Indanol substituted diamino pyrimidine carboxamides as dual ATM / DNA-PK inhibitors

Abstract

The present disclosure provides indanol substituted diamino pyrimidine carboxamides compounds of Formula I, its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, stereoisomers, polymorphs, or pharmaceutically active derivatives thereof as dual ATM / DNA-PK inhibitors. The present disclosure further provides compounds of Formulae la, lb, and Ic, its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, stereoisomers, polymorphs, or pharmaceutically active derivatives thereof. The present disclosure also provides process of preparing said compounds and methods thereof.

Description

INDANOL SUBSTITUTED DIAMINO PYRIMIDINE CARBOXAMIDES AS DUAL ATM / DNA-PK INHIBITORS FIELD OF INVENTION

[0001] The present disclosure relates to the field of medicinal chemistry and therapeutic agents. Particularly, the present disclosure provides indanol substituted diamino pyrimidine carboxamides as dual ATM / DNA-PK inhibitors. BACKGROUND OF THE INVENTION

[0002] An important mechanism that safeguards the genome and averts cancer- causing mutations is the DNA damage response (DDR). An important factor in the initiation and advancement of cancer is the cellular reaction to DNA damage. Families of phosphatidylinositol 3-kinase (PI3K)-like kinases (PIKKs), including DNA-PKcs, ATM, and ATR, primarily regulate DNA repair and transmit damage signals to the tumour suppressor p53, which can then induce cell cycle arrest, apoptosis, or senescence (Torgovnick A, Schumacher B., PMID25954303; Finzel A et al.; PMID: 27280387).

[0003] Ataxia telangiectasia mutant (ATM) and DNA-dependent Protein Kinase (DNA-PK) are serine / threonine protein kinases that function at the forefront of the DNA damage response (DDR). Their primary role is to detect DNA double-strand breaks (DSBs) and initiate subsequent repair mechanisms. Dysregulation or mutations in these kinases are associated with a variety of malignancies, making them attractive therapeutic targets (Carrassa L, et al. Cancer Treat Rev. 2020. PMID: 32892059; Curtin NJ. Br J Pharmacol.2013. PMID: 23682925).

[0004] Recent advancements have led to the development of small molecules that can inhibit either ATM or DNA-PK (Cheng, Binbin et al. European journal of medicinal chemistry vol.230 (2022): 114109. doi:10.1016 / j.ejmech.2022.114109). Dual targeting offers potential benefits over the inhibition of a single kinase, including enhanced disruption of DDR and a possible reduction in resistance mechanisms. Moreover, this dual inhibition might potentiate the effects of othercancer therapies, including radiation and chemotherapy, by hindering DNA repair and exacerbating DNA damage.

[0005] Therefore, there is a need in the art to develop therapeutic agents that selectively and efficiently inhibit both ATM and DNA-PK enzymes to enhance the efficacy of cancer therapies. SUMMARY OF THE INVENTION

[0006] In a first aspect of the present disclosure, there is provided a compound of Formula I, its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, stereoisomers, polymorphs, or pharmaceutically active derivatives thereof,Formula I wherein ring A is an optionally substituted 5 to 8 membered heterocyclyl ring; R1is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8heterocyclyl, C2-8heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl or C2-8 heterocyclyl; R3is selected from halogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; R is selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl; R4is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, deuterated C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl,or C2-8 heteroaryl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated C1-6 alkyl, C1-6haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, C1-6 alkoxy, C3-8 cycloalkyl, C1-6 aminoalkyl, or C1-6haloalkyl, wherein C3-8cycloalkyl is optionally further substituted with halogen or hydroxy; Z1, Z2, Z3, and Z4 are independently selected from N or CR6; X is selected from O or CR7; R6is selected from hydrogen, cyano, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; R7is selected from hydrogen, cyano, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; and n1is 0 or 1.

[0007] In a second aspect of the present disclosure, there is provided a process of preparing the compound as disclosed herein, the process comprising: reacting a compound of Formula C with a compound selected from Formula D, Formula G or Formula K and an amine of R4NH2which is optionally protected; and optionally deprotecting to obtain the compound of Formula I,wherein R’ is selected from hydroxy, amine, C1-6 alkoxy, or C1-6 alkylamino; ring A is an optionally substituted 5 to 8 membered heterocyclyl ring;R1 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl, wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl or C2-8 heterocyclyl; R3 is selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl; R is selected from hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; R4 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated C1-6 alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8 heteroaryl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, C1-6alkoxy, C3-8cycloalkyl, C1-6aminoalkyl, or C1-6 haloalkyl, wherein C3-8 cycloalkyl is optionally further substituted with halogen or hydroxy; Z1, Z2, Z3, and Z4are independently selected from N or CR6; X is selected from O or CR7; R6 is selected from hydrogen, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8 heteroaryl; R7 is selected from hydrogen, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl; and n1 is 0 or 1.

[0008] In a third aspect of the present disclosure, there is provided a combination comprising compounds of Formula I as disclosed herein with at least one additional therapeutic agent.

[0009] In a fourth aspect of the present disclosure, there is provided a combination comprising compounds of Formula Ia, Ib, and Ic as disclosed herein, with at least one additional therapeutic agent.

[0010] In a fifth aspect of the present disclosure, there is provided a pharmaceutical composition comprising the compound as disclosed herein with at least one pharmaceutically acceptable excipient.

[0011] In a sixth aspect of the present disclosure, there is provided a method of treating cancer in a subject, the method comprising administering the compound as disclosed herein or the combination as disclosed herein, or the pharmaceutical composition as disclosed herein to the subject in need thereof.

[0012] In a seventh aspect of the present disclosure, there is provided a method of treating a disease or condition mediated by ATM or DNA-PK or combinations thereof, in a subject, the method comprising administering the compound as disclosed herein or the combination as disclosed herein, or the pharmaceutical composition as disclosed herein to the subject in need thereof.

[0013] These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following detailed description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. DESCRIPTION OF THE INVENTION

[0014] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any or more of such steps or features. Definitions

[0015] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.

[0016] The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0017] The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. Throughout this specification, unless the context requires otherwise the word “comprise”, and variations, such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.

[0018] The term “including” is used to mean “including but not limited to”, “including” and “including but not limited to” are used interchangeably.

[0019] In the structural formulae given herein and throughout the present disclosure, the following terms have been indicated meaning, unless specifically stated otherwise.

[0020] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0021] The term “pharmaceutically acceptable salt” embraces salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methane sulphonic, ethane sulphonic, benzene sulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines.

[0022] The term “intermediates” refers to compounds that are useful in generating the target compounds. The intermediates are compounds are involved in the synthetic mechanism and are further ingested or consumed in the reaction to obtain the target compound. The intermediates may have structural similarities with respect to the target compound.

[0023] The term “pharmaceutically active derivatives” refers to compounds of Formula I, its derived or related compounds which are biologically active possess therapeutic effect, and are useful in treating, preventing, curing or diagnosing a disease, disorder, or condition.

[0024] The term “tautomer” refers to two or more isomers of a compound which exist together in equilibrium, and are readily interchanged by migration of an atom or group within the molecule.

[0025] The term “polymorphs” refers to crystal forms of the same molecule, and different polymorphs may have different physical properties, such as melting temperatures, heats of fusion, solubilities, dissolution rates and / or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice.

[0026] Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present disclosure, for example, for use as intermediates in the preparation of other compounds of Formula I, and their pharmaceutically acceptable salts. Thus, one embodiment of the disclosure embraces a compound of Formula I, and salts thereof. Compounds according to Formula I contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate,methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenyl acetate, propionate, butyrate, iso-butyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate, hydroxynaphthoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate), aminobenzenesulfonate, p- toluenesulfonate (tosylate), and naphthalene-2- sulfonate.

[0027] The term “solvate”, as used herein, refers to a crystal form of a substance which contains solvent.

[0028] The term “hydrate” refers to a solvate form of a substance wherein the solvent is water.

[0029] The term “complexes” as used herein, can be interchangeably used as “coordination complex” or “metal coordination complex” and the like. It refers to a complex of an organic compound with a metal that can be empirically differentiated from a simple metal salt of the organic compound based on physiochemical and / or spectroscopic properties, with a coordination complex typically having enhanced covalency as compared to a salt. Without limitation “complexes” as used herein also involve a combination of coordinate covalent bonds and / or ionic bonds. As used herein, the term “complexes” also includes molecules that lack an ionic component (e.g., such as a neutral coordination complex prior to deprotonation, where pKa of the coordination complex falls within a physiologically acceptable range).

[0030] The term “stereoisomers” refers to the isomeric forms of a molecule where the molecular formula and sequence of bonded atoms are similar but the three- dimensional orientation of the atoms are different. Enantiomers are two stereoisomers that are related to each other by a reflection, they are mirror images of each other that are non-superposable.

[0031] The compounds provided herein include the corresponding enantiomers and stereoisomers, that is, the pure form of the stereoisomers, in terms of geometrical isomer, enantiomer, or diastereomer, and the mixture of enantiomeric and stereoisomeric form of said compounds. Further, the mixture of enantiomeric and stereoisomeric forms can be resolved into their pure component by the methods known in the art, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallization, using chiral derivatizing agents, etc. Also, pure enantiomers and stereoisomers can be obtained from intermediates or metabolites and reagents that are in the form of pure enantiomers and stereoisomers by known asymmetric synthetic methods.

[0032] The term “optionally substituted” for a compound, refers to a group of compounds which include substituted and unsubstituted derivatives of the same compound wherein the substituted derivatives have one or more functional groups. In an aspect of the present disclosure, there is provided a compound of Formula I wherein the ring A is an optionally substituted 5 to 8 membered heterocyclyl ring.

[0033] The term “protected” refers to a derivative of a compound wherein the reactive functional group of the compound is protected or substituted with a group selected from alkyl silyl, esters, acetals, ethers, or the like.

[0034] The term “optionally protected” for a compound, refers to a group of compounds which include the compound and the protected derivative of the same compound. In an aspect of the present disclosure, there is provided a process of preparing the compound of Formula I, the process comprising reacting a compound of Formula C with an amine of R4NH2 which is optionally protected.

[0035] The term “alkyl” refers to saturated hydrocarbons having specified number of carbon atoms. For example, which are not limited, C1-6alkyl refers to an alkyl group having 1-6 carbon atoms. Alkyl groups may be straight or branched chained groups which may be optionally substituted. Representative branched alkyl groups have one, two, or three branches. Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, and isopropyl. One or more hydrogens of the alkyl groups may be optionally replaced with deuterium to term as “deuterated C1- 6 alkyl” such as CD3, CHD2, CDH2, CH2CD3, CD2CH3 and the like.

[0036] The term “alkenyl” refers to unsaturated hydrocarbons having specific number of carbon atoms and at least one double bond between carbon atoms. For example, which are not limited, C2-6 alkenyl refers to an alkenyl group having 2-6 carbon atoms. Alkenyl groups may be straight or branched chained groups. Representative branched alkenyl groups have one or two branches. Preferred alkenyl groups include, without limitation, ethenyl, n-propenyl, and isopropenyl.

[0037] The term “alkynyl” refers to unsaturated hydrocarbons having specific number of carbon atoms and at least one triple bond between carbon atoms. For example, C2-6alkynyl refers to an alkynyl group having from 2-6 carbon atoms. Alkynyl groups may be straight or branched chained groups which may be optionally substituted. Representative branched alkyl groups have one, two, or three branches. Preferred alkynyl groups include, without limitation, ethynyl, n- propynyl, or butynyl.

[0038] The term “alkoxy” refers to an alkyl group attached via an oxygen linkage to the rest of the molecule. For example, C1-6alkoxy refers to an alkyl group having from 1 - 6 carbon atoms attached via an oxygen linkage to the rest of the molecule. Preferred alkoxy groups include, without limitation, –OCH3 (methoxy), –OC2H5 (ethoxy) and the like.

[0039] The term “amino” refers to -NH2group.

[0040] The term “hydroxy” refers to -OH group.

[0041] The term “cyano” refers to -CN group.

[0042] The term “oxo” refers to =O group.

[0043] The term “halogen” refers to a halogen atom such as fluoro(F), bromo (Br), chloro(Cl) and iodo(I).

[0044] The term “haloalkyl” as used herein, refers to an alkyl group as defined herein, wherein one or more hydrogen of alkyl group is substituted with halogen atoms. Examples of haloalkyl include, but are not limited to trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, and the like.

[0045] The term “haloalkoxy” refers to an alkoxy group attached via an oxygen linkage to the rest of the molecule wherein one or more hydrogens of the alkoxygroup is substituted with one or more same or different halogen atoms. Examples of haloalkoxy include, but are not limited to trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, dichloromethoxy, chloromethoxy, and the like.

[0046] The term “cycloalkyl” refers to a saturated hydrocarbon ring having a specified number of carbon atoms. Examples of cycloalkyl include but are not limited to C3-8 cycloalkyl refers to a cycloalkyl group having from 3 to 8 member atoms. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, groups and the like. The cycloalkyl group can be optionally substituted.

[0047] The term “aminoalkyl” or “alkylamino” refers to an alkyl group wherein one or more hydrogens of the alkyl is(are) substituted with one or more amino groups. The “aminoalkyl” or “alkylamino” may be attached via amino linkage or through carbon to the rest of the molecule. Preferred aminoalkyl groups include, without limitation, -NHCH3, -N(CH3)2, and the like. The aminoalkyl group may be optionally substituted. In an aspect of the present disclosure, alkylamino groups include diamines, triamines and tetraamines.

[0048] The term “heterocyclic” and “heterocyclyl” refer to saturated or unsaturated rings containing specific number of carbon atoms with one or more heteroatoms and the heterocyclic group may be monocyclic, bicyclic, or polycyclic. The heterocyclic group may be fused, bridged, or spiral structures and may be optionally substituted. In certain embodiments, 'heterocyclyl' groups are saturated. In other embodiments, 'heterocyclyl' groups are partially saturated. In few embodiments, 'heterocyclyl' groups are unsaturated. In some embodiments, 'heterocyclyl' groups are partially unsaturated. 'Heterocyclyl' groups containing more than one heteroatom may contain different heteroatoms selected from N, S, and O. 'Heterocyclyl' groups may be substituted with one or more substituents as defined herein. 'Heterocyclyl' includes oxetanyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azepinyl, oxazepinyl, azabicyclo[3.1.0]hexanyl.

[0049] The term “heteroaryl” refers to a heterocyclic ring radical as defined above which is aromatic in nature. The heteroaryl ring radical may be attached to the mainstructure at any heteroatom or carbon atom resulting in the creation of a stable structure. The heteroaryl refers to an aromatic ring with one or more hetero atoms selected from N, O, or S with carbon ranging between 2 to 10.

[0050] A term once described, the same meaning applies for it, throughout the patent.

[0051] As discussed in the background, the existing therapeutic compositions inhibit either ATM or DNA-PK. In this view, there is a need in the art to develop a dual targeting therapeutic agent to provide cancer treatment. Further, dual inhibiting therapeutic agents might potentiate the effects of other cancer therapies, such as radiotherapy and chemotherapy, by hindering DNA repair and exacerbating DNA damage. Therefore, there is a requirement for the development of drug molecules that improve the outcome of radiotherapy and work synergistically as DNA damaging agents and offer a new approach for treating drug-resistant tumours, ultimately improving the effectiveness of cancer-treatment drugs and benefit-risk profile of cancer patients.

[0052] Accordingly, the present disclosure provides a compound of Formula I, its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, stereoisomers, polymorphs, or pharmaceutically active derivatives thereof,Formula I wherein ring A is an optionally substituted 5 to 8 membered heterocyclyl ring; R1 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C2-8 heterocyclyl, C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl or C2-8 heterocyclyl; R3 is selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl; R is selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; R4is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, deuterated C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8 heteroaryl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, C1-6 alkoxy, C3-8 cycloalkyl, C1-6 aminoalkyl, or C1-6 haloalkyl, wherein C3-8 cycloalkyl is optionally further substituted with halogen or hydroxy; Z1, Z2, Z3, and Z4are independently selected from N or CR6; X is selected from O or CR7; R6is selected from hydrogen, cyano, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8 heteroaryl; R7 is selected from hydrogen, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8 heteroaryl; and n1 is 0 or 1.

[0053] In another embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein ring A is an optionally substituted 5 or 6 membered heterocyclyl ring; R1 is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, C2-6heterocyclyl, or C2-6heteroaryl, wherein C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, C2-6 heterocyclyl, or C2-6 heteroaryl is optionally substituted with one or more groups selected fromhalogen, cyano, hydroxy, amino, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl or C2-6heterocyclyl; R3is selected from halogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, C2-6 heterocyclyl, or C2-6 heteroaryl; R is selected from hydrogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, C2-6heterocyclyl, or C2-6heteroaryl; R4is selected from hydrogen, C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, deuterated C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, C2-6 heterocyclyl, or C2-6 heteroaryl, wherein C1-4 alkyl, C2-4alkenyl, C2-4alkynyl, deuterated C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, C2-6heterocyclyl, or C2-6heteroaryl is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, C1-4 alkoxy, C3-6 cycloalkyl, C1-4 aminoalkyl, or C1-4 haloalkyl, wherein C3-8cycloalkyl is optionally further substituted with halogen or hydroxy; Z1, Z2, Z3, and Z4 are independently selected from N or CR6; X is selected from O or CR7; R6 is selected from hydrogen, cyano, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-6cycloalkyl, C2-6heterocyclyl, or C2-6heteroaryl; R7is selected from hydrogen, cyano, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6cycloalkyl, C2-6heterocyclyl, or C2-6heteroaryl; and n1is 0 or 1.

[0054] In yet another embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein ring A is 5 or 6 membered heterocyclyl ring; R1 is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, or C3-6cycloalkyl, wherein C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, or C3-6 cycloalkyl, is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-4alkoxy, C1-4haloalkoxy, C3-6cycloalkyl or C2-6heterocyclyl; R3is selected from halogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, or C1-4 haloalkoxy; R is selected from hydrogen, C1-4 alkyl, C1-4 alkoxy, C1-4haloalkyl, or C1-4haloalkoxy; R4is selected from hydrogen, C1-4alkyl, C2-4alkenyl,C2-4alkynyl, deuterated C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, or C1-4haloalkoxy, wherein C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, deuterated C1-4 alkyl, C1-4 haloalkyl, or C1-4 haloalkoxy, is optionally substituted with one or more groups selected fromhalogen, oxo, amino, amide, hydroxy, C1-4 aminoalkyl, or C1-4 haloalkyl; Z1, Z2, Z3, and Z4are independently CR6; R6is selected from hydrogen, cyano, halogen, C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, or C1-4 alkoxy; X is CR7; R7 is selected from hydrogen, cyano, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4alkoxy, or C1-4haloalkoxy; and n1is 0.

[0055] In an embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein ring A is a 5 membered substituted heterocyclyl ring; R1is selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4haloalkyl, or C3-6cycloalkyl, wherein C1-4alkyl, C2-4alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, or C3-6 cycloalkyl, is optionally substituted with one or more groups selected from halogen, hydroxy, amino, or C1-2alkoxy; R3is halogen or C1-3alkyl; R is hydrogen; R4is selected from hydrogen, C1-4 alkyl, or deuterated C1-6 alkyl; wherein C1-4 alkyl is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, C1-4 aminoalkyl, or C1-4haloalkyl; Z1, Z2, Z3, and Z4are independently CR6; R6is selected from hydrogen, halogen, or C1-4alkyl; X is CR7; R7is selected from hydrogen, cyano, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4alkoxy, or C1-4haloalkoxy; and n1is 0.

[0056] In an embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein ring A is selected from* point of wherein R1 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6alkoxy, C1-6haloalkoxy, C3-8cycloalkyl or C2-8heterocyclyl; Y is N or CR2, when Y is connected via double bond wherein R2 is selected from hydrogen,halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl; Y is O or S, when Y is connected via single bond; and n is selected from 0 to 3.

[0057] In an embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein ring A is selected from or* point of wherein R1is selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4haloalkyl, or C3-6 cycloalkyl, wherein C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, or C3-6 cycloalkyl, is optionally substituted with one or more groups selected from halogen, hydroxy, amino, or C1-2alkoxy; Y is N or CR2, when Y is connected via double bond wherein R2 is selected from hydrogen, halogen, C1- 6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8heteroaryl; Y is O or S, when Y is connected via single bond; and n is selected from 0 to 3.

[0058] In an embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein ring A is selected from* point of attachment wherein R1is selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, C2-6 heterocyclyl, or C2-6 heteroaryl, wherein C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6cycloalkyl, C2-6heterocyclyl, C2-6heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-4 alkoxy, or C1-4 haloalkoxy; Y is N or CR2, when Y is connected via double bond wherein R2is selected from hydrogen, halogen, C1-4alkyl, or C1-4alkoxy; Y is O, when Y is connected via single bond.

[0059] In an embodiment of the present disclosure, there is provided a compound as disclosed herein, wherein the compound is selected fromits pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, stereoisomers, polymorphs, or pharmaceutically active derivatives thereof, wherein R1 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6alkoxy, C1-6haloalkoxy, C3-8cycloalkyl or C2-8heterocyclyl; Y is N or CR2, when Y is connected via double bond wherein R2 is selected from hydrogen, halogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C2-c8heterocyclyl, or C2-8heteroaryl; Y is O or S, when Y is connected via single bond; n is selected from 0 to 3; R3 is selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; R is selected from hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; R4 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, deuterated C1-6alkyl, C1-6haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, C1-6alkoxy, C3-8cycloalkyl, C1-6aminoalkyl, or C1-6haloalkyl, wherein C3-8 cycloalkyl is optionally further substituted with halogen or hydroxy; Z1, Z2, Z3, and Z4are independently selected from N or CR6; X is selected from O or CR7; R6 is selected from hydrogen, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl; R7is selected from hydrogen, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; and n1 is 0 or 1.

[0060] In an embodiment of the present disclosure, there is provided a compound as disclosed herein, wherein R1is selected from C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C3-8 cycloalkyl or C2-8 heterocyclyl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C3-8 cycloalkyl, is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, or C2-8 heterocyclyl; Y is N or CR2, when Y is connected via double bond wherein R2 is selected from hydrogen, halogen, C1-6alkyl, or C1-6alkoxy; Y is O or S, when Y is connected via single bond; n is selected from 0 to 2; R3is selected from halogen, C1-6alkyl, C1-6alkoxy or C1-6 haloalkyl; R is selected from hydrogen, C1-6 alkyl, C1-6 alkoxy or C1-6haloalkyl; R4is selected from hydrogen, C1-6alkyl, deuterated C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, wherein C1-6alkyl, deuterated C1-6alkyl, C1-6haloalkyl, or C3-8 cycloalkyl, is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, C1-6 alkoxy, C3-8 cycloalkyl, C1-6aminoalkyl, or C1-6haloalkyl, wherein C3-8cycloalkyl is optionally further substituted with halogen or hydroxy; Z1, Z2, Z3, and Z4 are independently selected from N or CR6; X is selected from O or CR7; R6 is selected from hydrogen, cyano, halogen, C1-6alkyl, or C1-6haloalkyl; R7is selected from hydrogen, cyano, halogen, C1-6alkyl, or C1-6haloalkyl; and n1is 0 or 1.

[0061] In an embodiment of the present disclosure, there is provided acompound as disclosed herein, wherein R1is selected from CH3, CH2CH3,CH(CH3)2, CH2CH2CH3, CH2CHF2, CH2CF3, CH2CH2CHF2, CH2CH2OCH3, CH2CH2OCF3, CH2CH2OCHF2, CH2CH2CHOH, CH(CH3)CH2CH3, CH2CH2CN,Y is N or CR2when Y is connected via double bond where in R2is selected from hydrogen, F, CH3, CF3,or CHF2; Y is O or S when Y is connected via single bond; n is 0,1 or 2; R3is selected from CH3, F, Cl, CF3, or CHF2; R is selected from hydrogen, CH3, CF3, or OCH3; and R4is selected from hydrogen, CH3, CH2CH3, CD3, CF3, CH2CHF2; Z1, Z2, Z3, and Z4are independently selected from N or CR6; X is selected from O or CR7; R6 is hydrogen, or C1-6 alkyl; R7is hydrogen, or C1-6alkyl; and n1is 0 or 1.

[0062] In an embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein ring A is a 5 membered heterocyclyl ringselected from* point of attachment wherein R1is selected from C1-3alkyl, C2-4alkenyl, C2-4alkynyl, C1-3haloalkyl, or C3cycloalkyl, wherein C1-3alkyl, C2-4alkenyl, C2-4alkynyl, C1-3haloalkyl, or C3cycloalkyl is optionally substituted with one or more groups selected from C1-2 alkoxy; Y is N or CR2, when Y is connected via double bond wherein R2 is hydrogen; Y is O, when Y is connected via single bond; and R3is selected fromfluorine, or C1 alkyl; R is hydrogen; R4 is selected from hydrogen, C1-3 alkyl, or deuterated C1alkyl, wherein C1-3alkyl is optionally substituted with amino or hydroxy; Z1, Z2, Z3, and Z4 are CR6; R6 is hydrogen; X is CR7; R7 is hydrogen; and n1 is 0.

[0063] In an embodiment of the present disclosure, there is provided a compound of Formula Ia,Formula Ia its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, stereoisomers, polymorphs, or pharmaceutically active derivatives thereof, wherein R1is selected from C1-3alkyl, C2-4alkenyl, C2-4alkynyl, C2-3haloalkyl, or C3 cycloalkyl, wherein C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-3 haloalkyl, or C3 cycloalkyl is optionally substituted with one or more groups selected from C1-2alkoxy; Y is N or CR2, wherein R2is hydrogen; R3is selected from fluorine, or C1alkyl; R is hydrogen; R4 is selected from hydrogen, C1-3 alkyl, or deuterated C1 alkyl, wherein C1-3alkyl is optionally substituted with amino or hydroxy; Z1, Z2, Z3, and Z4 are CR6; R6 is hydrogen; X is CR7; R7 is hydrogen; and n1 is 0.

[0064] In an embodiment of the present disclosure, there is provided a compound of Formula Ib,Formula Ib its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, stereoisomers, polymorphs, or pharmaceutically active derivatives thereof, wherein R1 is selected from C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-3 haloalkyl, or C3 cycloalkyl, wherein C1-3alkyl, C2-4alkenyl, C2-4alkynyl, C2-3haloalkyl, or C3cycloalkyl is optionally substituted with one or more groups selected from C1-2 alkoxy; Y is O; R3 is selected from fluorine, or C1 alkyl; R is hydrogen; R4 is selected from hydrogen, C1-3alkyl, or deuterated C1alkyl, wherein C1-3alkyl is optionally substituted with amino or hydroxy, Z1, Z2, Z3, and Z4are CR6; R6is hydrogen; X is CR7; R7 is hydrogen; and n1 is 0.

[0065] In an embodiment of the present disclosure, there is provided a compound as disclosed herein, wherein the compound is selected from a. Compound 1: 2-((5-fluoro-1-isopropyl-1H-indazol-6-yl) amino)-4-(((1S,2R)- 2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide;b. Compound 2: 2-((5-fluoro-1-isopropyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(2-hydroxyethyl) pyrimidine-5- carboxamide;c. Compound 3: 2-((5-fluoro-1-isopropyl-1H-indazol-6-yl) amino)-4-(((1S,2R)- 2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-methylpyrimidine-5- carboxamide;d. Compound 4: 2-((1-allyl-5-fluoro-1H-indazol-6-yl) amino)-4-((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide;e. Compound 5: 2-((1-ethyl-5-fluoro-1H-indazol-6-yl) amino)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide;f. Compound 6: 2-((1-cyclopropyl-5-fluoro-1H-indazol-6-yl) amino)-4-(((1S,2R)- 2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-methylpyrimidine-5- carboxamide;g. Compound 7: 2-((6-fluoro-3-isopropylbenzo[d]isoxazol-5-yl) amino)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-methylpyrimidine-5- carboxamide;h. Compound 8: 2-((6-fluoro-3-isopropylbenzo[d]isoxazol-5-yl) amino)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(2-hydroxyethyl) pyrimidine-5-carboxamide;i. Compound 92-((5-fluoro-1-propyl-1H-indazol-6-yl) amino)-4-((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-methylpyrimidine-5-carboxamide;j. Compound 10: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((1- isopropyl-5-methyl-1H-indazol-6-yl) amino)-N-(methyl-d3) pyrimidine-5- carboxamide;k. Compound 11: 2-((1-allyl-5-methyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5- carboxamide;l. Compound 12: 2-((1-(2,2-difluoroethyl)-5-methyl-1H-indazol-6-yl) amino)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide;m. Compound 13: 2-((1-(3,3-difluoropropyl)-5-methyl-1H-indazol-6-yl) amino)- 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide;n. Compound 14: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- (2-hydroxyethyl)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine- 5-carboxamide;o. Compound 15: 2-((1-allyl-5-methyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(2-hydroxyethyl) pyrimidine-5- carboxamide;p. Compound 16: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- (methyl-d3)-2-((5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-6-yl) amino) pyrimidine- 5-carboxamide;q. Compound 17: 2-((1-(2,2-difluoroethyl)-5-methyl-1H-indazol-6-yl) amino)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(2-hydroxyethyl) pyrimidine-5-carboxamide;r. Compound 18: 2-((1-ethyl-5-methyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-methylpyrimidine-5-carboxamide;s. Compound 19: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2- ((1-(2-methoxyethyl)-5-methyl-1H-indazol-6-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide;t. Compound 20: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(2- hydroxyethyl)-2-((5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide;u. Compound 21: N-(2-aminoethyl)-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine- 5-carboxamide;v. Compound 22: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- ((S)-1-hydroxypropan-2-yl)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide;w. Compound 23: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- ((R)-1-hydroxypropan-2-yl)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide;x. Compound 24: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- ((R)-2-hydroxypropyl)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide;y. Compound 25: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-((1-hydroxycyclopropyl)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide;z. Compound 26: 4-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)- 2-((3-isopropyl -6-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) amino)-N- (methyl-d3) pyrimidine-5-carboxamide;aa. Compound 27: 2-((1-((R)-but-3-yn-2-yl)-5-methyl-1H-indazol-6-yl) amino)-4-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl- d3) pyrimidine-5-carboxamide;bb. Compound 28: 2-((1-((R)-sec-butyl)-5-methyl-1H-indazol-6-yl) amino)-4- ((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide;cc. Compound 29: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((1-isopropyl-5-methyl-1H-benzo[d] [1,2,3] triazol-6-yl) amino)-N- (methyl-d3) pyrimidine-5-carboxamide; anddd. Compound 30: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(2-hydroxyethyl)-2-(1-isopropyl-5-methyl-1H-benzo[d][1,2,3] triazol- 6-yl) amino) pyrimidine-5-carboxamide.

[0066] In an embodiment of the present disclosure, there is provided a process of preparing the compound as disclosed herein, the process comprising: reacting a compound of Formula C with a compound selected from Formula D, Formula G or Formula K and an amine of R4NH2 which is optionally protected and optionally deprotecting to obtain the compound of Formula I,wherein R’ is selected from hydroxy, amino, C1-6alkoxy, or C1-6alkylamino; wherein ring A is an optionally substituted 5 to 8 membered heterocyclyl ring; R1 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl, wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl or C2-8 heterocyclyl; R3 is selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8heteroaryl; R is selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;R4 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated C1-6 alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8cycloalkyl, C2-8heterocyclyl, or C2-8 heteroaryl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, C1-6 alkoxy, C3-8 cycloalkyl, C1-6 aminoalkyl, or C1-6 haloalkyl, wherein C3-8 cycloalkyl is optionally further substituted with halogen or hydroxy; Z1, Z2, Z3, and Z4are independently selected from N or CR6; X is selected from O or CR7; R6is selected from hydrogen, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; R7 is selected from hydrogen, cyano, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; and n1 is 0 or 1.

[0067] In an embodiment of the present disclosure, there is provided a process of preparing the compound as disclosed herein, the process comprising: reacting a compound of Formula C with a compound selected from Formula D, Formula G or Formula K and an amine of R4NH2 which is optionally protected, in the presence of a base and a coupling reagent and optionally deprotecting to obtain the compound of Formula I.

[0068] In an embodiment of the present disclosure, there is provided a process as disclosed herein, wherein the base is selected from triethylamine, diisopropylethylamine, pyridine, sodium hydride, potassium tertiary butoxide, sodium carbonate, potassium carbonate, or combinations thereof.

[0069] In an embodiment of the present disclosure, there is provided a process as disclosed herein, wherein the coupling reagent is selected from HATU((Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), CDI (Carbonyldiimidazole), EDCI(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), or combinations thereof.

[0070] In an embodiment of the present disclosure, there is provided a compound as disclosed herein, for use in the manufacture of a medicament.

[0071] In an embodiment of the present disclosure, there is provided a compound as disclosed herein, wherein the compound is an inhibitor of Ataxia telangiectasia mutant (ATM) or DNA-dependent Protein Kinase (DNA-PK) or combinations thereof.

[0072] In an embodiment of the present disclosure, there is provided a compound as disclosed herein, for use in treating cancer mediated at least in part by ATM or DNA-PK or combinations thereof.

[0073] In an embodiment of the present disclosure, there is provided a compound as disclosed herein, for use in treating cancer selected from cancer of adrenal gland, brain, bladder, breast, bone, colon, oesophagus, head, gastric, kidney, liver, lung, muscle, neck, pancreas, prostate, skin, thyroid or white blood cells, mediated at least in part by ATM or DNA-PK or combinations thereof.

[0074] In an embodiment of the present disclosure, there is provided a combination comprising of compounds of Formula I as disclosed herein, with at least one additional therapeutic agent.

[0075] In an embodiment of the present disclosure, there is provided a combination comprising compounds of Formula Ia, Ib, and Ic as disclosed herein, with at least one additional therapeutic agent.

[0076] In an embodiment of the present disclosure, there is provided a combination as disclosed herein, wherein the additional therapeutic agent is selected from a radiotherapeutic agent, a chemotherapeutic agent, or an immune checkpoint inhibitor.

[0077] In an embodiment of the present disclosure, there is provided a combination as disclosed herein, wherein chemotherapeutic agent is selected from poly ADP ribose polymerase (PARP) inhibitor, topoisomerase inhibitors, CDK4 / 6 inhibitor, BCl2 (B-cell lymphoma-2) inhibitor, Bcl-XL (B-cell lymphoma-extra- large) inhibitor, Anti-estrogen, anti-progesterone, KRas inhibitor, Braf inhibitor, EGFR inhibitor, angiogenesis inhibitor, phosphoinositide 3-kinase inhibitor (PI3K) inhibitor, tyrosine kinase inhibitor, signal transducer and activator of transcription 3 (Stat-3) inhibitor, Protein kinase B (AKT) inhibitor, c-Jun N-terminal kinase (JNK1 / K2) inhibitors, hypoxia-inducible factor 1 alpha (HIF-1a) inhibitor,extracellular signal-regulated kinase (ERK) inhibitor, cisplatin, oxaplatin, or combinations thereof.

[0078] In an embodiment of the present disclosure, there is provided a combination as disclosed herein, wherein the immune checkpoint inhibitor is selected from a programmed death-1 (PD-1) inhibitor, programmed death-ligand 1 (PD-L1) inhibitor, anti-PD1 antibody, anti-PD-L1 antibody, cytotoxic T- lymphocyte-associated protein 4 (CTL4), inhibitor, anti-CTL4 antibody, T cell immunoglobulin and ITIM domain (TIGIT) inhibitor, ecto-nucleoside triphosphate diphosphohydrolase 1(E-NTPDase, CD39) inhibitor, ecto-5'- nucleotidase(Ecto5'NTase, CD79) inhibitor, Protein tyrosine phosphatases non- receptor type 1 / 2 (PTPN1 / 2) inhibitors or combinations thereof.

[0079] In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising the compound as disclosed herein, with at least one pharmaceutically acceptable excipient.

[0080] In an embodiment of the present disclosure, there is provided a pharmaceutical composition as disclosed herein, wherein the composition is in the form of powder, tablet, liquid, or emulsion.

[0081] In an embodiment of the present disclosure, there is provided a method of treating cancer in a subject, the method comprising administering the compound as disclosed herein, or the combination as disclosed herein, or the pharmaceutical composition as disclosed herein, to the subject in need thereof.

[0082] In an embodiment of the present disclosure, there is provided a method as disclosed herein, wherein the cancer is selected from cancer of adrenal gland, brain, bladder, breast, bone, colon, oesophagus, head, gastric, kidney, liver, lung, muscle, neck, pancreas, prostate, skin, thyroid or white blood cells.

[0083] In an embodiment of the present disclosure, there is provided a method of treating a disease or condition mediated by ATM or DNA-PK or combinations thereof in a subject, the method comprising administering the compound as disclosed herein, or the combination as disclosed herein, or the pharmaceutical composition as disclosed herein, to the subject in need thereof.

[0084] In an embodiment of the present disclosure, there is provided a method of treating a disease or condition as disclosed herein, wherein the disease or condition is selected from cancer of adrenal gland, brain, bladder, breast, bone, colon, oesophagus, head, gastric, kidney, liver, lung, muscle, neck, pancreas, prostate, skin, thyroid or white blood cells.

[0085] Although the subject matter has been described in considerable detail with reference to certain examples and implementations thereof, other implementations are possible. Abbreviations The following abbreviations are employed in the examples and elsewhere herein: TLC- thin layer chromatography; HPLC -high pressure liquid chromatography; MPLC - medium pressure liquid chromatography; NMR - nuclear magnetic resonance spectroscopy; DMSO - dimethylsulfoxide; CDCl3 - deuterated chloroform; MeOD -deuterated methanol, i.e. D3COD; MS - mass spectroscopy; ESP (or ES) - electrospray; EI - electron impact; APCI - atmospheric pressure chemical ionization; THF - tetrahydrofuran; TBAF - Tetra-n-butylammonium fluoride DIPEA - N,N-Diisopropylethylamine; DCM - dichloromethane; MeOH - methanol; DMF -dimethylformamide; EtOAc - ethyl acetate; HATU - Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium); CDI - Carbonyldiimidazole;tBuXPhos Pd G3 - ditert-butyl-[2-[2,4,6-tri(propan-2- yl)phenyl]phenyl]phosphane;methanesulfonic acid;palladium;2-phenylaniline DIAD - Diisopropyl azodicarboxylate NMP- N-methyl pyrrolidone EDCI - 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; LC / MS - liquid chromatography / mass spectrometry; h - hour(s); min is minute(s); d - day(s); MTBD - N-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene; EDTA – ethylene diamine tetra acetic acid; TFA - trifluoroacetic acid; Mg / ATP – Magnesium in Adenosine triphosphate; v / v - ratio of volume / volume; Boc - t-butoxycarbonyl; Cbz - benzyloxycarbonyl; Bz - benzoyl; Atm - atmospheric pressure; rt -room temperature; mg - milligram; g denotes gram; µL - microliter; mL - milliliter; L - liter; µM - micromolar; nM-Nanomolar; mM - millimolar; M denotes molar; DMAP- dimethyaminopyridine; TBDMS -tert-butyldimethylsilyl; N - normal; nm – nanometer;i.v-intravenous; p.o-per oral; Vdss-Volume of distribution steady state; CL-Total Systemic Clearance ; t1 / 2-Half-life; ND-Not Determined; %F-Percent bioavailability; C0-initial concentration at 0 time points post IV bolus / infusion administration; AUC0-t-area under curve from 0 to last quantifiable time point; and Tmax -Time for maximum concentration. EXAMPLES

[0086] The following examples provide the details about the synthesis, activities and applications of the compounds of the present disclosure. It should be understood that the following is representative only, and that the invention is not limited by the details set forth in these examples. Materials and methods:

[0087] Evaporations were carried out by rotary evaporation in vacuo and work up procedures were carried out after removal of residual solids by filtration; temperatures are quoted as °C; operations were carried out at room temperature, that is typically in the range 18 to 26 °C and without the exclusion of air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere; column chromatography (by the flash procedure) was used to purify compounds and was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated; in general, the course of reactions was followed by TLC, HPLC, or LC / MS and reaction times are given for illustration only; yields are given for illustration only and are not necessarily the maximum attainable; the structure of the end products of the invention was generally confirmed by NMR and mass spectral techniques. Proton magnetic resonance spectra were generally determined in DMSO d6 unless otherwise stated, using a Bruker DRX 300 spectrometer or a Bruker DRX-400 spectrometer, operating at a field strength of 300 MHz or 400 MHz, respectively. In cases where the NMR spectrum is complex, only diagnosticsignals are reported. Chemical shifts are reported in parts per million downfield from tetramethylsilane as an external standard (* scale) and peak multiplicities are shown thus: s, singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets; dm, doublet of multiplets; t, triplet, m, multiplet; br, broad. Fast atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected or using Agilent 1100 series LC / MS equipped with Sedex 75ELSD, and where appropriate, either positive ion data or negative ion data were collected. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present). Reverse Phase HPLC was carried out using YMC Pack ODS AQ (100x20 mmID, S 5Å particle size, 12 nm pore size) on Agilent instruments; each intermediate was purified to the standard required for the subsequent stage and was characterized in sufficient detail to confirm that the assigned structure was correct; purity was assessed by HPLC, TLC, or NMR and identity was determined by infrared spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate. General process for the preparation of the compounds of Formula (I) Synthesis of Intermediates: Synthesis of 5-fluoro-1-isopropyl-1H-indazol-6-amine (Formula D)Step-1: Synthesis of 5-fluoro-1-isopropyl-6-nitro-1H-indazole (I’a):

[0088] To a stirred solution of 5-fluoro-6-nitro-1H-indazole (CAS: 1360952-20-0, 1 g, 5.520 mmol) in DMF (10 mL) under nitrogen atmosphere wasadded potassium carbonate (1.52 g, 10.998 mmol) followed by 2-iodopropane (CAS: 75-30-9; 1.1 mL, 11.020 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4 (sodium sulphate). The solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by silica gel (100-200 mesh, 50 g packed, flow rate 30 mL / minutes & 254-280 nm wavelength) Biotage column chromatography using ethyl acetate (0-30%) in petroleum ether and the peak was eluted with 10% of ethyl acetate in petroleum ether concentrated to afford the desired compound I’a as a pale brown solid. Yield: (0.61 g, 49.59%); LC_MS: Calc. for C10H10FN3O2: 223.21; Obs.: 224.1;1H NMR (400 MHz, DMSO-d6): ^ 8.74 (d, J = 6.40 Hz, 1H), 8.29 (s, 1H), 7.95 (d, J = 11.20 Hz, 1H), 5.25-5.18 (m, 1H), 1.49 (d, J = 6.80 Hz, 6H). Step-2: Synthesis of 5-fluoro-1-isopropyl-1H-indazol-6-amine (I’):

[0089] To a stirred solution of 5-fluoro-1-isopropyl-6-nitro-1H-indazole (I’a) (0.5 g, 2.24 mmol) in ethanol (15 mL) under nitrogen atmosphere was added NH4Cl (ammonium chloride, 0.6 g, 11.217 mmol) in 15 mL of water followed by iron (0.626 g, 11.208 mmol). The reaction mixture was heated at 80°C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to get a brown color residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the pure compound (I’; Formula D) as a pale brown solid. The obtained product was as such taken for next step without furtherpurification. Yield: (0.46 g, crude). LC_MS: Calc. for C10H12FN3: 193.23; Obs.:194.4 [M++H];1H NMR (400 MHz, DMSO-d6): ^ 7.74 (s, 1H), 7.31 (d, J = 8.00 Hz, 1H), 6.75 (d, J = 8.00 Hz, 1H), 5.37 (br s, 2H), 4.67-4.62 (m, 1H), 1.42 (d, J = 8.00 Hz, 6H).Synthesis of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide (II) (Formula C)Step-1: Synthesis of Ethyl 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxylate (IIb):

[0090] To a stirred solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (CAS:51940-64-8, 5 g, 22.620 mmol) in IPA (isopropyl alcohol, 100 mL) was added DIPEA (11.8 mL, 67.861 mmol) followed by (1S,2R)-1-amino-2,3-dihydro- 1H-inden-2-ol (IIa) (3.37 g, 22.588 mmol) under nitrogen atmosphere. The resulting reaction mixture was heated at 110 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford crude product. The obtained crude product was purified by silica gel (230- 400 mesh, 100 g packed, flow rate 30 mL / minutes & 254-280 nm wavelength) Biotage column chromatography using ethyl acetate (0-100 %) in petroleum ether and the peak was eluted with 94% of ethyl acetate in petroleum ether concentrated to afford the desired compound (IIb) as an off-white solid. Yield: (7.2 g, 95%); LC_MS: Calc. for C16H16ClN3O3: 333.77; Obs.: 334.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.07 (br s, 1H), 8.71 (s, 1H), 7.28-7.18 (m, 4H), 5.54 (br s, 1H), 4.58-4.55 (m, 1H), 4.34-4.27 (m, 2H), 3.20-3.15 (m, 1H), 2.87 (d, J = 16.40 Hz, 2H), 1.65 (s, 3H). Step-2: Synthesis of 2-Chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1- yl) amino) pyrimidine-5-carboxylic acid (IIc):

[0091] To a stirred solution of ethyl 2-chloro-4-(((1S,2R)-2-hydroxy-2,3- dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxylate (IIb) (5 g, 14.980 mmol) in a mixture of THF (100 mL) and water (30 mL) was added LiOH.H2O (0.94 g, 22.402 mmol) at room temperature under nitrogen atmosphere, and the resulting reaction mixture was allowed to stir at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The aqueous layer was neutralized with 1.5N HCl (until pH=3) and extracted with ethyl acetate, (2 x 200 mL), the organic layer dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude product (IIc) as off-white solid. The crude product was taken to the next step without further purification. Yield: (4.1g, 90%). LC_MS: Calc. for C14H12ClN3O3: 305.72; Obs.: 306.1 [M+-H]. Step-3: Synthesis of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1- yl) amino) pyrimidine-5-carboxamide (II):

[0092] To a solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (1.0 g, 3.27 mmol) in THF (10 mL), were added DIPEA (1.42 mL, 8.818 mmol) followed by HATU (1.49 g, 3.93 mmol) and ammonium chloride (0.7 g, 13.1 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3solution (5 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layer was dried over Na2SO4 and concentrated under a vacuum to get the crude product as a pale-yellow solid. The obtained crude product was further triturated with petroleum ether, the pale-yellow solid thrown out was allowed to settle and the supernatant was decanted. The solid was dried under high vacuo, to get desired compound (II; Formula C) as a pale- yellow solid. The crude product was taken to the next step without further purification. Crude Yield: (1.2 g, 79.1%). LC_MS: Calc. for C14H13ClN4O2: 304.73; Obs.: 305.1 [M++H].Synthesis of N-(2-((tert-butyldimethylsilyl) oxy) ethyl)-2-chloro-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide (III)

[0093] To a solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (0.50 g, 1.64 mmol) in THF (10 mL) at 0 °C, under nitrogen atmosphere DIPEA (1.71 mL, 9.81 mmol), HATU (0.74 g, 1.96 mmol) followed by 2-((tert-butyldimethylsilyl)oxy)ethan-1-amine (CAS: 101711-55-1, 0.34 g, 1.96 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3 solution (10 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4and concentrated under vacuo to afford the crude product as an off-white solid (III). Yield: (0.35 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C22H31ClN4O3Si: 463.05; Obs.: 463.10 [M++H]. Synthesis of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-methylpyrimidine-5-carboxamide (IV)

[0094] To a solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (0.35 g, 1.145 mmol) in THF(20 mL), were added DIPEA (0.6 mL, 3.444 mmol) followed by HATU (0.57 g, 1.499 mmol) and methylamine hydrochloride (0.16 g, 2.369 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3 solution (5 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layer was dried over Na2SO4and concentrated under a vacuum to get the crude product as an off-white solid. The obtained crude product was further triturated with petroleum ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid was dried under high vacuo, to get desired compound (IV) as an off-white solid. The crude product was taken to the next step without further purification. Yield: (0.42 g, crude); LC_MS: Calc. for C15H15ClN4O2: 318.76; Obs.: 319.2 [M++H];1H NMR (300 MHz, DMSO-d6): δ 9.69 (d, J = 8.10 Hz, 1H), 8.70 (br s, 1H), 8.55 (d, J = 7.50 Hz, 1H), 7.27-7.18 (m, 4H), 5.49-5.40 (m, 1H), 4.55- 4.51 (m, 1H), 3.17-3.12 (m, 1H), 2.87-2.70 (m, 2H), 1.25 (br s, 3H). Synthesis of 1-allyl-5-fluoro-1H-indazol-6-amine (V ; Formula D)Step-1: Synthesis of 1-allyl-5-fluoro-6-nitro-1H-indazole (Va):

[0095] To a stirred solution of 5-fluoro-6-nitro-1H-indazole (CAS: 1360952-20-0, 2.0 g, 11.04 mmol) in DMF (20 mL) under nitrogen atmosphere was added potassium carbonate (3.05 g, 22.08 mmol) followed by allyl bromide (CAS: 106-95-6; 1.60 g, 13.25 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for an hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (2 x 50mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 9% ethyl acetate in petroleum ether to yield the title compound Va as a white solid; Yield: (0.95 g, 38.93%). LC_MS: Calc. for C10H8FN3O2: 221.19; Obs.: 222.1 [M+-H].1H NMR (300 MHz, DMSO-d6): ^ 8.69 (s, 1H), 8.31 (s, 1H), 7.98 (d, J = 11.10 Hz, 1H), 6.07-6.02 (m, 1H), 5.23 (m, 2H), 5.17 (d, J = 15.90 Hz, 2H). Step-2: Synthesis of 1-allyl-5-fluoro-1H-indazol-6-amine (V)

[0096] To a stirred solution of 1-allyl-5-fluoro-6-nitro-1H-indazole (Va) (0.95 g, 4.29 mmol) in ethanol (15 mL) under nitrogen atmosphere was added NH4Cl (1.15 g, 21.47 mmol) in 25 mL of water followed by iron (1.20 g, 21.47 mmol). The reaction mixture was heated at 80 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to get brown residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was dried to get the title product V as a pale-yellow liquid; Yield: (0.8 g, 94.72%). LC_MS: Calc. for C10H10FN3: 191.21; Obs.:192.1 [M++H].1H NMR (300 MHz, DMSO-d6): ^ 7.76 (s, 1H), 7.33 (d, J = 11.40 Hz, 1H), 6.67 (m, 1H), 6.01-5.96 (m, 1H), 5.42 (br s, 2H), 5.17 (m, 1H), 4.99 (d, J = 12.00 Hz, 1H), 4.86 (s, 2H). Synthesis of 1-ethyl-5-fluoro-1H-indazol-6-amine (VI; Formula D)Step-1: Synthesis of 1-ethyl-5-fluoro-6-nitro-1H-indazole (VIa):

[0097] To a stirred solution of 5-fluoro-6-nitro-1H-indazole (CAS:1360952-20-0, 1.0 g, 5.521 mmol) in DMF (10 mL) under nitrogenatmosphere was added potassium carbonate (1.526 g, 11.04 mmol) followed by iodoethane (1.292 g, 8.281 mmol) at room temperature. The resulting reaction mixture was heated at 80°C under a nitrogen atmosphere for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by silica gel (100-200 mesh, 25 g packed, flow rate 30 mL / minutes & 254-280 nm wavelength) Biotage column chromatography using ethyl acetate (0-30 %) in petroleum ether and the peak was eluted with 10 % of ethyl acetate in petroleum ether concentrated to afford the desired compound VIa as a yellow solid. Yield: (0.7 g, 59.8 %); LC_MS: Calc. for C9H8FN3O2: 209.18; Obs.: 210.1 [M++H]. Step-2: Synthesis of 1-ethyl-5-fluoro-1H-indazol-6-amine (VI):

[0098] To a stirred solution of 1-cyclopropyl-5-fluoro-6-nitro-1H-indazole (VIa) (0.7 g, 3.35 mmol) in ethanol (25 mL) under nitrogen atmosphere was added NH4Cl (0.895 g, 16.7 mmol) in 25 mL of water followed by iron (0.934 g, 16.7 mmol). The reaction mixture was heated at 80°C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to get a brown color residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the pure compound (VI) as a brown solid. Note: The product was as such taken for next step without further purification Yield: (0.550 g, 91.7%, crude). LC_MS: Calc. for C9H10FN3: 179.20; Obs.: 180.3 [M++H].1H NMR (400 MHz,DMSO-d6): δ 7.73 (s, 1H), 7.31 (d, J = 11.6 Hz, 1H), 6.72 (d, J = 8 Hz, 1H), 5.39(s, 2H), 4.22 (q, J = 7.20 Hz, 1H), 1.33 (t, J = 7.20 Hz, 1H). Synthesis of 1-cyclopropyl-5-fluoro-1H-indazol-6-amine (VII; Formula D)Step-1: Synthesis of 5-fluoro-1-isopropyl-6-nitro-1H-indazole (VIIa):

[0099] To a stirred solution of 5-fluoro-6-nitro-1H-indazole (CAS: CAS:1360952-20-0, 0.5g, 2.760 mmol) in DCE (10 mL) under nitrogen atmosphere was added sodium carbonate (0.585 g, 5.521 mmol) followed by cyclopropyl boronic acid (0.474 g, 5.521 mmol) at room temperature. The resulting reaction mixture was heated at 70°C and in hot condition 2,2'-bipyridine (0.431g, 2.760 mmol) and cupric acetate monohydrate (0.551g 2.760 mmol) and the mixture was stirred at 70 °C under a nitrogen atmosphere for 3 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with Saturated aqueous solution of ammonium chloride (20 mL), and extracted with dichloromethane (2 x 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by silica gel (100-200 mesh, 25 g packed, flow rate 30 mL / minutes & 254-280 nm wavelength) Biotage column chromatography using ethyl acetate (0-30%) in petroleum ether and the peak was eluted with 10 % of ethyl acetate in petroleum ether concentrated to afford the desired compound VIIa as a yellow solid. Yield: (6.1 g, 42.19%); LC_MS: Calc. for C10H8FN3O2: 221.19; Obs.: 221.0 [M++H]. Step-2: Synthesis of 1-cyclopropyl-5-fluoro-6-nitro-1H-indazole (VII): [000100] To a stirred solution of 1-cyclopropyl-5-fluoro-6-nitro-1H-indazole (VIIa) (0.5 g, 2.26 mmol) in ethanol (15 mL) under nitrogen atmosphere was added NH4Cl (0.605 g, 11.3 mmol) in 15 mL of water followed by iron (0.631 g, 11.3 mmol). The reaction mixture was heated at 80°C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (100 mL).The filtrate was concentrated in vacuo to get a brown color residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the pure compound (VII) as a pale-yellow liquid. Note: The product was as such taken for next step without further purification Yield: (0.3 g, crude). LC_MS: Calc. for C10H10FN3: 191.21; Obs.: 192.2 [M++H]. Synthesis of 6-fluoro-3-isopropylbenzo[d]isoxazol-5-amine (VIII; Formula G)Step 1: Preparation of 1-(5-bromo-2,4-difluorophenyl)-2-methylpropan-1-one (VIIIa) [000101] To a stirred solution of 5-dibromo-2,4-difluorobenzene (CAS: 473416-91-0; 2.0 g, 7.35 mmol) in diethyl ether (30 mL) was cooled at -78°C and added n- butyllithium (4.1 mL, 8.09 mmol, 2M in THF) slowly over a period of 10 minutes. The reaction was stirred at the same temperature for 30 minutes at same temperature and N-methoxy-N-methyl isobutyramide (1.16 g, 8.83 mmol) was added and the reaction mixture was stirred at the same temperature for another an hour. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered, and concentrated to provide the title compound VIIIa as pale-yellow liquid. (Yield: 1.0 g, 47%). 1H NMR (400 MHz, DMSO-D6): δ 8.07-8.03(m, 1H), 6.98-6.93 (m, 1H), 3.39-3.30 (m, 1H), 1.2 (d, J = 6.8 Hz, 6H). LCMS not optimized.Step 2: Preparation of (E)-1-(5-bromo-2,4-difluorophenyl)-2-methylpropan- 1-one oxime (VIIIb) [000102] To a stirred solution of 1-(5-bromo-2,4-difluorophenyl)-2- methylpropan-1-one VIIIa (0.9 g, 3.42 mmol) in ethanol: water (10 mL:10 mL). Hydroxylamine hydrochloride (0.28 g, 4.11 mmol) and sodium acetate (0.34 g, 4.11 mmol) were added, and the resulting mixture was stirred at 70 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered on celite pad, washed with DCM and the filtrate was concentrated. The crude material was purified by flash chromatography (silica gel, 230-400 mesh, 3% ethyl acetate: hexane) to provide the title compound VIIIb as a yellow liquid. (Yield: 0.7g, 70%). LC-MS Calculated for C10H10BrF2NO is 278.10; Observed: 280.0 [M++2]. Step 3: Preparation of 5-bromo-6-fluoro-3-isopropylbenzo[d]isoxazole (VIIIc) [000103] To a stirred solution of (E)-1-(5-bromo-2,4-difluorophenyl)-2- methylpropan-1-one oxime VIIIb (0.7 g, 2.52 mmol) in DMF (10 mL). Cesium carbonate (3.28 g, 10.1 mmol) was added, and the reaction mixture was stirred at 75 °C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched to water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude material was purified by column-chromatography (silica gel; 60-120 mesh, 50% of ethyl acetate: hexane) to provide the title compound VIIIc as a yellow-liquid. (Yield: 0.35g, 53%).1H NMR (400 MHz, DMSO-D6): δ 7.90 (d, J = 5.4 Hz, 1H), 6.98-6.93 (d, J = 8.0 Hz, 1H), 3.39-3.32 (m, 1H), 1.48 (d, J = 6.8 Hz, 6H). LC-MS Calculated for C10H9BrFNO is 258.09; Observed: 259.95 [M++2]. Step 4: Preparation of N-(6-fluoro-3-isopropylbenzo[d]isoxazol-5-yl)-1,1- diphenylmethanimine (VIIId) [000104] To a stirred solution of 5-bromo-6-fluoro-3- isopropylbenzo[d]isoxazole VIIIc (0.35 g, 1 Eq, 1.36 mmol) in 1,4-dioxane (6 mL). Diphenyl methenamine (0.27 g, 1.49 mmol) and sodium tert-butoxide (0.2 g, 2.03 mmol) andtBuXPhos Pd G3 (0.12 g, 0.14 mmol) were added, and the resulting mixture was stirred at 110°C for 16 h under N2 atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched to water (50 mL) andextracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated. The crude material was purified by column-chromatography (silica gel, 230-400 mesh, 30% ethyl acetate: hexane) to provide the title compound VIIId as a pale-yellow liquid. (Yield: 0.25 g, 51%).1H NMR (400 MHz, DMSO-D6): δ 7.80 (d, J = 7.6 Hz, 1H), 7.53-7.41 (m, 3H), 7.27-7.26 (m, 2H), 7.15-7.11 (m, 3H), 6.95-6.93 (d, J = 7.6 Hz, 1H), 3.24-3.21 (m, 1H), 1.33 (d, J = 6.8 Hz, 6H). LC-MS Calculated for C23H19FN2O is 358.42; Observed: 359.15 [M++1]. Step 5: Preparation of 6-fluoro-3-isopropylbenzo[d]isoxazol-5-amine (VIII) [000105] To a stirred solution of N-(6-fluoro-3-isopropylbenzo[d]isoxazol-5-yl)- 1,1-diphenylmethanimine VIIId (0.25 g, 0.70 mmol) in methanol (4 mL). Potassium acetate (0.17 g, 1.74 mmol) and hydroxylamine hydrochloride (0.1 g, 1.40 mmol) were added and stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched to water (50 mL) and extracted with DCM (50 mL x 2). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to provide the title compound VIII as a brown mass. (Yield: 0.09g, 60%). LC-MS Calculated for C10H11FN2O is 194.21; Observed: 194.15 [M++1]. Synthesis of 5-fluoro-1-propyl-1H-indazol-6-amine (IX; Formula D)Step-1: Synthesis of 5-fluoro-6-nitro-1-propyl-1H-indazole (IXa): [000106] To a stirred solution of 5-fluoro-6-nitro-1H-indazole (CAS: 1360952-20-0, 0.6 g, 3.31 mmol) in DMF (10 mL) under nitrogen atmosphere was added potassium carbonate (0.916 g, 6.63 mmol) followed by 1-bromopropane (CAS: 106-94-5; 0.53 g, 4.31 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for an hour. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 9% ethyl acetate in petroleum ether to yield the title compound IXa as a white solid; Yield: (0.29 g, 32.3%). LC_MS: Calc. for C10H10FN3O2: 223.21; Obs.: 223.1 [M+-H]. Step-2: Synthesis of 5-fluoro-1-propyl-1H-indazol-6-amine (IX) [000107] To a stirred solution of 5-fluoro-6-nitro-1-propyl-1H-indazole (IXa) (0.29 g, 1.30 mmol) in ethanol (10 mL) under nitrogen atmosphere was added NH4Cl (0.347 g, 6.50 mmol) in 15 mL of water followed by iron (0.363 g, 6.50 mmol). The reaction mixture was heated at 80 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to get brown residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was dried to get the title compound IX as a pale-yellow liquid; Yield: (0.2 g, 79.68%). LC_MS: Calc. for C10H12FN3: 193.23; Obs.: 194.1 [M++H].1H NMR (400 MHz, DMSO-d6): ^ 7.74 (s, 1H), 7.31 (d, J = 11.20 Hz, 1H), 6.72 (d, J = 7.20 Hz, 1H), 5.38 (br s, 2H), 4.09 (t, J = 6.80 Hz, 2H), 1.83-1.76 (m, 2H), 0.87 (t, J = 3.60 Hz, 3H). Synthesis of 1-isopropyl-5-methyl-1H-indazol-6-amine (X; Formula D) [000108]Step-1: Synthesis of 1-isopropyl 5-methyl-6-nitro-1H-indazole (Xa):[000109] To a stirred solution of 5-methyl-6-nitro-1H-indazole (CAS: 72521- 00-7, 5 g, 28.223 mmol) in DMF (50 mL) under nitrogen atmosphere was added potassium carbonate (7.8 g, 56.446 mmol) followed by 2-iodopropane (5.6 mL, 56.446 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2 x 200 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by silica gel (60-120 mesh, 100 g packed, flow rate 25 mL / minutes & 254- 280 nm wavelength) Biotage column chromatography using ethyl acetate (0-30%) in petroleum ether and the peak was eluted with 8% of ethyl acetate in petroleum ether concentrated to afford the desired compound Xa as a pale-yellow gummy mass. Yield: (2.28 g, 36.85%); LC_MS: Calc. for C11H13N3O2: 219.24; Obs.: 220.1;1H NMR (300 MHz, DMSO-d6): ^ 8.55 (s, 1H), 8.34 (s, 1H), 7.83 (s, 1H), 4.06- 3.99 (m, 1H), 2.53 (s, 3H), 1.58-1.19 (m, 6H). Step-2: Synthesis of 1-isopropyl-5-methyl-1H-indazol-6-amine (X): [000110] To a stirred solution of 1-isopropyl 5-methyl-6-nitro-1H-indazole (Xa) (2.2 g, 10.035 mmol) in ethanol (20 mL) under nitrogen atmosphere was added saturated aqueous NH4Cl solution (20 mL) followed by iron (2.8 g, 50.173 mmol). The reaction mixture was heated at 80°C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to get a brown color residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the pure compound (X) as a pale brown solid. Note: The product was as such taken for next step without further purification Yield: (1.45 g, 76.35%). LC_MS: Calc. for C11H15N3: 189.26; Obs.: 190.1 [M++H];1H NMR (400 MHz,DMSO-d6):^7.66 (s, 1H), 7.28 (s, 1H), 6.61 (s, 1H), 5.04 (br s, 2H), 4.66-4.61 (m, 1H), 2.14 (s, 3H), 1.44 (d, J = 6.40 Hz, 6H). Synthesis of N-(2-((tert-butyl dimethyl silyl) oxy) ethyl)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((1-isopropyl-5-methyl-1H- indazol-6-yl) amino) pyrimidine-5-carboxamide. (XI)Step-1: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((1- isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxylic acid (XIa): [000111] To a stirred solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3- dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (0.8 g, 2.616 mmol), 1-isopropyl-5-methyl-1H-indazol-6-amine (X) (0.495 g, 2.615 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.6 mL; 2 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product (XIa). Yield: (1.42 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C25H26N6O3: 458.52; Obs.: 459.2 [M++H]. Step-2: Synthesis of N-(2-((Tert-butyl dimethyl silyl) oxy) ethyl)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((1-isopropyl-5-methyl-1H- indazol-6-yl) amino) pyrimidine-5-carboxamide (XI)[000112] To a solution of 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5- carboxylic acid (XIa) (1.4 g, 3.053 mmol) in DMF (20 mL) at 0 °C, under nitrogen atmosphere DIPEA (3 mL, 0.02 mol) was added (until pH= 8). Then HATU (1.51 g, 3.969 mmol) followed by 2-(tert-butyldimethylsilyl) oxy) ethan-1-amine (0.8 g, 4.562 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3solution (30 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under vacuo to afford the crude product as yellow gummy mass (XI). Yield: (1.52 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C33H45N7O3Si: 615.85; Obs.: 616.3 [M++H]. Synthesis of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide (XII)[000113] To a solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (0.76 g, 2.289 mmol) in THF (20 mL), were added DIPEA (2.4 mL, 13.788 mmol) followed by HATU (1.13 g, 2.971 mmol) and Methan-d3-amine hydrochloride (0.24 g, 3.402 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3 solution (5 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layer wasdried over Na2SO4 and concentrated under a vacuum to get the crude product as an off-white solid. The obtained crude product was further triturated with petroleum ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid was dried under high vacuo, to get desired compound (XII) as an off-white solid. The crude product was taken to the next step without further purification. Yield: (0.64 g, crude); LC_MS: Calc. for C15H12D3ClN4O2: 321.78; Obs.: 322.3 [M++H];1H NMR (300 MHz, DMSO-d6): δ 8.83 (br s, 1H), 7.58 (s, 1H), 7.56-7.15 (m, 4H), 6.80-6.77 (m, 1H), 5.42-5.34 (m, 1H), 4.25-4.24 (m, 2H), 2.92-2.70 (m, 2H). Synthesis of 1-allyl-5-methyl-1H-indazol-6-amine (XIII; Formula D)Step-1: Synthesis of 1-allyl-5-methyl-6-nitro-1H-indazole (XIIIa): [000114] To a stirred solution of 5-methyl-6-nitro-1H-indazole (CAS: 72521- 00-7, 1.50 g, 8.46 mmol) in DMF (30 mL) under nitrogen atmosphere was added Potassium carbonate (2.34 g, 16.93 mmol) followed by allyl bromide (CAS: 106- 95-6; 1.53 g, 12.70 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 13% ethyl acetate in petroleum ether to yield the title compound XIIIa as a pale-brown solid; Yield: (0.83 g, 45.3%). LC_MS: Calc. for C11H11N3O2: 217.23; Obs.: 218.0 [M++H].1H NMR (300 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.23 (s, 1H), 8.23 (s, 1H), 6.08-6.04 (m, 1H), 5.19 (br s, 1H), 5.20 (br s, 1H), 5.06 (d, J = 11.40 Hz, 2H), 2.55 (br s, 3H).Step-2: Synthesis of 1-allyl-5-methyl-1H-indazol-6-amine (XIII) [000115] To a stirred solution of 1-allyl-5-methyl-6-nitro-1H-indazole (XIIIa) (0.82 g, 3.77 mmol) in ethanol (20 mL) under nitrogen atmosphere was added NH4Cl (0.20 g, 3.77 mmol) in 20 mL of water followed by iron (1.054 g, 18.87 mmol). The reaction mixture was heated at 80 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (70 mL). The filtrate was concentrated in vacuo to get brown residue. The residue was diluted with water (70 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the title compound XIII as a pale brown solid; Yield: (0.3 g, 43.90%). LC_MS: Calc. for C11H13N3:187.25; Obs.:188.1 [M++H].1H NMR (400 MHz, DMSO-d6): δ 7.68 (s, 1H), 7.28 (s, 1H), 6.55 (s, 1H), 6.00-5.97 (m, 1H), 5.14-5.11 (m, 3H), 4.95 (d, J = 1.60 Hz, 1H), 4.83-4.81 (m, 2H), 2.14 (s, 3H). Synthesis of 1-(2,2-difluoroethyl)-5-methyl-1H-indazol-6-amine (XIV; Formula D)Step-1: Synthesis of 1-(2,2-difluoroethyl)-5-methyl-6-nitro-1H-indazole (XIVa): [000116] To a stirred solution of 5-methyl-6-nitro-1H-indazole (CAS: 72521- 00-7; 1.0 g, 5.644 mmol) in DMF (20 mL) under nitrogen atmosphere was added Potassium carbonate (1.560 g, 11.289 mmol) followed by 2-bromo-1,1- difluoroethane (1.226 g, 8.466 mmol) at room temperature. The resulting reaction mixture was heated at 90°C under a nitrogen atmosphere for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extractedwith ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by silica gel (100-200 mesh, 25 g packed, flow rate 30 mL / minutes & 254-280 nm wavelength) Biotage column chromatography using ethyl acetate (0-30%) in petroleum ether and the peak was eluted with 10 % of ethyl acetate in petroleum ether concentrated to afford the desired compound XIVa as a yellow solid. Yield: (1.3 g, 93%); LC_MS: Calc. for C10H9F2N3O2: 241.20; Obs.: 242.1 [M++H]. Step-2: Synthesis of 1-(2,2-difluoroethyl)-5-methyl-1H-indazol-6-amine (XIV): [000117] To a stirred solution of 1-(2,2-difluoroethyl)-5-methyl-6-nitro-1H- indazole (XIVa) (1.30 g, 5.389 mmol) in ethanol (20 mL) under nitrogen atmosphere was added NH4Cl (1.73 g, 32.33 mmol) in 25 mL of water followed by iron (0.903 g, 16.16 mmol). The reaction mixture was heated at 80°C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to get a brown color residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the pure compound (XIV) as a brown solid. Note: The product was as such taken for next step without further purification Yield: (1.0 g, 90.0%, crude). LC_MS: Calc. for C10H11F2N3: 211.22; Obs.: 212.2 [M++H]. Synthesis of 1-(3,3-difluoropropyl)-5-methyl-1H-indazol-6-amine (XV; Formula D)Step-1: Synthesis of 1-(3,3-difluoropropyl)-5-methyl-6-nitro-1H-indazole (XVa):[000118] To a stirred solution of 5-methyl-6-nitro-1H-indazole (CAS: 72521- 00-7, 50 g, 8.466 mmol) in THF (20 mL) under nitrogen atmosphere was added triphenylphosphine (2.664 g, 10.160 mmol) followed by DIAD (2.14 mL, 11.007 mmol) and 3,3-difluoropropan-1-ol (0.813 g, 8.466 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by silica gel (100- 200 mesh, 25 g packed, flow rate 30 mL / minutes & 254-280 nm wavelength) Biotage column chromatography using ethyl acetate (0-50%) in petroleum ether and the peak was eluted with 25% of ethyl acetate in petroleum ether concentrated to afford the desired compound XVa as a pale-yellow solid. Yield: (1.4 g, 60%); LC_MS: Calc. for C11H11F2N3O2: 255.22; Obs.: 254.9 [M+-H]. Step-2: Synthesis of 1-(3,3-difluoropropyl)-5-methyl-1H-indazol-6-amine (XV): [000119] To a stirred solution of 1-(3,3-difluoropropyl)-5-methyl-6-nitro-1H- indazole (XVa) (1.40 g, 5.485 mmol) in ethanol (20 mL) under nitrogen atmosphere was added NH4Cl (1.761 g, 32.913 mmol) in 25 mL of water followed by iron (0.919 g, 16.456 mmol). The reaction mixture was heated at 80°C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to get a brown color residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the pure compound (XV) as a yellow solid. Note: The product was as such taken for next step without further purification Yield: (1.0 g, 80.0%, crude). LC_MS: Calc. for C11H13F2N3: 225.24; Obs.: 226.1 [M++H].Synthesis of 2-((1-allyl-5-methyl-1H-indazol-6-yl) amino)-N-(2-((tert- butyldimethylsilyl) oxy) ethyl)-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden- 1-yl) amino) pyrimidine-5-carboxamide (XVI)[000120] Step-1: Synthesis of 2-((1-allyl-5-methyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine- 5-carboxylic acid (XVIa): [000121] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (0.17 g, 0.556 mmol), 1- allyl-5-methyl-1H-indazol-6-amine (X) (0.104 g, 0.555 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.2 mL, 1.112 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product (XVIa). Yield: (0.25 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C25H24N6O3: 456.51; Obs.: 455.2 [M+-H]. Step-2: Synthesis of 2-((1-allyl-5-methyl-1H-indazol-6-yl) amino)-N-(2-((tert- butyldimethylsilyl) oxy) ethyl)-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden- 1-yl) amino) pyrimidine-5-carboxamide (XVI): [000122] To a solution of 2-((1-allyl-5-methyl-1H-indazol-6-yl) amino)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxylic acid (XVIa) (0.25 g, 0.547 mmol) in DMF (6 mL) at 0 °C, under nitrogen atmosphere DIPEA (0.5 mL, 2.87 mmol) was added (until pH= 8). Then HATU(0.25 g, 0.657 mmol) followed by 2-(tert-butyl dimethyl silyl) oxy) ethan-1-amine (0.12 g, 0.684 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3solution (10 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under vacuo to afford the crude product as brown viscous liquid (XVI). Yield: (0.3 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C33H43N7O3Si: 613.84; Obs.: 613.3 [M+-H]. Synthesis of 5-methyl-1- 2-yn-1-yl)-1H-indazol-6-amine (XVII; FormulaD)Step-1: Synthesis of 5-methyl-6-nitro-1-(prop-2-yn-1-yl)-1H-indazole (XVIIa): [000123] To a stirred solution of 5-methyl-6-nitro-1H-indazole (CAS 72521-00-7, 1.00 g, 5.644 mmol) in DMF (10 mL) under nitrogen atmosphere was added potassium carbonate (1.56 g, 11.28 mmol) followed by 3-bromoprop-1-yne (0.671 g, 5.644 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (2 × 100 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 30 % ethyl acetate in petroleum ether to yield the title compound XVIIa as a pale-yellow solid; Yield:(0.6 g, 50%).1H NMR (400 MHz, DMSO-d6): δ 8.54 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 5.46 (s, 2H), 3.45-3.44 (m, 1H), 2.56 (s, 3H). Step-2: Synthesis of 5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-6-amine (XVII) [000124] To a stirred solution of 5-methyl-6-nitro-1-(prop-2-yn-1-yl)-1H- indazole (XVIIa) (0.600 g, 2.78 mmol) in ethanol (20 mL) under nitrogen atmosphere was added NH4Cl (0.894 g, 16.73 mmol) in 6.7 mL of water followed by iron (0.467 g, 8.364 mmol). The reaction mixture was heated at 80 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a Celite bed and washed with ethyl acetate (70 mL). The filtrate was concentrated in vacuo to get brown residue. The residue was diluted with water (70 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the title compound XVII as a pale brown solid; Yield: (0.4 g, 76%). LC_MS: Calc. for C11H11N3: 185.23; Obs.: 186.2 [M++H]. Synthesis of N-(2-((tert-butyldimethylsilyl) oxy) ethyl)-2-((1-(2,2- difluoroethyl)-5-methyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2-hydroxy-2,3- dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide (XVIII)Step-1: Synthesis of 2-((1-(2,2-Difluoroethyl)-5-methyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine- 5-carboxylic acid (XVIIIa): [000125] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (0.25 g, 0.817 mmol), 1-(2,2-difluoroethyl)-5-methyl-1H-indazol-6-amine (XIV) (0.17 g, 0.817 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.4 mL; 2 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 1.5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature, diluted with water (5 mL), neutralized by triethylamine, and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product (XVIIIa) as a brown liquid; Yield: (0.28 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C24H22F2N6O3: 480.48; Obs.: 481.4 [M++H]. Step-2: Synthesis of N-(2-((tert-butyldimethylsilyl) oxy) ethyl)-2-((1-(2,2- difluoroethyl)-5-methyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2-hydroxy-2,3- dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide (XVIII): [000126] To a solution of 2-((1-(2,2-Difluoroethyl)-5-methyl-1H-indazol-6- yl) amino)-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine- 5-carboxylic acid (XVIIIa) (0.3 g, 0.624 mmol) in DMF (10 mL) at 0 °C, under nitrogen atmosphere DIPEA (0.5 mL, 3 mmol) was added (until pH=8). Then HATU (0.31 g, 0.815 mmol) followed by 2-((tert-butyldimethylsilyl) oxy) ethan-1- amine (0.11 g, 0.627 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3solution (30 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under vacuo to afford the crude product as brown gummy mass (XVIII); Yield: (0.72 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C32H41F2N7O3Si: 637.81; Obs.: 638.3 [M++H]. Synthesis of 1-ethyl-5-methyl-1H-indazol-6-amine (XIX; Formula D)Step-1: Synthesis of 1-ethyl-5-methyl-6-nitro-1H-indazole (XIXa): [000127] To a stirred solution of 5-methyl-6-nitro-1H-indazole (CAS 72521- 00-7, 2.00 g, 11.29 mmol) DMF (20 mL) under nitrogen atmosphere was added potassium carbonate (3.12 g, 22.58 mmol) followed by iodoethane (1.0 mL, 11.30 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (2 × 100 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 13% ethyl acetate in petroleum ether to yield the title compound XIXa as an off-white solid; Yield: (1.30 g, 56.0%). LC_MS: Calc. for C10H11N3O2: 205.22; Obs.: 206.1 [M++H].1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.19 (s, 1H), 7.84 (s, 1H), 4.53 (q, J = 7.20 Hz, 2H), 2.52 (s, 3H), 1.49 (q, J = 7.20 Hz, 3H). Step-2: Synthesis of 1-ethyl-5-methyl-1H-indazol-6-amine (XIX) [000128] To a stirred solution of 1-ethyl-5-methyl-6-nitro-1H-indazole (XIXa) (1.30 g, 6.33 mmol) in ethanol (10 mL) under nitrogen atmosphere was added NH4Cl (2.03 g, 38.00 mmol) in 15 mL of water followed by iron (1.06 g, 19.00 mmol). The reaction mixture was heated at 80 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a Celite bed and washed with ethyl acetate (70 mL). The filtrate was concentrated in vacuo to get brown residue. The residue was diluted with water (70 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to getthe title compound XIX as a brown liquid; Yield: (1.00 g, 90.0 %). LC_MS: Calc. for C10H13N3: 175.24; Obs.: 176.1 [M++H].1H NMR (400 MHz, DMSO-d6): 1H- NMR (400 MHz, DMSO-d6): δ 7.65 (s, 1H), 7.26 (s, 1H), 6.59 (s, 1H), 5.07 (s, 2H), 4.19 (q, J = 7.20 Hz, 2H), 2.14 (s, 3H), 1.32 (t, J = 7.20 Hz, 3H). Synthesis of 1-(2-methoxyethyl)-5-methyl-1H-indazol-6-amine. (XX; Formula D)Step-1: Synthesis of 1-(2-methoxyethyl)-5-methyl-6-nitro-1H-indazole (XXa): [000129] To a stirred solution of 5-methyl-6-nitro-1H-indazole (CAS: 72521- 00-7, 2.00 g, 11.289 mmol) in DMF (20 mL) under nitrogen atmosphere was added potassium carbonate (3.12 g, 22.578 mmol) followed by 1-bromo-2- methoxyethane (1.569 g, 11.289 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by silica gel (100-200 mesh, 50 g packed, flow rate 30 mL / minutes & 254- 280 nm wavelength) Biotage column chromatography using ethyl acetate (0-30%) in petroleum ether and the peak was eluted with 15% of ethyl acetate in petroleum ether concentrated to afford the desired compound XXa as a yellow solid. Yield: (1.4 g, 52%); LC_MS: Calc. for C11H13N3O3: 235.24; Obs.: 236.1;1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.20 (s, 1H), 7.83 (s, 1H), 4.67 (t, J = 7.20 Hz, 2H), 3.75 (t, J = 6.80 Hz, 2H), 3.18 (s, 3H), 2.54-2.50 (m, 3H). Step-2: Synthesis of 1-(2-methoxyethyl)-5-methyl-1H-indazol-6-amine (XX): [000130] To a stirred solution of 1-(2-methoxyethyl)-5-methyl-6-nitro-1H- indazole (XXa) (1.40 g, 5.95 mmol) in ethanol (20 mL) under nitrogen atmospherewas added NH4Cl (1.910 g, 35.708 mmol) in 6.7 mL of water followed by iron (0. 997 g, 17.854 mmol). The reaction mixture was heated at 80°C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to get a brown color residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the pure compound (XX) as a pale brown solid. Note: The product was as such taken for next step without further purification Yield: (1.1 g, 90%). LC_MS: Calc. for C11H15N3O: 205.26; Obs.: 206.2 [M++H];1H NMR (400 MHz, DMSO-d6): ^ 7.67 (s, 1H), 7.25 (s, 1H), 6.60 (s, 1H), 5.07 (s, 2H), 4.30 (t, J = 5.20 Hz, 2H), 3.69 (t, J = 5.60 Hz, 2H), 3.19 (s, 3H), 2.14 (s, 3H). Synthesis of N-(2-((tert-butyldimethylsilyl) oxy) ethyl)-4-(((1S,2R)-2-hydroxy- 2,3-dihydro-1H-inden-1-yl) amino)-2-((5-methyl-1-(prop-2-yn-1-yl)-1H- indazol-6-yl) amino) pyrimidine-5-carboxamide. (XXI; Formula Ia)Step-1: Synthesis of 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-6-yl) amino) pyrimidine- 5-carboxylic acid (XXIa): [000131] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (0.2 g, 0.654 mmol), 5- methyl-1-(prop-2-yn-1-yl)-1H-indazol-6-amine (XVII) (0.12 g, 0.647 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.2 mL; 0.8 mmol) at roomtemperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature, diluted with water (5 mL), neutralized by triethylamine, and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product (XXIa) as a brown liquid; Yield: (0.27 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C25H22N6O3: 454.49; Obs.: 455.2 [M++H]. Step-2: Synthesis of N-(2-((Tert-butyldimethylsilyl) oxy) ethyl)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((5-methyl-1-(prop-2-yn-1-yl)- 1H-indazol-6-yl) amino) pyrimidine-5-carboxamide (XXI): [000132] To a solution of 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-6-yl) amino) pyrimidine-5- carboxylic acid (XXIa) (0.25 g, 0.550 mmol) in DMF (5 mL) & THF (5 mL) at 0 °C, under nitrogen atmosphere DIPEA (0.8 mL, 5 mmol) was added (until pH=8). Then HATU (0.27 g, 0.710 mmol) followed by 2-((tert-butyldimethylsilyl)oxy) ethan-1-amine (0.144 g, 0.821 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3 solution (30 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4and concentrated under vacuo to afford the crude product as yellow gummy mass (XXI); Yield: (0.43 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C33H41N7O3Si: 611.82; Obs.: 612.4 [M++H]. Synthesis of tert-butyl (2-(2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxamido) ethyl) carbamate (XXII)[000133] To a solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (0.25 g, 0.817 mmol) in THF (20 mL) at 0 °C, under nitrogen atmosphere DIPEA (0.5 mL, 2.87 mmol), HATU (0.4 g, 1.051 mmol) followed by Tert-butyl (2-aminoethyl)carbamate (0.16 g, 0.998 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3solution (10 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under vacuo to afford the crude product as an off-white solid (XXII). Yield: (0.39 g, crude). The obtained crude product was as such taken for next step without purification. LC_MS: Calc. for C21H26ClN5O4: 447.92; Obs.: 448.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.63 (br s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 7.25-7.13 (m, 5H), 5.50-5.41 (m, 2H), 4.54-4.53 (m, 1H), 3.23-3.09 (m, 6H), 1.37 (br s, 9H). Synthesis of (S)-1-((tert-butyldimethylsilyl) oxy) propan-2-amine (XXIII)[000134] To a solution of (S)-2-aminopropan-1-ol (CAS 2749-11-3; 1.00 g, 13.313 mmol) in DCM (30 mL) at 0 °C, under nitrogen atmosphere imidazole (1.18 g, 17.332 mmol) followed by tert-butyl dimethyl chlorosilane (3 g, 19.904 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water andextracted with dichloromethane (100 mL x 2). The combined organic layer was dried over Na2SO4and concentrated under vacuo to afford the crude product as colorless liquid (XXIII). Yield: (0.89 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C9H23NOSi: 189.37; Obs.: 190.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 3.33-3.30 (m, 2H), 2.82-2.77 (m, 1H), 0.92 (d, J = 6.40 Hz, 3H), 1.76 (br s, 2H), 0.88-0.85 (m, 9H), 0.03 (d, J = 7.60 Hz, 6H). Synthesis of N-((S)-1-((tert-butyldimethylsilyl) oxy) propan-2-yl)-2-chloro-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5- carboxamide (XXIV)[000135] To a solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (0.15 g, 0.490 mmol) in THF (20 mL) at 0 °C, under nitrogen atmosphere DIPEA (0.4 mL, 2 mmol), HATU (0.24 g, 0.631 mmol) followed by (S)-1-((tert-butyldimethylsilyl) oxy)propan-2-amine (XXIII) (0.16 g, 0.739 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3 solution (10 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4and concentrated under vacuo to afford the crude product as yellow gummy mass (XXIV). Yield: (0.17 g, crude). Note: The crude product was as such taken for next step without purification.LC_MS: Calc. for C23H33ClN4O3Si: 477.08; Obs.: 475.1 [M+-H].Synthesis of (R)-1-((tert-butyl dimethyl silyl) oxy) propan-2-amine (XXV)[000136] To a solution of (R)-2-aminopropan-1-ol (CAS 35320-23-1; 1.00 g, 13.313 mmol) in DCM (30 mL) at 0 °C, under nitrogen atmosphere imidazole (1.18 g, 17.332 mmol) followed by tert-Butyl dimethyl chlorosilane (3 g, 19.904 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane (100 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under vacuo to afford the crude product as colourless liquid (XXV). Yield: (1.34 g, crude). Note: The crude product was as such taken for next step without purification.1H NMR (300 MHz, DMSO-d6): δ 3.32-3.26 (m, 2H), 2.83-2.72 (m, 1H), 0.91-0.84 (m, 14H), 0.03 (m, 6H). Synthesis of N-((R)-1-((tert-butyl dimethyl silyl) oxy) propan-2-yl)-2-chloro-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5- carboxamide (XXVI[000137] To a solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxylic acid (IIc) (0.3 g, 0.981 mmol) in THF (20 mL) at 0 °C, under nitrogen atmosphere DIPEA (0.5 mL, 2.870 mmol), HATU (0.485 g, 1.275 mmol) followed by (R)-1-((tert-butyl dimethyl silyl)oxy)propan-2- amine (XXV) (0.37 g, 1.953 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3solution (10 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4and concentrated under vacuo to afford the crude product as yellow gummy mass (XXVI). Yield: (0.28 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc. for C23H33ClN4O3Si: 477.08; Obs.: 475.1 [M+-H]. Synthesis of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-((R)-2-hydroxypropyl) pyrimidine-5-carboxamide (XXVII)[000138] To a solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxylic acid IIc (0.20 g, 0.65 mmol)) and (R)- 1-aminopropan-2-ol (0.05 mL, 0.65 mmol) in THF (10 mL), were added DIPEA (0.3 mL, 1.64 mmol) followed by HATU (0.29 g, 0.79 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3solution (30 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layer was dried over Na2SO4 and concentrated under a vacuum to get the crude product as off- white solid (XXVII). Yield: (0.20 g, Crude). LC_MS: Calc. for C17H19ClN4O3: 362.81, Obs.: 363.1 [M++H]. Synthesis of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-((1-hydroxycyclopropyl) methyl) pyrimidine-5-carboxamide (XXVIII)[000139] To a stirred solution of 2-chloro-4-(1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino) pyrimidine-5-carboxylic acid IIc (0.3 g, 1.0 mmol) and HATU (0.6 g, 1 mmol) in THF (15 mL), 1-(amino methyl) cyclopropan-1-ol (0.09 g, 1 mmol) was added followed by addition of triethylamine (0.4 mL, 3 mmol) and the resulting mixture was stirred at an ambient temperature for 16 h. The reaction progress was monitored by TLC. After completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, 230-400 mesh, 1% MeOH:DCM) to provide the title compound 22-chloro-4-((1S,2R)-2-hydroxy-2,3- dihydro-1H-inden-1-yl) amino)-N-((1-hydroxycyclopropyl) methyl) pyrimidine-5- carboxamide XXVIII as an off- white solid. Yield (0.25 g, 70%); LC-MS Calculated for C18H19ClN4O3is 374.83; Observed: 375.10 [M++1]. Synthesis of 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((3- isopropyl-6-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) amino) pyrimidine-5-carboxylic acid (XXIX)Step 1: Synthesis of 6-methylbenzo[d]oxazol-2(3H)-one (XXIXa) [000140] To a stirred solution of 2-amino-5-methylphenol (CAS: 2835-98-5, 0.75 g, 6.09 mmol) in DCM (50 mL), bis(trichloromethyl) carbonate (0.54 g, 0.3eq, 1.83 mmol) was added followed by addition of triethylamine (5.1 mL, 6 eq, 36.5 mmol) at 0°C and the resulting reaction mixture was stirred at room temperature for 1 h. Then the progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into ice water (50 ml) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to provide the desired product 6- methylbenzo[d]oxazol-2(3H)-one XXIXa as yellow solid. Yield (0.24 g, 99%); LC- MS Calculated for C8H7NO2 is 149.15; Observed: 150.11 [M++1]. Step 2: Synthesis of 3-isopropyl-6-methylbenzo[d]oxazol-2(3H)-one (XXIXb) [000141] To a stirred solution of 6-methylbenzo[d]oxazol-2(3H)-one XXIXa (1.1 g, 1 eq, 7.4 mmol) in DMF (3 mL), NaH (0.35 g, 60% wt, 1.2 eq, 8.9 mmol) was added at 0 °C and stirred for 20 min at same temperature followed by addition of isopropyl iodide (CAS:75-30-9, 1.9 g, 1.5 eq 11.0 mmol). The resulting reaction mixture was stirred at 0 °C for 2 hours. The resulting reaction mixture was monitored by TLC. After completion, the reaction mixture was poured into icewater (50 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 230-400 mesh, 10% Ethyl acetate: hexane) to provide the desired product XXIXb 3-isopropyl-6- methylbenzo[d]oxazol-2(3H)-one as a pale-yellow solid. Yield (1.1 g, 78%); LC- MS Calculated for C11H13NO2 is 191.23; Observed: 191.95 [M++1].1HNMR (400 MHz, CDCl3): δ 7.02-6.94 (m, 3H), 4.56-4.50 (m, 2H), 2.65 (s, 3H), 1.52 (d, J = 6.8 Hz, 6H). Step 3: Synthesis of 3-isopropyl-6-methyl-5-nitrobenzo[d]oxazol-2(3H)-one (XXIXc) [000142] To a stirred solution of 3-isopropyl-6-methylbenzo[d]oxazol-2(3H)- one. XXIXb (1.1 g, 5.8 mmol) in TFA (30 mL) sodium nitrite (0.40 g, 5.8 mmol) was added gradually at ice-cold temperature and the resulting reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion, the mixture was poured into ice water, and the precipitated solid was collected by filtration and washed with water. The crude material was purified by flash chromatography (silica gel, 230-400 mesh, 30% Ethyl acetate: hexane) to provide the desired product 3-isopropyl-6-methyl-5- nitrobenzo[d]oxazol-2(3H)-one XXIXc as pale yellow solid. Yield (1.1 g, 81%); 1HNMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.26 (s, 1H), 7.61 (s, 1H), 7.05-6.98 (m, 2H), 6.07 (s, 1H), 4.59-4.52 (m, 2H), 2.65 (s, 3H), 2.38 (s, 3H), 1.41 (d, J = 6.8 Hz, 6H). Step 4: Synthesis of 5-amino-3-isopropyl-6-methylbenzo[d]oxazol-2(3H)-one (XXIXd) [000143] To a stirred solution of 3-isopropyl-6-methyl-5- nitrobenzo[d]oxazol-2(3H)-one XXIXc (1.1 g, 4.7 mmol) in methanol (10 mL). Palladium on carbon (0.1 g, 0.93 mmol) was added slowly under nitrogen atmosphere and stirred under hydrogen atmosphere at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the mixturewas filtered on celite pad, washed with methanol and the filtrate was concentrated. The crude material was purified by flash chromatography (silica gel, 230-400 mesh, 30% Ethyl acetate: hexane) to provide the desired product XXIXd 5-amino-3- isopropyl-6-methylbenzo[d]oxazol-2(3H)-one as a pale pink solid. Yield (0.7 g, 70%); LC-MS Calculated for C11H14N2O2is 206.25; Observed: 207.15[M++1]. 1HNMR (400 MHz, DMSO-d6): δ 6.91 (s, 1H), 6.64 (s, 1H), 4.77 (s, 2H), 4.39- 4.32 (m, 1H), 2.38 (s, 2H), 1.41 (m, 9H). Step 5: Synthesis of 4-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)- 2-((3-isopropyl-6-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) amino) pyrimidine-5-carboxylic acid (XXIX) [000144] In a 10 mL microwave vial, to a stirred solution of 2-chloro-4- (1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxylic acid IIc (0.25 g, 0.82 mmol) in NMP (2 mL), 5-amino-3-isopropyl-6- methylbenzo[d]oxazol-2(3H)-one XXIXd (0.19 g, 0.90 mmol) was added followed by addition of HCl in dioxane (0.1 mL, 1.23 mmol, 4N) and the reaction mixture was subjected to microwave irradiation at 120 °C for 1 h. After completion, the mixture was cooled to room temperature and quenched with water (20 mL) and filtered the solid. The crude material was purified by flash chromatography (silica gel, 230-400 mesh, 10% MeOH: DCM) to provide the title product XXIX 4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-2-((3-isopropyl-6- methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)amino)pyrimidine-5-carboxylic acid as an off- white solid. Yield (0.08 g, 21%); LC-MS Calculated for C25H25N5O5is 475.51; Observed: 476.15[M++1]. Synthesis of (R)-1-(but-3-yn-2-yl)-5-methyl-1H-indazol-6-amine (XXX)Step-1: Synthesis (R)-1-(but-3-yn-2-yl)-5-methyl-6-nitro-1H-indazole (XXXa): [000145] To a stirred solution of 5-methyl-6-nitro-1H-indazole (CAS:72521- 00-7, 2.00 g, 11.29 mmol) and (S)-but-3-yn-2-ol (CAS: 2614-69-4, 0.94 g, 13.55 mmol) in THF (20mL), triphenylphosphine (3.55 g, 13.55 mmol) was added followed by addition of DIAD (2.634 mL, 13.55 mmol) at 0 °C. The resulting reaction mixture was stirred for 25 °C for 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The crude material was purified by silica gel Biotage column chromatography by eluting with 10% ethyl acetate in petroleum ether to yield the desired product XXXa as a yellow solid; Yield: (1.4 g, 53%). LC_MS: Calc. for C12H11N3O2: 229.24; Obs.: 230.2[M++H].1H NMR (400 MHz, CD3OD): δ 8.43 (s, 1H), 8.14 (d, J = 0.80 Hz, 1H), 7.82 (s, 1H), 5.83-5.77 (m, 1H), 3.02 (d, J = 2.40 Hz, 1H), 2.62-2.56 (m, 3H), 1.59 (d, J = 6.40 Hz, 3H). Step-2: Synthesis of (R)-1-(but-3-yn-2-yl)-5-methyl-1H-indazol-6-amine (XXX) [000146] To a stirred solution of (R)-1-(sec-butyl)-5-methyl-6-nitro-1H- indazole (XXXa) (1.4 g, 6.107 mmol) in ethanol (10 mL) under nitrogen atmosphere was added NH4Cl (1.63 g, 30.54 mmol) in 15 mL of water followed by iron (1.70g, 30.54 mmol). The reaction mixture was heated at 80°C for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (40 mL). The filtrate was concentrated in vacuo to get a brown residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the title compound XXX as a brown solid; Yield: (1.2 g, 93.0%). LC_MS: Calc. for C12H13N3: 199.26; Obs.: 200.2[M++H]. 1H-NMR (400 MHz,CD3OD): δ 7.76 (d, J = 0.80 Hz, 1H), 7.37 (s, 1H), 6.89 (s, 1H), 5.47-5.49 (m, 1H), 2.87 (d, J = 2.40 Hz, 1H), 2.27 (d, J = 0.40 Hz, 3H), 1.76 (d, J = 7.20 Hz, 3H). Synthesis 2-((1-((R)-sec-butyl)-5-methyl-1H-indazol-6-yl) amino)-4-(((1S,2R)- 2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxylic acid (XXXI)Step-1: Synthesis (R)-1-(sec-butyl)-5-methyl-6-nitro-1H-indazole (XXXIa): [000147] To a stirred solution of 5-methyl-6-nitro-1H-indazole (CAS:72521- 00-7, 2.00 g, 11.29 mmol) and (S)-butan-2-ol (CAS: 4221-99-2, 1.04 mL,11.29 mmol) in THF (20 mL), triphenylphosphine (3.55 g, 13.55 mmol) was added followed by addition of DIAD (2.634 mL, 13.55 mmol) at 0 °C. Resulting reaction mixture was stirred for 25 °C at 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 10% ethyl acetate in petroleum ether to yield the desired product XXXIa as ayellow solid; Yield: (1.3 g, 49%). LC_MS: Calc. for C12H15N3O2: 233.47; Obs.: 234.1[M++H].1H NMR (400 MHz, CD3OD): δ 8.30 (s, 1H), 8.13 (s, 1H), 7.77 (s, 1H), 4.76-4.78 (m, 1H), 2.60 (d, J = 0.80 Hz, 3H), 2.06-2.09 (m, 1H), 1.92-1.95 (m, 1H), 1.58 (d, J = 4.40 Hz, 3H), 0.76 (m, 3H). Step-2: Synthesis of (R)-1-(sec-butyl)-5-methyl-1H-indazol-6-amine (XXXIb) [000148] To a stirred solution of (R)-1-(sec-butyl)-5-methyl-6-nitro-1H- indazole XXXIa (1.3 g, 5.57mmol) in ethanol (10 mL) under nitrogen atmosphere NH4Cl (1.49 g, 27.86 mmol) in 15 mL of water was added followed by addition of iron (1.55 g, 27.86 mmol). The reaction mixture was then heated at 80 °C for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (40 mL). The filtrate was concentrated in vacuo to get a brown residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was triturated with petroleum ether to get the desired product XXXIb as a brown solid; Yield: (1.1 g, 96.0%). LC_MS: Calc. for C12H17N3: 203.29; Obs.: 204.4[M++H].1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.40 (s, 1H), (s, H), 6.64 (s, 1H), 4.38-4.40 (m, 1H), 3.83 (s, 2H), 2.29 (d, J = 0.80 Hz, 3H), 2.08-2.12 (m, 1H), 1.85- 1.89 (m, 1H), 1.55 (d, J = 6.80 Hz, 3H), 0.80 (t, J = 7.60 Hz, 3H). Step-3: Synthesis of 2-(1-((R)-sec-butyl)-5-methyl-1H-indazol-6-yl) amino)-4- ((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5- carboxylic acid (XXXI) [000149] To a stirred solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3- dihydro-1H-inden-1-yl)amino) pyrimidine-5-carboxylic acid IIc (0.20 g, 0.65 mmol) and (R)-1-(sec-butyl)-5-methyl-1H-indazol-6-amine XXXIb (0.16 g, 0.78 mmol) in NMP (3 mL), 4M HCl in dioxane (0.2 mL, 0.98 mmol) was added at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 90 °C for 16 hours. The reaction progress was monitored by UPLC. Aftercompletion of the reaction, the reaction mixture was evaporated in vacuo to get the crude desired title product XXXI as brown gummy liquid. Yield: (0.50 g, 40%). LC_MS: Calc. for C26H28N6O3: 472.55; Obs.: 473.2[M++H]. Synthesis of 1-isopropyl-5-methyl-1H-benzo[d][1,2,3] triazol-6-amine (XXXII)Step-1: Synthesis of 6-bromo-1-isopropyl-5-methyl-1H-benzo[d] [1,2,3] triazole (XXXIIa) [000150] To a stirred solution of 6-bromo-5-methyl-1H-benzo[d] [1,2,3] triazole (CAS: 1388070-91-4, 3.00 g, 14.11 mmol) in DMF (20 mL) under nitrogen atmosphere, potassium carbonate (3.91 g, 28.32 mmol) was added followed by addition of 2-iodopropane (1.7 mL, 17.0 mmol) at room temperature. The resulting reaction mixture was heated at 80°C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 13% ethyl acetate in petroleum ether to yield the desired product XXXIIa as a Brown liquid; Yield: (0.400 g, 9.70%). LC_MS: Calc. for C10H12BrN3: 254.13; Obs.: 254.1 [M++H].1H NMR (300 MHz, DMSO-d6): δ 8.33 (d, J = 9.20 Hz, 1H), 8.01 (m, 1H), 5.25-5.16 (m, 1H), 2.53-2.49 (m, 3H), 1.63-1.59 (m, 6H). Step-2: Synthesis of tert-butyl (1-isopropyl-5-methyl-1H-benzo[d] [1,2,3] triazol-6-yl) carbamate (XXXIIb): [000151] To a stirred solution of 6-bromo-1-isopropyl-5-methyl-1H- benzo[d][1,2,3] triazole (III) (0.25g, 0.98mmol) and tert-butyl carbamate XXXIIa. (0.23 g, 1.97 mmol) in 1,4-Dioxane (10 mL), cesium carbonate (0.64g, 1.97 mmol) was added and degassed for 10 minutes, thentBuXPhos Pd G3 (0.083mg,98.4μmol) was added under nitrogen atmosphere. The resulting reaction mixture was heated at 100°C for 2 hours in a microwave. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was filtered and evaporated in vacuo to get the crude product. The crude compound was purified by silica gel (230-400 mesh, 25 g packed, flow rate 30 mL / minutes & 254-280 nm wavelength) Biotage flash column chromatography using ethyl acetate (0-100%) in petroleum ether and the peak was eluted with 30-40 % ethyl acetate was concentrated to yield the desired product XXXIIb as a Brown solid; Yield: (0.20 g, 58%). LC_MS: Calc. for C15H22N4O2: 290.37; Obs: 291.2[M++H]. Step-3: Synthesis of 1-isopropyl-5-methyl-1H-benzo[d] [1,2,3] triazol-6-amine (XXXII) [000152] To a solution of tert-butyl (1-isopropyl-5-methyl-1H- benzo[d][1,2,3]triazol-6-yl)carbamate XXXIIb (0.200 g, 0.68 mmol) in DCM (10 mL), 4M HCl in 1,4-Dioxane (1 mL, 3.44 mmol) was added at 0 °C, under nitrogen atmosphere and resulting reaction mixture was allowed to stir at room temperature for 2 hour. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude product. The crude product was dissolved in methanol: dichloromethane (1:1) and neutralized by amberlyst A21 free base (pH ~ 7.0). The reaction mixture was filtered, dried over sodium sulphate, and concentrated under reduced pressure to get the title product XXXII as a brown liquid; Yield: (0.17 g, 58.8%). LC_MS: Calc. for C10H14N4: 190.25; Obs.: 191.1[M++H]. Synthesis of compounds of FormulaCompound 1: 2-((5-fluoro-1-isopropyl-1H-indazol-6-yl) amino)-4-((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide[000153] To a stirred solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3- dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide (II) (0.6 g, 1.97 mmol) and 5-fluoro-1-isopropyl-1H-indazol-6-amine (I’) (0.380 g, 1.97 mmol) in NMP (5 mL) was added 4M HCl in dioxane (0.984 mL, 3.94 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude product as yellow gummy mass. The obtained crude product was purified by Prep-HPLC purification using 10 mM ammonium bicarbonate in water and acetonitrile, the product fractions were concentrated under vacuo to afford the desired compound as off-white solid. The product was further triturated with diethyl ether, the white solid thrown out was allowed to settle and the supernatant was decanted. The solid was dried under high vacuo, to get free base of the desired Compound 1 as light brown color solid; Yield: (0.148 g, 15.7%).LC_MS: Calc. for C24H24FN7O2: 461.50; Obs.:462.2[M++H].1H NMR (400 MHz, DMSO-d6): 1H-NMR (400 MHz, DMSO-d6): δ 9.89 (d, J = 8.00 Hz, 1H), 8.84 (d, J = 2.40 Hz, 1H), 8.64 (s, 1H), 8.39 (d, J = 6.80 Hz, 1H), 7.89 (s, 2H), 7.53 (d, J = 11.20 Hz, 1H), 7.35 (d, J = 7.20 Hz, 1H), 7.29-7.24 (m, 2H), 7.20-7.16 (m, 1H), 4.56-4.54 (m, 1H), 3.65 (br s, 1H), 3.05-3.20 (m, 1H), 2.93-2.89 (m, 1H), 1.12-1.08 (m, 3H), 0.98 (d, J = 6.40 Hz, 3H); HPLC Purity = 96.09%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 0.1 % TFA in water, Mobile Phase B: Acetonitrile.Compound 2: 2-((5-fluoro-1-isopropyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(2-hydroxyethyl) pyrimidine- 5-carboxamide[000154] To a stirred solution N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2- chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5- carboxamide (III) (0.15 g, 0.432 mmol), 5-fluoro-1-isopropyl-1H-indazol-6-amine (I’) (0.083 g, 0.432 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.32 mL; 2 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product as brown liquid. The obtained crude product was purified by Prep-HPLC purification using 10mM ammonium bicarbonate in water and acetonitrile to afford the desired compound as colorless gummy mass. The compound was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried under high vacuo, to afford the free base of desired product Compound 2 as an off-white solid. Yield: (0.020 g, 9.1%); LC_MS: Calc. for C26H28FN7O3: 505.55; Obs.: 506.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.81 (d, J = 7.60 Hz, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.65 (s, 1H), 8.40 (d, J = 6.40 Hz, 1H), 8.35 (t, J = 5.60 Hz, 1H), 7.89 (s, 1H), 7.51 (s, 1H), 7.35 (d, J = 7.20 Hz, 1H), 7.29-7.25 (m, 2H), 7.18 (t, J = 7.20 Hz, 1H), 5.68-5.64 (m, 1H), 5.47 (d, J = 4.40 Hz, 1H), 4.74-4.71(m, 1H), 4.56-4.54 (m, 1H), 3.65 (s, 1H), 3.52-3.49 (m, 2H), 3.33-3.29 (m, 2H), 3.13 (d, J = 4.80 Hz, 1H), 2.94 (s, 1H), 1.11-1.10 (m, 3H), 0.97-0.96 (m, 3H), HPLC Purity: 99.84%, Column: X-Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile phase: A: 0.1% TFA in water, Mobile phase: B: Acetonitrile. Compound 3: 2-((5-fluoro-1-isopropyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-methylpyrimidine-5- carboxamide[000155] To a stirred solution 2-Chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino)-N-methylpyrimidine-5-carboxamide (IV) (0.4 g, 1.255 mmol), 5-fluoro-1-isopropyl-1H-indazol-6-amine (I’) (0.242 g, 1.255 mmol) in NMP (4 mL) was added 4M HCl in dioxane (0.6 mL, 2 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water (1 mL), the solid thrown out was allowed to settle. The supernatant was decanted by filtration. Then the solid obtained was again stirred in 10% aqueous NaHCO3 solution for 10 minutes, the solid thrown out was allowed to settle. The supernatant was decanted by filtration. Then the solid obtained was again stirred in water, filtered, and dried under vacuo, to get pale brown solid. The solid was further washed with methanol, solid was dried under high vacuo to get free base of Compound 3 as an off-white solid. Yield: (0.312 g, 52.0%). LC_MS: Calc. for C25H26FN7O2: 475.53; Obs.: 476.3 [M++H];1H NMR (400 MHz, DMSO-d6): δ 10.56 (br s, 1H), 10.10 (br s, 1H), 8.79-8.71 (m, 2H), 8.30 (br s, 1H), 7.97 (s, 1H), 7.67 (d, J = 10.80 Hz, 1H), 7.40-7.22 (m, 4H), 5.65-5.62 (m, 1H), 4.59-4.57 (m, 1H), 3.68-2.92 (m, 3H), 2.76-2.70 (m, 4H), 1.10 (d, J = 6.40 Hz, 6H); HPLC Purity = 99.53%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile. Compound 4: Synthesis of 2-((1-allyl-5-fluoro-1H-indazol-6-yl) amino)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5- carboxamide[000156] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino) pyrimidine-5-carboxamide (IV) (0.10 g, 0.32 mmol), 1- allyl-5-fluoro-1H-indazol-6-amine (V) (0.062 g, 0.32 mmol) in NMP (3 mL) was added 4M HCl in dioxane (0.2 mL, 0.65 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL), neutralized by triethylamine, and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by Prep-HPLC purification using Ammonium bicarbonate in water and acetonitrile to afford Free base of the desired Compound 4 as an Off-white solid Yield: (0.035 g, 23%). LC_MS: Calc. for C24H22FN7O2: 459.49; Obs.: 459.1 [M++H].;1H NMR (400 MHz, DMSO-d6): δ 9.82 (d, J = 8.40 Hz, 1H), 8.83 (s, 1H), 8.62 (s, 1H), 8.31 (d, J = 6.40 Hz, 1H), 7.92 (s, 1H), 7.56 (d,J = 10.80 Hz, 1H), 7.30 (d, J = 7.20 Hz, 1H), 7.23 (t, J = 6.80 Hz, 2H), 7.14 (t, J = 8.00 Hz, 1H), 5.62-5.56 (m, 2H), 5.40 (d, J = 4.80 Hz, 1H), 4.95 (d, J = 9.20 Hz, 1H), 4.63 (d, J = 17.60 Hz, 1H), 4.55-4.52 (m, 1H), 4.40-4.24 (m, 2H), 3.42-3.36 (m, 1H), 3.14-3.13 (m, 1H), 2.88 (d, J = 16.40 Hz, 1H), 1.10 (t, J = 7.20 Hz, 1H).; HPLC Purity = 97.16%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A : 0.1% TFA in water, Mobile Phase B: Acetonitrile. Compound 5: 2-((1-ethyl-5-fluoro-1H-indazol-6-yl) amino)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide[000157] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino) pyrimidine-5-carboxamide (II) (0.1 g, 0.328 mmol) and 1- ethyl-5-fluoro-1H-indazol-6-amine (VI) (0.059 g, 0.328 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.16 mL, 0.656 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude product as brown color gummy liquid. The obtained crude product was purified by Prep-HPLC purification using 0.1% TFA in water and acetonitrile, the product fractions were concentrated under vacuo to afford the desired compound as off- white solid. The product was further triturated with diethyl ether, the white solid thrown out was allowed to settle and the supernatant was decanted. The solid was dried under high vacuo, to get the free base of desired compound 5 as an off-white solid; Yield: (0.017 g, 11%).LC_MS: Calc. for C23H22FN7O2: 447.47; Obs.:448.2[M++H].1H NMR (400 MHz, DMSO-d6): δ 10.15 (s, 1H), 9.25 (s, 1H), 8.63 (s, 1H), 8.34 (d, J = 6.40 Hz, 1H), 7.92 (s, 2H), 7.59 (d, J = 10.80 Hz, 1H), 7.34-7.24 (m, 4H), 7.18-7.15 (m, 1H), 5.67-5.63 (m, 1H), 5.30-5.60 (m, 1H), 4.57-4.55 (m, 1H), 3.17-3.11 (m, 3H), 2.90 (d, J = 16.40 Hz, 1H), 1.00-0.97 (m, 3H).; HPLC Purity = 98.99%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 0.1 % TFA in water, Mobile Phase B: Acetonitrile. Compound 6: 2-((1-cyclopropyl-5-fluoro-1H-indazol-6-yl) amino)-4-(((1S,2R)- 2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-methylpyrimidine-5- carboxamide[000158] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino)-N-methylpyrimidine-5-carboxamide (IV) (0.1 g, 0.314 mmol), 1-cyclopropyl-5-fluoro-1H-indazol-6-amine (VII) (0.060 g, 0.314 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.157 mL, 0.627 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCO3 solution (5 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 2). The organic layer was dried over Na2SO4 and concentrated under a vacuum to get the crude product. The obtained crude product was purified by Prep-HPLC purification using 0.1% TFA in water and acetonitrile to afford the desired Compound 6 as an off-white soli Yield: (0.009 g, 6.0%). LC_MS: Calc. for C25H24FN7O2 : 473.51; Obs.: 474.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 9.27 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 8.38 (d, J = 6.40 Hz, 1H), 7.87 (s, 1H), 7.60 (d, J = 10.80 Hz, 2H), 7.29- 7.20 (m, 3H), 7.16-7.13 (m, 1H), 5.67-5.64 (m, 1H), 4.57-550.00 (m, 1H), 3.11- 3.06 (m, 1H), 2.90-2.86 (m, 2H), 2.75-2.74 (m, 3H), 1.12-1.08 (m, 1H), 0.93-0.92 (m, 1H), 0.50-0.70 (m, 2H).; HPLC Purity = 97.41%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile. Compound 7: 2-((6-fluoro-3-isopropylbenzo[d]isoxazol-5-yl) amino)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-[000159] To a stirred solution of 2-chloro-4-(1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino)-N-methylpyrimidine-5-carboxamide IV (0.1 g, 0.31 mmol) I in NMP (2 mL).6-Fluoro-3-isopropylbenzo[d]isoxazol-5-amine VIII (0.07g, 0.38 mmol) was added followed by HCl in dioxane (0.15 mL, 0.63 mmol, 4M) and the reaction mixture stirred at 110°C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into saturated sodium bicarbonate solution to precipitate solid. The solid was filtered and dried under high vacuo to provide the title Compound 7 as a pale brown solid. (Yield: 0.03 g, 28%). 1H NMR (400 MHz, DMSO-D6):δ 9.67 (d, J =7.2 Hz,1H), 9.00 (brs, 1H), 8.52 (s, 2H), 8.22 (brs, 1H), 8.37 (d, J =7.2 Hz,1H), 8.27 (s, 1H), 7.70 (d, J =11.2 Hz, 1H), 7.29-7.12 (m, 4H), 5.51 (brs, 1H), 5.36 (d, J =3.6 Hz,1H), 4.48 (d, J = 3.8 Hz, 1H), 3.04 (d, J = 16.4 Hz, 1H), 2.85 (d, J = 16.4 Hz, 1H), 2.70 (m, 4H), 1.08 (s, 6H). LC-MS Calculated for C25H25FN6O3is 476.51; Observed: 477.22 [M++1].Compound 8: 2-((6-fluoro-3-isopropylbenzo[d]isoxazol-5-yl) amino)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(2-hydroxyethyl) pyrimidine-5-carboxamide[000160] To a stirred solution of N-(2-(tert-butyl dimethyl silyl) oxy) ethyl)- 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5- carboxamide III (0.08 g, 0.23 mmol) in NMP (2 mL). 6-Fluoro-3- isopropylbenzo[d]isoxazol-5-amine VIII (0.05 g, 0.28 mmol) was added followed by HCl in dioxane (0.11 mL, 0.46 mmol, 4M) and the reaction mixture stirred at 110°C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into saturated sodium bicarbonate solution to precipitate solid. The crude material was purified by flash chromatography (silica gel, 230-400 mesh, 5% MeOH: DCM) to provide the title Compound 8 as an off- white solid. Yield: (0.03 g, 28%).1H NMR (400 MHz, DMSO-D6): δ 9.68 (d, J = 6.8 Hz,1H), 9.01 (bs, 1H), 8.58 (s, 1H), 8.37 (d, J = 7.2 Hz, 1H), 8.29 (s, 1H), 8.70 (d, J = 7.2 Hz, 1H), 7.29-7.12 (m, 4H), 5.51 (brs, 1H), 5.37 (s, 1H), 4.69 (s, 1H), 4.49 (s, 1H), 3.47 (d, J = 5.2 Hz, 2H), 3.26 (s, 2H), 3.06 (s, 1H), 2.85 (d, J = 6.4 Hz ,1H), 1.01 (d, J = 6.8 Hz, 6H); LC-MS Calculated for C26H27FN6O4 is 506.54; Observed: 507.21 [M++1]. Compound 9: 2-((5-fluoro-1-propyl-1H-indazol-6-yl) amino)-4-((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-methylpyrimidine-5- carboxamide.[000161] To a stirred solution 2-Chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino)-N-methylpyrimidine-5-carboxamide (IV) (0.15 g, 0.470 mmol), 5-fluoro-1-propyl-1H-indazol-6-amine (IX) (0.091 g, 0.470 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.2 mL, 0.8 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL), neutralized by triethylamine, and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by Prep-HPLC purification using Ammonium bicarbonate in water and acetonitrile to afford the desired compound. The compound was further triturated with diethyl ether, the white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried under high vacuo, to get Compound 9 as an off-white solid; Yield: (0.064 g, 28.59%). LC_MS: Calc. for C25H26FN7O2: 475.53; Obs.: 476.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 10.59 (br s, 1H), 10.57 (br s, 1H), 8.71 (br s, 2H), 8.27 (d, J = 6.00 Hz, 1H), 7.98 (s, 1H), 7.68 (d, J = 10.80 Hz, 1H), 7.36-7.17 (m, 4H), 5.62-5.58 (m, 1H), 4.59-4.57 (m, 1H), 3.62-3.57 (m, 2H), 3.16-2.90 (m, 3H), 2.75 (s, 3H), 1.50-1.48 (m, 2H), 0.53-0.50 (m, 3H); HPLC Purity = 99.02%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Compound 10: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2- ((1-isopropyl-5-methyl-1H-indazol-6-yl) amino)-N-(methyl-d3) pyrimidine-5- carboxamide[000162] To a solution of 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5- carboxylic acid (XIa) (0.500 g, 1.090 mmol) and methan-d3-amine hydrochloride (0.092 g, 1.309 mmol) in DMF (10 mL), were added DIPEA (0.57 mL, 3.271 mmol) followed by HATU (0.497 g, 1.309 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by Prep-HPLC purification using Ammonium bicarbonate in water and acetonitrile to afford the desired Compound 10 as a pale-yellow solid; Yield: (0.240 g, 46%). LC_MS: Calc. for C26H26D3N7O2: 474.58; Obs.:475.3 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.73 (d, J = 8.40 Hz, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.48 (s, 1H), 7.32 (d, J = 7.20 Hz, 1H), 7.27-7.23 (m, 2H), 7.19-7.16 (m, 1H), 5.63-5.60 (m, 1H), 5.41 (d, J = 4.40 Hz, 1H), 4.52-4.49 (m, 1H), 3.80 (s, 1H), 3.08-3.03 (m, 1H), 2.90-2.86 (m, 1H), 2.38 (s, 3H), 1.10-1.02 (m, 6H) ; HPLC Purity = 99.67%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Compound 11: 2-((1-allyl-5-methyl-1H-indazol-6-yl) amino)-4-((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5- carboxamide.[000163] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide (XII) (0.15 g, 0.466 mmol), 1-allyl-5-methyl-1H-indazol-6-amine (XIII) (0.087 g, 0.464 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.4 mL, 2 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL), neutralized by triethylamine, and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by Prep-HPLC purification using Ammonium bicarbonate in water and acetonitrile to afford the desired compound. The compound was further triturated with diethyl ether, the white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried under high vacuo, to get Compound 11 as an off-white solid; Yield: (0.046 g, 20.88%). LC_MS: Calc. for C26H24D3N7O2: 472.57; Obs.: 473.1 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.50 (s, 2H), 8.23 (s, 1H), 8.05 (s, 1H), 7.86-7.19 (m, 6H), 5.63-5.36 (m, 4H), 4.92-4.37 (m, 4H), 3.17- 2.83 (m, 2H), 2.37 (s, 3H); HPLC Purity = 97.71%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 5 mM Ammonium bicarbonate in water, Mobile Phase B: Acetonitrile.Compound 12: 2-((1-(2,2-difluoroethyl)-5-methyl-1H-indazol-6-yl) amino)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide[000164] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide (XII) (0.120 g, 0.373 mmol) and 1-(2,2-difluoroethyl)-5-methyl-1H-indazol-6-amine (XIV) (0.0788 g, 0.373 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.186 mL, 0.746 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude product as brown color gummy liquid. The obtained crude product was purified by Prep-HPLC purification using ammonium bicarbonate in water and acetonitrile, the product fractions were concentrated under vacuo to afford the desired compound as an off-white solid. The product was further triturated with diethyl ether, the white solid thrown out was allowed to settle and the supernatant was decanted. The solid was dried under high vacuo, to get the free base of the desired Compound 12 as an off-white solid; Yield: (0.029 g, 16%).LC_MS: Calc. for C25H22D3F2N7O2: 496.54; Obs.:497.1 [M++H].1H NMR (400 MHz, DMSO-d6): 1H-NMR (400 MHz, DMSO-d6): δ 9.66 (d, J = 8.40 Hz, 1H), 8.51 (d, J = 8.00 Hz, 2H), 8.24 (s, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.54 (s, 1H), 7.10-7.28 (m, 4H), 6.11-5.96 (m, 1H), 5.56-5.53 (m, 1H), 5.35 (d, J = 4.40 Hz, 1H), 4.51-4.48 (m, 1H), 4.23-4.11 (m, 2H), 3.40-3.33 (m, 1H), 3.18-3.05 (m, 1H), 2.68-2.67 (m, 1H), 2.37-2.33 (m, 3H).; HPLC Purity = 99.94%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 0.1 % TFA in water, Mobile Phase B: Acetonitrile. Compound 13: 2-((1-(3,3-difluoropropyl)-5-methyl-1H-indazol-6-yl) amino)- 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide[000165] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide (XII) (0.120 g, 0.373 mmol) and 1-(3,3-difluoropropyl)-5-methyl-1H-indazol-6-amine (XV) (0.084 g, 0.373 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.186 mL, 0.746 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude product as brown color gummy liquid. The obtained crude product was purified by Prep-HPLC purification using ammonium bicarbonate in water and acetonitrile, the product fractions were concentrated under vacuo to afford the desired compound as off-white solid. The product was further triturated with diethyl ether, the white solid thrown out was allowed to settle and the supernatant was decanted. The solid was dried under high vacuo, to get the free base of desired Compound 13 as an off-white solid; Yield: (0.029 g, 15%).LC_MS: Calc. for C26H24D3F2N7O2: 510.56; Obs.:511.3 [M++H].1H NMR (400 MHz, DMSO-d6): 1H-NMR (400 MHz, DMSO-d6): δ 9.65 (d, J = 8.00 Hz, 1H), 8.52 (d, J = 4.00 Hz, 2H), 8.23 (s, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 7.52 (s, 1H),7.28 (d, J = 7.20 Hz, 1H), 7.23-7.19 (m, 2H), 7.13 (t, J = 7.60 Hz, 1H), 5.89 (m, 1H), 5.58-5.54 (m, 1H), 5.35 (d, J = 4.40 Hz, 1H), 4.49 (d, J = 4.80 Hz, 1H), 3.90- 3.40 (m, 2H), 3.00-3.10 (m, 1H), 2.80-2.90 (m, 1H), 2.53-2.50 (m, 3H), 2.10-2.08 (m, 2H). HPLC Purity = 99.38%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile. Compound 14: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- (2-hydroxyethyl)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide[000166] To a solution of N-(2-((tert-butyl dimethyl silyl) oxy)ethyl)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((1-isopropyl-5- methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide (XI) (1.5 g, 2.435 mmol) in THF (40 mL), TBAF (1.0 M solution in THF; 3.6 mL, 3.6 mmol) was added at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under vacuo to get the crude product as yellow gummy mass. The obtained crude product was purified by Prep-HPLC purification using 10mM ammonium bicarbonate in water and acetonitrile to afford the desired compound as colourless gummy mass. The compound was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried underhigh vacuo, to afford the free base of desired Compound 14 as an off-white solid. Yield: (0.42 g, 34.39%); LC_MS: Calc. for C27H31N7O3: 501.59; Obs.: 502.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.74 (d, J = 8.00 Hz, 1H), 8.62 (s, 1H), 8.44 (br s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 7.40 (s, 1H), 7.34-7.18 (m, 4H), 5.62-5.60 (m, 1H), 5.43-5.42 (m, 1H), 4.73-4.71 (m, 1H), 4.53-4.49 (m, 1H), 4.11-3.47 (m, 3H), 3.25-3.03 (m, 4H), 2.39 (br s, 3H), 1.10-1.01 (m, 6H); HPLC Purity: 99.82%, Column: X-Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile phase: A: 5 mM Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile. Compound 15: 2-((1-allyl-5-methyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(2-hydroxyethyl) pyrimidine- 5-carboxamide[000167] To a solution of 2-((1-allyl-5-methyl-1H-indazol-6-yl) amino)-N-(2- ((tert-butyldimethylsilyl) oxy)ethyl)-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino) pyrimidine-5-carboxamide (XVI) (0.35 g, 0.57 mmol) in THF (10 mL), TBAF (1.0 M solution in THF; 1.2 mL, 1.2 mmol) was added at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under vacuo to get the crude product as yellow gummy mass. The obtained crude product was purified by silica gel (100-200 mesh, 10 g packed, flow rate 25 mL / minutes & 254-280 nm wavelength) Biotage columnchromatography using (0-10%) methanol in dichloromethane and the peak was eluted with 4 % of methanol in dichloromethane, the product fractions were concentrated under vacuo to afford the desired Compound 15 as a pale-yellow gummy mass. The compound was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried under high vacuo, to afford the free base of desired Compound 15 as an off-white solid. Yield: (0.018 g, 6.34%); LC_MS: Calc. for C27H29N7O3: 499.58; Obs.: 500.1 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.66 (d, J = 8.00 Hz, 1H), 8.59 (br s, 1H), 8.48 (br s, 1H), 8.27 (br s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.52 (s, 1H), 7.23-7.17 (m, 4H), 5.37-5.36 (m, 1H), 4.95-4.92 (m, 1H), 4.73-4.35 (m, 6H), 3.51-3.38 (m, 5H), 3.19-3.15 (m, 2H), 2.37 (s, 3H); HPLC Purity: 95.075 %, Column: X-Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile phase: A: 0.1% TFA in water, Mobile phase: B: Acetonitrile. Compound 16: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- (methyl-d3)-2-((5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide[000168] To a solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide (XII) (0.200 g, 0.621 mmol), 5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-6-amine (XVII) (0.115 g, 0.621 mmol) in NMP (4 mL) was added 4M HCl in dioxane (0.6 mL, 2 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 3 hours. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was diluted with water (10 mL), neutralized by triethylamine, and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by Prep-HPLC purification using Ammonium bicarbonate in water and acetonitrile to afford the desired Compound 16 as a pale-yellow solid; Yield: (0.024 g, 7.9%). LC_MS: Calc. for C26H22D3N7O2: 470.55; Obs.: 471.5 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.70 (d, J = 8.00 Hz, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.25 (s, 2H), 7.87 (s, 1H), 7.53 (s, 1H), 7.29 (d, J = 7.20 Hz, 1H), 7.23-7.20 (m, 2H), 7.14-7.10 (m, 1H), 5.74- 5.73 (m, 1H), 5.62-5.58 (m, 1H), 4.67-4.62 (m, 1H), 4.55-4.51 (m, 1H), 4.36-4.31 (m, 1H), 3.25-3.24 (m, 1H), 3.18-3.17 (m, 1H), 2.88-2.84 (m, 1H), 2.39 (s, 3H). ; HPLC Purity = 96.34%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile. Compound 17: 2-((1-(2,2-difluoroethyl)-5-methyl-1H-indazol-6-yl) amino)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(2-hydroxyethyl) pyrimidine-5-carboxamide[000169] To a solution of N-(2-((tert-butyl dimethyl silyl) oxy) ethyl)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((1-isopropyl-5- methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide (XVIII) (0.6 g, 0.940 mmol) in THF (20 mL), TBAF (1.0 M solution in THF; 1.8 mL, 1.8 mmol) was added at 0 °C, under nitrogen atmosphere. The resulting reaction mixture wasstirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under vacuo to get the crude product as pale-yellow solid. The obtained crude product was purified by Prep-HPLC purification using 10mM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as colorless gummy mass. The compound was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried under high vacuo, to afford the free base of desired Compound 17 as an off-white solid. Yield: (0.034 g, 6.9%); LC_MS: Calc. for C26H27F2N7O3: 523.54; Obs.: 524.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.66 (d, J = 8.00 Hz, 1H), 8.59 (s, 1H), 8.50 (s, 1H), 8.29-8.27 (m, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.54 (s, 1H), 7.28-7.12 (m, 4H), 6.09 (m, 1H), 5.56-5.35 (m, 2H), 4.72-4.09 (m, 3H), 3.51-3.38 (m, 2H), 3.27-3.06 (m, 4H), 2.87-2.83 (m, 1H), 1.12 (br s, 3H); HPLC Purity: 96.96%, Column: X-Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile phase: A: 5 mM Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile. Compound 18: 2-((1-ethyl-5-methyl-1H-indazol-6-yl) amino)-4-(((1S,2R)-2- hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5- carboxamide.[000170] To a stirred solution of 2-chloro-4-(((1S,2R)-2-hydroxy-2,3- dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide (XII)(0.15 g, 0.46 mmol) and 1-ethyl-5-methyl-1H-indazol-6-amine (XIX) (0.081g, 0.46 mmol) in NMP (3 mL), was added 4M HCl in dioxane (0.2 mL, 0.93 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 90 °C for 2 hours. The reaction progress was monitored by UPLC. After completion of the reaction, the reaction mixture was washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo to get brown residue. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude. The obtained crude was purified by Preparative HPLC reverse phase ammonium bicarbonate in water and acetonitrile to afford desired Compound 18 as an off-white solid. Yield: (0.020 g, 9.22%), LC_MS: Calc. C25H24D3N7O2: 460.56; Obs.: 461.56 [M++H]:1H-NMR (300 MHz, DMSO-d6): δ 9.69 (d, J = 8.10 Hz, 1H), 8.54 (s, 1H), 8.44 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.81 (s, 1H), 7.49 (s, 1H), 7.29-7.31 (m, 1H), 7.21-7.25 (m, 2H), 7.13-7.17 (m, 1H), 5.58- 5.62 (m, 1H), 5.38-5.39 (m, 1H), 4.48-4.53 (m, 1H), 3.60-3.65 (m, 2H), 3.17-3.18 (m, 1H), 3.04-3.11 (m, 1H), 2.84-2.89 (m, 1H), 2.20-2.40 (m, 4H), 1.02 (s, 1H). HPLC Purity; 99.01%, Column: X-Bridge C8(50 X 4.6) mm,3.5μm, Mobile phase: A:0.1% TFA in water Mobile phase: B: ACN. Compound 19: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2- ((1-(2-methoxyethyl)-5-methyl-1H-indazol-6-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide.[000171] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide (XII) (0.15 g, 0.466 mmol), 1-(2-methoxyethyl)-5-methyl-1H-indazol-6-amine (XX) (0.095 g, 0.466 mmol) in NMP (4 mL) was added 4M HCl in dioxane (0.11 mL, 0.466 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product as brown liquid. The obtained crude product was purified by Prep-HPLC purification using 0.1%TFA in water and acetonitrile to afford the desired compound. The compound was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried under high vacuo, to afford the TFA salt of desired Compound 19 as a pale brown solid. Yield: (0.040 g, 17.0%). LC_MS: Calc. for C26H26D3N7O3: 490.58; Obs.:491.3 [M++H];1H NMR (400 MHz, DMSO-d6): ^ 10.33 (brs, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.03-7.90 (m, 2H), 7.62 (s, 1H), 7.32- 7.15 (m, 5H), 5.59-5.54 (m, 2H), 4.54 (s, 2H), 3.53-3.40 (m, 2H), 3.13-3.04 (m, 4H), 2.90-2.86 (m, 1H), 2.37 (s, 3H). HPLC Purity = 98.32%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile. Compound 20: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- (2-hydroxyethyl)-2-((5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide[000172] To a solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2-((5-methyl-1-(prop-2- yn-1-yl)-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide (XXI) (0.4 g, 0.653 mmol) in THF (10 mL), TBAF (1.0 M solution in THF; 1 mL, 1 mmol) was added at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layer was dried over Na2SO4and concentrated under vacuo to get the crude product as brown liquid. The obtained crude product was purified by Prep-HPLC purification using 10mM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as colorless gummy mass. The compound was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried under high vacuo, to afford the free base of desired Compound 20 as an off-white solid. Yield: (0.060 g, 18.43%); LC_MS: Calc. for C27H27N7O3: 497.56; Obs.: 498.2 [M++H];1H NMR (400 MHz, DMSO- d6): δ 9.70 (d, J = 7.60 Hz, 1H), 8.60 (s, 1H), 8.45 (br s, 1H), 8.32-8.26 (m, 2H), 7.87 (s, 1H), 7.53 (s, 1H), 7.30-7.10 (m, 4H), 5.62-5.59 (m, 1H), 5.38 (br s, 1H), 4.72-4.52 (m, 2H), 3.67-3.47 (m, 2H), 3.29-3.24 (m, 4H), 3.18-2.81 (m, 3H), 1.28 (br s, 3H); HPLC Purity: 95.00%, Column: X-Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile phase: A: 5 mM Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile.Compound 21: N-(2-aminoethyl)-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl) amino)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide[000173] To a stirred solution tert-butyl (2-(2-chloro-4-(((1S,2R)-2-hydroxy- 2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamido)ethyl)carbamate (XXII) (0.15 g, 0.334 mmol), 1-isopropyl-5-methyl-1H-indazol-6-amine (X) (0.064 g, 0.338 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.4 mL; 2 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product as brown liquid. The obtained crude product was purified by Prep-HPLC purification using 10mM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as colourless gummy mass. The compound was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried under high vacuo, to afford free base of desired Compound 21 as an off-white solid. Yield: (0.022 g, 13.13%); LC_MS: Calc. for C27H32N8O2: 500.61; Obs.: 501.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.72 (d, J = 8.00 Hz, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 8.25-8.17 (m, 2H), 7.81 (s, 1H), 7.48 (s, 1H), 7.48 (m, 4H), 5.63-5.60 (m, 1H), 5.41 (s, 1H), 4.49 (br s, 1H), 3.80 (br s, 1H), 3.22-3.03 (m, 4H), 2.90-2.65 (m, 4H), 2.50 (s, 3H), 1.12-1.10 (m, 6H); HPLC Purity: 94.55%, Column: X-Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile phase: A: 0.1% TFA in water, Mobile phase: B: Acetonitrile. Compound 22: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- ((S)-1-hydroxypropan-2-yl)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide[000174] To a stirred solution N-((S)-1-((tert-butyl dimethyl silyl) oxy)propan-2-yl)-2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide (XXIV) (0.15 g, 0.314 mmol), 1-isopropyl-5- methyl-1H-indazol-6-amine (X) (0.060 g, 0.317 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.4 mL; 2 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product as brown liquid. The obtained crude product was purified by Prep-HPLC purification using 10mM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as colorless gummy mass. The compound was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried under high vacuo, to afford the free base of desired Compound 22 as an off-white solid. Yield: (0.028 g, 17.27%); LC_MS: Calc. for C28H33N7O3: 515.62; Obs.: 516.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.74 (d, J = 8.00Hz, 1H), 8.63 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.92 (d, J = 8.00 Hz, 1H), 7.81 (s, 1H), 7.48 (s, 1H), 7.34-7.16 (m, 4H), 5.63-5.60 (m, 1H), 5.41 (d, J = 4.40 Hz, 1H), 4.73-4.53 (m, 1H), 4.50 (t, J = 4.40 Hz, 1H), 3.99-3.94 (m, 2H), 3.78 (br s, 1H), 3.48-3.43 (m, 1H), 3.08-2.86 (m, 2H), 2.34 (br s, 3H), 1.13-1.01 (m, 9H); HPLC Purity: 99.11%, Column: X-Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile phase: A: 5 mM Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile. Compound 23: 4-(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- ((R)-1-hydroxypropan-2-yl)-2-(1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide.[000175] To a stirred solution N-((R)-1-((Tert-butyl dimethyl silyl) oxy)propan-2-yl)-2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino) pyrimidine-5-carboxamide (XXVI) (0.25 g, 0.524 mmol), 1-isopropyl-5- methyl-1H-indazol-6-amine (X) (0.1 g, 0.528 mmol) in NMP (2 mL) was added 4M HCl in dioxane (0.4 mL; 2 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product as brown liquid. The obtained crude product was purified by Prep-HPLC purification using 10mM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as colorlessgummy mass. The compound was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid obtained was dried under high vacuo, to afford free base of desired Compound 23 as an off-white solid. Yield: (0.039 g, 14.43%); LC_MS: Calc. for C28H33N7O3: 515.62; Obs.: 516.2 [M++H];1H NMR (400 MHz, DMSO-d6): δ 9.73 (d, J = 8.00 Hz, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 7.92 (d, J = 8.00 Hz, 1H), 7.81 (s, 1H), 7.48 (s, 1H), 7.32-7.18 (m, 4H), 5.63-5.60 (m, 1H), 5.42-5.40 (m, 1H), 4.72- 4.49 (m, 2H), 3.98-3.96 (m, 1H), 3.78 (br s, 1H), 3.47-3.42 (m, 2H), 2.90-2.86 (m, 2H), 2.39 (br s, 3H), 1.11-1.01 (m, 9H); HPLC Purity: 98.95%, Column: X-Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile phase: A: 5 mM Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile. Compound 24: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- ((R)-2-hydroxypropyl)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide[000176] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl) amino)-N-((R)-2-hydroxypropyl) pyrimidine-5-carboxamide (XXVII) (0.20 g, 0.55 mmol), 1-isopropyl-5-methyl-1H-indazol-6-amine (X) (0.10 g, 0.55mmol) in NMP (3 mL) 4M HCl in dioxane (0.5 mL, 2.21 mmol) was added at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL),neutralized by triethylamine, and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude product was purified by Prep-HPLC purification using ammonium bicarbonate in water and acetonitrile to afford free base of the desired Compound 24 as an off-white solid. Yield: (0.045 g, 16%). LC_MS: Calc. for C28H33N7O3: 515.62; Obs.: 516.2 [M++H].;1H NMR (400 MHz, DMSO-d6 ): δ 9.70 (d, J = 8.00 Hz, 1H), 8.63 (s, 1H), 8.43 (s, 1H), 8.27 (t, J = 5.60 Hz, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.48 (s, 1H), 7.32 (d, J = 7.20 Hz, 1H), 7.27-7.24 (m, 2H), 7.17 (t, J = 8.00 Hz, 1H), 5.63-5.59 (m, 1H), 5.41 (d, J = 4.40 Hz, 1H), 4.72 (d, J = 4.80 Hz, 1H), 4.52 (d, J = 4.40 Hz, 1H), 3.78-3.73 (m, 2H), 3.16-3.13 (m, 2H), 3.08 (d, J = 4.40 Hz, 1H), 3.04 (d, J = 4.40 Hz, 1H), 2.50 (s, 3H), 1.10-1.02 (m, 9H), HPLC Purity = 99.21%, X -Bridge C8 (50 X 4.6) mm, 3.5μm, Mobile Phase A : Ammonium bicarbonate in water, Mobile Phase B: Acetonitrile. Compound 25: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- ((1-hydroxycyclopropyl)-2-((1-isopropyl-5-methyl-1H-indazol-6-yl) amino) pyrimidine-5-carboxamide[000177] In a 10 mL microwave vial to a stirred solution of 2-chloro-4- ((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-((1- hydroxycyclopropyl) methyl) pyrimidine-5-carboxamide XXVIII (0.10 g, 0.267 mmol) in NMP (1 mL). 1-Isopropyl-5-methyl-1H-indazol-6-amine X (0.055 g, 0.293 mmol) was added followed by HCl in dioxane (0.1 mL, 0.267 mmol) and thereaction mixture was subjected to microwave irradiation at 110 °C for 16 h. After completion, the reaction mixture was cooled to room temperature, concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 230-400 mesh, 1% MeOH : DCM) to provide the title Compound 254- (((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-N-((1- hydroxycyclopropyl)methyl)-2-((1-isopropyl-5-methyl-1H-indazol-6- yl)amino)pyrimidine-5-carboxamide as an off- white solid. Yield (0.030 g, 21%); LC-MS Calculated for C29H33N7O3is 527.63; Observed: 528.25 [M++1].1HNMR (400 MHz, DMSO-d6,): δ 9.68 (d, J =7.6 Hz, 1H), 8.65 (s, 1H), 8.44 (s, 1H), 8.28 (br s, 1H), 8.16 (s, 1H), 7.80 (1H), 7.48 (s, 1H), 7.32 (d, J = 7.27.26-7. Hz, 1H), 23 (m, 2H), 7.19-7.15 (m, 1H), 5.61 (t, J =5.6 Hz, 1H), 5.41 (s, 2H), 4.50 (d, J = 4.4 Hz, 1H), 3.76 (br s, 1H), 3.34 (s, 2H) 3.17-3.06 (m, 1H), 2.89-2.85 (m, 1H), 2.38 (s, 3H), 1.28-1.23 (m, 1H), 1.13-1.00 (m, 6H), 0.87-0.84 (m, 1H), 0.54 (s, 4H). Compound 26: 4-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2- ((3-isopropyl -6-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) amino)-N- (methyl-d3) pyrimidine-5-carboxamide.[000178] To a stirred solution of 4-(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden- 1-yl) amino)-2-(3-isopropyl-6-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) amino) pyrimidine-5-carboxylic acid (0.08 g, 0.17 mmol) in DMF (2 mL). Methan- d3-amine (0.06 g, 1.7 mmol) was added followed by DIPEA (0.1 mL, 0.50 mmol), HATU (0.1 g, 0.25 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 230-400 mesh, 5% MeOH: DCM) to provide the title Compound 26 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-2- ((3-isopropyl-6-methyl-2-oxo-2,3-dihydro benzo[d]oxazol-5-yl)amino)-N- (methyl-d3)pyrimidine-5-carboxamide as an off- white solid. Yield (0.04g, 42%); LC-MS Calculated for C26H25D3N6O4is 491.57; Observed: 492.6 [M++1].1HNMR (400 MHz, DMSO-d ,): δ 9.63-9.58 (m, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.17 (s, 1H), 7.56 (s, 1H), 7.26-7.11 (m, 5H), 5.49 (br s, 1H), 5.30 (m, 1H), 4.44 (br s, 1H), 3.87 (br s, 1H), 3.03-2.99 (m, 1H), 2.84-2.80 (m, 1H), 2.26 (s, 3H), 1.25- 1.24 (m, 1H), 1.15 (m, 5H). Compound 27: 2-((1-((R)-but-3-yn-2-yl)-5-methyl-1H-indazol-6-yl) amino)-4- ((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide[000179] To a stirred solution 2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (XII) (0.15g, 0.46 mmol) and (R)-1-(but-3-yn-2-yl)-5-methyl-1H-indazol-6-amine (XXX) (0.09 g, 0.46 mmol) in NMP (3 mL), was added 4M HCl in dioxane (0.2 mL, 0.93 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 90 °C for 3 hours. The reaction progress was monitored by UPLC. After completion of the reaction, the reaction mixture was evaporated in vacuo to get thecrude product as a brown liquid. The obtained crude was purified by Preparative HPLC reverse phase in ammonium bicarbonate in water and acetonitrile to afford desired product Compound 27 as an Off-white solid. Yield: (0.020 g, 9.7%), LC_MS: Calc. C27H24D3N7O2 Calc.:484.58; Obs.: 485.3[M++H]:1H NMR (400 MHz, DMSO-d6): δ 9.77 (d, J = 8.00 Hz, 1H), 8.55 (s, 1H), 8.36 (d, J = 10.80 Hz, 2H), 8.26 (s, 1H), 7.89 (d, J = 14.00 Hz, 1H), 7.52 (s, 1H), 7.32 (d, J = 7.60 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 1H), 5.65-5.62 (m, 1H), 5.43 (d, J = 4.40 Hz, 1H), 4.55-4.51 (m, 1H), 4.44 (s, 1H), 3.29 (d, J = 2.00 Hz, 1H), 3.23-3.18 (m, 2H), 2.90 (d, J = 16.40 Hz, 1H), 2.40 (s, 3H), 1.37 (d, J = 6.80 Hz, 3H). HPLC Purity: 98.22%, Column: Sunfire C18(50 X 4.6) mm, 5μm, Mobile phase:0.1% TFA in water and phase: B: ACN. Compound 28: 2-((1-((R)-sec-butyl)-5-methyl-1H-indazol-6-yl) amino)-4- ((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide[000180] To a solution of 2-((1-((R)-sec-butyl)-5-methyl-1H-indazol-6- yl)amino)-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)pyrimidine- 5-carboxylic (XXXI) (0.50 g, 1.06 mmol) and methan-d3-amine (0.054 g, 1.59 mmol,) in DMF (5 mL), were added DIPEA (0.07 mL, 3.17 mmol) followed by HATU (0.80 g, 2.12 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by UPLC, the reaction mixture was quenched with water (10 mL), and DMF was concentrated under reduced pressure. The crude product was diluted with EtOAc(20 mL) and washed with 10% aq NaHCO3solution (2 X 20 mL). Theorganic phase was dried under Na2SO4, and the solvent was filtered and evaporated in vacuo to get the crude product. The obtained crude was purified by Preparative HPLC reverse phase using ammonium bicarbonate in water and acetonitrile to afford the desired product Compound 28 as an Off-white solid. Yield: (0.045 g, 8.6 %), LC_MS: Calc. C27H28D3N7O2Cal:488.61.; Obs.: 489.3[M++H]:1H NMR (400 MHz, DMSO-d6): δ 9.77 (d, J = 8.00 Hz, 1H), 8.55 (s, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.49 (s, 1H), 7.33-7.18 (m, 4H), 5.59 (d, J = 5.20 Hz, 1H), 5.44 (d, J = 4.80 Hz, 1H), 4.53-4.50 (m, 1H), 3.61 (s, 1H), 3.07-3.01 (m, 1H), 2.90 (m, 1H), 2.38 (s, 3H), 1.75-1.71 (m, 1H), 1.32 (m, 1H), 1.10-1.04 (m, 3H), 0.35 (t, J = 7.20 Hz, 3H). HPLC Purity: 99.71%, Column: X-Bridge C8 (50 X 4.6) mm,3.5μm, Mobile phase: A: Ammonium bicarbonate in water, Mobile phase: B: ACN. Compound 29: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-2- ((1-isopropyl-5-methyl-1H-benzo[d] [1,2,3] triazol-6-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide[000181] To a stirred solution (2-chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro- 1H-inden-1-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (XII) (0.12 g, 0.37 mmol) and 1-isopropyl-5-methyl-1H-benzo[d][1,2,3]triazol-6-amine (XXXII) (0.085g, 0.45 mmol) in NMP (3 mL), was added 4M HCl in dioxane (0.2 mL, 1.49 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 90 °C for 16 hours. The reaction progress was monitored by UPLC. After completion of the reaction, the reaction mixture wasevaporated in vacuo to get the crude product as a brown liquid. The obtained crude was purified by Preparative HPLC reverse phase in ammonium bicarbonate in water and acetonitrile to afford the desired product Compound 29 as an Off-white solid. Yield: (0.014 g, 7.3%), LC_MS: Calc. C25H25D3N8O2 Calc.:475.57; Obs.: 476.10[M++H]: (1H NMR (400 MHz, DMSO-d6): δ 9.74 (d, J = 8.00 Hz, 1H), 8.57 (d, J = 2.80 Hz, 2H), 8.29 (m, 2H), 7.79 (s, 1H), 7.33 (d, J = 7.20 Hz, 1H), 7.28- 7.23 (m, 2H), 7.19-7.15 (m, 1H), 5.61-5.58 (m, 1H), 5.40 (d, J = 4.40 Hz, 1H), 4.51- 4.48 (m, 1H), 3.97-3.96 (m, 1H), 3.07 (dd, J = 4.40, 16.60 Hz, 1H), 2.90-2.86 (m, 1H), 2.45 (s, 3H), 1.22 (dd, J = 6.40, 16.80 Hz, 6H). HPLC Purity; 98.13%, Column: X-Bridge C8(50 X 4.6) mm,3.5μm, Mobile phase: Ammonium bicarbonate in water and phase: B: ACN. Compound 30: 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) amino)-N- (2-hydroxyethyl)-2-(1-isopropyl-5-methyl-1H-benzo[d][1,2,3] triazol-6-yl) amino) pyrimidine-5-carboxamide[000182] To a stirred solution N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2- chloro-4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5- carboxamide III (0.20g, 0.43 mmol) and 1-isopropyl-5-methyl-1H- benzo[d][1,2,3]triazol-6-amine XXXII (0.098g, 0.51 mmol) in NMP (3 mL), 4M HCl in dioxane (0.2 mL, 1.73 mmol) was added at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 90 °C for 16 hours. The reaction progress was monitored by UPLC. After completion of the reaction, the reaction mixture was evaporated in vacuo to get the crude product as a brown liquid. The obtained crude was purified by Preparative HPLC reverse phasein ammonium bicarbonate in water and acetonitrile to afford desired product Compound 30 as an Off-white solid. Yield: (0.019 g, 8.3%), LC_MS: Calc. C26H30N8O3: Calc.:502.58; Obs.: 503.2[M++H]:1H NMR (400 MHz, DMSO-d6): δ 9.75 (d, J = 8.40 Hz, 1H), 8.64-8.59 (m, 2H), 8.33 (d, J = 6.40 Hz, 2H), 7.79 (s, 1H), 7.33 (d, J = 7.20 Hz, 1H), 7.28-7.24 (m, 2H), 7.19-7.16 (m, 1H), 5.61-5.58 (m, 1H), 5.42 (d, J = 4.80 Hz, 1H), 4.74-4.71 (m, 1H), 4.52-4.48 (m, 1H), 3.93 (s, 1H), 3.52-3.47 (m, 2H), 3.31-3.25 (m, 3H), 2.46 (s, 3H), 1.21 (dd, J = 6.40, 18.40 Hz, 6H). HPLC Purity: 95.20%, Column: X-BridgeC8(50 X 4.6) mm,3.5μm, Mobile phase:0.1% TFA in water and phase: B: ACN. Biological Activity Biochemical inhibition of ATM by ELISA based homogeneous time- resolved fluorescence (HTRF) method. [000183] ELISA / EIA kinase assay was used to measure kinase activity of ATM enzyme. The experiment was performed as below: [000184] ATM (h) was incubated in assay buffer containing the compound of Formula I, 30 nM GST-cMyc-p53 and Mg / ATP (concentration as required). The reaction was initiated by the addition of the Mg / ATP mix. After incubation for 30 minutes at room temperature, the reaction was stopped by the addition of stop solution containing EDTA. Finally, detection buffer was added, which contained d2-labelled anti-GST monoclonal antibody, and a Europium-labelled anti-phospho Ser15 antibody against phosphorylated p53. The plate was then read in time- resolved fluorescence mode and the homogeneous time-resolved fluorescence (HTRF) signal was determined according to the formula HTRF = 10000 x (Em665nm / Em620nm). Assay Conditions: Substrate: 30 nM GST-cMyc-p53 ATP Concentration:10 µM Incubation: 40 min at room temperatureBiochemical inhibition of DNA-PK by ELISA based homogeneous time- resolved fluorescence (HTRF) method. [000185] ELISA / EIA kinase assay was used to measure kinase activity of DNA-PK enzyme. The experiment was performed as below: [000186] DNA-PK (h) was incubated in assay buffer containing 50 nM GST- cMyc-p53 and Mg / ATP (concentration as required). The reaction was initiated by the addition of the Mg / ATP mix. After incubation for 30 minutes at room temperature, the reaction was stopped by the addition of stop solution containing EDTA. Finally, detection buffer was added, which contained d2-labelled anti-GST monoclonal antibody, and a Europium-labelled anti-phospho Ser15 antibody against phosphorylated p53. The plate was then read in time-resolved fluorescence mode and the homogeneous time-resolved fluorescence (HTRF) signal was determined according to the formula HTRF = 10000 x (Em665nm / Em620nm). Assay Conditions: Substrate: 50 nM GST-cMyc-p53 ATP Concentration:10 µM Incubation: 40 min at room temperature [000187] Table 1 shows calculated IC50values of the compounds of Formula I against ATM and DNA-PK enzymes from the ELISA based homogeneous time- resolved fluorescence (HTRF) assay. Table 1ND- not determined. Measurement of growth inhibitor concentrations in cell lines HCT116 and A549 [000188] The compounds of Formula I exhibit potent inhibition of both ATM and DNA-PK enzymes from the PIKK Kinase family and cell proliferation of colorectal (HCT116) and lung (A549) cancer cells. [000189] HCT116 (ATCC; CCL 247), a human colon cancer cell line and A549 (ATCC;CCL 185), an adenocarcinomic human alveolar basal epithelial cell line were cultured in McCoy's 5A and F12K medium, respectively, supplemented with 10% FBS and 1% penicillin / streptomycin. The cells were maintained at 37 °Cin a humidified atmosphere with 5% CO2 to achieve exponential growth. Upon reaching 80% confluency, cells were dissociated using 0.5% trypsin / EDTA for subsequent experiments. Cell viability was determined using Resazurin based assay as a readout method. Cell density of 1×104cells were seeded in a 96-well plate with 150 μL of medium per well and incubated overnight at 37 °C in a CO2incubator. The following day, cells were exposed to varying concentrations of test compounds dissolved in 1% dimethyl sulfoxide (DMSO), alongside appropriate assay controls. Incubation continued for an additional 48 hours at 37 °C in a CO2incubator. Resazurin (50 μg / mL) was added to the culture medium in both compound-treated and untreated wells. A subsequent incubation period of 2-4 hours at 37 °C in a CO2 incubator was followed, and fluorescence signals were recorded at 530 nm excitation / 600 nm emission. GI50(50% growth inhibitory concentration) was considered as the lowest concentration at which 50% cell viability was observed. [000190] GI50 of the compounds of Formula I against HCT116 and A549 cancer cell-lines are presented in Table 2 in comparison with that of Doxorubicin. Table 2 shows the growth inhibitory concentration determination (GI50). Table 2Growth inhibitory concentration determination against different cancer types: Cell Lines: MDA-MB-231, MDA-MB-436, MDA-MB-468, UWB1.289 Kuramochi and OVCAR3 [000191] The representative compounds of Formula I are of interest due to their potent inhibition of ATM and DNA-PK enzymes and their ability to inhibit the growth of proliferating afore-mentioned cancer cell lines. [000192] Cells were cultured in respective culture medium (as per ATCC instructions). The cells were maintained at 37 °C in a humidified atmosphere with 5% CO2 to achieve exponential growth. Upon reaching 80% confluency, cells weredissociated using 0.5% trypsin / EDTA for subsequent experiments. Cell viability was determined using CellTiter-Glo as a readout method. Cells, adjusted to a density of 4,000 cells and seeded in a 96-well plate with 150 μL of medium per well and incubated overnight at 37 °C in a CO2 incubator. The following day, cells were exposed to varying concentrations of test compounds (Formula I) dissolved in 1% dimethyl sulfoxide (DMSO), alongside appropriate assay controls. Incubation continued for an additional 96 hours at 37 °C in a CO2 incubator. Cell viability assays were conducted according to the manufacturer’s specifications for CellTiter- Glo Luminescent Cell Viability Assay (Promega).CC50 (50% cytotoxic concentration) is considered as the lowest concentration at which 50% cell viability is observed. GI50 (growth inhibitory concentration) of the compounds of Formula I against various cancer cell-lines are presented in Table 3. Table 3: Growth inhibitory concentration determination (GI50)that the compounds of Formula I of the present disclosure inhibit various cancer cell lines of HCT116, A549, MDA-MB-231, MDA-MB-436, MDA- MB-468, UWB1.289 Kuramochi and OVCAR3 and suggested that dual target(ATM / DNA-PK) inhibition of compounds of Formula I translated into anti-proliferative activity. The observation implied that the compounds have synergistic activity in reducing the tumour burden when they were combined with radiation therapy, chemotherapeutic agents, or immunotherapy agents. Rodent pharmacokinetics(PK) study of selected compounds of formula I: Rodent PK Study: [000194] The PK study was conducted in male CD1 mice and SD rats to estimate plasma clearance, volume of distribution, terminal half-life, area under the curve (AUCo-t), peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), and absolute bioavailability (%F) following intravenous and oral administration routes. [000195] The detailed experimental design is provided in Table 4.Table 4q.s: quantity sufficient [000196] In summary, all animals in the intravenous (i.v. infusion) group were in the fed state, animals in oral groups were fasted overnight (6 hours) before dose administration, and food was provided 4 h post-dose administration. All animals received water ad-libitum during the study period. The compound10 and compound 14 were experimented on with mice and rats. [000197] The pharmacokinetic study design in Mice and Rats is provided in Table.4[000198] Blood samples (0.2 mL for rats and 0.025 mL for mice) were collected from the jugular vein (rats) and saphenous vein (mice) into tubes containing K2EDTA anticoagulant at the following sampling times: [000199] IV infusion: 0.25 h, 0.5, 0.58, 0.75, 1, 2, 4, 6, 8, and 24 hours [000200] PO: Predose, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hrs post-dose. [000201] Immediately following collection, blood samples were inverted to ensure mixing with anticoagulant and placed on wet ice. As soon as practically possible, samples were centrifuged (3000 rpm, 10 min, at 4°C), and the resultant plasma was decanted into appropriately labelled polypropylene tubes in 96-well plate format and stored in a freezer set to maintain a temperature of ≤-70°C until analysis. [000202] Plasma samples were analysed for a fit-for-purpose LC-MS / MS method with a lower limit of quantification. The pharmacokinetic parameters were calculated using the non-compartmental analysis tool of validated Phoenix® WinNonlin®software (Certara, USA version 8.4) with a linear up and log down method for estimating AUC. [000203] The mean (±SD) pharmacokinetic parameters of compound10 and compound 14 following i.v. infusion and oral dose administration in mice and rats are provided in the Table 5.Table 5* For i.v groups; # median (min-max); ND-not determined; i.v infusion for 30min Results were expressed in mean ± SD; n=3 animals / group. [000204] Compound 10 achieved very good oral bioavailability (%F) of 64, and compound 14 low bioavailability of 9.3%. The total systemic clearance of compound 10 was moderate to that of hepatic clearance and high volume of distribution >3x total body water (TBW). Whereas the compound 14 had moderate clearance than hepatic clearance and a high volume of distribution of 2x total body water (TBW) in rats. [000205] Compound 10 achieved good systemic exposure (AUC0-t14694 h*ng / mL) at a 30 mg / kg dose level. Whereas compound 14 achieved relatively less systemic exposure (AUC0-t, 2644 h*ng / mL) compared to compound 10 after oral administration at a dose level of 30 mg / kg in rats. [000206] In mice at 15 and 30 mg / kg post oral dose administration, Compound 10 and compound 14 had demonstrated good systemic exposures (AUC0-t,1650 and 1736 ng.h / mL) and Cmax(1050 and 595 ng / mL) with Tmaxof 0.5 and 2.0 hours. ADVANTAGES OF THE PRESENT DISCLOSURE[000207] The present disclosure provides compounds of Formula I, particularly of Formula Ia, Ib, and Ic that address the need for therapeutic agents which act as potent cancer treatment methods. The compounds of the present disclosure selectively and efficiently inhibit both ATM and DNA-PK enzymes to enhance the efficacy of traditional cancer therapies. It also improves the outcome of radiotherapy and synergistically act as a class of drugs which causes DNA damage. Further, the present disclosure provides a class of compounds that offer a new approach for treating drug-resistant tumours, ultimately improving the effectiveness and benefit-risk profile of cancer patients. Further, the compounds disclosed herein expands the application of dual inhibition in combination with standard of care drugs to a broad range of patients with different cancer sub-types. Moreover, the present disclosure provides a compatible yet convenient process for the synthesis of the disclosed class of compounds.

Claims

AMENDED CLAIMS received by the International Bureau on 13 October 2025 (1.10.2025)I / We claim:

1. A compound of Formula I, its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, stereoisomers, polymorphs, or pharmaceutically active derivatives thereofwherein ring A is selected from* point of attachment whereinRi is selected from C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl, wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl or C2-8 heterocyclyl;¥ is N or CR2, when ¥ is connected via double bond wherein R2 is selected from hydrogen, halogen, C1-6alkyl, C1-66lkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; Y is O or S, when Y is connected via single bond; n is selected from 0 to 3;R3 is selected from halogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;R is selected from hydrogen, C1-6alkyl, C1-6alkoxy, Ci-e haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;R4 is selected from hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated C1-6alkyl, C1-6haloalkyl, Ci-e alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl, wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated C1-6alkyl, C1-6haloalkyl, Ci-e haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, Ci-6 alkoxy, C3-8 cycloalkyl, C1-6aminoalkyl, or C1-6haloalkyl, wherein C3-8 cycloalkyl is optionally further substituted with halogen or hydroxy;Zi, Z2, Z3, and Z4 are independently selected from N or CRe;X is selected from O or CR?;Re is selected from hydrogen, cyano, halogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;R? is selected from hydrogen, cyano, halogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; and ni is 0 or 1.

2. The compound as claimed in claim 1, wherein the compound is selected fromits pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, stereoisomers, polymorphs, or pharmaceutically active derivatives thereof, whereinRi is selected from C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, Ci-e haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl, wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl or C2-8 heterocyclyl;Y is N or CR2, when Y is connected via double bond wherein R2 is selected from hydrogen, halogen, C1-6alkyl, Ci-e alkoxy, C1-6haloalkyl, Ci-e haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;Y is O or S, when Y is connected via single bond; n is selected from 0 to 3;R3 is selected from halogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;R is selected from hydrogen, C1-6alkyl, Ci-e alkoxy, Ci-e haloalkyl, Ci-e haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;R4 is selected from hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated Ci-6 alkyl, Ci-6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl, wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated C1-6alkyl, Ci-e haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, Ci-6 alkoxy, C3-8 cycloalkyl, Ci-e aminoalkyl, or C1-6haloalkyl, wherein C3-8 cycloalkyl is optionally further substituted with halogen or hydroxy;Zi, Z2, Z3, and Z4 are independently selected from N or CRe;X is selected from O or CR?;Re is selected from hydrogen, cyano, halogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;R? is selected from hydrogen, cyano, halogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; and ni is 0 or 1.

3. The compound as claimed in claims 1 to 2, wherein Ri is selected from C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, Ci-e alkoxy, C3-8 cycloalkyl or C2-8 heterocyclyl, wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e alkoxy or C3-8 cycloalkyl, is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl, or C2-8 heterocyclyl;¥ is N or CR2, when ¥ is connected via double bond wherein R2 is selected from hydrogen, halogen, C1-6alkyl, or C1-6alkoxy;Y is O or S, when Y is connected via single bond; n is selected from 0 to 2;R3 is selected from halogen, C1-6alkyl, C1-6alkoxy, or C1-6haloalkyl;R is selected from hydrogen, C1-6alkyl, Ci-e alkoxy, or Ci-e haloalkyl;R4 is selected from hydrogen, C1-6alkyl, deuterated Ci-e alkyl, C1-6haloalkyl, C3-8 cycloalkyl, wherein C1-6alkyl, deuterated C1-6alkyl, C1-6haloalkyl, or C3-8 cycloalkyl, is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, Ci- 6 alkoxy, C3-8 cycloalkyl, C1-6aminoalkyl, or Ci-e haloalkyl, wherein C3-8 cycloalkyl is optionally further substituted with halogen or hydroxy;Zi, Z2, Z3, and Z4 are independently selected from N or CRe;X is selected from O or CR?;Re is selected from hydrogen, cyano, halogen, C1-6alkyl, or C1-6haloalkyl; R? is selected from hydrogen, cyano, halogen, C1-6alkyl, or Ci-e haloalkyl; and ni is 0 or 1.

4. The compound as claimed in anyone of the claims 1 to 3, wherein Ri is selected from CH2CH3, CH3, CH(CH3)2, CH2CH2CH3, CH2CHF2, CH2CF3, CH2CH2CHF2, CH2CH2OCH3, CH2CH2OCF3, CH2CH2OCHF2, CH2CH2CHOH, CH(CH3)CH2CH3, CH2CH2CN,Y is N or CR2 when Y is connected via double bond wherein R2 is selected from hydrogen, F, CH3, CF3,or CHF2;Y is O or S when Y is connected via single bond; n is 0, 1 or 2;R3 is selected from CH3, F, Cl, CF3, or CHF2;R is selected from hydrogen, CH3, CF3, or OCH3; andR4 is selected from hydrogen, CH3, CH2CH3, CD3, CF3, CH2CHF2,Zi, Z2, Z3, and Z4 are independently selected from N or CRe;X is selected from O or CR?;Re is hydrogen, or C1-6alkyl;R? is hydrogen, or C1-6alkyl; and ni is 0 or 1.

5. The compound as claimed in anyone of the claims 1 to 4, wherein the compound is selected from a. Compound 11:: 2-((5-fluoro-l-isopropyl-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidine-5- carboxamide; b. Compound 2: 2-((5-fluoro-l-isopropyl-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-(2- hydroxy ethyl) pyrimidine-5-carboxamide; c. Compound 3: 2-((5-fluoro-l-isopropyl-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N- methylpyrimidine-5-carboxamide; d. Compound 4: 2-((l-allyl-5-fluoro-lH-indazol-6-yl) amino)-4-((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidine-5-carboxamide; e. Compound 5: 2-((l-ethyl-5-fluoro-lH-indazol-6-yl) amino)-4-(((lS,2R)- 2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidine-5- carboxamide; f. Compound 6: 2-((l-cyclopropyl-5-fluoro-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N- methylpyrimidine-5-carboxamide; g- Compound 7: 2-((6-fluoro-3-isopropylbenzo[d]isoxazol-5-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N- methylpyrimidine-5-carboxamide; h. Compound 8: 2-((6-fluoro-3-isopropylbenzo[d]isoxazol-5-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-(2- hydroxy ethyl) pyrimidine-5-carboxamide; i. Compound 9: 2-((5-fluoro-l-propyl-lH-indazol-6-yl) amino)-4-((lS,2R)- 2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-methylpyrimidine-5- carb oxami de.;J. Compound 1100:: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-((l-isopropyl-5-methyl-lH-indazol-6-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide; k. Compound 1111:: 2-((l-allyl-5-methyl-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide;1. Compound 1122:: 2-((l-(2,2-difluoroethyl)-5-methyl-lH-indazol-6-yl) amino)-4-(((l S,2R)-2-hydroxy-2,3 -dihydro- IH-inden- 1 -yl) amino)-N- (methyl-d3) pyrimidine-5-carboxamide; m. Compound 13: 2-((l-(3,3-difluoropropyl)-5-methyl-lH-indazol-6-yl) amino)-4-(((l S,2R)-2-hydroxy-2,3 -dihydro- IH-inden- 1 -yl) amino)-N- (methyl-d3) pyrimidine-5-carboxamide; n. Compound 1144:: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-(2-hydroxyethyl)-2-((l-isopropyl-5-methyl-lH-indazol-6-yl) amino) pyrimidine-5-carboxamide; o. Compound 15: 2-((l-allyl-5-methyl-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-(2- hydroxy ethyl) pyrimidine-5-carboxamide;P- Compound 1166:: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-(methyl-d3)-2-((5-methyl-l-(prop-2-yn-l-yl)-lH-indazol-6-yl) amino) pyrimidine-5-carboxamide; q- Compound 1177:: 2-((l-(2,2-difluoroethyl)-5-methyl-lH-indazol-6-yl) amino)-4-(((l S,2R)-2-hydroxy-2,3 -dihydro- IH-inden- 1 -yl) amino)-N-(2- hydroxy ethyl) pyrimidine-5-carboxamide; r. Compound 18: 2-((l-ethyl-5-methyl-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide; s. Compound 1199:: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-((l -(2 -m ethoxy ethyl)-5-methyl-lH-indazol-6-yl) amino)-N- (methyl-d3) pyrimidine-5-carboxamide;t. Compound 2200:: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-(2-hydroxyethyl)-2-((5-methyl-l-(prop-2-yn-l-yl)-lH-indazol- 6-yl) amino) pyrimidine-5-carboxamide; u. Compound 21 : N-(2-aminoethyl)-4-(((l S,2R)-2-hydroxy-2,3-dihydro- 1 H-inden- 1 -yl) amino)-2-(( 1 -isopropyl -5 -methyl- 1 H-indazol-6-yl) amino) pyrimidine-5-carboxamide;V. Compound 2222:: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-((S)-l-hydroxypropan-2-yl)-2-((l-isopropyl-5-methyl-lH- indazol-6-yl) amino) pyrimidine-5-carboxamide w. Compound 23: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-((R)-l-hydroxypropan-2-yl)-2-((l-isopropyl-5-methyl-lH- indazol-6-yl) amino) pyrimidine-5-carboxamide;X. Compound 24: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-((R)-2-hydroxypropyl)-2-((l-isopropyl-5-methyl-lH-indazol- 6-yl) amino) pyrimidine-5-carboxamide; y- Compound 25: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-((l-hydroxycyclopropyl)-2-((l-isopropyl-5-methyl-lH- indazol-6-yl) amino) pyrimidine-5-carboxamide; z. Compound 26: 4-((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-((3 -isopropyl -6-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide; aa. Compound 27: 4-((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-((3 -isopropyl -6-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide; bb. Compound 28: 2-((l-((R)-sec-butyl)-5-methyl-lH-indazol-6-yl) amino)- 4-((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-(methyl- d3) pyrimidine-5-carboxamide; cc. Compound 29: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-(( 1 -isopropyl-5 -methyl- lH-benzo[d] [1,2,3] triazol-6-yl) amino)-N-(methyl-d3) pyrimidine-5-carboxamide; anddd. Compound 3300:: 4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-N-(2 -hydroxy ethyl)-2-(l -isopropyl-5-methyl- 1H- benzo[d][l,2,3] triazol-6-yl) amino) pyrimidine-5-carboxamide.

6. A process of preparing the compound as claimed in claim 1, the process comprising: reacting a compound of Formula C with a compound selected from Formula D, Formula G or Formula K and an amine of R4NH2 which is optionally protected and optionally deprotecting to obtain the compound of Formula I,wherein R’ is selected from hydroxy, amine, C1-6alkoxy, or Ci-e alkylamino; ring A is an optionally substituted 5 to 8 membered heterocyclyl ring;Ri is selected from C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, Ci-e haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl, wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl or C2-8 heterocyclyl;R3 is selected from halogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;R is selected from hydrogen, C1-6alkyl, Ci-e alkoxy, Ci-e haloalkyl, Ci-e haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;R4 is selected from hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, deuterated Ci-6 alkyl, Ci-6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl, wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl,deuterated C1-6alkyl, Ci-e haloalkyl, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl is optionally substituted with one or more groups selected from halogen, oxo, amino, amide, hydroxy, -S(O)2-NH2, Ci-6 alkoxy, C3-8 cycloalkyl, C1-6aminoalkyl, or C1-6haloalkyl, wherein C3-8 cycloalkyl is optionally further substituted with halogen or hydroxy;Zi, Z2, Z3, and Z4 are independently selected from N or CR6;X is selected from O or CR7;Re is selected from hydrogen, cyano, halogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl;R? is selected from hydrogen, cyano, halogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-8 cycloalkyl, C2-8 heterocyclyl, or C2-8 heteroaryl; and ni is 0 or 1.

7. The process as claimed in claim 6, wherein the process is carried out in the presence of a base, and a coupling reagent.

8. The process as claimed in claim 7, wherein the base is selected from triethylamine, diisopropylethylamine, pyridine, sodium hydride, potassium tertiary butoxide, sodium carbonate, potassium carbonate, or combinations thereof.

9. The process as claimed in claim 7, wherein the coupling reagent is selected from HATU((Hexafluorophosphate Azabenzotri azole Tetramethyl Uronium), CDI (Carbonyldiimidazole), EDCI(l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide), or combinations thereof.

10. The compound as claimed in any one of the claims 1 to 5, for use in the manufacture of a medicament.

11. The compound as claimed in any one of the claims 1 to 5, wherein the compound is an inhibitor of Ataxia telangiectasia mutant (ATM) or DNA- dependent Protein Kinase (DNA-PK) or combinations thereof.

12. The compound as claimed in any one of the claims 1 to 5, for use in treating cancer mediated at least in part by ATM or DNA-PK or combinations thereof.

13. The compound as claimed in claim 12, wherein said cancer is selected from cancer of adrenal gland, brain, bladder, breast, bone, colon, oesophagus, head, gastric, kidney, liver, lung, muscle, neck, pancreas, prostate, skin, thyroid or white blood cells.

14. A combination comprising compounds of Formula I as claimed in claims 1 to 5 with at least one additional therapeutic agent.

15. A combination comprising compounds of Formula la, lb, and Ic as claimed in claims 2 to 5, with at least one additional therapeutic agent.

16. The combination as claimed in claim 14 or 15, wherein the additional therapeutic agent is selected from a radiotherapeutic agent, a chemotherapeutic agent or an immune checkpoint inhibitor.

17. The combination as claimed in claim 16, wherein the chemotherapeutic agent is selected from poly ADP ribose polymerase (PARP) inhibitor, topoisomerase inhibitors, CDK4 / 6 inhibitor, BC12 (B-cell lymphoma-2) inhibitor, Bcl-XL (B- cell lymphoma-extra-large) inhibitor, anti-estrogen, anti-progesterone, KRas inhibitor, Braf inhibitor, EGFR inhibitor, angiogenesis inhibitor, phosphoinositide 3 -kinase inhibitor (PI3K) inhibitor, tyrosine kinase inhibitor, signal transducer and activator of transcription 3 (Stat-3) inhibitor, Protein kinase B (AKT) inhibitor, c-Jun N-terminal kinase (JNK1 / K2) inhibitors, hypoxia-inducible factor 1 alpha (HIF-la) inhibitor, extracellular signal- regulated kinase (ERK) inhibitor, cisplatin, oxaplatin or combinations thereof.

18. The combination as claimed in claim 16, wherein the immune checkpoint inhibitor is selected from programmed death-1 (PD-1) inhibitor, programmed death-ligand 1 (PD-L1) inhibitor, anti-PDl antibody, anti-PD-Ll antibody, cytotoxic T-lymphocyte-associated protein 4 (CTL4), inhibitor, anti-CTL4 antibody, T cell immunoglobulin and ITIM domain (TIGIT) inhibitor, ectonucleoside triphosphate diphosphohydrolase l(E-NTPDase, CD39) inhibitor, ecto-5'-nucleotidase(Ecto5'NTase, CD79) inhibitor, Protein tyrosinephosphatases non-receptor type 1 / 2 (PTPN1 / 2) inhibitors, or combinations thereof.

19. A pharmaceutical composition comprising the compound as claimed in claim 1 to 5 with at least one pharmaceutically acceptable excipient.

20. The composition as claimed in claim 17, wherein the composition is in the form of powder, tablet, liquid, or emulsion.

21. A method of treating cancer in a subject, the method comprising administering the compound as claimed in claim 1 to 5 or the combination as claimed in claim 14 to 15 or the pharmaceutical composition as claimed in claim 18 to 19 to the subject in need thereof.

22. The method as claimed in claim 21, wherein the cancer is selected from cancer of adrenal gland, brain, bladder, breast, bone, colon, oesophagus, head, gastric, kidney, liver, lung, muscle, neck, pancreas, prostate, skin, thyroid or white blood cells.

23. A method of treating a disease or condition mediated by ATM or DNA-PK or combinations thereof to a subject in need thereof, the method comprising administering the compound as claimed in claim 1 to 5 or the combination as claimed in claim 14 to 18 or the pharmaceutical composition as claimed in claim 19 to 20 to the subject.

24. The method as claimed in claim 23, wherein the disease or condition is selected from cancer of adrenal gland, brain, bladder, breast, bone, colon, oesophagus, head, gastric, kidney, liver, lung, muscle, neck, pancreas, prostate, skin, thyroid or white blood cells.STATEMENT UNDER ARTICLE 19 PCTIn response to the International Searching Report (ISR) and the objections raised in the Written Opinion of the International Search Authority (ISA), the Applicant has amended the claims suitably.Claim 1 has been amended to incorporate the features of the claim 2 for which novelty has been acknowledged. Accordingly, claim 2 has been cancelled. The Applicant submits that the Document DI does not explicitly recite the compounds as claimed in claim lof the instant Application, therefore the claims are novel and inventive over the Document DI.

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