HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S Provisional Application No 62/631,437, filed February 15, 2018, the contents of which are incorporated herein by reference in their entirety

FIELD OF THE IN VENTION

[0002] This disclosure relates generally to therapeutics which play a crucial role in the control of the cell cycle and more particularly, compounds that inhibit eye! in -dependent kinases (CDK). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the trea tment of diseases associated with these pathway

BACKGROUND OF THE INVENTION

[0003] The cell cycle is a period between the successive divisions of a cell. During this period, the contents of the cell must be accurately replicated. The processes that permit the ceil to divide are very precisely controlled by a multitude of enzymatic reactions amongst which the protein kinase-triggered protein phosphorylation plays a major role. In eukaryotes, there are four main stages/phases of ceil cycle namely the Gap-1 (Gl ) phase, Synthesis (S) phase, Gap-2 (G2) and Mitosis (M) phases. An extended phase of Gap- 1 phase is coined as Gap-0 (GO) phase or Resting phase (Cancers 2014, 6, 2224-2242)

[0004] Uncontrolled proliferation is the hallmark of cancer and other proliferative disorders and abnormal cell cycle regulation is therefore common in these diseases. Cycim-dependeni kinases (CDK) constitute a heterodimeric family of se me/threonine protein kinases involved in cell cycle and transcription. They include two main groups: cell cycle CDK and transcriptional CDK. The functionality of CDK depends on specific interactions with regulatory proteins named cyc!ins which form heterodimeric complexes with their partners. These complexes are important regulators of the cellular processes, especially in the cell cycle progression

[0005] The human proteome contains 20 CDK along with 29 cyclins. CDK1, CDK2, CDK4 and CDK6 are generally considered ceil cycle CDK, whereas CDK7, CDK 8, CDK9 and CDK1 f are mainly involved in transcription regulation (Genome Biol 2014,15(6): 122, Nat Cell Biol 2009; ; 1 (1 1): 1275 -6) CDK5 is the prototype of atypical CDK: it is activated by the non-cyclm proteins p35 (or CdkSRl ) and p39 (or Cdk5R2) and has unique post-mitotic functions in neuronal biology, angiogenesis and cell differentiation. Proliferative signals induce the transition from the GO or Gl phases into S phase through the activation of the structurally related CDK4 and CDK6 [Development, 2013:140 (15): 3079-93, Biochern Pharmacol 2012;84(8):985~93. Nature 2014:510(7505):393--61. The binding of cychn D to CDK4 and to CDK6 promotes the phosphorylation of the transcriptional repressor retinoblastoma protein (RBI).

[0006] CDK hyperactivity is often observed m cancer reflecting their prominent role in ceil cycle and transcription regulation in cancer cells, the process of ceil division becomes unregulated, resulting in uncontrolled growth that leads to the development of a tumor. A number of mecha sms contribute to the dysreguiation of the cell cycle in malignant cells, including the amplification and hyperactivity of CDK4/6, or their genomic instability, which might cause CDK4/6 to become oncogenic drivers of cell replication. Usurping these mechanisms, cancer cells can continue to replicate by triggering the Gl to S phase transition. This process appears to be facilitated by shortening of the Gl phase. In a cancer cell, CDK4/6 antagonizes intrinsic tumor suppression mechanisms including cell senescence and apoptosis, which further augments the growth of a tumor. Cancer cells also upregu!ate other CDK and cyclins and decrease suppressive mechamsms such as intrinsic CDK inhibitors and tumor suppressor proteins. The overall effect of this type of cell cycle dysreguiation is malignant cell proliferation and the development of cancer (Clinical Breast Cancer 2016, 1526-8209).

[0007] Several CDK inhibitors have been reported (such as in WO2011101409 and

WO2011101417) or clinically developed. F!avopirido! and R-Roscovitine (Seliciciib), were the first generation of pan-CDK inhibitors with anti-tumor activity attributed to down-regulation of CDK9-mediated anti-apoptohc proteins, especially Mcl-1. Recently, a new generation of CDK inhibitors have been developed, advanced to clinical trials and approved for certain types of cancer. Dinaciciib, a selective inhibitor of CDK 1, CDK2, CDK 5, and CDK9, was directed towards refractory chronic lymphocytic leukemia while palbociclib was tested against advanced estrogen receptor (ER)-positive breast cancer as a selective inhibitor of CDK4 and CDK6. The development of more selective second and third generation CDK inhibitors, including specific

9 CDK4/6 inhibitors has led to a renewed enthusiasm for manipulating the cyclin D1 -CDK4/6 axis in cancer treatment. There are three FDA-approved CDK4/6 inhibitors presently:

Palboeiclib, Ribociclib and Abemaciclib.

[0008] The development of therapies, including monotherapies, for treatment of proliferati e disorders using a therapeutic targeted genericaiiy at CDK, or specifically at dual inhibition of CDK4 and CDK6, is therefore potentially highly desirable.

[0009] There is still a need for new CDK4/6 inhibitors. Compounds for the treatment of hyper-proliferative diseases preferably have at least one advantageous property selected from selectivity, potency, stability, pharmacodynamic properties and safety profile. In this regard, a novel class of CDK4/6 inhibitors is provided herein.

BRIEF SUMMARY OF THE INVENTION [0010] In one embodiment provided is a compound of Formula (J):

or a salt thereof wherein X, Y, Z, Rf Rf Rf Rf 1, and n are as detailed herein.

[0011] In some embodiments, provided is a compound of Formula (I):

or a salt thereof _, wherein X Y, A A L, Rf R Rf K K Rf i. m, n p rmd q are as detailed herein.

[0012] In score embodiments, provided is a compound of Formula (II):

or a salt thereof wherein X, V. ( ^' D, Rf IX, IX, IX, k . IX, 1, rn, n, p and q are as detailed herein

[0013] In some embodiments the compound of Formula (I) or a salt thereof is of Formula (I- A) as detailed herein.

[0014] In another aspect, provided is a method of treating cancer m an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound as detailed herein, such as a compound of any one of Formula (J), Formula (I ), Formula (II), (I-A), (I-B1 ) to (F-B12). (I -Cl) to (I-C23), or a pharmaceutically acceptable salt thereof Also provided is a method of modulating CDK4/6 in an individual, comprising administering to the individual a compound detailed herein or a salt thereof Also provided is a method of modulating CDK4/6 and one or more of CDK1 , CDK2, and CDK9 in an individual comprising administering to the individual a compound detailed herein, or a salt thereof Also provided is a method of inhibiting CDK4/6 m a cell, comprising administering a compound detailed herein, or a salt thereof to the ceil. Also provided is a method of inhibiting CDK4/6 and one or more of CDK1, CDK2, and CDK9 in a cell, comprising administering a compound detailed herein, or a salt thereof to the ceil. In some embodiments of the methods detailed herein, the methods comprise administration of a compound detailed herein, or a salt thereof as a monotherapy.

[0015] In another aspect, provided is a pharmaceutical composition comprising a compound detailed herein, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable earner or excipient. Kits comprising a compound detailed herein, or a salt thereof, are also provided. Kits may optionally include instructions for use, such as instructions for use m any of the methods detailed herein, for example, for use in the treatment of cancer. A compound as detailed herein, or a salt thereof, is also provided for the manufacture of a medicament for the treatment of cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG 1 shows the body weight changes of the mice m the different groups of a pharmacological study of test compound in a MC-38 mouse model.

[0017] FIG 2 shows the relative change of body weights (%) of the mice m the different groups of a pharmacological study of test compound i n a MC-38 mouse model.

[0018] FIG. 3 A and FIG. 3B show tumor growth curves of fee mice in the different groups of a pharmacological study of test compound in a MC-38 mouse model

[0019] FIGS. 4A-4D show individual tumor growth curves of the mice m fee different groups of a pharmacological study of test compound i n a MC-38 mouse model.

[0020] FIG. 5 shows tumor growth inhibition curves of the mice in the different groups of a pharmacological study of test compound in a MC-38 mouse model.

[0021] FIG. 6 shows time-io-end point Kap!an-Meier survival curves of the mice m the different groups of a pharmacological study of test compound in a MC-38 mouse model.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0022] Alkyl’’ refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (i.e. , Ci-Cio means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a“ - C o alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a ^' Ck-Ck alkyl”), 3 to 8 carbon atoms (a fofoCg alkyl”), 1 to 6 carbon atoms (a "‘CyC , alkyl”), 1 to 5 carbon atoms (a“CfeCi alkyl”), or 1 to 4 carbon atoms (a“Cr-Cfe alkyl”). Examples of alkyl include, but are not limited to, groups such as methyl ethyl, n-propyl, isopropyl n-butyl, t-but l isobutyl sec· butyl homologs and isomers of, for example n -pentyl, n-hexyl, n-heptyl, n-oetyl, and the like.

[0023] “Alkenyl’ as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of o!efmic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., CfoCio means two to ten carbon atoms). The alkenyl group may be in“cis” or “trans” configurations, or alternatively in Έ” or“Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a“CW alkenyl”), having 2 to 8 carbon atoms (a‘TfoCl alkenyl”), having 2 to 6 carbon atoms (a‘"C -Cs alkenyl”), or having 2 to 4 carbon atoms (a“CV Cfi alkenyl”). Examples of alkenyl include, but are not limited to, groups such as etheny! (or vinyl), prop-l-enyl, prop-2-enyl (or allyl), 2-methylprop-l -enyl, but-l-enyl, but-2-enyl, km ·3 · enyl, buta-l ,3~dienyl, 2-methylbuta-l ,3-dienyl, homologs and isomers thereof, and the like

[0024] “Alkylene” as used herein refers to the same residues as alkyl, but having bivaiency. Particular aiky!ene groups are those having 1 to 6 carbon atoms (a“C -Q, alkylene”), 1 to 5 carbon atoms (a“CfoCs alkylene”), 1 to 4 carbon atoms (a ^' (l~i.fi alkylene”) or 1 to 3 carbon atoms (a“Cfi-Cfi alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-€¾-). ethylene (- ( ^' I I t 1 1 ;··}. propylene (-CH ₂ CH ₂ CH ₂ -), butylene

( ( ^' l i t I kCf hi I k· ) and the like.

[0025] ’Alkynyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e. , having at least one moiety of the formula CºC) and having the number of carbon atoms designated foe. means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a“(VCfio aikynyf”), having 2 to 8 carbon atoms (a“( C* alkynyl”) having 2 to 6 carbon atoms (a“Crlfi alkynyl”), or having 2 to 4 carbon atoms (a“(V C.i alkynyl”). Examples of alkynyl include, but are not limited to, groups such as ethynyl (or aeetylenyl), prop-1 -ynyl, prop-2-ynyi (or propargy!) but-l-ynyl, but-2-ynyl, but-3-ynyl homologs and isomers thereon and the like.

[0026] “Aryl” refers to and includes polyunsaturated aromatic hydrocarbon groups. Aryl may contain additional fused tings (e.g., from 1 to 3 rings), including additionally fused aryl heteroary!, cycloalkyl, and/or heterocyclyi rings. In one variation, foe aryl group contains from 6 to 14 annular carbon atoms. Examples of ary l groups include, but are not limited to, phenyl, naphthyl, biphenyl and the like.

[0027] “Carbonyl” refers to the group ( O.

[0028] “Cyc!oa!kyr refers to and includes cyclic univalent hydrocarbon structures winch may be fully saturated, mono·· or polyunsaturated but which are non-aromatic, having the number of carbon atoms designated (e.g., C i-Cio means one to ten carbons) Cycioalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantly, but excludes ami groups. A cycioalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof A preferred cycioalkyl is a cyclic hydrocarbon having from 3 to 13 annular carbon atoms. A more preferred cycioalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C- -C _¾ cycioalkyl"). Examples of cycioalkyl include, but are not limited to, cyclopropyl, cyclobutyi, cyclopentyl, cyclohexyl, 1 -cydohexeny!, 3-cyciohexenyl, cycloheptyl, norbornyl, and the like.

[0029] "‘Halo” or“halogen” refers to elements of the Group 17 senes having atomic number 9 to 85. Preferred halo groups include fiuoro, ch!oro, bromo and iodo. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaioaryi, diha!oa!kyi, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halo; thus 4-diloro-3-fluorophenyl is within the scope of dihaioaryi. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a

“perhaloalkyl.” A preferred perhaloaikyl group is tnfluoroalkyl (~CF ). Similarly,

“perhaloa!koxy” refers to an alkoxy group in which a halogen takes the place of each 1 1 in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trif!uoromethoxy (-OCIA).

[0030] “Heteroaryl” refers to and includes unsaiurated aromatic cyclic groups having from 1 to 10 annular carbon atoms and at least one annular heteroatom including but not limited to heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatermzed A heteioaryl group can be attached to the rema inder of the molecule a t an annular carbon or at an annular heteroaiom. Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocycly! rings. Examples of heteroaryl groups include, bat are not limited to, pyridy!, pyrirmdyl, thiophenyl, furany!, thiazoiyl, pyrazoiyl, oxazolyl, isooxazolyl, mndazolyl, qumolyl, isoquinolyl, benzimidazolyl, benzpyrazolyi, benzotriazolyl, indole, benzothiazyi, benzoxazolyl, benzisoxazoiyi, imidaxopyndmy! and the like.

[00311 "‘Heterocycle” or“heterocycly G refers to a saturated or an unsaturated non-aromatic group having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatermzed. A heterocycly! group may have a single ring or multiple condensed rings, but excludes heteroaryl groups A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof In fused ring systems, one or more of the fused rings can be aryl or heteroaryl Examples of heterocycly! groups include, but are not limited to, tetrahydropyrany!, dihydropyranyl, pipendiny!, piperazinyt, pyrrolidinyl, thiazobnyl, thiazo!idinyl, tetrahydrofuranyl,

dihydrooxazo!yl, timydroisoxazoly!, dioxolanyl, morpholinyl, dioxanyl, tetrahydrothiopheny!, and the like.

[00.32] Oxo” refers to the moiety O

[0033] “Optionally substituted” unless otherwise specified means that group may be unsubstituted or substituted by one or more (e.g., 1 , 2, 3, 4 or 5) of the substituents listed for that group in winch the substituents may be the same of different, provided that the group’s normal valence is not exceeded. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3. 1 to 4 or 1 to 5 substituent

[0034] As used herein ^' "CDK” refers to one or more eye! in-dependent kinases CDK4/6 refers to both CDK4 and CDK6. Thus, inhibitors of CDK4/6 inhibit both CDK4 and CDK6. [0035] A“pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0036] As used herein,“treatment” or“treating” is an approach for obtaining beneficial or desired results including clinical results. For example, beneficial or desired results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals. In reference to cancers or other unwanted cell proliferation, beneficial or desired results include shrinking a tumor (reducing tumor size); decreasing the growth rate of the tumor (such as to suppress tumor growth): reducing the number of cancer cells, inhibiting, retarding or slowing to some extent and preferably stopping cancer cell infiltration into peripheral organs; inhibiting (slowing to some extent and preferably stopping) tumor metastasis; inhibiting tumor growth: preventing or delaying occurrence and/or recurrence of tumor: and/or relieving to some extent one or more of the symptoms associated with the cancer In some embodiments, beneficial or desired results include preventing or delaying occurrence and/or recurrence, such as of unwanted cell proliferation.

[0037] As used herein,“delaying development of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

[0038] As used herein, an“effective dosage” or“effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results. For prophylactic use beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity of or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of foe disease, its complications and intermediate pathological phenotypes presenting during development of foe disease. For therapeutic use, beneficial or desired results include ameliorating, palliating, lessening, delaying or decreasing one or more symptoms resulting from the disease increasing the quality of lift; of those suffering from the disease decreasing the dose of oilier medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. In reference to cancers or other unwanted cell proliferation, an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation. In some embodiments, an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay occurrence and/or recurrence An effective amount can be administered in one or more administrations, in the ease of cancer, the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (hi) inhibit, retard, slow to some extent and preferably stop cancer ceil infiltration into peripheral organs: (iv) inhibit (i.e. , slow to some extent and preferably stop) tumor metastasis: (v) inhibit tumor growdi, (vi) prevent or delay occurrence and/or recurrence of tumor, and/or (vb) relieve to some extent one or more of the symptoms associated with the cance An effective dosage can be administered in one or more administrations. For purposes of tins disclosure, an effective dosage of compound or a salt thereof, or pharmaceutical composition is an amount sufficient 10 accomplish prophylactic or therapeutic treatment either directly or indirectly. Ii is intended and understood that an effective dosage of a compound or salt thereof, or pharmaceutical

composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus an‘ ^‘ effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effecti e amount it) in conjunction with one or more other agents a desirable result may be or i achieved.

[0039] As used herein, the term“individual” is a mammal, including humans. An individual includes, but is not limbed to, human hov me horse, feline canine, rodent, or primate In some embodiments, the individual is human. The individual (such as a human) may have advanced disease or lesser extent of disease, such as low tumor burden. In some embodiments the individual is at an early stage of a proliferative disease (such as cancer) In some embodiments, the individual is at an advanced stage of a proliferative disease (such as an advanced cancer). [0040] Reference to“about’ a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to“about X” includes description of“X”.

[0041] It is understood that embodiments, aspects and variations described herein also include“consisting” and/or“consisting essentially of’ embodiments, aspects and variations

Compounds

[0042] in one aspect provided is a compound of the Formula (J):

or a salt thereof _, wherein:

, wherein

A is (X-C _& cycloalkyl, 4- to 7-membered heterocyeiyl, 5 to 7-membered heteroaryh or (A, aryl, each of which is optionally substituted with Rf

L is a bond,

B is hydrogen, C C ₆ cycloalkyl, '· · to 7-membered heterocyeiyl, 5- to 7 membered heteroaryl, aiyl, each of which is optionally substituted with Rf

C is (f -Cf cycloalkyl, 5- to 7-membered heterocyeiyl, 5- to 7-membered heteroaryl, or (f aryl, each of which is optionally substituted with Rf wherein C is fused to D; and

D is (f ~(f, cycloalkyl, 3- to 7-membered heterocyeiyl, 5- to 7-membered heteroaryh or Cf aryl, each of which is optionally substituted with Rf

each X and Y are independently N or CH, provided that at least one of X and Y is N: R ^* is hydrogen, Ck-Ck alkyl, Cz- , alkenyl, (¾-Ck alkynyl, Ck-Cg aikoxy, Ck-Ck cycloalkyl, 3- to 12- em bered heterocyclyl, 5- io 10-metnhered heteroaryl. CVC _M aryl, -(Ck- Cg a!ky!eneXCg-Cg cycloalkyl), -(Cj-Ck a!kylene)(3- to i2-membered heterocyclyl), -C(0)R ^i' y -(Ck-Cg aikylene)(5- to 10-membered heteroaryl) or -(C -Cg a!kyleneXCk-Ckg aryl), wherein R ^J is independently optionally substituted by halogen, oxo, -QR ^{J J} , -NRkR'k -€{0)11* ^' , -CN, (k-Ck cycioalkyl, or Cj-Ck alky! optionally substituted by oxo, -OH or halogen, provided that when Z is

oxo, then R ^l is Cg-Ck alkyl, (k-(k alkenyl, ( ^' ···().

alkynyl, (h-Cs aikoxy, Ck-Ck cycioalkyl, 3- to 12-metnhered heterocyclyl, 5- to 10-membered heteroaryl, C -Cir aryl, -(Ck-Ck alkylene)((k-Ck cycioalkyl), -C(0)R ^! k or -(Ck-Cg a!kylene)((k- Cfe aryl), wherein R· is independently optionally substituted by halogen, oxo, -OR ^' -C(0)R ^l k -CN, Ck-Cg cycioalkyl, or (k-(k alky! optionally substituted by oxo, -Oil or halogen;

each R is independently Cj-C alkyl, oxo, -NR ^{l l} R ^li , -CN, -C(0)R ^:iJ , -C(0)NR ^{: :} R’ ^z or halogen, wherein any two R groups are independently attached to same carbon or two different carbons;

each of R ' and R is independently Cj-Ck alkyl, CVCk cycioalkyl, (k-(k haloa!kyi, CYC.·. alkoxy, (k-Ck ha!oa!koxy, halogen or -OH;

each R ^' is independently (k-Ck alkyl, .. alkenyl, CYCk alkynyl, halogen, oxo, -CN, -OR ^{i 0} , -SR ¹⁰ , -NR ^{J J} R ¹² , -C(0)R°, -C(0)NR ^{5 i} R ^{i 2} , ·OPO ·\U Y k -NR ⁱ⁰ C(O)R ⁿ ,

-NR ⁱ C(O)NR ^u R ¹² , -S(0)R ¹⁰ , -S(0) _? R ^l °, -NR ^{J 0} S(O) ₂ R ^{J J} , -S(0) ₂ NR ^u R ¹² , Ck-Ck cycioalkyl, 3- to 12-membered heterocyclyl, -(CrCg a!ky!ene)ORY -(Ck-Cg alkyieneiSR - (C ^' - - Cg alkylenel C Y ¹² , -(C _r Cg alky!ene)C(0)R ⁵⁰ , -(C _r Cg alkvlene)C(0)NR ^{J J} R ¹² , -(Ck- Ck alky! eneJNR ⁱ⁰ C(O)R ^{5 !} , -(Ci-Cg alkylene)NR ¹⁰ C(O)NR ^{l l} R ¹² , ··(( :··( . alky!ene)SiO) ₂ R ⁱ⁰ , -(fk- Cg alkvlene)NR ¹⁰ S(O) ₂ R ⁿ , -(Ck-Ck alkviene)NR ¹ S(O) ₂ NR ^{5 5} R ^{i 2} , -(Ck- Cg nlkvlone sSiO) Y R ^: R ^: (CYCg alkylene)(Cg-Ck cycioalkyl), -(Cj-Ck a!kylene)(3~ to 12- membered heterocyclyl), wherein each R: is independently optionally substituted by halogen, oxo,

Cg alky!ene)CfO)R , Ck-Cg cycioalkyl, or Ck-Ck alkyl optionally substituted by oxo, -OH or halogen; each k ^': is independently oxo or R . or any two R ^': groups, when bound to the same carbon atom, are taken together with the carbon to which they are attached to form a Cb- C , cycioaikyl;

R ⁷ ts independently hydrogen, Crib, alkyl, C _.y O.·. alkenyl, Cb-Ck alkynyl, Cb-Cb, cycioaikyl, 3- to 6-membered heterocyclyl, -ORti -NR ⁿ R° -NR ⁱ⁰ C(O)Rfo -NR ⁱ⁰ C(O)NR ⁱⁱ R ¹² , - S( O) ^: . -NR ³⁰ S(O} _? R , -S(0) ₂ NR ⁿ R ⁱ² , -C(G)R ^J0 , -C(0)NR ^{J 1} R ¹² · -Kb-Cb alkylene)CN, -fCx- (¾ aikylene)OR ¹⁰ , -Kb-Cb a!kylenelSR ⁵ , -(Cx-C ₆ alkyl ene)NR ⁿ R ⁵² , -(Cx-C ₆ a!kylene)CF , _, -{C _r C- a ^j kylene)C(O)R ⁱ⁰ , -(C _r C ₃ alkylene)C(0)NR ^{l 5} R ⁵² , -Kb-Cb aikyienelNR^CiOlR", -(Cy CK alkylene)NR ¹⁰ C(O)NR ⁿ R ⁵² , -Kb-i ·. alkyiene)S(O) ₂ R ^{i 0} , ~(CyC ₃ alkylene)NR ^{i 0} S(O} ₂ R ^{i i} _>

-Kb Kb alkyiene)S(0) ₂ NR ^{l i} R ^; b, -(CyC ₃ alkyl eneXCyCg cycioaikyl), or -Kb R ^" : alkylene)(3- to 6-membered heterocyclyl), wheretn each R is independently optionally substituted by halogen, oxo, -OR ¹³ , · N R ^: RN -C(0)R ¹³ , -CN, ~|CyC ₃ alkyiene)OR ³³ , -(Cb-Cb alkylene)NR ⁵³ R ⁵⁴ , ~(C _¾ - Cb alkylene)C(0)R ^J , (Vi _>; cycioaikyl, or Cb-Cb alkyl optionally substituted by oxo, -OH or halogen;

Rb ^' is independently hydrogen, Cb -Cb alkyl, C ₃ -C ₀ cycioaikyl, -(Cj-C ₃ alkylene)(C ₃ -C ₆ cycioaikyl), Cb-Cb-; aryl, 5- to 6-membered heteroaryi or 3 · to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN, -OR ^: b -Nlfo ^' R ¹ , or Cb-Cb alkyl optionally substituted by halogen, -OH or oxo;

RN and II ^: are each independently hydrogen, Cb-Cb alkyl, Cb-Cb eyeloalkyl,

(b alkylene)(C ₃ -C ₆ cycioaikyl), ( .·.·( y aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN, -ORbb -NR ^1S R ^IS or Cb-Cb alkyl optionally substituted by halogen, -OH or oxo,

or R ^{! !} and R ^' are taken together with the ato to winch they attached to form a 3- to 6- membered heterocyclyl optionally substituted by halogen, oxo, or f b -C 1, alkyl optionally substituted by halogen,

R ^' and K ^{' *} are each independently hydrogen or f b -C 1, alkyl, wherein the ( = - i b alkyl of R ^{1 '} and R ^: bue optionally substituted by halogen, -ORb b -\R ^{: r} or oxo:

or R’ ^' and R ^{: '} are taken together with the atom to which they attached to form a 3- to 6- non: tiered heterocyclyl optionally substituted by halogen, oxo or CyCb alkyl optionally substituted by halogen or oxo; and R · ^' and K ^{' "} are each independently hydrogen, (CCA alkyl optionally substituted by halogen or oxo, ( C; alkenyl optionally substituted by halogen or oxo, or (VC; alkynyi optionally substituted by halogen or oxo;

or K ^{: r} and R ^{: '} are taken together with the atom to which they attached to form a 3 - to 6- membered heterocydyl optionally substituted by halogen, oxo or Grid alkyl optionally substituted by oxo or halogen;

1, nr, p and q are each independently 0, 1, 2 or 3, provided that at least one of m and I is not 0; and

n is 0, 1, 2, 3 or 4.

[0043] in some embodiments, provided is a compound of Formula (i):

or a salt thereof! wherein:

dyl, 5- to 7-rnembered heteroaryl, or ( ., aryl each of which is optionally substituted with E7;

L is a bond, Qfo, NH O. S, or S0 ₂

B is hydrogen, (VC. cycloalkyl, 3- to 7-rnembered heterocydyl, 5- to 7- membered heteroaiyh or Cfo aryl, each of winch is optionally substituted with K

C is (VC. cycloalkyl, 5- to 7-rnembered heterocydyl, 5- to 7-membered heteroaryl or C ₆ aryl, each of which is optionally substituted with K wherein C is fused to D; and D is CX-CX cycloalkyl, 3·· to 7-membersd heterocyclyl, 5- to 7- mem bered heteroaryl, or CX aryl, each of which is optionally substituted with R

each X and Y are independently N or ⁽ 1 1. provided that at least one of X and Y is N,

R ^: is hydrogen. CX -C alkyl, CX-CX alkenyl, (X-CX alkynyl, (X-C alkoxy, < X-CX cycloalkyl, 3-- to 12-membered heterocyclyl 5- to 10-membered heteroaryl, ( .. ·( aryl, -(CX- CX alkylene}i(X-(X cycloalkyl), -((X-CX alkyiene)(3- to 12-membered heterocyclyl), -C(0)R’ ^w _> -(CX-CX alkylene)(5- to 10-membered heteroaryl) or -(CX-CX alkylene)(C ₆ -Ci4 aryl), wherein k is independently optionally substituted by halogen, oxo, -OR ¹ 1 -NRYR'l -CX O sR -CM, ( , -( X cycloalkyl, or (X-CX alkyl optionally substituted by oxo, -OH or halogen, provided that when Z is

then R ^' is (X-CX alkyl, CX-CX alkenyl (X-CX alkynyl, (X -C alkoxy, (X-(X cycloalkyl 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, CX-CX,* aryl, -(CX -CX a ll lono K CX-CX cycloalkyl ), ( ^' 0)11 ^: l or -(CX-iX alk iene)(CX- aryl), wherein R; is independently optionally substituted by halogen, oxo, -OR ¹ 2 -\ R ^: dX ¹ -C(0)R ^J l -CM, (X-Cg cycloalkyl, or CX -CX alkyl optionally substituted by oxo, -OH or halogen; each R ² is independently CX-CX alkyl, oxo, -NR ^{¾ i} R ^{i 2} , -CM, -C(O)R ⁱ⁰ , -C(0)NR¾ ¹² or halogen, wherein any two R groups are independently attached to same carbon or two different carbons;

each of k and R ⁴ is independently (X-(X alkyl, CX-CX cycloalkyl, CX -CX haloalkyl, CX-CX alkoxy, CX-CX ha!oalkoxy, halogen or -OH;

each R; is independently Cj-CX alkyl, CX-CX alkenyl, CX-CX alkynyl, halogen, oxo, -CM, -OR ¹⁰ , -SR ^{i 0} , -NR ⁿ R ¹² , -( ^' (O nXX -CiOlNR^R ¹² , -0C(0)NR ^{5 i} R ^{J 2} , -NR ¹⁰ C(O)R ^u ,

-NR ¹ °C(0)NR ^{1 1} R ¹² , -SiO) ₂ R ^{i 0} , -NR ¹⁰ S(O) ₂ R ⁿ , -SiO^NR^R ¹² , CX-CX cycloalkyl, 3- to 1 2- membered heterocyclyl, -(CX -CX alky!ene)OR ⁿ ', -(Cj-CX a!kyiene)SR ^s X -(Cj- CX alkyl eneJNR ⁴⁴ R ⁱ² , -(CX-CX alkyl ene)C(())R ^{i 0} , -(CX-CX alkylene)C(0)NR ⁿ R ¹² , (iX- (X alkylene)NR ¹⁰ C(O)R ¹ 1 -(CX-CX alkylene)NR ^{i 0} C(O)NR ^{i i} R ^{i 2} , -(CX-CX alkylene)S(0) ₂ R ¹⁰ , -(CX- CX alkyl eneJNR ⁴ ’'S(0) ₂ R ⁴ 1 -(CX-CX a lio !enepti OPN R ^{' :} R ^: . -((X-CX alkylene)(CX-CX cycloalkyl), -((X-CX a1kylene)(3- to 12-membered heterocyclyl), wherein each ti is independently optionally substituted by halogen, oxo, -OR - (b alkylsne)NRh’R ^: b -{Ci-Cb alky!ene)C(0)R‘\ C ₃ -(b cycloaikyl, or C -CV, alkyl optionally substituted by oxo -OH or halogen,

each R° is independently oxo or R or any two R° groups, when bound to the same carbon atom, are taken together with the carbon to which they are attached to form a Cw

(b cycloalkyl;

R ⁷ is independently hydrogen, Crib alkyl, C _.y -C.·. alkenyl, Cg-C alkynyl, C C cycloaikyl, 3-- to 6-membered heterocyciyi, -C(Q)R ^J b ·( (0}\R ^{: !} R ^! -;(Y(\ aikyiene)CN, ··· ( ^' ··· C- ₃ alkylene)OR ⁱ⁰ , -(fo-Cb alkylene)SR ⁱ⁰ , -(C _r C ₃ alkyleneJNR^R ³² , -(Ci-C ₃ alkylene)CF ₃ , _, -(C - C ₃ alkylene)C(0)R’ °, --{(d -( ·. aikv!-meR iO}\iti ^: R ^{: '} ~(C _r C ₃ alkylene)NR ^{i 0} C(O)R ⁵⁵ , -{id - C- ₃ alkyl enejNR^CCOjNR^R ", -(C _r C- ₃ alkylene)S(0) _? R ^l °, (id -id alkylene)NR ¹ S(O) ₂ R ^u , -(CrC- ₃ alkylene)S(0) ₂ NR' 'R ^/ , ~(CrCd alkyleneXCb-Cb cydoalkyl), or -(CrC ₃ alkylene)(3- to 6-membered heterocyciyi), wherein each R' is independently optionally substituted by halogen, oxo, ~OR ⁿ , - R fobb -C(0)R ^{i 3} , -CN, did- id alkyieneiOR ¹³ , -{C -C ₃ aikylene)NR¾ ⁱ⁴ , -{C - alkyl ene)C(0)R b Cy-Cg cydoalkyl , or C C ₆ alkyl optionally substituted by oxo, -OH or halogen;

id is independently hydrogen, C ; ·( . alkyl, ( -,··( .·. cycloalkyl, ··(( ; ·( ·. alkyleneXCrCb cycloaikyl), Cy-Cfo aryl, 5- to 6-rnembered heteroaryl or 3-- 10 6-membered heterocyciyi each of winch is independently optionally substituted by halogen, oxo, -CN, -Old -NR^ fo or .· alkyl optionally substituted by halogen, -OH or oxo,

R ^" and K ^' are each independently hydrogen, .· alkyl, ·. cycloaikyl, -(( ; - Cb alkylene)(C3-C6 cycloaikyl), (b-Cy aryl 5- 10 6-membered heteroaryl or 3- to 6-mernbered heterocyciyi each of which is independently optionally substituted by halogen oxo, -CN, -OR d -NR ^{3 5} R ¹⁶ or ( fob alkyl optionally substituted by halogen, -OH or oxo;

or id and id are taken together with the atom to which they atached to form a 3- to 6- membered heterocyciyi optionally substituted by halogen oxo, or C -Cd alkyl optionally substituted by halogen;

Id and R'’ are each independently hydrogen or C -Cd alkyl, wherein the Ch-Cg alkyl of K and R ^’ are optionally substituted by halogen, -O ^' 1 -NR’tidti or oxo;

or R ^{1 '} and ^i÷ are taken together with the atom to which they attached to form a 3- to 6- membered heterocyciyi optionally substituted by halogen, oxo or Cd ··( ^" .·. alkyl optionally substituted by halogen or oxo; and R ^{' '} and R ^{' '} are each independently hydrogen, ( ; · ⁽ 1 alkyl optionally substituted by halogen or oxo, (fo-Ck alkenyl optionally substituted by halogen or oxo, or CfoCA alkynyi optionally substituted by halogen or oxo;

or R ^{: r} and R ^{: '} are taken together with the atom to which they attached to form a 3 - to 6- membered heterocyclyl optionally substituted by halogen, oxo or ( ^' :··( .·. alkyl optionally substituted by oxo or halogen;

1, nr, p and q are each independently 0, 1, 2 or 3; and

n ts 0, 1 , 2, 3 or 4

[0044] In some embodiments of Formula provides a compound of Formula (I):

or a salt thereon w herein X, Y. A, B, L, R\ R . k . R ^" , K ^' . R L m, n, p and q are as detailed herein for Formula (J ).

[0045] In some embodiments of Formula and provides a compound of Formula (II):

or a salt thereof, wherein X, Y, C, D, Rh R . R . R 7 R y R ^' y 1, m, n, p and q are as detailed herein for Formula (J).

[0046] Specific values listed below are values for a compound of Formula (I), Formula (I), or Formula (II) as well as all related formulae (e.g., Formula (i-A), (I-Bl) to (I-B12), and (I-Cl ) to (I-C23)), or a salt thereof It is to be understood that two or more values may combined. Thus it is to be understood that any variable for a compound of Formula (J), Formula (I), or Formula (II) as well as all related formulae may be combined with any other variable for a compound of Formula (I), Formula (I), or Formula (II) as well as all related formulae the same as if each and every combination of variables were specifically and individually listed. For example, it is understood that any specific value of R detailed herein for a compound of Formula (J), Formula (I), or Formula (II) as well as all related formulae may be combined with any other specific value for one or more of the variables A, B. C, D, X, Y, R . k . R R . R ^" . i m, n, p, and q the same as if each and every combination were specifically and individually listed

[0047] In some embodiments of a compound of Formula (I), A is CfoCy cycloaikyl, 4- to 7 membered heteroeyclyl, 5- to 7-membered heteroaryl or C ₍ , aryl, each of which is unsubstituted. In some embodiments of a compound of Formula (I), A is CYC _& cycloalkyl, 4- to 7-membered heteroeyclyl, 5 to 7-membered heteroary! or C .·. aryl, each of which is optionally substituted with Ry In some embodiments of a compound of Formula (I), A is C ₆ aryl optionally further substituted with R In some embodiments of a compound of Formula (I), A is phenyl optionally substituted with R ^' . In some embodiments of a compound of Formula (I), A is 5-· to 7-membered heteroary! optionally further substituted with Ry In some embodiments of a compound of Formula (I), A is selected from the group consisting of pyridine, pyrimidine, pyrazolyl, ihiazolyl, oxazolyl, isooxazolyl or imidazolyl, each of which is optionally substituted with Ry In some embodiments of a compound of Formula (I), A is 4- to 7-membered heteroeyclyl, optionally further substituted with R In some embodiments of a compound of Formula (I), A is piperidmyi, pyrrolidmyl, azetidmyi, dihydropyridme, or pyndone, each of optionally substituted with R . In some embodiments of a compound of Formula 0 ), A is CfoCV, cycloalkyl substituted with Ry In some embodiments A is cyclohexyl or cyclopentyl, each of optionally substituted with Ry In some embodiments of a compound of Formula 0 ), A is phenyl, pyridine, pyrimidine, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, imidazolyl, piperidinyl, pyrrolidinyb azetidinyi, pyridone, cyclohexyl, or cyclopentyl, each of which is unsubstituted. In some embodiments of a compound of Formula (I), A is phenyl, pyridine, pyrimidine, pyrazolyl, dnazolyl, oxazolyl, isooxazolyl, mudazo!yi, piperidinyl, pyrrolidinyl, azetidmyl, dihydropyridine, pyridone, cyciohexyl, or cyclopentyl, each of which is optionally substituted with R .

[0048] In some embodiments of a compound of Formula (I), B is hydrogen, CO

C ₆ cyeloaikyi, 3- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, or C ₆ aryl, each of which is optionally substi tuted with R" In some embodiments of a compound of Formula (I), B is C Ce cyeloaikyi, ' · to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, or C _¾ aryl, each of which is unsubstituted. In some embodiments of a compound of Formula (I), B is hydrogen. In some embodiments of a compound of Formula (I), B is 3- to 7- membered heterocyclyl optionally substituted with R ^u . In some embodiments of a compound of Formula (I), B is diazepanyi, azepanyl, piperazinyl, piperidinyl, pyrrolidinyl or azetidinyl, each of which is optionally substituted with R7 In some embodiments of a compound of Formula (I), B is 5- to 7- membered heteroaryl optionally substituted with R” In some embodiments of a compound of Formula (I), B is imidazolyl or pyrazolyl . each of which is optionally substituted with R° In some embodiments of a compound of Formul (1), B is phenyl optionally substitu ted wi th R7 In some embodiments of a compound of Formula (I), B is cyeloaikyi optionally substituted with R”. In some embodiments of a compound of Formul (1), B is eyciopentyl. cyciohexyl, or cyeloheptyl, each of which is optionally substituted with R” In some embodiments of a compound of Formula (I). B is hydrogen, diazepanyi, azepanyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, imidazolyl, pyrazolyl, phenyl, cyclopentyl, cyciohexyl, or cyeloheptyl, each of which is unsubstituted In some embodiments of a compound of Formula (I), B is hydrogen, diazepanyi. azepanyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, imidazolyl, pyrazolyl, phenyl, eyciopentyl, cyciohexyl, or cyeloheptyl, each of which is optionally

substituted with 117

[0049] In some embodiments of a compound of Formula (I), L is a bond, 4 1 1 -. -NH-, -<)·. - S-, -SO _?. -, -CO-, -NCHv-, -Si¾NH-,of -NHSO - In some embodiments of a compound of Formula (I), L is a bond, -O F-·, -Nil-·, - () , or -S-. In some embodiments L is a bond. In some embodiments, L is ·( 1 1 ·· In some embodiments, L is -Nil·-. In some embodiments, L is -S-. In some embodiments L is -0-. In some embodiments, L is -SO-··. In some embodiments, L is -CO-. In some embodiments, L is -\( 1 1 ·· In some embodiments, L is -NHSO -. In some embodiments L is -f n ^{: :} R ^: · In some embodimetns, L i -NRt'Y In some embodimeins, L is X R SO ·· In some embodimetns, L is -SO \R ^{: '} · In some embodiments, L is -SCFNFF

[0050] It is understood that any description of A for Formula (I) may be combined with any description of B and L for formula (I), the same as if each and every combination were specifically and individually listed

[00SI] In some embodiments of a compound of Formula (II), D is fused with C to form a 7- 12 membered bicyclic rmg having at least one aromatic ring, wherein C and D are optionally substituted with R; ^s and R". In some embodiments of a compound of Formula (II), D is fused with C to form a 7-12 membered bicyclic ring having at least one aromatic ring and at least one heteroatom selected from the group consisting of N, O, and S, wherein C and D are optionally substituted with R and Rf In some embodiments of a compound of Formula (II), D is fused with C to form a 7-12 membered bicyclic r g having at least one aromatic rmg and at least one nitrogen atom, wherein C and D are optionally substituted with R and R7 In some embodiments of a compound of Formula (H), D is fused with C to form a 7-12 membered bicyclic r g ha ving at least one aromatic rmg and at least one nitrogen atom, wherein C and D are optionally substituted with R and R”

[0052] In some embodiments, provided is a compound of Formula (FA),

or a salt thereof, wherein A, B. X, Y; If RF R7, IF, R . R ^: . 1, m, n, p, and q are as detailed herein for Formula (1).

[0053] In some embodiments, provided is a compound of any one of Formula (I-Bi) to (F B12), or a salt thereof 10054 some eni ocuments, rovjoed is any one oiformula (I-- I s to (I-

or a salt thereof w herein X, Y, Rf R:f R’, R ^" . k . 1C K . 1, m, n, p, and q are as described herein for Formula 0 } and t and f are each independently 0 1 2, or 3. In some embodiments, t is 0. In some embodiments, t is 0 or 1 In some embodiments, t is 0, 1, or 2. In some embodiments, f is 0. In some embodiments, f is 0 or 1. In some embodiments, f is 0, I , or 2.

[0055] In some embodiments of a compound of Formula (I), k is hydrogen, Cr-(Y alkyl, (b-· ( .. cycloalkyl, ( {0)R each of which (except hydrogen) is optionally substituted by halogen, oxo, -OR ⁱ³ , YR foFF -C(G)R ¹³ , -CN, ··{( ; ·( alkylene)OIl ^{! 5} , -(C _r C ₃ alkylene)NR¾ ^;4 , ··{ (>

(b alkylsne)C(0)R ^: b (b-Cs cycloalkyl, or C -Cb alkyl optionally substituted by oxo, -OH or halogen. In some embodiments of a compound of Formula (I), R is hydrogen, methyl, ethyl isopropyl, cyclopropyl, ·( (OKI CO 101 K or --CIFCFbOFI.

[0056] In some embodiments, provided is a compound of Formula (II):

ill),

or a salt thereof, wherein C--D, X, Y, k . R . R \ 1C Ry Ry !,, nr n, p and q are as described for Formula (11).

[0057] in some embodiments of a compound of Formula (1), Formula (1). or Formula (11), X is N and Y is N. in some embodiments of a compound of Formula (J), Formula (1), or Formula (II), X is N and Y is CH In some embodiments of a compound of Formula (J), Formula (i ), or Formula (31), X is CH and Y is N.

[0058] in some embodiments of a compound of Formula (J), Formula (1), or Formula (11),

R ^: is hydrogen, Ci-Cf, alkyl, C _2~ C ₆ alkenyl, C alkynyi, C -Cg alkoxy, Cf-Cf cycloalkyl, 3-- to 12-membered heterocyclyl, 5- to 10-membered heteroaryi, Cf-Cfo aryl, -C(0)R ^1,J , -(Cj- (F alkylsneXCF-Ck cycloalkyl), -((h-CF alkylene)(3- io 12-membered heterocyciyl), -ICi- CF a!kylene)(5- io lO-membered heteroaryl) or -(CF-CF alkylene)((VCi4 aryl), each of which is optionally substituted by halogen, oxo, --OR ¹ ', · ( ^' ; () ; NR ^{J J} R ^{i ÷} , -\R ^! FC F -C(G)R ^J k -CN, C -CF cycioa!ky!, or Cj-Ck alky! optionally substituted by oxo, -OH or halogen in some embodiments of a compound of Formula (I), Formula (I), or Formula (II), R: is hydrogen, C -Cg alkyl, Cr C ₆ cyeloaikyl, 3- to 12-membered heterocyciyl, 5- to 10-membered heteroary!, Ck- C ₄ aryl, - membered heterocyciyl), -(Ci-CF aikylene)(5- to 10-membered heteroaryl) or -{CrC _? alkylene)(C _6~

Ci4 aryl), each of which is unsubstituted in some embodiments of a compound of Formula (J), Formula (I), or Formula (II), R is CF-Ck alkyl, Cg-Cg alkenyl, O _.y Ck alkynyi, Ck-Cg a!koxy, CF- C _¾ cycloalkyl, 3- to 12-membered heterocyciyl, 5- to 1 0-membered heteroatyl, C .·.··( aryl, ~(Cy (F aiky!eneXCF-Ck cyeloaikyl), -C(0)R ^l F or -(CrC-g alkylene)(C6-Cj4 aryl), wherein R; is independently optionally substituted by halogen, oxo, -OR ^{1 '} , -NR^RtF -C(0)R ^J , -CN, CF-Cg cyeloaikyl, or Cj-Cs alky! optionally substituted by oxo, -OH or halogen. In some embodiments of compound of Formula (J), Formula (I), or Formula (II), R ¹ is CF-Ck alkyl, CF-Ck alkenyl, CF- (k aikyny!, CF-Cg aikoxy, Ck-Ck cyeloaikyl, 3- to 12-membered heterocyciyl, 5- to 10-membered heteroatyl, ( .·.·( aryl, or -Ci())R ⁱ , wherein IN is independently optionally substituted by halogen, oxo, -CN, C ₃ -C ₃ cyeloaikyl, or CF-Ck alkyl optionally substituted by oxo, -OH or halogen. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), k ^' is hydrogen, CF-Ck alkyl, -C(())R F'F, -(CF-Cg a!kyleneXCF-Ck cyeloaikyl). -· CF-CF aiky!ene)(5- to 10-membered heteroaiyl), or CF-Ck cyeloaikyl, each of winch is optionally substituted with halogen, oxo, -NFL· In some embodiments, R ^' is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyk cyclohexyl or cyclopropyl-methyl. In some embodiments, RF is isopropyl. In some embodiments of a compound of Formula (J), Formula (I), or Formula (ΪI), R ^! is CF-Ck alkyl.

[0059] In some embodiments of a compound of Formula (J), Formula (I ), or Formula (II), RF i selected from the group consisting of

wherein the wavy lines denote attachment points to the parent molecule. 100601 In some embodiments, R ^l is selected from the proup consisting; of

wherein the wavy lines denote attachment points to the parent molecule. In some embodiments,

[0061] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), n is 0. In some embodiments, n is 0 or 1. In some embodiments, n is 0 1 or 2. In some embodiments, n is 0 1 , 2, or 3.

[0062] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), each IF is independently C -Ce alkyl oxo, -NR ^{1 :} R ^: l --CN, or halogen. In some embodiments, each K is independently O.-Cs alkyl, oxo, or halogen. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), IF is oxo. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), Ef is -Nl E f In some embodiments of a compound of Formula (I), Formula (I), or Formula (II), E is -CN. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), K is -C(0}IFl In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), K is halogen, such as flu or o. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II). 11 is -Ce alkyl, preferably methyl or dimethyl attached to the same carbon. In some embodiments of a compound of Formula ( J), Formula (I), or Formula (II), groups ol !< (such as when more than one R is present) are oxo and methyl, independently attached to two different carbons In some embodiments of a compound of Formula (J). Formula (I), or Formula (II), groups of R are oxo and dimethyl, each independently attached to two different carbons. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), groups of Kf are oxo and -CN, each independently attached to two different carbons. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), groups of R are oxo and ·· \ R ^{: :} M ^: each

independently a ttached to two different carbons In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), groups of it are oxo and -C(G)R ⁱ ' ^J , each

independently attached two different carbon. In some embodiments of a compound of Formula (J). Formula (I), or Formula (II), groups of R are oxo and -C(0)NR"R ^,‘ \ each independently attached to two different carbons. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), groups of " are difluoro attached to the same carbon. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), groups of a are oxo and fluoro or difluoro, each independently attached to two different carbon In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), R is H

[0063] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), rn is 0 In some embodiments, rn is 0 or 1. In some embodiments, rn is 0. 1 , or 2 In some embodiments, m is 0, 1 , 2, or 3 In some embodiments, m is 0, 1, 2, or 3, provided that at least one of m and 1 is not 0

[0064] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), each R:’ is independently Ch-CR alkyl, CV( .·. cycloalkyl, (VCg haloalkyh CrCfe alkoxy, C _{; ~} C,. haloalkoxy, halogen, or -Oi . In some embodiments each R:’ is independently CVC ₆ alkyl, C ₃ - CuCs haloalkoxy or halogen. In some

embodiments, each k is independently fluoro, chloro, methyl, tnfluoromeihy! triiluoromethoxy, methoxy, and cyclopropyl In some embodiments, R ^' is halogen.

[0065] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), 1 is 0. In some embodiments, I is 0 or 1. In some embodiments, 1 is 0, 1 , or 2. In some embodiments. 1 is 0, 1 , 2, or 3 In some embodiments, 1 is 0, 1 , 2, or 3, provided that when Z is

oxo, then at least one of m and 1 is not 0. In some embodiments, 1 is 0, 1, 2 , or 3, provided that at least one of m and 1 is not 0.

[0066] In some embodiments of a compound of Formula (J), Formula (I), or Formula ( I), each R ^'* Is independently CR-Ck alkyl, CR-CR cycloalkyl, CR-CR haloalkyl, CR -CR alkoxy, ( ; ·( .· baloalkoxy, halogen, or -OH. In some embodiments each R ^' " is independently CVCR alkyl, CR- CR cycloaikyl, (R-Ck haloalkyl, V-Ck a iko . CR -CR haloalkoxy or halogen. In some

embodiments, each R ^" is independently fluoro, chloro, methyl, tnf!uoromeihy!, trifluoromethoxy, methoxy, or cyclopropyl. In some embodiments, IR is halogen.

[0067] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), each Rf and R ^“ is independently CR-CR alkyl, CR-CR cycloaikyl (R-(R haloalkyl, CR-CR alkoxy, CR -CR baloalkoxy, halogen, or -OH and 1 and m are independently 0, 1 , 2 or 3. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), each

R ^' and R ⁴ is independently CR -CR alkyl, (R-(R cycloaikyl, CR-CR haloalkyl, (R-CR alkoxy, CR -CR baloalkoxy, halogen, or -OH and 1 and are independently 0, 1 , 2 or 3, provided that when Z is

oxo, then at least one of m and 1 is not 0. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), each

R:’ and IF is independently CR Ck alkyl, <k~(k cycloaikyl CR-CR haloalkyl, CR-CR alkoxy, CR-CR baloalkoxy, halogen, or -OH and 1 and rn are independently 0, 1 , 2 or 3, provided that at least one of m and 1 is not 0. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), R ^' and R ⁴ are halogen. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), Rf is F and Rf is Cl. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), Rf is Cl and R ⁴ is F In some embodiments, both Rf and Rf are F [0068] in some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is CH; Y is N; and R and R ^' are independently Cr-CY alkyl, CYCf cycloalkyl, CVCf, haioalkyl, CrC _fj aikoxy, (YCff haloalkoxy, halogen or -OH. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is CH; and

R ^J and R ⁴ are independently hydrogen, Cr V, alkyl, (YC.·. cycioalkyi, (YCY haloalkyi, (YC·. alkoxy, CrC ₆ haloalkoxy, halogen or -OH. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is N; and Rf and IX are independently hydrogen, (YC.. alkyl, (YC.·. cycloalkyl, (YCY haloalkyi, C Ck alkoxy, C CY ha!oalkoxy, halogen or -OH.

[0069] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is CH; Y is N; R is F; and R ^'4 is F. In some embodiments of a compound of Formula (J),

Formula (I), or Formula (II), X is N; Y is CH; K ^' is F; and R ^" is F. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N, Y is N; R ^J is Cl; and R ^" is F. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is N, Ef is F; and R ^“ is Cl In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is CH: Y is N; E; is Cl; and R ^'4 is F In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is CH; Y is N: R ^' is F; and R ^" is Cl In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is CH; R is Cl; and R ⁴ is F In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is CH; R is F; and R ^" is Cl In some embodiments of a compound of Formula (J), Formula (I), or Formula (Hi X is N; Y is N; K is F; and R ⁴ is F

[0070] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is CH; Y is N; R is F and R ⁴ is F, and each k is independently hydrogen, Ci-Cf alkyl, oxo.

-CN, C(0)KY\ C(())NR R ⁱ or halogen. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is CH; Rf is F and R ⁴ is F; and each R is independently hydrogen, C -C _f , alkyl, oxo. --NR ^{! !} R ^lz , -CN, -C(0)R ^l \ ~C(O)NR”R ^: or halogen. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N, Y is N; K is F and R is F, and each R" is independently hydrogen, (Y(Y alkyl, oxo -NRXRY

CN, -C(0)R”', -C(())NR R ^Z or halogen In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is N; IN is F; R is F, and each R" is independently F, wherein each F is attached to same carbon or two different carbons. In some embodiments of a compound of Formula (I), Formula (I) or Formula (11), X is N; Y is N: IX is F, R ⁴ is F; and each

R is independently CYC ^' s alkyl, preferably methyl, each methyl attached to same carbon or two different carbon. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is N; R is F; IX is F; each k is oxo or methyl, each of winch is attached to two different carbons. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is N; R is F; IX is F; and each R ² is oxo or F, winch are attached to two different carbons. In some embodiments of a compound of F ormula (J), Formula (I), or Formula (11), X is N; Y is N; R ³ is F; R ⁴ is F; IX is oxo. In some embodiments of a compound of Formula (J), Formula (1), or Formula (II), X is N; Y is N; K ^' is F; k ^: is F; each R is independently hydrogen.

[0071] in some embodiments of a compound of Formula (I), Formula (1), or Formula (11), X is N; Y is N; each R ^J and R ⁴ is independently Cj-Q, alkyl, CYC.· cycioalky!, CrCs haloalkyi, CY C hko.w CYCf haloa!koxy, halogen, or -OH; each IX is independently hydrogen, Cj-Q, alkyl, oxo, -Nl MX . -CN, Ύ O ΪK Y ·( (0)NR ^{: S} R or halogen, any two R:" groups are independently attached to same carbon or two different carbon, and R ^; is hydrogen, C C _¾ alkyl, CYCs alkenyl, CYCr aikynyi, CrCg aikoxy, ( ^" ;··( ^" .·. cycioalkyl, 3- to 12-membered heterocyelyl, 5~ to 10- membered heteroaryl , CY ^' .Y ami, -C(0)R ¹¹ ', -(CYCF al Y !ene)((h-(f. cycioalkyl), ··(( ^' ;··

Ci aikyiene)(3- to 12-membered heterocyelyl), -(Cj-C; _? aiky!ene)(5~ to 10-membered heteroaryi) or (CYCfe alkylene)(C6 Ci4 awl), each of which is optionally substituted by halogen, oxo, -OR Y ~G(Q) NR ¹⁵ R ¹⁴ , -NR¾ ^;4 , -C(0)R ¹³ , -CN, C ₃ --C ₃ cycioalkyl, or Ci-C ₆ alkyl optionally substituted by oxo, -OH or halogen

[0072] In some embodiments of a compound of Formula (J), Formula (I), or Formula (11), X is CH, Y is N; each k and k ^" is independently Ci~C ₆ alkyl, CYC's ey chalky I, C ^' _: haiouikvi

Ci-CX alkoxy, CYCs haloalkoxy, halogen, or -OH, each IX is independently hydrogen, ( ^' ; ·( .·. alkyl, oxo, -NR ^{: :} RY -CN, ~C(0)RX', -( (OY ^' !< ^' or halogen, any two R groups are independently attached to same carbon or two different carbon; IX is Cs-Cfe alkyl CY

cycioalkyl, 3·· io 12-membered heterocyelyl, alkylene)((YCs cycioalkyl),

-(CYCh alky!ene)(3- to 12-membered heterocyelyl), or -XYC- alkyiene)(Cs-Ci4 aryl), each of winch is optionally substituted by halogen, oxo, -OR ^{1 '} ’ -C(O) NR’ ^{^} R' , -NR^R' ⁴ , -C(0)R ^{1 '} ,

-CN, CYCg cycioalkyl, or CYC ^' s alkyl optionally substituted by oxo, -OH or halogen . [0073] in some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is CH; each R ³ and R ⁴ is independently (Y-CY alkyl, G · ⁽ ), cycloalkyl. CVC ₆ haloalkyl, CrC _fj aikoxy, CY-CY haloalkoxy halogen, or -OH: each k is independently hydrogen, CYiY alkyl, oxo, or halogen, any two K groups are independently attached to same carbon or two different carbon: R ¹ :s C C^ alkyl, CY

C ₆ cyc!oalkyi, 3- to 12-membered heterocyclyl, -C(Q)R ^U ', -(CYCF alkyleneXCY-CY cycloalkyl), -(CYCk alkylene)(3- to 12-member ed heterocyclyl), or -(CYCY alkylene)(C6-Ci4 aryl), each of which is optionally substituted by halogen, oxo, -Ok ·( <;0) NRYRY -.YR ^{: '} R ^: -C(0)kY -CN. C -C _¾ cycloalkyl, or CYCk alkyl optionally substituted by oxo, -OH or halogen.

[0074] in some embodiments of a compound of Formula (I), Formula (I), or Formula (II), X is N; Y is N; each and R ⁴ is independently F; each R is independently hydrogen, CYCY alkyl, oxo, -\R ^{: :} R ^: . -CN, -C(0)R ^;' c -C(Q)NR ^l ¾N or halogen, any two k groups are independently attached to same carbon or two different carbon; R ¹ is hydrogen, CYC), lkyl ( ^' ·· ( ^' ·. alkenyl, C^- Cs aikynyl, Cj-Cg alkoxy, C CY cycloalkyl, 3- to 12-mem bered heterocyclyl, 5- to 10-membered heteroaryl, ( ^' .·.··( ^' ·. aryl, -(C C ₃ alkyleneXCY-CY cycloalkyl), -(Cj-C ₃ alkyl ene)(3- to 12- membered heterocyclyl), ··(( ^' ;··( ·. alkylene)(5- to 1 0-membered beteroaryl) or

(CrY alkylene)(C6-Cj4 awl), each of which is optionally substituted by halogen, oxo, -OR ^: - C(O) NR ^iJ E: ^l Y ~NR’ ^’ R ⁴ , -C(0)R‘Y -CN, Cj-Cg cycloalkyl, or Ci-C ₆ alkyl optionally substituted by oxo, -OH or ha logen.

[0075] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is N; each R and R is independently F; each R is independently hydrogen, CY-CY alkyl, oxo, -CN, -C(0)R ^l Y -C(0)NR“R‘ or halogen, any two R groups are independently attached to same carbon or two different carbon; R ¹ is CYCY alkyl, cycloalkyl, 3- to 12- membered heterocyclyl, -(( ; ·( . alkyleneXCY-CY cycloalkyl), -(CYC ₃ alkylene)(3- 10 12- mem bered heterocyclyl), or -(C -CY a!ky!eneXCYCY aryl ) each of which is optionally substituted by halogen, oxo, -OR ⁱ³ ’-C(0 NR% ³ Y --NR ¹³ R ⁱ⁴ , -CtOjR ¹³ , -CN, C ₃ -C ₈ cycloalkyl. or Cr-(Y alkyl optionally substituted by oxo, -OH or halogen.

[0076] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N: Y is N; each R ^' and R ⁴ is independently F; each IN is independently hydrogen or Y ··( ^' .·. alkyl, any two R" groups are independently attached to same carbon or two different carbon. IX is Ci-C _ft alkyl, (¾ (¾ cycloalkyl, 3- to 12-tnembered heterocyclyl, -(CrCX alkyleneKCh-CR cycioalkyl), -{Cr-CR aikylene)(3- to 12-membered heterocyclyl), or -(Ci-CR aik iene)(CR~

C aryl), each of which is optionally substituted by halogen, oxo, ~0R ^{! ,} ' -C(0) Mi ^: !X R N R ^" R ^: \ ~C(0)R' y -CN, CR-CR cycioalkyl, or CR-CR alkyl optionally substituted by oxo, -OH or halogen

[0077] in some embodiments of a compound of Formula (I), Formula (I), or Formula (II), X is N; Y is N; each R3 and R is independently F; each R is independently hydrogen or C -CR alkyl, any two IX groups are independently attached to same carbon or two different carbon;

R ^J is (R-CR alkyl, (R-Ce cycioalkyl, -(CrCR alkyieneXCR-CR cycioalkyl) or -(Ci-CR alkylene)((R- Cj aryl), each of which is optionally substituted by halogen, oxo, -OR -C(O) N R ^' R .

-NR ^l ¾X, ··( ^' ·; OdF ^' -CN, (R-CR cycioalkyl, or (R-CR alkyl optionally substituted by oxo, -OH or halogen.

[0078] In some embodiments of a compound of Formula (J), Formula (1), or Formula (II), X is N; Y i N; each R ^' and IX is independently F; each IX is independently hydrogen or CR-C .·. alkyl, any two R groups are independently attached to same carbon or two different carbon;

R ^! is C C _o alkyl, (VO· cycioalkyl or -(CR-CR alkyiene)(C-rC ₆ cycioalkyl), each of which is optionally substituted by halogen, oxo, ~OϊC -NR ^)J R ^1'* or CR-CR alkyl optionally substituted by oxo, -OH or halogen.

[0079] In some embodi ments of a compound of Formula (I), Formula (1), or Formula (II), X is N; Y is N; each " and ' is independently F; each R" is independently hydrogen, R ⁴ is CR CR alkyl or CRCR cycioalkyl, wherein R ^! is independently optionally substituted by halogen, oxo, -OR ^1J ’ tiN!IXtiX ⁴ or ( ; ·( .· alkyl optionally substituted by oxo, -OH or halogen in some embodiments of a compound of Formula (J) Formula (I), or Formula (II),, X is N; Y is N; each R ^:' and R ^' is independently F; each IX is independently hydrogen; IX is CR-CR alkyl, wherein R is independently optionally substituted by halogen, oxo, -O!X -MX ^' R ^{: !} o CR-CR alkyl optionally substituted by oxo, -OH or halogen. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is N; each R ^' and !XMs independently F, each R" is independently hydrogen; ^' is selected from the group consisting of

^ o

wherein the waw l ines denote attachment points to the parent molecule. In some embodiments of a compound of Formula O) Formula (ip or Formula 01) X is N; Y is N; each Rf and R ^' is independently F; each FT is independently hydrogen; R ^J is selected from the group consisting

wherein the wavy lines denote attachment points to the parent molecule. In some embodiments of a compound of Formula (3), Formula (1), or Formula (II), X is N; Y is N; each R; and 1C is independently F; each R" is independently hydrogen; R ⁵ is (VO. aim f

[0080] in some embodiments of a compound of Formula (J), Formula (I), or Formula (II), p is 0. In some embodiments of a compound of Formula (I), Formula (I), or Formula (II), p is 0 or 1. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), p is 0, I, or

[0081] In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), each R ^' is independently (VCy alkyl, halogen, oxo, ~CN, -OR ⁿ ', NR ^{! !} R y -C(0)R ^;,! ,

-C(Q)NRYR ^l , ( ^' :··( .·. cycloalkyl, 3- to 12-membered heterocyciy!, -(CrC ₃ alkylene)OR ^i' , -(( · ·

& alkylene)NR ⁵⁵ R ¹² , -(Ci-C ₃ alkylene)C(0)R ⁵⁰ , -(Ci-C ₃ alkylene)(C-rC ₆ cydoalkyl), -(C alkylene)(3- to 12-membered heterocyclyl), each of which is optionally substituted by halogen, oxo, -OR ¹³ , alkylene)OR ^{S 3} , ··(( ^' ;··

(F alkylene)NE ^iJ K Y -KV alkylene)C(0)K ^iJ , C3-C3 cydoalkyl, or C G, alkyl optionally substituted by oxo, -OH or halogen. In some embodiments each R^ is independently -CN, halogen, methoxy, oxo, trifluoromethoxy, -NH(CH ₃ ), -N(CH ₃ ) ₂ , (CFFINHtCFF), ~(CH ₂ )NH ₂ ,

(CH ₂ )N(Q¾) ₂ , -C(0)NI¾, -C(0)N(Cål ₃ ) ₂ , methyl, ethyl, isopropyl, cyclopropyl -CliFOH, - ( 1 FOCI | · N P( ⁽ l b ) L( ( l i Vf h p. -0(CH ₂ ) ₂ N(CH ₂ CH ₅ ) _? , or trifluoromethyl. In some embodiments, each k is independently -CN, halogen, methoxy, oxo, trifluoromethoxy, - NH(CIR), -NiCtR -(CH ₂ )NH(C¾), -(CH ₂ )NH ₂ , -(CH ₂ )N(C¾) ₂ , -C(0)N¾, -C(Q)N(CH _? } ₂ , methyl, ethyl, isopropyl, n-propyl, cyclopropyl, -

[0082] In some embodiments of a compound of Formula (J), Formula (I), or Formula (ΪΪ), q is 0 In some embodiments of a compound of Formula (J) Formula (I), or Formula (II), q is 0 or 1 In some embodiments of a compound of Formula (J), Formula (I) or Formula 01 ), q is 0 1 , or

·>

[0083] In some embodiments of a compound of Formula (J), Formula (I), or Formula (ID, each R" is independently ( ^' ···( ^' .·. alkyl, halogen, oxo, -CN, -NR ^{, ,} R , ~C(0)R ^:iJ , (Vi .. cycloalkyl, 3-- to 12-membered heterocyc!yi, ··· ( ^' ···( ^' , alkyleneiOR ¹ '’, o ( ^' · ··( ^' , ah- \Ίooo ·\ k ^{: :} u ^: . each of which is optionally substituted by halogen, oxo, --OR ^{1 '} , -NRARA -C(0)R \

-CN, -(C ₁ -C ₅ alkylene)OR ⁵ \ -(C ₁ -C ₅ aikylene)NR¾A -(C ₁ -C ₅ alkylene)C(0)R ^rj , ⁽ ·,·· ⁽ s cycloalkyl, or CrCk alkyl optionally substituted by oxo, -OH or halogen: or two R° groups when bound to the same carbon atom are iakon together with the carbon to which they are attached to form a Cv-Cb cycloalkyl hr some embodiments, each RAs independently ethyl, methyl, isopropyl, pyrrolidinyl, -N(C¾) ₂ , ·( 1 1 Oi ! oxo, -CiO _. -C 1 1 ·M !P 1 -( ^' P ·P 1 01 1 diflnoroethy!, -CH ₂ N(CH _? )2, -OH, or -C(Q)CH ₂ OH. In some embodiments, each IA is independently ethyl, methyl, isopropyl, pyrrolidinyl, cyclopropyl, methoxy, ·N; ( ^' P I · ·NP( l b. -CH ₂ OH, oxo, - C(0)CH ₂ NHCH ₃ -CH ₂ CH ₂ OH, dii!uoroethyl, ~a¾N(CH ₃ )x OH-NI k -OH, -C(0)CHA ⁾ H, - C(0)CH ₂ N(CH _? } ₂ , ·( tO)Nt ( = I b. -C(Q)NHC¾, -C(0)M _¾ -NHCtOjCHy -C(OjCH ₃ , -

[0084] In some embodiments of a compound of Formula (I), A, L and B together with Kf and R° are selected from the group consisting of:

wherein the wavy lines denote attachment points to the parent molecule and K is as described herein It is understood that each description of A and B may be combined with each description of X, Y. R ^z , R Ed, A . kh 1, m, n. p, and q the same as if each and every combination were

10085) In some embodiments of a compound of Formula tl). A and B together with R” and R ^' are selected from the group consisting of

SO

[0088] In some embodiments of a compound of Formula (II), C-D are selected from the srouo consisting of

7

r ¾}&r¾}&G^ ana t

[0093] It is understood that each description of C-D may be combined with each description of X, Y lib R\ R ^' . k ^' . R ^" . 1, m n n and o the same as if each and every combination were specmcaiiv ana mamcmairv ustect [0094] Also provided are salts of compounds referred to herein such as pharmaceutically acceptable sails. The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described it is understood that individual enantiomers and diastereomers are provided herein and their corresponding structures can be readily determined.

[0095] A compound as detailed herein may m one aspect be m a purified form and compositions comprising a compound m purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. Unless otherwise stated, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurity. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3%, 2%, 1% or 0 5% impurity

[0096] Representative compounds are listed in Table 1.

Table 1

(V\

H

H

_^

8

]

X 7 ··· ^'

N ^’

8

88

A' ^' i

9

s

[0097] In some embodiments, provided herein are compounds described in Table i, or a tautomer thereof, or a salt of any of tbe foregoing, and uses thereof

[0098] The embodiments and variations described herein are suitable for compounds of any formulae detailed herein, where applicable.

[0099] Representative examples of compounds detailed herein, including intermediates and final compounds according to the present disclosure are depicted herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual

[0100} T he compounds depicted herein may be present as salts even if salts are not depicted an it is understood that the present disclosure embraces all salts and solvates of tire compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, die N-oxides are also provided and described.

[0101] Where tautomeric forms may be present for any of the compounds described herein, each and every' tautomeric form is i ntended even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant forms m solution or when used according to the methods described herein

[0102] The present disclosure also i ncludes any or all of the stereochemical forms, i ncluding any enantiomeric or diastereomeric forms of the compounds described. The structure or name is intended to embrace all possible stereoisomers of a compound depicted All forms of the compounds are also embraced by the invention, such as crystalline or non- cryst lline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-race ic mixture.

[0103] The invention also intends isotopicaliy-kbeled and/or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopioal!y-dabeied compound of the formula (I) or variations thereof described herein, where a traction of one or more atoms are replaced by an isotope of the same element Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon nitrogen, oxygen, phosphorus, sulfur, chlorine, such as Ί I . Ή, ^{, !} C, ^{l ,} C, fob °N, O. ^"' S, ^{: N} I . ^t Cl Certain isotope labeled compounds (e.g. ^“ H and ^l ) are useful in compound or substrate tissue distribution studies. Incorporation of heavier isotopes such as deu terium (Ή) can afford certain therapeutic advantages resulting from greater metabolic stability for example, increased in vivo half-life or reduced dosage requirements and, hence may be preferred in some instances.

[0104] Isotopically-iabeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-iabeled reagents in place of the corresponding non-iabeied reagent.

[0105] The invention also includes any or all metabolites of any of the compounds described. The metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.

[0106] Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, ·. v. bag, and the like.

[0107] Preferably, the compounds detailed herein are orally bioavai!abie. However, the compounds may also be formulated for parenteral (e.g, intravenous) administration.

[0108] One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various form In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.

General synthetic methods

[0109] The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used m the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.

[0110] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid

Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate m one of the processes described.

[0111 j Chromatography, recrystaliization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a pro uct of a reaction.

[0112] Solvates and/or polymorphs of a compound provided herein or a salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometnc amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol Polymorphs include the different crystal packing arrangements of the same elemental composition of compound Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystaliization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate

[0113] In some embodiments, compounds of the Formula (I) or (II) may be syn thesized according to Scheme I .

Scheme 1

wherein A. _, B, C, D L, X. Y; IF . K . i< . k\ k ^' . R ^> ; 1. _, m, n, p and q are as described for Formula (J| Formula (I), or Formula (ll) .

Scheme 2

wherein A, B, C, D, L, X, Y; R’, R\ k ^' p and q are as described for Formula (J), Formula (I), or Formula (11). Scheme 3

wherein A, B, C, D, L, X, Y; R’, R\ R ^' p and q are as described for Formula (J), Formula (I), or Formula (11).

Scheme 4

wherein A. B, C, D, L X, Y; R ^: , R\ R:\ R ^" ; p and q are as described for Formula (J). Formula (I), or Formula (II) Scheme 5

wherein A, B, C, D, L. X Y; R\ R\ R\ R°; p and q are as described for Formula (J) _s Formula

AX x> x UiiA> ta sfca i Scheme 7

wherein A, B. C, D, L, X, Y; Rl Rl R . R°; p and q are as described for Formula (J), Formula (I), or Formula (II). Particular examples are provided in the Example Section below.

Pharmaceutical Compositions and Formulations

[0114] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral nasal, topical or rectal administration or a form suitable for administration by inhalation.

[0115] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.

[006] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier in another variation, methods of administering a compound are provided The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein

[01 17] A compound detailed herein or salt thereof may be formulated for any available delivery route including an oral, mucosal (e.g., nasal, sublingual, vaginal buccal or rectal), parenteral (e.g; , intramuscular, subcutaneous or intravenous), topical or transdermai delivery form A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g; , nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0118] One or several compounds described herein or a salt thereof can be used m the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermai patch vs. oral tablet), the carrier may be in various forms. In addition,

pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emu!gators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations ma be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g; , in Remington b Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 ^U ed. (2000), which is incorporated herein by reference.

[0119] Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, tale stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emuigators, sweeteners dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0120] Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a salt thereof can be formulated as a 10 mg tablet.

[01211 Compositions comprising a compound provided herein are also described In one variation, the composition comprises a compound or salt thereof and a pharmaceutically acceptable earner or excipient. In another variation, a composition of substantially pure compound is provided.

Methods of Use

[0122] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of any formula provide herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays. In some embodi ments of the methods detailed herein, the methods comprise administration of a compound detailed herein, or a salt thereof, as a monotherapy.

[0123] Provided herein is a method of treating a disease in an individual comprising administering an effective amount of a compound of Formula (J), Formula (I), Formula (11), (F A). (I-Bl) to (I-B 12), (T-C 1 ) - (I-C23) or any embodiment, variation or aspect thereof

(collectively, a compound of Formula (J). Formula (I), Formul (II), (I- A), (FBI ) to (FBI 2), (I- Cl) - (FC23))or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, to the individual Further provided herein is a method of treating a proliferative disease in an individual, comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (I-Bl 2). (FC!) - (F C23), or a pharmaceutically acceptable salt thereof to the individual. Also provided herein is method of treating cancer in an individual comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2) (FC! ) - (FC23)or a pharmaceutically acceptable salt thereof to the individual. In some embodiments the compound is administered to the individual according to a dosage and/or method of

administration described herein

[0124] In some embodiments, the cancer in the individual has one or more mutations or amplification or overexpression of the genes encoding cyciins or of the genes encoding the CDK or loss of endogenous INK4 inhibitors by gene deletion, mutation, or promoter

hypermethyiation, or other genetic events leading to overactivity of one or more of CDK1,

CDK2, CDK4, CDK6 and CDK9. In some embodiments, the cancer in the individual has one or more mutations or amplification or overexpression of the genes encoding cyciins or of the genes encoding the CDK or loss of endogenous GNK4 inhibitors by gene deletion, mutation, or promoter hypermethyiation, or other genetic events leading to overactivity of CDK4/6 and one or more of CDK! , CDK2, and CDK9.

[0125] In some embodi ments, there is provided a method of treating a cancer in an individual, comprising (a) selecting the individual for treatment based on (i) the presence of phosphorylation of the retinoblastoma (RhJ protein in the cancer, or (il) presence of mutations or amplification or overexpression of CDK4 or CDK6 in the cancer, and administering an effective amount of the compound of Formula (J), Formula (i), Formula (II), (I- A). (FBI) to (FBI 2), (F Cl ) - (FC23), or a pharmaceutically acceptable salt thereof, to the Individual In some embodiments, the cancer is assayed for the expression of phosphorylated Kb. In some embodiments, the cancer is assayed for the expression of CDK4 or CDK6 In some

embodiments, the CDK4 or CDK6 gene of the cancer is sequenced to detect the one or more imitations or amplifications. In some embodiments, the CDK4 or CDK6 gene is sequenced by biopsymg the cancer and sequencing the CDK 4 or CDK6 gene Bom the biopsied cancer. In some embodiments, the CDK4 or CDK6 gene is sequenced by sequencing circulating- tumor DNA (ctDNA) from the individual.

[0126] In some embodiments provided herein is a method of using a compound of Formula (J) Formula (I), Formula (II), (I-A) (FBI ) to (FBI 2), (I-C! ) - (I-C23) or any embodiment in the manufacture of a medicament for treatment of a disease. In some embodiments, provided herein is a method of using a compound of Formula (J), Formula (I), Formula 0 ), (I-A), (FBI) to (f-B 12), (I -Cl) - 0-C23) or any embodiment in the manufacture of a medicament for treatment of cancer.

[0127] In some embodiments a compound of Formula (J), Formula (1), Formula (II) (I- A), (KB1) to (KB12), (I -Cl ) - (I-C23) or a salt thereof is used to treat an individual having a proliferative disease, such as cancer as described herein In some embodiments the individual is at risk of developing a proliferative disease such as cancer. In some of these embodiments, the individual is determined to be at risk of developing cancer based upon one or more risk factors.

In some of these embodiments, the risk factor is a family history and/or gene associated with cancer.

[0128] The present compounds or salts thereof are believed to be effective for treating a variety of diseases and disorders. For example, in some embodiments, the present compositions may be used to treat a proliferative disease, such as cancer. In some embodiments the cancer is a solid tumor. In some embodiments the cancer is any of adult and pediatric oncology, myxoid and round cell carcinoma, locally advanced tumors, metastatic cancer, human soft tissue sarcomas, including Ewing's sarcoma, cancer metastases, including lymphatic metastases, squamous cell carcinoma, particularly of the head and neck, esophageal squamous cell carcinoma, oral carcinoma, blood cell malignancies, including multiple myeloma, leukemias, including acute lymphocytic leukemia, acute non lymphocytic leukemia, chrome lymphocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia, effusion lymphomas (body cavity based lymphomas), thymic lymphoma, cutaneous T cell lymphoma, Hodgkin's lymphoma, non- Hodgkin’s lymphoma, cancer of the adrenal cortex, ACTH-producing tumors lung cancer, including small cell carcinoma and nonsrnal! cell cancers, breast cancer, including small cell carcinoma and ductal carcinoma, gastrointestinal cancers, including stomach cancer, colon cancer colorectal cancer, polyps associated with colorectal neoplasia, pancreatic cancer, liver cancer, urological cancers, including bladder cancer including primary superficial bladder tumors, invasive transitional eell carcinoma of the bladder, and muscle-invasive bladder cancer, prostate cancer, malignancies of the female genital tract, including ovarian carcinoma, primary peritoneal epithelial neoplasms, cervical carcinoma, uterine endometrial cancers, vaginal cancer, cancer of the vulva, uterme cancer and solid tumors in tbe ovarian follicle, malignancies of the male genital tract, including testicular cancer and penile cancer, kidney cancer, including renal cell carcinoma, brain cancer including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cell invasion in the central nervous system, bone cancers, including osteomas and osteosarcomas, skin cancers, including melanoma, tumor progression of human sk keratmocytes, squamous cell cancer, thyroid cancer, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms's tumors, gall bladder cancer, trophoblastic neoplasms, hemangiopericytoma, and Kaposi's sarcoma.

[0129] In some embodiments, the cancer is defined by a molecular characteristic in some embodiments, the cancer is an estrogen receptor-posistive breast cancer. In some embodiments, the breast cancer is triple negative breast cancer In some embodiments, the cancer is a KRAS- mutant non-small cell lung cancer. In some embodiments, the cancer is mantle cell lymphoma defined by a translocation involving CCND1 resulting in cyclic Di overexpression.

[0130] in some embodiments, the compounds and compositions described herein cause G -S cell cycle arrest in a cell (such as a cancer cell) in some embodiments, the cancer cell is a cancer cell from any of the cancer types described herein. In some embodiments, arrested cells enter a state of apoptosis. In some embodiments, arrested ceils enter a state of senescence In some embodiments, provided herein is a method of causing GrS checkpoint arrest in a cell comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), ( FA) (FBI) to (I-B12). (I-Cl) - (I-C23) or a pharmaceutically acceptable salt thereof, to the ceil in some embodiments, the G .-S cell cycle arrest occurs in about 40% or more, about 50% or more, about 60% or more, about. 70% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more of cells in a cell population In some embodiments, the (11: S cell cycle arrest occurs in up to about 99%, up to about 98%, up to about 97%, up to about 96%, up to about 95%, up to about. 90%, up to about 85%, or up io about 80% of cells in the cell population.

[0131] In some embodiments, provided herein is a method of inducing senescence in a cell comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FB12). (FCi ) - (FC23)or a pharmaceutically acceptable sail thereof, to the cell. In some embodiments, senescence is induced in about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 8091; or more, about 85% or more. about 90% or more, about 95% or more, about 96% or more, about 97% or more about 98% or more or about 99% or more of cells in a ceil population. In some embodiments senescence is induced in up to about 99%, up to about 98%, up to about 97%, up to about 96%, up to about 95%, up to about 90%, up to about 85%, or up to about 80% of cells m the cell population.

[0132] In some embodiments, provided herein is a method of inducing apoptosis in a cell comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), (I- A), (i-Bl) to (1-B 12), (I-Cl ) - (I-C23)) or a pharmaceutically acceptable salt thereof, to the cell in some embodiments apoptosis is induced in about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more of cells in a ceil population. In some embodi ents, apoptosis is induced in up to about 99%, up to about 98%, up to about 97%, up to about 96%, up to about 95%, up to about 90%, up to about 85%, or up to about 80% of cells in the cell population

[0133] In some embodiments, provided herein is a method of inhibiting CDK4 or CDK6 in a cell comprising administering an effective amount of the compound of Formula (J), Formul (I), Formula (II), ( FA) (ffBl) to (I-BI2). (I-Cl) - (I-C23) or a pharmaceutically acceptable salt thereof, to the cell. In some embodiments, CDK4 or CDK6 is inhibited by about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 75% or more, about 80% or more, about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more. In some embodiments, CDK4 or CDK6is inhibited up to about 99%, up to about 98%, up to about 97%, up to about 96%, up to about 95%, up to about 90%, up to about 85%, up to about 80%, up to about 70%, or up to about 60%. In some embodiments, the activity of CDK4 or CDK6 is measured according to a kinase assay

[0134] In some embodiments, provided herein is a method of inhibiting one or more of CDKi CDK2, CDK4, CDK6, and CDK9 in a cell comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), (I -A), (I-B1 ) to (I-B12), (I-Cl) -- (I- C23) or a pharmaceutically acceptable salt thereof to the cell. In some embodiments, one or more of CDKI, CDK2, CDK4, CDK6, and CDK9 is inhibited by about 10% or more, about 20% or more about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 75% or more, about 80% or more, about 907b or more about 95% or more, about 967b or more, about 977b or more, about 987b or more, or about 99% or more. Or some embodiments, one or more of CDK1 , CDK2, CDK4, CDK6, and CDK9 is inhibited up to about 997b, up to about 98%, up to about 97%, up to about 96%, up to about 95%, up to about 90%, up to about 857b, up to about 807b, up to about 707b, or up to about 607b In some embodiments, the activity of one or more of CDKl, CDK2, CDK4, CDK6, and CDK9 is measured according to a kinase assay.

[0I35| in some embodiments, provided herein is a method of inhibiting DK4 or DK6 comprising contacting CDK4 or CDK6 with an effective amount of the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FC1) - (FC23) or a pharmaceutically acceptable salt thereof in some embodiments, the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FB12), (FCi) - (FC23)or pharmaceutically acceptable salt thereof binds to CDK4 or CDK6 with an Kffo of less than 1 mM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM. less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 1 nM, or less than 0.5 nM In some embodiments, the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FCI) - (FC23)or a pharmaceutically acceptable salt thereof binds to CDK4 or CDK6 with an IC50 between 0.1 nM and 1 nM, between 1 nM and 5 nM. between 5 nM and 10 nM, between 10 nM and 50 nM, between 50 nM and 100 nM, beween 100 nM and 200 nM. between 200 nM and 300 nM, between 300 nM and 400 nM, betwee 400 nM and 500 nM, between 500 nM and 600 nM, betwee 600 nM and 700 nM, between 700 nM and 800 nM, between 800 nM and 900 nM, or between 900 nM and 1 mM. In some

embodiments, the ICM is measured according to a kinase assay hi some embodiments, the IC50 is measured according to a cell proliferation assay

[006] In some embodiments, provided herein is a method of inhibiting one or more of CDKl . CDK2, CDK4, CDK6, and CDK9 comprising contacting one or more of CDKl , CDK2, CDK4, CDK6, and CDK9 with an effective amount of the compound of Formula (J), Formula (I) Formula (II), (FA), (FBI ) 1° (FBI 2), (FCI ) - (FC23) or a pharmaceutically acceptable salt thereof In some embodiments, the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FC I ) - (I-C23) or a pharmaceutically acceptable salt thereof binds to one or more of CDK1 , CDK2, CDK4, CDK6. and CDK9 with an IC50 of less than 1 mM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less limn 500 nM, less than 400 n , less than 300 M, less than 200 nM less than 100 nM, less than 50 nM, less than 10 nM less than 5 nM, less than 1 nM, or less than 0 5 nM. In some embodiments, the compound of Formula (J), Formula (I), Formula (II), (I- A), (I-Bl) to (I-B12), (FCl) - (FC23)or a

pharmaceutically acceptable salt thereof binds to one or more of CDK1, CDK2, CDK4, CDK6, and CDK9 with an IC _¾ o between 0.1 nM and 1 nM, between I nM and 5 nM, between 5 nM and 10 nM, between 10 nM and 50 nM, between 50 nM and 100 nM, beween 100 nM and 200 nM, between 200 nM and 300 nM, between 300 nM and 400 nM, betwee 400 nM and 500 nM, between 500 nM and 600 nM, between 600 nM and 700 nM, between 700 nM and 800 nM, between 800 nM and 900 nM, or between 900 nM and 1 mM. In some embodiments, the IC50 is measured according to a kinase assay In some embodiments, the KM is measured according to a cell proliferation assay.

[0137] In some embodiments, provided herein is a method of modulating CDK4/6 in an individual, composing administering to the individual a compound of Formula (J). Formula (I), Formula (II), (I-A), (FBI) to (FBI 2). (I-Cl) - (I-C23) or a pharmaceutically acceptable salt thereof , or a salt thereof In some embodiments, provided herein is a method of modulating CDK4 and CDK 6 in an individual, comprising administering to the individual a compound of Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (I-Cl ) - (FC23) or a

pharmaceutically acceptable salt thereof , or a salt thereof In some embodiments, provided herein is a method of modulating CDK4/6 and one or more of CDK! , CDK2, and CDK9 in an individual, comprising administering to the individual a compound detailed herein, or a salt thereof In some embodiments, provided herein is a method of modulating CDK4 and CDK 6 and one or more of CDK1, CDK2, and CDK9 m an individual, comprising administering to the individual a compound detailed herein, or a salt thereof In some embodiments, the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FC1 ) - (I-C23) or a

pharmaceutically acceptable salt thereof binds to one or more of CDK4/6 with an KM of less than 1 uM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 1 nM, or less than 0.5 nM. In some embodiments, the compound of Formula (j), Formula (I), Formula (31), (FA), (FBI) to (FBI 2), (I-Cl) - (F C23) or a pharmaceutically acceptable salt thereof binds to one or more of CDK4 and CDK6 with an ICfe of less than 1 mM, less than 900 nM, less than 800 nM, less than 700 nVl less than 600 nM, less than 500 nM, less than 400 nM less than 300 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 1 nM, or less than 0.5 nM. In some embodiments, the compound of Formula (J), Formula (I), Formula (11), (I- A), (I-Bl) to (I- B12), ( 1-C 1 ) - (l-C23)or a pharmaceutically acceptable salt thereof binds to one or more of CDK1 , CDK2, CDK4, CDK6, and CDK9 with an IO _¾ between 0.1 nM and 1 nM, between 1 nM and 5 nM, between 5 nM and 10 nM, between 10 nM and 50 nM, between 50 nM and 100 nM, beween 100 nM and 200 nM, between 200 nM and 300 nM, between 300 nM and 400 nM, betwee 400 nM and 500 nM, between 500 nM and 600 nM, between 600 nM and 700 nM, between 700 nM and 800 nM, between 800 nM and 900 nM, or between 900 nM and 1 mM In some embodiments, the IC50 is measured according to a kinase assay. In some embodiments, the IC50 is measured according to a cell proliferation assay

[0138] In one embodiment, tire compound or a salt thereof may enhance tire antitumour immunity by increasing the functional capacity of tumour cells to present antigen or by reducing the immunosuppressive population by suppressing their proliferation.

[0139] In some embodiments, provided herein is a method of inhibiting the proliferation of cell, comprising contacting the cell with an effective amount of the compound of Formula (J), Formula (I), Formula (II), (I-A), (FBI) to (I-B12), (I-CI) - (I-C23) or a pharmaceutically acceptable salt thereof In some embodiments, the compound of Formula (J). Formula (I), Formula (II), (IA-) , (I-Bl) to (I-RI 2), (I--C1 ) - (I-C23) or a pharmaceutically acceptable salt thereof is effective in inhibiting the proliferation of the cell with an E(¾o of less than 5 mM, less than 2 mM, less than 1 mM less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM. less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM In some embodiments the compound of Formula (J), Formula (I), Formula (II), (I-A), (I-Bi) to (I-RI2), (I-CI) - (I-C23) or a pharmaceutically acceptable salt is effective in inhibiting the proliferation of the cell with an ECtio between 10 nM and 20 nM, between 20 nM and 50 nM, between 50 nM and 100 nM between 100 nM and 500 nM, between 500 nM and 1 mM, beween 1 mM and 2 mM, or between 2 mM and 5 mM. In some embodiments the EC50 is measured according to a cell proliferation assay. Combination Therapy

[0140] As provided herein, the presently disclosed compounds or a salt thereof may affect the immune system. Accordingly, the present compounds or a salt thereof may he used in combination with other anti-cancer agents or immunotherapies. In some embodiments, provided herein is a method of treating a disease m an individual comprising administering an effective amount of a compound of Formula (J), Formula (I), Formula (II), (I- A), (BBi) to (FBI 2), (I-CI) - (I-C23), or any embodiment, variation or aspect thereof (collectively, a compound of Formula (J), Formula (I), Formula (II), (ϊ-Ά), (FBI ) to (BBI 2), (BC1) - (BC23) or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent to the individual. In some embodiments, the second therapeutic agent is a cancer immunotherapy agent or an endocrine therapy agent or a chemotherapeutic agent In some embodiments, the disease is a proliferative disease such as cancer.

[0141] In some embodiments, the additional therapeutic agent is a cancer immunotherapy agent. In some embodiments, the additional therapeutic agent is an mimunostimulatory agent. In some embodiments, the additional therapeutic agent targets a checkpoint protein (for example an immune checkpoint inhibitor). In some embodiments, the additional therapeutic agent is effective to stimulate, enhance or improve an immune response against a tumor.

[0142] In another aspect provided herein is a combination therapy for the treatment of a di ease, such as cancer. In some embodiments, there is provide a method of treating a di ease in an individual comprising administering an effective amount of Formul (J), Formula (I), Formula (IT), (BA), (BBi) to (BB12), (I-CI ) - (BC23), or any embodiment, variation or aspect thereof (collectively a compound of Formula (J), Formula (Ϊ), Formula (II), (IA-) , (I-Bl ) to (I-B12) (B Cl ) - (BC23), or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, in combination with a radiation therapy.

[0143] In some embodiments there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (I- A), (BBI) to (BBI 2), (I -Cl) - (I-C23)or any embodiment, variation or aspect thereof

(collectively Formula (J), Formula (I), Formula (II), (I- A), (BBI) to (BBI 2), (I-CI) - (I-C23)) or a pharmaceutically acceptable salt thereof _, and (b) administering an effective amount of an endocrine therapy agent. In some embodiments, the endocrine therapy is antiestrogen therapy. In some embodiments, the endocrine therapy is a selective estrogen receptor degrader (SERB, such as fu!vestrant). In some embodiments, the endocrine therapy is an aromaiase inhibitor (such as letrozole). in some embodiments, the combination of a CDK4/6 inhibitor and endocrine therapy causes enhancement of Gl -S cell-cycle arrest. In some embodiments, the combination of a CDK4/6 inhibitor and endocrine therapy canses enhanced entry into a senescent state. In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (I-Bl) to (FB12), (I-Cl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co administered with the endocrine therapy agent. In some embodiments, Formula (J), Formula (I), Formula (II), (I-A), (FBI) to (I-BI2). (T-C 1 ) - (I-C23) or a pharmaceutically acceptable salt thereof is administered I or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the endocrine therapy agent.

[0144] in some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (I- A), (FBI) to (FB12), (FC1) - (FC23), or any embodiment, variation or aspect thereof

(collectively, Formula (J), Formula (I), Formula (II), (IA-) , (FBI) to (FB12), (1-0 ) - (FC23)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a second chemotherapeutic agent. In some embodiments the chemotherapeutic agent is another kinase inhibitor in some embodiments, Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FCI) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-admini tered with the second chemotherape tic agent. I some embodiments, Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCI ) - (I-C23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours 4 or more hours, 8 or more hours, 12 or more hours 24 or more hours, or 48 or more hours) prior to or after the second chemotherapeutic agent.

[0145] Examples of chemotherapeutic agents that can be used in combination with Formula (J), Formula (I), Formula til ), (FA), (FBI) to (FBI 2), (FCI) - (I-C23) or a pharmaceutically acceptable salt thereof include DNA-targeted agents, a DMA alkylating agent (such as cyclophosphamide, mechloretha me, chlorambucil, melphalan, dacarbazine, or nitrosoureas), a topoisomerase inhibitor (such as a Topoisomerase I inhibitor (e.g. irinotecan or topotecan) or a Topoisomerase II inhibitor (e.g., etoposide or teniposide)), an anihracyciine (such as

daunorubicin, doxorubicin, epirubiein, idarubicin, mitoxantrone, or valrubicin), a histone deaceiyiase inhibitor (such as vormostat or romidepsin), a bromodomain inhibitor, other epigenetic inhibitors, a taxane (such as paciitaxel or docetaxei), a kinase inhibitor (such as bortezomib, eriotinib, gefitinib. imatunb, vemurafenib, vismodegib, ibrutinib), an anti- angiogenic inhibitor, a nucleotide analog or precursor analog (such as azacitidine, azathioprrne, capecitabme, cytarabine, doxiflundine, 5-fluorouracil, gemcitabme, hydroxyurea,

mercaptopurine, methotrexate, or tioguanine), or a platinum-based chemotherapeutic agent (such as cisplatm, carboplatin, or oxaliplatin), pemetrexed, or a combination thereof. In some embodiments, there is provide a method of treating a disease in an individual composing (a) administering an effective amount of Formula (J), Formula (I). Formula (II), (I-A), (FBI) to (F B12), (FC1) - (FC23), or any embodiment, variation or aspect thereof (collectively, Formula (J), Formula (I), Formula (II), (I-A). (FBI) to (FBI 2), (I-Cl ) - (FC23)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a kinase inhibitor (such as bortezomib, eriotinib, gefitinib, imatimb, vemurafenib, vismodegib, or ibrutinib). In some embodiments, Formula (J), Formula (I), Formula (II), (I-A), (FBI) to (FBI 2), (I-Cl ) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co administered with the kinase inhibitor In some embodiments. Fomm!a (J), Formula (I), Formula (II) (I-A), (FBI) to (FBI 2), (I-Cl) - (I-C23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the kinase inhibitor.

[0146] lu some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (F A), (I-Bl ) to (FBI 2) (I-Cl ) - (I-C23), or any embodiment, variation or aspect thereof

(collectively, Formula (J), Formula (I), Formula (II), (I-A), (FBI ) to (FBI 2) (I-Cl ) - (FC23)) or a pharmaceutically acceptable salt thereof and (b) administering an effective amount of a DM A damaging agent. In some embodiments. Formula (J), Formula (I), Formula (H), (I-A), (F Bl) to (FBI 2), (I-Cl) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to after, or simultaneously co-admmistsred wife the DM A damaging agent. In some embodiments, Formula (J), Formula (I) Formula (ΪΪ), (FA), (FBI ) to (FB12), (I-Cl ) - (FC23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours 4 or more hours, 8 or more hours. 12 or more hours 24 or more hours, or 48 or more hours) poor to or after the DNA damaging agent

[0147] In some embodiments there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (/), Formula (I), Formula (II), (F A), (FBI ) to (I-Bl 2), (FCI) - (FC23)), or any embodiment, variation or aspect thereof

(collectively, Formula (/), Formula (I), Formula (II), (I-A), (I-Bl) to (I-Bl 2), (FCI) - (FC23)) or a pharmaceutically acceptable salt thereof) and (b) administering an effective amount of a DM A alkylating agent (such as cyclophosphamide, mechiorethamine, chlorambucil, meipha!an, dacarbazme, or nitrosoureas). In some embodiments, Formula (I), Formula (I), Formula (II), (I- A), (I-Bl } to (FB12), (DO) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-administered with the DNA alkylating agent.

In some embodiments. Formul (J), Formula (I), Formula (II), (DA), (FBI) to (FBI 2), (DO) - (DC23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the DNA alkylating agent.

[0148] In some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (I), Formula (I), Formul (II), (I- A) (I-Bl ) to (I-Bl 2), (DC! ) - (FC23), or any embodiment, variation or aspect thereof

(collectively, Formula (J) Formula (I), Formula (II), (FA) (I-Bl) to (I-Bl 2), (DC! ) - (FC23)) or a pharmaceutically acceptable salt thereof and (b) administering an effective amount of a topoisomerase inhibitor (such as a Topoisomerase I inhibitor (e.g. , irinotecan or topotecan) or a Topoisomerase II inhibitor (e.g. eioposide or temposide)). In some embodiments, Formula (J), Formula (I), Formula (II), (FA) , (FBI) to (I-Bl 2), (FCi ) - (DC23) or a pharmaceutically acceptable salt thereof is administered prior to after, or simultaneously co-administered with the topoisomerase inhibitor. In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (I- Bl) to (FB12), (FCI ) - (DC23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the topoisomerase inhibitor [0149] In some embodiments, there is provide a method of treating a disease m an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula 01 ), (F A), (FBI) to (FBI 2), (FCl } -- (FC23), or any embodiment variation or aspect thereof

(collectively, Formula (J). Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCl } -- (FC23)) or a pharmaceutically acceptable salt thereof and (b) admi nistering an effective amount of an anthracycline (such as daunorubicm, doxorubicin, epirubicm, idarubicm, mitoxantrone, or valrubicm). In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (FBI) to (F B12), (FCl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-administered with the anthracycline. In some embodiments, Formula (J), Formula (I), Formula (II), (IA~) , (FBI) to (FBI 2), (FCl ) - (FC23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, B or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the anthracycline.

[0150] in some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (F A), (FBI) to (FBI 2), (FCl) - (FC23), or any embodiment, variation or aspect thereof

(collectively, Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCl) - (FC23)) or a pharmaceutically acceptable salt thereof) and (b) administering an effective amount of a histone deacety!ase inhibitor (such as vorinostat or romidepsin) In some embodiments. Formula 1 or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-adrmnisiercd with the histone deacety!ase inhibitor. In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FCl ) - (FC23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours. 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the instone deacetylase inhibitor.

[0151] In some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (B ), (F A), (FBI) to (FBI 2), (I -Cl) - (FC23), or any embodiment, variation or aspect thereof

(collectively. Formula (J), Formula (I), Formula (II), (I-A), (FBI) to (FB12), (I -Cl ) - (FC23)) or a pharmaceutically acceptable salt thereof) and ( b) administering an effective amount of a taxane (such as pac!itaxel or docetaxe!) In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (I -Cl) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-admimstered with the taxane. In some embodiments. Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (I-Cl) - (F C23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the taxane.

[0152] in some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (F A), (FB1 ) to (FBI 2), (FC1) - (FC23), or any embodiment, variation or aspect thereof

(collectively, Formula (J), Formula (I), Formula (II), ( A), (FB1) to (FBI 2), (FC1) - (FC23)) or a pharmaceutically acceptable salt thereof and (b) administering an effective amount of a nucleotide analog or precursor analog (such as azacitidine, azathioprine, eapecitabme, cytarabine, doxiflurid e, 5-fluorouracif gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or tioguanine). In some embodiments. Formula (J), Formula (I), Formula (II), (F A), (FBI) to (FBI 2), (FC1) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously coadministered with the nucleotide analog or precursor analog. In some embodiments. Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FB12), (FC1) - (FC23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours. 4 or more hours, 8 or more hours, 12 or more hours. 24 or more hours, or 48 or more hours) prior to or after the nucleotide analog or precursor analog.

[01 S3] In some embodiments there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (F A), (FBI) to (FBI 2), (I -Cl) - (FC23), or any embodiment, variation or aspect thereof

(collectively. Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (I -Cl) - (I-C23)) or a pharmaceutically acceptable salt thereof and (b) administering an effective amount of a platinum·· based chemotherapeutic agent (such as cisplaiin, carbopiatm or oxahp!aiin). In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (I-Cl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to after, or simultaneously co administered with the platinum-based chemotherapeutic agent. In some embodiments, Formula (J), Formula (I), Formula (11), (I-A), (I-Bl) to (I-B12), (l-Cl } - (I-C23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hoars, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the platinum- based chemotherapeutic agent

[0154] In some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (11), (I- A). (I-Bl) to (I-Bl 2), (I-Cl j - (I-C23), or any embodiment variation or aspect thereof

(collectively, Formula (J), Formula (I), Formula (iij, (I-A). (I-Bl) to (I-Bl 2), fl-Cl) - (I-C23)) or a pharmaceutically acceptable salt thereof and (b) administering an effective amount of pemetrexed. In some embodiments, Formula (J), Formula (1), Formula (II), (I-A), (I-Bl) to (I- B12), (I-C!) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-administered with the pemetrexed. In some embodiments, Formula (J). Formula (I), Formula (II), (I-A). (I-Bl) to (I-Bl 2), (1-0 ) - (I-C23) or a pharmaceutically acceptable salt thereof is administered I or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the pemetrexed.

[0155] In some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J). Formula (I), Formula (II), (I- A). (I-Bl) to (I-Bl 2), (I-Cl ) - (I-C23), or any embodiment variation or aspect thereof

(collectively, Formula (J), Formula (I), Formula (II), (I-A) (I-Bl) to (I-Bl 2), (I-Cl ) - (I-C23)) or a pharmaceutically acceptable sail thereof and (b) administering an effective amount of a Bruton’s tyrosine kinase (BTK) inhibitor In some embodiments, Formula (J), Formula (I), Formula (II), (IA-), (I-Bl ) to (I-Bl 2), (I-Cl) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior io, after, or simultaneously co-administered with the BTK inhibitor. In some embodiments, Formula (J), Formula (I), Formula (IT), (I-A), (I-Bl) to (I-RI2), (I-Cl ) - (I--C23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the BTK inhibitor.

[0156] In some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (I- A). (I-Bl) to (I-B12), (I -Cl) - (FC23) or any embodiment, variation or aspect thereof

(collectively. Formula (J), Formula (I), Formula (11), (FA), (I-Bl) to (I-Bl 2), (I -Cl) - (FC23)) or a pharmaceutically acceptable salt thereof and (b) administering an effective amount of a PI3K or Akt inhibitor. In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (I- B1 ) to (I-Bl 2), (FCl) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-administerecl with the PI3K or Akt inhibitor in some embodiments, Formula (J), Formula (I), Formula (11), (i-A), (I-Bl) to (I-B12), (FCl) - (1-C23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the PI3K or Akt inhibitor.

}01S7) In some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J). Formula (I), Formul (II), (F- A). (I-Bl) to (I-Bl 2), (FCl ) - (I-C23)), or any embodiment, variation or aspect thereof

(collectively, Formula (J). Formula (I), Formul (II), (I-A). (I-Bl) to (I-Bl 2), (FCl ) - (FC23)) or pharmaceutically acceptable salt thereof, and (b) administering an effeetive amount of a DNA damage repair (DDR) pathway inhibitor. In some embodiments, Formula (J), Formula (I), Formula (II), (IA-) , (I-Bl) to (I-Bl 2), (FCl) - (FC23)or pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-admmi stored with the DDR pathway inhibitor in some embodiments, Formula (J), Formula (I), Formula (II), (IA-) , (I-Bi) to (I- B12), (FCl ) - (I~C23)or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more h urs) prior to or after the DDR pathway inhibi or Examples of inhibitors of the DDR pathway include poly(ADP-ribose) polymerase (PARP) inhibitors (such as olaparib, rucaparib, niraparib, or taiazoparib), ataxia telangiectasia mutated (ATM) protein inhibitors, ataxia telangiectasia and RadS-reiated (AIR) protein inhibitors checkpoint kinase 1 iChkl ) inhibitors, or combinations thereof

[0158] In some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (I- A), (I-Bl ) to (FBI 2) (FCl ) - (I-C23), or any embodiment, variation or aspect thereof

(collectively, Formula (J), Formula (I), Formula (II), (I-A), (FBI ) to (FBI 2), (FCl ) - (I-C23)) or a pharmaceutically acceptable salt thereof! and (b) administering an effective amount of a PARP inhibitor (such as oiaparib, rueaparib, niraparib, or ialazoparib). In some embodiments, Formula (J), Formula (I), Formula (II), (I- A), (I-Bl) to (FBI 2), (i-Cl) - (I-C23) or a

pharmaceutically acceptable salt thereof is administered prior to, after or simultaneously co administered with the PARP inhibitor. In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (I-Bi) to (i B12), (I-Cl) -- (I-C23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the PARP inhibitor.

[0159] In some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (11), (I- A), (FBI ) to (FBI 2), (i-CI j - (I-C23)), or any embodiment, variation or aspect thereof

(collectively, Formula (J). Formula (I), Formula (II), (FA), (FBI ) to (I-Bl 2), (I-Cl ) - (I-C23)) or pharmaceutically acceptable salt thereof and (b) administering an effective amount of an ATM protein inhibitor In some embodiments, Formula (J), Formula (I), Formula (II). (FA), (F Bl) to (I-R12), (FC1) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-administered with the ATM protein inhibitor In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (I-B12), (FC1) - (FC23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the ATM protein inhibitor.

[0160] In some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J). Formula (I), Formula (II), (F A) (I-Bl ) to (FBI 2), (I-Cl ) - (FC23), or any embodiment variation or aspect thereof

(collectively, Formula (J). Formula (I), Formula (II), (FA), (I-Bl) to (I-Bi 2), (I-Cl ) - (FC23)) or a pharmaceutically aecep table salt thereof and (b) admini tering an effective amount of an ATR protein inhibitor. In some embodiments, Formula (J), Formula (I), Formula (II), ( A) (F Bl) to (FBI 2), (I-Cl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to after, or simultaneously co-adrmnistered with the ATR protein inhibitor. In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (I-B12), (I-Cl ) - (FC23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or alter the ATR protein inhibitor.

[0161} In some embodiments there is provide a method of treating a disease m an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula 01 ), (I- A), (FBI) to (I-ΊBI2), (FCl ) - (FC23), or any embodiment, variation or aspect thereof

(collectively, Formula (J), Formula (I), Formula (II), (I-A), (FBI) to (FBI 2), (FCl ) - (FC23)) or a pharmaceutically acceptable salt thereof) and (b) admi nistering an effective amount of an Chkl inhibitor. In some embodiments, Formula (J), Formula (I), Formula (II), (FA), (I-Bl ) to (I-B12), (FCl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-admimsierecl with the Chkl inhibitor. In some embodiments,

Formula (J), Formula (I), Formula (11), (I-A), (FBI ) to (FBI 2), (FCl) - (I-C23) or a

pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the Chkl inhibitor.

[0162] In some embodiments, there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formul (II), (I- A), (FBI) to (FBI 2), (FCl ) - (FC23)), or any embodiment, variation or aspect thereof

(collectively, Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FCl ) - (FC23)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a further CDK4/6 inhibitor. In some embodiments, Formula (J). Formula (I), Formula (II), (FA) (FBI) to (FBI 2), (FCl ) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously Co-administered with the further CDK4/6 inhibitor. In some embodiments, Formula (J), Formula (I), Formula (II), (IA-) , (FBI ) to (FBI 2), (FCl) - (FC23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the further CDK4/6 inhibitor

[0163] In another aspect, provided herein is a combination therapy which a compound of Formula (J), Formula (I), Formula (II ) (I-A), (FBI) to (FBI 2), (FCl ) -· (F-C23), or a salt thereof is coadministered (which may be separately or simultaneously) with one or more additional agents that are effective in stimulating immune responses to thereby further enhance stimulate or upregulaie immune responses in a subject. For example provided is a method for stimulating an unmune response in a subject comprising administering to tbe subject a compound of Formula (J), Formula (1), Formula {II), (I-A), (FBI) to (FBI 2), (FC1 ) - (FC23), or a salt thereof and one or more immunostimuiatory antibodies, such as an anti-PD-1 antibody, an anti-PD-Ll antibody and/or an anti-CTLA-4 antibody, such that an immune response is stimulated m the subject, for example to inhibit tumor growth. In one embodiment, the subject is administered a compound of formula Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCI) - (FC23) or a salt thereof and an anti-PD-1 antibody. In another embodiment, the subject is administered a compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCI) - (FC23), or a salt thereof and an anti-PD-Ll antibody. In yet another embodiment, the subject is administered a compound of Formula (J), Formula (I), Formul (II), (I-A), (FBI) to (FB12), (F Cl) - (FC23) or a salt thereof and an anti-CTLA-4 antibody In another embodiment, the immunostimuiatory antibody (e.g., anti-PD-1, anti-PD-L! and/or ami-CTLA-4 antibody) is a human antibody. Alternatively, the immunostimuiatory antibody can be, for example, a chimeric or humanized antibody (e g., prepared from a mouse anti-PD-1 , anti-PD-Ll and/or ami-CTLA-4 antibody).

[0164] In one embodiment, the present disclosure provides a method for treating a proliferative disease (e.g , cancer), comprising administering a compound of Formul (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCI) - (FC23), or a salt thereof and an anti- PD-i antibody to a subject. In further embodiments, a compound of Formula (J), Formula (I). Formula (II), ( A), (FBI ) to (FBI 2), (FCI) - (FC23) or a salt thereof is administered at a subtherapeutic dose, the anti- PD- 1 antibody is administered ai a subtherapeutic dose, or both are administered at a subtherapeutic dose In another embodiment, the present disclosure provides a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimuiatory agent, comprising administering a compoun of Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FCI ) - (I-C23 ), or a salt thereof and a subtherapeutic dose of anti-PD-1 antibody to a subject In certain embodiments the subject is human. In certain embodiments, the anti-PD-I antibody is a human sequence monoclonal antibody. [01 5} In one embodiment, the present invention provides a method for treating a hyperproliferative disease (e g., cancer), comprising administering a compound of Formula (J) Formula (I), Formula (II), (I -A), (I-Bl ) to (FBI 2), (I-Ci) - (I-C23), or a salt thereof and an anti- PD-Ll antibody to a subject. In further embodiments, a compound of Formula (J), Formula (I), Formula (II), (I- A), (FB 1 ) to (I-B 12), (I-CI ) - (I-C23) or a salt thereof is administered at a subtherapeutic dose, the anti-PD-Ll antibody is administered at a subtherapeutie dose, or both are administered at a subtherapeutic dose. In another embodiment, the present invention provides a method for altering an adverse event associated with treatment of a hyperproliferative disease with an imniunostimulatory agent, comprising administering a compound of Formula (J), Formula (I), Formul (II), (I- A). (I-B!) to (I-B! 2), (I-CI ) - (I-C23), or a salt thereof and a subtherapeutic dose of anti-PD-Id antibody to a subject. In certain embodiments, the subject is human. In certain embodiments, the anti-PD-Ll antibody is a human sequence monoclonal antibody

[0166] In certain embodiments, the combination of therapeutic agents discussed herein can be administered concurrently as a single composition in a pharmaceutically acceptable earner, or concurrently as separate compositions each in pharmaceutically acceptable carrier. In another embodiment the combination of therapeutic agents can be administered sequentially. For example, an ami-CTLA-4 antibody and a compound of Formula (J), Formul (I), Formula (II), (FA), (FBI ) to (FBI 2), (FC1 ) - (I-C23), or a salt thereof can be administered sequentially, such as anti-CTLA-4 antibody being administered first and a compound of Formula (J), Formula (I), Formula (II), (I-A), (I-B 1 ) to (FBI 2), (I-CI) - (I-C23), or a salt thereof second, or a compound of Formula (J), Formula (I), Formula (II), (I-A), (FBI ) to (FBI 2), (FC1 ) - (I-C23), or a salt thereof being administered first and anti-CTLA-4 antibody second. Additionally or alternatively, an anti-PD-l antibody and a compound of Formula (I), Formula (I), Formula (II), (I-A), (I-B I ) to (I-B12), (I -Cl ) - (FC23), or a salt thereof can be administered sequentially, such as anti-PD-l antibody being administered first and a compound of Formula (J), Formula (I) Formula (II), (I- A) (I-B 1 ) to (I-B 12) (FC 1 ) - (I-C23), or a salt thereof second, or a compound of Formula (I) Formula (I), Formula (II), (I-A) (FBI ) to (I-B 12), (I-CI ) - (I-C23), or a salt thereof being administered first and anti-PD-l antibody second. Additionally or alternatively, an anti-PD-Ll antibody and a compound of Formula (J), Formula (I ), Formula (II) (I-A), (I-Bl) to (I-Bl 2), (I-

Ci) - (I-C23), or a salt thereof can be administered sequentially, such as anti-PD-Ll antibody being administered first and a compound of Formula (I) Formula (I), Formula (II). (I -A) (I-Bl ) to 0-B12) (F-Cl ) - (I-C23), or a salt thereof second, or a compound of Formula (I) Formula (I), Formula (II), (I- A), (I-Bl) to (I-B 12), (I-Cl) - (I-C23), or a salt thereof being administered first and anti-PD-Ll antibody second.

[0167] Furthermore, if more than one dose of the combination therapy is administered sequentially, the order of the sequential administration can be reversed or kept in the same order at each time point of administration, sequential administrations can be combined with concurrent administrations, or any combination thereof

[0168] Optionally the combi na tion of a compound of Formula (J), Formula (I), Formula (II),

(I- A), (I-Bl) to (I-B 12), (I-Cl) - (I-C23), or a salt thereof can be further combined with an immunogenic agent, such as cancerous ceils, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.

[0169] A compound of Formula (I), Formula (I), Formula (II), (I--A), (I-Bl) to (I-B 12), (I- C! ) - (I-C23), or a salt thereof can also be further combined with standard cancer treatments. For example, a compound of Formula (I), Formula (I), Formula (II), (I- A), (I-Bl ) to (I-Bl 2), (I-Cl)

- (I-C23), or a salt thereof can be effectively combined with chemotherapeutic regimens. In these instances, it is possible to reduce the dose of other chemotherapeutic reagent administered with the combination of the instant disclosure. Other combination therapies with a compound of Formula (J), Formula (I), Formula (II). (I-A), (I-Bl ) to (I-B 12), (I-Cl) - (I-C23)), or a salt thereof include radiation, surgery, or hormone deprivation Angiogenesis inhibitors can also be combined with a compound of Formula (J), Formula (I), Formula (II), (I-A), (I-Bl ) to (I-Bl 2), (I-Cl) - (I-C23), or a salt thereof. Inhibition of angiogenesis leads to tumor cel l death, which can be a source of tumor antigen fed into host antigen presentation pathways.

[0170] In another example, a compound of Formula (J), Formula (I), Formula (II), (I-A), (I- B 1 ) to (I-B 12), (I-Cl ) - (I-C23)), or a salt thereof can be used in conjunction with anti -neopla tic antibodies By way of example and not wishing to be bound by theory, treatment with an anti- cancer antibody or an anti-cancer antibody conjugated to a toxin can lead to cancer cell death (e.g., tumor cells) winch would potentiate an immune response mediated by CTLA-4, PD-1 , PD F! or a compound of Formula (J), Formula (I), Formula (II), (I-A), (I-Bl ) to (I-Bl 2), (I-Cl) - (I- €23), or a salt thereof in an exemplary embodiment a treatment of a hyperproliferative disease (e.g., a cancer tumor) can include an anti -cancer antibody in combination with a compound of Formula (J), Formula (I), Formula (II), (I- A). (I-Bl) to (1-1312), (i-Cl) - (I-C23)or a salt thereof and anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-Ll antibodies, concurrently or sequentially or any combination thereof which can potentiate anti-tumor immune responses by the host. Other antibodies that can be used to activate host immune responsiveness can be further used in combination with a compound of Formula (J), Formula (I), Formula (31), (I- A), fi-Bl j to (I-B12), (I-Cl) - (1-C23) or a salt thereof.

[0171] In some embodi ments, a compound of Formula (J), Formula (1), Formula (II), (I- A), (I-Bl) to (I-B12), (i-Cl) - (I-C23), or a salt thereof can be combined with an anti-CD73 therapy such as an anti-CD73 antibody.

[0172] in yet further embodiments, the compound of Formula (J), Formula (1), Formula (11), (I- A), (1-B 1 ) to (1-BI 2), (i-C 1 ) - (I-C23), or a salt thereof is administered in combination with another CDK4 or CDK6 inhibitor or other CDK inhibitor.

Dosing and Method of Administration

[0173] The dose of a compound administered to an individual (such as a human) may vary with the particular compound or salt thereof the method of administration, and the particular disease, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount.

[0174] The effective amount of the compound may m one aspect be a dose of between about 0 01 and about 100 mg/kg. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e g , the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject ^' s health status, condition, and weight An exemplary dose is m the range of about from about 0 7 rng to 7 g daily, or about 7 rng to 350 rng daily, or about 350 mg to 1 .75 g daily, or about 1.75 to 7 g daily. [0175] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.

[0176] A compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual's life in one variation, the compound is administered on a daily or intermittent schedule The compound can be administered to an individual continuously (for example, at least once daily} over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a‘drug holiday’ (e.g. , once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more) Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein

[0177] The compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and iransdermai. A compound provided herein can be administered frequently at lo doses, known as 'metronomic therapy, or as part of a maintenance therapy using compound alone or in combination with one or more additional drugs. Metronomic therapy or maintenance therapy can comprise administration of a compound provided herein in eycles Metronomic therapy or maintenance therapy can comprise intra-turn oral admini tration of a compound provided herein

[0178] In one aspect, the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g , a human) an effective amount of a compound or salt thereof In some embodiments the route of administration is intra venous, intra-arterial, intramuscular or subcutaneous. In some embodiments the route of administration is oral. In still other embodiments, the route of administration is iransdermal.

[0179] The invention also provides compositions (including pharmaceutical compositions) as described herein for the use in treating, preventing, and/or delaying the onset and/or development of cancer and other methods described herein. In certain embodiments, the composition comprises a pharmaceutical formulation which is present in a unit dosage form.

[01 SO] Also provided are articles of manufacture comprising a compound of foe disclosure or a salt thereof composition, and unit dosages described herein m suitable packaging for use in the methods described herein. Suitable packaging is known m the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed

Ails

[01 SI] T he present disclosure further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits ma employ any of the compounds disclosed herein in one variation, the kit employs a compound described herein or a salt thereof The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of cancer.

[0182] Kits generally comprise suitable packaging The kits may comprise one or more containers comprising any compound described herein Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit

[0183] The kits may be in unit dosage forms, bulk packages (e.gi, multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use pharmacies ( .g. , hospital pharmacies and compounding pharmacies)

[0184] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present in vention. The instructions included with the kit generally include information as to the components and their administration to an individual.

[0185] T he invention can be further understood by reference to the following examples, which are provided by way of illustration and are not meant to be limiting.

EXAMPLES Synthetic Examples

Example- 1 : Synthesis of 5-jluoro~4~(8~jluoro~4~isopropyl~3, 4-dihydro-2H-henzo[bj[ 7, 4/oxazin-

[0186] Step-1 : Synthesis of 6-bromo-8-fluoro-4-isopropyi-2H-beo*o[h] [1 ,4]oxazm-

3(4H)-o«e: To a stirred solution of 6-bromo-8-fluoro-2H -benzoj b] [ 1 ,4]oxazin-3(4H)-one (7000 mg, 28.56 mmol, 1 equiv) in DMF (70 mL), was added NaH (60%) (2:282 mg, 57.12 mmol, 2 equiv) at 0 °C and stirred for 30 min at RT, followed by the addition of 2-aodopropane (5.6 mL, 57.12 mmol, 2 equiv). The reaction mixture was heated to 80 °C for 3 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture cooled to RT and quenched with ice-cold water (100 ml,) and extracted with EtOAc (150 mL x 3) Organic layer was washed with water (150 ml,) and brine solution (150 ml,). Organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain -bromo-S-f!uoro-d- isopropyl-2H-benzo[b][l,4|oxazin-3(4H)-oiie (2400 mg, 29%) as off white solid compou d.

LCMS 2SS [M+H] [0187] Step-2: Synthesis of 6-bromo-8-t1uoro-4-isopropyl-3, 4-dihydro-2B- henzojb j [I,4]oxazine: To a stirred solution of 6-bromo--8--iluoro-4--isopropyi--2H- benzo[b][ l,4]oxazm-3(4H)-one (1400 mg, 4.87 mmol, 1 equiv) in THF (14 L), was added BIT.DMS (9 7 mL, 7.66 mmol, 4 equiv) drop wise at 0 °C. The reaction mixture was heated to 80 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of die reaction, the reaction mixture was quenched with saturated solution of NaHCO (100 mL) and extracted with EtOAc (100 ml . x 3). The combined organic layer was washed with water (100 mL) and brine solution (100 mL). Organic layer was dried over anhydrous NafoCft and concentrated under reduced pressure to obtain 6-bromo~8~fii3oro~4~isopropyl~3, 4-dihydro~2H- benzo[b][l,4]oxazine (1200 mg, 90 %) as a yellow viscous compound

[0188] Step-3: Synthesis of 84I >rO 44sopropyl4H4,AA4>4etrame hyT4,3fo~

dioxaboroIan-2-y1)-3,4-dihydro-2H-ben¾o[b][l _» 4]oxa*ine: To a stirred solution of 6-bromo-8- fluoro-4-isopropy!-3. 4-dibydro-2H-benzo[b] [ 1 ,4]oxazine (1200 mg, 4.39 mmol , I equiv) in dioxane (12 mL), was added 4,4.5,5-tetramethyl-2-(4.4,5,5~tetramethyl-1 ,3.2-dioxaborolan~2~yl)- 1 ,3,2-dioxaboro!ane (1340 mg, 5.27 mmol, 1 2 equiv) and potassium acetate (1291 mg, 13.17 mmol, 3 equiv) Purge the reaction mixture with nitrogen gas for 15 min. After addition of Pd(dppf).DCM (179 mg, 0.219 mmol, 0.5 equiv) again purge with nitrogen for 5 min. The reaction mixture was heated to 100 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (100 ml, x 2) Organic layer was washed with brine (100 mL), dried over anhydrous NafoCft and concentrated under reduced pressure to obtain 8-ftuoro-4- isopropyl-6~(4,4,5,5Aetiameth i-l ,3,2-dioxaborolan-2-yi)--3,4-dihydiO 2H-benzo[b][l,4]oxazine ( 1000 mg, 69%) as a dark brown viscous compound.

LCMS 322.1 [M fH] ⁺

[0189] Step-4: Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yI)-8-fluoro-4-isopropyl-3, 4-d«hyclro-2H-ben*o[b] [l,4]oxa2me: To a stirred solution of 2, 4-dichlofo-5-fluofopyrimidine

(500 mg, 3.01 mmol, I equiv) and 8-fluoro-4-isopropyl-644,4,5,5-tetramethyi-l ,3,2··

diOxaborolan-2-yl)-3,4-dihydro-2Hfoenzo[ b :[ 1 4joxaxine (970.1 mg 3.01 mmol, 1 equiv) in THF: Water (1 : 1, 16 mL) was added Potassium carbonate (831 mg, 6.02 mmol, 2 equiv) and Pd(PPh ₃ )4 ( 174 mg, 0.15 mmol, 0 05 equiv). The reaction mixture was heated to 80 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (100 mL x 2), organic layer was washed with water ( 100 mL) and brine solution (100 ml,). The organic layer dried over anhydrous NafoCL and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-(2-chloro~5~ fluoropyrimidin-4-yi)-8-fluoro-4-isopropyi-3, 4-dihydro- 2H~benzo[b][l,4]ox:azine (800 mg,

82%) as a yellow solid compound.

LCMS 326 i XI M i ⁺

[0190] Step-5: Synthesis of tert-butyl 4-(6-(5-fluoro-4-(8-fluoro-4-isopropyl-3, 4- dihydro-2H-benzo(b]jl,4|oxazm-6-yl)pyrimitlln-2-ylamlno)pyr� �d«a-3-yl)piperazine-l- carboxylate: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3, 4- dihydro-2H-benzo[b] 1 _> 4]oxazine (300 mg. 0.923 mmol, 1 equiv) in Dioxane (10 ml,), was added tert-butyl 4-i0-arninopyridm-3-y!)piperazine-i -carboxylate (282.3 mg, 1.015 mmol, 1 1 equiv) and cesium carbonate (451 .4 mg, 1.384 mmol, 1.5 equiv). The reaction mixture was aerated with nitrogen gas far 30 min. followed by the addition of palladium acetate (4 2 g, 0 018 mmol, 0 02 equiv) and BINAP (23 mg, 0 036 mmol , 0 04 equiv) again purged nitrogen for 5 min. The resultant reaction mixture w¾s heated to 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with EtOAc (25 mL) Solid observed was filtered and washed with EtOAc (20 ml,) to obtain tert-butyl 4-(6-(5-tluoro-4-(8-tluoro-4-isopropyl-3, 4~dihydro~2H-benzo[bj[ l ,4joxaxin~6~ yl)pyrimidin-2-y!amino)pyridm-3 -yl)piperazine-1 -carboxylate (190 mg, 36%) as a greenish solid compound.

LCMS 568.3 [M fH] ⁺

[0191] Step-6:: Synthesis of 5~flm>ro-4-(8~fluoro-4~isopropyl-3, 4-dihydro-2M- benzo[b][l,4]oxaz«n-6-yl)-N-(5-(piperaz«n-1-yl)pyridin-2-y i)pyrimidin-2-aniine: Tert-butyl 4-(6-(5-fiuoro-4-(8-fiuoro-4-isopropyl-3, 4-dihydro-2H-benzo[bj[ I,4]oxazin--6--yl)pynmidin-2- yiammo)pyridiw3-yi)piperazme-4-carboxyiate (190 mg 0.335 mmol, 1 equiv) was taken in 1.25 M HCI in ethanol (5 L) and the resultant reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under vacuum to obtain 5-fluoro-4-(8-fluoro-4-isopropyi-3, 4-dihydro-2H- benzo b:] l ,4joxazm-6-yl}-N-(5-(ptperazm-4 -yl}pyridin-2-yI)pyrmiidm-2-armne (180 mg, 100%) as a pale yellow solid compound.

LCMS 468.2 jMfH] ⁺

1HNME (400 MHz, DMSO-dg ) d 9.04 (d, J = 7.4 Hz, 2H), 8.67 (d, J = 3.7 Hz, 1 1 0. 8.01 (d, ./= 2.9 Hz,IH), 7.91 (s, 1H), 7.77 (d, J = 9.5 Hz, 1H), 7 42 (s, 1H), 7 19 (d, 7 11.5 Hz, Hi),

4.36 - 4.21 (s, 2H), 4.17 - 4.07 (m, 1H), 3.38 (t, J= 5.1 Hz, 4H), 3.32 (d, J = 4.3 Hz, 2H), 3.26 (s, 4H), 1 19 (d, J- 6.5 Hz, 611).

Example-2: Synthesis qf 8dluoro-6-(5dluoro-2-(5-(piperazin-l-yl)pyridin-2-ylammo)pyr imidin~ 4~yl)~4-isopropyl-2H-benso[b jl ,4]ocaήh-3(4H)-ohb (Compound 2):

[ 01921 Step- 1 : Synthesis of 6-broino-8-fl«oro-4-isopropyi-2H-benzo|b [l,4]oxazwa- 3(4Il)-one: To a stirred solution of 6-bromo-8-fluoro-2H-benzo] b)] l ,4joxazm--3(4H)-one (7000 mg, 28.56 mmol, 1 equiv} m DMF (70 rnL), was added Nail (60%) (2282 mg, 57 12 mmol, 2 equiv) at 0 C and stirred at RT for 30 min, followed by the addition of 2-iodopropane (5 6 mL, 57.12 mmol, 2 equiv). The reaction mixture was heated to 80 °C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (100 ml,) and extracted wit EtOAc (150 mL ^c 3) Organic layer was washed with water (150 mL), brine solution (150 mL). Organic layer was dried over anhydrous NafoCL and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-hromo-8-fluoro-4-isopropyl-2H-benzo[b][l ,4]oxazin- 3(41 ft. one (2400 mg, 29%) as an off white solid compound. LCMS 288 [M fH] ^”

[0193] Step-2: Synthesis of 8-fluoro-4-isopropyi-6-(4,4,5,5-tetramethyl- J ,3,2- dioxaboro!an-2-yl)~2H~beBzo[b] [ 1,4] oxazin-3(4H)-one: To a stirred solution of 6-bromo-8- fluoro-4tisopropyl-2H-benzofb]f l,4]oxazin-3(4H)-one (1000 mg, 3.48 mmol, 1 equiv) and 4,4,5,5 tetramet!iyl-2-(4,4,5,5-tetramethyl l ,3,2-dioxaborolan-2-yl)-1 ,3,2-diOxaborolane (1062 mg, 4 18 mmol, 1.2 equiv) in Dioxane was added Potassium acetate (1023 mg, 10.44 mmol, 3 equiv). Purge the reaction mixture with nitrogen gas for 15 mm. After addition of Pd(dppf) DCM (142 mg, 0.174 m ol, 0.05 equiv) again purged nitrogen for 5 mm. The reaction mixture was stirred at 100°C for 4 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (30 ml ) and extracted with EtOAc (100 ml, 2) Organic layer was washed with brine (100 ml,), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain 8~fIuoro~4~isopropyl~6~(4,4,5,5- tetramethyI-l ,3,2-dioxaboro1an-2-yl)-2H-benzo[b][1 ,4]oxazin-3(4H)-one ( 950 mg, 76%) as a dark brown viscous compound.

LCMS 336.1 [M+HjL

[0194] Step-3: Synthesis of 6-(2-ch1oro-5-fluoropyrimidin-4-yI)-8-fluoro-4-isopropy1- 2H-benzo[b] [ 1 ,4]oxazin-3(4H)-one: To a stirred solution of 2, 4-dichloro- 5~fluoropyriraid ine

(450 mg, 2.71 mmol, 1 equiv), 8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxahorolan-2 · yl)-2H-benzo[b][! ,4]oxazin-3(4H)-one (908.4 mg, 2 71 mmol. 1 equiv), Potassium carbonate (748 mg, 5 42 mmol, 2 equiv) in THF; Water (1 : 1 ) (16 ml,), w¾s added (8:8 ml,) Pd(PPh ₃ )4 (157 mg, 0.135 mmol, 0.05 equiv). The reaction mixture was heated to 80 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 ml,) and extracted with EtOAc (100 ml, ^x 2) Organic layer was washed with water (100 ml,) and brine solution (100 ml,). Organic layer was dried over anhydrous Na ₂ S04 and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combiflash to obtain 6--(2--chloro-5-fluoropynmidin-4-y!)-8-iluoro- 4-isopropyi-2H benzo[bj[ l,4]oxazin-3(4H)--one (270 g, 29%) as a white solid compound.

LCMS 340 [M fH] ⁺

[0195] Step-4:: Synthesis of tert-butyl 4-(6-(5-flworo-4-(8-flworo-4-«sopropyI-3-oxo-3,4- dihydro-2H-benz©[b][i,4]oxazi«-6-yI)pyrhmdin-2-yIaMmo)pyrH iin-3-yl)piperazme-J- carhoxyiate: To a solution of 6-(2-chloro-5-fiuoropyrimidin-4-yi)-8-fluoro~4-isopropyi-2H- benzol b 1 jd ,4joxazm--3(4H)-one (240 mg, 0.707 mmol, 1 equiv) m Dioxane (10 inL), was added ten-butyl 4-(6-ammopyndm-3-yl)piperazme-l-carboxyiaie (21 7 mg, 0.778 mmol, 1.1 equiv) and cesium carbonate (346 mg, 1.06 mmol, 1.5 equiv). The reaction mixture was aerated with nitrogen gas for 30 mm., followed by the addition of palladium acetate (3.2 mg 0.014 mmol,

0.02 equiv) and BINAP (17.6 mg, 0.028 mmol, 0.04 equiv) again purged nitrogen for 5 mm. The resultant reaction mixture was heated to 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture v¾s diluted with EtOAc (25 niL). Solid observed was filtered and washed with Et()Ac(20 ml) to obtain tert-butyi 4-(6-(5-fluoro-4-(8-fluoro-4-isopropyi-3-oxo-3,4-dihyd.ro-2H -benzo[b][l ,4]oxazin-6- yl)pyrimidm 2-yiauuno)pyridin-3-yl)piperazme-i Carboxylate (125 mg, 30%) yellow solid compound.

LCMS 582.3 [MTH] "

[0196] Step-5: Synthesis of 8-fluoro-6-(5-fluoro-2-(5-(piperazia-l-yl)pyridiii-2- yIamin0)pyrimidin~4~yI)-4-is0propyl-2H~ben¾o[bj[l _» 4]oxazin-3(4H)~one: Tert-buty! 4-(6~(5~ fluoro-4-(8 fluoro-4-isopropyi-3 OxO 3,4-dihydro-2H benzo[b][l,4]oxazim6-yl)pynmidm~2~ ylamino)pyridin-3-yl)piperazine-l -carboxylate (125 mg, 0 215 mmol . 1 equiv) was taken in 1.25M HC1 in ethanol (5 ml.) and the resultant reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by [.CMS After completion of the reaction, the reaction mixture was concentrated under vacuum to obtain 8-fluoro-6-(5-fluoro-2-(5-(piperaz.in-l-yl) pyndin-2-ylamino) pynmidim4-yl)-4-isopropyl-2H-benzo| b]| l ,4 joxazm-3(4Hi--one (120 g, 100%) as a yellow solid compound

LCMS 482.2 [M fH] ⁺

*HNM (400 MHz, DMSO-de ) d 8.97 (s, 2H), 8.72 (d, ./ 3.5 Hz, 1H| 8.04 (d, J === 3.0

Hz, IH), 7.96 (d, J === 9 1 Hz, 1H), 7.84 (s, 1H), 7.66 (d, 7 10.8 Hz. 2H), 4 83 - 4.81 (M, 1H),

4.78 - 4.76 (s, 2Ή), 3.36 (t, / 5.0 Hz. 4H), 3 26 (q, 4.4 Hz, 4H), 1.51 (d. J ------ 7.0 Hz, Oi l)

Example-3: Synthesis of 5~jluoro-4-(8-jluoro-3, 4-dihydro-2H~benzo/bjfl, 4/oxazin-6-ylJ~N-(5 (piperazin- 1 -yl)pyridin-2~yl)pyritnidm~2-amine (Compound 3):

[0197] Step-1: Synthesis of 6-{2-chloro-5-flaoropyrimidin-4-yl)-8-fl«oro-3,4-dihy ro- 2H-benzo[b] [l,4]oxazine: To a stirred solution of 2, 4~dichloro-5-fiuoropyrimidine (4000 mg, 24.09 mmol, 1 equiv), 8~iluoro-6~(4,4,5,5-tetrameiliyl-l ,3,2-dioxahorolan-2-yi)-3,4-dihydro-2H- benzo[b][l ,4]oxazine (6722 mg, 24 09 mmol 1 equiv), Potassium carbonate (6649 mg, 48.18 rnmol, 2 equiv), FdtPPfng (1391 mg, 1 2 mmol 0.05 equiv) in THF: Water (1 : 1,40 mL) were charged. The reaction mixture was heated to 80 °C for 16 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water ( 100 mL) and extracted wit EtOAc (150 mL * 3). Organic layer was washed with water (150 mL), brine solution (I 50 mL). Organic layer was dried over anhydrous NafoCL and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi -flash to obtain 6--(2--cb!oro-5-fluoropyrimidin-4-yl)--8--fluoro-3, 4--dihydro-2B- benzoj b] | 1 ,4 joxazine (3400 mg, 50%) as a brown color solid compound.

LCMS 284 [MtH] ⁺

(0198j Step-2: Synthesis of tert- utyl 4-(6-(5-fluoro-4-(8-fl«oro-3, 4-clihydro-2H- benzo[b] [ 1 ,4) oxazin-6-y I )pyrimidin-2- iamino )pyridin-3-yl)piperazine- 1-car boxylate: To a solution of 6-(2-ch!oro-5-f!uoropyrlnudin-4--yi)-8-f!uofo-3,4-dihydro--2 H-benzoj b ^~ jj 1 ,4]oxazme (200 mg, 0.706 mol, I equiv) m Methyl isobutyl ketone (6 mL), was added tert-butyl 4-16-· aminopyridin~3~yl)piperazine-l-carbGxylate (216 mg, 0.776 mmol, 1 1 equiv) and cesium carbonate (345 mg, 1.059 mmol, 1.5 equiv). The reaction mixture was aerated with nitrogen gas for 30 m., followed by the addition of palladium acetate (3.1 mg, 0.014 mmol, 0.02 equiv) and BINAP (18 mg, 0 028 mmol, 0.04 equiv) again purged nitrogen for 5 min The resultant reaction mixture was heated to 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, tin: reaction mixture was diluted with water (25 mL) and extracted with EtOAc (50 mL x 3). Organic layer was washed with water (50 mL) and brine solution (50 l,). Organic layer was dried over anhydrous Na^SCft and concentrated under reduced pressure to obtain crude compound, which was purified with reverse phase HPLC to obtain tert-butyl 4-(6-(5-fluoro-4-(8-fluoro-3, 4-dihydro-2H-benzo[b] [ 1 ,4]oxazin-6-yl)pyrimidin- 2-ylaniino)pyridin-3-yl)piperazine~l~carboxylate (90 mg. 25%) as a yellow solid compound.

LCMS 526 [M+H] ⁺

[0199] Step-3: Synthesis of 5-fl«oro-4-(8-fl«oro-3, 4-dihydro-2H-ben*o b][l,4)oxa2«n-6- yl)-N~(5~(piperazm-l-yl)pyridin-2-yl)pyrimidin-2-amine: Tert-butyl 4-(6-(5-fluoro-4-(8- fluoro-3.4-dihydro-2H-benzo[bl[1 ,4]oxazm-6-yl)pyrimidin-2-ylamino)pyridin~3-yl)piperazine-l- carboxy!ate (90 mg, 0 133 mmol, 1 equiv) was taken in 1 .25M HC1 in ethanol (5 mL) and the resultant reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under vacuum to obtain 5-i1uoro-4-(8-i1uoro-3, 4-dihydro-2H-benzo[b][l ,4]oxazin-6-y!)-N-(5-(piperazin-l- yl)pyridin-2-y!)pynmidin 2 amine (70 mg, 97%) as a pale yellow solid compound.

LCMS 426 [Mall] ^f

¹ HNMR (400 MHz, Meihano!-d, ) d 8.65 (d, J = 3.9 Hz, !H), 8.25 (dd, ./ 9 7, 2.6 Hz, 1H),

7.89 (d, J = 2.7 Hz, 1H), 7.51 (d, J = 9.6 Hz, 1H), 7.33 (d, J = 11 3 Hz, 2H), 4.33 (t, J = 4.3 Hz, 21 1). 3.56 - 3 49 (m, 4H), 3.48 - 3 41 (m, 4H), 1.29 (t, J= 3.2 Hz, 2H).

Example-4: Synthesis ofN-(5-((4-ethylpiperami-l-yl) methyl) pynchn-2-yI)~5~fluoro~4~(8~fluoro~ 4-isopropyl-3, 4-dihydro-2H-henzo[b J[J 4)oxazm-6-yt)pynmidin-2~ mine (Compound 4):

[0200] Step-1: Synthesis of 6-bromo-8~fluoro-4~isopropyi-2H~bea*o[b] [l,4]oxa*in~ 3(4H)-oiie: To a stirred solution of 6 bromo--8--fkioro--21T-benzoib][l,4]oxazin- 3(4H)--one (7 0 g, 28 56 mmol, 1 equiv) in DMF (70 ml,), was added NaH (60%) (2.282 g, 57.12 mmol . 2 equiv) at 0 C and stirred for 30 min at RT, followed by the addition of 2-iodopropane (5.6 ml,, 57 12 mmol, 2 equiv) The reaction mixture was heated to 80 °C for 3 h. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture cooled to RT and quenched with ice-cold water (100 ml,) and extracted wit EtOAc (150 ml, a 3y organic layer was washed with water (150 ml,) and bone solution (150 ml,) Organic layer dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-brorno-8-†1uoro-4-isopropyl-2H- benzo[b] [ 1 ,4] oxazi n-3 (4H)-one (2.40g, 29%) as off white solid compound.

LCMS 288 [M-i-H] "

[0201] Step-2: Synthesis of 6-bromo-8-fluoro-4-isopropyl 3, 4-dihydro~2Il- benzo[b] [l,4]oxazrae: To a stirred solution of 6-bromo-8-fluoro-4-isopropyl-2H- benzofb] [ 1 ,4] oxazi n-3 (4H)-one (1400 mg, 4.87 mmol, 1 equiv) in THF (14 ml,), was drop wise added B!¾ DMS (9.7 ml,, 7.66 mmol, 4 equiv) at 0 C The reaction mixture was heated to 80 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was quenched with saturated solution of NaFiCCh (100 mi . } and extracted with EtOAc (100 ml, 3) The combined organic layer was washed with water (100 niL) and brine solution ( 100 niL). Organic layer dried over anhydrous NafoCft and concentrated under reduced pressure to obtain 6-bromo-8-iluoro-4-isopropyl-3, 4-dihydro-2B-·

benzo[bj[l,4]oxazme (1200 mg 90 %} as a yellow viscous compound. LCMS 274 [M-i-Hj

[0202] Step-3: Synthesis of 8-fluoro-4-isopropyi-6-(4,4,5,5-tetramethyi- J ,3,2- dioxaboro!an-2-yl)~3,4-ilihydro-2H~beiizo(b]|I,4]oxa*ine: To a stirred solution of 6-bromo-8- f!uoro-4-isopropyb3, 4-dlhydro-2H benzo[b|il ,4]oxazme (1200 mg, 4.39 mmol. 1 equlv) m dioxane (12 mL), was added 4,4,5,5-tetramethyl~2~(4,4,5,5-tetramethyl-l,3,2-dioxaborola n-2~yl)- 1,3,2-dioxaboro!ane (1340 mg, 5.27 mmol, 1 2 equiv) and Potassium acetate (1291 mg, 13 17 mmol, 3 equiv) Aerated the reaction mixture with nitrogen gas for 15 minutes. After addition of Fd(dppf) DCM (179 mg, 0.219 mmol, 0 5 equiv) again purge nitrogen for 5 nun. The reaction mixture was healed to 100 °C for 4 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (100 ml, ^c 2), organic layer was washed with brine (1 00 ml,). Tire organic layer dried over anhydrous Na^SCL and concentrated under reduced pressure to obtain 8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyj-l ,3,2-dioxaborolan-2-yI)-3,4-dihydro-2H- benzo[b][l,4]oxazine ( 1000 mg, 69%) as a dark brown viscous compound.

LCMS 322. 1 [MAR] ^÷

[0203] Step-4: Synthesis of 6-(2-chloro-5-flaoropyrimidin-4-yI)-8-fl«oro-4-isopropyl-3,

4-dihydroH2H-benzo[b] [l,4]oxazme: To a stirred solution of 2, 4-dichloro-5-fluoropyrimidine (500 mg, 3.01 mmol, 1 equiv) and 8~fluoro~4~isopropyl~6~(4,4,5.5~tetramethyI-! ,3,2- dioxaborolam2-yl)-3,4--dihydro--2!:I-benzo[b][l ,4]oxazine (970.1 mg, 3.01 ol, 1 equiv) in THF: Water (1 : 1, 16 mL) was added Potassium carbonate (831 mg, 6 02 mmol. 2 equiv) and PdiPFlvft (1 74 rng, 0.1 5 mmol, 0.05 equiv). The reaction mixture was heated to 80 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (100 mL 2), organic layer was washed with water (100 mL) and brine solution (100 mL) The organic layer dried over anhydrous Na ₂ SO* and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi -flash to obtain 6--(2-chloro-5- fluoropyrimidin-4-yl)-8-fluoro--4-isopropyi-3, 4-diliydro-2B-benzo[b]|d ,4]oxazme (800 mg,

82%) as a yellow solid compound.

LCMS 326 jM-i-H] ! 0204] Step-5: Synthesis of N-(5-((4-ethyIpiperazm-l -yl) methyl) pyridin-2-yl)-5-tluoro- 4-(8-flooro-4-isopropyi-3,4-dihyclro-2H-benzofb][l ₅ 4)oxazin-6-yt)pyrimidin-2-amine: To a solution of 6-(2-chloro-5-fluoropyrmiidin-4-yl)-8~fluoro-4-isopropyl-3, 4-dihydro~2H- benzo[b][l ,4]oxazine (200 mg, 0.676 mmol, 1 equiv) in Dioxane (10 mL), was added 5~((4~ ethylpiperazin-l-yi)methyl)pyndin-2-amine (149 mg, 1.015 m o!, 1.1 equiv) and cesium carbonate (301 mg, 0 923 mmol, 1.5 equiv). The reaction mixture was aerated with nitrogen gas for 30 m ., followed by the addition of palladium acetate (3 mg, 0.012 mmol, 0.02 equiv) and BINAP (15.3 mg, 0 024 mmol, 0.04 equiv) again purge nitrogen for 5 in The resultant reaction mixture was heated to 100 °C for 16 h. Progress of the reaction was monitored hy TLC and LCMS. After completion of the reaction , the reaction mixture was diluted with water (25 ml) extracted with EtOAc (100 ml), organic layer was dried over anhydrous Na^SCft and

concentrated under reduced pressure to obtai crude which was purified by reversed phase HPLC to obtain N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4 -(8-fluoro-4- isopropyl-3,4-dihydro-2H-ben o[b][l,4]oxazin-6-yl)pyrimidin-2-amine (35 mg) as a yellow solid compound.

LCMS 510.1 [NHΉ]

1H MR (400 MHz, Methanohdfi d 8.45 (s, 1H), 8.32 (s, 1H), 8.21 (s, HI), 7.76 (d, / 8.7

Hz, 1H), 7.54 (s, 1H), 7.30 - 7.22 (m, HI), 4 33 (t, J= 4 3 Hz, 2H), 4.23 (p, / 6.7 Hz, HI),

3 57 (s, 21 1). 3 35 (t, ./ 4 5 Hz. 2H) _: 85 (s. 2H), 2 66 1 27 (d, / 6.6 Hz, 61 i )

1.15 (t 7 7.2 Hz, 3H)

Examples : Synthesis of5~fiuoro-4-(8~fluoro-4-isopropyi-3, 4~dikydro-2H~benzofbJfl, /oxazm~

[0205] Step-1 : Synthesis of 6-bromo-8-fluoro-4-isopropyi-2H-ben*o[h] [1 ,4]oxa*in-

3(4H)-one: To a stirred solution of 6--bromo--8--flaofo--2H benzo[b][ l ,4]oxaxin-3(4H) One (7000 mg, 28.56 mmol, 1 equiv) in DMF (70 mL), was added NaH (60%) (2282 mg, 57.12 m ol, 2 equiv) at 0 C and stirred for 30 min at RT, followed by the addition of 2- odopropane (5.6 ml,, 57.12 mmol, 2 equiv). The reaction mixture was heated to 80 °C for 3 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture cooled to RT and quenched with ice-cold water (100 ml,) and extracted wit EtOAc (150 ml x 3), organic layer was washed with water ( 150 ml,) and brine solution ( 150 ml,). Organic layer dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 0-bromo-8-fluoro-4-isopropyI-2H~ benzo[b][! ,4]oxazin-3(4H)~one (2d00 mg, 29%) as off white solid compound.

LCMS 288 [M-HR] ⁺

[0206] Step-2: Synthesis of 6-bromo-8-fluoro-4-isopropyl-3 _¾ 4~dihydro-2H- benxo[b] [lL4]oxaxfee: To a stirred solution of 6-bromo~8~iluoro~4~isopropyl~2H- benzo[b][l ,4]oxazin-3(4H)~one (1400 mg, 4.87 mmol, 1 equiv) in THF (14 ml,), was drop wise added B1L.DMS (9 7 ml,, 7.66 mmol, 4 equiv) at 0 C The reaction mixture was heated to 80 °C for 16 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated solution of NaHCCft (100 ml,) and extracted with EtOAc (100 ml, ^x 3) The combined organic layer was washed with water (100 ml ,) and brine solution (100 ml ,). Organic layer dried over anhydrous NasSCft and concentrated under reduced pressure to obtain 6-bromo-8-fluoro-4- isopropyl-3, 4-dihydro-2H- benzo[b] [ 1 ,4] oxazine (1200 mg, 90 %) as a yellow viscous compound.

LCMS 274 [M FHj ⁺

[0207] Step-3: Synthesis of 8-!1«oro-4-isopropyl-6-(4, 4,5, 5-tetraniethyI-1,3,2- dioxaboroIan-2-yl)-3,4-dihydro-2H-benzo[b][l,4]oxaz«nei To a stirred solution of 6-bromo-8- fl uoro-4-i sopropy 1 -3 , 4-dihydro-2H-benzo[b][l ,4]oxazine (1200 mg, 4 39 mmol. 1 equiv) m dioxane (12 ml,), was added 4,4,5,5-tsirameihyl-2-(4,4,5 5 ietraniethyl-l ,3,2~diOxaborolan-2-y!)~ 1 ,3,2-dioxaboro!ane ( 1340 g, 5.27 mmol, 1.2 equiv) and Potassium acetate (1291 mg, 13 17 mmol, 3 equiv). Aerated the reaction mixture with nitrogen gas for i 5 minutes. After addition of Pd(dppi) DCM ( 179 mg, 0.219 mmol, 0.5 equiv) again purge nitrogen for 5 min. The reaction mixture was heated to 100 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction the reaction mixture was diluted with water (30 niL) and extracted with EtOAc (100 ml, 2). organic layer was washed with brine ( 100 mL). The organic layer dried over anhydrous Na SCft and concentrated under reduced pressure to obtain 8-fliK>rG-4-isopropyl-6-(4,4,5,5-tetrainethyLl,3,2-diox:a borolan-2-yi)-3,4~dihydro~2H- benzo[b][! ,4]oxazme ( 1000 mg, 69%) as a dark brown viscous compound.

LCMS 322.1 i XI ! f j ⁺

[0208] Step-4: Synthesis of 6-(2-chIoro-5-fltioropyrimidm-4-yl)-8-t1uoro-4-isopropyI-3, 4-dihydro-2H-benzo[b] |I,4|oxaz«ae: To a stirred solution of 2, 4-dichloro-5-fluoropyrimidine (500 mg, 3.01 mmol, 1 equiv) and 8~fluoro~4~isopropyl~6~(4,4,5.5-tetramethyi-l,3,2- dioxaboro!an-2-yl) 3,4-dihydro-2H benzo[b|i!,4]oxazine (970.1 mg, 3.01 mmol, 1 equiv) in THF; Water (1 : 1, 16 mL) was added Potassium carbonate (831 mg, 6 02 mmol , 2 equiv) and PdiPPlyft (174 mg, 0 1 5 mmol, 0.05 equiv) The reaction mixture was heated to 80 °C for 4 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (30 ml,) and extracted with EtOAc (100 mL x 2), organic layer was washed with water (100 ml,) and brine solution (100 ml,). The organic layer dried over anhydrous N SCE and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-(2-chloro~5~ fluoropyrimidin-4-yi)-8-fluoro-4-isopropyl-3, 4-dihydro-2H-benzo[b]| l ,4]oxazine (800 rng, 82%) as a yellow solid compound

LCMS 326 [M fHj ⁺

[0209] Step-5: Synthesis of tert-butyi 4-(2-((5~flaoro-4-(8~flaoro-4~isopropyi-3,4~ dihydro-2II-benzo[b][i,4]oxazm-6-yl}pyrimidin-2-yl)amino)pyr «dm-4-yi)piperazine~l~ carhoxylate: To a solution of 6-(2-chlorO 5--fiuoropyrimidin-4-y!)-8-fluoro-4-isopropyft3, 4- dihydro-2H--benzo| b][l ,4]oxazme (150 mg. 0.461 mmol, 1 equiv) in Dioxane (10 ml,), was added tert-butyi 4-(2-arninopyndin-4-yl)piperazine-l -carboxylate (141 mg, 0 507 mmol, 1.1 equiv) and cesium carbonate (225.4 mg, 0.691 mmol, 1 5 equiv). The reaction mixture was aerated with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.009 mmol, 0.02 equiv) and BINAP (12 mg, 0.018 mmol, 0 04 equiv) again purge nitrogen for 5 min. The resultant reaction mixture was stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. Alter completion of me reaction, the reaction mixture was diluted with EtOAc (25 ml,). Solid observed was filtered and washed with Et()Ac(20 mi,) to obtain tort·· butyl 4--(2-((5-fluoro-4-(8-fluoro-4-isopropyb3,4 dihydro--2H-benzo[b][i ,4]oxazin--6-- yl)pyrmiidin~2~yl)amino)pyridin-4-yi)piperazine-l -carboxylate ( 140 mg, 53%) as a yellow solid compound.

LCMS 568.3 [M+H]

[0210] Step-6: Synthesis of S-t1uoro-4-(8-t1uoro-4-isopropyI-3, 4-dfliydro-2H-benzo[b] [l, 4]oxazin-6-yl)~ -(4-(piperazin-l-yl)pyridm-2-yl)pyrimiilIn-2-arame: Tert- butyl 4-(2-((5- fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[bl[l ,4]oxazm-6-yl)pyrimidin~2~ yl)ammo)pyndin-4-yl)piperazine~l ~carboxyiate (140 mg, 0.246 mmol, 1 equiv) was taken in 1 .25M HC1 in ethanol (5 i,) and the resultant reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by I, CMS. After completion of the reaction, the reaction mixture was concentrated under vacuum to obtain 5~iluoro~4~(8~iluoro~4~isopropyl~3, 4-dihydro- 2H-benzo[b][l , 4]oxazin-6~yl)-N~(4-(piperazin-l ~yl)pyridin-2-yl)pyrimidin~2~amine (1 10 mg, 83%) as a yellow solid compound.

LCMS 468.2 [M+H]

¹ HNMR (400 MHz, METHANOL-d ₄ ) d 8.61 (d, J = 3.95 Hz, 1H), 8.02 (d, J= 7 24 Hz, 1H), 7.50 (s, 1H), 7.31 (d, 7 1 1.40 Hz, 1 H), 6 95 - 7.03 (m, 1 H), 6 66 (d, J= 2. 19 Hz, 1H), 4.31

4.37 (m, 2H), 4.22 (m, HI), 92 (s, 4H), 3.42 (s, 4H), 3.37 - 3 50 (m, 2H), 1.2 1 33 (d, 6H)

Example-6: Synthesis of 5-fluoro-4-(8-fluoro-4-isopropyi-3, 4-dihydro-2H-benzo[bj /!/, 4/oxazin- 6-yl)-N-(4-(4-methylpiperazin-l-yl)phenyi)pynmidin-2-amine (Compound 6):

[0211 j Step-1 : Synthesis of 6-bromo-8-fluoro-4-isopropyi-2H-ben*o[h] [1 ,4]oxa*in-

3(4II)-o«e: To a stirred solution of 6-brGnio-8-fiuoro-2H-benzo[h][l ,4]oxazin-3(4H)-one (7000 mg, 28.56 mmol, 1 equiv) in DMF (70 mL), was added NaH (60%) (2282 mg, 57.12 m ol, 2 equiv) at 0 C and stirred for 30 min at RT, followed by the addition of 2- odopropane (5.6 ml,, 57.12 mmol, 2 equiv). The reaction mixture was heated to 80 °C for 3 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture cooled to RT and quenched with ice-cold water (100 ml,) and extracted wit EtOAc (150 mL x 3), organic layer was washed with water ( 150 ml,) and brine solution ( 150 ml,). Organic layer dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 0-hromo-8-fluoro-4-isopropyi-2H~ benzo[b][! ,4]oxazin-3(4H)-one (2400 mg, 29%) as off white solid compound.

LCMS 288 [M-HR] ⁺

(0212] Step-2: Synthesis of 6-bromo-8-fluoro-4-isopropyl-3 _¾ 4~dihydro-2H- bemzo[b] [L4]oxazlne: To a stirred solution of 6-bromo~8~iluoro~4~isopropyl~2H- benzo[b][! ,4]oxazin-3(4H)~one (1400 mg, 4.87 mmol, 1 equiv) in THF (14 ml,), was drop wise added B1L.DMS (9 7 ml,, 7.66 mmol, 4 equiv) at 0 C The reaction mixture was heated to 80 °C for 16 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated solution of NaHCCL (100 ml,) and extracted with EtOAc (100 mL ^x 3) The combined organic layer was washed with water (100 ml ,) and brine solution (100 ml ,). Organic layer dried over anhydrous NasSCft and concentrated under reduced pressure to obtain 6-bromo-8-fluoro-4- isopropyl-3, 4-dihydro-2H- benzo[bj[l,4]oxazme (1200 mg, 90 %) as a yellow viscous compound.

LCMS 274 [M FHj ⁺

[0213] Step-3: Synthesis of 8-f1«oro-4-isopr«py1-6-(4, 4,5, 5-tetramelhyI-1,3,2- dioxaboroIan-2-yl)-3,4-dihydro-2H-benzo[b][l,4]oxaz«nei To a stirred solution of 6-bromo-8- fl uoro-4-i sopropy 1 -3 , 4-dihydro--2!:I-benzo[b][ l ,4]oxazine (1200 mg, 4 39 mmol. 1 equiv) m dioxane (12 mL), was added 4,4,5,5-tsirameihyl-2-(4,4,5 5-tetraniethyl-h3,2~diOxaborolan-2-y!)~ 1 ,3,2-dioxaboro!ane ( 1340 g, 5.27 mmol, 1.2 equiv) and Potassium acetate (1291 mg, 13 17 mmol, 3 equiv). Aerated the reaction mixture with nitrogen gas for i 5 minutes. After addition of Pd(dppi) DCM ( 179 mg, 0.219 mmol, 0.5 equiv) again purge nitrogen for 5 min. The reaction mixture was heated to 100 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction the reaction mixture was diluted with water (30 niL) and extracted with EtOAc (100 ml, 2). organic layer was washed with brine ( 100 mL). The organic layer dried over anhydrous Na SCft and concentrated under reduced pressure to obtain 8-fliK>rG-4-isopropyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxab orolan-2-yi)-3,4~dihydro~2H- benzo[b][! ,4]oxazme ( 1000 mg, 69%) as a dark brown viscous compound.

LCMS 322.1 i XI ! f j ⁺

[ 0:2141 Step-4: Synthesis of 6-(2-chIoro-5-fltioropyrimidm-4-yl)-8-t1uoro-4-isopropyI-3,

4-dihydro-2H-benzo(b] jl,4joxazme: To a stirred solution of 2, 4-dichloro-5-fluoropyrimidine (500 mg, 3.01 mmol, 1 equiv) and 8~fluoro~4~isopropyl~6~(4,4,5.5-tetramethyi-l,3,2- dioxaborolan-2~yl)-3,4-dihydro-2H-benzofbl[l,4]oxazine (970.1 mg, 3.01 mmol, 1 equiv) in THF; Water (1 : 1, 16 mi,) was added Potassium carbonate (831 mg, 6 02 mmol , 2 equiv) and PdiPPlyft (174 mg, 0 1 5 mmol, 0.05 equiv) The reaction mixture was heated to 80 °C for 4 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (30 ml,) and extracted with EtOAc (100 ml, x 2), organic layer was washed with water (100 ml,) and brine solution (100 ml,). The organic layer dried over anhydrous Na^SCft and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-(2-chloro~5~ fluoropyrimidin-4-yi)-8-fluoro-4-isopropyl-3, 4-dihydro-2H-henzo[b]P ,4]oxazine (800 mg, 82%) as a yellow solid compound.

LCMS 326 [M fHj ⁺

[0215] Step-5: Synthesis of 5-f! uoro~4~(8-f! uoro-4-lsopropyl-3, 4-dihydro-2H~ benz©[b][l,4]oxaziR-6-yI)~N-(4-(4-raethyipiperaziR-l-yI)phe nyi)pyrimidin-2-asnine: To a solution of 6-(2-chloro-5-fluoropynrnidm-4-yl)-8-fluoro-4-isopropyl-3, 4-dihydro-2H~ benzo[b][! ,4]oxazine (150 mg, 0 461 mmol. 1 equiv) m Dioxane (10 mL), was added 4-(4- methy!piperazin-l-yl)aniline (97 mg, 0 507 mmol, 1.1 equiv) and cesium carbonate (225.4 mg. 0.691 mmol, 1.5 equiv). The reaction mixture was aerated with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 g, 0.009 mol, 0 02 equiv) and BINAP (12 mg, 0.018 mmol, 0.04 equiv) again purge nitrogen for 5 min. The resultant reaction mixture was heated to 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with EtOAc (25 niL) Solid observed was filtered and washed with EtOAc (20 mL) to obtain crude compound which was purified by- reverse phase HPLC to afford 5-fluoro-4-(8~fluoro-4-isopropyl-3,4-dihydro-2H- benzo bl[l,4]oxazin-6-yl)-N~(4-(4-methylpiperazin-l -yl}phenyl)pyrmiidin~2-amine (100 mg, 45%) as a yellow solid compound.

LCMS 481.2 [M÷H] ⁺

*H MR (400 MHz, Methanol-d ) d 8.40 ( , ./ = 3 95 Hz, 1 1 1 ;. 7.44 · 7.59 (m, 7 8 77 Hz,

2H), 7.40 (s, 1H), 7.12 (d, J = 11.62 Hz, 1H), 6 74 -· 6.90 (m, 7 8.99 Hz, 2H), 4.25 (s, 2H), 4.03 4.12 (m, 1H), 3.25 (s, 2H), 3.03 (s, 4Ή), 2.44 (s, 4H), 2.18 (s, 3H), 1 14 (d, 7 6.36 Hz, 6H).

Example -7: Synthesis of E(6-(2-((5-((4-ethyIpipen^zirmEy!)meihyIjryndm-2-yIjammo)-5- fliioropyriffiidin 4 yl)~8fliioro~2, 3aEh)Ero-4H-Eenzofb I f 1 E Joxaz -EyUethan- Eone

j0216| Step- !:; Synthesis of 6-(2-chl0ro-5-flu0r0pyrimidm-4-yl)~8-fluoro-3y4-ilifaydr0-

2H~beiizo[h] j 1,4 joxazine: 6-(2-chloro-5-fluoropyrmiidin~4-yl)~8~fluoro-3,4-dihydro-2H- benzoib|[I,4 joxazine (9243 mg, 33 12 mmol, 1.1 equiv), 2,4-dichloro~5~fluoropyrimidine (5.0g , 30.12 mmol, 1.0 equiv). Potassium carbonate (8 3 g, 60.24 mmol, 2 equiv), but hPh b (1.74g, 1 50 mmol, 0 05 equiv) and THF: Water (1 : 1= 40 mL) were charged The reaction mixture was allowed to stir at 80 °C for overnight. Progress of the reaction was monitored by TLC and I.CMS. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL * 2), organic layer was washed with water (200 mL), brine solution (200 rnL) and dried over anhydrous Na^SO. Concentrated under reduced pressure to obtain crude compound, which was purified by ether and pentane washing, recrystallization to obtain 6 (2 ChlorO 5 iluoropynmidim4-yl) 8 tIuorO 3,4 dihydrO 2H benzo[b)[l ,4 joxazine (4000 rng,) as a yellow solid compound

y S o LCMS 284 [M-i-Hj

[0217 Step-2: Synthesis of l-(6-(2-chIoro-5-fiuoropyrimidm-4-yl)-8-fluoro-2 _i 3-d«hyclro-

4H-benzo|h] {l,4|oxaz«i~4-yl)ethan~l~oiie: To a stirred solution of 6-(2-chloro-5- fluoropyrimidirs~4~yl)-8-fluoro-3,4 dihydtO 2H-benzoib [l,4]oxaziiie (300 mg, 1.06 mmol, 1 equiv) in DCM (20 mL), was added triethy! a mo (0 37m!, 2 65 mmol, 2.5 equiv) at 0 C Stir the reaction mixture for 30 mm. at RT, followed by the addition of acetyl chloride (124 mg, 1.59mmol). The reaction mixture was allowed to stir at RT for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted wit EtOAc (50 mL >< 3), organic layer was washed with NaHCQ- (! 00 ml,), brine solution (100 ml,) and dried over anhydrous Su SO _; Concentrated under reduced pressure to obtain crude compound, which was purified by recrystallization in ether and pentane to obtain l -(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2,3-dihydro-4 H- benzo[b] [1 ,4]oxazin-4-yl)ethan- 1 -one (200 mg) as off white solid compound.

LCMS 326 [MΉB] ⁺

[0218] Step-3: Synthesis of l-(6-(2-((5~((4~ethylpiperazia-l-yi)methyi)pyridia-2- yl)amino)-5-fluoropyrimidin-4-yl)-8-f!uoro-2,3-dihydro-4H-be nzo(bJ [l,4]oxa*in-4-yl)ethan-

Lone; To a solution of l -(6-(2-chjoro-5-fiuoropyrimidin-4-y])-8-fluoro-2,3-dihydro-4 H · benzo[bl[l,4]oxazin~4~y!)etban~! -one (200 mg, 0.676 mmol, 1 equiv) in Dioxane (10 ml,), was added 5-((4-eihylpipeiaziml-y!)methyl)pyridin--2-amine (162 mg, 0 738 mmol, 1.1 equiv) and cesium carbonate (299 mg, 0.918 mmol, 1.5 equiv). The reaction mixture was aerated with nitrogen gas for 30 min , followed by the addition of palladium acetate (6.8 mg. 0.030 mmol,

0.05 equiv) and BINAP (19.12 mg, 0.030 mmol, 0 05 equiv). The resultant reaction mixture was stir ai 100 °C for 16 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (50 ml,) and extracted wit EtOAc (50 ml, 2), organic layer was washed with NaPICCti (100 mL), brine solution (50 mL x 3) and dried over anhydrous Na SCft. Concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase combi-flash chromatography to obtain l-(6-(2- ((5-((4-ethylpiperazm-l -y]}methy!)pyridin-2-yi)ammo)-5~fluoropyrimidin-4-yl)-8-fluo ro-2,3 dihydro-4H--benzo[b]p ,4]oxazin-4-yi)ethan-] -one (50mg, 97 84%) as a yellow solid compound

LCMS 510.1 [M t H]

84 ^s tlNMiR (400 MHz, DMSO-de) d 9.96 (s, IH), 8.66 (d, / 3.95 Hz, HI), 8 12 8.28 (m

2H), 7.62 7.77 (m, 2H) 4.34 - 4.54 (m, 2H), 3.92 - 4.03 (m, IH), 3 43 (s, 2H), 2 21 2.44 (m 7H), 0.97 (t, J = 7.24 Hz, 2= 1 )2 = - 2.44 (m, I OH), 0.97 (t, 7 7.24 Hz, 3H).

Exampie-8 : Synthesis of cycloprop}’l{6~(2~((5~((4~ethyIpiperazi?i~J~y!)methyi)pyri dm~2~ yl)ammo}~5~fJuoropyrimidm 4 yI}~8~fJuoro~2,3 dihydro-4H-hemo[b] fiA]oxazin~4~yl)nieihanone

(Compound 8):

[0219] Step-1:: Synthesis of (6-(2-chIoro-5-fiuoropyrimidin-4-yl)-8-fluoro-2 dihydro- 4H-benzo[b] [l,4]oxa*in-4-yl)(cyclopropyl)inethanone: To a stirred solution of 6-(2-ehloro-5- iluoropymmdin-4-yl)-8-fluoro-3,4-dihydro-2H-benzo[b](l,4]oxa zine (300 mg, 1.06 mmol, 1 equiv) in DCM (10 mL), was added tnethyl amine (0.37ml. 2,65 mmol, 2 5 equiv) ai 0 °C.

Stirred the reaction mixture for 30 min at RT, followed by addition of cyciopropanecarbonyi chloride (165 mg, 1 59 mmol). Hie reaction mixture was allowed to stir at RT for I6h Progress of the reaction was monitored by TLC and LCMS. Alter completion of the reaction, the reaction mixture was diluted with water (50 ml,) and extracted wit EtOAc (50 mL x 3) organic layer was washed with NaHCO* (100 mL) brine solution (100 mL) and dried over anhydrous NafoCL. Concentrated under reduced pressure to obtain crude compound, which was purified by recrysiailizalion in ether and pentane to obtain (6-i2-ehloro~5~fIuoropymnidin-4-yi)-8-fluoro- 2,3-dihydro-4H-benzo[b][ l,4]oxazin-4-yl)(cyciopropyl)methanone (300 mg) as off white solid compound.

LCMS 352 [MH4]

[0220] Step-2:Synthesis of cydopropyi(6-(2-((5-((4-ethyipipera2in-I-yi)methyl)pyridin- 2-yl)ammo)-5-fluoropyrimidm-4-yl)-8-!1uoro-2 _i 3-d«hyclro-4H-ben*o!b] [l,4]oxa2iii-4- yi)metbanone: To a solution of (6-(2-chloro-5-fluoropyrmiidin~4-yl)~8~fluoro-2,3-dihydro-4H - benzo[b][ l,4]oxazin-4-yl)(cyciopropyl)methanone (200 mg, 0.676 mmol, 1 equiv) in Dioxane (10 mL), was added 5-((4-ethylpiperazin- 1 -yl )methyl)pyridin-2-amine (162 mg, 0.738 m ol, 1.1 equiv) and cesium carbonate (299 mg, 0.918 mmol 1 5 equiv). The reaction mixture was aerated with nitrogen gas for 30 min followed by the addition of palladium acetate (6.8 g, 0.030 mmol, 0.05 equiv) and BINAP (19.12 mg, 0.030 mmol, 0.05 equiv). The resultant reaction mixture was stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 niL) and extracted wit EtOAc (50 mL ^x 2), organic layer was washed with Na!ICCti (100 ml), brine solution (50 ml, ^x 3) and dried over anhydrous NafoCfo Concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase combi-flash chromatography to obtain cycloprGpyl(6-(2-((5-((4~ethylpiperazin-l -yl)methyi)pyridin~2~yl)ammo)~5~

fo30ropyrimidin 4-yl)~8~fluoro~2,3-dihydro-4H~benzo[b][ l ,4]oxazin-4-y1)rnethanone (80rng) as yellow solid compound.

LCMS 536 [MLB] ⁺

*H NMR (400 MHz, DMSG-de) d 9 98 (s, 1 H), 8 66 (d, J= 3.95 Hz, 1H), 8.43 fbr. s„ i l l ;. 8.11 - 8 27 (m, 2H), 7.63 - 7 80 f , 2H), 4.47 (t, J= 4. 17 Hz, 2H), 4.09 (br. s , 2H), 3 42 (s, 3H), 2.38 (br s., 3H), 2.24 - 2 35 f , 4H), 2. 1 1 - 2.24 (m, 5H), 0.94 - 1.06 (m, 3H), 0.89 (dd, / 3.73,

6.80 Hz, 21 1 }

Example-9: Synthesis of4~(4~(4~aminocyclohexyi)~S~fluoro~3, 4-dihydro~2H~

henzofhj [ l,4]oxazin-6-yl)-N-(5-((4-el.hy]piperaz n-l-yi)meihyl)pyridin-2-yl)-5-fluorofyyrimidin-

[0221] Step- 1 : Synthesis of tert- butyl (4-(6-(2-((5-((4-ethylpiperazin-l- yl)methyl)pyridm-2-yl)amino)-5-fliioropyrimid«n-4-yl)-8-tlu oro-2 3-dfliydro-4H- benzojb j [1,4] oxaz«B-4-yl)cyciohexyl)carbamate: To a solution of 4-(4-((tert- butoxyearbonyl)amino)cyciohexyl)-6~(2~chloro-5-fluoiOpyrimid in-4-yi)-8-fluoro-2H- benzo[b] [l ,4]oxazm-4-ium (100 mg, 0.31 mmol, 1 equiv) in dioxane (4 mL), was added 5-((4- ethylpiperazin-l-yl)rnethy!)pyridin-2-amine (82 nig, 0 34 mmol, 1 1 equiv), and cesium carbonate (151 mg 0.47 mmol. 1 5 equiv). The reaction mass was degassed by the purging nitrogen for 10 min. After 10 mm, BINAP (6.5 mg, 0.0123 mmol, 0.04 equiv), and Pd(OAc) ₂ (1.4 mg, 0.0062 mmol, 0.02 equiv) were added, followed by nitrogen purging for 10 min.

Resultant reaction mixture was stirred at 100 °C for 16 h. Reaction was monitored by 1 ( ^' MS. After completion of reaction, reaction mass was diluted with water (5 mL) and extracted with EtOAc (3x1 OmL). Organic layer was passed through the anhydrous NafoCfi, filtered and concentrated the organic layer under reduced pressure to afford 200 mg crude desired product. Crude compound was purified by combi-flash and further purified by reverse phase HPLC to afford 30 mg tert-butyl (4-(6-(2-((5-((4-ethyIpiperazin-l-yl)methyl)pyridin-2-yl)ami no)-5- fiuoropyriinidin-4-yf}-8-fluoro-2,3~dihydro~4H-benzo[b][l,4] oxaz:in~4~yi)cyclohexyI)carbamate.

LCMS 665 [M+Hjf

[0222] Step-2: Synthesis of 4-(4-(4-amiaocyclohexyl)-8~fluoro-3 _> 4-dihydro-2H~ benzo[b]jI,4ioxaz«B-6-yl)-N-(S-((4-ethy!pipei in-l-yl)methyl)pyridin-2-yl)~5”

fluoropyrimidin-2-amine: To a solution of tert-butyl (4-{6-(2-((5~((4~ethy!piperazin-l - yl)methy!)pyridin-2-yl)amino)-5-fluoropyrimidin-4-y!)-8-fluo ro-2,3-dihydro-4H- benzo[b][l ,4]oxazin-4-yl)cyclohexyl)carbamate (20 mg) m 1.25M ethanolic HCI (3 mL) The resultant reaction mixture was stirred at 40 ^: C for 16 h. Reaction was monitored by ! .( MS. After completion of reaction, filtered the solid product and washed with diethyl ether and dried under reduced pressure to afford 10 mg of 4-(4-(4-aminocyclohexyl)-8-iluoro-3,4-dihydro-2H- benzo b] l ,4]oxazin-6-yl)-N-(5-((4-ethylpiperazm-l -yl)methyl)pyridin-2-yl)-5-fluoropyrimidin- 2-amine hydroeh!ori de. , ethanol-i 4) d 8.73 (s, 1H), 8.65 - 8.42 (m, 21 h. 7.69 (t, ./ 13.2 Hz,

IHi 7.57 (s,l H), 7 38 (d, / 1 1.3 Hz, i l l ) 4.36 id ./ 25.9 Hz, 4H) 3.96 - 3 36 (m, 14H), 3.20

(d, J ------ 18.4 Hz, 5H), 2.18 (s, 2H), 2.03 i 88 i m 5H), 1.76 (s, 7H), 1 .45 - 1.22 (m 6H), 1 .21 (s

4H), 0.89 (dd, J ----- 16 3 7.6 Hz, 2H).

Example- 10: Synthesis of 5-fluoro-4-(8-fluoro-4-isopropyI-3,-l~dihydro~2H-be ofhJfJ4joxazm- 6-yl)~M-(5-(3-methylpiperazin-l-yi)pyndm-2-yi)pyrimidin-2-am ine (Compound 10):

[0223] Step- 1. ^* Synthesis of tert-butyi 4-(6~((5-fluoro~4~(8-fluoro~4-isopropyl-3,4- dihydro-2H-benzo[b]il _» 4]oxa¾in-6-yi)pyrimi in-2-y1)amino)pyridm-3-yl)-2- raethyipiperazine-l-earboxylate: To a solution of 6-(2-c-hIoro-5-fluoropyrimidm-4-y!)-8- fluoro-4-isopropyl-3,4-dibydro-2H-benzo[b] [ 1 ,4]oxazine ( 100 mg, 0 31 mmol , 1 equiv) in dioxane (5 ml..), was test-butyl 4-(6-ammopyridin-3-yl)~2-methylpiperaziiie-l -carboxylate (98 mg, 0.34 mmol, 1 1 equiv), and cesium carbonate (151 mg. 0.47 mmol, 1.5 equiv). The reaction mass was degassed by the purging nitrogen for 10 min After 10 min. BINAP (7 7 mg, 0 0123 mmol, 0 04 equiv), and PdiOAcfo (1.4 mg, 0.0062 mmol, 0 02 equiv) were added, followed by nitrogen purging for 10 min. Resultant reaction mixture was stirred at 100 °C for 28 h Reaction was monitored by LCMS. After completion of reaction, reaction mass was diluted with water (5 niL) and extracted with EtOAc (3 x !O L). Organic layer was passed through the anhydrous NafoCN, filtered and concentrated the organic layer under reduced pressure to afford 200 mg crude desired product Crude compound was purified by combi-flash and further purified by reverse phase 1 114 ( to afford 50 mg of tert-butyi 4-(6-((5-tIuoro-4-(8-tIuoro-4~isopropyl-3,4- dihydro-2H~benzo| bin ,4]oxaxin-6-yi)pynrmdin-2-yi)amino)pyridin-3-yl) 2-methylpiperaxine-1 - carboxylate.

LCMS 582

[0224] Step-2: Synthesis of S-fluorG-d^S-fluoro-d-isopropyl-Syi-dihydro-lil- benzofblll^joxazm-d-ylJ-N^S^S-methylpipeimm-l-yljpyridin-l-j ^pyrimidm-l-amiiie: To a solution of tert-butyi 4-(6-((5-fiuoro-4-(8-fiuoro-4-isopropyl-3,4-dihydro-2å-j- benzolb][l, 4 joxazin-6-yi)pyrimidin-2-y!)amino)pyridin-3-yj) 2-meihyj piperazine- 1 -carboxylate

(50 mg) in 1.25M ethanoiic HCi (3 nxL) The resultant reaction mixture was stirred at RT for 16 h. Reaction was monitored by LCMS. After completion of reaction, filtered the solid product and purified by reverse phase HPLC to afford 13 mg of 5-fluoro-4-(8-fluoro-4-isopropy!-3,4- dihydro-2H-benzo| b] [1 ,4]oxazin-6-yi}-N-(5~(3~methylpiperazin- 1 -yj)pyndm~2~yl)pyrimidin-2- amine hydrochloride. LCMS 482 [M÷Hf

¾ NMR (400 MHz, Methanol-foi) 6 8 40 (d, 4 0 Hz 1 H), 8 18 id, - 9.1 Hz, I B), 8.04 - 7.98 (m, 1H), 7.50 (q, J = 4 2, 3.5 Hz, 2H), 7.24 (d, J = 11 6 Hz, 1H), 4.36 - 4.29 (m, 21 ft. 4.21 (p, ./= 6.8 Hz, 1 H), 3.62 (t, J = 13.8 Hz, 2H), 3 39 - 3.33 (m, 2H), 3.26 (s, 3H), 3.21 - 3 13 (m, 1 H), 2.88 (t, J ^:::: 11.6 Hz, HI), 2 59 0. ./ 11.3 Hz, 1 I B. 1.94 (s, 4H), 1 27 (dd, .7= 10.9, 6 4 Hz,

12H), 0.90 (s, 1H).

Example- 11 : Synthesis of 5-fluoro-N-(2-fluoro-4-(piperazin-l-yI)phenyI)-4-(8~fluoro-4 -

[0225] Step-1: Synthesis of tert-butyl 4-{3-fluoro-4-{{5-fluoro-4-{8-fluoro-4-isopropyI- 3,4~d«hydro-2H-beRzo[b][l,4]oxazm-6-yi)pyr«nMdm-2-yl}afnmo )phenyl)p«pera2:ine-l- carboxylafe: To a solution of 6-(2-chloro-5-fIi oropyrimidin-4-yl)-8-f3uoro-4-isopropyl-3 4- dihydro-ZH-benzo[b] [ 1 ,4]oxazine (100 mg, 0 31 mmo!, 1 equiv) m dioxane (4 ml ,), was tert- butyl 4-(4-ainino-3-fiuorophenyl)piperazine-l-carboxylate (101 mg 0.34 mmol, 1.1 equiv), and cesium carbonate ( 151 mg, 0.47 mmol, 1 5 equiv). The reaction mass was degassed by the purging nitrogen for 1 0 min. After 10 min, BINAP (7 7 mg, 0.0123 mol, 0.04 equiv), and Pd(OAc) ₂ (1.4 mg, 0.0062 mmol, 0.02 equiv) were added, followed by nitrogen purging for 10 min. Resultant reaction mixture was stirred at 100 °C for 24 h. Reaction was monitored by LCMS. After completion of reaction, reaction mass was diluted with water

(5 ml . ) and extracted with EtOAc (20mL x 3 j. Organic layer was passed through foe anhydrous Na SCft, filtered and concentrated foe organic layer under reduced pressure to afford crude desired product. Crude compound was purified by purified by reverse phase HPLC to afford 75 mg of tert-butyl 4-(3~fluoro-4-((5~fluoro-4-(8~fluoro-4-isopropyl-3,4-dihydro -2H- benzo[b][l,4]oxazin 6-yijpynnudm-2-yi)amuiojpheny!)prperazine--l--carboxyiate.

LCMS 585 [M÷H] 10226] Step-2: Synthesis of S-t1uoro-N-(2-(luoro-4-(piperazui-l-yl)phenyI)-4-(8-fl«oro- 4- isopropyl-3,4-dihydro-2H-ben2o b] [l,4]oxa2m-6-yl)pyrimidui-2-amine: To a solution of tert- butyi 4-(3~fluoro-4-((5~fluoro-4-(8~fluoro-4~isopropyl-3,4-dihydiO -2H~benzo[b][l,4]ox;azin-6- yl)pyrimidin~2~yl)amino)phenyl)piperazme~l~carboxylate ("5 mg) in 1.25M ethanolic HC! (3 niL) The resultant reaction mixture was stirred at 50 °C for 1 h. Reaction was monitored by LCMS. After completion of reaction filtered the solid product and dried under reduced pressure to afford 71 mg of 5~fluoro-N-(2-ftuoro-4-(pipera:zm-l~yl)phenyl)-4-(8-f!uoro-4 -isopropyi-3,4~ dihydro-2H-benzofbl[l,4]oxazin-6-yl)pyrimidm~2~aminehydrochl oride.

LCMS 485 [M+Hf

NMR (400 MHz, Methanol-fol) 6 8.40 (d, ./ = 4.5 Hz, HI), 7.64 (d, J = 9.3 Hz, IH), 7.50 (s, 1H), 7.30 (d, J = 11.4 Hz, 1H), 7.02 - 6.89 (m, 2H), 4 37 - 4.30 (m, 2H), 4 10 (h, ./= 5.6 Hz, !H), 3.50 (s, 4H), 3.39 (s, 3H), 1.22 (d, ,/= 6.1 Hz, Oi l)

Example- 12: Synthesis of5~fiuoro-N-(3~fiuoro-4-(pipefxmn-l~yl)phenyl)-4-(8-flnoro- 4- isoprapyl~5, 4~diiiydro~2H~henzo[h( jp4]oxazin~6~yi)pyrimidln~2~mnine hydrochloride

[0227] Step-1: Synthesis of tert-but l 4-(2-fl«oro-4-((5-fluoro-4-(8-fluoro-4-isopropyl- 3,4-dihydro-2H-ben¾o[b][l,4|oxazin-6-yl)pyrimidin-2-yI)afnH H))phenyl)piperazine-l- carhoxyiate: To a solution of 6-(2-chloro--5--iluoropynmidln-4--yl)-8-fluoro-4-isopropy 1-3,4- dihydro-2H-benzo[b]p ,4]oxazine (100 mg, 0.31 mmol, 1 equiv) in dioxane (4 mL) was added ten-butyl 4-(4-amino-2-iIuorophenyt)pipsrazine-1 -carhoxyiate (82 mg, 0 34 mmol, 1.1 equiv), and cesium carbonate (151 mg 0.47 mmol, 1 .5 equiv). The reaction mass was degassed by the purging nitrogen for 10 min. After 10 m , BINAP (6.5 mg, 0.0123 mmol, 0.04 equiv), and Pd(OAc) ₂ (1.4 mg, 0.0062 m ol, 0 02 equiv) were added, followed by nitrogen purging for 10 min. Resultant reaction mixture was stirred at 100 °C for 16 h Reaction was monitored by LCMS. After completion of reaction, reaction mass was diluted with water (5 mL) and extracted with EtOAc ( 10 mL x 3). Organic layer was passed through the anhydrous Na SCti, filtered and concentrated the organic layer under reduced pressure io afford 200 g crude desired product. Crude compound was purified by combi-flash and further purified by reverse phase HPLC to afford 30 mg of tert- butyl 4-(2~fluoro-4-((5~fluoro-4-(8~fluoro-4-isopropyl-3,4-dihydro -2H- benzo[b][l,4]oxazm-6-yl)pyrmiidin~2~yl)amino)phenyl)piperazm e~l ~carboxy ^j ate.

LCMS 585 [MMl

|0228j Step-2: Synthesis of S-t1«oro-N-(3-Huoro-4-(piperazin-l-y!)phenyI)-4-(8-fliioro- 4-

«sopropyi-3,4-dihyt1ro-2H-benzo b] (l,4)oxazin-6-yi)pyrimidin-2-ainine hydrochloride: To a solution of tert-buty! 4-(2-fluoro-4-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro -2H- benzo[bl [l,4]oxazin-6-yl)pyrimidin-2-yi}ammo)phenyl)piperazine- 1 -carboxylate (20 mg) m 1.25M ethanolic HCI (3 mb). The resultant reaction mixture was stirred at 40 °C for 16 h.

Reaction w¾s monitored by LCMS. After completion of reaction, filtered the solid product and washed with diethyl ether and dried under reduced pressure to afford 10 g of 5-fluoro-N-(3- f! uoro-4-(piperazin~ 1 ~yl)phenyI)-4-(8-f1uoro-4-isopropyI-3,4~dihydro-2H-beoz:o b][l,4]oxazin-6- yl)py rim idin- 2-amine hydrochloride

LCMS 485 j ÷H3 ⁺

*H NMR (400 MHz, Methanol-fol) d 8 38 (d„ / 4 3 Hz, I I If 7.82 (dd, / 14.9, 2 5 Hz,

1H), 7.56 (s, !H), 7.36 - 7.29 (m, 1 H), 7.29 - 7.23 (m, 1 H), 7 07 (t, 7 9 2 Hz, 1H), 4.37 - 4.19

(m, 31 1} 3 44 - 3.25 (m, I Oi l }. 2 68 (d, J= 1 5.3 Hz, 1 1 1). 1.55 (s, 2H), 1.32 - 1 27 (m, 3H), 1 .26 (d, ./ 6.6 Hz, 6HS 0.88 (dd, J === 12 7, 6.8 Hz, 2H).

Example-13: Synthesis ofN-(5~fluoro-4~(8~fliioro-4~isopropy]~3, 4-dihydro-2H-

[0229] Step- 1 : Synthesis of tert- butyl 6-((5-fluoro-4-(8-fl«oro-4-isopropyI-3,4-dihydro-

2H-ben2o|b [l,4]oxazm-6-yl)pyri idin-2-yl)amino)-3,4-dihydroisoqumoline-2(lH)- carboxylate: To a solution of 6-f2-chloro-5-fluoropyrimidin~4-yl)~8-fluoro-4-isopropyl-3,4 - dihyclro-2H-benzo[b] 1 ,4]oxazme (200 mg, 0.61 mmol, 1 equiv) in dioxane (10 mL), was added tert-butyi 6-annno-3,4 dihydroisoqmnohne-2(l Hpcarbox late (168 mg, 0 67 mmol, 1 .1 equiv} and cesium carbonate (298 mg 0.91 mmol. 1.5 equiv). Hie reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (3 mg, 0.01 mmol, 0.02 equiv) and BINAP (15 mg, 0.02 mmol. 0.04 equiv). Hie resultant reaction mixture was allowed to stir at 100 °C for 16 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mL) and extracted with EtOAc (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous NafoCft and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyi 6-((5-f!uoro-4-(8-fiuoro-4- isopropyj-3,4~dihydro~2H-ben o[b][l,4]oxazin-0~yl)pyrimidm-2-yI)ammo)-3,4- dihydroisoquinoline~2(lH) Carboxylate (80 mg, 24%) as a yellow solid compound

LCMS 538 4[M+Hjf

[02:30] Step-2: Synthesis ofN~(5~fluoro-4~(8-fluoro-4~isopropyi-3,4 _" dihydro-2H- benzo[b]il _» 4]oxa¾in-6-yi)pyrimidin-2-yl)- 2^,4-tetrahydroisoquinolin-6-ainine: A solution of ten-butyl 6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,d-dihydro-2H-benzo[b] [1 ,4]oxazim6- yl)pyrimidm~2-yl)ammo)~3,4-dihydroisoqumoline-2(1 H)-carboxyIate (90 mg, 0.11 mmol, 1 equi v) in 1 25 M HC! in ethanol (5 ml,) was allowed to stir for Ih at 50 °C Progress of the reaction was monitored by I, CMS. After completion of the reacti on, solvent was removed under reduced pressure to obtain N-(5-fluoro-4-(8-fluoro-4-isopiOpyl-3,4-dihydro-2!:I- benzo[b][l,4 |oxazin-6-yl)pyrimidin-2-yl)-l ,2,3,4-tetrahydroisoquino!in-6-annne (40 mg. 91%) as a brick red color solid compound

LCMS 438.4 [MH-B

¾NMR (400 MHz, DMSO-A6) 6 9.75 (s, 1 H), 9.41 (s, 1 H), 8.58 (d, J --- 3.9 Hz, IH), 7.68 - 7 59 (m,2H), 7.40 (s. I B), 7 15 (dd, J- 15.4, 10.0 Hz. 2B), 4 30 (t, J --- 4 2 Hz, 2H), 4.16 (dt, J ----- 25 2, 5.7 Hz,3H), 3.33 (dt, J --- 1 7 4, 4.3 Hz, 4H), 2.98 (t, / 6.3 Bz, 2B), 1 19 fd, J ---- 6.5 Bz,

6B).

Example-14: SyrUhesis of 5~fluoro~N~(3~fluoro~4~(4~meth\4piperazin~ I ~yi) phenyl)-4-(8-fiisoro-4- isopropyl~3, 4-dihydro-2H-henso[bJ[J 4] oxazin-6-yl) pyrimidin-2-amine (Compound 14):

[02:31] Step-1: Synthesis of tert-butyi 4-(2-fl«oro-4-((5-flluoro-4-(8-fliuoro-4-isopiOpyi- 3,4-d«hydiO-2H-henzo[b][l,4!oxazia-6-yi)pyrimidm-2-yl)ammo) phenyl)piperaziiie-l- carboxylate: To a solution of 6-(2-chloro-5-fiuoropyrimidin-4-yI)-8-fluoro-4-isopropyI-3,4 ~ dihydro-2H-benzo[b] [ 1 ,4]oxazine (300 mg, 0 92 mmol, 1 equiv) in dioxane (10 ml,), was added tert-butyi 4~(4-ammo-2-f]uoropheny{)pipera ine-i-carhoxylate (300 mg, 1.01 mmol, 1.1 equiv) and cesium carbonate (450 mg, 1 38 mmol. 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min. , followed by the addition of palladium acetate (4 g, 0.01 mmol, 0 02 equiv) and BINAP (23 mg, 0 03 mmol. 0 04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and 1 .CMS After completion of the reach ou. diluted with water (30 mL) and extracted with EtOAc (100 ml,). Orgame layer was washed with water (50 ml,) and brine solution (50 ml ,). Organic layer was dried over anhydrous Na SCft and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi ⁽ lash to obtain tert-butyi 4-(2-fluoro-4-((5-fluoro-4-(8- fluoro-4-isopropyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)p yrimidin-2- yl)ammo)pbenyl)piperazine-l -carboxylate (95 mg, 18%) as a yellow solid compound.

LCMS 584 [M-i-Hlf

[0232] Step-2:; Synthesis of 5~flm>ro-N-(3-fluor©-4-(pipera¾m~l~yl) pi iyI)~4~(8~fl«oro~

4-isopropyI-3y4-dihydro-2H-henzo(b] jJ ,4]oxazi«-6-yI)pyrhnidin-2-anmie: A solution of tert- butyi 4-(2-f!uoro-4-((5-f!uoro-4-(8-f!uoro-4-isopropyl-3,4-diliydr o-2B-benxo[b]S 1 ,4]oxazm--6- yl}pyrimidin-2-yi)amino)phenyl)piperazine-l -carboxylate (85 mg, 0 15 mmol, 1 equiv) in 1 .25 til HCI in ethanol (5 ml,) was allowed to stir for 1 h at 50 °C Progress of the reaction was monitored by LCMS. After completion of the reaction solvent was removed under reduced pressure to obtain 5-flnoro-N-(3-fluoro-4-(piperazin- l-yl) phenylV4-(8-fiuoro-4- isopropyl-3, 4- dihydro-2H-benzo[b] [ 1„ 4] oxazin-0-yl)pyrimidin-2-amine (80 mg. 95%) as an orange colour solid compound.

LCMS 484 [M H]

[0233] Step-3: Synthesis of 5-fl«oro-N-(3-tluoro-4-(4-methylpipera*m-l-yI) phenyI)-4- (S-fluoro-4-isopropyl-3, 4-dihydro-2H-benzo|b| (1, 4] oxazin-6~yl) pyrimidin-2-amine: To a stirred solution of 5~fli3oro~N-(3-fluoro-4-(piperazin~l-yl) pheny!y4-(8-iTuoro-4-iSopropy!-3, 4- dihyclro-2H-benzo[b][1 , 4] oxazin-6-yl}pyrimidin-2-amine (80 mg. 0 15 mmol, 1 equiv) in DCE (5 niL), was added HCHO in water (0.02 i . 0.46 mmol, 3 equiv), acetic acid (0.05 ml,, 0.75 mmol, 5 equiv) The reaction mixture was allowed to stir at RT for 1 h. The reaction mixture was cooled to 0 °C. NaCNBH- (29 mg, 0.46 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with EtOAc (50 ml, ^c 2). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5~fluoro~N-(3-fluoro-4-(4-me†hylpiperazin~l -yl)phenyl)-4-(8-fluoro-4- isopropyl-3, 4-dihydro- 2H-benzo[b][l ,4]oxazin-6-y])pyrimidin-2-amine (15 g, 19%) as a yellow solid compound. LCMS 499 i \l I P

*HNMR (400 MHz, DMSOM6) d 9 78 (s, l i ft. 8 57 (d, J= 3.9 Hz, 1H), 7.78 (dd, J = 1 5.2, 2.5 Hz, ] H),7.45 - 7.35 (rn, 2H), 7.16 (d, / 11.6 Hz, i l l). 7 03 (t, J --- 9 3 Hz, 1H), 4.30 (i, J ---

4 1 Hz, 2H), 4.15 (p, ./=== 6 7 Hz, 1H), 3.13 - 2.95 (m, 10H), 2.63 (s, 3H) 1.19 (d, J === 6.4 Hz 6H) iCumpk:-! 5: Synthesis ofN-(5-J?uoro-4-(8-Jh oro-4-isopropyi-3,4-dihydro-2H-

[0234] Step-1: Synthesis of tert-butyi 5-((5-fluoro-4-(S-flaoro-4-isopropyi-3,4- ihydro- 2H-benzofb1 (l,4]oxazin-6-yl)pyriraidin-2-yI)amino}-3,4-dihy roisoquinoline-2{lH)- carhoxyiate: To a solution of 6-(2-chloro-5--fluoropynmidln-4-yl)-8-iIuoro-4-isopropy 1-3,4- dihydro-2H-benzo[b]p ,4]oxazine (200 mg, 0.61 mmol, 1 equiv) in dioxane (10 mL), was added ten-butyl 5~amino-3,4-dihydrGiscqmnohne-2(1 H)-carbcxylate (168 mg, 0.67 mmol, 1 1 equiv) and cesium carbonate (298 mg, 0.91 m ol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (3 mg, 0.01 mmol, 0.02 equiv) and BINAP (15 mg, 0.02 mmol, 0.04 equiv). Hie resultant reaction mixture was allowed to stir at 100 °C for 16 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mL) and extracted with EtOAc (100 mL). Organic layer was -washed with -water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous NaACL and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to ten-butyl 5-((5-fluoro-4-(8~fluoro-4-isopropy!-3,4- dihydro-2H-benzo[b][l ,4]oxazin-6-yl)pyrimidin~2~yl)amino)~3,4-dihydroisoquino!ine -2{l H) - carhoxyiate (120 g, 36%) as yellow solid compound.

LCMS 538 4[M+Hjf

[0235] Step-2;; Synthesis of N-(S-flnoro-4-(8-flnoro-4-isopropyi 3,4-dihydro-2H

benzo[b]il _» 4]oxazin-6-yi)pyrimidin-2-yl)- 2^,4-tetrahydroisoquinolin-5-ainine: A solution of ten-butyl 5-((5-fiuoro-4-(8-fiuoro-4-isopropyl-3,4-dihydro-2H-benzo[b] [l 4]oxazin 6- yl)pyrimidin-2-yl)amino)-3,4-dihydroisoqumoline-2() H)-carboxylate (70 mg, 0.1 3 m ol, 1 equiv) m 1.25 M HC1 m ethanol (5 mil,) was allowed to stir for i h at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent -was removed under reduced pressure to obtain N~(5~£luofo-4~(8~iluofo-4~isopropy!~3,4 dihydro~2H~

benzo[bl[l,4 |oxazin-6-yl)pynrnidm-2-yi)-! ,2,3,4-tetrahydroisoquinolm-5-amme (55 mg. 89%) as a brick red color solid compound

LCMS 438.4 [Mt-Hf

(400 MHz, DMSO-46) 6 9.45 id. ./ 5.7 Hz, 1 H), 9.01 (s, 1 H). 8.48 (d, J - 4.0

Hz, 1 1 1) 7 59(d, J ------ 7 9 Hz. I B), 7 33 (s, I B), 7 25 (t, J - 7.8 Hz, I B), 7 07 (dd, J- 28.2, 9.6 Hz,

2H), 4.27 (q, J - 5 3, 4.6 Hz, 4B), 4 04 (h, J- 6.8 Bz, ! H), 3.31 (dt, J ---- 24.7, 4.6 Hz, 4B), 2 97 it,

J ^:::: 6.3 Bz, 2H), 1.1 5 (d, J -6.5 Hz, 6H) Example-! 6: Synthesis qfN~(S~fluoro~4~(8~fluoro~4~isopropyi~3, 4-dihydro-2H~

[0236] Step-1: Synthesis of tert-butyl 7-((5-fluoro-4-(S-flaoro-4-isopropyi-3,4- ihydro- 2H-benzo[b1 (l,4]oxazin-6-yl)pyriraidin-2-yI)amino}-3,4-dihy roisoquinoline-2{lH)- carboxylate: To a solution of 6-(2-diloro-5-fluoropyrimidin-4 -yl)-8-fluoro-4-isopropyl-3 _> 4- dihydro~2H--benzo[b][l,4]oxazme (200 mg 0.61 mmol, 1 equiv) n dioxane (10 mL) was added tert-butyl 7-ammo~3,4--dibydroisoquinoime--2(l H)~carboxylaie (1 68 mg, 0 67 mmol, 1.1 equiv) and cesium carbonate (298 mg, 0.91 mmol, 1 .5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (3 rng, 0.01 mmol, 0.02 equiv) and BINAP (15 mg, 0.02 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with EtOAc (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous Na ₂ SO* and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyl 7-((5-fluoro-4-(8-f!uoro-4- iSopropyl-3,4--dihydro-2H-benzo[b][1 ,4]oxazin--6--yi}pyrimidin-2-yi)amino)-3,4- dihydroisoquino!ine- 2(1 H)-carboxy late (100 mg, 30%) as a yellow solid compound.

LCMS 538 4 (M+H] ⁺

! 0237] Step-2: Synthesis of N-(5-fluoro-4-(8-fluoro-4-isopropyi-3,4-dihydro-2H- henzojbj [1 ,4]oxa2:in-0-yl)pyrimidin-2-yl)-i,2,3,4-tetrahydroisGq«iino lin-7-amme: A solution of tert-butyl 7-ii5-fiuoro-4-(8-fluoro-4-isoprop l-3,4-dihydro-2B-benzo[b][l ,4]oxazm-6- yl)pyrimidin-2-yi)amino)-3,4-dihydroisoqiiinoline-2{ lH)-carboxylaie (90 mg, 04 1 mmol 1 equiv) in 1 25 M HC1 in ethanol (5 nil,) was allowed to stir for 1 h at 50 °C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain N-(5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][l ,4]oxazin-6-yl)pyrimidin-2-yi)-l,2,3,4-tetrahydroisoquinolin -7-amine (80 mg, 79%) as a brick red color solid compound. LCMS 438.4 j U i

^! HNMR (400 MHz DMSO-A6} 6 9.75 (s, 1 Pi ), 9.41 (s, I H), 8.58 (d, J - 3.9 Hz, IH) 7.68 - 7.59 (m, 2H), 7.40 (s, 1H), 7.15 (dd, J = 15.4, 10 0 Hz, 2H), 4.30 (t, J= 4.2 Hz, 4H), 4.16 (dt, J = 25.2, 5.7 Hz, HI), 3 33 (dt, J = 17.4, 4.3 Hz, 4Hj, 2.98 (t, ./= 6.3 Hz, 211), 1.19 (d, J = 6.5 Hz, 6H).

Example-! 7: Synthesis of S~fluoro~N~(3~fluoro~4~(4~isopropylpiperazm~ 1-yi) phenyl)-4-(8- fluoro~4~isopropyl~3,4~dihydro-2H~benzo[b][l,4]oxa _å in-6-yi)pyrifnidin-2-amine (Compound 17):

[0238] Step-1: Synthesis of 5-fluoro-lN-(3-fluoro-4-(4-isopropylpiperazin-l-yi) pfaenyl)- 4-(S-fl«oro-4-isopropyi-3,4-dihydro-2H-benzo[b] [l _» 4joxazin-6-yi)pyrimidin-2-araine: To a stirred solution of 5-f1uoro~N-(3-fluoro-4-(piperazin-l-yl)phenyI)-4-(8-fiuoro-4 -isopropyl-3,4 - dihydro-2H-benzo[b] 1 _> 4]oxazin-6-yi)pyrimidin-2-arnine (30 mg. 0 06 mmol, 1 equiv) in DCE (5 ml-), was added Acetone (0 01 ml-, 0 18 mmol, 3 equiv), acetic acid (0.01 ml.-, 0 3 mmol, 5 equiv). The reaction mixture was allowed to sin at RT for Ih The reaction mixture was cooled to 0 °C. NaCNBHs (1 1 trig, 0.18 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS After completion of the reaction, the reaction mixture was diluted with wa er (25 ml-) and extracted with EtOAc (50 mL x 2). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous Na^SO* and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5-fiuoro-N-{3-f3uoro-4-{4-isopropylpiperazin-l -y!)phen i)--4-(8-iluoro-4- iSopropyi-T4 dihydro--2!:Lbenzo[b]j 1 ,4joxazm--6--yi}pyrinudin--2--amine (5 mg, 15%) as a yellow solid compound.

LCMS 527 jMfH] *I3NM (400 MHz, DMSO-76) 6 9 71 (s, I N ). 8 56 (d, 7 4.0 Hz, 1 H), 7 72 (dd, 7 15.4,

2 5 Hz, 1H),7.44 (s, 1 H), 7.37 (d 7 8.2 Hz, 1 H), 7. 1 5 (d, J - I 1 5 Hz, 1H) 6.96 (t, 7 9.4 Hz,

1 H), 4.30 (t, 7 = 4.4Hz, 2H), 4.13 (dp, 7 = 15 2, 5.9, 5.3 Hz, 1H), 3 18 - 3.04 (m, 2H), 2 94 (t, 7 4 0 Hz, 4H), 2 58 (t, 7 -4.8 Hz, 4H), 2.08 (s, HI), 1.18 (d, 7 6.5 Hz, 6H), 1.00 (d, 7 6.5 Hz,

6H)

Example- 18: Synthesis of 5-fluoro-N-(3-fluoro-4-(pipendm~4~yl) phenyl)~4~(8-fiuoro~4~ isopropyl-3, 4~dihydro~2H~bemofb][l, 4] oxazin-6-yI) pyrimidm-2-amine (Compound 18):

[0239] Step-1: Synthesis of tert-butyl 4-{2-fluoro-4-{{5-fluoro-4-{8-fluoro-4-isopropyI- 3,4-dihydro-2H-ben2:o[b][l _» 4joxazm-6-yi)pyrimidin-2-yi}araino)pheny!)piperidine-l - carboxylaie:To a solution of 6-(2-ch!oro-5-†1uoropyrimidin-4-yl)~8~iluoro-4-isopropyl~3 ,4- dihydro-ZH-benzo[b] [ 1 ,4]oxazine (150 mg. 0 46 mmo!, 1 equiv) m dioxane (10 mL), was added tert-butyl 4-(4-ammo-2-f]uorophenyl)piperidine-! -carhoxylate (148 mg 0 50 mmo!. 1.1 equiv) and cesium carbonate (225 mg 0 69 mmol. 1.5 equiv) The reaction mixture was degassed with mtrogen gas for 30 rnin , followed by the addition of palladium acetate (3 mg, 0.009 mmol, 0 02 equiv) and BINAP (12 mg, 0 018 mmol 0.04 equiv) The resultant reaction mixture was allowed m stir at 100 °C for 16 h Progress of tire reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 ml.} and extracted with ethyl acetate ( 100 mi .;. Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude winch was purified by normal phase combi flash to tert-butyl 4-(2-iluoro-4-((5-fluoro-4- (8-fluoro-4-isopropy 1-3, 4-dihydro-2H-benzo[b][l ,4]oxazirs-6-yl)pymni din-2- yi)amino)pheny!)pipsridine-d-carboxyiate (80 mg 30%) as a yellow solid compound.

LCMS: 584[M÷H] ⁺

[0240 Step-2: Synthesis of 5-fluoro-N-(3-tl«oro-4-(piperidin-4-yi) phenyl)-4-( 8-tl uoro- 4-isopropyI-3, 4-dihydro-2H-benzo[b] (1, 4] oxazm-6-yl) pyrimi<iin-2-amine: A solution of tert-butyl 4-(2-f1uoro-4-(C5-fiuoro-4-C8-fluoiO-4-isGprGpyl-3,4~dihydro ~2H-benzo[b][l,4]oxazin~ ⁱ -yi}pykmidin-2-yi)amino}pheny!)piperidme--l --carboxy!ate (50 mg, 0.08 mmol, I equiv} 1 25 M HCI in ethanol (5 ml,) was allowed to stir for Hi at 50 °C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain 5-fli3oro~N-(3-fluoro-4-(piperidin-4-yl) phenyl)-4-(8-fluoro-4-isopropyl-3, 4- di!iydro-2H-benzo[bl[1 , 4] oxazin-6-yl)pyrimidin-2-amine (34 mg, 83%) as a brick red color solid compound.

LCMS: 484 [M+H] "

¾ NMR: (400 MHz, DMSO-H6) d 9.93 (s, 1H), 8.84 (d, J = 11 4 Hz, 1H), 8.62 (dd, ./ =

15.0, 7.6 Hz,IH), 7.80 (dd. ./ 13 6, 2.4 Hz, 111), 7.45 (d, = 7.5 Hz _s 2H), 7.16 (dd, J = 11 0, 5.6

Hz, 21 H. 4.30 (t, J =4.1 Hz, 2H), 4.17 (p, ./= 6.6 Hz, Hi), 3.40 - 3 28 (m, 411), 3.13 - 2 96 (m, 311), 1.88 (h, ./= 4.0 Hz, 4H),1.19 (d, J = 6.5 Hz, 611)

Example-} 9: Synthe is ofN-(5-fluoro-4-(8-fluoro-4-isopropyi-5, 4-dihydro~2H- benza[h]fl, 4]oxazin-6-yl)pyrimidin-2~yr)~2~isopropyl~lJ2, 3,4~tetrahydraisoqumolin~7~amine (Compound 19):

[0241] Step-1: Synthesis of tert-butyl 7-{{5-fluoro-4-(8-fluoro-4-«sopropyI-3,4-dihydro~ 2H-benzo[b] [l,4]oxa*in-6-yl)pyrimidiH 2-yl)amino)-3,4~dihydro«soquinoline-2(iH)- carboxylate: To a solution of 6-(2-chloro-5-fluoropyrimidm-4-yl)-8-fluoro-4-isopropyl-3,4- dihydro-ZH-benzo[b][l ,4]oxazine (200 mg, 0.61 mmol, 1 equiv) m dioxane (10 mL), was added tert-butyl 7-amino-3,4-dihydroisoquinoiine-2(lH)-carboxylate ( 168 mg, 0.67 mmol, 14 equiv) and cesium carbonate (298 mg, 0.91 mmol, 1.5 equiv). The reaction mixture was degassed with mtrogen gas for 30 min., followed by the addition of palladium acetate (3 mg, 0.01 mmol, 0 02 equiv) and BIMAP (15 mg, 0 02 mmol 0 04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of foe reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 no . ·. Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, winch was purified by normal phase combi flash to obtain text- butyl 7-((5-fluoro-4-(8- £luorO 4 isopropyl 3,4-dihydro-2H benzo| blil ,4]oxazin-6-yl)pyrmiidim2~yi)ammo)-3,4·- dihydroiSoquinolme-2(lH)-carboxylate (100 mg, 30%) as a yellow solid compound.

LCMS: 538.4[M+H] ⁺

[0:2421 Step-2: Synthesis of M-(S-fluoro-4-(8~fluoro-4-isopropyI~3,4 iBhydro-2H~ benzo[b][l,4]oxazin-6~y!)pyri idm-2-yl)-l^ 3,4-tetrahydro«soquinolin~7~amme: A solution of tert-butyl 7~((5-fluoro~4-(8-†1uoro~4 -isopropyl~3,4-dihydro-2H~benzo[h][1 ,4]oxazm-6- yi)pyrimidm 2 yj}ammo} 3,4-dihydroisoquino!ine-2i!H)~carboxykte (40 mg, 0.07 mmol, 1 equiv) in 1.25 Mi HCi in ethanol (5 mL) was allowed to stir for 1 h at 50 °C. Progress of the reaction was monitored by I, CMS. After completion of the reaction, solvent was removed under reduced pressure to obtain N-(5-f1uoro-4-(8-fluoro-4-isopropy]-3.4-dihydro-2H- benzo[b][! ,4]oxazin-6-yl)pyrimidin-2-yl)- i 2,3,4-tetrahydroisoquino ^j in-7-amine (30 mg, 94%) as a brick red color solid compound.

LCMS: 438 4 [M+H] ⁺

[0243] Step-3: Synthesis of N-(5-fluoro-4-(8~iIuoro-4-isopropyl~3,4-dihydro-2H~ benzo[b][I,4]oxazin-6-y!)pyrimidin-2-yI)-2-isopropy!-l _» 2^L4-tetrahydroisoquinoIia-7- amine: To a stirred solution of N-fS-fiuoro-d-iB-fiuoro- -isopropyj-S^-dihydro-dH- benzolbjl l joxazm-e-ynpyrimidin-ti-yl)-·] ,2,3,4-tetraliydroisoqumolim7-amine (50 mg, 0 1 mmol, 1 equiv) in DCE (5 mL), was added Acetone (0.02 mL, O.dmmol, 3 equiv), acetic acid (0 03 mL, 0.5 mmol, 5 equiv) The reaction mixture was allowed to stir at RT for i h. The reaction mixture was cooled to 0 °C. NaCNB!iL (19 mg, 0.3 mmol, 3 equiv) was added to above mixture and raise the temperature to RT The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS After completion of the reaction the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (50 mL x 2). Organic layer was washed with water (50 mL) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase 1 I Pi .0 io afford N-(5-fluoro-4-(B-iluoro-4-isopropyl-3,4-dihydro-ZH- benzoib][i,4]oxazm-6-yi)pyriniidin-2-yi)-2 isopropyhl,2,3,4 tetra!iydroisoqimioiin-7-anime (10 mg, 20%) as a yellow solid compound.

LCMS: 480 [M+H] "

^MR: (400 MHz, DMSOM6) d 9.57 (s, IHj, 8.54 (d, J = 3 9 Hz, 1H), 7.49 (dd, ./ = 8.3,

2.3 Hz, IHj, 7 44 - 7.37 (m, 2H), 7 16 (d, ./= 1 1.5 Hz, 1 H), 6.98 (d, ./= 8.3 Hz, 1H), 4.29 (t, 7

4.4 Hz, 2H), 4 12 (p,J - 6.7 Hz, IHj, 3.60 (s, 2H), 3.30 (t, J= 4.4 Hz, 2H), 2.84 (dq, J = 14 6, 8.1, 7.3 Hz, !H), 2.72 (t, ./= 5.5Hz, 2H), 2.67 (t, J = 5.7 Hz, 2H), 1.18 (d, J = 6 5 Hz, 6H), 1.05 (d, J = 6.5 Hz, 6H).

Example-20 : Synthe is ofN~(5~fluoro~4~(8~fluoro~4~isopropyi~5, 4~dihydro~2H~

benzofh] (1, joxazin-6-yI)pyrimidin-2-yI)~2~isopropyI~J 2, d, 4~tetrahydroisoquinoIin~5~amine (Compound 20):

[0244] Step-1; Synthesis of tert-buty! S-((5-fll«oro-4-(8-fliuoro-4-isopropyl-3,4-dihytlro- 2H~benzo{b| |I,4joxaeln-6-yl)pyrimidia~2~yl)amino)-3,4-dlhydroisoqumolin e-2(iH)~ carboxylaie:To a solution of 6-i2-chloro-5-†1uoropyrimidin~4~yl)~8~fiiK>ro-4-isoprop yl-3,4- dibydro-2H-benzo[b] [ 1 ,4]oxazine (200 mg, 0 61 mmol, 1 equiv) in dioxane (10 ml,), was added tert-buty! 5~amino-3.4~dihydroisoquinoIine~2(lH)-carboxylate (168 mg, 0.67 mmol, 1 1 equiv) and cesium carbonate (298 mg, 0 91 mmol , 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min, followed by the addition of palladium acetate (3 mg, 0 01 mol, 0.02 equiv) and BINAP (15 mg, 0 02 mmol. 0 04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for 16 h Progress of tire reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate ( 100 mL). Organic layer was washed with water (50 xnL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, winch was purified by normal phase combi flash to tert-butyi 5-((5-iIuoro-4-(8-imoro-4- isopropyl-3 ^, 4-dihydro-2H-benzo[bl[ l,4]oxazm-6-yl)pyrin ⁱ idin ^~ 2 ^~ yl)amino) ^~ 3,4- dibydroisoquinolme-2(lH)-carboxylate ( 120 mg, 36%) as a yellow solid compound.

LCMS: 538.4 [M÷H] ^÷

[0245] Step-2 Synthesis of N -( S-t1uoro-4-( 8-fluoro-4-isopropyl-3,4-dihy dro-2H- benzo j b j ( 1 ,4) oxazin-6~yl)pyri idin~2-yl)-l,2,3,4-tetrahydroisoqumolin~5-amiBe: A solution of tert-butyi 5~((5-fli3oro~4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[b l[l ,4]oxazin-6- yl)pyrknidm-2-yi)ammo}-3,4~dihydroisoquinoline~2(lH)-earbox: ylate (50 mg, 0.09 mmol, 1 equiv) in 1.25 Mi HC1 in ethanol (5 L) was allowed to stir for lb at 50 °C. Progress of the reaction was monitored by I, CMS. After completion of the reaction, solvent was removed under reduced pressure to obtain N-(5-f1uoro-4-(8-f]uoro-4-isopropyl-3.4~dihydro-2H- benzo[b][l ,4]oxazm-6-yl)pyrimidin-2-yl)~ i,2,3,4-tetrahydroisoquino ^j in~5~amine (35 mg, 88%) as a brick red color solid compound.

LCMS: 438 4 [M+H] ⁺

[0246] Step-3: Synthesis of N-(5-fluoro-4-(8~fluoro-4-isopropyl~3,4-dihydro-2H~ benzo[b][i,4]oxazin-6-yI)pyrimidin-2-yI)-2-isopropy!-l _» 2^L4-tetrahydroisoquinoIm-5-amin:

To a stirred solution of N-(5-iluoro-4-(8-iluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][l ,4]oxazin--6-yl)pyrimidii>2-yl)-l ,2,3,4-tetraiiydioisoqumolin-5 -amine (50 mg, 0 1 mmol, 1 equiv) in DCE (5 mL), was added Acetone (0.02 mL, 0 3mrnol, 3 equiv), acetic acid (0 03 mL, 0.5 mmol, 5 equiv) The reaction mixture was allowed to stir at RT for 1 h The reaction mixture was cooled to 0°C. NaCNBI-fi (19 mg, 0 3 mmol, 3 equiv) was added to above mixture and raise the temperature to ITT The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS After completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (50 mL x 2). Organic layer was washed with water (50 mL) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford N--(5--fluoro-4--{8--fluoro-4--isopropyL3,4-dihydro-2H-· benzolbli! l,4 ^~ ioxazin~6-yl)pyrirnidm-2-yl)--2-isopropyl- 1 ,2,3, 4--tetraliydroisoquinolm-5-arnme (15 mg, 30%) as a yellow solid compound.

LCMS: 480 [M+H] "

(400 MHz, DMSO-H6) 6 8.78 (s, 1 1 ) }. 8.46 (cl ./ 4.0 Hz, 1H), 7.38 - 7.29 ( , 2H), 7.13 - 7 06(m, 2H), 6.89 (d, J = 7.6 Hz, 1H), 4,27 (t, J = 4 4 Hz, 2H), 4.03 - 3.97 (m, 1 1 0. 3.64 (s, 211), 3.26 (t, 7 4 3 Hz, 2H), 2.86 - 2.79 (m, 1H), 2.69 (d, J = 5 7 Hz, 21 0. 2.65 (d, J 5.4 Hz, 2H),1 1 1 (d, J = 6.5 Hz, 6H), 1 04 (d, 7 6.5 Hz, 611)

Example-21: Synthesis of 5~((5~fluoro~4~(8~fluoro~4~isopropyi~3, 4-dihydro-2H~henzo[b] [ l, 4/ oxazin~6~yi) pynmidm~2~yl) amino)~2~(piperazin~l ~yi) henzonitiile (Compound 21):

[0247] Step-1: Synthesis of tert-butyi 4-(2-cyaao-4-((5-fluoro-4-(8-fluoro-4-isopropyl- 3,4-dihydiO-2H-henzo[b][l,4!oxazia-6-yi)pyrimidm-2-yl)ammo)p henyl)piperazme-l- carboxylate: To a solution of 6~(2-chloro-5-fiuoropyrimidin-4-yI)-8-fluoro-4-isopropyI-3,4 ~ dibydro-2H-benzo[b] [ 1 ,4]oxazine (150 mg, 0 46 mmol, 1 equiv) m dioxane (10 ml..), was added tert-butyi 4-(4~amino-2-cyanophenyI)piperazine-l-carboxylate (1 68 mg, 0 67 mmol, 1.1 equiv) and cesium carbonate (225 mg, 0 69 mmol , 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min. , followed by the addition of palladium acetate (2 g, 0.009 mmol, 0 02 equiv) and BINAP (12 mg, 0 018 mmol 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of foe reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi (lash to obtain tert-butyi 4-(2-cyano~4-((5- fhioro-4-(8-fhioro-4-isopropyl-3,4~dihydro-2H-benzo[bj[l,4]o xazin-6-yl)pyrirmdin-2- y!)annno)pbenyi)piperazine-! -earboxylate (100 mg, 37%) as a yellow solid compound. LOIS: 592 [M+H]

[0248 Step-2: Synthesis of 5-((5-fl«oro-4-(8-fluoro-4-isopropyi-3, 4-dihydro-2H- benzo[b][l, 4] oxazin~6~yi) pyrimidm-2-yl) amino)-2~(piperazm-l-yl) benzonitriie:A solution of tert-butyl 4~(2~cyano-4-((5-fluoro-4-(8-fluorG-4-isopropyl-3,4-dihydro- 2H- benzo[b][l,4]oxazin-6-yl)pynmidin~2-yl)amino)phenyl)piperazi ne~I~carboxyiate (100 mg, 0.16 mmol, 1 equiv) m 1.25 M HC1 m ethanol (5 niL) was allowed to stir for 1 h at 50 °C. Progress of the reaction was monitored by LCM8. After completion of the reaction, solvent was removed under reduced pressure to obtain 5-((5-fluoro-4-(8-fluoro-4-isopropyl-3.4-dihydro-2H- benzo[bl[l,4]oxazin-6-yl)pyrimidin~2~yl)amino)~2~(piperazin- l-yl)benzomtrile (80 mg, 97%) as a brick red compound.

LCMS: 492 [M+H] ^÷

\!I\ ^: .MR:: (400 MHz, DMSOv/6) d 9.95 (s, i l·.9.28 (s, 1H), 8.61 (d, .7=37 Hz, 1H), 8.18

|d../ 2411/.1H).7.91 (dd, J= 9.1, 2.6 Hz, IH),735 (s, HI), 723 (d, =8.9Hz, 1H), 7.14 id,

7 11.2 Hz, i i P.4.29 (:../ Aib 2H), 4.12 (p, J = 6.6 Hz, 1H), 3.28 (d../ 172 Hz, 10! If

1.18 (d, .7=64 Hz, 6H).

Example-22: Synthesis ofN-(5~fiuoro-4-(8~fiuoro-4~isopropyl~3, 4-dihydro-2H~

benza[h]fl,4]oxazin-6-yl)pyrimidin-2~yr)~2~isopropyl~lJ2, 3,4~tetrahydroisoqumoUn~6~amine

[0249] Step-1: Synthesis of tert-butyl 6~((5~flu©ro~4-(8~flu©ro~4-isopr©pyl-3,4-dihydro- 2M-benzo[b [l,4]oxazM~6~yI)pyrira«din-2-yl)asmn©)-3,4-dihydrois©i|ui m>Iine-2{lII)- carboxylate:To a solution of 6 (2-ch!oro-5-iiuoropynrnidm-4-yl)--8--i!uoro-4-isoprop l~34- dihydro-2H~benzo[b][l 4]oxazine (200 mg, 0 61 mmol, 1 equiv) m dioxane (10 mL), was added tert-buiyi 0-amino-3,4-dihydroisoquinoiine-2(lH)-carboxylate ( 168 mg, 0.67 mmol, 1.1 equiv) and cesium carbonate (298 mg, 0 91 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (3 mg, 0 01 mmol, 0.02 equiv) and BINAP (15 mg, 0.02 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi-flash to obtain tert-butyl 6-((5-f!uoro-4-(8- iluoro~4~isopropy!~3,4 dibydro-2H~benzo[b][l ,4]oxazin-6-yl)pyrimidm 2-y!)aminoV3,4 dihydroisoquinoline-2(I Hyearboxy!ate (80 g, 24%) as yellow solid compound.

LCMS: 538. fi M i l : ⁺

[0250] Step-2: Synthesis of M-(5-fluoro-4-(8~fluoro-4-isopropyI~3,4 dihydro-2H~ benzo[b][2,4]oxazin~0~yI)pyrimidin-2~yI)-1^ 4-tetrahydr0is©qu noHn~6~amme: A solution of tert-butyl 6-((5-fluoro-4-(8-fluoro-4-isopropyb3,4-dihydro-2H-benzo[b)( l ,4]oxazm-6- yl)pyrimidm-2-yl)ammo)-3,4-dihydroisoquinoline-2(lH)-carboxy !ate (30 mg, 0.05 mmol, I equiv) in 1.25 Mi HO in ethanol (5 mL) was allowed to stir for 1 h at 50 °C Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent r.¾ removed under reduced pressure to obtaiu N-(5-fhioro-4-(8-fhioro-4-isopropyl-3.4-dihydro-2H- benzo[b][l ,4]oxaziu-6-yl)pyrimidin-2-yl)-l,2,3,4-tetraliydroisoqurnoli n-6-amine (22 mg, 9254) as a brick red color solid compound.

LC S; 439.4 [M+H] ⁺

[0251] Step-3: Synthesis of N^S-fluoro-^S-fluoro-^isopropyl-Syt-dihydro-ZB- benzolb joxaziR-e- pyrimidin- -yl^Z-isopropyl-LZ^yi-teirahydroisoiimnolin- - mine: To a stirred solution of N-(5-f3uoro-4-(8-f3uoro-4-isopropyl-3,4-dihydro-2H- benzolbl] ! ,4]oxaziri-6-yl}pyriuudin-2-yl)-l,2,3,4-ietrahydroisoquinoli n 6-amine (50 mg, 0.1 mmol, 1 equiv) in DCE (5 mL), was added acetone (0.02 mL 0.3 ob 3 equiv), acetic acid (0.03 mL 0.5 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for 1 b The reaction mixture was cooled to 0 °C NaCNBLfi (19 mg, 0.3 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for lh. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with ethyl acetate (50 ml, * 2). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford N~(5-fluoro~4~(8-fluoro~4-isopropyb3,4-dihydro-2H~ benzoibl[l,4 ]oxazin-6-yl)pyrmiidin~2~yl)-2-isopropyhl,2,3,4 tetraliydroisoqumohn-6~amine (10 mg, 20%) as a yellow solid compound.

LCMS: 480 | M+H]

[0252] Step-1: Synthesis of tert-butyl 4-(5-((5-fluoro-4-(8-fluoro-4-isopropyI-3,4- dihydro-2H-benzoib][l,4]oxazin~0~yI)pyrimidin-2-yl)amino)pyr idin-2~yI)p perazme-l- carboxylaie:To a solution of 6-(2-ch!oro-5-f!uoropyrimidin~4~yl)~8~fTuoro-4-isopropyl-3,4 - dihydro-ZH-benzo[b] [ 1 ,4]oxazine (100 mg, 0 3 mmol, 1 equiv) in dioxane (10 ml,), was added tert-butyl 4-(5-aminopyridin~2~yl)piperazine-I-earboxylate (94 mg. 0.33 mmol, 1 .1 equiv) and cesium carbonate ( 147 mg, 0.45 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 rnin , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 mmol. 0 04 equiv) The resultant reaction mixture was allowed m stir at 100 °C for 16 h. Progress of foe reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 il,) and extracted with ethyl acetate (100 ml .;. Organic layer was washed with water (50 mL) and brine solution (50 ml .}. Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude winch was purified by normal phase combi flash to obtain tert- butyl 4--s>-((5-fiuoro--4--(8- fluorO 4 isopropyl 3,4-dihydro-2H benzo|blii,4 oxazin-6-yl)pyrmiidim2-yi)ammo)pyndm-2·- yl)piperazine-l --carboxyiate (50 mg, 29%) as a yellow solid compound.

LCMS: 568 [M+H] ⁺

(02S3| Step-2: Synthesis of 5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro-2H- benzo[b](l,4]oxazin-6~y!)-N-(6”(piperazin-I~y!)pyridia~3~y !)pyrimidin-2~amlne: A solution of ten-butyl 4-(5-((5-fluoro-4-(8-fluoro-4-isopropyl-3.4-dihyclro-2H-benz o[bl 1 ,4]oxazm-6- yl)pyrimidin-2-yl)amino}pyridin~2~yl)piperazine-l-carboxylat e (50 mg, 0.08 mol, 1 equiv) in 1.25 M HC1 in ethanol (5 mi,) was allowed to stir for i h at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain 5-f1uoro~4~(8-f1uoro~4~isopropyl~3, 4-dihydro~2H-benzo[b][L4]oxazin~6~yl)~ N-(6-(piperazin-l-yl)pyridin-3-yl)pyrimidin-2-amine (40 g, 91%) as a yellow solid compound.

LCMS: 468 [M+H] ⁺

1HNMR: (400 MHz, DMSOv/6) d 9 67 (s, 1 1 11. 9 14 (s, 1 H), 8 57 fdd, J = 9.2 , 3.3 Hz, 21 1)

8.01 (d, J =9 2 Hz, i l l). 7.37 (s, I H), 7 17 - 7.10 (m, 1 H), 7 07 (s, HI), 4 29 ft, .7= 4.3 Hz, 2H),

4.1 1 (p, 7 6 6 Hz,IH), 3.71 (d, J = 6.0 Hz, 4H), 3.30 (t, J= 4.4 Hz, 2H), 3.21 (d, ./ 5.4 Hz,

4H), 1.17 (d, .7=6.5 Hz, 6H).

Example-24: Synthesis of 5-fluoro~N-{3-fluoro-4-{l-methyipipe din~4~yI) phenyl}~4~(8~fluoro~4~

carhoxyiate: To a solution of 6-(2-chloro-5-fiuoropyrimidin-4-y{)-8-fluoro~4-isopropyl-3,4 - dihydro-2H-benzo[b][l,4]oxazine (150 mg, 0.46 mmol, 1 equiv) in dioxane (10 mL) was added ten-butyl 4~(4~amino-2-fluorophenyl)piperidine-l-carboxylate (148 mg, 0.50 mmol, 1.1 equiv) and cesium carbonate (225 mg, 0 69 mmol. 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (3 mg, 0.009 mmol, 0 02 equiv) and BINAP (12 mg, 0.018 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 b Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to ten-butyl 4-(2-fluoro-4-((5-fluoro-4- (8-fluoro-4-isopropyj-3,4~dihydro-2H-benzo b](l ,4]oxazin-6~yl)pynmidin-2- yl)amino)phenyj)piperidine~l ~carboxyjate (200 mg, 74%) as a yellow solid compound

LCMS: 584[M÷H] ⁺

[0255] Step-2: Synthesis of 5-fluoro-N~(3~fluoro-4~(piperidin~4~y!) pfaenyl)~4~(8~fluoro- 4-isopropyI-3, 4-dlhydro-2H-benzo[b] [1, 4] oxazm-6-yi) pyrimidiR~2~amine: A solution of tert-butyl 4-(2-fluoro-4-((5-fluoro-4-(8-fluoro-4-isopropyh3,4-diliydro -2H-benzo[b][1 ,4]oxazm- 6-yl)pyrimidin-2-yl)amino)phenyl)piperidme-l-carboxylate (200 mg, 0.34 mmol, 1 equiv) 1 25 M HCI m ethanol (5 ml,) was allowed to stir for ih at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent w¾s removed under reduced pressure to obtain 5-fluoro-N-(3-iluoro-4-(piperidin-4-yl) phenyl)-4-(8-iluoro-4-isopropyl-3, 4- dihydro-2!:I-benzo[b][l , 4] oxazin-6-yl)pyrimidin-2-amine (150 mg, 90%) as a yellow solid compound.

LCMS: 484 [M+H] ⁺

[0256] Step-3: Synthesis of 5-fl oro-N-(3-fiuoro-4-(l-methylpiperidin-4-yI) phenyi)~4~ (8-flMoro-4-«sopr pyI-3, 4-dihydro-2H- benzo [b] [1,4] oxazin-6-y I )pyr<midin-2-amine: To a stirred solution of 5-iluoro-N (3--fluoro-4-(piperidin-4--y!) phenyl)-4-(8-f!uoro-4-isopropyl-3, 4- dihydro-2H-benzof b] 1„ 4] oxazin-6-yl)pyrimidin-2-amine (100 mg, 0.2 mmol, I equiv) m DCE (5 mL), was added Formaldehyde (40% in water) (0.02 mL, 0.61 mmol, 3 equiv), acetic acid (0.05 mL, 1 0 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for Ih The reaction mixture was cooled to 0°C NaCNBI-L (38 mg, 061 mmol, 3 equiv) was added to above mixture and raise the temperature to RT The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (50 mL x 2) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was puniled by reverse phase HPLC to afford 5-fluoro-N-(3-fluoiO-4-(l-methylpiperidin-4- yl)phenyl}4(8fluorO4isopropyl3,4-dihydro-2Hbenzo|blil,4]oxaz in-6-yi)pyrimidim2~amine (15 mg, 15%) as a yellow solid compound.

LCMS: 498 [M+H] ⁺

*H MR: (400 MHz, DMSO-A6) d 988 (s, 1H), 860 (d, ./ 3.9 Hz, Hi), 8.28 (s, Hi), 7.75

(dd, J= 13.7,2.2 Hz, 1H), 7.45 (s, ill}.7.40 (dd, ft = 86, 2.2 Hz, 111).7.24 - 713 (m, 2H), 4.30 (t, ft= 43 Hz, 2H) , 4.17 (p, ft ^:=: 6.5 Hz, Hi), 331 (t,ft=45Hz, 2H), 2.87 (d, ./= ! 1.1 Hz, 211}

2.40 (s, III}.2.20 (s, 3H), 1.98 (td,ft= 109, 4.4 Hz, 2H), 1.69 fod ft 12.0, 83 Hz, 411 } 118 (d, ft= ^: 6.5 Hz, 6H)

Exampie~25: Synthesis ofN-(4-(4-(dhnethylamina) pipehdin-i-yl)~3~fluorophenyl)~5~fluoro~4~ (8~fluoro~4~isopropyi~3, -dihydro-2H~henzo[h J [ 1 ,4(ox zin~6~yi/pyrimidm~2~amine (Compound 25):

10257] Step-li Synthesis l-(2-fluoro-4-nitrophenyl)-N, -dimethyi{)iperi t«-4-amine: To a stirred solution of 1 , 2-diiluoro-4-mtrobsnzene (400 mg, 25 mmol, 1 equiv) m DMSO (10 mL), was added DIPEA (1.7 mL, 10 mmol, 4 equiv) and N, N-dimethylpiperidin-4-amine (556 mg, 2.76 mmol, 1.1 equiv). The resultant reaction mixture w¾s allowed to stir at 100° for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with ice water (10 mL), solid observed was filtered and dried o under vacuum to obtain l -(2-fluoro-4-nitrophenyl)-N, N-dimethylpiperidin-4-amine (600 mg. 89%) as a yellow solid compound.

LOIS: 268 [M+H] ⁺

(02S8| Step-2: Synthesis of l-(4-a ioo-2-tl«orophenyl)- , N-climethyipiperidm-4- araine:To a stirred solution of l-(2~fluoro-4-mtrophenyl)~N, N-dimethylpiperidin-4-amme (500 mg, 1 87 mmol, 1 equiv) in ethanol (8 ml ..· water (2 mL), was added iron powder (315 mg, 5.61 mmol, 3 equiv) and ammonium chloride (202 mg, 3 74 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for Hi. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EtoAc (100 mL). Organic layer was washed with water (50 mL) and brine (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain l-(4-amino-2-fluorophenyl)~N, N-dimethylpiperidm-4-a me (400 g, 90%) as dark brown solid compound.

LCMS: 238 [M+H]

[0259] Step-3: Synthesis of N~(4~(4~(dimethylammo) p«peridin-l~yl)-3-fluoropheayl)-5- fluoro-4-(8-fluoro-4-«sopiOpy!-3, 4-dihydro-2H-benzo[h]jl,4[oxazm-6-yl)pyrimitlln~2” amine: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3,4 -dihydro- 2H~benzo[b][l ,4]oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 mL), was added l-(4- amino-2-tluorophenyI)-N, N-dimethylpiperidin-4-amine (78 mg, 0 33 mmol, 1 1 equiv) and cesium carbonate ( 147 mg, 0.45 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 mmol. 0 04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of foe reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 L) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain N-(4-(4-(dimethylami«o)piperidi«~ l -y! }-3-fiuorophenyl)-5~fluoro-4-(8~fluoro-4-isopropyl-3,4-dihyd ro-2H-benzo[ b][ l ,4]oxazin-6- y!)pyrirmdm-2-armne (20 mg, 12%) as a yellow solid compound

LC .VIS: 527 [M4-H] *I3NM : (400 MHz, DMSO-A6) d 9.74 (s, H I ). 8.57 (d, 7 4.0 Hz, HI), 8 29 (s, HI), 7 72

(dd, J ^:::: 15 3,2.5 Hz, H i) 7.44 (s, HI), 7.36 (dd, J - 8.8, 2.5 Hz, 1 H), 7.16 (d, 1 1.4 Hz, HI),

6.97 (t, ./ 9.4 HzJH), 4 30 (t, J = 4 4 Hz, 2H), 4.16 (p, ./ = 6.6 Hz, IH), 3 30 (dd, 7 9.6, 5 2

Hz, 4H), 2.63 - 2.54 (m, 2H), 2 22 (s, 7H), 1 84 (dd, J= 12.7, 3.6 Hz, 2H), 1.54 (tt, ./= 13.3, 6.7 Hz, 211), 1.18 (d../ 6.5 Hz, 6H).

Example-26: Synthesis of 5-f!uoro~4~{8 f!uoro~4-isopropyI-3 _> 4 dihydro~2H

[0260] Step-1: Synthesis 4-(2-f! uoro-4-nitrophenyl) morpholine:

To a stirred solution of morpholine (2 5 ml,, 28 mmol, 4.5 equiv) m THF (15 ml,), was added 1, 2~difluoro-4-ni†robenzene (1000 mg, 6.28 mmol. 1 equiv) at 0°C. Raise the temp to RT and the mixture was allowed to stir for 2h at RT Progress of the reaction was monitored by TLC and LCMS. After completion of foe reaction, the mixture was diluted with water (100 mil,) and extracted w ith EtoAc (200 ml,). Organic layer was washed w ith water (50 ml,) and brine (50 niL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 4-(2-fiuoro-4-niirophenyl) morpholine (1000 mg, 70%) as a yellow solid compound.

LCMS: 227 [M+H]

[02611 Step-2: Synthesis of 3-iliioro-4-morphoIinoa«tme:

To a stirred solution of 4-(2~iluoro-4-mtrophenyl) morpholine (400 mg, 1.76 mmol, 1 equiv) in ethanol (8 ml u. water (2 ml . ; was added iron powder (297 g, 5 3 mmol, 3 equiv) and ammo um chloride (190 mg 3.52 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for Ih Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with water (30 ml . ) and extracted with EtoAc

(100 niL). Organic layer was washed with water (50 rnL) and br e (50 rnL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, winch was purified by normal phase combi flash to obtain 3 -iluoro-4-morpholinoamline (240 nig, 69%) as a dark brown solid compound

LCMS: 197 [M+H] ⁺

[0262 j Step-3: Synthesis of 5-fluoro-4-(8-fluoro-4-feopropyl-3, 4-dihydro-2H- ben*o b][l,4)oxa2in-6-yl)-N-(3-fluoro-4-inorpholmophenyI)pyrhmdm-2 -amine:

To a solution of 6-{2-chloro-5-fluoropyrmiidin~4-yl)~8-fluoro-4-isopropyl-3,4 -dihydro-2H- benzolbll l,4]oxazine (100 mg, 0 3 mmol, 1 equiv) m droxane (10 nil,), was added 3~fluoro~4~ morphoimoani!me (66 mg, 0.33 mmol, 1 1 equiv) and cesium carbonate (147 mg 0.45 mmol,

1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm. followed by the addition of palladium acetate (2 mg, 0.006 mmol 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase KPLC to obtain 5-i1uoro-4-(8-fluoro-4-isopropy]-3,4-dihydro-2H-benzo[b][l,4 ]oxazin-6-yl)-N-(3- fiuoro-4-morpho]inopheny!)pyrimidin-2-amine (20 mg, 13%) as a yellow solid compound.

LCMS: 486 [M+H] ⁺

¾NMR: (400 MHz, DMSO-J6) 6 9.75 (s, i l l ). 8.56 (d, ./ 3.9 Hz, IH) 7.75 (dd, J --- 1 5 5,

2.5 Hz, 1 H),7.43 (s, IH), 7.41 - 7.35 (m, IH), 7.20 - 7.12 (m, I B), 6 98 (t, J --- 9 4 Hz, i l l ). 4.30 (t, J ----- 4 2 Hz, 2H),4.1 5 in. J ------ 7.7, 7.1 Hz, I H) 3.74 (t, J ------ 4.6 Hz, 4H), 3.30 (d, J ----- 4.5 Hz, 2B),

2.94 (t, J ---- 4.6 Bz, 4H), 1.1 8 (d, J ------ 6.5 Hz, 6H).

Example-27: Synthesis of5-fluoro-N-(3-fluoro-4-(4-(pyrrolidm-l-yl) piperidin-l-yi) phenyl)~6~ (8-fluoro-4-isopropyl-3, 4-dikydro-2H-henzo[h [1.4joxazm-6-yl)pyndm-2-amine (Compound 27):

[0263] Step- 1 : Synthesis of ^" 1 -(2-fluoro-4-«tropheayi) piperidm-4-o«e:

To a stirred solution of 1 , 2-difluoro-4-nitrobenzene (3000 mg. 18.8 mmol, 1 equiv} in ACN (30 mL), was added DIPEA (6.6 mL, 37.6 mmol, 2 equiv) and piperidin-4-one (2906 mg 18.8 mmol. 1 equiv). The resultant reaction mixture was allowed to stir at 80° for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with EtoAc (200 mL), washed with 10% HC! (100 mL) and brine (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain l (2-fluoiO-4-nitrophenyl) piperidin-4-one (4200 mg, 94%) as a yellow solid compound. LCMS: 239 [Mali]

[0264] Step-2;; Synthesis l~(2~fluoro-4~aitrophenyl)-4-(pyiTolidm-l-yl) piperidine:

To a stirred solution of l-(2-iluoro-4-nitrophenyl) piperidin-4-one (2000 mg, 8 4 mmol, 1 equiv) m ΊΉR (20 mL), was added pyrrolidine (ImL, 1 1 76 mmol, 1.4 equiv), sodium acetate (1033 mg, 12.6 mmol, 1 .5 equiv), and acetic acid (1 mL) The resultant reaction mixture was allowed to stir at RT for 1 h. Sodium borohydride (570 mg, 1 5 mmol, 1.5 equiv) was added to above mixture and the resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with EtoAc (100 ml, ^/ 2). Organic layer was washed with water (100 ml,) and brine (1 00 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtai 1 -(2-fliioro-4-nitrophenyl)-4-(pyrrolidin-l-y1) piperidine (2000 mg, 81%) as a yellow solid compound

LCMS: 294 [M+Hj |Ό265) Step-3: S nthesis of 3-flaoro-4-(4-(pyrroIidm-l-yl) piperidin-l-yl) aniline:

To a stirred solution of l-i2-fiuoro-4-nitrophenyl}-4-(pyrrolidin-l -yl) piperidine ( 1000 mg, 3.4 mmol, 1 equiv) in ethanol (10 mL), water (3 niL), was added iron powder (573 nig, 10.2 mmol. 3 equiv) and ammonium chloride (367 mg, 6 8 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for i h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction the mixture was diluted with water (50 mL) and extracted with EtoAc (100 mL ^x 2). Organic layer -w s -w shed with water (50 mL) and brine (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 3- fluoro-4-(4-(pyrrolidin-l-yl) piperidin-l-yl) aniline (700 mg, 78%) as a dark brown solid compound.

LCMS: 264 [MLB) ⁺

[0266] Step-4: Synthesis 5-fluoro-N-(3~fiuoro-4-(4~(pyrrolidm-l-yl) piperidin-l-yi) phenyi)-6-(8-fluoro-4-isopropyl-3, 4-dihydro-2H-henzo f b) [ | oxazia-6-yl)pyridin-2-amine:

To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3, 4-dihydro- 2H- benzo[b][l ,4]oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 mid, was added 3-fluoro-4~(4- (pyrrolidin-1 -yl) piperidin-l-yl) aniline (87 rag, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg. 0 45 mmol, 1.5 equiv) The reaction mixture was degassed with nitrogen gas for 30 min. followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0 012 mmol, 0.04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for 16 h Progress of the reaction was monitored by TLC and [.CMS After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate ( 100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain 5-fl uoro-N-(3-fluoro-4-(4-(pyiTolidin-l-yl)piperi din-1 - yl)pheriyi)-6-(8-fluoro-4-isopropy!-3,4-dihydro-2H-benzo b|[l,4]oxazm-6-yl)pyiidin-2-amine (40 mg, 24%) as a yellow solid compound

LCMS: 553.5 [M+H] ^÷

*HNM : (400 MHz, DMSO-76) 6 9.71 (s, IH), 8.56 (d, 7 4.0 Hz, 1 H), 7 71

15 3Hz, I H), 7.44 (s, I H), 7.36 (d ./ 8.9 Hz, I H), 7.16 (d, J --- 1 1.6 Hz, IH), 6.97 (t ./ 9.4 Hz,

I H), 4 33 -4.26 (m, 2H) 4.15 (dq, J - 14 0, 7.5, 6.9 Hz I H), 3 33 - 3.21 (m, 3H), 2.65 (s, 3H), 2.56 (d, J ----- 5.1 Hz,4H), 2 12 Id, ./ 10.6 Hz, 1 H), 1.98 - 1.90 (m, 2H), 1.69 (t, ·/ 5.1 Hz, il l)

[0267] Step-1: Synthesis tert-butyl 4-(2,3-difluoro-4-((5~fluoro-4-(8~fluor0-4~isopropyl-

3,4-dihydro~2H~benzo[b] [l,4|oxazin-6~yI)pyrimidin-2~yl)amino)phenyl)pipera¾ine-l- carboxylate:

To a solution of 6~(2-chloro-5-fluoropyrimidin-4-yI)-8-f1uoro-4-isopropyI-3,4 ~dihydro-2H- benzo[b] [ 1 ,4] oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 ml,), was added tert-butyl 4- (4~amino-2,3-dif3uorophenyl)piperazine-l-carboxylate (103 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate ( 147 mg, 0.45 mmol, 1 5 eqiuv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 mmol. 0 04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of foe reaction was monitored by TLC and LG MS After completion of the reaction, diluted with water (30 ml ,) and extracted with ethyl acetate ( 100 niL). Organic layer was washed with water (50 l,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain tert-butyl 4-( 2,3-difluoro-4-((5-fluoro-4-(8- iiuoro-4 isopropyi--3,4-dihydro-2H--benzo!blP ,4joxazin-6-y!)pyruTndin-2- y!)amino)phenyi)piperaxine-l -car boxy late (90 mg, 4856) as a yellow color solid compound.

LCMS: 603 [M+Hj ⁺

[0268] Step-2: Synthesis of N-(2, 3-dif1uoro-4-(pipera*m-l-yI) phenyI)-5-fluoro-4-(8- fluoro-4-isopropyI-3, 4-dihydro-2H- benzo [b] [ 1,4] oxazm-6-y l)py ri idin-2-amme: A solution of obtain tert-butyl 4-(2,3-difiuoro-4-((5-fiuoro-4-(8-fluoro-4-isopropyl-3,4-dih ydro- 2H-benzo[b][l,4]oxazin~6-yl)pyritnidin-2-yl)anuno)phenyl)pip erazine-] -carboxyiate (90 mg, 0.14 mmol, 1 equiv) in 1.25 M HCI in ethanol (5 mL) was allowed to stir tor In at 50°C.

Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain N-(2, 3-difiuon>4-(piperazm-l-yl) pheny!VS-fluoro-

4-(8-fluoro-4-isopropyi-3, 4-dihydro-2H-benzo[b][l,4]ox:azin-6-yi)pyrimidin~2-amine (60 mg.

75%) as a brown color solid compound.

LCMS: 503 [M+H] ⁺

1HNME: (400 MHz, DMSO-A6) d 9 35 (s, 1H), 8 88 (d, 7 19.7 Hz, 1 H), 8.51 (d, 7 3.9

Hz, 1 1 1). 7 33(d, J = 7.0 Hz, 2H), 7.10 (d, 7 = 11.7 Hz, 1H), 6.90 (t, J = 8.9 Hz, 1H), 4.31 - 4 23 (m, 21 1} 4 03 (p, =6.8 Hz, !H), 3.26 (q, ./ 6 4, 5.7 Hz, l ul l }. 1.15 (d, J = 6.4 Hz, 6H).

Example-29: Synthesis of S-fluoro-d-fS-fluoro-d-isopropyl-S, 4-dihydro~2H~

henzo[h][i, 4(oxazin-6~yl}~N~(3~tnethoxy-4-(piperazin-i~yl)phenyi)py imid ~2~amine

[0269] Step- 1 : Synthesis tert-butyl 4-(2-inethoxy-4-mtrophenyl) piperazine- J- carhoxyiate:

To a stirred solution of l-fluoiO-2-methoxy-4-nitrobenzene (1000 mg, 5.8 mmol, 1 equiv) in NMP (15mL), was added K2CG3 (1601 mg, 11 6 mmol, 2 equiv) and tert-butyl piperazine- 1 - carboxylate (1632 mg, 8.77 mmol, l Sequiv) The resultant reaction mixture was allowed to stir at 100 °C for 3h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the mixture was diluted with water (50 mLj and extracted with EtOAc (100 nrl. x2). Organic layer was washed with water (50 rnL) and brine (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-hulyl 4- (d-methoxy-d-ntirophenyl) piperazine- 1-carboxy late (1200 mg, 61%) as a dark brown solid compound.

LCMS: 338 [M+H] ⁺

[0:270] Step-2: Synthesis of tert-buty! 4-(4-amiiio-2-methoxypfaenyl) piperazine-1- carboxyiate:

To a stirred solution of tert-buty! 4-(2-methoxy-4-nitrophenyl) piperazine- 1 -carboxylate (400 mg. 1.18 mmol, 1 equiv) in ethanol (8 ml ), writer (2 mL), wras added iron powder (297 mg, 3 56 mmol, 3 equiv) and ammonium chloride (190 mg, 2 36mmoi, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for lb Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with water (30 ml,) and extracted with EtoAc (100 mL) Organic layer was washed with water (50 mL) and brine (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyi · ^' · · (4-ammo-2-methoxyphenyi)piperazine~1 ~carboxy!ate (250 mg, 69%) as a dark brown solid compound.

LCMS: 308 [M+H]

[0271] Step-3: Synthesis of tert-buty! 4-(4-((5-fluoro-4-(8-fluoro-4-isopropyI-3,4- dihydro-2H-benzoib][i,4]oxazin-6-yI)pyrimidin-2-yI)amino)-2- imethoxyphenyI)pipera¾ ^j ne- l-carboxylate:

To a solution of 6-(2-chjoro-5-†1uoropyrimidin-4-yl)~8~iluoi -4~isopropyl~3,4-dihydro-2H~ benzo[b][l ,4]oxazine (100 mg, 0 3 mmol. 1 equiv) m dioxane (10 ml,), was added tert-buty! 4- (4-ammo-2-methoxypbenyl)piperazine-l -earboxylaie (101 mg, 0.33 mmol, I d equiv) and cesium carbonate (147 rng, 0.45 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 rng, 0 006 rnmo!, 0.02 equiv) and BINAP (8 mg, 0.012 m ol, 0.04 equiv). The resultant reaction mixture was allowed to s ir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain tert-butyl 4-(4-((5-fiuoro-4-(8-fluoro-4- isopropyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)pyrimidin~ 2~yl)amino)~2~

methoxyphenyl)piperazine-l-earboxylate (40 mg, 22%) as a yellow color solid compound.

LCMS: 597 [M+H]

[0272] Step-4: Synthesis of 5-fluoro-4-(S-iluoro-4-isopropyl-3, 4-dihydro-2H- benzo[b][l,4]os:azi«-6-yi)~N-(3-methoxy-4-(pipei in-l-yl)pheayl)pyri idin-2-amiae;

A solution of obtain tert-butyl 4-(4-((5-iluoro-4-(8-fluoro-4-isopropyI-3,4--dihydro--2H- benzoib][l,4]oxazin-6-y!)pyrimidin-2-yl)amino)-2-methoxyplie nyl)piperazme-I-carboxylaie (40 mg, 0 06 mmol, 1 eqitiv) m 1.25 M HCI in ethanol (5 mi,) was allowed to stir for I h at 50 °C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain 5-fIuoro-4-(8-fIuoro-4-isopropyl-3, 4-dihydro-2H- benzo[b][l ,4]oxazin-6-yl)-N-(3-raethox> ^, -4~(piperazin-l -yl)phenyl)pyrimidin-2~amine (20 mg, 56%) as a brown color solid compound.

LCMS: 497 [M+H]

HNMR : (400 MHz, DMSO-76) d 9.59 (s, 1H), 9.00 (d, 7 = 5 7 Hz, !H), 8.55 (d, 7 3 8

Hz, 1H), 7.46(d, ./= 2.3 Hz, HI), 7 39 (s, HI), 7 37 - 7.25 (m, HI), 7 19 (d, J= I 1 .4 Hz, 1H),

6.88 (d, J = 8.6 Hz, 1H},4.34 - 4.25 (m, 2H), 4 12 (p, J= 6.3 Hz, HI), 79 (s, 4H), 3.34 - 3.27

(m, 213), 3.27 - 3 17 (m, 4H), 3.13 li . / 7o Hz, 3H), 1.18 (d. - 6.4 Hz, 6H).

Example-30: Synthesis of5-chioro-N-(3-fluoro-4-(piperazin-l-yi) phenyl ^" }~4~{8~fluoro~4~ !sopmpy!· j. 4-dihydro-2H-henzo[h] jl , 4joxazin-6-yl)pyrimidin-2-amine (Compound 30):

! 0273] Step-l : Synthesis of 6-(2, 5-dichloropyri idio-4-yi)-8-flaoro-4-isopropyl-3, 4- dihyd ro-2H- benxo j b | [1,4] oxazine:

To a stirred solution of 2,4,5-tnchloropyrinudine (300 mg. 1.64 mmol, I equiv) m THF: Water P · I 10 l,) was added, 8-fluoro-4-isopropy!-6-(4,4 5,5-teirameihyl-d,3,2--dioxaboro!an--2-yl)-·

3.4-dihydro-2H-benzo[b][l,4]oxazine (529 mg, 1.64 mmol, 1 equiv). Potassium carbonate (453 mg, 3 28 mmol, 2 equiv) and PdfPPfoft (95 mg, 0.08 mmol, 0.05 equiv). The reaction mixture was allowed to stir at 80°C for 4 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 ml,) and extracted wit ethyl acetate (100 ml, * 2). Organic layer was washed with water (100 ml) and brine solution (100 ml ). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-(2,5~dichloropyrimidin-4-yl)~B-tiuoro~4~isopropyh3,4 dihydrO 2H-benzo[b][l,4]oxazine (350 mg, 62%) as a yellow solid

LCMS: 342 [M+H] "

[0274] Step-2: Synthesis tert-butyl 4-(4-((5-chioro-4-(8-fiuoro-4-isopropyl-3, 4-dihydro-

2H~benzo[b] [l,4]oxazin-6-yl)pyriimidin-2-yI)aimino)-2-f!uorophenyI)pipe razine-l- carboxylaie:

To a solution of 6-{2-chloro-5-i1uoropyrimidin~4-yl)~8~fluoro-4~isopropyl~3, 4-dihydro- 2H~ benzo[b][l ,4]oxazine (100 mg, 0.3 mmol , 1 equiv) in dioxane (10 ml,), was added tert-butyl 4- (4-amino-2,3-difluorophenyl)piperazine-l -carboxylate (103 mg, 0.33 mmol, 1 1 equiv) and cesium carbonate (147 rng, 0.45 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 rng, 0 006 mol, 0.02 equiv) and BINAP (8 mg. 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mi,) and extracted with ethyl acetate (100 ml,) Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, winch was purified by reverse phase HPLC to tert-butyl 4-(4--((5--chloro-4-(8-ftuoro-4-isopropyl-

3.4-dihydro-2H -benzoj b] ] 1 ,4 ]oxazin-6-y 1 )pyrimidin-2-y i)amino)-2-f1 uorophenyl)piperazine- 1 - carboxylate (70 mg, 40%) a yellow color solid compound. LCMS: 601 [M+H]

[0275] Step-3: Synthesis of 5-chloro-N-(3-fluoro-4-(piperazin-l-yi) pheny l)-4-( 8-fluoro- 4-isopropyI-3 _> 4-dihy dro-2H-benzo b] [ 1 ,4] oxazin-6-y 1 ipyrini idm-2-amine:

A solution of obtain tert- butyl 4-(4-((5-chloro-4-i8-fiuoro-4-isopropyl-3,4~dihydro-2H- benzo[b][l,4]oxazin-6-yl)pynmidin~2-yl)amino)~2-fluorophenyl )piperazine~l~carboxylate (70 mg, 0 1 1 mmol, 1 equiv) m 1.25 M HC1 in ethanol (5 ml,) was allowed to stir for 1 h at 50 °C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain 5~chioro-N~(3~fluoro~4~(piperazin-l -yi) phenyl)-4-(8- fluoro-4-isopropyl-3, 4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)pyrimidin-2-amine (50 mg, 79%) as a brick red color solid compound.

LCMS: 501 [M+H] ^r

ti tiMMR:: (400 MHz, DMSO-J6) d 9.97 (s, l i ft. 9.10 (s, i l l) 8.58 (8, 1 H), 7 78 (dd, J= 15.2, 2 5 Hz, 1 H), 7.41 (dd, ,/= 8.8, 2 3 Hz, l i ft. 7.13 (s, I H), 7 04 (t, J= 9 4 Hz, 1 H), 6 99 (d, J= 1 1.2 Hz, 1H), 4 32-- 4 25 (m, 2H), 4.09 (s, !H), 3.34 - 3.27 (m, 2H), 3.27 - 3.19 (m, 4H), 3 1 6 (dd, J= 6.9, 3.4 Hz, 11 1 }. 1 17(d, / 6.5 Hz, 6H)

Example-31: Synthesis ofN~(2,5-difluoro~4~(piperazin~I-ylJpheriyl)-5~fluoro-4-(8~f luoro-4~ isoprop\4~3, 4-dihydro-2H~benzofbffI _> 4]oxazin~6~ylJpyrimidin~2~amine (Compound 31):

[0276] Step-1: Synthesis of tert-butyi 4-(2,5-dif!uoro-4-nitrophenyI)piperaz.ine~l~ carboxylate:

To a solution of i ,2,4-trifluoro~5~nitrobenzene (500 mg, 2.85 mmol, I equiv) and IfoCCti (432 mg, 3.13 mmol, 1 1 equiv) in DMF (10 L), was added a solution of tert-butyl piperazine- 1 - carboxylate (526 rng, 2 85 rnmoi, 1 equiv) in DMF (5 ml,) ai 0 °C . The resultant reaction mixture was allowed to stir at 0 °C for 15 min followed by RT overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, precipitated salt removed by filtration and filtrate diluted with ethyl acetate (50 mL). Organic layer was washed with cold water (30 mL x 3) and brine solution (30 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain text- butyl 4-(2,5--difluoro-4- nitrophenyi)piperazme-l Carboxyiate (950 mg, 97 3%) as a yellow color solid compound LCMS: 344.2 [M+H

[0:277 j Step-2: Synthesis of tert-butyl 4-(4-amino-225-diflu0ropheByl)piperazine-l - carboxyiate:

To a solution of tert-butyl 4-(2,5-difluoro~4~nitiOphenyl)piperazine-l-carboxylate (200 mg,

0.538 mmol, 1 equiv) m Ethanol : Water (1 : 1 ) (20 mL), was added NLUCI (63 mg, 1.66 mmol. 2 equiv) and Fe dust (98 mg, 1 166 mmol, 3 equiv) at RT The resultant reaction mixture was allowed to reflux at 90 °C for 3h. Progress of the reaction was monitored by TLC and I, CMS. After completion of the reaction, reaction mixture filtered through seine bed and filtrate concentrated up to dry. Residue obtained dissolved in EtOAe (50 mL) and organic layer washed with water (30 ml,) and brine solution (30 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by column chromatography (eluted 20% EtOAe in Hexane) to obtained tert-butyl 4-(4-amino~2,5- difluoropheny!)piperazme- 1 -carboxyiate (130 mg, 71 .4%) as a brown color solid compound.

LCMS: 314.4 [M-Hl] "

| 0278) Step-3: Synthesis of tert-butyl 4-(2,5-difluoro-4-((5-fluoro-4-(S~fluoro-4- isopropyI-3,4-dihydro-2H-benzo[b] [l,4]oxazin-6-yI)pyrimidin-2- yI)amino)phenyi)piperaz;ine-l-earboxylaie::

To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3,4 -dihydro-2H- benzo[b][l ,4]oxazine (100 mg, 0 31 mmol, 1 equiv) in dioxane (10 ml,), was added tert-butyl 4- (4-anuno-2,5-difiuorophenyl)piperazine~1 -carboxyiate (106 mg, 0 34 mmol, 1.1 equiv) and cesium carbonate (1 50 mg, 0 46 mmol, 1.5 equiv) The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 equiv) and BINAP (8 mg. 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC arid LCMS. After completion of the reaction, diluted with water (30 mL) arid extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to tert-butyl 4-(2,5~difluoro-4-((5-fluoro-4-(8-fluoro- 4- isopropyi- 3,4-dihydro-2H-benzo[b][! ,4]oxazin-6~yl)pyrimidin-2-yl}amino)phenyl)piperazine- 1 -carboxylate (50 mg, 27%) as a yellow color solid compound.

LCMS: 603.5 [M÷H] ⁺

[0279) Step-4: Synthesis of N-^S-difiuoro^ipiperazin-l-yl pfaenyO-S-fluoro^iS- fluoro^isopropyl-Syi-dihydro^II-benzojblJlyijoxazin-fi'-yOpy rimidin-l-amme:

A solntion of tert-butyl 4-(2,5-difluoro-4-((5~fluoro-4~(8~fluoro-4~isopropyl~3,4-dih ydro-2H- benzo[b][l,4]oxazin-6-yl)pyrimidin-2-yi)amino)phenyl)piperaz ine-l-carboxylate (50 mg, 0.083 mmol, 1 equiv) in 1 .25 M HC1 in ethanol (5 mL) was allowed to stir for Ih at 50°C. Progress of die reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain N~(2,5-dif!uoro-4-(piperazin~l~yl)phenyl)-5-f!uoro-4-(8-f!uo ro- 4-isopropyi-3,4~dihydro~2H-benzo(b](l,4]oxazin~6~yl)pyrimidi n-2-amine (30 mg, 72.11%) as a red color solid compound

LCMS: 503.4 jM÷H] ⁺

¾NM : (400 MHz, DMSOv/6) d 9.2-4 (for. s . 21 1). 8 53 (d, J= 3.51 Hz, 1 1 1). 7.68 (dd, J =

7.45, 13 59 Hz, IH), 7.36 (s, IH), 6.98 - 7.20 (m, 2H), 4.26 (br s„ 2H), 4.04 (br. s., 1H), 3.22 (d, J = 7.89 Hz, I OH), 1.09 - 1.25 (m, 6H).

Example-32: Synthesis of 5-ftiioro-N-(3-jhioro-4-(piperazin- l-yl) phenyl)-4~(8-jhioro-4- isopropyl-2-methyl-3,4-dihydro-2H-benzo[b [J4]oxazm~6~yl)pyrimidin~2~amine (Compound 32):

[028G] Step-1: Synthesis of 2-araino-4-hromo-6-fl«orophenoi :

To a stirred suspension of 4-bromo-2-fluoro-6-nitrophenol (15 g, 63 55 mmol , 1 equiv) in ethanol (400 ml,), was added stannous chloride monohydrate (60 g, 317.8 mmol, 5 equiv) at room temperature The reaction mixture was refluxed at 80°C for 3 h. Progress of the reaction was monitored by TLC and i .CMS After completion of the reaction, reaction mass concentrated the reaction poured on tee-cold water (500 rnL) and was basified by 3N NaOH solution up to pH 10 and was extracted with ethyl acetate (350 ml, ^x 3), orga c layer was washed with water (150 ml,} and brine solution (150 ml,}. Organic layer dried over anhydrous sodium sulphate and concerttrated under reduced pressure to afford 2-ammo-4-bromo-6-iluorophenol (1 1 g}.

LCMS: 207 [M4-H} ⁺ , 209 [M+2HG

[0281] Step-2: Synthesis of 4~bromo-2-fiuoro-6-(i$epropyIaniim>)phem>I:

To a stirred solution of 2-amino-4-bromo-0-fluorophenol (500 mg, 2.4 mmol, 1 equiv) m 1,2 dichloroethane (10 tnL), was added acetone (21 1 1 mg, 4.8 mmol 2 equiv) followed by addition of acetic acid (540 mg, 12 mmol, 5 equiv ) at 0 C. The reaction mixture was stirred at room temperature for 30 minutes. To ibis was added sodium triaceiox borohydnde (1010 mg, 4.8 mmol, 2 equiv) at 0 C. Resultant mixture was stirred at room temperature tor 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (40 mL) and was extracted with ethyl acetate (40 ml, ^x 2). The combined orgamc layer -w s -w shed with water ( 15 mL) and brine solution ( 15 mL). Orgamc layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 4-bronu>2-f1uoro-6-(tsopropyla ino)phenoi (480 mg)

LCMS: 248 [M+fff, 250 [M+2H] ⁺

[0:282] Step-3: Synthesis of 6-bromo-8~fluoro-4~isopropyi-2- ethyi-2H- ben*o[b] [l,4]oxa*in-3(4H)-onet

To a stirred solution of 4-bromo-2-fluoro-6- isopropyiamino)phenol (2 g, 8 1 mmol, 1 equiv) in chloroform (40 mL), was added NaHC03 (3 4 g, 40.5 mmol, 5 equiv) at 0 C, followed by addition of benzyl triethyl ammonium chloride ( 1.84 g, 8. 1 mmol, 1 equiv ) at 0 C. The reaction mixture was stirred at 0 C for 5 mm. To this was added 2-chloropropanoyi chloride (1.02 g,

8.1 mmol, 1 equiv) at 0 C. Resultant mixture was stirred at 0 C for 1 h and then at 60 C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated Na2C03 solution (100 ml,) and was extracted with DCM (100 ml, 2) The combined organic layer was washed with water (15 ml,) and bone solution (15 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 6-bromo-8-fluoro-4-isopropyl-2-methyl-2H- benzo[b][l,4]oxazm~3(4H)-one (1.5 g)

LCMS: 302 304 [M÷2Hf

[0283] Step-4: Synthesis of 6-bromo-8-f!uoro-4-isopropyI-2-methyI-3,4-dihydro-2H- henzo [b] [ 1,4] oxazin e:

To a stirred solution of 6-bromo-8-iluoro-4-isopropyl-2-methyl-2H-ben o|b][l,4]oxazin-3(4H)- one (1000 mg, 3.32 mmol, 1 equiv) in THF (14 ml ,), was drop wise added BI¾.DMS (1 ml,,

13.3 mmol, 4 equiv) at 0 C. The reaction mixture was stirred at 50°C for 16 h. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was quenched with water (50 ml ,) and extracted with ethyl acetate (100 ml, x 3). The combined organic layer was washed with water (50 ml ,) and brine solution (50 ml ,) Organic layer dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 6- bromo-8-f!uoro-4-isopropy!-2-methy!-3,4--dihydro--2H-benzo[ b][ 1 ,4joxazine (700 mg).

LCMS: 288 [M÷H] ⁺ , 290 [M+2H} ⁺

[0284] Step-5: Synthesis of 8-fl«oro-4-isopropyl-2-methyl-6-(4,4,5,5-tetramethy!-l,3,2- dioxaboroian-2-yI)-3,4-dihydro-2H-henzo{b] [1 ,4]oxazi»e: To a stirred solution of 6-brorao-8- fluoro-4-isopropyl-2-rnethyl-3 4-dihydro-2H-benzo bl ] ,4]oxazine (200 mg, 0 7 mmol, 1 equiv) in dioxane (4 niL), was added 4,4,5,5-tetfainethyl-2-(4,4,5,5-tetramethyi~] ,3,2-dioxaborolan-2- yl)-l,3.2-dioxaborolane 094 mg, 0 76 mmol, 1.1 equiv) and potassium acetate (100 mg, 1.05 mmol, 1.5 equiv). Aerated the reaction mixture with nitrogen gas for 15 minutes. After addition of PdC12(dppf) DCM (24 g, 0.034 mmol, 0.05 equiv) again purge nitrogen for 5 mm. The reaction mixture was stirred at 100°C for 4 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 niL * 2), organic layer was washed with brine (20 niL). The organic layer dried over anhydrous sodium sulphate and concentrated under reduced pressure purified by combiflash to afford 8-fiuoro-4-isopropyl-2-methyl-0-{4,4.5,5-tetrarnethyl- l,3,2 dioxaborojan-2wl) 3,4 dihydrO 2H benzo[b([l ,4]oxazme (170 mg).

LCMS: 336 [M÷H] ⁺

[0285] Step-6: Synthesis of 6-(2-chloro-5-fluoropyrimidm-4-yl)~8-fluoro-4~isopropyi-2- methyl-3,4-dihydro-2H-benzo[b]jl,4[oxazme:

To a stirred solution of 2, 4-dichloro~5~fluoropyrimidine (0 75 g, 4.5 mmol, 1 equiv) and 8- fluoro-4-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dk>xaborolan-2-yl)-3,4-dihydro-2H- benzo[b][l ,4]oxazine (1 5 g, 4 5 mmol, 1 equiv) in THF: Water (1 : 1. 20 mL) was added potassium carbonate (0.93 g, 6 75 mmol . 1 5 equiv) and Pdi PPh ft (0.259 g, 0 226 mmol. 0.05 equiv). The reaction mixture was heated to 80 f for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 ml,) and extracted with ethyl acetate (100 ml, ^c 2), organic layer was washed with water (100 mL) and brine solution (100 mL). The organic layer dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to afford 6-(2-chloro-5~fluoropyriraidin-4~yl)-8-ftuoro-4-isopropyl- 2~methyl-3,4-dihydro-2B-benzo[b][l ,4]oxazine (0.8 g) as a yellow solid compound

LCMS: 340 [M-i-Hlf

[0286] Step-7: Synthesis of iert-bidyl 4-(2-fluoro-4-((5-fluoro 4-(8-fluoro-4-isopropyi-2- raethyl-3,4-dihydro-2H-ben*o[b][l,4]oxazin-6-yl)pyr«midin-2 -yl)amino)phenyl)pipera*me- l~carboxylate: To a solution of 6-(2-chioro-5-fiuoropyriinidin-4-yi)-8-fluofo-4-isopropyi-2- methyi-3, 4-dihydro-

2H--benzo[bjp ,4]oxazine (60 mg 0.18 mmol, 1 equiv) in Dioxane (3 mL), was added tert-buiyl 4-(4-arnino-2-(luorophenyl)piperazme-l -carboxylate (57 mg, 0.19 mmol, 1.1 equiv) and cesium carbonate (88 mg, 0.27 mmol. 1.5 equiv). The reaction mixture was aerated with nitrogen gas for 10 min. followed by the addition of palladium acetate (4 mg, 0.02 mmol, 0.1 equiv) and BIMAP (22 mg, 0.036 mmol, 0 2 equiv) again purged nitrogen for 5 min. The resultant reaction mixture was stirred at 100 °C for 16 h. Progress of the reaction was monitored by TLC and I .CMS. After completion of the reaction, the reaction mixture was diluted with wetter (10 mL) and extracted with EtOAc (15 mL). The organic layer dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase KPLC to afford of tert-butyl 4-(2-fluoro-4-((5-fluoro-4-(8-fluoro-4-isopropyl-2-methyl-3, 4-dihydro-2H- benzo[b][l,4]oxazin~6~yl)pyrimidin-2-yI)arnmo)pheny])piperaz ;ine-l -carbox late (50 mg) LCMS: 599 i X 1 I H

[0287] Step-8: Synthesis of 5-f!uoro-N-(3-fiuoro-4-(pipera*in-l-yl)phenyl)-4-(8-fI«oro- 4- isopropyi-2-raethyi-3,4- ihydro-2H-ben¾o[b][l _» 4]oxa* ^j n-6-yl)pyriimidin-2-ara ^j ne:

Tert-butyl 4-(2-fluoro-4-((5-fluoro-4-(8-fluoro-4-isopropyl-2-methyl-3, d-dihydro-2H- benzo[b][! ,4 ]oxazin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazine-l-carbox ylate (50 mg. 0.083 mmol, 1 equiv) veas taken m 1 25 M HC1 m ethanol (4 ml,) and the resultant reaction mixture was stirred at 50°C for 2 h Progress of the reaction was monitored by LCMS After completion of the reaction, the reaetion mixture was concentrated under vacuum to obtain 5-fluoro-N-(3- iluoro~4~(piperazm~i -y! iphenyi)~4~(8~-f!uoro~4~isopropyi~2~meihyi~3,4-dihydro~2!:L

benzo[bj[l,4]oxazin-6-y!)pynmidm-2~arnine (20 mg) as a HC1 salt

LC S: 499 [MMl

d f VMbft (400 MHz, DMSO-foS) d 9.82 (s, 1H), 9 03 (d, / 8.5 Hz, 2H) 8.58 (d. / 3.9 Hz,

IH), 7 81(dd J 1 5 3, 2 4 Hz 1 1 1) 7 41 (d, .7- 9.2 Hz, 2H), 7.1 6 (d, - 1 1 .7 Hz, I H), 7.05 (t, 7 - 9 4 Hz, 1H),4 29 (p, 7.5 Hz, I H), 4.16 (p, - 6.7 Hz, 1H), 3.45 (d, J === 12 2 Hz, IH), 3.27 - 3 21 (m, 4H), 3.16 (t, J ---- 4.7 Hz, 4H), 2.88 (dd, J === 12.7 7.5 Hz, 1 H), 1.36 (d, J ^:::: 6.2 Hz,

3H), 1.21 (d, / 6.7 Hz, 3H), 1.15 (d, J === 6.5 Hz, 3H). Example-33: Synthesis of 5~fiuoro-4-{8~fiuoro-4~isopropy}~3, 4~dihydro~2H~

benzo[h] [J4]oxazin-6-yi N~{6~( I ~methylpiperidin-4-y])pyridin-3-y])pyritnidin-2-amifte (Compound 33):

[0288] Step- !:; Synthesis of tert-butyl 5-ammo-3', 6’-difayilro-[2, 4 ^, ~bipyridine]- 1 *(2’H)- carboxy!ate: To a solution of 6-bromopyridin-3-amine (1000 mg, 5 8 mmol, 1 equiv) in dioxane (15 ml,), was added tert-butyl 4-(4. 4. 5, 5-tetramethybL 3, 2-dioxaborolan-2-y])-3, 6- dihydropyridine-l (2H)-carboxylate (1797 mg, 5.8 mmol, 1 equiv) and sodium carbonate (1844 mg, 17.4 mmol, 3 equiv) The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of Pd(PPh3) ₂ CI ₂ (204 mg, 0 29 mmol, 0.05 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mi, a 2) Organic layer was washed with water (100 ml,) and brine solution (100 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, winch was purified by normal phase combi flash to tert-butyl 5-amino-3 ^! ,6'-dihydro-[2,4 ^! -bipyridi«e]-]‘(2Ή)- carboxy!ate (900 mg, 56%) as a yellow oil compound.

LCMS: 276 [MfH] ⁺

[0289] Step-2: Synthesis of tert-butyl 4-(5-ammopyridm~2~yl) piperidine-i-carboxylate:

To a stirred solution of tert-butyl 5-amino-3 y 6’-dihydn>[ 2, 4’-bipyridine]-r(2’H)-carboxy]ate (900 mg, 3 2 mmol, 1 equiv) in methanol (10 l,), was added Pd/C (20% w/w) (180 mg) under Hi atm. The resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, the mixture was passes through cehie bed and the filtrate was concentrated under reduced pressure to obtain tert- butyl 4- (5-aminopyridin-2~yl) piperidine-l -carboxylate (800 nig, 88%) as a transparent oil compound.

LOIS: 278 [M f!Tj ⁺

[0290] Step-3: Synthesis of tert- butyl 4-(5-((5-i1tioro-4-(8-i1tioro-4-isopropyI-3,4- clihydro-2H-ben¾o[b]!i,4|oxa2;in-6-yI)pyrimidin-2-yI)aini« o)228yricli«e-2-yi)piperidme-l- carboxylate: To a solution of 6-(2-ehloro-5-fluoropyrimidin~4-yl)~8-fluoro-4-isopropyl-3,4 - ddiydro-2H-benzo[b][1 ,4 oxazme (1 50 mg. 0.46 mmol, 1 equiv) in dioxane (10 mL), was added tert-butyl 4-(5-aminopyridin-2-yl) pipendine-l-carboxylate (141 mg, 0.50 mmol, 1 1 equiv) and cesium carbonate (225 mg, 0 69 mmol, 1.5 equiv) The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.009 mmol, 0.02 equiv) and BINAP (12 mg, 0.018 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 1 00 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which w¾s purified by normal phase combi flash to obtain tert-butyl 4-(5~((5~fluoro~4~(8~ fiuoro-4-isopropyl-3,4-dihydro-2H-benz:o[b][! ,4]oxazin-6-yl)pyrimidin~2~yl)amino)pyridin-2- yl)piperidme~l -carboxylate (60 g, 23%) as yellow solid compound.

LCMS: 567 [M÷H] "

[0291] Step-4: Synthesis of 5-f! uoro-4~(8-f! uoro~4-isopropyl-3, 4-dihydro-2H~ benz©[b][i,4]©xaziR-6-yl)~N-(6-(piperidin-4-yl)pyridm-3-yl )pyrinHdin-2-arame: A solution of tert-hulyl 4-(5-((5-fiuoro-4-(8-fluoro-4-isopropy]-3,4-dihydro-2H-benzo [b][l,4]oxazin-6- y!)pyrirnidin-2-yi)amino)pyridin~2~yi)piperidine-i -carboxyiate (60 g, 0 1 mmol. 1 equiv) m 1.25 M HCl in ethanol (5 mL) was allowed to stir for 1 h at 50°C. Progress of the reaction was monitored by LCMS After completion of the reaction, solvent was removed under reduced pressure to obtain 5-fluoro-4-(8-fluoro-4-isopropyj-3, 4-dihydro-2H-benzo[b][i,4]oxazin-6-yl)- N-{6-(pipendin-4-yl}pyridin-3-yl)pyrmiidm-2-aniine (50 mg, 94%) as a yellow solid compound.

LCMS: 467 [M fH] ⁺

[0292] Sfep-5: Synthesis of 5-fl«or©-4-(8-fl«or©-4-isopropyl-3, 4-dihydro-2H- ben*o[b][l,4)oxa2in-6-yl)-N-(6-(l- ethyIpiperidin-4-yI)pyridin-3-yI)pyrimidin-2-ainine: To a stirred solution of 5-f!uoro-4-(8-f!uoro-4-isopropyl-3 4-dihydro-2H-benzo[b) [ 1 ,4]oxazin-6-y i)- N-(6-(piperidin-4-yl)pyridin-3-yl)pyriraidm-2-amine (50 mg, 0.09 mmol, 1 equiv) in DCE (5 niL), was added Formaldehyde (40% m water) (0.01 nil,, 0 29 mmol, 3 equiv), acetic acid (0.02 mL, 0.45 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for Hi. Hie reaction mixture was cooled to 0°C. NaCNBfL (18 mg, 0.29 mmol, 3 equiv) was added to above mixture and raise the temperature to RT The reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (50 mL x 2) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5-fluoro-4-(8-fluoro-4-isopropy]-3.4-dihydro-2H- benz:o[b][l 4]oxazin-6-yl)-N-(6-(l-methylpiperidin-4-yi)pyridiii-3-y])py rimidin-2-amiiie (7 g, 15%) as a yellow color solid compound.

LCMS: 481 [Mali] ^f

sHNMS: (400MHz ,DMSO-d ₆ ) d 9 79 (s, 1 H), 8.84 (br. s., 1 H), 8.57 (d, ,/= 3.9 Hz, 1 H),

brorno-8-fluoro-2H-benzo[bj[ l 4 oxazin-3(4H)-one (700 mg, 2.85 mmol, 1 equiv) in DMF (10 mi .; was added K ·( ()·. (789 mg, 5.71 mmol, 2 equiv) and methyl iodide (0.4 mL, 5.71 mmol 2 equiv). The reaction mixture was allowed to stir at 80°C for 3 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 mL), solid observed was filtered dried under vacuum to obtain 6-bromo-8-fiuoro- 4-methyl-2H-benzofbl[l,4]oxazin-3(4H)-one (700 mg, 95%) as an off white solid compound.

LCMS: 260 [M+H] ⁺

(0294| Step-2: Synthesis of 6-hrom©-8-ffuoro-4-methyl-3, 4-dihy ro-2H- benzo|b| [l,4|oxazme: To a stirred solution of 6-bromo-8-f!uoro-4-methyl-2H- benzo[bl[l,4]oxazm-3(4H)-One (700 mg, 2 7 mmol, 1 equiv) in THF (15 mL), was added

BH .DMS (1 mL, 10.8 mmol, 4 equiv) at 0 C drop wise The reaction mixture was allowed to stir at 80°C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was quenched with saturated solution of NallCCfi (1 00 ml..) and extracted with ethyl acetate (100 ml.. ^c 2). Organic layer was washed with water (100 mL). dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6-bromo-8-f1uoro-4-methyl-3,4-dihydro-2H-benzo[b][l ,4]oxazine (650 mg, 98%) as a yellow viscous compound.

LCMS: 246 [Mali] ^f

[0295] Step-3; Synthesis of 8-fiuoro-4-methyl-6-(4,4 _> 5,S-tetramethyI-i,3,2~dioxaborolan-2- yl)-3,4-dihydro-2H-benzo[b][l,4]oxazine: 6-brorao-8-fluoro-4-meihyl-3,4-dihydro-2H- benzo[b][! ,4]oxazine (650 mg, 2 65 mmol. 1 equiv), 4,4,5,5-tetrame4hyl~2~(4,4,5,5-ietramethyl- l ,3,2 dioxaboroian-2-yi)--! ,3,2-dioxaboroiane (809 mg, 3 18 mmol. 1 2 equiv), Potassium acetate (779 mg, 7.95 mmol, 3 equiv) and dioxane (10 ml.) were charged in a 25 ml, glass botle Purged the reaction mixture with nitrogen gas for 15 min , Pd(dppf)G2. DCM (108 mg, 0 13 mmol, 0.05 equiv) was added to above mixture and the reaction mixture w¾s allowed to stir at 100°C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction the reaction mixture was diluted with water (30 mL) and extracte with ethyl acetate (100 i . x 2). Organic layer was washed with brine (50 mL) an water (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 8-fluoro-4-methyl 0-(4,4,5,5~tetraineth l-l ,3,2-diGxaborolan-2~yl)-3,4-dihydiO-2H- benzo[b] [ 1 ,4 Joxazine ( 700 mg 90%) as a dark brown viscous compound.

LCMS: 294 [MfH] ⁺

[0296] Step-4: Synthesis of 6-(2-chloro-5-fluoropyrim5dm-4- l)-8-tl uoro-4-methyl-3,4- dihydro-2H~benzo[hjjl,4[oxazme: To a stirred solution of 2, 4-diehloro-5-fluoropyrimidine

(400 mg, 2.19 mmol, 1 equiv) in THF: Water (5 mL: 5 ml,) was added 8-fluoro-4-methyl-6- (4,4,5,5-tetramethyi-L3,2-dioxaborolan-2-yl)-3,4~dihydro-2H- benzo[b][L4]oxazine (642 g, 2.19 mmol, 1 equiv), Potassium carbonate (607 mg, 4.39 m ol, 2 equiv) and PdfPPlyft (127 g, 0.1 mmol, 0 05 equiv). The reaction mixture was allowed to stir at 80°C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 ml,) and extracted wit ethyl acetate (100 ml, * 2). Organic layer was washed with water (100 ml,) and brine (100 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-(2~chloro-5-fluoropyrimidin-4-yl)- 8~fluoro-4~methyl-3,4-dihydro-2H-benzo[b] [ 1 ,4]oxazine (360 mg, 55%) as a yellow solid compound.

LCMS: 298 [M-HB] ⁺

[0297] Step-5: Synthesis of tert-butyi 4-(2-f!«oro-4-((5-flaoro-4-(8-flaoro-4-methyI-3,4- d ^j hydro-2H-benz.o[b]ii _» 4]oxaz ^j n-6-yi)pyr ^j midin-2-yl)amino)phenyI)p ^j peraz.me-l- carhoxylate: To a solution of 6-(2-chloro-5-t]uoropyrimidin-4-yi)-8-iluoro-4-metbyl-3,4- dihydro-2H--benzo[b][L4]oxazme (100 mg. 0.33 mmol, 1 equiv) in Ehoxane (10 ml,), was added tert-butyi 4-(4-armno-2-fluorophenyl)piperazine-] -carboxylate (109 mg, 0.37 mmol, 1.1 equiv) and cesium carbonate (161 mg, 0.49 mmol, 1 5 equiv). The reaction mixture was purged with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 equiv) and BINAP (8 mg. 0.013 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. Alter completion of the reaction the reaction mixture was diluted with water (30 mL) and extracted wit ethyl acetate (100 ml ). Organic layer was washed with water (50 mi,) and brine (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain tert- butyl 4--(2-iluoro4--((5-iluoro4-(8-iluoro4-msthyh-3 4--dihydrO 2H--benzoib][ l,4 joxazin-6- yl)pyritnidin-2-yl)amino)phenyl)piperaz e-] -carhoxyiate (70 mg. 70%) as a yellow solid compound.

LCMS: 557[M+H;

10298] Step-6: Synthesis of 5-t1uoro-N-(3-fluoro-4-(piperazm-l -yl) phenyl)-4-(8-flnoro- 4-methyl-3, 4-dihydro-2H-benzo[b] (l,4]oxazin~6~y!)pyrimidin-2-amine: tert-butyl 4-(2- fluoro-4-((5-fluoro-4-(8-fluoro-4-niethyl-3,4-dihydro-2H-ben zofblf l,4]oxazin-6-yl)pyrimidm~2·- yl)amino)phenyi)piperazine4-Carboxyiate (70 mg, 0.12 mmol, 1 equiv) was taken m 1.25 M HCI m ethanol (5 mL) and the resultant reaction mixture was allowed to stu at 50°C for Ih. Progress of die reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under iyopiulizer to obtain 5-fluoro- N-(3-fluoro-4-(piperaziii- l -y])phenyl)-4-(8-fluoro-4-methyl-3,4-dihydro-2H- benzoj¾][l ,4]oxazin-6-yl)pyriinidin-2-amine (45 mg, 73%) as a brick red color solid compound.

LCMS: 457[M+Hj

1HNMR: (400 MHz, DMSCL46) d 9 83 (s, 1 H), 9 33 (s, 1 H), 8 58 (d, J= 3.9 Hz, IH), 7.86

(dd, J= 1 5.5, 2.5 Hz, IH), 7.42 - 7 34 (m, IH), 7.30 (s, IH), 7.26 - 7.17 (m, IH), 7.06 (t, J = 9.4 Hz, IH), 4.37 (t, 7 4 3 Hz, 2H), 3.37 (·. J = 4.3 Hz, 2H), 3.26 - 344 (m, 8H), 2.96 (s, 3H).

Example-35: Synthesis of 4-(4~ethyl-8-fluoro~3 _> 4-dihydro-2H-bemofh [1, 4ioxazm~6~yl)~5~

[0299] Step-1: Synthesis of 6- 6-brorao-4-ethyl-8-fluoro-2H-ben*o[b][l,4]oxa*in-3(4H)-one:

To a stirred solution of 6-bromo-8-f1uoro-2H-benzo[b][l ,4]oxazin-3(4H)~one (700 mg, 2.85 mmol, 1 equiv) in DMF (10 ml,), was added K TO (789 mg, 5.71 mmol, 2 equiv) and ethyl iodide (0.5 L, 5.71 mmol, 2 equiv}. The reaction mixture was allowed to stir at 80°€ for 3 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 mL), solid observed was filtered dried under vacuum to obtain 6-bromo~4-ethyi-8-fluoro-2H-benzo[bl[ l,4]oxazin-3(4H)-one (700 g, 90%) as an off white solid compound.

LCMS: 274 [M+H] ⁺

! 0300] Step-2: Synthesis of 6-bromo-4-ethyi-8-fliioro-3, 4-dihydro-2H- benzojbj j L4 joxazme: To a stirred solution of 6-bromo-4-ethyb 8~ffucro~2H- benzo[b][ l,4]oxazin-3(4H)-one (700 nig, 2.7 mmol, 1 eqiuv) in THF ( 10 mL), was added BLft.DMS (1 mL, 10 8 mmol, 4 equiv) at 0 C drop wise. The reaction mixture was allowed to stir at 80°C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated solution of NaHCXL (100 mL) and extracted with ethyl acetate (100 mL ^c 2) Organic layer was washed with water (100 ml,), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6-bromo-4-ethyl-8-fluoro-3,4-dihydro-2H-benzo[b][ l ,4]oxazine (600 mg, 90%) as a transparent oil compound.

LCMS: 260 [MLB] ⁺

[0301] Step-3: Synthesis of 4-ethyl-8-fluoro-6-(4 _» 4 5-tetraraethyl- 3,2-dioxaboroian-2-yI)- 3,4-dihydro~2H~benzo[bj[l,4]oxazine: 6-bromo-4-ethyI-8-f1uoro-3,4~dihydro-2H- benzo[b] [ 1 ,4] oxazine (600 mg, 2.31 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetrame†hyl~ l ,3 2-dioxaborolan-2-yl)-l,3,2-dioxaboroiane (706 mg, 2.77 mmol, 1 .2 equiv), Potassium acetate (679 rng, 6 93 mmol, 3 equiv) and dioxane ( 15 mL) were charged m a 25 mL glass bottle. Purged the reaction mixture with nitrogen gas for 15 min., Pd(dppf)Q2. DCM (94 mg, 0.11 mmol, 0.05 equiv) was added to above mixture and the reaction mixture was allowed io stir at 100°C for 3 h. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate ( 100 mL - 2). Organic layer was washed with brine (50 L) and water (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 4-ethyi~8-fluoro~6~(4,4,5,5-tetramethy] l,3,2 dioxaborolan-2-yl) 3,4-dihydfo-2H- benzo[b][l,4]oxazi«e ( 700 mg, 90%) as a dark brown viscous compound. LCMS: 308 [MfH] ^”

[0302 Step-4: Synthesis of 6-(2-chloro-5-fluoropyrimidm-4-yl)-4-ethyl-8-fl«oro-3,4- dihydro-2H~benzo[hjjl,4[oxazme: To a stirred solution of 2, 4-diehloro-5-fluoropyrimidine

(300 mg, 1.8 mmol, 1 equiv) in TH : Water (1 : 1 = 10 mLj was added 4-ethyi-8-fluoro-6- 4, 4,5,5- tetramethyi-l ,3,2-dioxaborolan-2-yl}-3,4-dihydro-2H-benzo[b] [1.4]oxazine (555 mg, 1.8 mmol,

1 equiv), Potassium carbonate (499 mg, 3.6 mmol, 2 equiv) and Pd(PPh ₃ )4 (104 mg, 0 09 mmol, 0.05 equiv). The reaction mixture was allowed to stir at 80°C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mLj and extracted wit ethyl acetate (100 mL ^c 2) Organic layer was washed with water (100 mL) and brine (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-(2-chioro-5-fluoropyrimidin-4-yl)-4-ethyi-8- fluoro-3,4-dihydro-2H-benzo[b] [ 1 ,4]oxazine (150 mg, 27%) as a yellow solid compound.

LCMS: 312 [M+H] ^f

[030:3] Step-5: Synthesis of tert-butyi 4~(4-((4-(4-etfayl-8-fluoro-3, 4-dihydro-2H- benz.o[b]ii _» 4]oxazin-6-yi)-5-fluoropyrimidin-2-yl)amino)-2-fluorop henyI)piperaziHie-l- carboxylaie: To a solution of 6~(2-chloro-5-fluoropyrimidin-4-yl)-4-ethyl-8-fluoro-3,4-dih ydro-

2H~benzo[b][! ,4]oxazine (100 mg, 0 32 mmol, I equiv) m Dioxane (10 mL). was added tert- butyi 4-(4-amino-2-†1uorophenyl)piperazine-l -carboxylate (104 mg. 0.35 mmol, 1 . 1 equiv) and cesium carbonate ( 157 mg, 0.48 mol, 1 .5 equiv). The reaction mixture was purged with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 013 mmol. 0 04 equiv) The resultant reaction mixture was allowed m stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted wit ethyl acetate ( 100 mL) Organic layer was washed with water (50 mL) and brine (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain tert- butyi 4-(4-((4-(4-ethyl-8-fluoro-3,4-dihydrO 2H-benzo[bl[l ,4]oxazin-6-yl )-5-fluoropyrimidin-2·· y!)amino)-2-iluoropheny!)piperazine- b-carboxylaie (60 mg, 33%) as a yellow solid compound.

LC .VIS: 571 [M+H] [0304] Step-6: Synthesis of 4-(4-ethyl-8-!1uoro-3, 4-dihydro-2H-hen«o{b] [1 ,4]oxa*in-6- yI)-5-fluoro- -(3-fluoro-4-(piperazin-l-yl)phenyl)pyri idin-2-amme: Tert-butyl 4-(4-((4--(4-· ethyl~8~fluoro~3,4-dihydro-2H~benzo[b][l,4]oxazin-6-yl)-5-fl uoropyrimidin-2-yl)amino)-2- fluorophenyl)piperazine~l~carboxyiate (60 mg, 0.1 mmol, 1 equiv) was taken in 1.25 M HCi in ethanol (5 mb) and the resultant reaction mixture was allowed to stir at 50°C for lh. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophilizer to obtain 4-(4-ethyl-8-fluoro- 3,4-dihydro-2H-benzo b] l,4]oxazin-6-yl)-5-fluoro-N~(3~fluoro-4~(piperazin-l - yl}phenyl)pyrimidin~2~amine (40 mg, 75%) as a brick red color solid compound.

LCMS: 471 [M+H] ^÷

1HNME: (400 MHz, DMSOM6) d 9 81 (s, H i ) 9 19 (d, 7 6.7 Hz, Hi), 8.58 (d, ./= 3.9

Hz, i l l ;. 7.80 fob. / 15.1, 2 4 Hz, 1H), 7.39 (dd, 7 11.6, 9.1 Hz, 1H), 7.30 (s, !H), 7.19 -

7.00 (m, 2H), 4 32 ft, ,7=4.1 Hz, 2H), 3.49 - 3.37 (m, 4H), 3.26 - 3.13 (m, 8H), 1.13 (t, J = 7.0 Hz, 3H).

Example-36: Synthesis of 5~fluoro~N~(3~fluoro~4~(prperazm~l~yi ) phetiyl)-4-(8-Jkioro- -propyI-3,

(0305| Step-1: Synthesis of 6-bromo-8-fluoro-4-propyl-2H-henzo[b| j1,4 j oxazin-3( 4H)-one:

To a stirred solution of 6-bromo~8~fIuoro~2H-benzo[b][l,4]oxazin-3(4H)-one (700 mg, 2 85 mmol, 1 equiv) in DMF (10 ml,), was added I , _'( () (789 g, 5 71 mmol, 2 equiv) and iodopropane (0.6 ml,, 5.71 mmol, 2 equiv). The reaction mixture was allowed to stir at 80°C for 3 h Progress of the reaction was monitored by TI,C and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 ml,), solid observed was filtered dried under vacuum to obtain 6-broino--8-fluoro-4--propyl--2!T-benzo[b][L4joxazm-3(4H)-on e (750 mg 92%) as an off white solid compound

LCMS: 288 [M f!Tj ⁺

[0306] Step-2: Synthesis of 6-hroiKO-8-fl«oro-4-propyl-3,4-d«hydro-2H- benzo|b] [l,4]o5azme: To a stirred solution of 6-bromo-8-fluoro-4-propyl-2H- benzo[bl[l,4 oxazm-3(4H)-One (750 mg, 2 6 mmol, 1 equiv) in THF (10 niL), was added B¾.DMS 0 mL, 10.4 mmol, 4 equiv) at 0 C drop wise The reaction mixture was allowed to sti r at 80°C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated solution of NaHCO- ( 100 mL) and extracted with ethyl acetate (100 mL * 2). Organic layer was washed with water (100 mL). dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6foromO 8 i!uorO 4 propyb3,4-dihydrO 2]:Lbenzo[b][L4]oxazine (650 mg, 91%) as a transparent oil compound.

LCMS: 274 [Mali] ^f

[0307] Step-3: Synthesis of 8-fluoro-4-propyl-6-(4,4,5,5-tetramethyl~l,3^~dioxahorolan-2 - yl)-3,4-dihydro-2H-ben¾o[b] [ 1,4] examine: 6-bromo-8-fluoro-4-propyl-3,4-dihydro-2H- benzo[b][! ,4]oxazme (650 mg,, 2.31 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- l ,3,2 dioxaborolan-2-yl} l ,3,2-dioxaborolane (725 mg, 2 85 mmol , 1 2 equiv), Potassium acetate (676 mg, 6.93 mmol, 3 equiv) and dioxane (1 5 ml.) were charged in a 25 ml.. glass bottle. Purged the reaction mixture with nitrogen gas for 15 min , Pd(dppf)G2. DCM (94 mg, 0 1 1 mmol, 0 05 equiv) was added to above mixture and the reaction mixture was allowed to stir at 100°C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 ml.) and extracted with ethyl acetate (100 ml, x 2). Organic layer was washed with brine (50 mL) and water (50 mL) Organic layer w¾s dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 8-fiuoro-4-propyl~6 (4,4,5,5-tetrameth l-l ,3,2-dioxaborolan-2-yl)-3,4-dihydio-2H- benzo[b][l ,4joxazme ( 650 mg 85%) as a dark brown viscous compound.

LCMS: 322 1 [M÷H] ⁺

[0308] Step-4: Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fiuoro-4-propyi-3, 4- clihydro-2H-ben¾o(b] [1 ,4]oxaa>;i«e: To a stirred solution of 2 4-dichloro-5 -fluoropyriraidine (300 mg. 1.8 mmol, I equiv} TI-JF: Water (1 : 1 ^::: 10 mL) was added 8-fluoro-4-propyl-6- (4,4,5,5-ietramethy]-l,3,2-dioxaboroian-2-yi)-3,4--dihydfO 2H-benzoibj[ l ,4 ^~ joxazine (580 mg,

1.8 mmol, 1 equiv), Potassium carbonate (499 mg, 3.6 mmol, 2 equiv) and Pd(PPh3) ₄ (104 mg, 0.09 mmol, 0.05 equiv). The reaction mixture was allowed to stir at 80°C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted wit ethyl acetate (100 mL x 2) Organic layer was washed with water (100 mL) and brine (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-(2-chloro-5-fluoropyrimidin-4-yl)- 8-fluoro-4-propy!-3,4~dihydro-2H-benzo[b][l,4]oxazine (200 mg, 34%) as a yellow solid compound.

LCMS: 326 [M+H] "

[0309] Step-5; Synthesis of tert-butyl 4-(2-fluoro-4-((5-fluoro-4-(8-fluoro-4-propyl-3,4” dihydro-2H-benzo[b][l,4]oxazin-6-y!)pyri idm-2-yl)ammo)phenyl)piperazine-l- carboxylate: To a solution of 6~(2-chloro-5-fluoropyrimidin-4-yI)-8-fluoro-4-propy!-3.4~ dihyd.ro-2H-benzo[b] [ 1 ,4]oxazine (100 mg, 0 32 mmol, 1 equiv) in Dioxane (10 mL). was added tert-butyl 4~(4-amino-2-f]uorophenyl)piperazine-I-carhoxyiate (100 mg, 0.33 mmol, 1 1 equiv) and cesium carbonate (147 mg, 0 45 mmol , 1.5 equiv). The reaction mixture was purged with nitrogen gas for 30 in , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 013 mmol. 0 04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted wii ethyl acetate ( 100 mL). Organic layer was washed with water (50 mL) and brine (50 L) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain tert- butyl 4-(2-fluoro-4-((5-fluorO 4-(8-fluorO 4-propyi-3 4-dihydro-2Il-benzoibl[l,4]oxazin-6· yi)pynmidm-2-yi)ammo)phenyi}piperazme-l -carboxylate (50 mg, 28%) as a yellow solid compound

LCMS; 585[M+H] 10310] Step-6: Synthesis of 5-t1uoro-N-(3-fluoro-4-(piperazm-l -yl) phenyt)-4-(8-flnoro-

4-propyl-3, 4-dihydro-2H-ben«o{b| [ J ,4]oxa2i»-6-yI)pyrimidm-2-ai «e: tert- butyl 4-(2- fluoro-4-((5-fluoro-4-(8-fluoro-4-propyl-3,4-dihydro-2H-benz o[b][l,4]oxazin-6-yl)pyrimidm~2~ yl)amino)phenyl)piperazine-l-carboxylate (50 mg, 0.08 mmol, 1 equiv) was taken m 1.25 M HCi in ethanol (5 mL) and the resultant reaction mixture was allowed to stir at 50°C for lh. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophikzer to obtain 5-fluoro- N-(3-fluoro-4-(piperazin-l-yl)phenyl)-4-(8-fluoro-4-propyl-3 ,4-dihydro-2H- benzo[b][l,4]oxazin-6-yl)pynmidin-2-amine (35 mg, 78%) as a brick red color solid compound.

LCMS: 485 [M+Ή]

1HNME: (400 MHz, DMSOM6) 6 9 82 (s, 1 H), 9 30 - 9.23 (m, 1 H), 8 58 (d, J = 3.9 Hz,

IH), 7.79 dd, ./= 1 5.3, 2.4 Hz, HI), 7 42 (dd, J= 8.8, 2 4 Hz, 1H), 7.27 (s, 1 H1 744 (d, / 1 1.2

Hz, 1H), 7.05 (t, J= 9.4Hz, 1H), 4.30 (t, J = 4.3 Hz, 2H), 3.43 (t, J= 4.3 Hz, 2H), 3.31 (t, / 7.3

Hz, 2H), 3.26 - 3.13 (m, 81 1} 1 .6 : (h, J = 7.4 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H).

Example-37 : Synthesis of -fS-fluoro- -fS-fiuoro-d-isopropyl-S, 4~dihydro~2H- henzofhj [ Ί ,4] xazin~6~ylJpy>rimidin~2~yl)-N -dimethyl-2, 3~dihydro~l H-indene-2,5~diamine

(Compound 37):

[0311 Step-1: Synthesis N, -dmiethyl-5-mtro-lH-inden-2-amine: To a stirred solution of 5-nitro-l ,3-dibydro-2H-inden-2-one (1000 mg, 5.64 mmol, I equiv) m THF (15 mL), was added dimethyl amine (2 M in THF) (5 6 mL, 1 1.2 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was dilated with ice water (50 ml . ) and extracted with EtoAc (100 ml, >< 2). Organic layer was washed with water (100 mL) and brine (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under

Z.> h reduced pressure to obtain obtain N, N-dimeihyh5-nitrofi B-inden-2-arnine (800 mg 69%) as a brown crystal solid compound.

LOIS: 205 [MfB] ⁺

[0312 j Step-2: Synthesis of N2, N2-d nethyI-2, 3-dfliydro-i H-mdene-2, 5-diamine: To a stirred solution of N, N-dimethyl~5~mtiO-rH~inden-2-amine (800 mg, 3.9 mmol, 1 equiv) in methanol (10 mL), was added Pd/C (20% w/w) (160 mg) under ¾ atm. The resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the mixture was passes through ceiite bed and the filtrate was concentrated under reduced pressure to obtain N2, N2-dimethyl-2, 3-dihydro-lH- indene-2, 5-diamine (600 mg, 87%) as a dark brown solid compound

LCMS: 177 [MAI] "

[0313] Step-3: Synthesis of MS-(S-fluoro-4-(8-fluoro-4-isopropyl~3, 4~dihydro-2H- benzo|b|[l,4|oxazin-6~yl)pyrimidm-2-yl)-N2,N2~dimethyl~2,3-d ihydrO”lH~indene-2,5- diamine: To a solution of 6~(2-chloro-5-fluoropyrimidin-4-yl)-8-f1uoro-4-isopropyl-3,4 ~dihydro- 2H-benzo[bl[l,4]oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 mL), was added N2, N2- dimetbyl-2, 3-dihydro-lH-indene-2, 5-diamine (58 mg. 0.33 mmol, 1 .1 equiv) and cesium carbonate (147 mg, 0.45 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0 006 mmol . 0 02 equiv) and BINAP (8 mg, 0 012 mmol, 0.04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 ml.) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain N5-(5-f3uoro-4-(8-f3uoro-4- ⁱ sopropyl-3,4-dihydro-2H-benzo[b][l ,4]oxazin-6-yj)pyrimidin-2-y!) ^~ N2,N2-dimethy! ^~ 2,3- dihydro- lH-mdene~2,5--diamme (5 mg, 4%) as a brown solid compound.

LC S: 466 [M÷Hj ⁺

*HNM (400 MHz, DMSO-r/6) d 9.57 (s, 1H), 8.53 (d, ./ 4.1 Hz I B), 8 43 - 8.32 (m,

1H), 7.63 (sJ H), 7 46 (d, J ^:::: 8.1 Bz, I B), 7 41 is, I B), 7.1 5 (d, J ^:::: 1 1 .7 Bz, M B. 7.08 (d, J - 8.1 Hz, H I) 4.33 -4.21 (m, 2H), 4.13 (di, 7 - 13.1 , 7.3 Hz, HI), 3.34 - 3 27 tm, 3H), 2.95 (h. ./ 6 7, 5.6 Hz, 2H), 2.73 (td,7 - 14.5, 13.6, 6.1 Hz, 2H), 2 20 (s, 6H), 1.19 (d, J- 6.5 Hz, oi l)

Exampie~38: Synthesis o/N~(6~(4~(dimeihyi amino) piperidin-l-yi) pyridin~3~y )-5-fluoro~4-(8-

[0314] Step-1: Synthesis N, N-dimethyH-(5-nitropyridin-2-yI) piperidin~4~antine: To a stirred solution of 2-chlon>5-rmropyridme (500 mg, 3.16 mmol, 1 equiv) in DMF (10 ml.), was added K2C03 (654 mg. 4 74 mmol, 1.5 equiv) and N, N-dimethylpiperidin-4-amine (405 mg, 3 16 mmol, 1 equiv). The resultant reaction mixture was allowed to stir at 100° C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the mixture was diluted with ice water ( 50 L), solid observed was filtered and dried under vacuum to obtain N,N-dimeihyl-l-(5-nitropyridin-2-yl)piperidin-4-amine (700 mg, 89%) as a yellow solid compound.

LCMS: 251 [M H] ^f

[0315] Step-2:: Synthesis of 6~(4-(dimethyI amine) piperidin-l-yl) pyridin-3~amine: To a stirred solution of N,N-dimethyl-l-(5-niiropyridin-2-yl)piperidin-4-amine (500 mg. 2 mmol, 1 equivj m ethanol (9 mid, water (3 L), was added iron powder (336 mg, 6 mmol, 3 equiv) and ammonium chloride (216 mg, 4 mmol, 2 equiv). The resultant reaction mixture was allowed to strr at 90° for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture vvas passes through celite bed and the filtrate was concentrated under reduced pressure to obtain 6--(4-(dimethy! amino) piperxdin-l-y!) pyrxdin-3 -amine (400 mg, 91%) as a dark brown viscous compound.

LCMS: 221 [MM!] ⁺

[0316] Step-3: Synthesis of N-(6~(4~(dunethyl amino) piperidin-l-yl) pyridin-3-yl)-5- fl«oro-4-(8-flaoro-4-isopropyl-3,4-dihydro-2H-ben*o!b] [l,4)oxa2iii-6-yl)pyrimid -2- amine: To a solution of 6-(2-chioro-5-iluoropyrimidm-4-yl)-8-fluoro-4-isopropyl-3,4- dihydro- 2H~benzo[b][l ,4]oxazine (100 mg, 0 3 mmol, I equiv) m dioxane (10 niL), was added 6-(4- (dimethyl amino) piperidin-l -yl) 241yridine-3-amine (73 nig, 0 33 nimol, 1.1 equiv) and cesium carbonate (147 mg, 0 45 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 m , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0 012 mmol, 0.04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mb) and extracted with ethyl acetate (100 mb). Organic layer was washed with water (50 mb) and brine solution (50 mb). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain N-(6-(4-(dimethy!amino)piperidin- 1 -yl)241 yridine-3-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2 H-benzo[b][ l ,4]oxazm-6- y!)pyrimidin 2-amine (3 mg, 2%) as a yellow solid compound

LCMS: 510 [M+H] ⁺

1HNM (400 MHz, DMSO-76) d 9.37 (s, 1 H), 8 48 (d, 7-4.4 Hz, 2 H), 8.32 (br. S., 1 H), 7.79 (dd, 7-9 0, 2.4 Hz, 1 H), 7 42 (br. S., 1 H), 7.13 (d, 7-1 1 .0 Hz, 1 H), 6 82 (d, 7-8.8 Hz, 1 H), 4.29 (br. S., 2 H), 4.22 (d, 7-12.3 Hz, 2 H), 4 04 - 4.14 (m, 1 H), 3.29 (br S., 2 H), 2 74 (t,

./ 1 1.6 Hz, 2 H), 2 34 (d, 7 12.7 Hz, 1 1 11. 2.22 (s, 6 H), 1.82 (d, 7-11.0 Hz, 2 H), 1 38 (d, .7-9.2 Hz, 2 H), 1.05 - 1 23 (m . 6 1 1)

Example- 39: Synthesis of 4~((5~fiuoro~4~(8~fluoro~4~isopropyl~3, 4~dihydro-2H~

benzofh //2 , 4 joxazi - 6-y!jpyrim idm-2-y!jam ino)~l 2 3 \ 6’-tetrahydro-lH- 1 , ’~b ipyiidi /·· 2- one (Compound 39):

[0317] Step-1: Synthesis of (i&'Z -N _> N~d«methyl~N ^, -(2-oxo-1^2-dihytlropyridin~4~ yl}formtmui amide: 4-aminopyriclin-2(lH)~one (200 mg, 1.8 mmol, 1 equiv) was taken in 1,1- dimethox;y-N,N-cliinethyimethanamine (4 mL) and the resultant reaction mixture was stirred at 80°C for 2 b Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under vacuum to afford (E4^-N,N-dimethyl-NT- (2~oxo-I,2-dihydropyridin-4-yd)formimidamide (220 mg).

LCMS: 166 [M÷H] ⁺

Step-2: Synthesis of tert-butyl (£^ )-4-(4-(((dimethyiammo)methylene)ammo)-2- oxopyTidm-l(2H)-yl)piperidine-l-carboxylate: To a solution of (i:22) N,N-dimethyI N ^! -(2- oxo~l, 2 dihydropyridin-4-yl)forminudannde (500 mg, 3 mmol, 1 equiv) in DMF (10 nil,), was added tert-butyl 4-bromo-3,6-dihydropyridme-l(2H)-carboxylate (730 mg, 4 5 mmol, 1.5 equiv) followed by addition of potassium carbonate (700 mg, 5.1 mmol, 1.7 equiv), Cui (57 mg, 0.3 mmol, 0.1 equiv), L-pro!me (68 mg, 0 6 mol, 0.2 equiv) . The resultant reaction mixture was sbrred at 1 00 °C for 16 h. Progress of the reaction was monitored by TLC and I, CMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 ml,). The organic layer dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by making HCL salt to afford tert-butyl (E)-4-(4-(((dimethylamino)methylene)amino)-2-oxopyndm- 1 (21 ! b

y])piperidine-l -earboxy!aie (1 50 rng). LCMS:347 [M+Hjf [0319] Step-3: Synthesis tert-butyl 4-amino- 2-0X0-3%0 ^, -dihydro-2II-[l,4 ^, -bipyriidme]- 1’(2’ H)-carboxylate: To a solution of tert-butyl (E)-4-(4-(((dimethyiamino)methylene)a ino)-2- oxopyridin-i{ZH)~yl)pipendine-i-carboxylate (135 mg, 0.4 mmol, 1 equiv) m ethanol (5 ml), was added ethylene diamine (35 mg, 0 6 mmol. 1.5 equiv. The resultant reaction mixture was stirred at 80 °C for 3 h. Progress of the reaction was monitored by TLC and I .CMS. After completion of the reaction the reaction mixture was concentrated, diluted with water (10 mL) and extracted with EtOAc (10 mL). The organic layer dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl 4-amino~2~oxo-3',6'~dihydro~2H-[l,4'~ bipyridine]-T(2'H}-earboxylate (98 mg). LCMS: 292 I M H i

[0320] Step-4: Synthesis of tert-butyl 4-((5-fluoro-4-(8-fluoro-4-isopropyl-3 _> 4-clihydro-2H~ benzo j b j [ 1 ,4) oxazin-e-yijpyrimidin-l-yljaminoj-l-oxo-S’^’-dihydro-lH- l 1 ,4'-bipyridine]~ r(2'H}-c.arboxylate: To a solution of 6~(2~chlorO 5-fluoropyrimidin-4 yl)-8-fluoro-4-isopropyti 2-methyl-3,4-dibydro-2H-benzo[b] [ 1 ,4]oxazine (100 mg, 0 3 mmol, t equiv) m dioxane (3 ml.), was added tert-butyl 4-amino-2-oxo-3',6 ^! -dihydro-2H-[t .4 ~bipyridine]~r(2'H)-carboxylate (98 mg, 0.33 mmol, 1 1 equiv) and cesium carbonate ( 146 mg, 0 45 mmol, 1 5 equiv). The reaction mixture was aerated with nitrogen gas for 10 mi followed by the addition of palladium acetate (6 mg, 0 03 mmol, 0.1 equiv) and BINAP (37 mg, 0 06 mmol, 0.2 equiv) again purged nitrogen for 5 min. The resultant reaction mixture was stirred at 1 00 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (10 L) and extracted with EtOAc (15 mL). The organic layer dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound used directly for next step. 100 g of tert-butyl 4~((5-iiuoro~4-(8-iluoro~4-isopropyl~3 4- dihydro-2H-benzoj b] ]Ί ,4]oxazm-6-yl)pynrmdm-2-y liammo)-2-oxo-3 ,6 ^! -dihydro-2H-] l ,4 ^s - bipyridine]-r(2 ^, å-])-carbox late obtained as a crude. LCMS: 581 [M flTf

[0321] Step-5:: Synthesis of 4-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benKo[b] [l,4]oxa¾½-6-y!)pyrimidin-2-y8)amino)-l ^hS^'-tetrahydro-SH-jl^-bip ridin]- 2· one: tert-butyl 4-{(5-fluoro-4-{8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[ bj[L4]oxazin-6- yl)pyrimidin-2-yl)amino)-2-oxo-3',6'-dihydiO-2H-[l ,4 ^! -bipyridinej-r(2'i ^} )-carboxyTate (100 mg, 0.17 mmol, 1 equiv) was taken in 1 .25 M HCi in ethanol (4 ml,) and the resultant reaction mixture was stirred at 50°C for 2 h Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under vacuum purified by reverse phase HPLC to afford 4-((5-fiuoro-4-(8-fiuoro-4-isopropyi-3,4-dihydro-2å-j- benzoib][i,4]oxazin-6-y!)pyrimidin~2-yl)aniino)~T.2 ^< ,3 ^> ,6 ^! -ietrahydro-2H [l ,4 ^! -bipyridm] 2-one (4 mg). LCMS: 481 [M÷Hf

1HNMR: (400MHz ,METHANOL-d ₄ ) d 8 50 i d. ./ 3.9 Hz, 1 H), 7.53 (s, 1 H), 7.41 · 7 34

(m, 1 H), 7 26 (br. s., 1 H), 6.73 (d, ./= 7.5 Hz, 1 H), 5.95 (br s., 1 H), 4 58 (hr. s„ 1 H), 4,41 · 4.19 (m, 2 H), 3.81 (br. s., 1 H), 3.48 (br s., 1 H), 3 41 (d, 7 6.6 Hz, 1 H), 2.69 (br s., 1 H),

1.39 ·· 1 12 (m, 3 H).

Example-40 : Synthesis of 5~chioro~4~(8~chioro~4~isopropyI~3, 4~dihydro~2H~

benzofh]fl,4 oxazin~6~yJ)~N~(3~fluoro~4~(piperazm~l~yi)phenyl}pyrimidm~2~ amine (Compound 52}

[0322] Step-1: Synthesis of 6-bromo-8-cMoro-4~isopropyi-2H-benzo[b]jI,4ioxazm-

3(4H)~oi¾e: To a stirred solution of 6-bromo-8-chloro-2H-benzo[b][1.4]oxazin-3(4H)-one (2000 mg, 7 6 mmol, 1 equiv) in DMF (20 ml,), was added NaH (610 mg, 15.2 mmol, 2 equiv) and isopropyl iodide (1 5 ml,, 15.2 mmol, 2 equiv). The reaction mixture was allowed to stir at 80 ^C C for 3 h. Progress of the reaction was monitored by TLC and I, CMS. After completion of the reaction, the reaction mixture was diluted with water (100 ml,) and extracted with ethyl acetate (100 ml, x 2) Organic layer was washed with brine (1 00 ml,) and water (100 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (.·· bromO -8--ch!oro-4 isopropyi~2H~benzoj b]n ,4joxazm~3(4H)--one (700 mg, 95%) as an off white solid compound. LCMS: 260 | M 1 11

[0323] Step-2: Synthesis of 6-bromo-8-chlor -4~isopropyl-3,4~dihydro-2H- henzo[hj [l,4]oxazine: To a stirred solution of 6-brorno-8-chloro-4-isopropyl-2H- benzoibjil,4]oxazm-3(4H)--one (650 nig, 2.1 mmol 1 equiv) in THF (15 mL), was added BfL.DMS (2 M in THF) (4 mL, 8.5 mmol, 4 equiv) at 0 C drop wise. The reaction mixture was allowed to stir at 80°C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated solution of NaHCCL (50 mL) and extracted with ethyl acetate (100 mL x 2). Organic layer was washed with water (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6-bromo-8-chloro-4-isopropyl-3,4~dihydro-2H-benzo[b][l ,4]oxazine (550 mg, 89%) as a transparent oil compound. LCMS: 290 [M÷H]

[0324] Step-3: Synthesis of 8-cbioro-4-isopropyl-6~(4,4,S,5-tetrametfayi~l,3,2~

dioxaborolan-2-yl)-3,4-dihytlro-2H-benzo[b]{l,4|oxaz¥e: 6-bromo-8-chioro-4-i sopropy 1-3 ,4- diliydro-2H-benzo[b][l ,4 oxazme (550 mg, 1.9 mmol, 1 equiv), 4,4, 5,5-tetramethyl-2-(4, 4,5,5- tetramethyfti,3,2-dioxaborolan-2 yl)H,3,2-dioxaborolane (725 mg, 2.8 mmol, 1.5 equiv), Potassium acetate (466 mg, 4 7 mmol, 2.5 equiv) and dioxane (1 0 ml,) were charged in a 25 ml, glass bottle. Purged the reaction mixture with nitrogen gas for 15 min., Pd(dppf)G2. DCM (78 mg, 0.09 mmol, 0 05 equiv) w¾s added to above mixture and the reaction mixture was allowed to stir at 1 00°C for 3 h Progress of the reaction w¾s monitored by TLC and LCMS After completion of the reaction, the reaction mixture w¾s diluted with water (30 ml,) and extracted with ethyl acetate (100 ml, x 2). Organic layer was washed with brine (100 mL) and water (100 L). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 8-chloro-4--isopropyl--6-(4,4,5,5-tetramefoyl-l ,3,2~diQxaborolan-2-yl)-3,4- dihydro-2H-benzo[b][l,4]oxazine ( 600 mg, 94%) as a dark brown viscous compound. LCMS: 338 [M-i-H] ⁺

[0325] Step-4:: Synthesis of 8-chloro-6-(2, 5-dkhioropyrimidin-4-yl)-4-isopropyi-3, 4- dlhydro~2H-benzo[b] [1 ,4]OC8ZHH¾: TO a stirred solution of 2,4,5-trichloropyiimidine (160 g, 0 87 mmol, 1 equiv) in THF; Water (1 : 1 ^::: 10 ml,) was added 8-chloro-4-isopropy!-6-(4,4,5 5~ tetramethy! -1,3 ,2-dioxaborolan-2-y l)-3 ,4-dihy dro-2H-benzo[b] [ 1 ,4]oxazme (296 mg, 0 87 mmol, 1 equiv), Potassium carbonate (240 mg, 1 74 mmol 2 equiv) and PdyPPiqft (50 mg, 0.04 mmol, 0.05 equiv) The reaction mixture was allowed to stir at 80 C for 3 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, foe reaction mixture was diluted with water (30 mL) and extracted wit ethyl acetate ( 100 mL x 2). Organic layer was washed with water (100 L) and brine (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound which was purified by normal phase combi-flash to obtain 8-ehloro-6-(2,5~diehloropynmidm-4-yl)~4~ isopropyi-3,4-dihydro-2H-benzo[b][1 ,4]oxazme (300 mg, 80%) as a yellow solid compound. LCMS: 358 [M÷H] "

[0326] Step-5: Synthesis of tert-butyi 4-(4-( ( 5-chloro-4~(8-cWoro-4-isopropyl-3,4- dihydro-2H-hen¾©[b]j ,4 oxa2i«-0-yI)pyrhmdin-2-yI)ainino)-2-flu©rophenyi)pipera¾i «e-l- carboxylate: To a solution of 8-chloro~6-(2,5-dichloropyrimidin~4~yl)-4-isopropyl-3,4-dihy dro- 2H-benzo[b][1 ,4]oxazme (100 mg, 0.28 mmol, 1 equiv) in Dioxane ( 10 mL), was added tert- butyl 4-(4-amino-2-fluorophenyl)piperazine-l -carboxylate (91 mg, O.Bmmoi, 1.1 equiv) and cesium carbonate (137 mg, 0 42 mmol, 1.5 equiv) The reaction mixture was purged with nitrogen gas for 30 min., followed by the addition of palladium acetate (1 2 mg, 0 005 mmol, 0 02 equiv) and BINAP (7 mg, 0.011 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted wit ethyl acetate (100 ml.). Organic layer was washed with water (50 ml,) and brine (50 ml.). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain tert-butyl 4-(4-((5-chloro-4-(8-chloro-4-isopropyl-3,4-dihydro-2H-benzo [b][l ,4]oxazm-6- yi)pyrimidin-2-yl)amino)-2-fiuorophenyl)piperazine~I-earboxy late (30 mg 16%) as a yellow solid compound. LCMS: 617 j 1 11

[0327] Step-6: Synthesis of 5-chloro-4-(S-chIoro-4-isopropyI-3,4-dihydro-2H- benzo[b][1,4|oxaziR-6-yI)-N-(3-flMoro-4-(piperazbi-i-yI)phen yi)pyr«midin-2-ainine: Tert- butyl 4-f4-((5-chioro-4-C8-chloro~4~isopropyl~3,4-dihydro-2H~benzo [b][l ,4]oxazin-6- yl)pyrirnidin-2-yl)amino)-2-fluorophenyl)piperazine-l-carbox ylate (30 mg, 0.04 mmol, 1 equiv) was taken in 1.25 M HQ in ethanol (5 mL) and the resultant reaction mixture was allowed to stir at 5G°C for l b. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophilizer to obtain 5-chloro-4-(8-ch!oro-4-isopropyl-3,4-dihydro-2H-benzo[ b] ] 1 ,4]oxazin-6- yl}-N-(3-iluoro-4-(piperazin-l-yl)phenyl)pyriniidm-2-annne (25 mg 93%) as an orange color solid compound. LCMS: 517 [M÷H] 3 ^! HNMR (400 MHz, DMSOM6) d 9.97 (s, 1H), 8.93 (s, 1H), 8.58 (s, 1H), 7.79 (dd, J === 15 3, 2.5 Bz, IH), 7.40 (dd, 7 9.0, 2 5 Hz, 1H), 7.25 (s, 1H),

7.16 (d, J = 2 0 Hz, 1H), 7 04 (t, J = 9 3 Hz, 1H), 4.33 (t,7 = 4.2 Hz, 2H), 4 1 1 (p _s J = 6.7 Hz, 1H), 3.30 (t, J = 4.1 Hz, 2H), 3.24 (s, 4H), 3.15 (t, ./= 4.9 Hz, 4H),1.17 (d, J = 6.4 Hz, 6H)

Jjcamp!e—ίI : Symthesis o/N~(5~(4-(dimethy!ammo) piperidin- 1 -yi) pyridin-2-yI)~5~fiuoro~4~(8~ fluoro~4~isopropyI~3. 4-dihydro~2H-benzo b] [J4loxazm-6-\4)pyrim4din-2-~amine.i(3ompound 436)

[0328] Step-1: Synthesis N, N-dimethyH-(6-nitropyridin-3-yI) piperid )~4~amine: To a stirred solution of 5-bromo-2-nitropyridine (500 mg. 2 47 mmol, 1 equiv) in DMF (10 mL). was added IfoCCft (683 mg, 4 95 mmol, 2 equiv) and N, N-dimethylpiperidin-4-amine (316 mg, 2.47 mmol, 1 equiv) The resultant reaction mixture was allowed to stir at 100°C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 mL) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain N, N-dimethyi-l- (6-nitropyridin-3-yl) piperidin-4-amine (500 mg, 81 %) as a yellow solid compound LCMS: 251 [M-f-H] ⁺

[0329] Step-2: Synthesis of 5-(4-(d«methylamino) piperldhi-I-yl) pyridm-2-asnine: To a stirred solution of N, N-dimethyi-l-(6-nitropyridin-3-yl) pipendm-4-am e (500 g. 2 mmol, 1 equiv) in ethanol (7 mL), water (3 mL), was added iron powder (336 mg, 6 mmol 3 equrv) and ammonium chloride (216 g, 4 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 9 ^; ft; ^' for I h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through cehte bed and the filtrate was concentrated under reduced pressure to obtain 5-(4-(dimethylamino) piperidin- 1-yl) pyridin-2-amine (350 mg, 80%) as a dark brown solid compound LCMS: 221 [M+Hj ^’ [0330] Step-3: Synthesis of N-(5~(4~(dimethylaaiino) plperidin-I-yl) pyridin-2-yl)-5- fl«oro-4-(8-flaoro-4-isopropyl-3,4-dihyclro-2H-ben*o!b] [l,4]oxa2in-6-yl)pyrimid«i-2- amine: To a sointion of 6-(2-ehloro~5~fli3oropyriniidin~4~yl)-8-fluorG-4-iscpropyl-3 ,4-dihydro- 2H-benzo[b][l ,4]oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane ( 10 niL), was added 5~(4~ (dimethyiamino) piperidiml-yl) pyridim2- amine (73 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.45 mmol. 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg. 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction v¾s monitored by TLC and 1 ( ^' MS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,) Organic layer was washed with water (50 ml,) and brine solution (50 l,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain N~(5~(4~(dimethylarmno)piperidin- l-yl)pyridin-2-yI)-5-fluoro-4-(8-fluoro-4-isopropyI-3,4-dihy dro-2H-benzo[b][L4]oxazin-6 · yl)pyrimidin-2-armne (12 mg, 8%) as a yellow solid compound LCMSs 510 [M+H] q ¹ HMMR (400 MHz, DMSO-i 6) d 9 64 (s, 111)., 8 55 (d, J= 4.0 Hz, 1H), 8.46 (s, I I I). 8.04 - 7 96 (m,2H), 7 46 9.1, 3 1 Hz, HI), 7.17 (d, ,/ === 11.6 Hz, HI), 4 30 (1, 7 === 4 3 Hz, 2H), 4.15(p, / 6.6 Hz, HI), 3 64 (dd 7 12.3, 4.4 Hz, 2H), 3 34 - 3.27 (m, 31 1). 2 72 - 2.61 (m,2H),

2 19 (s, 61:1), 1 89 - 1.80 (m, 2H), 1 50 (qd, 7 12.1, 3.8 Hz, 2H), 1 19 (d, / 6.5 Hz, 6H)

Example-42: Synthesis of4-((5~fluoro-4~(8~fluoro-4~isopropyl~3, 4-dihydro-2H- benzo[b _j [l,4]oxazin~6~yiJpyrimidhi~2-yi)amino)~l~(pperidin~4~y i}pyn.din~2(lH}~one:

(Compound 437)

[0331] Step-1: Synthesis of tert-butyl 4-(4-amino-oxopyridm-l(2H)-yl) piperidine- 1- carboxylate: To a stirred solution of ten-butyl 4-amino~2~oxo-3 ^! ,6 ~dihydro~2H- L4 ⁱ ~ bi pyridine] - 1’(2O)~carbox late (95 mg. 0.33 mmol, I eqoiv) in methanol (4 ml,), was added Platinum oxide (25 mg, 0.1 1 mmol, 0 3 equiv) at RT The reaction mixture was allowed to stir at RT for 2h Progress of the reaction was monitored by TLC and 1 CMS After completion of the reaction, the reaction mixture was passed through cea!ite bed Filtrate was concentrated to afford tert-butyl 4~(4-amino-2-oxopyridin~I(2H)-y]) piperidine- 1 -carboxylate (90 mg) as off white solid compound I,CM8: 294 j 1 11

[0332] Step- 2: Synthesis of tert-butyl 4-(4-((5~flaoro-4-(8~flaoro-4~isopropyi-3,4~ dihydro-2H-benzo[blii _» 4]oxarin-6-yl)pyrimidin-2-yl)an ino)-2-oxopyridin-l(2H)- yl)piperidine-l-carboxyIate: To a solution of 6-(2-chloro-5-iluoropynmidin-4-yi)-8-fluoro-4- isopropy!-2~methy!-3,4~dihydro-2!:I-benzo[b][! ,4]oxaxme (70 mg, 0 21 mmo!, I equiv) in dioxane (3 mb), was added 4-(4-amino-2-oxopyridin-l(2 )-yl)piperidme-l-carboxylate (68 mg, 0.23 mmoi, 1 1 equiv) and cesium carbonate ( 102 mg, 0 31 mmol, 1.5 equiv) The reaction mixture was aerated with nitrogen gas for 10 min. followed by the addition of palladium acetate (5 mg, 0 03 mmol, 0.1 equiv) and BINAP (26 mg, 0 06 mmol, 0.2 equiv) again purged nitrogen for 5 min. The resultant reaction mixture was stirred at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was dilated with water ( 10 niL) and extracted with EtOAe (15 ml ). The organic layer dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound used directly for next step. 140 mg of tert-butyl 4-i4-((5-fluoro-4-(8-fluoro-4-isGpropyl-3 4- dihydro~2H--benzo[b]p ,4]oxazin~6-yI)pyriinidin-2-y!)ammo)-2-oxopyridm--l{2H)-yI)p ipendme-·

1 -carboxylate obtained as a crude. LCMSt 583 [M+H]

[0333 Step-3: Synthesis of 4-((5-fluoro-4-(8-(luoro-4-isopropyl-3,4- ihydro-2H- benzo[b][l,4]oxazin-6~yl)pyri idin-2-yl)amino)-i-(piperidin-4~y!)pyridia~2(lH)-OBe: A solution of tert-butyl 4-(4-((5-chloro-4~(8~fluoro-4~isopropyl~3,4-dihydro-2H~

benzo[b][l,4]oxazm-6-yl)pyrimidin~2-yl)amino)~2-fluorophe nyl)piperazme~l~carboxylate (70 mg, 0 1 1 mmol, 1 equiv) in 1.25 M HCi in ethanol (5 ml,) was allowed to stir for I h at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and crude was purified by reverse phase HPLC to obtain 4-((5- fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[bl[l ,4]oxazm-6-yl)pyrimidin~2~yl)amino)~ 1 -(piperidin-4-y i)pyrid -2(lH)-one (16 mg) as an off white solid compound. LCMS: 483

[M+H] 4 'HNMR (400 MHz, DMSO-46) d 9 98 (s, I H), 8 68 (d, J= 3.9 Hz, IH), 8.35 (d, J = 10.8 Hz, 21 1). 7 52 (d, J= 7.6 Hz, I H), 7 44 (s, IH), 7.17 (d, ./ 1 1 .8 Hz, IH), 7.13 (d. J = 2.5

[0334] Step-1: Synthesis of tert-butyl 4-(4-amino-2~(trifluoromethyl) phenyl)-3, 6- dihydropyridiiie-1 ( 2H)-carboxylate: To a solution of 4-bromo-3-(trifluoromethyl)aniline (1000 mg, 4 18 mmol, 1 equiv} m dioxane (15 niL), was added tert-butyl 4-(4, 4, 5, 5-tetrametliyi-i , 3, 2-dioxaborolan-2-yl)-3, 6~dihydropyndtne-l(2H)-carboxylate (1292 mg, 4 18 mmol, I eqtuv) and sodium carbonate (1053 mg, 12.5 mmol, 3 equiv) The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of Pd (PPhfoCfi (242 mg, 0.2 mmol, 0.05 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 ml, ^c 2) Organic layer was washed with water (100 mL) and brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyi 4~(4~amino-2-(trifluoromethyl) phenyi)-3, 6-clihydropyridine-l (2H)-carboxylate (1200 mg, 87%) as a brown solid compound LCMS: 373 [M+H] ⁺

[03:35] Step-2: Synthesis of tert-butyi 4-(4-amino-2~(trifluorometfayi) phenyl) piperidine-

1 -carboxylate: To a stirred solution of tert-butyi 4-(4-ammo~2~(trifluoromethyl) phenyl)-3, 6- di!iydropyridine-l(2H)-carboxylate (500 mg, 1.34 mmol, 1 equiv) m methanol (5 ml,), was added Pt0 ₂ (20% w/w) (100 mg) under I¾ atm. The resultant reaction mixture was allowed to stir at RT for overnight Progress of the reaction was monitored by LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(4-amino-2-(trif1uoromethyl) phenyl) piperidine-!- carboxylate ('400 mg, 87%) as a transparent oil compound LCMS: 345 [MAR] ^”

[03:36] Step-3: Synthesis of tert-butyi 4-(4-((S-fluoro-4-(8-fluoro-4-isopropyi-3,4- dihydro-2H-benzoib][i,4]oxazin-6-yI)pyrimidin-2-yI)amino)-2- (trifiuoromethyl)phenyi)piperidine-i-carboxylate: To a solution of 6-(2-chloro-5- iluoropyrimidin~4~yi)-8-fiuorO 4-isopropyi-3,4 dihydro-2H-benxo[bj[] ,4joxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 ml,), was added tert-butyi 4-(4-amino-2-(trifiuoromethyl) phenyl) pipendine-1 -carboxylate (114 mg, 0.33 mmol, 1 .1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 m ol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 L) and brine solution (50 L). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by norma! phase combi flash to obtain tert-butyi 4-(4-((5-iluoro-4-(8-iluoro-4-isopropyl-3,4-dihydro-2H- benzoibi[ l,4 joxazin-6-yt)pyranidur-2-yt)ammo)-2-(triiluoromethyi)phenyt) piperidine-4-· carboxylate (100 nig, 51%) as a yellow solid compound. LCMS: 634 [M+H]’

j 0337] Step-4: Synthesis of 5-fIaoro-4-(8-flaoro-4-isopropyl-3, 4-dihydro-2H- ben¾o(b]|l ,4|oxa2:in-6-yI)-N-(4-{piperidm-4-yl)-3-(triliuoromethyl)phe nyl)pyriniidm-2- amine: A solution of ten-butyl 4 (4-((5-iIuoro-4-(8-iIuoro-4-isopropyl-3,4 dihydn 2H- berszo[bl[! ,4]oxazin-6-yl}pynmidm 2 yi}ammo} 2 (trifluoromeihyl)phesiyi)pipendine-l- carboxylate ( 100 mg, 0 15 mmol, 1 equiv) in 1.25 M HC1 in ethanol (5 mi,) was allowed to stir for lb at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain 5-fluoro-4~(8-fluoro-4~ isopropyl-3, 4-dibydro-2H-benzoib]ii ,4]oxazin-6-yl)-N-(4-(plpendin-4-yi)-3- (trifluoromethyi)phesiyl)pyrimidin-2 amme (10 mg, 12%) as a yellow solid compound. LCMS: 534 10.04 (s, 1H), 8.63 (d, ./ = 3.9 Hz, i l l) 8.54 -

8.40 (m, 1 H) , 8 25 (d, J= 2 4 Hz, 1 1 1). 8.05 - 7.97 (m, i l l) 7 42 (d, ,/= 8.7 Hz, HI), 7 37 (s, HI), 7.18 (d, J = 1 1 .6 Hz, I I I }. 4.30(1, ./ 4 2 Hz, 2H), 4.12 (h, J= 6 6 Hz, H i). 3.37 (d, ./= 12.0 Hz, 2H), 3.14 - 3 00 (m, ti l). 1.98 - 1 78 (m. 11 1 }. 1.18 (d, J = 6 5 Hz, 6H).

Example-44: Synthesis of N~(4~(4~(dimethyIamino)piperidin-J-yI)~3~(tnfluoromethyI}phe iiyi}-5- fiuoro~4~(8~fiuoro~4~isoprop\4~3, 4-dihydro-2H~henzo[h)[l 4]oxazin~6~ylJpyrimidin~2~

[0338] Step-1: Synthesis N, N-dimethyI-l-(4-nitro-2-(trifluorofnethyl) phenyi) piperidin-

4-amine: To a stirred solution of l-bronio-4-nitro-2-(trif!uoromethy!) benzene (500 nig, 1 85 mmol, 1 equiv) in DMF (10 nil,) was added TEA (0.5 nil,) and N, N--dimethylprperidin -4-amine

(237 mg, 1.85 mmol, I equiv). The resultant reaction mixture was allowed to stir at 100° for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 nil x 2). Organic layer was washed with water (50 ml,) and brine solution (50 ml . }. Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain N N -dimethyl-- 1 - (4-nitro-2-(trif]iioromethyl} phenyl) piperidin-4-amine (500 xng, 85%) as a yellow viscous compound. LCMS: 3 ) 8 [M+H]

[0339] Step-2: Synthesis of l-(4-amino-2-(trifluoromethyl) pheny!)-N, N- dimethyipiperi<iin-4-am£ne: To a stirred solution of N, N-dimethy i - 1 -(4-nitro-2-

(trifluoromethyl) phenyl) pipendin-4-amme (500 mg, 1.5 mmol, 1 equiv) in ethanol (7 ml,), water (3 niL), was added iron powder (265 mg, 4.7 m ol, 3 equiv) and ammonium chloride ( 162 mg, 3 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for lh. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through ceiite bed and the filtrate was concentrated under reduced pressure to obtain 1 -(4-amino- 2-(trifli3oromethyl) phenyl)~M, N-dimethyipiperidin-4-amine (400 mg, 88%) as a dark brown solid compound LCMS: 288 |M+£f|

[0340] Step-3: Synthesis of M-(4-(4~(climeihylamino)piperidin~I~yl)~3~

(trifluoromethyd)phenyl)-S-ll orO 4-iS-ll oro-4-isopropyd~:3,4-clihydro-2B- benzo [b] [ 1,4] oxazin-6-yi)pyrimidwt»-2-amine: To a solution of 6-(2-chloro-5-fluoropyrimidin-

4-yl)-8-fluoro-4-isopropy!-3, 4-dihydro- 2H-henzo[b][l ,4]oxazine (100 mg, 0 3 mmol, 1 equiv) dioxane (10 ml,), was added l-(4-amino-2-(trifluoromethyl) phenylpN, N-dimethylpiperidin-4- amine (95 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg. 0 45 mmol, 1.5 equiv)

The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0.012 mmol, 0 04 equiv). The resultant reaction mixture w¾s allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer w¾s washed with water (50 ml,) and brine solution (50 niL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by reverse phase HPLC to obtain N-(4-(4-(dimethylamino)piperidin-l-yl)-3-(qiiluoromeibyl)phe nyl)-5-(luoro-4-(8- fluoro-4-isopropy]-3,4-dihydro-2H-benzo[b|[l,4]oxazin-6-yl)p yiirnidin-2-amme (40 mg. 23%) as a yellow solid compound. LCMS: 577 jM HTj ~ ¾NMR (400MHz, DMSO-fo} 6 9.92 (s,

1 H), 8 60 (d, 7 4.0 Hz, I H), 8 24 Is, 1 1 1) 8.17 (s, 1 H), 7.97- 7.90 (m, 1H), 7.46 (d, 7 8.8 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J ^::: 1 1.5 Hz, 1H), 4.30 (t, J --- 4.2 Hz, 2H),4.12 (p, J- 6.8 Hz, I ), 3.63 - 3.55 (th, 1H), 3.30 (t / 4.8 Hz, 4H), 2.93 (d, J === 1 1.1 Hz, 2H), 2.72 (t ,% 1 1.1 Hz, 2H), 2 23 (s, 71 ! } 1.82 (d, J ^:::: 12.0 Hz, 2B), 1.58 - 1 43 (m, 2H), 1.17 (d, J - 6.5 Hz, 6H).

Example-45: Synthesis of N7-(5-fluoro-4-(8-fluoro-4-isopropyl-3, 4~dihydro~2H- benzo[hj[l,4]oxazin-6-yl)pyrimidin-2-yl)-N2 _> N2-dimethyl-l,2,3, 4-teirahydronaphthaiene-2 7- diamine (Peak-1) (Compound 206) and Example-46: Synthesis of N6-(5-fiiioro-4-(8-ftuoro-4- isopropyl~3,4-dihydro-2H~benzofh)fl,4/oxazin~6-yi)pyr idin-2-yi)-N2.N2-dimeihyi-l,2, 3, 4-

[0341] Step-1 :: Synthesis of N, N-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-2~amine: To a stirred solution of 3, 4--dihydronaphthalen-2(lH)--one (5000 nig, 34.2 mmol 1 equiv) in THF (50 mL), was added NaCNBHti (2155 mg, 34.2 mmol, 1 equiv), ZnCL (2326 mg, 17.1 mmol, 0.5 equiv) and dimethyl amine (2M in TFH) (17 mL, 34.2 mmol, 1 equiv). The resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitore by LCMS. After completion of the reaction, solvent was removed under reduce pressure and IN HCI (100 ml,) was adde to above residue The acidic solution was washed with ethyl acetate (100 ml, ^x 2), then made alkaline with aq. 5M NaOH solution (50 mL) and extracted with EtoAC ( 100 ml, ^x 3). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain N, N-dimethyl-l, 2, 3, 4-tetrahydronaphthaien~2~amme (950 g, 15%) as a yellow oil compound LCMS: 176 [MH1]

[0342] Step-2: Synthesis of N, -dmiethyi-7-nitro-l, 2, 3, 4-tetrahydronaphthalen-2- amine and N, N-dimethy!-6-nitro-l, 2, 3, 4~tetrahydronaphthaien-2-amine: To a stirred solution of N, M-dimethyl-l , 2, 3. -tetrahydronaphthalemO- amine (950 mg, 5.4 mmol, I equiv) in THF (5 mL), was added HN03 (0.9 mL, 21 7 mmol, 4 equiv) at 0°C. The resultant reaction mixture was allowed to stir at RT for overnight Progress of the reaction was monitored by LCMS. After completion of the reaction the mixture was diluted with ice water (20 ml . ; then made alkaline with aq. 5M NaOH solution ( 10 mL) and extracted with EtoAC (100 mL x 2). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a mixture of N, N-dimettiylw-nitro·-! , 2, 3, d-tetrahydronaphthalenfo-a ine and N, N-dimethyl~6~mtro-l, 2, 3, 4-tetrahydronaphtiialen-2-amine (700 mg, 58%) as a yellow oil compound. LCMS: 221 [M+H] ^"

[0343] Step-3: Synthesis of N2,N2-dimethyl~ 1,2,3,· 4~ietraliydroiiaphthaIeiie~2,7-cliamine and !S2,lS2-dimethyl-l,2,3,4-tefrafaydroiiiaphtfealeiiie-2,6~dia ffime: To a stirred solution of a mixture of N, N-dimethyl-7-nitro-l, 2, 3, 4-tetrahydronaphthalen-2-amine and N, N-dimethyl-6- mtro-d, 2, 3, 4-tetraiiydronaphthalen-2-amine (500 mg, 1 87 mmol, 1 eq v) in ethanol (9 mL). water (3 mL), was added iron powder (535 mg, 9 5 mmol, 3 equiv) and ammonium chloride (335 mg, 6.2 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for I h.

Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was passes through eelite bed and the filtrate was concentrated under reduced pressure to obtain a mixture of N2,N2-dimethyl-l ,2,3,4-tetrahydronaphthalene-2,7-diamine and N2,N2-dimethybl,2,3,4-tetraliydronaphthalene~2,6-diamme (550 g, 91%) as brown solid compound. LCMS: 191 [M+H] '

[0344] Step-4: Synthesis of N7-(5-f!uoro-4-(8-f!uoro-4-jsopropyl-3 _» 4-dihydro-2H- benzo[b][l _» 4]oxa**n-6-yi)pyrimidin-2-yl)-N2dS ^T 2-dimethyH,2 _» 4-te rahydronaphthalene- 2,7-diamine and N6-(5-fl«oro-4-(8-fl«oro-4-isopropyl-3,4-dihydro-2H-ben¾o (b]fl,4]oxa*in- 6-yl)pyrimidin-2-yl)-N2 _! ^2-dimethyi-i, 2 3 _» 4-tetrahydronaphthalene- 2, -diamine: To a solution of 6-(2-chloro-5-t1uoropyrimidin-4-yl)-8-iluoro-4-isopropyl-3,4 -dihydro-2H- benzo[b] [ 1 ,4] oxazine (150 rag, 0.46 ramol, 1 equiv) and in dioxane (10 ml.), was added a mixture of N2,N2-dimethyl~ 1,2,3, 4-tetiahydronaphthalene-2, 7-diamine and N2,N2-dimethyl- 1 ,2, 3, 4-tetrahydronaphihalene-2, 6-diamine (97 mg, 0.5 mmol, 1 1 equiv), followed by the addition of cesium carbonate (225 mg, 0 69 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.009 m ol, 0 02 equiv) and BINAP (1 1 mg, 0 018 mmol, 0.04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and i .C MS After completion of the reaction, diluted with water (30 inL) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 niL) and brine solution (50 niL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain two peaks as N7- (5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[b][l, 4]oxazin-6-yl)pyrimidin-2-yl)~ N2,N2-dimethyi-l, 2,3, 4-tetrahydronaphthalene-2, 7-diamine and N6-(5-fluoro-4-(8-fluoro-4- isopropyl-3,4-dihydro-2H-benzo[bl[ l,4]oxazm-6-yl)pyrimidin ^~ 2 ^~ yl)-N2,N2-dimethyl-l ,2,3,4- tetrahydronaphthaiene-2, 6-diamine (5 mg and 15 mg, 9%) as a yellow solid compound. LCMS: 480 [M÷H] ^f ; PEAK-1 : ⁱ HNME (DMSO-d ₆ , 400MHz): d 9.86 (br. s , 1 H), 8.46 (d, 7 - 4 0 Hz,

1H), 7.46 (d, ,7-7.5 Hz, 1 H), 7.32 (s, 1 H), 7 17 (t, J 7 7 Hz, 1H), 7.10 (d, .7=12.3 Hz, 1 H),

6.98 (d, .7-7 9 Hz, 1 H), 4.27 (br. s, 2 H), 4.01 (p, 7 - 6 5 Hz, !H), 3.51 (br. s., 2 H), 3.16 (d,

.7=1 1.0 Hz, 1 H), 2.90 - 3.05 (m, 2 H), 2.82 (d, 7 = 4.1 Hz, 6H), 2.28 (br. s, 1 H), 1 .93 (br. s., 1 H), 1.71 (d, ,7-6.6 Hz, 1 H), 1.49 (br s., 1 H), 1 14 ppm (t, .7-7.0 Hz, 6 H).

PEAK-2: ΪINMM (DMSO-d ₆ , 400MHz): d 9.61 (br s., 1 H), 8 55 (d, ,7-3.5 Hz, 1 H), 7.50 - 7.63 (m, 1 H), 7.47 (br. s. , 1 H), 7 39 (d, 7=6 6 Hz, 1 H), 7.17 (d, .7-1 1.4 Hz, 1 H), 6.93 - 7.05 (m, 1

H), 4.29 (d, .7-3.5 Hz, 2 H), 4.07 - 4.20 (m, 1 H), 3 51 (br. s., 2 H), 97 (br s., 1 H) 85 (br. s

H), 2 69 (d, 7-11.8 Hz, 6 H) _: 17 (d, .7-7.5 Hz, 1 H), 1.91 (br. s, 1 H), 1 72 (br. s , 1 H), 1 49

(br. s , 1 H), 1.19 ppm (d, ,7=6.6 Hz, 6 H).

Exam pie-47: Synthesis of 4-(8-chioro-4-isopropyi-3, 4-dihydro-2ii~henzofh][f 4joxazin-6-yi)-5-

[0345] Step-1: Synthesis of 6-broitno-8-chIoro-4-isopropyl-2H-benzo[b] [1 ,4]oxazin~ 3(4H)-one: To a stirred solution of 6-bromo~8~chioro-2H~benzo[h][l ,4]oxazm-3(4H)-one (2000 mg, 7.6 mmol, 1 equiv) m DMF (20 ml,), was added Nail (610 g, 15 2 mmol, 2 equiv) and isopropyl iodide (1 .5 mL, 15.2 mmol 2 equiv). The reaction mixture was allowed to stir at 80°C for 3 h Progress of the reaction was monitored by TLC and 1.( ^' MS After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). Organic layer was washed with brine ( 100 mL) and water ( 100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6- bromo~8-ChlorO 4-isopropyl-2H-benzo[bl[] ,4 oxazm-3(4H)-One (700 mg, 95%) as an off white solid compound. LCMS: 260 [M+H] ^"

[0346] Step-2: Synthesis of e-bromo-S-chloro- -isopropyl^ -tllhydro-lH- benzojb j ( 1,4]oxazine: To a stirred solution of 6-bromo-8-chloro-4-isopropyl-2H- benzo[bl[] ,4]oxazm 3(4H)-One (650 mg, 2 1 mmol, 1 equiv) in THF (15 mL), was added BH- .DMS (2 M in THF) (4 mL, 8.5 mmol, 4 equiv) at 0 C drop wise. The reaction mixture was allowed to stir at 80°C for overnight. Progress of the reaction was monitored by TLC and I, CMS. After completion of the reaction, the reaction mixture was quenched with saturated solution of NalfCO (50 ml,) and extracted with ethyl acetate (100 ml, ^c 2). Organic layer was washed with water (100 ml,), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6-bromo-8-chloro-4~isopropyl~3, 4-dihydro- 2H~benzo[b][l ,4]oxazine (550 g, 89%) as a transparent oil compound LCMS: 290 [M÷H] ^’

[0347] Step-3: Synthesis of 8~chior0-4-isopropyi~6-(4,4,5,5~tetramethyM,3 _¾ 2- d ^j oxaboroIan-2-yl)-3,4-dihydro-2H-benzo[b]fl _» 4]oxaz ^j ne: 6-bromo-8-chloro-4-isopropyl-3.4- dihydro--2H-benzo[bj[l ,4]oxazine (550 mg, 1 9 mmol, 1 equiv). 4,4,5,5-tetrametiiyl-2-(4,4,5,5- ieixamethyl-l ,3,2-dioxaborolan-2~yl)-l ,3.2-dioxaborolane (725 mg, 2.8 mmol, 1.5 equiv).

Potassium acetate (466 mg, 4.7 mmol, 2.5 equiv) and dioxane (10 mL) were charged m a 25 mL glass bottle. Purged the reaction mixture with nitrogen gas for 15 min , Pd(dppf)Cl2. DCM (78 mg, 0.09 mmol, 0.05 equiv) was added to above mixture and the reaction mixture was allowed to stir at 100°C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate ( 100 mL - 2). Organic layer was washed with brme (100 ml,) and water (100 mL). Organic layer was dried over anhydrous sodi m sulphate and concentrated under reduced pressure to obtain 8--chloro-4-isopropyh6-{4,4 5,5--ietrameth !- 1 ,3,2--dioxaborolan-2- i)--3 4- dihydro-ZH~benzo[b][l ,4]oxazine ( 600 mg, 94%) as a dark brown viscous compound. LCMS: 338 [M fH] ⁺

|0348j Step-4: Synthesis of 8-chloro-6-(2-chIoro-5-lluoropyrimidin-4-y I )-4-isopropyI-

3,4-dihydro-2H-benzo( bj [l _» 4]oxazine: To a stirred solution of 2, 4-dich loro-5 -fluoropyrimi dine

(150 g, 0.9 mmol, 1 equiv) in P II Water ; 1 : i 10 mL) was added 8-chloro-4-isopropyl-6- (4,4,5, 5~tetraniethyl-l , 3, 2-dioxaborolan~2~yl).-3, 4-dihydro- 2H-benzo[b][l,4]oxazine (305 mg,

0.9 mmol, 1 equiv), Potassium carbonate (248 mg, 1.8 mmol, 2 equiv) and PdiPPhfo (52 mg, 0.04 mmol, 0.05 equiv). The reaction mixture was allowed to stir at 80°C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted wit ethyl acetate (100 mL). Organic layer was washed with water (50 ml,) and brine (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 8-ch]oro-6-(2-chloro-5-tluoropyrimidin-4-yl)-4- isopropyl-3,4~dihydro~2H-benzo[b][l,4]oxazine (300 mg, 81%) as a yellow solid compound. LCMS: 342 [M+H] ^r

[0349] Step-5: Synthesis of tert-butyl 4-(4-((4-(8-e.hIoro-4-isopropyl-3,4-dihydro-2H- benzo[b][l,4]oxazi«-^ yi)~S-fluoropyrimidm-2-yi)ammo)-2-fluoropheiiyl)piperazine-l - carboxy!ate: To a solution of 8-ch!oro~6-(2-chloro-5~fluoropyrimidin-4-yi)-4-isopropyl-3,4 - dihydro-2H-benzo[b] [ 1 ,4]oxazine (100 mg, 0.29 mmol, 1 equiv) in Dioxane (10 ml,), was added tort-butyl 4-(4-armno-2-fluorophenyl)piperazine-l -carboxylate (95 mg, 0 32 mmol. 1.1 equiv) and cesium carbonate (142 mg, 0.43 mmol, 1 5 equiv). The reaction mixture was purged with nitrogen gas for 30 min., followed by the addition of palladium acetate (1 3 mg, 0.005 mmol,

0.02 equiv) and B1NAP (7 mg, 0.01 ol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mi,) and extracted wit ethyl acetate (100 ml,) Organic layer was washed with water (50 ml,) and brine (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain tert-butyl 4-(4-{(4-(8-chloro-4-isopropyl-3,4-dihydro-2H-benzo[bj[ L4]oxazin-6-yi)-5- fluoropyriniidin-2-yl)amino} 2-fluorophenyl)piperazme-l-carbox late (30 mg 17%) as a yellow solid compound LCMS: 601 jM+Hj ^’

10350] Step-6: Synthesis of d-CS-cfeloro^-isopropyi-S^-diife drG-lH- btmzolbHJ ^loJUizin.^i-yl^S-fiuoiO-N-lS-fluoro-^Cpiperazin-l-yQ henytjpyrimiditi-l- amine: tert-butyl 4- 4- 4-(8-chloro-4-isopiOpyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-5- f!uoropyrimidm~2-yl)amino)~2-f!uorophenyl)piperazine~1 ~carboxylate (30 mg. 0.05 mmol, 1 equiv) was taken in 1.25 M HC1 in ethanol (5 mLj and the resultant reaction mixture was allowed to stir at 50°C for Ih. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophiiizer to obtain 4-(8-ehloro-4-isopropyi-3.4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)-5-fiuoro-N~(3~iluoro-4~(piperazin-l -yi)phenyl)pyrimidin~2~amine (25 mg, 93%) as a brick red color solid compound. LCMS: 501 [M+H] 7 ¾NMR (400 MHz, DMSO-A6) 5 9.82 (s. 1H), 9.18 (s, IH), 8.58 (d, .7= 3.8 Hz, i l l) 7 81 (dd, ./== 15.0,2.5 Hz, IH), 7.51 (s, 1 1 1). 7.39 (dd, J = 8.7, 2.3 Hz, IH), 7.36 (s, IH), 7.04 (t, ./ 9.3 Hz, IH), 4.33 (d, J= 4.0 Hz, 2H), 4 16 ip, J= 6.7

Hz, IH), 3.31 (t, ,7- 4.2 Hz, 2H), 3 23 (q, ,7- 4.3 Hz, 4H), 3.20 - 3 13 (m,4H), 1.19 (d, ,/= 6.5 Hz, 6H)

Example-48: Synthesis of2~(dimethylamino)-l-(4-(4-((5-fluora-4-(8-fiuora-4-isoprop yl-3, 4- dihydro~2N~henzo[h / f 1 ,4 oxazin~6~yi)j}'rimiiiin~2~yi)a mo)phenyI}piperasin~ I -yijethan- 1 -one.

( Compound 440)

[0351] Step-1: Synthesis of 5-flaoro-4-(8-flaoro-4-isopropyi-3,4-dihydro-2H- henzo[h] [ 1,4] oxazin-6-yI)-N-(4-(piperazin- l-y!)phenyl)pyriraidin-2-amine: A solution of tert- butyl 4-(4-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo (b][l,4]oxazin~6~ yl)pyrimidin-2-yi}amino}pheny1)piperazme-l -carboxylate (1 10 mg, 0 19 mmol , 1 equiv) in 1 25 M HQ in ethanol 14 inL) was allowed to sdr for 1 h at 50 °C. Progress of the reaction was monitored by LCMS. After completion of the reaction solvent was removed under reduced pressure to obtain 5-fluoro-4- 8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[b][1.4]oxazin~6-yl )~ N-(4-(piperazin-l-yi)phenyl)pyrimidin-2-amine (70 mg) as an oily residue. LCMS: 467 [M+H]

[0352] Step-2: Synthesis of 2-(dimethyiammo)-l~(4~(4~((5~fiaoro~4~(8~fi«oro~4~

isopropyi-3,4-dihydro-2H-ben2o[b] [l,4]oxa2«n-6-yl)pyrimid«i-2- yl)amino)phenyi)piperazin~l~yi)ethaB-l-one; To a solution of 5-f!uoro-4-(8-f!uoro-4- isopropyl- 3,4-dihydro-2H-benzo[bl[] ,4]oxazin-0-yl}-N~(4~(piperazin-l -yl}phenyl)pyrimidin~2~ amine (70 nig, 0.15 mmol, 1 equiv) in DMF (4 niL) was added dimethyl glycine (24 mg, 0 22 mmol, 1.5 equiv) followed by addition of HATH (84 mg, 0.22 mmol, 1.5 equiv) and DIPEA (48 mg, 0.37 mmol, 2 5 equiv). Resultant mixture was allowed to stir at room temperature for 2 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (10 l.) and extracted with EtOAc (15 ml-). Organic layer was washed with water (50 mL ^c 6) and brine (50 ml..), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound was purified by reverse phase HPI.C to afford 2-(dimethylamino)-l-(4-(4-((5-fluoro-4-(8-fluoro-4-isopropy] -3.4-dihydro-2H- benzo[b] [1 ,4]oxazm-6-yl)pyrimidin-2-yl)amino)phenyl)piperazm- 1 -yl)ethan- 1 -one (10 mg) as a pale yellow solid. LCMS: 552 [M+H] ⁺ ; 1HNMR (400 MHz, DMSO-A6) 6 9.45 (s, 1H), 8.50 (d, ./ 4 0 Hz. 1H), 8.34 (s. HI), 7 60 (d, ./=== 8.5 Hz, 2H), 7 43 (s, 1 H), 7 15 (d, ,/== 1 1.6 Hz, 1 H), 6.91 (d, J ----- 8.5 Hz, 2H), 4.29 (i, ft 4.3 Hz, 2H). 4.13 (p, ./ 6.6 Hz, l i ft. 3.68 (i ft 4.9 Hz, si ft. 3.59 ft . J ---- 4.9 Hz, 2H), 3.30 (t, / 4.4 Hz, 2! ft. 3 10 (s, 2! ft. 3 06 (t, ./ 4.9 Hz. 2H), 3.03

(d, J ------ 5.5 Hz, si ft. 2.19 (s, id ft. 1.19 (d, ft === 6 5 Hz, 61 ft.

Example-49: Synthesis of 2~(dimel.hyhwiino)~l~(4~(6-((5-jhioro-4-(8-ftiioro-4-isoprop yl-3, 4~ dihydro-2H~hemo[hl [ l,4]oxazin~6~ylfyyrimidin~2-y!)ammo}pyndin-3~y}}piperazin~l~ yl)e†han-l~ one. {Compound 441)

[0353] Step-1: Synthesis tert-butyl 4-(6~aitropyri<Jin-3-yl) piperazine-l-carboxylate: To a stirred solution of 5~bromo~2~mtropyndme (1500 mg, 7.4 mmol, 1 equiv) in DMSO (1 0 ml.), was added ·( O (1 532 mg, 11 1 mmol, 1 equiv), water (5 ml.) and tert-butyl piperazine- Ί- earboxyiate (2072 mg, 11 1 mmol, 1 equiv). The resultant reaction mixture was allowed to stir at 100°C for overnight. Progress of the reaction was monitored by LCMS After completion of the reaction, diluted with water (100 ml,), solid observed was filtered and dried under vacuum to obtain tert-butyl 4-(6-- iropyndm--3--y! [piperazine- 1 -carhoxyiate (1800 mg, 79%) as a yellow solid compound. LCMS: 309 j M 1 11

[0354] Step-2: Synthesis of tert-butyl 4-(6-aminopyridin-3-yl) piperazine-l-carboxyiate:

To a stirred solution of tert-butyl 4-(6-nltropyndin-3-yl)piperazine-l -carhoxyiate (500 mg, 1 6 mmol, 1 equiv) in ethanol (8 ml.), water (2 ml.), was added non powde (269 mg, 4.8 mmol, 3 equiv) and ammonium chloride (173 mg 3 2 mol, 2 eq v). The resultant reaction mixture was allowed to stir at 90° for lb Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(6-aminopyridin-3-yl) piperazine- 1- carboxyiale (350 mg, 78%) as a dark brown solid compound. LCMS: 279 [M+foj

[0355] Step-3: Synthesis of tert-butyl 4~(6~((5-fluoro~4~(8-flu©ro~4-is©propyl-3,4- dihydro-2II-benzo[b][i,4]oxazm-6-yl)pyrimidin-2-yl)amino)pyr «d«n-3-yi)piperazine~l~ carhoxyiate: To a solution of 6-(2-chloro-5-fiuoropyrimidin-4-yi)-8-fluoro-4-isopropyi-3,4 - dihydro-2H-benzo[b][l,4]oxazine (150 mg, 0.46 mmol, 1 equiv) in dioxane (10 mL), was added tert-butyl 4-(6-aminopyndm-3-yl} piperazine- 1 -carhoxyiate (141 mg 0.5 mmol, 1.1 equiv) and cesium carbonate (225 mg, 0.69 mmol, 1 5 squiv). The reaction mixture was degassed with mitogen gas for 30 min. followed by the addition of palladium acetate (2 mg, 0.009 mmol, 0.02 equiv) and BINAP (12 mg, 0.018 mmol, 0.04 eqiuv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain tert-butyi 4~(6-((5-fluoro-4-(8- fluoro-4-isopropyl-3,4-dihydro-2H-benzofbl[l,4]oxazin-6-yl)p yrimidin~2~yl)ammo)pyridin-3- yl)piperazine-l -carboxylate (100 mg, 38%) as a yellow color solid compound LCMS: 568 [M+H]

[0356] Step-4: Synthesis of 5-fluoro-4~(8-fluoro-4-isopropyi-3, 4-difaydro-2H~ benzo[b][l,4]oxazin~6~yI)-N-{5-Cpiperazin~l-yI)pyridin-2~yI) pyriitmdin~2~amine: ten-butyl 4- (6-((5-fluoro-4-(8-fluoro-4-isopropyl-3, _' ^; hdihydro-2H-benzo[bj[l .4]oxazin-6-yl)pyrimidin-2- yl)amino)pyndin-3-yl)piperazine-l -carboxylate (100 mg, 0 17 mmol, 1 equiv) was taken in 1 25 M HC1 in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for 1 h. Progress of the reaction was monitored by I, CMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophilizer to obtain 5-fluoro- 4~{8~-£luoro~4~isopropy!~3, 4-dihytiro-2H-ben o[b][l ,4]oxazin-6-yl)-N-(5-(piperazin-l- y])pyridm-2-yi)pyrimidin-2-amme (85 mg. 97%) as a brown solid compound. LCMS: 468

[M+H]

[0357] Step-5: Synthesis of 2-(d«methylamino)-l-(4-(6-((5-flM ro-4-(8-fl ro-4- isopropyl-3, 4-dihydro-2H-ben*o[b] [l,4]oxazin-6-yl)pyrimidin-2-yl)amino)pyr«dm-3- yl)pipera¾m-l-yI)ethan-l-one: To a stirred solution of 5 -ft uoro-4-(8-ft uoro-4-isopropy i -3 , 4- dihydro-2H-benzo! b][l,4]oxazm-6-yl)-N-(5 -(piperazm-1 -yl)pyridin-2-yl)pynmidin-2-amine (70 mg, 0.13 mmol, 1 equiv) in DMF (5 mL), was added dimethylgiycine (17 mg, 0.16 mmol, 1 2 equiv) DIPEA (0.09 mL 0.52 mmol, 4 equiv) and HATH (89 mg, 0.23 mmol, 1 8 equiv). The reaction mixture was allowed to stir for overnight at RT. Progress of the reaction was monitored by TLC and LCMS. Alter completion of foe reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 ml, - 2) Organic layer was washed with water (50 mL) brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase MPLC to obtain 2-(dimethylamino)~I~(4-(6-((5-f!uoro-4-(8-f!uoro-4-isopropyi -3,4~ dihydro-TH-benzo[b]ii,4]oxazim6-yI)pynmidm-2-yi)armno)pyridm --3 yl)piperaziml -yi)ethaml· one (25 mg, 32%) as yellow color solid compound. LCMS: 553 M H i ‘H MR (400 MHz, DMSO- 6) d 9.71 (s, 1H), 8.56 (d, J = 4.0 Hz, HI), 8 07 - 8.00 (m, 2H), 7.46 (sJH), 7.42 (dd, ./ = 9.2, 3.0 Hz, Hi), 7 17 (d, ,/= 1 1.5 Hz, HI), 4.30 (t, J = 4,2 Hz, 2H), 4, 15 (p, J= 6.6Hz, IHj, 3.70 (t, J = 4,8 Hz, 2H), 3 61 (t, J = 5 3 Hz, 21 k 3.23 (t, J = 4.8 Hz, 2H), 3.16 - 3.04 (m, 6H),

2.19 (s, 6H), 1.19 (d, ./ = 6.5 Hz, 611).

Example-50: Synthesis of5-fluoro-4-(8-fluoro-4-isopropyl-3, 4~dihydro~2H-benzofh]fl,4joxazin-

[0358] Step-1: Synthesis of tert-butyl 6-nitro-3 ^> ,6"-dihydro-|3,4' ^' -bipyrldlne]-l ^> (2 ^! II)-· carhoxyiate : To a solution of 5--bromo-2--nriropyridine (10 g, 49 mmol, 1 equiv) in dioxane (90 mL) and water ( 10 mL), was added tert-butyl 4-(4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan- 2-yl}-3, 6-dihydropyridine-l (2H)-carbox late (15 23 g,49 mmol, I equiv). Sodium carbonate (15 58 g, 147 mmol, 3 eq.) was added to reaction mixture at ambient temperature and nitrogen was purged for I Sminutes. Pd( tiPfo p( > ( 343 mg. 0.49 mmol, I mol%) was added and nitrogen was again purged for 10 minutes . Reaction mixture was heated at 100 °C for 16 h TLC (50 % ethyl acetate: hexane) showed that starting material was consumed. After completion of reaction, solvent was removed under reduced pressure Ethyl acetate (1000 inL) was added to reaction mixture and organic phase was separated. Ethyl acetate layer was washed with water (200 inL x 3), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude. Crude product was purified by Combi-Flash to afford tert-butyl 6-miro- 3 ^! ,6 ^, ~dihydro-[3,4‘ bipyridine]--r(2 ^< H) Carboxylate (10.2 g , 67.5 %) as white solid. LCMS: 276 [M+H]

[0359] Step-2: Synthesis of tert-butyl tert-butyl 4~(6-am«uopyridin-3-yl)piperidiae-l- carboxyiate: To a stirred solution of tert-butyl 6-mtro-3 ^! ,6'-dihydro-[3,4'-bipyridine]-r(2'H)- carboxy!ate (10 2 g, 33.4 mmol, 1 equiv) in ethanol (400 ml,), w¾s added Pd/C (10% w/w, 2 g). The resultant reaction mixture was stir at ambient temperature for 2b under hydrogen balloon TLC (50% EA: hexane) showed that starting material was consumed. After completion of the reaction, the mixture was passes through celite bed winch was washed with ethanol (100 ml, x 2). Filtrate was concentrated under reduced pressure to afford tert-butyl tert-butyl 4-(6- aminopyridin-3-yI)piperidine-I-carhoxyIate (10 g, >100%) as a transparent oil. LCMS: 278 [M+H] ^÷

[0360] Step-3: Synthesis of tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyI-3, 4~ dihydro-2H-benzo[b][l,4]oxazin~0~yI)pyrimidin-2-yl)amino)pyr idin-3~yI)p peridine-l- carboxylate: To a solution of 6-(2-ch!oro-5-†]uoropyrimidin-4-yl)-8~iTuoro~4~isopropyl-3 .,4- dihydro~2H~benzo[bj[l ,4joxaxine (10.6 g, 32 mmol, 1 equiv) in dioxane (160 ml,), was added tert-butyl 4-(5-aminopyridin-2-yl) piperidine- 1 -carboxylate (10 g, 36 mmol. 1.1 equiv) and cesium carbonate (20 8 g, 64 mmol, 2 equiv) and nitrogen was purged for 15minutes.

Palladium acetate (2 mg, 0.009 m ol, 0.02 equiv) and BINAP (12 mg, 0 018 mmol, 0 04 equiv) were added and nitrogen was again purged for 10 minutes. Reaction mixture was heated at 100 °C for 16 h. TLC (50 % ethyl acetate: hexane) showed that starting material was consumed.

Alter completion of reaction solvent was removed under reduced pressure. Ethyl acetate ( 1000 ml .; was added to reaction mixture and organic phase was separated. Ethyl acetate layer was washed with water (200 ml, x 3), dried over anhydrous sodium sulphate, fil ered and concentrated under reduced pressure to a Herd crude. Crude product was purified by Combi- Flash using 0-40% ethyl acetate: Hexane to a fiord ten-butyl 4-(6-((5-iIuoro-4-(8-rluoro-4- isopropy!-3, 4-dihydro-2H-benzo[bl[! ,4]oxazm-6-yl}pyriimdm-2 yi)ammo}pyridm-3- yl)pipendine-l -earboxylate (7 g, 38%) as a yellow solid compound. LCMS: 567 1 % H i ^÷

[0361] Step-4: Synthesis of 5-fluoro-4-( 8-t1uoro-4-isopropyI-3 _» 4-dihydro-2H- benzojb j | 1,4[ oxaztn -6-yl) -N-(5-(piperidin-4-yl)pyr«din-2-yi)pyrmMdin-2-amme

hydrochloride: A solution of tert-butyi tert-butyl 4~(6~((5-fluoro~4-(8-fluoro~4-isopropyl-3,4- dihydro-2H-benzo[bl[l,4]oxazin~6-yl)pyrimidm~2~yl)amino)pyri dm-3-y ^j )piperidme~l~ carboxylate (7 g, 0.1 mmol, 1 equiv) was charged m ethanol (60 ml ..· and 4 M HCI in Dioxane (40 mL) was added into it. Solution was stirred for lb at 50 °C. TLC (50% ethyl acetate: hexane) and LCMS showed that starting material was consumed. After completion of the reaction, solvent was removed under reduced pressure and basified with saturated NaHC03 (-100 ml.) till pH=7-8. Solid obtained was filtered under vacuum and washed with water (100 mL x 3).

Compound was further dried m vacuum to afford 5-fluoro-4-(8-fluoro-4-isopropyI-3,4-dihydro~ 2H-benzo[b][l,4]oxazin -6-yl) -N~(5-(piperidin-4~yl)pyridm-2-yl)pyrimidin-2-amme

hydrochloride (5.2 g, 90 2%) as a yellow solid LCMS: 467 [M+H] ^:

[0362] Step-5: Synthesis of 5-fluoro-4~(8-fluoro-4-isopropyi-3,4~dihydro-2H- benzo[b]ii _» 4]oxa¾ln-6-yl)-N-(5-(l-imethyIpiperidin-4-yI)pyridin- 2-yI)pyrimidin-2-ainine: To a stirred solution of 5~iluoro-4~(8~iluoro~4~isopropyl~3, 4~dihydro-2H-benzo[b][l,4]oxazin-6-yI)- N-(6-(piperidin-4~yl)pyridin-3-yj)pyrimidir!-2-amine (4 g, 8.56 mmol, 1 equiv) in DCE (40 ml.), was added Formaldehyde (40% in water) (2 31 g, 77 04 mmol, 9 equiv), acetic acid (2.57 g.

42.8 mmol, 5 equiv). The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was cooled to 0°C. NaCNBBU (1.61 g, 25.68 mmol, 3 equiv) was added to above mixture and reaction mixture was allowed to come ai ambient temperature. The reaction mixture was stirred at ambient temperature for 2h. TLC (10% MeOH: DCM) and LCMS showed that starting material was consumed. After completion, the reaction mixture was diluted with water (50 mL) and concentrated under reduced pressure. Saturated bicarbonate solution 1100 mL) was added in to crude material and solid obtained was filtered under vacuum. Crude material was purified by silica gel chromatography (#100-200) using 0-7% MeOH: DCM to afford free base of 5-iluoro-4-(8-iluoro-4-isopropyl-3,4-dihydro-2H-benzo b] I,4]oxaxin-6-yi)- N-(5-(l inethyipiperidin-4-yl)pyndin-2-yl)pyri idin 2 -amine (1.42 g, 34.5 %) as a yellow solid LCMS: 481 [M+H] ^÷

! 0363'] Step-6: Synthesis of 5-fluoro-4-( 8-t1uoro-4-isopropyI-3 _» 4-dihydro-2H- ben¾o(b]jl,4joxa¾i«-6-yI)-N-(5-(i-methyipiperidin-4-yl)py r«din-2-yl)pyrimidin-2-amme hydrochloride : In 250 mL RBF, 5-fluoro-4-(8~fluoro-4-isopropyl-3,4-dihydro-2H- benzG[b][1 ,4]oxazin-6-yl)-N~(5~(i-methylpipendin~4~yl)pyridin-2-yl)pyr imidin-2-amine free base ( 1.41 g, 2 93 mmol leq.) was suspended m ethanol (100 mL) and heated to reflux till the suspension became clear solution. Reaction mixture was cooled to ambient temperature

Hydrochloric acid, 35% (61 1 mg, 5 86 mmol, 2 eq.) dissolved m ethanol (10 mL) was added to reaction mixture drop wise at ambient temperature Reaction mixture -was stirred at same temperature for 30 minutes. Reaction mixture was concentrated under reduced pressure. MTBE (100 mL) was added to reaction mixture and solid obtained was filtered under vacuum. Solid compound was washed with Methyl test butyl ether (100 mL) and dried in vacuum oven at 55 ^' Ll for 16h to afford 5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[b][l ,4]oxazin-6-yI)-N- (5-(l-methylpiperidin-4-yr)pyridin-2-yl)pyrimidin-2-amine hydrochloride salt of tittle compound (1.57 g, 96.9 %) as yellow solid. LCMS: 481 [M+l] g ¾ NMR (400 MHz, DMSOv/6, HCi salt): 6 10.61 (br. s , 1 H), 8 75 Li. 1 3 51 Hz, 1H), 8.24 ( s., 1 H), 8 01 (s„ 1H), 7.92 (d, J = 8.77

Hz, i l l :. 7.44 (s., 1H), 7.22 (d, J = 1 1 .40 Hz, 1H), 4.31 (s., 2H), 4.06 - 4.23 (m, HI), 3 50 (d, J 1 2 28 Hz, 214), 3.32 (m, 2H), 3.06 (m, 1H), 2.90 (m, 3H), 2 77 (m, 2H), 2.03 (m 214), 1 97 (m, 214), 1 20 (d, J === 6 58 Hz, 614); UPLC-LCMS: 99.9389; HPLC:99.05%

Example-51 : Synthesis of 5-fluoro~4~(8-fluoro~4-isopropyi-3, 4-dihydro-2H- benzofh] ll joxazin-6-yI)-N-(4-flnoro-5-(piper din-4-yi)pyndin-2-) i)pynmidin-2- amine. (Compound 7731

OO

[0364 Step-1: Synthesis of tert-bntyl 6-amino-4-fluoro-3*, ’-dihydro-fS, 4’-bipyridme|- i ^* (2’H)~carboxylate: Io a solution of 5-brorno~4~fli3oropyridm-2-arnine (500 mg, 2.6 mmol, 1 equiv) in dioxane (10 mL), was added tert-butyl 4-(4,4,5,5-tetramethyl~I,3,2-dioxaborolan-2-yl)- 3,6-dihydropyridme-l (2H)-carboxylate (809 mg, 2.6 mmol, 1 equiv) and sodium bicarbonate (655 mg, 7.8 mmol, 3 equiv) The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of Pd ( PPh 4 · (150 mg, 0 13 mmol, 0 05 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with water (30 ml,) and extracted with ethyl acetate (1 00 ml, ^c 2). Organic layer was washed with water (100 mL) and brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-bntyl 6-amino-4-fluoro-3',6 ^! -dihydro-[3,4'-bipyiidine]-r(2 ^! H)-carboxylate (600 mg, 78%) as a yellow oil compound LCMS: 294 | fo 1 1 !

[0365] Step-2: Synthesis of tert-bntyl 4~(6~amino-4-fiuoropyridm-3-yl) piperidine-i- carhoxylate: To a stirred solution of ten-butyl 6-am o-4~iluoro-3 ^! , 6 ^, -dihydro-[3, 4’~ bipyiidine]-l '(2'H)-carboxylate (300 mg, 1.02 mmol. 1 equiv) in methanol (10 mL), was added Pd/C (20% w/w) (60 mg) under 1 1 · atm The resultant reaction mixture was allowed to stir ai RT for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, the mixture was passes through eehte bed and the filtrate was concentrated under reduced pressure to obtain tert-butyi 4-(6-a ino-4-fluoropyridin-3-yl) piperidine- 1 -carboxyiate (150 mg, 50%) as a white solid compound. LCMS: 296 [MH1] ^’

[0366] Step-3: Synthesis of tert-butyi 4-(4-flu©ro-6-((5-fluoro-4-(8-fluoro-4-is©propyl·- 3y4-dihydro-2H-benzo(b] jil,4|oxazin-6-yl)pyrhnuli»-2-yI)aini»©)pyridla-3-yl)pipe ridi«e-l- carboxyiate: To a solution of 6~(2~chloro-5-fluoropyriinidm-4-yl)-8-fluoro-4-isopiOpyl-3,4 ~ dihydro-2H-benzo[b]li,4]oxazme (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 niL), was added tert-butyi 4~(6~amino-4~f!uoropyridin-3-yl) piperidine- 1 -carboxyiate (97 mg, 0 33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyi 4 (4 fluoro-6 ((5-fluorO 4 (8-fluorO 4 isopropyi 3,4-dihydro~2H benzo[b][i,4]oxazin~6~ yl)pyrimidm-2-yi)auuno)pyridin-3-yl)piperidine-l -carboxylate (17 mg, 951 ) as a yellow solid compound. LCMS: 585 [M+H] '

[0367] Siep-4: Synthesis of 5-fluoro-4-(8-fluoro-4-lsopropyI-3, 4~dlhydro-2H- benzo[b][i,4]oxaz«n-6-yl)-N-(4~flm>ro-5-(piperidin-4~yl) pyrMm-2~yr)pyrimidin-2-aniiRe: A solution of tert-buty! 4-(4-fluoro-6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4--dihydr o--2!:I- benzo[b][l,4]oxazm-6-yl)pynrnidm-2-yl)ammo)pyridin-3--y!)pip eridine-l -carboxyiate (17 mg, 0.02 mmol, 1 equiv) in 1 25 M HC! in ethanol (5 ml,) was allowed to stir for lh at 50°C.

Progress of the reaction was monitored by LCMS After completion of the reaction, solvent was removed under reduced pressure to obtain 5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro-2H~ benzo[bj[l,4]oxazm-6-y!)-N-(4-i!uoro-54piperidin-4-y!)pyndm- 2-yi)pyrimidm--2--amine (1 3 g, 87%) as a yellow solid compound. LCMS: 485 [M+H] HNMR (400MHz, DMSO-ds) 6 10.48 (s, I Hh 8.86 (d, J ----- 1 1.2 Hz, 1H), 8.69 (d, J --- 3 8 Hz, 1H), 8.21 (d, J --- 10 6 Hz, 1H), 8.08 (d, J - 1 6 Hz, I l l s. 7.48 (s, IH), 7.19 (d, J - 1 1.6Hz, 1 H), 4.31 (t, ,7- 4.2 Hz, 2H), 4.1 9 (p, J- 6.7 J v Hz 1 P) 3 37 id, ·/ 12.5 Hz, 1 1 ) ·. 3.32 (t, 7 4.4 Hz 2H) 3.06 (dt ./ 19.1, 8.9 Hz, 4H), 2 01 -

1 90 (m, 4H), 1.19 (d, J --- 6.5 Hz,6H)

Example-52: Synthesis qfN- (5-fluoro-4-(8-fluoro-4-isopropyl-3.4-dihydro-2H~

benzo[h] l4.,4]oxazin-6-yl)pyrimidin-2-yl)~5~meihyl~4,5,6, 7~ietrahydropyrazolo[ 1 ,5-a]pyrazin-2- amine. (Compound 444)

[0368] To a solution of 6-(2-chloro~5~fluoropyrimidin~4~yl)-8-fluoro-4-isopropyl-3,4 - dihydro-2H-benzo[b][l,4]oxazine (100 mg, 0.3 mmol, 1 equiv) m dioxane ( 10 niL), was added 5-methyl-4,5,6,7 tetrahydiOpyrazolo[l ,5-a]pyrazin-2-amine (97 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0 012 mmol , 0 04 equiv). The resultant reaction mixture was allowed to stir a t 100 °C for overnight. Progress of the reaction was moni tored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,) Organic layer was washed with water (50 ml,) and brine solution (50 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by recrystallization with methanol to obtain N-(5-fluoro-4-(8-fluoro-4- isopropyj-3,4-dihydro-2H-benz:o[b][l,4|oxazin-6-yl)pyrimidm- 2-yl)-5-methyj-4,5,6,7 - tetrahydropyrazolo[I,5-a]pyrazin-2-amine (30 mg, 22%) as a yello solid compound IX >1.8: 442 [M-i-H] ", *H MR (400MHz, DMSO-de) d 9.82 (s, III) 8.49 (d, ,/ === 4.0 Hz, 1H), 7.45 (s, IH). 7.15 (d, J 1 1 5Hz, 1 H), 6 41 (s, i l l ) 4.30 (t, J - 4.3 Hz, 2H), 4 12 (dq, ./== 10.1, 5 3, 4.6 Hz, 1 1 1). 3 96 (t, 7 5.4 Hz 2H) 3.54 (s, 2H) 3.25 (s, 2H) 2 83 (t, J === 5 5 Hz, 2H), 2.38 (s, 3H),

1 19 (d, J- 6.5 Hz, 6H)

Example-53: Synthesis of l-(2~fluoro-4-((5~fluoro-4~(8~fluoro~4~isopropyl~3, 4-dihydro-2H- benzo[b][l,4]oxazin~6-ylJpyrimidin-2-yl)amino)phenyl)piperid in-4-ol. f Compound 445)

[0369] Step- !:; Synthesis of l-(2-fluoro-4-nitiOpheByl) piperidin-4-oi: To a stirred solution of 1, 2~difluoro-4-nitrobenzene ( 1000 mg, 6.28 mmol, 1 equiv) in methanol (15 mL), was added TEA (1.7 mL, 9.43 mmol, 2 equiv) and piperidin~4~ol (953 mg, 12.5 m ol, 1.5 equiv). The resultant reaction mixture was allowed to stir at 60°C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (100 ml..), solid observed was filtered and dried under vacuum to obtain l~(2 -fluoro~4~

nitrophenyl)piperidin-4-ol (1300 mg, 86%) as a yellow solid compound LCMS: 241 i \ M ! j ^”

[0370] Step- 2: Synthesis of l~(4~amino-2-f!uorophenyI) piperidin-4-ol: To a stirred solution of l -(2-fluoro-4-nitrophenyl)piperidin-4-ol (500 mg, 2.08 mmol, 1 equiv) in ethanol (8 ml. , water (2 ml..), was added iron powder (350 mg, 6.25 mmol, 3 equiv) and ammonium chloride (225 mg, 4.16 mmol, 2 equiv) The resultant reaction mixture was allowed to stir at 90° for Ih Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain l-(4-aminO -2-fluorophenyl) piperidim4-oi (350 mg, 80%) as a dark brown solid compound. L IS:: 211 j 1 11

[0371] Step-3: Synthesis of l-(2-fluoro-4-((5-fluoro-4-(8-fluoro-4-isopropyI-3,4-dihydro - 2H-benzo[h| [l,4]oxa*in-6~yI)pyrim«dm-2-yi)amino)phenyl)piperidin-4-oh To a solution of 6- f2-chloro-5-iluoropyrimidin~4~yl)-8-ftuoro-4- isopropyl-3, 4-dihydro-2H-ben2:o[b][l ,4joxazine (100 mg. O.Smmol, 1 equiv) m dioxane (10 ml.), was added l~(4-amino-2- fluorophenyl)piperidin-4-ol (69 mg, 0.33 ol, 1 1 equiv) and cesium carbonate (147mg, 0 47mmol, 1 .5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0 012 mmol, 0 04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction diluted with water (30 mL) and extracted with ethyl acetate ( 100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by recrystallization with methanol to obtain l-(2-fluoro-4-((5-fluoro-4-(8-fluoro-4- isopiOpyi-3,4-dihydro-2H-benzo[bl[l,4]oxazin-6-yl)pyrimidin- 2-yi)amino}phenyl)piperidin-4-ol (70 mg, 45%) as a yellow color solid compound. 1 , IS: 500 [M÷H] ⁺ ; OB Ml (400 MHz, DMSOvfo) d 9.72 (s, !H), 8.56 (d, J = 4,0 Hz, 1 H), 7.71 (dd, ./ 15.2, 2.5 Hz, 1 H r 74.1 (s, 1H),

7.35 (dd, J = 8.9, 2.4 Hz, IHj, 7.16 (d, J = 11 5 Hz, 1H), 6.97 (t, ./ 9.4 Hz, !Hj, 4.68 (d, ./ 4.1

Hz, IH), 4.33 - 4.26 (m, 2H), 4 15 (h, J= 6.7 Hz, 1 H), 3 58 (tt, J = 8.5, 4.3 Hz, Hi), 3.31 (s, 2H),3.16 (dt, J = 10.0, 4.4 Hz, 2H), 2.71 (d, ./= 9.5 Hz, 21 1) . 1.83 (dt, J= 12.2, 4.2 Hz, 21 0. 1.61 - 1.47 (m,2H), 1 .18 (d, ./= 6 4 Hz, 6H).

Example-54 : Synthesis of 5~fIuoro~4~(8~fIuoro~4~isopropyI~3, 4~dihydro~2H~

[0372] Step-1: Synthesis of 4-(6-nitropyrldhn-3-yI) morpholine: To a stirred solution of 5- bromo-2-nitropyndine (500 mg, 2 47 mmol. 1 equiv) m DMSO (10 mL), was added TEA (0.7 mL, 4.94 mmol, 2 equiv) and morpholine (323 mg, 3.7 mmol, 1 5 equiv). The resultant reaction mixture was allowed to stir at 100°C for overnight Progress of the reaction was monitored by TLC and 13 MS. After completion of the reaction, diluted with water (100 ml.), solid observed was filtered and dried under vacuum to obtain 4-{6-intropyridin-3--yl)inorphohne (500 mg, 97%) as a yellow solid compound. 3LCMS: 210 jMHTj ~

[0373] Step-2: Synthesis of S-morpholinopyridm-l-ainine: To a stirred solution of 4-(6- miropyridin-3--yl)morphohne (500 mg, 2.39 mol, 1 equiv) in ethanol (8 mL), waiter (2 mL), was added iron powder (402 mg, 7.17 mmol, 3 equiv) and ammonium chloride (258 mg, 4 78 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for 1 h. Progress of the reaction was monitored by TLC and LCMS. Alter completion of foe reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain 5- morphoiinopyndin-2-amxne (300 mg, 70%) as a dark brown solid compound LCMS: IB0

[M-i-B] ⁺

[0374] Step-3: Synthesis of S-!1uoro-4-( 8-!1uoro-4-isopropyI-3, 4-dfliydro-2H- ben¾o[b]|l,4|oxa¾in-6-yI)-N-(5-morphoIinopyridin-2-yi)pyr nidin-2-amine: To a solution of 6-(2~chioiO-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3,4 -dihydro-2H-benzo[b] 1 ,4]oxazine (100 mg, 0.3mmol, 1 equiv) in diosane (10 mL), was added 5-morpholinopyridin-2-amine (59 mg, 0.33 mmol, 1 1 equiv) and cesium carbonate (147mg, 0.47mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BiNAP (8 mg, 0.012 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 nxL) Organic layer was washed with water (50 ml,) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain 5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dibydro-2H-benzo[b][l ,4]oxazin-6-yl)-N-(5- morpbolinopyridin-2-yl)pyrimidin-2-amine (40 mg, 28%) as a yellow color solid compound.

LCMS: 469 [M+H] ^r ; ^s HNMS (400 MHz, DMSOM6) 6 B.53 (d, ./= 3.9 Hz, HI), B 00 (d, /

9.3 Hz, 21 !) 7 42 (s, HI), 7 38(dd, J 9 1 , 3.1 Hz, 1H), 7.15 (d. ·/ 11.7 Hz, i l l }. 4.31 - 4 24

(m, 21 1 } 4.1 1 (p, ./ 6.6 Hz, 1 H) 3.74 (1.9 === 4 7 Hz, 4H), 3.28 (i ./ 4.3 Hz, 2H) 3.07 (t 7

4.8 Hz, 41 1 } 1.16 (d. ./ 6.5 Hz, oi l)

Example-55: Synthesis of l-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3, 4~dihydro~2H~

benzo[b][J4]oxazin-6-yi)pynmidin-2~yi)amino}pyridin~3~yl) pipendin-4~oL (Compound 447 )

[0375] Step-1: Synthesis of l-(6~nitropyridin~3~yl) piperidin~4~ol: To a stirred solution of 5--bromo--2--nitropyndme (1000 mg, 4 95 mmol 1 equiv) in DMSO (15 mL) was added K ₂ CO:, (1366 mg, 9.9 mmol, 2 equiv) and piperidm-4-ol (750 mg, 7 42 mmol, 1 .5 equiv). The resultant

979 reaction mixture was allowed to stir at 100°C for overnight Progress of foe reaction was monitored by LCMS. After completion of the reaction diluted with water (100 L), solid observed was filtered and dried under vacuum to obtain l ~(6-nitropyridin-3~yl)pipendin-4-oi (900 mg, 82%) as a yellow solid compound. LCMS: 224 [MH1] ^”

[0376] Step-2: Synthesis of l-(6-aminopyridin~3~y!) piperidin-4-ol: To a stirred solution of 1 ~(6~nitropyridin-3-yl)piperidin-4-ol (500 mg, 2.24 mmol, 1 equiv) in ethanol (8 mL), water (2 mL), was added iron powder (377 mg, 6.72 mmol, 3 equiv) and ammonium chloride (242mg, 4.48 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for Ih. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate -was concentrated under reduced pressure to obtain 1 -(6~ammopyridm-3-yl)piperidm-4-oi (350 g, 81%) as a dark brown solid compound LCMS: 194 [MLH] ⁺

[0377] Step-3: Synthesis of l-(6-((5-fluoro-4-(S-fiuoro-4-isopropyl-3,4-dihydro-2H” benz©[b]iL4joxazin-6-yi)pyrimidin-2-yl)ammo)pyridin-3-yI)pi peridm-4-oh To a solution of 6~(2~chioro-5-fluoropyrimidin-4-y!)-8-f!uoro-4-isopropy!-;L4 ~dihydro-2H-benzo[b]p ,4]oxazine (100 mg, 0.3mmol, 1 equiv) in dioxane (10 mL). was added i-(6-aminopyridin-3-yl)piperidin~4- ol (64 mg, 0.33 mmol, 1 1 equiv) and cesium carbonate (147mg, 0.47mmol, 1.5 equiv) The reaction mixture was degassed with nitrogen gas for 30 m., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0.012 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by reorystalbzation with methanol to obtain l-(6-((5-fhioro-4-(8-fluoro-4-isopropyl-3,4-dihydro~2H- benzo[b|(l,4]oxaz:in-6-yl)pymmdm-2-yl)ammo)pyndin-3-yj)piper idin-4-ol (20 mg, 14%) as a yellow color solid compound. LCMS: 483 jM+H j T‘H MR (400 MHz DMSO-c/6) 6 8 69 (d,

J ---- 3.6 Bz, I H), 8.00 - 7 91 (m, IH) 7.88 (d, A - 3 0 Hz, IH), 7 70 (d, J- 9.3 Hz, I H), 7.38 (s,

1H), 7.19 (d, J ----- 1 1 4 Hz, IH), 4.29 (t J ------ 4.2 Hz, 2H), 4.12 (p, J --- 6.6Hz 1 I I) 3 67 (p, J ---- 6.8, 6.1 Hz, 3 Pi), 3.30 (L J ^:::: 4.2 Hz 2H), 2 95 (L J --- 10 7 Hz, 2H), 1.85 (dd, 7 i 2.8, 4.9 Hz, 2H), 1.51 (dtd, J ------ 13 1 , 9.0, 3.8 Hz, 2H), 1 17 id, J- 6.5 Hz, 6H).

Example-56: Synthesis of 5~fiuoro-4-{8~fiuoro-4~isopropy}~3, 4~dihydro~2H~

beftzo[h][J4]oxazin-6-yi N~{l~(piperidin-4-yl)-lH-pyrazoi-4-y})pyrimidin-2-amme.

(Compound 448)

[0378] Step-1: Synthesis of tert-butyi 4-(4-nitro- IH-py razoi- 1 - i) piperidine-1 - carboxy!ate: To a stirred solution of ten-butyl 4-bromopiperidine-l-carboxylate (1000 mg, 8.7 mol, 1 equiv) is DMF (15 ml,), was added Cs ₂ C0 ₃ (5672 mg, 17.4 mmol, 1 equiv) and 4-nitro- IH-pyrazo!e (2693 mg, 10.2 mmol, 1 2 equiv). The resultant reaction mixture was allowed to stir at 120°C for overnight. Progress of the reaction was monitored by TLC and I,CMS. After completion of the reaction diluted with water (100 mL) and extracted with ethyl acetate (150 mi,X 2). Organic layer was washed with water (100 mL) and brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyi 4-(4-mtro-!H- pyrazol-l-yi)piperidine~I~carboxyiate (2500 mg, 96%) as a white solid compound. LCMS: 241 j M-t-But+H]

[0379] Step-2: Synthesis of tert-butyi 4-(4-amino-lH-pyrazol- 1-yl) piperidine- 1- carboxylate: To a stirred solution of tert-butyi 4-(4-nitro-l H-pyra oi-l -yl)piperidine-l- carboxylate (1000 mg, 3.37 mmol, 1 equiv) in ethanol (10 mL), water (3mL), was added iron powder (566 mg, 10 1 1 mmol, 3 equiv) and ammonium chloride (364 mg, 6.74 m ol, 2 equiv).

The resultant reaction mixture was allowed to stir at 90° for lb Progress of the reaction was monitored by TLC and LCMS. Alter completion of the reaction, the mixture was passes through celiie bed and the filtrate was concentrated under reduced pressure to obtain tert- butyl 4-(4- ammo-lB-pyrazol-l -yi) piperidine- 1 -carboxylate (400 mg, 44%) as a dark brown solid compound. LCMS: 267 [M+TT

[0380] Step-3: Synthesis of tert-butyl 4-(4-((5-fluoro-4-(8-fluoro-4-isopropyl-3, 4- d«hyclro-2H-ben*o b][l,4)oxa2m-6-yl)pyrimidm-2-yl)ammo)-ltl-pyra¾oH-yl)piper� �diae-l- carboxylate: To a solution of 6~(2~chloro-5-fluoiOpyrimidm-4-yl)-8-fluoro-4-isopiOpyl-3,4~ dihydro-2H-benzo[b]il,4]oxazine (100 mg, O.Bmmoi, 1 equiv) m dioxane (10 ml,), was added tert- butyl 4~(4~amino-lH-pyrazol~1 ~yl) piperidine- 1 -carboxylate (88 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147mg, 0.47mmol, 1.5 equiv). Hie reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0 012 mmol , 0 04 equiv). The resultant reaction mixture was allowed to stir a t 100 °C for overnight. Progress of the reaction was moni tored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,) Organic layer was washed with water (50 ml,) and brine solution (50 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain ten-butyl 4-(4~((5~fluoro~4~(8~ fluoro-4-isopropyl-:L4~dihydro-2H-benzo[blp ,4]oxazin-0-y})pyrirmdin-2-yi)amino)-IH~pyrazol- l-y!)piperidme-l -carboxylate (20 mg, 12%) as a yellow color solid compound. LCMS: 556 j M H i ^÷

[0381] Step-4: Synthesis of 5-fI«oro-4-(8-fI«oro-4-isopropyl-3, 4-dihydro-2H- ben*o[b][i,4]oxaz«n-6-yl)-N-(l-(piperidin-4-yI)-1H-pyra*ol- 4-yI)pyrimidin-2-amine: tert- buiyl 4-{4-((5~iluoiO-4-(8~iluoiO-4-isopropyl-3,4-dihydro-2B-benzo [b][1 ,4joxaziri 6- yl)pyrimidin-2~yl)amino)-lH-pyrazol~1 -yljpiperid me- 1 -carboxylate (mg, mmol. 1 equiv) was taken in 1 .25 Ml HCI in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for lb. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophilizer to obtain 5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro-2H-benzo[bj[ l,4]oxazin-6-yl)-N-( l ·· (piperidin-4-yl)-] H-pyrazol-4-yl}pyrimidin-2-amine (1 5 mg, 83%) as an orange color solid compound LCMS: 456 [M+B] T (400 MHz, DMSO-z/6) 6 9.53 <s, I B), 8.50 y \. J 3.9 Hz, 1 å-]), 7.88 (s, 111).7.64 (s, 1H), 7.34 (s, 1H), 7.13 (d, J - 11.6 Hz, 1H) 4.44 (it, 7

100,51 Hz, 1H), 4.30(17- 43 Hz, 2H), 4.12 (p, J - 66 Hz, 1H), 3.39 (d, 7- 12.7 Hz, 2H),

3.31 ft.7 43!!v 2H), 3.04 (q, 7- 111 Hz, 2H), 2.14(4,7-11.0, 52 Hz, 4H), 1.18(6,7-6.5

Hz, 6H).

Example-57: Synthesis of 2~(dimethylamino)~ I ~(4-(2-fhioro-4-((5-fhioro-4-(8-fiisoro-4-isopropyl- 3A-dihydro-2ii~benzoih]j l,4]oxazin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin- 1 -yi)ethan- 1 - one. (Compound 449)

[0382] To a solution of 5-fluoro-N-(3-fluoro-4-(piperazin-l-yl)phenyl)-4-(8-fluoro-4 - isopropyl-3,4-dihydro-2H-benzo[b][l ,4]oxazm-0-yl)pyrimidin-2-amme hydrochloride (50 mg,

0.1 mmol, 1 equiv) in DM; (3 mL) was added dimethyl glycine (16 mg, 0.15 mmol, 1.5 equiv) followed by addition of RAT!I (57 mg 0.15 mmol, 1.5 equiv) and DIPEA (33 mg, 025 mmol 2.5 equiv) Resultant mixture was allowed io stir at room temperature for 2 h. Progress of the reaction was monitored by LCMS. After completion of the reaction the reaction mixture was dilated with water (10 mL) and extracted with EtOAe (12 mL). Organic layer was washed with water (5 mL x 6) and brine (5 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound was purified by reverse phase HPLC to afford 2-(dimethyiammo)··] {4-(2-fiuoro-4-((5fiuoro-4-(8fiuoro-4isopropyi-34-dihydro-2H · benzo[b][l,4]oxazin-6- ^y l)pyrmiidin ^~ 2 ^~ yl)amino)phenyl}piperazin-l-yl)ethan-l-one (30 mg) as a pale yellow solid. LCMS: 570 IM HI ft til A MR (400 MHz, DMSO--76) d 9.76 (s, 1H), 8.57 (d, 7= 3.9 Hz, IHj, 7.77 (dd, 7 - 150, 2.5 Hz, IHj, 743 (s, 1H), 7.41 - 7.34 (m, HI), 716 (d, till.8 Hz, ;1H 699 (t, 7 - 94 Hz, Hi;.4.34 - 4.27 (m, 2111.4. Ip (p, ./ 6.7 Hz, IHj, 3.67 (s, 2Hj,

3.60 (t, 7 - 5.0Hz, 211}.3.22 (s, 31 H.2.93 (dt,7- 18.9, 5.3 Hz,8H), 2.25 (s, 61 H.1.19 (d,7- 65 Hz, 6H).

Example-58: Synthesis of 2-(dimethyiamino)~l ~(4~(6~((5~fluoro~4~(8~fluoro~4~isopropyl~3, 4- dihydro~2H-henzofbil4,4)oxazin~6-yI)pyrimidin~2~}9)ammo)pyri din~3-yl)piperidin~l~}9)ethan~l~ one. (Compound 450)

[038:3] Step-1: Synthesis of 2-(dimethyiammo)-l~(4~(6~((S~fiaoro~4~(8~fi«oro~4~

isopropyi-3,4-dihytlro-2H-benzo[b] [l,4]oxazin-6-yi)pyri idin-2-yi)a ino)pyridin~3~ yl }piperidin- l-yi)ethan- ί-one: To a stirred solution of 5~fluoro-4~(8~fluoro-4~isopropy{~3 _> 4- dihydro-2H-benzo[b][l ,4]oxazin-6-yl)~N-(5-{piperidin-4-yI)pyridin-2~yl)pyrimidin- 2-amine (160 mg, 0.31 mmol, 1 equiv) in DMF (3 ml,), was added dimethyl glycine (39 mg, 0.38 mmol, 1.2 equiv), DIPEA (0.2 ml,, 1 24 mmol, 4 equiv) and HATU (212 mg, 0.55 mmol, 1.8 equiv) The reacti on mixture was allowed to stir for 3h at RT. Progress of the reaction was monitored by TLC and 1 CMS After completion of the reaction, the reaction m ixture was diluted wi th water (10 ml,), solid observed was filtered and purified by recrystal fixation with methanol to obtain 2- (dimethyiaraino)-l-(4-(6-((5-f3uoro-4-(8-fluoro-4-jsopropyl- 3,4-dihydro-2H- benzo[b}[l ,4]oxazm-6-y!)pyrimidin-2-yi)araino)pyridin-3-yi)piperidin-l -y])ethan-l-one (100 mg, 65%) as an off white color solid compound LCMS: 552 [M4-H] ^" , (400 MHz,

DMSO-i 6) d 9.92 (s, III), 8.61 (d, ./ === 3 8 Hz, 1H), 8.20 (d, 7 2.5Hx, I B), 8 14 (d, / 8.6 Bx,

I B), 7 61 (dd, ./- 8.6, 2 6 Hz, 1H), 7.47 (s, !H), T i v i d. / 11.8 Hx, I B), 4.52 (d, J === 1 3 0 Hz,

1H) 4.30 (t, J ---- 4.3 1 lx. 2B), 4.16 (p, ./ 6.4 Hz, 1 H) 3.86 (d, J === 14.0 Hz, 2H), 3.39 (d, J ===

12.7 Bz, 2B), 3.1 5 (dd J ------ 1 5.7, 9.1 Hx, 1 H), 2 93 - 2.67 (m, 3H), 2.62 (s, oi l }. 1.90 - 1.81 (m,

2H), 1.64 (t, -/ 12.2Hz, I B), 1 .57 - 1.43 6.5 Hx 6H).

Example-59: Synthesis of2-(dimethylamino)-l-(4-(2-fluoro-4-((5-fluoro-4-(8-fluoro- 4-isopropyl-

3, 4 dih dro~2H-bemo[b // .4(oxazm-6~yl)pynmldin~2~yl)amino)phenyl)pipendm~l~yi)ethan~ l~ one. (Compound 451)

10384] Step-1: Synthesis of 2-(dimethyla ino)-l -{4-(2-ilnoro-4-((5-flnoro-4-(8-iluoro-4- isopropyl-3,4-dihydro-2H-ben2ob][l,4]oxa2m-6-yl)pyrimid«i-2 - yl)amino)phenyl)piperidin-l-yl)ethan-l-one: To a stirred solution of 5-fluoro-N-(3-fluoro-4-

(piperidin-4-yl)phenyl)-4-(8-fluoro-4-isopropyl-3,4-dihyd ro-2H-benzo[b][l,4]oxazin~6- yl)pyrimidin-2-amine (180 mg, 0.34 mmol, 1 equiv) in DMf (3 niL), was added dimethyl glycine (43 mg, 0.41 mmol, 1.2 equiv), DiPEA (0.2 ml,, 1.24 mmol, 4 equiv) and HATH (233 mg, 0.61 mmol, 1.8 equiv). The reaction mixture was allowed to stir for 3h at RT. Progress of die reaction was monitored by TLC and 1 ( ^' MS. After completion of the reaction the reaction mixture was diluted with water (10 ml,), solid observed was filtered and purified by reverse phase HFLC to obtain 2-(dimethylamino)-l-(4-(2-fluoro-4-((5-fluoro-4-(8-fluoro-4- isopropyl- 3,4dibydrO2H~benzo[b][l,4]oxazm-6yl)pyrimidin~2-yl)amino)phe nyl)piperidin-l-yi)ethan-l- one (40 g, 23%) as a yellow color solid compound. LCMS: 569 [M+H]2 ¾NMR (400 MHz, DMSOw/6) d 9.87 (s, 1H), 8.59 (d, J = 3.9 Hz, 1H), 7.76 (dd, ./ 136, 2.1 Hz, 1H),7.45 (s, 1H),

7.40 (dd, ,/= 8.7, 2.2 Hz, 1H), 723 -7.12(m, 2H),450 (d,J= 12.1 Hz, 1H), 4.33-426(m,

211).4.17 (dd, ./ 12.9, 6.5 Hz, 2H), 334 - 3.27 (m, 211).3.07 (dq, ./ 45.8, 11.8, 105 Hz, 4H),

2.61 (d, 7 12.4 Hz, 111) 2.19 (s, Oil) 179 - 1.70 (m, 2H), 161 id;../= 14.4, 7.3 Hz, !H), 1.49

(id, J ----- 125,43 Hz, ill).1.18 (d, 7 6.5 Hz 6H).

Example-60: Synthesis of 4~(4~((5~fliioro~4~(8~fkioro~4~isopropyl~S,4-dihydro~2H~

benzo[b][l,4]oxazin-6-ylJp)mmidin-2-y])amno)~lH-pyrazol-l -yi)cyclohexan-l-ol. (Compound 452)

78 [0385] Step-J : Synthesis of 4-oxocydohexyi methanesulfonate: To a stirred solution of 4 hydroxycyclohexan-1 -one ( 1000 mg, 8.7 mmol, 1 equiv) in DCM ( 15 mL), was added TEA (1 .2 niL, 8.7mmol, 1 equiv). Cool the reaction mixture to 0°C, followed by the addition of mesyi chloride (0.7 mL, 8.7 mmol, 1 equiv). Raise the temp. To RT and the resultant reaction mixture was allowed to stir for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 mid and extracted with DCM ( 100 mL x 2). Organic layer was washed with water ( 100 mL) and brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 4- oxocyclohexyl methanesulfonate (1300 mg, 77%) as a yellow oil compound.

[0386] Step-2: Synthesis of 4-(4~nitro-lH-pyrazol-l-yl) cyclohexan-l-one: To a stirred solution of 4-oxocyclohexyl methanesulfonate (600 mg, 5.3 m ol, 1 equiv) in DMF (10 mL), was added K -C O (1463 mg, I0 6mmol, 2 equiv) and 4-nitro-l H-pyrazole (1223 mg, 6 37 mol 1 2 equiv). The resultant reaction mixture was allowed to stir at 80°C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 mL) and extracted with EtOAc (100 ml, 2) Organic layer was washed with water (100 ml,) and brine solution (100 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain 4-(4-nitro-lH-pyraz:ol~l~yl)eyclohexan-l -one (400 mg, 36%) as a brown solid compound. LCMS: 210 [M+H]

[0387] Step-3: Synthesis of 4-(4-mtro-lB-pyrazol-l-yi) cyciohexan-l-ol: To a stirred solution of 4-(4-nitro-IH-pyrazoftl-yl) cyclohexan-l -one (400 mg, 1 .91 mmol, 1 equiv) in methanol (10 mL), was added NaBI-ft (145 mg, 3.82 mmol, 2 equiv) at 0°C. Raise the temp to RT the resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, solvent was removed under reduced pressure, residue obtain was diluted with water (50 mL) and extracted with ethyl acetate (1 50 rnL) Organic layer was washed with water (50 ml,) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, winch was purified by normal phase Combi flash to obtain 4- (4-nitro-l H-pyrazoi-I-yl)cyciohexan-1 -ol (400 mg 87%) as an off white solid compound.

LCMS: 212 [M÷H] ⁺ [0388] Step-4: Synthesis of 4-(4-ammo-lH-pyrazoi-l-yI) cydohexan-l-ol: To a stirred solution of 4-(4-mtro-iH-pyfazoi-l -yl)cyciohexan-l -ol (300 nig, 1.42 mmol, 1 equiv) in ethanol (8 mL), water (2 ml,), was added iron powder (239 mg, 4.26 mmol, 3 equiv) and ammonium chloride ( 1 54 mg, 2.84 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for Hi. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain 4-(4-amino- l H~pyrazol-l -yl) eyclohexan- 1 -ol (350 mg, 78%) as a dark brown solid. LCMS: 182 [M+H]

[0389] Step-S: Synthesis of 4-(4-( ( 5-fluoro-4-( 8-fluoro-4-isopropy!-3,4-dihydro-2H~ henzo[b][l,4[oxazin-6-yl)pyrimidin-2-yl)amino)-lH~pyrazol-l- yl)cyclohexan-l-ol: To a solution of 6 (2 Ch!oro- 5-fluoropyrmiidin~4~yl)-8-fluoro-4-isopropyl-3,4 dihydrO 2H- benzo[bl[l,4]oxazme (100 mg, 0.3mmol . I equiv) m dioxane (10 ml,), was added 4-(4-amino- IH-py razol-1 - I)cyclohexan~ 1 -ol (60 mg, 0.33 mmol, 1 1 equiv) and cesium carbonate (147mg, 0.47mmoi, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 equiv) and BINAP (8 g, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 ml ,) and extracted with ethyl acetate (1 00 ml ,). Organic layer was washed with water (50 mL) and brine solution (50 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reciysta!hzaiion with methanol to obtain 4-(4-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4- dihydro--2!:I-benzo[bj [ ! ,4]oxazin--6--yi)pyrimidin~-2~-y!)ammo)~-lH--pyrazoi-1 -yi)cyc!ohexan-d--ol (10 mg, 7%) as a yellow eolor solid compound. LCMS: 471 j M H i ’HNMR (400 MHz. DMSO-A6) o 9 48 (s, 1 1 1 ) 8 48 (d. 7 3.9 Hz, i l l ). 7.88 is, i l l ). 7.53 (s, 1 H). 7.35(s, I B), 7 13 i d 4 1 1.6 Hz, I B), 4 65 (d, ,7 - 4.4 Bz, I B), 4 30 it, ,/ - 4.3 Hz, 2B), 4 18 - 4.00 (m 2H),3.48

(td, _· / 10.2, 9 6, 4.4 Hz, 1H), 3.39 (d, J === 12.7 Hz, 2H), 1 .95 (di, J --- 25.3, 7.8 Bz, 4H), 1.75 ltd,

7 14.3, 1 3.7 7.0 Bz, 2H), b40 - 1.25 (m, 2B), 1 .18 (d, J - 6.5 Bz, 6B).

Example-61 : Synthesis qf4~(6~((5~fluoro~4~(8~fluoro~4~isopropy]~3,4~dihydro~2H~

benzojh) [ l,4]oxazin~6~y!)pyrimidin~2~y!}amino)pyridin~3-yi)~N)N~dimei hyl iperazine~l~ carboxamide (Compound 453)

T O O

[0390] Step-1 : Synthesis tert-butyl 4-(6-nitropyridin-3-yl) piperazine-l-carboxylate: To a stirred solution of 5~bromo~2mitropyridme (1500 mg, 7.4 mmol, 1 equiv) in DMSO (1 0 ml,). _, was added k ·( 0. (1 532 mg, 11 1 mmol, 1 equiv), water (5 ml,) and tert-butyl piperazine-· 1- earboxylate (2072 mg, 11.1 mmol, 1 equiv). The resultant reaction mixture was allowed to stir at 100°C for overnight. Progress of the reaetion was monitored by 1 .CMS After completion of the reaction, diluted with water ( 100 niL) solid observed was filtered and dried under vacuum to obtain tert-butyl 4-(0-nitropyridm-3-yl)piperazi«e-] -carboxylate (1800 mg, 79%) as a yellow solid compound. LCMS: 309 [Mt H] ^’

[0391] Step-2: Synthesis of tert- butyl 4-(6-aminopyridin-3-yI) piperazlne-l-carboxylate:

To a stirred solution of tert-butyl 4-(0-nitropyridm-3-yl}piperazi«e-] -carboxylate (500 mg, 1 6 mmol, 1 equiv) in ethanol (8 ml), water (2 niL), was added iron powder (269 mg 4.8 mmol, 3 equiv) and ammonium chloride (173 mg, 3 2 mmol, 2 eq iv). The resultant reaction mixture was allowed to stir at 90° for I h Progress of the reaction HS monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through cebte bed and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(6-aminopyridin~3~yl) piperazine-1 - carboxylate (300 mg, 67%) as a dark brown solid compound. LCMS: 279 [M+H]

[0392] Step-3: Synthesis of tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-lsopropyl-3,4- dihyclro-2H-ben*o[b][l,4]oxa2m-6-yl)pyrimidm-2-yl)ammo)pyrid m-3-yi)piperazine-l- carboxylate; To a solution of 6~(2-chioro-5-iluoropyrimidm-4-yl)-8-fluoro-4-isopropyl-3,4~ dihydro-2H-benzo[b]il,4]oxazine (100 mg, 0.3 mmol, 1 equiv) m dioxane (10 ml,), was added tert-butyl 4~(6-ammopyridin-3-yl) piperazine-1 -carboxylate (97 mg, 0.33 m ol, 1.1 equiv) and cesium carbonate ( 147 mg, 0.47 mmol, 1 5 squiv). The reaction mixture was degassed with mitogen gas for 30 min. followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 eqiuv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mi . ·. Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain tert-butyi 4~(6-((5-f!uoro-4-(8- fluoro-4-isopropyl-3,4-dihydro-2H-benzoibl[l,4]oxazin-6-yl)p yrimidin ^~ 2 ^~ yl)ammo)pyridin-3- yftpiperazine-l -carboxy!ate ( 100 mg, 57%) as a yellow color solid compound LCMS: 568 [M+H]

[0393] Step-4: Synthesis of 5-fl«oro-4~(8-fl«oro-4-isopropyl-3, 4-tllhydro-2H~ benzo[b][l,4]oxazin~6~yI)-N-{5-{piperazin~l-yI)pyridin-2~yI) pyrimidin~2~amine: ten-butyl 4- (6-((5-fluoro-4-(8-fluoro-4-isopropyl-3, _' ^; tidihydro-2H-benzo[bj[l .4]oxazin-6-yl)pyrimidin-2- yl)ammo)pyndm-3-yi)piperazine-l -carboxylate (100 mg, 0 17 mmol , 1 equiv) was taken in 1 25 M HC1 in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for 1 h. Progress of the reaction was monitored by I, CMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under iyophilizer to obtain 5-fluoro- 4~{8~-fiuoro~4~isopropy!~3, 4-dihyclro-2H-ben o[b][l ,4]oxazin-6-yl)-N-(5-(piperazin-l- yl)pyridm-2-yi)pyrimidm-2-amme (80 mg. 90%) as a brown solid compound. LCMS: 468

[M+H]

[0394] Step-5: Synthesis of 4-(6-((5-fiuoro-4-(8-fiuoro-4-isopropyl-3,4-d«hydr -2H- benzo[hj [l,4]oxazln-6-yI)pyrlmldln-2-yi)anilno)pyridin-3-yi)-N,N dlmethyiplperazlne-I- carboxamide: To a stirred solution of 5-fluoro-4-(8~fluoro-4-isopropyl-3, 4-dihydro-2H- benzo[b][ l ,4]oxazin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin- 2-amme (60 mg. 0.11 mmol, 1 eqiuv) in DCM (3 ml,), was added DIPEA (0.05 ml,, 0 33 mmol. 3 equiv). Cool the temp to 0 °C, followed by the addition of dimethylcarhamie chloride (0.01 L 0.17 mmol, 1 .5 equiv). Raise the temp to RT and the reaction mixture was allowed to shr for 2h at R I Progress of the reaction was monitored by LCMS Alter completion of the reaction the reaction mixture was diluted with DCM (30 mL) and washed with water (30 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain 4-(6-((5-fiuoro-4-(8-fiuoro-4-isopropyl-3,4- dihydro-2H-benzo[b] ] ,4]oxazm-6-yi}pyrimiclin-2-yl)amino}pyridin~3-yl)~N,N- dimethyipiperaxme-i -carboxamide (12 mg, 19%) as a yellow color solid compound. LCiVISs 539 [MeH] ⁺ ; 1HNMR (400 MHz, MSO-hc; d 9.70 (s, 1H), 8.56 (d, ./ = 4 0 Hz, l i b. 8.07 - 8.00 (m, 2H), 7.46 (s,Hl), 7.41 (dd, 7 9.2, 3.0 Hz, H i ) 7 17 (d, 7 1 1.8 Hz, HI), 4.30 (t, J

4.5 Hz, 2H), 4.14 (p, 7 6.7 Hz, IHj, 3.27 (q, J = 6 6, 5.1 Hz, 6H), 3.11 (t, 7 5.0 Hz, 4H), 2 78

(s, 6H), 1 19 (d, J- 6.5 Hz, 6H).

Example-62 : Synthesis of 4~(6~((5~fluoro~4~(8~fluoro~4~isoprofjyl~3, 4~dihydro~2H~

bemofbjfJ joxazin-6-yI)pyrimdin-2-yI)ammo)py’fidi?i~3~yI)-]Sf N~dmethyIpiperidme~!~ carboxamide. (Compound 454)

(0395| Step- 1 : Synthesis of 4-(6-((5-iluorG-4-(8-iluorG-4-isopropy1-3,4-dihydro-2B- benzo(b][l,4)oxazin-6-yl)pyrimid«n-2-yl)am«no)pyridm-3-yl) -N,N-d iethyIpiperidine-i- carboxamide: To a stirred solution of 5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro-2H- benzo[bl[l,4]oxazin-6-yl)-M-(5-(piperazin-l-yl)pyridm-2-yl)p yrimiclin-2-amine (60 mg, 0.1 1 mmol, 1 equiv) in DCM (3 niL), was added DIPEA (0.05 mL, 0.33 mmol, 3 equiv). Cool the temp to 0 °C, followed by the addition of dimethylcarbamic chloride (0.01 mL, 0.17 mmol, 1.5 equiv). Raise the temp to RT and the reaction mixture was allowed to stir for 2h at RT. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with DCM (30 mL) and washed with water (30 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4- dihydro-2H-benzo[b][l,4]oxazin-0-yi)pyrimidin-2-y ^j )ammo)pyridin ^~ 3-yi) ^~ N.N- dimethylpiperidine-1 -carboxamide (35 mg, 5556) as a yellow color solid compound. LCMS: 538 [M+H] d ¹ HNMR (400 MHz, DMSO-76) d 9 91 (s, HI), 8 61 (d, 7 4.0 Hz, 1H), 8.20 (d, 7

2.5Hz, 1 1 1 }. 8.12 (d, J = 8.6 Hz, 1H), 7.63 (dd, ./ 8 7, 2.6 Hz, 1 1 1). 7.48 (s, 1 1 1 }. 7.19 (d, J

28 t 1 1.5 Hz, 1 H),4.30 (t, J ^::: 4.2 Hz, 2H) 4.16 (p, 7 - 6 7 Hz, 1H), 3.66 (d, ,7 - 12 7 Hz, 2H), 3.30 (d, J- 4.8 Hz, 2H), 2 85 - 2.67 (m, 9H), 1 77 (del, 7 13.0, 4.0 Hz, 2H), 1 60 (qd, J ^:::: 12.5, 3 9

Hz, 2H), 1.19 (d, J= 6.5 Hz, 6H).

Example-63: Synthesis of 2-(dimethylammo)- ! (7f(5~j1uoro~4f8~j1uoro~4~isopropyl~3, 4- dihydro~2H~henzo[bj[l,4]oxazin~6~yiJpyrimidin~2~yl)amino)~3 ~dihydroisoquinohn~2(lH)~ yi)ethan~l~one. (Compound 455)

[0396] Step-1: Synthesis of 2-(dίmethylamino)-l~(7~((5~flu©r<>4 ·(8 ·flu©r<>4 ·ίsopr©p l· 3 4~dίh dro-2H-beRzo[b] l,4]© azίn-6- l)pyrίmidίn-2- ^}amίno)-3,4~dίh dr©i8©qMinoίm- 2(lH)-yl)ethan-l-one: To a stirred solution ofN-(5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydfo- 2H-benzo[ b]| l ,4]oxazin-6-yl)pyri idin-2-y!)-l,2,3,4-tetfahydroisoquxnolin-7-amine (80 g,

0 16 mol, I equiv) in DMF (2 nil,), was added dimethyiglyeine (21 mg, 0 2 mmol, 1 equiv), ET _¾ N (0.02 ml .. 0.2 mmol, 1 .2 equiv), HOBt (27 mg, 0 2 mmol, 1.2 equiv) and EDCYHCi (38 mg, 0.2 mmol, 1 2 equiv). Allow to stir the mixture for overnight at RT. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (10 ml,) and extracted with ethyl acetate (30 ml, >< 2). Organic layer was washed with water (50 ml,), brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain 2-(dimethyianiino)-l-(7-((5-fluoro-4-(8-fluoro-4- isopiOpyl-3,4-dihydro-2H-benzo bl l,4]oxazin-6-yl)pyrimidin-2-yi)amino}-3,4

dihydroisoquinol in~2(l H)-y i)ethan- 1 -one (15mg, 17%) as a yellow color solid compound.

LCMS: 523 [MHi] ⁺ ; ⁱ HNME (400 MHz, DMSO-i 6) d 9.64 (d, J = 2.9 Hz, 1H), 8.56 (d, ./ 4.0 Hz, IH), 7.62 - 7.53 (m, 2H},7 41 (s, 1 H), 7 20 - 7.04 (m, 2H), 4.62 (d, 7 59.5 Hz, 2H),

4.30 (t, / 4.3 Hz, 211), 4 14 (p, 7 7.0 Hz,!H), 3.70 (dt, J = 34.7, 5.8 Hz, 2H), 3 30 (d, J= 4.8

Hz, 2H), 3.15 (s, 2H), 2.78 (dt, 7 39.7, 5.5 Hz, 21 1} 2.20 (s, Oi l) 1 19 (d, J= 6.5 Hz, 6H).

Example-64: Synthesis of 2-(dimethyiamino)-l~{6~((5~fluorO~4~(8~fluoro~4~isopropyl~3, 4- dihydro~2H~bemofb][l,4]oxaåin~6~yI)pyrifnidin~2~yl)amino)~3 ,4~dihydroisoquinoHn~2(lH)~ yl ethan-l-one. (Compound 456)

[0397] To a stirred solution of N-(5-†1uoro-4-{8-†1uoro-4-isopropyl-3 4-dihydro-2H- benzo[b][\l ,4]oxazm-6-y ^j )pyrimidin-2-yl)~l,2,3,4-tetiahydroisoquino3in-6-amine (80 mg, 0 16 mmol, 1 equiv) in DMF (2 mL), was added dimethylgiycine (21 nig, 0 2 m ol, 1 equiv), EΊ2N (0 02 mL 0.2 mmol, 1.2 equiv) HOBt (27 mg, 0 2 mmol, 1 2 equiv) and EDC.HC1 (38 mg 0.2 mmol, 1 .2 equiv). Allow to stir the mixture for overnight at RT Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (10 L) and extracted with ethyl acetate (30 mL x 2) Organic layer was washed with water (50 mL), hrine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain 2-(dimethyiamino)-l -(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4- dihydro-2H-benzo[b][1 ,4]oxazm-6-yi)pyrimiclin-2-yi)amino)-3,4-dihydroisoqumolin-2 (lH)- yl)ethan-l-one (20 mg, 23%) as a yellow color solid compound. LCMS: 523 [M+H] ft ¾NMR (400 MHz, DMSOM6) d 9.63 (s, 1H), 8.56 (d, ./ = 3 9 Hz, 1H), 7.64 - 7.46 (m, 2H), 7.40 (s,lH), 7.21 - 7 12 (m, HI), 7.07 (d, 7 8.2 Hz, 1H), 4.65 (d, J = 64 5 Hz, 2H), 4.30 (t, 7 4.3 Hz, 2H),4.12 (dt, 7 = 1 1.3, 6.3 Hz, 1 H), 3.70 (dt, J = 32.6, 5 8 Hz, 2H), 3.30 (d, J = 4 8 Hz, 2H), 3.16 (s, 2H), 2 75 (dt, J = 39.4, 5 5 Hz, 2H), 2.19 (d, = 6 3 Hz, til l ;. 1 .19 (d, J = 6.5 Hz, 6H).

Example-65 : Synthesis of (2~fluoro~4~((5~fluoro~4~(8~fluoro~4~isopropyI~3, 4~dihydro~2H~ benzofh] jl ]oxazin 6 yl)pyrimidin 2-yl _j aiMrK)phenyl)(morpholino}meihanone. (Compound 457)

Step-2

[0398] Step-1: Synthesis of (4-amino-2-fluorophenyl) (morphoiino) methanone: To a stirred solution of 4-ammo-2-fluorobenzoic acid (1000 mg, 6.45 mmol, I equiv) in DMF (5 mL), was added morpholine (0 8 mL, 9.67 m ol, 1.5 equiv), DIPEA (4 5 mL, 25.8 mmol, 4 equiv) and HAΊΌ (4408 mg, 1 1.6 mmol 1.8 equiv) The reaction mixture was allowed to stir for 3h at RT. Progress of the reaction was monitored by TLC and LC MS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL * 3). Organic layer was washed with water (100 mL), brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (4-amino-2-fluorophenyl)(morpholino)methanone (1200 mg, 83%) as a brown color viscous compound. LCMS: 225 [M÷H]

[0399] Step-2; Synthesis of (2-fluoro-4-((S-fluoro-4-(8-fluoro-4-isopropyl-3 _> 4~tlIhydro- 2H~benzo{b| |I,4joxa*In~6-yI)pyrimidia~2~y!)amino)pheayl)(morpholino)met hanone; To a solution of 6 (2 Chloro- 5-fluoropyriniidin~4~yi)-8-fluoro-4-isopropyi-3,4 dihydrO 2H- benzo[b][l,4]oxazme (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 mL), was added (4-amino-2~ fluorophenyj)(morpholino)raethanone (74 mg, 0 33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0 47 mmol, 1.5 equiv) The reaction mixture was degassed with nitrogen gas for 30 m ., followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 ml) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 mil,) and brine solution (50 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain (2-fiuoro-4-((5-iluoro-4-(8-iluoro-4-isopropyl- 3,4~dihydro-2H-benzo[b][l,4]oxazin~6~yl)pyriimdin-2-yl)amino )phenyj)(morpholino)methanone (50 mg, 32%) as a yellow color solid compound. LCMS; 514 j M H i ONMR (400 foi l/. DMSO-A6) o 10 18 is, I B), 8 65 i d. / 3.8 Hz, I B , 7.96 (dd, J - 13.2 2.0 Hz,IH), 7.49 (dd, J ----- 8.3 2.0 Hz, I B), 7.43 (s, ! H), 7.32 (t, J- 8.2 Hz, I I I) 7 17 id, J- 1 1.5 Bz, I B), 4 30(1, ./ - 4.3 Bz, 21 1) 4.16 {h, ./ 6.6 Bz, i ll), 3.58 - 3 52 im, 8H), 3.29 (d, ,/ - 7.8 Hz, 211) 1.18 (d, J - 6 5 Hz, 6H).

Example-66: Synthesis of {2~ftiioro-4~{{5~ftiioro~4~{8~fliioro~4~isopropyl~3 -dihydro-2H~ benzofhfjd,4}oxazin-0-y})pyrimidm-2-y!)amino)phenyi)(4-hydro xypiperidin-l-yl)meihcmone. (Compound 458} ifcsO

[0400] Step-1 : Synthesis of (4-amino-2-fluorophenyI) (4-hydroxypiperiilin-l-yI) methanone: To a stirred solution of 4--amino-2-iluorobenzoic acid (1000 nig, 6 45 mmol 1 equiv) in DMF (5 mL), was added piperidm-4-ol (967 nig, 9.67 mmol, 1.5 equiv), DIPEA (4.5 mL, 25.8 mmol, 4 equiv) and HATH (4408 mg, 11.6 mmol, 1.8 equiv). The reaction mixture was allowed to stir for 3h at RT. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with wuter (50 mL) and extracted with ethyl acetate (100 mL x 3). Organic layer was washed with water ( 100 mL), brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (4-amino-2-fiuorophenyl) (44iydroxypipendiml -y!) methanone (1200 mg, 78%) as a brown color viscous compound. LCMS: 239 [M+H]

[0401] Step-2: Synthesis of (2-fluoro-4-((S-fluoro-4-(8-fluoro-4-isopropyl-3 _> 4~tlihydro- 2H~benzo{b| |T,4joxa*ln~6-yl)pyrimidia~2~y!)amiao)pheayl)(4-hydroxypiper idm-l- yl)methanone: To a solution of 6~(2~chloro-5-fluoropyrimidin-4-yi)-8-fluoro-4-isopropyi-3,4 ~ dihydro-2H-benzo[b] [ 1 ,4]oxazine (100 mg, 0.3 mmol, 1 equiv) m dioxane (10 ml,), was added (4~amino-2-fluorophenyl)(4 hydroxypiperidimAyl)methanone (79 mg, 0.33 mmol, 1 .1 equiv) and cesium carbonate (147 mg, 0 47 mmol , 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0 012 mmol , 0 04 equiv). The resultant reaction mixture was allowed to stir a t 100 °C for overnight. Progress of the reaction was moni tored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, Much was purified by normal phase Combi flash to obtain (2-fluoro-4-((5-fluoro-4-(8- fluoro-4-isopropyl-3,4-dihydro-2H-benzo b|[l,4]oxazin-6-yl)pyiirnidin-2-yl)amino)phenyl)(4- hydroxypiperidin-I-yl)methanone (40 mg, 25%) as a pale yellow color solid compound LCMS: 528 [M-ί-H] ⁺ ; 1HNMR (400 MHz, DMSO-r/6) d 10.15 (s, 1H), 8.65 (d, J --- 3 9 Hz, 1H), 7.94 (dd, ./ 13.1 , 2.0 Hz, I B), 7.51 - 7.41 (m, 21 1} 7 28 it, J ------ 8.2 Hz, I B), 1 1.6 Hz, I B),

4.30 (t, J = 4.3 Hz, 2H), 4.16(h, J= 6.6 Hz, I B), 4 03 (d, ./ = 12.9 Hz, 111), 3.73 (dp, J = 8.6, 4.2, 3.7 Hz, 2H), 3 32 (t, J ------ 4 3 Hz, 2H),3.21 (t, 7 - 1 1.3 Hz, I B), 3 09 0 ./ P .6 Hz. I B), 1 77 (s,

HI), 1.68 (d, ./ = 7.3 Hz, 111), 1.35 (dt, .7=24 5, 10.6 Hz, 2H), 1.18 (d, J = 6.5 Hz, 6H).

Example-67: Synthesis of {6~{{5~fl oro~4~{8~fluoro~4~isopropyi~3, 4-dihydro~2H~

benzo{b][l,4]oxazm~6~yl)pynffiidm~2~yl)amino)pyridin-3-yl ){morpholmo)rnethanone.

(Compound 459)

[0402] Step-1: Synthesis of (6-aminopyridin~3~yI) (morpholine) methanone: To a stirred solution of 6-arninonicotinie acid (1000 mg, 7 24 mmol, 1 equiv) in DMF (5 mL), was added morpholine (0.8 ml,, 9.65 mmol, 1.5 equiv),, DIPEA (5 mL, 29 mmol, 4 equiv) and HATH (4940 mg, 13 mmol, 1.8 equiv). The reaction mixture was allowed to stir for 3h at RT Progress of the reaction was monitored by TLC arm LCMS After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 ml, 3) Organic layer was washed with water (100 mL), brine solution (1 00 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (6-aminopyridin- 3-yl) (morphohno) methanone (1200 mg, 80%) as a brown color viscous compound. LCMS:

208 [M÷H] ⁺

[0403] Step-2:: Synthesis of (6~((5~flu©ro~4-(8~flu©ro~4~isopr©pyl-3,4-dihydro-2II- benzofb][l,4]oxazm-6-yl)pynmidin-2-yi)amino)pyridin-3-yl)(mo rpholmo)inethaiiote: To a solution of 6-(2-chloro-5-tluoropyrimidin-4-yl)-8-iluoro-4-isopropyl-3,4 -dihydro-2H- benzo[b] [ 1 ,4] oxazine (100 rug, 0.3 mmol, 1 equiv) in dioxane (10 mL), was added (6- anunopyridin-3-yl)(rnorpholino)methanone (68 mg, 0 33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1 .5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and 1 ( ^' MS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 niL) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain (6-((5-fluoro-4-(8-fluoro-4- isopropyj-3,4-dihydro-2H-ben o[b][l,4]oxazin-6-yl)pyrimidin-2-yi)amino)pyridin-3- yl)(morphoiino)methanone ( 40 g, 26%) as an off white color solid compound LCMS: 497 [M+H] ^÷ : ^s HNMS (400 MHz, DMSOM6) d 10.34 (s. 1H), 8.67 (d, 7= 3 9 Hz, l i ft. 8.38 (s, i l l ;. 8.28 (d, 7 8 7Hz, 1H), 7.85 - 7 78 (m, i l }. 7.-48 (s, 1H), 7.20 (d, 7 = i 1 7 Hz, !H), 4.31 (t, J =

4.3 Hz, 21 1) 4 17 (p, 7 8 2. 7.5 Hz, 1H), 3.62 (d, J= 4.7 Hz, 4H), 3.54 (s, 4H), 3.30 (d, J = 4.8 Hz, 2H) 1.23 (s, 6H).

[0404] Step-3: Synthesis of (6-((5-fl«oro-4-(8-fl«oro-4-isopropyl-3,4-dihydro-2H- benzo[b][i,4]oxazin-6-yI)pyrimidin-2-yI)amino)pyridin-3-yl)( morphoi ^j no)raethanonet (6-

((5-fluoro-4-(8-fluoro-4-isopropyI-3, 4-dihydro- 2H-benzo[b] [1 ,4]oxazin-6-yl)pyrimidin-2- yl)ammo)pyndm-3~yi)(Morphoiiuoi methanone (10 mg. 0.02 mmol, 1 equiv) was taken in 1 25 M HQ m ethanol (5 mL) and the resultant reaction mixture was allowed to stir at RT for !h. Solvent was removed under reduced pressure and the residue was dried under lyophilizer to obtain (6-((5-t1uoro-4-(8-†1uoro-4-isopropyl-3,4-dihydro-2H-benzo [b][l ,4]oxazm-6- yl)pyrirmdin-2-yl)amiiio)pyridin-3-y!)(moipholmo)rnethanone ( HC1 salt) (5 g, 45%) as a yellow color solid compound. LCMS: 497 [M+H] ; ¾NMR (400 MHz, DMSO--76) d 10.89 (s, 1H), 8.72 (d, J - 3.8 Hz, I I I ;. 8.41 (d. 7 2 21 b. i l l }. 8.1 5 (d, - 8.7 Hz, Ί H), 7.95 (dd, 7 - 8.6,

2.3 Hz, i l l ) 7.46 (s, 1 H), 7.25 - 7 17 (m, Ί H), 4.31(1, 7 - 4 2 Hz, 2H), 4.17 (p, 7 - 6 4 Hz, 1 1 1 ). 3 62 (s, 4H), 3 54 (s, il l) 3 31 ft, - 4.2 Hz, 2H), D id 7 6.5 Hz, 6H).

Example-68: Synthesis of (6~((5~fluoro~4~(8~fluoro~4~isopropyl~3.4-dihydro-2H~

benzo[h][l,4]oxazin-6-yl)pyrimidin-2-yl)amino)pyridin-3-y ])(4~hydroxypiperidin~l~

yljmethamne. (Compound 460)

189

[0405] Step-1 : Synthesis of (6-aminopyridm-3-yl) (4-hydroxypiperidin-l -yl) methanone:

To a stirred solution of 6-a mo coimic acid (1000 mg, 7.24 mmol, 1 equiv) in DMF (5 mL), was added piperidin-4-ol (975 mg, 9.65 mmol, 1 .5 equiv), DIPEA (5 mL, 29 mmol, 4 equiv) and HATH (4940 mg, 13 mmol, 1 .8 equiv). The reaction mixture was allowed to stir for 3 h at RT. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL ^c 3)

Organic layer was washed with -water ( 100 mL), brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (6- aminopyridin-3-yl)(4-hydroxypiperidin-l -yl)methanone (1200 mg, 75%) as a brown color viscous compound. I, CMS; 222 [M+H]

[0406] Step-2;; Synthesis of (6-((S-fluoro-4-(S-fluoro-4-isopropyl-3, 4-dihydro- 2H- henzo[b][i,4|oxazin-6-yl)pyrimitlin-2-yl)amino)pyridia-3-yl) (4-hydroxypiperidin~l~ yl)methanone: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yI)-8-f1uoro-4-isopropyI-3,4 ~ dihydro-2H-benzo[b] [ 1 ,4]oxazine (100 mg, 0 3 mmol, 1 equiv) m dioxane (10 ml,), was added

(6~aminopyridm 3~yi)(4 hydroxypiperidin~l~yl)methanone (73 mg, 0 33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 mmol. 0 04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction diluted with water (30 mL) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain (6-((5-fluoro-4-(8-fluoro-4- isopropyi 3 4-dihydro-2H--benzoiblil,4]oxazin-6-yl)pyrimidin-2-yl)ammo)p yndin--3--yl)(4-· hydroxypiperidin-l-y!)methanone (50 mg 32%) as a yellow color solid compound LCMS; 51 1

[M+Hj 7 'HNMR (400 MHz, DMSO-46) 6 1 0.31 (s, 1H),8.64 (d, J --- 3.8 Hz, 1H) 8.33 (d, J 2.4 Hz, J å-]), 8.25 (d, / 8.7 Bz, IH), 7.76 idd 7 8.4, 2.5 Hz, 1H), 7.46 (s, 1H), 7.19 (d, J ---

11 5 Hz, I l l s. 4.80 (d, J - 3.9Bz, Ί H), 4.29 (t, - 4.2 Hz, 2H), 4.1 5(p, J - 7 1 Hz, IH), 3.74 (di, ./ 0 9. 5.3 Hz, 2H), 3.30 (1 7 - 4.2 Hz, 2= I ) 3 21 (id, 7 - 10.2, 9.4, 5.3 Hz,3H), 1.76 (d, 7 - 11 9

Hz, 2H), 1.45 - 1.30 (m, 2H), 1 18 (d, 7 6.5 Hz, 6H)

Example-69: Symthesis ofN~(4~((4-eihyipiperazin~l~yi) methyl)-3~fluorophenyl)~5~fhioro~4~(8~ fluoro~4~isopropyl~3, 4~dihydro~2H~benzo[bj i J4joxazm-6-yl)pynmidin-2~amine. (Compound 461)

[0407] Step-1: Synthesis of l-(bromomethy!)-2-fluoro-4-nitrobenzeae: To a stirred solution of 2-fluoro-Hmeibyl-4-mtrobenzene (1000 mg, 6.4 mmol, 1 equiv) in CCfi (1 5 ml,), was added NBS (1139 mg, 6.4 mmol, 1 equiv) and AIBN (210 mg, 1.28 mmol, 0 2 equiv). The resultant reaction mixture was allowed to stir at 80°C for overnight. Progress of the reaction was monitored by I, CMS and TLC. After completion of the reaction, diluted with water (50 ml,), and extracted with ethyl acetate (150 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain l -(bromomethyl)-2-fluoro-4-nitrobenzene (400 mg, 27%) as an off white solid compound.

[04081 Step-2: Synthesis of 1 -ethy!~4~( 2-f! uoro-4-nitrobeazyl) piperazine:: To a stirred solution of 1 -{hromomethy I)-2-f! uoro-4-nitrobenzene (300 mg, 1 .29 mmol, 1 equiv) in ACN (5 ml,), was added 1 -ethyl piperazine (442 mg. 3.87 m ol, 3 equiv). The resultant reaction mixture was allowed to sti at RT for lb Progress of the reaction was monitored by LCMS and NMR.

After completion of the reaction, diluted with water (30 ml,), and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain l-ethyl-4-(2-fluoro-4-nitrobenzyl) piperazine (300 mg, 87%) as a yellow' oily compound. LCMS: 268 [MHl] ^÷

[0409] Step-3: Synthesis of 4-((4-etfaylpiperazin- I~y!) metfayl)-3-fluor<>aiiiline: To a stirred solution of l~ethyi-4-(2-fluoro-4-nitrobenzyl)piperazine (300 mg, 1.12 mmol, 1 equiv) in ethanol (5 mL), water (1 mL), was added iron powder (189 mg, 3 37 mmol, 3 equiv) and ammonium chloride (121 mg, 2.24 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for I h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through cehte bed and the filtrate was concentrated under reduced pressure to obtain 4-((4-ethylpiperazin~l-yl) methyi)-3-fluoroaniiine (200 mg, 75%) as a dark brown solid compound. LCMS: 238 [M+H]

[0410] Step-4: Synthesis of N~(4~((4-ethylpiperazm-l-yl) methyl)~3~fluoropfaenyl)-5- fluoro-4-(8-fluoro-4-«sopiOpy!-3, 4-dihydro-2H-benzo[b]jl,4[oxazm-6-yl)pyrimitlln~2” amine: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3,4 -dihydro- 2H~benzo[b][l ,4]oxazlne (100 mg, 0 3 mmol, 1 equiv) in dioxane (10 ml..), was added 4-((4- ethy!piperazin-l -yi)methyl)-3-fluoroaniline (78 mg, 0.33 mmol, 1 1 equiv) and cesium carbonate (147 mg, 0 47 mmol , 1.5 equiv). The reaction mixture w¾s degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg. 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction diluted with water (30 mL) and extracted with ethyl acetate (100 L). Organic layer was washed with water (50 mL) and brine solution (50 mb) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reorystalhzation with methanol to obtain N-(4-((4-ethylpiperazin-l ~ yi}methyl)--3--fiaorophetyi)-5-i!uoro--4-(8-iluoro--4-isopro pyi-3,4--dihydn>2H- benzo[b]jd ,4joxazin--6--y!}pyrlrmdin--2--amine (40 mg, 25%) as a yellow color solid compound. LCMS: 527 [M÷H] ⁺ ; (400 MI L. DMSOM6) d 9.93 (s, IH) 8.61 (d, J === 4 0 Hz, IH),

7 82 - 7.73 (m,lH), 7.49 -- 7.39 (m, 2) I s. 7.30 - 7.13 (m, 2H), 4.30 it, J === 4 2 Hz, 2H), 4.16 ih. J

' ^' O - 7.9, 7 3 Hz, i l l ). 3.45(s, 2H), 3.31 (d, ./ 4.6 Hz, 2H), 2.38 (s, 8H) 2.31 (q, J === 6 9 Hz, 2P ).

1.18(d, J - 6.4 Hz, 6H), 0.97 (t J ^:::: 7. 1 Hz, 3H).

Example-70: Synthesis of N-(4-({4~(dimeihyI ammo) piperidin- l-yl) methyl)~3~fluorophenyl)~5- fluoro~4~(8~fluoro~4~isopropyl~3, 4~dihydro~2H-benzo[h] ( J4 oxazin-6-yl)pyrimidin-2-amine.

(Compound 462 )

[0411] Step-1: Synthesis of l-(broraometfay!)-2-fiuoro-4-i»trobenzene: To a stirred solution of 2-finoro- lmiethyh4-mtrobenzene (1 000 mg, 6.4 mmol, 1 equiv) in CCL· (1 5 ml,), was added NBS (1 139 mg, 6.4 mmol, 1 equiv) and ATBN (210 mg, 1 28 mmol, 0 2 equiv). The resultant reaction mixture was allowed to stir at 80°C for overnight. Progress of the reaction was monitored by I, CMS and TLC. After completion of the reaction, diluted with water (50 ml,), and extracted with ethyl acetate (1 50 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain l -(bromomethyl)-2-f!uoro-4-nitrobenzene (400 mg, 27%) as an off white solid compound LCMS: 234 [M-i-H] ⁺

[0412] Step-2: Synthesis of l-(2-fluoro-4-nitrobenzyI)-N, N-dimethylpipericHn-d-amine:

To a stirred solution of l -(bromomethyl)-2-fluoro-4-nitrobenzene (300 mg, 1 .29 mmol, 1 equiv) m ACN (5 ml,), was added N,N dimethylpiperidin--4-amme (495 mg. 3 87 mmol, 3 equiv). The resultant reaction mixture was allowed to stir at RT for i h. Progress of the reaction was monitored by LCMS and NMR After completion of the reaction, diluted with water (30 mL) and extraeted with ethyl acetate (1 00 ml,) Organic layer was washed with water (50 ml,) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain l-(2-†1uoro-4-nitrobenzyj)-N N- dimethyipipericlin-4-amine (300 mg 83%) as a yellow oily co pound LCMS: 282 [M+H]

[0413] Step-3: Synthesis of J -(4-ammo-2-fluorobenzyl)- , N-dimethytpiperidin-4- amine: To a stirred solution of l-(2-fluoro-4-nitrobenzyl)-N, N-dimethylpiperidin-4-amine (300 mg, 1 06 mmol, 1 equiv) in ethanol (5 ml .· water (1 mL), was added iron powder (179 mg, 3.2 nimo!, 3 equiv) and ani omum chloride (1 14 mg, 2 12 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for Hi. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain l-(4-amino-2-fluorobenzyl)-N. N- dimethylpiperidin-4-amine (250 mg, 93%) as a dark brown solid compound LCMSs 252

[M+Hf

[0414] Step-3: Synthesis of N-(4~((4-(dimethyl amino) piperidin-l-yi) methyl )-3- fll«oropheay!)-5-fluoro-4-(S-fluoro-4-isopropyl-3, 4-dihyd ro-2H- benzo [b] [ 1 ,4] oxazin-6~ yl)pyrimidin-2-amine: To solution of 6-(2-chloro-5~fluoropyriraidin-4-yl)-8-fluoro-4- isoprop I-3 ,4-dihydro-2H-benzo[b] 1 ,4]oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 mL). was added l-(4-amino-2-fluorohenzyl)~N.N-dimeihylpiperidin-4-amine (83 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0 47 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and B!INAP (8 mg, 0.012 rnol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mil,) and brine solution (50 rnL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by recrystallization with methanol to obtain N-(4- ((4-(dimetbylaminoSpipendin--l--yl)metbyl)-3 -fluorophenyi)-5~fliioro-4-(8~fliioro-4-isopropyT 3,4-dihydro--2H-benzoj b]j4 ,4joxazm--6--y!)pyrimidin--2--amme (50 mg, 30%) as a yellow color solid compound. LCMS: 541 (400 MHz, DMSO-%6) d 9.92 (s, 1 H), 8 61 (d,

,%3 5 Hz, 1 H), 8.23 (s, 1 H), 7 77 (d, JM3.2 Hz 1 H) 7.36 - 7.50 (m, 2 B), 7.25 (s, 1 H), 7.17 (d ./= ^:: 1 1 .8 Hz, 1 H), 4 30 (br. s., 2 B), 4.17 (br. s., 1 H), 3.44 (s, 3 H), 3 31 (br. s„ 2 H), 2.84 (d. J ^::: l 1.0 Bz, 2 H), 2 1 1 - 2.28 (m 6 H) Ϊ .94 (t, 1 1.2 Bz, 2 H), 1.72 (d, =1 l.B Hz, 2 H) 1.38 (d, ./ 9 2 Hz, 2 H), 1.18 ppm (d, =6 6 Hz, 6H).

Example-71: Synthesis of (4~(dimeihylamino)piperidin-l-yl)(2~fluoro-4~((5~fluoro~4~(8 ~fluoro-4~ isopropyl~3A-dihydro-2H~benzo[h][l,4]oxazin-6-yl)pyrimiclin- 2-yl)amino)phen\>!)methanone. (Compound 463}

[0415] Step- 1 : Synthesis of (4-ammo-2-fl«orophenyl) (4-(dimethyIamino) plperidm-l-yi) metha one: To a stirred solution of 4-amino--2--fluorobenxoic acid (500 nig, 3.22 mmol. 1 equiv) in DMF (5 rnL), was added N, N-dimsihylpipsndm-4--anune (619 mg, 4 83 mmol, 1.5 equiv), DIPEA (2.2 ml .. 13 mmol, 4 equiv) and HATB (2203 g, 6 mmol. 1 .8 equiv). The reaction mixture was allowed to stir for 3h at RT. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate ( 100 mL * 3). Organic layer was washed with water (100 mL). brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (4-ammo~2~fluorophenyl) (4-(dmiethylanuno) piperidin-1 -yt) methanone (700 mg, 82%) as a brown color viscous compound. LCMS: 266 [M+H] ⁺

[0416] Step-2: Synthesis of (4-(dirøethyίamMø) i erίdm-l-yί)(2-fhlorø-4-((5-ί ^' hlorø-4- (8-fiuorø”4-^sopIΌpyl-3y4”dihyxlro-2H-benzojb)(ly4|oxa zin-6-yl)p rimidm-2- yi}amino)phenyl)methanoBe: To a solution of 6-(2-chioro-5-fluoropyrimiclin-4-yl)-8-flooro-4- isopropyl- 3,4-dihydro-2H-benzo[b][l,4]oxazme (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 mL). was added (4-amino-2-fluorophenyl)(4-(dimethylamino)piperidin-l -yl)methanone (88 rag. 0.33 mmol, 1 . t equiv) and cesium carbonate (147 mg, 0.47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 rain , followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 mmol, 0.04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate ( 100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and

concentrated under reduced pressure to obtain crude, which was purified by norma! phase Combi flash to obtain (4-(dimethylammo)pipendm~l~yl)(2-fluoro-4-((5-fluGrG-4-(8~fl uGro-4- isopropyl- 3,4-dihydro-2H-benzo[b] l,4]oxazin-6-yl)pyrimidin-2-yl)amino)phenyl)methanone (35 mg, 21 %) as a yellow color solid compound. LCMS: 555 [MAH] ^{” !} HNM¾ (400 MHz, DMSO-H6) 6 10.16 (s, 1 H r 8.65 (d, AM.5 Hz, 1 H), 8.18 (s, 1 H), 7 95 (d, ,7-13.2 Hz, 1 H), 7.37 - 7.55 (m, 2 H), 7.30 (d, .7-8.3 Hz, 1 H), 7.17 (d, 7-11.8 Hz, 1 H), 4.44 (hr. s , 1 H), 4.30 (br. s., 2 H), 4.06 -

4.20 (m. 1 H), 3 50 (br. s. , 2 H), 3.31 (br. s, 2 H), 3.03 (br s., 1 H), 2.79 (d, ,7-1 1.4 Hz, 1 H),

2.20 K. o I f ). 1.83 (br. s., 1 H), 1.73 (d, 7=11 4 Hz, 1 H), 1.31 (br. s. , 2 11), 1.18 ppm (d, ,7-6 6 Hz, 6 H).

Example-72: Synthesis of {4~ethylpipera n~l~yI)(2-fiuoro-4-((5-fiuoro-4-(8-fiuoro-4-isopropyl- 3,4~dihydro~2H-benzofb/fl, 4loxazin-6-yl)pyrimidm~2~yI)amino)phenyi)meihamme. (Compound 464)

(0417 j Step- 1 : Synthesis of (4-amino-2-fl«orophenyl) (4-ethylpiperazin-l-yi)

meihanone: To a stirred solution of 4-amino-2-fluorobenzoic acid (500 mg, 3.22 mmol, 1 equiv) in DMF (5 mL), was added 1-ethylpiperazine (551 mg, 4.83 mmol, 1.5 equiv), DIPEA (2.2 mL, 13 mmol, 4 equiv) and HATH (2203 mg, 6 mmol , 1 8 equiv). The reaction mixture was allowed to stir for 3h at ft ! . Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, die reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 ml, ^c 3). Organic layer was washed with water (100 mL), brine solution (100 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (4~amino-2-fiuorophenyl) (4-ethyipiperazin-l -y{) methanone (700 mg, 86%) as a brown color viscous compound. LCMS: 252 [MAH] 10418] Step-2: Synthesis of (4-eth ^pipera^in-l-yI)(2-liuoro-4-((5-fluoro-4-(8-flBoro-4- is© rop l·3,4-d^h drø-2IΪ-benzø b] { joxazm-6- l}pyrimid^a-2- yl}amino)phenyi)methanoBe: To a solution of 6-(2-cWoro-5-fluoropyrimidm-4-yl)-8-fluoro-4- isopropyi- 3,4-dihydro-2H-berszo[bl[l,4 oxazme (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 niL), was added (4mmmO 2fouorophenyl)(4-ethylpiperaziml -yi)methanone (83 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 g, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and 1 CMS After completion of the reaction, diluted with water (30 ml-) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 niL) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain (4- ethyipiperazin-l-yl)(2-fIuoro-4-((5-fluoro-4-(8-fluoro-4-iso propyl-3 4-dihydro-2H- benzo[b][l ,4]oxazm-6-yi)pyrimidin-2-yl)araino)phenyl)raethanone (50 mg, 30%) as a yellow color solid compound LCMS: 541 [M+H] ^r ; ^! HNM (400 MHz, DMSOv/6) d 10.17 (s, 1 H), 8 65 (d, ,03.9 Hz, 1 H), 7.95 (d, =12 7 Hz, 1 H), 7.38 · 7 52 (m, 2 H), 7.29 (i, >8 3 Hz, 1 H), 7.17 (d, >1 1 .4 Hz, 1 H), 4 30 (br. s„ 2 H), 4.04 - 4 20 (m, 1 H), 3 62 (br. s., 2 H), 3.31 fbr. s.. 4H) 2 15 - 2.43 (m, Oi l). 1 18 fd. 7 6.0 Hz, 6 H), 1.00 ppm (t >7.2 Hz, 3 H).

Example-73: Synthesis of4-(2~fluoro-4-((5~fluoro-4~(8~fluoro~4~isopropy ~3, 4-dihydro-2H- benzo[b][l,4]oxazin-6-ylJpyrhmdin-2-yl)am fto)phenyI)thiomorphohne /, i-fooxhfe. (Compound 465)

0 ^* 7

[0419] Step-l : Synthesis 4-(2-fluoro-4-nitrophenyl) thiomorphoiine: To a stirred solution of 1 , 2-difluoro-4--nitrobenzsne (500 mg, 3.14 mmol, 1 equiv) m ACN ( 10 mil was added DIPEA (0.8 niL, 4.71 mmol, 1.5 equiv) and thiomorpholine (388 mg, 3.76 mmol, 1.2 equiv). The resultant reaction mixture was allowed to stir at 80° for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with ice water (50 inL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain to obtain 4-(2-f!uoro-4-mtropheny!) thiomorpholine (700 mg, 92%) as a brown oily compound. LCMS: 243[M+H] ^:

[0420] Step-2: Synthesis 4-(2-fluoro-4-nitrophenyl) thiomorpholine 1, 1 -dioxide: To a stirred solution of 4-(2-iluoro-4-nitro phenyl) thiomorpholine (500 mg, 2.06 mmol, 1 equiv) in methanol: water (1 : 1 = lOmL), was added oxone (1586 mg, 5.16 mmol, 2.5 equiv). The resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, solvent was completely removed under reduced pressure and the residue mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain to obtain 4~(2-fluoro-4-nitrophenyl) thiomorpholine 1 , 1 -dioxide (400 mg, 71%) as a yellow solid compound. LCMS: 251 [M+H] |042I) Step-3: Synthesis of 4-(4-amino-2-fluorophenyI) thiomorphoiine 1, 1 -dioxide: To a stirred solution of 4-(2-fluoro-4-nitrophenyi) thiomorphoiine 1 , 1 -dioxide (200 mg. 0.72 mmol,

1 equiv) in ethanol (6 mL), water (2 niL). was added iron powder (123 mg, 2.1 mmol, 3 equiv) and ammonium chloride (78 mg, 1.44 mmol, 2 equiv) The resultant reaction mixture was allowed to stir at 90° for ! h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through ce!tie bed and the filtrate was concentrated under reduced pressure to obtain 4-(4-amino-2-fluorophenyl) thiomorphoiine 1, 1- dioxide (150 g, 84%) as an off white solid compound. LCMS: 245 [M÷H]

[0422] Step-4: Synthesis of 4-(2-fluoro-4-((S-fluoro-4-(S-fluoro-4-isopropyl-3,4-dihydro - 2H~benzolb]|T,4joxa*in-6-yl)pyriraidin~2~yl)amino)pheny!)thi omorpfaoline 1,1-dioxide: To a solution of 0-(2-chloro-5-fluoropyrimidin-4-yl)~8-fii3oro~4~isopropyl~3. 4-dihydro-2H~ benzo[b][l,4)oxazme (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 mL), was added 4-{4-amino~2~ fluorophenyl (thiomorphoiine 1 ,1 -dioxide (81 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.45 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 mil.) and brine solution (50 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain 4-(2-fluoro-4-((5-fluoro-4-(8-fluoro-4-isopropy!-3,4·· dihydro-2!:I-benzo[b][l ,4]oxaxin-6-yj)pyrimidin -2-y!)amino)pheny!)thiomorpho!ine 1 ,1 -dioxide (45 mg, 27%) as a yellow color solid compound. LCMS:: 534 j M H i ΌNME. (400 MHz. DMSO-A6) o 9 82 (s, 1 H), 8.58 (d, MB 5 Hz, 1 H), 7.81 (dd, 7-15.1 , 2.4 Hz, 1 H), 7.28 - 7.47 (m, 2 H), 6.99 - 7.21 (m, 2 H), 4.30 (d, ,04.4 Hz, 2 H), 4 15 (d, ,7-6.6 Hz, 1 H), 3.37 - 3.52 (m, 4 H), 3.26 (hr s., 6 H), 1 06 1.26 ppm (m, 6H).

Exam pie-74: Synthesis of 5-fluoro-N-(3-ftuoro-4-(l-met.hylpiperidin~4-yl) phenyi)-4~(8~fiuoro~4~ meihy!-3, 4-dihydro-2H-henzo/ b } ί 1 , 4]oxazin-6-yl)pyrimidin-2-amme. (Compound 466} o

[0423] Step-1: Synthesis of tert-huty! 4-(2-fiuoro-4-( ( 5-fiuoro-4-( 8-fluoro-4-methyi-3,4~ dihydro-2H-benzo(h]jl,4 oxazm-6-yl)pyrimiilIn-2-yl)amIno)pheny!)piperidine-l- carboxylate: To a solution of 6-f2-chloro-5-fluoropyrmiidin~4-yl)~8~fluoro-4-methyl-3,4- dihydrG-2H-benzG[b][1 ,4]oxazine (100 mg. 0.33 mmol, 1 equiv) in Dioxane (10 mL), was added tert-butyl 4-(4-amino-2-fluorophenyi)piperidine~l~carboxyiate (109 mg, 0.37 mmol, 1.1 equiv) and cesium carbonate (161 mg, 0.49 mmol, 1 5 equiv). The reaction mixture was purged with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 equiv) and BINAP (8 mg. 0.013 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 1 00 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (30 ml,) and extracted wit ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi flash to obtain tert-butyl 4-(2-fluoro-4-((5-fiuoro-4-(8-†]uoro-4-me†hyi-3,4-dihydr o-2åi-henzo[b][l ,4]oxazm-6- y ^j )pyrimidin-2-yl)amino)phenyl)piperidme-l-carboxylate (150 mg, 80%) as a yellow solid compound. LCMS: 556 [M+H]

[0424] Step-2: Synthesis of 5-f!uoro~N-(3-fiuoro-4-(piperidin-4-yl) phenyl )-4-(8-fiuoro- 4-methyI~3, 4-d«hydro-2H-benzo[b] [1,4] oxazin-6-y i)pyr«nMdm-2-asnine: tert-butyl 4-(2- fluoro-4-((5-fluoro-4-(8-fluoro-4-rnethy!-3,4-dihydro-2H-ben zo b| l,4]oxazin-6-yl)pyiirnidin-2- yl)amino)phenyl)piperidine-l -carboxylate (150 mg, 0.27 mmol, 1 equiv) was taken in 1.25 M HQ in ethanol (5 mL) and the resultant reaction mixture was allowed to stir at 50°C for 1 h. Progress of the reaction was monitored by LCMS. After completion of the reaction solvent was removed under reduced pressure and the residue was dried under lyophihzer to obtain 5-fluoro- N-(3-fluoro-4-(piperidin-4-yl)phenyl)~4-(8-f!uoro-4-methyl~3 ,4-dihydro-2H~

benzo[b][l,4]oxazin-6-yl)pynmidin~2~amine (100 mg, 75%) as a brick red color solid compound. LCMS: 456 fM+R] ^"

[0425] Step-3: Synthesis of S-t1uoro-N-(3-(luoro-4-(l-i«ethyIpiperidm-4-yi) phenyl)-4- (8-fluoro-4-methyl-3, 4-dihydro-2H-beB*o|b[[l,4 oxazia~6~y!)pyrimidin-2-amine: To a stirred solution of 5-fluoro-N-(3~fluoro-4-(piperidin-4~yl)phenyi)-4-(8-fluoro-4 -methyi-3,4- dihydro-2H-benzo[b]il,4]oxazin~6-yl)pyrmiidm-2-aniine (100 mg, 0.2 mmol, 1 equiv) in DCE (5 mb · was added Formaldehyde (40% in water) (0 02 mL, 0.61 m ol, 3 equiv), acetic acid (0.05 rnL, 1.0 mmol , 5 equiv). The reaction mixture was allowed to stir at RT for lb. The reaction mixture was cooled to 0°C. NaCNBH (38 mg, 0.61 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for lb Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 mb } and extracted with ethyl acetate (50 mL x 2) Organic layer was washed with water (50 mb} and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5--fluoro--N-(3 -fluoro-4-(] -methylpiperidin-4- y!)phenyl)-4-(8~iluoTo-4-methyl-3,4-dihydro-2H-benzo[b][ l ,4]oxazin-0-yl)pyrimidin-2-amine (40 mg, 42%) as a yellow color solid compound LCMS: 470 I M H i A H!NMR (400 MHz DMSOvfo) o 9 90 (s, 1 H), 8.60 (d, fo ^:: 3 9 Hz, 1 H), 8.16 (s, 1 H), 7.83 (d, / i t 0 Hz, 1 H), 7.39 (d, / 6 6 Hz 1 H) 7.32 (s, 1 H), 7 15 - 7.28 (m, 2 H), 4.28 - 4.43 (rn, 2 H), 3.30 - 3 44 (m, 2 H), 3.11 (d, J---\ ! .4 Hz, 2 H), 2 96 (s, 3 H), 2.80 (hr s., 1 H), 2 43 (s 5 H) 1.78 ppm (br. s., 4 H).

Example-? 5: Synthesis c rfN~(4~(4-(dimethylammo ) piperidin-l-y )-3-fIuoropkenyI}-5-fIuoro-4- (8-fluoro-4-meihyl-3,4-dihydro-2H-benzo[b [J4 oxaz -6-yl}fyyrimidin-2-amine. (Compound 467 )

Step-1

[0426 j Step-1: Synthesis of -(4-(4-(iliraethylamino) piper«dm-l-yl)-3-fluoropheny!)-5- fluoro-4-(S- ^{ luoro-4-methyi-3,4-dihydro-2H-ben*o|b| [l,4 oxazin~6~yi)pyrimidin-2-amine:

To a solution of 6-{2-diloro-5-fluoropyrimidin- _' ⁱ i-yl)-8-fluoro-4-met yl-3,4-dihydro-2H- benzo[b|[l ,4]oxazine (100 me. 0.33 mmol I equiv) in Dioxane (10 oil-}, was added l -(4-amino- 2-fluorophenyl)-N.N-dimethylpiperidin-4-amine (88 mg, 0.37 mmol, 1 1 equiv) and cesium carbonate (161 mg, 0.49 mol, 1 5 equiv). The reaction mixture was purged with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0 006 mmol. 0.02 equiv) and BINAP (8 mg, 0 013 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with wa ter (30 ml.) and extracted wit ethyl acetate (100 ml ,). Organic layer was washed with water (50 ml,) and brine (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain N-(4- (4-(dimethylamino)piperidin-1 ~yi)-3-fkiGropheny!)-5-fiuoro-4-(8-fiuoro-4-methy 1-3, 4-dihydro- 2H-benzo[b][l ,4]oxazin-6-yl)pyrimidin-2-amine (30 mg, 18%) as a yellow color solid compound. LCMS: 499 [M+Hj ⁺ ; *HNMR (400 MHz, DMSO-76) d 9.73 (s, I hi), 8.57 p i. ,03.9 Hz, 1 H), 8.23 (br. s., 1 H), 7.79 (d, 7-14.5 Hz, 1 H), 7.30 - 7.38 (m, 2 1 1} 7 22 id, 7 i 1.8 Hz, 1

H), 6.99 (t, ,7-9.4 Hz, 1 H), 4.38 (br. s., 2 H), 3.37 (hr s., 2 H), 3 30 id, ,7-1 1.0 Hz, 2 H), 2.96 (s,

3 H), 2.54 - 2.69 (m, 3 H), 2 24 is, 6 H), 1 .85 (d, 7-10.5 Hz, 2 H), 1.55 ppm (d, 7-9 2 Hz, 2 H)

Example-76: Synthesis qfN-(4-(4--(dimeihyiaimno ) piperidin-l-yl)~3~fluoropheny!)~5~fluoro~4~ (8-ftuoro-4-propyi-3, 4-dihydro~2H~benzo[bj ( L4]oxc n~6~ylypyrimidin~2~amine (Compound 468)

[0427] To a solution of 6-(2-chloro~5-fluoropyrimidin~4~yl)-8-fluoro-4-propyI-3,4-di hydn> 2H~benzo[b|[l ,4]oxazine (100 mg, 0 32 mmol, 1 equiv) m Dioxane (10 mL), was added l-(4- amino~2~fluorophenyI}-N,N~dimethyIpiperidin-4-amine (78 mg. 0 33 mmol, 1.1 equiv) and cesium carbonate ( 147 mg, 0.47 mmol, 1.5 eqmv). The reaction mixture was purged with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 013 mmol. 0 04 equiv) The resultant reaeti on mixture was allowed m stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and expected wii ethyl acetate ( 100 mL) Organic layer was washed with water (50 mild and brine (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain N~(4~ (4-(dimethylamino}piperidin-d-yl)-3-fiuorophenyl)-5 -i!uoro-4-(8-i!uoro-4-propyl-3,4-dihydro·· 2H--benzoibjp ,4joxazin-6-yl)pyrimidm-2-amine (30 mg 19%) as a yellow color solid compound LCMS: 527 [M+B] 7 (400 MHz, DMSO-76} 6 9.72 (s, 1 H), 8.56 (d, 7-3 5

Hz, 1 H), 8 26 (hr. s., I H), 7.71 (d 7-1 5.3 Hz, 1 H), 7 38 (d, ,7-8.3 Hz, 1 H), 7.28 (br. s., 1 H), 7.14 (d, ./ ! 1.4 Hz, 1 H), 6 98 (t, 7-9.4 Hz, 1 H), 4.30 (br. s„ 2 H), 3.43 (br. s., 2 H), 3.31 (br s., 4 H), 2 56 2.71 (m 3 H) 2.23 (s, 6 H), 1.84 (d, ./ 1 1 .4 Bz, 2 H), 1 42 - 1.70 (m 4 H) 0.89 ppm (t, 7-7.2 Bz, 3 H).

Example-??: Synthesis of 5~fluoro~4~{8~fluoro~4~isopropyl~3 _s 4-dihydro-2H~

henzo[biiJ4loxazin~6~yI)~N~{3~f}uoro~4~thiomorphoiinophen yi)pyrimidin~2-amine. ( Compound 469 )

[0428] Step-1: Synthesis 4-(2-fluoro-4-nitrophenyl) thiomorpholine: To a stirred solution of 1 , 2-difiuoro~4-mtrobenzene (500 mg, 3.14 mmol, 1 equiv) in ACN (10 ml) was added DIPEA (0.8 niL, 4.71mmol, 1.5 equiv) and thiomorpholine (388 mg, 3 76 mmol, 1.2 equiv) The resultant reaction mixture was allowed to stir at 80° for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml } and brine solution (50 ml,}. Organic layer was dried over anhydrous sodiu sulphate and concentrated under reduced pressure to obtain to obtain 4-(2-fluoro-4-nitrophenyl) thiomorpholine (700 mg, 92%) as a brown oily compound LCMS: 243 [M+H]

[0429] Step-2: Synthesis of 3-fiuoro-4-thiomorphoIinoaniIine: To a stirred solution of 4- (2-fluoro-4-nitrophenyl)thiomorpholine (300 mg, 1 23 mmol, 1 equiv) m ethanol (6 ml,), water (2 ml,), was added iron powder (208 mg, 3.7 mmol, 3 equiv) and ammonium chloride (133 mg, 2.45 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for Ih. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through eelite bed and the filtrate was concentrated under reduced pressure to obtain 3-fluoro-4-ihiomorpholmoaniline (200 rng, 76%} as a yellow color solid compound. LCMS: 213 [M+H] ^÷

[0430] Siep-3: Synthesis of 5-fl«oro-4-(8-fl«oro-4-isopropyl-3, 4-dihydro-2H- benzo[b][l,4]oxaz«n-6-yl)-N-(3~flm>r©-4~thionu>rphoH nophenyI)pyrimidiR-2-aHMne: To a solution of 6-(2-ch]oro-5-t1uoropyrimidin-4-yl) ^~ 8-iluoro ^~ 4 ^~i sopropyl ^~ 3,4-dihydro-2H ^~ benzo[bj[l,4]oxazme (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 ml,), tvas added 3-fluoro-4- ihiomorphoimoanilme (70 g, 0.33 mol, 1.1 equiv) and cesium carbonate (147 mg, 0.45 mmol, 1.5 equiv). The reaction mixture was degassed w th nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv ). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. Alter completion of foe reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by reverse phase HPLC to obtain 5-fluoro~4~(8-fluoro~4-isopropyl~3,4-dihyclro-2H~benzo[b][l ,4]oxazin-6- yiVN--(3 Puoro--4--thiomorphoimophenyi)pynmidm-2-amine (10 mg, 6%) as a yellow color solid compound. LCMS: 502 [M+H] ⁺ ; *HNMR (400 MHz, DMSO-76) d 9.69 (br. s., 1 H), 8.52 (d,

7 3.9 Hz, 1 H), 7.70 (s, 1 H), 7.74 (s, 1 H), 7.41 (br s., 1 H), 7 34 (d, 7-8.3 Hz, 1 H), 7.14 (d,

AH 1.8 Hz, 1 H), 7 00 (t, 7-9.2 Hz, 2 H), 4.28 (br. s , 2 H), 4.06 - 4.17 (m, 1 H), 3.29 (br. s., 2 H), 3.09 - 3.20 (m, 4 H), 2.73 (br. s., 4 H), 1.16 ppm (d, 7-6.6 Hz, 6 H).

Example-78: Synthesis of 4~(4~cyclopeniyI~8~fJuoro~3, 4 dihydro-2H-hemo[b] [I ]ocaήh~6~nI) N-(4-(4-(dimethylamino}piperidin~l~yl)-3-fiuorophem4)-5-flii oropynmidm~2~amine. (Compound 470}

[0431] Step-1 : Synthesis of 4-bromo-2-(cycIopentyiamino)-6-t1uorophenoI: To a stirred solution of 2-amino-4-bfomo-6-rluorophenol (3000 nig, 14 63 mmol, 1 equiv) in DC r (30 ini . } was added cyclopentanone (3687 n g, 43.89 nnnol 3 equiv), acetic acid (4 2 mL, 1.0 mmol,

73.15 equrv). The reaction mixture was allowed to stir at RT for Ih. The reaction mixture was cooled to 0°C. NaBH (OAC) ₃ (9305 mg. 43.89 mmol, 3 equiv) vvas added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for Ih. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). Organic layer was washed with water (150 rnL) and brine solution (150 ml,). Organic layer was dried over anhydroas sodium sulphate arid concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to afford 4-bromo-2-(cydopenty!amino)- 6--f!uorophenol (3600 mg, 90%) as a dark brown viscous compound. LCMS: 274 [M+H]

[0432] Step-2: Synthesis of 6-bromo-4-cycIopeatyi-8-f1ooro-2H-bea«o{b][l ,4]oxa*in- 3(4H)-oiie: To a stirred solution of 4~bromo-2~(cyclopentyiammo}-6-iluorophenol (3000 mg, 10.9 mmol, 1 equiv) in chloroform (30 ml,), was added NaHCO (4578 mg, 54.5 mmol, 5 equiv) and Benzyftri ethyl ammonium chloride (2485 mg, 10 9 mmol, 1 equiv). The reaction mixture was allowed to stir at RT for Ih. The reaction mixture was cooled to 0°C, followed by die addition of chloroacetyl chloride (0.9 ml,, 10.9 mmol, 1 equiv). The reaction mixture was allowed to stir at 0°C for I h. Raise the temp to 70 °C and reaction mixture was allowed to stir for overnight Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (100 ml,) and extracted with ethyl acetate (150 ml, x 3) Organic layer was washed with water (150 ml,) and brine solution (150 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by column chromatography to afford 6~bromo~4~ eycfopentyl 8 fluoro-2H benzo[b][L4]oxazim3(4H) One (1000 mg. 29%) as a brown color solid compound. LCMS: 314 [M+H]’

[0433] Step-3: Synthesis of 6-br©m©-4-eycIopentyl-8~fluoro~3, 4-dihydro-2H- benz©[b] [l,4]oxazrae: To a stirred solution of 6-hromo-4-cyclopentyl-8-fluoro-2H- benzo[b] [ 1 ,4] oxazi n-3 (4H)-one (1000 mg, 3.19 mmol, 1 equiv) in THF (15 ml,), was added BBU.DMS (2 hi in THF) (6 3 mL, 12.7 m ol, 4 equiv) at 0 C drop wise The reaction mixture was allowed to stir at 50°C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction the reaction mixture was quenched with saturated solution of NaHCO (50 L) and extracted with ethyl acetate (100 mL x 2). Organic layer was washed with water (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6-bromo-4-eyciopenty1-8~fluoro-3,4-dihydro-2H- benzo[bj[ l,4|oxazine (900 mg, 94%) as a transparent oil compound. LCMS: 300 I \ M P ^"

[0434] Step-4: Synthesis of 4-cydopentyl-8-fiuoro-6-(4,4,5,5-tetramethyl-l ,3,2- dioxaboroian-2-yI)-3 _> 4-dihydro-2H-bea«o[b] [1 ,4]oxa*i»e: 6-bromo-4-cyclopentyl-8-fluoro- 3 4-dihydn>2H-benzoibl[ 1,4 joxazine (900 mg 3.01 mmol. 1 equiv), 4,4,5,5~teixamethyl-2- (4,4,5,5-tetfameihyl-l ,3,2-dioxahoroian-2-yi)-l ,3,2-dk)xaborolane (1 147 mg, 4.51 mmol, 1.5 equiv), Potassium acetate (735 mg, 7.5 mmol, 2 5 equiv) and dioxane (10 niL) were charged m a 25 niL glass bottle. Purged the reaction mixture with nitrogen gas for 15 mat, Pd(dppf)CI2

DCM (123 mg, 0.15 mmol, 0 05 eq v) was added to above mixture and the reaction mixture was allowed to stir at 100 ( for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 ml,) and extracted with ethyl acetate (100 ml, * 2). Organic layer was washed with brine (100 mL) and water (100 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 4-cydopentyl-8-f1uoro~6-(4M,5.5~te†ramethyl-! ,3,2- dioxaboroiam2 y!)~3,4 dihydrO 2H~benzo[b][l ,4]oxazine ( 1000 mg, 96%) as a dark brown viscous compound. LCMS: 348 [M+H]

[0435] Step-5: Synthesis of 6-(2-chloro-5-fluoropyrimidm-4-yl)-4-cyciopentyl-8-fluoiO-

3,4~dihydro-2H-benzo[b] [L4]oxazme: To a stirred solution of 2, 4-dichIoro-5-f1uoropyrimidine (450 mg. 2 7 mmol, 1 equiv) in H II Water (1 : i 10 ml,) was added 4-eyclopenty!-8-f!uon>6- (4,4,5,5-tetramethy!-l ,3,2-dk>xaboro]an-2-yl)-3,4-dihydro-2H-benzo[b][l ,4]oxazine (941 g,

2 7 mmol, 1 equiv), Potassiu carbonate (745 mg, 5.4 mmol, 2 equiv) and Pd(PPh ₃ )4 (156 mg, 0.13 mmol, 0.05 equiv). The reaction mixture was allowed to stir at 80°C for 3 h. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (50 ml,) and extracted wit ethyl acetate (150 ml,). Organic layer was washed with water (50 mL) and brine (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6 (2-chloro-5-f!uoropyrimidin-4-yi)-4- cyciopentyI-8-rfooro-3,4-dihydro-2H-benzo[b][l 4joxazins (300 g, 32%) as a yellow solid compound. LCMS: 352

[0436] Step-6: Synthesis of 4-(4-cyclopentyi-8-fluoro-3,4-d«hydro-2H- benzo[b][1,4]oxaziR-6-yI)-N-(4-(4-(diraethyiara«no)piper«d in-1-yi)-3-fl orophenyl)-5- fluoropyrimidm-2-amine: To a solution of 6-(2-chloro-5-iluoropynmidin-4-yl)-4-cyclopentyl· 8-fluoro-3,4-dihydro-2Hfoenzo[ b]! 1 4joxaxine (100 mg, 0.28 mmol, 1 eqmv) in Dioxane (10 mL), was added 144-ammo-2-fiuoropheny!)-N,N-dimethy!piperidin-4-amine (74 mg 0.31 mmol, 1 .1 equiv) and cesium carbonate (137 mg, 0.42 mmol, 1.5 equiv) The reaction mixture was purged with nitrogen gas for 30 min., followed by the addition of palladium acetate (1 3 mg, 0.005 mmol, 0.02 equiv) and BINAP (7 nig, 0.01 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted wit ethyl acetate (100 ml_). Organic layer was washed with water (50 mL) and brine (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain 4-(4-cyclopentyL8-fluoro~3,4-dihydro-2H~benzo[b][l,4]oxazin- 6-yi)-N-(4-(4- (dimethylamino)piperidin-i-yl)~3~fluorophenyi)-5-f]uoropyrim idm-2-amine (20 g, 13%) as a brick red color solid compound LCMS: 553 [M+H] ’HNMR (400 MHz, DMSOM6) 6 9 76 (s, 1 H), 8.57 (s, I H), 7.73 (dd, J=1 5.1 , 2.4 Hz, I H), 7.34 - 7.48 (m, 2 H), 7.16 (d, ,7-1 1 .8 Hz, 1 H), 7.02 (d, ,7=9.6 Hz, 1 H), 4.31 (br s.„ 2 H), 4 27 (br. s. , I H), 3.34 - 3 48 (m, 4 H), 3.33 (br s.,

I H), 2.78 (d, ,7=4.8 Hz, 6 H), 2.53 - 2.69 (m, 2 H), 2.09 (d, ./ 1 1 0 Hz, 2 H), 1.89 (d, ,7-8.3 Hz, 2 H), 1.78 (d, ,7-8.3 Hz, 2 H), 1.45 - 1 .74 ppm (m, 6 H).

Example- 79: Synthesis of4-(4~e}>ciope yi-8-/hioro-3, 4-dihydro-2H~benzofbj[l, 4]oxazin~6~yl)~

[0437] Step-1 : Synthesis of tert-butyi 4-(4-((4-(4-cydopentyl-8-fluor©-3, 4-dihydro~2H- b£«zo[b] [l ₅ 4]oxazbi~0-yI)~5~fhioropyrhmdm~2~yl)ammo)~2~fl«oroph{ ;nyi}piperidme-l- carboxylate: To a solution of 6-(2-chloro-5-t1uoropyrimidin-4-yl)-4-cyclopentyl-8-†1uoro -3,4- dihydro-2H--benzo[b][l ,4]oxazme (200 mg. 0.56 mmol, 1 equiv) in Dioxane (10 ml,), was added tert-butyi 4-(4-amino-2-fluorophenyl)piperidme-4 -carboxylate (184 mg 0.62 mmol, 1.1 equiv) and cesium carbonate (274 mg 0.84 mmol, 1 .5 equiv). The reaction mixture was purged with nitrogen gas for 30 mm. followed by the addition of palladium acetate (3 mg, 0 01 1 mmol, 0.02 equiv) and BIMAP (14 mg, 0 022 mmol, 0.04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction vvas monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 ml,) and extracted wit ethyl acetate (100 l,). Organic layer was washed with water (50 mL) and brine (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified column chromatography to obtain ten- butyl 4--(4-((4-(4-cyciopentyi-A-fouoro--3,4-dihydro-2H--benzo[b][ L4]oxazm-6-y!) 5·- fluoropyrimidin~2-yl)amino)-2-fluorophenyl)piperidme- l Carboxylaie (170 mg, 49%) as a yellow solid compound. LCMS: 610 [MAH] ^r

[0438] Step-2: Synthesis of 4-(4-cyciopeatyl-8-fluoro-3, 4-dihydro-2H- benzo[b][l,4]oxazi«-^ yi)~S-fl«o*'o-N-(3~fluoro-4~(piperitlin~4-yI)phenyl)pyrimid ia-2-amine: tert-butyl 4-(4-((4-(4-C3'clopenty!-8-fluoro-3,4-dihydro-2H-benzo[b][l ,4]oxazm-6-yl)-5- fluoropyrimidin-2-yi}arnino)-2-fluoropheny])piperidine~l~car boxy]ate (1 70 mg, 0 27 mmol, 1 equiv) was taken in 1.25 M HCi in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for 1 h. Progress of the reaction was monitored by I, CMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophilizer to obtain 4~(4-cyclopentyi-8-fhioro-3,4~dihydro~2H-benzo[b][L4]oxaz:in ~ 6-y!)-5-fluoro-N-(3-fluoro-4-(piperidin-4-yl)phenyl)pyrimidi n-2-amine (130 mg, 86%) as a briek red color solid compound LCMS: 510 [MAH]

[0439] Step-3: Synthesis of 4-(4-cyxIopen tyl- fluoro-3, 4~dft»ydro-2H- henzo[h] [ i ,4] oxazin-6-y'I)-5-fl«oro-N-(3-f! uoro~4~{ 1 -raethyipiperidin-4-yl)phenyI)pyT«midin-

2-amine: To a stirred solution of 4-(4-cyclopenlyl-8-fluoro-3,4-dihydro-2H- benzo[b]j l ,4]oxazm-6-yl)-5-fiuoro-N-(3-fluoro-4-(piperidin-4-yl)pheny{ )pyrimidin-2-amine (70 mg, 0 12 mmol, 1 equiv) in DCE (5 mL), was added Formaldehyde (40% water) (0.01 ml,, 0 38 mmol, 3 equiv). acetic acid (0.03 mL, 0 6 mmol, 5 eq v). The reaction mixture was allowed to stir at RT for !h. The reaction mixture was cooled to 0°C. NaCNB!L (23 mg, 0.38 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS.

After completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (50 ml, >< 2). Organic layer was washed with water (50 mL) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 4-(4-eyclGpentyl~8~fluGro-3,4-dihydro-2H-benzo[b][l,4]oxazin -6-yl)-5-fluoro~]Si-(3- fluoro-4-(l -methyl piperidin-4-yl)phenyl)pyrimidin-2-amine (7 mg, 10%) as a light orange color solid compound. LCMS: 524 I M H i 4 1HNME, (400 MHz, DMSOv/6) 5 9.94 (s, I 1 1 ). 8.61 (d, ./ 3.9 Hz, 1 H), 7.82 (s, 1 H), 7.36 - 7 54 (m, 2 H r 7.18 (d, ./ 8.8 Hz, 2 H), 4.32 (hr. s , 3 H),

3.51 (d, >=13.2 Hz, 2 H), 3.34 (hr. s , 2 H), 3.12 (d, >41 0 Hz, 2 H), 3.00 (hr. s., I H), 2.81 (s, >4.8 Hz, 3 H), 1.80 - 2.04 (m, 6H), 1.69-1.60 ppm (m, 6 H).

Excmiple~8 ^Q : Synthesis of l~(6-((5-fluoro-4~(8-fluoro-4~isopropyl-3, 4~dihydro-2H~

benzo[h][J4]oxazin-6~yJ)pyrimidin-~2~yJ)ammo)pytidin~3~yl )-4-methylpiperazin-~2-~one.

(Compound 472)

[0440] Step-1 : Synthesis tert- butyl 4-(6-nitropyridin-3-yl)-3-oxopiperazine-l- carboxylate: I o a solution of 5-hromo-2-nitropyridine ( 1000 mg, 4.95 mmol, I equiv}

Dioxane (10 ml,), was added tert-butyl 3-oxopiperazme-l -carboxy!ate (990 mg, 4 95 mmol,

1 equiv) and cesium carbonate (4034 mg, 12 3 mmol, 2.5 equiv) The reaction mixture was purged with nitrogen gas for 30 min., followed by the addition of Pd ₂ (dba) ₃ (227 mg, 0 24 mmol, 0.05 equiv) and Xantphos (230 mg, 0 39 mmol, 0.08 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 ml) and extracted wit ethyl acetate (1 50 rnL x2). Organic layer was washed with water (100 rnL) and brine (100 rnL) Organic layer was dned over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi flash to obtain tert-butyl 4-(6-nitropyriclin-3-yl)-3-oxopiperazine-1 -carboxylate (500 mg, 37%) as a yellow solid compound. LCMS: 323 I M 1 11 ^÷

(0441 Step-2: Synthesis of tert-buty! 4-(6-a inopyridia~3~y!)-3-oxopiperazine-l- carboxyiate: To a stirred solution of tert-buty! 4-(6-miropyridm-3-y!)-3-oxopiperazme·-! - carboxylate (500 mg, 1.55 mol, 1 equiv) in ethanol (8 ml,), water (2 mL), was added iron powder (261 mg, 4 65 mmol, 3 equiv) and ammonium chloride (167 mg, 3.1 mmol, 2 equiv).

The resultant reaction mixture was allowed to stir at 90° for Ih Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through ceiite bed and the filtrate w¾s concentrated under reduced pressure to obtain tert-buty! 4-(6- aminopyridin-3-yI)-3-oxopiperazine-l-carboxylate (300 mg, 77%) as a brown color solid compound. 1,018:: 293

(0442] Step-3: Synthesis of tert-buty! 4-(6-((5-fl«oro-4-(8-fl«oro-4-isopropyI-3,4- dihydro-2H-benzo b](l,4]oxazin-6-y!)pyri idm-2-yl)amino)pyridia~3~y!)-3~oxopiperazme- l-carboxylate: To a solution of 6-(2-chloro-5-fluoropyriiTiidm-4-yI)-8-f1uoro-4-isopropy]-3, 4~ dibydro-2H-benzo[b] [ 1 ,4]oxazine (100 mg, 0 33 mmol, 1 equiv) m Dioxane (10 mi,), was added tert-buty! 4~(6-ammopyridin~3~yl)-3-oxopiperazme-l-carboxyla†e (96 mg, 0.37 mmol, 1.1 equiv) and cesium carbonate (161 mg, 0 49 mmol. 1.5 equiv) The reaction mixture tea purged with nitrogen gas for 30 ruin , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 013 mmol. 0 04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with -water (30 ml,) and extracted wit ethyl acetate ( 100 mL). Organic layer was washed with water (50 mil,) and brine (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi flash to obtain tert-buty I 4-(6-((5-imoro-4-(8-imoro-4-isopropyl-3,4-dihydro-2H-benzo[b ]| l,4joxazin-6- yl)pynmidm-2-yl)ammo)pyndin-3-yl)-3-oxopiperazine-l -carboxyiaie (140 mg, 79%) as a yellow solid compound. LCMS: 582 I M · I I I ^÷ ! 0443] Step-4: Synthesis of l-{6-((5-ilnoro-4-(8-flnoro-4-isopropyI-3,4-clihydro-2H- ben¾o(b] l,4]oxa¾in-6-yI)pyr niclin-2-yI)ainino)pyridin-3-yi)pipera2in-2-one

hydrochloride: tert-butyi 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyi-3,4~dihydro~2H- benzo[b][l,4]oxazin-6-yl}pyrimidm-2-yi)ammo)pyridin~3-yl)~3~ oxopiperazine-l-earboxylate (140 mg 0 24 mmol, 1 equiv) was taken m 1 25 M HCI m ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for I h. Progress of the reaction was monitored by LCMS. After completion of the reaction solvent was removed under reduced pressure and the residue was dried under lyophibzer to obtain l- 6-{(5-fluoro-4-(8-fluoro-4-isopropyl-3,4- dihydro-2H-benzo[b] 1 ,4]oxazin-6-yl}pyrimidin-2-yi)amino)pyridin~3-yl)piperazin-2 -one hydrochloride (120 mg, 96%) as a brick red color solid compound LCMS: 482 [M+H]

[0444] Step-S: Synthesis of l-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- ben?.o[h] f 1,4] oxazin-6-yi)pyrimidin-2-yl)araino)pyridin-3-yI)-4-methyIpipe ra¾in-2-one: To a stirred solution of 1 -{6-((5-fiuoro-4-(8~fluoro-4-isopropyi-3, 4-dihydro- 2H-benz:o[b][i ,4]oxazim 6-y])pyrimidin-2-yl)amino)pyridin-3-yi)piperazin-2-one (60 mg, 0.1 1 mmol, 1 equiv) in DCE (3 ml,), was added Formaldehyde (40% in water) (0.01 ml,, 0 33 mol, 3 equiv), acetic acid (0 03 ml,, 0 55 mmol, 5 equiv) The reaction mixture was allowed to stir at RT for Ih The reaction mixture was cooled to 0°C. NaCNBEU (21 mg, 0 33 mmol, 3 equiv) was added to above mixture and raise the temperature to RT The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS After completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with DCM (50 ml, ^x 2) Organic layer was washed with water (50 ml 4 and brine solution (50 ml 4 Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude. Much was purified by reverse phase HPLC to afford l~(6-((5-nuoiO-4-(8-fiuoiO-4-isopropyj-3,4-dihydro-2H- benzoibl[ l,4 joxazin-6-yi)pyrimidin-2-y!)annno)pyridm--3--yi)-4--meihy!pi petazin-2-one (5 mg, 9%) as a yellow color solid compound. LCMS: 496 [M÷H] ⁺ ; (400 MHz, DMSO-%6) d

10.21 (s, 1 H), 8 65 (d. 7 5.9 Hz, I H), 8.18 - 8.34 (m, 2 H), 7.73 (dd, 9.0, 2.4 Hz, 1 H), 7.48 (br s., 1 H), 7 20 (d, , Ml 1.4 Hz, 1 H), 4 30 (br. s., 2 H), 4.15 (d, J-6.6 Hz 1 H), 3.93 (br. s , 3 H), 3 78 (m, 3 H). 3.30 (t, J === 4 2 Hz, 2H), 2.86 (br. s., 3 H), 1.01 1.30 ppm (m, 6 H). Example-81 : Synthesis of 5~fiuoro-N-(3~fiuoro-4-(hexahydropyrrolo[ 1 ,2-a]pyrazin~2(lH)~ yi)phenyl)-4-(8~fluoro-4-isopropyi-3,4~dihydro~2H-henzo[b j [ 1 ,4]oxazin~6~yi)pyrimidin~2~amine.

[0445] Step- !:; Synthesis of 2-(2~fl«oro-4~nitropheiiyl)octahydropyrrolo[l,2-a]pyraziiie :

To a stirred solution of 1 ,2-diilnoro~4~mtrobenzene (1 000 mg. 6 28 mmol, 1 equiv) in DMT (10 mL), was added octahydropyrroio[] ,2-a]pyrazine (950 mg, 7.54 mmol, 1 2 equiv) followed by addition of K2C03 (1 300 mg. 9 42 mmol, 1.5 equiv) Resultant mixture was allowed to stir at 100° for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with water (20 mL), and was extracted with EtOAc (25 mL) Organic layer was washed with water (20 mL x 6) and brine (5 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound was triturated from hexane to afford 2-(2-fluoro-4-nitrophenyl)octahydropyrrolo[l ,2-a]pyraz.ine (1000 mg) as a colorless oil. LCMS: 267 i \ L H i ^"

[0446] Step-2: Synthesis of 3-fluoro-4-(hexahydropym>Io[l,2-a]pyra*in-2(i II)- yl)aniiine: To a stirred solution of 2-(2-fluoro-4-nitrophenyl)octahydropyrrolo[l ,2--a]pyrazine (1000 mg. 3.77 mmol, 1 equiv) in ethanol (8 mil), water (3 ml), was added iron fillings (2000 mg, 37 7 mmol, 10 equiv) and ammonium chloride (2000 mg, 37.7 mmol, 10 equiv) The resultant reaction mixture was allowed to stir at 90 °C for 2 h. Progress of the reaction was monitored by TLC and LCMS. Alter completion of (he reaction, the mixture was concentrated under vacuum diluted with water (20 ml) and extracted with EtoAc (20 ml). Organic layer was washed with water (10 ml) and brine (10 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 3--fiuoro-4--{hexahydropyrro!op ,2- a]pyrazin-2(l H)-yl)aniline (800 mg, 8296) as a dark brown solid compound. LCMS: 236 [M+H]

[0447] Step-3: Synthesis of S-t1uoro-N-(3-Huoro-4-(hexaliydropyrroio[l,2-a]pyra2in-

2(lH)-yl)phenyl)-4-(8-t1uoro-4-isopropyI-3 _» 4-dihydro-2H-beo*o[h] j 1 ,4]oxa*m-6- yi)pyri idin-2-amme: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fiuoro-4- isopropyi-3,4--dihydro--2H-benzo[b1[ 1 ,4joxazine (60 mg, 0.18 mmol, 1 equiv) m dioxane (4 niL). was added 3--fluoro-4-(hexahydropyrroio[i,2-a]pyrazim2(lH)-yl)amiine (51 mg, 0.24 mmol, 1.2 equiv) and cesium carbonate (90 mg, 0.27 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 10 min., followed by the addition of palladium acetate (6 mg, 0 018 mmol, 0.1 equiv) and BINAP (24 mg, 0 036 mmol, 0.2 equiv). Hie resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TEC and LCMS. After completion of the reaction, diluted with water (10 niL) and extracted with ethyl acetate (10 niL) Organic layer was washed with water (5 mL) and brine solution (5 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which w¾s purified by reverse phase KPLC to obtain 5-fluoro-N-(3-fluoro-4- (hexahydropyrrolo[l,2-a]pyrazin-2(l H)~yl)phenyl)-4-(8-fluoro-4-isopropyi-3,4~dihydro~2H- benzo[b][l ,4]oxazm-6-y])pyrimidin-2-amme (15 mg, 1 1%) as a yellow solid compound. LCMS: 525 [MH1] ", I hYHM: (400 MHz, DMSO-r/6) d 10.1 6 (s, 1 1 1). 9.83 (d, J = 3.1 Hz, l i ft. 9.74 (s.

IH), 8.59 (d, J= 3.9Hz, 1H), 7.83 (dd, / 15.1 Hz, 1H), 7.40 (d, ./= 10.7 Hz, 2P) 7 16 (d,

7 1 1.5 Hz, I H), 7.13 - 7.04 (m, i l l). 4.30 (t, 7 4.2 Hz, 2H), 4 1 6 (;,. J= 6.6 Hz, IH), 3.90 -

3 83 (m, 1 H). 3.66 (dd, - 19.4, 12.3 Hz, 2H), 3.45 (44, - 26.2, 1 1.2 Hz, 2H), 3.34 (a, I 4H), 3.17 (t. J ---- 3.8 Hz, I H), 3.12 - 2 91 (m, 21 h. 2.23 - 1 95 (m, 4H), 1.63 (t ,/- 10.2 Hz, OH). 1.1 9

(d, / 6.5 Hz, 7H).

Example-82: Synthesis of l-(4~(6~((5~fluoro~4~(8~fluoro~4~isopropyl~3, 4-dihydro-2H~ benzo[b][J4]oxazin-6-ylJpyrhmdin-2-yl)am fto)pyridin-3-yl)piperazm~l~yl}ethan~l~one.

[0448] Step-l : Synthesis l-(4-(6-n«tropyridl«-3-yI) piperazhi-l-yl) ethan-l-one: To a stirred solution of 5-broino-2-mtropyridme (500 mg, 2.47 mmol, 1 equiv) in DMSO (10 ml,) was added TEA (0.7 inL, 4 9 mmol, 1 .5 equiv) arid l-(piperazin-1 -yl)efhan-1 -one (474 nig, 3.7 mmol, 1 .2 equiv) The resultant reaction mixture was allowed to stir at 120 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with ice water (50 mL) and extracted with ethyl acetate ( 100 ml ..·. Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain to obtain l--(4--(6- nitropyriclin-3-yl) piperazm-d-y!) ethan-l -one (250 mg, 40%) as a brown solid compound.

LCMS: 251 [Mali] "

[0449] Step-2: Synthesis of i-(4~(6~aminopyridia-3-yl) piperazm-l-yl) ethan-l-one; To a stirred solution of l-(4-(6-nitropyridin-3-yl)piperazin-l-yl)ethan-l-one (250 mg, 1 mmol, 1 equiv) in ethanol (6 mL), water (2 mL), was added iron powder (168 mg, 3 mmol, 3 equiv) and ammonium chloride (108 mg, 2 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for Ih Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the mixture was passes through cetite bed and the filtrate was concentrated under reduced pressure to obtain l~(4~(6~aminopyridin-3~yl)piperazin-l-yl)ethan-l-one (200 mg, 91%) as dark brown color solid compound. LCMS: 221 [M+H]

[0450] Step-3: Synthesis of l-(4-(6-((5-fluoro-4-(8-fluoro-4-isopropy!-3,4-dihydro-2H- benzo[b][l,4]oxazin-6-yI)pyrimidin-2-yI)aitnino)pyndin-3-y!) piperazin-l-yI)ethan-l-oae: To solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3,4 -dihydro-2H- benzo[b][l ,4]oxazine (100 mg, 0 3 mmol. 1 equiv) in dioxane (10 ml,), was added l-(4-(6- aminopyridin-3-yl)piperazin-l -yl)ethan-l -one (73 mg. 0.33 mmol, 1 .1 equiv) and cesium carbonate (147 mg, 0.45 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0 006 mmol. 0.02 equiv) and BINAP (8 mg, 0 012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir ai 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 uti l and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain l-(4-i6-((5-fiuoro-4-(8-fluoro-4- isopiOpyi-3,4-dihydro-2H-benzo| b]| l ,4]oxazin-6-yl)pyrimidin-2-yi)amino)pyridin-3- y!lpiperaziml -yfiefhaml -one ( 10 mg, 6%) as an off white color solid compound. LCMS: 510 | M 1 1 1 7 'HNMR (400MHz, DMSO-d ₆₎ d 9.73 (s, 1 H), 8.57 (d, ,7-3.9 Hz, 1 H), 7 98 8.11 (m, 2 H), 7 36 7.50 (m, 2 H), 7.17 (d, =11 0 Hz, I H), 4.30 (br. s„ 2 H), 4.15 (br. s , 1 H), 3.59 (br. s , 4 H), 3.31 (d, J = 4 6 Hz, 2H), 3.13 (br s., 2 H), 3 07 (br. s. _s 2 H) 05 (s, 3 H), 1.19 ppm (d.

, =6.6 Hz, 6 H)

Example-83: Synthesis of 5~fluoro~4~(8~fluoro~4~isopropyi~ 3, 4-dihydro-2H~henzo[b }[/, 4]oxazin~ 6~yi}-N~(5~(4~{meihylm!fonyi)pipen n~l~yi)pyridin~2~yi)pyrimiciin~2-amine. (Compound 975;

(0451 j Step-1: Synthesis of i~(metfay!sulfonyi)-4-(6-nitrop>Tidm-3-yl)pipera*ine: To a cooled suspension of l-(6-nitropyridin-3-yl)piperazine (1600 mg, 6.55 m ol, 1 equiv) in DCM (30 ml,) was added TEA (3.5 ml .. 19 65 mmol . 3 equiv) at 0 °C followed by addition of esyi chloride (905 mg, 7.85 mmol, 1 2 equiv) at 0 ^C C Resultant mixture was allowed to stir at room temperature for 16 b Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (20 ml,) and extracted with DCM (30 ml,) Organic layer was washed with water (20 ml, x 3) and brine (5 ml,), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 1 ~(metbylsulfonyl)-4~(6~ nitropyridin-3-y] (piperazine (1600 mg) as an oil LCMS: 588 [MH1] ^’

[0452] Step-2: Synthesis of 5-(4-(methyIsuIfonyl)piperazin-l-yI)pyridin-2-aimine: To a stirred solution of l-(methylsu]fonyl)-4-(6-nitropyridin-3-yl)piperazine (1000 mg. 3.5 mmol, 1 equiv) m ethanol (8 ml,), water (3 ml,), was added iron fillings (1 900 mg. 35 mmol, 10 equiv) and ammo um chloride (1960 mg, 35 mmol, 10 eqmv). The resultant reaction mixture was allowed to stir ai 80 °C for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was concentrated under vacuum diluted with water (20 ml,) and extracted with EtoAc (20 ml,). Organic layer was washed with water (10 mL) and bone (10 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 5-(4-(methy Isulfony l)piperazin- 1 -yl)pyridin-2-amine (800 g, 82%) as a dark brown solid compound. LCMS: 257 [M+H] [0453] Step-3: Synthesis of 5-fluoro-4-( 8-t1uoro-4-isopropyI-3 _» 4-dihydro-2H- henzo j b j [1 ,4] oxazi«-6-yI)-N-( 5-(4-(methylsuIfonyl)pipera2m-l-yi)pyridm-2-yl)pyrumdm-2- amine: To a solution of 6- 2-ehloro~5~iTuoropyrimidin~4~yl)-8-fliKirG-4-isopropyl-3,4-d ihydro- 2H-benzo[b][l ,4]oxazine (3? mg, 0.1 1 mmol, 1 equiv) m dioxane (3 niL), was added 5-(4~ (methylsulfonyl)piperazin-l-yl)pyndin-2-amine (32 mg, 0.13 mmol, 1.2 equiv) and cesium carbonate (71 mg, 0.22 mmol. 2 equiv). The reaction mixture was degassed by nitrogen gas for 10 mm., followed by the addition of palladium acetate (2.4 mg, 0.01 1 mmol, 0.1 equiv) and BINAP (14 mg, 0.022 mmol, 0 2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (10 ml,) and extracted with ethyl acetate (10 ml,). Organic layer was washed with water (5 ml,) and brine solution (5 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain 5-fluoro-4-{8-fluoro-4-isopropyl-3,4-dihydn>2H- benzo[b](l,4]oxazin-6~yl)-N~(5-(4-(meihylsu!fonyl)piperazin- 1 -yi)pyridin~2-y{)pyriraidin-2~ amine (5 mg, 8%) as a yellow solid compound LCMS: 546 [M+H] 3 *HNMR: (400 MHz, CHLOROFORM^) d 8.24 (t, J= 7.3 Hz, 1H), 7.90 (s, 1H), 7.35 (s, 1H), 7.31 (s, OH), 7.22 (d, J ----- 12 6 Hz, 1H), 4.30 (t, J ------ 4.4 Hz, 1H) 4.12 (s, OH), 3.32 (d, ,/ === 10 8 Hz, 53H), 3.21 (s, 2H),

2.80 (s, IH), 1.18 (d, J --- 6 4 Hz, 4H).

iiwtfwp/c-dti; Synthesis of 5-jhioro-N-(3-ftiioro-4-(l-met.hylpiperidin~4-yl) phenyi)-4~(8~fiuoro~4~

[0454] Step- 1 : Synthesis of 6-bromo-8-fluoro-4-isobutyl-2H-benzo|b] [l,4]oxazin-3(4H)- one: To a stirred solution of 6-bromo-8-rluoro-2H-benzo[b ||d ,4]oxazm-3(4H)--one (2500 mg, 10.1 mmol, 1 equiv) in DMF (20 mL), was added K · ⁽ O-. (2801 mg, 20.3 mmol, 2 equiv) and b- iodo-2-mefoylpropane (2.3 mL 20.3 mmol, 2 equiv). The reaction mixture was allowed to stir at 80°C for 3 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 2). Organic layer was washed with water ( 100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6~bromo~8~flnoro-4~isobutyl·- 2H-benzo[b][] ,4]oxazin-3(4H)-one (2300 mg, 75%) as a brown color solid compound. LCMS: 302 [MAI] ⁺

[0455] Step-2: Synthesis of 6-hro o-8-fluoro-4-isobutyl-3,4-dihydro-2H”

henzojhj j 1,4 joxazme: To a stirred solution of 6-bromo-8-fluoro-4-isobutyi-2H- benzoibli l,4]oxazin- 3(4H)-one (2000 mg, 6.6 mmol, 1 equiv) in THF (20 mL), was added BPL.DMS (2M in THF) (13 mL, 26.6 mmol, 4 equiv) at 0 C drop wise. The reaction mixture was allowed to stir at 60 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. A fter completion of the reaction , the reaction mixture was quenched with saturated solution of NaHCCL (100 ml,) and extracted with ethyl acetate (100 ml, x 2). Organic layer was washed with water (100 L), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6-bromo-8-i1uoro-4-isobutyl~3,4-dihydro-2H~benzo[b][i ,4]oxazine (1800 mg, 94%) as a transparent oily compound. LCMS; 288 [M+H]

[0456] Step-3: Synthesis of S-fluoro-^isobut Le-C^^S-tetramethyl-l _j Sdi- To a stirred solution of 6-bromo-B- fluoro-4-isobuty 1-3 ,4-dihydro-2H-benzo[b] [ 1 ,4]oxazine (1800 mg, 6.27 mmol, 1 equiv) in dioxane (20 mL), was added 4,4,5,5-tetramethyl-2-(4,4,5,5-teiramethyl-l,3,2-dioxaborola n-2-y])- 1 ,3,2-dioxaboiolane (2390 mg. 9 4 mmol, 1.5 equiv). Potassium acetate ( 1536 mg, 1 5.6 mmol, 2.5 equiv) and). Purged the reaction mixture with nitrogen gas for 1 5 ruin , Pd(dppf)C12. DCM (256 mg. 0 78 mol, 0.05 equiv) was added to above mixture and the reaction mixture was allowed to stir at 100°C for 3 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, foe reaction mixture was diluted with water (100 L) and extracted with ethyl acetate (1 50 ml, >< 2). Organic layer was washed with brine (150 L) and water (150 L) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 8-fluoro-4-isobutyl-6-(4,4,5,5-tetramethyL] ,3 2-dioxaboroian-· 2-yl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazme (2000 mg, 95%) as a dark brown viscous compound. LCMS: 336 [M+H]

10457] Step-4: Synthesis of 6-(2-cfeloro-5-fIuoropy »idi«-4-yl)-8-11iioro-4-isofeuiyi-3,4- dihy<iro-2H-benxo b][l,4]oxazme: lb a stirred solution of 2, 4-dichloto-5-fluoropyri xdine

(1000 mg. 6.02 mmol, 1 equiv) in THF: Water 0 : 1= 20 niL) was added 8-fluoro-4-isobutyi-6- (4,4,5,5~tetrameihyl l ,3,2-dioxaboroian~2~yl)-3,4 dihydro- 2H-benzoib][i,4]oxazine (2018 mg, 6.02 m ol, 1 equiv). Potassium carbonate (1662 mg, 12.04 mmol, 2 equiv) and Pd/ Pin g (347 mg, 0 3 mmol, 0.05 equiv) The reaction mixture was allowed to stir at 80°C for 4 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted wit ethyl acetate (150 mL ^c 2) Organic layer was washed with water (100 mL) and brine (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-(2-ch!oro-5~fluoropyrimidin-4-yl)- 8-fluoro-4-isobuty!-3,4-dihydro-2H-benzo[b][l ,4]oxazine (1300 g, 64%) as a yellow solid compound. LCMS: 340 [M+H]

[0458] Step-5: Synthesis of tert-butyl 4-(2-fluoro-4-((5-fiuoro-4-(8-fiuoro-4-isobutyi-3,4- dihydro-2H-benzo(h]jl 4joxazm-6-yl)pyrimiilIn-2-yl)amIno)pheny!)piperidine-l- carboxylate: To a solution of 6-(2-chloro-5-i1uoropyrimidm~4-yl)~8~fluoro-4~isobutyl-3,4 - dih dro-2H-benzo[b] [1,4] oxazine (70 mg. 0 2 mmol, 1 equiv) in Dioxane (5 ml,), was added tert-butyl 4-(4-amino-2~i!uQrophenyl)piperidine-I-earboxylate (63 mg. 0.22 mmol, 1 .1 equiv) and cesium carbonate (98 mg, 0.3 mmol, 1 .5 equiv). The reaction mixture was purged with nitrogen gas for 30 min., followed by the addition of palladium acetate (1 mg, 0.008 mmol, 0.02 equiv) and BINAP (5 mg. 0.004 mmol, 0.04 equiv). The resultant reaction mixture w¾s allowed to stir at 1 00 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with wa ter (30 ml,) and extracted wit ethyl acetate (100 rnL). Organic layer was washed with water (50 ml,) and brine (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi flash to obtain tert-butyl 4-(2-fiuoro-4-(t5-fiuoro-4-t8-fluoro-4-isobutyl-3,4-dihydro- 2H-benzo[ bj[ l 4joxaxm-6- y!}pyrHnidin-2-yi)amino}phsnyl)piperidine-l -cafboxylate ( 100 mg, 83%) as a yellow solid compound. LCMS: 598 [M+H]

10459] Step-6: Synthesis of S-t1uoro-N-(3-(luoro-4-(piperidin-4-yi) phenyl)-4-(8-liuoro- 4-lsobutyI-3, 4-dfliydro-2H-ben2o[b] [l,4]oxaz«i-6-yl)pyri idin- 2-amine: tert-buty! 4-(2- fluoro-4-((5-fluoro-4-(8-fluoro-4-isobutyi-3,4~dihydro~2H-be nzo b] L4]oxazin-6~yl)pyriinidm- 2-yl)amino)phenyl)piperidine-l-carboxylate (100 mg, 0 16 mmol, 1 equiv) was taken in 1.25 M HC1 in ethanol (5 mL) and the resultant reaction mixture was allowed to stir at 50°C for lh. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophilizer to obtain crude compound, which was purified by making HC! salt to afford 5MuorO N-(3-f!uoro-4-(pipendin-4- yl)phenyl)-4-(8-fluoro-4-isobutyl-3, 4-dihydro- 2H-benzo[b][l,4]oxazin-6-yl)pynmidin-2-amine (90 mg, 83%) as a yellow color solid compound. I, CMS: 498 [M+H]

j 0460] Step- ?); Synthesis of 5-fluoro-N~(3~fluoro-4~( l~methylpiperidin~4~y!) phenyl)~4~

(8-fluoro-4-isobutyl-3, 4-dihydro-2H-benzo b1 [ 1 ,4] oxazin-6-yI)pyrimidm-2-amine: To a stirred solution of 5-fiuoro-N~(3~fIuoro~4~(piperidm~4~y!)phenyl)-4-(8-fluoro-4- isobutyl~3,4- dihydro-2H-benzo[b] [ 1 ,4]oxazin-6-y!)pyrimidin-2-amine (70 mg, 0.14 mmol, 1 equiv) in DCE (5 ml,), was added Formaldehyde (40% water) (0 02 ml,, 0.42 mmol, 3 equiv), acetic acid (0.04 ml,, 0.72 mmol. 5 equiv). The reaction mixture was allowed to stir at RT for lh. The reaction mixture was cooled to 0°C. NaCNBH (27 mg, 0.43 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for lh. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with ethyl acetate (50 ml, 2) Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HP LX) to afford 5--fluoro--N-(3 -iluoro-4-(l -methylpiperidin-4- yl)phenyl)-4-(8-fluoro-4-isobulyl-3,4-dihydro-2H-benzo[h](l, 4]oxaz:in-6-yl)pymmdm-2-arnine (5 mg, 7%) as a yellow solid compound. LCMS: 512 i \ i · i l l ⁺ , ^l K MM (400MHz, DMSO-fo) 6 9.93 (s, 1 H), 8.61 (d, J=3.9 Hz, 1 I I) 7 78 (d, ,7=13.6 Hz, 1 H), 7.46 (d, 7=7 5 Hz, I I f ). 7.21 - 7.32 (m, 2 H), 7 01 - 7.21 (m, 1 H), 4.30 (h s., 2 H), 3 47 (hr s. , 2 H), 3 33 (br. s. , 2 H), 3.13 (d, ./ 6.6 Hz, 2 H), 2.85 for s., 2 H), 2 67 (hr. s., 3 1 1} 2.08 (d ./ 6. 1 Hz, 2 H), 1.86 (br s., 4 H), 0.90 ppm

Example-85: Synthesis qfN~(5~(J4~diazepan~l~yI)pyridin~2~yO~5~fluoro~4~(8-fluoro~4 ~ isopropy]~3A~dihydro~2H~henzo[hj[l,4]oxazin~6~yi)pyrimidin~2 ~ mine. (Compound 477)

[0461] Step-1: Synthesis tert-butyl 4-(6-nitropyridin-3-yl)-l, 4~diazepane~l~carboxylate:

To a stirred solution of 1 , 2-di†1uoro-4-nitrobenzene (500 mg, 2.47 mmol, 1 equiv) m DMSO (10 mL) was added k ·( 0. (682 mg, 4.9 mmol, 2 equiv) and tert-butyl 1 , 4-diazepane-I-carboxylate (743mg, 3 76 mmol, 1 .5 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overmght. Progress of foe reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with ice water (50 mL) and extracted with ethyl acetate ( 1 50 mL) Organic layer was washed with water (50 mL) and urine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain to obtain tert-butyl 4~(6-nitropyridin-3-yl)~ 1 ,4-diazepane-l -carboxylate (550 mg, 69%) as a brown oily compound.

LCMS: 323 [M+H] ^÷

[0462] Step-2: Synthesis of tert-butyl 4-(6-aminopyrid«B-3-yl)-l, 4-dia*epane-l- carboxylate: To a stirred solution of tert-butyl 4-(6-nitropyridin-3-yl)-l ,4-diazepane-l- carboxylate (550 mg, 1.7 mmol, 1 equiv) in ethanol (6 mL), water (2 mL), was added iron powder (287 mg, 5.12 mmol, 3 equiv) and ammonium chloride (184 mg, 3.4 m ol, 2 equiv).

The resultant reaction mixture was allowed to stir at 90° for Hi. Progress of the reaction was monitored by TLC and LCMS Alter completion of the reaction, the mixture was passes through celiie bed and the filtrate was concentrated under reduced pressure to obtain tert- butyl 4-(6- ammopyridin-3-yi)-l, 4-diazepane-l -carboxyiate (400 mg, 80%) as a dark brown color viscous compound. LCMS: 293 [M+H] ^÷

[0463] Step-3: Synthesis of tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyi-3,4- d«hyclro-2H-ben*o b][l,4)oxa2m-6-yl)pyrimidm-2-yl)ammo)pyridia-3-yi)-i,4-diaa! ;epane-l- carboxyiate; To a solution of 6~(2-chloro-5-iluoiOpyrimidin-4-yl)-8-fluoro-4-isopiOpyl-3,4 ·- dihydro-2H-benzo[b]il,4]oxazine (100 mg, 0.3 mmol, 1 equiv) m dioxane (10 mL), was added tert- butyl 4~(6~ammopyndin-3-yl)-l , 4-diazepane-l -carboxyiate (96 mg, 0 33 mmol, 1.1 equiv) and cesium carbonate (14? mg, 0.45 mnio!, 1.5 equiv). Hie reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.006 m ol, 0 02 equiv) and BINAP (8 mg, 0 012 mmol , 0 04 equiv). The resultant reaction mixture was allowed to stir a t 100 °C for overnight. Progress of the reaction was moni tored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain ten-butyl 4-{6-((5-fluoro-4-(8~ fluoro-4-isopropyj-3,4-dihydro-2H-benzo[b] l,41oxazin-6-yi)pyrimidin-2-yj)amino)pyridin-3- yl)- 1 , 4-diazepane-l -carboxylate (50 mg, 28%) as a yellow color solid compound. LCMS: 582 j M H i ^÷

[0464] Step-4: Synthesis of N-(5-(l,4-diazepfm-I-yi)pyrldl5s-:2-yi)-5-fluoro-4-(8-fluoro -4- isopropyl-3, 4-dihydro-2H-henzo[b] [1 ,4]oxazhi-0~yI)pyrhmd*n-2~anmie: tert-butyl 4-(6-((5- fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benz.o[b][l ,4]oxazin-6-yi)pyrimidin-2- yj)ammo)pyridin~3~yl)-l , 4-diazepane-l -carboxyiate (35 mg, 0 06 mmol. 1 equiv) was taken in 1 25 M HCi in ethanol (5 mL) and the resultant reaction mixture was allowed to stir at RT for Ih Solvent was removed under reduced pressure and the residue was dried under lyophihzer to obtain N-(5--( !,4-diazepan~l -yi}pyridim2-y!)-5-iluoro-4-(8-iluoro-4-isopropy!-3,4-dihydr o--2H- benzo[b][l,4]oxazi«~0-yl)pymnidm-2-ami«e ( HC1 salt) (30 mg, 97%) as a yellow color solid compound. LCMS: 482 [M+H] ⁺ ; ¾NM (400MHz, DMSG-de) d 9.26 (hr. s., I 1 1 }. 8.72 (d,

./ 1 Hz, 1 H), 7.86 (hr. s , 1 H), 7.68 - 7.84 (m, 2 1 11 7.39 (s, I H), 7.19 (d, 7 M 4 Hz 1 H) 4.31 (d, ./ 1 5 Hz, 2 H), 4 06 4.21 (m, I H), 3.77 (hr s., 2 H), 3 53 (hr s„ 2 1 1) 3 28 3.37 ( , 4 H), 3.16 (hr. s., 2 å-]), 2.1 1 (br. s., 2 H) 1.06 · 1 26 ppm (m, 6 H}.

Fdcample~86: S^ ihesis qfN-(5 (!, 4-diazejxm-l-yI) pyridin~2~yl)-4~(4~cydopeniyi~8-fluoro~3, 4-

[0465] Step-1 : Synthesis of tert-butyi 4-(6-nitropyri in-3-yI)- 1, 4-dia*epane-l- carboxylate: To a stirred solution of 1, 2-diiluoro-4-mttobenzene (500 mg, 2.47 mmol, 1 equiv) m DM SO (10 ml), was added KA ^' O (682 mg, 4 9 mmol, 2 equiv) and tert-butyi 1, 4- diazepane-i-carboxylate (743mg, 3.76 mmol, 1.5 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with tee water (50 mL) and extracted with ethyl acetate (150 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain to obtain tert-butyi 4-(6-nitropyridin-3~yl)-l , 4-diazepane-l- carboxylate (550 mg, 69%) as a brown oily compound. LCMS: 323 [M+H]

[0466] Step-2: Synthesis of tert-butyi 4-(6-aminopyridin-3-yl)-l, 4-dia*epane-l- carboxy!ate: To a stirred solution of ten-butyl 4-{6-nitropyridin-3-yl)-l ,4-diazepane-l - earboxy!ate (550 mg, 1 7 mmol, 1 equiv) in ethanol (6 mid, water (2 mid, was added iron powder (287 mg, 5.12 mmol, 3 equiv) and ammonium chloride (184 mg, 3 4 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 90° for Ih. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the mixture was passes through ceiite bed and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(6- aminopyridin-3-yiH , 4-diazepane-l -carboxylate (400 mg, 80%) as a dark brown color viscous compound. LCMS: 293 [M+H]

[0467] Step-3: Synthesis of tert-butyl 4-(6-((4-(4-cyclopentyi-8-iliioro-3,4-dihy ro-2H- ben*o[b][l,4]oxa*in-6-yl)-5-fliioropyrimid«n-2-yl)am«no)py ridm-3-yl)-i ,4-dia2;epane-l- carboxylate: To a solution of 6 (2 Chloro-5-imoropyrimidm-4-yl)-4-cyclopentyl-8-iluoro-3,4- dihydro-2H-benzo| b]n ,4]oxazme (100 mg. 0.3 mmol, 1 equiv) in dio ane (10 niL), was added tert-butyl 4 (6-ammopyndin-3-yl)-L4-diazepane-i-carboxylaie (92 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.45 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 1 00 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which w¾s purified by reverse phase HPLC to obtain tert-butyl 4-(6-((4-(4-cyclopenty!~8- iluoro~3,4-dihydro-2H~benzo]b][I ,4]oxazin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yi)- 1 , 4-diazepane-l-carboxylate (20 mg, 12%) as a yellow color solid compound LCMS: 608 [M+H]

[0468] Step-4: Synthesis of N-(5-(1 , 4-diazepan-l-yl) pyridm-2-yl)-4-(4-cydopentyI~8- Ifeoro-3, 4-dihydro-2II-benzo [b] [1,4] oxazin-6-y l)-5-fl uoropy rimid in-2-amine: tert-butyl 4-

(6-((4-(4-cyclop< tyi-8-f1uoro-3,4-dihydro-2H _~ benz.o|b]| l ,4]oxazin-6-y!)-5-t1uoropyrimidin-2- yl)amino)pyridm-3-yl)-L4-diazepane-I-carboxyiate (mg, mmol, i equiv) was taken in 1.25 M HG in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at RT for lh.

Solvent was removed under reduced pressure and the residue was dried under lyophilizer to obtain N-(5-(l ,4-diazepan-1 ~yl)pyridin-2-yl)-4-(4-cyclopentyl-8-fluoro-3,4-dihydro-2H- benzo[b][l ,4joxazm-6-yl}-5-fiuoropyriimdin-2-amine ( HC! salt) (7 mg, 78%) as a yellow color solid compound LCMS: 508 [M÷H] ⁺ ; ¾NMR (400MHz, DMSO~d ₆ ) d 9 12 (br. s. , 1 H), 8.69 (hr. s , 1 H), 7.84 (br. s , 3 H), 7.43 (br s., 1 H), 7 20 (d, JMO. I Hz, 1 H), 4.33 (br. s., 2 H), 4.26 (br. s , 1 H) 3.76 (br. s, 2 H), 3.52 i d. / 5 1 Hz, 1 i n. 3.35 (br. s„ 3 H) 3.26 (br. s . 2 i n. 3.17 (br. s., 3 H), 2.10 (br. s„ 2 å-]), 1.88 (br. s., 1 i . 1.71 (br. s, 2 H), 1.62 ppm (br s„ 4 H)

Example-87: Synthesis of 5~fluoro-4~(8~fluoro-4~isobut\>l~3, 4~dihydro~2H-benzofh] [ 1, 4joxozin-

[0469] Step-1: Synthesis of tert-butyl 4-(6-((5-fiuoro-4-(8-fiuoro-4-isob«tyI-3,4-dihydro- 2H-ben¾o(b]fl,4]oxa*in-6-yl)pyriimidin-2-y!)amino}pyridin-3 -yi)piperi ine-l-carboxyIate: To a solution of 6-(2-chloro-5-fluoropyiirnidin-4-yl)-8-fluoro-4-isobutyl-3,4 -dihydro-2H- benzo[b] [ 1 ,4] oxazine (70 mg, 0.2 mmol, 1 equiv) in Ehoxane (5 ml.), was added tert-butyl 4-(6- aminopyridm-3-yl)piperidine-l-carboxyiate (63 mg, 0.22 mmol, 1 . 1 equiv) and cesium carbonate (98 mg, 0 3 mmol, 1.5 equiv) The reaction mixture was purged with nitrogen gas for 30 min. followed by the addition of palladium acetate (1 mg, 0.008 mmol, 0.02 equiv) and BINAP (5 mg, 0.004 mmol, 0 04 equiv). Hie resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. Alter completion of the reaction tbe reaction mixture was diluted with water (30 mb) and extracted wit ethyl acetate ( 100 mL) Organic layer was washed with water (50 ml . ) and brine (50 mL) Organic layer was dried over anhydrous sod mm sulphate and concentrated under reduced pressure to obtain crude compound, winch was purified by normal phase combi hash to obtain tert-butyl 4~(6~((5-fli3oro~4~(8-fluoro~4~isobuiyl-3,4-dihydro-2H-benzo [b][l,4]oxazm~6- yl)pyrimidin~2-yi)amino)pyndm-3-yi)pipendine-l-carboxyiate (100 g, 83%) as a yellow solid compound. LCMS: 581 [M+H] ^"

[0470] Step-2: Synthesis of 5-fluoro-4-(8-fluoro-4-isobutyi-3, 4- lhydro-2H- benzo[b][l,4]oxazin-6~y!)-N-(S-(piperklln-4-yl)pyridm-2-yl)p yrimitlln-2-am«ae: tert-butyl 4- (6-( 5-fluoro-4- 8-f]uoro-4-isobutyl~3,4-dihydro-2H~benzo[b][l ,4]oxazm-6-yi)pyrimidin-2- yl}amino)pyridin-3-yl)piperidine-l -cafboxylate (100 mg, 0.17 mmol, I equiv) was taken in 1 .25 M HCi in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for !h. Progress of the reaction was monitored by LCM8. After completion of the reaction, solvent was removed under reduced pressure and the resi ue was dried under lyophilizer to obtain crude compound, which was purified by making HCI salt to afford 5-fluoro~4~(8-fluoro~4~isobuiyl-3,4- dihydro-2H-benzofb] [l,4]oxazin-6-yl)~N-f5-f pi peridin-4-yi)pyridm-2~yl)pyrimidm- 2-amine (70 mg, 84%) as a yellow color solid compound LCMS: 481 [M÷H]

[0471 Step-3: Synthesis of 5-fl«oro-4-(8-fl«oro-4-isobutyi-3, 4-dlhydro-2H- benzo[b][l,4]oxazin-6~yi)-N-(S-(l-methylpiperklin-4-yl)pyrid in-2-yl)pyrimitlin~2-amine: To a stirred solution of 5-fluoro~4-(8-fluoro-4-isobutyl-3,4-dihydro-2H-benzo[b][l,4] oxazin-6-yl)~ N-(5-(piperidin-4-yl)pyridm-2-yl)pyrimidin-2-amme (70 mg. 0.14 mmol, 1 equiv) in DCE (3 ml,), was added Formaldehyde (40% in water) (0 02 mL, 0/12 mmol, 3 equiv), acetic acid (0.04 mL, 0.72 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for lb. The reaction mixture was cooled to 0 ^C C NaCNBIR (27 mg, 0 42 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for lb Progress of the reaction was monitored by I, CMS. After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with ethyl acetate (50 ml, 2) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5-fluoro-4-(8-fluoro-4-isobutyl-3,4-dihydro-2H- benzo[b][! ,4]oxazin-6-yj)-N-(5-(1 -methylpipendin-4-yi)pyridim2-yl)pyrimidm-2-amine (3 mg, 4%) as a yellow color solid compound. LCiVISs 495 M/Ή] ’IINMR (400MHz, DMSO-ds) d 9 88 (s, 1 H), 8.61 (d, >3 5 Hz, 1 H), 8.32 (br. s.. I I n. 8.05 ·· 8 21 (m, 1 H), 7 63 (d, ./==8.8 Hz, 1 H), 7 29 (hr s„ 1 H), 7 16 (d, J-l 1.4 Hz, 1 H), 4.30 (br s., 2 H), 3 46 (hr. s., 2 H), 343 p i. ./ 7.5 Hz, 2 H), 2 96 (br. s., I H), 2.85 ( br. s. 1 H), 2.19 (s, 3 H), 2 05 Id, 7 14.5 Hz, I H), 1 .96 (t,

./ 10. 1 Hz, 1 H), 1.54 - 1.77 (m, 4 H), 1.45 (br. s , 2 H), 0.91 ppm (d, / ^::: 6.6 Hz, 6 H).

Example-88: Synthesis of N-(4-(4-(dimeihylamino) pipendin-l-yl)-3~fluorophenyl)~5~ftuoro~4~ (8-ftiioro-4-isohuiyl~ 3, 4-dihydro-2H~henzo[b j [1 , 4]oxazin~6~yl}pyrmidin~2-amine (Compound 480)

[0472] To a solution of 6 (2 Chlorofo-t!uoiOpyrimidim4 yl)~8 fluoro~4~isobutyi 3,4 dihydiO 21:I~benzo[b][l ,4]oxazine (100 mg, 0 29 mmol, 1 equiv) in Dioxane (5 n ;! } was added l-(4- arnino-2-fiuoiOphenyi)-N,N~dnnethylpiperidin-4-amme (76 mg 0 32 mmol, 1.1 equiv) and cesium ear donate ( 141 mg, 0.43 mmol, 1 5 equiv). The reaction mixture was purged with nitrogen gas for 30 min followed by foe addition of palladium acetate (1.3 mg. 0 005 mmol, 0.02 equiv) and BINAP (7 mg, 0 01 mmol 0.04 equiv) The resultant reaction mixture was allowed to stir ai 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction foe reaction mixture was diluted with water (30 ml,) and extracted wit ethyl acetate ( 100 mL). Organic layer was washed with water (50 mL) and brine (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain N-(4-(4-(dmiediylammo)pipendm--l -yl)--3--iluoropheny!)o-iIuoro-4-{8-iIuoro-4usobutyi·- 3,4-dihydro-2H-benzo[b3[l ,4]oxazin-6-yl)pyrimidin-2-amine (12 mg, 8%) as a yellow solid

0.90 ppm (d 7 67 Hz, 6 H).

Example-89: Synthesis N-(5-fhiGro-4-(8-f!uoro-4-isopropyl-3, 4~dihydro~2H- benzofh([J4joxazin-6-yl)pyrmidm-2-yl}~5,6, 7 _> 8-ieirahydro~l, 6~naphihyridln~2-amim.

(Compound 481}

thesis of tert-butyl 2-ehIoro-7,8-dihydro-l,6-naphthyridine-6(5B)- carboxylate: To the solution of 2~chloro-5,6,7,8-tetrahydro-l,6-naphthyridine (2000mg,

1 1.9mol, l equiv), taken m DCM (30mL), was added DIPEA (1.84g, 14.28mmol,1.2equiv) At (PC then was added Boe Anhydride (2.850mg,18.08mmol, 1 1 equiv (.Resulted reaction mixture was allow to stir RT for 2h. Progress of Reaction was monitored by LCMs/TLC. After completion the reaction mixture was diluted with water and extracted with DCM (200mL) organic layer was washed with water (30rnL) and brine soiudon(40rnL), resulted organic layer was dried over anhydrous sodium sulphate and purified by combi-flash column to tert-butyl 2- chioro-7, 8-dihydro·· l ,6-naphthyridine-6(5H)--carboxylate (2.2g of x%) as yellow colour solid LCMS: 269 [M+H]

[0474] Step-2: Synthesis of tert-butyl 2-((diphenyhnethyiene)amino)-7,8-d«hydro-1,6- naphthyridine-6(5H)-carboxyIate: To the solution of tert-butyl 2-chloro-7,8-dihydro-l,6- naphthyridine-6i5H)-carboxylate (1 g. 3.73mmoi, l equiv), taken m dioxane(20mL) was added diphenylmethanimine ( 0 74g, 4 13nunoL l . lequiv), cesium carbonate (2.42 g, 7.46 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 5 min., followed by the addition of I'd -dba (340 mg, 0.37 mmol, 0 1 equiv) and xanthphos (740 mg 0 74 mmol, 0.2 equiv) The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (50 l ) and extracted with ethyl acetate (200 mL) Organic layer was washed with water (100 nil,) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyl 2-((dipheny hnethylene)annno)-7,8-dihydro-- 1 ,6-naphthyridine-6(5H}-- carboxy!ate ( l . lg)as a yellow solid compound LCMS: 414 [M÷H] ^’ [0475] Step-3: Synthesis of tert-butyl 2-ami«o-7, 8-dihydro- 1 ,6-naphthyridine-6(5H)- carboxylate: To a solution of tert-butyl 2-iidiphenylmsthyiens)ammo) 7,8-dihydro-1 ,6- naphthyridme-6(5H)~carboxyiate (1469mg, 3 5mmol,iequiv) taken in methanoI(25mL), was added hydroxylamme hydrochloride (476mg, 7mmoi, 2equiv) resulted reaction mixture allowed to stir at RT for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with et!iy! acetate (100 mL). Organic layer was washed -with water (20 mL) and brine solution (30 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which -w s purified by normal phase combi flash to obtain tert-butyl 2- ((diphenylmethylene)amino)-7.8-dihydro- 1 fo-napbthyndniefoiSHj-carboxylate (0.57g of 95 83%) as a yellow solid compound LCMS; 250 [M+H]

[0476] Step-4: Synthesis of tert-butyl 2-((S-fluoro-4-(8-fluoro-4-isopropyl-3,4-tlihydro- 2H-benzo|b] {l,4|oxaz«i“6-yl)py*'»*»idin-2-yi)a iiio)-7,8-diliytlro-i,6-naphthyridiae-6(5H)- carboxy!ate: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3 _> 4- dihydro-2H-benzo[b] 1 ,4]oxazine (100 mg. 0.31 mmol, 1 equiv) in dioxane (4 mL), was added tert-butyl 2-i(diphenylmethylene)ammo)-7,B-dihydro-L6-naphthyridine-6(5 H)~carboxylate (84 mg, 0.33 mmol, 1 2 equiv) and cesium carbonate (151 mg, 0.46 mmol, 1 .5 equiv). The reaction mixture was degassed by nitrogen gas for 1 0 min. , followed by the addition of palladium acetate (7 rng, 0 031 mmol, 0.1 equiv) and BINAP (39 rng, 0 062 mmol, 0.2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (10 mL) and extracted with ethyl acetate (1 0 ml,). Organic layer was washed with water (5 ml,) and brine solution (5 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl 2-{{5-iiuoro-4-{8 iiuoro-4-isopropy]-3,4-dihydro-2H- benzoj b] j 1 ,4]oxazin-6-y 1 )pyrimidin-2-y i)amino)-7,8-dihydro- 1 ,6-naphthyridine-6( 5H)- carboxylate ( 135 mg crude). Used directly for next step LCMS: 539 [Mill] ^“

[0477] Step-5: Synthesis of N-(5-IIuoro-4-(8-fIuoro-4-isopropyl-3,4-dihydro-2H- benzo[b]{l,4joxazm-6-y!)pyrmndm-2-yl)-5,0 _> 7,8-tetrahydro-l,6-«aphthyrHim-2-amme: A solution of tert-butyl 2-{(5-fluoro-4-{8-fluoro-4-isopropyl-3,4-dihydro-2H-benxo[ bj[l 4]oxaxin- 6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-] ,6-naphtiiyndine-6i5H)-carboxylaie (135 g crude) in 1.25 M HQ in ethanol (5 mL) was allowed to stir for 1 h at 50°C. Progress of the reaction was monitored by LCMS After completion of the reaction, solvent was removed under reduced pressure to obtain crude which was purified by reverse phase HPLC to afford N-(5-fluoro-4-(8- fluoro-4-isopropyl-3.4-dihydro-2H-benzo[b] 1 ,4]oxazin-6-yl)pyrimidin-2-yl)-5,6,7,8~tetTahydro~ 1 ,6-naphthyridm-2-amine (20 mg) as a pale yellow solid compound. LCMS: 439 [M+H] ‘MN.MR: (400 MHz, DMSO--A6) d 9.83 (s, l i ft. 8.59 (d, J = 4.0 Hz, l i ft 8 30 - 8.20 (mJHj, 8.01 (d, J ^:::: 8.4 Hz, l i ft. 7.51 (s, l i ft. 7 41 (d, 7 - 8.5 Hz, Hi), 7.19 (d, J = 1 1.6 Hz, Hi), 4.30 (t,

[0478] Step-1: Synthesis of 6-brorao-4-c.yclobutyl-8-fluoro-2H~benzo[b | 1 l,4]oxazin~

3(4H)-one: To a stirred solution of 6-bromo-8-fluoro-2H-benzo[b|[l ,4]oxazm-3(4H)-one (2500 mg, 10.1 mmol, 1 equiv) in DMF (20 ml,), was added f· CO (661 8 mg, 20 3 mmol, 2 equiv) and bromocyclobutane (1.9 ml,, 20.3 mmol, 2 equiv). The reaction mixture was allowed to stir at 80°C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with wa ter (100 ml,) and extracted with ethyl acetate (1 50 ml, x 2). Organic layer was washed with water ( 100 mL). dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6-bromo-4- cydobutyi-8-fiuoro-2H-benzo[h][l ,4]oxazm~3(4H)-one (2500 rng, 82%) as a brown color viscous compound LCMS: 300 [M+H] ^’

[0479] Step-2: Synthesis of 6-brom©-4-cydobutyl-8-flu©ro-3, 4-d«hydro-2H- benz©[bj [l,4]oxazine: To a stirred solution of 6-hromo-4-cyclobutyj-8-fluoro-2H- benzojb]j l,4joxazm-3(4H)--one (2000 rng, 6.6 mmol, 1 equiv) in THF (20 ml,), was added BH .DMS (2M in THF) ( 13 mL 26.8 mmol, 4 equiv) at 0 C drop wise. The reaction mixture was allowed to stir at 5G°C for overnight Progress of foe reaction was monitored by TLC and LCMS After completion of foe reaction, the reaction mixture was quenched with saturated solution of NaHCO- ( 100 mL) and extracted with ethyl acetate (100 mL * 2). Organic layer was washed with water (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 6-bromo~4~cyclobutyl-8-iluoro-3,4-dihydro-2H-benzo[bl(l,4]ox azine (1100 mg, 58%) as a transparent oily compound. LCMS: 286 [MAH]

[0480] Step-3: Synthesis of 4-cyciobutyi-8-fluioro-6-(4,4,5 _» S-tetrai«ethyI-I _» 3,2- dioxaboroian-2-yl)~3,4-dihydro-2H-benzo(h]|I,4]oxa*ine: 6-bromo-4-cyclobutyl-8-fluoro-3,4- dihydro-2H-benzo[b]il,4]oxazine (1 100 mg, 3.8 m o!, 1 equiv), 4,4,5, 5~tetramethyl-2-(4,4, 5,5- tetramethyi-l,3,2-clioxaborolan-2-yl)-l,3,2-dioxaborolane (1471 mg, 5 7 mmol, 1.5 equiv), Potassium acetate (931 mg, 9.5 mmol, 2 5 equiv) and dioxane (15 mL) were charged in a 25 mL glass bottle. Purged the reaction mixture with nitrogen gas for 15 min. , Pd(dppf)C12. DCM (1 55 mg, 0 19 mol, 0.05 equiv) was added to above mixture and the reaction mixture was allowed to stir at 100 °C for 3 b Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL ^c 2) Organic layer was washed with brine (50 mid and water (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 4-cyclobutyl-8~fluoiO-6-(4,4,5,5--tetramediyLI.3,2--dioxabor olan-2-yi)-3,4- dihydro- 2H-benzo[b][l 4]oxazme ( 1200 mg, 93%) as a dark brown viscous compound. LCMS: 334 [MAH] "

[0481] Step-4: Synthesis of 6-(2-chloro-5-fl«oropyrimidin-4-yI)-4-eyclobutyI-8-fluoro-3 , 4-dihydro-2H-benzo[b] [l,4]oxazme: To a stirred solution of 2, 4-dichloro-5--fluoropyrimidine (600 mg, 3 16 mmol, 1 equiv) in THF. Water (1 : 1 ^::: 1 6 rnL) was added 4--cyclobutyL8~-ikioro~-6~· (4,4,5,5--tetrarnediyl--L3,2--dioxaboro!an-2-yl) 3,4-dihydiO 2H--benzo[b][l ,4]oxazine (1200 mg, 3.6 mmol, 1 equiv), Potassium carbonate (998 mg, 7 22 mmol, 2 equiv) and PdCPPlyft (208 mg, 0.18 mmol, 0 05 equiv). The reaction mixture was allowed to stir at 80 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted wit ethyl acetate (100 mL x 2). Organic layer was washed with water (100 mL) and brine (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6ft2-ch!oro-5-ftuoropyranidim4-yi)·- 4-cyclobutyl-8-fluoro-3,4-dihydro~2H-benzo[b][l,4]oxazme (500 mg, 41%) as a yellow color solid compound LCMS: 338 i \ l l l j

[0482] Step-5: Synthesis of l-(2-((4-(4-cyc!obutyl-8-fluoro-3,4-d«hydiO-2H- betzo(b]jlyt]oxa¾in-0-yI)-5-fluoropyrhnidin-2-yI)ainino)-7, 8-dihydro-l,6-naphthyridin- 6(5H)-yi)-2,2~dimethylpr<>pan~l~oae: To a solution of 6-(2-cMoro-5-fluoropyrimidin-4-yl)-4- cyciobutyl~8~iluoro~3,4-dihydro-2H~benzo[b][l,4]ox:azine (100 mg, 0 29 mmol, 1 equiv) in Dioxane (5 ml), was added tert-butyl 2-amino- 7, 8-dihydro- l,6~naphthyridine-6(5H)- carboxylate (81 g, 0.32 mmol, 1.1 equiv) and cesium carbonate ( 142 g. 0 43 mmol, 1.5 equiv). The reaction mixture was purged with nitrogen gas for 30 mm., followed by the addition of palladiu acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (7 mg, 0.013 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 rnL) and extracted wit ethyl acetate (100 ml,). Organic layer was washed with water (50 mL) and brine (50 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi flash to obtain 1 -(2-((4~(4~cyclobu†yl-8-ftuoro-3,4-dihydro-2H- benzo[b][l ,4]oxazin-6-yl)-5-t1uoropyrimidin-2-yl)amino)-7,8-dihydro-l ,6-naphthyndin-6(5B)- y l)-2,2-diraeih lpropan- 1 -one (100 mg, 61%) as a yellow color solid compound. LCMS: 551 [M-f-H]

[0483] Step-6: Synthesis ofN-(4-(4-eyclobutyI-8-fluoro-3,4~dibydro-2H- benzo[bj [J ,4]oxazin-6-yI)-5-fl«oropyriinidm-2-yl)-5,6,7,8-tetrahydro- J ,6-naphthyrid«n-2- amine: 1 -(2~((4~(4-eycJobutyl-8-fluoro-3, 4-dihydro- 2H-benzo[b][l ,4]oxazm-0-yl)-5- fluoropymmdm-2-yl)ammo)-7,8-dihydro-l,6-naphthyridin-6(5H)-y l)-2,2-diraethylpropan-l-one (100 mg, 0. 18 mmol, 1 equiv) was taken in 1.25 M HCl in ethanol (5 mL) and the resultant reaction mixture was allowed to stir at 50°C for I h Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain the residue winch was purified by reverse phase HPLC to obtain N-(4-(4-cyelobutyl-8-fluoro- 3 4-dihydro-2H-benzoibjil,4]oxazin-6-yl)-5-fluoropynmidm-2-yl) 5 6,7,8-tetrahydro-i,6·· naphthyridin-2-amine (20 mg, 24%) as a light orange color solid compound. LCMS: 451 [M+H] SI1NM:R (400MHZ, DMSO-dft d 10.12 (s, 1 1 1} 9 04 (hr. s., I H), 8.64 (d, -3.9 Hz, 1 H),

8.15 (d, ./ 8 3 Hz, 1 H), 7.64 (d, ./ 8.8 Hz, 1 H), 7 36 (s, 1 H), 7.27 (s, 1 H), 4 37 (d, .7-3.9 Hz, 2 H), 4.27 (br. s., 2 H), 3.89 · 4.09 (m, 1 H), 3.51 (br. s , 2 H), 3.31 (br. s., 2 H), 3 01 (t, ./ - 7 Hz, 2 H), 2.27 (br s., 2 H), 2 14 (d, ,7-11.0 Hz, 2 H), 1.73 ppm (dt, ,7-9 4, 4.9 Hz, 2 H).

Exampie~9l ; Synthesis qfN--(5-4hioro--4--(8-4hioro--4-4sohuiyi--3, 4-dihydro-2H- henso[b][l,4]oxazin~6~yl)pyrimidin~2~yl)-5, 6, 7,8-teirahydro~J 6~naphlhyridin~2~amme.

(Compound 483)

[0484] Step-1 : Synthesis of tert-butyl 2-((5-fluoro-4-(8-flaoro-4-isobutyl-3,4-dihydro- 2H~benzo{b| |I,4joxaein-6-yl)pyrimidin~2~yl)amino)-7,8-tlihydro-l,6~naph thyridiae-6(5H)~ carboxyiate: To a solution of 6~(2~chloro-5-fluoiOpyrimidin-4-yl)-8-fluoro-4-isobutyl~3,4- dihydro-2H-benzo[b]iI,4]oxazine (100 mg, 0.31 m ol, 1 equiv) in dioxane (4 ml,), was added tert-butyl 2-amino-7,8-dihydro-l ,6-napbthyridine-6(5H)-carboxylate (81 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (188 mg, 0.58 mmol, 2 equiv). The reaction mixture was degassed by nitrogen gas for 10 mm., followed by the addition of palladium acetate (7 mg, 0 03 mmol, 0.1 equiv) and BINAP (36 mg, 0 06 mmol , 0 2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (10 ml,) and extracted with ethyl acetate (10 nil,) Organic layer was washed with water (5 ml.,) and brine solution (5 ml.,). Organic layer was dried oyer anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl 2-

((5-iluoro-4-(8-iluoro-4-isohutyl-3,4-dihytiro-2H-benzo[b ][I ,4]oxazin-6-yl)pyrimidin-2- yl)amino)-7,8-dihydro-l 6-naphthyridme-6(5H)-carboxylaie (135 rng crude). Used directly for next step. LCMS: 553 [M-i-BTj

[0485] Step-2: Synthesis of N-(5-flnoro-4-(8-flnoro-4-isob«tyl-3,4-dihydro-2H- henzo[b j [ 1,4] oxazin-6-yI)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1 ,6-naphthyr«dm-2-amine: A solution of tert-butyl 2-((5-fluoro-4-(8-fluoro-4-isohutyl-3,4-dihydro-2H-benz.o[h] [l ,4]oxazm-6- yl)pyriuudin--2-yl)amino)--7,8-dihydro-h6--naphthyndine--6i5 H)-carboxylaie (135 g crude) in 1 25 M HCi m ethanol (5 L) was allowed to stir for I h at 50°C Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude which was purified by reverse phase HPLC to afford N-(5-fluoro-4-(8- fiuon 4 isobuiyl- 3,4-dihydro-2H-benzo[b][! ,4]oxazm-6-yi}pyriimdm 2 yi)- 5,6,7,8-tetrahydro- l,6-naphthyridin~2-amine (10 mg) as a pale yellow solid compound. LCMS: 453 [Mali] 1HNMR: (400 MHz, DM80-76} d 9.74 (s, III), 8.57 (d, 7 4.0 Hz, IH), 8.29 (s, IH), 7.72 (dd,

./ 15.3,2.5 Hz, I H), 7.44 (s, III), 7.36 (dd, 7 8.8, 2.5 Hz, I H), 7 16 (d, - 1 1.4 Hz, III), 6.97

(t, · 9.4 Hz,IH), 4.30 (t, 7 = 4.4 Hz, 2H), 4.16 (p, 7 = 6 6 Hz, IH), 3.30 (dd, J = 9.6, 5.2 Hz,

4H), 2.63 - 2.54 (m, 2H), 2.22 (s, 7H), 1.84 (dd, J= 12.7, 3 6 Hz, 2H), 1.54 (tt, 7- 13.3, 6.7 Hz, 21 1). 1.18 (d,J- ^: 6 5 Hz, 6H)

Example-92: Synthesis of l-~(6~((5~fluoro~4~(8~fluoro~4~isopropy ^! l~3, 4-dihydro-2H~

benzo{b]fl,4]oxazm~6~yl)pynffiidm~2~yl)amino)pyridin-3-yl )~4~methylpiperidin-4-ol.

[0486] Step-1: Synthesis of 4-meihyI-l-(6-nitropyridin~3~yI) piperidin-4-ol To a stirred solution of 5-bromo-2-nitropyridine (500 mg, 2.47 mmol, 1 equiv) m DMSO (10 ml,), was added K ₂ CO (683 mg, 4.95 mmol, 2 equiv) and 4-methyipiper din-4-ol (427 mg, 3.7 mmol, 1 5 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 ml ,), solid observed was filtered and dried under vacuum to obtain 4-meth l-1 -(6-nitropyridin-3- yl)piperidin-4-ol (500 mg. 85%) as a yellow solid compound. LCMS: 238 [M-HIj ^’

[0487] Step-2: Synthesis of l-(6-aminopyr«din-3-yi)-4-raethyipiperidin-4-ol: To a stirred solution of 4-methyl- 1 -(6-nitropyridin-3-yl)piperidin-4-o] (200 mg, 0 84 mmol, 1 equiv) in methanol (10 mL), was added Pd/C (20% w/w) (40 mg ) The resultant reaction mixture was allowed to stir at RT for Hi Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain l -(6-ammopyridin-3-yl)-4-methylpiperidin-4-ol (150 mg, 86%) as a white color solid compound. 1 , IS: 208 [M÷H] ⁺

[0488] Step-3: Synthesis of l-(6-((5-flaoro-4-(8-flaoro-4-isopropyl-3,4-dihyclro-2H- benzo j b j [ 1 ,4) oxazin-6~y!)pyrimidin-2-yl)amino)pyridin~3-yl)~4~methylpiper idin-4~ol: To a solution of 6~(2~chloro-5-fluoropyrimidm-4-yi)-8-fluoro-4-isopropyi-3,4~ dihydro~2H- benzo[b][ l,4]oxazine (100 mg, 0 3 mmol, 1 equiv) m dtoxane (3 l,), was added 1 -(6- ammopyridim3-yl)-4-meihylpiperidm-4-ol (68 mg, 0.33 mmol, 1 .1 equiv) and cesium carbonate (147 mg, 0 47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by recrystallization with methanol to obtain 1 -(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4- dihydro-2H-benzo[b]p ,4]oxazin-6-yi)pyrimidin-2-yl)amino)pyridin~3-yl)~4~methylpi peridin-4- ol (120 g, 78%) as a yellow color solid compound. I, CMS: 497 [M+H] : Il MS (400MHz,

DMSO-de) d 9 63 (s, 1 H), 8 55 ( , >=3.9 Hz, 1 H), 7.90 ·· 8 08 (m, 2 H), 7 46 (s, 1 H), 7.37 (dd, >=9.0, 2.9 Hz, 1 H), 7 17 (d, >=11.8 Hz, 1 H), 5.75 (s, 1 H), 4 23 - 4.32 (m, 2 H), 4.05 - 4.17 (m,

1 H), 3.24 (d, >=12.3 Hz, 4 H), 2 97 - 3.12 (m, 2 H), 1 .57 (d, >=4 4 Hz, 4 H), 1.05 - 1 30 ppm (m, 9 H).

Example-93: Synthesis of (l-(6-((5~fluoro-4~(8~fluoro-4~isopropy ^! l~3, 4-dihydro-2H- henzofb] [ l,4]oxazin~6~ylJpyrimidin~2-yl)ammo)pyhdm-3-yl)piperidin~d-y l)methanol.

[0489] Step-l : Synthesis of (l-(6-nitropyridin-3-yl) piperidin-4-y!) m thanol:: lb a stirred solution of S -bromofo-nitropyridine (500 mg, 2 47 mmol, 1 equiv) in DMSO (10 L), was added K 7 Ό-. (683 mg, 4.95 mmol, 2 equiv) and pipendm~4~ylmethanol (427 mg. 3 71 mmol,

1 5 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 mL), solid observed was filtered and dried under vacuum to obtain (l~(6~mtropyridin~3- yljpiperidm-4-yl) ethanol (330 mg, 56%) as a yellow solid compound. LCMS: 238 [M+H]

[0490] Step-2: Synthesis of (l-(6~aminopyridm-3-yl) piperidin-4-yl) methanol: To a stirred solution of (l-(6-nitropyridin-3-yl) piperidin-4-yl) methanol (200 mg, 0.84 mmol, 1 equiv) in methanol ( 10 mL), was added Fd/C (20% w/w) (40 mg). The resultant reaction mixture was allowed to stir at RT for I h. Progress of the reaction was monitored by TLC and LCMS.

After completion of the reaction, the mixture was passes through ceiite bed and the filtrate was concentrated under reduced pressure to obtain (l-(6-aminopyridin-3-yl) piperidin-4-yl) methanol (150 mg, 86%) as a white color solid compound LCMS: 208 [M÷H] ^”

[0491] Step-3: Synthesis of ( l-(6-((5-fluoro-4-(8~fluoro-4~isopropyl-3,4-dihydro-2H- benzo[h][l,4]oxazin-6-yl)pyrin»idin-2-yl)araino)pyridin-3-y l)piperidin-4-yi)raethanoI: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3 4-dihydro-2H- benzo[b][l,4]oxazme (50 mg, 0.15 mmol, I equiv) in dioxane (3 mL), was added (l -(6- aminopyridin-3-yI)piperidin-4-yl)methanol (35 mg, 0.16 mmol, 1 1 equiv) and cesium carbonate (73 mg, 0.23 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (1 mg, 0.003 mol, 0.02 equiv) and BINAP (4 rng, 0.006 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by recrystaHization with methanol to obtain ( 1 -(6-((5-fluoro-4-(8-fluoro-4-isopropyl- 3 4-dihydfO 2H--benzoib![!,4 joxazin-6-yi)pyrimidin-2-y!)anuno)pyndm--3--yi)piperidin-4-� � yi)methanoi (8 mg, 1 1%) as a yellow color solid compound. LCMS: 497 [M+H] h 'tlNMR

(400MHz, DMSQ-de) 6 9.64 (s, I H), 8.55 (d J - 4.0 Hz, I H), 8 03 - 7.95 (m, 2B), 7.46 (s,IH), 7.37 (dd, J - 9.1, 3.2 Hz, HI), 7.17 (d, J ^::: 11 7 Hz, HI), 4.49 (t, J - 5.4 Hz, H i). 4.33 - 4 26

(m,2H), 4.15 (p, J - 6.6 Hz, 1H), 3.63 (d, J - 1 1.9 Hz, 2H), 3.30 (s, 3H) 2 57 (m, 2H)

1.81 - 1.72 (rn,2H), 1.48 (d, J = 1 1.2 Hz, 2H), 1.27 (dt, J = 12 2, 6.4 Hz, 2H), 1.18 (d, J = 6.5 Hz, 6H).

Example-94: Synthesis of l~(6~((4~(4~cycIobut\>?~8-fluoro~3, 4-dihydro~2H-henzo[b] [1 ,4 Joxazin-

[0492] Step-1: Synthesis of l~(6~nitr©pyridiR~3-yI) piperidin~4~ol: To a stirred solution of

5--bromo--2-nitropyndme (500 mg, 2 47 mmol 1 equiv) in DMSO (10 mL) was added ELCCL (683 mg 4 95 mmol, 2 equiv) nd piperidin-4-ol (500 mg 4 95 mol, 2 eq v). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 mL), solid observed was filtered and drie under vacuum to obtain 1 -(6-nitropyridin-3-y 1 )pipendin-4-oi (400 mg, 73%) as a yellow solid compound. LCMS: 224 [MHTj

[0493] Step-2; Synthesis of l-(6-aminopyridm-3-yi) piperidin-4-oI: To a stirred solution of l -(6-nitropyridin-3-yl)piperidin-4-ol (400 mg, 1 79 mmol, 1 equiv) in methanol (10 mL), was added Pd/C (20% w/w) (80 mg ). The resultant reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain l -(6-aminopyridm-3-yl) prperidin-4-ol (300 mg, 87%) as a white color solid compound LCMS: 194 [M÷H] "

[0494] Step-3: Synthesis of l-(6-((4-(4-cyclobutyI-8-fluoro-3, 4-dihydro-2H- benzo[b][l,4]oxazin-6~yi)-S-fluoropyrimidin-2-yl)amino)pyrid in~3~yl)piperidin-4-oi: To a solution of 6~(2~chloro-5-fluoropyrimidm-4-yi)-4-cyclobutyl~8-fluoro~3,4 -dihydro-2H~ benzo[b][ l,4]oxazine (70 mg, 0.2 m ol, 1 equiv) m dioxane (3 mL), was added 1 -(6- aminopyridin- --yi)piperidin-4-o! (44 mg, 0.22 mol, 1 1 equiv) and cesium carbonate (98 mg, 0.3 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (1 mg, 0 004 mmol, 0.02 equiv) and BINAP (5 mg, 0 008 mmol, 0.04 equiv). The resultant reaction mixture was allowod to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 nil,) and extracted with ethyl acetate (100 ml,) Organic layer was washed with water (50 l,) and brine solution (50 nil,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by recrysta!iization with methanol to obtain ] -(6~((4~(4-cyciobutyl-8-fluoro-3,4-dihydro-2H- ben o[b][l 4]oxazin-6~yl)-5-fluoropyrinhdm-2-yl)aniino)pyridin~3 -yi)piperidin~4~o! (30 mg, 30%) as a yellow color solid compound. LCMS: 495 [M÷H] h ¹ HNMR (400MHz, DMSO-dg) 6

[0495] Step-1: Synthesis of 4-(6-nitropyridin-3~yl) morpholine: To a stirred solution of 5- bromo-2-miropyndine (500 mg, 2.47 mmol, 1 equiv) m DMSO (10 niL), was added TEA (0.7 niL, 4.94 mmol, 2 equiv) and morpholine (323 mg, 3.7 mmol, 1 .5 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (50 ml,), solid observed was filtered and dried under vacuu to obtain 4~(6~mtropyridim3wi)morphoiine (400 mg, 77%) as a yellow solid compound. I, CMS: 210 [M+H] ^f [0496] Step-2: Synthesis of 5- orpholinopyridm-2-aini»e: To a stirred solution of 4-(6- nitropyridin-3-yl) orpholine (400 mg, 1 .9 mmol, 1 equiv) m methanol (10 inL), was added Pd/C (20% w/w) (80 mg). The resultant reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through ceiite bed and the filtrate was concentrated under reduced pressure to obtain 5-morpholinopyridin-2-amme (300 mg, 88%) as a white color solid compound. LCMS: 180 [M+H]

[04971 Step-3: Synthesis of 4-(4-cyclobutyI-8-liuoro-3, 4-dihydro-2H- benzo jbj [ 1 ,4) oxazin-6~yl)-S-fluoro-N-(S-morpholinopyridin-2-yl)pyri idm-2-amine: To a solution of 6~(2~chloro-5-fluoropyrimidm-4-yi)-4-cyclobutyl~8-fluoro~3,4 -dihydro-2H~ benzo[b][ l,4]oxazine (70 mg, 0.2 mmol, 1 equiv) m dioxane (3 L), was added 1 ~(6~ amiiiopyridin-3-yl)piperidin-4-ol (39 mg, 0.22 mmol, 1.1 equiv) and cesium carbonate (98 mg, 0 3 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (1 mg, 0.004 mmol, 0 02 equiv) and BINAP (5 mg, 0.008 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reeiy stall ization with methanol to obtain 4-(4-cyclobutyl-8-fiuoro-3,4-dihydro-2H- benzo[b}[ l ,4]oxazin-6-yl)-5-fiuoro-N-(5-morpholinopyridin-2-yl)pyrimid in-2-amine (30 mg, 30%) as a yellow color solid compound LCMS: 481 | M 1 11 ΉN > 1 K (400 MHz, DMSO-d ₆ ) d 9 71 (s, 1 H), 8.56 (d, Aft 5 Hz, 1 1 11 7.93 · 8. 12 (m, 2 H), 7.43 (d, 7 8 8 Hz 1 H) 7.35 (s, 1 H), 7.26 (d, 4 1.8 Hz, 1 H), 4.37 i br. s , 2 H), 3.92 · 4 09 (m, 1 H), 3 61 3.77 (m 4 H) 3.35 (s , 2 H), 2 98 3.18 (m 4 H) 2.25 (br. s, 2 H), 1.99 - 2.20 (m, 2 H), 1.58 1.81 ppm (m, 2 H).

Example-96: Synthesis of l-(6~((5~fluoro~4~(8~fluoro~4~isobutyI~3, 4-dihydro-2hI~

henzofhj f l,4]oxazin~6-ylJpyrtinidin-2-yl)am fto)pyridin-3-yl)piperidin-4-ol. (Compound 488)

[0498] Step-1: Synthesis of l-(6-nitropyridin-3-yl) piperidin~4~oi: To a stirred solution of

5-bromo-2-nitropyndine (500 rug, 2 47 mmol 1 eqmv) m DMSO (10 mL) was added 4 O : (683 mg 4 95 rnmol, 2 equiv) and piperidin-4-oί (500 mg 4 95 rnmol, 2 eq v). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by I ,CMS. After completion of the reaction diluted with water (50 L), solid observed was filtered and dried under vacuum to obtain l-(6-riitropyridin-3-yl)piperidin-4-ol (400 mg, 73%) as a yellow solid compound. LCMS: 224 [Mti!]

[0499] Step-2: Synthesis of l~(6-aminopyr«dm-3-yi) piperidin~4~oI: To a stirred solution of l -(6-nitropyridin-3-yi)piperidin-4-ol (400 mg, 1 79 mol, 1 eqmv) in methanol (10 mL), was added Pd/C (20% w/w) (80 mg ) The resultant reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain 1 -(6-arnmopyndm--3-yl) prperidin-4-ol (300 g, 87%) as a white color solid compound LCMS: 194 [MvHj

[OSOOI Step-3: Synthesis of l-(6-((5-f1uoro-4-(8-fluoro-4-isobutyI-3 _» 4-dihydro-2H- ben*o[b][l,4]oxa*in-6-yi)pyrimidit-2-yl)ammo)pyridin-3-yl)pi peridm-4-oi: To a solution of

6-(2 Chioro-5~fluoropyrimidin-4-yl) 8-fluorO 4 isobutyi- 3,4-diliydro-2H-benzo[b][l,4]oxazine (80 mg, 0 23 mol, 1 equiv) m dioxane (3 mL). was added l-(6-ammopyridin~3~yl)piperidin-4~ ol (50 mg, 0 25 mmol, 1.1 eqmv) and cesium carbonate (113 mg, 0.35 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate 0 mg, 0 005 mmol, 0.02 eqmv) and BINAP (6 mg, 0 009 mmol, 0.04 eqmv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml.) and extracted with ethyl acetate (100 l .) Organic layer was washed with water (50 ml. and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, winch was purified by recrystallization with methanol to obtain 1 -(6-((5-{luoto-4-(8-fluoro-4-isobuty 1 -3,4-dih dro-2H - benzo[b][l,4]oxazin-6-yl)pynmidin~2~yl)amino)pyndm-3-yl}pipe ridin-4-oi (50 mg, 43%) as a yellow color solid compound. LCMS: 497 (400MHz, DMSO-d ₆ ) d 9.64 (s, 1

H), 8.56 (d, ./ 8 v Hz, 1 1 1} 7 93 8.08 (m, 2 H), 7.38 (dd, 7-9 0, 2.9 Hz, 1 H), 7 25 (s 1 H) 7.14 (d, 7- 1 1 8 Hz, 1 1 1 } 4 69 id, M3.9 Hz, 1 H), 4.29 (br s., 2 H), 3 52 - 3.69 (m 1 H) 3.45 (br s., 4 H), 3 12 (d, 7-7.0 Hz, 2 H), 2.82 (t 7-9.6 Hz, 2 H), 1 .98 - 2.14 (m 1 H) 1.83 (d, 7-9 2 Hz 2 H) 1.33 - 1.58 (m. 2 H ), 0.91 ppm (d, 7 6 0 Hz, 6 H)

Example-97: Synthesis of 5-fluoro-4-(8-fluoro-4-isobutyl-3, 4-dihydro-2H~benzo[h] [ l, 4]oxazin-

10G C, Overnight

Step-1

[0501] To a solution of 6-(2-chloro-5-fiuoropyrimidin-4-yl)-8-iluoro-4-isobui i-3,4-dihydrO 2H~benzo[b][l ,4]oxazine (80 mg, 0 23 mmol, 1 equiv) m dioxane (3 niL), was added l -(6- aminopyridm-3-yl)pipendm-4-ol (45 mg, 0.25 ol, 1.1 equiv) and cesium carbonate (1 13 g, 0.35 mmol, 1 .5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (1 mg, 0.005 ol, 0.02 equiv) and BINAP (6 mg, 0.009 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of foe reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml) and brine solution (50 ml ). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain 5~fiuoro~4~(8~fiuoro~4~isobutyl-3,4-dihydro-2H- benzo[b][l,4]oxazin-6-yl)~]S!-(5-morphohnopyridin-2-yi)pyrim idin-2-amine (60 mg, 53%) as a yellow color solid compound LCMS; 483 [M+H] ft H!NME {400MHz, DMSO-dfti 6 9 69 (s 1 H), 8.57 (d, 7-3.9 Hz, 1 H), 7 89 - 8.11 (m, 2 H), 7.63 (br. s., 1 H), 7.27 (s, 1 H), 7.15 (d, 7-1 1 0 Bz 1 H) 4.29 (br. s., 2 H), 3.66 3.91 (m, 4 H), 3.45 (br. s , 2 H), 2.87 - 3.16 (m, 6 H), 1.89 · 2 13 (m, 1 H), 0 91 ppm p i. ./ 6.6 Bz, 6 H).

Example-98: Synthesis qf2~{4~(6~((5~fiuoro~4~(8~fluoro~4~isopropyl~3,4-dihydro-2H~ benzo[hj [J4]oxazin~6~yl)pyrimidin~2~yl)a nino)pyridin~3~y])piperazin~ I ~yl)ethan~l ~oi

[0502] Step-1: Synthesis of 2-(4-(6~nitropyridin-3~yI) piperazin-l-yl) ethan-l-ol: To a stirred solution of 5-bromo~2-mtropyridine (500 mg, 2 47 mmol, 1 equiv) m DMSO (10 ml,). was added k T ^' Oh (683 mg, 4.95 mmol, 2 equiv) and 2-(piperazin-l -yl) ethan-l-ol (482 mg, 3 71 mmol, 1.5 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 ml,), solid observed was filtered and dried under vacuum to obtain 2-(4-(6- mtropyri din~3~yl)piperazin- 1 -y l)ethan- 1 -ol (300 mg, 48%) as a yellow solid compound. LCMS: 253 [M-i-H] "

[0503] Step-2: Synthesis of 2-(4-(6-aminopyridin-3-yl) piperazin-l-yl) ethan-l-ol: To a stirred solution of 2-(4-(6-nitropyndin-3-yi) piperazin-l-yl) ethan-l-ol (200 mg, 0.79 mmol, 1 equiv) in methanol (10 mL), was added Pd/C (20% w/w) (40 rng). The resultant reaction mixture was allowed to stir at RT for l b. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, dm mixture was passes through celite bed and the filtra te was concentrated under reduced pressure to obtain 2-(4-(6-aminopyridin-3-yl) piperazin-l -yl) ethan- l -ol ( 150 mg, 85%) as a white color solid compound LCMS: 223 : \ L i ft

[0504] Step-3: Synthesis of 2-{4-{6- 5-fiuoro-4- 8-fiuoro-4-i8opropyI~3,4-dihydr©-2H- befϊzo(b]jl,4]oxazi -6- I) rilniίlίn-2- I afm o) tίdίn-3- ·i)pίperazM-l- l)ethan-l-ol: To a solution of 6-i2-ehloro-5-fluoropyfimidm-4-yi)-8-i1uoro-4~isopropyi-3,4- dihydro-2H- benzo[b][l ,4]oxazine (100 mg, 0 3 mmol, 1 equiv) in dioxane (3 mL), was added 2-(4-(6- anunopyndin-3-yi)piperazm-l -yl)ethan-l -o! (73 nig, 0 33 mmol, 1 .1 equiv ) and cesium carbonate (147 mg 0.47 mmol, 1 .5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and 1 ( ^' MS. After completion of the reaction, diluted with water (30 niL) and extracted with ethyl acetate (100 niL) Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by recrystallization with methanol to obtain 2-(4-(6-((5-f!uoro-4-(8- f!uoro-4-isopropyl-3,4~dihydro-2H-benzo[blp ,4]oxazin-0-yi)pyrimidin-2-yl)amino)pyridin-3- yl)piperazm-l-yl)ethan-l-ol (30 mg, 1954) as a yellow color solid compound. LCMS; 512

[M+H] ^÷ : ^s HNMS (400MHz, DMSO-de) 6 9.69 (s, I H), 8 56 fd, ,4=3.9 Hz, 1 H), 7.93 - 8.09 (m, 2 H), 7.46 (br s., 1 H), 7 36 (d, / 2.6 Hz, 1 H), 7.17 (d, J=\ 1 8 Hz, I H), 4.44 (t, / 535 Hz, 1 H), 4.30 (br. s., 2 H), 4.05 - 4 20 (m, 1 H), 3 47 - 3.61 (m, 2 H), 3.30 (s, 2H), 3.1 1 (br s., 4 H), 2 57 (br s., 4 H), 2.29 - 2.46 ppm (m, 2 H), 1.18 (d, I = 6.5 Hz, 6H).

Example-99: Synthesis of2~(i~(6~((S~fluoro~4~(8~ftuoro~4~isopropyl~3, 4-dihydro-2H~ benzo[b][ l,4]oxazin-6-ylJpyrimidin-2-yl)amifto)pyhdift-3-}>})piper idin-4-yl)ethan-l-ol

(Compound 491)

[0505] Step-1: Synthesis of 2-(l-(6-nitropyridin~3~yi) piperidin-4-yl) ethan-l-ol: To a stirred solution of 5-bromo-2-mtropyridine (500 mg, 2.47 mmol, 1 equiv) in DMSO (10 rnL), was added K ₂ C0 ₃ (683 mg, 4.95 mmol, 2 equiv) and 2-(piperidin-4~yl) ethan-l -ol (449 mg, 3 71 mmol, 1.5 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reacti on was moni tored by I, CMS. After completion of the reaction, diluted wi th water (50 ml-}, solid observed was filtered and dried under vacuu to obtain 2-{l pi·..

_ ^' nitfopyridh 3-y]}piperidin-4-yl)ethan-l-ol (500 mg, 81%) as a yellow solid compound. LCMS: 252 [M+!Tj ⁺

[0506] Step-2: Synthesis of 2-(l-(6-aminopyridin-3-yl) piperidi«-4-yI) ethan-l-ol: To a stirred solution of 2-(! ~(6~miropyridin-3-y!) piperidin-4-yi) ethan-l -ol (200 mg, 0.79 mmol, 1 equiv) m methanol (10 niL), was added Pd/C (20% w/w) (40 mg). The resultant reaction mixture was aliowed to stir at RT for In. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through ceike bed and the filtrate was concentrated under reduced pressure to obtain 2-(l -(6-aminopyndin-3-yi) piperidin-4-yl) ethan- l -ol (150 mg, 85%) as a white color solid compound. LCMSs 222 [M+H]

[0507 Step-3: Synthesis of 2-(l-(0-((S-fluoro-4-(8-fluoro-4-is0propyi-3,4-diJiydrG-21:l · benzo[b]( )ox^i«-6-yl)pyrimidia-2-yl)amino)pyridin~3~yl)piperidin-4~y l)ethan-l-ol: To a solution of 6~(2~chloro-5-fluoropyrimidin-4-yi)-8-fluoro-4-isopropyi-3,4 ~dihydro~2H- benzo[b][ l,4]oxazine (100 mg, 0 3 mmol, 1 equiv) m droxane (3 ml,), was added 2-(l-(6- anlinopyridin~3-yl)piperidin~4~y!)ethan~l~o! (73 mg, 0.33 mmol, 1.1 eq v) and cesium carbonate (147 mg, 0.47 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0 006 mmol , 0 02 equiv) and BINAP (8 mg, 0 012 mol, 0.04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by 11% and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml.,). Organic layer was washed with water (50 ml,) and brine solutio (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure io obtain crude, which was purified by recry stall ization with methanol to obtain 2-(1 -(6~((5~fiuoro-4~(8~ iluoro-4-isopropy!-3,4--dihydro~2!:I-benzo[b][l ,4]oxazm~6~yj)pyrimidin~-2~y!)amino)pyfidm-3 - yl)piperidin-4-yl)ethan-l-ol (40 mg, 25%) as a yellow color solid compound LCMS: 51 1

[M+H] :i ME (400MHz, PMSO-d. · d 9.64 (s, 1 H), 8.55 (d, ./ 3.9 Hz, 1 H), 7 90 - 8.04 (m, 2 H) 7.47 (s, 1 H), 7 37 tdd, ===9.0, 2 9 Hz, 1 H), 7.1 7 (d, ./ 1 1.4 Hz, 1 H), 4 37 (br. s., 1 H),

4 30 (br. s., 2 H), 3.95 - 4.21 (m,I H), 3.60 (d, ./ 1 2.3 Hz, 2 H), 3 48 (br. s„ 2 H), 3.30 (s, 2H), 2.56 - 2.71 (m, 2 H), 1 75 (d, ,/=== 1 1.8 Hz, 2 H), 1 .51 (br s., 1 H), 1 31 - 1 .42 (m, 2 H), 1.20 - 1.31 (m, 2 H), 1 .18 ppm (s, 6 H). Jdcamp!e-IOO: Symthesis of I~{6~((5~fluoro~4~(8~fiuoro~4~isopropyI~3, 4~dihydro~2H~ beftzo[h][l,4]oxazin-6-yl)pwimidin-2-yl)atnino)pyridin-3-y]) pyrrolidin-3~ol. (Compound 492)

[0508] Step-1: Synthesis of l-(6-nitropyridin-3-yI)pyrroiidin-3-oi: To a stirred solution of

5-bromo-2-nitropyridine (1000 mg, 4 9 mmol, 1 equiv) in ACN (10 ml,), was added pyrrolidin- 3~o! (640 mg, 7.4 mmol, 1 5 equiv) followed by addition of K2C03 (1010 mg, 7.4 m ol, 1 5 equiv) Resultant mixture was allowed to stir at 80° for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with water (15 mL) and was extracted with EtOAc (25 mL) Organic layer dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound was trtiurated from hexane to afford 1 ~(6-nitropyridin-3 -yl) pyrrolidin-3-ol (1000 mg) as a yellow solid compound. LCMS: 588 j 1 11 ^’

[0509] Step-2: Synthesis 1 -(<^aminopyridin~3~yl) py.m>Ikftn~3~oI: To a stirred solution of 1 -(6-nitropyridin-3 -yl) pyrrolidin-3-ol (100 mg, 0.47 ol, 1 equiv) in methanol (8 ml,), was added 10wi.% Pd/C (20 mg). 2L hydrogen balloon was pressurized over reaction. The resultant reaction mixture was allowed to stir at room temperature for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was filtered carefully through cealite bed. Filtrate was concentrated under reduced pressure to obtain l-(6- armnopyridin-3-yl) pyrroiidin-3-ol (85 mg 82%) as a dark brown solid compound. LCMS: 180 [MLB] ⁺

[0510] Step-3: Synthesis of l-(6-((5-iluoro-4-(8-iliioro-4-isopropyI-3,4-clihydro-2H- ben¾o(b]jl,4]oxa¾i«-6-yI)pyrhnuli»-2-yI)aim«o)pyridin-3 -yi)pyrroIidm-3-ol: To a solution of

6--(2- ch!oro-5-iiuofopyrum din-4-yi)-8-fluoro-4 -isopropyl -3, 4-dihydro~2H-benzo! b]n 4]oxaxms (120 mg, 0.37 mmol, 1 equiv) in dioxane (3 mL), was added l -(6-ammopyndin-3-y!)pyrrotidm·· 3-ol (72 mg, 0.4 mmol, 1.2 equiv) and cesium carbonate (240 mg, 0 74 mmol, 2 equiv). The reaction mixture was degassed by nitrogen gas for 10 m., followed by the addition of palladium acetate (8 mg, 0.037 mmol, 0.1 equiv) and BINAP (46 mg, 0.074 mmol, 0.2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 1 6 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (10 niL) and extracted with ethyl acetate (10 niL). Organic layer was washed with water (5 ml,) and brine solution (5 ml). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain 1 - (6-((5-fiuoro-4-(8-fluoro-4-isopropyi-3,4-dihydro~2H-benzo[b ][L4]oxazm~6~yl)pyrimidin-2- yl}amino)pyridin-3-yl)pyrrolidm-3-oi (25 mg, 19 %) as an off white solid compound. LCMS: 469 jM-i-H] ⁺ ; ^! HNM8 (400 MHz, DMSOuft) 6 ppm 1.19 (d, >6.58 Hz, 4 B) 1 .91 (hr. s., 2 H) 2 06 (hr. s„ 2 B) 3.08 (d, >9 65 Hz, 2 H) 3.43 (br s., 2 H) 4.15 (br. s , 2 H) 4 30 ( br. s. , 1 H)

4.41 (br. s , 1 H) 4 97 (d, >3.51 Bz, 1 H) 6.96 (d, >1 1 .84 Hz, 1 B) 7.48 (br. s , I H) 7.65 ( br. s. , 1 H) 7.93 (d, >8 77 Hz, 1 11} 8.52 (d, >3.95 Hz, 1 H) 9 46 (s, 1 H)

Jdcamp!e-101 : Synthesis of I~{6~((5~fluoro~4~(8~fiuoro~4~isopropyI~3, 4~dihydro~2H~

benzojh _j [ l,4]oxazin-6-yi)pyr idin-2-yi)amino)pyndm-3-\4)~4-(hydroxymeiii\4)piperidin-4-ol

(Compound 493)

[OSH] Step-1: Synthesis of 4-{hydroxymethyl)-l-(6-nitr©pyridin-3-yl) piperidin-4-ob To a stirred solution of 5--bromo--2--nitropyridme (400 mg, 1 98 mmol 1 equiv) in DMSO (10 mL), was added >( ^' ( ⁾ (820 mg, 5.95 mmol, 2 equiv) and 4-( hydroxymethyl) piperidin-4-oi (661 mg 3.96 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 L) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 4-ihydroxymethyl)-l -(6-nitropyridin-3-yl) piperidin-4-ol (200 mg, 40%) as a yellow solid compound. 1.0 IS: 254 [M+H]

[0512] Step-2: Synthesis of l-(6-am«iopyr«din-3-yl)-4-(hydroxymethyl) piperidin-4-oh

To a stirred solution of 4-(hydroxymethyl)-l -(6-nitropyridm~3~yl) piperidin-4-ol (200 mg, 0.79 mmol, 1 equiv) in methanol (10 mL), was added Pd/C (20% vv/vv) (40 mg). The resultant reaction mixture was allowed to stir at RT lor 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through cel so bed and the filtrate was concentrated under reduced pressure to obtain l-(6-aminopyridin-3-yl)~4~ (hydroxymethyl) piperidin-4-ol (120 mg. 68%) as a dark brown color viscous compound.

LCMS: 224 [MfoH] ^÷

10513] Step-3: Synthesis of l-(6-((5-iltioro-4-(8-fltioro-4-isopropyI-3,4-c1ihydro-2H- ben¾o(b]| l,4|oxa2;i«-6-yI)pyrimic1i«-2-yI)ai«i«o)pyridm-3-yi)-4-( hyc1roxyi«ethyI)piperidm-

4~ol: To a solution of 6- 2-chloro~5~fli3oropyrimidm-4~yl)-8-fluoro-4-isopropyl-3,4-di hydro-2H- benzo[b][l,4]oxazme (100 mg, 0.3 mmol, 1 equiv) in dioxane (3 mL), was added i--(6-- aminopyridin-3-yi)-4- hydroxymethyl)piperidin-4-oi (74 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0 47 mmol , 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 nun., followed by the addition of palladium acetate (2 mg. 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0.012 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain l ~(6-((5-iluoro-4-(8-iluoro-4- isopropyi--3,4~diiiydiO 2II--benzo]bl] l,4]oxazm-6~yl)pynmidm-2-yi)amino)pyridin-3--yl)-4- (hydroxymethyl)piperidin-4-ol (8 mg, 5%) as a yellow color solid compound. LCMS: 513

[M+H] ^÷ : ^s HNMS (400MHz, DMSO-de) 6 9.62 (s, 1 H), 8 55 (d, / 3.0 Hz, 1 H), 7.83 - 8.04 (m, 2 H), 7.46 (s, 1 H), 7.26 - 7.39 (m, 1 H), 7.17 (d, .fo .4 Hz, 1 H), 4 29 (d, 4=3.9 Hz, 2 H), 4.05 - 4.21 (m, 1 H), 3.30 (s, 2H), 3.22 fbr. s., 4 H), 2.91 - 3.12 (m, 2 H), 1 59 - 1.76 (m, 2 H), 1.44 (d, 4=13.2 Hz, 2 H), U 8 ppm (d, 4=6.6 Hz, 6 H).

Example- 102: Synthesis of l~(6-((5-fluoro-4-(8-fluoro-4-isopropyi-3, 4-dihydro-2H~

hemofhJfi, 4/oxazin-6-yl}pyrimidm-2~yl)amirio)pyridio~3~yi)-3-meihylpyr rohdiri-3-o l

( Compound 494)

j 0514] Step- !:; Synthesis of 3-methyl- l-(6-nitropyridin-3-yl) pyrrolidin-3-ol: To a stirred solution of 5-bromo-2-mtropyridine (500 mg, 2.47 mmol, 1 equiv) in ACN (10 mL), was added hftCCft (1023 mg, 7.41 mmol, 3 equiv) and 3-meihyipyrrolidin- 3-Ol (500 mg, 4.95 mmol 2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 3 -methyl- 1 ~(6~mtropyridim3~y!) pyrrolidin-3-ol

(500 mg. 91%) as a brown viscous compound LCMS: 224 [M÷H] ^”

[0515] Step- 2: Synthesis of i~(6~aminopyridra-3-y )-3-methy pyrroIidin-3~oI: To a stirred solution of 3-methyI-l -(6-nitropyridm-3-yI)pyrroIidin-3-ol (200 mg, 0.89 mmol, I equiv) in methanol (10 mL), was added Pd/C (20% w/w) (40 mg) The resultant reaction mixture was allowed to stir at RT for lb. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain l-(6-aminopyridm-3-yl)-3-methylpyrrolidm-3-oj (150 mg, 87%) as color a dark brown solid compound. LCMS: 194 [MH-Ή] ^÷

(0516] Step-3: Synthesis of l-(6-((5-flaoro-4-(8-flaoro-4-isopropyl-3, 4-dihydro~2H~ benzo[b][l,4]oxa: n-6-yl)pyr«midin-2-yl}ammo)pyridin-3-yl)-3-snethylpyrroHdin -3-ol: To a solution of 6-(2-chloro-5-t1uoropyrimidin-4-yl)-8-iluoro-4-isopropyl-3,4 -dihydro-2H- benzo[b] [ 1 ,4] oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (3 mL), was added l-(6- aminopyridm-3-yl)-3-methylpyrro!idm-3-ol (64 rag, 0.33 mmol, 1 1 equiv) and cesium carbonate (147 mg, 0 47 mmol. 1.5 equiv) The reaction mixture was degassed with nitrogen gas for 30 nun., followed by the addition of palladium acetate (2 mg. 0.006 mmol, 0 02 equiv) and BINAP IB mg, 0.012 inmoh 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate ( 100 L) Organic layer was washed with water (50 xnL) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, winch was purified by reverse phase HPLC to obtain l~(6~((5~fli3oro~4~(8-fluoro~4~ isopropyl-3,4-dihydro-2H-benzo[bl[ l,4]oxazm-6-yl)pyrimidin~2~yl)amino)pyridin-3-yl)-3- mediylpyrrolidin-3-oi (25 mg, 17%) as a yellow color solid compound. LCMS: 483 I M H i 7 *HNM (400MHz, DMSO-ds) d 9.45 (s, 1 H), 8.52 (d, .4-3.9 Hz, 1 H), 7 92 (d, ,4-8.8 Hz I H) 7.62 (d, 4-2.6 Hz, 1 H), 7 47 (s, I H), 7.16 (d, 4-12 3 Hz, 1 H), 6.75 · 7 00 (m, 1 H), 4 30 (hr. s„ 2 H), 4 03 4.21 (m I H), 3.38 (d, 4-7 9 Hz, 2 H), 3.24 · 3 37 (m, 2 H), 3 09 3.23 (m 2 H) 1.79 - 2.04 (m, 2 H), 1 36 (s, 3 H), 1 .19 ppm (d, ,4-6.6 Hz, 6 H).

Example- 103: Synthesis ofN-(5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro~2H- henzo[bi[J4]oxazm-6~yl)pyrimidift~2~yl)-3-(l-meihyipiperidin ~4~yi}i$oxazol-5-amine.

(Compound 495)

[0517] Step-1: Synthesis of l-(tert-butyi) 4-methyl piperidine~l,4-dkarhoxyiate: To a solution l-(tert-butoxycarbonyl)pipexidine-4-carboxylic acid (2000 mg. 8.69 m ol, 1 equrv) in

DMF (25 mL), was methyl iodide (0 694ml , 10.25 mrno!) 1.2 eqmv) was added drop wise under nitrogen and potassium carbonate ( 1200 mg, 8.69 mmol, 1 equiv) The resultant reaction mixture was allowed to s ir at RT for 3h. Progress of the reaction was monitored by NMR and

TLC. Alter completion of die reaction, reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 ml, >< 2). Organic layer was washed with water (100 ml )

Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtained desired product l-(tert-butyl) 4-niethyl piperidine- 1 ,4-dicar boxy late

(1760mg, ) as a yellow oil compound LCMS: ELSD 244 [MTH] [0518] Step-2: Synthesis of tert- butyl 4-(2-cyanoacetyi) plperidine-l-carboxylate: To a stirred solution of h-(iertfoutyl) 4-methyl pipendine-l,4-dicarboxylate (500 mg, 2.04mmol 1 equiv) in THF (10 niL). was added methyl cyanide (0 56mg, 5equiv.}, and poiass m-- terbutoxide(689mg, 3equiv). 1he resultant reaction mixture was allowed to stir at RT fbrlh. Progress of the reaction was monitored by Ή NMR. After completion of the reaction, the mixture was added aquas ammonium chloride solution (60 ml) resulted solution was diluted with water (20 iiiL) and extracted with ethyl acetate (100 ml,). Organic layer was washed with brine solution (50 ml_). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain of tert-buty! 4-(2-cyaiioacetyl)piperidine-l -carboxylate as a light yellow oil compound. LCMS: ELSD 253 [M+H] ⁺

[0519] Step-3: Synthesis of tert- butyl 4-(5-arainoisoxazol-3-yi) piperidine- 1-carboxylate:

To a solution of tert-buty! 4-(2-cyanoacetyl) piperidine- 1 -carboxylate (500 mg, 1.98 mmol . 1 equiv) in methanol (10 ml,) in sealed tube, was added hydroxy!armne hydrochloride (275mg, 3 96 mmol, 2equiv), sodium acetate (324mg, 3.96mmol, 2equiv). The resultant reaction mixture was allowed to stir at RT for 20-24h. Progress of the reaction was monitored by TLC and I, CMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml-). Organic layer was washed with water (20 ml-) and brine solution (30 ml-). Organic layer w¾ dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert- butyl 4-(5- aminoiSOxazo!--3--yj)pipendme-! -carboxyl ate (80mg, 73%) as a yellow solid compound. LCMS: 267 ⁺

[0520] Step-4: Synthesis of isrt-bidyl 4-(5-((5-fiuoro-4-(8-fiuoro-4-isopropyl-3,4- dihydro-2H~henzo[b][l,4]©xazin-6-yI)pyrisnidin-2~yI)aMino)i soxa*oi-3-yl}piperidine-l- carboxylaie: To the solution of 6-(2-chloro-5-f3uoropyrimidin-4-yl)-8-fluoro-4-isopropyj-3,4 - dihydro-ZH-benzo[b] [ 1 ,4]oxazine (100 mg, 0 3 mmol, 1 equiv) was added dioxaue(6ml) and tert-buty! 4-(5-ammolsoxazol-3-y!)pipsndme-l-carboxy!ate(90mg ,0 .33mmol, 1.1 equiv), cesium carbonate(l 49mg, 0.45mmoh 1 5eqmv), resulted reaction mixture was degassed with mitogen for 5min thereafter was added Pd(()ac) _2, (8mg, 0.03 mmol, 0 1 equiv), BIN AP(38mg 0.06mmol, 0 2mmol), esulted reaction mixture was allowed to stir for 15h at 100°C. Progress of the reaction was monitored by LCMS After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with ethyl acetate (50 ml, >< 2). Organic layer was washed with water (20 ml,) and brine solution (25 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by combi-flash to obtain tert-butyi 4-(5-((5-fluoro-4-(8-fluoro-4-isopropy!-3,4-diliydro-2H- benzo b][l,4]oxazin-6-yl)pyrimidin-2-yi)amino)isoxazol-3-yl)piperi dine-l-carboxylate (180 g, 22%) as a yellow solid compound. LCMS: 556 [M+H] ^”

[0521] Step-5: N-(5-fl«oro-4-(8-fl«oro-4-isopropyl-3,4-dfliydro-2H-ben2o[ b] [l,4]oxazm- 6-yl)pyrimidM-2-yi)-3-(piperidm-4-yi)isoxazol-5-amine: tert-butyl 4-(5-((5-fluoro-4-(8-fluoro-

4-isopropyJ-3,4~dihydro-2H-benzo b][l,4]oxazin-6-yl)pyrimidin-2-yi}amino)isoxazol-3·- yijpiperidme-l-carboxylate (200 mg, 0.179 mmol, 1 equiv) was taken in 1 25 M HC! in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for Ih Progress of the reaction was monitored by I, CMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophilizer to obtain N-(5-fluoro-4-(8-fluoro-4- isopropyl-3,4-dibydro-2H-benzo[b][l ,4]oxazin-6-yl)pyrimidin-2-yl)-3-(l-metbylpiperidin-4- yl)isoxazol-5-amine (1 50 mg, 81%) as a buck red color solid compound. LCMS: 456 [M+H]

[0:522] Step-6: Synthesis of N~(5~fl«oro~4~(8 fl«oro-4~isopropyi-3,4~dihyclro~2fl- benzo[b]il _» 4]oxazin-6-yi)pyrimi ^j n-2-yl)-3-(l-raethylpipendin-4-y!)isoxazol-5-aitnine: To a stirred solution of N-(5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro- 2H-benzo[b][l , 4]oxazin-6- yl)pyrimidin-2-yl)-3-(l-me†hyipiperidin-4-yl)isoxazol-5-am ine (50 mg, 0 109 mmol, 1 equiv) m DCF, (3 ml,), was added Formaldehyde (40% in water) (0.01 nil , 0.29 mmol, 3 equiv), acetic acid (0 02 ml,, 0.45 mmol 5 equiv) The reaction mixture was allowed to stir at RT for ! h. The reaction mixture was cooled to 0°C. NaCNBBU (18 mg, 0.29 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT tor overnight. Progress of foe reaction was monitored by LCMS After completion of the reaction foe reaction mixture was diluted with water (25 ml,) and extracted with ethyl acetate (50 ml,

2). Organic layer was washed with water (50 mi,) and brine solution (50 mi,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by reverse phase HPLC to afford N-(5-fiuoro-4-(8-fiuoro-4-isopropyi-3,4- dihydro-2H-benzo| b][l 4]oxaxin-6-yl)pyriinidin-2-yl)-3-(l -methyipiperidin-4-yl)isoxazoio· amine (7 mg, 61%) as a yellow color solid compound LCMS: 471 [M-i-Hj ^÷ ; ¹ H NMfi (400 MHz, Methanol·· L) d 8 48 (d, 7 3.9 Hz, 1 H), 7 48 (s, i l l) 7 29 - 7 21 (m, H i) 6 36 01.7 - 3 4

Hz, HI), 4.33 (t, 7 4.3 Hz, 2= 11. 4 22 (p, 7 - 6.7 Hz, 111), 3.35 (d, 7 4.0 Hz, 511), 3.15 (d, 7

=12.4 Hz, 311), 2.83 (t, 7= 12.0 Hz, 111), 2.54 - 2 46 (m, 511), 2.08 (t, 7= 16.7 Hz, 311), 1.90 (q, 7 = 12 4Hz, 2= 11. 1 29 (s, 111), 1 26 (dd, 7= 6.6, 3.3 Hz, 611)

Example- / 77; Synthesis of5~fluoro~4~(8~ftuoro~4~isopropyi~3, 4-dihydro-2H- hemo[b] fi ]oxazin~6~yl) N (l-(l~meikylpiperidm-4-yl)-lli~imidazol~4~yl)pyrimidm~2-amin e

(Compound 496)

[0523] Step·· ! ;; Synthesis of tert-butyl 4-((methyIsulfonyl ) oxy) plperidine-l-carboxylate:

To a stirred solution of tert-butyl 4-hydroxypiperidme-i -carboxy!ate (5000 mg, 24 87 mmol, 1 equiv) m DCM (50 mL), was added TEA (5 ml,, 34 8 mmol, 1.4 equiv). Cool the reaction mixture to Q°C, followed by the addition of rnesy! chloride (2 5 mL, 34.8 mmol, 1 4 equiv). Raise the temp to RT and the resultant reaction mixture was allowed to stir for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (100 ml,) and extracted with DCM (150 ml, ^c 2) Organic layer was washed with water (100 ml,) and brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl 4-((methyIsulfony!)oxy)piperidme-l- carboxy!ate (5000 mg, 72%) as an off white solid compound. LCMS: ELSD 280 [M+H] ^f

[0524] Step-2: Synthesis of tert-butyl 4~(4~mtro- IH-imidazoI- l-yl) piperidlne-l- carboxy!ate: To a stirred solution of tert-butyl 4~((methyisulfonyl) oxy) piperidine- 1- earboxylate (4000 mg, 14 3 mmol, 1 equiv) in DMF (30 ml,), was added C¾C03 (9324 mg, 28 6 mmol, 2 equiv), TBAI (1055 mg, 2 86 mmol, 0 2 equiv) and 4-mtro--l H-imidazoie (810 mg, 7.16 mmol, 0.5 equiv). The resultant reaction mixture was allowed to stir at 80°C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (100 ml) and extracted with EtQAc ( 150 mL ^x 2). Organic layer was washed with water (100 mL) and brine solution (100 l,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain tert-butyi 4-(4-nitro-lH-imidazol-l -yi)pipericline-l-carboxyiate (550 nrg, 13%) as an off white solid compound. LCMS: 297 [M+H]

[0:525] Step-3; Synthesis of tert-butyi 4-(4-aramo-lH-imklazol-l-yi) piperidine-!- carboxylate; To a stirred solution of tert-buty! 4-(4-nitro-lH-imidazol~l ~yl) piperidine-1- carboxy!ate (550 mg, 1 85 mmol, 1 equiv) m methanol (10 mL), was added Pd/C (20% w/w)

(1 10 mg). The resultant reaction mixture was allowed to stir at RT for ! h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain test- butyl 4 (4-amino-lH imidazol-i-yl) piperidine-1 -carboxylate (450 mg. 91%) as a brown color viscous compound. LCMS: 267 [M+H] ^”

[0526] Step-4: Synthesis of tert-butyi 4~(4~((5~fluoro~4~(8~fluoro-4~isopropyI-3,4~ dihy dro-2H-benzo [b] [ 1 ,4] oxazin~6~yI)pyrimidin-2~yI)amino)~ lH-imidazoi~ l-yl)piperidine- l-carboxylate: To a solution of 6-(2-chloro-5-fluoropyriimidiii-4-yI)-8-fluoro-4-isopropyl-3 ,4~ dibydro~2H-benzo]bj[l ,4]oxazine (500 mg, 1 53 mmol, 1 equiv) m dioxane (5 ml,), was added tert-bulyl 4-(4-amino-l H-imidazoj-I-yl)piperidine-! -carboxylate (450 mg, 1 69 mmol. 1.1 equiv) and cesium carbonate (748 mg, 2.29 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladiu acetate (7 mg,

0.03 mmol, 0.02 equiv) and BINAP (38 mg, 0.06 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyi 4- (4-((5-fluoro--4-(8-iluoro--4-isopropyi-3,4 dihydrO 2H-benzo[b]] L4]oxazin-6-yl)pyrunidin-2- yl)a ino)-l H-iinidazol-l-y!)piperidine-l -carboxyiate (600 mg, 70%) as a brown color viscous compound. LCMS: 556 [M+H] ^’

[0527] Step-5: Synthesis of 5-fluoro-4-( 8-t1uoro-4-isopropyI-3 _» 4-dihydro-2H- benzojh j |l ,4j oxaa>;i«-6-yI)-N-( 1 -(piperidm-4-yl)-lH- nida2ol-4-yl)pyri idin- 2-amine: tert- butyl 4-(4~((5~fli3oro~4~(8~fli3oro~4~isopropyl~3,4-clilwdiO-2H~be nzo[b][l,4]oxazin-0- yl)pyrmiidin~2~yl)amino)~IH-imidazol-1 -yl)piperidme-l-carboxylate (600 mg, 1.08 mmol, 1 equiv) was taken in 1.25 M HC1 in ethanol (10 mL) and the resultant reaction mixture was allowed to stir at 50°C for Ih. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude compound, which was purified by making HCi salt to afford 5-fluoro-4 5-fiuoro~4~(8-fiuoro~4- isopropyl-3,4-dihydro-2H-benzo[b][ l,4]oxazin-6-yl)~]S!-0-(piperidm-4-yi)-lH-imidazol~4- yl)pyrimidin-2-amine (400 mg, 8151 ) as an orange color solid compound. LCMS: 456 [M+H]

[0528] Step-6: Synthesis of S-fluoro- -CS-fluoro- -isopropyl-S^-dihydro- H- henzo[b][i,4[oxazin-6-yl)-N-(l-(l-methylpiperidm-4-yl)-lH-im idazol-4-yi)pyTiffiidia-2- amine: To a stirred solution of 5-fluoro-4-(8-fluoro-4-isopropyI-3,4-dihydro-2H- benzo[b][l,4]oxazin~6~yl)-N-(I-(piperidm-4-yl)~lH-imidazo!-4 -yl)pyrimidin-2-arnine (50 mg,

0 1 mmol, 1 equiv) m DCE (5 ml,), was added Formaldehyde (4056 in water) (0 01 mL, 0.3 mmol, 3 equiv), acetic acid (0 03 ml,, 0.5 mmol, 5 equiv) The reaction mixture was allowed to stir at KT for Ih. The reaction mixture was cooled to 0°C. \af Stil l (19 mg, 0.3 mmol , 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for lb. Progress of the reaction was monitored by LCMS After completion of the reaction, the reaction mixture was diluted with water (25 L) and extracted with ethyl acetate (50 ml, x 2). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPI .C to afford 5-iluoro-4-(8-iluoro-4- isopropyl-3,4~dihydro~2H-benzo[b][l,4]oxazin-0-yl)-N-(l-(I-m e†hy]piperidin-4-yl)-lH- iinidazol-4-yl)pyrimidin-2 -amine (6 mg, 1 3%) as a yellow color solid compound. LCMS: 470 [M+H] ^÷ : ⁱ HNMR (400MHz, DMSO-de) 6 9.68 (br s.„ 1 H), 8 50 (br. s. , 1 1 1). 7.56 (hr. s., 1 H), 7.39 (br. s , 1 H), 7.32 (br. s., 1 H), 7.17 (s. I H). 4.30 (br. s , 2 H), 4.13 (d, ./ 7 8 Hz, 1 H), 3.31 (br. s , 2 H) 3.08 (br. s , 2 H), 2.90 i d. 7-7 3 Hz, 2 H), 2.08 (br. s„ 3 H) 2.00 (br. s., 2 H), 1 .97 (br s., 2 H), 1.01 - 1 .29 ppm ( , 7 H).

Example- 105: Synthesis of 5~fluoro-4~(8~fluoro-4~isopropyl~ 3. 4~dihydro~2H- benzo[h] [J4]oxazin-6-yi N~(l~(l ~methylpiperidin-4-yl)~l H-pyrazoi-4-y?)pyrimidm-2~amine.

[0529] Step-1: Synthesis of tert-bntyl 4-((methyls«IfonyI) oxy) piperidine- l-carboxyiate: To a stirred solution of tert-butyl 4-hydroxypipendme-l-carboxylaie (1000 mg, 4.97 mmol, 1 equiv) in DCM (1 5 mL). was added TEA (1 nil, 6.96 mmol, 1.4 eq v). Cool the reaction mixture to 0°C, followed by the addition of mesyl chloride (0.5 mL. 6.96 mmol, 1.4 equiv). Raise the temp to RT and the resultant reaction mixture was allowed to stir for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 mL) and extracted with DCM (100 ml, s 2). Organic layer was washed with water (100 ml.) and b ne solution (100 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl 4-((methylsulfony!)oxy)piperidine-l - carboxylate (1200 mg, 86%) as a off white solid compound

[0530] Step- 2: Synthesis of tert-butyl 4-(4-nitro- 1 H-p razol- l-yl) piperidine-l- carboxylate: To a stirred solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (500 mg, 1.79 mmol, 1 equiv) in DMF (10 ml,), was added C¾CCh (1 167 mg, 3 58 mmol, 2 equiv), TBAI (133 mg, 0.36 mmol, 0 2 eqmv) and 4-nitro-lH-pyrazole (101 mg, 0.89 mmol, 0.5 equiv). The resultant reaction mixture was allowed to stir at 80°C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 ml,) and extracted with EtOAc ( 100 niL x 2). Organic layer was washed with water (100 rnL) and brine solution (100 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain tert- butyl 4-(4-nitro~lH-pyrazol-l -yi)pipericline~I -carboxyiate (400 mg, 75%) as a brown viscous compound. LCMS: 297 fM+R] ^"

[0531] Step-3: Synthesis of tert- butyl 4-(4-amino-lH-pyrazoI-l-yl) piperidine !- carboxyiate: To a stirred solution of tert-butyl 4-(4-nitro- 1 H-pyrazoi- 1 -y!) piperidine- 1- carboxylate (200 mg, 0.67 mmol, 1 equiv) in methanol (10 mL), was added Pd/C (20% w/w) (40 mg). The resultant reaction mixture was allowed to stir at RT for !h. Progress of the reaction was momtored by TLC and LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(4- anmio-!H-pyrazoi-!-yl) piperidine- 1 -carboxyiate (150 mg, 83%) as a brown color viscous compound. LCMS: 267 [M+H]

[0532] Step-4: Synthesis of tert-butyl 4-(4-((5-fiuoro-4-(8-fiuoro-4-isopropyl-3 _¾ 4- dihydro-2H-benzo[b]jl,4[oxazm-6-yl)pyrimitlln-2-yl)amlno)-lH ~pyrazol-l-yi)piperid«ae-l” carboxyiate: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fIuoro-4-isopropyl-3,4 - dihydro~2H-benzo[b][l,4]oxazine (100 mg. 0.3 mmol, 1 equiv) in dioxane (5 mL), was added tert-butyl 4-(4-amino-lH-pyrazol-l -yj)piperidine-l-carboxylate (90 mg, 0.33 mmol, 1 .1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 rng, 0 006 mol, 0.02 equiv) and BINAP (8 mg. 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 1 00 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mL and extracted with ethyl acetate (100 ml). Organic layer was washed with water (50 ml and brine solution (50 ml). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by recrystallizafion with methanol to obtain tert-butyl 4-(4~((5-iluoro~ 4-(8-fluofo-4-isopropyi-3,4-dihydro-2H-ben2o] b]] l ,4]oxazin-6-yl)pyrimxdin-2-yi)amino)-rH- pyrazol-1 -yi)piperidine-l -carboxyiate (150 mg 88%) as a yellow color solid compound LCMS: 556 [0533] Step-5: Synthesis of 5-fluoro-4-( 8-!1uoro-4-isopropyI-3, 4-dfliydro-2H- ben¾o(b][i ,4joxa2;i«-6-yI)-N-(l-(piperidm-4-yl)-lH-pyra*ol-4-yi)pyrim idm-2-amine: tert- bistyi 4-(4~((5~ili3oro~4~(8~fli3oro~4~isopropyl~3,4-dihydiO-2H~ben zo[b][l,4]oxazin-0- yl)pyrmiidin~2-yl)amino)~lH-pyrazol-l -yl)piperidine-l-carboxylaie (150 mg, 0.27 mmol, 1 equiv) was taken in 1.25 M HC1 in ethanol (5 mL) and the resultant reaction mixture was allowed to stir at 50°C for Ih. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under iyophilizer to obtain crude compound, which was purified by making HCi salt to afford 5-fiuoro~4~(8-fiuoro~4-isopropyl~3,4-dihydro-2H~benzo[b][l ,4]oxazin-6-yi}-N-(1 - (pipendinfo-ylMH-pyrazokd-y!jpyrmiidm-d-amine (100 mg, 81 %) as an orange color solid compound. LCMS: 456 [M+H]

[0534] Step-6: Synthesis of 5-fluoro-4~(8-fl«oro-4~isopropyl-3,4~dihydro-2H- benzo[b][l,4]oxazin-6~y!)-N-(l-(l-methyipiperklin-4-yl)~lH-p yrazoi-4-yi)pyrimidm-2- amine: To a stirred solution of 5~fluoro~4~(8~fluoro~4~isopropyl~3,4-dihydro-2H~

benzo[b][l ,4]oxazin-6-yl)-N-(l -(piperidin-4-yl)-lH-pyrazo]-4-yl)pyrimidin-2~amine (100 mg,

0.2 stimol, 1 equiv) in DC 1. (5 ml,), was added Formaldehyde (40% water) (0.03 stiL, 0 6 mmol, 3 equiv), acetic acid (0.05 mL, 1 0 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for Ih. The reaction mixture was cooled to 0°C. NaCNBFft (38 mg, 0.6 stimol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for I h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with ethyl acetate (50 mL ^x 2) Organic layer was washed with water (50 ml,) and brine solution (50 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5-†1uoro-4-(8-fluoro-4- isopropyl-3,4-dihydro-2H-benzo| b|| l ,4]oxazin-6-yl)-N-(l -(1 -methy lpiperidxn-4-y 1)- 1 H-pyrazoi - 4-y]}pyrimidin-2-amine (10 mg, 10%) as a yellow color solid compound. LCMS: 470 [M+H] ; ¾NMR (400MHz, DMSO~d ₆ ) 6 9 48 (s, 1 H), 8.48 (d, ./ 3 0 Hz, 1 H), 7.90 (s, 1 1 11. 7.56 (hr s . 1 H), 7.35 (s. 1 H) 7.13 (d, v i 1 8 Hz, 1 H), 4.29 (hr. s.. 2 H). 3.98 ·· 4 17 (m, 2 H), 3 30 (hr. s.. 2 H). 2.85 1 .4 Hz, 2 H), 2 20 (s, 3 H), 1.98 - 2.1 1 (m, 2 H), 1.69 ·· 1 98 (m, 4 H), 1 18 ppm (d. _· / 6·.6 Hz, 6 H). Example~IQ6: Synthesis of 5~fluoro~4~(8~fliioro~4~isopropyi~ 3, 4~dihydro~2H~

benzo[h] [J4]oxazin-6-yl)~N~{5~( I ~methylpyrf olidin~3~yi}pyridin~2~yi}pyrimidin~2~amine.

(Compound 498)

[0535] Step-1: Synthesis of tert-butyl 3-(6-nitropyrid«B-3-yl)-2,5-dihydro-lH-pyrroie-l- carboxylate: To a stirred solution of 6-bromo-8-f!uoro-2H-benzo[b]ll ,4]oxazin-3(4H)-one (700 mg, 2.85 mmol, 1 equiv) in DMF (10 ml,), was added K ₂ CO ₃ (789 mg, 5.71 mmol, 2 equiv) and ethyl iodide (0.5 ml,, 5.71 mmol, 2 equiv). The reaction mixture was allowed to stir at 80°C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 ml ), solid observed was filtered dried under vacuum to obtain 6-bromo-4-ethyl-8-fluoro-2H-benzo[b][l ,4]oxazm-3(4H)-one (700 mg, 90%) as an off white solid compound. LCMS: 274 [M+H] ^r

Step-2: Synthesis of tert-butyl 3 (6-ammopyridin-3-yl) pyrrolidine-l-carboxyiate: To a stirred solution of tert-butyl 3-(0-nitropyridin-3-yl)-2,5-dihydro-IH-pynOle-I-carhoxyla† e (100 mg, 0 3 mmol, equiv) in ethanol (3 mL), was added PdC (20 me A 2 mmol, 1 eq v) The resultant reaction mixture was allowed to stir at RT for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through cehte bed and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(6- aminopyridin-3-yl) pyrrolidine-l-carboxyiate (90 mg, 91%) as a brown Solid compound LCMS: 264 [M÷H] ⁺

[0536] Step-3: Synthesis of tert-butyl 3-(6-((5-fluoro-4-(8-fluoro-4-is©propyl-3,4- dihydro-2II-benzo[b][J,4|oxazHi-6-yI)pyriinidm-2-yl)amino)py ridin-3-yl)pyrroHdine-l- carhoxyiate: To the solution of 6-{2-chlofo-5-iIuofopyrunidm-4-yl)-8-iluoro-4-isopfopyl-3,4- · dihydro~2H-benzo[b][l,4]oxazine (150 mg, 0.46 mmol, 1 equiv) was added dioxane (5ml) and ten-butyl 3~(6-aminopyridin-3~yl)pyrrolidine-l -earboxylate (145mg ,0 0 50mmol, 1.1 equiv), cesium carbonate(224mg, 0.69mmoi, i .oequiv), resulted reaction mixture was degassed with nitrogen for 5mm thereafter was added PdfOacfo (1 img, 0.046mmol, 0 1 equiv), BIN AP (57mg, 0.09mmol, 0.2mmol), esulted reaction mixture was allowed to stir for 15h at 100°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (40 mL x 2). Organic layer was washed with water (35 nil,) and brme solution (25 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which w¾s purified by combi-flash to get tert-butyl 3-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][l,4)oxazm~6~yl)pynmidin-2-yi)amino)pyridin-3-yl)pyr rolidme-l-carboxyjate

(190mg,16 %) as a yellow solid compound LCMS: 553 [M÷H] ^”

[0537 ! Step-4: Synthesis of 5-fluoro-4~(8-fluoro-4~isopropyl-3,4~dihydro-2H- benzo[b][l,4]oxazin-6-yI)-N-(5-(pyrro!idin-3-yI)pyndin-2-y!) pyriitnidin-2-amine: To the solution ten-butyl 3-(6-((5~fluoro-4~(8~fiuoro~4~isopropyl~3,4-dihydro-2H~benzo [b][l ,4]oxazin- 6~yl)pynmidin-2-yl)amino)pyridin-3-yl)pyrrolidine-l-carboxyl ate (190mg, 0.44 mmol, 1 equiv) was taken m 1 25 M HQ m ethanol (5 mL) and the resultant reaction mixture was allowed to stir ai 50°C for 3h. Progress of the rea ction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under

!yophihzer to get 5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[b][l,4 ]oxazin-6-yl)- N-(5~(pyrrolidin-3-yi)pyridm-2-yl)pyrimidm-2-amine (99 rng, 39%) as a brick red color solid compound. LCMS: 453 [M+H]

[0538] Step-5: Synthesis of 5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][I,4]oxaziR-6-yI)-N-(5-(l-methylpyrroIidiR-3-yI)pyri din-2-yI)pyrimidm-2-amine:

To a stirred solution of 5-iliioro-4-(8-iluoro-4-isopropyl-3,4-dihydro-2H-benzo[b][l, 4]oxazim6- yl)-N-(5-(pyrrolidin-3-yT)pyridin-2-yl)pynmidin-2-amine (99 mg, 0.44mmoh 1 equiv) in DCE (5mL), was added Formaldehyde (40% in water) (0 66 mL, 0.19 mmol, 3 equiv), acetic acid (0.2 mL, 1. Immoi, 5 equiv). The reaction mixture was allowed to stir at RT for 1 h. The reaction mixture was cooled to 0°C. NaCNB!L (4 Img, 0.66 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for 4h. Progress of the reaction was monitored by LCMS After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 ml ^c 2) Organic layer was washed with water (15 mL) and brine solution (20 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5-fluoro-4-(8-fluoro-4-isopropyi-3,4~dihydro-2H- benzo[bl[l,4]oxazin-6-yl)-N-(5-(d -methylpyrrohdin ^~ 3 ^~ yl)pyridin-2-yl)pyrimidin ^~ 2 ^~ amine 18 mg, 99 %) as a yellow color solid compound, LCMS: 471 [M÷H] ^’ ; ⁵ HNMR (400 MHz, Methanotifo!) d 8 44 i d. ./ 4.1 Hz, Hi), 8.30 (d, ./ 8.8 Hz, HI), 8.18 (s, 1H),7.79 - 7.71 (m,

1H), 7.52 (s, 1H), 7.29 - 7.21 (m, 1H), 4.33 (t, / 4 3 Hz, 2H), 4.22 (p, ./= 6 6 Hz, I H), 3.57 - 3.44 (m, HI), 3 35 (t, / 4.4 Hz, 4H), 3 14 - 3.03 (m, HI), 3 03 - 2.93 (m, 1H), 2.77 (t, / 9.5

HzlH), 2.61 (s, 3H), 2.43 (dq, / 14.3, 8 2 Hz, 1H), 2.02 (dt, J = 13.3, 7.6 Hz, 1H), 1.26 (d, ./

6.6 Hz,7H).

Example- 107: Sytiihesis ofS-Jluoro~4~(8-fl oro~4~isopropyl~3,4~dihydro~2H~

henzofb][l,4]oxazin~6~yl)-N-(3~(l~methylpipehdin-4-yl)~lH -pyrazoi-5-yl}pynmidin-2-a!nme.

(Compound 499)

]05:39] Step-1: Synthesis of tert-butyi 4-(5-aramo-lH-pyrazo!-3-yl) piperkline-1- carboxylate: To a solution of ten-butyl 4-(2~cyanoacetyl) piperidine- 1-carboxy late (100 mg, 0.4 mmol, 1 equiv) in ethanol (4 mi,) m sealed tube, was added hydrazine hydrate (0.12 ml,, 2 4 mmol, 6equiv) The resul tant reaction mixture was allowed to sttr at 8CftC for 4h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (20 ml ) and brine solution (30 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by normal phase combi flash to obtain tert- butyl 4-(5-amtno-iH-pyrazol-3-yl)piperidine-l-carboxylate (80mg, 73%) as a yellow solid compound. LCMS: 267 [M+H]

[0540] Step-2: Synthesis of tert-butyi 4-(5-((5-fluor0-4-(8-fluoro-4-isopropyI-3,4- d«hyclro-2H-ben*o b][l,4)oxa2m-6-yl)pyrimidm-2-yl)ammo)-ltl-pyra¾oI-3-yl)pipe ridme-l- carboxyiate: To the solution of 6-(2-chioro-5-fluoropyrimidin-4-yl)-8-fli3oro~4~isopropyl~3, 4- dihydro-2H-benzo[b]ii,4]oxazine (150 mg, 0.46 m ol, 1 equiv) was added dioxane(5ml) and tert-butyi 4-(5-ammo-lH-pyrazol~3-yl)pipendine-l-earboxylate (145mg ,0 Q.50mmol, 1.1 equiv), cesium carbonate(223mg, 0.69mmoi, i .oeqmv), resulted reaction mixture was degassed with nitrogen for 5mm thereafter was added PdfOacfo (lOmg, 0.046mmol, 0 1 equiv), BINAP (57mg, 0.09mmol, 0 2mmol), resulted reaction mixture was allowed to stir for 15h at 100°C. Progress of the reaction was monitored by I, CMS. After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with ethyl acetate (50 ml, x 2). Organic layer was washed with water (30 ml,) and brine solution (20 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by combi-flash to tert-butyi 4-(5~((5-fIuoro-4~(8-fluoro-4-isopropyl-3,4-dihydro-2H- ben o[b][l,4]oxazin~6~yi)pyrimidin-2-yi)armno)-l H-pyrazol-3-y])piperidine~l -carboxyiate (180mg,46 %) as a yellow solid compound LCMS: 556 [M÷Hj

[0541] Step-3: 5-fluoro-4-(8-fiuoro-4-i8opropyl-3,4-dihydro-2H-benzo[b] [1,4|oxazin-6- yl)-N-(3-(piperidin-4-yl)-lH-pyrazol-5-yl)pyrimidin-2-afn«n e: tert-butyi 4-(5-((5-fluoro-4-(8- fluoro-4-isojwopyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)p yritmdin-2-yl)amino)-l H-pyrazol-

3-yl)piperidme-l -carboxyiate (250 nig, 0.44 m ol, 1 equiv) was taken m 1 25 M HC1 in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for lb Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophilizer 5-fluoro-4-(8-fluoro-4-isopropyl- 3,4-dihydro-2H-benzoj b][ 1 ,4]oxazin--6-yl)--N-(3-(pipendm-4-yi)-1 H-pyraxo!-5-y i)pyrimi din-2- a ine (200 mg, 44%) as a brick red color solid compound. LCMS: 456 [M+H] ^"

[0542] Step-4:: Synthesis of 5-fluoro-4-(8-fluor©-4-isopropyl-3,4-dihydro-2H- benzo[b][i,4] xaz«n-6-yl)-N-(3-(l-methylpiperMin-4-yl)-1H-pyrazol-5-yl)py rimidHi-2- amine: To a stirred solution of 5 iIuoro-4--(8--fluoro-4--isopropyl--3 4-.dihydto-2H-· benzol b] ] 1 ,4]oxazin-6-yl}-N-(3-(piperidin-4~yl)-l H-pyrazol-5-yl)pyrimidin-2 -amine (200 mg. 0.44mmoi, 1 equiv) in DCE (35mL), was added Formaldehyde (40% in water) (0.3 niL, 0.19 mmol, 3 equiv), acetic acid (0 013 mL, 2.1 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for 1 h. The reaction mixture was cooled to 0°C. NaCNBlR (79 mg, 1 .29 mmol. 3 equiv) was added to above mixture and raise die temperature to RT. The reaction mixture was allowed to stir at RT for 4h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL x 2). Organic layer was washed with water (30 mL) and brine solution (30 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5-fluoro-4-(8- fluoro-4-isopropy]-3.4-dihydro-2H-benzo[b][l,41oxazin-6-yl)- N-(3~(l -methylpiperidin-4~yl)-l H- pyrazol-5-yl)pyrimidin-2-amine. (14 mg, 93%) as a yellow color solid compound, LCMS: 470 [M+H] ^÷ : ^s HNMS (400 MHz, Methanohr/4) d 8.48 (d, ./ 3.9 Hz, 1 1 1 }. 7x18 (s, i l l }. 7.29 -

7.21 (m, I I I ). 6 36 (d„/= 3 4 Hz, i l l). 4.33 (t, J = 4.3 Hz, 2H), 4.22 (p, ./ 6 7 Hz, IH), 3.35 (d, J= 4.0 Hz, 5H) . 3 1 5 (d, 7 1 2 4 Hz, 31 11. 2.83 (t, J = 12 0 Hz, IH), 2.54 - 2.46 (m, 51 11. 2.08 (t, X 16.7 Hz. 3 H), 1 .90 (q, / 12.4Hz, 21 1 ;. 1.29 (s, IH), 1.26 (dd, J === 6 6, 3.3 Hz, 6H).

Exampie-108: Synthesis of5~fiuorG~4~(8~fiuoro~4~isoproj7yl~3 4~dihydro~2H~

henzoib _j [ S4]oxazm~6-yi N-(5-(piperidin-4-yl)jyyrimidin -2 yl)pyrimidin -2-amine. (Compound

500)

[0543] Step-1 : Synthesis of tert-butyl 4-(2-aminopyrimidm-5-yl)-3 _» d-dihydropyridme- l(2H)-carboxyiate: lb a solution of 5-bromopynmidm-2-amine ( 1000 mg, 5.7 mmol, 1 equiv) m dioxane (12 niL), water (2 ml,) was added tert-butyl 4-(4,4,5,5-ietramefhyfil,3,2- dioxaborolan-2-yl)-3.6-dihydropyricline~l(2H)-earboxylate (2143 mg, 6 93 mmo!, 1.2 equiv) and potassium carbonate (2360 mg, 17.1 mmol, 3 equiv) The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of Pd (dppf) Cl _{2 .} DCM (233 mg, 0.28 mmol, 0.05 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with water (50 ml,) and extracted with ethyl acetate (100 ml, * 2). Organic layer was washed with water (100 ml,) and brine solution (100 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to tert-butyl 4-(2-aminopyrirnidin-5-y])-3, 6- dihydropyridme~l(2H)-carboxylate (1000 mg, 63%) as a brown solid compound. LCMS; 277 [M+H] ^÷

[0544] Step-2; Synthesis of tert-butyl 4~(2~aminopyrimi in~5-yi) piperidine- 1- carboxy!ate: To a stirred solution of tert-butyl 4~(2~aminopyrimidim5-yl)~3, 6-dihydropyridine- l(2H)-carboxy!aie (400 nig, 0.72 mmol, 1 equiv) in ethanol (5 ml,), was added Pd/C (20% w/w) (85 mg) under IIP atm. The resultant reaction mixture was allowed to stir at RT for 4 h Progress of the reaction was monitored by LCMS. After completion of the reaction, the mixture was passes through cehte bed and the filtrate was concentrated under reduced pressure to obtain tert- butyl 4~(2-aminopyrimidin-5-yi) piperidine-1 -carboxylate (360 mg, 90%) as an off white color solid compound LCMS; 279 [M÷H]

[0545] Step-3; Synthesis of tert-butyl 4-(2-((5-flworo-4-(8-flworo-4-isopropyI-3,4- dihydro-2H-henzo[b][i,4]oxazin-6-yI)pyriinidin-2-yl)amino)py riinidin-5-yl)piperidine-l- carboxylate; To a solution of 6-(2-chloro-5-fluoropyrirnidin-4-yl)-8-f3uoro-4-isopropyl-3, 4- dihydro~2H~benzo[bj[l ,4joxaxine (200 mg, 0 61 mmol, 1 equiv) in dioxane (5mL). was added tert-butyl 4-(2-aminopyrimidin-5-yi}piperidine- 1 -carboxylate (188 mg, 0.67 mmol 1.1 equiv) and cesium carbonate (298 mg, 0.91 mmol, 1.5 equiv) The reaction mixture was degassed with itogen gas for 30 min. followed by the addition of palladium acetate (3 mg, 0.01 mmol, 0.02 equiv) and BINAP (15 mg, 0.02 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. Alter completion of the reaction diluted with water (30 ml,) and extracted with ethyl acetate (1 00 ml ). Organic layer was washed with water (50 ml,) and brine solution (50 mi,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-buty! 4-(2-((5-fluoro-4-(8- f!uoro-4-isopropyi- 3,4-dihydrO 2H-benzo[bin ,4]oxazin-6-yl)pyrimidin-2-yl)amino)pyrimidin-5- yljpiperidme- l-Carboxylate (150 mg, 43%) as a yellow solid compound LCMS: 568 [M÷H]

(0546 j Step-4: Synthesis of 5-fluoro-4-(S-iluoro-4-isopropyl-3, 4-dihydro-2H- benzo[b](l,4]oxazin-6~y!)-N-(S-(piperklln-4-yl)pyrimidin~2~y l)pyrimidia~2~amlne: A solution of tert-butyl 4-(2-((5-fluoro-4-(8-fluoro-4-isopiOpyi-3,4-dihydro-2H- benzo[b][l,4]oxazin-6-yl)pyrimidin-2-yl)amino)pyriniidin-5-y l)piperidine-l-carbox:ylate (150 mg, 0 26 mmol, 1 equiv) in 1.25 M HQ in ethanol (5 mi,) was allowed to stir for I h at 50°C. Progress of the reaction was moni tored by I, CMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude, winch was purified by reverse phase HPLC to obtain 5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro-2H~benzo[h][l ,4]oxazm-6-yl)-N-(5~ (piperidin-4-yl)pyrimidin-2-yl)pyrimidin-2-amine (25 mg, 20%) as a yellow color solid compound. LCMS: 468 [M+H] ⁺ ; 1HNMR (400MHz, DMSO-d ₆ ) 6 10.35 (s, 1 .M r 8.63 (d,

./ ' v Hz, 1 H), 8 48 (s, 2 H), 7.57 (s, 1 H), 7.21 (d, 7 i 1.7 Hz, 1 H), 4 29 (br s., 2 H), 3 99 - 4.16 (m, 1 H), 3 30 (br. s., 2 11), 3.18 (d, J=9.3 Hz, 2 H), 2 56 -- 2.84 (m, 3 H), 1.84 (d, =12.2 Hz, 2 1 11. 1.66 (d, / 12.7 Hz, 2 H), 1.19 ppm (d, .7=6.8 Hz, 6 H).

Exampie-109: Synthesis ofN-(5-(l~eihyipiperidin~4~yl) pyiidln~2~yl)~5~fluoro~4~(8~fiuoro~4~ isopropyl~3, 4-dihydro-2H-benso[b [J 4)oxazin~6~yl)pyrimldin~2~am e. ( Compound 501)

[0547] Step-1: Synthesis of N-(5-(l-eihylpiperidin-4-yI) pyridin-2-yl)~5~fluoro~4~(8~ fl«oro-4-isopropyi-3,4-dihydro-2H-benzo[b]fl _» 4]oxa* ^j n-6-yl)pyriimidin-2-araine: To a stirred solution of 5-fiuoro-4-(8-fiuoro-4-isopropyl-3,4-dihydro-2H-henzo[b][l ,4Joxa in-6-yl)-N-(5- {piperidin-4-yl)pyridin~2~yi)pyrimidin-2-amine (80 mg, 0.16 mmol, 1 equiv) in DCE (5 mL) was added Acetaldehyde (0.01 mL, 0 48 mmol, 3 equiv), acetic acid (0.04 mL 0.8 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for 1 h. The reaction mixture was cooled to 0°C NaCNBLL (18 mg, 0 48 mmol, 3 equiv) was added to above mixture and raise the temperature to room temperature. The reaction mixture was allowed to stir at RT for Hi. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with wnter (25 mL) and extracted with ethyl acetate (50 mL ^c 2) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by recrystallization with methanol to afford N-(5-(l -ethylpiperidin-4-yl)pyridin-2 -yl)-5-fluoro-4-(8- fiuoro-4-isopropy!-3,4-dihydro-2H-benzo[b][ l ,4]oxazin-6-yl)pyrimidin~2~amine (70 mg, 82%) as a yellow color solid compound. LCMS: 495 [MΉH] ΉNME (400MHz, DMSO-de) 6 9.89 (s, 1 H), 8.60 (d, ./ .1 9 Hz, 1 H), 8.1 8 (s, 1 H), 8.11 (d, 9-8.8 Hz, 1 H), 7.62 (d, ./ 8 8 Hz, 1 H), 7.48 (s, 1 H), 7.18 (d, 7-1 1.4 Hz, 1 H), 4 30 (br. s., 2 H), 4.02 · 4.21 (m, 1 H), 3.30 (br s., 2 H) 2.98 (d, 7-10.1 Hz, 2 H), 2.35 (br s., 2 H), 1 97 (br. s., 3 H), 1.76 (d, 7-10.5 Hz, 2 H), 1 65 (d,

7 9 2 Hz, 2 H), 1.19 (d, 7-6.6 Hz, 6 H), 1.02 ppm (t, 7-7 2 Hz, 3 H).

Example- 110: Synthesis of 7-{(5-fluoro-4-(S-fluoro-4-isopropyl-3,4-dihydro~2H- hemo[b] fi ]oxazin~6~yl}pyrimidin~2~yl)amino}-3, 4-dihydroisoq irK lm-l(2li)~one. _[ Campound

502}

[0548] To a solution of 6~(2~chioro-5-fluoropyrimidin-4-yl)-8-f!uoro-4-isopropy!-3.4 - dihydro~2H-benzo[b][l,4]oxazine (100 g, 0.3 mmol, 1 equiv) in dioxane (5 mL). was added 7- amirio-3,4-dihydroiSoquinolm--l (2H)-one (54 mg, 0.33 mmol, 1 1 equiv) and cesiu carbonate

(147 mg. 0 47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 m . followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP

(8 mg, 0 012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for

3h. Progress of the reaction v¾ monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 IGL) and extracted with ethyl acetate ( 100 xnL). Organic layer was washed with water (50 xnL) and brine solution (50 xnL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 7- 5-fluoro-4- 8-fluoro-4-isopropyi-3,4~dihydro~2H-benzo[b][l,4]oxazm- 6-yl)pyrimidin-2-yi)ammo)-3,4-dihydroisoqumolm-lC2H)~one ( 5 mg. 4%) as a yellow color solid coxnpound. LCMS; 452 [M H] g *HNMR (400MHz, DMSO-d ₆ ) d 9.76 (s, 1 H), 8.57 (d,

7 3 0 Hz, 1 H), 8.25 (d, .>2.2 Hz, 1 H), 7 89 (hr. s„ 1 H), 7.81 (dd, >8.3, 2.6 Hz, 1 H), 7.41 (s,

1 H), 7.12 7.25 (m, 1 H), 4 23 4.32 (xn, 2 H), 4.05 - 4.21 (m, 1 H), 3.30- 3.39 (br. s , 4 H), 2.85 (t, >6.4 Hz, 2 H), 1 16 (d, >6.6 Hz, 6 H).

Example-I l l: Synthesis of5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro-2H~

benzo[h] [J4]oxazin-6-yl)-N~(6~meihy?~5-( l -methylpiperidin-4~yl)pyridin~2~yl)pyrimidin~2~

[0549] Step-1: Synthesis of tert- butyl 6-amino-2~methyl~3 6*-dihydro-|3, 4’- feipyridiiiie]-l*(2*il)-earbexylate: To a solution of 5-bromopyrimidm-2-amine (1000 nig, 5.37 mmol, 1 equiv) in dioxane (12 ml,), water (2 ml,) was added tert-butyl 4-(4,4,5,5-†etramethyl~ l ,3,2-dioxaborolan-2-yI)-3,6-dihydropyridine-l(2H)-carboxylat e (1994 g, 6 45 mmol, 1.2 equiv) and potassium carbonate (1482 mg, 17 1 mmol, 2 equiv). The reaetion mixture was degassed with nitrogen gas for 30 min , followed by the addition of Fd (dppf) Cfi .DCM (219 mg, 0.26 m ol, 0 05 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with water (50 xnL) and extracted with ethyl acetate ( 100 mL x 2). Organic layer was washed with water (100 rnL) and brine solution (100 rnL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyl 6-ammo-2- niethyl-3 ^! ,6'-dihydro-[3,4'~bipyridine]~r(2'H)-carboxylate ( 1300 mg, 84%) as an off white color solid compound. LCMS: 277 [M+H] ^”

[0550] Step-2: Synthesis of tert-butyl 4-(6-amino-2-methylpyridm-3-yl) piperidine- 1- carboxylate: To a stirred solution of tert-butyl 6-amino-2-methyl-3', 6 ^' -dihydro-[3, 4 - bipyridine]-r(2'H)-carboxylate (400 mg, 1.38 mmol, 1 equiv) in ethanol (5 mL), was added Pd/C (20% w/w) (40 mg) under ft _? atm. The resultant reaction mixture was allowed to stir at RT for 4 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the mixture was passes through ce!ite bed and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(6~amino~2-methylpyridm-3-yl) piperidine-l -carboxylate (380 mg, 9434) as an off white color solid compound LCMS: 292 i \ j · H j

[0551] Step-3:; Synthesis of tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropy!-3,4- dihydro-2H-benzo[b|[l,4]oxazin-6-yl)pyri idin-2-yl)amino)-2-methylpyridin~3~ yi )piperidine-l -c rboxyl ate: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4- isopropyi-3,4~dihydro~2H-benzo[bl[l,4]oxazine (100 rag, 0.3 mmol, 1 equiv) in dioxane (10 mL), was added tert-butyl 4-(0-amino-2~me†hy!pyridm-3-yl)piperidine-l -carboxylate (96 mg, 0.33 mmol, 1 .1 equiv) and cesium carbonate (147 mg, 0 47 mmol, 1.5 equiv) The reaction mixture was degassed with nitrogen gas for 30 rain , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyl 4-{6-((5-i¼oro-4-(8-i¼oro-4-isopropyl-3,4-dihydro-2H- benzo[b][i ,4joxazin-6 y!}pyrimidin-2-y ^j )amino)-2-mediyipyridm-3-y!)pipendme-!-carboxy!ate (120 mg, 67%) as a yellow solid compound. LCMS: 581 [M÷H] ^÷ 10552] Step-4: Synthesis of 5-fIaoro-4-(8-flaoro-4-isopropyl-3, 4-clihydro-2H- ben¾o(b]|l,4|oxa2:in-6-yI)-N-{6-methyl-5-{piperid«n-4-yl)p yr«dm-2-yl)pyrimidm-2-amme: A solution of tert-buty! 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo b][l,4]oxazin-6-yl)pyriinidm-2-yi)ammo}-2-meihylpyridin~3~yl )pipendine-l-earboxylate (120 mg 0 22 mmol, 1 equiv) m 1.25 M HCi m ethanol (5 niL) was allowed to stir for I h at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain 5-fluoro-4- 8-fluoro-4-isopropyi-3, 4- dihydro-2H-benzo[b][l,4]oxazin-6-yl)~N- 6-inethyi-5- pipericlin-4-yi)pyridin-2-yl}pyriinidin-2- amine (100 mg, quantitative yield) as a yellow color solid compound LCMS: 481 [M+H]

[0553] Step-5: Synthesis of 5-fl«oro-4~(8-fl«oro-4-isopropyl-3, 4-i1Ihydro-2H~ benzo[b](l,4)oxazin-6~yi)-N-(6-methy!~5-(l-metfay!piperk1in- 4-yl)pyridm-2-y!)pyrimidin~2 _” amine: To a stirred solution of 5~fluoro~4~(8~iluoro~4~isopropyl~3,4-dihydro-2H~

benzo[b][l ,4]oxazm-6-y])-N-(6-methyl-5-(piperidin-4-yl)pyridin-2-yi)py rimidin-2-amine (60 mg, 0 12 mmol, 1 equiv) in DCF (5 ml,), was added Formaldehyde (40% in water) (0 01 ml,, 0 37 mmol, 3 equiv), acetic acid (0.03 ml,, 0 6 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for Ih. The reaction mixture was cooled to 0°C. NaCNBIH (23 mg, 0.37 mmol, 3 equiv) was added to above mixture and raise the temperature to RT The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by I, CMS.

After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with ethyl acetate (50 ml, 2) Organic layer was washed with water (50 mL) and brine solution (50 ml,) Organic layer was dried over anhydrous sodium sulphate and

concentrated under reduced pressure to obtain crude which was purified by reorysial!ization with methanol to afford 5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2f1-benzo b] [ 1 ,4]oxazin-6- yi}--N-(6-methy!-5-(1 -methylpiperidin-4-yl)pyridin-2-yl)pyrimidin~2~amine (20 mg, 32%) as a yellow color solid compound LCMS: 495 [M+H] ^; ; 'HNMR (400MHz, DMSO-ds) d 9.74 (s, 1 H), 8.58 (d, ,%3.9 Hz, 1 I II. 8.00 (d, 7=8.3 Hz, I H), 7.41 - 7.61 (m, 1 H), 7 19 (d, 7=1 1.7 Hz, 1 H), 4 30 for s., 2 H), 4 02 - 4.22 (m, 1 H), 3.31 (hr s., 2 H), 2 88 (d, 701.2 Hz, 2 H), 2.59 (d, 701 2 Hz. 2 H). 2.44 (s, 3 H), 2 20 (s, 3 H), 1.99 (t 700.3 Hz, 2 H), 1 .46 - 1.75 (m, 3 H), 1.19 pprn (d, 7 6 4 Hz. 6 H). Examp!e-112: Synthesis of 5~fluoro~4~(8~fluoro~4~isopropyi~ 3, 4~dihydro~2H~

benzo(h [J4]oxazin~6~yi)~N~(I~(piperidin~4~y})~lH~itnidazol-4~yi)pyr imidin~2~amine.

[0554] Step-1: Synthesis of tert-butyl 4-((methy!sulfoay!) oxy) piperidine- l-carboxyiate:

To a stirred solution of 4-hydroxycyciohexan~I-one (5000 mg, 24.87 mmol, 1 equiv) in DCM (50 mL), was added TEA (5 ml,, 34 8 mmol, 1 4 equiv). Cool the reaction mixture to 0 ^C C, followed by the addition of rnesyi chloride (2 5 mL, 34.8 mmol, 1.4 equiv). Raise the temp to RT and the resultant reaction mixture was allowed to stir for overnight. Progress of the reaction was monitored by I, CMS. After completion of the reaction, diluted with water (100 ml,) and extracted with DCM (150 ml, ^c 2). Organic layer was washed with water (100 mL) and brine solution (100 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl 4-((methylsulfonyi) oxy) piperidine-1 -carboxylate (5000 mg 72%) as an off white solid compound.

[0555] Step- 2: Synthesis of tert-butyl 4-C4-niiro-1H~iitnidazoM -yi) piperidine-1- carb xylafe: To a stirred solution of tert-butyl 4-((roethyisulfonyi) oxy) piperidine-1 - carboxylate (4000 mg, 14.3 mmol, 1 equiv) in DMF (30 mL), was added Cs ₂ C03 (9324 mg, 28.6 mmol, 2 equiv), TBAi (1055 mg, 2.86 mmol, 0.2 equiv) and 4-nitro- I H-imidazole (81 0 mg, 7 16 mmol, 0.5 equiv). The resultant reaction mixture was allowed to stir at 80°C for overnight.

Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (100 mL) and extracted with EtOAc (1 50 ml, x 2). Organic layer was washed with water (100 ml,) and brine solution (100 mil,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain tert- butyl 4-(4--mtro-4H--imidazo!-1 -yilpipendine-i -carboxylate (550 mg, 13%) as an off white solid compound. LCMS: 297 [M+H] '

(05S6| Step-3: Synthesis of tert- butyl 4-(4-amino-lH-imidazol~l~yl) piperidlne-l- carboxyiate: To a stirred solution of tert-butyi d-fo-miro-I H-imidazoi-I-yl) piperidine- 1- carboxylate (550 mg, 1.85 mmol, 1 equiv) in methanol (10 ml,), was added Pd/C (20% w/w)

(1 10 mg). The resultant reaction mixture was allowed to stir at RT for Ih. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through ce!ite bed and the filtrate was concentrated under reduced pressure to obtain tert- butyl 4-(4-ammo-l H-iniidazoi i-yl) piperidine- 1 -carboxylate (450 mg, 91 %) as a brown color viscous compound LCMS: 267 [M÷H] ^’

[0557] Step-4: Synthesis of tert-butyi 4-(4-( ( 5-fiuoro-4-( 8-fluoro-4-isopropyl-3,4- dihydro-2H-benzo[b]jl,4[oxazm-6-yl)pyrimidin-2-yl)ammo)-lH~i midazoi-l-yl)piperkline~

I -carboxylate: To a solution of 6-(2-chloro-5-fluoropyrimidin- _' ^; tiyl)~8-fluoro~4~isopropyh3,4- dihydro-2H-benzo[b][l,4]oxazine (500 mg. 1.53 mmol, 1 equiv) in dioxane (5 ml,), was added tert-butyi 4-(4-amino- lH-imidazol- 1 - I)pi peridi ne~ 1 -carbox late (450 rag, 1.69 ramo!, 1.1 equiv) and cesium carbonate (748 mg, 2 29 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (7 mg,

0 03 mmol, 0 02 equiv) and BINAP (38 mg, 0.06 mmol , 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert- butyl 4- (4-((5-iluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-henzo[b ][l ,4]oxaz;m-6-yl)pyrimidin-2- y!)amino -l H-imidazol-l-yl)piperidine-l-carboxylate (600 mg, 70%) as a brown color viscous compound. LCMS: 556 [M+H] l·

[0558] Step-5: Synthesis of 5-fi uoro-4-( 8-fi uoro-4-isopropyl-3, 4-dihydro-2H- benzojh j [1 ,4[ oxazi«-6-yI)-N-( 1 -(piperidm-4-yl)-lH-hnulazol-4-yl)pyrmndin- 2-amine: tert- butyi 4-(4-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo [h][ i,4]oxazin-6·· y 1 )pyrimidin-2-y l)amino)- IH-imidazol- 1 -yl)piperidine- 1 -carboxylate ( 100 mg, 0.18 mmol, I equiv) was taken in 1 .25 M HCI in ethanol (10 mL) and the resultant reaction mixture was allowed to stir at 50°C for I h. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude compound, which was purified by making HCI salt to afford 5-fluoro-4 5-fluoro-4-(8-fiuoro-4- isopropyi- 3,4-dihydro-2H-benzo[bin ,4]oxazm 6-yi} N (!-(prperidm-4-y!)-lH- imidazo! 4·- yl)pyrimidin-2-amine (15 mg, 18%) as a yellow color solid compound. LCMSi 456 [M+H] ^;l H MR (400MHz, DMSO-fo) d 9.65 (br. s„ 1 H), 8.50 (br. s . 1 H), 7.53 (br. s., 1 H), 7.39 (br s., 1 H), 7.31 (br s., 1 H), 7 15 id, ,fol 1.2 Hz, 1 H), 4.30 (br s., 2 H), 3 92 4.19 (m 1 H) 3.31 (br. s. 2 11) 3.10 (d, 7 ^:::: 10.3 Hz, 2 H), 2.65 (d, . Cl 1.7 Bz, 2 H), 1.97 (br s., 2H), 1.76 (d, 7 ^:::: ! 0 3 Hz, 2 H), 1.18 ppm (d, ./ 6 4 Hz, 6 H).

Example- 113: Synthesis of 5~fluoro~4~(8~fluoro~4~ isopropyl-3. 4-dihydro-2H- benzojh) [ l,4]oxazin-6-y!)-N-(5~(piperidin-4-y!)pyrazin~2-yi)jyyrimids n-2 imine. (Compound 505)

[0:559] Step-1; Synthesis of tert- butyl 4-(5-aminopyrazin~2~yl)-3,6-dihydropyrid«ae- 1 (2H)-car oxylate; To a solution of 5-bromopyrimidin-2-amine ( 1000 mg, 5 7 mmol, I equiv) m dioxane (12 mL), water (2 mL) was added tert-butyl 4-(4,4,5,5-tetrarnethyl-l,3,2- dioxaborolan-2-y!)- 3,6-di!iydropyridine-l(2H)-carboxylate (2143 mg, 6 93 mmol, 1.2 equiv) and potassium carbonate (2360 mg, 17.1 mmol, 3 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of Pd (dppf) Cl _{2 .} DCM (233 mg, 0.28 mmol, 0.05 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reacti on was monitored by TLC and LCMS. After completion of the reaction , reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 ml, 2) Organic layer was washe with water (100 ml,) and brine solution (100 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, winch was purified by normal phase combi flash to obtain tert- butyl 4-(5~aminopyrazin-2-yl)-3.6- dthydropyndine- ! (2H)--carboxyiate (1000 mg, 63%) as a brown solid compound. LCMS: 277 [M+H] ⁺

[0560] Step-2: Synthesis of tert- butyl 4-(5~aminopyra*in~2~yl) piperidine- 1-carboxy!ate:

To a stirred solution of tert-buty! 4-(5-ammopyrazin-2-yl)~3, 6-dihydropyridine-l(2H)- carboxylate (400 mg, 1 44 mmol, 1 equiv) m ethanol (5 mL), -w s added Pd/C (20% w/w) (80 mg) under ¾ atm. The resultant reaction mixture was allowed to stir at RT for 4 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the mixture was passes through cetite bed and the filtrate was concentrated under reduced pressure to obtain test-butyl 4- (5~aminopyrazin-2-y!) piperidine- 1 -carboxylate (400 mg, 99%) as an off white color solid compound. LCMS: 279 [M+H]

[0561] Step-3: Synthesis of tert-buty! 4-(5-((5-fluoro-4-(8-fluoro-4-isopropyi-3,4- dihydro-2H-benzo[b][l,4]oxazin-6-yi)pyri idm-2-yl)amino)pyrazin-2-yi)piperidin -l” carboxylate: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-f1uoro-4-isopropyl-3,4 ~ dihydro-2H-benzo[b] [ 1 ,4]oxazine (200 mg, 0 61 mmol, 1 equiv) in dioxane (5mL), was added tert-butyi 4~(5-aminopyrazin-2-yi)piperidme~l -carboxylate (187 mg, 0.67 mmol, 1 . 1 equiv) and potassium carbonate (168 mg, 1.22 mmol, 2 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of Pd2(dba) ₃ (56 mg. 0.06 mmol, 0.1 equiv) and X-phos (58 mg, 0.12 mmol, 0 2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction v¾ monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 L) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by normal phase combi flash to obtain tert- butyl 4--{5--((5-fiuoro--4-(8- fiuoro-4--isopropy!-3,4-dihydro-2H--benzo[b!P ,4]oxazm~6-yl)pynmidin-2-yi)amino)pyrazm~2- yl)piperidine-l -carboxylate (250 mg, 7263) as a yellow solid compound. LCMS: 568 [M+H] ⁺ [0562] Step-4: Synthesis of 5-fIaoro-4-(8-flaoro-4-isopropyl-3, 4-clihydro-2H- benzo(b]jl,4]oxazi«-6-yI)-N-{5-{piperidin-4-yl)pyrazin-2-yl )pyriiniili«-2-amine: A solution of tert-butyl 4-(5-((5-fluoro-4-(8-fluoro-4-isGpropyl-3,4-dihydro-2H-benzo [b][l,4]oxazin-6- yl)pyrimidin~2~yl)amino)pyrazm-2-yl)piperidine-l -carboxylate (250 mg, 0 44 mmol, 1 equiv) in

1.25 M HCi in ethanol (5 ml ..· was allowed to stir for lb at 50°C. Progress of the reaction was momtored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain 5-iluoro-4-(8- f!uoro~4-isopropyi-3,4-dihyclrG-2H~benzo[b][1 ,4]oxazin-6-yi}-N-(5~(piperidin~4~yl)pyrazin~2~ yl)pyrimidin-2-amine (2 mg, 1%) as a yellow color solid compound. LCMS: 468 I M H i ^r ; *HNMR (DMSO-de ,400MHz): d 10.31 (br. s., 1 H), 9.38 (br s., 1 H), 8 65 (d, ,7-3.4 Hz 1 H)

8.25 (br. s., 1 H), 7.50 (br. s , 1 H), 7.20 (d, >=10.8 Hz, I H), 4.31 (br. s., 2 H), 4.15 (d, >7.3 Hz, 1 H), 3.31 (br s., 7 H), 3 17 (br s., 2 H), 2 86 (br. s., 2 H), 1.02 ·· 1 30 ppm (m, 6 H).

Example- 114: Synthesis of l-(4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- henzofbj ,4]oxazm-6~yl)pyrimidift~2~yl)amino}pyridin~3~yl)piperazin-l -yl)~2~hydroxyethan~ I - one. (Compound 506)

[0563] To a stirred solution of 5~iluoro~4~(8~tiuoro~4usopropyi~3 4 dihydro--2H~

benzo[b][l ,4]oxazm-6-yl)-N-(5-(piperazm-l-y])pyridm-2-yi)pyrimidin-2-a mme (50 mg 0.1 mmol, 1 equiv) in DMF (5 n ;! } . was added 2-hydroxyacetie acid (12 mg, 0 1 6 mmol, 1.2 equiv) DIPEA (0 05 ml,, 0 3 mmol, 3 equiv) HOBt (22 mg, 0 16 mmol, 1 5 equiv) and EDC.HCL (31 rng, 0 16 mmol, 1.5 equiv). The reaction mixture was allowed to stir for overnight at RT

Progress of the reaction was monitored by TEC and LCMS. After completion of the reaction, solid observed in the reaction mixture was filtered , washed with water (10 uiL) and dried under vacuum to obtain 1 -(4--(6-{(5-iiuoro-4-{8-iiuoro-4usopropyl-3,4-dihydro--2H- benzoibl[l,4]oxazin-6-yl)pyrimidm--2--yi)ammo)pyndin--3--yl) piperazm--l --yi)-2-hydroxyethan-4-· one (20 mg, 36%) as yellow color solid compound LCMS; 525 j M-HBI ft ftINME (400MHz, DMSO-dg) S 9.74 (s, 1 H), 8 57 (d, >3.9 Hz, 1 H), 7.92 - 8.1 5 (rn, 2 H), 7.29 -- 7 55 (m, 2 H), 7.1 7 (d, ./ 2 2 Hz, 1 1 1} 4 64 it, 7 5 4 Hz, 1 H), 4.30 (br. s„ 2 H), 4.14 (d, 7-5 9 Hz, 3 å-]), 3.63

(bf s., 2 H), 3 51 (br. s„ 2 å-]), 3.31 (br. s., 2 H), 3 11 (br. s„ 4 H), 1.19 ppm (d, ,7-6.4 Hz, 6 H).

Example - 115: Synthesis of 4~((5~fluoro~4~(8~fluoro~4~isopropyi~3, 4-dihydro-2H~

[0564] lb a solution of 6-(2--chtoro-5-ituoropyrmndm-4-y l)-8-f!uoro-4-isopropy 1-3,4- dihydro~2H-benzo[b][l,4]oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (5 mL), was added 4- ammobenzenesuiibnamide (57 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. Auer completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brute solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which -was purified by reverse phase MPLC to afford 4-((5~fluoro-4~(8~fluoro-4~isopropyl~3,4-dihydro-2H-benzo[b] [l,4]oxazin- 6-y!)pyrimidim2-yi)amino)benzenesu!fonamide (25 mg, 18%) as a yellow color solid compound. LCMS: 462 [ de) d 10.14 (s, 1 H), 8 65 (d, 7-3.9 Hz, 1 H),

7.81 - 7.98 (m, 7-8.8 Hz, 2 H), 7.63 - 7.81 (m, 7-8.8 Hz, 2 H), 7.45 (s, 1 H), 7 06 - 7.24 (m, 3 H), 4.31 (br. s , 2 H), 4.15 (d, 7-7 3 Hz, I H), 3.31 (br. s., 2 H), 1.21 ppm (d, 7-6 4 Hz, 6 H).

Example-116: Symhesis ofN~(5~fluoro~4~(8~fluoro~4~isopropyI~3 -dihydro-2H~

benzo[bjll.,4]oxazin~6~yl)pwimidm~2~yI)~4~(piperidin~4~yl )ihiazol~2~amme. (Compound 508)

[0565] Step- l : Synthesis of tert-butyl 4-(2-bromoacetyI) piperidine-l-carboxylate: To a solution of tert-butyl 4-acetylpipendme-l -carboxylate (500 mg, 2.21 mmol, 1 equiv) m dry ΊΉT (5 niL), was added LiHMDS (4 mL, 2.42 mmol. 1.1 equiv) dropwise at -78 °C -within 15 mm., resulting mixture was stirred at -78 °C for !h. To this was added TMSC! (0.5 mL, 2.42 mmol,

1.1 equiv) drop-wise at -78 °C. The reaction mixture was warmed to 0 °C for 10 min and then at room temperature for 20 min. Again was cooled to -78 °C. To tins was added Bromine (0.06 mL, 2.21 mmol, 1 equiv) dropwise at -78 °C The resultant reaction mixture was allowed to stir at room temperature for 15 min. Progress of the reaction was monitored by TLC and 1 ( ^' MS. After completion of the reaction, diluted with Na2S2()3 solution (10 ml,) and M 14(1 solution (1 0 ml-) Reaction mass extracted with ethyl acetate (15 mL). Organic layer was washed with water (5 mL) and brine solution (5 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl 4-(2-bromoacetyl) piperidine- 1- carboxyiate as crude, winch was purified by combi flash by using 100-200 mesh silica gel column. Yield : 350 mg. LCMS: ELSD 306 [M+H] ⁺

[0566] Step- 2: Synthesis of tert-butyl 4-(2-aiminothiazol-4-yI) piperidine- 1-earboxyiate:

To a stirred solution of tert-butyl 4-(2-bromoacetyl) piperidine-l-carboxylate (200 mg, 0.65 mmol, 1 equiv) in IP A (5 ml-), was added thiourea (99 mg, 1.3 mmol, 2 equiv). Resultant mixture was allowed to stir at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was concentrated, diluted with water (10 ml-), and was extracted with EtOAc (1 5 ml-). Organic layer dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound was triturated from hexane to afford tert-buiyi 4-(2-aminothiazol-4-y1) piperidine-1 -carboxyiate (1 50 mg) as an oily compound. LCMS: 284 [M+H]

[0567] Step-3: Synthesis of tert-butyl 4-(2-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4- d«hyclro-2H-ben*o[b][l,4]oxa2m-6-yl)pyrimidm-2-yl)am«no)th iazoi-4-yI)piperidine-i- carboxyiate: To a solution of 6~(2~chloro-5-fluoiOpyrimidin-4-yl)-8-f!uoro-4-isopiOpyl-3,4 ~ dihydro-2H-benzo[b][l,4]oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (4 L), was added tert-butyl 4~(2~aminothiazol-4-yl)piperidine-l-carboxylate (94 mg, 0.33 mmol, 1 1 equiv) and potassium carbonate (62 mg, 0 45 mmol, 1.5 equiv). The reaction mixture was degassed by nitrogen gas for 10 m., followed by the addition of Pd2(dba)3 (27 mg, 0.03 mmol, 0.1 equiv) and Xphos (28 mg, 0.06 mmol, 0.2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (10 ml,) and extracted with ethyl acetate (10 ml,). Organic layer was washed with water (5 mL) and brine solution (5 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl 4-(2- ((5~fluoro~4~(8-fluoro~4~isopropyb3,4-dihydrO 21:Lbenzo[b][l ,4 ]oxazin 6 y!)pyrimidin-2- yl)amino)thiazol~4~yl)piperidine-l -carboxyiate (130 mg) as an oily crude residue which used directly for next step LCMS: 573 [M÷H]

[0568] Step-4: Synthesis of N-{5-fluoro-4-{8-fluoro-4-isopropyI-3,4-dihydro~2H- henzo[b] [ 1,4] oxazin~6~yI)pyrimidin-2~yI)-4-(piperidin-4~yI)thiazoi~2-amin e: A solution of tert-butyl 4-(2-((5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro- 2H-benzo[b][l 4]oxazin-6- yl)pyrirmdin-2-yl)amino)thiaz.oj-4-yl)piperidme-l -carboxyiate (130 g crude) in 1 25 M HCI in ethanol (5 mL) was allowed to stir for 1 h at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction solvent was removed under reduced pressure to obtain crude which was purified by reverse phase HPLC to afford N-(5-f!uoro-4-(8-iluoro-4-isopropy!- 3,4-dihydro-2!:Lbenzo[b][l ,4]oxazin-6-yi)pyrimidin-2-y!)-4-(piperidin-4-y!)thiazoi-2-a mme (1 8 rng) as an off white solid compound LCMS: 473 [M+H] ^s IINMS (400MHz, DMSO-d _< s) d 8 61 - 8.55 for 21 1} 8 50 is, OH), 8.63 - 8.55 (m, 2H), 8.59 - 8 53 (m, 2H), 8.51 (s, OH), 8.65 8.52 (m, 3H). 7.71 (s, 1 H), 7 36 (d, 7 1 1.7 Hz, 1 H), 6.67 (s, 1 H), 4.38 - 4 32 (m, 2H), 2.73 -

2 63 (m, 4H), 2.61 - 2 59 ( , 1H), 4.32 - 4.24 (m, 1H), 3.40 - 3.32 (m, 3H), 2.82 (d, 7 9.4 Hz 1 H), 2 61 (s, 41 1} 8 62 - 8.53 (m, 21 1} 2 22 - 2 13 (m, 21 ) ·. 1.91 (t, 7 12.7 Hz, 21 1} 8 63 -

8 52 (m. 3H), 1.28 (d, J --- 6 6 Hz, 7H).

Example-! I 7: Synthesis ofN~{4~(4~cyeiopentyi~8~fl oro~3, 4~dihydro~2H~benzofhj j J 4joxa _å in-6-

[0569] Step-1 : Synthesis of tert- butyl 2-((4-(4-cycIopentyi-8-ffuoro-3, 4-dihydro~2H- b£nzo[b] [l ₅ 4]oxazbi~0-yI)~5~fl«oropyrhmdm~2~yl)ammo)~7,8-dihydro -l,6-iiaphi:hyndine~ 6(5Il)-carhoxylate: To a solution of 6-(2-chioro-5-fluoropyrimidin-4-yl)-4-cyciopentyl-8- fliioro-3,4-diliydro-2H-benzo! bj! l 4 oxazins (40 mg, 0 1 1 mol, I equiv) m dioxane (5 niL), was added tert- butyl 2-ammo-7,8--dihydro--l,6-naphthyridme-6(5B>carboxyiate (31 mg, 0.12 mmol, 1.1 equiv) and cesium carbonate (54 mg, 0.16 mmol, 1 .5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (1 g, 0.002 mmol, 0.02 equiv) and BINAP (3 mg, 0.004 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 niL) and extracted with ethyl acetate (100 ml..). Organic layer was washed with water (50 ml,) and brine solution (50 l,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to tert-butyl 2-((4- 4- cyciopentyi-8-fluoro-3,4-dihydro-2H-benz:o[b][ ! ,4]oxazin-6-yl)~5~iluoropyrimidin~2~yl)armno)~ 7,8-dihydro-l ,6~naphthyridine-0(5H)-carboxyla†e (50 mg, 78%) as a yellow color solid compound. LCMS: 565

[0570] Step-2: S thesis of N-(4-(4-cyclopentyi-8-fluoro-3,4-dihydro-2H- feenze[fe] jly4joxa: ¾-0-yl) 5 fIuoFopyrimkl -2 yl )-§,&, 7, 8~tetFalmlro~l,0-napfaihy!riidin~2~ amine: A solution of tert-butyl 2~((4 -(4 -cyclopentyl-8-fluoro-3,4 -dihydro~2H- ben o[b][l 4|oxazin-6-yl)-5-fluoropyrimidin-2-yl)amiiio)-7,8-dihydro-L6 -naphtbyridine-6(5H)- carboxy te (50 mg, 0 08 mmol, 1 equiv) in 1.25 M HC1 in ethanol (5 niL) was allowed to stir for lb at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain N--(4--i4--cyciopentyh8-fluoro-3,4--dihydn>2H- benzoibl [ 1 ,4]oxazin-6-yl)~ 5-flu oropyrmiidin-2~yl)-5, 6,7, 8-tetrahydro- 1 ,6~naphthyridin-2-aniine (8 mg, 20%) as a yellow color solid compound LCMS: 465 [MMd] blINME (400MHz,

DMSO-d _f c) d 9.76 (s, 1 H), 8 53 (d, .7-3.9 Hz, 1 H), 7.94 (d, ./ 8 3 Hz, 1 H), 7.46 (br. s. 1 H} 7.33 (d, ./ 8 .3 Hz, 1 H), 7 13 (d, ,7-12.2 Hz, 1 H), 4.30 (br s., 2 H), 4 02 4.22 (m, 1 H), 3.81 (br s., 2 H), 3.31 (br. s, 2 H), 3.00 (br s., 2 H), 2 67 (br. s., 2 H), 1 83 ( br. s , 2 H), 1.64 (br. s„ 2 H), 1.54 ppm (br s., 4 H).

Example- 118: Synthesis of l~(4~(6-((5-fluoro-4-(8-fluoro~4-isopropyl-3,4~dihydro~2E- henzo[bl[L4]oxazin~6~yl)pyximidin~2~yl)amino}pyridin~3~ylJpi pexidin~l~yl)-2-hydroxyeihan-l- one (Compound 5/0)

[0571] Step-1: Synthesis of l-(4-(6-((5-fluoro-4-(8-fluoro-4-isopropyI-3,4-dihydro-2H- henzo[h] [ 1,4] oxazin-6-yI)pyrimidin-2-yl)amino)pyridin-3-yl)piperidin- l-y!)-2- hydroxyethan-l-one: To a stirred solution of 5-f1uoro-4-(8-f1uoro-4-isoprop l-3,4~dihydro-2H- benzo[b][l ,4]oxazin-6-yl)-N-(5-(piperidm-4-yl)pyridin-2-yl)pyriraidin- 2-araine hydrochloride (80 mg, 0.17rnmol, 1 equiv) in DMF (5mL), was added EDC/HC1 (49mg, 0.256mmoi, l Sequiv), 1 101:0 (35mg, 0 256mmol, 1 .Sequiv), DIPEA (0 2 mL, 0.5i3mmoi, 3 equiv). The reaction mixture was allowed to stir ai RT for overnight. Progress of the reaction was monitored by [.CMS After completion of the reaction, the reaction mixture was filtered and washed with water to get yellow solid of l -(4-(6-((5-iluoro-4-(8-iluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][l ,4]oxazin-6-yl)pyrimidin-2-yi)araino)pyridin-3-yl)piperidiri -l-yl)-2-hydroxyethan-l - one. (05 mg, 94.60%) as a yellow color solid compound. LCMS: 525 i \ l· 1 1 1 ⁺ , !M NME (400 MHz, DMSO-A6) 6 9 93 is, 1 H), 8 61 id, ./- 4 0 Hz, H i }. 8.20 (d, ,/ - 2.5 Hz, Ί H), 8.13(d, J- 8.6 Hz, 1 H), 7.62 (dd, J- 8.6, 2.5 Hz, l H), 7.48 (s, 1 H), 7 19 id, J- 1 1.5 Hz, 1 H), 4.55 - 4 45 (m,2H), 4.34 - 4.27 (m, 2H), 4.14 (dt, - 13 2, 6.5 Hz, 11 1 }. 3.79 (d, J - 1 3.2 Hz, 1H), 3.31 (d, J

3 /8 ---- 4.6 Hz, 211), 3.07 (t ./ 12.8 Hz, 1H), 2.81 (tt, / 12.3, 3.5 Hz, 1H), 2.68 (d, J --- 11 2 Hz, HI),

1.81 (d, J- 13.0Hz, 21 1 ). 1.68 - 1.43 (m, 2H), 1 .23 (s, HI), 1 .19 (d, J - 6.5 Hz, 6H).

Example-119: Synthesis of (2.6-dimethylmorpholmo)(6~((5-flnoro~4-(8-fluoro~4-isopropyl -3, 4- dihydro~2H~benzo[h] [1 , 4joxazin-6-yl)pyrimidm-2~yl)amino)pyridin~3~yi}meihanone

(Compound 511)

[0572] Step-1: Synthesis of (<^aminopyridin-3-yl)(2,6-dimethyImorpholmo)methanoiie:

To a stirred solution of 6-armnofiicotmic acid (1000 mg, 7.24 mmol, 1 equiv) in DMF (10 ml,), was added 2,6-dimeihylmorphohne (1250 mg, 10.8 mmol 1.5 equiv), DIPEA (5 on .. 29 mmol 4 equiv) and BATH (4952 mg, 13 mmol 1.8 equiv) Die reaction mixture was allowed to stir for overnight at RT. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (50 mL), solid observed was filtered and dried under vacuum to obtain (6-ammopyridm--3--y!}{2,6-dimethyimorphoimo)methanone (800 mg 69%) as an off white color solid compound. LCMS: 236 I M · H i

[0573] Step-2: Synthesis of (2 _> 6-dimethylmorphoIino)(6-((5-IIaoro-4-(8-fIaoro-4- isopropyI-3,4-clihydro-2H-hen¾o[b] i ,4]oxa2:in-6-yI)pyrimidin-2-yI)ainino)pyridm-3- yI)methnnone: To a solution of 6-(2-chloro-5-fluoropynmidin-4-yi)-8-fluoro-4-isopropy 1-3,4- dihydro-2H-benzo[b] 1 ,4]oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 mL), was added (6-aminopyridin~3-yl)(2,6-dimethylmorpholino)methanone (78 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0 47 mmol, 1.5 equiv) The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dned over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by norma! phase Combi Cash to obtain (2,6-dimethylmorphoimo)(6- ((5 fluoro-4 (B-fluorO 4 isopropyl 3,4-dihydro-2H benzo b ] l ,4]oxazin-6-yl)pyrinudin-2- yl)amino)pyriclin-3-yl)methanone (20 mg, 12%) as a yellow color solid compound. LCMS: 525 [M-f-H] ‘HNMR (400MHZ, DMSO- . · d 10 34 (s, 1 H), 8.67 (d, %3 4 Hz, 1 H), 8.37 (s, 1 H), 8 28 (d, ,7-8.8 Hz, 1 H), 7.80 (dd, 7 8 8. 2.0 Hz, 1 H), 7.49 (s, 1 H), 7.20 (d, ./ ! 1.7 Hz, 1 H), 4.31 (br. s , 2 H), 4.05 - 4.21 (m, I H), 3.55 (d, .7-5.9 Hz, 2 H), 3 31 (br. s., 4 H), 2.51 (hr. s„ 2 H), 1.19 (d, JMS.4 Hz, 6 H), 0 91 - 1 .16 ppm (m, 6 H).

Jjcamp!e-J 20: Symthesis of I~(6~((S-fluoro~4~(8-fluoro~4~isopropyi~3,4~dihydro~2H~

benzofh/[J4joxazin~6~yi)p} ^> rimidin~2~yi)amino)pyridin~3~y )piperazin~2-one. (Compound 512)

[0574] Step-1: Synthesis tert-butyl 4~(6-mtropyrid n-3-yl)~3-oxopiperazine-l- carboxylafe: To a solution of 5-hromo~2-mtropyridine (500 mg, 4.95 mmol, 1 equiv) m Dioxane (10 mL), was added tert-butyl 3-oxopiperazine-l-carboxylate (990 mg, 4.95 mmol, 1 equiv) and cesium carbonate (4034 nig, 12 3 mmol, 2.5 equiv). The reaction mixture was purged with nitrogen gas for 30 m ., followed by the addition of Pd ₂ (dba) ₃ (227 mg, 0.24 mmol, 0.05 equiv) and XATPHOS (230 mg, 0 39 mmol, 0.08 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted wit ethyl acetate ( 1 50 mL x2). Organic layer was washed with water ( 100 mL) and brine (100 mL) Organic layer was dried over anhydrous sod um sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi flash to obtain tert-butyl 4-{6-nitfopyridm-3-yl)-3-oxopiperazins-] ~carbox laie (250 nig, 37%) as a yellow solid compound. LCMS: 323 [MΉB] ^’

[0575] Step-2: Synthesis of tert- butyl 4-(6-ammopyr lo-3-yl)-3-oxopipera2ine-i - carboxylate: To a stirred solution of tert-butyl 4-i6-nitropyndm-3-yl}-3-oxopipsraxine-1 carboxylate (250 mg, 0 77 mmol, 1 equiv) in methanol (5 ml), was added Pd/C (20% w/w) (50 g) under 1 1 ·. atm 1he resultant reaction mixture was allowed to stir at RT for 4 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the mixture was passes through cehte bed and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4- (6-ammopyridm-3-yi)-3-oxopiperazine-l-carboxylate (200 mg, 88%) as an off white color solid compound. LCMS: 293 [M+H] ^*

[0576] Step-3; Synthesis of tert- butyl 4-(6-((5~fluoro-4~(S~fluoro-4~isopropyl-3,4 dihydro-2H-benzo[b](l,4]oxazin-6-yl)pyri idm-2-yl)amino)pyridia~3~y!)-3~oxopiperazme- 1-carhoxylate: To a solution of 6-(2-chioro-5-iluoropyrmudm-4-yl)-8-fluoro-4-isopropyl-3,4~ dibydro-2H-benzo[b] [ 1 ,4]oxazine (200 mg, 0 6 mmol, 1 equiv) in Dioxane (10 ml,), was added tert-butyl 4-(6-aminopyridin~3~yl)~3~oxopiperazme-l-carboxylate (198 mg, 0.66 mmol, 1.1 equiv) and cesium carbonate (293 mg, 0.9 mmol, 1 5 equiv). The reaction mixture was purged with nitrogen gas for 30 min , followed by the addition of palladium acetate (3 mg, 0 012 mmol, 0.02 equiv) and BINAP (1 5 mg, 0 024 mmol, 0.04 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction the reaction mixture was diluted with water (30 ml,) and extracted wit ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi flash to obtain tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isoprop i-3,4-dihydro-2H-benzo[b][l,4]oxazin-6- yl)pyrirmdm-2-yl)antino)pyridin-3-yi)-3-oxopiperazine-! -carboxyiate (100 mg, 28%) as a yellow solid compound LCMS: 582 [M+H]

[0577] Step-4:: Synthesis of 1-(6-((5-fluoro-4-(8-fluor<>-4-isopropyl-3,4-dihydro-2 H- benzo[b][l,4]oxaz«n-6-yl)pyr«midm-2-yl)amino)pyridin-3~yl) piperazin-2-one: tert-butyl 4-(6- ((5-f!uoro-4-(8-f!uoro-4-isopropyi-3,4-dihydro-2H-benzoj b][l ,4joxazm-6-y!)pyrimidin-2- y!}amino)pyridin-3-yi)-3-oxopiperazme-l-cafboxy!ate ( 100 mg, 0.17 mmol, 1 equiv) was taken in 1 .25 M 1 K Ί in ethanol (5 mL) and the resultant reaction mixture was allowed to stir at 50°C for I h. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain 5-fluoro-4-(8-fluoro-4-isGpropyl-3,4-dihydro-2H-benzo[b][l,4 ]oxazin~6~ yl)-N~(5~(piperidin~4~yl)pyrazin~2~yl)pyrimidin-2-amine (40 mg, 48%) as a yellow color solid compound. LCMS: 482 ^A HNMR (400MHz, DMSO-de) b 10.11 (s, 1 H), 8 64 (d,

7 3 0 Hz, 1 H), 8.27 (d, 7-2.4 Hz, 1 H), 8 21 (d, 7-8.8 Hz, 1 H), 7.72 (dd, 7-9 3, 2.4 Hz, 1 H), 7.49 (s, 1 H), 7 19 Id, 7-1 1.2 Hz, 1 H), 4.30 (hr s., 2 H), 4 16 (hr s„ 1 H), 3 62 it, 7-5 4 Hz, 2 H), 3.40 (br. s, 2 H), 3.35 (m 2 H) 3.03 (t, 7-5.1 Hz, 2 H), 1.19 ppm Id, 7-6.4 I IT. 6 I I I.

Example-121 : Synthesis ofN~(2-(dimeihyiamino) ethyi)~4~((5~fluoro~4~(8~fluoro~4~isopropyl~3, 4- dihydro-2H--bemofbj/J4Joxazm--6--yI)t:yrimidin--2-yI)amino)b enzenesulfimamide. (Compound 5 )

[0578] Step-1: Synthesis of N~(2~(dimethylammo) etfay!)-4-nitrobenzenesulfoaamide: To a stirred solution of 4-nitrobenzenesulfonyl chloride (500 mg, 2 26 mmol, 1 equiv) m DCM (06 mL), was added Triethylamine (.4 ml, 4 52 mmol, 2 equiv) and Nl , Nl-dimethylethane-l , 2- diamine ( 4ml, 4.52 mmol, 2 equiv). The reaction mixture was allowed to stir at RT for 5 h. Progress of the reaction was monitored by TLC and ! .( MS. After completion of the reaction, the reaction mixture was diluted with water (20 ml) extracted with ethyl acetate (25 mL * 2)

Orgamc layer was washed with water (1 5 ml,) and brine solution (20 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford of N-(2-(dimethylamino)ethyl)-4- nitiobenzenesulfbnamide. LCMS: 274 I M H i ^f

[0579] Step-2: S thesis of 4-amiao-N~(2~(dimethylarnino) ethyl) benzenesulfonamide:

To a stirred solution of N-(2-(dimethylarmno) eihy!)-4-~m†robenzenesulfbnamide (470 mg, 1 74 mmol, i equiv) in ethanol (08 mL), was added Pd/C (100 mg, 0.087 mmol, 0 05 equiv) ai RT The reaction mixture was allowed to stir at RT for 3h. Progress of the reaction was monitored by TLC arid LCMS. After completion of the reaction, the reaction mixture was passed through ceiide filter. Organic layer was washed with water (20), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 4~amino-N-(2-(dimethylammo) ethyl) benzenesuifonarnide (277 mg, 99 %) as brown compound. LCMS: 244 [M÷H]

{0580j Step-3: Synthesis of N-(2-(dimeihylam«no)ethyl)-4-((5-fltioro-4-(8-iltioro-4- isopropyI-3,4-dihydro-2H-ben«o[b] i,4joxa2;i«-6-yI)pyrimidm-2- yl)amino)benze»esuifonamide: To the solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8- fluoro-4-isopropyl-3,4-dihydro-2H-benzo[b][l,4]oxazine (100 mg, 0.3 mmol, 1 equiv) was added dioxane (5ml) and 4mn:miO N-(2Admiethyiammo)ethy!)benzenesu!fbnamide (82mg, 0.033mmol, 1.1 equiv), cesium carbonate! 146mg, 0.0.46mmoi, i .5eqmv), resulted reaction mixture was degassed with nitrogen for 5 min thereafter was added Pd(Oac) ₂ (07mg, 0 031 m ol, 0 1 equiv), BINAP (38mg, 0.056mmol, 0.2mmol), resulted reaction mixture was allowed to stir for 15h at 100°C Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with ethyl acetate (40 mL x 2) Organic layer was washed with water (35 ml,) and brine solution (25 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by combi-flash to get N-(2-(dimethylamino)ethyl)-4-((5- fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2!:I-benzo[b][l ,4]oxazin-6-yi)pyrimidin-2- yl)amino)benzenesulfonamide (35mg,99.90%) as a yellow solid compound LCMS: 533 I M H i ft ^! .U NMR (400 MHz, Medianoftfofi 6 8.44 id. ./ 4.1 Hz, 1 H). 8.30 (d, ./ 8.8 Hz, l i ft. 8.18

(s, 1 H),7.79 - 7.71 (m, I B), 7 52 (s, I B), 7 29 - 7.21 (m, l i ft 4 33 (t, / 4.3 Hz, 2B), 4 22 (p, J === 6 6 Hz, 1H),3 57 - 3.44 (m, I B), 3.35 ft / 4.4 Bz, 4B), 3 14 - 3.03 (m, l i ft 3.03 - 2.93 (m,

I ), 2 77 (t, ft - 9 5 Hz, I B), 2.61 (s, l i ft. 2.43 <dq ft - 14.3, 8.2 Hz, I B), 2.02 p it ft 13.3, 7 6 Hz, l i ft. 1.26 (d, ft ^::: 6.6 Hz,7B)

Example-122: Synthesis ofN-(5-fluoro-4-(S-fluoro-4-isopropyl-3, 4-dihydro-2H- henzofhj [ l,4]oxazin-6-ylJp)mmidin-2-yl)-5~(piperidin~4-yl)thiazoI~2-a mine. (Compound 514)

[0581] Step-1: Synthesis of tert-butyi 4-(2-((5-flaoro-4-(8-flaoro-4-isopropyi-3,4- dihydro-2H-benzo[b]ii _» 4]oxa¾in-6-yi)pyrimidin-2-yl)an»ino)thia*oI-5-yI}pip eridine-l- carboxylate: To a solution of 6-(2-chloro-5-f!uoropyrimidir!-4-yl)~8~ili!oro-4~isopropyl~3 ,4- dihydro-2H--benzo[b][l,4]oxazme (100 mg 0.3 mmol, 1 equrv) In dioxane (4 mL) was added tert- butyl 4-(2-amifiothiazol-4-y3)piperidine-l~carboxylate (94 mg, 0 33 mmol, 1.1 equiv) and potassium carbonate (62 mg, 0.45 mmol, 1.5 equrv). The reaction mixture was degassed by nitrogen gas for 10 m ., followed by the addition of Pd2(dba)3 (27 mg, 0.03 mmol, 0 1 equiv) and Xphos (28 mg, 0 06 mmol, 0.2 equiv) The resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction diluted with water ( 10 mL) and extracted with ethyl acetate ( 10 mi . · Organic layer was washed with water (5 mL) and brine solution (5 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyi 4-(2- ((5-fluorO 4-(8~fluoro-4-isopropyl-3,4-dihydro--2H-benzo[b][l,4]oxazin- 6-y!)pyrimidim2- yl)ammo)thiazol-5-yl)piperidme-l -carboxylate (135 mg) as an viscous crude residue which used directly for next step. LCMS: 573 [MrH] ^”

[0582] Step-2: Synthesis of N-(5-flmoro-4-(8-flmoro-4-isopropyi-3,4-dihyi!ro~2H- benzojbj [ 1 ,4] oxazin-6~yl)pyrimidin-2-yl)-5-(piperidin-4-yl)thiazol-2-am« Be: A solution of tert-butyi 4-(2-((5-fluoro-4-(8-fluoro-4-isGpropyl-3,4-dihydro~2H-benzo [b][l,4]oxazin~6~ yl)pyrimidin-2-yl)amino}thiazol~5~yl)piperidine-l-earboxylat e (135 mg crude) in 1.25 M HCi in ethanol (5 mL) was allowed to stir for I h at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude which was purified by reverse phase HPLC to afford N-(5-fluoro-4-(8-fluoro-4-isopropyl- 3,4-dihydro-2H-benzo[b][l ,4]oxazm-6-yl)pyrimidin-2-yl)-5~(piperidin-4~yl)thiazo ^j -2-amine (10 g) as an off white solid compound. LCMS: 473 [MTH] ’HNfMR (400 MHz, DMSO-c/6) d

9.74 (s, IH), 8.57 (d, 7 4.0 Hz, i l l) 8 29 (a. 1 1 1) 7 72 (dd, 7 15.3,2.5 Hz, 1 1 1). 7.44 (s, HI),

7.36 (del, J— 8 8 2.5 Hz, I H), 7 16 (d, J= 1 1.4 Hz, IH), 6.97 (t, ,/= 9.4 Hz,IH), 4.30 (t, = 4.4 Hz 2H), 4 16 (p, / 6.6 Hz, I B), 3.30 (del ./ 9.6, 5.2 Hz, 4H), 2 63 - 2.54 (m, 2H), 2 22 (s,

7H), 1.84 (dd, 9 - 12.7, 3.6 Bz, 2H), 1.54 (tt, 7 - 13 3, 6.7 Hz, 2H), 1.18 (d, - 6.5 Bz, 6B)

Example-123: Synthesis of N-{5-(2, 6~dimethy?morphoUno}pyridin~2~yl}-5-ftiioro-4-(8-ftiioro-4-

(0583 j Step-1: Synthesis of 2,6-ilirae4hy!-4-(6-nitropyridin~3~y!)raorpholine: To a stirred solution of 5-bromo-2-nitropyridine (500 mg, 2.47 mmol, 1 equiv) in DMSO (10 mL), was added TEA (0.7 mL. 4.94 mmol, 2 equiv) and 2, 6-dimethyImorpboiine (426 mg. 3.7 mmol, 1.5 eqmv). The resultant reaction mixture was allowed to stir at 100°C for overnight. Progress of the reaction was monitored by TEC and LCMS After completion of the reaction, diluted with water (100 ml,), solid observed was filtered and dried under vacuum to obtain 2,6-dimethyl-4-(6- nitropyridin-3-y])morpholine (500 g, 85%) as a yellow solid compound. I, CMS: 238 [M+H] ^f

(0584] Step-2: Synthesis of 5-(2, 6-dimethylmorphoIino) pyridin-2-aitnine: To a stirred solution of 2, 6-dimethyl-4-(6-nitropyridin-3-yl) morpholine (200 mg. 0.84 mmol, 1 equiv) in methanol (5 ml,), was added Pd/C (20% w/w) (50 mg) under ¾ atm. The resultant reaction mixture was allowed to stir at RT for 4 h. Progress of the reaction was monitored by LCMS.

After completion of the reaction, foe mixture was passes through eel he bed and the filtrate was concentrated under reduced pressure to obtain 5-(2, 6-dimethylmorphoiino) pyridin-2-amine (150 mg. 86%) as an off white color solid compound. LCMS: 208 [MCI!]

[0585] Step-3: Synthesis of N-(5-(2,6-dimethyimorpholmo)pyridin~2~yI)~5~fl«oro-4~(8~ fl«oro-4-isopropyl-3,4-dihydro-2H-benzo[b][l,4|oxa*in-6-yl) pyrimidin-2-arn«ne: To a solution of 6-(2-chloro-5-iluoropynmidin-4-yl)-8~Puoro-4-isoprop ft3,4-dihydrO -2H·· benzo[b][l ,4]oxazine (100 mg, 0 3 mmol. 1 equiv) m dioxane (5 ml,), was added 5-(2,6- dimethyimorpho!ino)pyridim2~-amine (68 mg, 0 33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.47mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 nun., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of foe reaction was monitored by TLC and 1.CMS After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain N-(5-(2,6-dimethylmorpholino)pyridin-2~yl)-5-fluoro- 4-(8-i!aoro-4-isopropyI-3,4--dihydro--2H-benzo[b][!,4]oxazin -6--y!)pyrimidin-2-amine (80 mg, 52%) as a yellow color solid compound. LCMS: 497 (M+H) :‘HNMR (400MHz, DMSO-de) 6

9 69 (s 1 H), 8.56 (d, >=3.9 Hz, 1 å-]), 7.92 8.06 (m, 2 H), 7.46 (s, 1 H), 7.38 (d, >=2.4 Hz, 1 H), 7.17 (d >1 1.2 Hz, 1 H), 4.1 8 - 4.39 (m, 2 H), 3.99 - 4.15 (m, 1 H), 3.64 - 3.76 (m, 2 H), 3 54 (d, >10.8 Hz, 2 H), 3.16 (d, >=8 3 Hz, 1 H), 2.82 (dd, > .5, 5.6 Hz, 1 H), 2.26 (t, >1 1.0 Hz, 2 H), 1.09 ·· 1.30 ppm (m, 12 H)

Example- 124: Synthesis o/N-(5-((4-(cyclopropylmeihyi) piperazin-l-yl) methyl) pyridin-2-yl)~5~ fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro-2H~benzo[b j [ l ,4joxazin-6-yl)pyrimidin-2-amine.

(Compound 516)

[0586] Step-1: Synthesis of tert-butyi 4~((6~aminopyr«dm-3-yi) methyl) piperazine- 1- carhoxylate: To a stirred solution of 6-arnmomcotmaldehyde (500 mg, 8.19 mmol, 1 equiv) in DCE (15 mi l. was added tert-butyl piperazme-d-carboxyiate (1830 mg, 9.8 mmol, 1 2 equiv), acetic acid (2.3 mL, 41 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for l b. The reaction mixture was cooled to 0°C, followed by the addition of Na (OAC) BH (2604 mg 12.2 mmol, 1 .5 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by 1.CMS Alter completion of the reaction, the reaction mixture was diluted with saturated solution of NaHCO _? (50 mL) and extracted with ethyl acetate (100 mL - 2) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyi 4~((6~ammopyndin-3-yl) methyl) piperazine- 1 -earboxylate (500 mg, 21 %) as a brown color viscous compound. LCMS: 293 [M+H] ⁺

[0587] Step-2: Synthesis of tert-buiyl 4-((0-((5-ffuoro-4-(8-ffuoro-4-isopropyi-3,4- d ^j hydro-2H-benzo[b](l,4]oxazm-t^yl)pyrimidw-2-yi)amwo)py ridin-3~

yi)metfayi)piperazine-i-carhoxyiate: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yi)-8- fluofo-4-isopropy!- 3,4-ddiydrO 2H-benzo[bl[] ,4]oxazme (500 mg, 1.53 mmol, 1 equiv) in dioxane (10 mL), was added tert- butyl 4-((6~aminopyridin-3-yl)methyi)piperazine-l -carboxylate (494 mg, 1 .69 mmol, 1 1 equiv) and cesium carbonate (748 mg, 2.29 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (7 mg, 0 03 mmol , 0.02 equiv) and BINAP (38 mg, 0 06 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (50 ml,) and extracted with ethyl acetate (100 ml, ^c 2). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain teit-butyl 4-((6-((5-fhioro-4-(8-fluoro-4-isQpropyl- 3,4-dihydiO 2II benzo|b][l ,4|oxazim6-yl)pynmidin-2-yl)an:uno)pyridin--3--yi}methyl)pip erazine-· foearboxylaie (700 g, 78%) as a brown solid compound LCMS: 582 I M H i ^f

[0588] Step-3; Synthesis of 5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][ly4]oxazin-6~yl)-N-(5-(piperjkzin-l-ylmetftyl)pyrid in-2-yi)pyrimidit-2-ainine: A solution of tert-butyl 4-((6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][l ,4]oxazm-6--y])pyrinudin--2-yl)amino)pyridin-3 -yl)meihyl)piperazine-1 -carboxyiate (700 mg, 1.2 mmol, 1 equiv) in 1 25 M HC1 in ethanol (10 ml,) was allowed to stir for ih at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude compound, which was purified by making HC! salt to afford 5-fluoro-4-(8-iIuoro-4-isopropyl-3,4-dihydro-2H-benzofb][l ,4]oxazin- 6-yl}-N-(5-(piperazm-l -ylffiethyl)pyridm-2-yl)pyriniidm-2-amme (500 mg, 86%) as a yellow solid compound LCMS;: 482 j Mt H] ^’

! 0589] Step-4: Synthesis of N-(5-((4-(cyciopropyhnethyl) piperazin-l -yl) methyl) pyridin-2-yl)-S-flooro-4-(8-flooro-4-isopropyi-3, 4-dlhydro-2H-benzo j bj jl l,4|oxazin-6- yl)pyriraidiii-2-amine: To a stirred solution of 5-f!uoro-4-(8-f!uoro-4-isopropyl-3,4-dihydro-

2H-benzofbl[l ,4]oxazin-6-yl)-M- 5-(piperazin-l-ylmethyl)pyridin-2-yl)pyrimidin-2-aniine ( 100 mg, 0.2 mmol, 1 equiv) in DCE (3 mL), was added cyclopropanecarbaldehyde (52 mg, 0.61 mmol, 3 equiv), acetic acid (0 06 mL, 1.0 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for 1 h. The reaction mixture was cooled to 0°C. NaCKBLn (38 mg, 0.61 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for Ih. Progress of the reaction was monitored by LCMS. After completion of the reacti on, the reaction m ixture was diluted wi th water (25 ml,) and extracted wi th ethyl acetate (50 mL x 2) Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which v/as purified by reverse phase HPLC to afford N-(5-((4- (cyc!opropy!methyl)piperazin l y!)methy!)pyridin 2 yi) 5-fitsoiO 4 (8-fitsorO 4 isopropyb3,4 dihydro-2H-benzo[b] [ 1 ,4]oxazin-0-yi)pyrimidin-2-amine (45 mg. 41%) as a yellow solid compound. LCMS: 536 [M+H] ; 1HNM (400MHz, DMSO-d*) d 10.01 (s, i l l ·. 8.62 < d. ./

3 8 Hz, IH), 8.17 (d, J ------ 8 4 Hz, 2H), 7.64(dd, J --- 8.6. 2.4 Hz, 1 1 1) 7 51 (s, I H), 7.19 (d J-

1 1.5 Hz, I H), 4.30 (t, /=== 4.3 Hz, 2H), 4 17 (p, J ^:::: 6.6Hz, IH), 3.43 (s, 2H), 3.31 (t, J --- 4.4 Hz, 2H), 2.40 (s, 8H), 2.14 (d, J --- 6 5 Hz, 2H), 1 19(d, 7 6.5 Hz, 6H), 0.79 (p, 7 6.2 Hz, IH).

0.43 (d, J ----- 7.6 Hz, 2H), 0.04 (d, J --- 4 9 Hz, 2H).

Exam pie- 125: Synthesis ofN-(5-jhioro-4-(8-fluoro-4-isopropyl-3, 4-dikydro-2H- ben2o[hifl.4ioxazm-6-yI)fynmidm-2-yI)-6-(l-meihyipipetidin-4 ~yI)}mida2in-3-amme

(Compound 517)

[0590] Step- 1. ^* Synthesis of tert-butyi 4-(6-aminopyridazin~3~yi)-3,6-dihydropyridme- i(2H)~earboxyiate: To a stirred solution of 6-bromopyridazin-3 -amine (668 mg, 3.34 mmol, 1 equiv) in Dioxane: water (8+2mL), was added tert-butyi 4-(4.4,5,5-tetramethyl-l ,3.2- dioxaborolan-2-yl)-3,6-dibydropyridine-l {2H)-carboxyIate (1200 mg, 3.34mmol . 1 equiv }, Na ₂ CO ₃ (J 062rng, 10.02mmol, 3equlv ) and Pd(PPh ₃ )Cl ₂ (120mg, 0.167mmol, 0.05equiv).The resultant reaction mixture was allowed to stir at lOCLC for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted water (50 ml ,) and extracted with EtoAc (50 ml , x 2). Organic layer was washed with water (30 ml,) and brine (50 ml,). Organic layer tea dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain of tert-butyi 4-(6-aminQpyridazin-3-yl)-3,6-dihydropyridme- !(2H)-earboxylaie (10 g, 96.17%) as a brown solid compound LCMS: 277 [Md-H] ^’

[0591] Step-2: Synthesis of tert-butyi 4~(6~aminopyridazin-3-yl) piperidine-lea rhoxylate: To a stirred solution of tert-butyi 4-(6-aminopyridazin-3-yl)-3,6-dihydropyrldine- 1 (2H)--carboxylate (200 mg, 0.72 mmol, i equiv) in ethanol (04 ml,), was added PdC (lOOmg, 0.087 mmol, 0.05 equiv) at RT. The reaction mixture was allowed to stir at RT for 3h Progress of the reaction t as monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was passed through cehde filter. Organic layer was washed with water (20), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyi 4-(6- anunopyridazin-3-yl) piperidine- 1 -carboxy!ate (140 mg, 97.10%) as brown compound. LCMS: 279 | M H i ⁺ [0592] Step-3: Synthesis of tert-buty! 4-(6-((5-flaoro-4-(8-flaoro-4-isopropyi-3,4- dihyilr0-2H-benzojbij[l,4]oxazm-6-yi)pyrimidin-2-yl)amino)py ridazin-3-yl)piperidme-l- carboxyiate: To the solution of 6-(2-chioro-5-fluoropynmidm-4-yl)-8-fTuoro~4~isopropyl~3,4- dihydro-2H-benzo[b][l,4]oxazine (200 mg. 0.6 mmol, 1 equiv) was added dioxane (5mi) and ten-butyl 4~(6-ammopyndazm-3-yl)piperidine-l -carboxylate ( 185mg, 0.67mmoi, l. leqmv), cesium carbonate(297mg, 0.91mmol, i .5equiv), resulted reaction mixture was degassed with nitrogen for 5mm thereafter was added PdfOacfo (14mg, 0.061 mmol, 0 1 equiv), BINAP (76 g. 0. ! 22mmoL 0.2equiv),resulted reaction mixture was allowed to stir for 15 h at I00°C Progress of the reaction was monitored by LCMS After completion of die reaction, the reaction mixture was diluted with water (20 ml,) and extracted with ethyl acetate (30 ml, x 3). Organic layer was washed with water (35 ml,) and brine solution (15 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by combi-flash to get tert-buty! 4-(6-((5-f1uoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][l,4]oxazin-6~yl)pyrimidin-2-yI)arnino)pyridazin-3-y l)piperazine-1 -carboxyiate, (360mg, 33 41%) as a light Brown solid compound. LCMS: 568 [M+H]

[0593] Step-4: Synthesis of N-(5-fluoro-4-(8~fluoro-4-isopropyl~3,4-dihydro-2H~ benzo[b][1,4]oxazin~6~yI)pyrimidin-2~yI)-6-(piperidin-4-yI)p yridazin-3-amine

hydrochloride: To the solution of tert-buty] 4-(6~((5~fktoro-4~(8~fluoro~4~isopropyl~3,4- dihydro-2H-benzo b|[l,4]oxazin-6-yl)pyrirnidin-2-yl)amino)pyridazin-3-yl)pipe razine-l - carboxyiate (360rng, 0.81 mmol, 1 equiv) was taken in 1.25 M HQ in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for 3h. Progress of the reaction was monitored by LCMS After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under lyophilizer to get N-(5~iIuoro-4-(8~iluofo-4~isopropyl~ 3 4-dihydro-2i ^} -benzo| b]| l ,4]oxazin-6-yl)pyrimidin-2-yi)-6-(l-methyipiperidin-4-yl)pyr idazin- 3 -amine as a brick red color solid compound. LCMS: 468 [M+H]

[0594] Step-5: Synthesis ofN-(5-fluoro-4-(8~fluoro-4-isopropyl-3,4-dihydro-2B- benzo(b]! l,4|oxazin-6-yI)pyriiniclin-2-yI)-6-(l-iRethyIpiperidin-4-yI )pyrida2m-3-ainine: To a stirred solution of N-{5--fiuoro-4--{8--fiuoro-4--isopropy]--3,4-dihydro-2H--ben zo[b]p ,4]oxazm-6- yl)pyrimidm-2-yi)-6-(l -inethylpipendin-4-yl)pyridazin--3--amine (1 50 mg, G.32mmol, 1 equiv) in DC h (6mL), was added Formaldehyde (40% in water) (0.33 mL, 0 96 mmol, 3 equiv), acetic acid (0 2 ml .. 1 . Innnoi, 5 equiv). Hie reaction mixture was allowed to stir at RT for Hi The reaction mixture was cooled to 0°C. NaCNBEU (60mg, 0.91 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for 4h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (20 ml.) and extracted with ethyl acetate (25 ml. * 2). Organic layer was washed with water (1 5 ml.) and brine solution (20 ml.). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford N~(5-f!uoro~4~(8-f!uoro~4-isopropyl~3.4-dihyclro-2H~ benzo[b][l,4]oxazin-6-yl)pynmidin _~ 2-yl) _~ 6 _~ (l _~ methylpiperidm _~ 4 _~ yl)pyriclazin-3-amine (8 mg,

98.22%) as a yellow color solid compound. LCMS: _' 482 [M+H] ^: ) ^* HNMR (500 MHz, DMSO- d6) d 10.58 (s, i l l ;. 8.64 (d, 1 = 3.7 Hz, 1H), 8.32 (d, I = 9.2 Hz, 1H), 7 56(d, J = 9.3 Hz, 1H), 7.45 (s, 1 1 1). 7.18 (d, J = 1 1.5 Hz, 1 H), 4 30 ft, J = 4.3 Hz, 2H), 4.14 (p, I = 6.6 Hz i l l ; 2.89 (d,

J = 1 1 .3 , 2.00 (dd, J = 12 7, 9.8 Hz, 2H),1.87

1.73 (m, 5H), U8 (d, I = 6.5 Hz, 6H).

Example-126: Synthesis ofN-(5-(4-(aminomethyl) pipendin-l-yl) pyridin-2-yl)-5~fluoro-4-(8~ fluoro-4-isopropyl-3, 4-dihydro-2H~benzo[h]fl 4]oxazin~6~yi)pymmidin~2~amine. (Compound

518}

[0595] Step· ! ;; Synthesis of tert-butyl ((l-(6-nitropyridi«-3-yI) piperidm-4-yl) methyl) carbamate. To a stirred solution of 5-bromo-2-nitropyridine (200 mg, 0 99 mmol, 1 equiv) in DMSO (5 ml.), was added k 4 CL (273 mg, 1.98 mmol, 2 equiv) and tert-butyl (pipendin-4- ylmethyi) carbamate (424 mg, 1.98 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 raL), solid observed was filtered and dried under vacuum to obtain tert-butyl (( l-(6-nitropyndin-3-yl)piperidin-4-yi)methyi)carbamate (200 mg, 59%) as a yellow color solid compound LCMS: 337 [M÷H]

[0596] Step-2: Synthesis of ^" tert-hutyl ((l-(6-aminopyridm-3-yi) pipericlin-4-yI) methyl) carbamate: To a stirred solution of tert-buty! ((l-(6-nitropyndm-3-yi) piperidin-4-yl) methyl) carbamate (200 mg. 0.59 mmol, 1 equiv) in methanol (10 mL), was added Pd/C (20% w/w) (40 mg). The resultant reaction mixture was allowed to stir at RT for Ih. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was passes through cehte bed and the filtrate was concentrated under reduced pressure to obtain tert-buty! ((l-(6- aminopyndm-3-y!) piperidin-4-y!) methyl) carbamate (150 mg, 82%) as a brown color viscous compound. LCMS: 307 [M+H] ⁺

(0597 Step-3: Synthesis of tert-buty! ((l-(6-((5~fluoro-4-(8~fluoro-4-isopropyl-3,4- dihydro-2H-benzo(h]jl,4joxazm-6-y!)pyrimitlin-2-yl)amino)pyr «d«n-3-yl)piperidm-4- yl)methy!)carbamate: To a solution of 6-(2-chloro-5-fluoropyrimidin~4~yl)-8-fluoro-4- isopropyl~3,4 dihydrO 2H~benzo[b][l ,4]oxazine (100 mg, 0 3 mmol, 1 equiv) in dioxane (5 ml,), was added tert-buty! ((l-(6-aminopyridin~3~yl)piperidin-4-yl)raethyl)carbaraate (101 mg, 0 33 mmol, 1 1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1 5 equiv). The reactio mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0.012 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (1 00 rnL) Organic layer was washed with water (50 ml.) and brine solution (50 ml,) Organic layer was dried over anhydrous sodium sulphate and

concentrated under reduced pressure to obtain tert-buty! ((l -(6-((5-fluoro-4-(8-fiuoro-4- isopropy!-3,4-dihydro-2!:I-benzo[b][l ,4]oxazin--6-yl)pyrimidin-2-yl)amino)pyridm-3- y])piperidin-4-yl)methyl)carbamate (160 mg, 87%) as a brown color viscous compound. LCMS: 596 [M-i-H] ⁺

[0598] Step-4: Synthesis of N-(5-(4-(aminoinethyi) piperidin-] -y!) pyridin-2-yI)-5- fl«oro-4-(8-fluoro-4-isopropy!-3,4-dihydro-2H-benzo[b] [l,4]oxazin-6-yl)pyrimidin-2- amine: tert-buty! ((l -(6-ii5-fiuoro-4-i8--fiuoro-4-isopropyl-3,4-dihydro-2H-benzo [b][! ,4joxazin- 6wl}pyrimidin-2-yl)amino}pyridin-3-yl)piperidm-4-yi)methyl}c arbamate (160 mg, 0.26 mmol, 1 equiv) was taken in 1 .25 M HCI in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for I h. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain N~(5~(4-(aminomethyl)piperidm-l-yl)pyridin-2- yl)~5~iIuoro~4~(8-f!uoro~4~isopropyl~3.4-dihydro-2H~benzo[b] [l ,4]oxazin-6-yl)pyrimidin-2- amine (80 mg, 60%) as a yellow color solid compound L TS: 496 [MH1] ft T hWhR (400 MHz, DMSO- ό) d 9.66 (s, 111), 8.55 (d, ./ 4.0 Hz, IH), 8.05 - 7.96 (m, 2H), 7.46 (s, IH), 7.39

(dd, J = 9 1 , 3.0 Hz, IH), 7.21 - 7 13 (m, IH), 4.30 (t, ./ 4.3 Hz, 2H), 4.14 (hept,/- 7.0 Hz,

IH), 3.64 (d, ./= 12.0 Hz, 21 1) 3 30 (t, ./ 4 2 Hz, 2H), 2.75 - 2.57 (m, 4H), 1.82 (d, / 12.6

Hz, 2H), 1.62 (s, H), 1.37 - 1 20 (m, 2H), 1.18 (d, J = 6 5 Hz, 6H).

Example- i 27: Synthesis ofN-(5~((4~cyclopentyipiperazm-l-yI) meihyl) py ^! ridin~2~yI)-5-fluoro-4- (8~fiuoro-4~isopropyl~3, 4~dihydro~2H-benzofh][l,4]oxaåin-6-yI)pyiimidin-2-amine (Compound

579,1

[0599] Step-1:: Synthesis of tert-butyl 4-{{6-arainopyridin-3-yl) methyl) piperazine~l~ carfeoxylaie: To a stirred solution of 6-aminomcotmaidehyde (500 xng, 8.19 mmol. 1 equiv) in DCE (1 5 ffiL), was added tert-butyl prperazine-4--carboxyiate ( 1830 xng, 9.8 mmol. 1.2 equxv), acetic acid (2.3 mL, 41 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for l b. The reaction mixture was cooled to 0°C. followed by the addition of Na (OAC) Bi i (2604 mg, 12.2 mmol, 1 .5 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT lor 1 h. Progress of the reaction was monitored by 1.( ^' MS Alter completion of the reaction, the reaction mixture was diluted with saturated solution of NaHCO _? (50 mL) and extracted with ethyl acetate (100 mL - 2) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyi 4-((6-ammopyndm-3-ylj methyl) piperazine- 1 -earboxylate (500 mg, 21%) as a Brown color viscous compound. LCMS: 293 [M+H] ⁺

[0600] Step-2: Synthesis of tert-butyi 4-((0-((5-ffuoro-4-(8-ffuoro-4-isopropyI-3,4- d«hyclro-2H-ben*o!b][l,4)oxa2m-6-yl)pyrimidm-2-yl)ammo)pyri dm-3- yl)metfayi)pipera*ine-l-carhoxylate. To a solution of 6-(2-ehloro-5-fluoropyrimidin-4-yl)-8- fluoro-4-iSOpropy!- 3,4-ddiydrO 2H-benzo[bl[] ,4]oxazme (500 mg, 1.53 mmol, 1 equiv) in dioxane (10 mL), was added tert-butyi 4-((6~aminopyridin-3-yl)methyi)piperazine-l -carboxylate (494 mg, 1 .69 mmol, 1 1 equiv) and cesium carbonate (748 rag, 2.29 m ol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (7 mg, 0 03 mmoh 0.02 equiv) and BINAP (38 mg, 0 06 mmol 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (50 ml . I and extracted with ethyl acetate (100 ml . ^c 2). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyi 4--((6-((5-iluoro-4-(8-iluoro-4-usopropy!- 3,4-dihydro-2Il benzo|b][l ,4|oxazin-6-yl)pyrimidin-2-yi)amino)pyndin-3--yi)methyl)pipe razine- 1-earboxylaie (700 rng, 78%) as a brown solid compound. LCMS: 582 j M I I I ^f

[0601] Step-3: Synthesis of 5-fluoro-4-(8-fluoro-4-isopropyl-3,4-diljydro-2H- benz©[b][i,4]oxaziR~6-yI)~N-C5-{piperaziR~i-yInKiihyr)pyrid iR~2-yI)pyrimMm~2~anHne. A solution of tert-butyi 4-((6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][l ,4]oxazm-6--yl)pyrimidin~2~yi)araino)pyridin-3 -yi)ineihy!)piperazine-! -carboxyiate (700 mg, 1 .2 mmol, 1 equiv) in 1 25 M HC I m ethanol (10 mL) was allowed to stir for lh at 50 °C. Progress of the reaction was monitored by LCMS After completion of the reaction, solvent was removed under reduced pressure to obtain crude compound, which was purified by making HCI salt to afford 5-iluofo-4-(8-iluofo-4-isopropyi-3,4-dihydro-21Lbenzo[b][1 ,4]oxazm-6-y!)-N- (5-(piperazin-l-ylmethyi)pyridin-2-y])pyriinidin-2-aimne (500 mg, 86%) as a yellow solid compound. LCMS: 482 [M+H]

[0602] Step-4: Synthesis of N-(S-((4-cyci openly Ipiperazin-l-yl) methyl) pyriili»-2-yI)-5- fluoro-4-(8-fluoro-4-is©propyl-3, 4-clihydro-2H-henzo{b] jJ ,4[oxazi«-6-yI)pyrimidin-2- amine: To a stirred solution of 5-fluoro-4-(8-fluoro-4-isopropyi-3,4~dihydro~2H- benzo[b][l,4]oxazin-6-yl)-N~(5-(piperazin-] -ylmethyi)pyridin-2-yl)pyrimidin-2-amine (100 mg, 0.2 mmol, 1 equiv) DCE (3 mL), was added cyclopentanone (52 mg, 0.61 mmol, 3 equiv), acetic acid (0.06 ml,, 1.0 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for In. The reaction mixture was cooled to 0 °C. NaCNBIft (38 mg, 0.61 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for Ih. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with ethyl acetate (50 ml, 2) Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford N~(5-((4-cyclopentylpiperazinH- yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-3,4 -dihydro-2H-ben o[b][l 4]oxazin-6- yl)pyrimidin-2-amine (25 mg, 15%) as an off white color solid compound. I, CMS: 550 [M+H] 7 \0\MR (400 MHz, DMSOM6) 6 9.97 (s, l i ft. 8.62 (d, ./= 3.9 Hz, 1 1 1) 8 20 - 8. 13 (m,2H),

[0603] To a solution of 6-(2--chioro-5-fluoropynmidin-4- l)-8-fluoro-4-isopropy 1-3,4- dihydro~2H-benzo[b][l,4]oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (5 mL) was added 3- ammobenzenesulfbnamide (57 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 m ., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowod to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 4-((5-fluoro-4-(8-fluoro-4-isopropyl-3 4-dihydro-2H-benzo[b][l ,4]oxazin- 6 yl)py ^r imidin-2-yi)amino)benzenesulfbnamide (50 mg, 35%) as a yellow color solid compound. LCMS: 462 [M+H] ’HNMR (400 MHz, DMSOM6) d 1 0.04 (s, !H), 8.62 (d, ./= 3.9 Hz, 1 I I) 8.27 (t / 1.9 Hz, HI), 7 99 (d, J= 7.9 Hz, HI), 7.52 - 7.37 (m, H I). 7.31 (s, 21 1). 7.20 (d, ti l l.5 Hz, 1 1 1 ). 4.30 (t, ti 4.3 Hz, 2H},4. ! 5 (h, ./= 6.5 Hz, 1 1 1) 3 30 (d, / 4.5 Hz, 2H), 1 1 8 (d,

J 6.5 Hz, 6H)

Example- 129: Synthesis of6-((5-fiuoro-4-(8-fluoro-4-isopropyl-3,4~dihydro~2H- benzo[h]fl, 4]oxazin-6-yl}pyrimidin-2~yl)amino}nicotinamide. (Compound 521)

j0604| Step-1: Synthesis of 6-aminonicotinamide: A stirred solution of methyl 6- aminonicotinate (300 mg, 1.97 mmol, 1 equiv) in Liq. ammonia (5 ml,), was allowed to stir at 70 °C for overnight Progress of the reaction was monitored by TLC and I CMS After completion of the reaction, the solvent was completely removed under reduced pressure to obtain 6- aminomeotinamide (250 mg, 93%) as a yellowish color solid compound LCMS: 138 [MMl] ^’

[0605] Step-2: Synthesis of 6-((5-flu0ro-4-(8-fluoro-4-«sopiOpy!-3,4-difayilro-2H- henzo[h] [ 1,4] oxazin~6~yI)pyrimidin-2~yI )atnino)nicotinatnide: To a solution of 6-(2-chloro-5- fluoropyrimidin-4-yl)-8-f!uoro-4-isopropyl-3,4-dihydro-2H-he nzo] b] j l ,4]oxazme (100 nig, 0.3 mmol, I equiv} in dioxane (3 niL), was added 6-aminomcotmamide (45mg, 0.33 mmol 1.1 equiv) and potassium carbonate (104 mg, 0.75 mmol, 2.5 eqmv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of Pd (dppf) C12.DCM ( 12 mg, 0.015 mmol, 0.05 eqmv) and X-Phos (14 mg, 0.03 mmol, 0.1 eqmv). The resultant reaction mixture was allowed to stir at 100 °C for 3h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate ( 100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was puntred by reverse phase HPLC to obtain 6-((5-fluoro-4-(8- fluoro-4-isopropyl-3,4-dihydro-2H-benzo[b][ l ,4]oxaz.in-6-yl)pyrimidin~2-yl)amino)nicotinamide (5 mg, 4%) as a yellow color solid compound I, CMS: 427 [M+H] f ¾NMR (400 MHz, DMSOv/6) d 10.39 (s, 1H), 8.80 (d, J = 2.4 Hz, IH), 8.68 (d, ./ 3 8 Hz, !H), 8.28(d, ./ 8.8 Hz,

1H), 8.18 (dd, ./= 8.8, 2.4 Hz, IH), 8.00 (s, IH), 7.49 (s, IH), 7.37 (s, IH), 7.20 (d, .7=1 1 .5 Hz, IH), 4.31 (t, / 4.3 Hz, 21 1). 4 17 (h, J= 6.8 Hz, 1 H), 3.35 (s, 2 H), 1.20 (d, ./= 6.5 Hz, 6H).

Example-130: Synthesis of -fIuoro-4-(8~fluoro-4-isopropyl-3, 4~dihydro~2H~

henzofbJ[l,4Joxazm~6~yi)-N-(4~((4~methyIpiperazin~I~yi)si iJbnyl)phenyI}pyrimidin-2-amme. (Compound 522)

[0606] Step-1: Synthesis of tert-butyl 4-( (4-nitrophenyl) sulfonyl) piperazine-i- carhoxyiate. To a stirred solution of 4-nitrobenzenesu!fony! chloride (129mg, 0 58 mmol, 1 .3 eqmv) in DCM (2ml) was added DIPEA (0 1 mL, 0 59mmol, 1 .1 equiv ), and tert-butyl piperazine- 1-carboxyiate (!OOmg, 0.0.54mmoi, 1 equiv).1he resultant reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction the mixture was diluted water (50 ml,) and extracted with DCM (50 ml, x 2). Organic layer was washed with -w ter (20 mL) and brine (20 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tern butyl piperazine- l-Carboxy late. (70 mg, 88 75%) as a slightly yellow solid compound. LCMS: 272 [M÷H] ⁺

[0607] Step-2: Synthesis of tert-butyl 4-((4-aminophe«yI) sulfonyl) piperazlne-l- carboxylate: To a stirred solution of tert-butyl 4-((4-nitrophenyl) suifony!) piperazine- 1- carboxylate (200 mg, 0.53 mmol, 1 equivj m ethanol: Water (8÷2ml), was added Fe (filling), NH4CI (300mg. 5.39 mmol, l Oequiv). The resulted reaction mixture was allowed to stir at 80°C for 2h. Progress of the reaction -was monitored by TLC and LCMS. After completion of the reaction, tire reaction mixture was passed through ce!ide filter. Organic layer was washed with water (20), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl 4-((4-aminophenyl) suifony!) piperazine- 1 -carboxylate (120 mg, 99 10%) as brown compound. LCMS: 242 [M+H]

[0608] Step-3: Synthesis of tert-butyl 4-((4-((5~fiuoro-4-(8~fiuoro-4-isopropyl-3,4- dihydro-2H-benzo[b]jl,4[oxazm-6-yl)pyr«mklin-2-yl)amino)phe nyl)sulfonyl)piper¾Eine-i- carboxylate: To the solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3,4 - dihydro-2H-benzo[b][l,4]oxazine (1 0mg.0.539mmol, l equiv) was added dioxane (5ml) and tert-butyl 4-((4-armnopheny!)su!fony!)piperazine-1 -carboxylate (175mg,0 539mrno!, lequiv), cesium carbonate(258mg, 0.791 mmol, l Sequiv), resulted reaction mixture was degassed with nitrogen for 5min thereafter tea added Pd(Qae)y (20mg, 0.053mmol, 0. lequiv), BINAP (80mg, 0 122mmol, 0.2equiv), resulted reaction mixture was allowed to stir for 15h at 100°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with -water (25 ml,) and extracted with ethyl acetate (30 ml, ^c 3). Organic layer was washed with water (35 ml,) and brine solution (15 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by combi-flash to obtain tert-butyl 4-((4-((5-fluoro-4-(8-fluoro-4-isopropyf-3,4-dibydro-2H- benzoj bjjd ,4 ]oxazin-6-y!}pyrimidin-2-yl)amino)phenyl)sulfonyl)piperazine - 1 -carboxylate (160mg, 43.13%) as a light brown solid compound LCMS: 531 [M+H] ^” [0609] Step-4: Synthesis of 5-fluoro-4-( 8-t1uoro-4-isopropyI-3 _» 4-dihydro-2H- ben¾o(b]!l,4joxa¾i«-6-yI)-N-(4-(pipera¾i«-l-yIsnlfonyi) phenyi)pyriin in-2-amine: To the solution tert-butyi 4~((4-((5-fluoro4-(8-fluoro4-isopropyl-3,4-dihydrG-2H-benzG[ b][l ,4]oxazin- 6-y!)pyrimidin~2~yl)amino)phenyljsulfonyljpiperazirse-] -carboxy!ate (150mg, 0.52 mmol, 1 equiv) was taken in 1.25 M HCi in ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for 3b Progress of die reaction was monitored by LCM8. After completion of the reaction, solvent was removed under reduced pressure and the residue was dried under iyophilizer to get 5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihyclro-2H- benzo[b][l,4]oxazin-6-yl)-M-{4-{piperazin-l-ylsulfonyl)pheny l)pyrimidin-2-amine (50 mg, 41.46%) as a brick red color solid compound. I, CMS: 531 [M+H]

[0610] Step-S: Synthesis of 5-fluoro-4-(8-fluoro-4-isopropyl-3 _> 4-dihydro-2H~

henzo[b][i,4[oxaz«B-6-yl)-N-(4-((4-methyipiperaz«B-l-yl )sulfonyi)phenyi)pyTiffiidia-2- amine: To a stirred solution of 5-tluoro-4-(8-tluoro-4-isopropyl-3 4-dihydro-2H- benz:o[b][l 4|oxazin-6-yl)-N-(4-(piperazin-l-ylsulfonyl)pheiiyl)pyrimidi n-2-amine (300 mg, 0.63mmol, 1 equiv) in DCE (6ml,), was added Formaldehyde (40% in water) (0 33 ml,, 0.96 mmol, 3 equiv), acetic acid (0 2 ml,, 1. I mol, 5 equiv). The reaction mixture was allowed to stir at RT for 1 h. The reaction mixture was cooled to 0°C. NaCNBTL (60mg, 0 91 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed lo stir at RT for 4h. Progress of the reaction was monitored by LCMS After completion of the reaction, the reaction mixture was diluted with water (20 mil,) and extracted with ethyl acetate (25 ml, x 2). Organic layer was washed with water (15 ml,) and brine solution (20 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HFLC to afford 5-iluoro-4-(8-iluoro-4- isopropyi--3,4-dihydfO 2H--benzoibl:T,4]oxazm-6-y!)--N--(4--ii4--meihylpiperazin-l - yl)sulfonyl)phenyl)pyrimidin-2-amine (10 mg, 98 22%) as a yellow color solid compound, LCMS: 545 [M÷H] ⁺ ; 'ilNMR (400 Mi ft. DMSO ·<:<¾) d 10.30 (s, 111), 8.67 (d, ft - 3 8 Hz, !H), 8 44 (s, 1 H), 8 02 (d, 7 8.5Hz, 2 1 ). 7.64 (d, J === 8 5 Hz, 2H), 7 44 (s, i l l ). 7.19 (d, 7 11.8 Hz,

1 H), 4 31 (t, J === 4 2 Hz, 2H), 4 16(p, J - 6 6 Hz, 1 H), 3 32 {! . J - 4.5 Hz, 11 ) 3.14 1s, 21 1} 2.94 - 2.83 (m, 4H), 2 35 (t, J === 4 6 Hz, 6H),2.13 (s, 3H), 1.19 (d, J ^:::: 6 5 Hz, 611) Example-131 : Synthesis of 4~(S~fluoro~4~(8~fluoro~4~isopropyi~3,4~dihydro~2H~ beftzo[h][J4]oxazin-6-yi)pyrimidin-2-ylatnino)~N~(2~mefhox\& gt;ethyl)bemenesulfonamide.

(Compound 523)

[0611 Step-1: Synthesis of N-( 2-methoxy eth i)-4-nitro-ben*enes«Ifonamide: A stirred solution of 4--niirobenzenesulibnyi chloride (l OOmg, 0.45 mmol, 1 equiv) in DCM (5nd) was added DIPEA (0.2mL, 0.59mmol, 1.1 equiv ), and 2-methoxyethanamine (l OOmg, 0.54mmoi, 1 equiv). The resultant reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted water (20 mL) and extracted with DCM (15 ml, x 2). Organic layer was washed with water (20 mL) and brine (20 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain N-(2-methoxyethyl)-4-mtro-benzenesulfonamide (70 mg, 88.75%) as a slightly yellow solid compound. LCMS: 260 [M÷H]

[0612] Step-2: Synthesis of 4-a ino-N~(2~methoxyethyl)benzenesulfonamide: To a stirred solution of NA2uirethoxyethyiy4-mtro--benzenesu!ibnamide (200 mg, 0.76 mmol, 1 equiv) in ethanol: Water (8+2ml), was added I c (filling), N!LCl (407mg, 7 6 mmol, lOequiv). The resulted reaction mixture was allowed to stir at 80°C for 5h. Progress of the reaction was monitored by TLC and l .f MS. After completion of the reaction, the reaction mixture was passed through celide filter. Organic layer was washed with water (30), dried over anhydrous sodium sulphate and concentrated under reduced pressure to 4-amino~N-(2- methoxyethyl)benzenesulfonarnide (129 mg, 99.10%) as brown compound LCMS: 242 i M - 1 1 ]

[0613] Step-3: Synthesis of 4-(S-fluoro-4-(8-fluoro-4-isopropyl-3,4-tlihydro-2H~ ben?.o[b] [ 1,4] oxazin-6-yi)pyrimidm-2-yiamlno)-N-(2~imethoxyethyl)ben*enesu H©naitmde: To the solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3, 4-dihydro- 2H- benzo[b][l,4]oxazine (130mg,0.53mmoh 1 equiv) was added dioxane (5ml), (2Z)-N4~(2~ methoxy ethyl )penta-2, -diene- i ,4~diamme(175mg,0 539 mol,i equiv), cesium carbonate(258mg, 0.791 mmol, 1.Sequiv), resulted reaction mixture was degassed with nitrogen for 5min thereafter was added Pd(Oac) _2, (20mg, 0.053mmoL O. lequiv), BINAP (80mg,

0.122mmol, 0.2equiv), resulted reaction mixture was allowed to stir for I5h at 100°C. Progress of the react on was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mLj and extracted with ethyl acetate (30 mL ^c 3) Organic layer was washed with water (35 mL) and brine solution (15 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated un er reduced pressure to obtain crude, which was purified by Reverse phase HPLC to 4~(5-fli3oro~4~(8-f!noro~4~isopropyl~3,4-dihydro-2H~

benzo[b][l,4]oxazin-6-yl)pynmidin-2-ylamino)-N-(2-methoxy ethyl)benzenesulfonamide (75mg, 98.13%) as a yellow colour solid compound. LCMS: 520 [M+H] ; ΉNME (400 MHz, DM50- d6) 6 10.19 (s, I I B. 8.65 (d, ,/= 3.9 Hz, 1 1 1) 7 94 (d, J= 8.7 Hz, 2H), 7 70(d, ./ 8 6 Hz, 2H),

7.54 (t, ,7= 6.0 Hz, HI), 7 44 (s, HI), 7 22 - 7.14 ( , 1H), 4.31 (t, ,7= 4.3 Hz, 21 11.4. 1 5 (p, J = 6.6 Hz, 1 1 1 }. 3.29 (d, J = 6.0 Hz, 2H), 3.17 (s, 3H), 2.88 (q, ./ 5 9 Hz, 2H), 1.20 (d, 7 6.5Hz,

7H).

Example ~ 132: Synthesis of 5~fluoro~4~(8~fluoro- 4~isopropyl~3 4-dihydro-2H~

benzofhffl, 4foxazin-6-yI}~N~(5~{(4-(2-melhoxysthyi)piperazin-l-yI}methy I}pyridm-2- yl)pyrimid ~2~amme. ( Compound 524)

[0614] To a stirred solution of 5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][l,4]oxazin-6-yl)-N-(5-(piperazin-l-ylmethyl)pyridin -2-yl)pyrimidin-2-amine ( 500 mg, 1.03 mmol, 1 equiv) in DMR (8 mL), was added I LOO (200 mg, 1 98 mmol, 2 eqniv) and 1 ·· bromo-2-methoxyethane (1000 mg, 1 .58 mmol, 2 eqniv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 mLj, extracted with ethylacetate (30 mL x 3): water(30 ml,) resulted organic layer and dried under vacuum thereafter organic layer was purified by reverse phase chromatography to 5-i]uoro-4-(8-i]uoro-4-isopropyl-3 ,4~dihydro~2H- ben o[b][l,4|oxazin-6-yl)-N-(5-((4-(2-methoxyethyl)piperaziii-l -y])methyl)pyridin-2- yl)pyrimidin-2-amine (0.05 mg, 93.83%) as a yellow color solid compound LCMS: 540 [M+H] 7 ^! HNMR (400 MHz, DMSOM6) d 9.98 (s, 1H), 8.62 (d, J --- 4 0 Hz, IH), 8. 17 (d, J --- 8 6 Hz, 2H), 7.64(dd, J ^:::: 8 4, 2 5 Hz, IH), 7.51 (s, IH), 7.19 (d, J - 1 1.7 Hz, HI), 4.30 (t, J - 4 3 Hz,

2H) 4.17 (p, ./= 6.6Hz, 1H), 3.42 (d l J = 1 1.7, 2.45

1.20 (d, = 6.5 Hz, 611).

Example~I33: Synthesis qfN~(5~(4~aminopiperidin-l-yl) pyridin~2~yl)-5-fluoro-4-(8-fluoro-4-

[0615] Step-1: Synthesis of tert-butyl ( l-(6-nitropyridin-3~y!) piperkIIn-4-yl) carbamate. ^* To a stirred solution of 5-bromo-2-mtropyridine (300 mg, 1.48 mmol, 1 equiv) in DMSO (5 niL), was added K. ; ( ( ⁾ (410 mg, 2.97 mol, 2 equiv) and tert-butyl piperidm-4-yicarbamate (594 mg, 2.97 mnio!, 2 equiv). The resultant reaction mixture was allowed to stir at 100 °C lor overnight.

Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 ml,), solid observed was filtered and dried under vacuum to obtain test-butyl (l -(6- nitropyridin-3-y])piperidin-4-yl)earbamate (400 mg, 8356) as a yellow color solid compound. LCMS: 323 [M+H] ^÷

[0616] Step- 2: Synthesis of tert-botyl ( i -C6-aminopyridin-3~yI) piperidln-4-yl)

carbamate: To a stirred solution of test-butyl (1 -(6-mtropyridin-3-yl) piperidirs-4-yl) carbamate (200 mg, 0.62 mmol, 1 equiv) in metfsanol (10 snL), was added Pd/C (20% w/w) (40 mg). The resultant reaction mixture was allowed to stir at ET for 1 h. Progress of the reaction was monitored by fl .C and LCMS After eosnpletion of the reaction, the mixture was passes through eehte bed and the filtrate was concentrated under reduced pressure to obtain tert-butyl (i-(6- aminopyridin-3-y!) piperidin-4-y!) carbamate ( 150 mg, 82%) as a purple color solid compound. LCMS: 293 [M+H] ^÷

[0617] Step-3: Synthesis of tert-butyl (l-(6-((5-ffuoro-4-(8-ffuoro-4-isopropyl-3,4- d«hyclro-2H-ben*o!b][l,4]oxa2m-6-yl)pyrimidm-2-yl)ammo)pyri dia-3-yi)piperidm-4- yl)carba ate: To a solution of 6-(2-chloro-5-fluoropyriinidin-4-yi)-8-fluoro-4-isopiOpyl-3, 4·- dihydro-2H-benzo[b] [l,4]oxazine (100 mg, 0. 3 mmol, 1 equiv) m dioxane (5 ml,) was added ten-butyl (l~(6~ammopyridin-3~yi)piperidin-4-yi)carbamate (96 mg, 0.33 mmol, 1 .1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,) Organic layer was washed with water (50 ml,) and brine solution (50 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl (i (6-((5 iluoro-4-(8 iluoro-4-isopropyti3,4~dihydro~2Hfoenzo[b][1 ,4]oxazm-6~ yl)pyrimidin~2-y{)araino)pyridin-3-yi)piperidin-4-yj)carbama te (1 50 mg, 84%) as brown color viscous compound LCMS: 582 i \ j · H j ^’

[0618] Step-4: Synthesis of N-(5-(4-aitmnopjperidin~i-yI) pyridm-2-yi)-5-fiuoro-4-C8- fluoro-4-isopropyl~3, 4-dihy ro~2H-benzo[b] ,4] oxazin-6-yI )pyrimidin-2~aitnine: tert-butyl

{ l --{6 ((5 iluoro--4 (8-~iluoro--4 i8opropyi-3,4~dihydn>2H--benzo[b] [l ,4]oxazin~-6~-y!)pynmidm-2- yl)amino)pyndm-3-y])pipeiidin-4-yl)carbamate (150 mg, 0 26 mmol, I equiv) was taken in 1 .25 M HQ m ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for 1 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain N~(5-(4-aminopiperidin-l-yj)pyridm-2-yi)-5-fluoro-4-(8-fluor o-4-isopropyi-3,4-dihydro- 2!:I-benzo[b][l ,4]oxazm~6--y!)pyrimidim2~amme (60 mg, 48%) as a yellow color solid compound. LCMS: 482 [M+H] ⁺ ; ^;ί HNM¾ (DMSO-d ₆ ,400MHz): 6 9.68 (s, 1 H), 8 56 i d. ,%3 9 Hz, I H), 7.84 - 8 05 (m, 2 H), 7 46 (s, 1 H), 7.39 (dd, fofo8, 2.6 Hz, 1 H), 7. 17 (d, , Al l .4 Hz, 1 H), 4.30 (br. s., 2 H), 4.02 - 4.18 (m, I Hi 3.63 (d, Aft 2.3 Hz, 2 H), 3 30 (br. s„ 2 H), 2.98 (br. s . 1 H), 2.74 (t J ^::: l 1.6 Hz, 2 H), 1.90 (d, .7-11.4 Hz 2 H), 1.53 (d, 7-9.6 Hz, 2 H), 1 19 ppm (d, ·/ 6.1 Hz, 6 H).

Example-134: Synthesis of 5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro-2H- benzo[hj[l,4]oxazin-6-yl}-N~(5~((4~meth\dpiperazin-I-yl}meth yl}pyridin-2-yl}pyrimidin-2-amine. (Compound 789}

[0619] Step-1: Synthesis of 5~fluoro-4-(8~flm>rQ-4-isopropyl-3,4-dihydro-2H- ben*o[b][i,4]oxazin-6-yl)-N-(5-((4-inethyIpiperazin-l-yl)fne thyl}pyrid«n-2-yl)pyr«midin-2- amine: To a stirred solution of 5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- ben o[b][l,4]Qxazifi-6~yl)-N-(5-(piperazifi~l~ylmethyl)pyridin-2 -yl)pyrimidifi~2~amine (100 mg, 0 2 mmol, 1 equiv) m DCE (3 ml,) was added formaidehyde(40 % in water) (0.03 mL, 0.61 mmol, 3 equiv), acetic acid (0.06 mL, 1 .0 mmol, 5 equiv). T ^' he reaction mixture was allowed to stir at RT for lb The reaction mixture was cooled to 0°C NaCNBlL (38 mg, 0 61 mmol, 3 equiv) was added to above mixture and raise tbs temperature to RT The reaction mixture was allowed to stir at RT for lb Progress oi me reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 ml,) and extracted with etbyl acetate (50 mL - 2) Organic layer was washed with water (50 mL) and brine solution (50 L). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5-f!uoro-4-(8- fluorO 4 isopropyl 3,4-dihydro-2H benzo[blii,4]oxazin-6-yl)-N--(5--((4 metiiylpiperazin~ l~ yl)methyl)pyridin-2-yi)pyrimidin-2-aniine (10 mg, 10%) as an off white color solid compound. LCMS: 496 9 97 (s 1 H) 8.62 (d, 7 3 9 Hz, 1 H),

8.06 - 8.23 (th, 1 H), 7 64 (d, 7-10.5 Hz, 1 H), 7.51 (s, 1 H), 7.19 (d, ,% ) 1 .8 Hz, 1 H), 4 31 (br. s., 2 H), 4.04 - 4.21 (m, 1 H) 3.43 (s, 2H), 3.30 (t 7 4.2 Hz, 2H), 2.35 (d, ./ i 8.9 Hz, 8 H), 2.15 (s, 3 H), 1 20 ppm (d, ./ 04 Hz, 6 H).

Example- 135: Synthesis of 2-fhioro-4-((5-fl oro-4-(8-fl oro-4-isopropyl-3, 4~dihydro~2H- henzo[bi[l }oxazin-6~yl)pyrimidin~2~yl)amino}benzafflide. (Compound 790}

[0620] Step-·! :; Synthesis of 2-f1«oro-4-((5-f1iioro-4-(8-fliioro-4-isopropyl-3,4-dihydro -

21 ^; I-ben«o[b| [i,4]oxa*in-6-yI)pyrimidin-2-yl)amino)ben«onitrile: To a solution of 6-(2- chioro-5-fluoropynmidin-4-yl)-8-iluoro-4--isopropyl-3,4-dihy dro-2H-benzo[b][ L4]oxaz s(500 mg, 1 .53 mmol, 1 equiv) in dioxane (5 mL), was 4-amino-2-iIuofobenzomtfils (280 mg, 1 .69 mmol, 1 .1 equiv) and cesium carbonate (745 mg, 2.29 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (35mg, 0.153 mmol, 0 02 equiv) and BINAP (191 mg, 0.36 mmol, 0.2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 L) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 2-f!i3oro~4~((5-f!uoro~4~(8-f!uoro~4-isopropyL3,4-dihyclro-2 H~ benzo[b][l ,4]oxazin-6-y])pyrimidin-2-y!)amino)benzonitrile (400 mg, 84%) as a brown color viscous compound. I, CMS; 426[MHETj ^”

[0621] Step-2;; Synthesis of 2~fluoro-4-((5~fl«oro-4~(S~ft«oro~4~isopropyl-3,4~clihydro - 2H-ben¾o(b][l,4]oxa*in-6-yl)pyriitnidin-2-y!)amino}ben¾ara ide: To a solution of 2~fluoro~4~

((5 iluoro~4 (8 iluorO 4 isopropyi 3 4 dihydrO 2H benzo[bl[l ,4joxazm 6 yi)pyrirmdin-2 yl)amino)benzonitrile (200 mg. 0.46 mmol, 1 equiv) in DMSO (5 ml,), was added K ₂ CO ₃ O 26 mg, 0.93 mmol, 2 equiv) and I KT (80mg, 1 84 mmol, 4 equiv). The resultant reaction mixture was allowed to stir at RT for 2h. Progress of the reaction was monitored by TLC and I, CMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to and purified by reverse phase Chromatography to obtain 2-fluoro-4-((5-fluoro-4-(8~fluoro-4- isopropyl-3,4-dihydro-2H-benz.o[b][l ,4]oxazin-6-yl)pyrimidin-2-yl)araino)benzamide (5 mg. 99.48%) as a light yellow color solid compound. LCMS: 444 [M-i-BTj T l \ M R (400 MHz, DMSO-fo) d ppm 8.26 (d, ./ 7 S , 8.25Hz, 1H) 8 10 (d, ,%8.20 Hz, 1 H) 7.81 (t, ./ 8.26 Hz, 1 H) 7.5 (s, 1 H) 7.42(d, 1 H) 8 20 (dd. 1 H) 4 32 (d, 3H), 3.45 (s, 1 H) 1 .23 (s 6 H).

Example- 136: Synthesis of 4-((5-jhioro-4-(8-fluoro-4-isopropyl-3, 4~dihydro~2H- benzo[b]fJ4]oxazin-6-yi)pynmidin-2~yl)amino}-N-(piperid n~4~ytybenzenesu{fonam de.

(Compound 791)

[0622] Step- 1 : Synthesis of tert- butyl 4-( (4-nitrophenyl) sulfonyi) piperazine- 1- carhoxyiate. To a stirred solution of 4-nitrobenzenesulfonyl chloride (500 mg. 2.26 mmol, lequiv) m DCM (10 ml,) was added TEA (0.5mL, 3.39 mmol, 1 Sequi v ), and tert-butyl piperazine-] -carboxyiate (407 mg, 4.07 mmol 1.8 equivf The resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by TEC and LCMS. After completion of the reaction, the mixture was diluted water (50 ml,) and extracted with DCM (50 mi x 2). Organic layer was washed with water (50 ml,) and brine (50 L). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl piperazine-] -carboxyiate. (500 mg, 57%) as a light brown color solid compound. LCMS: 386 [M÷H] ^÷

[0623] Step-2: Synthesis of tert-butyl 4-((4-amiaophenyi) sulfonyi) piperazine-1- carboxyiate: To a stirred solution of tert-butyl 4-((4-nitrophenyi) sulfonyi) piperazine- 1- carboxyiate (200 mg, 0.51 mmol, 1 equiv) in in methanol (10 ml,) was added Pd/C (20% w/w)

(40 mg) under ¾ at The resultant reaction mixture was allowed to stir at RT for 4 h. Progress of the reaction was monitored by I, CMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate w¾s concentrated under reduced pressure to obtain tert- butyl 4-(6-aminopyridin-3-yl)-3-oxopiperazine-l -carboxyiate (160 mg, 86%) as an off white color solid compound. LCMS: 356 [M+H] ^’

[0624] Step-3: Synthesis of tert-butyl 4-((4-((5-ffuoro-4-(8-ffuoro-4-isopropyl-3,4- d«hyclro-2H-ben*o!b][l,4]oxa2m-6-yl)pyrimidm-2-yl)am«no)ph eayl)suifonyI)piperaziae-l- carboxyiate: To a solution of 6 (2-chlon>5-iIuoropyrimidm-4 yl)-8-f!uoro-4-isopropyl-3,4 dihydro-2H-benzo[b]iI,4]oxazme (100 mg, 0.3 mmol, 1 equiv) ni Dioxane (10 niL). was added tert-butyl 4~(6~ammopyridin-3-yl)-3-Gxopiperazme-l-carbGxylate (117 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.47 mmol, 1.5 equiv). The reaction mixture was purged with mtrogen gas for 30 min., followed by the addition of palladium acetate (2 mg, 0 006 mmol, 0.02 eq v) and B1NAF (8 mg, 0 012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 ml ) and extracted wit ethyl acetate (100 ml-). Organic layer was washed with water (50 ml,) and brine (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo[b][i,4]oxazin~6~yl)pyri idm-2-yi)amino)pyndin-3-yl)-3-oxopiperazine-l Carboxylate (150 mg. 76%) as a brown color viscous compound LCMS: 645 [MH4] ^’

[0625] Step-4: Synthesis of 4-{{5-fluoro-4-{8-fhioro-4-isopropyI-3,4-dihydro~2H~ henzo[b] [ 1,4] oxazin-6-yI)pyrimidin-2-yI)aitnino)-N-( piperidm-4-yi)ben¾enesulf©nami e: tert-butyl 4-(6-((5-ftuoro-4-(8-ftuoro-4-isopropyl-3, 4-dihydro- 2H-benzo[bJ[l 4]oxazin-6- y!)pyfinhdin-2-y!)affiino)pyndin~3~y!) 3 Oxopipefazme-! -carboxy!ate (150 mg, 0 23 mmol. I equiv) was taken in 1.25 M HQ m ethanol (5 ml,) and the resultant reaction mixture was allowed to stir at 50°C for 1 h. Progress of the reaction was monitored by LCMS. After completion of the reaction solvent was removed under reduced pressure to obtain crude, which was purified by reverse phase 1 I P! / ^' to obtain 4-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro- 2H-benzo| b:| l ,4]oxazin-6-yl)pyrinndin-2-yl)amino)-N-(piperidim4-yl)benzen esulfonanude (2 mg, 2%) as a yellow color solid compound. LCMS: 545 [M-fflj ^" , HNMR (DMSO-de , 400MHz): 6 10.21 (br. s , 1 H), 8.65 (for. s, 1 H), 7.94 (d, ,%8 3 Hz, 2 H), 7.71 (d, J= 7.9 Hz, 2 H), 7 60 (br s., 1 H), 7 44 (br. s„ 1 H), 7.1 8 (d, ,/Q 2.3 Hz, 1 H), 4 31 (br. s., 2 H), 4.16 (br. s.. 1 H), 3 39 (m, 2 H), 3.17 (br s., 1 H), 2 99 (br. s„ 2 å-]), 2.92 (br. s., 2 H), 2 09 (br s„ 1 H), 1 54 (br s., 2 H), 1.36 (br. s„ 2 H), 1 .20 m (d, ,7-6.1 Hz, 6 H).

Example-137: Synthesis of 5-Jluoro~N-(3-fluoro-4-((4-methyipipemzin-l-yiJmeihyl)phenyl )-4~(8- fluoro~4~isopropyl~3.4-dihydro-2H~henzo[bj[l,4]oxazin~6~yi)p yrimidin-2-amine. (Compound

⁷ 92)

[0626] Step-1: Synthesis of l-{2-f!uoro-4-nitrobenzyl)~4~n»ethylpipera2:ine : To a stirred solution of 1 -{hromomethy I)-2-f! uoro-4-nitrobenzene (300 mg, 1 .29 mmol, 1 equiv) in THE (10 ml . · was added 1-methylpiperaziiie (386 mg, 3.87 mmol. 3 equiv) and DIPEA (0.7 mL, 3.87 mmol, 3 equiv) The resultant reaction mixture was allowed to stir at ET for overnight. Progress of the reaction was monitored by I, CMS and NMR After completion of the reaction, diluted with water (30 mL). and extracted with ethyl acetate (1 00 ml..). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodiu sulphate and concentrated under reduced pressure to obtain l-(2-†1uoro-4-nitrobenzyl)-4- nethylpiperazine (300 mg, 92%) as a yellow viscous compound Idl ^' d IS:: 254 [M+H] ^"

[0627] Step-2: Synthesis of 3-fiMoro-4-((4-inethylpipera¾in-l-yI)methyI)aniIine : To a stirred solution of I-(2-†]uoro-4-nurobenzyi)~4-methylpiperazme (300 g, 1.1 8 mmol, 1 equiv) m in methanol (10 mL), was added Pd/C (20% w/w) (60 mg) under I¾ aim. The resultant reaction mixture was allowed to stir at ET for 1 h. Progress of the reaction was monitored by LCM1S. After completion of the reaction, the mixture was passes through cellte bed and the filtrate was concentrated under reduced pressure to obtain 3-fluoro-4-((4-methylpiperazin-l- y!)raeihy!)ani!me (200 mg, 75%) as an off white color solid compound. LCMS: 224 [M-i-H]

[0628] Step-3: Synthesis of 5-fi ui>ro-N-(3-fiuoro-4-((4-methyIpiperazin- 1 - yl)methyI)phenyl)-4-(8-f1uoro-4-isopropyl-3,4-dihydro-2H-ben zo[h][l,4]oxa*in-6- yi)pyri idin-2-amme: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fiuoro-4- isopiOpy!-3,4-dihydro-2H-benzo| b]| l ,4]oxazine (100 mg, 0 3 mmol, 1 equiv) in dioxane (10 mL), was added 3-iluoro-4-((4--mefhylprpetazin--h-yl)meihyl}amline (74 nig, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0 47 mmol 1.5 equiv) The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by INC and LCMS After completion of the reaction, diluted with water (30 niL) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 mL) and brine solution (50 ml . ·. Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain 5-fIuoro-N--(3-- f!uoro-4-((4-methy!piperazin~l -yl)methyl)phenyl)-4-(8-fluoro-4-isopropyi-3,4-dihydro-2H- benzo[b][l ,4]oxazm-6-y])pyrimidin-2-amme (50 mg, 3274) as a yellow color solid compound. LCMS: 513 [MH4] ⁺ ; ¹ HNMR (DMSO-ds ,400MHz); d 9 93 (s, 1 H), 8.61 (d, .7=3 9 Hz, I H), 7.77 (dd, .7=12.9, 1.5 Hz, I H), 7 37 - 7.52 ( , 2 H), 7.22 - 7.29 (m, 1 H), 7.17 (d, Aft 1.0 Hz, 1 H), 4.30 (t, .7=3.9 Hz, 2 H), 4 17 (s, i H), 3.44 (s, 2 H), 3 1 3 - 3.39 (m, 2 H), 2.38 (br s., 4 H), 2.33 (br s. , 4 H), 2 15 (s, 3 H), 1.18 ppm (d, .7=6.6 Hz, 6 H).

Example- 138: Synthesis of 5-fluoro~4-(8~fluoro-4-isopropyl-3.4-dihydro-2H- henzofb][l,4]oxazin~6~yl)-N-(5~(l~methylpipehdin-4-yl)~6~(tn fluoramelhyl)pyridin-2- yi)pynmidin-2-amme (Compound 841)

[0629] Step-1: Synthesis of tert- butyl e-ammo-l-iirifluoroiRethyli-S^-dih dro-p^’- bipyriilIne]-i’(2 ^* H)~carboxy!ate: lb a solution of 5-bromo~6-(tnfluorometliyl)pyridm-2-amine (500 mg, 2.07 mmol, 1 equiv) m dioxane : water (10 ml, : 3 l ..· was added tert-butyl 4-(4, 4, 5, 5-tetrameihyl-l, 3, 2-dioxaborolan-2-yl}-3 6-dihydropyridine-l (2B)-carbox iate (705 mg 2.28 mmol, 1.1 equiv) and sodium carbonate (329 mg, 3.11 mmol. 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of hdi PPh fo l· (72 mg,

0.1 mmol, 0.05 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 6 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL ^c 2) Combined organic layer was washed with water (30 mid and brine solution (30 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash by using 100-200 mesh silica gel column to afford tert-butyl 6-amino-2-(trifluoromethyl)-3^6 ^, -dihydro-[3,4'-bipyridine]-l ^, (2 ^, H)- carboxylate (450 mg, 63 %) as an offwhite solid compound compound. LCMS: 343 [M+H]

[0630] Step-2: Synthesis of tert-butyl 4-(6-ammo-2-(trifluoromethyl)pyrklIn~3- yl)piperidine-l-carboxylate: To a stirred solution of tert-butyl 6-amino-2-(trif!uoromethyl)- 3',6'-dihydro-(3,4 ^! -bipyridine]-l '(2H)-carboxylate (200 mg, 0 58 mmol, 1 equiv) in methanol (10 mL), was added Pd/C (10 wt. %) (40 mg) under 1 1 atm. The resultant reaction mixture was allowed to stir at RT for 6h. Progress of the reaction was monitored by LCMS After completion of the reaction, the mixture was passes through eelite bed and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(6-amino-2-(trif1uoromethy!)pyridin-3-yl)piperidine-l- earboxylate (1 80 g, 90%) as an off white solid compound LCMS: 345 [M÷H]

[0631] Step-3: Synthesis of tert-butyl 4-(6-((5-fluoro-4-(S-fluoro-4-isopropyl-3,4- djhydro-2H-benzo[b]ii _» 4]oxa¾jn-6-yi)pyrjmidin-2-yl)amino)-2-(trifluoromethy I)pyridin-3- yl)piperidine-l-carboxylate: To a solution of 6~(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4- isopropyl~3,4-dihydro-2H~benzo[b][l ,4]oxazine (150 mg, 0.45 mmol, I equiv) m dioxane (6 ml ,), was tert-butyl 4-(6-amiuo-2-(trifluoiomethyi)pyndim3-yl)piperidine-Lcarboxy late (175 mg, 0.5 mmol, 1 1 equiv) and cesiu carbonate (224 mg. 0.69 mmol, 1 .5 equiv). The reaction mixture was degassed with nitrogen gas for 10 mm., followed by the addition of palladium acetate (10 mg, 0.046 mmol, 0 1 equiv) and BINAP (57 mg, 0.092 mmol, 0 2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (10 ml ,) and extracted with ethyl acetate (1 5 rnL) Organic layer was washed with water (10 ml,) and brine solution (10 L). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by norma! phase combi flash by using 100-200 mesh silica gel column to obtain tert-buty! 4-(6-((5-fluoro-4-(8-fluoro-4- isopiOpyl-3,4-dihydro-2H-benzo b][l,4]oxazin-6-yl)pyriinidin-2-yl)amino)-2- (tnfluoromethyI)pyridm-3-yl)piperidine~1 -carboxyiate (120 mg, 41 %) as a yellow solid compound. LCMS: 635 [M+tf

[06:32] Step-4: Synthesis of 5-flluoro-4-(8-fluoro-4-«sopiOpyl~3,4-dihydro-2H~

ben¾o[b]|i ,4[oxa2:i«-6-yI)-N-(5-(piperidm-4-yl)-6-(trilluoromethyl)py ridm-2-yl)pyrimidm-

2-amine hydrochloride: A solution of tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4- dihydfo-2H benzo[b]il,4]oxazin-6-y!)pyfmiidm-2-yl)ammo)-2-(trlf!uoromet hy!)pyridm-3- yl}piperidine-i-carboxylate (120 mg, 0.2 mmol, 1 equiv) in 1.25 M HC1 in ethanol (4 mL) was allowed to stir for lb at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain 5-fluoro-4-(8- fluoro-4-isopropyl-3.4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)- N-(5~(piperidin~4~yl)-6- (trifluoromethyl)pyridm-2-yl}pyrimidin-2-amine hydrochloride (90 mg, 84%) as a yellow solid compound. LCMS: 535

[0633] Step-5: Synthesis of 5-fluoro-4-(8~fl«oro-4-isopropyl~3,4-clihydrO 2H~

henzo[b][l,4|oxaz«B-6-yl)-N-(5-(i-methylpiperidm-4-yl)-6 -(4rifluoromethyl)pyritlin~2” yl)pyrimidin-2-amine : To a stirred solution of 5~fluoro-4-(8~fluoro-4-isopropyl-3,4-dihydro- 2H-benzo[b][l ,41oxazin-6-yl)-N-(5-(piperidin-4-yI)-6-(trifluoromethyl)pyr idin-2-yl)pyrimidin-2- amine (100 mg, 0.19 mmol, 1 equiv) in DCE (5 ml,), was added Formaldehyde (30% in water) (84 mg, 0.93 mmol, 5 equiv), acetic acid (57 mg, 0 93 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for Ih The reaction mixture was cooled to 0°C NaCNBTL (23 mg, 0 38 rnmo!, 2 equiv) was added to above mixture and raised the temperature to RT. The reaction mixture was allowed to stir at RT for 4h. Progress of the reaction was monitored by LCMS After completion of the reaction, the reaction mixture was diluted with water (20 ml,) and extracted with ethyl acetate (20 rnL x 2). Organic layer was washed with water (20 ml,) and brine solution (20 mL). Organic layer was dried over anhydrous sodium sulphate and

concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5-iluoro~4~(8-iluoro~4-isopropyl~3,4-dihydro-2H~benzo[b][l ,4]oxazm-6-yi)-N-(5-(1 - methylpipendin-4-yi)-6-(trifluoroniethyl)pyridin-2-yl)pynmid in-2-amine ( 15 mg, 14 %} as a solid compound. LCMS: 549 jM+H j ‘II MR (400 MHz, Methanol-44) d 8.61 (d, /- 8.8 Hz, Hi), 8.47 (d, 7 4.0 Hz, Hi), 7.94 (d, J = 8.9 Hz, H I ) 7 53 (s, 1 H), 7 30 - 7.22 (m, Hi), 4.33 (t,

./ 4.4 Hz, 1 H), 4 24 i n../ = 6 5 Hz, 1H), 3.23 (d, J = 12.0 Hz, 3H), 3 04 (s, 2H) _: 52 (d, J= 19.5

Hz, 511), 2.16 (s, OH), 1.96 -1.86 (m, 4H), 1 32 - 1.21 (m, 6H)

Example- i 39: Synthesis ofN-(5-(4-((dimeihyiamino)meihyi)piperidin-l-yi)pyridin-2-y} )~5~ fluoro-4-(8~fluor -4-isopropyl-3,4-dihydro~2H-benzo[b fl,4]oxa n~0~yI)pyrimidm~2~csmiie. (Compound 842)

[0634] Step-1: Synthesis of !NdN-dimethyi-l-(l-(6-nitropyridin-3-yl)piperidin-4- yl)methan amine: To a stirred solution of S-bromo-d-nitropyridine (500 nig, 2.46 mmol, 1 equiv) in DMSO (8 ml.), was added N,N-dime†hyl-l -(piperidin-4-yl)methanamine (635 mg. 2 95 mmol, 1 2 equiv) and K i O : (679 mg, 4 92 mmol, 2 equiv). The resultant reaction mixture was allowed to stir at 100 ^C C for overnight. Progress of the reaction was monitored by LCMS and NMR. After completion of the reaction, diluted with ice water (30 mL), solid observed was filtered and dried under vacuum to obtain N,N-dime†hy!-l ~(1 -(6-mtropyridin~3-yl)piperidin-4- yljmethanannne (500 mg, 77%) as a yellow color solid compound, LCMS: 265 [M+H] ^r

[0635] Step- 2: Synthesis of 5-(4-((dimethyl amino) methyl) piperidin-l-yl) pyridin-2- amine: To a stirred solution of N, N-dimethyl-l-(l-(6-nitropyridin-3-yl) piperidin-4-yI) methanamine (200 mg, 0 75 mmol 1 equiv) in in methanol (10 ml.), was added Pd/C (20% w/w) (40 mg) under H ₂ atm The resultant reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain 5-(4~ ((dimethyl ammo) methyl) piperidm-1 -yl) pyridin-2-amine (150 mg, 85%) as an off white color solid compound. LCMS: 235 [M-HTG Step-3: Synthesis of N-{5-{4-(( imethylamino)inethyI)piperidin-l-yl)pyridm-2-yl)-5-iluoro- 4-(8-f1«oro-4-isopropyi-3,4-dihyclro-2H-ben*ofb][l ₅ 4joxa*in-6-yl)pyrmiidin-2-amme: To a solution of 6-{2-chloro-5-fluoropyrmiidin-4-yl)~8~fluoro-4-isopropyl-3,4 -dihydro-2H- benzo[b][l,4]oxazme (100 mg, 0.3 mmol, 1 equiv) in dtoxane (10 mL), was added 5-(4- ((dimethyi amino)methyl)pipendin~l~yl)pyridin-2-amine (77 mg. 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0.47 m ol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and B1NAP (8 mg, 0.012 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 ml,) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to obtain N~(5~(4~

((dimethylamino)methyl)piperidin~l ~yi)pyridin-2-y])-5-fluoro-4-(8-fluoro-4-isopropy)-3,4- dihydro-2H-benzo[b] 1 ,41oxazin-6-yi)pyrimidin-2-amine (20 mg, 12%) as a yellow color solid compound. LCMS: 524 [M+H] ; HNMR: (DMSO-de , 400MHz): 6 9.66 (s, 1 H), 8 56 (d,

./ ' 4 Hz, I H), 7.82 ·· 8 09 (m, 2 H), 7 47 (br. s., 1 H), 7.28 · 7 43 (m, I H), 7.17 (d, / 1 2 3 Hz,

1 H) 4.30 (br. s , 2 H), 4.16 (d, ./ 6 0 Hz, 1 H), 3.61 (d, 7 12.3 Hz, 2 H) 3.25 (br. s , 2 H), 2.52 - 2 73 (m, 3H) 2.12 (s, 6 H), 2 08 (d, ,%7.9 Bz, 2 H), 1.79 (d, fob 0 5 Hz, 2 H), 1.58 (br. s , 2 H), 1.10 - 1.29 ppm (m 6 H).

Example- 140: Synthesis of S~fluoro~ ~(8-fluoro~ ~isopropyl~3, 4-dihydro-2N- benzo[h]ll joxazin-6-yI)-N-(5-(4~methoxypiperidin-l-yl)pyridin-2-yl)pyr imidin-2-amine hydrochloride. (Compound 843)

[0636] Step-1: Synthesis of 5~(4~methoxypiperidin-l-yl)~2-n«tropyridine: To a stirred solution of 5-bromo-2-niiropyridine (500 mg, _, 2 46 mmol, 1 equiv) in 1)5 ISO (8 mL), was added l ~4~me†hoxypipendme (567 mg, 4 92 mmol 2 equiv) and K AO (679 mg, 4.92 mmol, 2 equiv) The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by LCMS and NMR. After completion of the reaction, diluted with water (30 mL) solid observed was filtered and dried under vacuum to obtain 5-(4-methoxypiperidin--l-· y!)-2-mtropyridine (500 mg 86%) as a yellow color solid compound LCMS: 238 [M+H] ^"

[0637] Step-2: Synthesis of 5~(4-*nethoxypiperidin-l -yl)pyridm-2-ainine: To a stirred solution of 5-(4-methoxypiperidin-l -yl)~2~mtropyridi«e (200 g, 0.84 mmol, 1 equiv) in in methanol (10 ml,), was added Pd/C (20% w/w) (40 mg) under Hp atm. The resultant reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS.

After completion of the reaction, the mixture was passes through celite bed and the filtrate was concentrated under reduced pressure to obtain 5-(4-methoxypiperidin-l -yi)pyridin-2 -amine (150 mg, 86%) as an off white color solid compound. LCMS: 208 i \ ! · H I

[0638] Step-3: Synthesis of 5~fluoro-4-(8~fluoro-4-isopropyl-3,4-dihydro-2II- ben*o[b|[l,4]oxaz«n-6-yl)-N-(5-(4-methoxypiperidin-l-yl)pyr idin-2-yl)pyrimidin-2-amine:

To a solution of 6--(2--chloro-5-iluoropyrimidin-4-yl)-8--fluoro-4-isopropyl 3 4--dihydro-2II·· benzo[b][l,4]oxazine (100 mg 0.3 mmol, 1 equiv) in dioxane (10 L), was added 5-(4- methoxypiperidm-l-yl)pyndm~2~amme (69 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (147 mg, 0 47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min. followed by foe addition of palladium acetate (2 mg, 0.006 mmol, 0 02 equiv) and BINAP (8 mg, 0 012 mmol, 0 04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate ( 100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was puniled by reverse phase HPLC to obtain 5-fiuoro4-(8-fluoro4-isoprGpyl-3,4-dihydro~2H- benzo[b][l ,4]oxazin-6-yl)-N~(5-(4-methoxypipericlin-l-yl)pyridin-2-yl) pyrimidin-2-amine (110 mg, 72%) as a yellow color solid compound LCMS: 497 [MHI] ^’

[0639] Step-4: Synthesis of 5-fluoro-4-(8-fl«oro-4-feopropyl-3,4-dihydro-2H- benzo|b|(l,4)oxazin-6~yl)-N(5-(4-methoxypiperidia-l-yi)pyrid in-2-yi)p>Timidia-2-amine hydrochloride: 5-fluoro-4-(8-iluoro-4- isopropyl-3 ,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)~N- (5-(4~methoxypiperidin-l-yl)pyridin-2-yl)pyrimidin-2-amine (30 mg, 0 06 mmol, 1 equiv) was taken in 1 25 M HQ in ethanol (5 mL) and the resultant reaction mixture was allowed to stir at RT for 1 h. Solvent was removed under reduced pressure and the residue was dried under lyopbdizer to obtain 5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[b][l ,4]oxazin-6- yl)-N-(5-(4-methoxypiperidiii- l -yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride (20 g, 67%) as a brmk red color solid compound. LCMS: 497 [M+H] ⁺ ; *HNMR: (DMSO-d ₆ ,400MHz, HC1 salt): 61 1.66 (br. s., I H), 8.77 (d, ./ 1 5 Hz, I H), 8 1 1 - 8.30 (m, 1 H), 7.94 (hr s., 1 H), 7 72 (hr. s , 1 H), 7.39 (s, I H), 7 20 (d, , Ad 1.0 Hz, I H), 4.24 - 4.38 (m, 2 H) 4.14 (dt JM3.2, 6 6 Hz, 1 H), 3 50 (br. s„ 3 H), 3.32 (br. s.. 2 H) 3.28 (s, 3 H), 3 07 (br. s., 2 H), 1.97 (br. s.. 2 H) 1.60 (br. s . 2 H), 1.18 ppm (d, / 6 0 Hz, 6 H).

Exampie~141: Synthesis of 5~fluoro~4~( ^" 8~fluoro~4~isopropyl~3, 4~dihydro~2li~

henzofh] [1, 4 oxazm~6~yl}~N~(6~methoxy~5~(l~meihylprperidm~4~yl)pyridm~2~y l)pyrrmidin~2~ amine. (Compound S44)

[0640] Step- 1 : Synthesis of tert-butyl 6-amino-2-methoxy-3’ _» 6*-dihydro-[3,4*- bipyridmej-l *( 2 ^* M)-carboxy late: lb a solution of 5-bromo-6-inethoxypyridin-2-arnine (200 mg, 0 98 mmol, 1 equiv) m dioxane : water (10 ml : 3 mL), was added tert-butyl 4-(4, 4, 5, 5- tetramethyi-1, 3, 2-dioxaborolan-2-yl}-3, 6-dihyclropyridine~l(2H)-carboxylate (334 mg, 1.08 mmol, 1.1 equiv) and sodium carbonate (158 mg, 1.47 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of Pd(PPh ₃ ) ₂ Cl ₂ (34 mg, 0.049 mmol, 0.05 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 6 h. Progress of the reaction was monitored by TLC and LCMS. Alder completion of the reaction, reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL ^c 2) Combined organic layer was washed with water (30 ml,) and bone solution (30 mL) Organic layer was deed over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash by using 100-200 mesh sihca gel column to afford tert-butyl 6~amino-2-methoxy-3',6'-dihydro-[3.4 ~bipyridine]~r(2'H)- carboxylate (210 mg, 70 %) as an offwhite solid compound compound. LCMS: 306 [M+H]

[0641] Step-2: Synthesis of tert-buty! 4-(6-amino-2-methoxypyridm-3-yl)piperidine-i- carboxylate: To a stirred solution of tert-butyl 6-amino-2-methoxy-3 ,6’-dihydro-[3,4'- bi pyridine] - 1 '(2'H)~carboxy late (300 mg, 0.98 mmol, 1 equiv) in methanol (10 ml,), was added Pd/C (10 wt %) (50 mg) under (· atm Tbe resultant reaction mixture w¾s allowed to stir at RT for 6b Progress of the reaction w¾s monitored by LCMS. After completion of the reaction, the mixture was passes through eelite bed and the filtrate was concentrated under reduced pressure to afford tert -butyl 4-(0-a ino-2-niethoxypyndin-3-yi)piperidi«e- l -carboxylate (270 mg, 88%) as a transparent oil compound. LCMS: 308 j M+H] ^’

[0642] Step-3: Synthesis of tert-butyl 4~(6-((5-fluoro-4~(8-fluoro-4-isopropyl-3,4- d«hyclro-2H-ben*o!b] [l,4]oxa2«n-6-yt)pyrimid«i-2-yl)amwao)-2-methoxypyricli«- 3- y i)piperidine~ l-carboxylate: To a solution of 6-(2-chloro-5-iluoropynniidxn-4-yl)-8-fluoro-4- isopropyi 3,4~dihydro-2H benzo| b]| l ,4]oxazine (100 mg, 0.31 mmol, 1 equiv) in dioxane (3 niL), was added tert-butyl 4-(5-aminopyriclin-2-yl) piperidine-l-carboxylate (104 mg, 0.33 mmol, 1.1 equiv) and cesium carbonate (151 mg, 0.46 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 10 mm., followed by the addition of palladium acetate (7 nig, 0.03 mmol, 0.1 equiv) and BINAP (39 mg, 0.06 mmol, 0.2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (10 ml,) and extracted with ethyl acetate (15 ml ). Organic layer was washed with water (10 ml,) and brine solution (10 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyl · ^' · · (6-((5-fluoro-4-(8-fluoro-4-isopropyi-3,4-dihydro~2H-benzo(b ][i,4]oxaz:in~6~yl)pyriraidin-2~ yl)amino)-2~me†hoxypyridin-3-yI)piperidine-l -carhoxyla†e (90 mg, 49%) as a yellow solid compound. LCMS: 597 [M+H] ¹

[064:3] Step-4: Synthesis of 5-fluoiO-4-(8-fluoiO-4-isopropyl~3 -difaydro-21li~

benz©[b]iL4j©xa¾in-6-yl)-N-(6-itneihoxy-5-(piperidin~4 ~y!)pyridin-2-yl)pyriiimdin~2~amme hydrochloride: A solution of tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3, 4-dihydro- 2H- benzo[b] [l,4]oxazin-6~yl)pyrimidin-2-yi)atnino)-2-methoxypyridin-3-y I)piperidme~l~ carboxylate (120 mg, 0 2 mmol, 1 equiv) in 1.25 M HQ in ethanol (4 ml,) was allowed to stir for lb at 50°C Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain 5-fiuoro~4-(8-fiuoro-4- isopropyl--3,4~dihydrO 2H--benzoj b]j l,4 joxazin~6~y!) N (6 methoxy--5--{pipendin--4-yl )pyridin~2~ yl)pynrmdm-2-amme hydrochloride (90 mg, 90%) as a yellow solid compound. LCMS: 497 j M H i [0644] Step-5: Synthesis of 5-fluoro-4-( 8-t1uoro-4-isopropyI-3 _» 4-dihydro-2H- ben¾o(b]!i ,4[oxa2i«-0-yI)-N-(6-methoxy-5-(l-tiethyIpiperidm-4-yl)pyri din-2-yI)pyrhmdin- 2~amine : To a stirred solution of 5~iluoro~4~(8~iluoro~4~isopropyl~3,4-dihydro-2H~

benzG[b][1 ,4]oxazin-6-yl)-N~(6~methoxy-5-(piperidin-4-yf)pyndin-2-yl)p yrimidin-2-amine hydrochloride salt (200 mg, 0.4 mmol, 1 equiv) in BCE (5 niL), was added Formaldehyde (30% in water) (180 mg, 2 mmol, 5 equiv), acetic acid (120 mg, 2 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for Ih. The reaction mixture was cooled to 0°C. NaCNBH- (49 mg, 0 8 mmol, 2 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for 4h. Progress of the reaction was monitored by LCMS. After completion of the reaction , the reaction mixture was diluted with water (20 ml ) and extracted with ethyl acetate (20 mL ^c 2) Organic layer was washed with water (20 ml.) and brine solution (20 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which w¾s purified by reverse phase KPLC to afford 5~fluoro~4~(8~fluoro~4~isopropyl~3,4-dihydro-2H~benzo[b][l ,4]oxazin-6-yl)-N-(0- methoxy-5-(l-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-a mine (6 mg, 15 %) as a yellow color solid compound. LCMS: 51 1 [M÷H] ⁱ HNMR: (400 MHz, Methanolvftl) 6 8 43 (d, J— 4 1 Hz, IH), 7.92 (d. 7 8 1 Hz, !H), 7.53 (s. 1H),7.50 (d, J ^:::: 8.2 Hz, IH), 7.26 (d, J --- 1 1 6 Hz,

HI), 4 33 (t, J ----- 4 3 Hz, 2H), 4.24 (p, ./ 6.6 Hz. I H), 3.96(s, 3H) 3.58 (d, J ------ 12 2 Hz, 2H),

3 36 (d, J- 4.9 Hz, 21 1} 3 20 - 3.02 (m, 3H), 2.91 (s, 3H), 2.1 1 (d, J M4.3 Hz, 2H), 2 00 (dd, J - 17.6, 7 3 Hz, 2H), 1 .27 (d, / 6.6 Hz, 6H).

Example-142: Synthesis of 6~{(5-ftuoro~ -(8-ftuoro~4-isopropyl-3, 4-dihydro-2H~

benzo[h]ll joxazin-6-yI)pynmidin-2-yi)amino}-3-(l-meihy]piperidin-4-yl) picoUnonitnle. (Compound 845)

[0645] Step-1: Synthesis of tert-bntyl 6-amino-2-cyano-3*,6’-dfliydro- 3,4’-bipyr ine]- l ^* (2’H)~carboxylate: Io a solution of 6-ami no-3-bromopicoiinonitrile (200 mg, 1.01 mmol, 1 equiv) in dioxane (4 mL), was added tert-bntyl 4 (4,4,5,5-ietrametlrybl,3,2-diOxaboroian-2-y!V 3,6-dihydropyndme-l (2H)~carboxylate (376 mg, 1.2 mmol, 1 equiv) and a solution of sodium carbonate (318 mg, 3 03 mmol. 3 equiv). The reaction mixture was degassed with nitrogen gas for 15 mm., followed by the addition of Pd (PPlnfiCfi (36 mg. 0 05 mmol, 0.05 equiv) The resultant reaction mixture was allowed to stir at 100 °C for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with water (30 ml.) and extracted with ethyl acetate (100 ml, ^c 2) Organic layer was washed with water (100 ml,) and brine solution (100 mi,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash ro obtain tert-butyl 6-ammo-2-cyano-3',6'-dihydro-[3,4 ^! -bipyridme]- r(2’H)-carboxylate (200 mg. 66%) as an off white color solid compound. LCMS: 301 [M+H]

[0646] Step-2: Synthesis of tert-butyl 4~(6~amino~2-cyanopyridin-3-yI)piperidme-l- carboxy!a e: To a stirred solution of ten-butyl 0-amino~2~cyano-3',6'-dihydro-[3.4 ~bipyridine]~ r(2Tf)-carboxylate (200 mg, 3 2 mmol, i equiv) in ethanol (10 ml,), was added Pd/C (20% w/w) (40 mg) under !L atm. The resultant reaction mixture was allowed to stir at RT for 4h. Progress of the reaction was monitored by LCMS. After completion of the reaction the mixture was passes through oehte bed and the filtrate was concentrated under reduced pressure to obtain tert- butyl 4~(6-amino-2-cyanopyridin-3-y]) piperidine- 1-carboxylate (180 mg, 90%) as a dark brown solid compound LCMS: 303 [M÷H] [0647] Step-3: Synthesis of tert-butyi 4-(2-cy aao-6-( ( 5-!1uoro-4-( 8-!1uoro-4-isopropyI- 3,4-dihydro-2H-benzo[b] l,4|oxazia-6-yi)pyr niclin-2-yI)ainino)pyridui-3-yl)piperidiae-l- carboxyiate: To a solution of 6~(2~chloro-5-fluoropyriinidm-4-yf)-8-fluoro-4-isopiOpyf-3,4 ~ dihydro-2H-benzo[b][l,4]oxazine (150 mg, 0.46 mmol, 1 equiv) in dioxane (10 niL), wa added tert-butyi 4~(6~ammo-2-cyanopyridin-3-y1)piperidine-1 ~carboxylate (151 mg, 0.50 mmol, 1.1 equiv) and cesium carbonate (225 mg, 0.69 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas lor 30 mm., followed by the addition of palladium acetate (2 mg, 0.009 mmol, 0.02 equiv) and BINAP (12 mg, 0.018 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and I CMS After completion of the reaction, diluted with water (30 ml ) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyi 4- (2 CyanO 6 ((5-i!uorO 4 (8-i!uorO 4-isopropyb3,4 dihydrO 2H benzo[b1j[i ,4]oxazm-6- yl)pyr!mid!n-2-yj)an:uno)pyridim3-yl)piperidine-l -carboxylate (200 mg, 74%) as a brown viscous compound. I, CMS: 592 [M+H] ^f

[0648] Step-4: Synthesis of 6-((5-fiuoro-4-(8-fiuoro-4-isopropyi~3 -dihydro~2H~ ben?.o[h] ,4] oxazin-6-yi)pyrimidin-2-yl)an»ino)-3-(piperidin-4-yi)picoIi nonitrile hydrochloride: A solution of tert-butyi 4-(2-cyano-6-((5-fluoro-4-(8-f1uoro-4-isopropy]-3.4- dihydro-2H-benzo[b][l 4]oxazin-6-yl)pyriniidin-2-yl)amino)pyridin-3-yl)piperidine- I- carboxyiate (200 rng, 3.38 mmol, 1 equiv) in 1.25 M I it i in ethanol (5 inL) was allowed to stir for lb at 50°C Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain 6-((5-t1uoro-4-(8-†1uoro-4- isopropyl-3, 4-dihydro-2H-benz.o[b][l ,4]oxazin-6-yl)pyrimidin-2-yl)araino)-3-(pipeiidin-4- yl)picolmonitrile hydrochloride (150 mg, 90%) as a yellow solid compound. LCMS:492 [M+H]

[0649] Step-5: Synthesis of 6-((5-flaoro-4-(S-flaoro-4-isopropyi-3,4- ihydro-2H- benzo[b][i,4]©xaz«n-6-yl)pyr«midin-2-yl)amino)-3-{:I-snet hyIpiperidm-4-yl)pte©Iinonitrile:

To a stirred solution of 6-((5-†1uoro-4-(8-†]uoro-4-isopropy]-3 4-dihydrQ-2H- benzofbj [ 1 ,4]oxazin-6-y l)pyrimidin-2-yl)arnino)-3 -(piperidin-4-yl)pi colinon tril e hydrochloride salt ( 100 mg. 0.2 mmol, 1 equiv) in DCE (3 L), was added Formaldehyde (40% in water)

(0.02 mL 0.6 mmol. 3 equiv), acetic acid (0 06 mL, 1 0 mmol, 5 equiv). The reaction mixture was allowed to stir at RT for I h The reaction mixture was cooled to 0°C. NaCNBLu (39 mg, 0.6 mmol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for lh. Progress of the reaction was monitored by LCM8.

After completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (50 mL x 2). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 6~((5-f1uoro~4~(8-f1uoro~4 -isopropyl~3,4-dihydro-2H~benzo[b][1 ,4]oxazin-6- yl)pyrimidin-2-yI)amino)-3-(l -methylpiperidin-4-yl)picolmonitri!e (5 mg, 5%) as a yellow color solid compound LCMS: 506 [M÷H] ft ¹ HNMR: (DMSO-ds ,400MHz): 5 10.54 (s, I H), 8 66 (d, 2=3 9 Hz, I H), 8.43 (d, 7=6.8 Hz, 1 H), 7.94 (d, 7=6.2 Hz, 1 H), 7.47 (s, 1 H), 7 19 (d,

7 1 17 Hz, 1 H), 4.30 (d, 7=6 9 Hz, 2 H), 4.09 - 4 20 (m, 1 1 1 ) 3.25 (br s., 2 H), 2 91 (d, 7=1 1 .0 Hz, 2 H), 2.76 (br s., 1 H), 2 21 (s, 3 H), 1 .98 (d, 7=4 1 4 Hz, 2 H), 1.75 (br. s., 4 H), 1.00 - 1.24 ppm (m, 6 1 1).

Example- / 43: Synthesis of 5~fiuo?o~4~(S-fluo?o~4~isopropyi~3 4~dihydro~2H~

benzo[h][L 4joxazm-6~yr)~N-(6-fluoro-S-(l-methyipipe}idin~4~yl}py}idin~ 2~yl} mimidm~2~ amine. (Compound 846}

[0650] Step-l : Synthesis of tert-butyl 6-aini«o-2-f1ooro-3 ^, _» 6 ^, -dihyclro-[3 _» 4*-bipyrid«ie]- ’(2’ H)-carboxyIate: To a solution of 5-bromo-6-fiuoropyridin-2-amine (500 nig 2.1 mmol, 1 equiv) m dioxane : water (10 mL : 3 mL), was added tert-butyl 4-(4. 4. 5, 5-tetramethy!-l. 3. 2- dioxaborolan-2--y!)-3, 6-dihydropyndine-l(2H)-carboxylate (714 mg, 2.31 mmol, 1.1 eqiuv) and sodium carbonate (333 mg, 3.15 m ol, 1.5 equiv). The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of Pd(PPh ₃ ) ₂ Cl ₂ (74 mg, 0.11 mol, 0.05 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 6 h Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL ^c 2) Combined organic layer was washed with water (30 ml,) and brine solution (30 ml,) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash by using 100-200 mesh silica gel column to afford tert- butyl 6~amino-2-fluoro-3f6 ~dihydro~[3,4 ^S bipyridine] P(2 H)-carboxylate (400 mg, 55 %) as an offwhite solid compound. LCMS: 294 [M+H]

[0651] Step-2: Synthesis of tert-butyl 4-(6~amino~2~fluoropyritlm-3-yi)piperidine~i~ carboxy!ate: To a stirred solution of ten-butyl 0-amino-2~fIuoro-3',6'-dihydro-[3,4'-bipyridme]- r(2Tl)-carboxylate (400 mg, 1 53 mmol, I equiv) in methanol (15 mL). w¾s added Pd/C (10 wt. %) (80 mg) under i n atm. The resultant reaction mixture w¾s allowed to stir at RT for 6h Progress of the reaction was monitored by I, CMS. After completion of the reaction, the mixture was passes through eelite bed and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(6-ammo-2-f ^j uoropyridin-3~yl)piperidine-l-carboxylate (370 mg, 80%) as an off white solid compound. LCMS: 296 [M÷H] ^~~

[0652] Step-3:; Synthesis of tert-butyl 4-(2-fluoro-6-((5-fluoro-4-(8-fluoro-4-lsopropyI- 3,4~dihydr©-2H-benz©[b| [L4}oxazm-6-yi)pyrimid n-2-yl)am no)pyridin-3-yl)piper dine~l- carboxylate: To a solution of 6-(2-chloro-5-fluoropyrirnidin-4-yl)-8-f3uoro-4-isopropyl-3 4- dihydro-ZH-benzo[b] [ 1 ,4]oxazine (150 mg, 0 45 mmol, 1 equiv) m dioxane (10 ml,), was added tert-butyl 4-(6-ami no-2-fl uoropyri din-3 -yl)piperidme- 1 -carboxylate (147 mg, 0.5 mmol, 1 1 equiv) and cesium carbonate (224 mg, 0.69 mmol, 1 5 equiv). The reaction mixture was degassed with nitrogen gas for 10 mm., followed by the addition of palladium acetate (10 mg, 0.046 mmol, 0.1 equiv) and BINAP (57 mg, 0.092 mmol, 0 2 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water ( 10 mL) and extracted with ethyl acetate (1 5 mL). Organic layer was washed with water (10 mL) and brine solution (10 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash by using 100-200 mesh silica gel column to obtain text- butyl 4-(2-fluoro-6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4- dihydro-2H-benzo[b] 1 ,4]oxazin-6-yi)pyrimiclin-2-yl)amino)pyridin~3-yl)piperidine -l- carboxyiate (120 mg, 44 %) as a yellow solid compound. LCMS: 585 [MLH] ^’

[065:3] Step-4: Synthesis of 5-flluoro-4-(8-fluoro-4-isopiOpyl-3,4-dihydro-2H- ben¾o[b]! l,4[oxa¾i«-6-yi)-N-{6-fluoro-5-{piperidm-4-yl)pyridm-2-yl) pyrimidm-2-amme hydrochloride: A solution tert-butyl 4-(2-fluoro-6-((5-f!uoro-4-(8-fluoro-4-isopropyl-3,4- dihydro-2H-benzo[bl[l,4]oxazin~6-yl)pyrimidm~2~yl)amino)pyri din-3-yl)piperidine~l ~ carboxyiate ( 120 mg, 0 2 mmol, 1 equiv) in 1.25 M HO in ethanol (4 mL) was allowed to stir for Ih at 50°C. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain 5-fluoro~4-(8-fluoro-4- isopropyj-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-N-(6-t1uo ro-5-(piperidin-4-yl)pyridin-2- yl)pyrimidin-2-amine hydrochloride (90 mg, 84%) as a yellow solid compound. LCMS: 485 [M+H] ^÷

[0654] Step-5: Synthesis of S-fluoro-d-CS-fluoro-d-isopropyl-S^-dihydro- H- benzo[b]ii _» 4]oxazin-6-yi)-N-(6-fluoro-5-(i-itnethyIpiperidin-4-yI )pyridin-2-yI)pyriraidin-2- amine : To a stirred solution of 5-fluoro-4-(8-f1uoro-4-isopropyl-3,4-dihydro-2H- benzo[bl[i,4]oxazm~6~yl) N-(6-fluoro-5-(piperidin-4-yl)pyndni 2 yj)pyrimidin-2-amnie (105 mg, 0.22 mmol, 1 equiv) in DCE (5 ml,), was added Formaldehyde (30% in water) (97 mg, 1 08 mmol, 5 equiv), acetic acid (65 mg, 1.08 mmol, 5 equiv) The reaction mixture was allowed to stir ai RT for lb The reaction mixture was cooled to 0°C NaCNB!L (27 mg, 0 44 mmol. 2 equiv) was added to above mixture and raised the temperature ro RT The reaction mixture was allowed to stir ai RT for 4h Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (20 L,) and extracted with ethyl acetate (20 mL ^x 2) Organic layer was washed with water (20 ml,) and brine solution (20 ml ,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford 5-fluoro-4-(8- fluoro-4-xsopropyl-3,4-dihydro-2H-benzo[b]| l,4]oxa2in-6-yl)-N-(6-fluoro-5-(l -methyipiperidm·- 4-yl)pyridm-2-yl)pyrmiidin~2~amme (21 mg, 20 %} as a solid compound. LCMS: 499 [M÷H] ^MR: (400 MHz, MethanoLfol) d 8 45 (d, ./ 3.9 Hz, Hi), 8.22 (dd, 4 8.2, 1.6 Hz, i H),

7.74 (dd, ./ 10.0, 8.2 Hz, I H), 7 50 (s, I H), 7 25 (d, ./ 1 1.9 Hz, HI), 4.33 (t, ./ 4.3 Hz, 2H),

4.22 (p, ./= 6.7 Hz,IH), 3.53 (d, J = 12.4 Hz, 2H), 3 35 (t, J = 4 4 Hz, 2H), 3.12 - 2.99 (m, 3H), 2.85 (s, 3H), 2.15 - 1.97 (m,4H), 1.26 (d, ./ 6.5 Hz, 6Hj.

Example- 144: Synthesis of N-(6~cycbpropyi-5-(l -methyl piperidw~ ~yl) pytidin-2~yl)~5~fiuoro~4~ (8~fluoro-4~isoprop}4-3, 4-dihydro-2H-bemofb jfJ4joxazi?i~0~y!)pyrimidi?i~2~amme (Compound

847) and Example- 145: Synthesis of 5~fluoro~4~(8~fluoro-4~isopropyl~3, 4-dihydro-2H~ henso[b [l,4]oxazin~6~yl)-N-(5-(l~methylpiperidm-4-yl)~6~propy ^! lpyridm-2-yl}pyrimidm-2- amine (Compound 848)

[0655] Step 1 : Synthesis of 6-cyciopropyipyridin-2-amme: To a solution of 6- bromopyridm-2-amine (2000 mg, 1 1 .6 mmol, 1 equiv) Toluene (20 L), was added cyclopropylboronic acid (1996 mg, 23.2 mmol 1 equiv) and a solution of potassium phosphate (4930 mg, 23 2 mmol, 3 equiv) m water (10 mL) T ^' he reaction mixture was degassed with nitrogen gas for 15 min followed by the addition of Pd (OAc) ? 1262 mg, 1 .16 mmol, 0 1 equiv) and tricyclohexylphosphine (488 mg, 1 .74 mmol, 0 1 5 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight in a sealed tube. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with -w ter (100 mL) and extracted with ethyl acetate (150 mL 2) Organic layer was washed with water (100 mL) and brine solution (100 mL) Organic layer was dned over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain 6-cyclopropyipyridin~2~amine (1000 mg, 64%) as a yellow oil compound. LCMS: 135 [M÷H] "

[0656] Step-2: Synthesis of S-hro o-6-cyclopropylpyridin-2-a ine: To a stirred solution of 6-cyclopropylpyridin-2-amine (900 mg, 6.7 mnio!, 1 equiv) m DMF (10 mL), was added NBS (1196 mg, 6.7 mmol, 1 equiv) The resultant reaction mixture was allowed to stir at RT for lb. Progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, diluted with water (50 mL), and extracted with ethyl acetate (150 mL). Organic layer was washed with water (50 ml,) and brme solution (50 L). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain 5-bromo-6-cydopropylpyndin-2-amme (900 mg, 63%) as an off white solid compound. LCMS: 213 [M+H] ^:

[0657] Step-3: Synthesis of tert-butyi 6-am«BO-2-c.yciopropyl-3 ^, ,6*-dihydro-[3,4’- feipyridme|-L(2 ^! ll) Carboxyiate: To a solution of 5-bronio-6-eyclopropylpyridin-2-amme (800 mg, 3.77 mmol, 1 equiv) in dioxane (8 mL), was added tert- butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-ddiydropyndine-l(2H)-carboxylate (1399 mg, 4 5 mmol, 1.2 equiv) and a solution of sodium carbonate (1 188 mg, 1 1 3 mmol, 3 equiv) I water (2 mL). The reaction mixture was degassed with nitrogen gas for 15 min., followed by the addition of Pd (PPlifoCL (132 mg. 0 18 mmol, 0.05 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, reaction mixture was diluted with water (30 ml,) and extracted with ethyl acetate (100 mL ^x 2) Organic layer was washed with water (100 ml,) and brine solution (100 mL) Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain tert-butyi 6- amino-2-cy clopropyl-3’.6'-dihydro-[3,4 ^, -bipyridine]-r(2'H)-carboxylate (800 mg, 67%) as an off white color solid compound. LCMS: 316 [M+H] [0658] Step-4: Synthesis of tert-butyl 4-(6-ammo-2-cyciopropylpyridm-3-yl)pipend«ie- l-carboxylate and synthesis of tert-butyl 4-(6-ammo-2-propyIpyri in-3-yI)piperidine-l- carboxyiate: To a stirred solution of tert-butyl 6-aniino-2-cyclopropyi-3',6'-dihydro-[3.4 ^! - bipyndmeH’foTfpcarboxylate (300 mg. 0.95 mmol, 1 equiv) in ethanol (10 ml,), was added Fd/C (20% w/w) (60 mg) under I L atm. The resultant reaction mixture was allowed to stir at RT for 4 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the mixture was passes through cehte bed and the filtrate was concentrated under reduced pressure to obtain a mixture of tert-butyl 4-(6-ammo--2--cycIopropyipyndin-3-y!) piperidine-i -earboxylate and tert-butyl 4-(6-amino-2-propylpyridin-3-yl)piperidine-l-earboxylate (250 mg, 83%) as an off white solid compound. LCMS: 318 [M+H] ^: , 320 [M+H]

[0659] Step-5:: Synthesis of tert-butyl 4-(2-cyciopiOpyl-6-((5-fluoro-4-(8-fluoro-4- isopropyi-3,4-dihytlro-2H-benzo[b] (l,4]oxazin-6-yi)pyri idin-2-yi)a ino)pyridin~3~ yl)piperidine-l-carboxylate and synthesis of tert-butyl 4-(6-( (S-fluoro^-lS-fluoiO^- isopropyl-S^dihyilro^H-benzojbj l joxazin-e-ylJpyrimidiii^y amiiio)^

propylpyridin-3-yi)piperidine-l-carboxylate: To the solution of mixture of tert-butyl 4~(6~ ammo-2-cyclopropylpyridin-3-yl) piperidine- 1-carboxy late and tert-butyl 4-(6-amino~2~ propy!pyndin-3-yl)piperidine~l -earboxylate (1 50 mg, 0 46 mmol, 1 equiv) in dioxane (10 ml,), was added a mixture of tert-butyl 4~(6~amino-2-cydopropylpyridin-3~yi)piperidme-l- carboxy!ate and tert-butyl 4-( 6-amino- 2-propylpyridin-3-yl)piperidine-l-carboxylate (160 mg, 0.50 mmol, 1 .1 equiv) and cesium carbonate (225 mg, 0 69 mmol, 1.5 equiv) The reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 g, 0.009 mmol, 0.02 equiv) and BINAP (12 mg 0 018 mmol, 0.04 equiv). The resultant reaction mixture was allowed to stir at 100 °C for overnight. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mi,) and extracted with ethyl acetate (100 ml,). Organic layer was washed with water (50 ml,) and brine solution (50 ml,). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase combi flash to obtain a mixture of tert-butyl 4-(2-cyc]opropyi-6-{{5--fiuoro-4--{8--iiuoro-4--isopropy]--3 ,4- dihydro-2H-benzo[b]il4]oxazin-6-yi)pyrimidm-2w!)ammo)pyridin -3-yi)piperidine-l - earboxylate and tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H- benzo[bj [ l,4]oxazin-6-yl)pyrirnidm--2--yi)ammo)-2--propylpyridin--3-- yi)piperi dine- b-carboxy late (200 mg, 71 %) as a brown viscous compound. LCMS: 607 [M4Ή] , 609 [M+H]

[0660] Step-6; Synthesis of N-(6-cyciopropyi-5-(piperidin-4-yT}pyridin-2-yi)-5-flnoro-4- (8-flaoro-4-isopropyi-3,4-dihydro-2H-ben*o!b][l,4]oxa2m-6-yi )pyrimidm-2-amme hydrochloride and synthesis of 5-ffaoro-4-(8-ffuoro-4-isopropyi-3,4-dihydro-2H- benzo(b]jl,4]oxazin-6-yI)-N-(5-(piperidin-4-yl}-6-propylpyri din-2-yI)pyrhnidin-2-ainine hydrochloride: A solution of a mixture of tert-buiyl 4--(2--cyclopropyl--6--((5-fluoro--4-(8-fluoro--

4-isopropyl-3,4~dihydro~2H-benzo[b][L4]oxazm-6~yl)pyrimid m-2-yl}amino)pyridin-3- yi)pipendme~ l-Carboxyiate and tert-butyi 4~(6~((5-fluoro~4-(8-fIuoro~4-isopropyl-3,4-dihydrG-

2H-benzo[b][l ,4]oxazm-6-yl)pyrimidin ^~ 2 ^~ yl)ammo) ^~ 2 ^~ propylpyridin-3-yl)piperidine ^~ l ^~ carboxylate (200 mg, 0.33 mmol, 1 equiv) in 1 25 M HCi in ethanol (5 mL) was allowed to stir for I h at 50 °C Progress of the reaction -w s monitored by LCMS. After completion of the reaction, solvent was removed under reduced pressure to obtain a mixture of N-(0-cyclopropyl-

5-(piperidiii-4-y])pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-i sopropyl-3,4-dihydro-2H- benzo[b] [l ,4]oxazin-6-yl)pyrimidin-2-amine hydrochloride and 5-fluoro-4-(8~fluoro-4- isopropyl-3 ,4-dihydro-2H-benzo[b][l 4]oxazin-6-yl)-N-(5-(piperidin-4-yl)-6-propylpyndiii-2- yl)pyrimidin-2-amine hydrochloride (140 g, 84%) as a yellow solid compound LCMS: 507 [M+H] \ 509 [M+H] ⁺

[0661] Step-?;; Synthesis of N-(6-cyciopropyi~S-(i-methyipiperidin~4-yl)pyridin-2~yi)~S~ fInoro-4-{8-fIu©ro-4-is0pr©pyI-3,4-dihydro~2H-benzo}¥| [:M]oxazin-6~yI)pymmdin-2-aitmne and synthesis of 5-fluoro-4-(8-fluoro-4-isopropyI-3,4-dihydro-2H-benzo[b][i,4 ]oxazin-6-yI)- N-(5-(i-itnethyIpiperidin-4-yI}-6-propy!pyridin-2-y!)pyriitn idin-2-aminei To the sto red solution of mixture of N-(6-cyclopropyl-5-(piperidm-4-yI)pyridin~2~yl)~5~fluoro-4~( 8~f!uoro-4~ isopropyl-3, 4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)pyrimidm-2-atnme and 5-fluoro-4-(8-fluoro- 4~isopropy!~3,4 dihydro--2H~benzo[b][! ,4]oxazm--6--yi}~N-(5-~(piperidim4-yi)--6--propyipyridin~-2~ y!)pyrimidin-2-amine (hydrodhlonde salt) (1 00 mg, 0.197 mmol, 1 equiv) m DCE (3 ml), was added Formaldehyde (40% in water) (0.02 mL 0.59 mmol 3 equiv). acetic acid (0 06 ml.. _, 1 0 mmol, 5 equiv) The reaction mixture was allowed to stir at RT for 1 h The reaction mixture was cooled to 0°C. NaCNBIfo (37 mg, 0.59 m ol, 3 equiv) was added to above mixture and raise the temperature to RT. The reaction mixture was allowed to stir at RT for lb Progress of the reaction was monitored by I .( ^' MS After completion of the reaction the reaction mixture was diluted with water (25 mi n and extracted with ethyl acetate (50 L 2) Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to afford Peak! as N-(6-cyciopiOpyi-5-(l-methyipiperidm-4-yl)pyridin-2- yl)~5~iIuoro~4~(8-f!uoro~4~isopropyl~3.4-dihydro-2H~benzo[b] [l ,4]oxazin-6-yi)pynmidin-2- amine (15 mg, 14.5 %) as a yellow colored solid compound and Peak2 as 5-fluoro-4-(8-fluoro-4- isopropyi- 3,4-dihydro-2H-benzo[bin ,4]oxazin-0-yl}-N~(5~(i~methylpiperidm~4~yl)-6- propylpyridm-2-yl)pyrmiidin~2~amine (15 mg. 14.5 %) as a yellow colored solid compound. PEAK-1: LCMS: 521 [MHlf:‘HNMR: (DMSO-d6 ,400MHz): d 9.56 (br s., 1 H), 8 61 (d, j-4zi Hz, 1 H), 7.94 (d, 1-8.3 Hz, 1 H), 7.30 - 7.54 (m, 2 H), 7.22 (d, 1=4 4 Hz„ 1 H), 4.31 (br s. , 2 H), 4 06 - 4.18 (m, 1 H), 3.53 (d, J— 12.3 Hz, 2 H), 3.30 (br. s, 2 H), 3.15 (d, J— 12.3 Hz, 2 H), 2.81 (s, 3 1 11. 2.25 (br. s, 2 H), 1.99 - 2.15 (m, 2 H), 1 .84-1.89 (m, 2 H), 1 1 1 - 1.30 (m, 6 H), 1 .04 (br. s., 2 1 1 } 0.90 ppm (br. s. , 2 H).

PEAK-2: LCMS: 523 j M 1 1 : 7 'HNMR: (DMSO-d _{6 ,} 400MHz): 6 9 73 (s, 1 H), 8.60 (d, .7=3.9 Hz, 1 H), 8.02 (d, .7—9 2 Hz, 1 H), 7.41 - 7.61 (m, 2 H), 7.20 (d, .7-11.4 Hz, 1 1 11. 4 30 (br. s., 2 H), 4.03 - 4.27 (m, 1 H), 3.30 (br s. , 2 H), 3.13 (m, 3 1 11. 2 55 - 2 73 ( , 5 H), 1.74 (br. s., 4 H), 1.45 - 1 69 (m, 4 1 1 } 1.08 - 1 .29 (m, 6 H), 0.97 ppm (t, .7=7.2 Hz, 3 H)

[0662] Compounds 40-46, 48-51 , 53-177, 179-205, 207-435, 525-787 and 791-840 may be synthesized by the general synthetic schemes 1 -7 or according to the experimental details as exemplified in Examples 1-145 using the appropriate starting materials and reagents.

Biological Examples

Example BE In Vitro Kinase inhibition /tifo Determination

[0663] ICso values of compounds against CDK4 and CDK6 were determined by

luminescence using retinoblastoma as substrate. Kinase assays were performed in kinase buffer (#PV6135, Invitrogen, Life Technologies Grand Island, NY) where total reaction volume was 30 gL/well in 96-well half area white plates (#3693, Costar}. One microliter of 25 -"test compounds at specific concentrations (e.g., final concentration range: 0 1 nM - 200 nM) were mixed with 1 0 mI . of 2.5 xkinase (5 nM, CDK4 #PR8064A arid CDK6 #PR8422B, Invitrogen) solution and 14 i.il of 4x mixed solution with retinoblastoma (1 mM, #12-439, EMD Mills pore, Haywood, CM) and ATP (25 mM, #¥7038, Promega, Madison, WT). The plates were covered and incubated for 2 h at room temperature At the end of incubation. 25 mΐ, of stop solution - ADP Glo reagent (#V7002, Promega) was added. After incubation for 45 min at room temperature, 50 m! . of detection reagent (##V7002, Promega) was added. Readings were taken at 15 min and 45 min incubation alter detection reagent was added in a Synergy Neo Plate reader (BioTek, Winooski) at Single excitation of 340 nm and Dual emission at 495 nm and 520 nm respectively. 1he following equations were used in the CDK4 and CDK6 assay data analysis. Percent inhibition (100 -% activity) was fitted to the“four-parameter logistic model” in XLfit for determination of IC50 values.

Equation 1 : Percent conversion of enzyme ^:::: 100- {(RLU _{No Drog-No enzyme} * 100)/ RLE _NO riiTig-Esszyisse ;

Equation 2: Percent conversion at each data point 100- {(RLU _Averag d _DrugWHzyn!s AiOO)/

RLU No dui jynzy me }

Equation 3: Percent Inhibition^ QQ*(%Conversion _{each da} w _roίki /% Conversion _Ei ^ _aie )

[0664] ICso values of compounds against CDK1 (cyclrn B) were determined by Z’-LYTE™ These screening assays were performed at Invitrogen Life Technologies (Grand Island, NY)on a low volume NBS, black 384-well plate (#4514, Corning). 0.1 mΐ, of 1 00 x test compound in 100% DMSO (at specific solutions) were mixed with 2.4 pL of Kinase Buffer (50 mM I ILPLS pH 7.5, 0 01 % BR!J-35, 10 mM MgCfo 1 mM EGTA), 5 u! . of 2x Kinase (3.5 - 46.4 ng CDKl /cyclin ByPeptide (2 mM Ser/Thr 18), and 2.5 mΐ, of 4 ^x ATP solution (34 mM). The plates were shaken for 30 seconds, and incubated for 60 minutes at room temperature. Development Reagent Solution (5 m.E of 1 : 1024 dilution) was added to the plates followed with another 30- second plate shake, and the plates were further incubated at roo temperature for one hour. The plates were read on fluorescence plate reader with Dual emission at 445 nm and 520 nm

[0665] ICso values of compounds against CDK2 (cycl A) were determined by Z'-LYTE™ These screening assays were performed at Invitrogen Life Technologies (Grand Island, NY) on a low volume NBS, black 384-well plate (#4514, Corning). 0.1 m.I . of 100 x test compound m 100% DMSO (at specific solutions) were mixed with 2.4 pi . of Kinase Buffer (50 mM HEPES pH 7 5, 0.01% BRIJ-35, 10 mM MgCfe 1 mM EGTA), 5 id . of 2' Kinase ( 1.22 · 10 3 ng CDK2/eyclm A)/Peptide (2 mM Ser/Thr 12), and 2.5 pL of 4 x ATP solution (31 mM). The plates were shaken for 30 seconds, and incubated for 60 minutes at room temperature. Development Reagent Solution (5 mΐ, of 1 : 1024 dilution) was added to the plates followed with another 30- second plate shake and fee plates were further incubated at room temperature for one hour. The plates were read on fluorescence plate reader with Dual emission at 445 ran and 520 nm.

[0666] I€50 values of compounds against CDK5 (p25) were determined by Z'-LYTE™ These screening assays were performed at Invitrogen life Technologies (Grand Island, NY) on a low volume NBS, black 384-well plate (#4514, Corning). 0.1 pi, of 100 x test compound in 100% DMSO (ai specific solutions) were mixed with 2.4 pL of Kinase Buffer (50 mM HEPES pH 7 5, 0.01% BRIJ-35, 10 mM MgCk, 1 mM EGTA), 5 pi, of 2 Kinase (0.1 8 ·· 2 ng

CDK5/p25)/Peptide (2 pM Ser/Thr 12), and 2.5 mΐ, of 4*ATP solution (1 7 pM). The plates were shaken for 30 seconds, and incubated for 60 minutes at room temperature. Development Reagent Solution (5 pL of 1 :4096 dilution) was added to the plates followed with another 30-second plate shake and the plates were further incubated at room temperature for one hour. The plates were read on fluorescence plate reader with Dual emission at 445 nrn and 520 mm

[0667] The following equations were used for Z'-LYTE™ Screening Assay Data Analysis. Percent inhibition ( 100 -% activity) was fitted to the“four- parameter logistic model in XLfit for determination of IC5 values.

[0668] Kfio values of compounds against CDK7 (cyclin H) were determined by Adapta™ Assay at Invitrogen Life Technologies (Grand Island, NY) whew iota! reaction volume was 1 0 uL/well in low volume, white 384-well plate (#4512, Corning). 0. IGG mE of IGG >< test compound in 100% DMSO (at specific solutions) were mixed with 2.4 mE of HEPES (3G mM), 2.5 mE of 4 ^:< ATP solution ( 153 mM) and 5 pL of 2 - Substrate/Kinase mixture (the 2*

CDK7/cyclin H/MNAT1 / CDK7/9tide mixture was prepared in 50 mM HEPES pH 7 5, 0.GI% BRIJ-35 10 mM MgCL, 1 mM EGTA). The final IG mΐ, Kinase Reaction consisted of 5 - 38.75 ng CDK7/cyclin I-EMNA ^' P and 200 mM CDK7/9tide m 32.5 mM HEPES pH 7 5 0.005% BRIi- 35, 5 mM MgCfi 0.5 mM EGTA. The plates were shaken for 30 seconds, centrifuged for I min at 1000xg, and incubated for 6G minutes at room temperature. 5 gL of Detection Mix (prepared in TR-FEET Dilution Buffer; the Detection mix consists of EDTA (30 mM), Eu-anti-ADP antibody (6 «M) and ADP tracer, and contains the KG..·· concentration of tracer for 5-150 mM All ⁵ ) was added to the plates roll owed with another 30-second plate shake and centrifugation for 1 min at lOOifog, and the plates were further incubated at room temperature for one hour. The plates were read on fluorescence plate reader with Dual emission at 615 nrn and 665 nm.

[0669] The following equations were used for Adapta™ Assay Data Analysis The

ATP/ ADP standard curve was fit to model number 205 (sigmoidal dose-response model) in XLfit. The dose response curve was also curve fit to model number 205

^* SC = Standard Curve

[0670] ICso values of compounds against CDK2 (cyc!m El) were determined by

LanthaSereen™ Eu Kinase Binding Assay at Invitrogen Life Technologies (Grand Island, NY) ) where total reaction volume was 16 mE/well m low volume, white 384-well plate (#784207, Greiner). 0.16 mΐ, of 100 x test compound in 100% DMSO (at specific solutions) were mixed with 3.84 m! . of Kmase Buffer (50 inM HEPES pH 7.5, 0.01 % BRU-35, 10 mM MgCfo 1 mM EGTA), 8 0 n! . of 2 ^x Kinase (2.5 nM)/ Antibody (Eu-anti-GST, 2 nM) Mixture and 4.0 mE of 4 x Tracer (Tracer 236, 100 iiM). The plates were shaken for 30 seconds, and incubated for 60 minutes at room temperature. The plates were read on fluorescence plate reader with Dual emission at 615 nm and 665 nm. [0671] IC _¾ values of compounds against CDK9 (cycl K) were determined by LanthaScreen ^{1 4} Eu Kinase Binding Assay at bmtrogen Life Technologies (Grand Island, NY) where total reaction volume was 16 mΐ,/well m low volume, white 84-well plate (#784207, Greiner). 0.16 mE of 100 x test compound in 100% DMSO (at specific solutions) were mixed with 3.84 nl of Kinase Buffer (50 mM HEPES pH 7.5, 0 01% BR1J-35, 10 mM MgCL, 1 mM EGTA), 8.0 pi . of 2* Kinase (5 nM)/ Anti body (Eu-anti-TIis, 2 nM) Mixture and 4.0 mE of 4 ^x Tracer (Tracer 236, 100 nM). The plates were shaken for 30 seconds, and incubated for 60 minutes at room temperature. The plates were read on fluorescence plate reader with Dual emission at 61 5 nm and 665 nm„

[0672] 1(7.:: values of compounds against FMS kinase were determined by LanthaScreen™

Eu Kinase Binding Assay at Invitrogen (Life Technologies Grand Island, NY) where total reaction volume was 10 a ! . in low-volume 384-well plates (#451 1 , Corning). Serially diluted compounds (3-fold) were incubated with kinase (1.25 nM) for 10 min, following which a mixture of ATP (10 mM) (#A1852, Sigma, St-Louis, MO) and f!uorescent-PoiyGT substrate (200 nM) (#PV3610, Invitrogen, life Technologies Grand Island, NY) was added and incubated in dark at room temperature for 1 h. After 1 h, 10 pi . stop solution containing Terbium labeled antibody (4 oM) (#PV3529, Invitrogen, Life Technologies Grand Island, NY) and EDTA (#E5134, Sigma, St-Louis, MO) (20mM) in TR-FRET dilution buffer (# PV3574, Invitrogen, Life Technologies Grand Island. NY) was added Readings were taken in a Synergy Neo Plate reader (BioTek, Winooski) at single excitation of 340 nm and Dual emission at 495 nm and 520 nm respectively.

[0673] The following equations were used for LanthaScreen Eu Kinase Binding Assay Data Analysis. Percent inhibition (100 --% activity) was fitted to the‘ ^‘ four-parameter logistic model” in XLfit for determination of IC50 values.

[0674] I€50 values of compounds against the RBKd kmase were performed by Reaction Biology Corporation Briefly, this assay was conducted m buffer (Tns-HCl 40 m\ i (pH7.5), Ortho vanadate 3 IISM _> MgCti 20 rnM. DTT 2 mM, CHAPS 0.05% DMSO 1%). RBKd kinase was added to the reacti n solution and mixed gently The lest compounds in 100% DMSO (at specific solutions) were mixed with me kinase reaction mixture to achieve the final compounds at pro-defined concentrations (e.g., range - 0 5 nM to 100 mM) by Acoustic technology

(Echo550; nanoliter range) After incubating for 1 0 min at room temp ATP was added into the reaction mixture to initiate the reaction followed by a 30-nun incubation at 30°C. After quenching the reaction with ADP-Glo reagent the plates were incubated for 40 min The Detection Mixture was added, and the plate was incubated for an additional 30 min At the end of incubation, luminescence was measured. For data analysis, the luminescence w¾s converted into mM ADP production based on ADP standard curves. The nonlinear regression to obtain the standard curve and IC50 values were performed using Graphpad Prism software (La Jolla CA).

[0675] I€50 values of compounds disclosed herein against the kinases listed above are given in Table 2 below.

Table 2

ND: Not Determined

Example B2. Determination of potency of compounds in cancer cell proliferation assay as a single agen t.

[0676] The effects of test compounds were studied in seven cel! Ones with various histotypes The cancer cells (Table 3) were harvested during the !ogaritiunic growth period and counted. Adjust cell concentrations to the appropriated number with respective medium and add 90 mΐ . ceil suspensions to 96-well plates. After cells were seeded, the plates were shaken gently to distribute cells evenly and incubated at 37 °C, 5% ( O on day 1.

Table 3: Cell Culture Conditions

[0677] Cells were treated with test compounds at 7 to 9 concentrations within a desired concentration range (e.g. 1.1 nM - 10 mM) on day 2 by series diluting the test compound stock solution (10 mM in DMSO) with culture medium. Treatment duration was in the range of 24-168 hr, depending on the ceil type Cell viability was assessed by Cell Titer-G!o® as recommended by Promega (Cat. No. : G7572), or by Brdu ELISA assay or resazurin assay, as recommended by Sigma Aldrich (Cat. No.: 11647229001 and R7017, respectively) post treatment.

[0678] Cell viability data were plotted using GrapiiPad Prism (version 5, GraphPad

Software, Inc., San Diego, CA) In addition, a nonlinear regression model with a sigmoidal dose response and variable slope within GraphPad Prism was used to calculate the KAo value of individual test compounds. KAo values are given in Table 4. Additional compounds, treated for 24-168 hours, are shown m Table 5.

ND: Not Determined

Table 5

ND: Not Determined

[0679] Effects of compound 24 on cell proliferation in additional cell lines (Table 6} were studied. Cells were harvested during the logarithmic growth period and counted. The cell concentrations were adjusted to the appropriate concentrations with their respective media, and 90m! ceil suspensions were added to 96-well plate When cells were added, the plate was shaken gently to distribute cells evenly. The cells were incubated at 37 ^C C. 5% ( 02. The next day, cells were treated with the test compound. 3X serial dilutions of compound stock solutions were prepared wife respective solvents. The stock solution was diluted with culture medium to make 10 x working solutions. 1 Om1 ( iOX) drug solution was dispensed in each well (triplicates for each concentration). The plate was incubated for 72hrs in a humidified incubator at 37°C with 5% C02. For plate leading, CTG solution was thawed and equilibrated to room temperature. 50ul of CTG was added per well the contents were mixed for 2mm on the plate shaker, and a 1 Omin incubation was done before recording the luminescence signal using an Envision plate reader (PerkinElmer).

Table 6. Inhibition of cancer ceil proliferation by compound 24.

[0680] Additional test compounds will be studied in the same andfor other cancer cell tines using similar proliferation methods with possible variables, such as ceil seeding densities anchor incubation durations. The cell cycle phase distribution post treatment of test compounds will be studied using flow cytometer using DAPI staining Cellular senescence will be evaluated after continuously treating cells for a long time (e.g., 14 days) followed by staining cells lines for Senescence associated- -galactosidase (SApGAL)

Example B3 Determination qfpRb levels

[0681 j Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pEb, which is a clinically relevant biomarker associated with CDK4 or CDK6 inhibition. As a confirmatory measure of functional activity of CDK4/6, the Ser780 phosphorylation state of RBI was assessed. MCF-7 ceils were plated at 2 5 ^c ΐq ^' to 3.0 * 10° cells/well in ό-well cell-culture plates and incubated at 37 "C for 24 h in MEM medium supplemented with 10% FBS. Cells were treated for 24 b with a medium containing test compound at various concentrations (e.g , 0.01. 0.1, 1 mM) or with DMSO (<i%) m duplicate. Alter incubation period the media was removed, and cells were rinsed once with ice-cold PBS and lysed with 0.2 mi . of Cell Lysis Buffer containing 1 mM PMSF and Protease Inhibitor Protein concentration was estimated following Bradford method. The lysis and the pRB measurements were performed following the manufacturer's ELISA kit protocols and buffers (Cell Signaling Technology, Cat. No.: 13016C). oRb inhibition of test compounds were calculated as percentage of vehicle control. Values are given in Table 7

Table 7

[0682] The effects of selected test compounds in additional cancer cell lines on clinically relevant biomarkers associated with CDK4 or CDK6 inhibition (e.g., pRB and thymidine kinase (TK)) is assessed using h i . ISA or Western Blotting methods with selective antibodie

Example Iff Determination of potency and combination ffects of compounds in cancer ceil proliferation assays using combination therapy

[0683] Effects of test compounds on cell proliferation is studied in additional cancer cell lines, such as estrogen reeeptor over-expressing cancer cells, in the combination of another anti cancer therapy (e.g , an aromatase inhibitor and/or a selective estrogen receptor degrade for breast cancer) using CTG, resazurin and/or Brdu assays. Cells seeded in a 96-well plate are treated with single agents to obtain a dose response curve for each agent Cells are also treated with combinations of the drugs, based on a matrix generated by combining the two drugs at all different combinations of the doses used in the dose response curves. In place of a combination matrix method, a fixed drug ratio dilution method in which drugs are combined in a fixed ratio of 5 or more dilutions may also be used. The combined treatment effect such as additive, synergistic, or antagonistic, is determined using the median-effect principle (Chou TC. Cancer Res 2010;70:440-6 ), with the combination index (Cl) value indicating an additive effect (Cl I h synergism (Cl < 1 ), or antagonism (Cl > 1 ) m drug combinations.

Example B5 In vivo Pharmacology Studies in xenograft or syngeneic models

[0684] The anti-tumor activity of test compounds is studied against various human tumor xenograft or syngeneic models in mice for example, in breast cancer tu or models. For breast cancer tumor models, effects of test compounds on Rb-Positive or Rb-Negative tumors as a single agent or in combination with another anti-cancer therapy is determined by evaluating the difference of tumor volume between treatment group against the vehicle control group. The phosphorylation status of serine-780 on Rb is evaluated in tumor tissue and compared with antitumor response in Rb-Positive xenograft model(s). Additional pharmacodynamic end points (e.g., FoxMl, E2FL c-Myc, and cyclin Dl) are studied in tumor tissues collected at various time points post treatment. Induction of senescence is evaluated in tumor samples from various treatment groups by measuring SApGAL,

Example B6 In vivo Pharmacology Study in MC-38 mouse model

[0685] The therapeutic efficacy of compound 24 in the treatment of the MC- 38 murine colorectal cancer model was evaluated m combination with an anti mPD-1 antibody. Cultured MC-38 cells were harvested and re-suspended in base medium at a density of 1 xl0 ce!!s/mL v/ith viability greater than 90%. Female C57BL/6 mice were inoculated subcutaneously at the right flank with 1 x 10” cells in 0.1 mL base medium for tumor development The treatments were started on day 5 after tumor inoculation when the tumor size readied 45-72 mnr (average tumor size 56 mm”). The test article was administered to the mice according to the predetermined regimen as shown in the experimental design table (Table 8) Formulations were prepared as in Table 9 below

Table 8, Groups and Treatments for Efficacy Study

Vehicle was 0.5% HPMC Methocel K 100 LV + 0.1% Polysorbate 80 (pH adjusted to 3.8 with citric acid for both compounds)

^' Table 9, Formulation Preparation

Note: Ensured that formulation was homogenous immediately before use by somcation and vigorous vortex.

[0686] Body Weight Change

All treatments groups were well- tolerated. Mean ( SEM) body weight change and relative change (%} m female C57BL/6 mice bearing MC-38 tumors are shown in FIG 1 and FIG. 2. In FIG. 1 , data points represent group mean body weight. Error bars represent standard error of the mean (SEM). In FIG 2, data points represent percent group mean change in body weight. Error bars represent standard error of the mean (SEM).

[0687] I itmor Measurements and Endpoints

Tumor sizes were measured three times a week in two dimensions using a caliper and the volume was expressed in mm using the formula: V ^::: 0.5 a x b where a and b are the long and short diameters of the tumor, respectively. The tumor sizes were then used for the calculations of both tumor gr _f C _'J or·-..wth inhibition (TGI ) and T/C values.

TGI is calculated for each group using the formula listed below:

TGI (%) ! ^: '· ^ V ;,.;;; ;,,,.;;: ; _:; · I V ¾ j iji g>ay0 _, 1 I ^ 3 Y, ., r v Vehicle _. DsyOjj ^X S W

W _Treat a _e m _¾vN is the average tamer volume of a treatment group on a given day, TV _{Tr ;i.iiiiei!; Diiy0} is the average tumor volume of the treatment group on the first day of treatment, TYv _ei wo D^N IS the average tumor volume of the vehicle control group on a given day, and IV _e oo _e o _av o is the average tumor volume of the vehicle group on the first day of treatment

The T/C value (in percent) is an indication of antitumor effectiveness and calculated as below:

T/C (%) ^:::: RTV Treatment/ RT V eoi ttol ^x 1 0 %

(RTS ^' _Treatment : Tv mean RTV of foe treatment group; RTVcy _ntroi; the mean RTV of foe vehicle treated group).

RTV (relative tumor volume) ^::: TVo _avN /TVo _av o.

TV _DayN snct f V _Day o is the tumor volume on day IN and Day 0 respectively. I /O. fob) V 4Z% is considered as significant antitumor activity and < 10% is considered as highly significant anti umor activity by the National Cancer Institute criteria.

Mean ± SEM of tumor volume over tune in female C57BL/6 mice bearing MC-38 tu ors dosed with vehicle, anti-mPD-1 , compound 24 and anti-mPD-i + compound 24 is shown in Table 10. Calculated tumor growth inhibition is shown in Table 1 1.

Table Ί0. Tumor Volume over Time

Tumor volume (rmnfV

Anti- Anti- mPD-1 compound 24

mPD-1 lOmg/kg

Vehicle

compound 24 I Omg/kg

lOmg/kg

lOmg/kg

0 57 ±3 56 ±3 56 ±4 58 · 4

94 ±8 89 ±12 88 ±5 89±I3

213 ±30 1 64 +20 1 27±20 165+20

400 ±56 228 +35 152 ±37 280+47 9 754 +128 343 ±70 164 +86 462+62

1 342 929+1 97

12 659 ±1 77 246 +126

+187

Note: a. Mean + SEM, For Group 1 and 2 n 1 0, lor group 3 and 4 u 5

Table 11. Mea + SEM Tumor Growth Inhibition Calculation Based on TV Measurements at Day 12

Tumor Size

TV T/C

Treatment (samMB TGI (%) ø value ^{11 p}

value" at day 1 at day 12 (%)

Vehicle 1342 +187 23 62 + 3 31

Anti- mPD-i (10

659 +177 1 1.99 + 3.44 50.76 53.06 <0.001 tng/kg)

Anti- mPD-i (10

001 compound 24 10

rng/kg

compound 24 10

929+197 15 59 + 2 41 66.00 32.19 <0.01

mg/kg

Note:

a. Mean + SEM

b All groups compared to group 1

e. Combination group compared to group 2

Tumor growth curves are shown in FIG 3A and FIG 3B Data points represent group mean, error bars represent standard error of the mean (SEM). Indivi dua l tumor growth curves are shown in FIGS 4A-4D Tumor growth inhibition curves are shown in FIG. 5

[0688] Survival Curves

The time-to-end point Kaplan-Meier survival curves were plotted using Graphpad and presented m FIG 6 Endpoint is defined as tumor volume reaching 2000 mnr

[0689] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced in light of the above teaching. Therefore, the description and examples should not be construed as limiting the scope of the invention.