"SUBSTITUTED 2-AMINO PFRIMIDINE DERIVATIVES AS KINASE INHIBITORS"

This application claims the benefit of Indian provisional application number 39/CHE/2013 filed on 04 ^th January 2013 and 3029/CHE/2013 filed on 05 ^th July 2013 which hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to substituted 2-amino pyrimidine derivatives of formula (1) which are useful as kinase inhibitors.

The present invention relates also to the process for preparation of compounds of present invention and pharmaceutical composition thereof and their use for the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder associated where there is an advantage in inhibiting kinase enzyme activity, and more particularly PI3K or at least one of such target.

BACKGROUND AND PRIOR ART

Protein kinases play crucial role in regulating the different cell processes which include, but are not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation, signaling process and various regulatory mechanisms, by adding phosphate groups to the target protein residues (Hardie, G. and Hanks, S., The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995). This phosphorylation event acts as molecular on/off switches that can modulate or regulate the target position biological function. Phosphorylation of targeted proteins occurs in response to a variety of extracellular signals. The appropriate protein kinase functions in signaling pathways to activate or deactivate. Uncontrolled signaling due to defective control of protein phosphorylation is known to contribute to various diseases. In the case of cancer, kinases are known to regulate many aspects of the cell growth, invasion that intrudes upon and destroys adjacent tissues and sometimes metastasis, or spreading to other locations in the body via lymph or blood.

Phosphatidylinositol (PI) 3-kinases (PI3Ks) are ubiquitous lipid kinases that function both as signal transducers down stream of cell surface receptors and in constitutive intracellular membrane and protein trafficking pathways. PI is known to play an important role in intracellular signal transduction. Cell signaling via 3'-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g. malignant transformation, growth factor signaling, inflammation, and immunity (Rameh et al (1999) J. Biol Chem, 274:8347-8350). The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (also referred to as PI3-kinase or PI3K), was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylate phosphatidylinositol (PI) and its phosphorylated derivatives at the 3'-hydroxyl of the inositol ring (Panayotou et al (1992) Trends Cell Biol 2:358-60).

All PI3Ks are dual-specificity enzymes with a lipid kinase activity that phosphorylates phosphoinositides at the 3-hydroxy position, and a less well characterized protein kinase activity (such as AKT, PDK1 and PKB). The lipid products of PI3K catalysed reactions comprising phosphatidylinositol(3,4,5)-trisphosphate [PI(3,4,5)P3], [PI(3,4)P2] and [PI(3)P] act as second messengers apparently by recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as Akt and phosphoinositide-dependent kinase-1 (PDK1). Binding of Akt to membrane PIP3s causes the translocation of Akt to the plasma membrane, binding Akt into contact with PDK1, which is responsible for activating Akt. The tumor-suppressor phosphatase i.e. Phosphatase and tensin homolog (PTEN), dephosphorylates PIP3 and therefore acts as a negative regulator of Akt activation. The PI3-kinases Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Vivanco et al ; Nature Rev. Cancer 2: 489 (2002); Phillips et al ; Cancer 83 :41(1998)). mTOR also known as mammalian target of rapamycin or mechanistic target of rapamycin is a protein which in humans is encoded by the FRAP1 gene also belongs to the phosphatidylinositol 3-kinase-related kinase protein family.

Presently, the PI3-kinase enzyme family has been divided into three classes based on their substrate specificities. Class I PI3Ks can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-biphosphate (PIP2) to produce phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4-biphosphate, and phosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate, whereas Class III PI3Ks can only phosphorylate PI.

The initial purification and molecular cloning of PI3-kinase revealed that it was a heterodimer consisting of p85 and pi 10 subunits (Otsu et al., Cell , 65:91-104 (1991); Hiles et al., Cell , 70:419-29 (1992)). Since then, four distinct Class I PI3Ks have been identified, designated PI3K α, β, δ, and γ, each consisting of a distinct 110 kDa catalytic subunit and a regulatory subunit. More specifically, three of the catalytic subunits, i.e., pi 10a, ρΐ ΐθβ and ρΐ ΐθδ, each interact with the same regulatory subunit, p85; whereas ρΐ ΐθγ interacts with a distinct regulatory subunit, plOl. As described below, the patterns of expression of each of these PI3Ks in human cells and tissues are also distinct. Though a wealth of information has been accumulated in recent past on the cellular functions of PI 3-kinases in general, the roles played by the individual isoforms are largely unknown.

The delta (δ) isoform of class I PI3K has been implicated, in particular, in a number of diseases and biological processes. PI3K5 is expressed primarily in hematopoietic cells including leukocytes such as T-cells, dendritic cells, neutrophils, mast cells, B-cells, and macrophages. PI3K5 is integrally involved in mammalian immune system functions such as T-cell function, IB- cell activation, mast cell activation, dendritic cell function, and neutrophil activity. Due to its integral role in immune system function, PI3K δ is also involved in a number of diseases related to undesirable immune response such as allergic reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis, autoimmune diseases such as lupus, asthma, emphysema and other respiratory diseases. Other class I PI3K involved in immune system function includes ΡΒΚγ, which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus.

WO2009/081105A1, WO2008/118454A1, WO2008/11455A1, WO2008/118468A1, WO2009/088986A1, WO2009/088986A1, WO2010/057048 Al, WO2011/146882A1, WO2013/012915A1, WO2013/012918A1 and WO2013032591A1 describe various series of quinoline and quinozoline derivatives that are structurally relates to each other and are stated to be useful to inhibit the biological activity of human PI3K and to be used in treating PI3K mediated diseases or disorders. The novel 2-amino pyrimidine derivatives of formula (1) according to the present invention may possess inhibitory activity of one or more protein kinases including PI3K, Akt, m- TOR, and are, therefore, expected to be useful in the treatment of kinase-associated diseases or disorders.

SUMMARY OF THE INVENTION

The present invention relates to substituted 2-amino pyrimidine derivatives of formula (1) which are useful as kinase inhibitors.

In one aspect of the present invention relates to the compound of formula (1)

or a pharmaceutically acceptable salts or a pharmaceutically acceptable stereoisomers thereof; wherein,

Ring A is bicyclic heterocyclyl ring containing 1-5 heteroatoms/heterogroups independently selected from N and -C(O)-;

R is selected from hydrogen, halogen and alkyl;

R is selected from an optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are selected from alkyl and halogen;

R ³ is selected from hydrogen and alkyl;

R ⁴ is selected from hydrogen, alkyl, alkoxyalkyl and heterocyclyl;

and R ⁵ is selected from -S(0) ₂ R ^5a , -S(0) ₂ NR ^5a R ^5b , -NHS(0) ₂ R ^5a and -C(0)NHR ^5a ;

R ^5a is selected from hydrogen and alkyl;

R ^5b is selected from hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are independently selected from halogen and alkyl;

alternatively, R ^5a and R ^5b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered heterocyclyl ring; wherein the optional substituent is alkyl;

R ⁶ is selected from hydrogen, alkyl, halo, haloalkyl, nitro and amino;

R 7 and R 8 are independently selected from hydrogen or alkyl;

R is selected from hydrogen, , , optionally substituted heterocyclyl; wherein the optional substituent is selected from alkyl or alkoxy;

alternatively, R 8 and R 9 may be taken together with the carbon atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-4 heteroatoms/heterogroups independently selected from N, S and -C(O)-;

R ¹⁰ is selected from

each R ^a is independently selected from hydrogen and alkyl;

each R ^b and R ^c are independently selected from hydrogen, alkyl, cycloalkyl and optionally substituted heterocyclyl; wherein the optional substituent is alkyl;

alternatively, R ^b and R ^c can be taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N and O; and

'n' is an integer selected from 1 and 2. In another aspect of the present invention, it relates to the pharmaceutical composition comprising substituted 2-amino pyrimidine derivatives of formula (1) and process for preparing them.

In further another aspect of the present invention, it relates to the use of compounds of formula (1), its pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, including mixtures thereof in all suitable ratios wherever applicable as a medicament for the treatment and prevention of disorders or diseases by inhibitory action on enzymes- PI3K, AKT and m-TOR thereof.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention provide substituted 2-amino pyrimidine derivatives of formula (1) which are useful as kinase inhibitors.

One of the embodiment of the present invention provide the compound of formula (1)

(1)

or a pharmaceutically acceptable salts or a pharmaceutically acceptable stereoisomers thereof; wherein,

Ring A is bicyclic heterocyclyl ring containing 1-5 heteroatoms/heterogroups independently selected from N and -C(O)-;

selected from hydrogen, halogen and alkyl;

R is selected from an optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are selected from alkyl and halogen;

R ³ is selected from hydrogen and alkyl;

R ⁴ is selected from hydrogen, alkyl, alkoxyalkyl and heterocyclyl; selected R and

R ⁵ is selected from -S(0) ₂ R ^5a , -S(0) ₂ NR ^5a R ^5b , -NHS(0) ₂ R ^5a and -C(0)NHR ^5a ;

R , 5a i ·s selected from hydrogen and alkyl;

R ^5b is selected from hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are independently selected from halogen and alkyl;

alternatively, R ^5a and R ^5b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered heterocyclyl ring; wherein the optional substituent is alkyl;

R ⁶ is selected from hydrogen, alkyl, halo, haloalkyl, nitro and amino;

R 7' and R 8° are independently selected from hydrogen or alkyl;

R is selected from hydrogen,

optionally substituted heterocyclyl; wherein the optional substituent is selected from alkyl or alkoxy;

alternatively, R 8 and R 9 may be taken together with the carbon atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-4 heteroatoms/heterogroups independently selected from N, S and -C(O)-;

R is selected from each R ^a is independently selected from hydrogen and alkyl;

each R ^b and R ^c are independently selected from hydrogen, alkyl, cycloalkyl and optionally substituted heterocyclyl; wherein the optional substituent is alkyl;

alternatively, R ^b and R ^c can be taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N and O; and

'n' is an integer selected from 1 and 2.

The embodiment below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.

According to one embodiment, specifically provided are compounds of formula (1), in which Ring A is selected from

According to yet another embodiment, specifically provided are compounds of formula (1), in which R ¹ is selected from hydrogen, halogen (such as fluoro) and alkyl (such as methyl).

According to yet another embodiment, specifically provided are compounds of formula in which

According to yet another embodiment, specifically provided are compounds of formula (1), in which R ³ is hydrogen and alkyl (such as methyl).

According to yet another embodiment, specifically provided are compounds of formula (1), in which R ⁴ is hydrogen, alkyl (such as ethyl), alkoxyalkyl (such as -(ϋί ₂ ) ₂ 0Ο¾) and heterocyclyl (such as pyridine). Accordin to yet another embodiment, specifically provided are com ounds of formula

According to yet another embodiment, specifically provided are compounds of formula (1), in which R ⁶ is hydrogen or amino.

According to yet another embodiment specifically provided are compounds of formula

(1), in which R 7 and R 8 are alkyl (such as methyl).

According to yet another embodiment, specifically provided are compounds of formula

According to yet another embodiment, specifically provided are compounds of formula

(1), in which R ¹⁰ is selected ,

According to yet another embodiment, specifically provided are compounds of formula (1), in which 'n' is an integer selected from 1 and 2.

According to yet another embodiment of the present invention, the compound of formula (1) is a compound of formula (la)

wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A and ' n' are same as defined in formula (1), or a

pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.

According to preceding embodiment, specifically provided are compounds of formula (la), in which ring A is selected from

According to yet another embodiment of the present invention, the compound of formula (1) is a compound of formula (lb)

wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A and 'n' are same as defined in formula (1), or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.

According to preceding embodiment, specifically provided are compounds of formula

(lb), in which ring A is

According to one of the preceding embodiment, specifically provided are compounds of formula (lb), in which R ⁵ is -S(0) ₂ R ^5a ; wherein R ^5a is alkyl (such as methyl and isopropyl).

According to further yet another embodiment of the present invention, the compound of formula (1) is a compound of formula (lc)

wherein, R 1 , R 2", R 3 ^J , R 4", R V', R 8°,R9", A and 'n' are same as defined in formula (1), or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.

According to preceding embodiment, specifically provided are compounds of formula (lc wherein Rin A is selected from

According to further yet another embodiment of the present invention, the compound of formula (1) is a compound

wherein, R ¹ , R ² , R ³ , R ⁴ , R ¹⁰ , A and ' n' are same as defined in formula (1), or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.

According to preceding embodiment, specifically provided are compounds of formula

(Id), wherein Ring A is

In yet another particular embodiment of the present invention, the compound of formula ( 1 ) is selected from the group consisting of

Comp. Compound Name

No

1. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl) amino) pyrimidin-5-yl) acrylic acid; (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5 -yl) acrylamide ;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-isopropylacrylamide;

(E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(piperazin-l-yl)prop- l-en-l-yl)pyrimidin-4 yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-( l-((2-amino-6-methyl-5-(3-morpholino-3-oxoprop- 1 -en- 1 -yl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-cyclopropylacrylamide;

tert-butyl 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihyd ro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)cyclopropanecarb oxylate;

2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihyd roquinazolin-2-yl) propyl) amino)pyr imidin- 5 - yl)cyclopropanecarboxylic acid ;

(E)-tert -butyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihyd ro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylate;

(E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylate;

2-( 1 -((2-amino-5-(( lE,3Z)-3-(hydroxyimino)but- 1 -en- 1 -yl)-6-methylpyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-ethyl 3-(2-amino-4-methyl-6-((l-(2-(4-methylpiperazin-l-yl)quinoli n-3-yl) propyl) amino)pyr imidin- 5 - yl)acry late ;

(E)-3-(2-amino-4-methyl-6-(( 1 -(2-(4-methylpiperazin- 1 -yl)quinolin-3-yl)propyl) amino)pyrimidin- 5 - yl)acr ylic acid ;

(Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)but-2-enoic acid;

(Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(tert-butyl)but-2-enamide;

(Z)-2-(l-((2-amino-6-methyl-5-(4-morpholino-4-oxobut-2-en-2- yl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one; (Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-cyclopropylbut-2-enamide;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(pyridin-2-yl)acrylamide;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(pyridin-3-yl)acrylamide;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(pyridin-4-yl)acrylamide;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(thiazol-2-yl)acrylamide;

(E)-2-( l-((2-amino-6-methyl-5-(3-oxo-3-(lH-pyrazol- l-yl)prop- 1-en- l-yl)pyrimidin- 4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-methylacrylamide;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-ethylacrylamide;

2-(l-((2-amino-6-methyl-5-vinylpyrimidin-4-yl)amino)propyl)- 5-methyl-3-phenyl quinazolin-4(3H)-one;

(E)-ethyl 3-(2-amino-4-methyl-6-((l-(l-methyl-4-oxo-5-phenyl-4,5-dihyd ro-lH- pyrazolo[3,4-d]pyrimidin-6-yl)propyl)amino)pyrimidin-5-yl)ac rylate;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(6-methylpyridin-2-yl)acry lamide;

(E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(pyrrolidin-l-yl)prop -l-en-l-yl)pyrimidin- 4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(piperidin-l-yl)prop- l-en-l-yl)pyrimidin-4- yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N,N-dimethylacrylamide;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-ethyl-N-methylacrylamide; (Z)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihyd ro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylat e;

(E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihyd ro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylat e;

(Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylic acid;

(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylic acid;

(E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(pyrrolidin-l-yl)prop -l-en-l-yl) pyrimidin- 4-yl) amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-2-yl)vinyl)pyrimid in-4-yl) amino)propyl) -5-fluoro-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(2-(4-methylthiazol-2-yl)vinyl )pyrimidin-4-yl)amino) propyl) -5-fluoro-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((5-(2-(lH-imidazol-4-yl)vinyl)-2-amino-6-methylpyr imidin-4-yl)amino) propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((5-(2-(lH etrazol-5-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl)amino) propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;

(E)-2-( l-((5-(2-( lH-tetrazol-5-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl) amino) propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(3-oxobut-l-en-l-yl)pyrimidin- 4-yl) amino) propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((5-(2-(lH-imidazol-4-yl)vinyl)-2-amino-6-methylpyr imidin-4-yl)amino) propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(2-(6-methylpyridin-2-yl)vinyl )pyrimidin-4- yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(2-(5-methylpyridin-2-yl)vinyl )pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-2-yl)vinyl)pyrimid in-4-yl)amino)propyl) -5-methyl-3-phenylquinazolin-4(3H)-one; (E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-3-yl)vinyl)pyrimid in-4-yl) amino)propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-4-yl)vinyl)pyrimid in-4-yl) amino)propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-5-(2-(3-methoxy-6-methylpyridin-2-yl)viny l)-6-methylpyrimidin- 4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(2-(3-methylpyridin-2-yl)vinyl )pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(2-(4-methylpyridin-3-yl)vinyl )pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-5-(2-(6-methoxypyridin-3-yl)vinyl)-6-meth ylpyrimidin-4-yl) amino) propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(2-(l-methyl-lH-tetrazol-5-yl) vinyl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-( l-((2-amino-6-methyl-5-(2-(thiazol-2-yl)vinyl)pyrimidin-4-yl ) amino) propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;

(E)-2-(l-((2-amino-6-methyl-5-(2-(l-methyl-lH-imidazol-2-yl) vinyl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihyd roquinazolin-2-yl) propyl)amino)pyrimidin-5-yl)cyclopropanecarboxamide;

(E)-6-methyl-N4-(l-(2-(4-methylpiperazin-l-yl)quinolin-3-yl) propyl)-5-(2-(pyridin- 2-yl)vinyl)pyrimidine-2,4-diamine;

(E)-5-(2-(6-methoxypyridin-3-yl)vinyl)-6-methyl-N4-( 1 -(2-(4-methylpiperazin- 1 -yl) quino lin- 3 - yl)propyl)pyrimidine-2 ,4-diamine ;

(E)-ethyl 3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydro-lH -pyrazolo [3,4-d]pyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)a crylate;

(E)-3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydr o-lH-pyrazolo [3,4-d] pyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid;

(E)-ethyl 3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4-dihy dro quinazolin2- yl)propyl) amino )- 6- methylpyr imidin- 5 - yl) aery late ; (E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4- dihydroquinazolin-2- yl)propyl)amino )- 6-methylpyr imidin- 5 - yl) acrylic acid ;

(E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4- dihydroquinazolin-2- yl)propyl)amino )- 6-methylpyr imidin- 5 - yl) acrylamide ;

(E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4- dihydroquinazolin-2- yl)propyl)amino)-6-methylpyrimidin-5-yl)-N-(pyridin-3-yl)acr ylamide;

(E)-2-(l-((5-(2-(lH-tetrazol-5-yl)vinyl)-2-amino-6-methylpyr imidin-4-yl)amino) propyl)-3-(4-fluorophenyl)-5-methylquinazolin-4(3H)-one;

(E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin-l-y l)quinolin- 3 - yl) propyl) amino)pyr imidin- 5 - yl) aery late ;

(E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin -l-yl)quinolin-3-yl) propyl) amino)pyr imidin- 5 - yl)acry lie acid ;

(E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin -l-yl)quinolin-3-yl) propyl) amino)pyr imidin- 5 - yl)acry lamide ;

(E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2 -(4-methylpiperazin-l- yl) quino lin- 3 - yl)propyl)pyrimidine-2 ,4-diamine ;

(E)-ethyl 3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl)pro pyl)amino) pyr imidin- 5 - yl)acry late ;

(E)-3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl )propyl)amino) pyrimidin-5-yl)acrylic acid;

(E)-3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl )propyl)amino) pyr imidin- 5 - yl)acry lamide ;

(E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(2-thiomorp holinoquinolin-3- yl)propyl)pyrimidine-2,4-diamine;

(E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquinolin -3-yl) propyl) amino)pyr imidin- 5 - yl)acry late ;

(E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquin olin-3-yl)propyl) amino)pyrimidin- 5 - yl)acr ylic acid ;

(E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquin olin-3-yl)propyl) amino)pyrimidin- 5 - yl)acr ylamide ; 77. (E)-5-(2 lH etrazol-5-yl)vinyl)-6-methyl-N4-(l 8-methyl-2-thiomorpholino quino lin- 3 - yl)propyl)pyrimidine-2 ,4-diamine ;

78. (E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2-morpholinoquinolin-3-y l) propyl) amino)pyrimidin- 5 - yl)acr ylate ;

79. (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-morpholinoquinolin -3-yl) propyl)

amino)pyrimidin- 5 - yl)acr ylic acid ;

80. (E)-5-(2-(lH etrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2-morpholinoqui nolin -3 -yl)propyl)pyrimidine-2,4-diamine ;

81. (E)-5-(2-(3-methoxypyridin-2-yl)vinyl)-6-methyl-N4-(l-(8-met hyl-2-morpholino quino lin- 3 - yl)propyl)pyrimidine-2 ,4-diamine ;

82. (E)-6-methyl-5-(2-(l-methyl-lH-tetrazol-5-yl)vinyl)-N4-(l-(8 -methyl-2-morpholino quino lin- 3 - yl)propyl)pyrimidine-2 ,4-diamine ;

83. (E)-ethyl 3-(2-amino-4-((l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methy lquinolin -3-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate;

84. (E)-3-(2-amino-4-((l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-m ethylquinolin-3-yl) propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid;

85. N4-(l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin-3 -yl)propyl)-6- methyl-5-((E)-2-(l-methyl-lH-tetrazol-5-yl)vinyl)pyrimidine- 2,4-diamine;

86. N4-(l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin-3 -yl)propyl)-5-((E)-2- (3-methoxypyridin-2-yl)vinyl)-6-methylpyrimidine-2,4-diamine ;

87. 5-((E)-2-(lH-tetrazol-5-yl)vinyl)-N4-(l-(2-((2S,6R)-2,6-dime thylmorpholino)-8- methylquinolin-3-yl)propyl)-6-methylpyrimidine-2,4-diamine;

88. (E)-4-(3-(l-((2-amino-5-(2-(3-methoxypyridin-2-yl)vinyl)-6-m ethylpyrimidin-4-yl) amino)propyl)-8-methylquinolin-2-yl)thiomorpholine 1, 1-dioxide;

89. (E)-3-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin -2-yl) propyl)amino)pyrimidin-5-yl)methylene)pyrrolidine-2,5-dione; and

90. (Z)-5-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin -2-yl)propyl)amino)pyrimidin-5-yl)methylene)thiazolidine-2,4 -dione,

or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof. In further yet another particular embodiment of the present invention, the compound of formula ( 1 ) is selected from the group consisting of

5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazo lin-2-yl)

104.

propyl)amino)pyrimidin-5-yl)-N-(2-fluorophenyl)pyridine-3-su lfonamide;

5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazo lin-2-yl)

105.

propyl)amino)pyrimidin-5-yl)-N,N-dimethylpyridine-3-sulfonam ide;

2-(l-((2-amino-5-(5-(pyrrolidin-l-ylsulfonyl)pyridin-3-yl)py rimidin-4-yl)

106.

amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;

N-(tert-butyl)-5-(2-(ethylamino)-4-((l-(5-fluoro-4-oxo-3-phe nyl-3,4-

107.

dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)pyridine- 3-sulfonamide;

5-(2-(ethylamino)-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-

108.

yl)propyl)amino)pyrimidin-5-yl)pyridine-3-sulfonamide;

N-(tert-butyl)-5-(4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-

109.

yl)propyl)amino)-2-((2-methoxyethyl)amino)pyrimidin-5-yl)pyr idine-3-sulfonamide;

2-(l-((2-amino-5-(5-((3,3-dimethylpyrrolidin-l-yl)sulfony l)pyridin-3-yl)pyrimidin-4-

110.

yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;

5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazo lin-2-

111.

yl)propyl)amino)pyrimidin-5-yl)-N-(2-chlorophenyl)pyridine-3 -sulfonamide;

5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazo lin-2-

112.

yl)propyl)amino)pyrimidin-5-yl)-N-(2,2,2-trifluoroethyl)pyri dine-3-sulfonamide;

5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin azolin-2-

113.

yl)propyl)amino)pyrimidin-5-yl)-N-(2,3-difluorophenyl)pyridi ne-3-sulfonamide;

5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin azolin-2-

114.

yl)propyl)amino)pyrimidin-5-yl)-N-(2,3-dichlorophenyl)pyridi ne-3-sulfonamide;

5-(4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2 -yl)propyl)amino)-2-

115.

(pyr idin-2- ylamino)pyr imidin- 5 - yl)pyridine- 3 - sulfonamide ;

2-(l-((2-amino-5-(5-(methylsulfonyl)pyridin-3-yl)pyrimidin-4 -yl)amino)propyl)-5-

116.

fluoro-3-phenylquinazolin-4(3H)-one;

2-(l-((2-amino-5-(5-(isopropylsulfonyl)pyridin-3-yl)pyrimidi n-4-yl)amino)propyl)-5-

117.

fluoro-3-phenylquinazolin-4(3H)-one;

2-(l-((2-amino-5-(5-(propylsulfonyl)pyridin-3-yl)pyrimidin-4 -yl)amino)propyl)-5-

118.

fluoro-3-phenylquinazolin-4(3H)-one; N-(5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin azolin-2-

119.

yl)propyl)amino)pyrimidin-5-yl)pyridin-3-yl)ethanesulfonamid e;

N-(5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin azolin-2-

120.

yl)propyl)amino)pyrimidin-5-yl)pyridin-3-yl)propane-2-sulfon amide;

N-(5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin azolin-2-

121.

yl)propyl)amino)pyrimidin-5-yl)pyridin-3-yl)methanesulfonami de;

2-(l-((2-amino-5-(l-(isopropylsulfonyl)-2,3-dihydro-lH-pyrro lo[2,3-c]pyridin-4-

122.

yl)pyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenylquinazolin- 4(3H)-one;

2-(l-((2-amino-5-(l-(methylsulfonyl)-2,3-dihydro-lH-pyrro lo[2,3-c]pyridin-4-

123.

yl)pyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenylquinazolin- 4(3H)-one; and

5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin azolin-2-

124.

yl)propyl)amino)pyrimidin-5-yl)-N-(tert-butyl)nicotinamide,

or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.

In further yet another particular embodiment, the definition of "compounds of formula (1)" inherently includes all stereoisomers of the compound of formula (1) either as pure stereoisomer or as a mixture of two or more stereoisomers. The word stereoisomers include enantiomers, diasteroisomers, racemates, cis isomers, trans isomers and mixture thereof.

The absolute configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1% of the other isomers. Thus when a compound of formula (1) is for instance specified as (R), this means that the compound is substantially free of (S) isomer; when the compound of formula (1) is for instance specified as E, this means that the compound is free of the Z isomer; when the compound of formula (1) is for instance specified as cis isomer, this means that the compound is free of the trans isomer.

In yet another embodiment, the compounds and pharmaceutically compositions of the present invention are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of PI3K/Akt/m-TOR pathway kinase contribute to the pathology and/or symptomology of such diseases and/or disorders. Such diseases and/or disorders mediated by one or more of these kinases are provided herein.

In yet another embodiment, the compounds and pharmaceutically compositions of the present invention are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of PI3K kinase; more particularly ΡΒΚγ and PI3K5 isoforms.

According to preceding embodiment, the compounds of formula ( 1) are inhibitors of specific PI3K5 isoform and are used in the treatment and/or prevention of diseases and/or disorders associated with aberrant, abnormal or deregulated activity of PI3K5 isoform.

According to one of the preceding embodiment, the compounds of formula (1) are specific dual inhibitors of ΡΙ3Κγ and PI3K5 isoforms and are used in the treatment and/or prevention of diseases and/or disorders associated with aberrant, abnormal or deregulated activity of PI3K5 and ΡΙ3Κγ isoforms.

Diseases and/or disorders associated with aberrant, abnormal or deregulated activity of PI3K/Akt/M-TOR pathway kinases include, but are not limited to allergic disorders and/or autoimmune and/or inflammatory diseases and/or conditions associated with inflammation and pain, cancers, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders, muscle diseases and/or disorders respiratory diseases and/or disorders, pulmonary disorders, genetic developmental diseases, neurological and neurodegenerative diseases/or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases and/or disorders, ophthalmic/ocular diseases and/or disorders, wound repair, infection and viral diseases. In particular, the compounds according to the present invention possess potential of providing cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas but not limited to leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, etc.

Without limiting the scope of present invention, the following definitions are provided in order to aid those skilled in the art in understanding the detailed description of the present invention. "Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; in particular alkyl is Q-Qo alkyl group which may have 1 to 10 (inclusive) carbon atoms in it; in more particular alkyl is Ci-C ₆ alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is C _\ - C ₄ alkyl group which may have 1 to 4 (inclusive) carbon atoms in it. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert -butyl, isopentyl, neopentyl, and isohexyl. An alkyl group can be unsubstituted or substituted with one or more suitable groups.

"Alkoxy" refers to the group alkyl-0- or -O-alkyl, where alkyl group is as defined above. Exemplary Ci-Cioalkyl group containing alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, zso-propoxy, n-butoxy and i-butoxy. An alkoxy group can be unsubstituted or substituted with one or more suitable groups.

" Alkoxy lalkyl" refers to the an alkyl group substituted with one or more alkoxy groups; the alkyl group and alkoxy group are same as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with alkoxy group. Representative examples of an alkoxyalkyl group includes but are not limited to -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , - CH ₂ CH ₂ OCH ₂ CH ₃ and the like

"Halogen" or "halo" includes fluorine, chlorine, bromine or iodine.

"Haloalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with - F,- CI,- Br or -I. Representative examples of an haloalkyl group include, but are not limited to -CH ₂ F, -CC1 ₃ , -CF ₃ , -CH ₂ C1, -CH ₂ CH ₂ Br, - CH ₂ CH ₂ I, -CH ₂ CH ₂ CH ₂ F, - CH ₂ CH ₂ CH ₂ C1, -CH ₂ CH ₂ CH ₂ CH ₂ Br, -CH ₂ CH ₂ CH ₂ CH ₂ I, - CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ Br, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ I, -CH ₂ CH(Br)CH ₃ , -CH ₂ CH(C1)CH ₂ CH ₃ , and - CH(F)CH ₂ CH ₃ .

"Nitro" refers to -N0 ₂ group.

"Amino" refers to an -N- group, the nitrogen atom of said group being attached to a hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or any suitable groups. Representative examples of an amino group include, but are not limited to -NH ₂ , -NHCH ₃ and -NH-cyclopropyl. An amino group can be unsubstituted or substituted with one or more of the suitable groups.

"Aryl" refers to an optionally substituted monocylic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. Examples of a C6-C14 aryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. Aryl group can be unsubstituted or substituted with one or more suitable groups;

"Cycloalkyl" refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a cycloalkyl include, but are not limited to cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-l-yl, octahydro-lH- inden-2-yl and decahydro-lH-benzo[7] annulen-2-yl. A cycloalkyl can be unsubstituted or substituted with one or more suitable groups.

The term "Heterocyclyl" includes the definitions of "heterocycloalkyl" and "heteroaryl". The term "Heterocycloalkyl" refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(0) ₂ , NH and C(O). Exemplary heterocycloalkyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4- dioxanyl and the like. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups;

"Heteroaryl" refers to a saturated, monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatoms selected from oxygen, sulfur and nitrogen. Examples of C5-C10 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4- triazole, l-methyl-l,2,4-triazole, lH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. A heteroaryl group can be unsubstituted or substituted with one or more suitable groups.

"Hetero atom" refers to a sulfur, nitrogen or oxygen atom.

"Hetero group" refers to -C(O)-, -S(O), -NH and S(0) ₂ .

"Bicyclic ring containing 1-5 heteroatoms/groups" refers to a saturated, partially saturated or unsaturated bicyclic ring, in which 9 to 12 of the ring carbon atoms have been independently replaced with a heteroatom/heterogroups such as N, O, S,-C(0)-, -S(O), -NH and S(0) ₂ . Representative examples of a 9 to 12 membered ring include, but are not limited to quinazolin-4(3H)-one, quinoline, lH-pyrazolo[3,4-d]pyrimidin-4(5H)-one, 3H-pyrrolo[3,4- d]pyrimidin-4(7H)-one, pyrido[2,3-d]pyrimidin-4(3H)-one and the like.

"Optionally substituted or substituted" as used herein means that at least one or two hydrogen atoms of the optionally substituted group has been substituted with suitable groups as exemplified but not limited to alkyl, alkenyl, alkoxy, alkynyl, aryl, amido, amino, carboxy, cyano, cycloalkyl, guanidine, halogen, imidamide, hydroxy, nitro, haloalkyl, haloalkoxy, heterocyclyl, oxo(=0), thio(=S), -P(0) ₃ H, -P(0) ₂ NH ₂ , -P(0) ₂ NH(alkyl), -P(0) ₂ NH(cycloalkyl),- P(0) ₂ NH(heterocyclyl), -P(0) ₂ NH(aryl), -C(0)(alkyl), -C(0)(aryl), -C(0)(cycloalkyl), - C(0)(heterocyclyl), or two substituents on the same carbon atom combined together to form an optionally substituted 3-8 member ring containing 0-3 heteroatoms independently selected form N, O and S in any stable combination;

"Comprise" or "Comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable derivatives" is taken to mean an active ingredient, which comprises a compound of the formula (1) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.

The use of the term "including" as well as other forms, such as "include", "includes" and

"included" is not limiting.

As used herein, the terms "treat", "treating" or "treatment" encompass either or both responsive and prophylaxis measures, e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms. The terms "treat," "treating" or "treatment", include, but are not limited to, prophylactic and/or therapeutic treatments.

As used herein the terms "subject" or "patient" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other embodiments, the subject can be a normal subject. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.

As used herein the term "therapeutically effective amount" refers to a sufficient amount of a compound or a composition being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.

"Pharmaceutically acceptable" means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).

A therapeutically effective amount of a compound of the formula (1) and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to lOmg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.

In a further aspect, the present invention relates to a process for preparing 2-amino pyrimidine derivatives of formula (1)

An embodiment of the present invention provides the compounds according to formula (1) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. The intermediates or compounds synthesized herein may be used in the further step with isolating or without isolating. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.

In a further aspect, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as ² H ("D"), ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ 0, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ C1, ¹²³ I and ¹²⁵ I. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. The abbreviations used in the entire specification may be summarized herein below with their particular meaning.

Ac ₂ 0(Acetic anhydride); ACN (acetonitrile); Ar (Argon); brine (NaCl solution); BINAP (2,2'-bis(diphenylphosphino)-l, l'-binaphthyl); bs (broad singlet); C ₂ Cl ₆ (hexachloroethane) ; CDCI3 (deuteriated chloroform); CS ₂ CO3 (cesium carbonate); °C (degree Celsius); d (doublet); CH ₂ C1 ₂ /DCM (dichloromethane); dd (doublet of doublet); diLHCl (diluted hydrochloric acid); DIPEA/DIEA (Ν,Ν-Diisopropylethylamine); DMAP (dimethylaminopyridine) ; DME (dimethoxyethane); DMF (dimethylformamide) ; DMSO(Dimethylsulfoxide); DMSO-d ₆ (Deuteriateddimethylsulfoxide); EDC.HC1 (l-(3-Dimethyl aminopropyl)-3-carbodiimide hydrochloride); ES-MS (Electrospray Ionisation Mass Spectrometry)EtOH (ethanol); Et ₃ N (Triethylamine); Et ₂ 0 (diethyl ether); g (gram); H (hydrogen); ¹ H (proton NMR); Hz(Hertz); h (hours); HCl (hydrochloric acid); H ₂ 0 (water); HOBT (1 -Hydroxy benzotriazole); HPLC (High- performance liquid chromatography); IPA (Isopropylalcohol); J (coupling constant); K ₂ C0 ₃ (potassium carbonate); LC/MS (Liquid chromatography-mass spectrometry) ;LiOH (Lithium hydroxide); mmol (millimol); M (molar); ml (milli litre); mg (milli gram); m (multiplet); MeOH (methanol); MHz (mega hertz); MS (ES) (mass spectroscopy-electro spray); min (minutes); m/z (molecular weight); Na ₂ C0 ₃ (Sodium carbonate) ; NaHC0 ₃ (Sodium bicarbonate); N ₂ (nitrogen); NaBH ₄ (Sodium borohydride); Na ₂ S0 ₄ (Sodium sulphate); nm (nano molar); NMP (N- Methylpyrrolidone); NMR (nuclear magnetic resonance spectroscopy); NIS (N-

Iodosuccinamide) ; O/N (Overnight range: 8 to 8 hrs); PDA (photo diode array detector); Pd ₂ (dba) ₃ (tris dibenzylidene acetone) dipalladium; Pd(OAc) ₂ (Palladiumdiacetate); Pd(dppf)Cl ₂ ([l, l'-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane; Pd(Pph ₃ ) ₄ (Tetrakis (triphenylphosphine)palladium, P0C1 ₃ (Phsophorousoxychloride); ppm-δ (parts per million); R.T(Room temperature range: 20 to 40°C); S (singlet); S0C1 ₂ (thionylchloride); t (triplet); TLC (Thin Layer Chromatography); THF (tetrahydrofuran); TFA (trifluoroaceticacid); TPP (Triphenylphosphine); TMSI (Trimethylsulfoxoniumiodide); q (Quartet); μπι (micro molar); PCI ₅ (Phosphorous pentachloride) ; Br ₂ (bromine); h (hours); CH ₃ COOK (potassiumacetate), Oxone (Potassium peroxy monosulfate); KH ₂ P0 ₄ (potassium dihydrogen phosphate); μηι (micro molar); LC/MS (Liquid chromatography-mass spectrometry); m/z (molecular weight); HPLC (High-performance liquid chromatography); ES- MS (Electrospray Ionisation Mass Spectrometry) etc. General modes of preparation:

Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.

A general approach for the synthesis of compounds of general formula (I) is depicted in below schemes. As used herein the below schemes the terms 'R ¹ ', 'R ² ', 'R ³ ', 'R ⁴ ', 'R ⁵ ', 'R ⁶ ',

'R 7 ', 'R 8 ', 'R 9 ', 'R 10 ', 'n', Q and 'A' represents all the possible substitutions as disclosed in formula (1).

A general approach for the synthesis of critical intermediates of the present invention are depicted in scheme-a, scheme-b and scheme-c.

S

The general approach for the synthesis of intermediate of formula G is depicted in scheme-a. The intermediate of formula A reacts with acetic anhydride to give aldehyde compound of formula B. On cyclization of compound of formula B in presence of POCl ₃ gives compound of formula C, which on reaction with R in presence of suitable base gives compound of formula D. On reaction of compound of formula D with Grignard reagent (alkyl magnesium halide) under suitable conditions results in the formation of compound E, which on chlorination with thionyl chloride gives the compound of formula F. Amination of compound of formula F in presence of Aq. ammonia gives compound of formula G.

Scheme-b: The general approach for the synthesis of intermediate- K is depicted in scheme-b. The compound of formula H reacts with R -amine and compound of formula I in presence of triphenylphosphine to give compound of formula J, which on deprotection results in the formation of compound of formula K.

S

The general approach for the synthesis of intermediate-R is depicted in scheme-c. The compound (S)-2-aminobutanoic acid reacts with pthalic anhydride (L) to give intermediate M. the intermediate M on reaction with intermediate N in presence of SOCl ₂ gives intermediate O, which on reaction with R -NH in presence of triphenylphosphite gives intermediate P. The intermediate P on cyclisation in presence of EDC.HC1 and HOBT gives the intermediate Q, which on reaction with hydrazine.hydrate gives the intermediate R.

A general approach for the synthesis of compounds of the present invention is depicted in scheme- 1.

Scheme- 1:

The general approach for the synthesis of compound of formula 1A, IB, 1C and ID are depicted in scheme- 1. On reaction of compound of formula 1.1 with compound of formula 1.2 in presence of DIPEA at suitable conditions results in the formation of compound of formula 1.3. The compound of formula 1.3 on Suzuki coupling with compound of formula 1.4 and 1.5 respectively in presence of suitable palladium catalyst. The Pd-catalyzed C-C coupling reaction can be carried out in suitable polar solvents such as DMF, propionitrile, ACN, THF or DMSO and the like, in a suitable organic bases such as TEA, DIPEA and the like by using catalysts such as Pd(OAc) ₂ , Pd(PPh ₃ ) ₂ Cl ₂ or Pd ₂ (dba) ₃ and the like, at a temperature of about 100-130°C to give compound of formula (1A) and (IB) respectively. The compound of formula 1.3 on heck coupling with compound 1.6 in presence of suitable palladium catalyst, suitable ligands such P(o-tolyl) ₃ , P(m-tolyl) ₃ , BINAP or P(p-tolyl) ₃ and the like, under standard heck coupling condition gives compound of formula (1C). The compound (1C-A) was prepared similar to the procedure depicted in the compound of formula (1C) by using compound 1.3 and compound 1.7, wherein the compound (1C-A) further undergoes cyclization with TMSI in presence of base such as NaH at appropriate conditions results in the compound of formula (ID).

EXPERIMENTAL

The procedure for the compounds of formula (1) are detailed herein below stepwise including the general synthesis of various intermediates involved in process of manufacture of the compounds according to the present invention. The scope of the processes according to the present invention for preparing compounds of formula (1) shall not construed limited to the depictions as given below, however, it also covers obvious workable changes of steps either prior or later during the entire process.

The specifics of the process for preparing compounds of the present invention are detailed in the experimental section.

In the following, the present invention shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the invention.

Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.

Analysis for the compounds of the present invention unless mentioned, was conducted in the general methods well known to the person skilled in the art. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples, describing in detail the analysis of the compounds of the invention.

It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

The HPLC data provided in the examples described below were obtained as followed. HPLC (Method A): ColumnName: Inertsil ODS3V (150 mm x 4.6 mm), 5μπι

Column_Serial-no: 3JI84045 at a flow of 1 ml/15min gradient MobilePhase_used: A: 0.1M KH ₂ P0 ₄ (PH6.5); B: ACN.

Diluents: MeOH+ACN+H ₂ 0 (Sonicated); Wavelength: PDA 210.00nm.

(Method B): Column name: XTerra RP18 (250 mm x 4.6 mm), 5μπι

Column_Serial-no: 01933823313683 at a flow of lml/15min gradient

MobilePhase_used: A: 0.1M KH ₂ P0 ₄ (PH6.5); B: ACN.

Diluents: MeOH+ACN+H ₂ 0 (Sonicated); Wavelength: PDA 215.00nm.

(Method C): Column_name: Symmetry Shield RP18 (150 mm x 4.6 mm), 5μπι

Column_Serial-no: 01613610313630 at a flow of lml/15min gradient

MobilePhase_used: A: 0.1M KH ₂ P0 ₄ (PH6.5); B: ACN.

Diluents: MeOH+ACN+H ₂ 0 (Sonicated); Wavelength: PDA 210.00nm.

(Method D): Column_name: Chromolith RP18 (100 mm x 4.6 mm)

Column_Serial-no: UM8078/066 at a flow of lml/15min gradient

MobilePhase_used: A: 0.01M KH ₂ P0 ₄ (PH6.5); B: ACN.

Diluents: DMSO+ACN+MeOH+H ₂ 0 (Sonicated); Wavelength: PDA 210.00nm.

The MS data provided in the examples described below were obtained as followed: Mass spectrum: LC/MS Agilent 6120 Quadrapole LC/MS

The NMR data provided in the examples described below were obtained as followed: 1H- NMR: Varian 400 MHz.

Examples:

The procedure for the preparation of compounds of formula (1) are detailed herein below stepwise including the general synthesis of various intermediates involved in process of preparation of the compounds according to the present invention. The scope of the processes according to the present invention for preparing compounds of formula (1) shall not construed limited to the depictions as given below, however, it also covers obvious workable changes of steps either prior or later during the entire process.

Intermediate- 1: Synthesis of 4-chloro-2-(2, 5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl pyrimidine (ID)

(i) Ethyl acetoacetate, K ₂ C0 ₃ , ethanol, 80°C, overnight; (ii) POCl ₃ , 100°C, Overnight:

(iii) NIS, ACN, Methanol, Reflux, 8 h; (iv) 2,5-Hexanedione, PTSA, Toluene, 140°C, Overnight.

Step-(i): 2-amino-6-methylpyrimidin-4-ol ( 1A)

Ethyl acetoacetate ( 1 g, 7.6 mmol), guanidine hydrochloride (0.72 g, 7.60 mmol) in ethanol (30 ml) and potassium carbonate ( 1.15 g, 36.0 mmol) are stirred at 80°C for overnight. The mixture is allowed to cool to room temperature. Then the precipitate formed was filtered off and dried (0.8 g, 80%). MS (ES) m/z 126 (M+l) ⁺ .

Step-(ii): 4-chloro-6-methylpyrimidin-2-amine ( IB)

POCl ₃ ( 15 ml) was added to intermediate- 1 A (0.8 g, 6.4 mmol) at 0-5°C and refluxed the reaction mixture for overnight. Then the reaction mixture was poured slowly into the crushed ice, the precipitate is filtered and dried under vacuo to get the crude compound as yellow solid (0.5 g, 51 %).1H-NMR (400 MHz, DMSO-J ₆ ) δ 6.98 (s, 2H), 6.56 (s, 1H), 2.21 (m, 3H). MS (ES) m/z 144 (M+l) ⁺ .

Step-(iii): 4-chloro-5-iodo-6-methylpyrimidin-2-amine ( 1C)

NIS (0.1 18 g, 0.52 mmol) was added to intermediate- 1B(0.05 g, 0.35 mmol) in ACN ml) and methanol (0.7 ml), refluxed the reaction mixture for 5 h. Then the solvent is eliminated in vacuo to get the crude compound as yellow solid (0.02 g, 31%). ¹ H-NMR (400 MHz, DMSO- de) δ 7.13 (s, 2H), 2.47 (s, 3H). MS (ES) m/z 269 (M+l ) ⁺ .

Step-(iv): 4-chloro-2-(2, 5-dimethyl- l H-pyrrol- l -yl)-5-iodo-6-methylpyrimidine ( ID)

To a stirred solution of intermediate- 1C (0.2 g, 0.74 mmol) and 2,5-hexanedione (0.29 g,

2.6 mmol) in toluene ( 10 ml), was added PTSA (0.01 g). The reaction mixture was stirred at 140°C for overnight using dean-stark trap. Then the residue was diluted with water ( 10 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic phases were dried over sodium sulphate and concentrated. The residue was chromato graphed on 100-200 mesh silica gel eluting with 100% hexane as eluent to achieve the pure product as a yellow solid (0.025 g, 10%). 1H-

NMR (400 MHz, DMSO-J ₆ ) δ 5.89 (s, 2H), 2.79 (s, 3H), 2.37 (s, 6H). MS (ES) m/z 348 (M+ l) Intermediate-2: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(2-(4- methylpiperazin-l-yl)quinolin-3-yl)propyl)pyrimidin-4-amine (2G)

(i) Ac ₂ 0, 0°C - R.T, 4 ; (ii) POCl ₃ , DMF, 0°C - Reflux, Overnight; (iii) 1-methylpiperazine, K ₂ C0 ₃ , DMSO, 100°C, 48 h; (iv) Ethylmagnesium bromide, THF, -15°C - R.T, 4 h; (v) SOC1,, DCM, 0°C - Reflux, 4h; (vi) Aqueous ammonia,

Sealed tube, 100°C, Overnight; (vii) Intermediate- ID, DIPEA, IP A, Microwave, 110°C, 40 min;

Step-(i): N-phenylacetamide (2A)

Acetic anhydride (5 ml, 53.7 mmol) was added to aniline (5 g, 53.7 mmol) at 0°C and the reaction mixture was stirred for 4h at room temperature. Then the reaction mixture is poured into ice water, the precipitate was separated by filtering and dried under vacuo to give the crude compound as white solid (5 g, 70%). *H-NMR (400 MHz, DMSO-J ₆ ) δ 9.9 (bs, 1H), 7.50(d, 2H, J=8.0 Hz), 7.28 (t, 2H, J=8.0 Hz), 7.0 (t, 1H, J=7.3 Hz), 2.00 (s, 3H). MS (ES) m/z 136 (M+l) ⁺ . Step-(ii): 2-chloroquinoline-3-carbaldehvde (2B)

DMF (8 ml, 111.1 mmol) was added to POCl ₃ (28 ml, 185.1 mmol) at 0-5°C and then intermediate-2A (5 g, 37.0 mmol) was added. The mixture was stirred at 100°C for overnight. Then the reaction mixture is poured into the ice water, the precipitate was separated off by filtering and dried under vacuo to give the crude compound as yellow solid (3 g, 42%). 'H-NMR (400 MHz, DMSO-Je) δ 10.39 (s, 1H), 9.0 (s, 1H), 8.30 (d, 1H, J=8.3 Hz), 8.0 (m, 1H), 7.90 (m, 1H), 7.70 (m, 1H). MS (ES) m/z 192 (M+l) ⁺ .

Step-(iii): 2-(4-methylpiperazin- l-yl)quinoline-3-carbaldehvde (2C)

To a stirred solution of 1-methylpiperazine (7.7 g, 78.5 mmol) and K ₂ C0 ₃ (21.6 g, 157.0 mmol) in DMSO, intermediated (10 g, 52.3 mmol) was added and stirred for 48 h at 100°C. Then the cooled residue was diluted with water (100 ml) and extracted with ethyl acetate (2 x 300 ml). The combined organic phases were dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 3% methanol in dichloromethane to give the title compound as a yellow solid (5 g, 38%). 'H-NMR (400 MHz, DMSO-Je) 510.0 (s, 1H), 8.60 (s, 1H), 8.0 (d, 1H, J=7.8 Hz), 7.7 (s, 2H), 7.4 (d, 1H, J=8.9 Hz), 3.4 (m, 4H), 2.5 (m, 4H), 2.20 (s, 3H). MS (ES) m/z 256 (M+l) ⁺ .

Step-(iv) : 1 -(2-(4-methylpiperazin- 1 - yl)quinolin-3 - vDpropan- 1 -ol (2D)

To a stirred solution of intermediate-2C (10 g, 39.2 mmol) in THF (100 ml), was added ethyl magnesium bromide (30 ml) at -15°C and stirred at room temperature for 4 h. The obtained residue was cooled to 0°C and acidified with dil.HCl then extracted with water (100 ml) and ethyl acetate (3 x 150 ml). The combined organic phases were dried over sodium sulphate and concentrated under vacuo to get the desired product as a yellow solid (8.0 g, 10%). 'H-NMR (400 MHz, DMSO-Je) δ 8.24 (s, 1H), 7.83 (d, 2H, J=7.6 Hz), 7.59 (m, 1H), 7.39-7.37 (m, 1H), 5.28 (s, 1H), 4.79-4.75 (m, 1H), 3.22-3.05 (m, 8H), 2.25 (s, 3H), 1.74-1.67 (m, 2H), 0.87 (m, 3H). MS (ES) m/z 285 (M+l) ⁺ .

Step-(v): 3-(l-chloropropyl)-2-(4-methylpiperazin-l-yl)quinoline (2E)

SOCl ₂ (0.4 ml, 4.90 mmol) was added to intermediate-2D (0.25 g, 0.9 mmol) in DCM at 0°C. The reaction mixture was refluxed for 4 h. DCM was then eliminated in vacuo and the residue was washed with excess of diethyl ether to get desired compound. 'H-NMR (400 MHz, DMSO-Je) δ 8.27 (s, 1H), 7.88 (d, 1H, J=8.3 Hz), 7.76 (d, 1H, J=8.0 Hz), 7.69-7.65 (m, 1H), 7.48-7.45 (m, 1H), 5.06-5.04 (m, 1H), 4.20-4.14 (m, 1H), 3.97-3.73 (m, 3H), 3.54-3.48 (m, 3H), 2.99-2.98 (m, 1H), 2.86 (s, 3H), 2.29-2.25 (m, 2H), 1.04-1.02 (m, 3H). MS (ES) m/z 304 (M+l) ⁺ .

Step-(vi) : 1 -(2-(4-methylpiperazin- 1 - yl)quinolin-3 - vDpropan- 1 -amine (2F)

Ammonium hydroxide (5 ml) and intermediate-2E (0.2 g) in a sealed tube was heated to

100°C for overnight. The reaction mass was cooled to room temperature and extracted with ethyl acetate (2 x 20 ml). The combined organic phases were dried over sodium sulphate and concentrated under vacuo to get the desired product. 'H-NMR (400 MHz, DMSO-Je) δ 8.28 (s, 1H), 7.88 (d, 1H, J=8.3 Hz), 7.76 (d, 1H, J=8.0 Hz), 7.67-7.65 (m, 1H), 7.48-7.45 (m, 1H), 4.07 -

4.03 (m , 1H), 3.32-3.03 (m, 8H), 2.25 (s, 3H), 1.66-1.62 (m, 2H), 0.82 (t, 3H, J=6.7 Hz).

Step-(vii): 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(2-(4-m ethylpiperazin-l-yl) quinolin-3-yl)propyl)pyrimidin-4-amine (2G)

To a stirred solution of intermediate-2F (0.2 g, 0.68 mmol) and intermediate- ID (0.25 g, 0.75 mmol) in IPA (2 ml), DIPEA (0.4 ml) was added and stirred at 110°C for 40 min in CEM

Microwave. Then the cooled residue was diluted with water (10 ml) and extracted with ethyl acetate (2 x 10 ml). After brine wash, the combined organic phases were dried over sodium sulphate and concentrated. The residue was chromato graphed on 100-200 mesh silica gel eluting with 1% methanol in dichloromethane to give the title compound as a yellow solid (0.2 g, 50%). 'H-NMR (400 MHz, DMSO-Je) δ 8.34 (s, 1H), 7.80 (m, 2H), 7.60 (m, 1H), 7.40 (m, 1H), 6.94 (d, 1H, J=8.3 Hz), 5.7 (s, 2H), 5.40 (m, 1H), 3.40 (m, 6H), 2.8 (m, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.0 (s, 6H), 0.9 (m, 3H). MS (ES) m/z 596 (M+l) ⁺ .

Intermediate-3: Synthesis of 2-(l-((2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl pyrimidin-4- l)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one (3C)

(i) Trip enyl phosphite, Pyridine, 70 ^C C, 8h; (ii) TFA, DCM, 10°C - RT, Overnight; (iii) Intermediate- ID, DIPEA, IPA,

Microwave, 110°C, 40 min. Step-(i): tert -butyl (l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propy l)carbamate (3A1

To a stirred solution of 2-amino-6-methylbenzoic acid (5.0 g, 33.1 mmol) and Boc-L-2- aminobutyric acid (6.72 g, 33.1 mmol) in pyridine (20 ml), was added triphenylphosphite (25.68 g, 82.8 mmol). The reaction mixture was stirred at 70°C for 2 h, and then aniline (3.6 g, 39.7 mmol) was added and stirred for another 6 hrs at same temperature. The obtained mixture was diluted with sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2 x 10 ml). After brine wash, the combined organic phases were dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 15% ethyl acetate in hexane to give the title compound as a yellow solid (2.5 g, 20%). 'H-NMR (400 MHz, CDCI ₃ ) δ 7.62-7.60 (m, 5H), 7.37 (d, 1H, J=7.8 Hz), 7.58-7.50 (m, 1H), 7.28-7.22 (m, 1H), 5.50 (d, 1H, J=8.8 Hz), 4.39 - 4.38 (m, 1H), 2.80 (s, 3H), 1.77-1.74 (m, 1H), 1.42 (s, 9H), 1.40 (s, 1H), 0.77-0.74 (m, 3H). MS (ES) m/z 394 (M+l) ⁺ .

Step-(ii): 2-( l-aminopropyl)-5-methyl-3-phenylquinazolin-4(3H)-one (3B)

To a stirred solution of intermediate-3A (3.5 g, 8.90 mmol) in DCM (35 ml), was added TFA (15 ml) at 10°C. The reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After the reaction was completed, TFA was removed under vacuum and neutralized with sodium bicarbonate solution then extracted with ethyl acetate (2 x 100 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product as a yellow solid (2.2 g, 90%). MS (ES) m/z 294 (M+l) ⁺ .

Step-(iii): 2-(l-((2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methylpyrirm din-4-yl)amino) propyl)-5-methyl-3-phenylquinazolin-4(3H)-one (3C)

The process of this step was adopted from intermediate-2G by using intermediate-3B and intermediate- ID as starting compounds. 1H-NMR (400 MHz, DMSO-J ₆ ) δ 7.71-7.70 (m, 2H), 7.69-7.60 (m, IH), 7.56-7.51 (m, IH), 7.48-7.29 (m, 2H), 7.11 (d, IH, J=8.3 Hz), 6.85 (d, IH, J=8.3 Hz), 5.82 (s, 2H), 5.03 (bs, IH), 4.21 (m, IH), 2.81 (s, 3H), 2.59 (s, 3H), 2.13 (s, 6H), 1.87 (m, IH), 1.68 (m, IH), 0.79 (m, 3H). MS (ES) m/z 605 (M+l) ⁺ .

Intermediate-4: Synthesis of 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)- 5-methyl-3-phenylquinazolin-4(3H)-one (4B)

(i) n-Butanol, Sealed tube, 140°C, Overnight; (ii) S, ACN, Methanol, 80°C, 3h;

Step-(i): 2-(l-((2-amino-6-methylpyrimidin-4-yl)amino)propyl)-5-methyl -3-phenyl

quinazolin -4(3H)-one (4A)

To a solution of intermediate- IB (0.3 g, 2.09 mmol) and intermediate-3B (0.55 g, 1.80 mmol) in n-butanol were stirred at 140°C for overnight in sealed tube. The n-butanol was eliminated in vacuo and the residue was chromatographed on 100-200 mesh silica gel eluting with 4% methanol in dichloromethane to give the title compound as a yellow solid (0.25 g, 24%). 'H-NMR (400 MHz, DMSO-J ₆ ): δ 8.64 (s, IH), 7.70-7.66 (m, IH), 7.59-7.52 (m, 5H), 7.38 (d, IH, J=16 Hz), 7.03 (s, 2H), 5.94 (s, IH), 4.48 (s, IH), 2.72 (s, 3H), 2.16 (s, 3H), 1.87 - 1.16 (m, 2H), 0.83 (t, 3H, J=7.3 Hz). MS (ES) m/z 401 (M+l) ⁺ . Step-(ii): 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)-5 -methyl-3^heny quinazolin-4(3H)-one (4B)

To a stirred solution of intermediate- (4 A) (0.25 g, 0.62 mmol) in acetonitrile (5 ml) and methanol (7 ml), NIS (0.21 g, 0.93 mmol) was added and refluxed for 3 h. Excess of solvents were eliminated in vacuo to get the crude compound as yellow color solid (0.2 g, 61%). ¹ H-NMR (400 MHz, DMSO-Je) δ 11.04 (s, 1H), 7.74-7.72 (m, 1H), 7.57-7.51 (m, 5H), 7.34 (d, 2H, J= 3 Hz), 6.80 (s, 2H), 4.78 (s, 1H), 2.70 (s, 3H), 2.35 (s, 3H), 1.61-1.58 (m, 2H), 0.70-0.68 (m, 3H). MS (ES) m/z 527 (M+l) ⁺ .

Intermediate-5: Synthesis of Ethyl 5-amino-l-methyl-lH-pyrazole-4-carboxylate (5)

(I) Et ₃ N, Elhanol, 70°C, Overnight; (5)

To a stirred solution of methyl hydrazine sulfate (10 g, 59.17 mmol) and (E)-ethyl 2- cyano-3-ethoxyacrylate (8.5 g, 59.17 mmol) in ethanol (100 ml) was added Et ₃ N (18 ml, 177.5 mmol) and stirred at 70°C for overnight. Then the solvent is eliminated in vacuo and the residue was purified by chromatography on 100-200 mesh silica gel, eluting with 30% ethyl acetate in hexane to give the title compound as a yellow solid (8 g, 94%). ^! H-NMR (400 MHz, DMSO-Je) δ 7.43 (s, 1H), 6.20 (bs, 2H), 4.16 (m, 2H), 3.54 (s, 3H), 1.24 (t, 3H, J=7 Hz). MS (ES) m/z 169.9 (M+l) ⁺ .

Intermediate-6: Synthesis of 6-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)- l-methyl-5-phenyl-lH-pyrazolo[3, 4-d]pyrimidin-4(5H)-one (6G)

(i) Et ₃ N, Toluene, 120°C, 12 li; (ii) SOCl ₂ , Reflux, overnight; DIPEA, Toluene, 0°C-R.T, overnight; (iii) C ₂ C1 ₆ , TPP, DCM, R.T, 4 h; Aniline, R.T, Overnight; (iv) K ₂ C0 ₃ , DMF, 100°C, Overnight; EDC.HC1, HOBT, Et ₃ N, R.T, Overnight;(v) NH ₂ NH ₂ .H ₂ 0, Ethanol, Reflux, 4 h; (vi) n-butanol, Sealed tube, 140°C, Overnight; (vii) NIS, ACN, Methanol, 80°C, 3 h.

Step-(i): (S)-2-(L3-dioxoisoindolin-2-yl)butanoicacid (6A)

To a stirred solution of phthalic anhydride (1.48 g, 10.0 mmol) and (S)-2-aminobutanoic acid (1.03 g, 10.0 mmol) in toluene (20 ml), was added triethylamine (0.13 ml, 1.0 mmol). The obtained mixture was heated to 120°C for 12 h and distilled under a reduced pressure to remove toluene. The solid obtained was filtered under suction and washed with excess of water to give the desired product as a yellow solid (2.7 g, 90%). 'H-NMR (400 MHz, DMSO-J ₆ ) δ 12.0 (brs, 1H), 7.88 (m, 4H), 4.53 (m, 1H), 2.08 (m, 2H), 0.81 (t, 3H, J=7.4 Hz).

Step-(ii): (S, Z)-2-(l, 3-dioxoisoindolin-2-yl)-N-(4-(ethoxycarbonyl)-l-methyl-lH-py razol -5-yl)butanimidicacid (6B)

Intermediate- 6 A (14.8 g, 100.0 mmol) was taken in SOCl ₂ (50 ml) and was refluxed for overnight. After elimination of SOCl ₂ in vacuo, to the obtained residue in toluene DIPEA (15 ml, 120.0 mmol) and intermediate- 5 (16.9 g, 100.0 mmol) was added at 0°C and stirred was for overnight at room temperature. The obtained residue was diluted with sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with hexane / ethyl acetate (85: 15) to give the title compound as a yellow solid (23 g, 60%). ¹ H-NMR (400 MHz, DMSO-J ₆ ) δ 10.25 (s, IH), 7.96-7.88 (m, 4H), 7.81 (s, IH), 4.80-4.73 (m, IH), 4.19 (m, 2H), 3.60 (s, 3H), 2.33-2.25 (m, IH), 2.12-2.04 (m, IH), 1.26 (t, 3H, J=5 Hz), 0.87 (t, 3H, J=8 Hz). MS (ES) m/z 383 (M-l). Step-(iii): (S, Z)-ethyl 5-((2-(L3-dioxoisoindolin-2-yl)-l-(phenylamino)butylidene)am ino)-l- methyl- 1 H-pyrazole-4-carboxylate (6C)

Hexachloroethane (14.16 g, 60.0 mmol) was added to a stirred solution of intermediate- 6B(19.2 g, 50.0 mmol) and triphenylphosphine (15.72 g, 60.0 mmol) in DCM (20 ml).The obtained mixture was stirred at room temperature for 4 h, then aniline (5.6 g, 90.0 mmol) was added and continued stirring for overnight. The obtained mixture was diluted with sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with hexane / ethyl acetate (50:50) to give the title compound as a yellow solid (25 g, 55%). ¹ H-NMR (400 MHz, DMSO-J ₆ ) δ 9.24 (s, IH), 7.86-7.84 (m, 4H), 7.35-7.20 (m, 5H), 7.05-7.00 (m, IH), 4.95-4.65 (m, IH), 4.00 -3.98 (m, 2H), 3.32 (s, 3H), 2.33-2.26 (m, 2H), 1.19 (t, 3H, J=7 Hz), 0.87 (t, 3H, J=8 Hz). MS (ES) m/z 460 (M+l) ⁺ .

Step-(iv): (R)-2-(l-(l-methyl-4-oxo-5-phenyl-4,5-dihvdro-lH-pyrazolo[3, 4-dlpyrimidin-6-yl) propyDisoindoline- 1 ,3-dione (6D)

To a stirred solution of intermediate-6C( 11.45 g, 25.0 mmol) in DMF (20 ml), K ₂ C0 ₃ was added (6.9 g, 50.0 mmol). The reaction mixture was stirred at 100°C for overnight and allowed to cool. To the obtained mixture, Et ₃ N (5.05 ml, 0.05 mmol), EDC.HCl (9.55 g, 50.0 mmol) and HOBT (6.75 g, 50.0 mmol) were added and stirred at room temperature overnight. Then the residue was diluted with water (20 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with hexane / ethyl acetate (50:50) to give the title compound as a yellow solid (2.58 g, 25%). ¹ H-NMR (400 MHz, DMSO-Je) δ 8.12 (s, IH), 7.86-7.85 (m, 2H), 7.84-7.83 (m, IH), 7.76-7.73 (m, 3H), 7.34 (t, IH, J=7 Hz), 6.99 (t, IH, J=8 Hz), 6.80-6.77 (m, IH), 5.06-5.04 (t, IH, J=7 Hz), 3.96 (s, 3H), 2.50-2.23 (m, 2H), 0.87 (t, 3H, J=7 Hz). MS (ES) m/z 414 (M+l) ⁺ .

Step-(v): (R)-6-(l-aminopropyl)-l-methyl-5-phenyl-lH-pyrazolo[3,4-dlpy rimidin-4(5H)-one (6E)

To a stirred solution of intermediate-6D(1.03 g, 2.0 mmol) in ethanol was added hydrazine hydrate (0.5 ml, 10.0 mmol). The reaction mixture was refluxed for 4 h and distilled under a reduced pressure to remove the solvent. The residue was chromatographed on 100-200 mesh silica gel eluting with methanol/dichloromethane (10:90) to give the title compound as a yellow solid (0.35 g, 50%). *H-NMR (400 MHz, DMSO-J ₆ ) δ 8.00 (s, IH), 7.67-7.54 (m, 3H), 7.50-7.40 (m, IH), 7.30-7.24 (m, IH), 3.97 (s, 3H), 3.23-3.19 (m, IH), 2.27-1.71 (m, 3H), 1.49- 1.35 (m, IH), 0.86 (t, 3H, J=7 Hz). MS (ES) m/z 284 (M+l) ⁺ .

Step-(vi): (R)-6-( l-((2-amino-6-methylpyrimidin-4-yl)amino)propyl)- l-methyl-5-phenyl- 1H- pyrazolo[3,4-dlpyrimidin-4(5H)-one (6F)

The process of this step was adopted from intermediate-4A by using intermediate-6E and intermediate- IB. *H-NMR (400 MHz, DMSO-J ₆ ) δ 8.89 (bs, IH), 8.12 (s, IH), 7.59-7.51 (m, 5H), 7.28 (bs, 2H), 5.98 (s, IH), 4.53 (bs, IH), 3.92 (s, 3H), 2.19 (s, 3H), 1.98-1.86 (m, IH), 1.68-1.64 (m, IH), 0.68 (t, 3H, J=7.3 Hz). MS (ES) m/z 391 (M+l) ⁺ .

Step-(vii): (R)-6-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propy l)-l-methyl-5-phenyl -lH-pyrazolor3,4-dlpyrimidin-4(5H)-one (6G)

The process of this step was adopted from intermediate-4B from intermediate-6F. ¹ H-

NMR (400 MHz, DMSO-J ₆ ) δ 8.10(s, IH), 7.64-7.49 (m, 5H), 6.20 (d, IH, J=8.3 Hz), 6.06 (bs, 2H), 4.74-4.70 (m, IH), 3.95 (s, 3H), 2.28 (s, 3H), 1.79-1.76 (m, IH), 1.56-1.53 (m, IH), 0.65 (t, 3H, J=7.4 Hz). MS (ES) m/z 517 (M+l) ⁺ .

Intermediate-7: Synthesis of 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)- 5-fluoro-3-phenylquinazolin-4(3H)-one (7D)

(7D)

(i) Triphenyl phosphite, Pyridine, 70°C, 8 h; (ii) TFA, DCM, 10°C - RT, Overnight; (iii) n-Butanol, Sealed tube,

140°C, Overnight; (iv) NIS, ACN, Methanol, 80°C, 3h

Step-(i) and (ii): The process of these steps was adopted from intermediate-3B using 2-amino-6- fluorobenzoic acid. MS (ES) m/z 298 (M+l) ⁺ .

Step-(iii) and (iv): This process of these steps was adopted from intermediate-3B usingintermediate-7B. MS (ES) m/z 531 (M+l) ⁺ .

Intermediate-8: Synthesis of Ethyl 5-amino-l,3-dimethyl-lH-pyrazole-4-carboxylate (8)

(i) Et ₃ N, Ethanol, 70°C, Overnight;

The process of this step was adopted from intermediate- 5 using ethyl 2-cyano-3- ethoxybut-2-enoate. MS (ES) m/z 184 (M+l) ⁺ .

Intermediate-9: Synthesis of (R)-6-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino) propyl)-l,3-dimethyl-5-phenyl-lH-pyrazolo[3,4-d]pyrimidin-4( 5H)-one (9G)

(i) Et ₃ N, Toluene, 120°C, 12 h; (ii) SOCl ₂ , Reflux, overnight; DIPEA, Toluene, 0°C-R.T, overnight; (iii) C ₂ C1 ₆ , TPP, DCM, R.T, 4 h; Aniline, R.T, Overnight; (iv) K ₂ C0 ₃ , DMF, 100°C, Overnight; EDC.HC1, HOBT, Et ₃ N,

R.T, Overnight; (v) NH ₂ NH ₂ .H ₂ 0, Ethanol, Reflux, 4 h; (vi) n-butanol, Sealed tube, 140°C, Overnight; (vii)

NIS, ACN, Methanol, 80°C, 3 h.

The process of this step was adopted from intermediate-6G using phthalic anhydride and (S)-2- aminobutanoic acid. MS (ES) m/z 531 (M+l) ⁺ .

Intermediate-10: Synthesis of 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino) prop l)-3-(4-fluorophenyl)-5-methylquinazolin-4(3H)-one (10D)

(i) Triphenyl phosphite, Pyridine, 70°C, 8 h; (ii) TFA, DCM, 10°C - RT, Overnight; (iii) n-Butanol, Sealed tube, 140°C,

Overnight; (iv) NIS, ACN, Methanol, 80°C,3 h Step-(i) and (ii): The process of these step were adopted from intermediate-3B using 2-amino-6- methylbenzoic acid. MS (ES) m/z 312 (M+l) ⁺ .

Step-(iii) and (iv): The process of these steps were adopted from intermediate-4B using intermediate- 1 OB. MS (ES) m/z 545 (M+l) ⁺ .

Intermediate-11: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(8- methyl-2-(4-methylpiperazin-l-yl)quinolin-3-yl)propyl)pyrimi din-4-amine (11G)

(i) Ac ₂ 0, 0°C - R.T, 4 h; (ii) POCl ₃ , DMF, 0°C - Reflux, Overnight; (iii) 1-methylpiperazine, K ₂ C0 ₃ , DMSO, 100°C, 48 h;

(iv) Ethylmagnesium bromide, THF, -15°C - R.T, 4 h; (v) SOCl ₂ , DCM, 0°C - Reflux, 4 h; (vi) Aqueous ammonia, Sealed tube, 100°C, Overnight; (vii) Intermediate- ID, DIPEA, IP A, Microwave, 110°C, 40 min;

The process of this step was adopted from intermediate-2G using o-toluidine .MS (ES) m/z 610 (M+l) ⁺ .

Intermediate-12: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(2- thiomorpholinoquinolin-3-yl)propyl)pyrimidin-4-amine (12G)

(i) Ac ₂ 0, 0°C - R.T, 4 h; (ii) POCl _: „ DMF, 0°C - Reflux, Overnight; (iii) Thiomorpholine, K ₂ C0 ₃ , DMSO, 100°C, 48 h;

(iv) Ethylmagnesium bromide, TFIF, -15 ^D C - R.T, 4 h; (v) SOCl ₂ , DCM, 0°C - Reflux, 4 h; (vi) Aqueous ammonia, Sealed tube, 100°C, Overnight; (vii) Intermediate-ID, DIPEA, IP A, Microwave, 110°C, 40 min;

The process of this step was adopted from intermediate-2G using from aniline. MS (ES) m/z 599 (M+l) ⁺ . Intermediate-13: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(8- methyl-2-thiomorpholinoquinolin-3-yl)propyl)pyrimidin-4-amin e (13G)

(i) Ac ₂ 0, 0°C - R.T, 4 h; (ii) POCl,, DMF, 0°C - Reflux, Overnight; (iii)Thiomorpholine, K ₂ C0 ₃ , DMSO, 100°C, 48 h;

(iv) Ethylmagnesium bromide, THF, -15°C - R.T, 4h; (v) SOCl ₂ , DCM, 0°C - Reflux, 4 h; (vi) Aqueous ammonia, Sealed tube, 100°C, Overnight; (vii) Intermediate-ID, DIPEA, ΓΡΑ, Microwave, 110°C, 40 min;

The process of this step was adopted from intermediate-2G using o-toluidine. MS (ES) m/z 613 (M+l) ⁺ .

Intermediate-14: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(8- methyl-2-morpholinoquinolin-3-yl)propyl)pyrimidin-4-amine (14G)

(i) Ao ₂ 0, 0°C - R.T, 4 h; (ii) POCl ₃ , DMF, 0°C - Reflux, Overnight; (iii) Morpholine, K ₂ C0 ₃ , DMSO, 100°C, 48 h;

(iv) Ethylmagnesium bromide, THF, -15°C - R.T, 4h; (v) SOCl ₂ , DCM, 0°C - Reflux, 4h; (vi) Aqueous ammonia,

Sealed tube, 100°C, Overnight; (vii) Intermediate-ID, DIPEA, IP A, Microwave, 110°C, 40 min;

The process of this step was adopted from intermediate-2G using o-toluidine. MS (ES) m/z 597 (M+l) ⁺ .

Intermediate-15: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-N-(l-(2-((2S,6R)-2,6- dimethylmoipholino)-8-methylquinolin-3-yl)propyl)-5-iodo-6-m ethylpyrimidin-4-amine

(15G)

(i) Ao ₂ 0, 0°C - R.T, 4 h; (ii) POCl ₃ , DMF, 0°C - Reflux, Overnight; (iii) (2S,6i?)-2,6-dimethylmorpholine, K ₂ C0 ₃ , DMSO,

100°C, 48 h; (iv) Ethylmagnesium bromide, THF, -15°C - R.T, 4 h; (v) SOCl ₂ , DCM, 0°C - Reflux, 4 h; (vi) Aqueous ammonia, Sealed tube, 100°C, Overnight; (vii) Intermediate-ID, DIPEA, IP A, Microwave, 110°C, 40 min;

This process was adopted from intermediate-2G using o-toluidine. MS (ES) m/z 625 (M+l) ⁺ .

Intermediate-16: Synthesis of 4-(3-(l-((2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl pyrimidin-4-yl)amino)propyl)-8-methylquinolin-2-yl)thiomoiph olinel,l-dioxide (16E)

Step-(i): To a stirred solution of intermediate- 13D (0.2 g, 0.6 mmol) in DCM was added m- CPBA (0.57 g, 0.3 mmol) and stirred at room temperature for 12 h. Then quenched with aquesous solution of NaHC0 ₃ and extracted with ethyl acetate (2 x 15 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated to achieve the crude product as yellow oil (0.13 g, 60%). MS (ES) m/z 351 (M+l) ⁺ . Step-(ii): To a solution of intermediate- 16B(0.05 g, 0.14 mmol) in ethanol was added Re-Ni (0.05 g, 0.3 mmol) and stirred at room temperature for 12 h under H ₂ atmosphere.Then the reaction mixture was filtered through celite and concentrated the filterate to achieve the crude product as a brown pasty compound (0.026 g, 55%). MS (ES) m/z 335 (M+l) ⁺ .

Intermediates 16C, 16D and 16E are prepared according to the procedure depicted in intermediate-2. MS (ES) m/z 645 (M+l) ⁺ .

Intermediate-17: 4-chloro-5-iodopyrimidin-2-amine (17B)

(17A) (17B)

(i) POC1 ₃ , 100°C, 12h; (ii) NIS, DMF, room temperature, 12h.

Step-(i): 4-chloropyrimidin-2-amine (17A)

POCI ₃ (100 ml) was added to 2-aminopyrimidin-4-ol (10 g, 90.0 mmol) at 0°C and refluxed the reaction mixture for 12 h. After the reaction was completed, it was poured slowly onto the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow solid (5 g, 43 %). MS (ES) m/z 130 (M+l) ⁺ .

Step-(ii): 4-chloro-5-iodopyrimidin-2-amine (17B)

NIS (15 g, 60.0 mmol) was added to intermediate- 17A (5 g, 30.0 mmol) in DMF (50 ml), stirred the reaction mixture for 12 h. After the reaction was completed, it was poured slowly onto the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow solid (7 g, 71 %). MS (ES) m/z 256 (M+l) ⁺ .

Intermediate-18: 5-iodo-6-methyl-N4-(l-(8-methyl-2-morpholinoquinolin-3-yl)pr opyl) pyrimidine-2,4-diamine (18G)

(18D) (18E) (18F)

(vii) Reflux, 12h;

4h; (v) SOCl ₂ , Sealed tube, utanol,100°C,

Step-(i): N-(o-tolyl)acetamide (18A)

Acetic anhydride (5 ml, 53.7 mmol) was added to o-toluidine (5 g, 53.7 mmol) at 0°C and allowed to room temperature. The mixture was stirred at the same temperature for 4h. After the reaction was completed, it was poured slowly into the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as white solid (5 g, 70 %). MS (ES) m/z 150 (M+l) ⁺ .

Step-(ii): 2-chloro-8-methylquinoline-3-carbaldehyde (18B)

DMF (8 ml, 111.1 mmol) was added to POCl ₃ (28 ml, 185.1 mmol) at 0°C to 5°C and then intermediate- 18A (5 g, 37.0 mmol) was added. The mixture was stirred at 100°C for 12 h. After the reaction was completed, it was poured slowly into the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow solid (3 g, 42 %). MS (ES) m/z 206 (M+l) ⁺ .

Step-(iii): 8-methyl-2-morpholinoquinoline-3-carbaldehyde (18C)

To a stirred solution of morpholine (7.7 g, 78.5 mmol) and K ₂ C0 ₃ (21.6 g, 157.0 mmol) was taken in DMF, add intermediate- 18B (10 g, 52.3 mmol) to the reaction mixture. The reaction mixture was stirred at 100°C for 48 h. The progress of the reaction was monitored by TLC. The reaction mixture cooled to room temperature, water (100 ml) was added and the extracted the aqueous layer with ethyl acetate (2 x 300 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product, which was purified by column chromatography using 100-200 mesh silica gel and 3 % methanol in dichloro methane as eluent to achieve the pure product as a yellow solid (5 g, 38 %). MS (ES) m/z 257 (M+l) ⁺ .

Step-(iv): l-(8-methyl-2-morpholinoquinolin-3-yl)propan-l-ol (18D)

To a stirred solution of intermediate- 18C( 10 g, 39.2 mmol) in THF (100 ml), was added ethyl magnesium bromide (30 ml) at -15°C. The reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to 0°C and acidified with dil.HCl then extracted with water (100 ml) and ethyl acetate (3 x 150 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired product as a yellow solid (8.0 g, 10 %). MS (ES) m/z 287 (M+l) ⁺ .

Step-(v): 4-(3-(l-chloropropyl)-8-methylquinolin-2-yl)morpholine (18E)

SOCl ₂ (4.90 mmol) was added to intermediate- 18D (0.25 g, 0.9 mmol) in DCM. The reaction mixture was refluxed for 4 h. The progress of the reaction was monitored by TLC. DCM was removed from the reaction mixture under reduced pressure. Crude was washed with excess of diethyl ether to get desired compound as yellow solid (0.2 g, 72 %). MS (ES) m/z 305 (M+l) ⁺ . Step-(vi) : 1 -(8-methyl-2-morpholinoquinolin-3-yl)propan- 1 -amine ( 18F)

Ammonium hydroxide (5 ml) was added to intermediate- 18E (0.2 g) in a sealed tube. The above mixture was heated to 120°C for 12 h. The reaction mass was cooled to room temperature and extracted with ethyl acetate (2 x 20 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired product (0.05 g, 82 %). MS (ES) m/z 286 (M+l) ⁺ .

Step-(vii): 5-iodo-6-methyl-N4-((2-(4-methylpiperazin-l-yl)quinolin-3-yl )methyl)pyrimidine- 2.4-diamine (18G)

The mixture of intermediate- 18F (0.035 g, 0.13 mmol), intermediate- 1C (0.046 mg, 0.19 mmol) and DIPEA (0.03 6g, 0.26 mmol) in n-butanol (2 ml) was stirred at 100°C for 48 h. The progress of the reaction was monitored by TLC. The reaction mixture cooled to room temperature, water (100 ml) was added and then extracted the aqueous layer with ethyl acetate (2 x 300 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product which was purified by column chromatography using 100-200 mesh silica gel and 3 % methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (0.006 g, 10 %). MS (ES) m/z 519 (M+l) ⁺ . Intermediate-19: 5-iodo-N4-(l-(8-methyl-2-morpholinoquinolin-3-yl)propyl)pyri midine- 2,4-diamine (19)

The process of this step was adopted from intermediate- 18G by using intermediate- 18F and inter mediate- 17. MS (ES) m/z 505 (M+l) ⁺ .

Intermediate-20: 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)-5 -fluoro-3- phenylquinazolin-4(3H)-one (20C)

Step-(i): tert-butyl(l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2-yl)propyl)carbamate (20A

To a stirred solution of 2-amino-6-fluorobenzoic acid (5.0 g, 33.1 mmol) and Boc-L-2- aminobutyric acid (6.72 g, 33.1 mmol) in pyridine (20 ml), was added triphenylphosphite (25.68 g, 82.8 mmol). The reaction mixture was stirred at 70°C for 2 h, then aniline (3.6 g, 39.7 mmol) was added, stirring was continued for another 5h at same temperature, monitor the reaction by TLC, after the reaction was completed, it was cooled to room temperature and extracted with sodium bicarbonate solution (20 ml) and ethyl acetate (2 x 10 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product. Which was purified by column chromatography using 100-200 mesh silica gel and 15% ethyl acetate in hexane as eluent to achieve the pure product as a yellow solid (2.5 g, 20 %). MS (ES) m/z 398 (M+l) ⁺ .

Step-(ii): 2-( l-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (20B)

To a solution of intermediate-20A (3.5 g, 8.90 mmol) in DCM (35 ml), was added TFA (15 ml) at 10°C. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After the reaction was completed, TFA was removed under vacuum and neutralized with sodium bicarbonate solution then extracted with ethyl acetate (2 x 100ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product as a yellow solid (2.2 g, 90 %). MS (ES) m/z 298 (M+l) ⁺ .

Step-(iii): 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)-5 -fluoro-3-phenyl quinazolin-4(3H)-one (20C)

The process of this step was adopted from intermediate- 18G by using intermediate-20B and intermediate- 1C. MS (ES) m/z 531 (M+l) ⁺ .

Intermediate-21 : 2-(l-((2-amino-5-iodopyrimidin-4-yl)amino)propyl)-5-fluoro-3 -phenyl quinazol -4(3H)-one (21A)

The process of this step was adopted from intermediate- 18G by using intermediate-20B and intermediate- 17. MS (ES) m/z 517 (M+l) ⁺ .

Intermediate 22: 2-(l-((2-amino-5-iodopyrimidin-4-yl)amino)propyl)-5-methyl-3 -phenyl quinazolin-4(3H)-one (22C)

(1) Triphenyl phosphite, pyridine, 70°C, 7h; (11) TFA, DCM, 10°C-RT, 12h; (22C) (iii) DIPEA, n-Butanol, 1 10°C, 12h.

Step-(i): tert-butyl(l-(5-methyl-4-oxo-3-phenyl-3^-dihydroquinazolin-2 -yl)propyl)carbamate (22A)

To a stirred solution of 2-amino-6-methylbenzoicacid (5.0 g, 33.1 mmol) and Boc-L-2- aminobutyric acid (6.72 g, 33.1 mmol) in pyridine (20 ml), was added triphenylphosphite (25.68 g, 82.8 mmol). The reaction mixture was stirred at 70°C for 2 h, and then aniline (3.6 g, 39.7 mmol) was added, stirring was continued for another 5 h at same temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature and extracted with sodium bicarbonate solution(20 ml) and ethylacetate (2 x 10 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product, further purified by column chromatography using 100-200 mesh silica gel and 15 % ethyl acetate in hexane as eluent to achieve the pure product as a yellow solid (2.5 g, 20 %). MS (ES) m/z 394 (M+l) ⁺ .

Step-(ii): 2-( l-aminopropyl)-5-methyl-3-phenylquinazolin-4(3H)-one (22B)

The process of this step was adopted from intermediate-20B by using intermediate-22A.

MS (ES) m/z 294 (M+l) ⁺ .

Step-(iii): 2-( l-((2-amino-5-iodopyrimidin-4-yl)amino)propyl)-5-methyl-3-ph enylquinazolin-4 (3H)-one (22C)

The process of this step was adopted from intermediate- 18G by using intermediate-22B and intermediate- 17. MS (ES) m/z 514 (M+l) ⁺ .

Intermediate-23: 4-chloro-N-ethyl-5-iodopyrimidin-2-amine (23B) (23A) (23B)

(i) ethanamine, Et ₃ N, n-Butanol, 70°C _; 3h; (ii) NIS, DMF, 50°C, 3h.

Step-(i): 4-chloro-N-ethylpyrimidin-2-amine (23 A)

To a stirred solution of 2,4-dichloropyrimidine (3.0 g, 20.13 mmol) and ethanamine (1.97 g, 24.16 mmol) in n-butanol (20 ml), was added triethylamine (5.57 ml, 40.27 mmol) . The reaction mixture was stirred at 70°C for 3 h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature and extracted with sodium bicarbonate solution(20 ml) and ethyl acetate (2 x 10 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product, further purified by column chromatography using 100-200 mesh silica gel and 15 % ethyl acetate in hexane as eluent to achieve the pure product as a yellow solid (2.12 g, 67 %). MS (ES) m/z 158 (M+l) ⁺ .

Step-(ii): 4-chloro-N-ethyl-5-iodopyrimidin-2-amine (23B)

NIS (4.2 g, 19.1 mmol) was added to intermediate-23A (1 g, 6.36 mmol) in DMF (10 ml), stirred the reaction mixture for 3 h at 50°C. After the reaction was completed, it was poured slowly onto the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow color solid (0.52 g, 28 %). MS (ES) m/z 284 (M+l) ⁺ .

Intermediate-24 was prepared by following similar procedure as depicted in intermediate- 23, by using approprite raw materials at suitable conditions.

Intermediate-25 : 4-chloro-5-iodo-N-(pyridin-2-yl)pyrimidin-2-amine (25B)

Step-(i): 4-chloro-N-(pyridin-2-yl)pyrimidin-2-amine (25A)

To a stirred solution of 4-chloropyrimidin-2-amine (1 g, 7.75 mmol), 2-bromo-pyridine (1.46 g, 9.3 mmol) and xantphos (0.44 g, 0.775 mmol) in 1,4-dioxane (10 ml) was added K ₂ CO ₃ (3.20 g, 23.25 mmol) and purged with argon gas for 10 minutes. pd ₂ (dba) ₃ (0.700 g, 0.775 mmol) was added under argon atmosphere. The reaction mixture was stirred for 16 h at 120°C. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was cooled to room temperature, filtered through celite, washed celite bed with ethyl acetate and concentrated under reduced pressure to get the crude compound, which was purified by column chromatography using 100-200 mesh silica gel and 30% ethyl acetate in hexane.as eluent to achieve the pure product as a white solid (0.61 g, 38.3 %).

Step-(ii): 4-chloro-5-iodo-N-(pyridin-2-yl)pyrimidin-2-amine (25B)

To a stirred solution of intermediate-25A (0.5 g, 2.42 mmol) in DMF (10 ml), was added NIS (0.81 g, 3.63 mmol) at room temperature. Stirred the reaction mixture for 3 h at 50°C. After the reaction was completed, cool the reaction mixture temperature to rt, it was poured slowly onto the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow color solid (0.46 g, 57.5 %).

Intermediate-26: 2-(l-((2-(ethylamino)-5-iodopyrimidin-4-yl)amino)propyl)-5-f luoro-3- phenylquinazolin-4(3H)-one (26)

(i) DIPEA, n-ButanoU 10°C,12h. (26) Step-(i): 2-(l-((2-(ethylamino)-5-iodopyrimidin-4-yl)amino)propyl)-5-f luoro-3-phenyl quinazolin-4(3H)-one (26)

The process of this step was adopted from intermediate- 18G by using intermediate-20B and intermediate-23B. MS (ES) m/z 545 (M+l) ⁺ .

Below intermediates were prepared by following similar procedure as depicted in intermediate 26, by using approprite raw materials at suitable conditions.

Intermediate-29: (5-(N-(tert-butyl)sulfamoyl)pyridin-3-yl)boronic acid (29C)

Step-(i): 5-bromopyridine-3-sulfonyl chloride (29A)

To a stirred solution of pyridine-3-sulfonic acid (2.0 g, 12.57 mmol) in POCl ₃ (3.27 ml, 21.3 mmol) was added PCI5 (3.92 g, 18.8 6mmol) at room temperature. The reaction mixture was stirred for 18 h at 125-130°C. The progress of the reaction was monitored by TLC. After the reaction was completed, excess of POCI ₃ was removed under reduced pressure. To this Br ₂ (1.6 g, 10.5 mmol) was added at room temperature and stirred for 4 h at 130°C. Excess of bromine was removed from the reaction mixture and it was extracted with water (15 ml) and ethyl acetate (2 X 15 ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude, which was purified by column chromatography using 100-200 mesh silica gel and 2% methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (1.5 g, 46.5 %). MS (ES) m/z 257 (M+l) ⁺ . Step-(ii): 5-bromo-N-(tert-butyl) pyridine-3-sulfonamide (29B)

To a solution of intermediate-29A (2.0 g, 7.7 rnmol) in DCM (6 ml) was added tert-butyl amine (1.08 g, 11.6 mmol) at 0°C. Then reaction mixture was stirred for 12 h at room temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15 ml) and ethyl acetate (2 X 15 ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude, which was purified by column chromatography using 100-200 mesh silica gel and 1 % methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (1 g, 43 %). MS (ES) m/z 294 (M+l) ⁺ .

Step-(iii): (5-(N-(tert-butyl)sulfamoyl)pyridin-3-yl)boronic acid (29C)

To a solution of 5-bromo-N-(tert-butyl)pyridine-3-sulfonamide (29B) (0.5 g, 1.7 mmol) in 1,4-dioxane (15 ml) was added 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.65 g, 2.5 mmol), Pd(dppf)Cl ₂ , DCM complex (0.069 g, 0.08 mmol) and Potassium acetate (0.5 g, 5.1 mmol) under argon atmosphere. The reaction mixture was stirred for 12 h at 100°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure to get the crude .Which was purified by column chromatography using 100-200 mesh silica gel and 2 % methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (0.6 g, crude). MS (ES) m/z 259 (M+l) ⁺ .

Following intermediates are prepared by using similar procedure as depicted in intermediate -29, by using approprite raw materials in presence of suitable reagents, ractants and solvents at suitable conditions. Most of these intermediates were used in the next step without further purification. Structure information and characterization data are given in below table.

Intermediate-44: (5-(meth lsulfonyl)pyridin-3-yl)boronic acid (44C)

(i) N-BuLi,Dimethyl Disulfide, -78°C to RT ,5 h (ii) Oxone,Aq NaHC0 ₃ ,THF+Methanol,RT ,4h; (iii)

4,4,4',4 ^, ,5,5,5 ^, ,5 ^, -octamethyl-2,2 ^, -bi(l,3,2-dioxaborolane), CH ₃ COOK, PdCl ₂ (dppf) ₂ DCM complex,l,4- dioxane,110°C,12h.

Step-(i): 3-bromo-5-(methylthio)pyridine (44A)

To a stirred solution of 3,5-dibromopyridine (1.0 g, 4.22 mmol) in diethyl ether (20 ml) was added 2.5M n-BuLi (1.68 ml, 4.22 mmol) at -78°C .The reaction mixture was stirred for 4 h at-78°C. Dimethyl sulphide (400 mg, 4.22 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC. Reaction mixture was quenched with water and the product was extracted with diethyl Ether (2x50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude product this was taken up for next step without purification (1 g, crude). MS (ES) m/z 204 (M+l) ⁺ .

Step-(ii): 3-bromo-5-(methylsulfonvi)pyridine (44B)

To a solution of 3-bromo-5-(methylsulfonyl)pyridine (1.0 g, 4.9 mmol) in THF (25 ml) and methanol (7 ml) was added oxone (6 g, 39.2 mmol ) portion wise at RT. To this reaction mixture was added aq NaHC0 ₃ (25 ml) solution was added up to P ^H of the reaction becomes to basic. Stir the reaction mass at room temperature for 4 h. The progress of the reaction was monitored by TLC. The reaction mixture was extracted with ethyl acetate (2 X 15 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude, which was triturated with 20% ethyl acetate and n- hexane offered pure compound as solid.(100 mg, 9 %). MS (ES) m/z 237.9 (M+l) ⁺ .

Step-(iii): (5-(methylsulfonyl)pyridin-3-yl)boronicacid (44C)

To a solution of 3-bromo-5-(methylsulfonyl) pyridine (1 g, 4.237 mmol) in 1,4-dioxane (30 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.6 g, 6.355 mmol), Pd(dppf) ₂ Cl ₂ .DCM complex (0.172 g, 0.02 mmol) and Potassium acetate (1.03 g, 10.59 mmol) under argon atmosphere. The reaction mixture was stirred for 12 h at 100°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure to get the crude (0.7 g, crude). MS (ES) m/z 201 (M+l) ⁺ .

Intermediate-45: 5-(methylsulfonyl)pyridin-3-yl)boronicacid

octamethyl-2,2'-bi(l,3,2-dioxaborolane), CH ₃ COOK, PdCl ₂ (dppf) ₂ .DCM complex, 1,4-dioxane, 90°C, 2h.

Step-(i): 3-(benzylthio)-5-bromopyridine (45 A)

To a stirred solution of 60% NaH (2.02 g, 84.42 mmol), phenylmethanethiol (10.46 g, 84.42 mmol) in DMF (250 ml) at 0°C and stirred the reaction mixture for 15 min at 0°C. 3,5- dibromopyridine (20 g, 84.42 mmol) was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred at 90°C for 1 h. The progress of the reaction mixture was monitored by TLC. After the reaction was completed, quenched the reaction mixture with water. The reaction mixture was extracted ethyl acetate (2 X 100 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude product. This was purified by silica gel column chromatography eluted at 5% ethyl acetate in hexane (20 g, 84.63 %). MS (ES) m/z 257 (M+l) ⁺ . Step-(ii): 5-bromopyridine-3-thiol (45B)

To a solution of intermediate-45A (20 g, 71.42 mmol) in toluene (400 ml) was added AICI ₃ (16.19 g, 121.42 mmol) at 0°C. Then reaction mixture was stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC. Quenched the reaction mixture with ice water. The reaction mixture was extracted with ethyl acetate (2 X 150 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude material (25 g) which was carried out for further steps without any purification. MS (ES) m/z 294 (M+l) ⁺ .

Step-(iii): 3-bromo-5-(isopropylthio)pyridine (45C)

To a stirred solution of intermediate-45B (3 g, 15.78 mmol) in THF (30 ml) was cooled to 0°C. Then DIPEA (6.11 g, 47.63 mmol) was added followed by 2-bromopropane was added to the reaction mixture at 0°C and the reaction mixture was stirred for 4 h at RT. The progress of the reaction was monitored by TLC. After the reaction was completed, quenched the reaction mixture with ice water. The reaction mixture was extracted with ethyl acetate (2 X 100 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude. This was taken up for Next step without purification (3.6 g, crude). MS (ES) m/z 232 (M+l) ⁺ .

Step-(iv): 3-bromo-5-(isopropylsulfonyl)pyridine (45D)

To a solution of 3-bromo-5-(isopropylthio)pyridine (1.5 g, 6.46 mmol) in methanol (80 ml) was added oxone (9.92 g, 32.32 mmol) at RT. Then reaction mixture was stirred for 12 h at room temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, distill of the methanol under vacuum. The residue was diluted with water, it was extracted with ethyl acetate (2 X 45 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude.which was purified by column chromatography using 100-200 mesh silica gel and 20 % ethyl acetate in hexane as eluent to afford the target compound. (1.1 g, 64.7 %). MS (ES) m/z 264 (M+l) ⁺ .

Step-(v): 5-(methylsulfonyl)pyridin-3-yl)boronicacid (45E)

To a solution of 3-bromo-5-(isopropylsulfonyl)pyridine (1 g, 3.78 mmol) in 1,4-dioxane (10 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.44 g, 5.68 mmol), Pd(dppf) ₂ Cl _2. DCM (0.015 g, 0.18 mmol) and potassium acetate (1.11 g, 11.36 mmol) under argon atmosphere. The reaction mixture was stirred for 2 h at 90°C in a sealed tube.. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure to get the crude product (1 g, crude). MS (ES) m/z 230 (M+l) ⁺ .

Intermediate-46 was prepared by following similar procedure as depicted in intermediate- 45, by using approprite rawmaterials in presence of suitable reagents, reactants and solvents at suitable conditions

Intermediate-47: 5-(ethylsulfonamido)pyridin-3-yl)boronicacid (47B)

Step-(i): N-(5-bromopyridin-3-yl)ethanesulfonamide (47 A)

To a stirred solution of 5-bromopyridin-3-amine (1 g, 5.78 mmol) in DCM (15 ml)was added pyridine (1.36 g, 17.34 mmol) and ethanesulfonylchloride (1.1 g, 8.67 mmol) at 0°C.and the reaction mixture was stirred for 12 h at RT. The progress of the reaction was monitored by TLC. After the reaction was completed, distill off the solvent under vacuum to the residue ice cold water was added, and stirred for 30 min, solid was precipitated, filtered off the solid and dried under vacuum to get the desired compound as light brown color solid (1.2 g crude) Step-(ii): 5-(ethylsulfonamido)pyridin-3-yl)boronicacid (47B) To a solution of intermediate-47A (0.8 g, 3.01 mmol) in 1,4-dioxane (30 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.16 g, 4.528 mmol), Pd(dppf) ₂ Cl ₂ . DCM complex (0.245 g, 0.30 mmol) and Potassium acetate (0.737 g, 7.52 mmol) under argon atmosphere. The reaction mixture was stirred for 16 h at 100°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure afforded the crude material ( 1 g, crude). MS (ES) m/z 259 (M+l).

Intermediates listed in below table weree prepared by following similar procedure as depicted in intermediate-47, by using approprite rawmaterials in presence of suitable reactants, reagents and solvents at suitable conditions.

Intermediate-50: l-(alkylsulfonyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-2,3- dihydro- 1 H-py rrolo [2,3-c] pyridine (50 J)

Step-(i): 3-bromo -5-nitropyridine-4-ol (50A)

To a stirred solution of 3-nitropyridine-4-ol (20 g, 142.85 mmol) in water was added bromine (9.2 ml, 178.56 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature and 3 h at 50°C. The reaction mixture was cooled to room temperature the precipitated solid was filtered to afford the crude material (25 g, 80 %). 1HNMR (400 MHz, DMSO-d6) δ: 12.73 (bs, 1H), 8.0 (d, J=l Hz, IH), 8.35 (s, 1H), MS (ES) m/z 217 (M+), 219 (M+2).

Step-(ii): 3-bromo -4-chloro-5-nitropyridine (50B)

To a stirred solution of intermediate-50A (5.0 g, 22.83 mmol) in POCl ₃ (17.46 g, 114.16 mmol) was added N,N-Diethylaniline (4 g, 27.39 mmol) at 10°C temperature. The reaction mixture was stirred for 3 h at 100°C. POCl ₃ was concentrated under reduced pressure and the residue was poured into ice cold water. The solid obtained was filtered to afford the target compound (4 g, 74 %). *HNMR (400 MHz, DMSO-d6) δ: 9.20 (s, 1H), 9.17 (s, 1H), MS (ES) m/z 237 (M+l).

Step-(iii): Diethyl 2-(3-bromo-5-nitropyridin-4-yl)malonate (50C)

To a suspension of 60% NaH (315 mg, 13.13 mmol) in DMF (5 ml) was added diethyl malonate (1.35 g, 8.47 mmol) drop wise at 0°C. The reaction mixture was stirred for 45 min at 0°C. 3-bromo-4-chloro-5-nitropyridine (1 g, 4.23 mmol) was added in DMF (1 ml) at 0°C. Stirred the reaction mixture at rt for a period of for 2 h. The reaction mixture was poured in ice water. The product extracted with ethyl acetate (3 XI 00 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material was purified by column chromatography using 100-200 mesh silica gel and 15% ethyl acetate in hexane as eluent to afford the desired compound as a yellow liquid (0.8 g, 52 %). *HNMR (400 MHz, DMSO-d6) δ: 9.22 (d, J=2.9 Hz, 1H), 5.64 (s, 1H), 4.21-4.11 (m, 4H), 1.17 (t, J=7.3 Hz, 6H), MS (ES) m/z 361 (M+), 363(M+2,) .

Step (iv): Ethyl 2— (3-bromo-5-nitropyridin-4-yl)acetate (50D)

To a suspension of diethyl 2-(3-bromo-5-nitropyridin-4-yl)malonate (4 g, 11.07 mmol) and LiCl (1.17 g, 27.68 mmol) in DMSO (2 ml) and water (0.5 ml) at room temperature. The reaction mixture was stirred for 3 h at 150°C. The reaction mixture was cooled to room temperature and poured into ice water. The product was extracted with ethyl acetate (3 X 100 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material was purified by column chromatography using 100-200 mesh silica gel and 8 % ethyl acetate in hexane as eluent to afford the desired compound as a yellow liquid (2.5 g, 78 %). MS (ES) m/z 289 (M+). 292 (M+2).

Step-(v): Ethyl-2-(3-amino-5-bromopyridin-4-yl)acetate (50E)

To a stirred solution of ethyl 2-(3-bromo-5-nitropyridin-4-yl)acetate (0.500 g, 1.73 mmol) in IPA (10 ml) was added ammonium chloride (183 mg, 3.46 mmol) and iron powder (289 mg, 5.19 mmol) at RT. The reaction mixture was stirred for 30 min at 80°C. The reaction mixture was filtered through celite washed with ethyl acetate. The organic layer was collected and concentrated under reduced pressure to get the crude product. (300 mg, crude). MS (ES) m/z 259 (M+).

Step-(vi): Ethyl 2-(3-bromo-5-pivalamidopyridin-4-yl)acetate (50F)

To a stirred solution of ethyl-2-(3-amino-5-bromopyridin-4-yl)acetate (2.0 g, 7.72 mmol) and TEA (2.33 g, 23.1 mmol) in DCM (40 ml) was added Pivolyl Chloride (2.32 g, 19.30 mmol) at 10°C. The reaction mixture was stirred for overnight at room temperature. The reaction mixture was poured in ice water. The product was extracted with ethyl acetate (3 X 100 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material, was purified by column chromatography using 100-200 mesh silica gel and 20 % ethyl acetate in hexane as eluent to afford the desired compound as a yellow liquid (2 g, 86 %). MS (ES) m/z 343 (M+).

Step-(vii): N-(5-bromo-4-(2-hydroxyethyl)pyridin-3-yl)pivalamide (50G)

To a stirred solution ofethyl 2-(3-bromo-5-pivalamidopyridin-4-yl) acetate (1.0 g, 2.92 mmol) in THF & EtOH (1: 1) 10 ml was added NaBH ₄ (555 mg, 14.6 mmol) at 10°C. The reaction mixture was stirred for 4 h at room temperature. Solvent was concentrated under reduced pressure. The reaction mixture was poured in ice water. The product was extracted with ethyl acetate (3 X 50 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material was purified by column chromatography using 100-200 mesh silica gel and 3% methanol in dichloromethane as eluent to afford the desired compound as brown solid. (600 mg, 68 %), ^! HNMR (400 MHz, DMSO-d6) δ 9.02 (bs, 1H), 8.83 (s, 1H), 8.41 (s, 1H), 4.03 (s, 2H), 3.02 (s, 2H), 2.89 (bs, 1H), 1.25 (s, 9H). MS (ES) m/z 301 (M+). Step-(viii): 4-bromo-2,3-dihydro-lH-pyrrolor2,3-clpyridine (50H)

To a stirred solution of N-(5-bromo-4-(2-hydroxyethyl) pyridin-3-yl)pivalamide (1.0 g, 3.32 mmol) in Con HC1 (30 ml) was reflux for 48 h. Solvent was removed under reduced pressure, and the residue was diluted with water, basified with saturated sodium bicarbonate solution (10 ml). The product was extracted with ethyl acetate (3 X 50 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material was purified by column chromatography using 100-200 mesh silica gel and 3% methanol in dichloro methane as eluent to afford the desired compound as brown solid. (600 mg, 90 %). ^! HNMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.70 (s, 1H), 6.08 (bs, 1H), 3.53-3.48 (m, 2H), 2.29-2.94 (m, 1H). LCMS (ES) m/z 199 (M+), 201 (M+2).

Step-(ix): 4-bromo- l-(methylsulfonyl)-2,3-dihydro- lH-pyrrolor2,3-c1pyridine (501)

To a stirred solution of4-bromo-2,3-dihydro-lH-pyrrolo[2,3-c]pyridine (0.5 g, 2.51 mmol) and TEA (507 mg, 5.025 mmol) in DCM (20 ml)was added methanesulfonylchloride (429 mg, 3.71 mmol) at 10°C. The reaction mixture was stirred for overnight at room temperature. The reaction mixture was poured in ice water. The product was extracted with DCM (3x 100 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material, was purified by column chromatography using 100-200 mesh silica gel and 20 % ethyl acetate in hexane as eluent to afford the desired compound as yellow solid. (650 mg, 93 %), 1HNMR (400 MHz, DMSO-d6), δ 8.38 (s, 2H), 4.02 (t, J=8.8 Hz, 2H), 3.17 (t, J=8.8 Hz, 2H), 3.13 (s, 3H), MS (ES) m/z 277 (M+), 279 (M+2).

Step-(x): l-(methylsulfonyl)-2,3-dihvdro-lH-pyrrolo[2,3-clpyridin-4-yl )boronicacid (50J)

To a solution of 4-bromo- l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[2,3-c]pyridine (0.6 g, 2.16 mmol) in 1,4-dioxane (15 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (0.825 g, 3.24 mmol), Pd(dppf) ₂ Cl _2. DCM complex (0.088 g, 0.10 mmol) and potassium acetate (0.424 g, 5.1 mmol) under argon atmosphere. The reaction mixture was stirred for 12 h at 100°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure to get the crude required compound (0.6 g, crude). MS (ES) m/z 243 (M+l). Intermediate- 51 was prepared by following similar procedure as depicted in intermediate- 50, by using approprite rawmaterials in presence of suitable reactants, reagents and solvents at suitable conditions.

Intermediate-52: (5-(tert-butylcarbamoyl)pyridin-3-yl) boronic acid (52B)

(52A) (52B)

(i)HATU,DIPEA,Tert -Butyl Amine,DMF,RT,16h (II)4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborola ne),

C¾COOK, PdCl ₉ (dppf).DCM, l,4-dioxaneJ20°CJ6h.

Step-(i): 5-bromo-N-(tert-butyl)nicotinamide (52A)

To a stirred solution of 5 -bro mo nicotinic acid (1.0 g, 4.975 mmol) in DMF (5 ml) at room temperature, HATU (2.8 g, 7.462 mmol) and DIPEA (2.6 ml, 14.92 mmol) were added at room temperature. The reaction mixture was stirred for 30 min at RT. tert-Butyl amine (0.63 ml, 5.97 mmol) was added at RT. The reaction mixture was stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After the reaction was completed, Quenched the reaction mass with ice water, solid precipitated .filter off the solid and washed with chilled water dried under vacuum to get the desired compound as off white solid (0.91 g, 71.65 %).

*HNMR (400 MHz, DMSO-d6) δ 8.90 (d, J=1.4 Hz, 1H), 8.38 (t, J=1.5 Hz, 1H) 8.21 (d, J=2 Hz, 1H), 8.1 (bs, 1H), 1.38 (s, 9H), MS (ES) m/z 259 (M+2).

Step-(ii): 5-(tert-butylcarbamoyl)pyridin-3-yl)boronicacid (52B)

To a solution of 5-bromo-N-(tert-butyl)nicotinamide (0.5 g, 1.7 mmol) in 1,4-dioxane (5 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.740 g, 2.91 mmol), Pd(dppf)2Ci2 (0.158 g, 0.19 mmol) and Potassium acetate (0.381 g, 3.88 mmol) under argon atmosphere. The reaction mixture was stirred for 16 h at 120°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through celite and concentrated under reduced pressure to afford the crude material (0.5 g, crude), MS (ES) m/z 223 (M+l).

The present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds according to the invention.

Example-I: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylic acid (Compound-1)

Method- 1:

(Intermediate 3) (1.1) (1.2) (Compound-1)

(i) Ethylacrylate, Pd(dppf )C1 ₂ , Et ₃ N, DMF, Η ₂ θ, sealed tube, 100°C, Overnight; (ii) LiOH, THF, Ethanol, Η ₂ θ, Overnight, R.T;

(iii) Hydroxylamine hydrochloride, Ethanol, H ₂ 0, Reflux, Overnight.

Step-(i): (E)-ethyl 3-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methyl-6-((l-(5-methyl- 4-oxo-3-phenyl- 3 , 4-dihydroquinazo lin-2- yPpropyl) amino )pyrimidin-5 - yPacr ylate (1.1)

To a stirred solution of Intermediate-3 (2.0 g, 3.3 mmol) in DMF (6 ml) was added ethyl acrylate (0.7 g, 8.27 mmol), Pd(dppf)Cl ₂ (0.12 g, 0.16 mmol), Et ₃ N (1.6 ml, 16.5 mmol) and 0.5 ml of H ₂ O.The reaction mixture was stirred for overnight at 100°C. The obtained residue was diluted with water (15 ml) and extracted with ethyl acetate (2 X 15 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 2% methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (1.5 g, 79 %). ^! H-NMR (400 MHz, CDC1 ₃ ) δ 7.87 (d, 1H, J=17 Hz), 7.71-7.40 (m, 4H), 7.34-7.24 (m, 2H), 7.15 (d, 1H, J=7.0 Hz), 6.87 (d, 1H, J=8.3 Hz), 6.72 (d, 1H, J=16.6 Hz), 5.83 (s, 2H), 5.19-5.14 (m, 1H), 4.76-4.74 (m, 1H), 4.39 (q, 2H, J,=7.4 Hz, J ₂ =6.3 Hz), 2.82 (s, 3H), 2.46 (s, 3H), 2.17 (s, 6H), 1.89-1.82 (m, 2H), 1.45 (t, 3H, J=7 Hz), 0.75 (t, 3H, J=7.8 Hz). MS (ES) m/z 577 (M+l) ⁺ .

Step-(ii): (E)-3-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methyl-6-((l-(5-met hyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)armno)pyrirmdin-5-yl)acrylic acid (1.2) To a stirred solution of compound- 1.1 (1.2 g, 2.0 mmol) in THF: EtOH: H ₂ 0 (7: 2: 1) was added LiOH (0.5 g, 20.8 mmol). The reaction mixture was stirred for overnight at room temperature. The solvents were evaporated under vacuum and acidified using dil. HCl then diluted with water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The combined organic phases were dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 4% methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (1 g, 85%). ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 13.0 (bs, IH), 7.70- 7.62 (m, 4H), 7.57-7.47 (m, 2H), 7.41-7.13 (m, 4H), 6.45 (d, IH, J=16.1 Hz), 5.76 (s, 2H), 4.75- 4.71 (m, IH), 2.71 (s, 3H), 2.38 (s, 3H), 2.02 (s, 6H), 1.93-1.91 (m, 2H), 0.71 (t, 3H, J=7.3 Hz). MS (ES) m/z 549 (M+l) ⁺ .

Step-iii: (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2-yl) propyl) amino)pyr imidin- 5 - yl) aery licacid ( 1 )

To a stirred solution of compound- 1.2 (0.14 g, 0.25 mmol) in ethanol (6 ml) was added hydroxylamine hydrochloride (0.88 g, 12.7 mmol). The reaction mixture was refluxed for overnight. After the elimination of the solvents in vacuo, the residue was chromatographed using 100-200 mesh silica gel, eluting with 4% methanol in dichloromethane to give the title compound as a yellow solid (0.03 g, 25 %). ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 12.0 (bs, IH), 7.72-7.50 (m, 6H), 7.30 (d, IH, J=7.3 Hz), 6.91 (d, IH, J=6.4 Hz), 6.28 (bs, 2H), 6.24 (s, IH), 4.76-4.75 (m, IH), 2.70 (s, 3H), 2.20 (s, 3H), 1.85-1.80 (m, IH), 1.75-7.35 (m, IH), 0.63 (m, 3H). MS (ES) m/z 471 (M+l) ⁺ .

Method-2:

Step-(i): (E)-ethyl 3-(2-amino-4-methyl-6-(( l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2-yl)propyl)amino)pyrimidin-5-yl)acrylate ( 1.2) To a stirred solution of intermediate-4(0.52 g, 1 mmol) in toluene (6 ml) was added ethyl acrylate (0.1 g, 1.0 mmol), Pd(OAc) ₂ (0.02 g, 0.1 mmol), K ₂ C0 ₃ (0.2 g, 1.2 mmol), BINAP (0.12 g, 0.2 mmol) and 0.5 ml of H ₂ 0 and stirred for overnight at 120°C. The obtained mixture was diluted with water (15 ml) and extracted with ethyl acetate (2 X 15 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 5 % methanol in dichloro methane to give the title compound as a yellow solid (0.29 g, 60 %). MS (ES) m/z 499 (M+l) ⁺ .

Step-(ii): (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2-yl) propyl) amino) pyrimidin-5-yl) acrylic acid (Compound- 1).

The process of this step was adopted from step-(ii) of compound- 1 (method- 1). MS (ES) m/z 471 (M+l) ⁺ .

Example-II: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylamid e (Compound-2)

(1-2) (2.1) (Compound-2)

(i) 1 -hydroxy- IH-benzotriazole ammonium salt, EDC.HCl, DMF, 10°C- R.T, Overnight; (ii) Hydro xylamine.HCl,

Ethanol, H ₂ 0, Reflux, Overnight.

Step-(i): (E)-3-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methyl-6-((l-(5-met hyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)armno)pyrimidin-5-yl)acrylamid e (2.1)

1 -hydroxy- IH-benzotriazole ammonium salt (0.066 g, 0.437 mmol) and EDC.HCl (0.084 g, 0.437 mmol) are added at 10°C to a stirred solution of compound-1.2 (0.2 g, 0.36 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for overnight. The obtained mixture was poured into ice water. The solid formed was filtered under suction to give the title compound as a yellow solid (0.08 g, 40%). 1H-NMR (400 MHz, DMSO-J ₆ ) δ 7.70-7.66 (m, 2H), 7.52-7.44 (m, 3H), 7.40-7.23 (m, 6H), 7.13-7.11 (m, 1H), 6.44 (d, 1H, J=6.1 Hz), 5.74 (s, 2H), 4.68-4.67 (m, 1H), 2.71 (s, 3H), 2.35 (s, 3H), 2.00 (s, 6H), 1.92-1.90 (m, 1H), 1.75-1.72 (m, 1H), 0.73 (t, 3H, J=7.4 Hz). MS (ES) m/z 548 (M+l) ⁺ .

Step-(ii): (E)-3-(2-armno-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2-yl) propyl) amino )pyrimidin-5-yl)acrylamide (2) The process of this step was adopted from step-(iii) of compound- 1. 'H-NMR (400 MHz, CDCI ₃ ) δ 7.73 (bs, 2H), 7.69-7.52 (m, 6H), 7.35-7.32 (m, 2H), 7.26-7.24 (m, IH), 6.52 (bs, IH), 6.35 (d, 2H, J=16.1 Hz), 4.23-4.20 (m, IH), 2.81 (s, 3H), 2.32 (s, 3H), 2.06-2.01 (m, 2H), 0.77 (t, 3H, J=7.3 Hz). MS (ES) m/z 470 (M+l) ⁺ .

Example-Ill: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d i hydro uinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-N-isopropylacryl amide (Compound-3)

(!- ² ) (3.1) (Compound-3)

(i) Propan-2-amine, EDC .HC1, HOBT, Et ₃ N, DMF, 0°C - R.T, overnight; (ii) Hydroxylamine. HC1, Ethanol,

H ₂ 0, Reflux, Overnight.

Step-(i): (E)-3-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methyl-6-((l-(5-met hyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-N-isopro pylacrylamide (3.1)

To a stirred solution of compound- 1.2 (0.026 g, 0.43 mmol) in DMF (5 ml) was added propan-2-amine (0.066 g, 0.437 mmol), Et ₃ N (0.055 g, 0.54 mmol), EDC.HCl (0.14 g, 0.72 mmol) and HOBT (0.084 g, 0.54 mmol) at 0°C and stirred at room temperature for overnight. The obtained mixture was poured into ice water. The solid formed was filtered under suction to achieve the pure product as a yellow solid (0.09 g, 42%). ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.01 (d, IH, J=7.3 Hz), 7.69-7.66 (m, IH), 7.51-7.38 (m, 6H), 7.32-7.25 (m, 2H), 7.15-7.14 (m, IH), 6.45 (d, IH, J=16.1 Hz), 5.74 (s, 2H), 4.70-4.69 (m, IH), 4.02-4.01 (m, IH), 2.72 (s, 3H), 2.35 (s, 3H), 2.02 (s, 6H), 1.97-1.85 (m, IH), 1.80-1.62 (m, IH), 1.16-1.14 (s, 6H), 0.73 (t, 3H, J=7.4 Hz). MS (ES) m/z 590 (M+l) ⁺ .

Step-(ii): (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2-yl) propyl) amino)pyr imidin- 5 - yl) -N-isopropylacrylamide ( 3 )

The process of this step was adopted from step-(ii) of compound-2. 'H-NMR (400 MHz, DMSO-Je) δ 7.61-7.50 (m, 6H), 7.35-7.25 (m, 2H), 6.70 (d, IH, J=8.3 Hz), 6.22 (d, IH, J=15.3 Hz), 5.48 (d, IH, J=7.8 Hz), 5.06-5.02 (m, 3H), 4.31-4.20 (m, IH), 2.82 (s, 3H), 2.33 (s, 3H), 2.01-1.91 (m, 2H), 1.30 (d, 3H, J=6.4 Hz), 1.25 (d, 3H, J=6.4 Hz), 0.76 (t, 3H, J=7.5 Hz). MS (ES) m/e 512 (M+l) ⁺ . The below compounds were prepared by procedure similar to the one described in Example-Ill with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

7.70-7.65 (m, 2Η), 7.59-7.49 (m, 4Η), 7.42 (d, 1Η,

J=7.8 Hz), 7.28 (d, 1H, J=7.3 Hz), 6.18 (s, 1H), 5.90

16 (bs, 2H), 4.65-4.60 (m, 1H), 3.61-3.45 (m, 8H), 2.70

(s, 3H), 2.24 (s, 3H), 2.01 (s, 3H), 1.80-1.71 (m, 1H), 1.50-1.41 (m, 1H), 0.65-0.61 (m, 3H); MS (ES) m/z 554 (M+l) ⁺ .

8.04 (d, 1H, J=4 Hz), 7.65 (d, 2H, J=8.0 Hz), 7.57- 7.50 (m, 5H), 7.39 (d, 1H, J=l l Hz), 7.28 (d, 1H,

17 Η ₂ Ν χ Ν ΝΗ ^Η J=7.0 Hz), 5.78 (s, 2H), 4.64 (m, 1H), 2.71 (s, 3H),

2.08 (s, 5H), 1.96 (s, 3H), 1.74-1.72 (m, 1H), 1.37- 1.35 (m, 1H), 0.68-0.62 (m, 3H), 0.44-0.43 (m, 2H); MS (ES) m/z 524 (M+l) ⁺ .

Example-IV: Synthesis of (E)-tert-butyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3- phenyl-3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidin-5-yl)acrylate (Compound-9)

(i) tert- u\y\ acrylate, Pd(dppf )C1 ₂ , Et ₃ N, DMF, H ₂ 0, Sealed tube, 100°C, Overnight; (ii) Hydroxylamine.HCl,

Ethanol, H ₂ 0, Reflux. Overnight

Step-(i): (E)-tert-butyl 3-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methyl-6-((l-(5-methyl- 4-oxo-3- phenyl-3^-dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl )acryl^^ (9.1)

The process of this step was adopted from step-(i) of compound- 1 in method- 1 by using intermediate-3 as starting compound. MS (ES) m/z 604 (M+l) ⁺ .

Step-(ii): (E)-tert-butyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4dihydr o quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylate (9)

The process of this step was adopted from step-(iii) of compound- 1 in method- 1 .1H- NMR (400 MHz, DMSO-J ₆ ) δ 7.72-7.60 (m, 2H), 7.58-7.50 (m, 5H), 7.33 (d, 1H, J=7 Hz), 7.10- 7.00 (m, IH), 6.40-6.27 (m, 3H), 4.81-4.80 (m, IH), 2.72 (s, 3H), 2.23 (s, 3H), 1.98-1.80 (m, 2H), 1.53 (s, 9H), 0.64 (t, 3H, J=8 Hz). MS (ES) m/z 527 (M+l) ⁺ .

The below compounds were prepared by procedure similar to the one described in Example-IV with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Example-V: Synthesis of tert-butyl 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)cyclo propane carboxylate (Compound-7) and 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihyd ro quinazoli -2- l)propyl)amino)pyrimidin-5-yl)cyclopropanecarboxylic acid (Compound-8)

Step-(i): tert -butyl 2-(2-amino-4-methyl-6-(( l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2-yl)propyl)amino)pyrimidin-5-yl)cyclopropane carboxylate (Compound-7)

To a stirred solution of NaH (0.04 g, 0.9 mmol) and TMSI (0.21 g, 0.9 mmol) in DMF (5 ml) was added pre dissolved solution of compound-9 (0.026 g, 0.43 mmol,) at 0°C and stirred at room temperature for 30 min. Then the residue was diluted with water (15 ml) and extracted with ethyl acetate (2 X 15 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 5% methanol in dichloromethane to give the title compound as a yellow solid (0.06g, 37%). 'H-NMR (400 MHz, DMSO-J ₆ ) δ 7.63-7.51 (m, 5H), 7.47 (t, 1H, J=8 Hz), 7.35- 7.24 (m, 2H), 5.80-5.78 (m, 2H), 4.91-4.86 (m, 1H), 2.80 (s, 3H), 2.26 (s, 3H), 1.89-1.99 (m, 4H), 1.43 (s, 9H), 0.89-0.74 (m, 5H). MS (ES) m/z 541 (M+l) ⁺ .

Step-(ii): 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihyd roquinazolin-2-yl) propyl)amino)pyrimidin-5-yl)cvclopropanecarboxylic acid (Compound-8)

TFA (0.2 ml) was added at 0°C to a stirred solution of compound-7 (0.035 g, 60.0 mmol) in DCM (5 ml) and stirred at room temperature for 16 h. After the elimination of excess of solvents in vacuo, the residue was chromatographed using 100-200 mesh silica gel , eluting with 4% methanol in dichloromethane to give the title compound as a yellow solid (0.012 g, 41 %). 'H-NMR (400 MHz, DMSO-Je) δ 12.10 (brs, 1H), 7.73-7.71 (m, 1H), 7.69-7.26 (m, 7H), 7.24- 7.08 (m, 2H), 4.81-4.80 (m, 1H), 2.72 (s, 3H), 2.23 (s, 3H), 2.22-1.84 (m, 2H), 1.35-1.15 (m, 3H), 0.85-0.63 (m, 4H). MS (ES) m/z 485 (M+l) ⁺ .

Example- VI: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acryl ate (Compound-10)

(Com pound- 1.1) (Compound-10)

(i) Hydroxylamine hydrochloride, Ethanol, H ₂ 0, reflux, overnight

The process of this step was adopted from step-(iii) of compound- 1 from method- 1 by using compound- 1.1 as starting material. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 7.78-7.60 (m, 2H), 7.58-7.51 (m, 6H), 7.32-7.30 (m, 1H), 7.05-7.03 (m, 1H), 6.35 (d, 1H, J=17.8 Hz), 4.80-4.77 (m, IH), 4.25-4.22 (m, 2H), 2.72 (s, 3H), 2.23 (s, 3H), 1.85-1.61 (m, 2H), 1.31 (d, 3H, J=7.8 Hz), 0.63 (t, 3H, J=7.3 Hz). MS (ES) m/z 499 (M+l) ⁺ .

Example- VII: Synthesis of 2-(l-((2-amino-5-((lE, 3Z)-3-(hydroxyimino)but-l-en-l-yl)-6- methylpyrimidin-4-yl)amino)propyl)-5-methyl-3-phenylquinazol in-4(3H)-one (Compound- 11)

(intermediate-3) (H-l) (Compound-11)

(i) Methyl vinylketone, Pd(dppf )C1 ₂ _ Et ₃ N, DMF, H ₂ 0, Sealed tube, 100°C, Overnight; (ii) Hydroxylamine. HCl,

Ethanol, II ₉ O, Reflux, Overnight.

Step-(i): (E)-2-(l-((2-(2,5-dimethyl-lH-pyrrol-l-yl)-6-methyl-5-(3-oxo but-l-en-l-yl)pyrimidin-4- yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one (11.1)

The process of this step was adopted from step-(i) of compound- 1 from method- 1 by using intermediate-3 as starting material.MS (ES) m/z 547 (M+l) ⁺ .

Step-(ii): 2-(l-((2-amino-5-((lE,3Z)-3-(hydroxyimino)but-l-en-l-yl)-6-m ethylpyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one (11)

The process of this step was adopted from step-(iii) of compound- 1. 'H-NMR (400 MHz,

DMSO-Je) δ 10.6-9.80 (bs, IH), 7.62-7.52 (m, 4H), 7.46-7.42 (m, 2H), 7.33-7.26 (m, IH), 6.69 (d, IH, J=16.6 Hz), 6.55-6.50 (m, IH), 4.94-4.90 (m, 3H), 3.50-3.45 (m, IH), 2.80 (s, 3H), 2.22

(s, 3H), 2.17 (s, 3H), 1.84-1.71 (m, 2H), 0.76 (t, 3H, J=7.4 Hz). MS (ES) m/z 484 (M+l) ⁺ .

Example- VIII: Synthesis of (E)-3-(2-amino-4-methyl-6-(l-(2-(4-methylpiperazin-l-yl) quinolin-3-yl)propylamino)pyrimidin-5-yl)acrylicacid (Compound-13)

The process of this step was adopted from step-(ii) of compound- 1 from method-2 by g compound-12 as starting material. MS (ES) m/z 460 (M+l) ⁺ . Example-IX: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phi dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-N-(pyrid in-2-yl)acrylamide

(Compound-18

The process of this step was adopted from step-(i) of compound-3. 'H-NMR (400 MHz, DMSO-Je) δ 10.27 (s, IH), 8.84 (s, IH), 8.16-8.14 (m, 2H), 7.69-7.41 (m, 9H), 7.36 (d, 2H, J=7.3 Hz), 7.17 (d, IH, J=7.4 Hz), 6.44 (d, IH, J=15.7 Hz), 6.21 (bs, 2H), 4.68-4.66 (bs, IH), 2.80 (s, 2H), 2.20 (s, 3H), 1.77-1.68 (m, 2H), 0.70-0.61(m, 3H). MS (ES) m/z 547 (M+l) ⁺ .

The below compounds were prepared by procedure similar to the one described in Example-IX by using suitable starting material with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

(m, IH), 0.73 (t, IH, J=6.9 Hz). MS (ES) m/z 565 (M+l,

100%).

Example-X: Synthesis of 2-(l-((2-amino-6-methyl-5-vinylpyrimidin-4-yl) amino) propyl)-5- methyl-3-phenylquinazolin-4 3H)-one (Compound-25)

(Intermediate-4) (Compound-25)

(i) 2,4,6-trivinyl-l,3,5,2,4,6-trioxatriborinane, Pd(PPh ₃ ) ₄ , K ₂ C0 ₃ , Toluene,

Ethanol, H ₂ 0, Sealed tube, 100°C, Overnight;

To a stirred solution of intermediate-4 (0.2 g, 0.38 mmol) in toluene (2 ml): ethanol (2 ml) (1: 1), was added 2,4,6-trivinyl-l,3,5,2,4,6-trioxatriborinane (0.12 g,0. 49 mmol), Pd(Pph ₃ ) ₄ (0.046 g, 0.04 mmol), K ₂ C0 ₃ (0.2 g, 1.52 mmol) and 0.5 ml of H ₂ 0 and stirred for overnight at 100°C. The obtained mixture was diluted with water (15 ml) and extracted with ethyl acetate (2 X 15 ml). After brine wash, the combined organic phases were dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 3% methanol in dichloro methane to give the title compound as a yellow solid (0.048 g, 30%).1H- NMR (400 MHz, DMSO-J ₆ ) δ 7.68-7.41 (m, 7H), 7.29 (d, IH, J=8 Hz), 6.69-6.61 (m, IH), 6.36 (d, IH, J=7 Hz), 5.90-5.85 (bs, 2H), 5.51-5.46 (m, IH), 4.65-4.61 (m, IH), 2.71 (s, 3H), 2.15 (s, 3H), 1.81-1.79 (m, IH), 1.77-1.57 (m, IH), 0.63 (t, 3H, J=7 Hz). MS (ES) m/z 427 (M+l) ⁺ .

Example-XI: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(l-methyl-4-oxo-5-phenyl- 4,5-dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl)propyl)amino)py rimidin-5-yl)acrylate (Compound-26)

(Intermediate-6) (Compound-26)

(i) Ethyl acrylate, Pd(OAc) ₂ ,ΒΙΝΛΡ, K ₂ C0 ₃ , Toluene, H ₂ 0, Sealed tube, 120°C, Overnight The process of this step was adopted from step-(i) of compound- 1 from method-2 by using intermediate-6 as starting compound. 1H-NMR (400 MHz, DMSO-Je) δ 7.60-7.45 (m, 5H), 6.79 (d, 1H, J=7.8 Hz), 6.085 (d, 2H, J=l 1.8 Hz), 5.39 (bs, 1H), 4.79-4.78 (m, 1H), 4.21-4.19 (m, 2H), 3.99 (s, 3H), 2.26 (s, 3H), 1.96-1.70 (m, 2H), 0.89-0.85 (m, 3H), 0.64-0.61 (m, 3H). MS (ES) m/z 489 (M+l) ⁺ .

Example-XII: Synthesis of (Z)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-meth ylacrylate (Compound-32) and (E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihyd roquinazolin- 2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylate (Compound-33)

The process of this step was adopted from step-(i) of compound- 1 from method-2 by using intermediate-4 as starting compound and separated by coloumn chromatography.

'H-NMR (400 MHz, DMSO-Je) δ 7.68-7.47 (m, 6H), 7.36 (d, 2H, J=7.8 Hz), 7.28 (d, 1H, J=7.6 Hz), 6.11 (d, 1H, J=7.6 Hz), 5.92 (bs, 2H), 4.59-4.58 (m, 1H), 4.26-4.20 (m, 2H), 2.71 (s, 3H), 2.01 (s, 3H), 1.76 (s, 3H), 1.65-1.62 (m, 2H), 0.90-0.83 (m, 3H), 0.62-0.58 (m, 3H). MS (ES) m/z 513 (M+l) ⁺ ; and

'H-NMR (400 MHz, DMSO-Je) δ 7.67-7.46 (m, 6H), 7.37-7.35 (m, 2H), 7.26 (d, 1H, J=7.3 Hz), 6.22 (d, 1H, J=12.3 Hz), 5.60 (brs, 2H), 5.21 (brs, 1H), 4.48 (s, 1H), 4.23-4.18 (m, 2H), 2.70 (s, 3H), 2.00 (s, 3H), 1.76-1.62 (m, 2H), 1.30 (s, 3H), 0.59-0.55 (m, 3H). MS (ES) m/z 513 (M+l) ⁺ respectively.

Example-XIII: Synthesis of (Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methyl acrylic acid (Compound-34) and (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-d ihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylicacid (Compound-35)

(Compound-32) (Compound-33) (Compound-34) (Compound-35)

(i) LiOH, THF, Ethanol, H ₂ 0, Overnight, R.T;

The process of this step was adopted from step-(ii) of compound- 1 in method- 1 by using ompound-32 and compound-33 as starting compounds.'H-NMR (400 MHz, DMSO-Je) δ 7.67- 7.42 (m, 7H), 7.27 (d, IH, J=7 Hz), 7.02 (s, IH), 5.74 (bs, 2H), 4.64-4.62 (m, IH), 2.70 (s, 3H), 1.94 (s, 3H), 1.67 (m, 3H), 1.49-1.45 (m, 2H), 0.63-0.61 (m, 3H). MS (ES) m/z 485 (M+l) ⁺ ; and 'H-NMR (400 MHz, DMSO-Je) δ 7.65-7.61 (m, 2H), 7.59-7.52 (m, 2H), 7.49-7.42 (m, 3H), 7.23 (d, IH, J=7.4 Hz), 5.67 (s, IH), 5.41 (bs, 2H), 4.93 (bs, IH), 4.36 (s, IH), 2.70 (s, 3H), 2.09 (s, 3H), 1.84 (s, 3H), 1.72-1.68 (m, 2H), 0.63-0.60 (m, 3H). MS (ES) m/z 485 (M+l) ⁺ .

Example-XIV:

Synthesis of (E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(pyrrolidin-l-yl)prop -l-en-l- yl)pyrimidin-4-yl)amino ropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Compound-36)

(Intermediate-7) (Compound-36)

(i) l-(pyrrolidin-l-yl)prop-2-en-l-one, Pd(OAC) ₂ ΒΓΝΑΡ, ₂ C0 ₃ , Toluene,

H ₂ Q, Sealed tube, 110°C,16 h;

The process of this step was adopted from step-(i) of compound- 1 in method-2 by using intermediate-7 as starting compound *H-NMR (400 MHz, DMSO-J ₆ ) δ 7.75-7.70 (m, 2H), 7.68- 7.58 (m, 3H), 7.48-7.41 (m,3H), 7.13-7.11 (m, IH), 6.57 (d, IH, J=15.6 Hz), 6.10 (d, IH, J=8.8 Hz), 5.05-5.02 (m, IH), 4.62 (brs, 2H), 3.5-3.6 (m, 4H), 2.30 (s, 3H), 2.0-1.8 (m, 6H), 0.78 (t, 3H, J=7.8 Hz). MS (ES) m/z 528 (M+l) ⁺ .

Synthesis of (E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-2-yl)vinyl)pyrimid in-4-yl)amino) propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Compoudn-37)

(Intermediate-7) (Compound-37)

(i) 2-vinylpyridine, Pd(OAC) ₂ , BDSfAP, K ₂ C0 ₃ , Toluene, H ₂ 0, Sealed tube, 100°C,4 h;

The process of this step was adopted from compound-36 by using intermediate-7 as starting compound ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.60 (d, 1H, J=4 Hz), 7.81-7.78 (m, 2H), 7.62-7.41 (m, 8H), 7.32-7.24 (m, 2H), 6.97 (d, 2H, J=15 Hz), 6.20 (s, 2H), 4.72-4.61 (m, 1H), 2.28 (s, 3H), 1.87-1.80 (m, 1H), 1.70-1.65 (m, 1H), 0.69 (t, 3H, J=7.3 Hz). MS (ES) m/z 508(M+1) ⁺ .

Example-XV: Synthesis of (E)-2-(l-((2-amino-6-methyl-5-(2-(4-methylthiazol-2-yl)vinyl ) pyrimidin-4-yl)amino ropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Compound- 38)

(Intermediate-7) (Compound-38)

(i) 4-methyl-2-vinylthiazole, Pd(dppf )C1 ₂ Et ₃ N, DMF, H ₂ 0, Sealed tube, 100°C,16 h;

The process of this step was adopted from compound-36 by using intermediate-7 as starting compound. 1H-NMR (400 MHz, DMSO-J ₆ ) δ 7.81-7.80 (m, 1H), 7.63-7.51 (m, 8H), 7.19 (s, 1H), 6.86-6.85 (m, 1H), 6.07 (brs, 2H), 5.933 (s, 1H), 4.67 (s, 1H), 2.40 (s, 3H), 2.20 (s, 3H), 1.93-1.53 (m, 2H), 0.87-0.66 (m, 3H). MS (ES) m/z 528 (M+l) ⁺ .

The below compounds were prepared by procedure similar to the one described in Example-XV using suitable starting material with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table. 1.23

m/z (s,

Example-XVI: Synthesis of 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phi hydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)cyclopropan ecarboxamide

(Compound-56)

The process of this step was adopted from step-(i) of compound-2 by using compound-8 as starting compound. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 7.69-7.49 (m, 9H), 6.25 (brs, 2H), 4.8- 4.75 (m, 1H), 3.64-3.45 (m, 2H), 3.5 (brs, 2H), 2.72 (s, 3H), 2.08 (s, 3H), 1.8-1.7 (m, 2H), 0.73- 0.83 (m, 2H), 0.64 (t, 3H, J=7.7 Hz). MS (ES) m/z 484 (M+l) ⁺ .

Example-XVII:

Synthesis of (E)-6-methyl-N4-(l-(2-(4-methylpiperazin-l-yl)quinolin-3-yl) propyl)-5-(2- (pyridin-2-yl)vinyl)pyrimidine-2,4-diamine (Compound-57)

,

Step-(i): (E)-2-(2.5-dimethyl-lH-pyrrol-l-yl)-6-methyl-N-(l-(2-(4-meth ylpiperazin-l-yl) quinolin-3-yl)propyl)-5-(2-(pyridin-2-yl)vinyl)pyrimidin-4-a mine (57.1) The process of this step was adopted from compound-36 by using intermediate-2 as starting compound. MS (ES) m/z 573 (M+l) ⁺ .

Step-(ii): (E)-6-methyl-N4-(l-(2-(4-methylpiperazin-l-yl)quinolin-3-yl) propyl)-5-(2-(pyridin-2- yl)vinyl)pyrimidine-2,4-diamine (Compound-57)

The process of this step was adopted from step-(iii) of compound- l.'H-NMR (400 MHz, DMSO-Je) δ 8.56 (d, IH, J=3.9Hz), 8.13 (s,lH), 7.88-7.72 (m, 3H), 7.64-7.55 (m, 3H), 7.39-7.35 (m, IH), 7.24-7.21 (m, IH), 6.82 (d, IH, J=16.1 Hz), 6.70 (d, IH, J=7.3 Hz), 5.81 (brs, 2H), 5.32-5.27 (m, IH), 3.70 (m, 2H), 3.3-3.0 (m, 2H), 2.66-2.57 (m, 4H), 2.26 (s, 6H), 1.88-1.81 (m, 2H), 0.94 (t, 3H, J=7.3 Hz). MS (ES) m/z 495 (M+l) ⁺ .

Synthesis of (E)-5-(2-(6-methoxypyridin-3-yl)vinyl)-6-methyl-N4-(l-(2-(4- methylpiperazin- l-yl)quinolin-3-yl)propyl)pyrimidine-2,4-diamine (Compound-58)

The process for preparation of compound-58 was adopted from compound-57 by using intermediate-2 as starting compound. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.3 (d, IH, J=1.9 Hz), 8.16 (s, IH), 8.13 (d, IH, J=2.4 Hz), 8.10-8.08 (m, IH), 7.77 (d, 2H, J=8.3 Hz), 7.60 (t, IH, J=7.3 Hz), 7.40 (t, IH, J=7.3 Hz), 7.10 (d, IH, J=16.1 Hz), 6.88 (d, IH, J=8.8 Hz), 6.68 (d, IH, J=16.1 Hz), 5.9-5.75 (m, 2H), 5.35-5.29 (m, IH), 3.87 (s, 3H), 3.85-3.84 (m, 2H), 3.32-3.06 (m, 2H), 2.78-2.67 (m, 4H), 2.50 (s, 3H), 2.26 (s, 3H), 1.84-1.80 (m, IH), 1.77-1.71 (m, IH), 0.85 (t, 3H, J=7.3 Hz). MS (ES) m/z 525 (M+l) ⁺ .

Example-XVIII: Synthesis of (E)-ethyl 3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5- dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl)propyl)amino)-6-met hylpyrimidin-5-yl)acrylate (Compound-59) and (E)-3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydr o-lH- pyrazolo[3,4-d]pyrimidin-6-yl)propyl)amino)-6-methylpyrimidi n-5-yl)acrylic acid (Compound-60) (Interne diate-9) (Compound-59) (Compound-60)

(i) Ethyl acrylate, Pd(OAc) ₂ , BINAP, K ₂ C0 ₃ , Toluene, H ₂ 0, Sealed tube, 120°C, Overnight:

(i) LiOH, THF, Ethanol, H ₂ 0, Overnight, R.T;

Step-(i): (E)-ethyl 3-(2-amino-4-((l-(1 -dimethyl-4-oxo-5-phenyl-4,5-dihydro-lH-pyrazolo[3,4- dlpyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acryla te (Compound-59)

The process of this step was adopted from step-(i) of compound- 1 in method-2 by using intermediate-9 as starting compound. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 7.73-7.72 (m, IH), 7.59- 7.44 (m, 5H), 6.8 (brs, IH), 6.27 (s, 2H), 6.23-6.21 (m, IH), 4.78 (m, IH), 4.15-4.12 (m, 2H), 3.84 (s, 3H), 2.47 (s, 3H), 2.39 (s, 3H), 1.81-1.62 (m, 2H), 1.27-1.23 (m, 3H), 0.64-0.60 (m, 3H). MS (ES) m/z 503 (M+l) ⁺ .

Step-(ii): (E)-3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydr o-lH-pyrazolo[3,4- dlpyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acryli c acid (Compound-60)

The process of this step was adopted from step-(ii) of compound- 1 in method-2. 'H-NMR (400 MHz, DMSO-Je) δ 7.61-7.44 (m, 5H), 6.55 (brs, IH), 6.16 (s, 2H), 4.74 (s, IH), 3.9-3.8 (m, 2H), 2.38 (s, 3H), 2.18 (s, 3H), 1.76-1.59 (m, 2H), 1.23 (s, 3H), 0.64-0.61 (m, 3H). MS (ES) m/z 475 (M+l) ⁺ .

Compound-61 and Compound-62: Synthesis of (E)-ethyl 3-(2-amino-4-((l-(3-(4- fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)prop yl)amino)-6-methyl pyrimidin-5-yl)acrylate (Compound-61) and (E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5- methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)-6-meth ylpyrimidin-5-yl)acrylic acid (Compound-62)

(Intermediate-10) (Compound-61) (Compound-62)

(i) Ethyl acrylate, Pd(OAc) ₂ , BINAP, K ₂ C0 ₃ , Toluene, H ₂ 0, Sealed tube, 120°C, Overnight

(ii) LiOH, THF, Ethanol, H ₂ 0, Overnight, R.T;

The process for preparation of compound-61 and compound-62 were adopted from compound-59 and compound-60 by using intermediate-10 as starting compound. 'H-NMR (400 MHz, DMSO-Je) δ 7.74 (d, IH, J=16.1 Hz), 7.70-7.62 (m, IH), 7.60- 7.54 (m, 3H), 7.40 (d, IH, J=1.5 Hz), 7.39-7.38 (m, IH), 7.31 (d, IH, J=7.4 Hz), 7.03 (d, IH, J=6.9 Hz), 6.38 (brs, 2H), 6.33 (d, IH, J=16.1 Hz), 4.80-4.78 (m, IH), 4.24-4.19 (m, 2H), 2.72 (s, 3H), 2.23 (s, 3H), 1.85- 1.82 (m, IH), 1.65-1.61 (m, IH), 1.33-1.28 (m, 2H), 0.66 (t, 3H, J=7.4 Hz). MS (ES) m/z 517 (M+l) ⁺ . and

'H-NMR (400 MHz, DMSO-Je) δ 12.8-11.2 (brs, IH), 7.68-7.55 (m, 5H), 7.43-7.39 (m, 2H), 7.29 (d, IH, J=7.4 Hz), 6.79 (d, IH, J=5.9 Hz), 6.26 (d, IH, J=16.7 Hz), 6.22-6.20 (brs, 2H), 4.79-4.74 (m, IH), 2.71 (s, 3H), 2.2 (s, 3H), 1.88-1.80 (m, IH), 1.75-1.58 (m, IH), 0.67 (t, 3H, J=7.3 Hz). MS (ES) m/z 489 (M+l) ⁺ .

Example-XIX: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4- methylpiperazin-l-yl)quinolin-3-yl)propyl)amino)pyrimidin-5- yl)acrylate (Compound-66)

(i) Ethyl acrylate, Pd(dppf )C1 ₂ , Et ₃ N, DMP, H ₂ 0, sealed tube, 100"C, Overnight; (ii) Hydroxylamine hydrochloride,

Ethanol, H ₂ 0, Reflux, Overnight.

The process for preparation of compound-66 was adopted from compound-9 by using intermediate- 11 as starting compound. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.104 (s, IH), 7.77 (d, IH, J=15.7 Hz), 7.575 (d, IH, J=7.8 Hz), 7.449 (d, IH, J=6.9 Hz), 7.28-7.25 (m, IH), 6.99 (d, IH, J=7.8 Hz), 6.15 (s, 2H), 6.091 (d, IH, J=16.1 Hz), 5.33-5.28 (m, IH), 4.20-4.15 (m, 2H), 3.67 (m, 2H), 3.03 (m, 2H), 2.67 (m, 2H), 2.625 (s, 3H), 2.273 (s, 3H), 2.255 (s, 3H), 1.85-1.75 (m, 2H), 1.26 (t, 3H, J=7.4 Hz), 0.92 (t, 3H, J=7.3 Hz). MS (ES) m/z 504 (M+l) ⁺ .

Compound-67 and Compound-68: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2- (4-methylpiperazin-l-yl)quinolin-3-yl)propyl)amino)pyrimidin -5-yl)acrylic acid (Compound-67) and (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin -l- yl)quinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylamide (Compound-68)

The process for preparation of compound-67 and compound-68 were adopted from compound-59 and compound-60 by using compound-66 as starting compound.

Compound-67: ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 12.19 (s, IH), 8.27 (s, IH), 7.684 (d, IH, J= 6.1 Hz), 7.647 (d, IH, J=7.3 Hz), 7.51 (d, IH, J=7.3 Hz), 7.343 (t, IH, J=7.8 Hz), 6.4 (m, 2H), 6.046 (d, IH, J=16.1 Hz), 5.37-5.36 (m, IH), 3.5-3.4 (m, 6H), 3.0-3.2 (m, 2H), 2.839 (brs, 3H), 2.650 (s, 3H), 2.261 (s, 3H), 1.824 (m, 2H), 0.897 (t, 3H, J=7.4 Hz). MS (ES) m/z 476 (M+l) ⁺ ; and

Compound-68: ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.12 (s, IH), 7.602 (d, IH, J=7.8 Hz), 7.467 (t, IH, J=6.9 Hz), 7.30-7.26 (m, IH), 6.9 (s, IH), 6.69-6.67 (m, IH), 6.21-6.17 (d, IH, J=15.7 Hz), 5.98 (s, 2H), 5.31-5.30 (m, IH), 3.74-3.69 (m, 4H), 3.26-3.07 (m, 4H), 2.67 (s, 3H), 2.63 (s, 3H), 2.213 (s, 3H), 1.76-1.82 (m, 2H), 0.88 (t, 3H, J=7.4 Hz). MS (ES) m/z 475 (M+l) ⁺ .

Compound-69: Synthesis of (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2 - (4-methylpiperazin-l-yl)quinolin-3-yl)propyl)pyrimidine-2,4- diamine (Compound-69) (lntermediate-11) (69.1) (Compouns-69)

(i) 5-vmyl-L -tetrazole, Pd(dppf)Cl ₂ , Et ₃ N, DMF, H ₂ 0, Sealed tube, 100°C, 16 h; (ii) Hydroxylamine hydrochloride, Ethanol, H ₂ 0, Reflux, Overnight

The process for preparation of compound-69 was adopted from compound-57 by using intermediate- 11 as starting compound. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.142 (s, IH), 7.60 (d, IH, J=7.8 Hz), 7.460 (d, IH, J=6.9 Hz), 7.40 (d, IH, J=16.7 Hz), 7.282 (t, IH, J=7.3 Hz), 6.79 (m, IH), 6.771 (d, IH, J=16.1 Hz), 5.964 (s, 2H), 5.35-5.33 (m, IH), 3.72 (brs, 2H), 3.12 (brs, 2H), 2.81-2.73 (m, 4H), 2.63 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H), 1.829-1.739 (m, 2H), 0.916 (t, IH, J=6.8 Hz). MS (ES) m/z 500 (M+l) ⁺ .

Compound-70: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(2-thiomorpholino quinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylate (70)

The process for preparation of compound-70 was adopted from compound-9 by using intermediate-12 as starting compound. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.17 (s, IH), 7.75-7.8 (m, 3H), 7.59 (t, IH, J=6.9 Hz), 7.1 (t, IH, J=7.4 Hz), 7.04 (d, IH, J=7.8 Hz), 6.17 (brs, 2H), 6.10 (d, IH, J=16.2 Hz), 5.21-5.20 (m, IH), 4.21-4.16 (m, 2H), 3.86-3.82 (m, 2H), 2.87-2.80 (m, 4H), 2.32-2.29 (m, 2H), 2.25 (s, 3H), 1.98-1.91 (m, 2H), 1.25 (t, 3H, J=7.3 Hz), 0.95 (t, 3H, J=7.4 Hz). MS (ES) m/z 493 (M+l) ⁺ .

Compound-71 and Compound-72: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(2- thiomorpholinoquinolin-3-yl)propyl)amino)pyrimidin-5-yl)acry lic acid (Compound-71) and (E)-3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl )propyl)amino) pyrimidin-5-yl)acrylamide (Compound-72)

The process for preparation of compound-71 and compound-72 were adopted from compound-59 and compound-60 by using compound-70 as starting compound.

Compound-71 : *H-NMR (400 MHz, DMSO-J ₆ ) δ 12.02 (brs, IH), 8.19 (s, IH), 7.7-7.4 (m, 2H), 7.71 (d, IH, J=16.1 Hz), 7.59 (t, IH, J=7.4 Hz), 7.41 (t, IH, J=6.8 Hz), 6.94 (d, IH, J=7.3 Hz), 6.11 (brs, 2H), 6.05 (d, IH, J=16.2 Hz), 5.22-5.19 (m, IH), 3.87-3.82 (m, 2H), 2.90-2.81 (m, 4H), 2.24 (s, 3H), 1.90-1.71 (m, 2H), 0.95 (t, 3H, J=6.9 Hz). MS (ES) m/z 465 (M+l) ⁺ .

Compound-72: *H-NMR (400 MHz, DMSO-J ₆ ) δ 8.14 (s, IH), 7.78-7.76 (m, 2H), 7.61-7.59 (m, IH), 7.57-7.48 (m, 2H), 7.42-7.38 (m, 2H), 6.99 (brs, IH), 6.68 (d, IH, J=1.9 Hz), 6.21 (d, IH, J=15.6 Hz), 5.97 (brs, 2H), 5.20-5.19 (m, IH), 3.85-3.83 (m, 2H), 3.31 (brs, 2H), 2.9-2.79 (m, 3H), 2.21 (s, 3H), 1.82-1.74 (m, 2H), 0.94 (t, 3H, J=7.3 Hz). MS (ES) m/z 464 (M+l) ⁺ .

Compound-73: Synthesis of (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(2-thio morpholinoquinolin-3-yl)propyl)pyrimidine-2,4-diamine (Compound-73)

(Intermediate-12) (73.1) (Compound-73)

(i) 5-vinyl-lfl-tetrazole, Pd(dppf)Cl ₂ Et ₃ N, DMF, H ₂ 0, Sealed tube. 100°C, 16h; (ii) Hydroxylamine hydrochloride, Ethanol, H ₂ 0, Reflux, Overnight.

The process for preparation of compound-73 was adopted from compound-57 by using intermediate- 12 as starting compound. *H-NMR (400 MHz, DMSO-J ₆ ) δ 8.28 (d, IH, J=7.3 Hz), 8.19 (s, IH), 7.82-7.79 (m, 2H), 7.65-7.62 (m, IH), 7.52 (brs, 2H), 7.47-7.39 (m, 2H), 6.98 (d, IH, J=16.6 Hz), 5.375-5.363 (m, 2H), 3.66-3.62 (m, 4H), 2.89-2.78 (m, 4H), 2.396 (s, 3H), 1.98 -1.93 (m, IH), 1.86-1.80 (m, IH), 0.95 (t, 3H, J=6.4 Hz). MS (ES) m/z 489 (M+l) ⁺ . Compound-74: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2- thiomorpholinoquinolin-3-yl)propyl)amino)pyrimidin-5-yl)acry late (Compound-74)

(Intermediate- 13 ) (74.1) (Compound-74)

(i) Ethyl aerylate, Pd(dppf )C1 ₂ , Et ₃ N, DMF, H ₂ 0, sealed tube, 100°C, Overnight; (ii) Hydroxylamine hydrochloride, Ethanol, H ₂ 0, Reflux, Overnight.

The process for preparation of compound-74 was adopted from compound-57 by using intermediate- 13 as starting compound. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 7.82 (s, IH), 7.79 (d, IH, J=7.8 Hz), 7.52 (d, IH, J=7.8 Hz), 7.44 (d, IH, J=6.9 Hz), 7.29 (d, IH, J=6.4 Hz), 6.17 (d, IH, J=16.1 Hz), 5.52 (d, IH J=6.9 Hz), 5.34-5.32 (m, IH), 4.67 (brs, 2H), 4.31-4.26 (m, 2H), 3.92-3.86 (m, 2H), 3.48-3.43 (m, 2H), 2.95-2.92 (m, 4H), 2.71 (s, 3H), 2.33 (s, 3H), 1.89-1.78 (m, 2H), 1.35 (t, 3H, J=6.8 Hz), 0.95 (t, 3H, J=7.3 Hz).MS (ES) m/z 507 (M+l) ⁺ .

Compound-75 and Compound-76: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2- thiomorpholino quinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylic acid (Compound-75) and (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquin olin-3-yl)propyl) amino)pyrimidin-5-yl)acrylamide (Compound-76)

R.T, Overnight

The process for preparation of compound-75 and compound-76 were adopted from compound-59 and compound-60 by using compound-74 as starting compound.

Compound-75: *H-NMR (400 MHz, DMSO-J ₆ ) δ 12.6-11.6 (m, IH), 8.11 (s, IH), 7.71 (d, IH, J=16.2 Hz), 7.58 (d, IH, J=7.8 Hz), 7.45 (d, IH, J=6.9 Hz), 7.28 (t, IH, J=7.4 Hz), 6.96 (d, IH, J=7.4 Hz), 6.14 (brs, 2H), 6.04 (d, IH, J=15.6 Hz), 5.23-5.22 (m, IH), 3.88-3.34 (m, 2H), 2.92- 2.79 (m, 6H), 2.63 (s, 3H), 2.24 (s, 3H), 1.82-1.75 (m, 2H), 0.94 (t, 3H, J=7.3 Hz). MS (ES) m/z 479 (M+l) ⁺ .

Compound-76: ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.10 (s, IH), 7.59 (d, IH, J=7.8 Hz), 7.52-7.45 (m, 3H), 7.28 (t, IH, J=7.8 Hz), 6.99 (brs, 2H), 6.68 (d, IH, J=7.3 Hz), 6.20 (d, IH, J=7.3 Hz), 5.99 (brs, 2H), 5.22-5.21 (m, IH), 3.90-3.85 (m, 2H), 3.35-3.32 (m, 2H), 2.93-2.97 (m, 4H), 2.63 (s, 3H), 1.82-1.75 (m, 2H), 0.93 (t, 3H, J=7.3 Hz). MS (ES) m/z 478 (M+l) ⁺ .

Compound-77: Synthesis of (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2 - thiomor holinoquinolin-3-yl)propyl)pyrimidine-2,4-diamine (Compound-77)

(i) 5-vinyl-Lf/-tetrazole, Pd(dppf)Cl ₂ Et ₃ N, DMF, H ₂ 0, Sealed tube, 100°C,16 h; (ii) Hydroxylamine hydrochloride, Ethanol, H ₂ 0, Reflux, Overnight.

The process for preparation of compound-77 was adopted from compound-57 by using intermediate- 13 as starting compound. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.12 (s, IH), 7.59 (d, IH, J=7.9 Hz), 7.54 (d, IH, J=16.7 Hz), 7.46 (d, IH, J=6.8 Hz), 7.28 (t, IH, J=7.8 Hz), 7.04 (d, IH, J=6.8 Hz), 6.79 (d, IH, J=16.7 Hz), 6.16 (brs, 2H), 5.27-5.26 (m, IH), 3.39-3.35 (m, 2H), 3.35-3.34 (m, 2H), 2.93-2.82 (m, 4H), 2.63 (s, 3H), 2.29 (s, 3H), 1.83-1.72 (m, 2H), 0.96 (t, 3H, J=7.3 Hz). MS (ES) m/z 501 (M+l) ⁺ .

Compound-78: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2- morpholinoquinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylate (Compound-78)

(Intermediate- 14) (78.1) (Compound-78)

(i) Ethyl acrylate, Pd(dppf)Cl ₂ , Et ₃ N, DMF, Η,Ο, sealed tube, 100°C, Overnight; (ii) Hydroxylamine hydrochloride, Ethanol, H ₂ 0, Reflux, Overnight. The process for preparation of compound-78 was adopted from compound-57 by using intermediate- 14 as starting compound. *H-NMR (400 MHz, DMSO-J ₆ ) δ 7.793 (s, IH), 7.538 (d, IH, J=16.2 Hz), 7.484 (d, IH, J=7.3 Hz), 7.417 (d, IH, J=6.9 Hz), 7.252 (t, IH, J=7.3 Hz), 6.114 (d, IH, J=16.1 Hz), 5.989 (s, IH), 5.401-5.347 (m, IH), 4.249-4.196 (m, 2H), 3.907 (m, IH), 3.886-3.806 (m, 4H), 3.542-3.501 (m, 2H), 3.412 (q, IH, J = 6.9 Hz), 3.05-3.01 (m, 2H), 2.655 (s, 3H), 2.341 (s, 3H), 1.96-1.81 (m, 2H), 1.281 (t, 3H, J=7.4 Hz), 0.881 (t, 3H, J=6.8 Hz). MS (ES) m/z 491 (M+l) ⁺ .

Compound-79: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-morpholino quinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylic acid (Compound-79)

(Compound-78) (Compound-79)

(i) LiOH, THF, Ethanol, H ₂ 0, Overnight, R.T

The process for preparation of compound-79 was adopted from compound-60 by using compound-78 as starting compound. *H-NMR (400 MHz, DMSO-J ₆ ) δ 12.15 (s, IH), 8.160 (s, IH), 7.694 (d, IH, J=16.2 Hz), 7.60 (d, IH, J=7.8 Hz), 7.465 (d, IH, J=6.9 Hz), 7.290 (t, IH, J=7.8 Hz), 6.15 (brs, 2H), 6.265 (d, IH, J=15.7 Hz), 5.389-5.356 (m, IH), 3.898-3.861 (m, 2H), 3.798-3.760 (m, 2H), 3.646-3.617 (m, 2H), 3.018-2.990 (m, 2H), 2.636 (s, 3H), 2.239 (s, 3H), 1.76 (m, 2H), 0.919 (t, 3H, J=6.8 Hz). MS (ES) m/z 463 (M+l) ⁺ .

Compound-80: Synthesis of (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2 - morpholinoquinolin-3-yl)propyl)pyrimidine-2,4-diamine (Com ound-80)

The process for preparation of compound-73 was adopted from compound-57 by using intermediate- 14 as starting compound ¹ H-NMR (400 MHz, DMSO-J ₆ ) δ 8.15 (s, 1H), 7.61-7.27 (m, 3H), 6.85-7.10 (m, 2H), 6.16 (brs, 2H), 5.52-5.02 (m, 1H), 3.88-3.67 (m, 6H), 3.02-2.98 (m, 2H), 2.63 (s, 3H), 2.28 (s, 3H), 1.86-1.75 (m, 2H), 0.93 (t, 3H, J=6.9 Hz). MS (ES) m/z 487 (M+l) ⁺ .

The below compounds were prepared by procedure similar to the one described in compound-80 by using intermediate- 14 as starting compound with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Compound-83: (E)-ethyl 3-(2-amino-4-((l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methy l quinolin-3-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate (Compound-83) (i) Ethyl acrylate, Pd(dppf)Cl ₂ , Et ₃ N, DMF, H ₂ 0, sealed tube, 100°C, Overnight; (ii) Hydroxylamine hydrochloride,

Ethanol, II ₂ O, Reflux, Overnight.

The process for preparation of compound-83 was adopted from compound-57 by using intermediate- 15 as starting compound'H-NMR (400 MHz, DMSO-J ₆ ) δ 8.3 (s, IH), 7.64 (d, 3H, J=7.8 Hz), 7.50-7.48 (m, 3H), 6.066 (brs, 2H), 6.026 (d, IH, J=13.1 Hz), 5.6-5.5 (m, IH), 4.2- 4.19 (m, 4H), 3.39-3.37 (m, IH), 3.8-3.6 (m, IH), 2.67-2.63 (m, IH), 2.55 (s, 3H), 2.28 (s, 3H), 1.90-1.88 (m, 2H), 1.28 (t, 3H, J=7.4 Hz), 0.99-0.97 (m, 6H), 0.84-0.80 (m, 3H).MS (ES) m/z 519 (M+l) ⁺ .

Compound-84: Synthesis of (E)-3-(2-amino-4-((l-(2-((2S,6R)-2,6-dimethylmorpholino)-8- methylquinolin-3-yl)propyl)amino)-6-methylpyrimidin-5-yl)acr ylic acid (Compound-84)

(i) LiOH, THF, Ethanol, H ₂ 0, Overnight, R.T

The process for preparation of compound-84 was adopted from compound-60 by using compound-83 as starting compound. *H-NMR (400 MHz, DMSO-J ₆ ) δ 12.02 (brs, IH), 8.3 (s, IH), 7.64 (d, 3H, J=7.8 Hz), 7.50-7.48 (m, 3H), 6.066 (brs, 2H), 6.026 (d, IH, J=13.1 Hz), 5.6- 5.5 (m, IH), 4.2-4.19 (m, 4H), 3.39-3.37 (m, IH), 3.8-3.6 (m, IH), 2.67-2.63 (m, IH), 2.55 (s, 3H), 2.28 (s, 3H), 1.90-1.88 (m, 2H), 0.99-0.97 (m, 3H), 0.84-0.80 (m, 3H). MS (ES) m/z 491 (M+l) ⁺ .

Compound-85: Synthesis of N4-(l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin-

3-yl)propyl)-6-methyl-5-((E)-2-(l-methyl-lH-tetrazol-5-yl )vinyl)pyrimidine-2,4-diamine

(Compound-85)

(i) l-methyl-5-vinyl-LfT-tetrazole, Pd(dppf)Cl ₂ Et ₃ N, DMF, H ₂ 0, Sealed tube, 100°C,16 h;

(ii) Hydroxylamine hydrochloride, Ethanol, H ₂ 0, Reflux, Oveniiglit.

The process for preparation of compound-85 was adopted from compound-57 by using intermediate- 15 as starting compound. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.24 (s, IH), 7.61-7.59 (m, 2H), 7.46 (d, IH, J=6.9 Hz), 7.3 (t, IH, J=7.3 Hz), 6.84 (d, IH, J=7.8 Hz), 6.73 (d, IH, J=6.6 Hz), 5.97 (brs, 2H), 5.39-5.37 (m, IH), 4.35 (s, 3H), 3.93 (d, 2H, J=11.7 Hz), 3.89-3.78 (m, IH), 2.87-2.82 (m, IH), 2.66-2.64 (m, IH), 2.63 (s, 3H), 2.29-2.24 (m, IH), 2.27 (s, 3H), 1.85-1.81 (m, 2H), 1.18 (d, 3H, J=6.4 Hz), 1.0 (d, 3H, J=6.3 Hz), 0.84 (t, 3H, J=7.3 Hz). MS (ES) m/z 529 (M+l) ⁺ .

The below compounds were prepared by procedure similar to the one described in compound-85 by using intermediate- 15 as starting compound with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

8.26 (s, IH), 7.62 (d, IH, J=8.3 Hz), 7.49-7.43 (m, 2H), 7.32-

87 7.28 (m, 2H), 7.05-7.03 (m, IH), 6.82-6.7 (m, 2H), 6.50 (brs,

2H), 5.50-5.45 (m, IH), 3.97-3.94 (m, IH), 3.8-3.6 (m, 5H),

2.63 (s, 3H), 2.318 (s, 3H), 1.99-1.84 (m, 2H), 1.3-1.2 (m, 5H), 0.86-0.82 (m, 3H); MS (ES) m/z 515 (M+l) ⁺ .

Compound-88: Synthesis of (E)-4-(3-(l-((2-amino-5-(2-(3-methoxypyridin-2-yl)vinyl)-6- methyl pyrimidin-4-yl)amino)propyl)-8-methylquinolin-2-yl)thiomorph oline 1,1-dioxide (Compound-88)

(i) 3-methoxy-2-vinylpyridine, Pd(dppf)Cl ₂ Et ₃ N, DMF, H ₂ 0, Sealed tube, 100°C,16 h; (ii) Hydroxyl

hydrochloride, Ethanol, H ₂ 0, Reflux, Overnight.

The process for preparation of compound-88 was adopted from compound-57 by using intermediate- 16 as starting compound. ^! H-NMR (400 MHz, DMSO-J ₆ ) δ 8.236 (t, IH, J=2.9 Hz), 7.962 (s, IH), 7.628-7.491 (m, 4H), 7.474-7.274 (m, 2H), 7.208 (d, 2H, J=3Hz), 5.999 (s, IH), 5.360-5.342 (m, IH), 4.9 (m, IH), 4.160-4.112 (m, 2H), 3.968-3.855 (m, 2H), 3.827 (s, 3H), 3.49-3.47 (m, 2H), 3.260-3.206 (m, 2H), 2.698 (s, 3H), 2.382 (s, 3H), 1.896-1.798 (m, 2H), 0.880 (t, 3H, J=6.8 Hz). MS (ES) m/z 574 (M+l) ⁺ .

Example-XX: Synthesis of (E)-3-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)methylene )pyrrolidine-2,5-dione

(Compound-89)

(Intermediate-4) (89.1 ) (89.2) (Compound-89)

(i) CuCN, DMF, 150°C, 12 h; (ii) HCOOH, Re- i, 1 1C C, 4 h; (iii) 3-(triphenylphosphoranylidene) pyrrolidine-2, 5-dione, ethanol, 150°C, 30 min Step-(i): 2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3^-dihydroqu inazolin-2-yl)propyl) amino)pyrimidine-5-carbonitrile (89.1)

To a stirred solution of intermediate-4 (8.0 g, 15.2 mmol) in DMF (100 ml) was added CuCN (5.45 g, 60.8 mmol).The reaction mixture was stirred for 12 h at 150°C. Then the obtained residue was diluted with water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 2% methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (2.5 g, 38%). MS (ES) m/z 426 (M+l) ⁺ .

Step-(ii): 2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihvdroq uinazolin-2-yl)propyl) amino)pyrimidine-5-carbaldehyde (89.2)

To a stirred solution of compound-89.1 (2.5 g, 5.8 mmol) in formic acid (25 ml) was added Re- Ni (1 g).The reaction mixture was stirred for 4 h at 110°C.Then reaction mixture was filtered through celite and concentrated the filterate.The residue was chromatographed on 100-200 mesh silica gel eluting with 2% methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (0.5 g, 20%). MS (ES) m/z 429 (M+l) ⁺ .

Step-(iii): (E)-3-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydro quinazolin-2- yl)propyl)amino)pyrimidin-5-yl)methylene)pyrrolidine-2,5-dio ne (89)

To a stirred solution of compound-89.2 (0.07 g,0.16 mmol) in ethanol (2 ml) was added 3- (triphenylphosphoranylidene)pyrrolidine-2,5-dione (0.11 g, 0.32 mmol). The reaction continued in microwave condition at 150°C for 30 min. After the elimination of the solvents in vacuo , the residue was chromatographed using 100-200 mesh silica gel , eluting with 4% methanol in dichloromethane to give the title compound as a yellow solid (0.03 g, 25%). ¹ H-NMR (400 MHz, DMSO-Je) δ 12.2 (brs, 1H), 7.66-7.26 (m, 8H), 6.8 (brs, 1H), 6.52 (d, 1H, J=7.3 Hz), 6.18 (brs, 2H), 4.60-4.56 (m, 1H), 4.2-4.1 (m, 2H), 2.67 (s, 3H), 2.08 (s, 3H), 1.80-1.71 (m, 2H), 0.67 (t, 3H, J=7.3 Hz). MS (ES) m/z 510 (M+l) ⁺ .

Compound-90: Synthesis of (Z)-5-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrim^ (90) (89.2) (Compound-90)

(i) Thiazolidine-2,4-dione, Benzoic acid, Piperidine, Toluene, 140°C, 1 h

To a stirred solution of compound-89.2 (0.1 g, 0.23 mmol) in toluene (10 ml) was added thiazolidine-2,4-dione (0.032 g, 0.28 mmol), benzoic acid (0.0037 g, 0.03 mmol) and piperidine (0.00298 g, 0.035 mmol).The reaction was continued at 140°C for 1 h. After the elimination of the solvents in vacuo , the residue was chromatographed using 100-200 mesh silica gel , eluting with 4% methanol in dichloromethane to give the title compound as a yellow solid (0.01 g, 8%).1H-NMR (400 MHz, DMSO-J ₆ ) δ 12.2 (brs, 1H), 7.66-7.26 (m, 8H), 6.8 (brs, 1H), 6.52 (d, 1H, J=7.3 Hz), 6.18 (brs, 2H), 4.60-4.56 (m, 1H), 2.67 (s, 3H), 2.08 (s, 3H), 1.80-1.71 (m, 2H), 0.67 (t, 3H, J=7.3 Hz). MS (ES) m/z 528 (M+l) ⁺ .

Example-XXI: Synthesis of 5-(2-amino-4-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-N-(tert-butyl)p yridine-3-sulfonamide (Compound-91)

To a stirred solution of Intermediate-22 (0.2 g, 0.45 mmol) in 1,4-dioxane (6 ml) was added lntermediate-29 (0.12 g, 0.54 mmol), Pd(dppf)Cl ₂ (0.018 g, 0.022 mmol), K ₂ C0 ₃ (0.18 g, 1.36 mmol) and 0.5 ml of H ₂ 0. The reaction mixture was stirred for 12 h at 100°C. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15 ml) and ethyl acetate (2x15 ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure afforded the crude. Which was purified by column chromatography using 100-200 mesh silica gel and 3 % methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (0.02 g, 10 %). IH NMR (400 MHz, DMSO-d ₆ ) δ 8.92-8.87 (m, 2H), 8.22-8.21 (m, IH), 7.83-7.81 (m, 2H), 7.79-7.46 (m, 7H), 7.29-7.27 (m, IH), 6.61-6.59 (m, IH), 6.17 (bs, 2H), 4.65-4.63 (m, IH), 2.7 (s, 3H), 1.76- 1.71 (m, IH), 1.59-1.57 (m, IH), 1.22 (s, 9H), 0.64-0.60 (m, 3H). MS (ES) m/z 599 (M+l) ⁺ .

Compounds listed in below table are prepared by following similar procedure as depicted for the preparation of Example -XXI, by using approprite intermediates in presence of suitable reagents, reactants and solvents at suitable conditions. Structure information and characterization I data for the compounds are given in below table.

Biological Activity:

(i) PI3 Kinase TR-FRET Assay:

Compound inhibition for PI3K was determined in a homogenious TR-FRET assay using a PI3K assay kit obtained from Millipore, USA (cat # 33-016). The PI3 kinase catalyses the phosphorylation of phosphatidylinositol, 5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5- trisphosphate (PIP3) in the presence of ATP and Mg2+. The PIP3 product is detected by displacement of biotin-PIP3 from an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC). Excitation of Europium in the complex results in an energy transfer to the APC and a fluorescence emission at 665 nm.

Compounds to be tested were dissolved in DMSO and directly distributed in to 384- well plates at a volume of.0.5 ul. 14.5 ul of PI 10/P85a /PIP2 mixture was added to compound wells and incubated for 30 min at room temp for 60 min. P110/P85a was expressed in SF9 cells and purified in-house. 5 ng P110/P85a was used in the assay. The kinase reaction was started by the addition of ATP. The assay concentrations of both PIP2 and ATP were 10 μΜ. The reaction mixture was incubated for 30 minutes and was terminated by the addition of stop mix and detection mix. Fluorescence was measured at 615 and 665 nm upon excitation at 340 nm in a Victor V5 fluorimeter (Perkin Elmer, USA). The fluorescence emission ratio at 665 to 615 nm, proportional to the kinase activity, was plotted against the compound concentration to generate dose-response curves and IC50 values were determined.

(ii) mTOR kinase TR-FRET Assay:

Compound inhibition for mTOR kinase was determined in a homogenious TR-FRET assay using ULight-τρΊΟ S6K (Thr 389) peptide as substrate. mTOR enzyme was obtained from Millipore, USA. 5 μg mTOR was used in the assay. The reaction buffer was 50mM HEPES pH7.5, lmM EGTA, 3mM MnC12. Test compound was pre-incubated with mTOR for 30 min, and 50 nM Light-p70 S6K (Thr 389) Peptide was added along with 20 μΜ ATP. After incubating the reaction mixture for 30 min, 1 nM Eu- labeled anti-phospho-substrate antibody (obtained from Perkin Elmer, USA) was added. Fluorescence emission at 615 and 665 nM was measured upon excitation at 340 nM The compound dilution was carried out in 100% DMSO followed by a buffer dilution. The kinase reaction was incubated for lhr at room temperature followed by the addition of substrate- ATP mix and incubated for lhr at room temperature, the reaction was terminated by the addition of EDTA followed by the addition of detection mix. IC50 values were subsequently determined using a sigmoidal dose -response curve.

The compounds were screened at ΙμΜ concentration and the results are summarized in the table below along with the IC ₅₀ (μΜ) details for selected examples. The IC ₅₀ values of the compounds are set forth in below Table wherein "A" refers to an IC ₅₀ value of less than 0.01 μΜ, "B" refers to IC ₅₀ value in range of Ο.ΟΙμΜ to 0.1 μΜ and "C" refers to IC ₅₀ value of greater than 0.1 μΜ.

(iii) PI3 Kinase (gamma) TR-FRET Assay:

Compound inhibition for PI3K was determined in a homogenious TR-FRET assay using a PI3K assay kit obtained from Millipore, USA (cat # 33-016). The PI3 kinase catalyses the phosphorylation of phosphatidylinositol, 5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5- trisphosphate (PIP3) in the presence of ATP and Mg2+. The PIP3 product is detected by displacement of biotin-PIP3 from an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC). Excitation of Europium in the complex results in an energy transfer to the APC and a fluorescence emission at 665 nm.

Compounds to be tested were dissolved in DMSO and directly distributed into 384- well plates at a volume of 0.5 ul. 14.5 ul of PI3 kinase(pl20y) /PIP2 mixture was added to compound wells and incubated for 30 min at room temp for 60 min. PI3 kinase (ρ120γ) was procured from Millipore (cat No: 14-558). 150 ng of PI3 kinase (ρ120γ) was used in the assay. The kinase reaction was started by the addition of ATP. The assay concentrations of both PIP2 and ATP were 10 μΜ. The reaction mixture was incubated for 30 minutes and was terminated by the addition of stop mix and detection mix. Fluorescence was measured at 615 and 665 nm upon excitation at 340 nm in a Victor X5 fluorimeter (Perkin Elmer, USA). The fluorescence emission ratio at 665 to 615 nm, proportional to the kinase activity, was plotted against the compound concentration to generate dose -response curves and IC50 values were determined.

(iv) PI3 Kinase(delta) TR-FRET Assay:

Compound inhibition for PI3K was determined in a homogenious TR-FRET assay using a PI3K assay kit obtained from Millipore, USA (cat # 33-016). The PI3 kinase catalyses the phosphorylation of phosphatidylinositol, 5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5- trisphosphate (PIP3) in the presence of ATP and Mg2+. The PIP3 product is detected by displacement of biotin-PIP3 from an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC). Excitation of Europium in the complex results in an energy transfer to the APC and a fluorescence emission at 665 nm.

Compounds to be tested were dissolved in DMSO and directly distributed into 384- well plates at a volume of 0.5 ul. 14.5 ul of PI3 kinase(pl l05/p85a) /PIP2 mixture was added to compound wells and incubated for 30 min at room temp for 60 min. PI3 kinase (ρ120γ) was procured from Millipore (cat No: 14-604). 5 ng of PI3 kinase (ρ110δ/ρ85α) was used in the assay. The kinase reaction was started by the addition of ATP. The assay concentrations of both PIP2 and ATP were 10 μΜ. The reaction mixture was incubated for 30 minutes and was terminated by the addition of stop mix and detection mix. Fluorescence was measured at 615 and 665 nm upon excitation at 340 nm in a Victor X5 fluorimeter (Perkin Elmer, USA). The fluorescence emission ratio at 665 to 615 nm, proportional to the kinase activity, was plotted against the compound concentration to generate dose -response curves and IC50 values were determined.

The compounds were screened for selective inhibition of ΡΒΚγ and PI3K5 at 1 nM concentration and the results are summarized in the table below along with the IC ₅₀ (nM) details for selected compounds. The IC ₅₀ values of the compounds are set forth in below Table, wherein "A" refers to an IC ₅₀ value in less than 20 nM, "B" refers to IC ₅₀ value in range of 20.01 to 100 nM and "C" refers to IC ₅₀ value in range of 100.1 nM to 1000 nM. % inhibition of ΡΙ3Κγ and PI3K5 at^M concentration of selected compounds are set forth in below table.