Res. 2006, 12(23 ), 6869-6875).

Thus, in view of the link between protein kinase regulated cell functions and a host of diseases and disorders, in the recent times a great deal of efforts have been taken to develop molecules that function as protein kinase inhibitors, particularly the molecules which simultaneously inhibits several kinases, referred to as multi-kinase inhibitors.

The combination study of OSI906 or Linsitinib (OSI Pharmaceuticals/Astellas), a small molecule protein kinase inhibitor that targets IGF-1R and IR with proteasome inhibitor, a proteasome inhibitor, is in phase III clinical trials and phase II clinical trials for adrenocotical carcinoma and lung cancers respectively. Lapatinib (GlaxoSmithKline), a small-molecule protein kinase inhibitor, that targets both EGFR and HER2 kinase receptors has been approved by the United States Federal Drug Administration (USFDA) for the treatment of breast cancer and is in phase III clinical trials for gastric cancer and head and neck squamous cell carcinoma. Dasatinib (Bristol-Myers Squibb), a small molecule protein kinase inhibitor of Src family, has been approved by USFDA for chronic myelogenous leukemia and is in phase II clinical trials for NSCLC.

A multitargeted approach, wherein the ability of a single small molecule protein kinase inhibitor to target multiple kinase pathways has gained increasing attention in recent times. Sorafenib is a multikinase inhibitor targeting Raf serine/threonine kinases as well as different receptor tyrosine kinases including tyrosine-protein kinase Kit (c-Kit), Fms-like tyrosine kinase 3 (FLT-3), Vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) (Journal of Thoracic Oncology 2011, 6(11 ), SI 758-S1784).

PCT application publication number WO2008150799 A 1 discloses imidazopyridine compounds which are inhibitors of one or more kinases of IGF-1R family tyrosine kinase (particularly, IGF-1R and IR) and ErbB family kinases and are indicated to be useful for the treatment of breast cancer, sarcomas, lung cancer, prostate cancer, colorectal cancer, renal cancer, pancreatic cancer, haematological cancers, neuroblastomas, primary central nervous system (CNS) tumours, secondary CNS tumours, head and neck cancer, thyroid cancer, ovarian cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, buccal cancer, cancer of the mouth, gastrointestinal stromal tumour and skin cancer including melanoma.

PCT application publication number WO2010138576A1 discloses pyrimidine compounds which are inhibitors of kinases such as IGF-1R and are reported to be useful for the treatment of bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer and thyroid cancer in mammals.

Compounds having imidazo[2,l-b]thiazole scaffolds were found to exhibit kinase inhibitory activity, especially against IGF-1R, EGFR and ErbB2 kinases (Bioorg. Med. Chem. Letters, 2010, 20, 2452-2455).

Thus, in view of the critical role played by protein kinases in modulating cellular functions such as tumorigenesis, this class of enzymes have been targeted for developing small molecule inhibitors as potential therapeutic agents. From the above discussion, it is evident that over the past decade, several protein kinase inhibitors have entered clinical trials or are already approved for the treatment of proliferative disorders. However, there is still a continuing need for safe and efficacious small molecule inhibitors, which can target multiple kinase pathways, and can therefore be used in the treatment of diseases or disorders associated with abnormal activity of protein kinases, particularly, proliferative disorders.

Summary of the Invention

In one aspect, the present invention provides compounds of formula (I) as described herein or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.

In another aspect of the present invention, there are provided processes for the preparation of the compounds of formula (I).

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof; and at least one pharmaceutically acceptable carrier or excipient. In another aspect, the present invention provides the compounds of formula (I) or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof, which are multikinase inhibitors.

In a further aspect, the present invention provides a method for the treatment of a disease or disorder associated with abnormal protein kinase activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.

In another further aspect, the present invention provides use of the compound of formula I or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof; for the treatment of a diseases or a disorder associated with abnormal activity of protein kinases.

In a still further aspect, the present invention provides use of the compounds of formula (I) or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in ail ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof; in the manufacture of a medicament, for the treatment a diseases or a disorder associated with abnormal activity of protein kinases.

In another further aspect of the present invention, there is provided use of the compound of formula I or a pharmaceutically acceptable salt thereof in combination with one further therapeutically active agent for the treatment of a diseases or a disorder associated with abnormal activity of protein kinases.

According to the present invention, a diseases or a disorder associated with abnormal activity of protein kinases is a proliferative disorder. One or more further aspects of the present invention are discussed in detail herein below. The other objectives and advantages of the present invention will be apparent to those skilled in the art from the following description. Detailed Description of the Invention

In the first aspect, the present invention relates to a compound of formula (I):

formula (I)

wherein,

X is N or S;

Y is N or C;

Z is -CH₂- or S(0)„;

represents a single or a double bond between the ring atoms 1 and 2 or the ring atoms 2 and 3;

when X and Y are N and Z is S(0)_n and n is 0, then the bond between atoms 1 and 2 is a single bond and bond between atoms 2 and 3 is a double bond;

when X is S, Y is C and Z is -CH₂-, then the bond between atoms 1 and 2 is a double bond and the bond between atoms 2 and 3 is a single bond;

Ri and R₂ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (Ci-C₆)alkoxy, (C3-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, (C₃- Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Cio)aryl(Ci-C₆)alkyl-C(0), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇, -C(S)NR₆R₇ and -S(0)_pR₈; provided that at least one of Ri and R₂ is other than hydrogen;

R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (Ci-C₆)alkoxy, (C₃-C₁₂)cycloalkyl, (Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl, heterocyclyl, heteroaryl, -C(0)R₅, -C(0)NR₆R₇, -C(S)NR₆R₇ and -S(0)_PR₈; provided that one of R₃ and R₄ is other than hydrogen; or R₃ and R₄ together with the N atom to which they are attached can form a saturated or a partially unsaturated heterocyclic ring optionally containing 1 , 2 or 3 additional heteroatoms selected from O, N or S;

R5 is selected from the group consisting of (Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl;

R₆ and R are independently selected from the group consisting of hydrogen, (Ci-

C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl;

Rg is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₆-Cio)aryl, (C₃- Ci₂)cycloalkyl, heterocyclyl and heteroaryl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci- C₆)alkyl, halo(Ci-C₆)alkoxy, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, -0(C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -NH(Ci-C₆)alkyl, -N[(Ci-C₆)alkyl]₂, -C(0)(Ci-C₆)alkyl, - C(0)0(Ci-C₆)alkyl, -C(0)NH₂ and -C(0)NH(Ci-C₆)alkyl;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci- C₆)alkyl, halo(Ci-C₆)alkoxy, amino, cyano and nitro;

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci- C₆)alkyl, halo(Ci-C₆)alkoxy, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R₅, -C(0)0(Ci-C₆)alkyl, -C(0)NH₂, -C(0)NH(Ci-C₆)alkyl and -S(0)_pR₈; wherein R5, Rg and p are as defined above;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci- C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Ci₀)aryl-O-(Ci-C₆)alkyl, amino, cyano, nitro, -C(0)R₅ and -NHC(0)(Ci-C₆)alkyl; wherein R5 is as defined above;

heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci- C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R5 and -S(0)_pR8; wherein R5, Rg and p are as defined above;

halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine; or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N -oxide thereof.

Definitions

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

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

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

Within the context of the present invention, the term "(Ci-C₆)alkyl" or "alkyl", as used herein, alone or as part of a substituent group refers to an aliphatic group, including straight or branched chain alkyl group. A straight-chain or branched chain alkyl has six or fewer carbon atoms in its backbone, for instance, Ci-C₆ for straight chain and C3-C6 for branched chain. Suitable alkyl groups containing from one to six carbon atoms are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, 1-methylbutyl, secondary butyl, tertiary butyl, tertiary pentyl, neopentyl, 3-methylbutyl, 3,3-dimethylbutyl, 2-methylpentyl or 3-methylpentyl. Furthermore, unless stated otherwise, the alkyl groups may be unsubstituted or substituted with one or more groups, preferably one to three groups independently selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, - 0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₃-C₁₂)cycloalkyl, (C₆-Ci₀)aryl, -O(C₆-C₁₀)aiyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -NH(Ci-C₆)alkyl, -N[(Ci-C₆)alkyl]2, -C(0)(Ci- C₆)alkyl, -C(0)0(Ci-C₆)alkyl, -C(0)NH₂, -C(0)NH(Ci-C₆)alkyl and -C(S)NH(Ci-C₆)alkyl. Representative examples of substituted alkyl include, but are not limited to, hydroxymethyl, 2- chlorobutyl, trifluoromethyl, aminoethyl and benzyl.

Within the context of the present application, the term "(C₂-C8)alkenyl" or "alkenyl", as used herein, alone or as part of a substituent group, refers to an unsaturated straight or branched chain hydrocarbon radical containing at least one carbon-carbon double bond (two adjacent sp carbon atoms). For example, the term "(C₂-C8)alkenyl" refers to an alkenyl group having two to eight carbon atoms. Depending upon the placement of double bond and substituents if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis or trans. Examples of alkenyl include, but are not limited to, vinyl, allyl and 2-propenyl. Unless indicated otherwise, the alkenyl groups may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci- C₆)alkyl, amino, nitro and cyano.

Within the context of the present application, and as used herein, the term "(C₂-

C8)alkynyl" or "alkynyl" refers to an unsaturated, branched or straight chain having from two to eight carbon atoms and at least one carbon-carbon triple bond (two adjacent 'sp' carbon atoms). Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 3-propynyl and 4- butynyl. Unless stated otherwise, the alkynyl groups may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, nitro and cyano.

Within the context of the present application and as used herein, the term "halo(Ci- C₆)alkyl" or "haloalkyl" refers to radicals wherein one or more of the hydrogen atoms of the (Ci- C₆)alkyl group are substituted with one or more halogens. A monohalo(Ci-C₆)alkyl radical, for example, may have a chlorine, bromine, iodine or fluorine atom. Dihalo and polyhalo(Ci- C₆)alkyl radicals may have two or more of the same or different halogen atoms. Examples of halo(Ci-C₆)alkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl and difluoropropyl. Within the context of the present application and as used herein, the term "(Ci- C₆)alkoxy" refers to (Ci-C₆)alkyl having an oxygen radical attached thereto. The terms "(Ci- C₆)alkoxy" or "-0(Ci-C₆)alkyl" wherever used in this specification have the same meaning. Representative (Ci-C₆)alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and tert-butoxy. The (Ci-C₆)alkoxy or -0(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci- C₆)alkyl, hydroxy, halogen, amino and cyano.

Within the context of the present application and as used herein, the term "halo(Ci- C₆)alkoxy" or "haloalkoxy" refers to radicals wherein one or more hydrogen atoms of the (Ci- C₆)alkoxy group are substituted with one or more halogens. Representative examples of halo(Ci- C₆)alkoxy groups include, but are not limited to, difluoromethoxy (-OCHF₂), trifluoromethoxy (- OCF₃) or trifluorethoxy (-OCH₂CF₃).

As used herein, the term "(C₃-Ci₂)-cycloalkyl" or "cycloalkyl" whether used alone or as part of a substituent group, refers to a saturated or partially unsaturated cyclic hydrocarbon radical including 1, 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings. The term cycloalkyl includes bridged, fused and spiro ring systems. For example, (C₃-Ci₂)- cycloalkyl refers to a cycloalkyl group having 3 to 8 (both inclusive) carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, l,2,3,3a-tetrahydropentalene, adamantyl, norbornyl, tetrahydronaphthalene bicyclo[2.1.0]pentane, bicyclo[4.2.0]octane, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2-ene, spiro[3.3]heptane, and the like. Unless stated otherwise, (C₃- Ci₂)cycloalkyl may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci- C₆)alkyl, halo(Ci-C₆)alkoxy, (C₃-C 12)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro.

Within the context of the present invention and as used herein, the term "(C₃- Ci₂)cycloalkyl(Ci-C₆)alkyl" or "cycloalkylalkyl" refers to a cycloalkyl group bonded directly through an alkyl group, wherein the terms "cycloalkyl" and "alkyl" are as defined herein above. The cycloalkylalkyl group may be unsubstituted or when substituted the "cycloalkyl" and/or the "alkyl" group may be substituted with one or more groups defined above. The term "(C₃- Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0)" as used herein, refers to a cycloalkylalkyl group which is attached via a carbonyl group on the alkyl portion of the cycloalkylalkyl.

Within the context of the present application and as used herein, the term "(C₆-Cio)aryl" or "aryl" refers to a monocyclic or bicyclic hydrocarbon ring system having up to ten ring carbon atoms, wherein at least one carbocyclic ring is having π electron system. Examples of (C₆-C₁₀) aryl ring systems include, but are not limited to, phenyl or naphthyl. Unless indicated otherwise, aryl group may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, halogen, halo(Ci- C₆)alkyl, hydroxy, 0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₃-Ci₂)cycloalkyl, (C₆-Ci₀)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R₅, -OC(0)R₅, -C(0)OH, -C(0)0(Ci- C₆)alkyl, -C(0)NH₂ or -C(0)NH(Ci-C₆)alkyl and -S(0)_pR₈; wherein R₅, R₈ and p are as defined above. Aryl groups can be substituted in any desired position. For example, in monosubstituted phenyl, the substituent may be located in the 2-position, the 3-position, the 4-position or the 5- position. If the phenyl carries two substituents, they can be located in 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5-position. Examples of monosubstituted phenyl groups include, but are not limited to 2-fluorophenyl, 2-ethoxyphenyl, 2-ethylphenyl, 4- morpholinophenyl, (4-ethylpiperazin-lyl)phenyl or 4-(2-dimethylaminoethyl)phenyl. Examples of disubstituted phenyl groups include, but not limited to, 2, 6-difluorophenyl or 3, 5- difluorophenyl.

Within the context of the present application and as used herein, the term "0(C₆-Cio)aryl" or "aryloxy" refers to an (C₆-Cio)aryl group having an oxygen radical attached thereto. The terms aryloxy or -0(C₆-Cio)aryl wherever used in this specification denote the same meaning. Representative aryloxy groups include, but are not limited to, phenoxy or naphthoxy. -0(C₆- Cio)aryl is unsubstituted or substituted with one or more groups as defined herein above for the term "aryl".

Within the context of the present invention and as used herein, the term "(C₆-Cio)aryl(Ci- C₆)alkyl" or "arylalkyl" refers to (Ci-C₆)alkyl group substituted with an (C₆-Cio)aryl group, and said arylalkyl group is attached via the alkyl group, wherein the terms "(Ci-C₆)alkyl" and "(C₆- Cio)" are as defined herein above. The arylalkyl group may be unsubstituted or when substituted the "(Ci-C₆)alkyl" and/or the "(C₆-Cio)aryl" group may be substituted with one or more groups as defined herein above for the terms "(Ci-C₆)alkyl" and "(C₆-Cio)aryr'. Representative examples of arylalkyl groups include, but are not limited to, benzyl or 2-phenyl-ethyl.

Within the context of the present invention and as used herein, the term "(C₆-Cio)aryl(C₆- Cio)aryl" or "arylaryl" refers to (C₆-Cio)aryl group substituted with an (C₆-Cio)aryl group, and said arylaryl group is attached via the aryl group, wherein the term "(C₆-Cio)aryl" is as defined herein above. The "(C₆-Cio)aryl(C₆-Cio)aryl" group may be unsubstituted or when substituted either one or both of the aryl groups are substituted with one or more groups as defined herein above for the term "aryl". Examples of arylaryl groups include, but not limited to, biphenyl or binaphthyl.

The term "(C₆-Cio)aryl(C₆-Cio)aryl-C(0)" as used herein, refers to a arylaryl group which is attached via the carbonyl (-C=0) group.

Within the context of the present application and as used herein, the term "heterocyclyl" refers to 3- to 9-membered saturated or partially unsaturated monocyclic, bicyclic or a polycyclic ring system, preferably monocyclic or bicyclic ring system containing one or more hetero atoms, particularly one to three hetero atoms independently selected from the group consisting of: a nitrogen (N), a sulphur (S) and an oxygen (O) atom. Saturated heterocyclic ring systems do not contain any double bond, whereas partially unsaturated heterocyclic ring systems, contain at least one double bond, but do not form an aromatic system containing a hetero atom. Representative examples of saturated and partially unsaturated non-aromatic heterocyclic groups include, but are not limited to, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dihydropyran, tetrahydropyran, thio-dihydropyran, thiotetrahydropyran, piperidine, piperazine, morpholine, dihydrothiene, dihydropyridine, tetrahydropyridine, isoxazolidine or pyrazolidine. Polycyclic or bicyclic heterocyclic ring systems can comprise either fused rings in which two or more carbons are common to two adjoining rings, or bridged rings in which rings are joined through non-adjacent atoms. For instance, the fused heterocyclyl ring systems can comprise a 5 or a 6-membered heterocyclic ring fused with monocyclic aryl ring or a saturated or a partially unsaturated heterocyclic ring. Examples of fused heterocyclic rings include, but are not limited to, 1 ,3-benzodioxole, 1,3-benzothiazole or 2,3-dihydrobenzofuran. The bridged heterocyclyl ring systems may for instance, comprise a monocyclic or a bicyclic heterocyclic ring containing one or more alkylene bridges comprising 2 to 4 carbon atoms, wherein each bridge links two non-adjacent carbon atoms of the ring system. Examples of bridged heterocyclic rings include but not limited to oxobicyclo[2.2.1]heptane, azabicyclo[2.2.1]heptane, 8-oxa-3- azabicyclo[3.2.1]octane or 6-oxa-3-azabicyclo[3.1.1]heptane. The 'heterocyclyl' can be part of a bicyclic spiro ring. Examples of spiro heterocyclyl groups include, but are not limited to, 2-oxa- 6-aza-spiro[3.3]hexane, 2-oxa-6-aza-spiro[3.3]heptane, 2-oxa-6-aza-spiro[3.3]octane, 2-oxa-5- aza-spiro[3.4]heptane or 2-oxa-5-aza-spiro[3.4]octane.

Unless stated otherwise, heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci- C₆)alkyl, hydroxy, 0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl-0-(Ci-C₆)alkyl, amino, cyano, nitro, -C(0)R₅, -C(0)OH, -C(0)NH₂, and -NHC(0)(Ci-C₆)alkyl; wherein R₅ is as defined above.

Heterocyclyl monocyclic or bicyclic ring systems having an aromatic ring containing hetero atom/s are herein referred to as "heteroaryl". Within the context of the present invention and as used herein, the term "heteroaryl" refers to 3- to 10-membered aromatic monocyclic or bicyclic ring system containing one or more hetero atoms, preferably one to four identical or different hetero atoms selected from the group consisting of: nitrogen (N), sulphur (S) and oxygen (O) atom. Representative examples of heteroaryl include, but are not limited to, thiene, furan, pyridine, oxazole, thiazole, pyrazine, pyrimidine, pyrrole, pyrazole, isooxazole, triazole, tetrazole, pyridazine, isothiazole, benzo thiazole, benzooxazole, benzimidazole, quinoline or isoquinoline. Heteroaryl group may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C8) alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆) alkyl, halo(Ci-C₆)alkoxy, (C₃- Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R5, -OC(0)R5, - C(0)OH, -C(0)0(Ci-C₆)alkyl, -C(0)NH₂, -C(0)NH(Ci-C₆)alkyl, NHC(0)(Ci-C₆)alkyl and - S(0)_pR8 ; wherein R5, Rg and p are as defined above.

Within the context of the present invention and as used herein, the term "heterocyclyl(C₆-

Cio)aryl" or "heterocyclylaryl" refers to a heterocyclyl group bonded through an aryl group, wherein the terms "heterocyclyl" and "aryl" are as defined herein above. Unless stated otherwise, heterocyclylaryl group may be unsubstituted or when substituted the heterocyclyl and/or the aryl may be substituted with one or more substituents as defined herein above for the terms "heterocyclyl" and "aryl". Representative examples of heterocyclylaryl include, but are not limited to 4-(piperidin-l-yl)phenyl, 4-(4-ethylpiperazin-l-yl)phenyl or 4-morpholinophenyl. Within the context of the present invention and as used herein, the term "heterocyclyl- heteroaryl" refers to a heterocyclyl group bonded through a heteroaryl group, wherein the terms "heterocyclyl" and "heteroaryl" are as defined herein above. Unless stated otherwise, heterocyclyl-heteroaryl may be unsubstituted or when substituted the heterocyclyl and/or the heteroaryl may be substituted with one or more groups as defined herein above for the terms "heterocyclyl" and "heteroaryl" respectively Example of heterocyclylheteroaryl include, but is not limited to 4-(4-methylpiperazin-l-yl)pyridyl.

The term "heteroatom" as used herein, includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom or a (Ci-C₆) alkyl or any other appropriate group to satisfy the valency.

The term "halogen" or "halo" as used herein, unless otherwise indicated refer to bromine, chlorine, fluorine or iodine atom.

The term "amino" refers to the group "NH₂" which may be optionally substituted by one or more substituents. Representative examples of substituents include, but are not limited to, (Ci- C₄)alkyl or (C₆-Ci₀)aryl.

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

Within the context of this present application and as used herein the term "isotopic forms" or "isotopically labelled forms" is a general term used for isotopic forms of the compounds of formula (I), wherein one or more atoms of the compounds of formula (I) are replaced by their respective isotopes. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present invention. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2 H (deuterium or D) and 3 H (tritium or T), carbon such as ^UC, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N, oxygen such as ¹⁵0, ¹⁷0 and ¹⁸0, chlorine such as ³⁶C1, fluorine such as ¹⁸F and sulphur such as ³⁵S. Substitution with heavier isotopes, for example, replacing one or more key carbon-hydrogen bonds with carbon-deuterium bond may show certain therapeutic advantages, resulting from longer metabolism cycles, (e.g., increased in vivo half life or reduced dosage requirements), improved safety or greater effectiveness and hence may be preferred in certain circumstances.

Representative examples of isotopic forms of the compounds of formula (I) may include, without limitation, deuterated compounds of formula (I). The term "deuterated" as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), with a deuterium atom. For example, the compounds of formula (I) may include in the definitions of one or more of the various variables R_1; R₂, R₃, R₄, R₅, R₆, R₇ and Rg, wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deutrated-aryloxy, deuterated- cycloalkyl, deuterated-heterocyclyl, deuterated-aryl or deuterated-heteroaryl.

The term "deuterated-alkyl" refers to an (Ci-C₆)alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. That is, in a deuterated alkyl group, at least one carbon atom is bound to a deuterium. In a deuterated alkyl group, it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium. Analogously, the term "deuterated" and the terms deuterated-heterocyclyl, deuterated-heteroaryl, deuterated-cycloalkyl, deuterated-aryl and "deuterated-alkoxy" each refer to the corresponding chemical moiety wherein at least one carbon is bound to a deuterium.

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

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

The term "pharmaceutically acceptable salts" as used herein includes salts of the active compounds which are prepared with acids or bases, depending on the particular substituents found on the compounds described herein.

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

Within the context of the present invention and as used herein, the term "pharmaceutically acceptable solvate" or "solvate" describes a complex wherein the compound of formula (I) of the present invention, is coordinated with a proportional amount of a solvent molecule. Specific solvates, wherein the solvent is water, are referred to as hydrates.

Within the context of the present invention and as used herein, the term "prodrug" refers to compounds that are drug precursors, which following administration, release the therapeutically active compound (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof) in vivo via a chemical or metabolic process, for example, a prodrug on being brought to the physiological pH or through an enzyme action is converted to the therapeutically active compound.

Within the context of the present invention and as used herein the term "polymorph" or "polymorphic form" refers to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule in the crystal lattice.

Within the context of the present invention and as used herein interchangeably throughout this application, the terms "compound of formula (I)", "compounds of formula (I)", and "compounds of the present invention" include all the isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable polymorphs, N-oxides and S-oxides thereof. Further, in the context of the present invention, reference to the compounds of the present invention and/or the compounds of formula (I) may include reference to the compounds represented herein by the compounds of formula (la) and/or the compounds of formula (lb). The compound(s) of the present invention can also be referred to herein as "the active compound" or "the active ingredient".

The term, "therapeutically effective amount" as used herein means an amount of a compound of formula I or a pharmaceutically acceptable salt thereof; or a composition comprising the compound of formula I or a salt thereof, effective in producing the desired therapeutic response in a particular patient suffering from a disease or disorder associated with abnormal protein kinase activity. Particularly, the term "therapeutically effective amount" includes the amount of the compound, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject. In respect of the therapeutic amount of the compound, consideration is also given that the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment. The therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the disease or disorder being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized and other factors.

As used herein, the term "pharmaceutically acceptable carrier" refers to a material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof), to the target site without terminating the activity of the agent.

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

As used herein, the terms "treatment" "treat" and "therapy" is intended to mean to alleviate, slow the progression, attenuation or cure of existing disease or condition (e.g. disease or disorder associated with abnormal protein kinase activity). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the diseases or condition.

As used herein, the term "multi-kinase inhibitor" refers to a compound that exhibits a therapeutic effect by inhibiting more than one protein kinases. In other words multi-kinase inhibitor is a compound which does not specifically inhibit only one kinase as a molecular target, but primarily inhibits multiple protein kinases, at least two kinases.

As used herein, the term "disease or disorder associated with abnormal protein kinase (PK) activity" or "Protein kinase (PK)-related disorder" refers to a condition characterized by abnormal (i.e., diminished or, more commonly, excessive) PK catalytic activity, where the particular PK can be RTK (receptor tyrosine kinases) or STK (serine/threonine kinases). Abnormal PK catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs; (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth; or (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth. Excessive-activity of a PK refers to either amplification of the gene encoding a particular PK or its ligand, or production of a level of PK activity, which can correlate with a cell proliferation, differentiation and/or growth disorder such as cancer, inflammatory disorders, CNS disorders and autoimmune disorders. Embodiments

In an embodiment, the present invention relates to a compound of formula I, wherein, X is N, Y is N, Z is S(0)_n , wherein the integer n is as defined; and represents a single bond between the ring atoms 1 and 2 and a double bond between the ring atoms 2 and 3; or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I;

wherein, X is S, Y is C , Z is -CH₂- and represents a double bond between the ring atoms

1 and 2 and a single bond between the ring atoms 2 and 3;

or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.

In an embodiment, the present invention relates to a compound of formula (I);

wherein, Ri and R₂ are independently selected from the group consisting of hydrogen, (C₃- Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl(Ci-C₆)alkyl-C(0), - C(0)R₅, -C(0)NR₆R7 and -S(0)_PR8; provided that one of Ri and R₂ is other than hydrogen; or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N -oxide thereof.

In an embodiment, the present invention relates to a compound of formula (I);

wherein R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; provided that one of R₃ and R₄ is other than hydrogen; or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.

In an embodiment, the present invention relates to a compound of formula (I), wherein, X, Y and Z are as defined in the first aspect of the invention;

Ri and R₂ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, (C₃-Ci₂)cycloalkyl(Ci- C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, - C(0)NR₆R₇, -C(S)NR₆R₇ and -S(0)_pR₈; provided that one of Ri and R₂ is other than hydrogen;

R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-C₁₂)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, -C(0)R₅, -C(0)NR₆R₇, - C(S)NR₆R₇ and -S(0)_PR8; provided that one of R₃ and R₄ is other than hydrogen;

R₅ is selected from the group consisting of (Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl or heteroaryl;

R₆ and R₇ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; provided that at least one of R₆ and R₇ is hydrogen;

R₈ is (Ci-C₆)alkyl or (C₆-C₁₀)aryl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci- C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, -0(C₆-Cio)aryl, heteroaryl, amino, cyano, nitro, - NH(Ci-C₆)alkyl and -N[(Ci-C₆)alkyl]₂;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, cyano and nitro;

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, amino, cyano, nitro and -NHC(0)(C₁- C₆)alkyl;

heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, heterocyclyl, amino, cyano and nitro;

halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine; or a isotopic form, or a siereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.

In an embodiment of the present invention, provides compounds of formula (I) encompasses the compound of formulas

formula (la) wherein

R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Ci₀)aryl, heterocyclyl, heteroaryl, -C(0)R₅, -C(0)NR₆R₇, - C(S)NR₆R₇ and -S(0)_PR8; provided that one of R3 and R₄ is other than hydrogen;

R₈ is (Ci-C₆)alkyl or (C₆-C₁₀)aiyl;

p is an integer selected from 0, 1 or 2;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, (C₃- Ci₂)cycloalkyl, (C₆-Cio)aryl, -0(C₆-Cio)aryl, heteroaryl, amino, cyano, nitro, -NH(Ci-C₆)alkyl and -N[(Ci-C₆)alkyl]₂;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, cyano and nitro;

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, amino, cyano, nitro and -NHC(0)(Ci-C₆)alkyl; heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, heterocyclyl, amino, cyano and nitro;

halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine; or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.

In an embodiment, the compound of formula (I) encompasses the compound of formula (la); wherein,

Ri and R₂ are independently selected from the group consisting of hydrogen, (C3-

Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0)-, (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl, heteroaryl(Ci- C₆)alkyl-C(0)-, -C(0)R₅, -C(0)NR₆R₇ and -S(0)_pR₈; provided that one of Ri and R₂ is other than hydrogen;

R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; provided that one of R₃ and R₄ is other than hydrogen;

R₆ and R₇ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₆-Cio)aryl and (C₃-Ci₂)cycloalkyl; provided that at least one of R₆ and R₇ is hydrogen;

R₈ is (C₁-C₆)alkyl or (C₆-C₁₀)aryl;

p is an integer selected from 0, 1 or 2;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆- Cio)aryl, -O(C₆-C₁₀)aryl, heteroaryl, amino, -NH(Ci-C₆)alkyl and -N[(Ci-C₆)alkyl]₂;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, -0(Ci- C₆)alkyl and amino; (C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, hydroxy, amino and -NHC(0)(Ci-C₆)alkyl;

heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, heterocyclyl, amino, cyano and nitro;

halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine. In an embodiment, the compound of formula (I) encompasses the compound of formula (la); wherein,

Ri and R2 are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Ci₀)aryl, heteroaryl, (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆- Cio)aryl(Ci-C₆)alkyl-C(0), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇, -C(S)NR₆R₇ and -S(0)_PR8; provided that one of Ri and R2 is other than hydrogen;

R₃ and R₄, together with the N atom to which they are attached, can form a saturated or a partially unsaturated 3- to 9-membered heterocyclic ring optionally containing 1, 2 or 3 additional heteroatoms independently selected from the group consisting of O, N and S;

R5 is selected from the group consisting of (Ci-C₆)alkyl, (C₃-Ci2)cycloalkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl;

R₆ and R₇ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₆-Cio)aryl and (C₃-Ci2)cycloalkyl; provided that at least one of R₆ and R₇ is hydrogen;

R₈ is (C₁-C₆)alkyl or (C₆-C₁₀)aryl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, (C₃- Ci₂)cycloalkyl, (C₆-Cio)aryl, -0(C₆-Cio)aryl, heteroaryl, amino, cyano, nitro, -NH(Ci-C₆)alkyl and -N[(C₁-C₆)alkyl]₂;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, cyano and nitro;

heterocyclyl is 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, (C6-Cio)aryl-0-(Ci-C₆)alkyl, hydroxy, amino, cyano, nitro and - NHC(0)(Ci-C₆)alkyl;

heteroaryl is 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, (C₃-C9)heterocyclyl, amino, cyano and nitro;

halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine. In an embodiment, the compounds of formula (I) encompasses the compound of formula (la); wherein,

Ri and R₂ are independently selected from the group consisting of hydrogen, (C₃- Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl, heteroaryl(Ci- C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇ and -S(0)_pR₈; provided that one of Ri and R₂ is other than hydrogen;

R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci-

C₆)alkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; provided that one of R₃ and R₄ is other than hydrogen;

R₆ is hydrogen and R₇ is (C₃-Ci₂)cycloalkyl;

R₈ is (Ci-C₆)alkyl or (C₆-Ci₀)aryl; p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl, (C3-Ci₂)cycloalkyl, (C₆- Cio)aryl, -O(C₆-Ci₀)aryl, (C₃-Ci₂)heteroaryl, amino, -NH(d-C₆)alkyl and -N[(Ci-C₆)alkyl]₂;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, -0(Ci- C₆)alkyl and amino;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, amino and -NHC(0)(Ci-C₆)alkyl;

heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, heterocyclyl, amino, cyano and nitro;

halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.

Ri and R₂ are independently selected from the group consisting of hydrogen, (C₃- Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl(Ci-C₆)alkyl-C(0)-, -C(0)R₅, -C(0)NR₆R₇ and -S(0)_pR₈; provided that at least one of Ri or R₂ is not hydrogen;

R₃ and R₄ together with the N atom to which they are attached can form a saturated or a partially unsaturated 3- to 9-membered heterocyclic ring optionally containing one or two additional heteroatoms independently selected from the group consisting of O, N and S;

R₆ is hydrogen and R₇ is (C₃-Ci₂)cycloalkyl; R₈ is (Ci-C₆)alkyl or (C₆-C₁₀)aiyl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆- Cio)aryl, -O(C₆-C₁₀)aryl, heteroaryl, amino, -NH(C₁-C₆)alkyl and -N[(C₁-C₆)alkyl]₂;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, -0(Ci- C₆)alkyl and amino;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, (C₆-Ci₀)aryl-O-(Ci-C₆)alkyl, hydroxy, amino and -NHC(0)(Ci-C₆)alkyl;

In another embodiment, the compound of formula (I) encompasses the compound of formula (la); wherein,

R] is hydrogen; and

R₂ is selected from the group consisting of (Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇, -C(S)NR₆R₇ and -S(0)_pR₈; wherein R₅, R₆, R₇, R8, n and p are as defined above;

wherein, (Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆- Cio)aryl, heteroaryl and amino;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, -0(Ci- C₆)alkyl and amino;

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, amino, cyano and nitro;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy and amino;

heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, cyano and nitro;

Ri is hydrogen; and

R₂ is selected from the group consisting of heteroaryl, (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-

C(O), (C₆-Cio)aryl(Ci-C₆)alkyl-C(0), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇ and - S(0)_pR8; wherein R5, R₆, R₇, Rs, n and p are as defined above;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆- Cio)aryl, heteroaryl and amino;

(C3-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, -0(Ci- C₆)alkyl and amino; (C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, amino, cyano and nitro;

heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, cyano and nitro;

In another embodiment, the compounds of formula (I) encompasses the compound of formula (la); wherein,

Ri is hydrogen; and

R₂ is selected from the group consisting of (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆- Cio)aryl(Ci-C₆)alkyl-C(0) and heteroaryl(Ci-C₆)alkyl-C(0);

wherein,

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl and amino;

heteroaryl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, cyano and nitro;

Ri is hydrogen; and

R₂ is (C₆-Cio)aryl(Ci-C₆)alkyl-C(0);

wherein, (Ci-C₆)alkyl is substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, amino, cyano and nitro;

(C₆-Cio)aryl is substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen and -0(d-C₆) alkyl;

R] is hydrogen; and

R₂ is -C(0)R₅;

R₅ is selected from the group consisting of (Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl and amino;

heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci- C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, cyano and nitro;

halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine. In another embodiment, the compound of formula (I) encompasses the compound of formula (la);

wherein,

Ri is hydrogen; and R₂ is -C(0)NR₆R₇ or -S(0)_pR₈;

R₆ is hydrogen;

R₇ is (C₃-Ci₂)cycloalkyl;

R₈ is (C₁-C₆)alkyl or (C₆-C₁₀)aryl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-Cs)alkenyl, (C₂-C8)alkynyl, halogen, hydroxy, -0(Ci- C₆)alkyl and amino;

In another embodiment, the compound of formula (I) encompasses the compound of formula (la);

wherein

R₃ is hydrogen;

R₄ is selected from the group consisting of (Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, -C(0)R₅, -C(0)NR₆R₇, -C(S)NR₆R₇, and -S(0)_PR₈; wherein R₅, R₆, R₇, Rs, n and p are as defined above;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, -0(C₆-Cio)aryl, halogen, halo(Ci-C₆)alkyl, hydroxy, amino, NH(Ci-C₆)alkyl and -N[(Ci-C₆)alkyl]₂;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl and amino; (C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from (Ci- C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci- C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino and -NHC(0)(Ci-C₆)alkyl;

heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci- C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, (C3-C9)heterocyclyl, amino, cyano and nitro;

wherein,

R₃ is hydrogen;

R₄ is selected from the group consisting of (C₆-Cio)aryl, heteroaryl and heterocyclyl; wherein,

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl and amino;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino and -NHC(0)(Ci-C₆)alkyl;

wherein

R₃ and R₄ together with the N atom to which they are attached can form a saturated or a partially unsaturated 3- to 9-membered heterocyclic ring containing 1 or 2 additional heteroatoms independently selected from O, N or S;

wherein

heterocyclyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, -0(Ci- C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, (C6-Cio)aryl-0-(Ci-C₆)alkyl and amino; and

formula (lb)

wherein

Ri and R₂ are independently selected from the group consisting of hydrogen, (Ci-

C₆)alkyl, (C3-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, (C₃-Ci₂)cycloalkyl(Ci- C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, - C(0)NR₆R₇, -C(S)NR₆R₇ and -S(0)_pR₈; provided that one of Ri and R₂ is other than hydrogen;

R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Ci₀)aryl, heterocyclyl, heteroaryl, -C(0)R₅, -C(0)NR₆R₇, - C(S)NR₆R₇ and -S(0)_PR8; provided that one of R₃ and R₄ is other than hydrogen;

R5 is selected from the group consisting of (Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; R₆ and R are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; provided that at least one of R₆ and R is hydrogen;

R₈ is (C₁-C₆)alkyl or (C₆-C₁₀)aryl;

p is an integer selected from 0, 1 or 2;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, -0(C₆-Cio)aryl, heteroaryl, amino, cyano, nitro, -NH(Ci-C₆)alkyl and -N[(Ci-C₆)alkyl]₂;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, amino, cyano, nitro and -NHC(0)(Ci-C₆)alkyl;

halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine. In an embodiment, the compounds of formula (I) encompasses the compound of formula

(lb); wherein,

Ri and R₂ are independently selected from the group consisting of hydrogen, (C3- Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl, heteroaryl(Ci- C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇ and -S(0)_pR₈; provided that one of Ri and R₂ is other than hydrogen; R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; provided that one of R₃ and R₄ is other than hydrogen;

R₆ is hydrogen and R is (C₃-Ci₂)cycloalkyl;

R₈ is (C₁-C₆)alkyl or (C₆-C₁₀)aryl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, -0(Ci- C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Ci₀)aryl, -O(C₆-Ci₀)aryl, heteroaryl, amino, -NH(Ci-C₆)alkyl and -N[(Ci-C₆)alkyl]₂;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, amino and -NHC(0)(Ci-C₆)alkyl;

In an embodiment, the compounds of formula (I) encompasses the compound of formula (lb); wherein,

Ri is hydrogen; R₂ is selected from the group consisting of (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆- Cio)aryl(Ci-C₆)alkyl-C(0) and heteroaryl(Ci-C₆)alkyl-C(0);

R₃ is hydrogen;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci- C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino and -NHC(0)(Ci-C₆)alkyl;

heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci- C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, heterocyclyl, amino, cyano and nitro;

halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine. Representative compounds of formula I in accordance with the present invention include:

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrirmdin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-naphthamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrirmdin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-cyclohexylphenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b]thiazol-6- yl)phenyl)-2-phenylacetamide;

2^henyl-N-(3-(5-(2-((4-(piperidin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)acetamide;

N-(3-(5-(2-((4-(4-methylpiperidin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-phenylacetamide; N-(3-(5-(2-((3-(2-methylpiperidin-l-yl)propyl)am

b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)benzamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2,6-difluorobenzamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)cyclohexanecarboxamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-(2-fluorophenyl)acetamide;

2-(2-ethoxyphenyl)-N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)acetamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)cyclopentanecarboxamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)cyclobutanecarboxamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-(thiophen-2-yl)acetamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)cyclopropanecarboxamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)picolinamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)piperidine-l-carboxamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-3,3-dimethylbutanamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-3-methylbutanamide;

2-cyclopentyl-N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)acetamide; N-(3-(5-(2-((4-morpholinophenyl)amino)pyrimidin-4-y^

yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b]thiazol-6- yl)phenyl)cyclohexanecarboxamide;

(S)-N-(3-(5-(2-(2-(phenoxymethyl)morpholino)pyrimidin-4-yl)-2,3-dihydroimidazo[2, l- b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(4-acetamidopiperidin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydro imidazo[2, l-b]thiazol-6-yl)phenyl)-2-phenylacetamide;

l-cyclohexyl-3-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)urea;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)nicotinamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-3,5-difluorobenzenesulfonamide;

(lR,4S)-N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydro imidazo[2, l-b]thiazol-6-yl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)benzo[d] [ 1 ,3]dioxole-5-carboxamide;

N-(3-(5-(2-([l,r-biphenyl]-4-ylamino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b]thiazol-6- yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((6-(4-methylpiperazin-l-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-2,3-dihydro imidazo[2, l-b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(4-acetamidopiperidin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo [2, 1 -b]thiazol-6-yl)phenyl)-2-cyclohexylacetamide;

N-(3-(5-(2-((4-(2-(dimethylamino)ethyl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[ b]thiazol-6-yl)phenyl)-2-phenylacetamide;

2,6-difluoro-N-(3-(5-(2-((4-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)benzamide;

N-(3-(5-(2-((4-(2,6-dimethylmorpholino)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo b]thiazol-6-yl)phenyl)-2-phenylacetamide; N-(3-(5-(2-((4-(8-oxa-3-azabicyclo[3.2J]octan-3-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-(quinolin-6-ylamino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b]thiazol-6- yl)phenyl)cyclohexanecarboxamide;

N-(3-(5-(2-((4-((2S,6R)-2,6-dimethylmorpholino)phenyl)amino)pyrimidin-4-yl)-2,^

dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidaz b]thiazol-6-yl)phenyl)benzo[d] [ 1 ,3]dioxole-5-carboxamide;

N-(3-(5-(2-((4-bromophenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2, l-b]thiazol-6- yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidaz b]thiazol-6-yl)phenyl)-lH-benzo[d]imidazol-2-amine;

N-(3-(3-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)phenyl)-2-phenylacetamide;

N-(3-(3-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)phenyl)-3-methylbutanamide;

N-(3-(3-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)phenyl)-2-phenylacetamide;

3-methyl-N-(3-(3-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)phenyl)butanamide; and

N-(3-(3-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)phenyl)morpholine-4-carboxamide;

or a isotopic form, or a stereoisomeric form, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or an N-oxide thereof.

According to another aspect of the present invention, there are provided processes for the preparation of the compounds of formula I.

Thus, the compound of formula (I) can be prepared by various methods including using one or more methods well known to the person skilled in the art. Representative processes for the preparation of the compounds of formula (I) are described herein below and illustrated in the following schemes 1 and 2, but are not limited thereto. It will be appreciated by the person skilled in the art that within certain of the processes described herein, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent such as bases, solvents, coupling agents to be used in the reaction steps.

The starting compounds including the reactants and reagents as well as intermediates used in the following process are either commercially available or can be prepared according to standard procedures known in the art, for instance those reported in the literature references.

In the following scheme 1 wherein a process for the synthesis of the compounds of formula (I), particularly that of the compounds of formula (la) is depicted and the description of the process steps involved in the synthesis of the compounds of formula (la), the starting compounds are designated as compounds A and B, whereas the intermediates obtained in the synthesis of compounds of the present invention, are designated as compounds C, D, E, F, G, H, I and J, wherein the substituents have the same definition as provided for the compound(s) of formula la in one or more embodiments as described above, unless stated otherwise.

Compound of formula (la) The reaction steps in Scheme 1 consist of:

Step la

This process step involves reacting 2-bromo-l-(3-nitrophenyl)ethanone (compound A) in a solvent such as N, N-dimethyl formamide (DMF), N-methyl pyrrolidone (NMP) or ethanol (EtOH) with 4,5-dihydrothiazol-2-amine (compound B) in the presence of an inorganic base such as sodium carbonate (Na₂C0₃), potassium carbonate (K₂C0₃), cesium carbonate (Cs₂C0₃) or sodium bicarbonate (NaHC0₃) at a temperature ranging from 70 °C to 120 °C for lh to 2h, according to the method described in J. Med. Chem., 2006, 49(26), 7897-7901, to obtain compound (C).

Step lb

The compound (C) is acetylated using an acetylating reagent such as acetic anhydride or acetyl chloride in the presence of an acid, such as sulphuric acid (H₂SO₄) or a lewis acid such as aluminium trichloride (AICI₃) or boron trifluoride (BF₃) at 100 °C to 150 °C for lh to 5h, according to the method described in Organic Letters, 2005, 7, 4753, to obtain compound (D). Step lc

The compound (D) is reacted with N,N-dimethylformamide dimethyl acetal (DMF. DMA) in the presence of a solvent such as N-methyl pyrrolidine (NMP), N,N-dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) at 70°C to 90°C for 0.5h to 4h, according to the method described in Bioorganic and Medicinal Chemistry Letters, 2010, 20(8), 2452-2455, to obtain compound (E).

Step Id

The compound (E) is reacted with guanidine hydrochloride in the presence of an inorganic base such as Na₂C0₃, K₂C0₃ or Cs₂C0₃ and a solvent such as DMF, NMP or ethanol (EtOH) at 80 °C to 140 °C, for 16h to 18h, according to the method described in Bioorganic and Medicinal Chemistry Letters, 2010, 20(8), 2452-2455, to obtain compound (F).

Step le

In this step, a solution of the compound (F) in acetic acid is subjected to diazotization in the presence of sodium nitrite (NaN0₂) at 60 °C to 80 °C followed by the addition of an inorganic base such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or lithium hydroxide (LiOH) and stirring for lh, according to the method described in Bioorganic and Medicinal Chemistry Letters, 2010, 20(8), 2452-2455, to obtain compound (G).

Step If

In this step, the compound (G) is treated with a halogenating agent, for instance, a chlorinating agent such as phosphorous oxychloride (POCI₃), thionyl chloride (SOCl₂) or phosphorous pentachloride (PCI₅) at 60 °C to 120 °C for 0.5h to 6h, according to the method described in Bioorganic and Medicinal Chemistry Letters, 2010, 20(8), 2452-2455, to obtain compound (H).

Step lg

In this step, the compound (H) is reacted with an organic amine of formula R₃R₄NH

(wherein R₃ and R₄ are as defined above for the compound of formula (la)), in the presence of a solvent such as isopropyl alcohol (IPA) and an inorganic acid such as hydrogen chloride (HC1), at 110-130 °C for 17-19 h, according to the method described in Bioorganic and Medicinal Chemistry Letters, 2009, 19(3), 1004-1008, to obtain compound (J) (wherein R₃ and R₄ are as defined above for the compound of formula (la)).

Step lh

In this step, the compound (J) is subjected to catalytic reduction using a reducing agent such as stannous chloride or ammonium chloride and a catalyst such as iron or palladium respectively, in the presence of a solvent such as methanol (MeOH), EtOH or ethyl acetate at room temperature to 90 °C for 0.5h to 4h, according to the method described in J. Org. Chem., 1999, 64(6), 2110-2113, to obtain compound (K) (wherein R₃ and R₄ are as defined above for the compound of formula (la)).

Step li

In this step, the compound (K) is reacted with an acid chloride of formula RiCl or R₂C1 to obtain compound of formula (la), wherein Ri and R₂ are independently selected from the group consisting of hydrogen, (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Cio)aryl(Ci-C₆)alkyl- C(O), heteroaryl (Ci-C₆)alkyl-C(0) and C(0)R₅ (wherein R5 is as defined above for the compound of formula (la)), provided that one of Ri and R₂ is other than hydrogen; and R₃ and R₄ are as defined above for the compound of formula (la).

Alternatively, compound (K) is reacted with an isocyanate or isothiocyanate of formula

R₆R₇NCO or R₆R₇NCS] to obtain compound of formula (la), wherein Ri and R₂ are independently selected from the group consisting of hydrogen, -C(0)NR₆R₇ or -C(S)NR₆R₇, wherein, R₆ and R₇ are as defined above and provided that one of Ri and R₂ is other than hydrogen; and R₃ and R₄ are as defined above for the compound of formula (la).

Alternatively, compound (K) is reacted with a sulphonyl chloride of formula RgS(0)_pCl to obtain compounds of formula (la), wherein Ri and R₂ are independently selected from the group consisting of hydrogen and S(0)_pR8, wherein Rg and p are as defined above and provided that one of Ri and R₂ is other than hydrogen; and R₃ and R₄ are as defined above. This process step is carried out in accordance with the procedure described in Tetrahedron Letters, 201 1, 52(31), 3963-3968.

In the following scheme 2 wherein a process for the synthesis of the compounds of formula (I), particularly that of the compounds of formula (lb) is depicted and the description of the process steps involved in the synthesis of the compounds of formula (lb), the starting compounds are designated as compound 2A, whereas the intermediates obtained in the synthesis of compounds of the present invention, are designated as compounds 2B, 2C, 2D, 2E, 2F, 2G, 2H, 21, 2J and 2K, wherein the substituents have the same definition as provided for the compound(s) of formula lb in one or more embodiments as described above, unless stated otherwise.

Scheme 2:

Compound of formula (lb)

Scheme - 2

The reaction steps in Scheme 2 consist of:

Step 2a:

Cyclopentanone was dissolved in a solvent such as cyclohexane or toluene and anhydrous sodium sulphate was added in one portion under a nitrogen atmosphere. The mixture was cooled to 0 °C with an ice bath and pyrrolidine (compound 2A) was added drop wise over a 30 mins period. After the reaction mixture was stirred for additional 30 min at 0 °C, the ice bath was removed and the mixture was stirred overnight at room temperature. Sodium sulfate was removed by filtration and rinsed (washed) thoroughly with dry solvents such as cyclohexane or toluene. The combined filtrate and washings were concentrated to compound 2B. Step 2b:

A solution of aromatic bromide in organic solvents such as toluene or cyclohexane was added drop wise for 30 min to a solution of the compound 2B (109 mmol) in toluene. The mixture was heated under reflux for 3h to 4h, diluted, further refluxed for 4-5 h and cooled. The layers were separated. The aqueous phase was extracted with an organic solvent such as toluene or cyclohexane and the combined organic phase was dried over sodium sulfate and concentrated to obtain compound 2C.

Step 2c:

A solution of the compound 2C and La wesson's reagent in toluene- 1 ,2-dimethoxyethane was heated under reflux for 2h - 3h. The solvent is removed to obtain the compound 2D.

Step 2d

The compound 2D is acetylated using an acetylating reagent such as acetic anhydride or acetyl chloride in the presence of an acid such as sulphuric acid (H₂SO₄) or a lewis acid such as aluminium trichloride (AICI₃) or boron trifluoride {BF₃) at 100 °C to 150 °C for lh to 5h, to obtain compound 2E.

Step 2e

The compound 2E is reacted with Ν,Ν-dimethyl formamide dimethyl acetal (DMF. DMA) in the presence of a solvent such as N-methyl pyrrolidine (NMP), N,N-dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) at 70°C to 90°C for 0.5h to 4h, to obtain compound 2F.

Step 2f

The compound 2F is reacted with guanidine hydrochloride in the presence of an inorganic base such as Na₂C0₃, K₂CO₃ or CS₂CO₃ and a solvent such as DMF, NMP or ethanol (EtOH) at 80 °C to 140 °C, for 16h to 18h, to obtain compound 2G.

Step 2g

In this step, a solution of the compound 2G in acetic acid is subjected to diazotization in the presence of sodium nitrite (NaN0₂) at 60 °C to 80 °C followed by the addition of an inorganic base such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or lithium hydroxide (LiOH) and stirring for lh, to obtain compound 2H. Step 2h

In this step, the compound 2H is treated with a halogenating agent, for instance, a chlorinating agent such as phosphorous oxychloride (POCI₃), thionyl chloride (SOCl₂) or phosphorous pentachloride (PCI₅) at 60 °C to 120 °C for 0.5h to 6h, to obtain compound 21.

Step 2i

In this step, the compound 21 is reacted with an organic amine of formula R₃R₄NH (wherein R₃ and R₄ are as defined above for the compound of formula (lb)), in the presence of a solvent such as isopropyl alcohol (IPA) and inorganic acid such as hydrogen chloride (HC1), at 110-130 °C for 17-19 h, to obtain compound 2J (wherein R₃ and R₄ are as defined above for the compound of formula (lb)).

Step 2j

In this step, the compound 2J is subjected to catalytic reduction using reducing agents such as stannous chloride or ammonium chloride and catalyst such as iron or palladium respectively, in the presence of an appropriate solvent such as methanol (MeOH), EtOH or ethyl acetate at room temperature to 90 °C for 0.5h to 4h, to obtain compound 2K (wherein R₃ and R4 are as defined above for the compound of formula (lb)).

Step 2k

In this step, the compound 2K is reacted with an acid chloride of formula RiCl or R₂C1 to obtain the compound of formula (lb), wherein Ri and R₂ are independently selected from the group consisting of hydrogen, (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C6-Cio)aryl(Ci-C₆)alkyl- C(O), heteroaryl (Ci-C₆)alkyl-C(0) and -C(0)R₅ (wherein R5 is as defined above for the compound of formula (lb)), provided that one of Ri and R₂ is other than hydrogen; and R₃ and R4 are as defined above for the compound of formula (lb).

Alternatively, the compound 21 is reacted with an isocyanate or isothiocyanate having formula R₆R₇NCO or R₆R₇NCS to obtain compounds of formula (lb), wherein Ri and R₂ are independently selected from the group consisting of hydrogen, -C(0)NR₆R₇ or -C(S)NR₆R₇, wherein, R₆ and R₇ are as defined above for the compound of formula (lb) and provided that one of Ri and R₂ is other than hydrogen; and R₃ and R₄ are as defined above for the compound of formula (lb).

Alternatively, the compound 21 is reacted with a sulphonyl chloride [R₈S(0)_PC1] to obtain the compounds of formula (lb), wherein Ri and R₂ are independently selected from the group consisting of hydrogen and S(0)_PR8, wherein R$ and p are as defined above and provided that one of Ri and R₂ is other than hydrogen; and R₃ and R₄ are as defined above for the compound of formula (lb).

The schematic process of the present invention described herein, may further include an optional oxidation step. Those skilled in the art will recognize that the compounds of formula (la) obtained in Scheme 1 of the present invention may optionally be subjected to an oxidation step in the presence of an oxidizing agent, selected from, but not limited to, meta- chloroperbenzoic acid or oxone®, to obtain N-oxide or S-oxide of compounds of formula (la) respectively, wherein R_1; R₂, R₃ and R₄ are as defined above and n is 1 or 2.

Those skilled in the art will recognize that the compounds of formula (I) of the present invention, including the compounds of formula (la) and/or (lb) contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms, as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image cohort, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers and enantiomers, as well as mixtures thereof such as racemic mixtures, geometric isomers form part of the present invention.

When the compounds of formula (I) of the present invention including the compounds of formula (la) and/or (lb), contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixtures. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer- specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form.

Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation. Designation of a specific absolute configuration at a chiral carbon of the compounds of the invention is understood to mean that the designated enantiomeric form of the compounds is in enantiomeric excess (ee) or in other words is substantially free from the other enantiomer. For example, the "R" forms of the compounds are substantially free from the "S" forms of the compounds and are, thus, in enantiomeric excess of the "S" forms. Conversely, "S" forms of the compounds are substantially free of "R" forms of the compounds and are, thus, in enantiomeric excess of the "R" forms. Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50% relative to the other enantiomer. In a particular embodiment when a specific absolute configuration is designated, the enantiomeric excess of depicted compounds is at least about 90%. When a compound of formula (I) of the present invention has two or more chiral carbons it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereoisomer of such compounds and mixtures thereof.

In one embodiment, the compounds of formula (I) including the compounds of formula (la) and/or (lb), exists as tautomers, and it is intended to encompass all the tautomeric forms of the compounds within the scope of the present invention.

The isotopically labeled forms of compounds of formula (I), can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described above and in the subsequent section on examples by using an appropriate isotopically labelled reagent instead of non-labelled reagent. The present invention also includes within its scope pharmaceutically acceptable salts or solvates thereof of the compounds of formula I.

The term "pharmaceutically acceptable salts" as used herein refers to organic and inorganic salts of a compound of formula I of the present invention, depending on the particular group (acidic or basic group) present in the said compounds. When compounds of the present invention contain relatively acidic groups, base addition salts can be obtained by contacting the compounds of formula I with a sufficient amount of an appropriate base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts of the compounds of the present invention include their alkali metal salts such as sodium, potassium, calcium, magnesium, ammonium or organic base addition salt. Examples of pharmaceutically acceptable organic base addition salts include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like or other organic bases known to the person skilled in the art.

When compounds of the present invention contain relatively basic groups, acid addition salts can be obtained by contacting the compounds of formula I with a sufficient amount of an appropriate acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts particularly those derived from inorganic acids include hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, mono-hydrogensulfuric or hydriodic acids or other inorganic acids known to the person skilled in the art. Furthermore, examples of pharmaceutically acceptable acid addition salts include the salts derived from organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, j?-tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic or galacturonic acids or other organic acids known to the person skilled in the art. Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The compounds of formula I may be regenerated from their corresponding salts by contacting the salt with an appropriate base or acid depending on the type of salt and isolating the parent compound in the conventional manner. The compound may differ from the various salt forms in certain physical properties. An example of physical properties that may differ is solubility in polar solvents.

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

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

Additionally, in situations wherein tautomers of the compounds of formula I are possible, the present invention is intended to include all tautomeric forms of the compounds.

The present invention also encompasses within its scope prodrugs of the compound of formula I including that of the compounds of formula (la) and/or (lb),. Preferably, prodrugs are those compounds that are converted intracellularly, more preferably, where the cellular converting location is the site of therapeutic action. For instance, preferred prodrugs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid. Examples of pharmaceutically acceptable esters include lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di- substituted lower alkyl esters such as the pivaloyloxymethyl ester and the like conventionally used in the art (An introduction to Medicinal Chemistry, Graham. L. Patrick, Second Edition, Oxford University Press, pg 239-248; Prodrugs: Challenges and Rewards, Part 1 and Part 2, AAPS Press, Edited by Valentino J. Stella, Renald T. Borchardt, Michael J. Hagemon, Reza Oliyai, Hans Maag, Jefferson W. Tilley). In another further aspect, the present invention relates to pharmaceutical composition(s) containing a therapeutically effective amount of at least one compound of formula I including the compounds of formula (la) and/or (lb), or its pharmaceutically acceptable salt or solvate thereof and a conventional pharmaceutically acceptable carrier. The present invention also relates to a process for the production of a pharmaceutical composition, which includes bringing at least one compound of formula I, into a suitable administration form using a pharmaceutically acceptable and physiologically tolerable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries can be added.

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

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

The pharmaceutical composition(s) normally contain about 1 % to 99 %, for example, about 5 % to 70 %, or from about 10 % to about 30 % by weight of the compound of formula I or its pharmaceutically acceptable salt. The amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower that the specified range.

As is customary, the dosage range which is suitable in a specific case depends on the type of disease or disorder to be treated and on the state of the respective condition or disorder. The selected dosage level can be readily determined by a skilled medical practitioner in the light of the relevant circumstances, including the disease or disorder to be treated, the chosen route of administration including other factors such as age, weight and physical health and response of the individual patient (subject), pharmacokinetics, severity of the disease and other like factors known in the medical art. Actual dosage levels of the active ingredients i.e. the compounds of formula I in the pharmaceutical composition of this present invention can be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient (subject in need of the treatment), composition, and mode of administration without being toxic to the patient. Typically, the dose of the compounds of formula I or pharmaceutically acceptable salts thereof, which is to be administered, can cover a wide range. The dose to be administered daily is to be selected to suit the desired effect. A suitable dosage is about 0.01 mg/kg/day to about 200 mg/kg/day of the compound of formula I or its pharmaceutically acceptable salt, for example, about 0.1 mg/kg/day to 100 mg/kg/day of a compound of formula I or its pharmaceutically acceptable salt. If required, higher or lower daily doses can also be administered.

In addition to the compound of the formula I or its pharmaceutically acceptable salt and carrier substances, the pharmaceutical compositions can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. Pharmaceutical compositions can also contain two or more compounds of formula I or their pharmaceutically acceptable salts. Furthermore, in addition to at least one compound of formula I or its pharmaceutically acceptable salt, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.

In one aspect, the compounds of formula I or pharmaceutically acceptable salts thereof are multi-kinase inhibitors. In an aspect, the compounds of formula I or pharmaceutically acceptable salts thereof are inhibitors of the protein kinases selected from the group consisting of Insulin-like Growth Factor- 1 Receptor (IGF-1R), Insulin Receptors (IR), Vascular Endothelial Growth Factor Receptor (VEGF) and Platelet-Derived Growth Factor Receptors (PDGFR).

In one aspect, the present invention relates to a method for the treatment of a disease or a disorder associated with abnormal protein kinase activity, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease or a disorder associated with abnormal protein kinase activity.

In one aspect, the present invention provides use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or a disorder associated with abnormal protein kinase activity.

In an embodiment of the present invention, the disease or disorder associated with abnormal protein kinase activity is selected from the group consisting of an inflammatory disease, an allergic disorder, a pulmonary disease, diabetes, diabetes related disorder, acromegaly, angiogenesis, a proliferative disease, a CNS (central nervous system) disorder, a cardiovascular disease and an autoimmune disease.

Examples of an inflammatory disease include, but are not limited to, acute or chronic pain, arthritis, rheumatoid arthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, spondyloarthropathy, pulmonary disorder such as asthma, chronic obstructive pulmonary disease (COPD) or lung inflammation, inflammatory bowel disease, Crohn's disease, multiple sclerosis, ulcerative colitis, irritable bowel syndrome, idiopathic thrombocytopenic purpura (ITP) and pelvic inflammatory disease.

Examples of an allergic disorder include, but are not limited to, allergic rhinitis, allergic bronchitis, allergic sinusitis, dermatitis, atopic dermatitis, urticaria and asthma.

Examples of a pulmonary disease include, but are not limited to, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), lung inflammation, bronchitis obliteraus and primary pulmonary hypertension.

Examples of a proliferative disease include, but are not limited to, cancer, tumors, mastocytosis, associated myeloproliferative syndrome, urticaria pigmentosa, an epidermal hyperproliferation, psoriasis and prostate hyperplasia.

Examples of a cardiovascular disease include, but are not limited to, artherosclerosis, myocardial infarction, congestive heart failure and cardiac reperfusion injury.

Examples of a central nervous system disorder include, but are not limited to, brain injury, cerebrovascular disease, corticobasal degeneration, dementia, Parkinson's disease, Alzheimer's disease, vascular dementia, dementia with Lewy bodies and frontotemporal dementia.

Examples of an autoimmune disease include, but are not limited to, lupus, systemic lupus erythematosus (SLE), Sjogren's syndrome, urticarial, scleroderma, psoriasis and renal disease.

Examples of diabetes related diseases include, but are not limited to, diabetic retinopathy, retinal ischemia, and retinal neovascularization.

In an embodiment of the present invention, the disease or disorder associated with abnormal protein kinase activity is cancer.

Accordingly, the present invention relates to a method for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.

Further, the present invention relates to use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of cancer.

In one aspect, the present invention provides use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.

In an embodiment of the invention, cancer is selected from leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma and follicular lymphoma, astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyoma, melanoma, epithelial cancer, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, thymoma, thyroid cancer or testicular cancer.

In another embodiment of the invention cancer is selected from brain cancer, breast cancer, prostate cancer, epithelial cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, renal cell carcinoma or endometrial carcinoma.

The compounds of the present invention can be administered alone or in combination with other therapies suitable for the disease or disorder being treated. Where separate dosage formulations are used, the compound and the other therapeutic agent can be administered at essentially the same time (concurrently) or at separately staggered times (sequentially). The pharmaceutical combination is understood to include all these regimens. Administration in these various ways are suitable for the present invention as long as the beneficial therapeutic effect of the compound of formula I or a pharmaceutically acceptable salt thereof and the other therapeutic agent are realized by the patient at substantially the same time. Such beneficial effect is achieved when the target blood level concentrations of each active drug are maintained at substantially the same time.

The present invention encompasses use of the compound of formula I or a pharmaceutically acceptable salt thereof in combination with one further therapeutically active agent for the treatment of diseases or disorders associated with abnormal activity of protein kinases. For example, the compounds of the present invention are useful in combination with known anti-cancer agents. Combinations of the compounds of the present invention with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of therapeutic agents would be useful based on the particular characteristics of the therapeutic agents and the cancer involved. Such anti-cancer agents that can be used in combination with the compounds of formula I include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signalling, agents that interfere with receptor tyrosine kinases and cancer vaccines. The compounds of the present invention can be co-administered with radiation therapy.

It is understood that modifications that do not substantially affect the operability of the various embodiments of this invention are included within scope of the invention disclosed herein. Accordingly, the following examples are intended to illustrate but not to limit scope of the present invention.

The abbreviations and terms that are used herein:

Example 1

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydro imidazo[2,l- b]thiazol-6-yl)phenyl)-2-naphthamide (Compound 1)

Step la

Synthesis of 6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole

To a solution of 2-bromo-l-(3-nitrophenyl)ethanone (100 g, 410 mM) in anhydrous DMF (500 ml), 4,5-dihydrothiazol-2-amine (53 g, 519 mM) and Na₂C0₃ (174 g) were added and heated at 90 °C for 2 h. The reaction mixture was diluted with ice cold water (1.5 1) and the precipitate was filtered. The residue obtained was washed with ice cold water, concentrated and dried to afford the title compound 6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole, as a yellow solid. Yield: 98.4 g (97%);

1H NMR (DMSO-d₆, 300 MHz): δ 8.48 (s, 1H), 8.13-8.10 (d, J=7.8 Hz, 1H), 8.04-8.00 (m, 2H), 7.66-7.60 (t, J=7.8 Hz, 1H), 4.28-4.23 (t, J=7.2 Hz, 2H), 3.95-3.91 (t, J=7.2 Hz, 2H); MS: m/z 248 (M+l).

Step lb

Synthesis of l-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)ethanone

To a solution of 6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (compound of Step la, 25 g, 101.21 mM) in acetic anhydride (250 ml), A1C1₃ was added and heated at 130 °C for 3 days. The reaction mixture was cooled to room temperature, quenched with water followed by the addition of solid NaHC0₃ to adjust the pH as 8.0 to 8.5. The residue was filtered, washed with ethyl acetate (3x300 ml) and extracted with ethyl acetate (3x400 ml). The organic layer was washed with brine, dried over Na₂S04 and concentrated to afford a crude product, which was purified by flash column chromatography (silica gel, 40% ethyl acetate in petroleum ether) to afford the title compound l-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)ethanone. Yield: 11.2 g (40.0 %);

1H NMR (DMSO-de, 300 MHz): δ 8.39 (s, 1H), 8.31-8.28 (d, J=7.8 Hz, 1H), 8.08-8.05 (d, J=7.8 Hz, 1H), 7.78-7.72 (t, J=7.8 Hz, 1H), 4.55-4.50 (t, J=7.5 Hz, 2H), 4.03-3.98 (t, J=7.5 Hz, 2H), 2.14 (s, 3H); MS: m/z 290.1 (M+l).

Step lc

(E)-3-(dimethylamino)-l-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)prop-2-en-l- one DMF.DMA (5.4 g, 45.6 mM) was added to l-(6-(3-nitrophenyl)-2,3-dihydroimidazo [2,l-b]thiazol-5-yl)ethanone (compound of Step lb, 1 l.Og, 38.02 mM) in NMP and heated at 100 °C for 2 h. The reaction mixture was cooled, quenched using ice water and the precipitate was filtered. The residue was washed with cold water (3x250 ml), concentrated and dried to afford the title compound (E)-3-(dimethylamino)-l-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)prop-2-en-l-one. Yield: 10.4 g (79.4%);

^XHNMR (DMSO-de, 300 MHz): δ 8.48 (s, 1H), 8.19-8.16 (d, J=8.1 Hz, 1H), 8.10-8.07 (d, J=8.1 Hz, 1H), 7.70-7.64 (t, J=8.1 Hz, 1H), 7.64-7.59 (d, J=12.3 Hz, 1H), 5.12-5.08 (d, J=12.3 Hz, 1H), 4.43-4.38 (t, J=7.2 Hz, 2H), 3.98-3.94 (t, J=7.2 Hz, 2H), 3.06 (s, 3H), 2.56 (s, 3H); MS: m/z 345.1 (M+l).

Step Id

Synthesis of 4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)pyrimidin-2-amine

To a solution of (E)-3-(dimethylamino)-l-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)prop-2-en-l-one (compound of Step lc, 10.0 g, 29.07 mM) in NMP, guanidine hydrochloride (3.4 g, 58.14 mM) and K₂C0₃ was added and heated at 120 °C for 16 to 18 h. The reaction mixture was poured into ice cold water and the precipitate was filtered. The residue was washed with ice cold water (3x100 ml), concentrated and dried to afford the title compound 4-(6- (3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine as a yellow solid. Yield: 9.6 g (97.2%);

1HNMR (DMSO-d₆, 300 MHz): δ 8.38 (s, 1H), 8.17-8.15 (d, J=5.1 Hz, 2H,), 8.02-8.00 (d, J=7.5 Hz, 1H), 7.69-7.63 (t, J=7.8 Hz, 1H), 6.78 (s, 2H), 6.49-6.47 (d, J=5.1 Hz, 1H), 4.56-4.51 (t, J=7.2 Hz, 2H), 4.02-3.97 (t, J=7.2 Hz, 2H); MS: m/z 341.1 (M+l).

Step le

Synthesis of 4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)pyrimidin-2-ol

To a solution of 4-(6-(3-nitrophenyl)-2,3-dihydroimidazo [2,l-b]thiazol-5-yl)pyrimidin-

2-amine (compound of Step Id, 10 g, 29.41 mM) in acetic acid (7 ml, 588.23 mM) was heated at 60 °C, an aqueous solution of NaN0₂ (1.6 g, 35.3 mM) was added dropwise for a period of 30 min at 60 °C. The reaction mixture was stirred for lh at 60°C, cooled to RT and NaOH was added to adjust the pH as ranging from 8.0 to 9.0. The crude product obtained as a yellow solid was filtered, washed with water (2x50 ml), concentrated and dried to afford the title compound 4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)pyrimidin-2-ol as a pale yellow solid. Yield: 8.8 g (87.7%);

1H NMR (DMSO-de, 300 MHz): δ 11.77 (s, IH), 8.32 (s, IH), 8.25-8.24 (d, J=7.8 Hz, IH), 8.00- 7.98 (d, J=7.8 Hz, IH), 7.75-7.72 (d, J=6.6 Hz, IH), 7.73-7.68 (t, J=7.8 Hz, IH), 6.08 (d, J=6.6 Hz, IH), 4.59-4.54 (t, J=7.2 Hz, 2H), 4.03-3.98 (t, J=7.2 Hz, 2H); MS: m/z 342.1 (M+l).

Step If

Synthesis of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)-2,3-dihydroimidazo[2, 1 -b]thiazole

A solution of 4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-ol (compound of Step le, 10.0 g, 29.33 mM) was treated with P0C1₃ (50 ml) and heated at 90 °C for 2h. The reaction mixture was cooled to room temperature, excess chlorinating reagent was removed and the mixture cooled to 0 to 5 °C with ice. Aqueous NaOH was added to adjust the pH as ranging from 8.0 to 9.0, the residue washed with water and dried under vacuum to afford the title compound 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazole as a pale yellow solid. Yield: 8.2 g (78%);

XH NMR (DMSO-de, 300 MHz): δ 8.61-8.59 (d, J=5.4 Hz, IH), 8.39 (s, IH), 8.25-8.23 (d, J=8.1 Hz, IH), 8.03-8.00 (d, J=8.1 Hz, IH), 7.72-7.66 (t, J=8.1 Hz, IH), 7.37-7.35 (d, J=5.4 Hz, IH), 4.61-4.56 (t, J=7.2 Hz, 2H), 4.06-4.01 (t, J=7.2 Hz, 2H); MS: m/z 360.4 (M+l).

Step lg

Synthesis of N-(4-(4-ethylpiperazin- 1 -yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo

[2, 1 -b]thiazol-5-yl)pyrimidin-2-amine

To a solution of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)-2,3-dihydro imidazo[2,l- b]thiazole (compound of Step If) in IPA, 4-(4-ethylpiperazin-l-yl)aniline (commercially available) (0.571 g, 2.78 mM) was added at room temperature. The reaction mixture was heated at 120 °C for 18h. IPA was removed from the reaction mixture and the residue was diluted with water followed by addition of solid NaHC0₃ to adjust the pH as ranging from 8.0 to 9.0. The residue was extracted further with ethyl acetate and the organic layer was washed with brine, dried over Na₂S0₄, concentrated to obtain a crude product. The crude product was purified by flash column chromatography (silica gel, eluted with 4% EtOH in DCM) to afford the title compound N-(4-(4-ethylpiperazin- 1 -yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo [2, 1 - bjthiazol -5-yl)pyrimidin-2-amine as a pale yellow solid. Yield: 0.97 g (65.5%); 1H NMR (DMSO-de, 300 MHz): δ 9.41 (s, 1H), 8.36-8.34 (d, J=5.1 Hz, 1H), 8.32 (s, 1H), 8.17- 8.15 (d, J=8.1 Hz, 1H), 8.98-8.00 (d, J=7.5 Hz, 1H), 7.67-7.62 (t, J=8.1 Hz, 1H), 7.46-7.43 (d, J=8.4 Hz, 2H), 6.85-6.82 (d, J=8.4 Hz, 2H), 6.76-6.72 (m, 1H), 6.67-6.65 (d, J=5.1 Hz, 1H), 4.55-4.49 (t, J=7.5 Hz, 2H), 4.02-3.97 (t, J=7.2 Hz, 2H), 3.05 (m, 4H), 2.93 (m, 2H), 2.38-2.33 (m, 4H), 1.06-1.01 (t, J=6.9 Hz, 3H); MS: m/z 529.2 (M+l).

Step lh

Synthesis of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin- 1 -yl)phenyl)pyrimidin-2-amine

To a solution of N-(4-(4-ethylpiperazin-l-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine (compound of Step lg, lg, 18.9 mM), NH₄CI (5 g, 94.5 mM) and iron (5.27g, 94.5 mM) were added. The reaction mixture was heated at RT to 90 °C for 2h. The reaction mixture was then cooled to RT and filtered over celite bed. The filtrate was concentrated, residue was diluted with water and solid NaHC0₃ was added to adjust the pH to 8.5. The residue was then extracted with ethyl acetate (3x20 ml). The organic layer was washed with water and brine, dried over anhydrous Na₂S0₄ and concentrated in vacuum to afford the title compound 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)-N-(4-(4-ethyl piperazin-l-yl)phenyl)pyrimidin-2-amine as a pale yellow solid. Yield: 0.84 g (80%);

^XH NMR (DMSO-de, 300 MHz): δ 9.28 (s, 1H), 8.20-8.18 (d, J=5.1 Hz, 1H), 7.51-7.48 (d, J=8.4 Hz, 2H), 7.04-6.99 (t, J=7.8 Hz, 1H), 6.92-6.89 (d, J=8.4Hz, 2H), 6.72 (s, 1H), 6.61-6.58 (d, J=7.5 Hz, 1H), 6.55-6.53 (m, 2H), 5.12 (s, 2H), 4.56-4.51 (t, J=5.1 Hz, 2H), 3.97-3.93 (t, J=5.1 Hz, 2H), 3.34 (m, 4H), 3.07 (m, 4H), 2.40-2.34 (m, 2H), 1.06-1.01 (t, J=7.2 Hz, 3H); MS: m/z 499.3 (M+l).

Step li

Synthesis of N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)-2-naphthamide

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4-ethylpiperazin-l- yl)phenyl)pyrimidin-2-amine (compound of Step lh, 0.1 g) was dissolved in NMP and 2- naphthoyl chloride (42 mg, 0.220 mM) was added to the reaction mixture. The reaction mixture was stirred at RT for lh. The reaction mixture was diluted with diethyl ether, stirred for 5 min and ether was removed. The dilution of the reaction mixture with diethyl ether and removal of ether was repeated twice. The reaction mixture was further diluted with DCM and washed with aqueous saturated NaHC0₃. The organic layer was dried over anhydrous Na₂S0₄, concentrated to yield crude product which was purified by flash column chromatography (silica gel, eluted with 6% MeOH in DCM) to afford the title compound ((4-(4-ethylpiperazin-l- yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)-2-naphthamide. Yield: 0.069 g (53%);

'H NMR (CDC1₃, 300 MHz): δ 8.56 (s, IH), 8.46 (s, IH), 8.19-8.17 (d, J=5.7 Hz, IH), 8.00-7.97 (m, 3H), 7.92-7.90 (d, J=6.6Hz, IH), 7.83 (s, IH), 7.62-7.58 (m, 2H), 7.50-7.47 (d, J=8.4 Hz, 2H), 7.42-7.36 (m, 3H), 6.92-6.89 (d, J=8.7 Hz, 2H), 6.74-6.72 (d, J=5.7 Hz, IH), 4.54-4.49 (t, J=6.9 Hz, 2H), 3.870-3.82 (t, J=6.9 Hz, 2H), 3.57 (m, 4H), 3.16 (m,4H), 2.54-2.52 (m, 2H), 1.17- 1.15 (t, J= 6.9Hz, 3H); MS: m/z 653.5 (M+l).

Example 2

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo [2,1- b]thiazol-6-yl)phenyl)-2-phenylacetamide

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (compound of Step lh of Example 1) with 2- phenyl acetyl chloride by the method described in Step li of Example 1. Yield: 52.6%;

1H NMR (DMSO-d₆, 300 MHz): δ 10.87 (Br s, IH), 10.48 (s, IH), 9.76 (s, IH), 8.27-8.25 (d, J=5.4 Hz, IH), 7.86 (s, IH), 7.71-7.69 (d, J=7.8 Hz, IH), 7.52-7.50 (d, J=8.4 Hz, 2H), 7.39-7.24 (m, 6H), 7.20-7.17 (d, J=7.5 Hz, IH), 7.00-6.97 (d, J=8.7Hz, 2H), 6.57-6.55 (d, J=5.4 Hz, IH), 4.597 (t, J=6.9Hz, 2H), 4.07-4.02 (t, J=6.9Hz, 2H), 3.75-3.72 (d, J=8.1 Hz, 2H), 3.66 (s, 2H), 3.56-3.54 (d, J=6.0 Hz, 2H), 3.16-3.10 (m, 5H), 1.32-1.27 (t, J=7.2 Hz, 3H); m/z 617.6 (M+l).

Example 3

N-(3-(5-(2-((4-cyclohexylphenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b]thiazol -6-yl)phenyl)-2-phenylacetamide (Compound 3)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)-N-(4- cyclohexylphenyl)pyrimidin-2-amine with 2-phenyl acetyl chloride, according to procedure followed in Step li of Example 1. Yield: 33%;

1H NMR (DMSO-de, 300 MHz): δ 10.23 (s, IH), 9.49 (s, IH), 8.27-8.25 (d, J=5.1Hz, IH), 7.77 (s, IH), 7.67-7.64 (d, J=8.1Hz, IH), 7.57-7.54 (d, J=8.1Hz, 2H), 7.33-7.24 (m, 6H), 7.17-7.11 (m, 3H), 6.58-6.56(d, J=5.1Hz, IH), 4.58-4.53 (t, J=7.2Hz, 2H), 4.00-3.97 (t, J= 7.2Hz, 2H), 3.63 (s, 2H), 2.43 (m, IH), 1.80-1.69 (m, 4H), 1.40-1.34 (m, 5H); m/z 587.8 (M+l).

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-cyclohexyl phenyl)pyrimidin-2-amine was obtained by reduction of N-(4-cyclohexylphenyl)-4-(6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine using the same procedure and reagents as in Step lh of Example 1.

1H NMR (DMSO-de, 300MHz): δ 9.44 (s, IH), 8.24-8.22 (d, J=5.1 Hz, IH), 7.59-7.56 (d, J=8.1 Hz, 2H), 7.16-7.13 (d, J=8.1 Hz, 2H), 7.05-6.99 (t, J=7.8 Hz, IH), 6.72 (s, IH), 6.61-6.57 (m, 4H), 5.13 (br.s, 2H), 4.62-4.56 (t, J=7.2 Hz, 2H), 4.01-3.96 (t, J=7.2 Hz, 2H), 3.14 (s, 2H), 2.42 (m, IH), 1.77-1.69 (m, 5H), 1.41-1.34 (m, 2H); m/z 469.7 (M+l).

N-(4-cyclohexylphenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl) pyrimidin-2-amine was obtained by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)- 2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-cyclohexylaniline (commercially available) according to procedure followed in step lg of Example 1.

1H NMR (CDCI₃, 300 MHz): δ 8.55 (s, IH), 8.23-8.19 (m, 2H), 7.97-7.95 (d, J=7.8 Hz, IH), 7.58-7.53 (t, J=7.8 Hz, IH), 7.49-7.47 (d, J=8.1 Hz, IH), 7.23-7.20 (d, J=8.1 Hz, 2H), 7.15 (s, IH), 6.59-6.58 (d, J=5.1 Hz, IH), 4.54-4.49 (t, J=7.2 Hz, 2H), 3.91-3.85 (t, J=7.2 Hz, 2H), 3.24 (s, 2H), 2.52 (m, IH), 1.89 (m, 4H), 1.81-1.76 (m, 2H), 1.50-1.400 (m, 3H); m/z 499.6 (M+l).

Example 4

2-phenyl-N-(3-(5-(2-((4-(piperidin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo [2,1- b]thiazol-6-yl)phenyl)acetamide (Compound 4)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)-N-(4- (piperidin-l-yl)phenyl)pyrimidin-2-amine with 2-phenylacetyl chloride according to procedure followed in Step li in Example 1. Yield: 45.7%; 1H NMR (DMSO-d6, 300 MHz): δ 12.18 (br s, IH), 10.39 (s, IH), 9.96 (s, IH), 8.38-8.36 (d, J=5.4 Hz, IH), 7.83-7.80 (m, 3H), 7.73-7.70 (d, J=8.4 Hz, 2H), 7.67-7.65 (d, J=8.4 Hz, IH), 7.33 (m, 5H), 7.25 (m, IH), 7.16-7.16 (d, J=8.1 Hz, IH), 6.71-6.69 (d, J=5.7 Hz, IH), 4.64-4.60 (t, J=6.9 Hz, 2H), 4.03 (t, J=6.9 Hz, 2H), 3.64 (s, 2H), 3.48 (m, 4H), 2.08 (m, 2H), 1.90 (m, 2H), 1.76 (m, IH), 1.56 (m, IH); m/z 588.3 (M+l).

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(piperidin-l-yl) phenyl)pyrimidin-2-amine was obtained by reduction of 4-(6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(piperidin-l-yl)phenyl)pyrimidin-2-amine using the same procedure and reagents as in Step lh of Example 1. 4-(6-(3-aminophenyl)-2, 3- dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(piperidin-l-l)phenyl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)-N-(4-(piperidin-l-yl)phenyl) pyrimidin-2-amine was obtained by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)- 2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-(piperidin-l-yl)aniline according to procedure followed in Step lg of Example 1. 4-(6-(3-nitrophenyl)-2,3- dihydroimidazo[2, 1 -b]thiazol-5-yl)-N-(4-(piperidin- 1 -yl)phenyl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

Data for 4-(piperidin-l-yl)aniline: 1H NMR (DMSO-d₆, 300MHz): δ 6.68(d, J=8.4Hz, 2H), 6.48(d, J=8.4Hz, 2H), 4.53(s, 2H), 2.85(bs, 4H), 1.6(bs,4H), 1.46(d, J=4.5Hz, 2H); m/z 177.5 (M+l).

Example 5

N-(3-(5-(2-((4-(4-methylpiperidin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-phenylacetamide (Compound 5)

The title compound was prepared in an analogous manner as the compound 1 of Example

1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- methylpiperidin-l-yl)phenyl)pyrimidin-2-amine with 2-phenylacetyl chloride according to procedure followed in Step li of Example 1. Yield: 45.9%;

1H NMR (DMSO-d₆, 300 MHz): δ 11.72 (s, IH), 10.31 (s, IH), 9.91(s, IH), 8.36- 8.34 (d, J=6 Hz, IH), 7.81 (s, 3H), 7.65-7.62 (d, J=9 Hz, 2H), 7.31-7.28(m, 6H) 6.98-6.67(m, IH), 6.70-6.69 (d, J=3.9 Hz, IH), 4.58-4.53 (t, J=7.2 Hz, 2H), 4.00-3.97 (t, J=7.2 Hz, 2H), 3.63 (s, 2H), 3.508 (m, 3H), 1.85-1.74 (m, 5H), 1.23-1.17 (m, IH), 0.99 (s, 3H); m/z 602.2 (M+l).

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4-methylpiperidin-l- yl)phenyl)pyrimidin-2-amine was prepared by reduction of N-(4-(4-methylpiperidin-l- yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine according to the procedure followed in Step lh in Example 1. 4-(6-(3-aminophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4-methylpiperidin-l-yl)phenyl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

N-(4-(4-methylpiperidin-l-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)pyrimidin-2-amine was prepared by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-(4- methylpiperidin- 1 -yl) aniline according to procedure followed in Step lg of Example 1. N-(4-(4- methylpiperidin- 1 -yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, 1 -b]thiazol-5- yl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

Data for 4-(4-methylpiperidin-l-yl)aniline: 1H NMR(DMSO-d₆): δ 6.68(bs, 2H), 6.49(bs, 2H), 4.67(bs, 2H), 3.29(bs, 2H), 2.54(bs, 2H), 1.64(bs, 2H), 1.39(m, IH), 1.25(bs,2H), 0.94(d,3H,J = 6Hz); m/z 191.2 (M+l). Example 6

N-(3-(5-(2-((3-(2-methylpiperidin-l-yl)propyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo [2,1- b]thiazol-6-yl)phenyl)-2-phenylacetamide (Compound 6)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(3-(2- methylpiperidin- 1 -yl)propyl)pyrimidin-2-amine with 2-phenylacetyl chloride according to procedure followed in step li of Example 1. Yield: 56%;

1H NMR (DMSO-de, 300 MHz): 610.52 (s, IH), 8.31 (br s, IH), 8.12-8.10 (d, J=5.4 Hz, IH), 7.85 (s, IH), 7.70-7.67 (d, J=7.8 Hz, IH), 7.34 (m, 5H), 7.29-7.24 (m, 2H), 7.18-7.15 (d, J=7.2 Hz, IH), 6.45-6.43 (d, J=5.1 Hz, IH), 4.69 (t, 2H, J = 6.9 Hz), 4.05 (t, J=6.9 Hz, 2H), 3.66 (s, 2H), 3.40 (m, 2H), 3.09 (m, 3H) 1.99-1.97 (m, 3H), 1.78-1.68 (m, 6H), 1.32-1.30 (d, J= 5.7 Hz, 3H), 1.24 (s, IH); m/z 568.4 (M+l). 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(3-(2-methylpiperidin-l- yl)propyl)pyrimidin-2-amine was obtained by reduction of N-(3-(2-methylpiperidin-l- yl)propyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine according to procedure followed in Step lh of Example 1. m/z 450.7 (M+l). 4-(6-(3- aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(3-(2-methylpiperidin-l- yl)propyl)pyrimidin-2-amine was used in the subsequent reaction steps without purification.

N-(3-(2-methylpiperidin-l-yl)propyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l- b]thiazol-5-yl)pyrimidin-2-amine was prepared by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2, 1 -b]thiazole with 3-(2-methylpiperidin- 1 -yl)propan- 1 -amine (commercially available) according to the procedure followed in Step lg of Example 1.

^XHNMR (CDCI₃, 300 MHz): δ 8.51 (s, IH), 8.20-8.18 (d, IH, J=8.1 Hz), 8.11-8.10 (d, J=5.1 Hz, IH), 7.97-7.95 (d, J=7.5 Hz, IH), 7.58-7.52 (t, J=7.8 Hz, IH), 6.42-6.41 (d, J=5.1 Hz,), 6.25 (br s, IH), 4.68-4.64 (t, J=7.2 Hz, 2H), 3.95-3.90 (t, J = 7.2 Hz, 2H), 3.53 (m, 2H), 3.04 (m, 2H), 2.59 (m, 2H), 2.36 (m, IH), 1.92-1.89 (m, 4H), 1.75-1.72 (m, 4H), 1.20-1.18 (d, J=6.0 Hz, 3H); m/z 480.3 (M+l).

Example 7

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)benzamide (Compound 7)

1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with benzoyl chloride according to procedure followed in step li of Example 1. Yield: 58.2%;

1H NMR (DMSO-de, 300 MHz): δ 10.32 (s, IH), 9.38 (s, IH), 8.26-8.25 (d, J=4.5 Hz, IH), 8.00 (s, 2H), 7.96-7.94 (d, J=6.9 Hz, IH), 7.85-7.83 (d, J=7.5 Hz, IH), 7.60-7.49 (m, 5H), 7.38-7.33 (t, J=9.3 Hz, IH), 7.22-7.20 (d, J=7.2 Hz, IH), 6.94-6.91 (d, J=6.6 Hz, 2H), 6.60-6.58 (d, J=6.0 Hz, IH), 4.50-4.55 (m, 2H), 4.01-3.95 (m, 2H), 3.50-3.04 (m, 7H), 1.23-1.18 (m, 6H); m/z: 603.2 (M+l). Example 8

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyri

b]thiazol-6-yl)phenyl)-2,6-difluorobenzamide (Compound 8)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with 2,6-difluorobenzoyl chloride according to procedure followed in step li of Example 1. Yield: 49.6%;

XH NMR (DMSO-de, 300 MHz): δ 10.84 (s, IH), 9.40 (s, IH), 8.26-8.25 (d, J=4.5 Hz, IH), 7.89 (bs, IH), 7.71-7.69 (d, J=8.4 Hz, IH), 7.62-7.52 (m, 4H), 7.40-7.34 (t, J=7.2 Hz, IH), 7.27-7.25 (m, 3H), 6.95-6.93 (d, J=7.8 Hz, 2H), 6.59-6.57 (d, J=4.5 Hz, IH), 4.54-4.55 (m, 2H), 3.99-3.95 (m, 2H), 3.15-3.04 (m 7H), 1.23-1.17 (m, 6H); MS: m/z 639.3 (M+l).

Example 9

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydro imidazo[2,l- b]thiazol-6-yl)phenyl)cyclohexanecarboxamide (Compound 9)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with cyclohexanecarbonyl chloride according to procedure followed in step li of Example 1. Yield: 73.7%;

1H NMR (DMSO-d₆, 300 MHz): δ 10.99 (s, IH), 10.01 (s, IH), 9.71 (s, IH), 8.27-8.25 (d, J=5.1 Hz, IH), 7.84 (s, IH), 7.71-7.68 (d, J=7.8 Hz, IH), 7.54-7.52 (d, J=8.1 Hz, 2H), 7.36-7.31 (t, J=7.8 Hz, IH), 7.17-7.13 (d, J =7.8 Hz, IH), 7.00-6.97 (d, J=8.1 Hz, 2H), 6.56-6.55 (d, J=4.8 Hz, IH), 4.60 (t, J=6.9 Hz, 2H), 4.03 (t, J=6.9 Hz, 2H), 3.72 (m, 2H), 3.56 (m, 2H), 3.17-3.10 (m, 6H), 1.76 (m, 4H), 1.66 (m, IH), 1.41 (m, 2H), 1.32-1.28 (m, 3H), 1.23 (m, 4H); m/z 609.3 (M+l).

Example 10

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-fluorobenzamide (Compound 10)

1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with 2-fluorobenzoyl chloride according to procedure followed in step li of Example 1. Yield: 64.3%;

1H NMR (DMSO-de, 300 MHz): δ 10.53 (br s,lH), 9.63 (s, lH), 8.28 (d, J=6 Hz, IH), 7.95 (s, IH), 7.96-7.77 (d, J=6 Hz, IH), 7.67-7.62 (t, J=6 Hz, 2H), 7.40-7.24 (m, 3H), 7.43-7.30 (m, 3H), 7.26-7.24 (d, J=6Hz, IH), 6.99-6.96 (d, J=9 Hz, 2H), 6.59-6.58 (d, J=4.8Hz, IH) 4.70-4.5(m, 7H), 4.04-3.99 (t, J=6 Hz, 2H), 3.73-3.70(d, J=9 Hz, 2H), 3.52-3.52 (s, 2H), 3.15-3.09 (m, 3H), 1.32-1.27 (t, J=7.2 Hz, 3H); m/z 621.6 (M+l).

Example 11

2-ethoxy-N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2,l-b]thiazol-6-yl)phenyl)benzamide (Compound 11)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with 2-ethoxybenzoyl chloride according to procedure followed in step li of Example 1. Yield: 66.8%;

1H NMR (DMSO-d₆, 300 MHz): δ 10.19 (br s,lH), 9.50 (s, lH), 8.27 (d, J=4.8 Hz, IH), 7.90 (s, IH), 7.77-7.74 (d, J=7.8 Hz, IH), 7.69 (d, J=9 Hz, IH), 7.55-7.46 (m 3H), 7.41-7.35 (t, J=9Hz, IH), 7.24, 7.21 (d, J=9 Hz, IH), 7.17-7.14 (d, J=9 Hz, IH), 7.08-7.03 (t, J=6 Hz, IH), 6.97- 6.95 (d, J=6 Hz, 2H), 6.59-6.58 (d, J=4.8 Hz, IH), 4.59-4.55 (t, J=6 Hz, 2H), 4.19-4.17 (t, J=6.Hz, 2H), 4.14-3.9 (m, 6H), 3.74 (d, J=12 Hz, 2H), 3.55-3.51(d, J=12 Hz, 2H), 3.19-2.9 (m, 4H), 1.36- 1.34 (t, J=6 Hz, 3H), 1.27 (t, J=6 Hz, 3H); m/z 647.6 (M+l).

Example 12

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo [2,1- b]thiazol-6-yl)phenyl)cyclopentanecarboxamide (Compound 12)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with cyclopentanecarbonyl chloride according to procedure followed in step li of Example 1. Yield: 50.3%; 1H NMR (DMSO-de, 300 MHz): δ 11.06 (s, IH), 10.10 (s, IH), 9.71 (s, IH), 8.27-8.25 (d, J=4.8Hz, IH), 7.85 (s, IH), 7.69(d, IH), 7.54-7.52 (d, J=8.1 Hz, 2H), 7.57-7.31 (t, J=7.5 Hz, IH), 7.17-7.15 (d, J=7.2 Hz, IH), 7.00-6.97 (d, J=8.1 Hz, 2H), 6.56-6.55 (d, J=5.1 Hz, IH), 4.60 (t, J=6.9 Hz, 2H), 4.03 (t, J=6.9 Hz, 2H), 3.75-3.72 (d, J=9.0 Hz, 2H), 3.56-3.53 (d, J=7.2 Hz, 2H), 3.14-3.11 (m, 6H), 2.80 (m, IH), 1.83 (m, 2H), 1.67 (m, 4H), 1.55 (m, 2H), 1.32-1.28 (t, J=6.9 Hz, 3H); m/z 595.4 (M+l).

Example 13

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo [2,1- b]thiazol-6-yl)phenyl)cyclobutanecarboxamide (Compound 13)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with cyclobutanecarbonyl chloride according to procedure followed in step li of Example 1. Yield: 48.1%;

¾ NMR (DMSO-de, 300 MHz): δ 10.61 (s, IH), 9.89 (s, IH), 9.63 (s, IH), 8.27-8.25 (d, J=5.1 Hz, IH), 7.84 (s, IH), 7.69-7.67 (d, J=7.8 Hz, IH), 7.55-7.52 (d, J=8.4 Hz, 2H), 7.36-7.31 (t, J=7.8 Hz, IH), 7.17-7.15 (d, J=7.5 Hz, IH), 7.00-6.97 (d, J=8.7 Hz, 2H), 6.56-6.54 (d, J=5.1 Hz, IH), 4.59 (t, J=6.9 Hz, 2H), 4.10 (t, J=6.9 Hz, 2H), 3.75 (m, 2H), 3.54 (m, 2H), 3.26-3.23 (m, IH), 3.20-3.17 (m, 2H), 3.13-3.06 (m, 4H), 2.24-2.18 (m, 2H), 2.10-1.98 (m, 2H), 1.91-1.88 (m, IH), 1.80 (m, IH), 1.32-1.27 (t, J=6.9 Hz, 3H); m/z 581.3 (M+l).

Example 14

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-(thiophen-2-yl)acetamide (Compound 14)

1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with 2-(thiophen-2- yl)acetyl chloride according to procedure followed in step li of Example 1. Yield: 67.3%;

1H NMR (DMSO-d₆, 300 MHz): δ 10.94 (s, IH), 10.48 (s, IH), 9.62 (s, IH), 8.26-8.25 (d, J=5.1 Hz, IH), 7.82 (s, IH), 7.69-7.66 (d, J=7.5 Hz, IH), 7.54-7.51 (d, J=8.1 Hz, 2H), 7.38-7.32 (m,

2H), 7.20-7.17 (d, J=6.9 Hz, IH), 6.98-6.95 (m, 4H), 6.56-6.55 (d, J=5.1 Hz, IH), 4.57 (t, J=6.9 Hz, 2H), 4.00 (t, J= .9 Hz, 2H), 3.89 (s, 2H), 3.73-3.71 (d, J=7.8 Hz, 2H), 3.55 (d, J=7.8Hz, 2H), 3.16-3.09 (m, 6H), 1.32-1.27 (t, J=6.9 Hz, 3H); m/z 622.9 (M+l).

Example 15

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo

[2,l-b]thiazol-6-yl)phenyl)cyclopropanecarboxamide (Compound 15)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with cyclopropanecarbonyl chloride according to procedure followed in step li of Example 1. Yield: 42.2%;

1H NMR (DMSO-d₆, 300 MHz): δ 10.81 (s, IH), 10.41 (s, IH), 9.67 (s, IH), 8.28-8.26 (d, J=5.4 Hz, IH), 7.82 (s, IH), 7.70-7.68 (d, J=7.8 Hz, IH), 7.53-7.50 (d, J=8.1 Hz, 2H), 7.37-7.32 (t, J=7.8 Hz, IH), 7.17-7.15 (d, J=7.2 Hz, IH), 6.99-6.96 (d, J=8.4 Hz, 2H), 6.57-6.55 (d, J=5.4 Hz), 4.59 (t, J=6.9 Hz, 2H), 4.06 (t, J=6.9 Hz, 2H), 3.75-3.72 (d, J=8.4 Hz, 2H), 3.54 (d, J=8.4 Hz, 2H), 3.17-3.15 (m, 2H), 3.10-3.08 (m, 4H), 1.81 (m, IH), 1.32-1.27 (t, J=6.9 Hz, 3H), 0.79-0.78 (d, J=5.7 Hz, 4H); m/z 567.5 (M+l).

Example 16

[2,l-b]thiazol-6-yl)phenyl)picolinamide (Compound 16)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with picolinoyl chloride according to procedure followed in step li of Example 1. Yield: 74.3%;

1H NMR (DMSO-d₆, 300 MHz: δ 10.72 (s, IH), 9.33 (s, IH), 8.75 (s, IH), 8.25-8.23 (d, IH, J=4.8 Hz), 8.18 (s, IH), 8.15 (s, IH), 8.10-8.07 (t, IH, J = 7.2Hz), 7.92-7.89 (d, IH, J=7.5 Hz), 7.68 (m, IH), 7.47-7.45 (d, 2H, J=7.5 Hz), 7.40-7.35 (t, IH, J=7.8 Hz), 7.24-7.22 (d, IH, J=7.2 Hz), 6.88-6.85 (d, 2H, J=8.1 Hz), 6.59-6.57 (d, IH, J=4.8 Hz), 4.55 (t, 2H, J=6.9 Hz), 3.98 (t, 2H, J=6.6Hz), 3.18-3.16 (m, 2H), 3.05 (m, 4H), 2.40 (m, 4H), 1.03 (t, 3H, J=6.9 Hz); m/z 604.6 (M+l). Example 17

[2,l-b]thiazol-6-yl)phenyl)piperidine-l-carboxamide (Compound 17)

1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with piperidine-1- carbonyl chloride according to procedure followed in step li of Example 1. Yield: 40.9%;

XH NMR (DMSO-de, 300 MHz): δ 9.36 (s, IH), 5.60 (s, 2H), 8.51 (s, IH), 8.24-8.22 (d, J=5.1 Hz, IH), 7.67 (s, IH), 7.52 (m, 2H), 7.24-7.19 (t, J=7.8 Hz, IH), 7.03-7.00 (d, J=7.5 Hz, IH), 6.95-6.92 (d, J=8.1 Hz, 2H), 6.56-6.55 (d, J=5.1 Hz, IH), 4.58-4.53 (t, J=6.3 Hz, 2H), 3.99-3.95 (t, J=6.3 Hz, 2H), 3.422-3.40 (m, 4H), 3.01-2.98 (m, 6H), 1.68-1.65 (m, 4H), 1.58-1.56 (m, 4H), 1.55-1.48 (m, 2H), 1.24-1.96 (m, 3H); m/z 610.6 (M+l). Example 18

[2, 1 -b]thiazol-6-yl)phenyl)-3,3-dimethylbutanamide (Compound 18)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with 3,3- dimethylbutanoyl chloride according to procedure followed in step li of Example 1. Yield: 41.8%;

1H NMR (DMSO-d₆, 300 MHz): δ 10.82 (Br s, IH), 9.98 (s, IH), 9.67 (s, IH), 8.26-8.24 (d, J=5.1 Hz, IH), 7.85 (s, IH), 7.66-7.64 (d, J=7.8 Hz, IH), 7.54-7.52 (d, J=8.4 Hz, 2H), 7.36-7.31 (t, J=7.8 Hz, IH), 7.18-7.160 (d, J=7.2 Hz, IH), 7.00-6.97 (d, J=8.4 Hz, 2H), 6.58-6.56 (d, J=5.1 Hz, IH), 4.61-4.57 (t, J=6.0 Hz, 2H), 4.05-4.00 (t, J=6.0 Hz, 2H), 3.74-3.72 (m, 2H), 3.56-3.54 (m, 2H), 3.22-3.08 (m, 6H), 2.19 (s, 2H), 1.35-1.32 (t, 3H, J = 5.1 Hz), 1.00 (s, 9H); m/z 597.3 (M+l). Example 19

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyri

b]thiazol-6-yl)phenyl)-3-methylbutanamide (Compound 19)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with 3-methylbutanoyl chloride according to procedure followed in step li of Example 1. Yield: 54.8%;

XH NMR (DMSO-de, 300 MHz): δ 10.81 (Br s, IH), 10.00 (s, IH), 9.54 (s, IH), 8.25-8.24 (d, J=4.8 Hz, IH), 7.82 (s, IH), 7.66-7.63 (d, J=7.5 Hz, IH), 7.56-7.53 (d, J=8.1 Hz, 2H), 7.34-7.28 (t, J=7.5 Hz, IH), 7.17-7.14 (d, J=7.5 Hz, IH), 6.99-6.96 (d, J=8.1 Hz, 2H), 6.56-6.54 (d, J=4.8 Hz, IH), 4.59-4.55 (t, J=6.9 Hz, 2H), 4.02-3.98 (t, J=6.9 Hz, 2H), 3.74-3.71 (m, 2H), 3.56-3.53 (m, 2H), 3.18-3.07 (m, 6H), 2.19-2.17 (d, J=6.9 Hz, 2H), 2.10-2.01 (m, IH), 1.34-1.29 (t, J=5.7 Hz, 3H), 0.93-0.91 (d, J=6.0 Hz, 6H); m/z 583.3 (M+l). Example 20

2-cyclopentyl-N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2,l-b]thiazol-6-yl)phenyl)acetamide (Compound 20)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with 2-cyclopentyl acetyl chloride according to procedure followed in step li of Example 1. Yield: 47.5%;

1H NMR (DMSO-de, 300 MHz): δ 10.59 (Br s, IH), 10.00 (s, IH), 9.60 (s, IH), 8.26-8.24 (d, J=5.1 Hz, IH), 7.83 (s, IH), 7.66-7.63 (d, J=7.8 Hz, IH), 7.55-7.52 (d, J=8.1 Hz, 2H), 7.35-7.30 (t, J=7.8 Hz, IH), 7.17-7.15 (d, J=7.8 Hz, IH), 6.99-6.96 (d, J=8.1 Hz, 2H), 6.56-6.55 (d, J=5.1 Hz, IH), 4.59-4.57 (t, J= 6.9 Hz, 2H), 4.02-3.99 (t, J=6.9 Hz, 2H), 3.75-3.72 (m, 2H), 3.57-3.54 (m, 2H), 3.17-3.06 (m, 6H), 2.31-2.29 (d, J=6.6 Hz, 2H), 2.23-2.18 (m, IH), 1.72 (m, 2H), 1.59 (m, 2H), 1.52 (m, 2H), 1.32-1.27 (t, J=7.2 Hz, 3H), 1.18 (m, 2H); m/z 609.3 (M+l).

Example 21

N-(3-(5-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b]thiazol-6- yl)phenyl)-2-phenylacetamide (Compound 21) The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- morpholino)phenyl)pyrimidin-2-amine with 2-phenylacetyl chloride according to procedure followed in Step li of Example 1. Yield: 65.3%;

1H NMR (DMSO-de, 300 MHz): δ 10.22 (s,lH), 9.34 (s, IH), 8.23-8.21(d, J=6Hz, IH), 7.76 (s,lH), 7.66-7.64 (d, J=6Hz, IH), 7.52-7.49 (d, J=9 Hz, 2H), 7.32-7.22 (m, 6H), 7.17-7.14 (d, J=9Hz, IH), 6.91-6.88 (d, J=9 Hz, 2H), 6.53-6.51 (d, J=9Hz, IH), 4.55-4.50 (t, J=6Hz, 2H), 3.98-3.94 (t, J=6 Hz, 2H) , 3.75-3.72 (t, J=6Hz, 4H), 3.62 (s, 2H) , 3.05-3.02 (t, J=4.8Hz, 4H); m/z 590.5 (M+l).

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- morpholino)phenyl)pyrimidin-2-amine was obtained by the reduction of N-(4- morpholinophenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2- amine according to procedure followed in Step lh of Example 1. 4-(6-(3-aminophenyl)-2,3- dihydroimidazo[2, 1 -b]thiazol-5-yl)-N-(4-(4-morpholino)phenyl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

N-(4-morpholinophenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine was obtained by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)- 2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-morpholinoaniline according to procedure followed in Step lg of Example 1. N-(4-morpholinophenyl)-4-(6-(3-nitrophenyl)- 2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

Example 22

N-(3-(5-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b]thiazol-6- yl)phenyl)cyclohexanecarboxamide (Compound 22)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- morpholino)phenyl)pyrimidin-2-amine (prepared according to procedure given in Example 21) with cyclohexylcarbonyl chloride according to procedure followed in Step li of Example 1. Yield: 57.5%; 1H NMR (DMSO-de, 300 MHz): δ 9.94 (br s, IH), 9.76 (s, IH), 8.30-8.28 (d, J=6 Hz, IH), 7.83 (s, IH), 7.68-7.602 (m, 3H), 7.35-7.30 (t, J=9 Hz, IH), 7.25 (s, IH), 7.16-7.13 (d, J=9 Hz, 2H), 6.61-6.59 (d, J=6 Hz, IH), 4.60 (t, J=6.9 Hz, 2H), 4.05-4.03 (m, 5H), 3.88 (m, 4H), 3.27 (s, 3H), 2.32-2.28 (d, J=12 Hz, 2H), 1.76-1.66 (m, 3H), 1.37-1.23 (m, 4H); m/z 582.3 (M+l).

Example 23

(R)-N-(3-(5-(2-(2-(phenoxymethyl)morpholino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b] thiazol-6-yl)phenyl)-2-phenylacetamide (Compound 23)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of (R)-3-(5-(2-(2-(phenoxymethyl)morpholino)pyrimidin-4-yl)-2,3- dihydroimidazo[2,l-b]thiazol-6-yl)aniline with 2-phenylacetyl chloride, according to procedure followed in Step li of Example 1. Yield: 57.1%;

^XH NMR (DMSO-de, 300 MHz): δ 10.24 (br s, IH), 8.32 (s, IH), 8.23-8.21 (d, IH, J = 5.1 Hz),

7.75(s, IH), 7.65-7.63 (d, J=8.1Hz, IH), 7.33-7.31 (m, 5H), 7.28-7.25 ( m, 3H), 7.17-7.14 (d, J=9 Hz, IH), 6.99-6.93 (t, J=8.1Hz, 3H), 6.46-6.44 (d, J=5.1Hz, IH). 4.61-4.573 (t, J=6.9 Hz, 2H),

4.54-4.39 (d, J=12 Hz, IH), 4.09-4.07 (d, J=6 Hz, 2H), 4.012-3.96 (t, J=13 Hz, 3H), 3.86-3.82

(m, 2H), 3.36 (m, 3H), 3.09- 2.73 (m, 2H); m/z 605.2 (M+l).

(R)-3-(5-(2-(2-(phenoxymethyl)morpholino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)aniline was obtained by reduction of (R)-4-(4-(6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-yl)-2-(phenoxymethyl)morpholine according to the procedure followed in Step lh of Example 1.

1H NMR (DMSO-de, 300 MHz): δ 8.20(d, J = 6 Hz, 2H), 7.33-7.28 (t, J = 9 Hz, 2H), 7.03-6.93 (m, 3H), 6.69 (s, IH), 6.59-6.47 (m, 2H), 6.47-6.45 (d, J = 6 Hz), 5.76(s, IH), 5.1 l(s, 2H), 4.59- 4.5 l(m, 3H), 4.42-4.38 (d, J = 12 Hz, IH), 4.062 (s, 2H), 3.99-3.97 (m, 3H), 3.82 (m, IH), 3.61- 3.54 (t, J = 10.8Hz, IH), 3.08-3.01 (t, J = 11.1Hz, IH), 2.95-2.87 (t, J = 12Hz, IH); m/z 487.4 (M+l).

(S)-4-(4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)pyrimidin-2-yl)-2- (phenoxymethyl)morpholine was obtained by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (compound of step If, Example 1) with (S)-2- (phenoxymethyl)morpholine according to procedure followed in Step lg of Example 1. 1H NMR (DMSO-de, 300 MHz): δ 8.35 (m, 2H) , 8.16-8.13 (d, J=7.8Hz, IH), 8.00-7.97 (d, J=9 Hz, IH), 7.68-7.63 (t, J=8.1Hz, IH), 7.33-7.28 (t, J=9 Hz, 2H), 6.97-6.95 (d, J=9 Hz, 3H), 6.602- 6.58 (d, J=4.8 Hz, IH), 4.59-4.5 l(m, 3H), 4.42-4.38 (d, J=12 Hz, IH), 4.062 (s, 2H), 3.99-3.97 (m, 3H), 3.82 (m, IH), 3.61-3.54 (t, J=10.8 Hz, IH), 3.08- 3.01 (t, IH, J=l l.lHz), 2.95-2.87 (t, lH, J=12Hz); m/z 517.2 (M+l).

The data for (S)-2-(phenoxymethyl)morpholine: 1H NMR (DMSO-d₆, 300 MHz): δ 7.30-7.27 (m, 2H), 6.96-6.91 (m, 3H), 3.97-3.85 (m, 4H), 3.66 (m, IH), 3.03-2.98 (m, IH), 2.85-2.81 (m, 2H), 2.74-2.71 (m, IH); m/z 194.2 (M+l). Example 24

N-(3-(5-(2-((4-(4-acetamidopiperidin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydro

imidazo[2, l-b]thiazol-6-yl)phenyl)-2-phenylacetamide (Compound 24)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of N-(l-(4-((4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)acetamide with 2-phenylacetyl chloride according to procedure followed in Stepli of Example 1. Yield: 59%;

1H NMR (DMSO-de, 300 MHz): δ 12.71(s,lH), 10.39 (s, IH), 9.93 (s,lH), 8.36-8.34 (d, J=6 Hz, IH), 8.17 (s, IH), 7.83 (s, IH), 7.77 (s, 2H), 7.67-7.64 (d, J=9 Hz, 2H), 7.32-7.24 (m, 5H), 7.24- 7.16 (d, J=7.5 Hz, 3H), 6.69-6.68 (d, J=4.8 Hz, IH), 4.64- 4.59 (t, J=9 Hz, 2H), 4.05- 4.00 (m, 4H), 3.64 (s, 3H), 3.55-3.50 (m , 2H), 3.16 (s, IH), 2.08-2.01 (m, 3H), 184-1.81 (s, 3H); m/z 645.2 (M+l).

N-(l-(4-((4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2- yl)amino)phenyl)piperidin-4-yl)acetamide was obtained by the reduction of N-(l-(4-(4-(6-(3- nitrophenyl)-2,3-dihydroimidazo[2, 1 -b]thiazol-5-yl)pyrimidin-2-ylamino)phenyl) piperidin-4- yl)acetamide according to procedure followed in Step lh of Example 1.

1H NMR (DMSO-de, 300 MHz): δ 9.279 (s, IH), 8.19-8.18 (d, J=5.1Hz, IH), 7.84- 7.82 (d, J=7.2 Hz, IH), 7.50-7.47 (d, J=9 Hz, 2H), 7.02-6.99 ( t, J=9Hz, IH), 6.92-6.89 (d, J=9 Hz, 2H), 6.72 (s, IH), 6.60-6.5 l(m, 2H), 5.76 (s, IH), 5.12(s, 2H), 4.54- 4.52 (t, J=6Hz, 2H), 3.97-3.95 (t, J=6 Hz, 2H), 3.68-3.5 (m, 5H), 2.74-2.67(m, 3H), 1.80(s, 4H); m/z 527.1 (M+l).

N-(l-(4-(4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)pyrimidin-2-yl amino)phenyl)piperidin-4-yl)acetamide was obtained by reaction of 5-(2-chloropyrimidin-4-yl)- 6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazole (compound of step If, Example 1) with N- (l-(4-aminophenyl) piperidin-4-yl)acetamide according to procedure followed in Step lg of Example 1.

^XH NMR (DMSO-de, 300 MHz): δ 9.40 (s, IH), 8.35-8.32 ( t, J=6 Hz, 2H), 8.17-8.14 (d, J=9 Hz, IH), 8.00-7.98(d, J=6 Hz, IH), 7.84-7.82(d, J=7.2 Hz, IH), 7.67-7.61(t, J=8.1 Hz, 1H),7.44- 7.42(d, J=6 Hz, 2H), 6.85-6.82 (d, J= 8.4 Hz, 2H), 6.66 -6.65 (d, J=4.8 Hz, IH), 4.51-4.49 (t, J= 6 Hz), 4.01-3.99 (t, 6.8 Hz, 2H), 3.6(m, IH), 3.54-3.50 (d, J=12 Hz, 2H), 2.73-2.60 (m, 2H), 1.80 (s, 4H), 1.48-1.45 (m, 3H); m/z 557.1 (M+l).

NMR data for N-(l-(4-aminophenyl)piperidin-4-yl)acetamide: 1H NMR(DMSO-d₆, 300MHz): δ 7.8(d, J=7.5 Hz, 2H), 6.7(d, J=8.1 Hz, 2H), 6.49(d, J=8.1 Hz, 2H), 4.54(s, 2H), 3.57(bs, IH), 3.32(d, J = 17.7Hz, 2H), 2.55(t, J = 15.9Hz, 2H), 1.79(s, 3H), 1.48(t, J=9.6Hz, 2H); m/z 234.5 (M+l).

Example 25

l-cyclohexyl-3-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2,l-b]thiazol-6-yl)phenyl)urea (Compound 25)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with cyclohexyl isocyanate using THF as solvent and at RT for 16h to 18h. Yield: 51.3%;

'H NMR (DMSO-de, 300 MHz): δ 9.32 (s,lH), 8.36 (s, IH), 8.23-8.21 (d, J=6 Hz, IH), 7.48- 7.39 (m,3H) 7.24-7.18 (t, J=9 Hz, IH), 6.99-6.96 (d, J=9 Hz, IH), 6.89-6.86 (d, J=9 Hz, 2H), 6.52-6.51 (d, J=5.4 Hz, IH) 6.04-6.00 (d, J=9.6 Hz, IH), 4.55-4.51 (t, J=6.3 Hz, 2H), 3.06(s, 4H), 2.38-2.33 (m, 2H), 1.81-1.52 (m, 6H), 1.27-1.60 (m, 8H),1.06-1.04 (t, J=6.6 Hz, 3H); m/z 624.1 (M+l).

Example 26

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo [2,1- b]thiazol-6-yl)phenyl)nicotinamide (Compound 23)

1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with nicotinyl chloride according to procedure followed in step li of Example 1. Yield: 46.8%;

1H NMR (DMSO-de, 300 MHz): δ 10.62 (br s,lH), 10.40 (s, IH), 9.53 (s, IH), 9.16 (s, IH), 8.82 (s, IH), 8.42-8.39 (d, J=9 Hz, IH), 8.28-8.27 (d, J=3 Hz, IH), 8.016 (s, IH), 7.87-7.83 (d, J=12 Hz, IH) ,7.66-7.65 (s, IH), 7.55-7.52 (d, J=9 Hz, IH), 7.43-7.25 (m, 3H), 6.98-6.95 (d, J=9 Hz, 2H), 6.67-6.65 (m, IH), 4.60-4.49 (m, 2H), 4.04-3.9 ( t, J=12 Hz, 2H), 3.75-3.52 (m, 4H), 3.19- 2.98 (m , 6H), 1.30 (t, J=9 Hz, 3H); m/z 604 (M+l).

Example 27

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo [2,1- b]thiazol-6-yl)phenyl)-3,5-difluorobenzenesulfonamide (Compound 27)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with 3,5-difluorobenzene- 1 -sulphonyl chloride in DCM in the presence of pyridine at RT for lh. Yield: 75.7%;

1H NMR (DMSO-d₆, 300 MHz): δ 10.57 (br s,lH), 9.58 (s, IH), 9.44 (s, IH), 8.19 (d, J=5.1 Hz, IH), 7.65 (d, J=12 Hz, IH), 7.57-7.55 (d, J=5.4 Hz, IH), 7.41 (s, IH), 7.33-7.17 (m, 6H), 6.95- 6.93 (d, J=5.7 Hz, 2H), 6.40-6.38 (d, J=6 Hz, IH), 4.59-4.55 (t, J=6 Hz, 2H), 4.19-4.17 (t, J=6 Hz, 2H), 3.7 (d, J=12 Hz, 2H), 3.21-3.13 (m, 5H), 2.90-2.80 (m, 3H), 1.25 (t, J=6 Hz, 3H); m/z 672.6 (M+l).

Example 28

(lR,4S)-N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydro imidazo[2, l-b]thiazol-6-yl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (Compound 28)

1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with (1R, 4S)- bicyclo[2.2.1]heptane-2-carbonyl chloride according to procedure followed in step li of Example 1. Yield: 45.2%;

1H NMR (DMSO-de, 300 MHz): δ 10.3 (s, IH), 9.93 (s, IH), 9.40 (s, IH), 8.25-8.23 (d, J=4.8 Hz, IH), 7.79 (s, IH), 7.66-7.63 (d, J=7.2 Hz, IH), 7.56-7.53 (d, J=7.8 Hz, 2H), 7.30-7.25 (t, J=7.5 Hz, IH), 7.14-7.11 (d, J=7.8 Hz, IH), 6.96-6.93 (d, J=7.8 Hz, 2H), 6.56-6.54 (d, J=4.8 Hz, IH), 4.54 (t, J=6.9 Hz, 2H), 3.99-3.97 (t, J=6.9 Hz, 2H), 3.69-3.52 (m, 4H), 3.05 (m, 6H), 2.36 (m, 2H), 2.24 (m, 2H), 1.19-1.83 (m, IH), 1.48 (t, J=6.9 Hz, 3H), 1.34 (m, 2H), 1.30 (m, 2H), 1.08-1.05 (m, IH), 0.86 (m, IH); m/z 621 (M+l).

Example 29

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)benzo[d] [ 1 ,3]dioxole-5-carboxamide (Compound 29)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with benzo[d][l,3]dioxole-5-carbonyl chloride according to procedure followed in step li of Example 1. Yield: 49%;

1H NMR (DMSO-d₆, 300 MHz): δ 10.11 (s, IH), 9.31 (s, IH), 8.24-8.23 (d, J=4.8 Hz, IH), 7.96 (s, IH), 7.83-7.81 (d, J=7.2 Hz, IH), 7.58-7.55 (d, J=7.2 Hz, IH), 7.51 (s, IH), 7.45-7.42 (m, J=9 Hz, 2H), 7.33-7.30 (t, J=9 Hz, 1 H), 7.18-7.16 (d, J=6 Hz, IH), 7.06-7.03 (d, J=9 Hz, IH), 6.86- 6.83 (d, J=9 Hz, 2H), 6.58-6.55 (d, J=6 Hz, IH), 6.12 (s, 2H), 4.53 (m, 2H), 3.96.(m, 2H), 3.03 (m, 8H), 2.35-2.33 (q, J=6 Hz, 2H), 1.04-0.9 (t, 3H); m/z 647.2 (M+l). Example 30

N-(3-(5-(2-([l, r-biphenyl]-4-ylamino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b]thiazol-6- yl)phenyl)-2-phenylacetamide (Compound 30)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N- (biphenyl-4-yl)pyrimidin-2-amine with 2-phenyl acetylchloride according to procedure followed in Step li of Example 1. Yield: 54%;

1H NMR (DMSO-d₆, 300 MHz): δ 10.28 (s, IH), 9.78 (s, IH), 8.35-8.33 (d, J=5.1 Hz, IH), 7.81- 7.77 (m, 2H), 7.66-7.60 (m, 5H), 7.47-7.42 (t, J=7.5 Hz, 2H), 7.33-7.32 (m, 5H), 7.26 (m, IH), 7.20-7.17 (d, J=7.5 Hz, IH), 6.65-6.64 (d, J=5.1 Hz, IH), 4.628 (t, J=6.3 Hz, 2H), 4.05-4.00 (t, J=6.3 Hz, 2H), 3.63 (s, 2H); m/z 581.3 (M+l). 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-([l, l^/-biphenyl]-4- yl)pyrimidin-2-amine was obtained by the reduction of N-([l, l'-biphenyl]-4-yl)-4-(6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine according to procedure followed in Step lh of Example 1.

XH NMR (DMSO-de, 300 MHz): δ 9.69 (s, IH), 8.30-8.29 ( d, J=5.1Hz, IH), 7.83-7.80 (d, J = 8.1 Hz, 2H), 7.83-7.80 (t, J = 9 Hz, 3H), 7.44-7.42 (t, J = 7.2 Hz, 2H), 7.33-7.31 (d, J = 6.9 Hz, IH), 7.03-7.00 (t, 9.6 Hz, IH), 6.74 (s, IH), 6.62-6.53 (m, 3H), 5.76 (s, IH), 5.14 (s, 2H) 4.60- 4.58 (t, J = 6 Hz, 2H„ 3.99-3.97 (t, J = 6 Hz, 2H); m/z 463.2 (M+l).

N-([l,l^/-biphenyl]-4-yl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine was obtained by 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazole (compound of Step If, Example 1) with biphenyl-4-amine according to procedure followed in Step lg of Example 1. N-([l,l'-biphenyl]-4-yl)-4-(6-(3- nitrophenyl)-2,3-dihydroimidazo [2,l-b]thiazol-5-yl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

Example 31

N-(3-(5-(2-((6-(4-methylpiperazin-l-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2,l-b]thiazol-6-yl)phenyl)-2-phenylacetamide (Compound 31)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)pyrimidin-2-amine with 2-phenylacetyl chloride according to procedure followed in Step li of Example 1. Yield: 70.8%;

1H NMR (DMSO-d₆, 300 MHz): δ 10.39 (br. s, IH), 10.28 (s, IH), 9.57 (s, IH), 8.42 (s, IH),

8.27-8.25 (d, J=5.1 Hz, IH), 7.98-7.95 (d, J=8.4 Hz, IH), 7.81 (s, IH), 7.65-7.62 (d, J=7.8 Hz, IH), 7.33-7.28 (m, 5H), 7.26 (m, IH), 7.18-7.15 (d, J=7.8 Hz, IH), 7.03-6.99 (m, IH), 6.59-6.58

(d, J=5.1 Hz, IH), 4.55 (t, J=6.3 Hz, 2H), 4.00 (t, J=6.3 Hz, 2H), 3.63 (s, 2H), 3.00-3.50 (m, 8H),

2.82 (s, 3H); m/z 604.1 (M+l).

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(6-(4-methylpiperazin- l-yl)pyridin-3-yl)pyrimidin-2-amine was obtained by the reduction of N-(6-(4-methylpiperazin- l-yl)pyridin-3-yl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)pyrimidin-2- amine according to procedure followed in Step lh of Example 1. 4-(6-(3-aminophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)-N-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)pyrim amine obtained in this reaction step was used in the subsequent reaction step without purification.

N-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo [2,l-b]thiazol-5-yl)pyrimidin-2-amine was obtained by 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (compound of Step If, Example 1) with 6-(4- methylpiperazin-l-yl)pyridin-3-amine according to procedure followed in Step lg of Example 1. [N-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

NMR data for 4-(4-methylpiperazin-l-yl)aniline: 1H NMR(DMSO-d₆, 300 MHz): 7.58 (s, IH), 6.91-6.89 (d, J = 7.8 Hz, IH), 6.63-6.60 (d, J = 7.8 Hz, IH), 4.54 (s, 2H), 3.22-3.19 (m, 4H), 2.39-2.38 (m, 4H), 2.21 (s, 3H); m/z: 193.2 (M+l). Example 32

N-(3-(5-(2-((4-(4-acetamidopiperidin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)-2-cyclohexylacetamide (Compound 32)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of N-(l-(4-((4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)acetamide with 2-cyclohexylacetyl chloride according to procedure followed in Step li of Example 1. Yield: 47%;

^XH NMR (DMSO-de, 300 MHz): δ 9.88 (s, IH), 9.30 (s, IH), 8.22-8.21 (d, J=5.1 Hz, IH), 7.80- 7.81 (d, J=7.2 Hz, IH), 7.77 (s, IH), 7.63-7.61 (d, J=7.5 Hz, IH), 7.49-7.46 (d, J= 8.4 Hz, 2H), 7.31-7.25 (t, 8.1 Hz, IH), 7.15 (m, IH), 6.91-6.88 (d, J=8.4 Hz, 2H), 6.53-6.51 (d, J=5.1 Hz, IH), 4.53 (t, J=6.3 Hz, 2H), 3.96 (t, J=6.3 Hz, 2H), 3.51 (m, 2H), 2.71-2.67 (m, 3H), 2.18-2.16 (d, J=6.9 Hz, 2H), 1.80 (s, 3H), 1.65 (m, 4H), 1.34 (m, 2H), 1.24 (m, 6H); m/z 651 (M+l).

N-(l-(4-((4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2- yl)amino)phenyl)piperidin-4-yl)acetamide was obtained by the reduction of N-(l-(4-(4-(6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-ylamino)phenyl)piperidin-4- yl)acetamide according to procedure followed in Step lh of Example 1. N-(l-(4-((4-(6-(3- aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-4- yl)acetamide obtained in this reaction step was used in the subsequent reaction step without purification.

N-(l-(4-(4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)pyrimidin-2- ylamino)phenyl)piperidin-4-yl)acetamide was obtained by reaction of 5-(2-chloropyrimidin-4- yl)-6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (compound of Step If, Example 1) with N-(l-(4-aminophenyl)piperidin-4-yl)acetamide according to procedure followed in Step lg of Example 1. N-(l-(4-(4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2- ylamino) phenyl)piperidin-4-yl)acetamide obtained in this reaction step was used in the subsequent reaction step without purification.

Example 33

N-(3-(5-(2-((4-(2-(dimethylamino)ethyl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2, l- b]thiazol-6-yl)phenyl)-2-phenylacetamide (Compound 33)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(2- (dimethylamino)ethyl)phenyl)pyrimidin-2-amine with 2-phenylacetyl chloride according to procedure followed in Step li of Example 1. Yield: 71%;

1H NMR (DMSO-de, 300 MHz): δ 10.51 (s, 1H), 10.39 (s, 1H), 9.66 (s, 1H), 8.30-8.29 (d, J=5.1 Hz, 1H), 7.83 (s, 1H), 7.65-7.63 (m, 3H), 7.33 (m, 5H), 7.26-7.18 (m, 3H), 6.61-6.60 (d, J=5.1 Hz, 1H), 4.59 (t, J=6.3 Hz, 2H), 4.00 (t, J=6.3 Hz), 3.65(s, 2H), 3.22-3.17 (m, 2H), 2.98-2.95 (m, 2H), 2.80-2.78 (d, 6H, 4.5 Hz); m/z 575.9 (M+l).

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(2- (dimethylamino)ethyl)phenyl)pyrimidin-2-amine was obtained by the reduction of N-(4-(2- (dimethylamino)ethyl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine according to procedure followed in Step lh of Example 1. 4-(6-(3- aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(2-(dimethylamino)ethyl) phenyl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

N-(4-(2-(dimethylamino)ethyl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)pyrimidin-2-amine was obtained by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (compound of Step If, Example 1) with 4-(2- (dimethylamino)ethyl)aniline according to procedure followed in Step lg of Example 1. N-(4-(2- (dimethylamino)ethyl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thia

yl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

Example 34

2,6-difluoro-N-(3-(5-(2-((4-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)benzamide

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- methylpiperazin-l-yl)phenyl)pyrimidin-2-amine with 2,6-difluorobenzoyl chloride according to procedure followed in Step li of Example 1. Yield: 62%;

1H NMR (DMSO-de, 300 MHz): 10.69 (br s, 1H), 9.52 (s, 1H), 8.27-8.25 (d, 9Hz, 1H), 7.9 (s, 1H), 7.73-7.70 (d, J=9Hz, 1H), 7.62-7.5(m, 3H), 7.42-7.36 (t, J=9Hz, 1H), 7.28-7.23 (t, J=9Hz, 3H), 6.97-6.94(d, J=9Hz, 2H), 6.60-6.58 (d, J=6Hz, 1H), 4.56-4.53 (t, J=6Hz, 2H), 4.00-3.98(t, J=6Hz, 2H), 3.50-3.46 (d, J=12Hz, 2H), 3.17-2.98 (m, 4H), 2.82-2.81(d, J=3Hz, 2H), 1.23(s, 3H); m/z 625 (M+l).

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4-methylpiperazin- l-yl)phenyl)pyrimidin-2-amine was obtained by the reduction of N-(4-(4-methylpiperazin-l- yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine according to procedure followed in Step lh of Example 1. 4-(6-(3-aminophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4-methylpiperazin-l-yl)phenyl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

N-(4-(4-methylpiperazin-l-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)pyrimidin-2-amine was obtained by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (compound of Step If, Example 1) with 4-(4- methylpiperazin-l-yl)aniline according to procedure followed in Step lg of Example 1. N-(4-(4- methylpiperazin-l-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine obtained in this reaction step was obtained in the subsequent reaction step without purification. Example 35

N-(3-(5-(2-((4-(2,6-dimethylmorpholino)phenyl)amm^

b]thiazol-6-yl)phenyl)-2-phenylacetamide

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)-N-(4-(2,6- dimethylmorpholino)phenyl)pyrimidin-2-amine with 2-phenyl acetyl chloride according to procedure followed in Step li of Example 1 Yield: 93.59%.

^XH NMR (DMSO-de, 500 MHz): δ 10.21(s, 1H), 9.33(s, 1H), 8.22(d, = 5.0Hz , 1H), 7.76(s,

1H), 7.66(d, =7.5Hz, 1H), 7.51(d, = 8.50Hz , 2H), 7.32(m, 4H), 7.29(d, = 8.0Hz, 1H), 7.25(d, = 4.0Hz, 1H), 7.17(d, = 7.5 Hz , 1H), 6.90(d, = 9.00Hz , 2H), 6.52(d, / = 5 Hz,

1H), 4.53(bs, 2H), 3.98(t, = 7.0 Hz , 2H), 3.70(bs, 2H), 3.62(s., 2H), 3.49(d, = 10.0Hz, 2H),

2.2(t, = 10.0Hz, 2H), 1.16(d, = 6.0Hz, 6H); m/z 618.5 (M+l).

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(2,6- dimethylmorpholino)phenyl)pyrimidin-2-amine was prepared by reduction of N-(4-(2,6- dimethylmorpholino)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine according to the procedure followed in Step lh in Example 1. 4-(6-(3- aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(2,6- dimethylmorpholino)phenyl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

1H NMR(DMSO-d₆, 500MHz): δ 9.27(s, 1H), 8.20(d, = 5.0Hz, 1H), 7.52(d, = 8.5Hz, 2H), 7.03(dd, = 7.5Hz & 7.5Hz, 1H), 6.92(d, = 8.5Hz, 2H), 6.72(s, 1H), 6.6(d, = 7.50Hz, 1H), 6.53(t, = 5.0Hz, 2H), 5.12(s, 2H), 4.54(bs, 2H), 3.96(t, = 7.0Hz, 2H), 3.70(t, 2H), 3.50(d, = 11.5Hz, 2H), 2.22(t, = 11.0Hz, 2H), 1.16(d, = 6.0Hz, 6H) m/z 500.4 (M+l).

N-(4-(2,6-dimethylmorpholino)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)pyrimidin-2-amine was prepared by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-(2,6- dimethylmorpholino)aniline (prepared as per the procedure given in compound 35A). N-(4-(2,6- dimethylmorpholino)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification. Compound 35 A

Synthesis of 4-(2,6-dimethylmorpholino)aniline

The title compound was prepared as follows. To a solution of 2,6-dimethyl-4-(4- nitrophenyl)morpholine (prepared as per the procedure given in compound 35B) (10.0 g, 42.3 mmol) in ethanol (50.0 ml, 856 mmol), added ammonium chloride (11.32 g, 212 mmol), Iron (11.82 g, 212 mmol), water (10.0 ml, 555 mmol) stirred reaction mass at 90°C for 2 h. The reaction mass was cooled and filtered through the celite and evaporated to dryness. The compound was then added to saturated NaHC0₃ solution and stirred for 30 mins and then filtered to get 4-(2,6-dimethylmorpholino)aniline. 4-(2,6-dimethylmorpholino)aniline obtained in this reaction step was used in the subsequent reaction step (6.0g) Yield: 68.7 %

^XH NMR (DMSO-d₆300 MHz): δ 8.34(d d, = 5.0Hz, 1H), 8.06 (d, = 8.5Hz, 2H), 7.52(d, = 8.5Hz, 1H), 7.05(d, = 9.0Hz, 2H), 3.92(d, =12.5Hz, 2H), 3.66(bs, 2H), 2.53(t, =12.0Hz, 2H), 1.16(d, = 6.0Hz, 6H); m/z 207 (M+l).

Compound 35B

Synthesis of 2,6-dimethyl-4-(4-nitrophenyl)morpholine

The title compound was prepared as follows. To l-fluoro-4-nitrobenzene (6.00 g, 42.5 mmol) added acetonitrile (50.0 ml, 957 mmol) DIPEA (7.43 ml, 42.5 mmol) and 2,6- dimethylmorpholine (4.90 g, 42.5 mmol) stirred reaction mass at 90°C for overnight. The reaction mass was cooled and filtered to get 2,6-dimethyl-4-(4-nitrophenyl)morpholine ( 10.0 g) Yield: 98%

Example 36

N-(3-(5-(2-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)-2-phenylacetamide (Compound 36)

The title compound was prepared in an analogous manner as compound 1 of Example 1 involving reaction of N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-4-(6-(3-aminophenyl)- 2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine with 2-phenylacetyl chloride according to procedure followed in Step li of Example l.Yield: 72.7%.

1H NMR (DMSO-de, 500 MHz): δ 10.23(S, 1H), 9.30(bs, 1H), 8.20(bs, 1H), 7.76(bs, 1H), 7.65(bs, 1H), 7.46(bs, 2H), 7.32(bs, 5H), 7.25(bs, 1H), 7.16(bs, 1H), 6.79(bs, 2H), 6.51(s, 1H), 4.53(bs, 2H), 4.41(bs, 2H), 3.96(bs, 2H), 3.62(bs, 2H), 2.75(bs, 3H), 1.85-(bs, 5H). m/z 616.5 (M+l)

N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-4-(6-(3-aminophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine was prepared by reduction of N-(4-(8-oxa- 3-azabicyclo[3.2J]octan-3-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine according to the procedure followed in Step lh in Example 1. N-(4-(8-oxa- 3-azabicyclo[3.2J]octan-3-yl)phenyl)-4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol- 5-yl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

1H NMR(DMSO-d_6, 300 MHz): δ 9.24 (s, 1H), 8.18(s, 1H), 7.48(s, 2H), 7.03(s, 1H), 6.81(m, 3H), 6.56(m, 3H), 5.30(bs, 2H), 4.53(bd, = 5.7Hz, 4H), 3.91(bs, 2H), 3.44(bs, 2H), 2.76(bs,2H), 1.84(bs, 4H) m/z 498.5 (M+l)

N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine was prepared by reaction of 5-(2- chloropyrimidin-4-yl)-6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline (prepared as per the procedure given in compound 36A) according to procedure followed in Step lg of Example 1. N-(4-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

1H NMR(DMSO-d_6, 300 MHz_, ): δ 9.35(s, 1H), 8.34(dd, = 8.1Hz & 7.8Hz, 2H), 8.16(d, = 8.1Hz, 1H), 8.00(d, = 7.8Hz, 1H), 7.66(dd, = 8.1Hz & 7.8Hz, 1H), 7.43(d, = 8.1Hz, 2H), 6.74(d, = 8.7Hz, 2H), 6.65(d, = 5.1Hz, 1H), 4.51(t, = 6.6Hz, 2H), 4.4(bs, 2H), 4.01(t, = 7.2Hz, 2H), 3.27(bs, 4H), 2.69(bs, 4H), m/z 528 (M+l).

Compound 36 A

Synthesis of 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline

The title compound was prepared by the reduction of 3-(4-nitrophenyl)-8-oxa-3- azabicyclo[3.2.1]octane. 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline obtained in this reaction step was used in the subsequent reaction step without purification.

1H NMR (DMSO-de, 300MHz): δ 6.56(bd, 4H), 4.44(bd, 2H), 3.29(bd, 2H), 63(m,4H), 1.79(bs, 4H). m/z 205.1(M-l) Compound 36B

Synthesis of 3-(4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane

The title compound was prepared in an analogous manner as the compound 35B involving the reaction of l-fluoro-4-nitrobenzene with 8-oxa-3-azabicyclo[3.2.1]octane to obtain 3-(4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane. This compound was used in the subsequent reaction step without purification.

Example 37

N-(3-(5-(2-(quinolin-6-ylamino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b]thiazol-6- yl)phenyl)cyclohexanecarboxamide (Compound 37)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of N-(4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5- yl)pyrimidin-2-yl)quinolin-6-amine with cyclohexanecarbonyl chloride according to procedure followed in Step li of Example 1 Yield: 93.59%

1H NMR (DMSO-de, 500 MHz): 9.95(s, 1H), 9.85(s, 1H), 8.72(d, 1H), 8.42(dd, =5.00Hz & 10.2Hz, 2H), 8.19(d, / =8.0Hz, 1H), 7.94(bs, 2H), 7.83(bs, 1H), 7.65(d, = 8.0Hz, 1H), 7.43(bs, 1H), 7.28(d, = 8.0Hz, 1H), 7.18(d, =7.50Hz, 1H), 6.7 l(d, = 5.0Hz, 1H), 4.63(bs, 2H), 4.0(d, =6.50 Hz, 2H), 2.33(m, 1H), 1.79(m, 5H), 1.43 (m, 2H), 1.29(m, 3H); m/z 548.4 (M+l).

N-(4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-yl)quinolin- 7-amine was prepared by reduction of N-(4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol- 5-yl)pyrimidin-2-yl)quinolin-6-amine amine according to the procedure followed in Step lh in Example 1. N-(4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2- yl)quinolin-6-amine obtained in this reaction was used in the subsequent reaction step without purification.

1H NMR(DMSO-d₆ , 500MHz): δ 9.94 (s, 1H), 8.72(s, 1H), 8.37(d, = 4.5Hz, 1H), 8.24(d, = 8.0 Hz, 1H), 7.95(s, 2H), 7.44(m, 1H), 7.05(t, = 7.5 Hz, 1H), 6.76(s,lH), 6.71(d, = 4.5 Hz, 1H), 6.64(d, = 7.5Hz, 1H), 6.56(d, = 7.5Hz, 1H), 5.14(s, 2H), 4.64(s, 2H), 3.98(t, = 7.0Hz, 2H); m/z 438.5 (M+l).

N-(4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-yl)quinolin- 7-amine was prepared by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with quinolin-6-amine (Commercially available) as per the procedure given in step li of Example 1. N-(4-(6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-yl)quinolin-6-amine obtained in this reaction step was used in the subsequent reaction step without purification. Example 38

N-(3-(5-(2-((4-((2S,6R)-2,6-dimethylmorpholino)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2,l-b]thiazol-6-yl)phenyl)-2-phenylacetamide (Compound 38)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)-N-(4- ((2S,6R)-2,6-dimethylmorpholino)phenyl)pyrimidin-2-amine with 2-phenylacetyl chloride by the method described in Step li of Example 1. Yield: 40.4 %;

1H NMR (DMSO-d₆, 300 MHz): δ 10.22 (bs, 1H), 9.32 (bs, 1H), 8.22 (s, 1H), 7.76-7.65 (d, 2H), 7.50 (s, 2H), 7.32-7.17 (m, 6H), 6.89 (s, 2H), 4.53 (bs, 2H), 3.97 (bs, 2H), 3.69-3.48 (m, 7H), 2.70 (bs, 1H), 1.16 (s, 6H). m/z 618.3 (M+l).

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-((2S,6R)-2,6- dimethylmorpholino)phenyl)pyrimidin-2-amine was prepared by reduction of N-(4-((2S,6R)-2,6- dimethylmorpholino)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine according to the procedure followed in Step lh in Example 1. 4-(6-(3- aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-((2S,6R)-2,6- dimethylmorpholino)phenyl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification. 1H NMR(DMSO-d₆): δ 9.27 (s, 1H), 8.20 (d, J = 5.0 Hz, 1H), 7.52 (d, J = 8.5Hz, 2H), 7.03 (dd, J = 7.5Hz, 1H), 6.92 (d, J = 8.5 Hz, 2H), 6.72 (s, 1H), 6.6 (d, J = 7.50 Hz, 1H), 6.53 (t, J = 5.0 Hz, 2H), 5.12 (s, 2H), 4.54 (bs, 2H), 3.96 (t, J = 7.0 Hz, 2H), 3.70 (t, 2H), 3.50 (d, J = 11.5 Hz, 2H), 2.22 (t, J = 11.0 Hz, 2H), 1.16 (d, J = 6.0 Hz, 6H) m/z 500.4 (M+l) .

N-(4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-(6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine was prepared by reaction of 5-(2- chloropyrimidin-4-yl)-6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-((2S,6R)-2,6-dimethylmorpholino)aniline as per the procedure given in step li of Example 1. N-(4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-(6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

^ NMR (DMSO-de, 500 MHz):9.40 (bs, 1H), 8.36 (s, 1H), 8.34-8.33 (d, 1H, / = 5.0 Hz), 8.16- 8.14 (d, 1H, / = 8.0 Hz), 7.99-7.98 (d, 1H, / = 7.5 Hz), 7.65-7.62 (t, 1H, = 7.5 Hz), 7.46-7.10 (m, 4H), 6.84-6.82 (d, 2H, = 8.0 Hz), 6.67-6.66 (d, 1H, = 4.5 Hz), 4.52 (bs, 2H), 4.01-3.98 (t, 2H, = 7.0 Hz), 3.69 (bs, 2H), 3.47-3.45 (d, 2H, = 11 Hz), 2.30 (m, 1H), 2.21-2.17 (m, 2H), 1.16-1.10 (d, 6H, = 6 Hz), m/z 530.4 (M+l).

Example 39

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)benzo[d] [ 1 ,3]dioxole-5-carboxamide (Compound 39)

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (compound of Step lh of Example 1) with benzo[d][l,3]dioxole-5-carbonyl chloride by the method described in Step li of Example 1. Yield: 15.12%;

H NMR (DMSO-d₆ 300MHz): δ 10.11 (s, 1H), 9.31 (s, 1H), 8.24-8.23 (d, = 4.8 Hz, 1H), 7.96

(s, 1H), 7.83-7.81 (d, = 7.2 Hz, 1H, ), 7.58-7.55 (d, = 7.2 Hz, 1H), 7.51 (s, 1H), 7.45-7.42 (m, = 9 Hz, 2H), 7.33-7.30 (t, = 9 Hz, 1H), 7.18-7.16 (d, = 6 Hz, 1H), 7.06-7.03 (d, = 9Hz, 1H), 6.86-6.83 (d, = 9Hz, 2H), 6.58-6.55 (d, = 6Hz, 1H), 6.12 (s, 2H), 4.53 (m, 2H), 3.96.(m, 2H), 3.03 (m, 8H), 2.35-2.33 (q, / = 6Hz, 2H), 1.04-.9 (t, 3H), m/z 647.3(M+1).

Example 40

N-(3-(5-(2-((4-bromophenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2, l-b]thiazol-6- yl)phenyl)-2-phenylacetamide (Compound 40)

1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)-N-(4- bromophenyl)pyrimidin-2-amine with 2-phenylacetyl chloride according to procedure followed in Step li of Example 1 Yield: 63.8%

XH NMR (DMSO-d6, 300Mz 10.29(s, 1H), 9.81(s, 1H), 8.34(d, = 5.4Hz, 1H), 7.80(br s, 1H),

7.68-7.65(d, = 8.1Hz, 3H), 7.46(d, = 8.7Hz, 2H), 7.32(d, = 4Hz, 4H), 7.2(m, 1H), 7.19(d, = 7.2Hz, 1H), 6.65(d, = 5.1Hz, 1H), 4.60(t, / = 7.2Hz, 2H), 4.02(t, = 6.9Hz, 2H), 3.6 (s, 2H), MS(ES+): 583.5 (M+l), HPLC = 93.85%.

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4- bromophenyl)pyrimidin-2-amine was prepared by reduction of N-(4-bromophenyl)-4-(6-(3- nitrophenyl)-2,3-dihydroirmdazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine according to the procedure followed in Step lh in Example 1. 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)-N-(4-bromophenyl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

Yield = 80%; 1H NMR (DMSO-d6, 300Mz): δ 9.7 (s, 1H), 8.29(s, 1H), 7.69(br s, 2H), 7.47 (s, 2H), 7.02(s, 1H), 6.7-6.63(m, 4H),5.18(br s, 2H), 4.57(t, / = 7.2Hz, 2H), 4.04(t, = 6.9Hz, 2H), MS(ES+): 465.8 (M+l), HPLC = 96.89%

N-(4-bromophenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine was prepared by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)- 2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-bromoaniline N-(4- bromophenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrirmdin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.

Yield = 38.7%, 1H NMR (DMSO-d6, 300Mz): δ 9.84(br,s , 1H), 8.43(d, = 5.2Hz, 1H), 8.35(b, s, 1H), 8.17(d, = 8.1Hz, 1H), 8.01(d, = 7.5Hz, 1H), 7.67-7.63(t, = 6.9Hz, 3H), 7.41(d, =8.4Hz, 2H), 6.80(d, =5.1Hz , 1H), 4.57(t, = 7.2Hz, 2H), 4.04(t, = 6.9Hz, 2H). MS(ES+): 495.2 (M+l), HPLC = 97.79%

Example 41

N-(3-(5-(2-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2,l-b]thiazol-6-yl)phenyl)-2-phenylacetamide (Compound 41)

To a solution of N-(3-(5-(2-((4-bromophenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2,l-b]thiazol-6-yl)phenyl)-2-phenylacetamide (compound of Example 40) (25mg, 0.043 mmol), in 3 ml of dry dioxane, 2-oxa-6-azaspiro[3.3]heptane (16.99 mg, 0.171 mmol) was added and nitrogen was bubbled. Added palladium (II) acetate (4.81 mg, 0.021 mmol) and stirred the reaction mass at RT for 15 mins in microwave. The reaction mass was heated for 120 °C for 30 min and the reaction mass was filtered. The product was extracted with ethyl acetate and purification was done in DCM and methanol. Yield = 58.2 %; 1H NMR (DMSO-d6, 300Mz): δ 10.22(s, 1H), 9.23 (s, 1H), 8.19(d, / = 8Hz, 1H), 7.74(s, 1H), 7.66-7.62(d, = 12Hz, 1H), 7.41-7.39(d, = 8.1Hz, 2H), 7.32-7.21(m, 6H), 7.16-7.12(d, = 12Hz, 1H), 6.50-6.47(d, = 7.2Hz, 1H), 6.40-6.37(d, = 8.4Hz, 2H), 4.70(s, 4H), 4.52-4.44(m, 2H), 3.96-3.94(m, 2H), 3.92(s, 4H), 3.61(s, 2H); MS(ES+): 601.9(M+1), HPLC = 95.53%

Compound 41 A

Synthesis of 4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)aniline

To a solution of 6-(4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptanes (1 g, 4.54 mmol in 15 ml of methanol, added the Pd-C (500mg, 4.70mmol) and hydrogenation at RT for 30 mins. Filtered the reaction mass and concentrated the reaction mass to obtain product. Yield = 75 % H NMR (DMSO-d6, 300Mz): δ 6.47(d, = 8.1Hz, 2H), 6.22 (d, = 7.8Hz), 4.67 (br s, 4H), 4.39 (br s, 2H), 3.33 (br s, 4H) MS(ES+): 191.1(M+1); HPLC = 98.19%

Compound 41B

Synthesis of 6-(4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane

The title compound was prepared in an anologuous manner by which compound 35B was prepared involving the reaction of l-fluoro-4-nitrobenzene with 2-oxa-6-azaspiro[3.3]heptane. 1H NMR (DMSO-d6, 300Mz) δ 8.06(d, J = 9Hz, 2H), 6.46(d, J = 9Hz, 2H), 4.73(br s, 4H), 4.22(br s, 4H); MS(ES+): 221.1(M+1); HPLC = 93.64% Example 42

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo [2,1- b]thiazol-6-yl)phenyl)-lH-benzo[d]imidazol-2-amine (Compound 42)

The title compound was prepared by reacting 4-(6-(3-aminophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4-methylpiperidin-l-yl)phenyl)pyrimidin-2-amine (105 mg, 0.211 mmol) with 2-chlorobenzimidazole (35.3 mg, 0.232 mmol) in presence of IPA.HC1 (3 mL) in microwave condition (300 W) at 150°C for lh. After the completion of reaction, the reaction mixture was basified by saturated bicarbonate solution (15 mL) and the product was extracted in ethyl acetate (15 mL X 2). After the evaporation of ethyl acetate layers to get crude product which was then purified by using 10% methanol chloroform. Yield: 45.1 %; 1H NMR (DMSO-de, 300 MHz): δ 10.88 (bs, 1H), 9.49 (bs, 1H), 9.31 (bs, 1H), 8.23-8.22 (d, 1H, J = 5.1 Hz), 7.89 (s, 1H), 7.83-7.81 (d, 1H, J = 8.1 Hz), 7.45-7.28 (m, 5H), 7.02-6.84 (m, 5H), 6.61-6.59 (d, 1H, J = 5.1 Hz), 4.54 (bs, 2H), 3.97 (bs, 2H), 3.01 (bs, 4H), 2.49-2.45 (m, 4H), 2.36-2.34 (q, 2H, J = 6.6 Hz), 1.03-0.99 (t, 3H, J = 6.9 Hz), m/z 614.9 (M+l).

4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4-methylpiperidin-l- yl)phenyl)pyrimidin-2-amine was prepared by reduction of N-(4-(4-methylpiperidin-l- yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrirmdin-2-amine according to the procedure followed in Step lh in Example 1.

Example 43

N-(3-(3-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)phenyl)-2-phenylacetamide (Compound 43)

The steps involved in the preparation of compound of Example 43 are given below.

Step 43 a

Synthesis of l-(cyclopent-l-en-l-yl)pyrrolidine

Cyclopentanone (119 mM) was dissolved in cyclohexane and anhydrous sodium sulphate (416 mM) was added in one portion under a nitrogen atmosphere. The mixture was cooled to 0

°C with an ice bath and pyrrolidine 43a (594 mM) was added drop wise over a 30 mins period.

After the reaction mixture was stirred for additional 30 min at 0 °C, the ice bath was removed and the mixture was stirred overnight at room temperature. Sodium sulfate was removed by filtration and rinsed (washed) thoroughly with dry cyclohexane. The combined filtrate and washings were concentrated under reduced pressure to give crude oily product (orange in color), which was distilled under reduced pressure (69 °C/1 mmHg) to give colorless oil. Yield = 92%.

Step 43b:

Synthesis of 2-(2-(3-nitrophenyl)-2-oxoethyl)cyclopentanone

A solution of 3-nitro-phenacyl bromide (109 mmol) in toluene was added drop wise for 30 mins to a solution of 1-pyrrolidino-l-cyclopentene (109 mmol) in toluene. The mixture was heated under reflux for 3h, diluted cautiously with water, refluxed for 4h and cooled. The layers were separated. The aqueous phase extracted with toluene and the combined organic phase was dried over sodium sulfate and concentrated to oil. The crude reaction material was purified by silica gel column chromatography. Yield =16%. ^XH NMR (CDCI₃, 300 MHz) δ: 8.80 (s, 1H), 8.46 (d, 7 =7.8Hz, 1H), 8.32 (d, 7 =7.5Hz, 1H), 7.71 (t, 7 =8.1, 7.8Hz, 1H), 3.61 (dd, 7=3.6, 3.3 Hz, 1H), 3.16 (dd, 7=7.5, 7.5Hz, 1H), 2.73 (s, 1H), 2.40 (m, 2H), 2.23 (m, 1H), 2.14 (m, 1H), 1.93 (m, 1H), 1.66 (m, 1H). m/z: 248 (M+l).

Step 43c

Synthesis of 2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophene

A solution of 2-(2-(3-nitrophenyl)-2-oxoethyl)cyclopentanone (12.94 mmol) and 2,4- Bis(4-methoxyphenyl)-2,4-dithioxo-l,3,2,4-dithiadiphosphetane (14.24 mmol) in Toluene-1,2- Dimethoxyethane was heated under reflux for 2-3 hrs. After removal of the solvent in-vacuo, the residual oil was chromatographed on silica gel column using Pet ether/EtOAc as mobile phase. Yield = 79%

1H NMR (CDCI₃, 300 MHz) δ: 8.39 (s, 1H), 8.09 (d, 7 =7.8Hz, 1H), 7.86 (d, 7 =8.7Hz, 1H), 7.52 (t, 7=7.8, 8.1Hz, 1H), 7.28 (s, 1H), 2.97 (t, 7 =6.9, 6.9Hz, 2H), 2.80 (t, 7 =6.6, 6.9, 2H), 2.49 (p, 2H). m/z: 246.2 (M+l).

Step 43d:

Synthesis of l-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethanone

The solution of 2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophene (0.408 mmol) and AICI₃ (2.446 mmol) in DCM was cooled at 0 °C (Argon atmosphere). To the above stirring solution was added solution of Acetyl chloride (0.489 mmol) in DCM drop wise, and then the mixture was stirred at 0 °C for 30 mins at RT for overnight. The mixture was poured into saturated aqueous NaHC03. After stirring for 1 h, extraction was carried out with EtOAc. The combined organics were washed with brine and dried by passage through Na₂S04. The product was isolated by flash chromatography on silica gel. Yield = 51%.

1H NMR (CDCI₃, 300 MHz) δ: 8.30 (s, 1H), 8.27 (d, 7 =8.4Hz, 1H), 7.77 (d, 7 =7.8Hz, 1H), 7.59 (t, 7 =8.1, 7.8Hz, 1H), 2.99 (dd, 7 =7.5, 8.4 Hz, 4H), 2.53 (p, 2H), 2.28 (s, 3H)

Mass (m/z): 288 (M+l).

Step 43e:

Synthesis of (E)-3-(dimethylamino)-l-(2-(3-nitrophenyl)-5,6-dihydro-4H- cyclopenta[b]thiophen-3-yl)prop-2-en-l-one

To a solution of l-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl) ethanone (0.348 mmol) in NMP was added Ν,Ν-dimethylformamide dimethyl acetal (0.383 mmol) and heated it to 90 °C for 1 h. After completion of reaction, the mixture was diluted with diethyl ether and cooled for 2 h then filtered to obtain the product.

Mass (m/z): 343 (M+l), Yield =67%

Step 43f:

Synthesis of 4-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)pyrimidin-2- amine

(E)-3-(dimethylamino)-l-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)prop-2- en-l-one (0.292 mmol), K₂CO₃ (1.168 mmol), and guanidine hydrochloride (0.876 mmol) in N- methyl pyrrolidone were added to a round bottom flask and the mixture was heated to 100 °C. After stirring for 12 h, the mixture was cooled to room temperature and diluted with 100 mL of water. The mixture stirred for 30 rnins at room temperature and was filtered. The resulting solid was dissolved into CEbC /methanol and washed with brine. The organics were separated, dried over Na₂S0₄, filtered, and concentrated under vacuum to afford the desired product. The material was used in the next step without further purification.

1H NMR (CDCI₃, 300 MHz) δ: 8.27 (s, 1H), 8.14 (d, / =5.1Hz, 1H), 8.10 (d, =7.8Hz, 1H), 7.57

(d, / =7.5Hz, 1H), 7.41 (t, J =7.8, 7.8Hz, 1H), 6.39 (d, / =5.1Hz, 1H), 5.09 (brs, 2H), 2.94 (m,

2H), 2.84 (m, 2H), 2.45 (m, 2H)

Mass: 339 (M+l).

Step 43g:

A solution of 4-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3- yl)pyrimidin-2-amine (0.148 mmol) in AcOH was heated to 60 °C and then added a aqueous solution of sodium nitrite (0.222 mmol) and heated the mixture at same temperature for 90 min. After completion of reaction, it was cooled to 10 °C and then basified to pH 8 by 2N NaOH, resulting solid was then filtered, washed with water and dried.

Mass: 340 (M+l), Yield = 80%

Step 43h:

Synthesis of 2-chloro-4-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3- yl)pyrimidine The mixture of 4-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3- yl)pyrimidin-2-ol (0.103 mmol) and POCI₃ (0.103 mmol) taken in round-bottomed flask (RB flask) was heated at 80 °C for 2 h. The mixture was concentrated under vacuum to afford oil. The oil was added slowly to ice water in water bath, so the internal temperature did not rise above 20 °C. The mixture was allowed to stir for an additional 20 mins. While maintaining cooling, 10% NaOH was added to the mixture, until pH of 8-10. The resulting solid was filtered, washed with water, and dried under vacuum. Yield =76%

1H NMR (CDCI₃, 300 MHz) δ: 8.45 (d, / =5.1Hz, 1H), 8.26 (s, 1H), 8.23 (d, =8.1Hz, 1H), 7.63 (d, /=7.5Hz, 1H), 7.55 (d, /=7.8Hz, 1H), 6.99 (d, / =4.8Hz, 1H), 3.01 (d, / =6.3, 4H), 2.55 (m, 2H). Mass: 358 (M+l).

Step 43i:

Synthesis of N-(4-(4-ethylpiperazin-l-yl)phenyl)-4-(2-(3-nitrophenyl)-5,6-dihydro-4H- cyclopenta[b]thiophen-3-yl)pyrimidin-2-amine

In a RB flask fitted with rubber septum and Argon baloon, 2-chloro-4-(2-(3-nitrophenyl)- 5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)pyrimidine (0.140 mmol), p-TSA (0.279 mmol) and 4-(4-ethylpiperazin- 1 -yl)aniline (0.168 mmol) were taken in NMP. The reaction mixture was heated at 110 °C for 12-14 h. The reaction mixture was cooled, diluted with saturated aqueous NaHC0₃ and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na₂S04 and concentrated. The crude reaction mixture was purified by silica gel column chromatography. Yield = 87%

^XH NMR (CDC1₃, 300 MHz) δ: 8.33 (s, 1H), 8.30 (d, / =4.8Hz, 1H), 8.11 (d, / =7.8Hz, 1H), 7.61 (d, =7.5Hz, 1H), 7.43 (t, J =7.8, 8.1Hz, 1H), 7.25 (d, =8.7Hz, 2H), 6.96 (s, 1H), 6.82 (d, =8.4Hz, 1H), 6.56 (d, =5.1Hz, 1H), 3.17 (m, 2H), 3.03 (m, 2H), 2.92 (m, 2H), 2.65 (m, 4H), 2.52 (m, 4H), 1.27 (s, 2H), 1.16 (t, = 6.9, 7.2Hz, 3H). Mass: 527 (M+l)

Step 43j:

Synthesis of 4-(2-(3-aminophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-N-((4- ethylpiperazin- 1 -yl)phenyl)pyrimidin-2-amine

N-(4-(4-ethylpiperazin-l-yl)phenyl)-4-(2-(3-nitrophenyl)-5,6-dihydro-4H- cyclopenta[b]thiophen-3-yl)pyrimidin-2-amine (0.949 mmol) was taken in RB flask in mixture of solvents ethanol, THF, water in the ratio of 2:2: 1 respectively. Iron (2.85 mmol) and ammonium chloride (2.85 mmol) were added simultaneously to the mixture and reaction was heated to 80°C for 4 h. The reaction was cooled and passed through celite washed with THF and filtrate was concentrated. The solid obtained was treated with aqueous sodium bicarbonate, filtered washed with ethanol and then with petroleum ether. Yield = 80%

1H NMR (DMSO-d₆, 300 MHz) δ: 9.27 (brs, IH), 8.27 (d, 7 =4.8Hz, IH), 7.40 (m, 2H), 6.97 (t, 7 =7.8, 7.8Hz, IH), 6.87 (s, IH), 6.84 (s, 2H), 6.56 (s, IH), 6.50 (m, 2H), 6.37 (d, 7=7.5Hz, IH), 5.22 (brs, 2H), 2.90 (m, 4H), 2.82 (m, 4H), 2.38 (m, 2H), 1.35 (s, 2H), 1.23 (m, 2H), 1.17 (m, 2H), 1.05 (t, 7 = 6.9, 6.9Hz, 3H). Mass: 497 (M+l).

Step 43j:

Synthesis of N-(3-(3-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-5,6-dihydro- 4H-cyclopenta[b]thiophen-2-yl)phenyl)-2-phenylacetamide

The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(2-(3-aminophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-N-(4- (4-ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (prepared according to the procedure given for step 43j) with 2-phenylacetyl chloride according to procedure followed in scheme 2. Yield = 76%

^XH NMR (DMSO-de, 300 MHz) δ: 10.28 (brs, IH), 9.28 (brs, IH), 8.30 (d, 7 =4.8Hz, IH), 7.63 (s, IH), 7.61 (d, 7 =8.1, IH), 7.33 (m, 5H), 7.26 (m, 3H), 6.91 (d, 7 =7.5Hz, IH), 6.80 (d, 7 =8.4, IH), 6.54 (d, 7 =7.8, IH), 3.64 (m, 2H), 2.93 (m, 4H), 2.83 (m, 4H), 2.42 (m, 2H), 1.24 (t, 3H). Mass: 615 (M+l).

Example 44

N-(3-(3-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)phenyl)-3-methylbutanamide (Compound 44)

The title compound was prepared in an analogous manner as the compound of Example 43 involving reaction of 4-(2-(3-aminophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-N- ((4-ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine with isovaleryl chloride according to procedure followed therein. Yield =36%

1H NMR (DMSO-de, 300 MHz) δ: 9.96 (brs, IH), 9.21 (brs, IH), 8.28 (d, 7 =10.8Hz, IH), 7.66 (s, IH), 7.60 (d, 7 =6.6, IH), 7.35 (d, J=6.9Hz, IH), 7.24 (m, 2H), 6.96 (t, 7 15Hz, IH), 6.83 (m, IH), 6.54 (d, 7 =7.8, IH), 3.64 (m, 2H), 2.93 (m, 4H), 2.83 (m, 4H), 2.42 (m, 2H), 1.24 (m, 2H). Mass (m/z): 581.9 (M+l) Example 45

N-(3-(3-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)phenyl)-2-phenylacetamide (Compound 45)

The title compound was prepared in an analogous manner as the compound of Example

43 involving reaction of 4-(2-(3-aminophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-N- (4-morpholinophenyl)pyrimidin-2-amine with 2-phenylacetyl chloride according to procedure followed therein. Yield =32%

1H NMR (DMSO-d₆, 300 MHz) δ: 10.28 (brs, IH), 9.26 (brs, IH), 8.30 (d, 7 =4.5Hz, IH), 7.65 (s, IH), 7.60 (d, 7 =8.1, 2H), 7.31 (m, 4H), 7.26(m, 3H), 6.90 (d, 7 =7.5Hz, IH), 6.76 (d, 7 =8.1,

2H), 6.53 (d, J=4.5, IH), 3.71 (m, 4H), 3.62 (m, 2H), 2.98 (m, 4H), 2.92 (m, 2H), 2.82 (m, 2H),

2.39 (m, 2H). Mass: 588 (M+l).

4-(2-(3-aminophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-N-(4- morpholinophenyl)pyrimidin-2-amine was prepared by reduction of N-(4-morpholinophenyl)-4- (2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)pyrimidin-2-amine according to the procedure followed for the preparation of compound 43k in Example 43. 4-(2-(3- aminophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-N-(4-morpholinophenyl)pyrimidin-

2-amine obtained in this reaction step was used in the subsequent reaction step without purification. Yield: 85%

XH NMR (DMSO-de, 300 MHz) δ: 9.27(bs, IH), 8.27(d, 7 =4.8Hz, IH), 7.40(m, 2H), 6.97(t, 7 =7.8, 7.8Hz, IH), 6.87(s, IH), 6.84(s, 2H), 6.56(s, IH), 6.50(m, 2H), 6.37(d, 7 =7.5Hz, IH), 5.22(bs, 2H), 3.72(s, 4H), 2.96(m, 6H), 2.85(m, 2H), 2.42(m, 2H). m/z: 497

N-(4-morpholinophenyl)-4-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3- yl)pyrimidin-2-amine was prepared reaction of 2-chloro-4-(2-(3-nitrophenyl)-5,6-dihydro-4H- cyclopenta[b]thiophen-3-yl)pyrimidine (compound 43i of Example 43) with 4-morpholinoaniline according to procedure followed for the preparing compound 43j of Example 43. N-(4- morpholinophenyl)-4-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)pyrimidin- 2-amine obtained in this reaction step was used in the subsequent reaction step without purification. Yield: 92% ^XH NMR (CDCI₃, 300 MHz) δ: 8.39(s, 1H), 8.37(d, J=4.8Hz, 2H), 7.68(d, 7 =7.5Hz, 1H), 7.64(t, 7 =7.8, 8.1Hz, 1H), 7.48(d, 7 =8.7Hz, 2H), 7.21 (d, 7 =8.7Hz, 2H), 7.12(s, 1H), 6.67(d, 7 =8.4Hz, 1H), 3.72(s, 4H), 2.96(m, 6H), 2.85(m, 2H), 2.42(m, 2H).

m/z: 527 (M+l).

Example 46

3-methyl-N-(3-(3-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)phenyl)butanamide (Compound 46)

The title compound was prepared in an analogous manner as the compound of Example 43 involving reaction of 4-(2-(3-aminophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-N- (4-morpholinophenyl)pyrimidin-2-amine with isovaleryl chloride according to procedure followed therein. Yield = 30%.

1H NMR (DMSO-de, 300 MHz) δ: 9.96 (brs, 1H), 9.25 (brs, 1H), 8.30 (d, 7 =4.8Hz, 1H), 7.66 (s, 1H), 7.59 (d, 7 =8.1, 1H), 7.27 (m, 3H), 6.88 (d, 7 =7.2Hz, 1H), 6.75 (d, J=8.4, 1H), 6.55 (d, 7 =4.5, 1H), 3.72 (m, 4H), 2.98 (m, 4H), 2.92 (m, 2H), 2.82 (m, 2H), 2.39 (m, 2H), 2.17 (m„ 2H), 2.07 (m, 1H) Mass (m/z): 554 (M+l).

Example 47

N-(3-(3-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)phenyl)morpholine-4-carboxamide (Compound 47)

43 involving reaction of 4-(2-(3-aminophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-N-

(4-morpholinophenyl)pyrimidin-2-amine with morpholine-4-carbonyl chloride according to procedure followed in therein. Yield = 27%

1H NMR (DMSO-de, 300 MHz) δ: 9.23 (brs, 1H), 8.66 (s, 1H), 8.30 (d, 7 =4.8Hz, 1H), 7.59 (s,

1H), 7.46 (d, 7 =8.4, 1H), 7.24 (m, 2H), 7.17 (t, 7 =8.1, 7.8Hz, 1H), 6.76 (d, 7 =8.1Hz, 3H), 6.55

(d, 7 =4.5, 1H), 3.72 (m, 4H), 3.60 (m, 4H), 3.41 (m, 4H), 2.98 (m, 4H), 2.92 (m, 2H), 2.39 (m,

2H), Mass (m/z): 583 (M+l).

Pharmacological assays

The pharmacological activity of the compounds as multikinase inhibitors can be confirmed by a number of pharmocological assays known in the art. The exemplified pharmacological assay, given below, has been carried out with the compounds of the present invention synthesized in the above Examples.

Example 48

IGF-1R kinase assay

IGF-1R kinase activity was assayed using a time resolved fluorescence energy transfer (TR-FRET) in vitro kinase assay. IGFR kinase enzyme used for the assay was human IGF-1R purified from a baculovirus expression system using glutathione-sepharose column chromatography. The kinase reaction was conducted in a 384-well plate. The reaction buffer (Tris HC1 (50 mM; pH: 7.4), EGTA (1 mM), MgCl₂ (10 mM, DTT (2 mM), Tween-20 (0.01%)) for peptide phosphorylation contained, in final concentrations, human IGF-1R kinase enzyme (0.25 nM), poly GT peptide substrate (50 nM) and ATP (20 μΜ).

The test compounds (compounds of the present invention) in DMSO, were evaluated at various concentrations, their final concentrations in the assay ranging from 40 μΜ to 40 pM. The final concentration of DMSO in the assay was less than 1%.

IGFR kinase enzyme (2.5 μΐ) and various concentrations of the test compounds (2.5 μί) were incubated in the 384-well plate for 10 min at 23 °C followed by the addition of poly GT peptide substrate (Perkin Elmer; 2.5 μί). The kinase reaction was initiated by the addition of ATP (2.5 μί) followed by incubation for 1 h at 23 °C. The kinase reaction was stopped by the addition of EDTA (5 μί) (final concentration in the assay: 10 mM). Europium cryptate-labelled antiphosphotyrosine antibody PY20 (5 μΐ) (final concentration in the assay: 2 nM) was added and the mixture was equilibrated for 1 h at 23 °C. The intensity of light emission which was indicative of the quantum of substrate phosphorylation by the kinase enzyme was measured at 665 nm using Envision plate reader. The ability of the test compounds to inhibit substrate phophorylation which is indicative of the IGF-1R kinase inhibitory activity of the test compounds expressed as IC₅₀ values was determined by a four-parameter sigmoidal curve in Sigma plot or Graph pad.

Results: IGF-1R kinase inhibitory activity of the test compounds have been reported in Table 1 below. Table 1 : IGF-1R inhibitory activity of the test compounds

indicates IC₅₀ values ranging from >500 nM.

indicates IC₅₀ values ranging from 100-500 nM

indicates the IC₅₀ values ranging from 0.1-100 nM

Conclusion: The compounds of the present invention exhibited significant IGF-1R kinase inhibitory activity.

Example 49

EGFR kinase assay:

EGFR kinase activity was assayed using a TR-FRET in vitro kinase assay. EGFR kinase enzyme used for the assay was human EGFR purified from a baculovirus expression system using glutathione-sepharose column chromatography. The kinase reaction was conducted in a 384-well plate. The reaction buffer (Tris HC1 (50 mM) (pH 7.4), EGTA (1 mM), MgCl₂ (10 mM), DTT (2 mM), Tween-20 (0.01%)) for peptide phosphorylation contained, in final concentrations, human EGFR kinase enzyme (1 nM), peptide substrate (50 nM) and ATP (20 μΜ).

The test compounds (compounds of the present invention) in DMSO, were evaluated at various concentrations, their final concentrations in the assay ranging from 20 μΜ to 20 pM. The final assay concentration of DMSO less than 1%. EGFR kinase enzyme (1 nM, 2.5μί) and various concentrations of the test compounds (40 μΜ to 40 pM, 2.5μί) were incubated in the 384-well plate for 10 min at 23 °C followed by the addition of peptide substrate (CAGAGAIETDKEYYTVKD, Tyrl023; Source: Perkin Elmer). The kinase reaction was initiated by the addition of ATP followed by incubation for 1 h at 23 °C. The kinase reaction was stopped by the addition of EDTA (5 μί) (final concentration in the assay: 10 mM). Europium- labelled PT66 antibody (5 μί) (final concentration in the assay: 2 nM) was added and the mixture was equilibrated for 1 h at 23 °C. The intensity of light emission which was indicative of the quantum of substrate phosphorylation by the kinase enzyme was measured at 665 nm using Envision plate reader. The ability of the test compounds to inhibit substrate phophorylation which is indicative of the EGFR kinase inhibitory activity of the test compounds expressed as IC₅₀ values was determined by a four-parameter sigmoidal curve in Sigma plot or Graph pad. Results: EFGR kinase inhibitory activity of the test compounds have been reported in Table 2 below.

Table 2: EGFR inhibitory activity of the test compounds

+ indicates IC₅₀ values ranging from 500 nM to 5000 nM

++ indicates IC₅₀ values ranging from 100 nM to 500 nM

+++ indicates the IC₅₀ values ranging from 0.1 nM to 100 nM

Conclusion: The compounds of the present invention exhibited significant EGFR kinase inhibitory activity.

Claims

Claims:

1. A compound of formula (I):

formula (I)

wherein,

X is N or S;

Y is N or C;

Z is -CH₂- or S(0)„;

when X and Y are N and Z is S, then the bond between atoms 1 and 2 is a single bond and bond between atoms 2 and 3 is a double bond;

Ri and R₂ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C3-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, (C₃-Ci₂)cycloalkyl(Ci- C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, - C(0)NR₆R₇, -C(S)NR₆R₇ and -S(0)_pR₈; provided that at least one of Ri and R₂ is other than hydrogen;

R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-C₁₂)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, -C(0)R₅, -C(0)NR₆R₇, - C(S)NR₆R₇ and -S(0)_pR8 ; provided that one of R₃ and R₄ is other than hydrogen; or R₃ and R₄ together with the N atom to which they are attached can form a saturated or a partially unsaturated heterocyclic ring optionally containing 1, 2 or 3 additional heteroatoms selected from the group consisting of O, N and S;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci- C₆)alkyl, halo(Ci-C₆)alkoxy, (C₃-Ci)cycloalkyl, (C₆-Cio)aryl, -0(C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -NH(Ci-C₆)alkyl, -N[(Ci-C₆)alkyl]₂, -C(0)(Ci-C₆)alkyl, - C(0)0(Ci-C₆)alkyl, -C(0)NH₂ and -C(0)NH(Ci-C₆)alkyl;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci- C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, -0(C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₃-Ci₂)cycloalkyl, (C₆-Ci₀)aryl, -0(C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R5, -C(0)0(Ci-C₆)alkyl, - C(0)NH₂, -C(0)NH(Ci-C₆)alkyl and -S(0)_pR₈; wherein R₅, R₈ and p are as defined above; heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, (C₂-Cs)alkenyl, (C₂-C8) alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆- Cio)aryl, -0(C₆-Cio)aryl, heterocyclyl, heteroaryl, (C6-Cio)aryl-0-(Ci-C₆)alkyl, amino, cyano, nitro, -C(0)R₅ and -NHC(0)(Ci-C₆)alkyl; wherein R₅ is as defined above; heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆- Cio)aryl, -0(C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R5 and -S(0)_pR₈; wherein R5, R$ and p are as defined above;

2. A compound according to claim 1 represented by formula (la);

formula (la)

wherein

Ri and R₂ are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl,

(C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Cio)aryl(Ci-C₆)alkyl-C(0), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇, - C(S)NR₆R₇ and -S(0)_PR₈; provided that one of Ri and R₂ is other than hydrogen;

R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Ci₀)aryl, heterocyclyl, heteroaryl, -C(0)R₅, -C(0)NR₆R₇, -C(S)NR₆R₇ and -S(0)_PR₈; provided that one of R₃ and R₄ is other than hydrogen;

R5 is selected from the group consisting of (Ci-C₆)alkyl, (C3-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; R₆ and R are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; provided that at least one of R₆ and R is hydrogen;

R₈ is (C₁-C₆)alkyl or (C₆-C₁₀)aryl;

p is an integer selected from 0, 1 or 2;

wherein,

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, 0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;

3. A compound according to claim 1 or 2; wherein,

Ri and R₂ are independently selected from the group consisting of hydrogen, (C₃-

Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl, heteroaryl(Ci- C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇ and -S(0)_pR₈; provided that one of Ri and R₂ is other than hydrogen;

R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; provided that one of R₃ and R₄ is other than hydrogen;

R₆ and R₇ are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₆-Cio)aryl and (C₃-Ci₂)cycloalkyl; provided that at least one of R₆ and R₇ is hydrogen;

R₈ is (C₁-C₆)alkyl or (C₆-C₁₀)aryl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆- Cio)aryl, -O(C₆-Ci₀)aryl, heteroaryl, amino, -NH(Ci-C₆)alkyl and -N[(Ci-C₆)alkyl]₂;

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;

4. A compound according to claim 1 or 2; wherein, Ri and R₂ are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-C₁₂)cycloalkyl, (C₆-C₁₀)aiyl, heteroaryl, (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆- Cio)aryl(Ci-C₆)alkyl-C(0), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇, -C(S)NR₆R₇ and -S(0)_pR8; provided that one of Ri and R₂ is other than hydrogen;

R₆ and R₇ are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl,

(C₆-Cio)aryl and (C₃-Ci₂)cycloalkyl; provided that at least one of R₆ and R₇ is hydrogen;

R₈ is (Ci-C₆)alkyl or (C₆-C₁₀)aiyl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C8)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, cyano and nitro;

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C8)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;

heterocyclyl is 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C8)alkynyl, halogen, halo(Ci-C₆)alkyl, (C6-Cio)aryl-0-(Ci-C₆)alkyl, hydroxy, amino, cyano, nitro and - NHC(0)(Ci-C₆)alkyl; heteroaryl is 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, heterocyclyl, amino, cyano and nitro;

5. A compound according to claim 1 or 2; wherein,

Ri and R₂ are independently selected from the group consisting of hydrogen, (C3- Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl, heteroaryl(Ci- C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇ and -S(0)_pR₈; provided that one of Ri and R₂ is other than hydrogen;

R₃ and R₄ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; provided that one of R3 and R₄ is other than hydrogen;

R₆ is hydrogen and R₇ is (C₃-Ci₂)cycloalkyl;

R₈ is (Ci-C₆)alkyl or (C₆-C₁₀)aiyl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, -0(Ci-C₆)alkyl and amino;

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro; heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, amino and -NHC(0)(Ci-C₆)alkyl;

6. A compound according to claim 1 or 2; wherein,

Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl, heteroaryl(Ci- C₆)alkyl-C(0)-, -C(0)R₅, -C(0)NR₆R₇ and -S(0)_pR₈; provided that at least one of Ri or R₂ is not hydrogen;

R3 and R₄ together with the N atom to which they are attached can form a saturated or a partially unsaturated 3- to 9-membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms independently selected from the group consisting of O, N and S;

R₆ is hydrogen and R₇ is (C₃-Ci₂)cycloalkyl;

R₈ is (Ci-C₆)alkyl or (C₆-Ci₀)aryl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆- Cio)aryl, -O(C₆-Ci₀)aryl, heteroaryl, amino, -NH(d-C₆)alkyl and -N[(Ci-C₆)alkyl]₂;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, (C₆-Ci₀)aryl-O-(Ci-C₆)alkyl, hydroxy, amino and -NHC(0)(Ci-C₆)alkyl;

7. A compound according to claim 1 or 2; wherein,

R] is hydrogen; and

R_?. is selected from the group consisting of (Ci-C₆)alkyl, (C3-Ci2)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, (C₃-Ci2)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇, -C(S)NR₆R₇ and -S(0)_pR₈; wherein R₅, R₆, R₇, R8 and p are as defined above;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl, (C₃-Ci2)cycloalkyl, (C₆- Cio)aryl, heteroaryl and amino;

(C₃-Ci2)cycloalkyl is unsubstituted or substituted with one or more groups selected from group consisting of (Ci-C₆)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, hydroxy, -0(Ci- C₆)alkyl and amino;

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, amino, cyano and nitro;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, hydroxy and amino; heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, cyano and nitro;

8. A compound according to claim 1 or 2; wherein,

Ri is hydrogen; and

R₂ is selected from the group consisting of heteroaryl, (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl- C(O), (C₆-Cio)aryl(Ci-C₆)alkyl-C(0), heteroaryl(Ci-C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇ and - S(0)_PR8; wherein R5, R₆, R₇, Rs and p are as defined above;

wherein,

9. A compound according to claim 1 or 2; wherein,

Rj is hydrogen; and R₂ is selected from the group consisting of (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆- Cio)aryl(Ci-C₆)alkyl-C(0) and heteroaryl(Ci-C₆)alkyl-C(0);

wherein,

10. A compound according to claim 1 or 2; wherein,

Ri is hydrogen; and

R₂ is (C₆-Cio)aryl(Ci-C₆)alkyl-C(0);

wherein,

(Ci-C₆)alkyl is substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, amino, cyano and nitro;

(C₆-Cio)aryl is substituted with one or more groups selected from the group consisting of

(Ci-C₆)alkyl, halogen and -0(Ci-C₆)alkyl;

11. A compound according to claim 1 or 2; wherein,

Ri is hydrogen; and

R₂ is -C(0)R₅;

wherein,

(Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl and amino; (C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, -0(Ci- C₆)alkyl and amino;

12. A compound according to claim 1 or 2; wherein,

R] is hydrogen; and

R₂ is -C(0)NR₆R₇ or -S(0)_pR₈;

R₆ is hydrogen;

R₇ is (C₃-Ci₂)cycloalkyl;

R₈ is (Ci-C₆)alkyl or (C₆-C₁₀)aryl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein,

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, amino, cyano and nitro; halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.

13. A compound according to claim 1 or 2; wherein,

R' is hydrogen;

R4 is selected from the group consisting of (Ci-C₆)alkyl, (C₃-Ci2)cycloalkyl, (C₆-Cio)aryl, heterocyclyl, heteroaryl, -C(0)R₅, -C(0)NR₆R₇, -C(S)NR₆R₇, and -S(0)_PR₈; wherein R₅, R₆, R₇, Rg, n and p are as defined above;

wherein,

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C8)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl and amino;

(C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from (Ci-

C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C₆)alkyl, (C₂-Cs)alkenyl, (C₂-C8)alkynyl, halogen, halo(Ci- C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino and -NHC(0)(Ci-C₆)alkyl;

heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C8)alkynyl, halogen, halo(Ci- C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, heterocyclyl, amino, cyano and nitro;

14. A compound according to claim 1 represented by formula (lb);

R₈ is (Ci-C₆)alkyl or (C₆-Ci₀)aryl;

p is an integer selected from 0, 1 or 2;

wherein,

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C8)alkenyl, (C₂-C8)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, amino, cyano and nitro; (C₆-Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, -0(Ci-C₆)alkyl, halo(Ci-C₆)alkoxy, (C₆-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;

heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, halo(Ci-C₆)alkyl, hydroxy, amino, cyano, nitro and -NHC(0)(Ci-C₆)alkyl;

15. A compound according to claim 1 or 14; wherein,

Ri and R2 are independently selected from the group consisting of hydrogen, (C₃- Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆-Ci₀)aryl(Ci-C₆)alkyl-C(O), heteroaryl, heteroaryl(Ci- C₆)alkyl-C(0), -C(0)R₅, -C(0)NR₆R₇ and -S(0)_pR₈; provided that one of Ri and R₂ is other than hydrogen;

R3 and R₄ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₆-Cio)aryl, heterocyclyl and heteroaryl; provided that one of R₃ and R₄ is other than hydrogen;

R₆ is hydrogen and R₇ is (C₃-Ci2)cycloalkyl;

R₈ is (Ci-C₆)alkyl or (C₆-C₁₀)aiyl;

p is an integer selected from 0, 1 or 2;

n is an integer selected from 0, 1 or 2;

wherein, (Ci-C₆)alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, halogen, hydroxy, -0(Ci-C₆)alkyl, (C₃-Ci₂)cycloalkyl, (C₆- Cio)aryl, -O(C₆-Ci₀)aryl, heteroaryl, amino, -NH(Ci-C₆)alkyl and -N[(Ci-C₆)alkyl]₂;

(C₃-Ci₂)cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, halogen, hydroxy, 0(Ci- C₆)alkyl and amino;

16. A compound according to claim 1 or 2; wherein,

Ri is hydrogen:

R? is selected from the group consisting of (C₃-Ci₂)cycloalkyl(Ci-C₆)alkyl-C(0), (C₆- Cio)aryl(Ci-C₆)alkyl-C(0) and heteroaryl(Ci-C₆)alkyl-C(0);

R₃ is hydrogen;

R4 is selected from the group consisting of (C₆-Cio)aryl, heteroaryl and heterocyclyl; wherein,

17. A compound according to any one of claims 1 - 16, wherein the compound is

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-naphthamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(4-methylpiperidin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((3-(2-methylpiperidin-l-yl)propyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)-2-(2-fluorophenyl)acetamide; 2-(2-ethoxyphenyl)-N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)acetamide;

2-cyclopentyl-N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)acetamide;

N-(3-(5-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l-b]thiazol-6- yl)phenyl)-2-phenylacetamide;

l-cyclohexyl-3-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)urea; N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,l- b]thiazol-6-yl)phenyl)nicotinamide;

N-(3-(5-(2-((4-(2-(dimethylamino)ethyl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2 b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(2,6-dimethylmorpholino)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-((2S,6R)-2,6-dimethylmorpholino)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-bromophenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2, l-b]thiazol-6- yl)phenyl)-2-phenylacetamide; N-(3-(5-(2-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)amino)pyrimidin-4-yl)-2,3- dihydroimidazo[2, 1 -b]thiazol-6-yl)phenyl)-2-phenylacetamide;

N-(3-(5-(2-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2_^ b]thiazol-6-yl)phenyl)-lH-benzo[d]imidazol-2-amine;

or a isotopic form, or a stereoisomeric form, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or an N -oxide thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), as defined in claim 1 or 17, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or an N-oxide thereof, and a pharmaceutically acceptable carrier.

19. A method of inhibiting multikinase in a cell, comprising contacting the cell with a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 17, or a isotopic form, or a stereoisomeric form, or a tautomeric form, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or an N-oxide thereof.

20. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 17, or a isotopic form, or a stereoisomeric form, or a tautomeric form, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or an N-oxide thereof.

21. A method for the treatment of cancer according to claim 20 wherein the cancer is mediated by one or more kinases selected from the group consisting of IGFIR, EGFR, Src, Lck and aurora kinases.

22. A method according to claim 20 or 21, wherein the cancer is selected from the group consisting of leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoid leukemia, chronic lymphoid leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplasia syndrome, myeloproliferative neoplasms, diffuse large B-cell lymphoma and follicular lymphoma, astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyoma, melanoma, epithelial cancer, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, thymoma, thyroid cancer and testicular cancer.

23. A method according to claim 20 or 21, wherein the cancer is selected from the group consisting of brain cancer, breast cancer, prostate cancer, epithelial cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, renal cell carcinoma and endometrial carcinoma.

24. A method according to claim 20 or 21, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, breast cancer, multiple myeloma and sarcomas.

25. A method according to claim 20 or 21, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, breast cancer and multiple myeloma.

26. The use of compounds of formula (I) according to any one of claims 1 to 17, as multikinase inhibitors.

27. The use of a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for the treatment of cancer.

28. The use according to claim 27, wherein the cancer is selected from the group consisting of leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoid leukemia, chronic lymphoid leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplasia syndrome, myeloproliferative neoplasms, diffuse large B-cell lymphoma and follicular lymphoma, astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyoma, melanoma, epithelial cancer, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, thymoma, thyroid cancer and testicular cancer.

29. The use according to claim 27, wherein the cancer is selected from the group consisting of brain cancer, breast cancer, prostate cancer, epithelial cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, renal cell carcinoma and endometrial carcinoma.

30. The use according to claim 27, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, breast cancer and multiple myeloma.

31. Compound of formula (I) according to claim 1, or a isotopic form, or a stereoisomeric form, or a tautomeric form, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or an N-oxide thereof, for use in the treatment of cancer.