Triamino pyrimidine compounds as CDK7 inhibitors and methods thereof

Abstract

The present disclosure provides triamino pyrimidine compounds of Formula (I), its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, or pharmaceutically active derivatives thereof as CDK7 inhibitors. The present disclosure also provides pharmaceutical composition comprising said compounds. The present disclosure further provides process of preparing said compounds and methods thereof.

Description

TRIAMINO PYRIMIDINE COMPOUNDS AS CDK7 INHIBITORS AND METHODS THEREOFFIELD OF INVENTION

[0001] The present disclosure relates to the field of medicinal chemistry and therapeutic agents. Particularly, the present disclosure provides compounds which could be used for therapeutic applications for treatment of cancer.BACKGROUND OF THE INVENTION

[0002] Cyclin-dependent kinase 7 (CDK7) plays an important role in two cellular processes that are often dysregulated during oncogenesis which are (a) regulation of RNA polymerase Il-mediated transcription and (b) cell cycle progression as the CDK activating kinase Fisher, R. P. (2019) doi: 10.1080 / 21541264.2018.1553483). Traditionally, CDKs are classified into two exclusive sets: the cell-cycle CDKs (CDK1, 2, 4 and 6) and the transcriptional CDKs (CDK8, 9, 12 and 13). However, CDK7 functions in both of the above- mentioned cellular processes (Fisher, 2005. doi: 10.1242 / jcs.02718. ) with stringent modes of substrate recognition (Larochelle, S. et al., doi: 10.1038 / nsmbl028). The transcription associated CDKs are emerging as important targets and biomarkers in oncology. In contrast to the cell cycle associated CDKs, this family of CDKs play critical roles in regulating gene expression at multiple levels, including transcription, splicing, intronic polyadenylation, and epigenetics. Certain cancer types can also become addicted to dysregulated transcriptional programs of specific genes, whose high expression is facilitated by super enhancers (SEs) (Chipumuro, E. et al., doi: 10.1016 / j.cell.2014.10.024; Bradner, J. E., Hnisz, D. and Young, R. A., doi: 10.1016 / j.cell.2016.12.013; Fisher, R. P., doi: 10.1080 / 21541264.2018.1553483). CDK7 is enriched at SEs, including those that drive expression of oncogenes, and it seems to mediate this transcriptional addiction (Wang, Y. et al. (2015) doi: 10.1016 / j.cell.2015.08.063; Bradner, J. E., Hnisz, D. and Young, R. A. et. al., doi: 10.1016 / j.cell.2016.12.013; Fisher, R. P. et. al., (2019)doi: 10.1080 / 21541264.2018.1553483). It is closely coupled to the cellular metabolism in tumour cells by influencing glucose consumption and glycolysis (Ghezzi C, Wong A, et. al., doi: 10.1038 / s41467-019-13334-8; Yao Y, Ng JF, Park WD, et al. doi: 10.1182 / blood.2022018885). This indicates that CDK7 has larger global effects beyond cell cycle and transcription.

[0003] There were initial concerns about the toxicity of targeting CDK7 due to its role in normal cells Fisher, R. P. et.al., doi: 10.1242 / jcs.02718; Lolli, G. and Johnson, L. N. (2005) ‘CAK-Cyclin-Dependent Activating Kinase: A key kinase in cell cycle control and a target for Drugs? ’, Cell Cycle. PMID: 15876871). However, the development of highly specific inhibitors has resulted in effective reduction of tumor growth in vivo especially in combination with CDK4 / 6 inhibitors (Hazel, P. et al., doi: 10.1002 / cmdc.201600535; Patel, H. et al., doi: 10.1158 / 1535-7163). There is further evidence that transcription is dysregulated in cancer cells and that the transcription of certain genes is disproportionately sensitive to inhibition of transcription (Wang, Y. et al., doi: 10.1016 / j.cell.2015.08.063; Patel, H. et al., doi: 10.1158 / 1535-7163). Overexpression of components of the CDK7 complex has also been observed in various types of tumors, including various types of breast cancer (Patel, H. et al., doi: 10.1158 / 1535-7163; Teng, Y. et al., doi: 10.1016 / j.ejmech.2019.111641). This makes CDK7 an attractive target of anti-cancer drugs, and interest in the potential therapeutic use of CDK7 inhibitors in cancer is rapidly growing (Hazel, P. et al., doi: 10.1002 / cmdc.201600535; Teng, Y. et al., doi: 10.1016 / j.ejmech.2019.111641 ; Chou J, Quigley DA, Robinson IM, Feng FY, Ashworth A. et. al., doi: 10.1158 / 2159-8290.CD-19-0528).

[0004] Therefore, there is a need in the art to develop therapeutic agents that selectively and efficiently inhibit CDK7 to enhance the efficacy of cancer therapies. Furthermore, there is a dire requirement for the development of therapeutic drugs that overcome the limitations of the conventional drugs that inhibit CDK4 / 6 and thereby offer a new approach for treating drug-resistant tumors, ultimately improving the benefit-risk profile of cancer patients.SUMMARY OF THE INVENTION

[0005] In a first aspect of the present disclosure, there is provided a compound of Formula I, its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, or pharmaceutically active derivatives thereof,wherein Ri is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, or C3-8 heterocyclyl, wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl;Yi is N or C(=O);Y2 is selected from N, O, CR2, or NR3, wherein R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; wherein C1-6 alkyl is optionally substituted with Ci -6 alkoxy or hydroxy;R is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;Rs is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, Ci- 6 alkyl, C1-6 haloalkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from C1-6 alkyl, Ci-6 aminoalkyl, Ci-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein C1-6 alkyl or C3-8 heterocyclyl is optionally substituted with hydroxy, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C3-8 heteroaryl or C3-8 heterocyclyl; wherein C3-8 heterocyclyl is optionally substituted with one or more groups selected from oxo or C1-6 alkyl; p is 0 or 1 ;Re is selected from hydrogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, Ci-6aminoalkyl, C(=O)NR9aR9b, -NH-C(=O) R9 or -NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy or cyano;R9, Rgaand R9H are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein C1-6 alkyl, C1-6 aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -S-C1-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl or C3-12 heteroaryl is optionally substituted with one or more substituents selected from C1-6 alkyl; or R9aand R9bare combined together to form a C3-8 heterocyclyl optionally substituted with one or more substituents selected from oxo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 aminoalkyl;Zi, Z2, Z3, and Z4 are independently selected from N or CR10:Rio is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O, S, S=O, SO2, N-CH3, N-C(=O)CH3or CRn;R11 is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; nl is 0, 1 or 2; n2 is 0, 1 or 2; and n3 is selected from 0 to 3.

[0006] In a second aspect of the present disclosure, there is provided there is provided a process of preparation of compounds of Formula I as disclosed herein,the process comprising: reacting Formula (A) and Formula (B) followed by reacting with Formula (D) in the presence of a base to obtain the compound of Formula I,wherein, Ri is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or C3-8 heterocyclyl, wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl;Yi is N or C(=O);Y2 is selected from N, O, CR2 or NR3, wherein R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; wherein C1-6 alkyl is optionally substituted with Ci -6 alkoxy or hydroxy;R is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;Rs is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy; nl is 0, 1 or 2;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, Ci- 6 alkyl, C1-6 haloalkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from C1-6 alkyl, Ci- 6 alkoxy, C1-6 aminoalkyl, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein C1-6 alkyl or C3-8 heterocyclyl is optionally substituted with hydroxy, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C3-8 heteroaryl; wherein C3-8 heterocyclyl is optionally substituted with one or more groups selected from oxo or C1-6 alkyl; p is 0 or 1;Re is selected from hydrogen, amino, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6aminoalkyl, C(=O)NR9aR9b, -NH-C(=O) R9or -NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy, or cyano;R9, R9aand R9b are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein C1-6 alkyl, C1-6 aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -S-C1-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl or C3-12 heteroaryl is optionally substituted with one or more substituents selected from C1-6 alkyl; or R9aand R9b are combined together to form a C3-8 heterocyclyl optionally substituted with one or more substituents selected from oxo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 aminoalkyl;Zi, Z2, Z3, and Z4 are independently selected from N or CR10;Rio is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O, S, S=O, SO2, N-CH3, N-C(=O)CH3or CRn;R11 is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl , C1-6 alkoxy, or C1-6 haloalkoxy; n2 is 0, 1 or 2; and n3 is selected from 0 to 3.

[0007] In a third aspect of the present disclosure, there is provided a compound of Formula I as disclosed herein, for use in the manufacture of a medicament.

[0008] In a fourth aspect 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.

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

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

[0011] In a seventh 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 an eighth aspect of the present disclosure, there is provided a method of treating a disease or condition mediated by cyclin dependent kinase 7 or cyclin dependent kinase 7 with cyclin H and MAT1 or CDK-activating kinase (CAK) or combinations thereof to a subject in need thereof, 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 appended claims and detailed description. 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 depicts Mean tumor growth kinetics test compounds in athymic nude mice bearing subcutaneous HCT116 tumor. Values are represented as Mean ± SEM of 8 animals in each group, Statistical analysis carried out by two- way ANOVA followed by Bonferroni post-test. ****P<0.0001, in accordance with an embodiment of the present disclosure.

[0015] Figure 2 depicts Mean tumor weight (mg) of test compounds in athymic nude mice bearing subcutaneous HCT116 tumor at termination after treatment. Values are represented as Mean ± SEM of 8 animals in each group,Statistical analysis was carried out by one way ANOVA followed by the Dunnett test. ***P<0.001 in accordance with an embodiment of the present disclosure.

[0016] Figure 3 depicts Percentage (%) change in body weight of athymic nude mice-bearing subcutaneous HCT-116 tumor, values are represented as Mean ± SEM of 8 animals in each group, in accordance with an embodiment of the present disclosure.

[0017] Figure 4 depicts Mean tumor growth kinetics test compounds in athymic nude mice bearing subcutaneous MDA-MB-468 tumor, values are represented as Mean ± SEM of 8 animals in each group. Statistical analysis carried out by two-way ANOVA followed by Bonferroni post-test. ****P<0.0001, in accordance with an embodiment of the present disclosure.

[0018] Figure 5 depicts Mean tumor weight (mg) of test compounds in athymic nude mice bearing subcutaneous MDA-MB-468 tumor at termination after treatment, values are represented as Mean ± SEM of 8 animals in each group. Statistical analysis was carried out by one way ANOVA followed by the Dunnett test. ***P<0.001, in accordance with an embodiment of the present disclosure.

[0019] Figure 6 depicts Percentage (%) change in body weight of athymic nude mice-bearing subcutaneous MDA-MB-468 tumor, values are represented as Mean ± SEM of 8 animals in each group, in accordance with an embodiment of the present disclosureDESCRIPTION OF THE INVENTION

[0020] 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

[0021] 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.

[0022] 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.

[0023] 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.

[0024] The term “including” is used to mean “including but not limited to”, “including” and “including but not limited to” are used interchangeably.

[0025] In the structural formulae given herein and throughout the present disclosure, the following terms have been indicated meaning, unless specifically stated otherwise.

[0026] The term "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and / or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically- acceptable excipient(s) / carrier(s) utilized, the route of administration, and like factors within the knowledge and expertise of the attending physician.

[0027] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of soundmedical 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.

[0028] 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.

[0029] The term “intermediates” refers to compounds that are useful in generating the target compounds. The intermediates are compounds that 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. In an aspect of the present disclosure, the compounds of Formula la and Formula lb are two forms of the compound of Formula I.

[0030] 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.

[0031] The compounds discussed herein in many instances may have been named and / or checked with ACD / Name by ACD / Labs® and / or Chemdraw by C ambridgeS oft® .

[0032] 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.

[0033] 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.

[0034] 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-hydroxy ethanesulfonate, benzenesulfonate (besylate), aminobenzenesulfonate, p-toluenesulfonate (tosylate), and naphthalene-2- sulfonate.

[0035] The term “solvate”, as used herein, refers to a crystal form of a substance which contains solvent.

[0036] The term “hydrate” refers to a solvate form of a substance wherein the solvent is water.

[0037] 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).

[0038] 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.

[0039] The term “alkyl” refers to a saturated hydrocarbon chain having the specified number of carbon atoms. For example, which are not limited, Ci-6 alkyl refers to an alkyl group having from 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 such as CD3, CHD2, CDH2, CH2CD3, CD2CH3 and the like.

[0040] The term “alkenyl” refers to an unsaturated hydrocarbon chain having a specific number of carbon atoms and at least one double bond between carbonatoms. For example, which are not limited, Ci-6 alkenyl refers to an alkenyl group having from 1-6 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.

[0041] The term “alkynyl” refers to an unsaturated hydrocarbon chain having a specific number of carbon atoms and at least one triple bond between carbon atoms. For example, C2-6 alkynyl 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.

[0042] The term “alkoxy” refers to an alkyl group attached via an oxygen linkage to the rest of the molecule. For example, C1-6 alkoxy 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.

[0043] The term “amino” refers to -NH2 group.

[0044] The term “hydroxy” refers to -OH group.

[0045] The term “cyano” refers to -CN group.

[0046] The term “oxo” refers to =0 group.

[0047] The term “haloalkyl” as used herein, refers to an alkyl group as defined herein, wherein one or more hydrogen of alky group is substituted with halogen atoms. Examples of haloalkyl include, but are not limited to trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, and the like.

[0048] The term “haloalkoxy” refers to a haloalkyl group attached via an oxygen linkage to the rest of the molecule. Examples of haloalkoxy include, but are not limited to trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, dichloromethoxy, chloromethoxy, and the like.

[0049] 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 unsaturated. In few 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.

[0050] The term “heteroaryl” refers to an aromatic heterocyclic ring radical as defined above. The heteroaryl ring radical may be attached to the main structure 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.

[0051] 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 C3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, groups and the like. The cycloalkyl group can be optionally substituted.

[0052] The term “aminoalkyl” or “alkylamino” refers to an alkyl group as defined above attached via amino linkage to the rest of the molecule. For example, C1-6 aminoalkyl refers to an alkyl group having from 1 to 6 carbon atoms attached via amino linkage 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.

[0053] The term " CDK7 inhibitor" or "inhibitor of CDK7" as used herein, refers to compounds of Formula I which can effectively inhibit CDK7 enzymes. Thecompounds of Formula I also capable of inhibiting cyclin dependent kinase 7 with cyclin H and MAT1 or CDK- activating kinase (CAK) or combinations thereof.

[0054] A term once described, the same meaning applies for it, throughout the patent.

[0055] As discussed in the background, the existing therapeutic compositions treat the tumor growth by the inhibition of CDK4 / 6 enzyme and there is a need for therapeutic agents that selectively and efficiently inhibit CDK7 to enhance the efficacy of cancer therapies. Further the present disclosure aims to overcome the limitations of the current CDK4 / 6 inhibitor class of drugs and offer a new approach for treating drug-resistant tumors, ultimately improving the therapeutic effect of the drug and enhance the benefit-risk profile of cancer patients.

[0056] Accordingly, the present disclosure provides compound of Formula I, its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, or pharmaceutically active derivatives thereof for the inhibition of CDK7.

[0057] In an embodiment of the present disclosure, there is provided a compound of Formula I, its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, or pharmaceutically active derivatives thereof,wherein Ri is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, or C3-8 heterocyclyl, wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl;Yi is N or C(=O);Y2 is selected from N, O, CR2, or NR3, wherein R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; wherein C1-6 alkyl is optionally substituted with Ci -6 alkoxy or hydroxy;R is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;Rs is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, Ci- 6 alkyl, C1-6 haloalkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from C1-6 alkyl, Ci- 6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein C1-6 alkyl or C3-8 heterocyclyl is optionally substituted with hydroxy, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C3-8 heteroaryl or C3-8 heterocyclyl; wherein C3-8 heterocyclyl is optionally substituted with one or more groups selected from oxo or C1-6 alkyl; p is 0 or 1 ;Re is selected from hydrogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, Ci-6aminoalkyl, C(=O)NR9aR9b, -NH-C(=O)R9or -NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy or cyano;R9, R9aand R9b are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein C1-6 alkyl, C1-6 aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -S-C1-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl or C3-12 heteroaryl is optionally substituted with one or more substituents selected from C1-6 alkyl; or R9aand R9b are combined together to form a C3-8 heterocyclyl optionally substitutedwith one or more substituents selected from oxo, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 aminoalkyl;Zi, Z2, Z3, and Z4 are independently selected from N or CR10;Rio is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O, S, S=O, SO2, N-CH3, N-C(=O)CH3or CRn;R11 is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; nl is 0, 1 or 2; n2 is 0, 1 or 2; and n3 is selected from 0 to 3.

[0058] In another embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein Ri is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or C1-6 alkoxy, wherein C1-4 alkyl is optionally substituted with hydroxy, C1-4 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl;Yi is N or C(=O);Y2 is selected from N, O, or CR2; wherein R2 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently CR4, wherein R4 is selected from hydrogen, halogen, C1-4 alkyl, or C1-6 haloalkyl; wherein C1-4 alkyl is optionally substituted with C1-6 alkoxy or hydroxy;R is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, or Ci- alkoxy;Rs is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, or C3-4 cycloalkyl, wherein C1-4 alkyl is optionally substituted with C1-4 alkoxy or hydroxy;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, Ci- 6 alkyl, C1-6 haloalkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from C1-4 alkyl, Ci- 4 aminoalkyl, C1-4 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein C1-4 alkyl or C3-8 heterocyclyl is optionally substituted with hydroxy, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 aminoalkyl, C3-8 heteroaryl or C3-8 heterocyclyl; wherein C3-8heterocyclyl is optionally substituted with one or more groups selected from oxo or Ci-4 alkyl; p is 0 or 1 ;Re is selected from hydrogen, amino, Ci-6 alkyl, Ci-6 aminoalkyl, C(=O)NR9aR9b, - NH-C(=O)Rg or -NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy or cyano;R9, Rgaand Rgn are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein C1-6 alkyl, C1-6 aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -S-C1-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl or C3-12 heteroaryl is optionally substituted with one or more substituents selected from C1-6 alkyl; or Rgaand R9bare combined together to form a C3-8 heterocyclyl optionally substituted with one or more substituents selected from oxo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 aminoalkyl;Zi, Z2, Z3, and Z4 are independently selected from N or CR10:Rio is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O, N-CH3, N-C(=O)CH3or CRn;R11 is hydrogen, cyano, halogen, Ci- alkyl, C1-4 haloalkyl, Ci- alkoxy, or C1-4 haloalkoxy; nl is 0, or 1; n2 is 0 or 1 ; and n3 is selected from 1 to 3.

[0059] In yet another embodiment of the present disclosure, there is provided a compound of Formula I, as disclosed herein, wherein Ri is selected from C1-3 alkyl, C2-3 alkenyl, or C2-3 alkynyl, wherein C2-3 alkyl is optionally substituted with Ci alkoxy;Yi is N or C(=O);Y2 is O or CR2; wherein R2 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; when Yi is N, Y2 is CR2; and when Yi is C(=O), Y2 is O;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently CR4, wherein R4 is selected from hydrogen, halogen, or Ci alkyl;R is hydrogen;Rs is selected from hydrogen, or Ci alkyl;X is CR7 or NR7; R7 is selected from hydrogen, C1-6 alkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from CM alkyl, CM aminoalkyl, Ci- alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein CM alkyl or C3-8 heterocyclyl is optionally substituted with hydroxy, amino, CM alkyl, CM alkoxy, CM aminoalkyl, C3-8 heteroaryl or C3-8 heterocyclyl; wherein C3-8 heterocyclyl is optionally substituted with one or more groups selected from oxo or C 1-6 alkyl;P is 1;Re is selected from hydrogen, C1-6 alkyl, C(=O)NR9aR9b, -NH-C(=O)Rg or - NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy or cyano;R9, Rgaand Rgn are independently selected from hydrogen, CM alkyl, C2-4 alkenyl, CM haloalkyl, CM aminoalkyl, CM alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein CM alkyl, CM aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, CM alkyl, C3-6 cycloalkyl, CM alkoxy, CM haloalkyl, CM aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl or C3-12 heteroaryl is optionally substituted with one or more substituents selected from CM alkyl; or Rgaand R% are combined together to form a C3-8 heterocyclyl optionally substituted with one or more substituents selected from oxo, CM alkyl, CM haloalkyl, or CM aminoalkyl;Zi, Z2, Z3, and Z4 are independently CR10; Rio is hydrogen;Y is CRii; Rn is hydrogen; nl is 0; n2 is 1 ; and n3 is 1.

[0060] In an embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, wherein the compound of Formula I is selected from,Formula la Formula lb its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, or pharmaceutically active derivatives thereof, wherein Ri is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or C3-8 heterocyclyl, wherein C1-6 alkyl is optionally substituted with hydroxy, C3-6 cycloalkyl, or C3-8 heterocyclyl;Yi is N or C(=O);Y2 is N, O, CR2 or NR3, wherein R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; C1-6 wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy;R is selected from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 alkoxy;Rs is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy; nl is 0, 1 or 2;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, Ci- 6 alkyl, C1-6 haloalkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from C1-6 alkyl, Ci- 6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein C1-6 alkyl or C3-8 heterocyclyl is optionally substituted with hydroxy, amino, C1-6 alkyl, Cl -6 alkoxy, C1-6 aminoalkyl, C3-8 heteroaryl or C3-8 heterocyclyl; wherein C3-8 heterocyclyl is optionally substituted with one or more groups selected from oxo or C1-6 alkyl;Re is selected from hydrogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, Ci-6aminoalkyl, C(=O)NR9aR9b, -NH-C(=O)R9or -NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy or cyano; p is 0 or 1 ;R9, R9aand R9b are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein C1-6 alkyl, C1-6 aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -S-C1-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from C1-6 alkyl; or R9aand R9b are combined together to form a C3-8 heterocyclyl optionally substituted with one or more substituents selected from oxo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 aminoalkyl;Zi, Z2, Z3, and Z4 are independently selected from N or CR10 :Rio is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O, S, S=O, SO2, N-CH3, N-C(=O)CH3or CRn;R11 is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and n2 is 0, 1 or 2.

[0061] In another embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, wherein Ri is selected from C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, or C3-8 heterocyclyl, wherein C1-3 alkyl is optionally substituted with hydroxy, C3-6 cycloalkyl, or C3-8 heterocyclyl;Yi is N or C(=O);Y2 is N, O, CR2 or NR3, wherein R2 and R3 are independently selected from hydrogen, halogen, C1-3 alkyl, or C1-3 haloalkyl;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, halogen, C1-3 alkyl, or C1-3 haloalkyl; wherein C1-3 alkyl is optionally substituted with Ci -6 alkoxy or hydroxy;R is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, or C1-3 alkoxy;Rs is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, or C3-6 cycloalkyl, wherein C1-3 alkyl is optionally substituted with C1-6 alkoxy or hydroxy; nl is 0, 1 or 2;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, Ci- 6 alkyl, C1-6 haloalkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from C1-6 alkyl, Ci- 6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein C1-6 alkyl or C3-8 heterocyclyl is optionally substituted with hydroxy, amino, C1-6 alkyl, Cl -6 alkoxy, C1-6 aminoalkyl, C3-8 heteroaryl or C3-8 heterocyclyl; wherein C3-8 heterocyclyl is optionally substituted with one or more groups selected from oxo or C1-6 alkyl;Re is selected from hydrogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, Ci-6aminoalkyl, C(=O)NR9aR9b, -NH-C(=O)R9or -NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy or cyano; p is 0 or 1 ;R9, R9aand R9b are independently selected from hydrogen, C1-3 alkyl, C2-4 alkenyl, C1-3 haloalkyl, C1-3 aminoalkyl, C1-3 alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein C1-3 alkyl, C1-3 aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, -S-C1-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, C1-3 haloalkyl, C1-3 aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl or C3-12 heteroaryl is optionally substituted with one or more substituents selected from C1-3 alkyl; or R9aand R9bare combined together to form a C3-8 heterocyclyl optionally substituted with one or more substituents selected from oxo, C1-3 alkyl, C1-3 haloalkyl, or C1-3 aminoalkyl;Zi, Z2, Z3, and Z4 are independently selected from N or CR10 :Rio is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O, N-CH3, N-C(=O)CH3or CRn;R11 is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and n2 is 0, 1 or 2.

[0062] In an embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, wherein Ri is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy;Yi is N when — is a double bond and Y2 is N or CR2 wherein R2 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;Yi is C(=O) when — is a single bond and Y2 is O or NR3 wherein R3 is selected from hydrogen, C1-6 alkyl, or C1-6 haloalkyl;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; C1-6 wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy;R is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy;Rs is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy; nl is 0, 1 or 2;X is CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C(=O)Ci-6alkyl, C(=O)C3.6cycloalkyl, C(=O)CH2OH, C(=O)CH2OCH3,C(=O)CH2NH2, C(=O)CH2NHCH3, C(=O)CH2N(CH3)2,Re is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy;C 1-6 haloalkoxy, CH2OH, CH2OCH3, NH2, N(CH3)2,Zi, Z2, Z3, and Z4 are independently selected from N or CR10:Rio is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O or CR11;R11 is hydrogen, cyano, fluoro, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; n2 is 0 or 1.

[0063] In an embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, whereinRi is selected from CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, CH2CHF2, CH2CH2CHF2, CH2CH2OCH3, CH2CH2OCF3, CH2CH2OCF3, CH2CH2OCHF2, CH2CH2CHOH, CH(CH3)CH2CH3,YI is N when — is a double bond and Y2 is N or CR2, wherein R2 is selected from hydrogen, fluoro, or CH3;Yi is C(=O) when — is a single bond and Y2 is O or NR3, wherein R3 is selected from hydrogen, CH3, or CF3;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, fluoro, or CH3;R is selected from hydrogen, CH3, OCH3, or CF3;Rs is selected from hydrogen, CH3, CH2CH3, CF3, ornl is 0, 1 or 2;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is independently selected from hydrogen, CH3, CH2CH3, C(=O)CH3, C(=O)CH2CH3, C(=O)cyclopropyl, C(=O)CH2OH, C(=O)CH2OCH3, C(=O)CH2NH2, C(=O)CH2NHCH3, C(=O)CH2N(CH3)2,R6is selected from hydrogen, CH3, CH2CH3, CF3, CH2CH3, OCH3, OCF3, CH2OH,CH2OCH3, NH2, N(CH3)2,T1Zi, Z2, Z3, and Z4 are independently selected from N or CR10;Rio is hydrogen, cyano, fluoro, chloro, CH3, CF3, OCH3, or OCF3;Y is selected from O or CR11;R11 is hydrogen, or CH3; n2 is 0 or 1.

[0064] In an embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, wherein Ri is selected from CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, CH2CHF2, CH2CH2CHF2, CH2CH 0CH3, or - CH2-CH=CH2;Yi is N when — is a double bond and Y2 is CH;YI is C(=O) when — is a single bond and Y2 is O;R is hydrogen;Rs is hydrogen, or CH3;X is CR7, or NR7; R7 is independently selected from hydrogen, CH3, CH2CH3, C(=O)CH3, C(=O)CH2CH3, C(=O)cyclopropyl, C(=O)CH2OH, C(=O)CH2OCH3, C(=O)CH2NH2, C(=O)CH2NHCH3, C(=O)CH2N(CH3)2,Re is independently selected from hydrogen, CH3, CH2CH3, CF3, CH2CH3, OCH3, OCF3, CH2OH, CH2OCH3, NH2, N(CH3)2, -C(O)-NH-CH2-CH3, -C(O)-NH- CH(CH3)2, -NH-C(O)- CH2-CH3, -NH-C(O)-CH2-N(CH3)2, -C(=O)-NH-Zi, Z2, Z3, and Z4 are independently CH;Y is CH; and n2 is 0 or 1.

[0065] In an embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, wherein the compound is selected from a group consisting of: i. (S)-N-ethyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)- 2-((l-isopropyl-lH-indazol-6-yl)amino)pyrimidin-5-yl)piperidine-3- carboxamide (Example 1);ii.(S)-l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy- 2 -dihydro- 1 H-inden- 1 -yl)amino)pyrimidin-5-yl)-N-ethylpiperidine-3 - carboxamide (Example 3); iii. (S)-N-ethyl-l-(2-((5-fluoro-l-propyl-lH-indazol-6-yl) amino)-4-(((lS,2R)- 2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)piperidine-3- carboxamide (Example 4); iv. (lS,2R)-l-((2-((l-allyl-5-fluoro-lH-indazol-6-yl)amino)-5-((S)-3- (hydroxymethyl)piperidin-l-yl)pyrimidin-4-yl)amino)-2,3-dihydro-lH- inden-2-ol (Example 5); v. (S)-l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2.3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-N-isopropylpiperidine-3- carboxamide (Example 6); vi. 1 -(2-(( 1 -allyl-5-fluoro- 1 H-indazol-6-yl) amino)-4-((( 1 S ,2R)-2-hydroxy-2,3 - dihydro- IH-inden- 1 -yl) amino) pyrimidin-5-yl)-N-ethylpiperidine-4- carboxamide (Example 7); vii. l-((S)-4-(2-((l-allyl-5-fluoro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino)ethan-l-one (Example 8); viii. l-((S)-4-(2-((5-fluoro-l-(prop-2-yn-l-yl)-lH-indazol-6-yl)amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino)ethan-l-one (Example 9); ix. 1 -((S)-4-(2-((5-fluoro- 1 -isopropyl- lH-indazol-6-yl)amino)-4-((( 1 S ,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino)ethan-l-one (Example 10); x. l-((S)-4-(2-((5-fluoro-l-(2-methoxyethyl)-lH-indazol-6-yl)amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino)ethan-l-one (Example 11); xi. N-(l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2.3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl) propionamide (Example 12);xii. l-((S)-4-(2-((l-allyl-5-methyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino) ethan-l-one (Example 13); xiii. 2-(dimethylamino)-N-(l-(2-((l-ethyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4- yl) acetamide (Example 14); xiv. (S)-l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy- 2, 3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-N-cyclopropylpiperidine-3-carboxamide (Example 15); xv. N-( 1 -(2-(( 1 -allyl- lH-indazol-6-yl) amino)-4-((( 1 S ,2R)-2-hydroxy-2,3 - dihydro- IH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl)-2- (dimethylamino) acetamide (Example 16); xvi. 2-(dimethylamino)-N-(l -(4-(((lS, 2R)-2-hydroxy-2, 3-dihydro- IH-inden- 1- yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-indazol-6-yl)amino)pyrimidin-5- yl)piperidin-4-yl)acetamide (Example 17); xvii. l-((S)-4-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl) amino) pyrimidin-5-yl)-2-methylpiperazin- 1 -yl)-2- (methylamino) ethan-l-one (Example 18); xviii. (S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl) amino) pyrimidin-5-yl)-N-cyclopropylpiperidine-3- carboxamide (Example 19); xix. 1 -((S)-4-(2-(( 1 -allyl- lH-indazol-6-yl) amino)-4-((( 1 S ,2R)-2-hydroxy-2,3 - dihydro- IH-inden- 1 -yl) amino) pyrimidin-5-yl)-2-methylpiperazin- 1 -yl)-2- morpholinoethan-l-one (Example 20); xx. (lS,2R)-l-((2-((l-allyl-lH-indazol-6-yl) amino)-5-(4-((pyridin-2-ylmethyl) amino) piperidin-l-yl) pyrimidin-4-yl) amino)-2,3-dihydro-lH-inden-2-ol (Example 21); xxi. (S)-N-(l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl)-l- methylpyrrolidine-2-carboxamide (Example 22);xxii. (R)-N-(l-(2-((l-allyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)piperidin-4-yl)- 1- methylpyrrolidine-2-carboxamide (Example 23); xxiii. (S)-N-cyclopropyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-((l-(prop-2-yn- 1-yl)- lH-indazol-6-yl) amino) pyrimidin-5-yl) piperidine-3 -carboxamide (Example 24); xxiv. (S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N-(oxetan-3-yl) piperidine- 3-carboxamide (Example 25); xxv. (3S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N-(2,2- difluorocyclopropyl)piperidine-3-carboxamide (Example 26); xxvi. (R)-l-(2-((l-allyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)-N-cyclopropylpiperidine-3- carboxamide (Example 27); xxvii. N-((S)-l-(2-((l-allyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)piperidin-3- yl)cyclopropanecarboxamide (Example 28); xxviii. (S)-l-(2-((l-allyl-5-methyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2- hydroxy-2, 3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide (Example 29); xxix. (S)-l-(2-((l-allyl-4-fluoro-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy- 2, 3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-N-cyclopropylpiperidine- 3-carboxamide (Example 30); xxx. ((S)-l-(2-((l-allyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)piperidin-3-yl)(4- methylpiperazin-l-yl)methanone (Example 31); xxxi. (S)- 1-(4-((( IS, 2R)-2-hydroxy-2, 3-dihydro- IH-inden- l-yl)amino)-2-((l- (prop-2-yn-l-yl)-lH-indazol-6-yl)amino)pyrimidin-5-yl)-N- isopropylpiperidine-3-carboxamide (Example 32);xxxii. (S)-N-cyclopropyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)-2-((5-methyl-l-(prop-2-yn-l-yl)-lH-indazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamide (Example 33); xxxiii. ((S)-l-(4-(((lS ,2R)-2-hy droxy-2, 3 -dihydro- 1 H-inden- 1 -yl)amino)-2-(( 1 - (prop-2-yn-l-yl)-lH-indazol-6-yl)amino)pyrimidin-5-yl)piperidin-3- yl)(morpholino)methanone (Example 34); xxxiv. (S)-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)-2-((l-(prop-2-yn-l-yl)-lH-indazol-6-yl)amino)pyrimidin-5-yl)-N-(oxetan-3- yl)piperidine-3-carboxamide (Example 35); xxxv. (S)-N-cyclopropyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)-2-((2-oxo-3-(prop-2-yn-l-yl)-2,3-dihydrobenzo[d]oxazol-5- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamide (Example 36); xxxvi.(S)- 1 -(2-( 1 -(R)-but-3-yn-2-yl)- lH-indazol-6-yl) amino)-4-( 1 S ,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide (Example 37); xxxvii.(S)-l-(2-((l-(S)-but-3-yn-2-yl)-lH-indazol-6-yl) amino)-4-((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide (Example 38); xxxviii.(S)-N-cyclopropyl-l-(4-((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-( 1 -(prop-2-yn- 1 -yl)- lH-benzo[d] [1,2,3] triazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamide ((Example 39); xxxix.(S)-N-(2,2-difluoroethyl)-l-(4-((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine- 3 -carboxamide (Example 40); xl.(S)- 1 -(4-((( 1 S ,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1 -yl) amino)-2-(( 1 -(prop-2-yn-l-yl)-lH-benzo [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl)-N- (1 -methyl cyclopropyl) piperidine- 3 -carboxamide (Example 41); xli.(S)-l-(2-(l-(R)-but-3-yn-2-yl)-lH-benzo[d][l,2,3] triazol-6-yl)amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-N- cyclopropyl piperidine-3 -carboxamide (Example 42);xlii.(S)-N-cyclopropyl-l-(4-( IS, 2R)-2-hydroxy-2,3-dihydro- IH-inden- 1-yl) amino)-2-(l-isopropyl-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5- yl) piperidine-3 -carboxamide (Example 43); xliii.(S)-l-(2-((l-allyl-lH-benzo[d] [1,2,3] triazol-6-yl) amino)-4-((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide (Example 44); xliv.(S)-l-(2-((l-((R)-but-3-yn-2-yl)-lH-benzo[d][l,2,3]triazol-6-yl)amino)-4-((( IS, 2R)-2-hydroxy-2,3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-N- (2,2-difluoroethyl)piperidine-3-carboxamide (Example 45); xlv.(S)-l-(2-(l-(S)-but-3-yn-2-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino)-4- (( 1 S ,2R)-2-hydroxy-2,3 -dihydro- IH-inden- 1 -yl) amino) pyrimidin-5-yl)-N- cyclopropyl piperidine-3 -carboxamide (Example 46); xlvi.(3S)-N-(2,2-difluorocyclopropyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine- 3 -carboxamide (Example 47); xlvii. (S)-N-(2,2-difluoroethyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1- yl) amino)-2-(l -isopropyl- lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine- 3 -carboxamide (Example 48); xlviii.S)-l-(2-((l-((S)-but-3-yn-2-yl)-lH-benzo[d][l,2,3] triazol-6-yl)amino)-4- ((( IS, 2R)-2-hydroxy-2,3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-N- (2,2-difluoro ethyl) piperidine-3 -carboxamide (Example 49); xlix.(S)-l-(2-((l-((R)-but-3-yn-2-yl)-lH-benzo[d][l,2,3]triazol-6-yl)amino)-4- ((( IS, 2R)-2-hydroxy-2,3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-N- ((R)-2,2-difluorocyclopropyl)piperidine-3-carboxamide (Example 50); l.(S)-N-(( 1 S ,2R)-2-fluorocyclopropyl)- 1 -(4-((( 1 S,2R)-2-hydroxy-2,3 - dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1H- benzo[d][l,2,3]triazol-6-yl)amino) pyrimidin-5-yl)piperidine-3-carboxamide (Example 51); li.(S)-N-((lR,2R)-2-fluorocyclopropyl)-l-(4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1H-benzo[d][l,2,3]triazol-6-yl)amino) pyrimidin-5-yl)piperidine-3-carboxamide (Example 52); lii.(S)-N-((lS,2S)-2-fluorocyclopropyl)-l-(4-((lS,2R)-2-hydroxy-2,3-dihydro-IH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d][l,2,3] triazol-6- yl)amino) pyrimidin-5-yl)piperidine-3-carboxamide (Example 53); liii.(S)-N-((lR,2S)-2-fluorocyclopropyl)-l-(4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1H- benzo[d][l,2,3]triazol-6-yl)amino) pyrimidin-5-yl) piperidine-3- carboxamide (Example 54); liv. (S)-N-(( 1 S ,2R)-2-fluorocyclopropyl)- 1 -(4-(( 1 S ,2R)-2-hydroxy-2,3 - dihydro- IH-inden- 1 -yl) amino)-2-(( 1 -(prop-2-yn- 1 -yl)- lH-indazol-6-yl) amino) pyrimidin-5-yl) piperidine- 3 -carboxamide (Example 55); lv.(S)-N-(( 1 S ,2R)-2-fluorocyclopropyl)- 1 -(4-( 1 S ,2R)-2-hydroxy-2,3 -dihydro-IH-inden-l-yl) amino)-2-((l-isopropyl-lH-benzo[d][l,2,3] triazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamide (Example 56); lvi.(R)-N-((lS,2R)-2-fluorocyclopropyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro- IH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6- yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide (Example 57); lvii.(R)-N-cyclopropyl- 1 -(4-((( 1 S ,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1 -yl) amino)-2-(l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine- 3 -carboxamide (Example 58); lviii.(3S)-N-(2-fluorocyclobutyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine- 3 -carboxamide (Example 59); lix.(S)-N-((lR,2S)-2-fluorocyclobutyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6- yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide (Example 60); lx.(S)-N-((lS,2R)-2-fluorocyclobutyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6- yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide (Example 61);lxi.(S)-N-((lS,2R)-2-fluorocyclopropyl)-4-(4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1H- benzo[d][l,2,3]triazol-6-yl)amino)pyrimidin-5-yl)morpholine-2- carboxamide (Example 62); lxii.(S)-N-((lS,2R)-2-fluorocyclopropyl)-4-(4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1H- benzo[d][l,2,3]triazol-6-yl)amino)pyrimidin-5-yl)piperazine-2-carboxamide (Example 63); lxiii.(S)-N-((lS,2R)-2-fluorocyclopentyl)-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-IH-inden- l-yl)amino)-2-(( l-(prop-2-yn- 1 -yl)- lH-benzo[d] [1 ,2,3]triazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamide (Example 64); lxiv.(S)-N-((3S,4S)-4-fluorotetrahydrofuran-3-yl)-l-(4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1H- benzo [d] [ 1 ,2,3 ] triazol-6-yl)amino)pyrimidin-5-yl)piperidine-3 -carboxamide (Example 65).

[0066] In an embodiment of the present disclosure, there is provided a process of preparation of compounds of Formula I as disclosed herein, the process comprising: reacting Formula (A) and Formula (B) followed by reacting with Formula (D) in the presence of a base to obtain the compound of Formula I,Ri is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or C3-8 heterocyclyl, wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy, C3-6 cycloalkyl, or C3- 8 heterocyclyl;Yi is N or C(=O);Y2 is selected from N, O, CR2 or NR3, wherein R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; wherein C1-6 alkyl is optionally substituted with Ci -6 alkoxy or hydroxy;R is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;Rs is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy; nl is 0, 1 or 2;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, Ci- 6 alkyl, C1-6 haloalkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from C1-6 alkyl, Ci- 6 alkoxy, C1-6 aminoalkyl, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein C1-6 alkyl or C3-8 heterocyclyl is optionally substituted with hydroxy, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C3-8 heteroaryl; wherein C3-8 heterocyclyl is optionally substituted with one or more groups selected from oxo or C1-6 alkyl; p is 0 or 1;Re is selected from hydrogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, Ci-6aminoalkyl, C(=O)NR9aR9b, -NH-C(=O) R9 or -NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy, or cyano;R9, Rgaand Rgn are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein C1-6 alkyl, C1-6 aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -S-C1-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl or C3-12 heteroaryl is optionally substituted with one or more substituents selected from C1-6 alkyl; or R9aand R9bare combined together to form a C3-8 heterocyclyl optionally substituted with one or more substituents selected from oxo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 aminoalkyl;Zi, Z2, Z3, and Z4 are independently selected from N or CR10;Rio is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O, S, S=O, SO2, N-CH3, N-C(=O)CH3, or CRn;Rn is hydrogen, cyano, halogen, Ci-6 alkyl, Ci-6 haloalkyl , Ci-6 alkoxy, or Ci-6 haloalkoxy; n2 is 0 or 1 ; and n3 is selected from 0 to 3.

[0067] In another embodiment of the present disclosure, there is provided a process of preparation of compounds of Formula I as disclosed herein, the process comprising: reacting Formula (A) and Formula (B) to obtain Formula (C), followed by reacting Formula (C) with Formula (D) in the presence of a base to obtain the compound of Formula I.

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

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

[0070] In an embodiment of the present disclosure there is provided a process of preparation of compounds of Formula la as disclosed herein, the process comprising: a. reacting Formula (A) and Formula (B’), followed by reacting with Formula (D) in the presence of a base to obtain a compound of Formula (E); b.hydrolyzing the compound of Formula (E), followed by reacting with an amine (RbNFh) to obtain the compound of Formula la, wherein Re is -NHCORb.Scheme 1

[0071] In another embodiment of the present disclosure there is provided a process of preparation of compounds of Formula la as disclosed herein, the process comprising: a. reacting Formula (A) and Formula (B’) to obtain Formula (C), followed by reacting Formula (C) with Formula (D) in the presence of a base to obtain a compound of Formula (E); b. hydrolyzing the compound of Formula (E) to obtain Formula (F), followed by reacting Formula (F) with an amine (RbNEh) to obtain the compound of Formula la, wherein Re is -NHCORb.

[0072] In an embodiment of the present disclosure there is provided a process of preparation of compounds of Formula lb as disclosed herein, the process comprising: a. reacting Formula (A) and Formula (G) to obtain Formula (H), followed by reacting Formula (H) with Formula (D) in the presence of a base to obtain a compound of Formula (J); and b. treating of the compound of Formula (J) with a first acid to obtain Formula (K), followed by treating Formula (K) with a second acid (RbCOOH) to obtain the compound of Formula lb, wherein Re is - NHC(O)Rb.Scheme 2

[0073] In another embodiment of the present disclosure there is provided a process of preparation of compounds of Formula lb as disclosed herein, the process comprising: a. reacting Formula (A) and Formula (G), followed by reacting with Formula (D) in the presence of a base to obtain a compound of Formula (J); and b. treating of the compound of Formula (J) with an acid (RbCOOH) to obtain the compound of Formula lb, wherein Re is -NHC(O)Rb.

[0074] In an embodiment of the present disclosure, there is provided a process of preparation of compound of Formula la as disclosed herein, wherein the base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, sodium hydride, potassium tertiary butoxide, sodium carbonate, potassium carbonate, and combinations thereof.In an embodiment of the present disclosure there is provided a process of preparation of compounds of Formula la as disclosed herein, wherein the process is carried out in the presence of a coupling reagent selected from HATU((Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), CDI (Carbonyldiimidazole), EDCI(l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), or combinations thereof.

[0075] In an embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, for use in the manufacture of a medicament.

[0076] In an embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, wherein the compound is an inhibitor of cyclin dependent kinase 7 or cyclin dependent kinase 7 with cyclin H and MAT1 or CDK-activating kinase (CAK) or combinations thereof.

[0077] In an embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, for use in treating of cancer mediated at least in part by cyclin dependent kinase 7 or cyclin dependent kinase 7 with cyclin H and MAT1 or CDK-activating kinase (CAK) or combinations thereof.

[0078] In an embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, for the manufacture of a medicament for treating cancer mediated at least in part by cyclin dependent kinase 7 or cyclin dependent kinase 7 with cyclin H and MAT1 or CDK-activating kinase (CAK) or combinations thereof.

[0079] In an embodiment of the present disclosure there is provided a compound of Formula I as disclosed herein, 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.

[0080] 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.

[0081] In an embodiment of the present disclosure there is provided a combination comprising of compounds of Formula la and lb as disclosed herein, with at least one additional therapeutic agent.

[0082] In an embodiment of the present disclosure there is provided a combination as disclosed herein, wherein the additional therapeutic agent is selected from chemotherapeutic agent or immune checkpoint inhibitors.

[0083] In an embodiment of the present disclosure there is provided a combination as disclosed herein, wherein chemotherapeutic agent is selected from 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, topoisomerase inhibitors, 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, poly ADP ribose polymerase (PARP) inhibitor, cisplatin, oxaplatin or combinations thereof.

[0084] In an embodiment of the present disclosure there is provided a combination as disclosed herein, wherein the immune checkpoint inhibitors 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, ecto-nucleoside triphosphate diphosphohydrolase l(E-NTPDase, CD39) inhibitor, ecto-5'- nucleotidase(Ecto5'NTase, CD79) inhibitor, protein tyrosine phosphatases nonreceptor type 1 / 2 (PTPN1 / 2) inhibitors, or combinations thereof.

[0085] In an embodiment of the present disclosure there is provided a pharmaceutical composition comprising the compound of Formula I as disclosed herein, with at least one pharmaceutically acceptable excipient.

[0086] 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.

[0087] 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.

[0088] In an embodiment of the present disclosure there is provided a method of treating cancer in a subject, the method comprising administering an effective amount the compound as disclosed herein or the combination as disclosed herein, or the pharmaceutical composition as disclosed herein to the subject in need thereof.

[0089] In an embodiment of the present disclosure there is provided a method of treating cancer 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.

[0090] In an embodiment of the present disclosure there is provided a method of treating a disease or condition mediated by cyclin dependent kinase 7 or cyclin dependent kinase 7 with cyclin H and MAT1 or CDK-activating kinase (CAK) or combinations thereof to a subject in need thereof, 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.

[0091] 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.

[0092] Although the subject matter has been described in considerable detail with reference to certain examples and implementations thereof, other implementations are possible.AbbreviationsThe following abbreviations are employed in the examples and elsewhere herein:TLC- thin layer chromatography;HPLC -high pressure liquid chromatography;MPLC - medium pressure liquid chromatography;UPLC - Ultra Performance Liquid Chromatography;NMR - nuclear magnetic resonance spectroscopy;DMSO - dimethylsulfoxide;CDCI3 - deuterated chloroform;MeOD -deuterated methanol, i.e. D3COD;MS - mass spectroscopy;ESP (or ES) - electrospray;El - electron impact;APCI - atmospheric pressure chemical ionization;THF - tetrahydrofuran;DCM - dichloromethane;MeOH - methanol;DMF -dimethylformamide;DIPEA - N,N-DiisopropylethylamineHATU - Hexafluorophosphate Azabenzotriazole Tetramethyl UroniumEtOAc - ethyl acetate;LC / MS - liquid chromatography / mass spectrometry; h - hour(s); min - minute(s); d - day(s);MTBD - N-methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene;TFA - trifluoroacetic acid; v / v - ratio of volume / volume;Boc - t-butoxycarbonyl;Cbz - benzyloxycarbonyl;Bz - benzoyl;Atm - atmospheric pressure; rt -room temperature; mg - milligram; g denotes gram; pL - microliter; mL - milliliter;L - liter;p M - micromolar; nM-Nanomolar mM - millimolar;M denotes molar;DMAP- dimethy aminopyridine;TBDMS -tert-butyldimethylsilyl N - normal; and nm - nanometer.EXAMPLES

[0093] The following examples provide the details about the synthesis, activities and applications of the compounds of the present disclosure. It should be understood the following is representative only, and that the invention is not limited by the details set forth in these examples.Materials and methods:

[0094] 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 diagnostic signals are reported. Chemical shifts are reported in parts per million downfieldfrom 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 5A 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 (A) Synthesis of Intermediates:Synthesis of l-isopropyl-lH-indazol-6-amine. (I)Step-1: Synthesis of l-isopropyl-6-nitro-lH-indazole (la):

[0095] To a stirred solution of 6-nitro-lH-indazole (CAS: 7597-18-4, 10.0 g, 61.297 mmol) in DMF (100 mL) under nitrogen atmosphere was added potassium carbonate (K2CO3, 25.414 g, 183.89 mmol) followed by 2-Iodopropane (9.2 mL, 91.946 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 roomtemperature, diluted with water (100 mL), and extracted with ethyl acetate (2 x 100 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 (230-400 mesh, 100 g packed, flow rate 40 mL / minutes & 254-280 nm wavelength) Biotage column chromatography using ethyl acetate (0-30 %) in petroleum ether and the peak was eluted with 13 % of ethyl acetate in petroleum ether concentrated to afford the desired compound la as a pale-yellow color solid. Yield: (6.1 g, 52 %).

[0096] LC_MS: Calc, for C10H11N3O2: 205.22; Obs.: 206.1 [M++H], 'H NMR (400 MHz, DMSO-d6): 8.78 (s, 1H), 8.34 (s, 1H), 8.03-8.00 (m, 1H), 7.97- 7.94 (m, 1H), 5.31-5.24 (m, 1H), 1.52-1.50 (m, 6H).Step-2: Synthesis of 1 -isopropyl- l / 7-indazol-6-amine (I)

[0097] To a stirred solution of l-isopropyl-6-nitro-lH-indazole la (6.1 g, 29.75 mmol) in ethanol (60 mL) under nitrogen atmosphere was added ammonium chloride (NH4CI, 7.91 g, 148.78 mmol) in 40 mL of water followed by iron (8.30 g, 148.78 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 a brown color 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 pure compound I as brown color solid. Yield: (4.1 g, 78.84%).

[0098] LC_MS: Calc, for C10H13N3: 175.24; Obs.: 176.1 [M++H], 'H NMR (400 MHz, DMSO-d6): £7.70 (s, 1H), 7.35 (d, J = 8.80 Hz, 1H), 6.52-6.48 (m, 3H), 5.26 (s, 1H), 4.67-4.60 (m, 1H), 1.42 (d, J = 6.80 Hz, 6H).Synthesis of (S)-l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) Dyrimidin-5-yl)-N-ethylDiDeridine-3-carboxamide (II)Step-1: Ethyl (S)-l-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl) piperidine-3- carboxylate (lib)

[0099] A solution of 5-Bromouracil (CAS: 51-20-7, 6.00 g, 31.42 mmol) and ethyl (S)-piperidine-3-carboxylate (Ila, 5.927 g, 37.70 mmol) in pyridine (30 mL) was irradiated at 150 °C for 1.5 hours in the microwave. The progress of the reaction was monitored by UPLC. After completion of the reaction, acetonitrile (50 mL) was added and stirred for 15 minutes, filtered, and dried under a vacuum that affords the crude product. The crude product was triturated with methyl tert-butyl ether (20 mL) to get the pure desired product (lib) as an off-white solid. Yield: (5.1 g, 60.78%).[000100] LCMS: Calc, for C12H17N3O4: 267.28; Obs.:267.9 [M++H],Step-2: Synthesis of ethyl (S)-l-(2,4-dichloropyrimidin-5-yl) piperidine-3- carboxylate (He)[000101] A solution of ethyl (S)-l-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5- yl) piperidine-3-carboxylate lib (5.10 g, 19.08 mmol) in POCI3 (phosphoryl chloride, 75 mL, 0.80 mol) was heated at 100 °C for 16 hours under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure and the residue was basified using 10 % sodium bicarbonate solution (100 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 3). The organic layer was dried over sodium sulfate and concentrated under a vacuum to get the crude product. The obtainedcrude product was purified by silica gel (230-400 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 15 % of ethyl acetate in petroleum ether concentrated to afford the desired product lie as a pale-yellow color liquid. Yield: (3.30 g, 56.89%). LC_MS: Calc, for C12H15C12N3O2: 304.17; Obs.: 304.1 [M++H], 'H NMR (400 MHz, DMSO-d6): 8 8.54 (s, 1H), 4.05-4.11 (m, 2H), 3.48 (dd, J = 3.60, Hz, 1H), 3.46-3.45 (m, 1H), 3.05-3.02 (m, 1H), 2.99 (m, 1H), 2.71-2.68 (m, 1H), 1.99 (m, 1H), 1.82 (m, 1H), 1.18-1.16 (m, 3H), 1.58-1.58 (m, 2H).Step-3: Synthesis of (S)-l-(2,4-dichloropyrimidin-5-yl) piperidine-3-carboxylic add (lid)[000102] To a stirred solution of ethyl (S)-l-(2,4-dichloropyrimidin-5-yl) piperidine-3 -carboxylate He (3.30 g, 10.85 mmol) in a mixture of THF (30 mL) and water (30 mL) was added LiOH.H2O (0.68 g, 16.27 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), neutralized with 1.5N HC1, a product extracted with ethyl acetate, (2 x 50 mL), the organic layer dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford crude product lid as off white solid. The crude product was taken to the next step without further purification. Yield: (2.7g, 90.30%). LC_MS: Calc, for C10H11C12N3O2: 276.12; Obs.: 274.0 [M+-H],Step-4: Synthesis of (S)-l-(2,4-dichloropyrimidin-5-yl)-A-ethylpiperidine-3- carboxamide (He):[000103] To a solution of (S)-l-(2,4-dichloropyrimidin-5-yl) piperidine-3- carboxylic acid (lid) (1.000 g, 3.622 mmol) and ethane amine (2.716 mL, 5.432 mmol, 2M) in THF (10 mL), were added DIPEA (1.58 mL, 9.054 mmol) followed by HATU (1.652 g, 4.346 mmol) at 0 °C, under nitrogen atmosphere. 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 quenched with 10% aq. NaHCCh, stirred for 30 minutes, and theprecipitated solid was filtered and dried under vacuum to afford the crude product as an off-white solid. The crude product was triturated with methyl tert-butyl ether (10 mL) to get the pure compound He as an off-white solid; Yield: (0.51 g, 42.48%). LC_MS: Calc, for C12H16C12N4O: 303.13; Obs.: 304.8 [M++H],Step-5: Synthesis of (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino) pyrimidin-5-yl)- \ -ethylpiperidine-3-carboxamide (II):[000104] To a solution of (S)-l-(2,4-dichloropyrimidin-5-yl)-A- ethylpiperidine-3 -carboxamide (He) (0.500 g, 1.65 mmol) and ( lS,2 / ?)- l -amino- 2,3-dihydro-l / Z-inden-2-ol (Ilf) (0.295 g, 1.98 mmol) in 2-propanol (20 mL), was added DIPEA (0.639 g, 4.95 mmol) at room temperature, under nitrogen atmosphere and the resulting reaction mixture was heated at 110 °C for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure to afford the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 60% ethyl acetate in petroleum ether to yield the title compound II as an off-white liquid; Yield: (0.380 g, 53.81%). [000105] LC_MS: Calc, for C21H26CIN5O2 :415.81 ; Obs.: 416.1 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 7.83 (br s, 2H), 7.28-7.23 (m, 4H), 5.44-5.39 (m, 2H), 4.57 (br s, 1H), 3.18-3.02 (m, 5H), 3.01-2.61 (m, 5H), 1.76 (m, 1H), 1.65-1.56 (m, 2H), 1.01 , (m, 1H), 0.96 (t, J = 7.20 Hz, 3H).Synthesis of (S)-l-(2-chloro-4-(((lR,2S)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-ethylpiperidine-3-carboxamide (III)[000106] To a stirred solution (S)-l-(2,4-dichloropyrimidin-5-yl)-A- ethylpiperidine-3 -carboxamide (He) (0.3 g, 0.989 mmol) in isopropyl alcohol (IPA) (15 mL) was added DIPEA (1.03 mL, 5.93 mmol) followed by (17?, 25)- 1- amino-2,3-dihydro-177-inden-2-ol (Ilf) (0.177 g, 1.18 mmol) at room temperature,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 the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 80-85% ethyl acetate in petroleum ether to yield the title compound III as an off-white solid; Yield: (0.120 g, 29.26%).[000107] LC_MS: Calc, for: C21H26C1N5O2:415.92; Obs.: 416.2 [M++H],Synthesis of l-allyl-5-fluoro-lH-indazol-6-amine (IV)Step-1: Synthesis of l-allyl-5-fluoro-6-nitro-lH-indazole (IVa):[000108] To a stirred solution of 5-fluoro-6-nitro- 1 / 7- 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 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 IVa as a white solid; Yield: (0.95 g, 38.93%). LC_MS: Calc, for CioH8FN302: 221.19; Obs.: 222.1 [M+-H], 'H NMR (300 MHz, DMSO-dd): 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 l-allyl-5-fluoro-lH-indazol-6-amine (IV)[000109] To a stirred solution of l-allyl-5-fluoro-6-nitro-lH-indazole (IVa) (0.95 g, 4.29 mmol) in ethanol (15 mL) under nitrogen atmosphere was added NH4CI (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 compound IV as a pale-yellow liquid; Yield: (0.8 g, 94.72%).[000110] LC_MS: Calc, for C10H10FN3: 191.21; Obs.:192.1 [M++H], 'H 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 5-fluoro-l-propyl-lH-indazol-6-amine (V)CStep-1: Synthesis of 5-fluoro-6-nitro-l-propyl-lH-indazole (Va):[000111] 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 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 50 mL). The combined organic phase was dried over Na2SO4. The solvent was filteredand 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: (0.29 g, 32.3%). LC_MS: Calc, for C10H10FN3O2: 223.21; Obs.: 223.1 [M+-H],Step-2: Synthesis of 5-fhioro-l -propyl- l / 7-indazol-6-amine (V)[000112] To a stirred solution of 5 -fluoro-6-nitro-l -propyl- 1H- indazole (Va) (0.29 g, 1.30 mmol) in ethanol (10 mL) under nitrogen atmosphere was added NH4CI (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 V as a pale-yellow liquid; Yield: (0.2 g, 79.68%). LC_MS: Calc, for C10H12FN3: 193.23; Obs.: 194.1 [M++H], 'H NMR (400 MHz, DMSO-d6): 7.74 (s, 1H), 7.31 (d, J = 11.20 Hz, 1H), 6.72 (d, 7 = 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 (lS,2R)-l-((2-chloro-5-((S)-3-(hvdroxymethyl) piperidin-l-yl) pyrimidin-4-yl) ainino)-2.3-dihvdro- 1 H-inden-2-ol (VI)Step-1: Synthesis of ethyl (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3-dihydro- 177- inden -1-yl) amino) pyrimidin-5-yl) piperidine-3-carboxylate (Via)[000113] To a stirred solution of ethyl (S)-l-(2,4-dichloropyrimidin-5-yl) piperidine-3 -carboxylate (lie) (1.0 g, 3.288 mmol) in IPA (30 mL) was added DIPEA (3.44 mL, 19.73 mmol), followed by (15,27?)-l-amino-2,3-dihydro-177- inden-2-ol (Ilf) (0.588 g, 3.945 mmol) at room temperature, under nitrogenatmosphere. 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 the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 80-85% ethyl acetate in petroleum ether to yield the title compound Via as a pale-brown liquid; Yield: (0.90 g, 65.69%). LC_MS: Calc, for C21H25CIN4O3: 416.91; Obs.: 417.2[M++H],Step-2: Synthesis of (lS,2R)-l-((2-chloro-5-((S)-3-(hydroxymethyl) piperidin- 1-yl) pyrimidin-4-yl) amino)-2,3-dihydro-lH-inden-2-ol (VI)[000114] To a solution of ethyl (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl) amino)pyrimidin-5-yl)piperidine-3-carboxylate (Via) (0.700 g, 1.679 mmol) in THF (15 mL), were added Lithium aluminum hydride 2.0M solution in tetrahydrofuran (1.679 mL, 3.358 mmol) 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 quenched with sodium sulphate at 0 °C and stirred for 15 minutes. The residue was basified using 10% NaHCCh solution (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. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 80% ethyl acetate in petroleum ether to yield the title compound VI as an off-white solid; Yield: (0.500 g, 66 %). LC_MS: Calc, for Ci9H23ClN4O2:374.87; Obs.: 375.2 [M++H],Synthesis of (S)-l-(2-chloro-4-((( lS,2R)-2-hvdroxy-2.3-dihvdro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-isopropylpiperidine-3-carboxamide (VII)Step-1: Synthesis of ethyl (S)-l-(2-chloro-4-(((lS,2 / f)-2-hydroxy-2,3-dihydro-IH-inden-l-yl) amino) pyrimidin-5-yl) piperidine-3-carboxylate (Vila)[000115] To a stirred solution of ethyl (S)-l-(2,4-dichloropyrimidin-5-yl) piperidine-3 -carboxylate (He) (1.0 g, 3.288 mmol) in IPA (30 mL) was added DIPEA (3.44 mL, 19.73 mmol), followed by (lS,27?)-l-amino-2,3-dihydro-l / Z- inden-2-ol (Ilf) (0.588 g, 3.945 mmol) at room temperature, 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 the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 80-85% ethyl acetate in petroleum ether to yield the title compound Vila as a pale-brown liquid; Yield: (0.90 g, 65.69%). LC_MS: Calc, for C21H25CIN4O3: 416.91; Obs.: 417.2[M++H], Step-2: Synthesis of (S)-l-(2-chloro-4-(((lS,2 / f)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino) pyrimidin-5-yl) piperidine-3-carboxylic acid (Vllb):[000116] To a stirred solution of ethyl (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy- 2,3-dihydro-l / Z-inden-l-yl)amino)pyrimidin-5-yl)piperidine-3-carboxylate (Vila) (0.900 g, 2.16 mmol) in a mixture of THF (15 mL) and water ( 15 mL) was added LiOH.fLC) (0.300 g, 9.23mmol) at room temperature under nitrogen atmosphere. 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 (50 mL), neutralized with 1.5N HC1, and the product was extracted with ethyl acetate (2 x 100 mL). Theorganic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product Vllb as an off-white solid. The crude product was taken to the next step without further purification; Yield: (0.600 g, 66.6%). LC_MS: Calc, for C19H21CIN4O3: 388.85; Obs.: 389.1[M++H],Step-3: Synthesis of (S)-l-(2-chloro-4-(((lS,2 / f)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino) pyrimidin-5-yl)-N-isopropylpiperidine-3-carboxamide (VII):[000117] To a solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.200 g, 0.514 mmol) and propan-2-amine (CAS: 75-31-0, 0.030 g, 0.514 mmol, 2M) in THF (10 mL), were added DIPEA (0.269 mL, 1.543 mmol) followed by HATU (0.234 g, 0.617 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% NaHCOs solution (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 VII as pale-yellow solid. Yield: (0.15 g, 33 %). LC_MS: Calc, for C22H28C1N5O2:429.95; Obs.: 430.2 [M++H],Synthesis of tert-butyl (2-((S)-4-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro- IH-inden-l-yl) amino) pyrimidin-5-yl)-2-methylpiperazin-l-yl)-2-oxoethyl) (methyl)carbamate (VIII)Step-1: Synthesis of tert-butyl (S)-4-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5- yl) -2-methylpiperazine- 1 -carboxylate ( VUIb) :[000118] To a suspension of 5-Bromouracil (CAS: 51-20-7, 20.0 g, 104.72 mmol) and Villa (31.46 g, 157.08 mmol) in pyridine (300 mL) was heated to 110° C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and a (1:1) mixture of methyl tert-butyl ether and acetonitrile (200 mL) was charged. The reaction mixture was stirred, filtered, washed thoroughly with acetonitrile, and dried under vacuum to get pure product VUIb as a white solid. Yield: (19 g 58.0%). 'H NMR (300 MHz, DMSO-d6): 3 11.07 (s, 1H), 10.49 (s, 1H), 6.73 (d, J = 4.00 Hz, 1H), 4.13 (s, 1H), 3.72 (d, J = 17.20 Hz, 1H), 3.17-3.02 (m, 3H), 2.44 (dd, J = 4.80, 15.20 Hz, 1H), 2.36-2.28 (m, 1H), 1.41 (s, 9H), 1.20 (d, J = 8.80 Hz, 3H). LC_MS Calc, for C14H22N4O4: 310.35; Obs.: 211.0 (De Boc) [M++H],Step-2: Synthesis of (S)-2,4-dichloro-5-(3-methylpiperazin-l-yl) pyrimidine (VIIIc)[000119] To a suspension of VUIb (16.0 g, 51.55 mmol) in POC13 (240 mL) under nitrogen atmosphere and the resulting reaction mixture was stirred at 100 °C for 16 hours (clear solution). After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was basified using aq. sodium bicarbonate solution. The aqueous layer was extracted with 10% methanol in dichloromethane (3 X 500 mL). The organic layer was passed through sodium sulfate and concentrated under a vacuum to get a crude solid. The crude was washed with MTBE and dried under vacuum to get the crude product VIIIc as a pale brown solid. Yield: (12 g, 78%).LC_MS: Calc, for C9H12CI2N4: 247.12; Obs.: 249.1 [M++H],Step-3: Synthesis of tert-butyl (S)-(2-(4-(2,4-dichloropyrimidin-5-yl)-2-methyl piperazine-l-yl)-2-oxoethyl) (methyl)carbamate (Ville):[000120] To a stirred solution of VIIIc (2.48 g, 10.042 mmol) and VUId (2.0 g, 10.570 mmol) in THF (40 mL) were added DIPEA (5.52 mL, 31.711 mmol) followed by HATU (4.8231 g, 12.684 mmol) at 0°C under nitrogenatmosphere and the resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction progress is monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 10% aq. NaHCOs was diluted with water and extracted with ethyl acetate (2 X 50 mL). The organic phase was washed with water, and brine and dried under Na2SO4. The solvent was filtered and evaporated under a vacuum to get the crude product as a brown liquid. The crude compound was purified by silica gel (230-400 mesh, 50 g packed, flow rate 35 mL / minutes & 254-280 nm wavelength) Biotage flash column chromatography using ethyl acetate (0-100%) in petroleum ether and the peak was eluted with 60% ethyl acetate was concentrated to afford the desired compound (Ville) as a pale brown liquid. Yield: (1.3 g, 29%). LC_MS: Calc, for C17H25CI2N5O3: 418.32; Obs.: 318.1 [M+-Boc],Step-4: Synthesis of tert-butyl (2-((S)-4-(2-chloro-4-(((lS,2 / f)-2-hydroxy-2,3- dihydro- 1 / 7-inden-l-yl) amino) pyrimidin-5-yl)-2-methylpiperazin-l-yl)-2- oxoethyl) (methyl)carbamate (VIII)[000121] To a stirred solution of Ville (1.3 g, 3.10 mmol) and Ilf (0.51 mg, 3.418 mmol) in IPA (52 mL) under nitrogen atmosphere was added DIPEA (3.25 mL, 18.646 mmol). The resulting reaction mixture was then stirred at 110 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was concentrated under a vacuum to get the crude. The crude compound was purified by silica gel (230-400, 50 g, packed) Biotage flash column chromatography using methanol (0-10%) in ethyl acetate and the peak was eluted with 8% methanol in ethyl acetate was concentrated to afford the desired compound (VIII) as an off-white solid. Yield: (1.25g, 75.7%). LCMS: Calc, for C26H35CIN6O4: 531.05; Obs.: 531.2 [M++H],Synthesis of 5-fluoro-l-(prop-2-vn-l-yl)-lH-indazol-6-amine (IX)Step-1: Synthesis of 5-fluoro-6-nitro-l-(prop-2-yn-l-yl)-lH-indazole (IXa):[000122] To a stirred solution of 5-fluoro-6-nitro-l / / - indazole (CAS: 1360952-20-0, 1.0 g, 5.52 mmol) in DMF (10 mL) under nitrogen atmosphere was added potassium carbonate (1.52 g, 11.04 mmol) followed by 3-bromoprop-l-yne (CAS: 106-96-7; 0.675 g, 11.04 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 (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 10% ethyl acetate in petroleum ether to yield the title compound IXa as a white solid; Yield: (0.8 g, 66.11%). LC_MS: Calc, for C10H6FN3O2: 219.18; Obs.: 219.2 [M+-H],Step-2: Synthesis of 5-fluoro-l-(prop-2-yn-l-yl)-lH-indazol-6-amine (IX)[000123] To a stirred solution of 5-fluoro-6-nitro-l-(prop-2-yn-l-yl)-lH- indazole (IXa) (0.8 g, 3.65 mmol) in ethanol (15 mL) under nitrogen atmosphere was added NH4CI (0.975 g, 18.2 mmol) in 25 mL of water followed by iron (1.02 g, 18.2 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 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: (0.41 g, 59.42%). LC_MS: Calc, for CIOH8FN3: 189.19; Obs.:190.3 [M++H],Synthesis of 5-fluoro-l-isopropyl-lH-indazol-6-amine (X)Step-1: Synthesis of 5-fluoro-l-isopropyl-6-nitro-lH-indazole (Xa):[000124] To a stirred solution of 5-fluoro-6-nitro-l / / - indazole (CAS: 1360952-20-0, 1 g, 5.5 mmol) in DMF (10 mL) under nitrogen atmosphere was added potassium carbonate (1.45 g, 10.47 mmol) followed by 1 -bromopropane (CAS: 75-30-9, 1.33 g, 7.85 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 (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 Xa as a white solid; Yield: (0.6 g, 48.78%).LC_MS: Calc, for C10H10FN3O2: 223.21; Obs.: 224.1[M++H], 'H NMR (300 MHz, DMSO-dd): d 8.74 (m, 1H), 8.29 (s, 1H), 7.95 (d, J = 11.40 Hz, 1H), 5.28-5.15 (m, 1H), 1.49 (s, 6H).Step-2: Synthesis of 5-fluoro-l-isopropyl-lH-indazol-6-amine (X)[000125] To a stirred solution of 5 -fluoro- l-isopropyl-6-nitro-lH-indazole Xa(0.6 g, 2.68 mmol) in ethanol (10 mL) under nitrogen atmosphere was added NH4CI (0.71 g, 13.44 mmol) in 15 mL of water followed by iron (0.73 g, 13.44 mmol). 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 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 X as a pale-yellowliquid; Yield: (0.42 g, 82.35%). LC_MS: Calc, for C10H12FN3: 193.23; Obs.: 194.2Step-1: Synthesis of 5-fluoro-l-(2-methoxyethyl)-6-nitro-lH-indazole (Xia):[000126] To a stirred solution of 5-fluoro-6-nitro-lH-indazole (CAS: 1360952-20-0, 2.00 g, 11.04 mmol) in DMF (20 mL) under nitrogen atmosphere was added potassium carbonate (4.58 g, 33.13 mmol) followed by 1- bromo-2-methoxyethane (2.30 g, 16.56 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for 1 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 Xia as a paleyellow solid; Yield: (1.0 g, 33.8 %). LC_MS: Calc, for C10H10FN3O3: 239.21; Obs.: 239.1 [M-H]+.Step-2: Synthesis of 5-fluoro-l-(2-methoxyethyl)-lH-indazol-6-amine (XI)[000127] To a stirred solution of 5-fluoro-l-(2-methoxyethyl)-6-nitro-lH- indazole (Xia) (1.00 g, 4.180 mmol) in ethanol (10 mL) under nitrogen atmosphere was added NH4CI (1.12 g, 20.90 mmol) in 10 mL of water followed by iron (1.16 g, 20.90 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, thereaction 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 XI as Pale-yellow solid; Yield: (0.9 g, 94.97 %). LC_MS: Calc, for C10H12FN3O: 209.22; Obs.: 210.1[M+H]+.Synthesis of N-(l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) pyrimidin-5-yl) piperidin-4-yl) propionamide (XII)Step-1: Synthesis of tert-butyl (l-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl) piperidin-4-yl) carbamate (Xllb)[000128] A 100 mL round bottom flask was charged with 5-bromouracil (CAS: 51-20-7, 2.00 g, 10.47 mmol), tert-butyl piperidin-4-ylcarbamate (Xlla) (2.51 g, 12.57 mmol) and pyridine (10.00 mL). The resulting reaction mixture was stirred at 100 °C for 16 hours. The reaction progress was monitored by UPLC. The reaction mixture was cooled to room temperature, diluted with acetonitrile, stirred for 15 minutes, filtered, and dried under vacuum to afford the desired product (Xllb) as an off-white solid; Yield: (1.82 g, 52.1 %). LC_MS: Calc, for C14H22N4O4: 310.35; Obs.: 309.6[M-H]+and 311.0 [M++H];XH-NMR (400 MHz, DMSO-J6): 8 11.02 (s, 1H), 10.43 (d, 7 = 6.80 Hz, 1H), 6.82 (d, J = 9.60 Hz, 1H), 6.71 (s, 1H), 3.21 (t, J = 15.20 Hz, 2H), 2.36 (t, J = 14.80 Hz, 2H), 1.72 (d, J = 14.80 Hz, 2H), 1.46 (t, J = 16.00 Hz, 2H), 1.39 (s,9H).Step-2: Synthesis of tert-butyl (l-(2,4-dichloropyrimidin-5-yl) piperidin-4-yl) carbamate (XIIc)[000129] To tert-butyl (l-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl) piperidin-4-yl) carbamate (Xllb) (1.82 g, 5.864 mmol) was added POCI3 (46 g, 0.30 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was heated to 100 °C for 16 hours. The reaction mixture was cooled to room temperature, and POCI3 was removed under reduced pressure. The residue was dissolved in THF (50mL) and poured into crushed ice water (50 mL), basified with Na2CO3 (by adjusting pH~8) then, was added BOC2O (1.28 g, 5.864 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and ethyl acetate and separated into two layers. The aqueous layer was extracted with ethyl acetate (2 x 200mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as a brown gummy solid. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 20% ethyl acetate in petroleum ether to yield the title compound XIIc as a white solid; Yield: (0.83 g, 31 %). UPLC_MS: Calc, for C14H20CI2N4O2: 347.24; Obs.: 290.6[M-56]+ and 346.8 [M++H];XH-NMR (400 MHz, CDCI3): 6 8.21 (s, 1H), 4.53 (s, 1H), 3.67 (s, 1H), 3.42 (d, J = 12.40 Hz, 2H), 2.94-2.87 (m, 2H), 2.10 (q, J = 12.80 Hz, 1H), 1.61-1.66 (m, 3H), 1.47 (m, 9H).Step-3: Synthesis of l-(2,4-dichloropyrimidin-5-yl) piperidin-4-amine hydrochloride (Xlld)[000130] To a solution of tert-butyl (l-(2,4-dichloropyrimidin-5-yl) piperidin-4-yl) carbamate (XIIc) (0.82 g, 2.36 mmol) in DCM (10 mL), was added HC1 in Dioxane (13 g, 0.37 mol) 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. The reaction mixture was concentrated under reduced pressure to afford the crude product as an off-white solid. The obtained crude was triturated with MTBE, decanted and the solid was dried under vacuum to afford the desired compound Xlld as a white solid; Yield: (0.71 g, 78%). UPLC.MS Calc, for C9H13CI3N4: 247.200; Obs.: 246.9 [M++H],Step-4: Synthesis of A^-(l-(2,4-dichloropyrimidin-5-yl) piperidin-4-yl) propionamide (Xlle)[000131] To a solution of l-(2,4-dichloropyrimidin-5-yl) piperidin-4-amine hydrochloride (Xlld) (0.35 g, 1.23 mmol) in DCM (10 mL), were added TEA (0.375 g, 3.70 mmol) and propionyl chloride (0.126 g, 1.36 mmol) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction progress monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent and afford the crude product as a brown solid. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 80% ethyl acetate in petroleum ether to yield the title compound Xlle as a white solid. Yield: 0.2 g, 46.6%).[000132] UPLC.MS Calc, for C12H16CI2N4O: 303.19; Obs.: 302.19 [M++H]; 'H-NMR (400 MHz, CDCh): 6 8.22 (s, 1H), 5.38 (s, 1H), 4.00-4.04 (m, 1H), 3.44 (d, J = 12.40 Hz, 2H), 2.97-2.90 (m, 2H), 2.24 (q, J = 7.60 Hz, 2H), 2.12 (m, 2H), 1.68 (t, J = 7.60 Hz, 2H), 1.20 (t, J = 7.60 Hz, 3H).Step-5: Synthesis of A^-(l-(2-chloro-4-(((lS,2 / ?)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)pyrimidin-5-yl)piperidin-4-yl)propionamide (XII)[000133] To a solution of A-(l-(2,4-dichloropyrimidin-5-yl) piperidin-4-yl) propionamide (Xlle) (0.20 g, 0.660 mmol) and (15,27?)-l-amino-2,3-dihydro-l / Z- inden-2-ol (Ilf) (0.118 g, 0.792 mmol) in 2-propanol (10 mL), was added DIPEA (0.25 g, 1.98 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 110 °C for 24 hours. The reaction progress was monitored by UPLC and LCMS. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the crude product as a brown gummy solid. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 4% methanol in DCM to yield the title compound XII as an off-white solid; Yield: (0.11 g, 35.1%). UPLC.MS: Calc, for C21H26CIN5O2: 415.92; Obs.: 415.9 [M++H] and 413.9 [M+-H],Synthesis of l-allyl-5-methyl-lH-indazol-6-amine (XIII)CAS: 72521 -00-7Step-1: Synthesis of l-allyl-5-methyl-6-nitro-lH-indazole (XHIa):[000134] To a stirred solution of 5-methyl-6-nitro-lH-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 XHIa as a pale-brown solid; Yield: (0.83 g, 45.3%). LC_MS: Calc, for C11H11N3O2: 217.23; Obs.: 218.0 [M++H], 'H NMR (300 MHz, DMSO-d6): 3 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 l-allyl-5-methyl-lH-indazol-6-amine (XIII)[000135] To a stirred solution of l-allyl-5-methyl-6-nitro-lH-indazole (XHIa) (0.82 g, 3.77 mmol) in ethanol (20 mL) under nitrogen atmosphere was added NH4C1 (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 petroleumether to get the title compound XIII as a pale brown solid; Yield: (0.3 g, 43.90%). LC_MS: Calc, for CIIHI3N3: 187.25; Obs.:188.1 [M++H], 1H NMR (400 MHz, DMSO-d6): 8 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 l-ethyl-lH-indazol-6-amine (XIV)Step-1: Synthesis of l-ethyl-6-nitro-lH-indazole (XlVa):[000136] To a stirred solution of 6-nitro-l / Z-indazole (CAS: 7597-18-4, 3.0 g, 18 mmol) in DMF (30 mL) under nitrogen atmosphere was added sodium hydride (0.88 g, 28 mmol) at 0 °C, stirred for 30 min, then added iodoethane (4.3 g,28 mmol) at 0 °C, resulting reaction mixture allowed to stir at 27 °C for 1 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 (40 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over Na3SO4. 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 title compound XlVa as an off-white solid; Yield: (1.91 g, 54%). LC_MS: Calc, for C9H9N3O2: 191.19; Obs: 192.1 [M++H]. 1H NMR (400 MHz, DMSO-d6): 3 8.43 (s, 1H), 8.14 (s, 1H), 8.04 (d, J = 2 Hz,lH), 7.87-7.85 (m, 1H), 4.56 (qt, J = 7.20 Hz, 2H), 1.60 (t, J = 7.60 Hz, 3H).Step-2: Synthesis of l-ethyl-lH-indazol-6-amine (XIV)[000137] To a stirred solution of l-ethyl-6-nitro- 1H- indazole (XlVa) (1.800 g, 9.415 mmol) in ethanol (40 mL) under nitrogen atmosphere was added NH4CI (3.022g, 56.49 mmol) in 20 mL of water followed by iron (1.577 g, 28.24 mmol). The reaction mixture was heated at 80 °C for 3 hours. The progress of the reactionwas 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 material was purified by silica gel (Biotage) column chromatography by eluting with 50% ethyl acetate in petroleum ether to yield the title compound XIV as off-white solid. Yield: (1.41 g, 84%). LC_MS: Calc, for C9H11N3: 161.21; Obs.:162 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 7.70 (s, 1H), 7.35 (d, J = 1.60, 1H), 6.52-6.49 (m, 2H), 5.30 (s, 2H), 4.19 (q, J = 9.60, 2H), 1.32 (t, 7 = 9.60, 3H).Synthesis of tert-butyl (l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH- inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl) carbamate (XV)[000138] To a solution tert-butyl (l-(2,4-dichloropyrimidin-5-yl) piperidin-4- yl)carbamate (XIIc) (0.500 g, 1.440 mmol) and (15,27?)-l-amino-2,3-dihydro-lH- inden-2-ol Ilf (0.214 g, 1.440 mmol) in 2-Propanol (10 mL), was added DIPEA (0.465 g, 3.600 mmol) at room temperature, under nitrogen atmosphere and the resulting reaction mixture was heated at 110 °C for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure to afford the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 70% ethyl acetate in petroleum ether to yield the title compound (XV) as an off-white solid; Yield: (0.200 g, 30%). LC_MS: Calc, for C23H30CIN5O3 :459.98; Obs.: 460.2 [M++H],Synthesis of l-allyl-lH-indazol-6-amine (XVI)Step-1: Synthesis of l-allyl-6-nitro-lH-indazole (XVIa):[000139] To a stirred solution of 6-nitro-l / Z-indazole (CAS: 7597-18-4, 5.0 g, 30.65 mmol) in DMF (50 mL) under nitrogen atmosphere was added potassium carbonate (8.47 g, 61.30 mmol) followed by allyl bromide (CAS: 106-95-6; 3.70 g, 30.65 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 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 XVIa as a brown solid; Yield: (2.5 g, 32.99%). LC_MS: Calc, for C10H9N3O2: 203.20; Obs: 204.1 [M++H], 'H NMR (400 MHz, DMSO-dd): 3 8.74-8.73 (m, 1H), 8.35 (d, J = 1.20 Hz, 1H), 8.05-8.03 (m, 1H), 7.99-7.96 (m, 1H), 6.05-6.08 (m, 1H), 5.21 (d, J = 1.60 Hz, 2H), 5.19-5.18 (m, 1H), 5.11-5.05 (m, 1H).Step-2: Synthesis of 1 -allyl- l / 7-indazol-6-amine (XVI)[000140] To a stirred solution of l-allyl-6-nitro-l / Z-indazole (XVIa) (2.1 g, 10.33 mmol) in ethanol (15 mL) under nitrogen atmosphere was added NH4CI (2.76 g, 51.67 mmol) in 25 mL of water followed by iron (2.88 g, 51.67 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 layerwas dried over Na2SO4, filtered, and evaporated under a vacuum to get the crude product. The crude product was dried to get the title compound XVI as a brown solid; Yield: (1.3 g, 70.49%). LC_MS: Calc, for C10H11N3: 173.22; Obs.:174.1 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 7.73 (d, J = 0.80 Hz, 1H), 7.38-7.36 (m, 1H), 6.52-6.49 (m, 1H), 6.45-6.44 (m, 1H), 5.94-5.93 (m, 1H), 5.32 (s, 2H), 5.16-5.12 (m, 1H), 5.00-4.95 (m, 1H), 4.83-4.81 (m, 2H).Synthesis of (S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidine-3-carboxylic add (XVII)Vllb XVII[000141] To a stirred solution (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1-yl) amino) pyrimidin-5-yl) piperidine-3 -carboxylic acid (Vllb) (0.14 g, 0.360 mmol), 1 -allyl- l H-indazol-6-aminc (XVI) (0.063 g, 0.360 mmol) in NMP (2 mL) was added 4M HC1 in dioxane (0.2 mL, 0.8 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 (1 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 as brown liquid. The obtained crude product XVII was as such taken for next step without purification. Yield: (0.42 g, crude). LC_MS: Calc, for C29H31N7O3: 525.61; Obs.: 526.2 [M++H],Synthesis of l-((S)-4-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden- 1-yl) amino) pyrimidin-5-yl)-2-methylpiperazin-l-yl)-2-morpholinoethan-l- one (XVIII)Step-1: Synthesis of (S)-l-(4-(2,4-dichloropyrimidin-5-yl)-2-methylpiperazin- l-yl)-2-morpholinoethan-l-one (XVIIIb)[000142] To a solution of (S)-2,4-dichloro-5-(3-methylpiperazin-l-yl) pyrimidine (VIIIc) (0.300 g, 1.24 mmol) in THF (10 mL), were added TEA (0.338 mL, 2.428 mmol) and 2-morpholinoacetic acid (XVIIIa) (0.328 g, 1.578 mmol) at 0 °C, under nitrogen atmosphere. 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 quenched with water (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over Na2SO4 and concentrated under a vacuum to get the crude product as yellow gummy mass. The obtained crude product was taken to next step without purification to afford the title compound (XVIIIb) as a yellow gummy mass; Crude Yield: (0.50 g, crude) LC_MS: Calc, for C15H21C12N5O2: 374.27; Obs.: 374.1 [M++H],Step-2: Synthesis of l-((S)-4-(2-chloro-4-(((lS,2 / ?)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino) pyrimidin-5-yl)-2-methylpiperazin-l-yl)-2- morpholinoethan-l-one (XVIII):[000143] To a solution (S)-l-(4-XVIIIb) (oropyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-morpholinoethan-l-one (XVIIIb) (0.500 g, 1.34 mmol) and (15,27?)-l-amino-2,3-dihydro-lH-inden-2-ol (Ilf) (0.239 g, 1.60 mmol) in 2-Propanol (10 mL), was added DIPEA (0.931 g, 5.34 mmol) at room temperature, under nitrogen atmosphere and the resulting reaction mixture washeated at 100 °C for 2 hour. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure to afford the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 70% ethyl acetate in petroleum ether to yield the title compound (XVIII) as a pale-yellow gummy liquid; Yield: (0.3 g, 34.3%). LC_MS: Calc, for C24H31CIN6O3: 487.00; Obs.: 487.2[M++H],Synthesis of (lS,2R)-l-((2-((l-allyl-lH-indazol-6-yl) amino)-5-(4- aminopiperidin-l-yl) pyrimidin-4-yl) amino)-2,3-dihvdro-l H-inden-2-ol (XIX)[000144] To a stirred solution tert-butyl (l-(2-chloro-4-(((15,27?)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl) carbamate (XV) (0.150 g, 0.326 mmol), l-allyl-lH-indazol-6-amine (XVI) (0.056 g, 0.326 mmol) in NMP (3 mL) was added 4M HC1 in dioxane (0.5 mL, 0.652 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 7 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 XIX as a yellow gummy liquid; Yield: (0.210 g, 82%). LC_MS: Calc, for C28H32N8O :496.62; Obs.: 497.2 [M++H],Synthesis of 2-chloro-4-(lS,2R)-2-hvdroxy-2,3-dihvdro-lH-inden-l-yl) amino)-5-((S)-3-methyl-4-(methyl-L-prolyl) piperazin- 1-yl) pyrimidine. (XX)Ville XXb XXStep-1: Synthesis of 2,4-dichloro-5-((S)-3-methyl-4-(methyl-L-prolyl) piperazin- 1-yl) pyrimidine (XXb):[000145] To a solution of (S)-2,4-dichloro-5-(3-methylpiperazin-l-yl) pyrimidine (VIIIc) (0.200 g, 0.809 mmol) in THF (10 mL), were added DIPEA (0.352 mL, 2.02 mmol) followed by HATU (0.369 g, 0.971 mmol) and methyl-L- proline (XXa) (0.125 g, 0.971 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 quenched with water (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over Na2SO4 and concentrated under a vacuum to get the crude product as yellow gummy mass. The obtained crude product was taken to next step without purification to afford the title compound (XXb) as brown liquid; Crude Yield: (0.200 g, 16.1%). LC_MS: Calc, for C15H21C12N5O: 358.27; Obs.: 358.2 [M++H],Step-2: Synthesis of 2-chloro-4-(((lS,2 / ?)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)-5-((S)-3-methyl-4-(methyl-L-prolyl)piperazin-l-yl)pyrimidine (XX):[000146] To a solution 2,4-dichloro-5-((S)-3-methyl-4-(methyl-L- prolyl)piperazin-l-yl)pyrimidine (XXb) (0.350 g, 0.977 mmol) and (1S,27?)-1- amino-2,3-dihydro-l / Z-inden-2-ol (Ilf) (0.146 g, 0.977 mmol) in 2-Propanol (10 mL), was added DIPEA (0.68 mL, 3.91 mmol) at room temperature, under nitrogen atmosphere and the resulting reaction mixture was heated at 100 °C for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, thereaction mixture was cooled to room temperature, and concentrated under reduced pressure to afford the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 70% ethyl acetate in petroleum ether to yield the title compound (XX) as an off-white solid; Yield: (0.200 g, 10%). LC_MS: Calc, for C24H31CIN6O2: 471.00; Obs.: 471.2 [M++H],Synthesis of l-(prop-2-yn-l-yl)-lH-indazol-6-amine (XXI)Step-1: Synthesis of 6-nitro-l-(prop-2-yn-l-yl)-lH-indazole (XXIa):[000147] To a stirred solution of 6-nitro-l / Z-indazole (CAS 70315-70-7, 2.00 g, 12.26 mmol) in DMF (20 mL) under nitrogen atmosphere was added potassium carbonate (3.39 g, 24.52 mmol) followed by 3 -bromoprop- 1-yne (CAS: 106-96-7; 1.06 mL, 12.26 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 x 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 XXIa as an off-white solid; Yield: (1.00 g, 38.92%). LC_MS: Calc, for C10H7N3O2: 201.18; Obs.: 202.1 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 8.83 (s, 1H), 8.38 (s, 1H), 8.08-8.00 (m, 2H), 5.56 (s, 2H), 3.47 (m, 1H).Step-2: Synthesis of l-(prop-2-yn-l-yl)-lH-indazol-6-amine (XXI)[000148] To a stirred solution of 6-nitro-l-(prop-2-yn-l-yl)-l / Z-indazole (XXIa) (1.00 g, 4.97 mmol) in ethanol (10 mL) under nitrogen atmosphere was added NH4CI (1.32 g, 24.85 mmol) in 15 mL of water followed by iron (1.38 g,24.85 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 a 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 XXI as a brown liquid; Yield: (0.8 g, 90.9 %). LC_MS: Calc, for C10H9N3: 171.20; Obs.: 172.1 [M++H], 'H NMR (400 MHz, DMSO-dd): 3 7.74 (s, 1H), 7.38-7.36 (m, 1H), 6.55-6.52 (m, 2H), 5.41 (s, 2H), 5.06(d, J = 2.40 Hz,), 3.32 (s, 1H).Synthesis of (S)-l-(4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l-yl) amino)- 2-((l-(prop-2-vn-l-yl)-lH-indazol-6-yl) amino) pyrimidin-5-yl) piperidine-3- carboxylic acid (XXII)[000149] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.25 g, 0.64 mmol) and l-(prop-2-yn-l-yl)-l / / -indazol-6-amine (XXI) (0.11g, 0.64 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.3 mL, 1.29 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 mass was cooled to room temperature, diluted with water (5 mL), neutralized by triethylamine, and extracted with ethylacetate (2 x 10 mL). The organic phase was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product (XXII) as a brown liquid; Yield: (0.35 g, crude). LC_MS: Calc, for C29H29N7O3: 523.60; Obs.: 524.2.2 [M++H],Synthesis of N-((S)-l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-1-yl) amino) pyrimidin-5-yl) piperidin-3-yl) propionamide (XXIII)Step-1: Synthesis of tert-butyl (S)-(l-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5- yl) piperidin-3-yl) carbamate (XXIIIb)[000150] A solution of 5-bromopyrimidine-2,4(l / / ,3 / f)-dione (CAS: 51-20- 7, 10.00 g, 52.36 mmol) and tert-butyl (S)-piperidin-3-ylcarbamate (XXIIIa) (12.58 g, 62.83 mmol) in pyridine (50 mL) was irradiated at 150 °C for 1.5 hours in the microwave. The progress of the reaction was monitored by UPLC. After completion of the reaction, acetonitrile (100 mL) was added, stirred for 15 minutes, filtered, and dried under vacuum to afford the crude product. The crude product was triturated with methyl tert-butyl ether (50 mL) to get the pure compound XXIIIb as a brown solid. The crude product was taken to the next step without further purification; Yield: (7.0 g, crude). LCMS: Calc, for C14H22N4O4: 310.35; Obs.: 309.2 [M+-H],Step-2: Synthesis of tert-butyl ((S)-l-(2-chloro-4-(((lS,2 / f)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-3-yl) carbamate (XXIIIc):[000151] To a solution tert-butyl (S)-(l-(2,4-dichloropyrimidin-5-yl) piperidin-3-yl) carbamate (XXIIIb) (0.650 g, 1.872 mmol) and (15,27?)-l-amino- 2,3-dihydro-lH-inden-2-ol (Ilf) (0.335 g, 2.24 mmol) in 2-Propanol (10 mL), was added DIPEA (0.725 g, 5.616 mmol) at room temperature, under nitrogen atmosphere and the resulting reaction mixture was heated at 100 °C for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure to afford the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 70% ethyl acetate in petroleum ether to yield the title compound (XXIIIc) as an off-white solid; Yield: (0.4 g, 40%). LC_MS: Calc, for C23H30CIN5O3: 459.98; Obs.: 460.2 [M++H],Step-3: Synthesis of (lS,2 / f)-l-((2-((l-allyl-lH-indazol-6-yl) amino)-5-((S)-3- aminopiperidin-l-yl) pyrimidin-4-yl) amino)-2,3-dihydro-lH-inden-2-ol (XXIII)[000152] To a stirred solution tert-butyl ((S)-l-(2-chloro-4-(((lS,27?)-2- hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)piperidin-3- yl)carbamate (XXIIIc) (0.20 g, 0.43 mmol) and 1 -allyl- lH-indazol-6-amine (XVI) (0.075 g, 0.43 mmol) in NMP (4 mL) was added 4M HC1 in dioxane (0.217 mL, 0.869 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated in vacuo to get the crude product. The obtained crude product was taken to next step without purification to afford the title compound (XXIII) as a pale-yellow gummy liquid; Crude Yield: (0.200 g). LC_MS: Calc, for C28H32N8O: 496.62; Obs.: 495.2 [M+-H],Synthesis of (S)-l-(2-((l-allyl-5-methyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihvdro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidine-3- carboxylic acid. (XXIV)Vllb XXIV[000153] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.20 g, 0.51 mmol) and l-allyl-5-methyl-lH-indazol-6-amine (XIII) (0.096g, 0.51 mmol) in NMP (3 mL), was added 4M HCI in dioxane (0.2 mL, 1.03 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 mass was cooled to room temperature, diluted with water (5 mL), neutralized by triethylamine, and extracted with ethyl acetate (2 x 10 mL). The organic phase was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product (XXIV) as a brown liquid; Yield: (0.20 g, 30.0%). LC_MS: Calc, for C30H33N7O3: 539.64; Obs.: 540.2 [M++H],Synthesis of l-allyl-4-fluoro-lH-indazol-6-amine (XXV)Step-1: Synthesis of 1 -allyl -6- bromo-4- fluoro- 1 / 7- indazole (XXVa)[000154] To a stirred solution of 6-bromo-4-fluoro-lH-indazole (CAS: 885520-23-0, 3.0 g, 13.951 mmol) in DMF (20 mL) under nitrogen atmosphere was added potassium carbonate (2.89 g, 20.911 mmol) followed by 3 -bromoprop- 1-ene (1.68 g, 13.886 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 (20 mL), and extracted with ethyl acetate (2 x 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 7% ethyl acetate in petroleum ether to yield the title compound XXVa as a pale brown solid; Yield: (0.85 g, 23.88%). LC_MS: Calc, for CioH8BrFN2: 255.09; Obs.: 257.0 [M+-H], 'H NMR (400 MHz, DMSO-d6): 38.25 (s, 1H), 7.89 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.04-6.00 (m, 1H), 5.19 (d, J = 6.00 Hz, 1H), 5.19-5.14 (m, 2H), 5.08 (s, 1H).Step-2: Synthesis of N-(l-allyl-4-fluoro-lH-indazol-6-yl)-l,l- diphenylmethanimine (XX Vc)[000155] To a stirred solution of l-allyl-6-bromo-4-fluoro-lH-indazole(XXVa) (0.6 g, 2.352 mmol) in 1,4-dioxane (30 mL), Benzophenone imine (XXVb) (0.47 g, 2.593 mmol) and sodium tert-butoxide (0.34 g, 3.537 mmol) were added under nitrogen atmosphere. The reaction mixture was degassed for 3 minutes followed by tBuXPhos Pd-G3 (0.2 g, 0.236 mmol) was added. The reaction mixture was heated at 110 °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 diluted with water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under vacuo to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 20% ethyl acetate in petroleum ether to yield the title compound XXVc as a pale-yellow liquid; Yield: (1.3 g, crude). LC_MS: Calc, for C23HI8FN3: 355.42; Obs.:356.1 [M++H], 'H NMR (300 MHz, DMSO-de): 3 8.01 (s, 1H), 7.76-7.73 (m, 3H), 7.62-7. 51 (m, 3H), 7.32-7.30 (m, 2H), 7.20 (d, J= 4.40 Hz, 2H), 6.72 (s, 1H), 6.44-6.40 (m, 1H), 5.90 (m, 1H), 5.1-5.0 (m, 2H), 4.93-4.88 (m, 2H),Step-3: Synthesis of l-allyl-4-lluoro- l / 7-indazol-6-amine (XXV)[000156] To a stirred solution of N-(l-allyl-4-fluoro-l / Z-indazol-6-yl)-l,l- diphenylmethanimine (XXVc) (1.2 g, 3.376 mmol) in methanol (20 mL), potassium acetate (0.83 g, 8.457 mmol) followed by Hydroxylamine hydrochloride (0.47 g, 6.763 mmol) were added under nitrogen atmosphere. The reaction mixture was stirred 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 (20 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic layer was further washed with brine (50 mL), dried over Na2SO4, filtered, and evaporated under vacuo to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 18% ethyl acetate in petroleum ether to yield the title compound XXV as a pale brown solid; Yield: (0.41 g, 63.56%). LC_MS: Calc, for C10H10FN3: 191.21; Obs.:192.1 [M++H], 'H NMR (300 MHz, DMSO-de): d 7.82 (s, 1H), 6.27-6.26 (m, 2H), 6.00- 5.93 (m, 1H), 5.58 (br s, 2H), 5.16-5.13 (m, 1H), 4.97-4.92 (m, 1H), 4.82 (br s, 2H). Synthesis of (S)-l-(2-((l-allyl-4-fluoro-lH-indazol-6-yl) amino) -4- (((IS, 2R) -2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidine-3- carboxylic acid (XXVI)[000157] To a stirred solution (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1-yl) amino )pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb)(0.15 g, 0.385 mmol), l-allyl-4-fluoro-l / Z-indazol-6-amine (XXV) (0.074 g, 0.385 mmol) in NMP (2 mL) was added 4M HC1 in dioxane (0.2 mL, 0.8 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 (1 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 XXVI as brown liquid. The obtained crude product was as such taken for next step without purification. Yield: (0.18 g, crude). LC_MS: Calc, for C29H30FN7O3: 543.60; Obs.: 544.3 [M++H],Synthesis of 5-methyl-l-(prop-2-vn-l-yl)-lH-indazol-6-amine (XXVII)Step-1: Synthesis of 5-methyl-6-nitro-l-(prop-2-yn-l-yl)-lH-indazole (XXVIIa):[000158] To a stirred solution of 5-methyl-6-nitro-l / Z-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 x 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 XXVIIa as a pale-yellow solid; Yield: (0.6 g, 50%). 'H NMR (400 MHz, DMSO-d6): 3 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, 3HStep-2: Synthesis of 5-methyl-l-(prop-2-yn-l-yl)-lH-indazol-6-amine (XXVII) [000159] To a stirred solution of 5-methyl-6-nitro-l-(prop-2-yn-l-yl)-lH- indazole (XX Vila) (0.600 g, 2.78 mmol) in ethanol (20 mL) under nitrogen atmosphere was added NH4CI (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 a 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 XXVII as a pale brown solid; Yield: (0.4 g, 76%). LC_MS: Calc, for C11H11N3: 185.23; Obs.: 186.2 [M++H],Synthesis of (S)-l-(4-(((lS,2R)-2-hydroxy-2,3-dihvdro-lH-inden-l-yl) amino)- 2-((5-methyl-l-(prop-2-vn-l-yl)-lH-indazol-6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxylic acid (XXVIII)[000160] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.25 g, 0.64 mmol) and 5-methyl-l-(prop-2-yn-l-yl)-l / Z-indazol-6-amine (XXVII) (0.12g, 0.64 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.3 mL, 1.29 mmol) at room temperature, under nitrogen atmosphere. The resultingreaction mixture was heated to 90 °C for 16 hours. The reaction progress was monitored by UPLC. 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 10 mL). The organic phase was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product (XXVIII) as a brown liquid; Yield: (0.16 g, crude). LC_MS: Calc, for C30H31N7O3: 537.62; Obs.: 538.3 [M++H],Synthesis of 5-amino-3-(prop-2-vn-l-yl) benzordloxazol-2(3H)-one (XXIX)[000161] Step-1: Synthesis of 5-nitro-3-(prop-2-yn-l-yl) benzo[d]oxazol- 2(3H)-one (XXIXa):[000162] To a stirred solution of 5-nitrobenzo[d]oxazol-2(3 / / )-one (CAS 3889-13-2, 2.00 g, 11.10 mmol) in DMF (20 mL) under nitrogen atmosphere was added potassium carbonate (3.04 g, 22.09 mmol) followed by 3-bromoprop-l-yne (1.48 mL, 16.65 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 x 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 XXIXa as an off-white solid; Yield: (1.00 g, 38.92%). LC_MS: Calc, for C10H6N2O4: 218.17; Obs.: 218.9 [M++H], Step-2: Synthesis of 5-amino-3-(prop-2-yn-l-yl) benzo[d]oxazol-2(3H)-one(XXIX):[000163] To a stirred solution of 5-nitro-3-(prop-2-yn-l-yl) benzo [d]oxazol- 2(3H)-one (XXIXa) (2.00 g, 9.17mmol) in ethanol (10 mL) under nitrogen atmosphere was added NH4CI (2.45 g, 45.84 mmol) in 15 mL of water followed by iron (2.56 g, 45.84 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 a 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 XXIX as a brown liquid; Yield: (1.00 g, 43%). LC_MS: Calc. for CioH9N3: 171.20; Obs.: 172.1 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 7.00 (d, J = 8.40 Hz, 1H), 6.50 (s, 1H), 6.32 (s, 1H), 5.16 (s, 2H), 4.60 (s, 2H), 3.43 (s, 1H).Synthesis of (S)-l-(4-(((lS,2R)-2-hvdroxy-2,3-dihvdro-lH-inden-l-yl) amino)- 2-((2-oxo-3-(prop-2-vn-l-yl)-2,3-dihydrobenzo[d]oxazol-5-yl) _ amino) pyrimidin-5-yl) piperidine-3-carboxylic acid (XXX)[000164] To a stirred solution of benzol-(2-chloro-4-(((15,27?)-2-hydroxy- 2,3-dihydro-l / Z-inden-l-yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.25 g, 0.64 mmol) and 5-amino-3-(prop-2-yn-l-yl)benzo[d]oxazol-2(3H)- one (XXIX) (0.12g, 0.64 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.3 mL, 1.29 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 90 °C for 2 hours. The reaction progresswas monitored by UPLC. 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 10 mL). The organic phase was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product (XXX) as a brown liquid; Yield: (0.30 g, crude). LC_MS: Calc, for C29H28N6O5: 540.58; Obs.: 541.2 [M++H],Synthesis of l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N-ethylpiperidine-4-carboxamide (XXXI)Step-1: Synthesis of ethyl l-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl) piperidine-4-carboxylate (XXXIb)[000165] A 20 mL Biotage vial was charged with 5-bromopyrimidine- 2,4(lH,3 / f)-dione (CAS: 51-20-7, 3.00 g, 15.71 mmol), ethyl piperidine-4- carboxylate XXXIa (2.96 g, 18.85 mmol) and pyridine (10 mL) were added. The resulting reaction mixture was irradiated under the microwave at 150 °C for 1.5 hours. The reaction progress was monitored by UPLC. The reaction mixture was cooled to room temperature, diluted with acetonitrile, and stirred for 15 minutes, filtered, and dried under vacuum to afford XXXIb as an off-white solid; Yield: (2.55 g, 57.6%). LC_MS: Calc, for C12H17N3O4: 267.28; Obs.: 266.1[M-H]+and 268.0 [M++H]; 'H-NMR (400 MHz, DMSO-J6): 8 11.02 (s, 1H), 10.43 (d, J = 6.80 Hz, 1H), 6.82 (d, J = 9.60 Hz, 1H), 6.71 (s, 1H), 3.21 (t, J = 15.20 Hz, 2H),2.36 (t, J = 14.80 Hz, 2H), 1.72 (d, J = 14.80 Hz, 2H), 1.46 (t, J = 16.00 Hz, 2H), 1.39 (s, 9H).Step-2: Synthesis of ethyl l-(2,4-dichloro-l,2-dihydropyrimidin-5-yl) piperidine-4-carboxylate (XXXIc)[000166] To ethyl l-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl) piperidine- 4-carboxylate (XXXIb) (1.00 g, 3.741 mmol) was added POCI3 (16 g, 0.11 mol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was heated to 100 °C for 16 hours. The reaction mixture was diluted with water and ethyl acetate, separated into two layers, and the aqueous layer was extracted with ethyl acetate (2 x 50mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as a brown gummy solid. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 20% ethyl acetate in petroleum ether to yield the title compound XXXIc as a white solid; Yield: (0.25 g, 21%); UPLC.MS: Calc, for C10H15CI2N3O2: 304.17; Obs.: 303.9 [M++H]; 'H-NMR (400 MHz, CDCI3): 6 8.21 (s, 1H), 4.53 (s, 1H), 3.67 (s, 1H), 3.42 (d, J = 12.40 Hz, 2H), 2.94-2.87 (m, 2H), 2.10 (q, J = 12.80 Hz, 1H), 1.61-1.66 (m, 3H), 1.47 (m, 9H).Step-3: Synthesis of l-(2,4-dichloro-l,2-dihydropyrimidin-5-yl) piperidine-4- carboxylic add (XXXId)[000167] To a solution of ethyl l-(2,4-dichloro-l,2-dihydropyrimidin-5-yl) piperidine-4-carboxylate (XXXIc) (0.250 g, 0.822 mmol) in mixture of THF (2 mL) and water (2 mL) was added LiOH.H2O (0.052 g, 1.23 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and UPLC. The reaction mixture was diluted with water, neutralized with 1.5N HC1, and the product was extracted with ethyl acetate (2 x 20mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude desired compound XXXId as a white solid; Yield: (0.21 g, 62%). UPLC_MS Calc, for C10H13CI2N3O2: 276.12; Obs.: 275.9 [M++H] and 273.9 [M+- H],Step-4: Synthesis of l-(2,4-dichloro-l,2-dihydropyrimidin-5-yl)-2V- ethylpiperidine-4-carboxamide (XXXIe)[000168] To a solution of l-(2,4-dichloro-l,2-dihydropyrimidin-5-yl) piperidine-4-carboxylic acid (XXXId) (0.200 g, 0.724 mmol) and ethane amine (0.049 g, 1.09 mmol) in THF (5 mL), were added DIPEA (0.234 g, 1.81 mmol) followed by HATU (0.330 g, 0.869 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress monitored by TLC and UPLC. The reaction mixture was quenched with 10% aq. NaHCCh, stirred for 30 minutes, and the precipitated solid was filtered, and dried under vacuum to afford the crude compound XXXIe as an off-white solid; Yield: (0.105 g, 46.6%). UPLC_MS Calc, for C12H16CI2N4O: 303.19; Obs.: 303.0 [M++H] and 305.0 [M++2]; 'H-NMR (400 MHz, DMSO-J6): 8 8.52 (s, 1H), 7.84 (t, J = 5.20 Hz, 1H), 3.40 (d, J = 12.00 Hz, 2H), 3.11-3.04 (m, 2H), 2.82-2.79 (m, 2H), 2.27-2.22 (m, 1H), 1.69-1.77 (m, 4H), 1.01 (t, J = 7.20 Hz, 3H).Step-5: Synthesis of l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden- 1-yl) amino) pyrimidin-5-yl)- V-ethylpiperidine-4-carboxamide (XXXI) [000169] To a solution l-(2,4-dichloro-l,2-dihydropyrimidin-5-yl)-A- ethylpiperidine-4-carboxamide (XXXIe) (0.20 g, 0.660 mmol) and (15,27?)- 1- amino-2,3-dihydro-177-inden-2-ol (Ilf) (0.118 g, 0.792 mmol) in 2-propanol (10 mL), was added DIPEA (0.256 g, 1.98 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 110 °C for 24 hours. The reaction progress was monitored by UPLC. The reaction mixture was concentrated under reduced pressure to afford the crude product as a brown gummy solid. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 100% ethyl acetate to yield the title compound XXXI as an off-white solid; Yield: (0.2 g, 66%). UPLC.MS: Calc, for C21H26CIN5O2: 415.92; Obs.: 416.0 [M++H] and 413.9 [M+-H]; 'H-NMR (400 MHz, DMSO-J6): 87.87 (s, 1H), 7.80 (t, J = 5.20 Hz, 1H), 7.18-7.26 (m, 4H), 6.75 (d, J = 8.40 Hz, 1H), 5.54 (d, J = 5.20 Hz, 1H), 5.42 (q, J = 5.20 Hz, 1H), 4.54 (d, J = 4.40 Hz, 1H), 3.04-3.12 (m,5H), 2.86 (d, J = 16.40 Hz, 1H), 2.67-2.62 (m, 2H), 2.21-2.17 (m, 1H), 1.72-1.62 (m, 4H), 0.99 (t, J = 7.20 Hz, 3H).Synthesis of (lS,2R)-l-((5-(4-aminopiperidin-l-yl)-2-((l-ethyl-lH-indazol-6- yl) amino) pyrimidin-4-yl) ainino)-2.3-dihvdro-l H-inden-2-ol (XXXII)[000170] To a stirred solution tert-butyl (l-(2-chloro-4-(((15,27?)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)piperidin-4-yl)carbamate (XV) (0.150 g, 0.326 mmol), l-ethyl-lH-indazol-6-amine (XIV) (0.052 g, 0.326 mmol) in NMP (5 mL) was added 4M HC1 in dioxane (0.163 mL, 0.652 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 evaporated in vacuo to afford the desired product (XXXII) as brown gummy solid; Yield: (0.15 g, 49%). LC_MS: Calc, for C27H32N8O: 484.61; Obs.: 485.3 [M++H];Synthesis of (S)-l-(2-((l-aUyl-5-fhioro-lH-indazol-6-yl) amino) -4- (((IS, 2R) -2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidine-3- carboxylic acid (XXXIII)Vllb XXXIII[000171] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.600 g, 1.543 mmol) and l-allyl-5-fluoro-lH-indazol-6-amine (IV) (0.295 g, 1.543 mmol) in NMP (3 mL) was added 4M HC1 in dioxane (0.174 mL, 0.697 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated in vacuo to get the crude product XXXIII as pale-yellow liquid. Yield: (0.8 g, 95 %). LC_MS: Calc, for C29H3OFN703:543.60; Obs.: 544.3 [M++H],Synthesis of (lS,2R)-l-((5-(4-aminopiperidin-l-yl)-2-((l-(prop-2-vn-l-yl)-lH- indazol-6-yl) amino) pyrimidin-4-yl) amino)-2,3-dihvdro-l H-inden-2-ol (XXXIV)[000172] To a stirred solution tert-butyl (l-(2-chloro-4-(((15,27?)-2-hydroxy- 2,3-dihydro-l / Z-inden-l-yl) amino)pyrimidin-5-yl)piperidin-4-yl)carbamate (XV)(0.15 g, 0.32 mmol), l-(prop-2-yn-l-yl)-l / Z-indazol-6-amine (XXI) (0.05 g, 0.32 mmol) in NMP (3 mL) was added 4M HC1 in dioxane (0.3 mL) 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 40 mL). The combined organic layer was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crude product (XXXIV). Yield: (0.18 g, crude). Note: The crude product was as such taken for next step without purification. LC_MS: Calc, for C28H30N8O: 494.60; Obs.: 495.1[M++H],Synthesis of (R)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy- 2,3-dihvdro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidine-3-carboxylic acid (XXXV)Step-1: Synthesis of ethyl (R)-l-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl) piperidine-3-carboxylate (XXXVb) :[000173] To a solution of 5-bromopyrimidine-2,4(l / Z,3 / f)-dione (CAS: 51-20-7, 4.00 g, 20.94 mmol) and ethyl (7?)-piperidine-3-carboxylate (XXXVa) (3.30 g, 20.96 mmol) in pyridine (50 mL) was irradiated at 150 °C for 1.5 hours in the microwave. The progress of the reaction was monitored by UPLC. After completion of the reaction, acetonitrile (100 mL) was added, stirred for 15 minutes,filtered, and dried under a vacuum that affords the crude product. The crude product was triturated with methyl tert-butyl ether (50 mL) to get the pure compound XXXVb as an off-white solid; Yield: (3.00 g, 70.3%). LCMS: Calc, for C12H17N3O4: 267.28; Obs.:268.2 [M++H],Step-2: Synthesis of ethyl ( / f)-l-(2,4-dichloropyrimidin-5-yl) piperidine-3- carboxylate (XXX Vc):[000174] A solution of ethyl (7?)-l-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5- yl) piperidine-3-carboxylate (XXXVb) (3.00 g, 11.22 mmol) in POCI3 (45 mL,482.6 mmol) was heated at 100 °C for 16 hours under a nitrogen atmosphere. 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. The residue was basified using 10% NaHCCh solution (200 mL). The aqueous layer was extracted with ethyl acetate (120 mL x 3). The organic layer was dried over Na2SO4 and concentrated under a vacuum to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 20% ethyl acetate in petroleum ether to yield the title compound XXXVc as a pale-yellow liquid; Yield: (2.00 g, 58.5%). LC_MS: Calc, for C12H15C12N3O2: 304.17; Obs.: 304.1 [M++H],Step-3: Synthesis of ethyl ( / f)-l-(2-chloro-4-(((lS,2 / f)-2-hydroxy-2,3-dihydro- IH-inden-l-yl) amino) pyrimidin-5-yl) piperidine-3-carboxylate (XXXVd);[000175] To a stirred solution of Ethyl (S)-l-(2,4-dichloropyrimidin-5-yl) piperidine-3 -carboxylate (XXXVc) (2.0 g, 6.58 mmol) in IPA (30 mL) was added DIPEA (3.0 mL, 16.44 mmol), followed by (15,27?)-l-amino-2,3-dihydro-l / Z- inden-2-ol (Ilf) (0.98 g, 6.58 mmol) at room temperature, 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 the crude product (XXXVd). The crude material was purified by silica gel (Biotage) column chromatography by eluting with 80-85% ethyl acetate in petroleum ether to yield the title compound as a pale-brown liquid;Yield: (1.80 g, 62.02%). LC_MS: Calc, for C21H25CIN4O3: 416.91; Obs.: 417.2[M++H],Step-4: Synthesis of ( / ?)-l-(2-chloro-4-(((lS,2 / ?)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino) pyrimidin-5-yl) piperidine-3-carboxylic acid (XXXVe): [000176] To a stirred solution of ethyl (7?)-l-(2-chloro-4-(((15,27?)-2- hydroxy-2,3-dihydro- 1H- inden- l-yl)amino)pyrimidin-5-yl)piperidine-3- carboxylate (XXXVd) (4.32 g, 4.32 mmol) in a mixture of THF (15 mL) and water ( 15 mL) was added LiOH.H2O (0.300 g, 6.62 mmol) at room temperature under nitrogen atmosphere. 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 (50 mL), neutralized with 1.5N HC1, and the product was extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product XXXVe as an off- white solid. The crude product was taken to the next step without further purification; Yield: (1.200 g, 57.30%). LC_MS: Calc, for C19H21CIN4O3: 388.85; Obs.: 389.1[M++H],Step-5: Synthesis of ( / ?)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2 / f)-2- hydroxy-2,3-dihydro- 1 / 7-inden- 1 -yl) amino) pyrimidin-5-yl)-N- cydopropylpiperidine-3-carboxamide) (XXXV) :[000177] To a stirred solution of (7?)-l-(2-((l-allyl-l / Z-indazol-6-yl)amino)- 4-(((15,27?)-2-hydroxy-2,3-dihydro- 1H- inden- l-yl)amino )pyrimidin-5- yl)piperidine-3-carboxylic acid (XXXVe) (0.30 g, 0.77 mmol) and 1-allyl-lH- indazol-6-amine (XVI) (0.13g, 0.77 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.3 mL, 1.54 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 mass was cooled to room temperature, diluted with water (5 mL), neutralized by triethylamine, and extracted with ethyl acetate (2 x 10 mL). The organic phase was dried over Na2SO4, the solvent was filtered and evaporated in vacuo to get the crudeproduct (XXXV) as a brown liquid; Yield: (0.31 g, crude). LC_MS: Calc, for C29H31N7O3: 525.61; Obs.: 526.3 [M++H],Synthesis of (7?)-l-(but-3-vn-2-yl)-l / / -indazol-6-amine (XXXVI)CAS: 7597-18-4 XXXVIa xxxviStep-1: Synthesis of ( / ?)-l-(but-3-yn-2-yl)-6-nitro-lH-indazole (XXXVIa):[000178] To a stirred solution of 6- nitro- 1 / 7- indazole (CAS: 7597-18-4; 3.0 g,18 mmol) and (S)-but-3-yn-2-ol (CAS: 2914-69-4; 1.54g, 22mmol) in THF (30 mL) under nitrogen atmosphere, was added Triphenylphosphine (5.78 g, 22 mmol) at 0 °C, then added DIAD (4.46 g, 28 mmol). The resulting reaction mixture was allowed to stir at 25 °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 (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 40% ethyl acetate in petroleum ether to yield the title compound XXXVIa as a yellow solid; Yield: (2.3 g, 58%). LC_MS: Calc, for C11H9N3O2: 215.21; Obs: 216.1 [M++H], 'H NMR (400 MHz, DMSO-dd): 8 8.87-8.87 (m, 1H), 8.40-8.40 (m, 1H), 8.07-7.99 (m, 2H), 6.18-6.12 (m, 1H), 3.54 (d, J = 2.40 Hz, 1H), 1.78 (d, J = 7.20 Hz, 3H).Step-2: Synthesis of ( / ?)-l-(but-3-yn-2-yl)-lH-indazol-6-amine (XXXVI)[000179] To a stirred solution of (7?)-l-(but-3-yn-2-yl)-6-nitro-177-indazole (XXXVIa) (2.30 g, 10.69 mmol) in ethanol (25 mL) under nitrogen atmosphere, was added NH4CI (2.85 g, 53.44 mmol) in 25 mL of water followed by iron (2.98 g, 53.44 mmol). The reaction mixture was heated at 80 °C for 1 hour. 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 residue. Theresidue 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 (XXXVI) as brown solid. Yield: (1.8 g, 89%). LC_MS: Calc, for C11H11N3: 185.2; Obs.:186.2 [M++H], 'H NMR (400 MHz, DMSO-dd): 67.74 (d, J = 0.80 Hz, 1H), 7.38 (d, J = 8.80 Hz, 1H), 6.64-6.63 (m, 1H), 6.54-6.52 (m, 1H), 5.51-5.46 (m, 1H), 5.40 (s, 2H), 3.41 (d, J = 2.40 Hz, 2H), 1.69 (d, J = 6.80 Hz, 2H).Synthesis of (S)-l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-cvclopropylpiperidine-3-carboxamide (XXXVII)[000180] To a solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.800 g, 2.06 mmol) and Cyclopropanamine (CAS: 765-30-0: 0.141 g, 2.47 mmol,) in DMF (10 mL), were added DIPEA (1.08 mL, 6.17 mmol) followed by HATU (0.939 g, 2.47 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. The reaction mixture was quenched with water, DMF was concentrated under reduced pressure and 10% aq NaHCOs solution was added and extracted with ethyl acetate (2 times). The organic phase was dried under Na2SO4 and the solvent was filtered and evaporated in vacuo to get the crude desired product (XXXVII) as a brown gummy liquid; Yield: (0.85 g, 43%). LC_MS: Calc, for C22H26CIN5O2: 427.93; Obs.: 428.2 [M++H],Synthesis of (S)-l-(but-3-yn-2-yl)-lH-indazol-6-amine (XXXVIII)Step-1: Synthesis of (S)-l-(but-3-yn-2-yl)-6-nitro-lH-indazole (XXXVIlla):[000181] To a stirred solution of 6-nitro-l / Z-indazole (CAS: 7597-18-4, 3.00 g, 18.39 mmol) and (7?)-but-3-yn-2-ol) (CAS: 42969-65-3, 1.54g, 22.07 mmol) in THF (30 mL) under nitrogen atmosphere was added Triphenylphosphine (5.78 g, 22 mmol) at 0 °C, then added DIAD (4.46 g,28 mmol), resulting reaction mixture was allowed to stir at 25 °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 (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 40% ethyl acetate in petroleum ether to yield the title compound XXXVIlla as a yellow solid; Yield: (2.4 g, 59%). LC_MS: Calc, for C11H9N3O2: 215.21; Obs: 216.1 [M l H NMR (400 MHz, DMSO-dd): 6 8.87-8.87 (m, 1H), 8.40 (d, J = 0.80 Hz, 1H), 8.07-7.99 (m, 2H), 6.18-6.12 (m, 1H), 3.55 (d, J = 2.40 Hz, 1H), 1.78 (d, J = 7.20 Hz, 3H).Step-2: Synthesis of (S)-l-(but-3-yn-2-yl)-lH-indazol-6-amine (XXXVIII)[000182] To a stirred solution of (S)-l-(but-3-yn-2-yl)-6-nitro-l / Z-indazole (XXXVIlla) (2.40 g, 11.15 mmol) in ethanol (25 mL) under nitrogen atmosphere was added NH4CI (2.98 g, 55.76 mmol) in 25 mL of water followed by iron (3.11 g, 55.76 mmol). The reaction mixture was heated at 80 °C for 1 hour. 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 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 (XXXVIII) as a brown solid. Yield: (2.0 g, 99%). LC_MS: Calc, for C11H11N3: 185.2; Obs.:186.2 [M++H], 'H NMR (400MHz, DMSO-dd): 8 7.74 (d, J = 0.80 Hz, 1H), 7.38 (d, J = 8.40 Hz, 1H), 6.64 (s, 1H), 6.54-6.52 (m, 1H), 5.49-5.47 (m, 1H), 5.38 (s, 2H), 3.40 (d, J = 2.00 Hz, 1H), 1.69 (d, 7 = 6.80 Hz, 3H).Synthesis of l-(prop-2-vn-l-yl)-lH-benzo[d][l,2,3]triazol-6-amine (XXXIX)Step-1: Synthesis of 6-nitro-l-(prop-2-yn-l-yl)-lH-benzo[d] [l,2,3]triazole(XXXIXa):[000183] To a stirred solution of 5-Nitro benzotriazole (CAS 2338-12-7, 6.00 g, 36.56 mmol) in THF (60 mL) under nitrogen atmosphere, were added propargyl alcohol (CAS: 107-19-7: 2.459 g, 2.57 mL, 1.2 eq, 43.87 mmol) followed by triphenylphosphine (11.51 g, 1.2 eq, 43.87 mmol), followed by DIAD (8.871 g, 8.530 mL, 1.2 eq, 43.87 mmol) at 0°C. The resulting reaction mixture was allowed to stir continuously at RT for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (80 mL) and was extracted with ethyl acetate (2 x 80 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 XXXIXa as an off-white solid; Yield: (1.6 g, 21%). LC_MS: Calc, for C9H6N4O2: 202.17; Obs.: 203.2 [M++H], 'H NMR (400 MHz, DMSO-dd): 3 8.76 (s, 1H), 8.75-8.76 (m, 1H), 8.32-8.35 (m, 1H), 5.60-5.61 (m, 2H), 2.64-2.66 (m, 1H), 8.32-8.35 (m, 1H), 5.60-5.61 (m, 2H), 2.64-2.66 (m,lH), (m,lH).Step-2: l-(prop-2-yn-l-yl)-lH-benzo[d][l,2,3]triazol-6-amine (XXXIX)[000184] To a stirred solution of 6-nitro-l-(prop-2-yn-l-yl)-l / Z- benzo[d][l,2,3]triazole (XXXIXa) (1.6 g, 1 eq, 7.91 mmol) in ethanol (20 mL)under nitrogen atmosphere, was added NH4CI (2.12 g, 5eq, 39.57 mmol) in 20 mL of water followed by iron (2.21 g,5 eq, 39.57 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 was washed with ethyl acetate (70 mL). The filtrate was concentrated in vacuo to get a 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 XXXIX as a yellow solid; Yield: (1.3 g, 95.5%). LC_MS: Calc, for C9H8N4: 172.19; Obs.: 173.2 [M++H], 'H NMR (400 MHz, DMSO-d6): 37.84 (d, J = 8.40 Hz, 1H), 6.81- 6.80 (m, 1H), 6.79 (s, 1H), 5.34-5.30 (m, 2H), 4.07 (brs, 2H), 2.48 (t, J = 2.80 Hz, 1H).Synthesis of (S)-l-(4-(((lS,2R)-2-hvdroxy-2,3-dihvdro-lH-inden-l-yl) amino)-2-((l-(prop-2-vn-l-yl)-lH-benzo[d][l,2,31 triazol-6-yl)amino)pyrimidin-5- yl)piperidine-3-carboxylic acid (XL)[000185] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (4.00 g, 1 Eq, 10.3 mmol) and l-(prop-2-yn-l-yl)-l / Z-benzo[d][l,2,3]triazol-6- amine (XXXIX) (2.13 g, 1.2 Eq, 12.3 mmol) in NMP (10 mL), was added 4M HC1 in dioxane (1.50 g, 10.3 mL, 4 molar, 4 Eq, 41.1 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 90 °C for 3hours. The reaction progress was monitored by UPLC. After completion of the reaction, the reaction mass was cooled to room temperature. The reaction mass was then evaporated in vacuo to get the crude product (XL) as a brown liquid; Yield: (4 g, crude). LC_MS: Calc, for C28H28N8O3: 524.58; Obs.: 525.2 [M++H],Synthesis of (R)-l-(but-3-vn-2-yl)-lH-benzo[d][l,2,31triazol-6-amine (XLI)Step-1: Synthesis of ( / ?)-l-(but-3-yn-2-yl)-6-nitro-lH-benzo[d][l,2,3]triazole (XLIa):[000186] To a stirred solution of 6-nitro-l / Z-benzo[d][l,2,3]triazole (CAS 2338-12-7, 8.000 g, 1 eq, 48.74 mmol) in THF (60 mL) under nitrogen atmosphere, were added (S)-but-3-yn-2-ol (CAS 2914-69-4, 4.100 g, 4.6 mL, 1.2 eq, 58.49 mmol) followed by triphenylphosphine (15.34 g, 1.2 eq, 58.49 mmol) followed by DIAD (11.83 g, 11.37 mL, 1.2 eq, 58.49 mmol) at 0°C. The resulting reaction mixture was allowed to stir continuously at RT for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (80 mL) and was extracted with ethyl acetate (2 x 80 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in a vacuum 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 (XLIa) as a pale brown solid; Yield: (2 g, 18.3%). LC_MS: Calc, for C10H8N4O2: 216.20; Obs.: 217.1 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 8.84 (s, 1H), 8.32 (d, J = 6.80 Hz, 1H), 8.24 (d, J = 8.80 Hz, 1H), 6.06-6.00 (m, 1H), 2.75 (s, 1H), 2.05 (s, 3H).Step-2: (R)-l-(but-3-yn-2-yl)-lH-benzo[d][l,2,3]triazol-6-amine (XLI)[000187] To a stirred solution of (R)-l-(but-3-yn-2-yl)-6-nitro-lH- benzo[d][l,2,3]triazole (XLIa) (2 g, 1 eq, 9.25 mmol) in ethanol (20 mL) undernitrogen atmosphere, was added NH4CI (2.47 g, 5 eq, 46.25 mmol) in 20 mL of water followed by iron (2.58 g, 5 eq, 46.25 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 a 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 (XLI) as a yellow solid; Yield: (1.3 g, 75.5%). LC_MS: Calc, for C10H10N4: 186.22; Obs.: 187.2 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 7.83 (d, J = 8.00 Hz, 1H), 6.89 (s, 1H), 6.78 (d, J = 6.80 Hz, 1H), 5.84-5.78 (m, 1H), 4.05 (m, 2H), 2.58 (s, 1H), 1.91 (s, 3H).Synthesis of (S)-l-(2-((l-((R)-but-3-vn-2-yl)-lH-benzo[d][l,2.,3] triazol-6- yl)amino)-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XLII)[000188] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (3.000 g, 1 Eq, 7.715 mmol) and (7?)-l-(but-3-yn-2-yl)-l / Z-benzo[d][l,2,3]triazol- 6-amine (XLI) (2.13 g, 1.2 Eq, 12.3 mmol) in NMP (20 mL), was added 4M HC1 in dioxane (562.6 mg, 3.858 mL, 4 molar, 2 Eq, 15.43 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 90 °C for3 hours. The reaction progress was monitored by UPLC. After completion of the reaction mass was cooled to room temperature, reaction mass was evaporated in vacuo to get the crude product (XLII) as a brown liquid; Yield: (3 g, crude). LC_MS: Calc, for C29H30N8O3: 538.61; Obs.: 539.2 [M++H],Synthesis of l-isopropyl-lH-benzordiri,2,31triazol-6-amine (XLIII)CStep-1: l-isopropyl-6-nitro-lH-benzo[d] [1,2,3] triazole (XLIIIa):[000189] To a stirred solution of 6-nitro-l / Z-benzo[d][l,2,3]triazole (CAS 2338-12-7, 2.000 g, 1 eq, 12.19 mmol) in DMF (20 mL) under nitrogen atmosphere, were added 2-bromopropane (CAS 75-26-3, 1.799 g, 1.373 mL, 1.2 eq, 14.62 mmol) followed by K2CO3 (5.052 g, 3 eq, 36.56 mmol). The resulting reaction mixture continued stirring for 3 hours at 80 °C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 x 40 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 XLIIIa as a pale yellow solid; Yield: (0.35 g, 13.9%). LC_MS: Calc, for C9H10N4O2: 206.21; Obs.: 207.2 [M++H], 'H NMR (400 MHz, CDCh): 6 8.59-8.58 (m, 1H), 8.30-8.27 (m, 1H), 8.23-8.20 (m, 1H), 5.24-5.17 (m, 1H), 1.83 (d, J = 6.80 Hz, 6H)Step-2: l-isopropyl-lH-benzo[d][l,2,3]triazol-6-amine (XLIII)[000190] To a stirred solution of l-isopropyl-6-nitro-l / Z- benzo[d][l,2,3]triazole (XLIIIa) (0.350 g, 1 eq, 1.70 mmol) in ethanol (5 mL) under nitrogen atmosphere, were added NH4CI (454 mg, 5 eq, 8.49 mmol) in 5 mL of water, followed by iron (474 mg, 5 eq, 8.49 mmol) .The reaction mixture washeated at 80 °C for 1 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 (30 mL). The filtrate was concentrated in vacuo to get a brown residue. The residue was diluted with water (30 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 XLIII as a brown gum; Yield: (0.28 g, 91%). LC_MS: Calc, for C9H12N4: 176.22; Obs.: 177.2 [M++H], 'H NMR (400 MHz, CDCh): 6 7.83-7.81 (m, 1H), 6.78-6.75 (m, 1H), 6.65-6.64 (m, 1H), 4.96-4.89 (m, 1H), 4.02 (s, 2H), 1.73-1.68 (m, 6H).Synthesis of l-allyl-lH-benzo[d1[l,2,31triazol-6-amine (XLIV)CStep-1: Synthesis of l-allyl-6-nitro-lH-benzo[d][l,2,3]triazole (XLIVa)[000191] To a stirred solution of 6-nitro-l / Z-benzo[d][l,2,3]triazole (CAS: 2338-12-7, 1.5 g, 9.14 mmol) and 3-bromoprop-l-ene (CAS No: 106-95-6, 1.12g, 9.23 mmol) in DMF (20 mL) under nitrogen atmosphere was added Potassium carbonate (1.27 g, 9.23 mmol) at 0 °C, then added Tetra butyl ammonium bromide (0.29 g, 0.91mmol), resulting reaction mixture allowed to stir at 25 °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 (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 10% ethyl acetate in petroleum ether to yield the title compound (XLIVa) as a Brown solid; Yield: (0.20 g, 2.6%). LC_MS: Calc, for C9H8N4O2: 204.19; Obs: 204.8 [M+H],Step-2: Synthesis of l-allyl-lH-benzo[d][l,2,3]triazol-6-amine (XLIV)[000192] To a stirred solution of l-allyl-6-nitro-l / Z-benzo[d][l,2,3]triazole (XLIVa) (0.20g, 0.97 mmol) in ethanol (20 mL) under nitrogen atmosphere was added NH4CI (0.26 g, 4.90 mmol) in 15 mL of water followed by iron (0.26 g, 4.90 mmol). The reaction mixture was heated at 80 °C for 1 hour. 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 (25 mL). The filtrate was concentrated in vacuo to get a brown residue. The residue was diluted with water (25 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under vacuum to get the crude product (XLIV) as brown solid. Yield: (0.110 g, 64.0%). LC_MS: Calc. for C9Hi0N4: 174.2; Obs.:175.2 [M++H],Synthesis of (S)-l-(but-3-vn-2-yl)-lH-benzo[d][l,2,3]triazol-6-amine (XLV)Step-1: Synthesis of (S)-l-(but-3-yn-2-yl)-6-nitro-lH-benzo[d] [1,2,3] triazole (XLVa):[000193] To a stirred solution of 6-nitro-l / Z-benzo[d][l,2,3]triazole (CAS 2338-12-7, 8.000 g, 1 eq, 48.74 mmol) in THF (60 mL) under nitrogen atmosphere, were added (S)-but-3-yn-2-ol (CAS 42969-65-3, 4.100 g, 4.6 mL, 1.2 eq, 58.49 mmol) followed by triphenylphosphine (15.34 g, 1.2 eq, 58.49 mmol) followed by DIAD (11.83 g, 11.37 mL, 1.2 eq, 58.49 mmol) at 0°C. The resulting reaction mixture was allowed to stir continuously at RT for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (80 mL) and was extracted with ethyl acetate (2 x 80 mL). The combined organic phase was dried over Na2SO4. The solvent was filtered and evaporated in a vacuum to get the crude product. The crude materialwas purified by silica gel (Biotage) column chromatography by eluting with 30 % ethyl acetate in petroleum ether to yield the title compound (XLVa) as a pale brown solid; Yield: (2 g, 18.3%). LC_MS: Calc, for C10H8N4O2: 216.20; Obs.: 217.1 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 8.84 (s, 1H), 8.32 (d, J = 6.80 Hz, 1H), 8.24 (d, J = 8.80 Hz, 1H), 6.06-6.00 (m, 1H), 2.75 (s, 1H), 2.05 (s, 3H).Step-2: (S)-l-(but-3-yn-2-yl)-lH-benzo[d][l,2,3]triazol-6-amine (XLV)[000194] To a stirred solution of (S)-l-(but-3-yn-2-yl)-6-nitro-l / Z- benzo[d][l,2,3]triazole (XLVa) (2 g, 1 eq, 9.25 mmol) in ethanol (20 mL) under nitrogen atmosphere, was added NH4CI (2.47 g, 5 eq, 46.25 mmol) in 20 mL of water followed by iron (2.58 g, 5 eq, 46.25 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 a 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 (XLV) as a yellow solid; Yield: (1.3 g, 75.5%). LC_MS: Calc, for C10H10N4: 186.22; Obs.: 187.2 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 7.83 (d, J = 8.00 Hz, 1H), 6.89 (s, 1H), 6.78 (d, J = 6.80 Hz, 1H), 5.84-5.78 (m, 1H), 4.05 (m, 2H), 2.58 (s, 1H), 1.91 (s, 3H).Synthesis of (S)-l-(2-((l-((S)-but-3-vn-2-yl)-lH-benzo[d][l,2,31triazol-6- yl)amino)-4-(((lS,2R)-2-hvdroxy-2,3-dihvdro-lH-inden-l- yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XL VI)[000195] To a stirred solution of (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1H- inden- 1-yl) amino) pyrimidin-5-yl) piperidine-3 -carboxylic acid (Vllb) (0.200 g, 0.51 mmol) and (S)-l-(but-3-yn-2-yl)-l / Z-benzo[d][l,2,3]triazol- 6-amine (XLV) (0.095 g, 0.51 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.2 mL, 1.03 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 was evaporated in vacuo to get the crude desired product (XL VI) as brown gummy liquid. Yield: (0.20 g, 19.8 %). LC_MS: Calc, for C29H30N8O3: 538.61; Obs.: 539.2 [M++H],Synthesis of (S)-l-(2-chloro-4-((( lS,2R)-2-hvdroxy-2.3-dihvdro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-(2,2-difluoroethyl) piperidine-3-carboxamide (XL VII)[000196] To a stirred solution of (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb, 0.3 g, 1 eq, 0.7715 mmol) and 2,2-difluoroethan-l -amine hydrochloride (CAS: 430-67-1, 87.56 mg, 1.4 eq, 1.08 mmol) were added DIPEA (598 mg, 806 pL, 3 eq, 2.31 mmol) followed by T3P 50% in ethyl acetate (0.91 ml g, 2 eq, 1.545 mmol) at 0°C, under nitrogen atmosphere. The resulting reaction mixture was stirred at RT for 16 hours, under nitrogen atmosphere. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum to get the crudeproduct (XL VII) as color less gummy solid; Yield: (0.35 g, crude). LC_MS: Calc, for C21H24CIF2N5O2: 451.90; Obs.: 452.1 [M++H],Synthesis of (S)-l-(2-chloro-4-((( lS,2R)-2-hvdroxy-2.3-dihvdro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-((R)-2,2-difhiorocvclopropyl) piperidine-3- carboxamide (XL VIII)[000197] To a solution of (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.500 g, 1.3 mmol) and (R)-2,2-difluorocyclopropan-l -amine (CAS: 2089150-96- 7, 0.718 g, 7.72 mmol,) in Pyridine (2 mL), were added EDC.HC1 (0.499 g, 3.21 mmol) at RT, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with 10% aq NaHCOs solution. Added water and extracted with ethyl acetate (2 times). The organic phase was dried under Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product as a yellow solid. The obtained crude product was purified by isolera column chromatography (silica gel 100-200 mesh; 100 g snap, flow rate 60 mL / min; absorbance - 254 nm, 100% ethyl acetate in petroleum ether), The product fractions were concentrated to get the product (XL VIII) as white solid; Yield: (0.25 g, 34%). LC_MS: Calc, for C22H24C1F2N5O2: 463.91; Obs.: 464.2 [M++H],Synthesis of (S)-l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-(( lS.2R)-2-fluorocvclopropyl) piperidine-3- carboxamide (XLIX)[000198] To a solution of (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (2.00 g, 5.14 mmol) and (lS,2R)-2-fluorocyclopropan-l -amine (CAS: 141042-20- 8, 2.32 g, 30.9 mmol,) in Pyridine (2 mL), were added EDC.HC1 (2.46 g, 12.9 mmol) at RT, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with 10% aq NaHCO3 solution, added water and extracted with ethyl acetate (2 times). The organic phase was dried under Na2SO4. The solvent was filtered and evaporated in vacuo to get the crude product as a brown solid. The obtained crude product was purified by isolera column chromatography (silica gel 100-200 mesh; 100 g snap, flow rate 60 mL / min; absorbance - 254 nm, 100% ethyl acetate in petroleum ether). The product fractions were concentrated to get the product (XLIX) as an off white solid; Yield: (2.00 g, 66.7%). LC_MS: Calc, for C22H25CIFN5O2: 445.3; Obs.: 446.2 [M++H],Synthesis of (S)-l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-(( 1 R.2R)-2-fluorocvclopropyl) piperidine-3- carboxamide (L)[000199] To a solution of (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.150 g, 0.38 mmol) and (lR,2R)-2-fluorocyclopropan-l -amine (CAS: 143062-85- 5, 0.17 g, 2.31 mmol,) in Pyridine (ImL), were added EDC.HC1 (0.15g, 0.96 mmol) at room temperature, under a nitrogen atmosphere. The resulting reaction mixturewas stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 X 50 ml). The combined organic layer was washed with 1.5 N HC1 solution to remove excess pyridine. The solvent was filtered and evaporated in vacuo to get the crude product (L) as a brown solid; Yield: (0.12 g, 60 %). LC_MS: Calc, for C22H25CIFN5O2: 445.92; Obs.: 446.2 [M++H],Synthesis of (S)-l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-(( lS.2S)-2-fluorocvclopropyl) piperidine-3- carboxamide (LI)[000200] To a solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.150 g, 0.38 mmol) and (lS,2S)-2-fluorocyclopropan-l -amine (CAS:1638744- 20-3, 0.17 g, 2.31 mmol,) in Pyridine (1 mL), were added EDC.HCI (0.15g, 0.96 mmol) at room temperature, under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with a diluted solution of 1.5 N HC1 (20 mL) to remove excess pyridine. The solvent was filtered and evaporated in vacuo to get the crude product (LI) as a brown solid; Yield: (0.10 g, 54%). LC_MS: Calc, for C22H25CIFN5O2: 445.92; Obs.: 446.2 [M++H],Synthesis of (S)-l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-((lR,2S)-2-fluorocvclopropyl) piperidine-3- carboxamide (LII)[000201] To a solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.150 g, 0.38 mmol) and (17?,2S)-2-fluorocyclopropan-l -amine (CAS Number: 143062-83-3, 0.17 g, 2.31 mmol,) in Pyridine (1 mL), were added EDC.HC1 (0.15g, 0.96 mmol) at room temperature, under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2x 25 mL). The combined organic layer was washed with 1.5 N HC1 solution (10 mL) to remove excess pyridine. The solvent was filtered and evaporated in vacuo to get the crude product (LII) as a brown solid; Yield: (0.12 g, 65 %). LC_MS: Calc, for C22H25CIFN5O2: 445.92; Obs.: 446.2 [M++H],Synthesis of tert-butyl (2-((S)-l-(2-chloro-4-((lS,2R)-2-hvdroxy-2,3-dihydro-IH-inden-l-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamido) cyclopropyl) carbamate (LIII)[000202] To a solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid(VUIb) (0.200 g, 0.51 mmol) and tert-butyl (2-aminocyclopropyl)carbamate (CAS Number: 445479-35-6, 0.106 g, 0.61 mmol,) in Pyridine (ImL), were added EDC.HC1 (0.246 g, 0.96 mmol) at room temperature, under a nitrogen atmosphere.The resulting reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2x 20 mL). The combined organic layer was washed with 1.5 N HC1 solution (20 mL) to remove excess pyridine. The solvent was filtered and evaporated in vacuo to get the crude product (LIII) as a brown solid; Yield: (0.2 g, 52.5 %). LC_MS: Calc, for C27H35CIN6O4: 543.06.; Obs.: 543.2 [M++H],Synthesis of (R)-l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-((lS,2R)-2-fluorocvdopropyl) piperidine-3- carboxamide (LIV)[000203] To a solution of (7?)-l-(2-chloro-4-(((15,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid(XXXVe) (0.39 g, 1.00 mmol) and (15,27?)-2-fluorocyclopropan-l -amine (CAS: 141042-20-8, 0.45 g, 6.02 mmol,) in Pyridine (2 mL), were added EDC.HCI (0.39g, 2.5 mmol) at room temperature, under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with water (20 mL) and was extracted with ethyl acetate twice (2 X 20 mL). The combined organic layer was washed with IM HC1 solution to remove the excess of pyridine. The solvent was filtered and evaporated in vacuo to get the crude product (LIV) as a brown solid; Yield: (0.3 g, 46.7%). LC_MS: Calc, for C22H25CIFN5O2: 445.3; Obs.:446.2 [M++H], 1H-NMR (400 MHz, DMSO-d6): 3 8.58(q, J = 1.20 Hz, 1H), 8.03- 8.00 (m, 1H), 7.85-7.82 (m, 1H), 7.39-7.37 (m, 1H), 7.18-7.25 (m, 3H), 5.43-5.40 (m, 3H), 4.57-4.54 (m, 2H), 3.17 (dd, J = 4.80, 16.20 Hz, 2H), 3.00-2.87 (m, 3H), 2.60-2.55 (m, 2H), 1.80 (t, J = 8.80 Hz, 2H), 1.53-1.51 (m, 2H), 1.00-0.98 (m, 1H), 0.97-0.83 (m, 1H).Synthesis of (R)-l-(4-(((lS,2R)-2-hydroxy-2,3-dihvdro-lH-inden-l-yl) amino)- 2-((l-(prop-2-vn-l-yl)-lH-benzo[l,2,3]triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxylic acid (LV)[000204] To a stirred solution of (7?)-l-(2-chloro-4-(((15,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid(XXXVe) (0.15 g, 0.38 mmol) and l-(prop-2-yn-l-yl)-l / Z-benzo[d][l,2,3]triazol- 6-amine (XXXIX) (0.079 g, 0.46 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.2 mL, 1.54 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated at 90 °C for 4 hours. The reaction progress was monitored by UPLC. After completion of the reaction, the reaction mixture was evaporated in vacuo to get the crude desired product (LV) as a brown gummy liquid. Yield: (0.15 g, 31.6%). LC_MS: Calc, for C28H28N8O3: 524.58; Obs.: 525.2[M++H],Synthesis of (3S)-l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-(2-fluorocvclobutyl) piperidine-3-carboxamide £LVD[000205] To a solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.20 g, 0.51 mmol) and 2-fluorocyclobutan- 1 -amine (CAS Number: 2288709-22-6, 0.27g, 3.09 mmol,) in pyridine (2 mL), were added EDC.HC1 (0.25g, 1.29 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. The reaction mixture was quenched with water (20 mL) and was extracted with ethyl acetate twice (2 X 20 mL). The combined organic layer was washed with IM HC1 to remove the excess of pyridine. The solvent was filtered and evaporated in vacuo to get the crude product (LVI) as a brown solid; Yield: (0.20 g, 83.9%). LC_MS: Calc, for C23H27C1FN5O2: 459.95; Obs.: 460.2 [M++H],Synthesis of (S)-l-(2-chloro-4-((lS,2R)-2-hvdroxy-2,3-dihvdro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N-((lR,2S)-2-fluorocvclobutyl) piperidine-3- carboxamide (LVII)[000206] To a solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.20 g, 0.51 mmol) and 2-fluorocyclobutan- 1 -amine (CAS:2307487-65-4, 0.27g, 3.09 mmol,) in pyridine (2 mL), were added EDC.HC1 (0.25g, 1.29 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. The reaction mixture was quenched with water (20 mL) and was extracted with ethyl acetate twice (2 X 20 mL). The combined organic layer was washed with IM HC1 to remove the excess of pyridine. The solvent was filtered and evaporated in vacuo to get the crude product (LVII) as a brown solid; Yield: (0.20 g, 83.9%). LC_MS: Calc, for C23H27C1FN5O2: 459.95; Obs.: 460.2 [M++H],Synthesis of (S)-l-(2-chloro-4-(((lS,2R)-2-hvdroxy-2,3-dihydro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-((lS,2R)-2-fluorocvclobutyl) piperidine-3- carboxamide (LVIII)[000207] To a solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (Vllb) (0.20 g, 0.51 mmol) and 2-fluorocyclobutan- 1 -amine (CAS: 2920188-02-7, 0.27g, 3.09 mmol,) in pyridine (2 mL), were added EDC.HC1 (0.25g, 1.29 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. The reaction mixture was quenched with water (20 mL) and was extracted with ethyl acetate twice (2 X 20 mL). The combined organic layer was washed with IM HC1 to remove the excess of pyridine. The solvent was filtered and evaporated in vacuo to get the crude product (LVIII) as a brown solid; Yield: (0.20 g, 83.9%). LC_MS: Calc, for C23H27C1FN5O2: 459.95; Obs.: 460.2 [M++H],Synthesis of (S)-4-(2-chloro-4-((( lS,2R)-2-hvdroxy-2.3-dihvdro-lH-inden-l- yl) amino) pyrimidin-5-yl)-N-((lS,2R)-2-fluorocvclopropyl) morpholine fluorocyclopropyl) morpholine-2-carboxamide (LIX)Step-1: Synthesis of ethyl 4-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl) morpholine-2-carboxylate (LIXa)[000208] A solution of 5-bromopyrimidine-2, 4(177, 37 / )-dione (CAS: 51-20- 7, 10.00 g, 52.36 mmol) and ethyl (S)-morpholine-2-carboxylate (CAS: 1820569- 30-9) (13.31 g, 68.07 mmol) in pyridine (50 mL) was irradiated at 150 °C for 1.5 hours in the microwave. The progress of the reaction was monitored by UPLC. After completion of the reaction, acetonitrile (100 mL) was added, stirred for 15 minutes, filtered, and dried under a vacuum that affords the crude product. The crude product was triturated with methyl tert-butyl ether (50 mL) to get the pure compound LIXa as an off-white solid; Yield: (7.7 g, 54.64). LCMS: Calc, for C11H15N3O5: 269.26; Obs.: 270.1 [M++H],Step-2: Synthesis of ethyl (S)-4-(2,4-dichloropyrimidin-5-yl) morpholine-2- carboxylate (LIXb)[000209] A solution of ethyl (S)-4-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5- yl) morpholine-2-carboxylate (LIXa) (6.0 g, 22.28 mmol) in POCI3 (60 mL, 0.64 mmol) was heated at 100 °C for 16 hours, under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCCL solution (400 mL). The aqueous layer was extracted with ethyl acetate (3 x 120 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under a vacuum to get the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting 20% ethyl acetate in petroleum ether to yield the title compound LIXb as a brown liquid; Yield: (2.30 g, 33.72%). LCMS: Calc, for C11H13CI2N3O3: 306.14; Obs.:305.9 [M++H],Step-3: Synthesis of ethyl (S)-4-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3-dihydro- IH-inden-l-yl) amino) pyrimidin-5-yl) morpholine-2-carboxylate (LIXc)[000210] To a stirred solution of ethyl (S)-4-(2,4-dichloropyrimidin-5- yl)morpholine-2-carboxylate (LIXb) (0.400 g, 1.30 mmol) in IPA (20 mL), was added DIPEA (0.680 mL, 3.91 mmol), followed by (15,27?)-l-amino-2,3-dihydro- 177-inden-2-ol (Ilf) (0.233 g, 1.56 mmol), under a 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 reactionmixture was cooled to room temperature and concentrated under reduced pressure to afford the crude product. The crude material was purified by silica gel (Biotage) column chromatography by eluting with 90% ethyl acetate in petroleum ether to yield the title compound LIXc as off-white solid; Yield: (0.20 g, 36.56%). LC_MS: Calc, for C20H23CIN4O4: 418.88; Obs.: 419.1 [M++H],Step-4: Synthesis of (S)-4-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino) pyrimidin-5-yl) morpholine-2-carboxylic acid (LIXd) [000211] To a stirred solution of ethyl (S)-4-(2-chloro-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)morpholine-2- carboxylate (LIXc) (1.80 g, 5.88 mmol) in a mixture of THF (20 mL) and water (20 mL) was added LiOH.ILO (0.370 g, 8.81 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was stirred 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), neutralized with 1.5N HC1, and then extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product LIXd as a brown gummy liquid. The crude product was taken to the next step without further purification; Yield: (1.42 g, 87.11%). LC_MS: Calc, for C18H19CIN4O4: 390.82; Obs.: 391.8. [M+-H],Step-5: Synthesis of (S)-4-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino) pyrimidin-5-yl)-N-((lS,2R)-2-fhiorocyclopropyl) morpholine-2-carboxamide (LIX)[000212] To a solution of (S)-4-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)morpholine-2-carboxylic acid (LIXd) (0.30 g, 0.76 mmol) and (15,2R)-2-fluorocyclopropan-l-amine HC1 (CAS Number: 141042-20-8, 0.35 g, 4.61 mmol,) in Pyridine (2 mL), were added EDC hydrochloride (0.29 g, 1.92 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC, reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2x20 mL),Combined organic layer was washed with IM of HC1 to remove excess of pyridine. The solvent was filtered and evaporated in vacuo to get the crude product (LIX) as a brown solid; Yield: (0.3 g, 79.6%). LC_MS: Calc, for C21H23CIFN5O3: 447.9; Obs.: 448.2 [M++H],Example 1: (S)-N-ethyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)-2-((l-isopropyl-lH-indazol-6-yl) amino)pyrimidin-5-yl)piperidine-3-carboxamide[000213] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -y l)amino)pyri midin-5-y 1 ) - / V-ct h y lpiperidine-3-carboxamide (II) (Formula C, 0.120 g, 0.289 mmol) and 1 -isopropyl- l H-indazol-6-aminc (I) (Formula D, 0.06 g, 0.346 mmol) in NMP (5 mL), was added 4M HC1 in dioxane (0.11 mL, 0.433 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 mass was cooled to room temperature, diluted with water (5 mL), neutralized by triethylamine, and extracted with ethyl acetate (2 x 10 mL). The 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 5% methanol in DCM to yield the title compound Example 1 as an off-white solid; Yield: (0.105 g, 64.5%).[000214] LC_MS: Calc, for CsiffcsNsCL: 554.60; Obs.: 555.2 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.46 (br s, 1H), 8.44 (br s, 1H), 7.84 (t, J = 16.00 Hz, 3H), 7.51 (d, J = 8.40 Hz, 1H), 7.33 (d, J = 7.60 Hz, 1H), 7.26 (t, J = 7.20 Hz, 1H), 7.18 (t, J = 7.60 Hz, 1H), 7.04 (m, 1H), 5.64-5.60 (m, 2H), 4.65-4.62 (m, 1H), 3.78 (s, 1H), 3.16 (d, J = 4.00 Hz, 1H), 3.06-2.99 (m, 6H), 2.35 (m, 2H), 1.76 (m, 2H), 1.51 (m, 4H), 1.24 (m, 3H), 1.13 (d, J = 12.00 Hz, 6H); HPLC: Purity = 98.00%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 2:(S)-N-ethyl-l-(4-((lR,2S)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-((l-isopropyl-lH-indazol-6-yl) amino) pyrimidin-5-yl) piperidine-3- carboxamide[000215] To a stirred solution of (S)-l-(2-chloro-4-(((17?,2S)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -y l)amino)pyri midin-5-y 1 ) - / V-ct h y lpiperidine-3-carboxamide (III) (Formula C, 0.120 g, 0.289 mmol) 1 -isopropyl- l H-indazol-6-aminc (I) (Formula D, 0.055 g, 0.317 mmol) in NMP (2 mL) was added 4M HC1 in dioxane (0.14 mL, 0.577 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 TFA in water andacetonitrile to afford the desired compound Example 2 as an off-white solid; Yield: (0.062 g, 38.75%).[000216] LC_MS: Calc, for CsiffeNsCL: 554.70; Obs.: 555.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 39.32 (s, 1H), 8.49 (s, 1H), 7.89-7.88 (m, 1H), 7.82- 7.78 (m, 2H), 7.47 (d, J = 8.80 Hz, 1H), 7.35-7.32 (m, 2H), 7.28-7.25 (m, 1H), 7.21- 7.17 (m, 1H), 7.03 (m, 1H), 6.80 (s, 1H), 5.65-5.63 (m, 1H), 5.53 (d, J = 4.00 Hz, 1H), 4.63-4.60 (m, 1H), 3.75 (m, 1H), 3.19-3.15 (m, 2H), 2.99-2.95 (m, 6H), 2.42- 2.41 (m, 1H), 1.72 (m, 2H), 1.50 (m, 2H), 1.11-1.08 (m, 3H), 1.01-0.95 (m, 6H); HPLC Purity = 99.80%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 3: (S)-l-(2-((l-allyl-5-fhioro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- ethylpiperidine-3-carboxamideExample 3[000217] To a stirred solution (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl) amino) pyrimidin-5-yl)-N-ethylpiperidine-3-carboxamide (II) (Formula C, 0.20 g, 0.48 mmol) and l-allyl-5-fluoro-l / Z-indazol-6-amine (IV) (Formula D, 0.091 g, 0.48 mmol) in NMP (3 mL) was added 4M HC1 in dioxane (0.24 mL, 0.961 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated in vacuo to get the crude product. The obtained crude product waspurified by Prep-HPLC purification using ammonium bicarbonate in water and acetonitrile to afford the desired compound Example 3 as an off-white solid; Yield: (0.030 g, 10.9%).[000218] LC_MS: Calc, for C31H35FN8O2: 570.67; Obs.: 571.3 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 8.48 (d, J = 6.80 Hz, 1H), 8.15 (d, J = 2.80 Hz, 1H), 7.89-7.83 (m, 3H), 7.54-7.51 (m, 1H), 7.32-7.30 (m, 1H), 7.25-7.22 (m, 2H), 7.16-7.13 (m, 1H), 6.85 (s, 1H), 5.60-5.51 (m, 3H), 4.95-4.92 (m, 1H), 4.65-4.61 (m, 2H), 4.48-4.43 (m, 1H), 4.31-4.27 (m, 1H), 3.18-3.13 (m, 1H), 3.06-2.91 (m, 6H), 2.68 (s, 1H), 2.39-2.33 (m, 1H), 1.79-1.72 (m, 2H), 1.55 (s, 2H), 0.99-0.95 (m, 3H); HPLC Purity = 99.70%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 4: (S)-N-ethyl-l-(2-((5-fluoro-l-propyl-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide[000219] To a stirred solution (S)-l-(2 chloro-4-(((15,27?)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl) amino) pyri midin-5-y Ij-Mcthy lpipcridinc-3-carboxamidc (II) (Formula C, 0.15 g, 0.360 mmol), 5-fluoro-l-propyl-l / Z-indazol-6-amine (V) (Formula D, 70 mg, 0.362 mmol) in NMP (2 mL) was added 4M HC1 in dioxane (0.2 mL, 0.8 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 x20 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 10 mM NH4CO3 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 free base of Example 4 as an off-white solid; Yield: (0.079 g, 38%).[000220] LC_MS: Calc, for C31H37FN8O2: 572.69; Obs.: 573.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 8.50 (d, J = 6.80 Hz, 1H), 8.11 (s, 1H), 7.85 (dd, J = 5.20, 12.80 Hz, 3H), 7.50 (d, J = 11.20 Hz, 1H), 7.32-7.26 (m, 3H), 7.24 (d, J = 7.20 Hz, 1H), 7.13 (br s, 1H), 5.58 (d, J = 2.80 Hz, 2H), 3.68-3.35 (m, 3H), 3.31- 3.01 (m, 7H), 2.51 (br s, 1H), 1.53-1.48 (m, 6H), 1.12-0.95 (m, 4H), 0.53 (t, J = 7.60 Hz, 3H); HPLC Purity = 99.51%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 5 mM Ammonium bicarbonate in water, Mobile Phase B: Acetonitrile.Example 5: (lS,2R)-l-((2-((l-allyl-5-fluoro-lH-indazol-6-yl) amino)-5-((S)-3- (hydroxymethyl) piperidin-l-yl) pyrimidin-4-yl) amino)-2,3-dihydro-lH- inden-2-ol.[000221] To a stirred solution (lS,27?)-l-((2-chloro-5-((S)-3-(hydroxymethyl) piperidin-l-yl)pyrimidin-4-yl)amino)-2,3-dihydro-lH-inden-2-ol (VI) (Formula C, 0.150 g, 0.400 mmol), and l-allyl-5-fluoro-lH-indazol-6-amine (IV) (Formula D, 0.076 g, 0.348 mmol) in NMP (4 mL) was added 4M HC1 in dioxane (0.2 mL, 0.800 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 (10mL), 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 Example 5 as an off-white solid; Yield: (0.050 g, 23 %).[000222] LC_MS: Calc, for C29H32FN7O2: 529.62; Obs.: 530.2 [M++H]; 'H NMR (400 MHz, DMSO-d6):: 3 8.47 (d, J = 6.80 Hz, 1H), 8.21 (s, 1H), 7.89-7.85 (m, 2H), 7.55-7.52 (m, 1H), 7.32-7.22 (m, 4H), 7.17-7.10 (m, 1H), 6.77 (d, J = 5.20 Hz, 1H), 5.62-5.53 (m, 3H), 4.95-4.92 (m, 1H), 4.46-4.61 (m, 5H), 2.93-3.07 (m, 5H), 2.53 (s, 3H), 1.71 (s, 3H), 1.12-1.08 (m, 1H) ; HPLC Purity = 97.86%, X - Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 6: (S)-l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- isopropylpiperidine-3-carboxamidexamp e[000223] To a stirred solution (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)-N-isopropylpiperidine-3- carboxamide (VII) (Formula C, 0.150 g, 0.348 mmol), l-allyl-5-fluoro-lH- indazol-6-amine (IV) (Formula D, 0.066 g, 0.348 mmol) in NMP (3 mL) was added 4M HC1 in dioxane (0.174 mL, 0.697 mmol) at room temperature, under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 3 hours. The progress ofthe 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 Example 6 as an off-white solid; Yield: (0.048 g, 23%).[000224] LC_MS: Calc, for C32H37FN8O2: 584.70; Obs.: 585.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 8.47 (br s, 1H), 8.13 (br s, 1H), 7.88 (s, 2H), 7.66 (s, 1H), 7.52 (d, J = 11.20 Hz, 1H), 7.25-7.22 (m, 3H), 7.15 (d, J = 6.80 Hz, 1H), 5.55-5.52 (m, 3H), 4.94 (d, J = 9.60 Hz, 1H), 4.66-4.31 (m, 4H), 3.79 (d, J = 7.20 Hz, 1H), 3.13-3.01 (m, 4H), 1.62 (m, 4H), 1.11 (s, 4H), 1.00 (d, J = 6.80 Hz, 6H); HPLC Purity = 98.33%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 7: l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- ethylpiperidine-4-carboxamide[000225] To a stirred solution l-(2-chloro-4-(((15,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl) amino) pyrimidin-5-yl)-N-ethylpiperidine-4-carboxamide (XXXI) (Formula C, 0.15 g, 0.36 mmol) and l-allyl-5-fluoro-l / Z-indazol-6-amine (IV) (0.068 g, 0.36 mmol) in NMP (3 mL) was added 4M HC1 in dioxane (Formula D, 0.18 mL, 0.721 mmol) at room temperature, under nitrogen atmosphere. Thereaction mixture was heated at 90°C for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was 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 Example 7 as an off-white solid; Yield: (0.098 g, 48%).[000226] LC_MS: Calc, for C31H35FN8O2: 570.67; Obs.: 571.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 8.47 (d, J = 6.80 Hz, 1H), 8.20 (s, 1H), 7.89-7.87 (m, 2H), 7.81-7.78 (m, 1H), 7.54-7.52 (m, 1H), 7.31 (d, J = 7.20 Hz, 1H), 7.27-7.23 (m, 2H), 7.18-7.14 (m, 1H), 6.79-6.77 (m, 1H), 5.54-5.56 (m, 3H), 4.95-4.92 (m, 1H), 4.65-4.57 (m, 2H), 4.46-4.45 (m, 1H), 4.30-4.29 (m, 1H), 3.18-3.15 (m, 1H), 3.09-3.02 (m, 4H), 2.93-2.89 (m, 1H), 2.70-2.66 (m, 2H), 2.25-2.15 (m, 1H), 1.74- 1.71 (m, 4H), 1.02-0.98 (m, 3H). HPLC Purity = 98.35%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 8: l-(S)-4-(2-((l-allyl-5-fhioro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1-yl) amino) pyrimidin-5 -yl) -2- methylpiperazin-l-yl)-2-(methylamino) ethan-l-one[000227] To a stirred solution tert-butyl (2-((S)-4-(2-chloro-4-(((lS,27?)-2- hydroxy-2 -dihydro- 1 H-inden- 1 -yl) amino)pyrimidin-5-yl)-2-methylpiperazin- 1 - yl)-2-oxoethyl)(methyl)carbamate (VIII) (Formula e, 0.15 g, 0.282 mmol), 1-allyl- 5-fluoro-l / Z-indazol-6-amine (IV) (Formula D, 0.054 g, 0.282 mmol) in NMP (2mL) was added 4M HC1 in dioxane (0.14 mL, 0.565 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 lOmM Ammonium bicarbonate in water and acetonitrile to afford the gummy mass. The compound was further triturated with diethyl ether, the white solid thrown out was allowed to settle and the supernatant were decanted. The solid obtained was dried under high vacuo, to get free base of Example 8 as an off-white solid; Yield: (0.022 g, 12%).[000228] LC_MS: Calc, for C31H36FN9O2: 585.69; Obs.: 586.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 8.44 (d, J = 6.80 Hz, 1H), 8.19 (s, 1H), 7.89 (d, J = 6.00 Hz, 2H), 7.53 (d, J = 11.20 Hz, 1H), 7.27-7.22 (m, 4H), 6.77 (d, J = 8.00 Hz, 1H), 5.53 (d, J = 4.40 Hz, 3H), 4.94 (m, 1H), 4.67-4.58 (m, 7H), 3.12 (s, 3H), 2.87- 2.53 (m, 6H), 2.27 (s, 3H), 1.14 (m Hz, 3H); HPLC Purity = 93.52%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 5mM Ammonium bicarbonate in water, Mobile phase B: Acetonitrile.Example 9: l-((S)-4-(2-((5-fluoro-l-(prop-2-yn-l-yl)-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino)ethan-l-one[000229] To a stirred solution tert-butyl (2-((S)-4-(2-chloro-4-(((lS,27?)-2- hydroxy-2 -dihydro- 1 H-inden- 1 -yl) amino)pyrimidin-5-yl)-2-methylpiperazin- 1 - yl)-2-oxoethyl)(methyl)carbamate (VIII) (Formula C, 0.15 g, 0.282 mmol), 5- fluoro-l-(prop-2-yn-l-yl)-lH-indazol-6-amine (IX) (Formula D, 0.053 g, 0.282 mmol) in NMP (2 mL) was added 4M HC1 in dioxane (0.14 mL, 0.565 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 0.1 % TFA in water and acetonitrile to afford the gummy mass. 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 TFA salt of Example 9 as an off-white solid; Yield: (0.020 g, 12.5%).[000230] LC_MS: Calc, for C31H34FN9O2: 583.67; Obs.: 584.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 8.71 (br s, 1H), 8.45 (d, J = 6.80 Hz, 1H), 8.01 (s, 1H), 7.96 (br s, 1H), 7.71 (d, J = 10.80 Hz, 2H), 7.34 (d, J = 7.60 Hz, 2H), 7.30- 7.26 (m, 1H), 7.18-7.10 (m, 1H), 5.57 (br s, 1H), 4.80-4.75 (m, 1H), 4.65 (br s, 1H), 4.33-3.84 (m, 4H), 3.29-2.97 (m, 8H), 2.68-2.51 (m, 6H), 1.27-1.20 (m, 3H); HPLC Purity = 98.479%, Atlantis T3 (150 X 4.6) mm, 3pm, Mobile Phase A: 0.1% TFA in water, Mobile phase B: Acetonitrile.Example 10: l-((S)-4-(2-((5-fhioro-l-isopropyl-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino) ethan-l-oneVIII Example 10[000231] To a stirred solution tert-butyl (2-((S)-4-(2-chloro-4-(((lS,27?)-2- hydroxy-2 -dihydro- 1 H-inden- 1 -yl) amino)pyrimidin-5-yl)-2-methylpiperazin- 1 - yl)-2-oxoethyl)(methyl)carbamate (VIII) (Formula C, 0.10 g, 0.188 mmol) 5- fluoro-l-isopropyl-lH-indazol-6-amine (X) (Formula D, 0.043 g, 0.226 mmol) in NMP (2 mL) was added 4M HC1 in dioxane (0.94 mL, 0.377 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 0.1% Ammonium bicarbonate in water in water and acetonitrile to afford the desired compound Example 10 as an off-white solid; Yield: (0.023 g, 21.75%).[000232] LC_MS: Calc, for C31H38FN9O2: 587.70; Obs.: 588.3 [M++H]; 'H NMR (400 MHz, DMSO-d6) d 8.52 (d, J = 6.40 Hz, 1H), 8.20 (m, 1H), 7.88 (d, J = 11.80 Hz, 2H), 7.49 (d, J = 5.20 Hz, 1H), 7.34 (t, J = 8.40 Hz, 2H), 7.28 (t, J = 6.80 Hz, 1H), 7.20 (t, J = 7.60 Hz, 1H), 6.83 (d, J = 8.40 Hz, 1H), 5.59 (s, 1H), 4.60 (s, 2H), 4.33 (m, 2H), 3.83 (m, 3H), 3.14 (s, 2H), 2.94-2.90 (m, 3H), 2.68 (m, 3H), 2.32 (s, 3H), 1.20-1.18 (m, 6H), 1.07 (d, J = 6.40 Hz, 3H). HPLC Purity = 91.12%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 11: l-((S)-4-(2-((5-fhioro-l-(2-methoxyethyl)-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin- 5-yl)-2-methylpiperazin-l-yl)-2-(methylamino) ethan-l-one[000233] To a solution of tert-butyl (2-((S)-4-(2-chloro-4-(((lS,27?)-2- hydroxy-2,3-dihydro- 1H- inden- l-yl)amino)pyrimidin-5-yl)-2-methylpiperazin- 1- yl)-2-oxoethyl)(methyl)carbamate (VIII) (Formula C, 0.10 g, 0.18 mmol) and 5- fluoro-l-(2-methoxyethyl)-lH-indazol-6-amine (XI) (Formula D, 0.039 g, 0.18 mmol) in NMP (3 mL), was added 4M HC1 in Dioxane (0.027 g, 0.75 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 the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, and neutralized with 10% aq. NaHCOs, and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as a brown gummy solid. The obtained crude was purified by Preparative HPLC reverse phase (Ammonium bicarbonate in water and acetonitrile) to afford desired product Example 11 as an Off-white solid; Yield: (0.006 g, 5%).[000234] LC_MS: Calc, for: C31H38FN9O3: 603.70; Obs.: 604.3 [M+H]+and 1H-NMR (400 MHz, DMSO-J6): 3 8.53 (d, J = 6.80 Hz, 1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.51 (s, 1H), 7.31 (t, J = 8.00 Hz, 2H), 7.24 (t, J = 7.20 Hz, 1H), 7.16 (t, J = 7.20 Hz, 1H), 6.78 (d, J = 8.40 Hz, 1H), 5.62-5.56 (m, 2H), 4.60 (d, J = 4.80 Hz, 2H), 3.92-3.87 (m, 1H), 3.75-3.65 (m, 2H), 3.75-3.65 (m, 2H),3.20-3.15 (m, 2H), 3.02 (s, 4H), 2.99-2.85 (m, 5H), 2.31 (s, 4H), 1.36-1.18 (m, 4H), HPLC Purity = 94.13%, Column: X-Bridge C8(50 X 4.6)mm,3.5pm, Mobile phase: A:5mM Ammonium bicarbonate in water: B:ACN, Flow:1.0mL / min.Example 12: N-(l-(2-((l-allyl-5-fhioro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl) propionamide[000235] To a stirred solution of N-(l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)piperidin-4-yl)propionamide (XII) (Formula C, 0.100 g, 0.240 mmol), l-allyl-5-fluoro-lH-indazol-6-amine (IV) (Formula D, 0.045 g, 0.240 mmol) in NMP (4 mL) was added 4M HC1 in dioxane (0.12 mL, 0.480 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 Example 12 as a pale-yellow solid; Yield: (0.005 g, 3%).[000236] LC_MS: Calc, for C31H35FN8O2: 570.67; Obs.: 571.4 [M++H]; HPLC Purity = 93.75%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 13: l-((S)-4-(2-((l-allyl-5-methyl-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino) ethan-l-one[000237] To a solution of tert-butyl (2-((S)-4-(2-chloro-4-(((lS,27?)-2- hydroxy-2,3-dihydro- 1H- inden- l-yl)amino)pyrimidin-5-yl)-2-methylpiperazin- 1- yl)-2-oxoethyl)(methyl)carbamate (VIII) (Formula C, 0.13 g, 0.24 mmol) and 1- allyl-5-methyl-lH-indazol-6-amine (XIII) (Formula D, 0.045 g, 0.24 mmol) in NMP (3 mL), was added 4M HC1 in Dioxane (0.017 g, 0.49 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 the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, and neutralized with 10% aq. NaHCOs, and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as a brown gummy liquid. The obtained crude was purified by Preparative HPLC reverse phase (ammonium bicarbonate in water + ACN) to afford desired product Example 13 as an off-white solid; Yield: (0.016 g, 10%).[000238] LC_MS: Calc, for C32H39N9O2: 5:81.73; Obs.: 582.3 [M++H] ; 1H- NMR (400 MHz, DMSO-J6): 3 8.25 (s, 1H), 8.17 (s, 1H), 7.83 (s, 3H), 7.49 (s, 1H), 7.30-7.21 (m, 1H), 7.30-7.23 (m, 2H), 7.16-7.06 (m, 1H), 6.69 (d, J = 8.40 Hz, 1H), 5.64-5.61 (m, 1H), 5.48 (t, J = 8.00 Hz, 2H), 4.94 (m, 1H), 4.69 (s, 1H), 4.65 (s, 1H), 4.49-4.44 (m, 3H), 4.50 (s, 1H), 3.18 (m, 2H), 3.12-3.10 (m, 2H), 2.97-2.82(m, 5H), 2.45 (d, J = 5.60 Hz, 6H), 1.24 (br s, 3H). HPLC Purity; 90.52%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A:0.1% TFA in water Mobile phase: B: ACN, Flow:2.0mL / min.Example 14: 2-(dimethyl amino)-N-(l-(2-((l-ethyl-lH-indazol-6-yl) amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl) acetamide[000239] To a solution of (15,27?)-l-((5-(4-aminopiperidin-l-yl)-2-((l-ethyl- lH-indazol-6-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydro-lH-inden-2-ol (XXXII) (0.150 g, 0.161 mmol) and dimethylglycine (0.016 g, 0.514 mmol, 2M) in THF (10 mL), were added DIPEA (0.084 mL, 0.482 mmol) followed by HATU (0.073 g, 0.193 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 obtained crude product was purified by Prep-HPLC purification using formic acid in water and acetonitrile to afford the desired compound Example 14 as off-white solid; Yield: (0.060 g, 65%).[000240] LC_MS: Calc, for C31H39N9O2: 569.71; Obs.:570.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.31 (s, 1H), 8.48 (s, 1H), 8.16 (s, 2H), 7.90 (s, 1H), 7.77-7.77 (m, 1H), 7.72 (d, J = 8.00 Hz, 1H), 7.48 (d, J = 8.80 Hz, 1H), 7.35- 7.30 (m, 2H), 7.26-7.23 (m, 1H), 7.19-7.15 (m, 1H), 7.09-7.06 (m, 1H), 6.68 (d, J = 8.40 Hz, 1H), 5.66-5.63 (m, 2H), 4.64-4.62 (m, 1H), 3.64-3.51 (m, 1H), 3.04 (d, J = 11.20 Hz, 3H), 2.92-2.89 (m, 3H), 2.81-2.75 (m, 2H), 2.22 (s, 6H), 1.81-1.78(m, 2H), 1.56 (s, 2H), 0.97-0.93 (m, 3H). HPLC Purity = 99.18%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 15: (S)-l-(2-((l-allyl-5-fhioro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide[000241] To a solution of (S)-l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl)amino)-4-(((15,27?)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5- yl)piperidine-3-carboxylic acid (XXXIII) (0.150 g, 0.275 mmol) and cyclopropane amine (Formula D, 0.015 g, 0.275 mmol) in THF (10 mL), were added DIPEA (0.144 mL, 0.827 mmol) followed by HATU (0.125 g, 0.331 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% NaHCCh solution (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. The obtained crude product was purified by Prep-HPLC purification using Ammonium bicarbonate in water and acetonitrile to afford the desired compound Example 15 as an off-white solid; Yield: (0.030 g, 20 %).[000242] LC_MS: Calc, for C32H35FN8O2: 582.68.70; Obs.: 583.3 [M++H]; 'H NMR (400 MHz, DMSO-d6) : d 8.47 (d, J = 6.80 Hz, 1H), 8.19 (s, 1H), 7.89- 7.87 (m, 3H), 7.53 (d, J = 11.20 Hz, 1H), 7.31 (d, 7 = 7.60 Hz, 1H), 7.25-7.22 (m,2H), 7.16-7.13 (m, 1H), 6.86 (m, 1H), 5.51-5.54 (m, 2H), 4.92-4.95 (m, 1H), 4.55- 4.70 (m, 2H), 4.40-4.50 (m, 1H), 4.25-4.35 (m, 1H), 3.14-3.32 (m, 1H), 3.08-3.13 (m, 1H), 2.91-2.95 (m, 3H), 2.67-2.68 (m, 2H), 1.65-1.85 (m, 2H), 1.40-1.60 (m, 2H), 1.05-1.15 (m, 5H), 0.50-0.60 (m, 1H).; HPLC Purity = 99.59%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 16: N-(l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl)-2- (dimethyl amino) acetamide[000243] To a solution of (15,27?)-l-((2-((l-allyl-lH-indazol-6-yl)amino)-5- (4-aminopiperidin-l-yl)pyrimidin-4-yl)amino)-2,3-dihydro-lH-inden-2-ol (XIX) ( 0.210 g, 0.422 mmol) and dimethylglycine (0.043 g, 0.422 mmol) in THF (10 mL), were added DIPEA (0.368 mL, 2.114 mmol) followed by HATU (0.209 g, 0.549 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% NaHCCL solution (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 pale-yellow solid. The obtained crude product was purified by Prep-HPLC purification using Ammonium bicarbonate in water and acetonitrile to afford freebase of the desired compound Example 16 as an off-white solid; Yield: (0.097 g, 38 %).[000244] LC_MS: Calc, for C32H39N9O2; 581.73; Obs.: 582.3 [M++H], HPLC Purity = 95.75%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile. 1H-NMR (400 MHz, DMSO- d6) 3 9.30 (s, 1H), 8.42 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.67 (d, J = 8.40 Hz, 1H), 7.50 (d, J = 8.80 Hz, 1H), 7.33-7.23 (m, 3H), 7.18-7.11 (m, 2H), 6.66 (d, J = 8.40 Hz, 1H), 5.60-5.53 (m, 3H), 4.92 (d, J = 10.40 Hz, 1H), 4.63-4.58 (m, 2H), 4.36 (d, J = 4.40 Hz, 1H), 4.23 (d, J = 8.00 Hz, 1H), 3.78 (s, 1H), 3.20-3.16 (m, 1H), 3.02-2.95 (m, 3H), 2.91-2.80 (m, 2H), 2.77-2.75 (m, 2H), 2.19 (s, 6H), 1.80 (t, J = 10.00 Hz, 2H), 1.58 (m, 2H), 1.11 (s, 1H).Example 17: 2-(dimethylamino)-N-(l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro- IH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-indazol-6-yl) amino) pyrimidin-5-yl) piperidin-4-yl) acetamide[000245] To a solution of (lS,2R)-l-((5-(4-aminopiperidin-l-yl)-2-((l-(prop- 2-yn-l-yl)-l / Z-indazol-6-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydro-l / Z-inden- 2-ol (XXXIV) (0.18 g, 0.36 mmol) and dimethylglycine (0.03 mL, 0.36 mmol) in THF (10 mL), were added DIPEA (0.2 mL, 1.14 mmol) followed by HATU (0.17 g, 0.44 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% NaHCCL solution (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 crudeproduct as an off white solid. The obtained crude product was purified by Prep- HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as 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 product Example 17 as an off-white solid. Yield: (0.22 g, 10.0 %),[000246] LC_MS: Calc, for C32H37N9O2: 579.71; Obs.: 580.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.39 (s, 1H), 8.61 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.68 (d, J = 8.00 Hz, 1H), 7.51 (d, J = 8.80 Hz, 1H), 7.33 (t, J = 6.40 Hz, 2H),7.24 (t, J = 7.20 Hz, 1H), 7.17-7.15 (m, 2H), 6.70 (d, J = 8.00 Hz, 1H), 5.69-5.67 (m, 1H), 5.55 (d, J = 4.40 Hz, 1H), 4.67-4.62 (m, 2H), 3.27-3.24 (m, 4H), 3.02-2.76 (m, 7H), 2.19 (s, 6H), 1.79 (t, J = 11.20 Hz, 2H), 1.61-1.57 (m, 2H); HPLC Purity: 97.78%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile.Example 18: l-(S)-4-(2-((l-allyl-lH-indazol-6-yl) amino)-4-((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino) ethan-l-oneVIII Example 18[000247] To a stirred solution tert-butyl (2-((S)-4-(2-chloro-4-(((lS,27?)-2- hydroxy-2,3-dihydro- 1H- inden- l-yl)amino)pyrimidin-5-yl)-2-methylpiperazin- 1- yl)-2-oxoethyl)(methyl)carbamate (VIII) (Formula C, 0.2 g, 0.376 mmol), 1-allyl- l / Z-indazol-6-amine (XVI) (Formula D, 0.065 g, 0.376 mmol) in NMP (3 mb) wasadded 4M HC1 in dioxane (0.37 mL, 1.50 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 evaporated in vacuo to get the crude product. The obtained crude product was purified by Prep-HPLC purification using 10mm TFA in water and acetonitrile to afford to get of Example 18 as an off-white solid; Yield: (0.080 g, 37%). LC_MS: Calc, for C31H37N9O2: 567.70; Obs.: 568.3 [M++H]; 'H NMR (400 MHz, DMSO-dd): d 9.33 (s, 1H), 8.48-8.41 (m, 1H), 8.00-7.82 (m, 2H), 7.55- 7.50 (m, 1H), 7.33-7.31 (m, 2H), 7.27-7.23 (m, 1H), 7.19-7.13 (m, 2H), 6.79-6.75 (m, 1H), 5.62-5.55 (m, 3H), 4.94-4.91 (m, 1H), 4.63-4.59 (m, 3H), 4.43-4.18 (m, 3H), 3.40 (m, 1H), 3.28-3.16 (m, 2H), 3.00-2.78 (m, 6H), 2.31 (s, 3H), 2.28-1.11 (m, 4H). HPLC Purity = 95.02%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile phase B: Acetonitrile.Example 19: (S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N-cyclopropylpiperidine- 3-carboxamide[000248] To a solution of (S)-l-(2-((l-allyl-l / Z-indazol-6-yl)amino)-4- (((15,27?)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)piperidine- 3-carboxylic acid (XVII) (0.20 g, 0.38 mmol) and cyclopropane amine (0.03 mL, 0.457 mmol) in THF (10 mL), were added DIPEA (0.17 mL, 0.95 mmol) followed by HATU (0.17 g, 0.46 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction progresswas monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was basified using 10% NaHCOs solution (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. 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 Example 19 as an Off-white solid; Yield: (0.045 g, 21 %).[000249] LC_MS: Calc, for C32H36N8O2: 564.69; Obs.: 565.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.30 (s, 1H), 8.42 (s, 1H), 7.83-7.80 (m, 3H), 7.50 (d, J = 8.40 Hz, 1H), 7.28-7.13 (m, 5H), 5.58-5.51 (m, 3H), 4.93-4.91 (m, 1H), 4.63-4.61 (m, 2H), 4.10-4.09 (m, 3H), 3.18 (s, 2H), 2.96-2.53 (m, 5H), 2.51-2.50 (m, 1H), 1.75-1.53 (m, 4H), 0.58-0.55 (m, 2H), 0.36-0.33 (m, 2H); HPLC Purity = 99.07%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A : Ammonium bicarbonate in water, Mobile Phase B: Acetonitrile.Example 20: l-((S)-4-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-2- methylpiperazin- 1 -yl) -2-morpholinoethan- 1 -one[000250] To a stirred solution l-((S)-4-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)-2-methylpiperazin- 1 -y l)-2- morpholinoethan-l-one (XVIII) (Formula C, 0.100 g, 0.205 mmol) and 1-allyl-lH- indazol-6-amine (XVI) (Formula D, 0.035 g, 0.205 mmol) in NMP (4 mL) wasadded 4M HC1 in dioxane (0.103 mL, 0.411 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 lOmM 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 desired compound Example 20 as an off-white solid; Yield: (0.050 g, 39%).[000251] LC_MS: Calc, for C34H41N9O3: 623.76; Obs.:624.3 [M++H], 'H NMR (400 MHz, DMSO-d6): 9.33 (br s, 1H), 8.41 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.51 (dd, J = 8.80, Hz, 1H), 7.33-7.31 (m, 2H), 7.27-7.23 (m, 1H), 7.19-7.13 (m, 2H), 6.76 (d, J = 7.60 Hz, 1H), 5.60-5.55 (m, 3H), 4.92-4.94 (m, 1H), 4.59-4.63 (m, 2H), 3.95-4.39 (m, 4H), 3.45-3.58 (m, 4H).; HPLC Purity = 99.86%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1 % TFA in water, Mobile Phase B: Acetonitrile.Example 21: (lS,2R)-l-((2-((l-allyl-lH-indazol-6-yl) amino)-5-(4-((pyridin-2- ylmethyl) amino) piperidin-l-yl) pyrimidin-4-yl) amino)-2,3-dihydro-lH- inden-2-ol (BWC5070)XIX Example 21[000252] To a mixture of (15,27?)-l-((2-((l-allyl-lH-indazol-6-yl)amino)-5- (4-aminopiperidin-l-yl)pyrimidin-4-yl)amino)-2,3-dihydro-lH-inden-2-ol (XIX) (0.1 g, 0.201 mmol) and picolinaldehyde (25.88 mg, 0.241 mmol) in a dry MeOH (10 mL) / DCE (10 mL) were added acetic acid (0.2 mL), sodium acetate (82.59 mg, 1.007 mmol) and MPCNBH3 resin (0.1 g) at room temperature under nitrogen atmosphere. The resulting mixture continued to stir at room temperature for 1.5 hours. After completion of the reaction mixture, the reaction mixture was filtered, quenched with water (1 mL) and concentrated in vacuo to get crude. The obtained crude product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile, the product fraction was concentrated under vacuo to get gummy mass. The product was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant was decanted. The solid was dried under high vacuo, to afford free base of desired compound Example 21 as an off-white solid; Yield: (0.012 g, 10.17%).[000253] LC_MS: Calc, for C34H37N9O: 587.73; Obs.: 588.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.27 (br s, 1H), 8.49 (br s, 1H), 8.42 (s, 1H), 7.84- 7.81 (m, 2H), 7.75-7.74 (m, 1H), 7.51-7.45 (m, 2H), 7.31-7.13 (m, 6H), 6.70 (d, J = 8.40 Hz, 1H), 5.55 (br s, 3H), 4.93-4.90 (m, 1H), 4.62-4.58 (m, 2H), 4.35 (d, J = 4.80 Hz, 2H), 3.84 (s, 2H), 3.08-2.56 (m, 6H), 1.92 (m, 2H), 1.24 (m, 2H), 1.11 (m, 2H); HPLC Purity = 97.62%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 22: ((S)-4-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-2- methylpiperazin-l-yl) ((S)-l-methylpyrrolidin-2-yl) methanonexamp e[000254] To a stirred solution 2-chloro-4-(((15,27?)-2-hydroxy-2,3-dihydro- 1H- inden- l-yl)amino)-5-((S)-3-methyl-4-(methyl-L-prolyl)piperazin- 1- yl)pyrimidine (XX) (Formula C, 0.100 g, 0.212 mmol) and l-allyl-lH-indazol-6- amine (XVI) (Formula D, 0.036 g, 0.212 mmol) in NMP (3 mL) was added 4M HC1 in dioxane (0.212 mL, 0.849 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 Example 22 as an off-white solid; Yield: (0.020 g, 15%).[000255] LC_MS: Calc, for C34H41N9O2: 607.76; Obs.:608.3 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 9.34 (br s, 1H), 8.42 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.50-7.52 (m, 1H), 7.31-7.33 (m, 2H), 7.25-7.27 (m, 1H), 7.12-7.23 (m, 2H), 6.76 (d, J = -8.00 Hz, 1H), 5.54-5.59 (m, 3H), 4.93-4.90 (m, 1H), 4.59-4.63 (m, 3H), 4.37-4.41 (m, 2H), 4.11-4.21 (m, 1H).; HPLC Purity = 97.54%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1 % TFA in water, Mobile Phase B: Acetonitrile.Example 23: (S)-N-(l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl)-l- methylpyrrolidine-2 carboxamideXIX Example 23[000256] To a solution of (15,27?)-l-((2-((l-allyl-lH-indazol-6-yl)amino)-5- (4-aminopiperidin-l-yl)pyrimidin-4-yl)amino)-2,3-dihydro-lH-inden-2-ol (XIX) (0.100 g, 0.201 mmol) and methyl-L-proline (0.026 g, 0.201 mmol) in DMF (10 mL), were added DIPEA (0.105 mL, 0.604 mmol) followed by HATU (0.091 g, 0.241 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 obtained crude product was purified by Prep-HPLC purification using ammonium bicarbonate in water and acetonitrile to afford the desired compound Example 23 as a pale-yellow solid; Yield: (0.015 g, 11%).[000257] LC_MS: Calc, for C34H41N9O2: 607.76; Obs.:608.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): ): 3 9.29 (s, 1H), 8.71 (d, J = 2 Hz, 1H), 8.63 (d, J = 1.6 Hz, 1H), 8.41-8.37 (m, 1H), 7.91-7.87 (m, 2H), 7.82-7.82 (m, 1H), 7.67-7.64 (m, 1H), 7.52-7.49 (m, 2H), 7.33-7.23 (m, 3H), 7.18-7.12 (m, 2H), 6.68-6.66 (m, 1H), 5.57-5.52 (m, 3H), 4.92 (t, J = 1.6 Hz 2H), 4.64-4.60 (m, 2H), 4.45-4.36 (m, 1H), 4.22-4.08 (m, 1H), 3.75 (s, 1H), 3.20 (m, 2H), 3.03-3.00 (m, 2H), 2.82-2.77 (m, 2H), 2.60 (m, 2H), 2.00-1.70 (m, 5H), 1.60-1.50 (m, 2H). HPLC Purity = 93.32%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 24: (S)-N-cyclopropyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-indazol-6-yl) amino) pyrimidin- 5-yl)piperidine-3-carboxamide[000258] To a solution of (S)-l-(4-(((lS,27?)-2-hydroxy-2,3-dihydro-l / Z- inden-l-yl)amino)-2-((l-(prop-2-yn-l-yl)-l / Z-indazol-6-yl)amino)pyrimidin-5- yl)piperidine-3-carboxylic acid (XXII) (0.3 g, 0.57 mmol) and cyclopropane amine (0.039 mL, 0.57 mmol) in THF (10 mL), were added DIPEA (0.25 mL, 1.43 mmol) followed by HATU (0.26 g, 0.68 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 washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo to get a 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 product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as 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 desired product Example 24 as an off-white solid. Yield: (0.14 g, 43.3%).[000259] LC_MS: Calc, for C32H34N8O2: 562.68; Obs.: 563.2 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.39 (br s, 1H), 8.61 (s, 1H), 7.88 (d, J = 4.40 Hz,2H), 7.81 (s, 1H), 7.51 (d, J = 8.80 Hz, 1H), 7.31 (t, 7 = 7.60 Hz, 2H), 7.23 (t, J = 7.20 Hz, 1H), 7.13 (d, J = 7.60, Hz, 2H), 6.81 (d, 7 = 4.00, 1H), 5.54 (m, 2H), 4.65 (d, 7 = 4.40 Hz, 2H), 3.18-3.32 (m, 3H), 2.96-2.92 (m, 4H), 2.59-2.57 (m, 3H), 1.12-1.08 (m, 4H), 0.58-0.56 (m, 2H), 0.35-0.34 (m, 2H); HPLC Purity: 99.79%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile.Example 25: (S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N-(oxetan-3-yl) piperidine-3-carboxamide[000260] To a solution of (S)-l-(2-((l-allyl-l / Z-indazol-6-yl)amino)-4- (((lS,27?)-2-hydroxy-2,3-dihydro-l / Z-inden-l-yl)amino)pyrimidin-5-yl)piperidine- 3-carboxylic acid (XVII) (0.25 g, 0.475 mmol) in THF (10 mL), were added DIPEA (0.5 mL, 3 mmol) followed by HATU (0.235 g, 0.618 mmol) and oxetan-3-amine (0.045 g, 0.619 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% NaHCOs solution (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 yellow gummy mass. 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 ascolorless gummy mass. 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 TFA salt of Example 25 as an off-white solid; Yield: (0.055 g, 19.92%).[000261] LC_MS: Calc, for C32H36N8O3: 580.69 Obs.: 581.3 [M++H], 'H NMR (400 MHz, DMSO-d6): 8 9.41 (br s, 1H), 8.59 (d, J = 6.40 Hz, 1H), 8.40 (s, 1H), 7.87-7.83 (m, 2H), 7.53 (d, 7= 8.80 Hz, 1H), 7.33-7.23 (m, 3H), 7.18-7.11 (m, 2H), 6.91-6.88 (m, 1H), 5.60-5.52 (m, 3H), 4.93-4.90 (m, 1H), 4.59-4.75 (m, 6H), 4.35-4.45 (m, 3H), 4.15-4.25 (m, 1H), 3.18-3.10 (m, Hz, 1H), 2.93-3.01 (m, 4H), 2.50-2.56 (m, 1H), 2.45-2.50 (m, 2H), 1.73-1.90 (m, 2H), 1.50-1.56 (m, 2H).; HPLC Purity = 98.62%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 26: (3S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N-(2,2- difluorocyclopropyl) piperidine-3-carboxamide[000262] To a solution of (S)-l-(2-((l-allyl-l / Z-indazol-6-yl)amino)-4- (((lS,27?)-2-hydroxy-2,3-dihydro-l / Z-inden-l-yl)amino)pyrimidin-5-yl)piperidine- 3-carboxylic acid (XVII) (0.20 g, 0.381 mmol) in THF (10 mL), were added DIPEA (0.166 mL, 0.951 mmol) followed by HATU (0.174 g, 0.457 mmol) and 2,2- difluorocyclopropan- 1 -amine hydrochloride (0.046 g, 0.495 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 reducedpressure. The residue was basified using 10% NaHCCh solution (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 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 colorless gummy mass. 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 desired compound Example 26 as an off-white solid; Yield: (0.018 g, 7.5%).[000263] LC_MS: Calc, for C32H34F2N8O2: 600.67; Obs.: 601.3 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 9.31 (br s, 1H), 8.42 (s, 1H), 8.28 (d, J = 3.60 Hz, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.52-7.49 (m, 1H), 7.22-7.32 (m, 3H), 7.11-7.18 (m, 2H), 6.80-6.77 (m, 1H), 5.52-5.59 (m, 2H), 4.92 (d, J = 10.40, Hz, 1H), 4.61 (d, J = 16.00 Hz, 2H), 4.36 (m, 1H); HPLC Purity = 95.74%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1 % TFA in water, Mobile Phase B: Acetonitrile.Example 27: (R)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-((lS,2R)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N-cyclopropylpiperidine- 3-carboxamideXXXV Example 27[000264] To a solution of (R)-l-(2-((l-allyl-lH-indazol-6-yl)amino)-4-((( IS, 2R)-2-hydroxy-2, 3 -dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XXXV) (0.15 g, 0.28 mmol) and cyclopropane amine (0.02 mL, 0.38 mmol) in THF (10 mL), were added DIPEA (0.20 mL, 0.86 mmol) followed by HATU (0.13 g, 0.34 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 washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo to get a 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 product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as 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 desired product Example 27 (BWC5207) as an off-white solid. Yield: (0.100 g, 61.9%).[000265] LC_MS: Calc, for C32H36N8O2: 565.20; Obs.: 564.69 [M++H]; 'H NMR (400 MHz, DMSO-d6): 8 9.30 (br s, 1H), 8.41 (s, 1H), 7.88-7.81 (m, 3H), 7.50 (d, J= 8.80 Hz, 1H), 7.33-7.23 (m, 3H), 7.18-7.11 (m, 2H), 6.74 (m, 1H), 5.59- 5.47 (m, 3H), 4.92 (d, J = 1.20 Hz, 1H), 4.63-4.59 (m, 2H), 4.36-4.35 (m, 1H), 4.1O- 4.20 (m, 1H), 3.17-3.19 (m, 1H), 3.15-2.92 (m, 4H), 2.62-2.58 (m, 2H), 2.52-2.37 (m, 1H), 1.78-1.71 (m, 2H), 1.38-1.55 (m, 2H), 0.60-0.56 (m, 2H), 0.38-0.35 (m, 2H).; HPLC Purity: 99.79%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile.Example 28: N-((S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-3-yl) cyclopropane carboxamide[000266] To a solution of (15,27?)-l-((2-((l-allyl-lH-indazol-6-yl)amino)-5- ((S)-3-aminopiperidin-l-yl)pyrimidin-4-yl)amino)-2,3-dihydro-lH-inden-2-ol (XXIII) (0.2 g, 0.402 mmol) in THF (10 mL), were added DIPEA (0.2 mL, 1.208 mmol) followed by HATU (0.183 g, 0.483 mmol) and cyclopropane carboxylic acid (0.045 g, 0.523 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 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 colorless gummy mass. 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 desired compound Example 28 as an off-white solid; Yield: (0.096 g, 42%).[000267] LC_MS: Calc, for C32H36N8O2: 564.69; Obs.: 565.3 [M++H], 'H NMR (400 MHz, DMSO-d6): 9.29 (br s, 1H), 8.41 (s, 1H), 8.00 (d, J = 7.60 Hz, 1H), 7.86-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.32-7.31 (m, 2H), 7.30-7.22 (m, 1H), 7.16-7.12 (m, 1H), 6.67 (d, J = 8.40 Hz, 1H), 5.45-5.60 (m, 3H), 4.91-4.94 (m, 2H), 4.60-4.64 (m, 2H), 4.40 (m, 1H), 4.20-4.30 (m, 1H).; HPLC Purity = 99.71%, X - Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.Example 29: (S)-l-(2-((l-allyl-5-methyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide[000268] To a solution of ((S)-l-(2-((l-allyl-5-methyl-l / Z-indazol-6- yl)amino)-4-(((lS,27?)-2-hydroxy-2,3-dihydro-l / Z-inden-l-yl)amino)pyrimidin-5- yl)piperidine-3-carboxylic acid (XXIV) (0.2 g, 0.37 mmol) and cyclopropane amine (0.025 mL, 0.45 mmol) in DMF (10 mL), were added DIPEA (0.20 mL, 1.11 mmol) followed by HATU (0.17 g, 0.45 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 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 product was purified by Prep-HPLC purification using 10 mM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as 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 desired product Example 29 as an off-white solid. Yield: (0.090 g, 41.0%).[000269] LC_MS: Calc, for C33H38N8O2: 578.72; Obs.: 579.4 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 8.23 (br s, 1H), 7.87-7.83 (m, 3H), 7.77 (br s, 1H),7.48 (s, 1H), 7.30-7.14 (m, 4H), 5.49-5.46 (m, 3H), 4.93-4.55 (m, 5H), 3.14-2.51 (m, 9H), 2.36-2.33 (m, 3H), 1.76-1.51 (m, 4H), 0.57-0.54 (m, 4H); HPLC Purity: 99.79%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile.Example 30: (S)-l-(2-((l-allyl-4-fluoro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2, 3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cydopropylpiperidine-3-carboxamide[000270] To a solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl) amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XXVI) (0.15 g, 0.275 mmol) and cyclopropane amine (0.019 g, 0.332 mmol) in DMF (10 mL), were added DIPEA (0.5 mL, 3 mmol) followed by HATU (0.136 g, 0.357 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% NaHCCh solution (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 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 colorless gummy mass. The product was further triturated withdiethyl 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 desired compound Example 30 as an off-white solid; Yield: (0.064 g, 39.8%).[000271] LC_MS: Calc, for C32H35FN8O2: 582.68; Obs.: 583.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.43 (br s, 1H), 8.22 (br s, 1H), 7.89 (d, J = 4.80 Hz, 3H), 7.30 (d, J = 9.20, 12.20 Hz, 3H), 7.24 (d, J = 7.20, Hz, 1H), 7.08 (d, J = 12.40, 1H), 6.83-6.76 (m, 1H), 5.57-5.52 (m, 3H), 4.95 (d, J = 1.20 Hz, 1H), 4.64 (d, J = 4.00 Hz, 2H), 4.40 (m, 4H), 3.15 (d, J = 4.40 Hz, 1H), 3.01-2.92 (m, 3H), 2.59-2.56 (m, 1H), 2.50-2.34 (m, 3H), 1.53 (m, 2H), 0.59-0.55 (m, 2H), 0.36-0.34 (m, 2H); HPLC Purity = 98.54%, X-Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 5mM Ammonium bicarbonate in water, Mobile Phase B: Acetonitrile.Example 31: ((S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-3-yl)(4- methylpiperazin- 1 -yl)methanoneXVII Example 31[000272] To a solution of (S)-l-(2-((l-allyl-l / Z-indazol-6-yl)amino)-4- (((lS,27?)-2-hydroxy-2,3-dihydro-l / Z-inden-l-yl)amino)pyrimidin-5-yl)piperidine- 3-carboxylic acid (XVII) (0.25 g, 0.475 mmol) in DMF (10 mL), were added DIPEA (0.5 mL, 3 mmol) followed by HATU (0.235 g, 0.618 mmol) and 1- methylpiperazine (0.062 g, 0.619 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 using10% NaHCOs solution (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 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 colorless gummy mass. 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 desired compound Example 31 as an off-white solid; Yield: (0.023 g, 7.95%).[000273] LC_MS: Calc, for C34H41N9O2: 607.76; Obs.: 608.3 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 9.30 (br s, 1H), 8.44 (s, 1H), 7.82 (m, 2H), 7.49 (m, Hz, 1H), 7.34-7.22 (m, 5H), 6.78 (br s, 1H), 5.63-5.55 (m, 3H), 4.93-4.90 (m, 1H), 4.65-4.57 (m, 4H), 3.21-3.08 (m, 4H), 3.02-2.76 (m,6H), 2.01-.215 (m, 4H), 1.81-1.73 (m, 5H), 1.12 (s, 3H); HPLC Purity = 95.50%, X -Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile Phase A: 5mM Ammonium bicarbonate in water, Mobile Phase B: Acetonitrile.Example 32: (S)-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)- 2- (( 1 - (prop-2-yn- 1 -yl) - 1 H-indazol-6-yl) amino) pyrimidin-5 -yl) -N- isopropylpiperidine-3-carboxamide[000274] To a solution of (S)-l-(4-(((lS,27?)-2-hydroxy-2,3-dihydro-l / Z- inden-l-yl)amino)-2-((l-(prop-2-yn-l-yl)-l / Z-indazol-6-yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XXII) (0.15g, 0.28 mmol) and Propane-2-amine (0.016 mL, 0.29 mmol) in THF (10 mL), were added DIPEA (0.13 mL, 0.72 mmol) followed by HATU (0.13 g, 0.34 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 washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo to get a 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 product was purified by Prep-HPLC purification using 10 mM Formic acid in water and acetonitrile to afford the desired compound as 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 desired product Example 32 as an off-white solid. Yield: (0.010 g, 6.0 %).[000275] LC_MS: Calc, for C32H36N8O2: 564.69; Obs.: 565.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.37 (s, 1H), 8.60 (s, 1H), 7.89 (br s, 1H), 7.81 (s, 1H), 7.68-7.66 (m, 1H), 7.51 (d, J = 8.40 Hz, 1H), 7.32 (t, J = 6.80 Hz, 2H), 7.24 (t, J = 3.60 Hz, 1H), 7.25-7.23 (m, 2H), 6.85 (br s, 1H), 5.69-5.50 (m, 2H), 4.66- 4.61 (m, 2H), 4.01-3.76 (m, 2H), 3.18-2.92 (m, 6H), 2.41-2.39 (m, 1H), 1.80-1.60 (m, 4H), 1.11-1.00 (m, 7H); HPLC Purity: 96.69%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: 0.1% Formic acid in water, Mobile phase: B: Acetonitrile.Example 33: (S)-N-cyclopropyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-((5-methyl-l-(prop-2-yn-l-yl)-lH-indazol-6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide[000276] To a solution (S)-l-(4-(((lS,27?)-2-hydroxy-2,3-dihydro-l / Z-inden- l-yl)amino)-2-((5-methyl-l-(prop-2-yn-l-yl)-l / Z-indazol-6-yl)amino)pyrimidin-5- yl)piperidine-3-carboxylic acid (XXVIII) (0.15 g, 0.27 mmol) and cyclopropane amine (0.02 mL, 0.27 mmol) in THF (10 mL), were added DIPEA (0.12 mL, 0.69 mmol) followed by HATU (0.13 g, 0.34 mmol) at 0 °C, under nitrogen atmosphere. 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 washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo to get a 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 product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as 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 desired product Example 33 as an off-white solid. Yield: (0.030 g, 18%).[000277] LC_MS: Calc, for C33H36N8O2: 576.71; Obs.: 577.30 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 8.43 (d, J = 5.60 Hz, 1H), 7.88-7.82 (m, 3H), 7.77 (d, 7 = 3.20 Hz, 1H), 7.49 (s, 1H), 7.31-7.20 (m, 3H), 7.15-7.11 (m, 1H), 5.60-5.48 (m, 2H), 4.71-4.66 (m, 1H), 4.60-4.59 (m, 1H), 4.31 (d, 7 = 2.00 Hz, 1H), 3.23-3.17 (m, 3H), 2.98 (s, 1H), 2.93-2.89 (m, 3H), 2.60-2.56 (m, 2H), 2.37 (s, 4H), 1.75 (m,2H), 1.55 (m, 2H), 1.11 (s, 1H), 0.58-0.55 (m, 2H), 0.36-0.34 (m, 2H).HPLC Purity: 97.76%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile.Example 34: ((S)-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-indazol-6-yl) amino)pyrimidin-5- yl)piperidin-3-yl)(morpholino) methanoneXXII Example 34[000278] To a solution of ((S)-l-(4-(((lS,27?)-2-hydroxy-2,3-dihydro-lH- inden-l-yl)amino)-2-((l-(prop-2-yn-l-yl)-l / Z-indazol-6-yl)amino)pyrimidin-5- yl)piperidine-3-carboxylic acid(I) (0.2 g, 0.38 mmol) and morpholine (II) (0.03mL, 0.38 mmol) in DMF (10 mL), were added DIPEA (0.16 mL, 0.95 mmol) followed by HATU (0.174 g, 0.46 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 washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo to get a 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 product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as 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 desired product Example 34 as an off-white solid. Yield: (0.060 g, 26.0%).[000279] LC_MS: Calc, for C33H36N8O3: 592.70; Obs.: 593.2 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.38 (s, 1H), 8.61 (br s, 1H), 7.86 (s, 1H), 7.81 (br s, 1H), 7.51 (d, J = 8.80 Hz, 1H), 7.33 (t, J = 6.80 Hz, 2H), 7.24 (t, J = 7.20 Hz, 1H), 7.16-7.13 (m, 2H), 6.77 (br s, 1H), 5.69-5.62 (m, 2H), 4.67-4.59 (m, 2H), 4.09- 3.98 (m, 1H), 3.45-3.37 (m, 3H), 3.31-3.24 (m, 6H), 3.17-2.93 (m, 7H), 1.82-1.11 (m, 4H); HPLC Purity: 98.02%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Formic acid in water, Mobile phase: B: Acetonitrile.Example 35: (S)-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)- 2-((l-(prop-2-yn-l-yl)-lH-indazol-6-yl)amino)pyrimidin-5-yl)-N-(oxetan-3- yl)piperidine-3-carboxamide[000280] To a solution of (S)-l-(4-(((lS,27?)-2-hydroxy-2,3-dihydro-l / Z- inden-l-yl)amino)-2-((l-(prop-2-yn-l-yl)-l / Z-indazol-6-yl)amino)pyrimidin-5- yl)piperidine-3-carboxylic acid (XXII) (0.2 g, 0.38 mmol) and oxetan-3-amine (0.03mL, 0.38 mmol) in DMF (10 mL), were added DIPEA (0.16 mL, 0.96 mmol) followed by HATU (0.17 g, 0.45 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 washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo to get a brown residue. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was driedover Na2SO4, filtered, and evaporated under a vacuum to get the crude. The obtained crude product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as 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 desired product Example 35 as an off-white solid. Yield: (0.035 g, 16.0%).[000281] LC_MS: Calc, for C32H34N8O3: 578.68; Obs.: 579.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.38 (s, 1H), 8.61-8.57 (m, 2H), 7.89 (br s, 1H), 7.82 (s, 1H), 7.51 (d, J = 8.80 Hz, 1H), 7.32 (t, J = 6.80 Hz, 2H), 7.24 (t, J = 7.20 Hz, 1H), 7.16-7.12 (m, 2H), 6.83 (br s, 1H), 5.68 (t, J = 5.60 Hz, 1H), 5.51 (br s, 1H), 4.74-4.64 (m, 5H), 4.39-4.35 (m, 2H), 3.26-3.24 (m, 3H), 3.03-2.93 (m, 4H), 2.68-2.58 (m, 2H), 1.84-1.54 (m, 4H); HPLC Purity: 98.00%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: TFA in water, Mobile phase: B: Acetonitrile.Example 36: (S)-N-cyclopropyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-((2-oxo-3-(prop-2-yn-l-yl)-2,3-dihydrobenzo[d]oxazol-5- yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide[000282] To a solution (S)-l-(4-(((lS,27?)-2-hydroxy-2,3-dihydro-l / Z-inden- l-yl)amino)-2-((2-oxo-3-(prop-2-yn-l-yl)-2,3-dihydrobenzo[d]oxazol-5- yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XXX) (0.3 g, 0.55 mmol) and cyclopropane amine (0.03 mL, 0.55 mmol) in THF (10 mL), were addedDIPEA (0.20 mL, 1.39 mmol) followed by HATU (0.26 g, 0.66 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 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 product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as gummy mass. The compound was further triturated with diethyl ether, the off-white solid thrown out was allowed to settle and the supernatant were decanted. The solid obtained was dried under high vacuo, to afford desired product Example 36 as an off-white solid. Yield: (0.080 g, 25%), [000283] LC_MS: Calc, for C32H34N7O4: 579.68; Obs.: 580.20 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.25 (s, 1H), 8.28 (d, J = 6.80 Hz, 1H), 7.87-7.83 (m, 2H), 7.31-7.16 (m, 6H), 6.75 (br s, 1H), 5.59-5.49 (m, 2H), 4.62-4.60 (m, 1H), 4.29 (s, 2H), 3.24-2.90 (m, 6H), 2.60-2.56 (m, 2H), 2.50 (m, 1H), 1.75-1.52 (m, 4H), 0.58-0.55 (m, 2H), 0.36-0.32 (m, 2H); HPLC Purity: 98.62%, Column: X- Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile.Example 37: (S)-l-(2-(l-(R)-but-3-yn-2-yl)-lH-indazol-6-yl) amino)-4-(lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide[000284] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -y I Jami nojpyri midi n-5-y I J-Mcyclopropy Ipipcridi nc-3 - carboxamide (XXXVII) (0.400 g, 0.93 mmol) and (7?)-l-(but-3-yn-2-yl)-177- indazol-6-amine (XXXVI) (0.173 g, 0.93 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.2 mL, 3.74 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 was evaporated 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 Example 37 as an Off-white solid. Yield: (0.122 g, 22.6 %), LC_MS: Calc. C33H36N8O2:576.71.; Obs.: 577.3 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 9.42 (s, 1H), 8.65 (s, 1H), 7.89 (d, J = 5.60 Hz, 2H), 7.83 (s, 1H), 7.50 (d, J = 8.40 Hz, 1H), 7.38-7.31 (m, 2H), 7.28-7.24 (m, 1H), 7.19-7.14 (m, 1H), 7.11-7.09 (m, 1H), 6.88 (s, 1H), 5.68- 5.57 (m, 1H), 4.65-4.60 (m, 1H), 4.11 (s, 1H), 3.27 (d, J = 2.00 Hz, 2H), 3.08 (s, 2H), 3.02-2.92 (m, 4H), 2.59-2.56 (m, 2H), 1.76-1.73 (m, 2H), 1.54-1.48 (m, 2H), 1.34-1.24 (m, 3H), 0.59-0.54 (m, 2H), 0.38 (s, 2H). HPLC Purity:99.73%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A:0.1% TFA in water Mobile phase: B: ACN.Example 38: (S)-l-(2-((l-(S)-but-3-yn-2-yl)-lH-indazol-6-yl) amino)-4-((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cydopropylpiperidine-3-carboxamide[000285] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -y I Jami nojpyri midi n-5-y I J-Mcyclopropy Ipipcridi nc-3 - carboxamide (XXXVII) (0.400 g, 1.05 mmol) and (S)-l-(but-3-yn-2-yl)-l / Z- indazol-6-amine (XXXVIII) (0.195 g, 1.05 mmol) in NMP (3 mL), was added 4M HCI in dioxane (0.2 mL, 4.21 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 was evaporated 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 desired product Example 38 as an Off-white solid. Yield: (0.110 g,18.0 %), LC_MS: Calc. C33H36N8O2:576.71.; Obs.: 577.3 [M++H], 'H NMR (400 MHz, DMSO-d6): 39.33 (s, 1H), 8.55 (s, 1H), 7.88 (d, J = 4.00 Hz, 2H), 7.82 (s, 1H), 7.51 (d, J = 8.40 Hz, 1H), 7.31 (d, J = 7.20 Hz, 1H), 7.26-7.16 (m, 2H), 7.14-7.12 (m, 2H), 6.81 (s, 1H), 5.76-5.73 (m, 1H), 5.52 (s, 1H), 4.98 (d, J = 5.60 Hz, 1H), 4.64 (d, J = 4.00 Hz, 1H), 3.39 (d, J = 2.40 Hz, 2H), 3.24-3.22 (m, 1H), 3.01-2.91 (m, 4H), 1.78-1.72 (m, 2H), 1.53 (s, 2H), 1.20 (d, J = 6.80 Hz, 3H), 1.11 (s, 2H), 0.58-0.54 (m, 2H), 0.40-0.30 (m, 2H). HPLC Purity;99.18%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water: B: ACN.Example 39: (S)-N-cyclopropyl-l-(4-((lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-(l-(prop-2-yn-l-yl)-lH-benzo[d][l,2,3] triazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamideXXXVII Example 39[000286] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -y I Jami nojpyri midi n-5-y I J-Mcyclopropy Ipipcridi nc-3 - carboxamide (XXXVII) (0.300 g, 0.7 mmol) and l-(prop-2-yn-l-yl)-177- benzo[d][l,2,3]triazol-6-amine (XXXIX) (0.121g, 0.70 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.2 mL, 0.93 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 was evaporated 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 desired product Example 39 as an off-white solid. Yield: (0.070 g, 17 %), LC_MS: Calc. C3IH33N9O2:563.67; Obs.: 564.3 [M++H], 'H NMR (400 MHz, DMSO-d6): 39.61 (s, 1H), 8.78 (d, J = 1.60 Hz, 1H), 7.91-7.86 (m, 2H), 7.81 (d, J = 8.80 Hz, 1H), 7.40-7.38 (m, 1H), 7.34-7.22 (m, 3H), 7.14-7.11 (m, 1H), 6.86-6.84 (m, 1H), 5.65 (d, J = 2.40 Hz, 1H), 5.54 (d, J = 4.40 Hz, 1H), 5.19-5.14 (m, 1H), 4.65 (d, J = 4.80 Hz, 1H), 4.36-4.20 (m, 1H), 3.41-3.40 (m, 1H), 3.31 (s, 1H), 3.00-2.92 (m, 4H), 2.60-2.56 (m, 2H), 2.34-2.33 (m, 1H), 1.90-1.76 (m, 2H), 1.55-1.45 (m, 2H), 0.58- 0.55 (m, 2H), 0.36-0.34 (m, 2H). HPLC Purity; 97.36%, Column: X-Bridge C8(50 X 4.6) mm, 5pm, Mobile phase: A:0.1% TFA in water Mobile phase: B: ACN.Example 40: (S)-N-(2,2-difluoroethyl)-l-(4-((lS,2R)-2-hydroxy-2,3-dihydro- IH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide[000287] To a solution (S)-l-(4-(((lS,27?)-2-hydroxy-2,3-dihydro-l / Z-inden-1-yl)amino)-2-((l-(prop-2-yn-l-yl)-l / Z-benzo[d][l,2,3]triazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XL) (2.000 g, 1 eq, 3.813 mmol) and 2,2-difluoroethan-l -amine (CAS: 430-67-1 : 463.6 mg, 414 pL, 1.5 eq, 5.719 mmol) in DMF (20 mL), were added DIPEA (1.478 g, 1.99 mL, 3 eq, 11.44 mmol) followed by HATU (2.175 g, 1.5 eq, 5.719 mmol) at 0°C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, ice water was added to the reaction mixture, solid precipitated out. This was kept for stirring for 30min in ice water and then filtered off and washed thoroughly with ice water and dried under vacuum to get crude as pale brown solid. The obtained crude product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as a gummy mass. The compound was further triturated with diethyl ether, the off- white solid thrown out was allowed to settle down and the supernatant was decanted. The solid obtained was dried under a high vacuum, to afford the desired product Example 40 as an off-white solid. Yield: (0.55 g, 24.5%), LC_MS: Calc, for C30H31F2N9O2: 587.64; Obs.: 588.30 [M++H]; 'H NMR (400 MHz, DMSO- d6) 3 9.61 (s, 1H), 8.78 (s, 1H), 8.28-8.25 (m, 1H), 7.92 (s, 1H), 7.82 (d, J = 8.80 Hz, 1H), 7.40 (d, J = 10.00 Hz, 1H), 7.32-7.29 (m, 2H), 7.24 (t, J = 7.20 Hz, 1H), 7.14 (t, 7= 7.20 Hz, 1H), 6.85 (brs, 1H), 6.09-5.94 (m, 1H), 5.81-5.80 (m, 1H), 5.51 (brs, 1H), 5.17 (d, J = 8.00 Hz, 1H), 4.68-4.64 (m, 1H), 4.36-4.30 (m, 1H), 3.47- 3.43 (m, 2H), 3.40-3.39 (m, 2H), 3.33-3.27 (m, 1H), 3.02-2.92 (m, 4H), 2.51-2.48 (m, 1H), 1.82-1.74 (m, 2H), 1.74-1.56 (m, 2H). HPLC Purity: 99.94%, Column: X-Bridge C18(150 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water, Mobile phase: B: AcetonitrileExample 41: (S)-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl)- N-(l-methyl cyclopropyl) piperidine-3-carboxamide[000288] To a solution of (S)-l-(4-(((lS,27?)-2-hydroxy-2,3-dihydro-l / Z- inden-l-yl)amino)-2-((l-(prop-2-yn-l-yl)-l / Z-benzo[d][l,2,3]triazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XL) (0.200 g, 0.38 mmol) and 1-methylcyclopropan-l -amine (CAS : 88887-87-0, 0.027 mL, 0.38 mmol,) in DMF (10 mL), were added DIPEA (0.21 mL, 1.14 mmol) followed by HATU (0.174 g, 0.45 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by UPLC, reaction mixture was quenched with water, and DMF was concentrated under reduced pressure. 10% aq NaHCOs solution was added and extracted with ethyl acetate (2 times) the organic 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 in ammonium bicarbonate in water and acetonitrile to afford desired product Example 41 as an Off-white solid. Yield: (0.112 g, 50.6 %), LC_MS: Calc. C32H35N9O2:577.69.; Obs.: 578.2 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 9.60 (s, 1H), 8.78 (d, J = 1.60 Hz, 1H), 8.04 (s, 1H), 7.90 (d, J = 3.20 Hz, 1H), 7.82 (d, J = 9.20 Hz, 1H), 7.41-7.38 (m, 1H), 7.34-7.29 (m, 2H), 7.25-7.22 (m, 1H), 7.15-7.11 (m, 1H), 6.85 (s, 1H), 5.67-5.64 (m, 1H), 5.52 (d, J = 4.40 Hz, 1H), 5.20-5.15 (m, 1H), 4.66 (d, J = 5.20 Hz, 1H), 4.35-4.25 (m, 1H), 3.40 (s, 1H), 3.29-3.24 (m, 2H), 3.02-2.89 (m, 3H), 1.74-1.70 (m, 2H), 1.53 (s, 2H), 1.24-1.22 (m, 3H), 1.11 (s, 1H), 0.55-0.47 (m, 3H). HPLC Purity: 99.06%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water, Mobile phase: B: ACN.Example 42: (S)-l-(2-(l-(R)-but-3-yn-2-yl)-lH-benzo[d][l,2,3] triazol-6- yl)amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)pyrimidin-5-yl)-N-cyclopropyl piperidine-3-carboxamide[000289] To a solution of (S)-l-(2-((l-((7?)-but-3-yn-2-yl)-l / Z- benzo[d][l,2,3]triazol-6-yl)amino)-4-(((lS,27?)-2-hydroxy-2,3-dihydro-l / Z-inden- l-yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XLII) (1.00 g, 1.85 mmol) and cyclopropane amine (CAS:765-30-0, 0.02 mL, 2.22 mmol,) in DMF (10 mL), were added DIPEA (1.0 mL, 5.57 mmol) followed by HATU (0.847 g, 2.22 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by UPLC, reaction mixture was quenched with water and DMF was concentrated under reduced pressure. 10% aqueous NaHCOs solution was added and extracted with ethyl acetate (2 times). The organic 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 in ammonium bicarbonate in water and acetonitrile to afford desired product Example 42 as an Off-white solid. Yield: (0.57 g, 52.9 %), LC_MS: Calc. C32H35N9O2:577.69.; Obs.: 578.2 [M++H], 'H NMR (400 MHz, DMSO-d6): 3 9.63 (s, 1H), 8.78 (s, 1H), 7.92-7.87 (m, 2H), 7.83-7.80 (m, 1H), 7.38-7.36 (m, 2H), 7.33-7.24 (m, 2H), 7.19-7.13 (m, 1H), 6.85-6.80 (m, 1H), 5.66-5.57 (m, 2H), 4.64-4.63 (m, 2H), 3.42-3.38 (m, 1H), 3.24 (s, 1H), 3.03-2.94 (m, 4H), 2.94-2.56 (m, 2H), 2.34 (d, J = 1.60 Hz, 1H), 1.56- 1.55 (m, 7H), 0.59-0.56 (m, 2H), 0.36-0.34 (m, 2H). HPLC Purity: 99.61%,Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: 0.1% TFA in H2O, Mobile phase: B: ACN.Example 43: (S)-N-cyclopropyl-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-(l-isopropyl-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamideXXXVII Example 43[000290] To a stirred solution (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)-N-cyclopropylpiperidine-3- carboxamide (XXXVII) (0.200 g, 0.46 mmol) and 1 -isopropyl- 1H- benzo[d][l,2,3]triazol-6-amine (XLIII) (0.082g, 0.46 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.2 mL, 1.40 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 was evaporated 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 desired product Example 43 as an Off-white solid. Yield: (0.012 g, 4.3%), LC_MS: Calc. C3iH37N9O2:567.70; Obs.: 568.3 [M++H]:1H-NMR (300 MHz, DMSO-d6): 3 9.54 (s, 1H), 8.61 (s, 1H), 7.91- 7.87 (m, 2H), 7.77 (d, J = 8.00 Hz, 1H), 7.36-7.31 (m, 5H), 6.84 (s, 1H), 5.63-5.60 (m, 1H), 5.57-5.56 (m, 1H), 4.65-4.61 (m, 1H), 3.98-3.95 (m, 1H), 3.33-3.18 (m, 2H), 3.01-2.94 (m, 4H), 2.60-2.59 (m, 2H), 1.79-1.73 (m, 2H), 1.56-1.53 (m, 2H), 1.24-1.18 (m, 6H), 0.58-0.55 (m, 2H), 0.36-0.34 (m, 2H). HPLC Purity;95.23%,Column: X-Bridge C8(50 X 4.6) mm, 5pm, Mobile phase: A:0.1% TFA in water Mobile phase: B: ACN.Example 44: (S)-l-(2-((l-allyl-lH-benzo[d] [1,2,3] triazol-6-yl) amino)-4- ((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide[000291] To a stirred solution (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -y I Jami nojpyri midi n-5-y I J-A-cyclopropy Ipipcridi nc-3 - carboxamide (XXXVII) (0.200 g, 0.46 mmol) and 1-allyl- 1H- benzo[d][l,2,3]triazol-6-amine (XLIV) (0.082g, 0.46 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.2 mL, 0.93 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 was evaporated in vacuo to get the crude product as a brown liquid. The obtained crude was purified by Preparative HPLC reverse phase in 0.1% TFA in water and acetonitrile to afford desired product Example 44 as an Off-white solid. Yield: (0.012 g, 4.1%), LC_MS: Calc. C3iH35N9O2:565.68; Obs.: 566.2 [M++H]:1H-NMR (400 MHz, DMSO-d6): 3 10.36 (s, 1H), 8.30 (s, 1H), 7.99 (d, J = 8.80 Hz, 1H), 7.98-7.82 (m, 2H), 7.37-7.33 (m, 3H), 7.30-7.26 (m, 1H), 7.19-7.09 (m, 1H), 5.68 (s, 1H), 5.58-5.55 (m, 1H), 4.98 (d, J = 10.80 Hz, 2H), 4.69-4.64 (m, 3H), 3.68-3.42 (m, 1H), 3.42-3.38 (m, 1H), 3.17-2.98 (m, 3H), 2.61-2.61 (m, 1H), 2.50-2.38 (m, 2H), 1.76-1.74 (m, 2H) 1.56-1.50 (m, 2H), 1.12-1.08 (m, 1H), 0.58- 0.56 (m, 2H), 0.34-0.33 (m, 2H). HPLC Purity; 90.07%, Column: X-Bridge C8(50X 4.6) mm, 3.5pm, Mobile phase: A: ammonium bicarbonate in water Mobile phase: B: ACN.Example 45: (S)-l-(2-((l-((R)-but-3-yn-2-yl)-lH-benzo[d] [1,2,3] triazol-6- yl)amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)pyrimidin-5-yl)-N-(2,2-difluoroethyl)piperidine-3-carboxamide[000292] To a solution (5)- l-(2-((l-((R)-but-3-yn-2-yl)- 1H- benzo[d][l,2,3]triazol-6-yl)amino)-4-(((lS,27?)-2-hydroxy-2,3-dihydro-l / Z-inden- l-yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XLII) (1.500 g, 1 eq, 2.785 mmol) and 2,2-difluoroethan-l -amine (CAS 430-67-1, 338.7 mg, 302 pL, 1.5 eq, 4.177 mmol) in DMF (20 mL), were added DIPEA (1.080 g, 1.46 mL, 3 eq, 8.355 mmol) followed by HATU (1.588 g, 1.5 Eq, 4.177 mmol) at 0°C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, to the reaction mixture ice water was added, solid was precipitated out. This was kept stirring for 30 min with ice water and then filtered off and washed thoroughly with ice water and dried under vacuum to get crude as pale brown solid. The obtained crude product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as a 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 vacuum, to afford the desired product Example 45 as an off-white solid. Yield: (0.55 g, 24.5%),LC_MS: Calc, for C31H33F2N9O2: 601.66; Obs.: 602.30 [M++H]; 'H NMR (400 MHz, DMSO-dd): 3 10.65 (brs, 1H), 8.58 (s, 1H), 8.32-8.31 (m, 1H), 7.99 (d, J = 4.80 Hz, 1H), 7.91-7.89 (m, 1H), 7.40-7.35 (m, 3H), 7.31-7.29 (m, 1H), 7.25 (s, 1H), 7.20-7.18 (m, 1H), 7.12 (s, 1H), 7.00 (s, 1H), 6.91 (s, 1H), 5.68-5.64 (m, 2H), 4.68-4.65 (m, 1H), 3.46-3.44 (m, 4H), 3.39-3.36 (m, 2H), 3.01-2.97 (m, 3H), 1.81- 1.71 (m, 2H), 1.55-1.57 (m, 5H).HPLC Purity: 98.1%, Column: Sunfire C18 (50 x 4.6) mm 5pm, Mobile phase: A: TFA in water, Mobile phase: B: Acetonitrile.Example 46: (S)-l-(2-(l-(S)-but-3-yn-2-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino)-4-((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin- 5-yl)-N-cyclopropyl piperidine-3-carboxamide[000293] To a solution of (S)-l-(2-((l-((S)-but-3-yn-2-yl)-lH- benzo[d][l,2,3]triazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden- l-yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XLVI) (0.200 g, 0.37 mmol) and cyclopropane amine (CAS: 765-30-0 ) (0.021 g, 0.37 mmol,) in DMF (10 mL), were added DIPEA (0.2 mL, 1.11 mmol) followed by HATU (0.169 g, 0.45 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. The reaction mixture was quenched with water. DMF was concentrated under reduced pressure. 10% aqueous NaHCOs. solution was added and extracted with ethyl acetate (2 times). The organic phase was dried under Na2SO4, and the solvent was filtered and evaporated in vacuo to get the crude desired product as brown liquid. The obtained crude was purified by Preparative HPLC reverse phase inammonium bicarbonate in water and acetonitrile to afford desired product Example 46 as an Off-white solid. Yield: (0.013 g, 6.00 %), LC_MS: Calc. C32H35N9O2:577.69.; Obs.: 577.3 [M++H]:1H-NMR (400 MHz, DMSO-d6): 8 9.62 (s, 1H), 8.80 (s, 1H), 7.92-7.86 (m, 2H), 7.82 (d, J = 8.80 Hz, 1H), 7.38 (d, J = 2.00 Hz, 1H), 7.31 (d, 7 = 7.60 Hz, 1H), 7.21-7.18 (m, 2H), 7.13-7.09 (m, 1H), 6.88 (s, 1H), 5.81-5.77 (m, 1H), 5.60-5.56 (m, 2H), 4.68-4.67 (m, 1H), 3.72-3.71 (m, 1H), 3.34-3.24 (m, 1H), 3.02-2.93 (m, 4H), 2.60-2.52 (m, 3H), 1.76-1.73 (m, 2H), 1.53 (m, 2H), 1.10 (t, J = 7.20 Hz, 3H), 0.58-0.55 (m, 2H), 0.34-0.32 (m, 2H). HPLC Purity; 98.31%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in H2O Mobile phase: B: ACN.Example 47: (3S)-N-(2,2-difluorocyclopropyl)-l-(4-(lS,2R)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide[000294] To a solution of (S)-l-(4-(((15,2R)-2-hydroxy-2,3-dihydro-lH- inden- 1 -yl) amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1 / 7-bcnzo[ d] [1,2,3] triazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxylic acid (XL) (0.200 g, 0.38 mmol) and 2,2-difluorocyclopropan-l -amine HC1 (CAS: 105614-25-3, 0.042 g, 0.45 mmol,) in DMF (10 mL), were added DIPEA (0.2 mL, 1.14 mmol) followed by HATU (0.174 g, 0.45 mmol) at 0 °C, under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with water and DMF was concentrated under reduced pressure. 10% aq NaHCCh solution wasadded and extracted with ethyl acetate (2 times) the organic phase was dried under Na2SO4, and the solvent was filtered and evaporated in vacuo to get the crude desired product as brown liquid. The obtained crude was purified by Preparative HPLC reverse phase in 0.1% TFA in water and acetonitrile to afford desired product Example 47 as an Off-white solid. Yield: (0.014 g, 6.01 %), LC_MS: Calc. C31H31F2N9O2: 599.65.; Obs.: 600.2 [M++H]:1H-NMR (400 MHz, DMSO-d6): 3 10.19 (s, 1H), 8.55 (s, 1H), 8.30-8.32 (m, 2H), 7.98-7.96 (m, 1H), 7.82-7.86 (m, 1H), 7.42-7.37 (m, 4H), 7.36-7.33 (m, 2H), 7.29-7.21 (m, 2H), 5.65 (s, 2H), 5.28- 5.24 (m, 1H), 4.68 (s, 1H), 3.23-2.96 (m, 4H), 3.01-2.96 (m, 3H), 1.91-1.86 (m, 3H), 1.83-1.81 (m, 1H), 1.76-1.58 (m, 2H), 1.58-1.42 (m, 1H). HPLC Purity;98.87%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A:0.1% TFA in H2O: Mobile phase: B: ACN.Example 48: (S)-N-(2,2-difluoroethyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro- IH-inden-l-yl) amino)-2-(l-isopropyl-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide[000295] To a solution (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3-dihydro- 1H- inden- l-yl)amino)pyrimidin-5-yl)-A-(2, 2-difluoroethyl)piperidine-3- carboxamide (XLVII) (0.350 g, 1 eq, 0.775 mmol) and 1 -isopropyl- 1H- benzo[d][l,2,3]triazol-6-amine (XLIII) (164 mg, 1.2 eq, 0.929 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (56.5 mg, 0.387 mL, 4 molar, 2 eq, 1.55 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 LCMS. After completion of the reaction, the reaction mass was cooled to room temperature,reaction mass evaporated in vacuo to get the crude product. The obtained crude product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as 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 desired product Example 48 as an off-white solid. Yield: (20 mg, 5.4%), LC_MS: Calc, for C30H35F2N9O2: 591.67; Obs.: 592.4 [M++H], 'H NMR (400 MHz, DMSO-d6): 8 9.54 (s, 1H), 8.62 (d, J = 1.20 Hz, 1H), 8.28-8.25 (m, 1H), 7.91 (d, J = 4.80 Hz, 1H), 7.78 (d, J = 9.20 Hz, 1H), 7.28-7.35 (m, 4H), 7.20-7.15 (m, 1H), 6.85 (bs, 1H), 6.10-5.94 (m, 1H), 5.76 (s, 1H), 5.70-5.60 (m, 2H), 4.65-4.60 (m, 1H), 4.00 (bs, 1H), 3.41-3.45 (m, 2H), 3.20-3.15 (m, 1H), 3.02-2.94 (m, 4H), 2.59-2.56 (m, 1H), 1.85-1.75 (m, 2H), 1.59- 1.54 (m, 2H), 1.22-1.19 (m, 6H). HPLC Purity: 96.8%, Column: X-Bridge C8(50X4.6) mm, 3.5pm, Mobile phase: A: ammonium bicarbonate in water, Mobile phase: B: Acetonitrile.Example 49: (S)-l-(2-((l-((S)-but-3-yn-2-yl)-lH-benzo[d][l,2,3] triazol-6- yl)amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)pyrimidin-5-yl)-N-(2,2-difluoro ethyl) piperidine-3-carboxamide[000296] To a solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -y l)amino)pyri midin-5-y l)-A-(2,2-di fluoroethy l)piperidine-3- carboxamide (XL VII) (0.100 g, 1 eq, 0.221 mmol) and (S)-l-(but-3-yn-2-yl)-l / Z- benzo[d][l,2,3]triazol-6-amine (XLV) (41.2 mg, 1 eq, 0.221 mmol) in NMP (1 mL), was added 4M HC1 in dioxane (24.2 mg, 0.166 mL, 3 eq, 0.664 mmol) atroom temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 90 °C for 16 hours. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mass was cooled to room temperature, reaction mass evaporated in vacuo to get the crude product. The obtained crude product was purified by Prep-HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as 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 desired product Example 49 as an off-white solid. Yield: (20 mg, 15%), LC_MS: Calc, for C31H33F2N9O2: 601.66; Obs.: 602.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 8 9.63 (s, 1H), 8.80 (d, J = 1.20 Hz, 1H), 8.30-8.27 (m, 1H), 7.92 (d, J = 2.80 Hz, 1H), 7.82 (d, J = 8.80 Hz, 1H), 7.39-7.36 (m, 1H), 7.31 (d, J = 7.60 Hz, 1H), 7.22-7.18 (m, 2H), 7.13-7.10 (m, 1H), 6.87 (bs, 1H), 5.96-5.95 (m, 1H), 5.81-5.77 (m, 2H), 5.62-5.57 (m, 2H), 4.68- 4.65 (m, 1H), 3.72-3.71 (m, 1H), 3.71-3.43 (m, 2H), 3.28-3.23 (m, 2H), 3.02-2.93 (m, 4H), 1.75 (m, 2H), 1.55-1.54 (m, 2H), 1.11-1.09 (m, 3H). HPLC Purity: 99.06%, Column: X-Bridge C8 (50X4.6) mm, 3.5pm, Mobile phase: A: TFA in water, Mobile phase: B: Acetonitrile.Example 50: (S)-l-(2-((l-((R)-but-3-yn-2-yl)-lH-benzo[d][l,2,3]triazol-6- yl)amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)pyrimidin-5-yl)-N-((R)-2,2-difhiorocyclopropyl)piperidine-3- carboxamide[000297] To a stirred solution of (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -y 1 )ami no)pyri midi n-5-y 1 )-A-((R)-2,2- difluorocyclopropyl)piperidine- 3 -carboxamide (XL VIII) (0.250 g, 0.54 mmol) and (7?)-l-(but-3-yn-2-yl)-l / Z-benzo[d][l,2,3]triazol-6-amine (XLI) (0.100 g, 0.53 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.2 mL, 2.16 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 was evaporated 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 desired product Example 50 as an Off-white solid. Yield: (0.008g, 2%), LC_MS: Calc. C32H33F2N9O2:613.67.; Obs.: 614.2 [M++H], 1H-NMR (300 MHz, DMSO- d6) 8 9.62 (s, 1H), 8.79 (d, J = 1.20 Hz, 1H), 8.28 (s, 1H), 7.93 (s, 1H), 7.82 (d, J = 9.20 Hz, 1H), 7.39-7.35 (m, 2H), 7.30-7.24 (m, 2H), 7.17-7.14 (m, 1H), 6.85 (bs, 1H), 5.66-5.63 (m, 1H), 5.55 (s, 1H), 4.65-4.57 (m, 2H), 3.40 (s, 1H), 3.28-3.23 (m, 3H), 2.98-2.92 (m, 4H), 2.68-2.67 (m, 1H), 1.84-1.78 (m, 3H), 1.57-1.55 (m, 5H), 1.42-1.41 (m, 1H). HPLC Purity; 97.55%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A:0.1% TFA in water Mobile phase: B: ACN.Example 51: (S)-N-((lS,2R)-2-fluorocyclopropyl)-l-(4-(((lS,2R)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl)amino)-2-((l-(prop-2-yn-l-yl)-lH- benzo[d][l,2,3]triazol-6-yl)amino) pyrimidin-5-yl)piperidine-3-carboxamide[000298] To a stirred solution of (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1 / / - inden- 1 -yl)amino)pyrimidin-5-yl)-A-(( 15,27?)-2- fluorocyclopropyl)piperidine-3-carboxamide (XLIX) (0.1.50g, 3.36 mmol) and 1- (prop-2-yn-l-yl)-l / Z-benzo[d][l,2,3]triazol-6-amine (XXXIX) (0.69 g, 4.03 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (3.36 mL, 13.46 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 was evaporated 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 desired product Example 51 as an Off-white solid. Yield: (1.00g, 5.081%), LC_MS: Calc. C3iH32FN9O2:581.66.; Obs.: 582.2 [M++H], 1H-NMR (400 MHz, DMSO- e): 6 9.62 (s, 1H), 8.78 (d, J = 1.20 Hz, 1H), 8.03 (d, J = 4.00 Hz, 1H), 7.92 (s, 1H), 7.82 (d, J = 8.80 Hz, 1H), 7.41-7.38 (m, 1H), 7.34-7.28 (m, 2H), 7.25- 7.21 (m, 1H), 7.14-7.11 (m, 1H), 6.84 (bs, 1H), 5.67-5.64 (m, 1H), 5.53 (d, J = 4.40 Hz, 1H), 5.20-5.15 (m, 1H), 4.73-4.56 (m, 2H), 4.35-4.25 (m, 1H), 3.41-3.39 (m, 1H), 3.29-3.24 (m, 2H), 3.04-3.01 (m, 1H), 2.96-2.92 (m, 3H), 2.63-2.61 (m, 2H), 1.84-1.75 (m, 2H), 1.56 (bs, 2H), 1.03-0.97 (m, 1H), 0.86-0.80 (m, 1H). HPLC Purity;99.41%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A:0.1% TFA in water Mobile phase: B: ACN.Example 52: (S)-N-((lR,2R)-2-fluorocyclopropyl)-l-(4-(((lS,2R)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl)amino)-2-((l-(prop-2-yn-l-yl)-lH- benzo[d][l,2,3]triazol-6-yl)amino) pyrimidin-5-yl)piperidine-3-carboxamide[000299] To a stirred solution of (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1H- inden- 1 -yl)amino)pyrimidin-5-yl)-A-(( lR,2R)-2- fluorocyclopropyl)piperidine-3-carboxamide (L) (0.12 g, 0.26 mmol) and l-(prop- 2-yn-l-yl)-l / Z-benzo[d][l,2,3]triazol-6-amine (XXXIX) (0.046 g, 0.27 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.1 mL, 1.01 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated to 90 °C for 16 hours. The progress of the reaction 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 crude was purified by Preparative HPLC reverse phase using ammonium bicarbonate in water and acetonitrile to afford the desired product Example 52 as an off-white solid. Yield: (0.050 g, 32%), LC_MS: Calc. C3iH32FN9O2:581.66; Obs.: 582.3 [M++H]:1H-NMR (400 MHz, DMSO-d6): 3 9.61 (s, 1H), 8.78 -8.72 (m, 1H), 7.91 (d, J = 3.60 Hz, 2H), 7.82 (d, J = 8.80 Hz, 1H), 7.41-7.39 (m, 1H), 7.31 (dd, 7 = 7.20, 12.40 Hz, 2H), 7.24 (t, 7 = 7.20 Hz, 1H), 7.14 (q, 7 = 7.20 Hz, 1H), 5.67-5.64 (m, 1H), 5.52 (d, 7 = 4.00 Hz, 1H), 5.17 (dd, 7 = 2.40, 18.00 Hz, 1H), 4.66-4.64 (m, 2H), 4.29 (m, 1H), 3.40 (t, 7 = 2.40 Hz, 1H), 3.29-3.24 (m, 1H), 2.98-2.91 (m, 5H), 2.61-2.51 (m, 1H), 2.34-2.34 (m, 1H), 1.82- 1.71 (m, 2H), 1.51-1.46 (m, 2H), 1.31-0.81 (m, 1H), 0.84-0.82 (m, 1H). HPLC Purity; 99.20%, Column: X-Bridge C8 (50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water Mobile phase: B: ACNExample 53: (S)-N-((lS,2S)-2-fluorocyclopropyl)-l-(4-((lS,2R)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d][l,2,3] triazol-6-yl)amino) pyrimidin-5-yl)piperidine-3-carboxamide[000300] To a stirred solution of (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihy dro- 1 / / -inden- 1 -y 1) amino)pyrimidin- 5 -y 1) -N- (( 1 S,2S)-2- fluorocyclopropyl)piperidine-3-carboxamide (LI) (0.12 g, 0.26 mmol) and l-(prop- 2-yn-l-yl)-l / Z-benzo[d][l,2,3]triazol-6-amine (XXXIX) (0.046 g, 0.27 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.1 mL, 1.01 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 was evaporated in vacuo to get the crude product as a brown liquid. The crude product was purified by Preparative HPLC reverse phase using 0.1% TFA in water and acetonitrile to afford the desired product Example 53 as an off-white solid. Yield: (0.011 g, 4%), LC_MS: Calc. C3iH32FN9O2:581.66; Obs.: 582.3 [M++H]:1H-NMR (400 MHz, DMSO-d6): 3 8.53 (s, 1H), 8.00-7.84 (m, 3H), 7.41-7.33 (m, 4H), 7.27 (t, J = 6.80 Hz, 1H), 7.16 (t, J = 8.00 Hz, 1H), 5.65 (t, J = 6.40 Hz, 2H), 5.31-5.22 (m, 1H), 4.68-4.49 (m, 2H), 3.71-3.68 (m, 1H), 3.41 (q, J = 2.40 Hz, 2H), 3.38-3.23 (m, 2H), 3.02-2.90 (m, 3H), 2.39-2.34 (m, 2H), 1.81-1.70 (m, 2H), 1.63-1.36 (m, 2H), 1.24-1.08 (m, 2H), 0.85-0.81 (m, 1H). HPLC Purity; 94.71%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: 0.1% TFA in water Mobile phase: B: ACN.Example 54: (S)-N-((lR,2S)-2-fluorocyclopropyl)-l-(4-(((lS,2R)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl)amino)-2-((l-(prop-2-yn-l-yl)-lH- benzo[d][l,2,3]triazol-6-yl)amino) pyrimidin-5-yl) piperidine-3-carboxamide[000301] To a stirred solution of (S)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1 / / - inden- 1 -yl)amino)pyrimidin-5-yl)-A-(( 17?,2S)-2- fluorocyclopropyl)piperidine-3-carboxamide (LII) (0.12 g, 0.26 mmol) and 1- (prop-2-yn-l-yl)-17 / -benzo[d][l,2,3]triazol-6-amine (XXXIX) (0.046 g, 0.27 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.1 mL, 1.01 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 was evaporated in vacuo to get the crude product as a brown liquid. The crude product was purified by Preparative HPLC reverse phase using ammonium bicarbonate in water and acetonitrile to afford the desired product Example 54 as an Off-white solid. Yield: (0.020 g, 7.6%), LC_MS: Calc. C3iH32FN9O2:581.66; Obs.: 582.3 [M++H]:1H-NMR (400 MHz, DMSO-d6): 3 9.61 (s, 1H), 8.78 (d, J = 1.20 Hz, 1H), 8.02 (d, J = 4.00 Hz, 1H), 7.91 (d, J = 7.20 Hz, 1H), 7.82 (d, J = 9.20 Hz, 1H), 7.16 (t, J = 8.00 Hz, 1H), 7.40 (dd, J = 1.60, 9.00 Hz, 1H), 7.32 (t, J = 10.00 Hz, 2H), 7.24 (t, J = 7.20 Hz, 1H), 7.13 (t, J = 7.60 Hz, 1H), 5.66 (q, J = 5.20 Hz, 1H), 5.53 (d, J = 4.40 Hz, 1H), 5.17 (dd, J = 2.80, 17.80 Hz, 1H), 4.66-4.65 (m, 2H), 4.31-4.26 (m, 1H), 3.41-3.40 (m, 1H), 3.38-3.30 (m, 1H), 3.01-2.93 (m, 4H), 2.60 (t, 7 = 4.40 Hz, 2H), 1.81-1.71 (m, 2H), 1.60-1.48 (m, 2H), 1.00-0.98 (m, 1H), 0.96-0.81 (m, 2H), HPLC Purity; 99.72%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: 0.1% TFA in water Mobile phase: B: ACNExample 55: (S)-N-((lS,2R)-2-fluorocyclopropyl)-l-(4-((lS,2R)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-indazol-6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamideExample 55[000302] To a solution (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3-dihydro- l / Z-inden-l-yl)amino)pyrimidin-5-yl)-A-((lS,27?)-2-fluorocyclopropyl)piperidine- 3-carboxamide (XLIX) (0.100 g, 1 eq, 0.224 mmol) and l-(prop-2-yn-l-yl)-l / Z- indazol-6-amine (XXI) (38.4 mg, 1 eq, 0.224 mmol) in DMF (20 mL), was added 4M HC1 in dioxane (16.4 mg, 2 eq, 0.449 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 LCMS. After completion of the reaction mass was cooled to room temperature, reaction mass was concentrated under vacuo to get the crude product. The crude product was purified by Prep- HPLC purification using lOmM Ammonium bicarbonate in water and acetonitrile to afford the desired compound as a 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 vacuum, to afford the desired product Example 55 as an off-white solid. Yield: (37 mg, 28%), LC_MS: Calc, for C32H33FN8O2: 580.67; Obs.: 581.3 [M++H]; 'H NMR (400 MHz, DMSO-d6): 3 9.39 (s, 1H), 8.61 (s, 1H), 8.03 (d, J = 4.00 Hz, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.51 (d, 7 = 8.80 Hz, 1H), 7.31 (t, 7 = 7.60 Hz, 1H), 7.23 (t, 7 = 7.60 Hz, 1H), 7.14 (t, 7 = 8.40 Hz, 1H), 6.82 (s, 1H), 5.68 (t, 7 = 5.20 Hz, 1H), 5.54 (d, 7 = 4.00 Hz, 1H), 4.72-4.62 (m, 3H), 4.02-3.98 (m, 1H), 3.30-3.24 (m, 2H), 3.17 (d, 7 = 5.20 Hz, 1H), 3.08 (s, 1H), 3.02 (d, 7 = 11.20 Hz, 1H), 2.96- 2.92 (m, 2H), 2.62-2.56 (m, 2H), 1.84-1.82 (m, 2H), 1.75-1.56 (m, 2H), 1.56-1.01 (m, 2H), 0.91-0.99 (m, 2H). HPLC Purity: 99.3%, Column: X-Bridge C8 (50 x 4.6) mm 3.5pm, Mobile phase: A: TFA in water, Mobile phase: B: Acetonitrile.Example 56: (S)-N-((lS,2R)-2-2-fluorocyclopropyl)-l-(4-(lS,2R)-2-hydroxy- 2,3-dihydro-lH-inden-l-yl) amino)-2-(l-isopropyl-lH-benzo[d] [1,2,3] triazol- 6-yl) amino) pyrimidin-5-yl)piperidine-3-carboxamideExample 56[000303] To a stirred solution (S)-l-(2-chloro-4-(((lS,27?)-2-hydroxy-2,3- dihydro- 1 / / - inden- 1 -yl)amino)pyrimidin-5-yl)-A-(( 15,27?)-2- fluorocyclopropyl)piperidine-3-carboxamide (XLIX) (0.200 g, 0.45 mmol) and 1- isopropyl-l / Z-benzo[d][l,2,3]triazol-6-amine (XLIII) (0.094g, 0.53 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.2 mL, 1.79 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 was evaporated 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 desired product Example 56 as an Off-white solid. Yield: (0.112 g, 41.2%), LC_MS: Calc. C31H36 FN9O2:585.69; Obs.: 586.4[M++H], 1H-NMR (400 MHz, DMSO-J6): 3 9.56 (s, 1H), 8.62 (d, J = 1.20 Hz, 1H), 8.04 (d, J = 4.00 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J = 8.80 Hz, 1H), 7.25-7.25 (m, 4H), 7.16 (q, J = 7.60 Hz, 1H), 6.84 (s, 1H), 5.58 (t, J = 4.00 Hz, 2H), 4.73-4.56 (m, 2H), 3.97 (s, 1H), 3.17 (d, J = 4.00 Hz, 2H), 3.02-2.93 (m, 4H), 2.63 (d, J = Hz, 2H), 1.80 (m, 2H), 1.55 (d, J = 8.00 Hz, 2H), 1.20 (q, J = 6.40 Hz, 6H), 1.01 (m, 1H), 0.80 (m, 1H). HPLC Purity;96.62%, Column: X-Bridge C8(50 X 4.6) mm, 3.5pm, Mobile phase: A: Ammonium bicarbonate in water Mobile phase: B: ACN.Example 57: (R)-N-((lS,2R)-2-fluorocyclopropyl)-l-(4-(lS,2R)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide[000304] To a stirred solution of (R)-l-(2-chloro-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1 / / - inden- 1 -yl)amino)pyrimidin-5-yl)-A-(( 15,27?)-2- fluorocyclopropyl)piperidine-3-carboxamide (LIV) (0.15 g, 0.33 mmol) and 1- (prop-2-yn-l-yl)-17 / -benzo[d][l,2,3]triazol-6-amine (XXXIX) (0.69 g, 4.04 mmol) in NMP (3 mL), was added 4M HC1 in dioxane (0.2 mL, 1.35 mmol) at room temperature, under nitrogen atmosphere. The resulting reaction mixture was heated at 90 °C for 4 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 phase using ammonium bicarbonate in water and acetonitrile to afford the desired product Example 57 as an Off-white solid. Yield: (0.035g, 17%), LC_MS: Calc. C3iH32FN9O2:581.66.; Obs.: 582.2 [M++H]: 1H-NMR (400 MHz, DMSO-d6):<59.62 (s, 1H), 8.78 (s, 1H), 8.02 (d, J = 4.40 Hz, 1H), 7.91 ...

Claims

I / We claim:

1. A compound of Formula I, its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, or pharmaceutically active derivatives thereof,Formula I wherein Ri is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, or C3-8 heterocyclyl, wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl;Yi is N or C(=O);Y2 is selected from N, O, CR2, or NR3, wherein R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; wherein C1-6 alkyl is optionally substituted with Ci -6 alkoxy or hydroxy;R is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;Rs is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, Ci- 6 alkyl, C1-6 haloalkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from C1-6 alkyl, Ci- 6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein C1-6 alkylor C3-8 heterocyclyl is optionally substituted with hydroxy, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C3-8 heteroaryl or C3-8 heterocyclyl; wherein C3-8 heterocyclyl is optionally substituted with one or more groups selected from oxo or C1-6 alkyl; p is 0 or 1 ;Re is selected from hydrogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, Ci-6aminoalkyl, C(=O)NR9aR9b, -NH-C(=O)R9or -NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy or cyano;R9, R9aand R9b are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein C1-6 alkyl, C1-6 aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -S-C1-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl or C3-12 heteroaryl is optionally substituted with one or more substituents selected from C1-6 alkyl; or R9aand R9b are combined together to form a C3-8 heterocyclyl optionally substituted with one or more substituents selected from oxo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 aminoalkyl;Zi, Z2, Z3, and Z4 are independently selected from N or CR10;Rio is selected from hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O, S, S=O, SO2, N-CH3, N-C(=O)CH3, or CR11;R11 is selected from hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; nl is 0, 1 or 2; n2 is 0, 1 or 2; and n3 is selected from 0 to 3.

2. The compound of Formula I as claimed in claim 1, wherein the compound of Formula I is selected from,Formula la Formula lb its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, or pharmaceutically active derivatives thereof, wherein Ri is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or C3-8 heterocyclyl, wherein C1-6 alkyl is optionally substituted with hydroxy, C3-6 cycloalkyl, or C3-8 heterocyclyl;Yi is N or C(=O);Y2 is selected from N, O, CR2 or NR3, wherein R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; C1-6 wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy;R is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;Rs is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy; nl is 0, 1 or 2;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, Ci- 6 alkyl, C1-6 haloalkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from C1-6 alkyl, Ci- 6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein C1-6 alkyl or C3-8 heterocyclyl is optionally substituted with hydroxy, amino, C1-6 alkyl, Cl -6alkoxy, Ci-6 aminoalkyl, C3-8 heteroaryl or C3-8 heterocyclyl; wherein C3-8 heterocyclyl is optionally substituted with one or more groups selected from oxo or C1-6 alkyl;Re is selected from hydrogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, Ci-6aminoalkyl, C(=O)NR9aR9b, -NH-C(=O) R9 or -NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy or cyano; p is 0 or 1;R9, Rgaand R9H are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein C1-6 alkyl, C1-6 aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -S-C1-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl or C3-12 heteroaryl is optionally substituted with one or more substituents selected from C1-6 alkyl; or R9aand R9bare combined together to form a C3-8 heterocyclyl optionally substituted with one or more substituents selected from oxo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 aminoalkyl;Zi, Z2, Z3, and Z4 are independently selected from N or CR10 :Rio is selected from hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl , C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O, S, S=O, SO2, N-CH3, N-C(=O)CH3or CRn;R11 is selected from hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and n2 is 0, 1 or 2.

3. The compound as claimed in claim 1 or 2, wherein Ri is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy; Yi is N when — is a double bond and Y2 is N or CR2, wherein R2 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;Yi is C(=O) when — is a single bond and Y2 is O or NR3, wherein R3 is selected from hydrogen, C1-6 alkyl, or C1-6 haloalkyl; Y3 and Y4 are independently N or CR4,wherein R4 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; C1-6 wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy; R is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy; R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy; nl is 0, 1 or 2; X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C(=O)Ci-6alkyl, C(=O)C3-6 cycloalkyl, C(=O)CH2OH, C(=O)CH2OCH3; C(=O)CH2NH2, C(=O)CH2NHCH3, C(=O)CH2N(CH3)2,Re is independently selected from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy;C 1-6 haloalkoxy, CH2OH, CH2OCH3, NH2, N(CH3)2,ZI, Z2, Z3, and Z4 are independently selected from N or CR10; Rio is selected from hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; Y is selected from O or CR11; Rn is selected from hydrogen, cyano, fluoro, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; nl is 0, 1 or 2; and n2 is 0 or 1.

4. The compound as claimed in claim 1 or 2, wherein Ri is selected from CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, CH2CHF2, CH2CH2CHF2, CH2CH2OCH3, CH2CH2OCF3, CH2CH2OCF3, CH2CH2OCHF2, CH2CH2CH2OH, CH(CH3)CH2CH3,Yi is N when — is a double bond and Y2 is N or CR2, wherein R2 is selected from hydrogen, fluoro, or CH3;Y 1 is C(=O) when — is a single bond and Y2 is O or NR3, wherein R3 is selected from hydrogen, CH3, or CF3;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, fluoro, or CH3; R is selected from hydrogen, CH3, OCH3, or CF3; Rs is selected from hydrogen, CH3, CH2CH3, CF3,R6 is selected from hydrogen, CH3, CH2CH3, CF3, CH2CH3, OCH3, OCF3, CH2OH,CH2OCH3, NH2, N(CH3)2,Zi, Z2, Z3, and Z4 are independently selected from N or CR10;Rio is hydrogen, cyano, fluoro, chloro, CH3, CF3, OCH3, or OCF3;Y is selected from O or CR11;R11 is hydrogen, or CH3; and n2 is 0 or 1.

5. The compound as claimed in claims 1 to 4, wherein the compound is selected from a group consisting of: i.(S)-N-ethyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-((l-isopropyl-lH-indazol-6-yl)amino)pyrimidin-5-yl)piperidine-3- carboxamide (Example 1); ii.(S)-l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-N-ethylpiperidine-3- carboxamide (Example 3);iii.(S)-N-cthyl- l-(2-((5-flLioro-l -propyl- 1 H-indazol-6-y I) amino)-4-(((lS,2R)-2-hydroxy-2 -dihydro- 1 H-inden- 1 -yl)amino)pyrimidin-5-yl)piperidine-3 - carboxamide (Example 4); iv.(lS,2R)-l-((2-((l-allyl-5-fluoro-lH-indazol-6-yl)amino)-5-((S)-3-(hydroxymethyl)piperidin-l-yl)pyrimidin-4-yl)amino)-2,3-dihydro-lH- inden-2-ol (Example 5); v.(S)-l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2.3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-N-isopropylpiperidine-3 -carboxamide (Example 6); vi.1 -(2-(( 1 -allyl-5-fluoro- lH-indazol-6-yl) amino)-4-((( 1 S ,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1-yl) amino) pyrimidin-5-yl)-N-ethylpiperidine-4- carboxamide (Example 7); vii.l-((S)-4-(2-((l-allyl-5-fluoro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino)ethan-l-one (Example 8); viii.l-((S)-4-(2-((5-fluoro-l-(prop-2-yn-l-yl)-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino)ethan-l-one (Example 9); ix.l-((S)-4-(2-((5-fluoro-l-isopropyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino)ethan-l-one (Example 10); x.l-((S)-4-(2-((5-fluoro-l-(2-methoxyethyl)-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-2- methylpiperazin- 1 -yl)-2-(methylamino)ethan- 1 -one (Example 11); xi.N-(l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2.3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl) propionamide (Example 12); xii.l-((S)-4-(2-((l-allyl-5-methyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-2- methylpiperazin-l-yl)-2-(methylamino) ethan-l-one (Example 13);xiii.2-(dimethylamino)-N-(l-(2-((l-ethyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4- yl) acetamide (Example 14); xiv.(S)-l-(2-((l-allyl-5-fluoro-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2, 3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide (Example 15); xv.N-(l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl) piperidin-4-yl)-2- (dimethylamino) acetamide (Example 16); xvi.2-(dimethylamino)-N-(l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1- yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-indazol-6-yl)amino)pyrimidin-5- yl)piperidin-4-yl)acetamide (Example 17); xvii.1 -((S)-4-(2-(( 1 -allyl- lH-indazol-6-yl) amino)-4-((( 1 S ,2R)-2-hydroxy-2,3 - dihydro- IH-inden-l-yl) amino) pyrimidin-5-yl)-2-methylpiperazin-l-yl)-2- (methylamino) ethan-l-one (Example 18); xviii.(S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1-yl) amino) pyrimidin-5-yl)-N-cyclopropylpiperidine-3 -carboxamide (Example 19); xix.l-((S)-4-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-2-methylpiperazin-l-yl)-2- morpholinoethan-l-one (Example 20); xx.(lS,2R)-l-((2-((l-allyl-lH-indazol-6-yl) amino)-5-(4-((pyridin-2-ylmethyl) amino) piperidin-l-yl) pyrimidin-4-yl) amino)-2,3-dihydro-lH-inden-2-ol (Example 21); xxi.((S)-4-(2-((l -allyl- lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1-yl) amino) pyrimidin-5-yl)-2-methylpiperazin- 1-yl) ((S)-l-methylpyrrolidin-2-yl) methanone (Example 22); xxii.(R)-N-(l-(2-((l-allyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)piperidin-4-yl)- 1 - methylpyrrolidine-2-carboxamide (Example 23);xxiii.(S)-N-cyclopropyl-l-(4-((( IS, 2R)-2-hydroxy-2,3-dihydro- IH-inden- 1-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-indazol-6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide (Example 24); xxiv.(S)- 1 -(2-(( 1 -allyl- lH-indazol-6-yl) amino)-4-((( 1 S ,2R)-2-hydroxy-2,3 - dihydro- IH-inden-l-yl) amino) pyrimidin-5-yl)-N-(oxetan-3-yl) piperidine-3-carboxamide (Example 25); xxv.(3S)-l-(2-((l-allyl-lH-indazol-6-yl) amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N-(2,2- difluorocyclopropyl)piperidine-3 -carboxamide (Example 26); xxvi.(R)-l-(2-((l-allyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- 1 H-inden- 1 -yl)amino)pyrimidin-5-yl)-N-cyclopropylpiperidine-3 - carboxamide (Example 27); xxvii.N-((S)-l-(2-((l-allyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)piperidin-3- yl)cyclopropanecarboxamide (Example 28); xxviii.(S)-l-(2-((l-allyl-5-methyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy- 2, 3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide (Example 29); xxix.(S)-l-(2-((l-allyl-4-fluoro-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2, 3-dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)-N- cyclopropylpiperidine-3 -carboxamide (Example 30); xxx.((S)-l-(2-((l-allyl-lH-indazol-6-yl)amino)-4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- l-yl)amino)pyrimidin-5-yl)piperidin-3-yl)(4- methylpiperazin-l-yl)methanone (Example 31); xxxi.(S)- 1 -(4-((( 1 S ,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn-l-yl)-lH-indazol-6-yl)amino)pyrimidin-5-yl)-N- isopropylpiperidine-3-carboxamide (Example 32); xxxii.(S)-N-cyclopropyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)-2-((5-methyl-l-(prop-2-yn-l-yl)-lH-indazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamide (Example 33);xxxiii. ((S)-l-(4-(((lS, 2R)-2-hydroxy-2,3-dihydro- IH-inden- l-yl)amino)-2-((l- (prop-2-yn-l-yl)-lH-indazol-6-yl)amino)pyrimidin-5-yl)piperidin-3- yl)(morpholino)methanone (Example 34); xxxiv.(S)- 1 -(4-((( 1 S ,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1 -yl)amino)-2-(( 1 - (prop-2-yn-l-yl)-lH-indazol-6-yl)amino)pyrimidin-5-yl)-N-(oxetan-3- yl)piperidine-3 -carboxamide (Example 35); xxxv.(S)-N-cyclopropyl-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)-2-((2-oxo-3-(prop-2-yn-l-yl)-2,3-dihydrobenzo[d]oxazol-5- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamide (Example 36); xxxvi.(S)- 1 -(2-( 1 -(R)-but-3-yn-2-yl)- lH-indazol-6-yl) amino)-4-( 1 S ,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide (Example 37); xxxvii.(S)-l-(2-((l-(S)-but-3-yn-2-yl)-lH-indazol-6-yl) amino)-4-((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)-N- cyclopropylpiperidine-3-carboxamide (Example 38); xxxviii.(S)-N-cyclopropyl-l-(4-((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino)-2-(l-(prop-2-yn-l-yl)-lH-benzo[d][l,2,3] triazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamide ((Example 39); xxxix.(S)-N-(2,2-difluoroethyl)-l-(4-(( IS, 2R)-2-hydroxy-2,3-dihydro- IH-inden- 1- yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3 -carboxamide (Example 40); xl.(S)- 1 -(4-((( 1 S ,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1 -yl) amino)-2-(( 1 -(prop-2-yn-l-yl)-lH-benzo [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl)-N- (1 -methyl cyclopropyl) piperidine-3 -carboxamide (Example 41); xli.(S)-l-(2-(l-(R)-but-3-yn-2-yl)-lH-benzo[d][l,2,3] triazol-6-yl)amino)-4- (((1S, 2R)-2-hydroxy-2,3-dihydro- IH-inden- 1 -yl)amino)pyrimidin-5-yl)- N-cyclopropyl piperidine-3 -carboxamide (Example 42); xlii.(S)-N-cyclopropyl-l-(4-( IS, 2R)-2-hydroxy-2,3-dihydro- IH-inden- 1-yl) amino)-2-(l -isopropyl- lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin- 5-yl) piperidine-3 -carboxamide (Example 43);xliii.(S)-l-(2-((l-allyl-lH-benzo[d] [1,2,3] triazol-6-yl) amino)-4-((lS,2R)-2- hydroxy-2,3-dihydro- IH-inden- 1-yl) amino) pyrimidin-5-yl)-N- cyclopropylpiperidine-3 -carboxamide (Example 44); xliv.(S)-l-(2-((l-((R)-but-3-yn-2-yl)-lH-benzo[d][l,2,3]triazol-6-yl)amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)- N-(2,2-difluoroethyl)piperidine-3-carboxamide (Example 45); xlv.(S)-l-(2-(l-(S)-but-3-yn-2-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino)-4- ((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl) amino) pyrimidin-5-yl)- N-cyclopropyl piperidine-3 -carboxamide (Example 46); xlvi.(3S)-N-(2,2-difluorocyclopropyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3 -carboxamide (Example 47); xlvii. (S)-N-(2,2-difluoroethyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1- yl) amino)-2-(l-isopropyl-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3 -carboxamide (Example 48); xlviii.S)-l-(2-((l-((S)-but-3-yn-2-yl)-lH-benzo[d][l,2,3] triazol-6-yl)amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)- N-(2,2-difluoro ethyl) piperidine-3-carboxamide (Example 49); xlix.(S)-l-(2-((l-((R)-but-3-yn-2-yl)-lH-benzo[d][l,2,3]triazol-6-yl)amino)-4- (((lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)- N-((R)-2,2-difluorocyclopropyl)piperidine-3-carboxamide (Example 50); l.(S)-N-(( 1 S ,2R)-2-fluorocyclopropyl)- 1 -(4-((( 1 S,2R)-2-hydroxy-2,3 - dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)-lH- benzo[d][l,2,3]triazol-6-yl)amino) pyrimidin-5-yl)piperidine-3- carboxamide (Example 51); li.(S)-N-((lR,2R)-2-fluorocyclopropyl)-l-(4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)-lH- benzo[d][l,2,3]triazol-6-yl)amino) pyrimidin-5-yl)piperidine-3- carboxamide (Example 52);lii.(S)-N-((lS,2S)-2-fluorocyclopropyl)-l-(4-((lS,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1 -yl) amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1 H-benzo[d] [1,2,3] triazol- 6-yl)amino) pyrimidin-5-yl)piperidine-3-carboxamide (Example 53); liii.(S)-N-((lR,2S)-2-fluorocyclopropyl)-l-(4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1H- benzo[d][l,2,3]triazol-6-yl)amino) pyrimidin-5-yl) piperidine-3- carboxamide (Example 54); liv. (S)-N-(( 1 S ,2R)-2-fluorocyclopropyl)- 1 -(4-(( 1 S ,2R)-2-hydroxy-2,3 - dihydro- IH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-indazol-6-yl) amino) pyrimidin-5-yl) piperidine-3 -carboxamide (Example 55); lv.(S)-N-(( 1 S ,2R)-2-fluorocyclopropyl)- 1 -(4-( 1 S ,2R)-2-hydroxy-2,3 -dihydro-IH-inden-l-yl) amino)-2-((l-isopropyl-lH-benzo[d][l,2,3] triazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamide (Example 56); lvi.(R)-N-((lS,2R)-2-fluorocyclopropyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro-IH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol- 6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide (Example 57); lvii.(R)-N-cyclopropyl- 1 -(4-((( 1 S ,2R)-2-hydroxy-2,3-dihydro- IH-inden- 1 -yl) amino)-2-(l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3 -carboxamide (Example 58); lviii.(3S)-N-(2-fluorocyclobutyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro-lH- inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol-6-yl) amino) pyrimidin-5-yl) piperidine-3 -carboxamide (Example 59); lix.(S)-N-((lR,2S)-2-fluorocyclobutyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro-IH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol- 6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide (Example 60); lx.(S)-N-((lS,2R)-2-fluorocyclobutyl)-l-(4-(lS,2R)-2-hydroxy-2,3-dihydro-IH-inden-l-yl) amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d] [1,2,3] triazol- 6-yl) amino) pyrimidin-5-yl) piperidine-3-carboxamide (Example 61); lxi.(S)-N-((lS,2R)-2-fluorocyclopropyl)-4-(4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1H-benzo[d][l,2,3]triazol-6-yl)amino)pyrimidin-5-yl)morpholine-2- carboxamide (Example 62); lxii.(S)-N-((lS,2R)-2-fluorocyclopropyl)-4-(4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1H- benzo[d][l,2,3]triazol-6-yl)amino)pyrimidin-5-yl)piperazine-2- carboxamide (Example 63); lxiii.(S)-N-((lS,2R)-2-fluorocyclopentyl)-l-(4-(((lS,2R)-2-hydroxy-2,3-dihydro- lH-inden-l-yl)amino)-2-((l-(prop-2-yn-l-yl)-lH-benzo[d][l,2,3]triazol-6- yl)amino)pyrimidin-5-yl)piperidine-3-carboxamide (Example 64); lxiv.(S)-N-((3S,4S)-4-fluorotetrahydrofuran-3-yl)-l-(4-(((lS,2R)-2-hydroxy-2,3- dihydro- IH-inden- 1 -yl)amino)-2-(( 1 -(prop-2-yn- 1 -yl)- 1H- benzo[d][l,2,3]triazol-6-yl)amino)pyrimidin-5-yl)piperidine-3- carboxamide (Example 65).6. A process of preparation of compounds of Formula I as claimed in any one of the claims 1 to 5, the process comprising: reacting Formula (A) and Formula (B) followed by reacting with Formula (D) in the presence of a base to obtain the compound of Formula I,wherein Ri is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or C3-8 heterocyclyl, wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy, C3-6 cycloalkyl, or C3-8 heterocyclyl;Yi is N or C(=O);Y2 is selected from N, O, CR2 or NR3, wherein R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl;— refers to single bond or double bond between Y 1 and Y2;Y3 and Y4 are independently N or CR4, wherein R4 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl; wherein C1-6 alkyl is optionally substituted with Ci -6 alkoxy or hydroxy;R is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;Rs is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl is optionally substituted with C1-6 alkoxy or hydroxy; nl is 0, 1 or 2;X is selected from CR7, O, S, S=O, SO2, or NR7; R7 is selected from hydrogen, Ci- 6 alkyl, C1-6 haloalkyl, NH(CO)pRs, or C(=O)Rs; Rs is selected from C1-6 alkyl, Ci- 6 alkoxy, C1-6 aminoalkyl, C3-6 cycloalkyl, or C3-8 heterocyclyl, wherein C1-6 alkyl or C3-8 heterocyclyl is optionally substituted with hydroxy, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C3-8 heteroaryl; wherein C3-8 heterocyclyl is optionally substituted with one or more groups selected from oxo or C1-6 alkyl; p is 0 or 1;Re is selected from hydrogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, Ci-6aminoalkyl, C(=O)NR9aR9b, -NH-C(=O) R9 or -NHCH2R9; wherein C1-6 alkyl is optionally substituted with hydroxy, C1-6 alkoxy, or cyano;R9, Rgaand Rgn are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-8 heterocyclyl, C3- 12 heteroaryl, wherein C1-6 alkyl, C1-6 aminoalkyl, C3-6 cycloalkyl, C3-8 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -S-C1-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C3-12 heteroaryl or C3-8 heterocyclyl, wherein C3-8 heterocyclyl or C3-12 heteroaryl is optionally substituted with one or more substituents selected from C1-6 alkyl; or R9aand R9bare combined together to form a C3-8 heterocyclyl optionally substituted with one or more substituents selected from oxo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 aminoalkyl;Zi, Z2, Z3, and Z4 are independently selected from N or CR10;Rio is hydrogen, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;Y is selected from O, S, S=O, SO2, N-CH3, N-C(=O)CH3, or CRn;Rn is hydrogen, cyano, halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, or Ci-6 haloalkoxy; n2 is 0, 1 or 2; and n3 is selected from 0 to 3.

7. The process as claimed in claim 6, wherein the base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, sodium hydride, potassium tertiary butoxide, sodium carbonate, potassium carbonate, and combinations thereof.

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

9. The compound as claimed in any one of the claims 1 to 5, wherein the compound is an inhibitor of cyclin dependent kinase 7 or cyclin dependent kinase7 with cyclin H and MAT1 or CDK- activating kinase (CAK) or combinations thereof.

10. The compound as claimed in any one of the claims 1 to 5, for use in treating cancer mediated at least in part by cyclin dependent kinase 7 or cyclin dependent kinase 7 with cyclin H and MAT1 or CDK-activating kinase (CAK) or combinations thereof.

11. The compound as claimed in claim 10, 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.

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

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

14. The combination as claimed in any one of the claims 12 or 13, wherein the additional therapeutic agent is selected from chemotherapeutic agent or immune checkpoint inhibitors.

15. The combination as claimed in claim 14, wherein chemotherapeutic agent is selected from 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, topoisomerase inhibitors, protein kinase B (AKT) inhibitor, c-Jun N-terminal kinase (JNK1 / K2) inhibitors, hypoxiainducible factor 1 alpha (HIF-la) inhibitor, extracellular signal-regulated kinase (ERK) inhibitor, poly ADP ribose polymerase (PARP) inhibitor, cisplatin, oxaplatin or combinations thereof.

16. The combination as claimed in claim 14, wherein the immune checkpoint inhibitors 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 tyrosine phosphatases nonreceptor type 1 / 2 (PTPN 1 / 2) inhibitors, or combinations thereof.

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

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

19. A method of treating cancer 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 12 to 16 or the pharmaceutical composition as claimed in claim 18 to 19 to the subject.

20. The method as claimed in claim 19, 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.

21. A method of treating a disease or condition mediated by cyclin dependent kinase 7 or cyclin dependent kinase 7 with cyclin H and MAT1 or CDK-activating kinase (CAK) or combinations thereof to a subject in need thereof, the methodcomprising administering the compound as claimed in claim 1 to 5 or the combination as claimed in claim 12 to 16 or the pharmaceutical composition as claimed in claim 17 to 18 to the subject.

22. The method as claimed in claim 21, 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.