WO2018138739A1

WO2018138739A1 - Novel antiestrogenic heterocyclic compounds

Info

Publication number: WO2018138739A1
Application number: PCT/IN2018/050040
Authority: WO
Inventors: Biswajit Samanta; Nakul Pramodbhai AKOLKAR; Megha Shringesh DESAI; Poojan Kaushikbhai PATEL; Sairam V. V. M. Kalapatapu; Trinadha Rao Chitturi
Original assignee: Sun Pharma Advanced Research Company Limited
Priority date: 2017-01-27
Filing date: 2018-01-25
Publication date: 2018-08-02

Abstract

The present invention provides novel heterocyclic compounds of Formula I wherein A, B, E, ring Z, Y, L, ring X, D, m, n, R₇ and R₈ are as defined in the specification as estrogen receptor antagonists/degraders. The compound of Formula I can be used for the treatment of cancers mediated by estrogen receptors. (Formula I ).

Description

NOVEL ANTIESTROGENIC HETEROCYCLIC COMPOUNDS

RELATED APPLICATION This application claims the benefit of Indian Patent Application no. IN 201721003143 filed on January 27, 2017 which is hereby incorporated by reference.

FIELD OF THE INVENTION The present invention provides novel heterocyclic compounds as anticancer agents, especially as estrogen receptor (ER) antagonists/ degraders and process for their preparation.

BACKGROUND OF THE INVENTION Endogenous estrogen, 17 ?-estradiol (E2) shows a wide variety of biological activities in the reproductive systems, bone metabolism, and the cardiovascular systems, as well as the central nervous system. The link between estrogen and breast cancer growth and development has been well established. A number of strategies to inhibit the action of endogenous estrogen in estrogen receptor (ER) positive breast cancer are in practice. These include, selective ER modulators (SERMs) such as tamoxifen, which act as selective tissue- specific antagonist of ER in the breast; selective ER degraders (SERD) such as fulvestrant, which promote ER turnover; and aromatase inhibitors (AI) such as exemestane (steroidal), anastrozole and letrozole (nonsteroidal) which inhibit estrogen biosynthesis and are primarily used for postmenopausal women with ER- positive breast cancer. Unfortunately, many women with breast cancer initially respond well to tamoxifen or AI therapy but develop resistance over a period of time during treatment. In resistant form of breast cancer there is evidence that pro-growth signaling pathways downstream of estrogen receptor still play a significant role. Recently, there has been increasing clinical evidence that following treatment with AIs, resistance develop due to mutations in the ligand-binding domain of ER-a rendering it constitutively active even in the absence of ligand, leading to resistance. Currently fulvestrant is considered as a first- in-class SERD. Unfortunately, significant pharmaceutical liabilities of fulvestrant (requiring intramuscular injection of large volume) limit its widespread use. Therefore, development of an orally bio-available ER-antagonist especially with ER degrading properties would be beneficial to patients who have developed resistance to currently available therapies targeting ER activity. Many non-steroidal ER antagonists are reported in prior art. Journal of Medicinal Chemistry 2003 (46), 2945-2957 discloses ERa-selective tetrahydroisoquinoline ligands as estrogen receptor modulators. US patent No. 7015219 discloses 3-aryl-hydroxybenzoxazines and 3,4-dihydro-3-aryl- hydroxybenzoxazines as selective estrogen receptor beta modulators. Bioorganic & Medicinal Chemistry, 2006 (14), 3455-3466 discloses hydroxybenzoyl-3,4- dihydroquinoxalin-2(iH)-ones as ligands for estrogen receptors. Bioorganic & Medicinal Chemistry Letters, 2005 (15), 3912-3916 discloses dihydrobenzoxathin as ligands for selective estrogen receptor alpha modulators. US patent number 7138426 discloses pyrrolidinylethoxyphenyl benzoxanthins as estrogen receptor modulators. WJ O application WO2016174551A1 discloses 2H-chromene derivatives and WO 2016097072A1 discloses tetrahydro-pyrido [3, 4-b] indole compounds as estrogen receptor modulators. WJ O application WO 2016097071A1 discloses various compounds having azetidine or pyrrolidine ring in the side chain useful for the treatment of ER-related diseases or conditions. WO 2012084711 Al discloses N-substituted azetidine derivatives as ER-a antagonists wherein the azetidine ring is attached to selective estrogen receptor modulator fragment.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula I

and stereoisomers or pharmaceutically acceptable salts thereof, wherein

ring Z is a 5 to 10 membered mono- or bi-cyclic aromatic ring containing zero to 2 heteroatoms selected from nitrogen, oxygen and sulfur; m and n are integer independently selected from 1 and 2;

A is selected from a group consisting of -0-, -NH-, -S-, -N(Ci_3alkyl)- and -N(C_3-6 cycloalkyl)-;

E is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting of hydrogen, halogen, -COOH, -NH₂, -NH(C_1-3 alkyl), -N(C_1-3 alkyl)₂, -CN, -Ci-3 haloalkyl, -Ci_₃ alkyl, -OCi_₃ haloalkyl and -OCi_₃ alkyl;

B is selected from a group consisting of -R_ls -C(0)R₂, -C(0)N(R₂)₂ and -C(=NH)NHR₂, wherein Ri is selected from hydrogen and Ci_₂o linear or branched alkyl chain optionally interrupted with one or more radicals selected from -0-, -NR₃-, -S-, -SO-, -S(0)₂-, - CR₃=CR₃-, -C≡C-, -NR₃CO-, -CONR₃-, -NR₃CONR₃-, -NR₃C(0)0-, -OC(0)0- and -C₆H₄-; Ri is optionally further substituted with one or more groups selected from halogen, -C_3-6 cycloalkyl, -OR₄, -N(R₄)_2i -C(0)OCi_6 alkyl and phenyl unsubstituted or substituted with one or more groups selected from halogen, Ci_₆ alkyl and -OCi_₆ alkyl; wherein, R₄, at each occurrence, is independently selected from a group consisting of hydrogen and Ci_₆ linear, branched or cyclic alkyl;

R₂, at each occurrence, is independently selected from hydrogen, -C_1-6 alkyl, -C_1-6 haloalkyl, - C₃_6 cycloalkyl and -C₃_₆ halocycloalkyl;

R₃, at each occurrence, is independently selected from hydrogen, -C_3-6 cycloalkyl and -C_1-6 alkyl;

Y is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting of -R₅, -OR₅, halogen, -CN, -NR5COR5, -NR₅S0₂R₅, -OC(0)R₅, - OC(0)N(R₅)₂, and -OC(0)ORs; wherein R5, at each occurrence, is independently selected from a group consisting of hydrogen, Ci_₆ linear, branched or cyclic alkyl and Ci_₆ linear, branched or cyclic haloalkyl;

L is selected from -0-, -NH-, -N(C_1-6 alkyl)-, -N(C₃_₆ cycloalkyl)-, -N(C_1-6 haloalkyl)- and - N(C₃_6 halocycloalkyl)-; ring X is a 5 to 10 membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; D is mono-, di- or tri- substitution and at each occurrence is independently selected from a group consisting of -R₆, -OR₆, halogen, -CR₆=CR₆-COOH, -CN, -N(R₆)₂, -NR₆S0₂R₆, - NR₆CHO, -NR₆COR₆, -OC(0)R₆, -OC(0)N(R₆)₂, -NR₆CONR₆, -OC(0)OR₆, -Ci_₃ alkyl- N(R₆)₂ , -OP(0)(OH)₂ and 5 or 6 membered aryl or heteroaryl ring; wherein R₆ at each occurrence is independently selected from hydrogen and Ci_₆ linear, branched or cyclic alkyl; OR

D is a group selected from boronic acid and a 5 or 6 membered ring containing the C-O- Boron-O-C linkage wherein the ring is optionally substituted with one or more Ci_₃ alkyl group wherein the point of attachment of D to ring X is the boron atom; and

R₇ and R₈ are independently selected from hydrogen, Ci_₃ alkyl and Ci_₃ haloalkyl.

The compounds of present invention are antagonists/degraders of estrogen receptor and can be used for the treatment of diseases which are related to modulation of ER.

GLOSSARY

Pharmaceutically acceptable salts are particularly suitable for medical applications, due to their greater solubility in water compared with the starting or base compounds. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention may be salts of inorganic acids such as hydrochloric acid, hydrobromic acid, fumaric acid, phosphoric acid, and the like or of organic acids such as, for example, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, citric acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartartic acid, amino acids such as glutamic acid or aspartic acid, and the like. Examples of suitable pharmaceutically acceptable basic salts are ammonium salts, or suitable organic amines, such as tertiary monoamines, e.g. triethylamine or tris(2-hydroxyethyl)amine etc., alkali metal salts such as sodium salts and potassium salts and alkaline earth metal salts such as magnesium salts and calcium salts. The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, cis and trans isomers, enantiomers, conformers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.

The term "aromatic ring" or "aryl ring" refers to an aromatic radical having 6 to 10 carbon atoms, including monocyclic or bicyclic aromatic system. The bicyclic aromatic ring or aryl ring includes an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic ring. Typical aromatic ring or aryl ring includes, but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl and indenyl.

The term "heteroaryl ring" refers to 5 to 10 membered aromatic heterocyclic ring radicals with one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. The heteroaryl ring may be a mono- or bi-cyclic ring system and includes fused ring systems (at least one of which is aromatic). The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The examples of such heteroaryl ring includes, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl. The term "halogen", as used herein includes chloro, fluoro, bromo and iodo.

The term "alkyl" refers to a saturated hydrocarbon chain that includes carbon and hydrogen atoms in the backbone, either linear or branched, having from 1 to 20 carbon atoms, both inclusive unless defined otherwise. The length of the chain may vary and is defined by the expression, for example, Ci_₂o which means an alkyl chain having 1 to 20 carbon atoms. The term alkyl includes linear as well as branched alkyl. The examples of alkyl chain are methyl, ethyl, ^-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (i-butyl). Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be substituted or unsubstituted. The numbers or the range written as subscript in terms like "Ci_6" refers to the number of carbon atoms in the group. Thus the referred group may have 1, 2, 3, 4, 5 or 6 carbon atoms. The term "haloalkyl" refers to alkyl group substituted with one or more halogen radicals. The non-limiting examples of haloalkyl group includes fluoromethyl, difluromethyl, etc.

The term "cycloalkyl" or "cyclic alkyl" denotes a non-aromatic monocyclic ring. The size of the ring is described by the expression, for example C₃_₄ which denotes that the ring may have 3 or 4 carbon atoms. Wherever the ring size is not defined, the cycloalkyl or cyclic alkyl ring may contain 3 to 8 carbon atoms. The examples of cycloalkyl ring include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "halocycloalkyl" refers to a cycloalkyl ring substituted with one or more halogen radicals.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the present invention provides a compound of Formula I

and stereoisomers or pharmaceutically acceptable salts thereof, wherein

ring Z is a 5 to 10 membered mono- or bi-cyclic aromatic ring containing zero to 2 heteroatoms selected from nitrogen, oxygen and sulfur; m and n are integer independently selected from 1 and 2; A is selected from a group consisting of -0-, -NH-, -S-, -N(Ci_3alkyl)- and -N(C₃_6 cycloalkyl)-;

E is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting hydrogen, halogen, -COOH, -NH₂, -NH(Ci_₃ alkyl), -N(C_1-3 alkyl)₂, -CN, - Ci_₃ haloalkyl, -Ci_₃ alkyl, -OCi_₃ haloalkyl and -OCi_₃ alkyl;

B is selected from a group consisting of -R_ls -C(0)R₂, -C(0)N(R₂)₂ and -C(=NH)NHR₂, wherein Ri is selected from hydrogen and Ci_₂o linear or branched alkyl chain optionally interrupted with one or more radicals selected from -0-, -NR₃-, -S-, -SO-,-S(0)₂-, - CR₃=CR₃-, -C≡C-, -NR₃CO-, -CONR₃-, -NR₃CONR₃-, -NR₃C(0)0-, -OC(0)0- and -C₆H₄-; Ri is optionally further substituted with one or more groups selected from halogen, -C₃_6 cycloalkyl, -OR₄, -N(R₄)_2i -C(0)OCi_₆ alkyl and phenyl unsubstituted or substituted with one or more groups selected from halogen, -Ci_₆ alkyl and -OCi_₆ alkyl; wherein, R₄, at each occurrence, is independently selected from a group consisting of hydrogen and Ci_6 linear, branched or cyclic alkyl;

R₂, at each occurrence, is independently selected from hydrogen, -Ci_₆ alkyl, -Ci_₆ haloalkyl, - C₃_6 cycloalkyl and -C₃_₆ halocycloalkyl; R₃, at each occurrence, is independently selected from hydrogen, -C₃_6 cycloalkyl and -Ci_6 alkyl;

Y is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting of -R₅, -OR₅, halogen, -CN, -NR₅COR₅,-OS0₂R₅ -NR₅S0₂R₅, -OC(0)R₅, - OC(0)N(R5)₂, and -OC(0)ORs; wherein R5, at each occurrence, is independently selected from a group consisting of hydrogen, Ci_₆ linear, branched or cyclic alkyl and Ci_₆ linear, branched or cyclic haloalkyl;

L is selected from -0-, -NH-, -N(Ci_₆ alkyl)-, -N(C _₆ cycloalkyl)-, -N(Ci_₆ haloalkyl)- and - N(C₃_6 halocycloalkyl)-; ring X is a 5 to 10 membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; D is mono-, di- or tri- substitution and at each occurrence is independently selected from a group consisting of -R₆, -OR₆, halogen, -CR₆=CR_6, -COOH, -CN, -N(R₆)₂, -NR₆S0₂R₆, - NR₆CHO, -NR₆COR₆, -OC(0)R₆, -OC(0)N(R₆)₂, -NR₆CONR₆,-OC(0)OR₆, -C1-3 alkyl- N(R₆)₂ , -OP(0)(OH)₂ and 5 or 6 membered aryl or heteroaryl ring; wherein R₆ at each occurrence is independently selected from hydrogen or Ci_₆ linear, branched or cyclic alkyl; OR

D is a group selected from boronic acid and a 5 or 6 membered ring containing the C-O- Boron-O-C linkage wherein the ring is optionally substituted with one or more C_1-3 alkyl group wherein the point of attachment of D to ring X is the boron atom; and

R₇ and R₈ are independently selected from hydrogen, -C_1-3 alkyl and -Ci_₃ haloalkyl.

In an embodiment, ring Z is a 5 or 6 membered aromatic ring containing 0 to 2 heteroatoms selected from nitrogen, oxygen and sulfur. The examples of ring Z includes, but not limited to phenyl, thiophenyl, pyridyl, pyrimidinyl etc. In a preferred embodiment, ring Z is phenyl or pyridyl. In another preferred embodiment, ring Z is phenyl.

In another embodiment, the present invention provides a compound of Formula I, wherein A is selected from a group consisting of -0-, -NH-, -N(C_1-3 alkyl)- and -N(C_3-6 cycloalkyl)-. In another embodiment, A is -O- or -NH-. In a preferred embodiment, A is -0-. When Z is a 6 membered aromatic ring, the substitution A on ring Z may be at 2, 3 or 4 position with respect to the point of attachment of ring Z to the rest of molecule. In a preferred embodiment, Z is phenyl ring and A is attached at 3 or 4 position of the ring. In another embodiment, the present invention provides a compound of Formula I, wherein E is mono-, di- or tri-substitution. The phrase "E is mono- or di- or tri-substitution" means that the ring Z can have one, two or three E groups substituted on it selected independently from each other. In an embodiment, E is tri-substitution. In a preferred embodiment, E is di- substitution. In another preferred embodiment, E is mono-substitution. In another embodiment, E at each occurrence is independently selected from a group consisting of hydrogen, halogen, -COOH, -NH₂, -NH(Ci_₃ alkyl), -N(Ci_₃ alkyl)₂, -CN, -C₁-3 haloalkyl, -Ci_ ₃ alkyl, -OCi_₃ haloalkyl, and -OCi_₃ alkyl. In a preferred embodiment, E is hydrogen or halogen. In another preferred embodiment, E is halogen. In another preferred embodiment, E is fluoro. In another embodiment, the present invention provides a compounds of Formula I, wherein B is a Ci-₂₀ linear or branched alkyl chain optionally interrupted with one or more radicals selected from -0-, -NR3-, -S-, -SO-, -S(0)₂-, -CR₃=CR₃-, -C≡C-, -NR₃CO-, -CONR₃-, - NR₃CONR₃-, -NR₃C(0)0-, -OC(0)0- and -C₆H₄-; wherein, R₃, at each occurrence, is selected from hydrogen, -C₃_₆ cycloalkyl and -Ci_₆ alkyl.

The term "alkyl chain optionally interrupted with one or more radicals" means that the radicals is/are present in between the two carbon atoms of the alkyl chain. There may be more than one radicals present in the chain which can be placed adjacent to each other or separated by carbon atoms of the alkyl chain. For e.g. when B is ethyl interrupted with - CR₃=CR₃- (wherein R₃ is hydrogen) and -CON(R₃)- (wherein R₃ is methyl), it forms B having following structure

, wherein '[' is the point of attachment of group B to the nitrogen atom.

In a preferred embodiment, the present invention provides a compound of Formula I, wherein B is selected from hydrogen and CM_O linear or branched alkyl chain optionally interrupted with one or more radicals selected from -CR₃=CR₃-, -NR₃CO- and -CONR₃-; wherein R₃, at each occurrence is independently selected from hydrogen and -Ci_₆ alkyl.

In another embodiment, the group B can optionally be further substituted with one or more groups selected from halogen, -C₃_₆ cycloalkyl, -OR₄, -N(R₄)₂, -C(0)OCi_₆ alkyl and phenyl unsubstituted or substituted with one or more groups selected from halogen, -Ci_₆ alkyl and - OCi_₆ alkyl; wherein, R₄, at each occurrence, is a group selected from hydrogen and Ci_₆ linear, branched or cyclic alkyl. In a preferred embodiment, the group B can optionally be further substituted with one or more groups selected from halogen and -C₃_₆ cycloalkyl. In another preferred embodiment, group B is substituted with one or more halogen. In another preferred embodiment, B is Ci_₆ linear or branched alkyl chain optionally substituted with one or more groups selected from halogen and -C₃_₆ cycloalkyl. In another preferred embodiment, B is -Ci_₃ alkyl or -Ci_₃ haloalkyl. In yet another preferred embodiment, B is n-propyl, 3- fluoropropyl, 2-fluoro-2-methylpropyl, 3,3,3-trifluoropropyl, n-hexyl, n-decyl or cyclopropylmethyl. In another embodiment, B is selected from a group consisting of -C(0)R₂, -C(0)N(R₂)₂ and - C(=NH)NHR₂, wherein R₂, at each occurrence, is independently selected from hydrogen, -Ci_ ₆ alkyl, -Ci_₆ haloalkyl, -C₃_₆ cycloalkyl and -C₃_₆ halocycloalkyl.

In another embodiment, the present invention provides a compound of Formula I, wherein Y is mono-, di- or tri-substitution. The phrase "Y is mono- or di- or tri-substitution" means that the phenyl ring can have one, two or three Y groups substituted on it. In an embodiment, Y is di-substitution. In another embodiment, Y is tri-substitution. In a preferred embodiment, Y is mono-substitution. In another embodiment, Y at each occurrence is independently selected from a group consisting of -R₅, -OR₅, halogen, -CN, -NR₅COR₅, -NR₅S0₂R₅, -OC(0)R₅, - OC(0)N(R₅)₂, -OS0₂R5 and -OC(0)ORs; wherein R5, at each occurrence, is a group selected from hydrogen, Ci_₆ linear, branched or cyclic alkyl and Ci_₆ linear, branched or cyclic haloalkyl. In a preferred embodiment, Y is -OH, halogen, -OCi_₃ alkyl or -OCi_₃ haloalkyl. In another preferred embodiment, Y is -OH or -OCi_₃ haloalkyl. In yet another preferred embodiment, Y is -OH. When Y is mono-substitution, the substitution Y on phenyl ring may be at 2, 3 or 4 position with respect to the point of attachment of phenyl ring to the rest of molecule. In a preferred embodiment, Y is a mono-substitution and is at 4 position on the phenyl ring.

In another embodiment, the present invention provides a compound of Formula I, wherein L is selected from -0-, -NH-, -N(Ci_₆ alkyl)-, -N(C₃_₆ cycloalkyl)-, -N(Ci_₆ haloalkyl)- and - N(C₃_₆ halocycloalkyl)-. In a preferred embodiment, L is -0-. Ring X, along with the two atoms of the central ring, is a 5 to 10 membered mono- or bi- cyclic ring containing 0 to 4 heteroatoms. Ring X can be aromatic or non-aromatic. In an embodiment, ring X is a 6 to 10 membered mono- or bi-cyclic ring containing zero to 3 heteroatoms selected from oxygen, nitrogen and sulfur. In another embodiment ring X is selected from monocyclic ring such as phenyl, imidazolyl, pyrazolyl, thiophenyl, pyrazinyl and piperazinyl.

In another embodiment, the present invention provides a compound of Formula I, wherein the ring X is a bicyclic ring selected from a group of

wherein, ')' indicates the point of attachment of the group with the nitrogen of the central ring and ']' indicates point of attachment of the group with the L group of the central ring. The bicyclic ring can optionally contain an oxo group (=0) thus forming a group as provided below

wherein, ')' indicates the point of attachment of the group with the nitrogen of the central ring and ']' indicates point of attachment of the group with the L group of the central ring.

In another embodiment, ring X is selected from

In a preferred embodiment the ring X is phenyl. In another preferred embodiment, the ring X is

Ring X can be substituted with D, wherein D is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting of -R₆, -OR₆, halogen, - CR₆=CR₆-COOH, -CN, -N(R₆)₂, -NR₆S0₂R₆, -NR₆CHO, -NR₆COR₆, -OC(0)R₆, - OC(0)N(R₆)₂, -NR₆CONR₆, -OC(0)OR₆, -Ci_₃ alkyl-N(R₆)₂ , -OP(0)(OH)₂ and 5 or 6 membered aryl or heteroaryl ring; wherein R₆ at each occurrence is independently selected from hydrogen and Ci_6 linear, branched or cyclic alkyl. In a preferred embodiment, D is selected from -R₆, -OR₆, halogen, -OC(0)R₆, -OC(0)N(R₆)₂, -Ci_₃ alkyl-N(R₆)₂ , -OP(0)(OH)₂ and 5 or 6 membered aryl or heteroaryl ring; wherein R₆ at each occurrence is independently selected from hydrogen and Ci_6 linear, branched or cyclic alkyl. In another preferred embodiment, D is hydrogen or -OH. In another preferred embodiment, D is -OH. The phrase "D is mono- or di- or tri-substitution" means that the ring X can have one, two or three D groups substituted on it. In a preferred embodiment, D is mono-substitution.

In another embodiment, D is a group selected from boronic acid and a 5 or 6 membered ring containing the C-O-Boron-O-C linkage wherein the ring is optionally substituted with one or more Ci_₃ alkyl group wherein the point of attachment to ring X is the boron atom. Following are some representative moieties:

In another embodiment, the present invention provides a compound of Formula I, wherein R₇ and R₈ are independently selected from hydrogen, Ci_₃ alkyl and Ci_₃ haloalkyl. In a preferred embodiment, R₇ and R₈ are hydrogen or Ci_₃ alkyl. In another preferred embodiment, R₇ and R₈ are hydrogen. In another preferred embodiment, the present invention provides a compound of Formula I, wherein m and n are 1 thus forming an azetidinyl ring.

In a preferred embodiment, the present invention provides a compound of Formula la

Formula la wherein D, B, E ,Υ,Χ, Z, R₇ and R₈ are as defined earlier in the specification.

In another preferred embodiment, the present invention provides a compound of Formula lb

Formula lb wherein D, B, E ,Y, Z, R₇ and R₈ are as defined earlier in the specification. In another preferred embodiment, the present invention provides the compounds selected from the group consisting of:

( ?)-4-[3-Fluoro-5-(l-propyl-azetidin-3-yloxy)-phenyl]-3-(4-hydroxy-phenyl)-3,4- dihydro-2H-benzo[i,4]oxazin-7-ol;

( ?)-4-[3-Fluoro-4-(l-propyl-azetidin-3-yloxy)-phenyl]-3-(4-hydroxy-phenyl)-3,4- dihydro-2H-benzo[i,4]oxazin-7-ol;

(R)-4- { 3 -Fluoro-4- [ 1 -(3 -fluoro-propyl)-azetidin-3 -yloxy] -phenyl } -3 -(4-hydroxy-phenyl)- 3,4-dihydro-2H-benzo/7,4/oxazin-7-ol;

(R)-4- { 3 -Fluoro-4- [ 1 -(3 -fluoro-propyl)-azetidin-3 -yloxy] -phenyl } -3 -(4-fluoromethoxy- phenyl)-3,4-dihydro-2H-benzo/7,4/oxazin-7-ol;

( ?)-3-(4-Fluoromethoxyphenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4- dihydro-2H-benzo[l,4]oxazin-7-ol;

( ?)-3-(4-Fluoromethoxyphenyl)-4-[3-fluoro-5-(l-propylazetidin-3-yloxy)phenyl]-3,4- dihydro-2H-benzo[l,4]oxazin-7-ol;

f ?J-3-(4-Difluoromethoxyphenyl)-4-{ 3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4- dihydro-2H-benzo[l,4]oxazin-7-ol;

3- (4-Fluorophenyl)-4-[3-fluoro-5-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H- benzo[l,4]oxazin-7-ol;

3-(4-Fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H- benzo[l,4]oxazin-7-ol;

4- { ( ?)-5-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l,5,6,7-tetrahydro-8-oxa- 1,2,5- triazacyclopenta[b]naphthalen-6-yl}-phenol;

( ?)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4-fluoromethoxyphenyl)-3,4- dihydro-2H-benzo[i,4]oxazin-7-ol;

( ?)-3-(4-Difluoromethoxyphenyl)-4-[3,5-difluoro-4-(l-propylazetidin-3-yloxy)phenyl]- 3,4-dihydro-2H-benzo[l,4]oxazin-7-ol;

( ?)-4-[3-Fluoro-5-(l-propylazetidin-3-yloxy)phenyl]-3-(4-methoxyphenyl)-3,4-dihydro- 2H-benzo[l,4]oxazin-7-ol;

( ?)-4-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4-methoxyphenyl)-3,4-dihydro- 2H-benzo[l,4]oxazin-7-ol;

( ?)-3-(4-Fluoromethoxyphenyl)-4-[5-(l-propylazetidin-3-yloxy)pyridin-3-yl]-3,4- dihydro-2H-benzo[l,4]oxazin-7-ol; ( ?)-4-[3-Fluoro-4-(l-hexylazetidin-3-yloxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro- 2H-benzo[l,4]oxazin-7-ol;

( ?)-3-(4-Fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)-phenyl]-3,4-dihydro- 2H-benzo[l,4]oxazin-7-ol;

( ?)-4-[4-(l-Decylazetidin-3-yloxy)-3-fluorophenyl]-3-(4-fluoromethoxyphenyl)-3,4- dihydro-2H-benzo[i,4]oxazin-7-ol;

( ?)-4-[4-(l-Cyclopropylmethylazetidin-3-yloxy)-3-fluorophenyl]-3-(4- fluoromethoxyphenyl)-3,4-dihydro-2H-benzo[l,4]oxazin-7-ol;

(3 ?)-4-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4-hydroxyphenyl)-2-methyl- 3 ,4-dihydro-2H-benzo [ 1 ,4] oxazin-7-ol;

( ?)-4-[4-(Azetidin-3-yloxy)-3-fluorophenyl]-3-(4-fluoromethoxyphenyl)-3,4-dihydro-2H- benzo[l,4]oxazin-7-ol;

( ?)-3-(4-Fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(lH-pyrazol- 4-yl)-3,4-dihydro-2H-benzo[l,4]oxazine;

( ?)-8-Dimethylaminomethyl-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[l,4]oxazin-7-ol;

4-[( ?)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(lH-pyrazol-4-yl)-3,4- dihydro-2H-benzo [ 1 ,4] oxazin-3 -yl]phenol;

4{ ( ?)-6-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,6,7,8-tetrahydro-9-oxa- 2,3,6-triazacyclopenta[a]naphthalen-7-yl]phenol;

( ?)-6-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)-phenyl]-7-(4-methoxyphenyl)-3,6,7,8- tetrahydro-9-oxa-2,3,6-triazacyclopenta[a]naphthalene;

( ?)-6-{ 3,5-Difluoro-4-[l-(2-fluoro-2-methylpropyl)azetidin-3-yloxy]phenyl}-7-(4- fluorophenyl)-3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[a]naphthalene;

( ?)-6-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(3-fluoro-4-methoxyphenyl)- 3,6,7, 8-tetrahydro-9-oxa-2,3,6-triazacyclopenta [a]naphthalene;

(5)-6- [3 ,5-Difluoro-4-( 1 -propylazetidin-3-yloxy)phenyl] -7-(3 -fluoro-4-methoxyphenyl)- 3,6,7, 8-tetrahydro-9-oxa-2,3,6-triazacyclopenta [a]naphthalene;

( ?)-6-{ 3,5-Difluoro-4-[l-(3,3,3-trifluoropropyl)azetidin-3-yloxy)phenyl}-7-(4- fluorophenyl)-3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[a]naphthalene;

4- { 3 -Fluoro-4- [(R)- 1 -(3 -fluoropropyl)pyrrolidin-3 -yloxy] phenyl } -3 -(3 -fluoro-4- methoxyphenyl)-3,4-dihydro-2H-benzo[l,4]oxazin-7-ol; and

3-(2,4-Difluorophenyl)-4-{ 3-fluoro-4-[( ?)-l-(3-fluoropropyl)pyrrolidin-3-yloxy]phenyl}- 3,4-dihydro-2H-benzo[l,4]oxazin-7-ol. In another preferred embodiment, the present invention provides the compounds selected from a group consisting of:

4-{ ( ?)-5-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l,5,6,7-tetrahydro-8-oxa- 1,2,5- triazacyclopenta[b]naphthalen-6-yl}-phenol;

( ?)-4-[4-(l-Decylazetidin-3-yloxy)-3-fluorophenyl]-3-(4-fluoromethoxyphenyl)-3,4- dihydro-2H-benzo [1 , 4] oxazin-7 -ol ; and

( ?)-4-[4-(l-Cyclopropylmethylazetidin-3-yloxy)-3-fluorophenyl]-3-(4- fluoromethoxyphenyl)-3,4-dihydro-2H-benzo[l,4]oxazin-7-ol.

In another preferred embodiment, the present invention provides the compounds selected from a group consisting of:

( ?)-3-(4-Fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(lH-pyrazol-

4-yl)-3,4-dihydro-2H-benzo[l,4]oxazine;

4-[( ?)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(lH-pyrazol-4-yl)-3,4- dihydro-2H-benzo [ 1 ,4] oxazin-3 -yl]phenol; 4{ ( ?)-6-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,6,7,8-tetrahydro-9-oxa- 2,3,6-triazacyclopenta[a]naphthalen-7-yl]phenol;

( ?)-6-{ 3,5-Difluoro-4-[l-(3,3,3-trifluoropropyl)azetidin-3-yloxy)phenyl}-7-(4- fluorophenyl)-3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[a]naphthalene; and 4- { 3 -Fluoro-4- [(R)- 1 -(3 -fluoropropyl)pyrrolidin-3 -yloxy] phenyl } -3 -(3 -fluoro-4- methoxyphenyl)-3,4-dihydro-2H-benzo[l,4]oxazin-7-ol.

In yet another preferred embodiment, the present invention provides the compounds selected from a group consisting of:

3-(4-Fluorophenyl)-4-[3-fluoro-5-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H- benzo[l,4]oxazin-7-ol ;

(R)-4- [3 -Fluoro-4-( 1 -propylazetidin-3 - yloxy )phenyl] -3 -(4-methoxyphenyl)-3 ,4-dihydro- 2H-benzo[l,4]oxazin-7-ol;

( ?)-3-(4-Fluoromethoxyphenyl)-4-[5-(l-propylazetidin-3-yloxy)pyridin-3-yl]-3,4- dihydro-2H-benzo[l,4]oxazin-7-ol;

( ?)-4-[3-Fluoro-4-(l-hexylazetidin-3-yloxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro- 2H-benzo[l,4]oxazin-7-ol;

( ?)-3-(4-Fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)-phenyl]-3,4-dihydro- 2H-benzo[l,4]oxazin-7-ol; (3 ?)-4-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4-hydroxyphenyl)-2-methyl- 3,4-dihydro-2H-benzo[l,4]oxazin-7-ol;

( ?)-4-[4-(Azetidin-3-yloxy)-3-fluorophenyl]-3-(4-fluoromethoxyphenyl)-3,4-dihydro-2H- benzo[l,4]oxazin-7-ol; and

3-(2,4-Difluorophenyl)-4-{ 3-fluoro-4-[( ?)-l-(3-fluoropropyl)pyrrolidin-3-yloxy]phenyl}- 3,4-dihydro-2H-benzo[l,4]oxazin-7-ol.

In another embodiment, the compounds of the Formula I can be prepared by coupling a compound of Formula (1) wherein Q is a halogen and D, X & L are as defined earlier in the specification,, with the compound of Formula (2) wherein W is -ΟΗ or a suitable leaving groupsuch as halogen, mesylate, tosylate, triflate or nosylate, P is a protecting group such as ie/t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or fluorenylmethyloxycarbonyl (Fmoc) and Y, R₇ & R₈ are as defined earlier in the specification; to give a compound of Formula (3) wherein D, X, L, Q, P, Y, R₇ & R₈ are as defined earlier in the specification; which upon deprotection followed by intramolecular cyclization gives compound of Formula (4) wherein D, X, L, Y, R₇ & R₈ are as defined earlier in the specification. Buchwald reaction of compound of Formula (4) with the compound of Formula (5) wherein G is a halogen and Z, E, A, B, m & n are as defined earlier in the specification; gives the compound of Formula I. The process can be depicted as in Scheme 1.

Formula (4) Form ula I

Scheme 1 Alternatively, the compound of Formula I can be prepared by following the procedure as depicted in Scheme 2. Coupling of the compound of Formula (5) with compound of Formula (2) gives a compound of Formula (6) wherein W, P, Y, Z, E, A, B, R₇, R₈, m & n are as defined earlier in the specification. Coupling of the compound of Formula (6) with a compound of Formula (1) gives an adduct of the Formula (7) wherein D, X, L, Q, P, Y, Z, E, A, B, R₇, R₈, m & n are as defined earlier in the specification; which upon deprotection followed by intramolecular cyclization gives the compound of Formula I.

Formula (7) Form ula I

Scheme 2

Alternatively, the compound of Formula I can also be prepared by following the procedure as depicted in Scheme 3. Coupling of the compound of Formula (1) with compound of Formula (8) wherein W, Y, R₇ & R₈ are as defined earlier in the specification, gives compound of Formula (9) wherein D, X, L, Q, Y, R₇ & R₈ are as defined earlier in the specification. Reductive amination of the compound of Formula (9) gives a compound of Formula (10) wherein D, X, L, Q, Y, R₇ & R₈ are as defined earlier in the specification. Intramolecular cyclization of the compound of Formula (10) gives the compound of Formula (4). Buchwald reaction of the compound of Formula (4) with compound of Formula (5) gives the compound of Formula I.

Formula I Form ula (4)

Scheme 3 Alternatively, the compound of Formula I can also be prepared by following the procedure as depicted in Scheme 4. Displacement reaction of compound of Formula (11) wherein Z, E, A, B, m & n are as defined earlier in the specification; with compound of Formula (1) gives a compound of Formula (12) wherein D, X, L, Z, E, A, B, m & n are as defined earlier in the specification. Coupling of the compound of Formula (8) with compound of Formula (12) gives an adduct of Formula (13) wherein D, X, L, Y, Z, E, A, B, R₇, R₈, m & n are as defined earlier in the specification, which upon intramolecular cyclization gives the compound of Formula I.

The person skilled in the art will understand that if a substituent described herein is not compatible with the reaction conditions of the processes as depicted in schemes 1, 2, 3 and 4, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Salts of the compound of Formula I may be prepared in a. manner known to those skilled in the art. For instance, the acid addition salts of compounds of Formula I may be obtained by treating the compound of Formula ί having a functional moiety capable of forming acid addition salt with an acid in a suitable solvent. Alternatively, the compound of Formula I can be subjected to salt exchange, or treated with a suitable anion exchange reagent to obtain the desired acid addition salt.

Stereoisomeric mixtures can be separated into individual stereoisomers by means of suitable well known separation methods. Enantiomers may be resolved by well-known techniques for example, through the formation of diastereomeric salts with enantiomerically pure chiral acid or a base; by derivatization with a suitable chiral derivatizing agent and separation such as by fractional crystallization, fractional distillation or by kinetic resolution such as enzymatic or chemical hydrolysis of the derivatized isomer. Alternatively, the enantiomers may be resolved by means of chromatography, for example by chiral HPLC, using a chiral chromatographic stationary phase.

Table 1 provides few exemplary compounds of Formula I.

Table 1

7. Ph 4-0 -(CH₂)₂CH₃ 3-F 0 4-OCHF₂ 1 1 H H R

8. Ph 5-0 -(CH₂)₂CH₃ 3-F 0 4-F 1 1 H H RS

9. Ph 4-0 -(CH₂)₂CH₃ 3-F 0 4-F 1 1 H H RS

10. Ph 4-0 -(CH₂)₂CH₃ 3-F 0 4-OH 1 1 H H R

11. Ph 4-0 -(CH₂)₂CH₃ 3,5- 0 4-OCH₂F 1 1 H H R

Di-F

12. Ph 4-0 -(CH₂)₂CH₃ 3,5- 0 4-OCHF₂ 1 1 H H R

Di-F

13. Ph 5-0 -(CH₂)₂CH₃ 3-F 0 4-OCH₃ 1 1 H H R

14. Ph 4-0 -(CH₂)₂CH₃ 3-F 0 4-OCH₃ 1 1 H H R

15. 5-0 -(CH₂)₂CH₃ H 0 4-OCH₂F 1 1 H H R

16. Ph 4-0 -(CH₂)₅CH₃ 3-F 0 4-OH 1 1 H H R

17. Ph 4-0 -(CH₂)₂CH₃ 3-F 0 4-F 1 1 H H R

50. Ph 4-0 -(CH₂)₂CH₃ 3-F 0 4-OCH₃ 1 1 H H R

51. Ph 4-0 -(CH₂)₂CH₃ 3-F 0 4-OCH₃ 1 1 H H R

52. Ph 4-0 -(CH₂)₂CH₂F 3-F 0 3- F, 1 2 H H RS

4- OCH₃

53. Ph 4-0 -(CH₂)₂CH₂F 3-F 0 2,4- 1 2 H H RS

Di-F

#: ')' represents the point of attachment to the nitrogen atom and ']' represents the point of attachment to L.

+: One of the compounds is S and the other is R isomer.

The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.

EXAMPLES

General Method of Preparation

The compounds described herein, including compounds of Formula I can be prepared by reaction schemes depicted in Schemes 1, 2, 3 and 4. Furthermore, in the following examples, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof are envisioned as part of the present invention. The compounds obtained by using the general reaction scheme may be of insufficient purity. These compounds can be purified by any of the methods for purification of organic compounds known in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. Additionally the compounds can be converted into its acid addition salts or base addition salts as mentioned earlier in the specification, by dissolving the compounds in the appropriate solvent followed by the treatment with appropriate acid or base. All solvents and reagents were used as obtained from commercial sources unless otherwise indicated. 1H-NMR spectra were recorded on Bruker spectrometer operating at 400 MHz or

500 MHz.

Example 1; Preparation of (/?)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl1-3-(4- hvdroxyphenyl)-3,4-dihydro-2H-benzo|7,41oxazin-7-ol (Compound No. 2).

Step I: (R)-N-(tert-Butoxycarbonyl)amino-2-(5-benzyloxy-2-bromophenoxy)-l-(4- benz loxyphenyl)ethylamine

Z)z^'-isopropylazodicarboxylate (20.06 mL, 0.102 mol) was added to a stirred mixture of (R)-2- (ieri-butoxycarbonyl)amino-2-(4-benzyloxyphenyl)ethanol (25.0 g, 0.07 mol), 5-benzyloxy- 2-bromophenol (20.32 g, 0.072 mol) and triphenylphosphine (24.8 g, 0.094 mol) in tetrahydrofuran (375 mL) under nitrogen atmosphere. Reaction mixture was stirred for further 4 hours at ambient temperature. Z)z^'-isopropylazodicarboxylate (4.3 mL, 0.021 mol) was added and stirring was continued for additional 12 hours at ambient temperature. The mixture was cooled to 0-5 °C, water was added and extracted with ethyl acetate. The combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gave residue, which was purified by column chromatography (silica gel, ethyl acetate:n-hexane, 8:92) to get ( ?)-N-(ieri-butoxycarbonyl)amino-2-(5-benzyloxy-2-bromophenoxy)- l-(4-benzyloxy phenyl)ethylamine.

Step II: (/?)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-benzyloxy phenyl)ethylamine.

Trifluoroacetic acid (22 niL) was added to a stirred solution of ( ?)- V-(ie/ -butoxycarbonyl)- 2-(5-benzyloxy-2-bromophenoxy)- l-(4-benzyloxyphenyl)ethylamine (11 g, 0.018 mol) in dichloromethane (55 mL) at 0-5 °C and then stirred at ambient temperature for 1 hour. Reaction mixture was diluted with dichloromethane and made alkaline (pH~9) with aqueous saturated sodium bicarbonate solution. Organic layer was separated, washed with water followed by brine solution and then dried over anhydrous sodium sulfate. Removal of dichloromethane under reduced pressure gave residue, which was purified by column chromatography (silica gel, ethyl acetate:dichloromethane, 40:60) to get ( ?)-2-(5-benzyloxy- 2-bromophenoxy)- l-(4-benzyloxy phenyl)ethylamine.

Ste III: (/?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzoA ,4/oxazine.

Potassium ie/t-butoxide (2.35 g, 0.021 mol) was added to a stirred mixture of (R)-2-(5- benzyloxy-2-bromophenoxy)-l-(4-benzyloxyphenyl)ethylamine (8.12 g, 0.016 mol), tris (dibenzylideneacetone)dipalladium (0.516 g, 0.0006 mol) and 2,2'-Ws(diphenylphosphino)- Ι, Γ-binaphthyl (0.7 g, 0.001 mol) in toluene (100 mL). Reaction mixture was then heated at 100 °C for 3 hours under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulfate. Removal of ethyl acetate under reduced pressure gave residue, which was triturated with dichloromethane to get ( ?)-7-benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[i,4]oxazine.

Step IV: 3-(4-Bromo-2-fluorophenoxy)azetidine-l-carboxylic acid tert-butyl ester

Diisopropyl azodicarboxylate (8.65 mL, 0.043 mol) was added dropwise to a stirred mixture of 3-hydroxyazetidine-l-carboxylic acid te/t-butyl ester (5.71 g, 0.032 mol), 4-bromo-2- fluorophenol (6.0 g, 0.031 mol) and triphenylphosphine (10.69 g, 0.041 mol) in a mixture (1: 1) of toluene (42 mL) and tetrahydrofuran (42 mL) under nitrogen atmosphere at room temperature. The resultant reaction mixture was then heated to reflux for 5 hours at 110 °C. The mixture was cooled to ambient temperature, concentrated and degassed under reduced pressure at 50 °C. The mixture (80 mL) of n-hexane : ethyl acetate (85: 15) was added to the residue and contents were stirred vigorously for 30 minutes. Solid thus obtained was filtered under vacuum and washed with same mixture. Combined filtrate was concentrated and degassed under reduced pressure at 50 °C to give residue, which was purified by column chromatography (silica gel, ethyl acetate:n-hexane, 5:95) to get 3-(4-bromo-2- fluorophenoxy)azetidine-l-carboxylic acid ieri-butyl ester. Step V: 3-(4-Bromo-2-fluoro henoxy)azetidine

Trifluoroacetic acid (20 mL) was added to a stirred solution of 3-(4-bromo-2- fluorophenoxy)azetidine-l-carboxylic acid ieri-butyl ester (10.0 g, 0.031 mol) in dichloromethane (100 mL) at 0-5 °C and then stirred at room temperature for 1 hour 30 minutes. The mixture was diluted with dichloromethane (30 mL) and made alkaline (pH~9) with aqueous saturated sodium bicarbonate solution. Organic layer was separated, washed with water followed by brine solution and dried over anhydrous sodium sulfate. Dichloromethane was removed under reduced pressure to get 3-(4-bromo-2- fluorophenoxy ) azetidine . Step VI : 3-(4-Bromo-2-fluoro henoxy)-l-propylazetidine

Glacial acetic acid (0.05 mL) was added to a mixture of 3-(4-bromo-2- fluorophenoxy)azetidine (0.5 g, 0.0022 mol) and propionaldehyde (0.237 mL, 0.0033 mol) in a mixture of dichloromethane (7 mL) and methanol (3 mL) at room temperature and stirred for lhr. Sodium cyanoborohydride (0.314 g, 0.005 mol) was then added to the reaction mixture at room temperature and stirred for lhr. Reaction mixture was quenched with water and contents were concentrated under reduced pressure. Water was added to the residue and extracted with dichloromethane. Combined organic layer was washed with brine solution and dried over anhydrous sodium sulfate. Dichloromethane was removed under reduced pressure to give a residue, which was purified by column chromatography (silica gel, methanohdichloromethane, 5:95) to get 3-(4-bromo-2-fluorophenoxy)-l-propylazetidine.

Step VII: (/f)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-[3-fluoro-4-(l-propylazetidin-3- loxy)phenyl] -3,4-dihydro-2H-benzo /,4/oxazine

Sodium ie/ -butoxide (0.118 g, 0.0012 mol) was added to a stirred mixture of (R)-7- benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[i,4]oxazine (0.373 g, 0.00088 mol), 3-(4-bromo-2-fluorophenoxy)- l-propylazetidine (0.235 g, 0.00081 mol), palladium(II) acetate (0.019 g, 10 mol %) and tri ieri-butylphosphine (0.017 mL, 50 % solution in toluene, 5 mol %) in toluene (8 mL). Reaction mixture was heated at 105 °C for 2 hours under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to give a residue, which was purified by column chromatography (silica gel dichloromethane:methanol, 98:02) to get ( ?)-7-benzyloxy-3-(4-benzyloxyphenyl)- 4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazine.

Step VIII: (R)-4-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4-hydroxyphenyl)- 3,4-dihydro-2H-benzoA 4/oxazin-7-ol

5 % Palladium on charcoal (0.043 g, 50 % wet) followed by ammonium formate (0.215 g, 0.0034 mol) were added to a solution of ( ?)-7-benzyloxy-3-(4-benzyloxyphenyl)-4-[3-fluoro- 4-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazine (0.216 g, 0.00034 mol) in a mixture (8 mL) of methanol: 1,4-dioxane (1 : 1) at room temperature. The resultant reaction mixture was heated at 70 °C for 20 minutes. It was allowed to cool, filtered through celite bed and washed with methanol: 1,4-dioxane (1 : 1) mixture. Combined filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, dichloromethane:methanol, 95:5) to get ( ?)-4-[3-fluoro-4-(l- propylazetidin-3-yloxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo i,47oxazin-7-ol.

Example 2: Preparation of 3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyll-3,4-dihydro-2H-benzo 7,4/oxazin-7-ol (Compound No. 9),

-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethanone

Anhydrous potassium carbonate (0.74 g, 0.0054 mol) was added to a stirred solution of 5- benzyloxy-2-bromophenol (1 g, 0.036 mol) in acetone (20 mL) and stirred for 30 min. 2- Bromo-l-(4-fluorophenyl)ethanone (0.78 g, 0.036 mol) was added to the reaction mixture and stirred for 2 hours at room temperature. Reaction mixture was then filtered and inorganic solids were washed with acetone. Combined filtrate was concentrated at 50 °C under reduced pressure to give crude product, to which, a solution of 6% ethyl acetate in n-hexane was added and stirred for 1 hour. Solid thus obtained was filtered and dried under reduced pressure to get 2-(5-benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethanone.

Step II : 2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethylamine

Ammonium acetate (1.67 g, 0.02 mol) was added to a solution of 2-(5-benzyloxy-2- bromophenoxy)-l-(4-fluorophenyl)ethanone (0.9 g, 0.0021 mol) in methanol (15 mL) at room temperature and stirred for 15 minutes. Sodium cyanoborohydride (0.27 g, 0.0042 mol) was added to reaction mixture and then heated at 65 °C for 4 hours. Reaction mixture was concentrated under reduced pressure at 40 °C. Residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. Combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product. 3N HC1 solution (10 vol) was added to the residue to get clear solution, which was washed with diisopropyl ether (10 vol). Aqueous solution was then basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get 2-(5-benzyloxy-2-bromophenoxy)-l- (4-fluorophenyl)ethylamine.

Step III : 7-Benzyloxy-3-(4-fluorophenyl)-3,4-dihydro-2H-benzoA ,^7oxazine

Potassium ie/t-butoxide (0.157 g, 0.0014 mol) was added to a stirred solution of 2-(5- benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethylamine (0.415 g, 0.001 mol), tris(dibenzylidineacetone)dipalladium (0.046 g, 0.00005 mol) and 2,2'- bis(diphenylphosphino)-l, -binaphthyl (0.063 g, 0.0001 mol) in toluene (10 mL) at room temperature under nitrogen atmosphere and then heated at 105 °C for one and half hours. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to give crude liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane, 10:90) to get 7-benzylozy-3-(4-fluorophenyl)-3,4-dihydro-2H- benzo/7,4/oxazine.

Step IV: 7-Benzyloxy-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phen l]-3,4-dihydro-2H-benzo/7,4/oxazine

Palladium acetate (0.005 g, 0.00002 mol) followed ίή-tert butyl phosphine (0.02 mL, 0.00004 mol, 50 % solution in toluene) were under nitrogen atmosphere added to a stirred solution of 7-benzyloxy-3-(4-fluorophenyl)-3,4-dihydro-2H-benzo/7,4/oxazine (0.15 g, 0.00044 mol) and 3-(4-bromo-2-fluorophenoxy)-l-propylazetidine (0.12 g, 0.00044 mol) in toluene (10 mL) at room temperature and stirred for 10 minutes. Sodium ie/ -butoxide (0.060 g, 0.0006 mol) was added to reaction mixture and then heated at 105 °C for 1 hour. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to give crude liquid, which was purified by column chromatography (silica gel 230-400 mesh, methanol :dichloromethane (2 : 98) to get 7-benzyloxy-3-(4-fluorophenyl)-4-[3-fluoro-4-(l- propylaetidine-3-yloxyl)phenyl]-3,4-dihydro-2H-benzo/7,4/ oxazine. Step V: 3-(4-Fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4- dihydro-2H-benzo/7,4/oxazin-7-ol

5 % Palladium on charcoal (0.036 g, 50 % wet) followed by ammonium formate (0.22 g, 0.0035 mol) were added to a stirred solution of 7-benzyloxy-3-(4-fluorophenyl)-4-[3-fluoro- 4-(l-propylazetidine-3-yloxyl)phenyl]-3,4-dihydro-2H-benzo i,47 oxazine (0.185 g, 0.00035 mol) in a mixture (1: 1) of methanol (4 mL) and 1,4-dioxane (4 mL). The resultant reaction mixture was heated at 70 °C for 30 minutes. Reaction mixture was cooled to room temperature, filtered through celite bed and washed with a 1: 1 mixture of methanol and 1, 4- dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with ethyl acetate. Combined organic layer washed with water followed by brine solution and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to give crude liquid, which was purified by column chromatography (silica gel 230-400 mesh, methanol : dichloromethane (5 : 95) to get 3-(4- fluorophenyl)-4-[3-(4-fluoro-4-(l-propylazetidine-3-yloxy)phenyl]-3,4-dihydro-2H- benzo/ 1,4] oxazine-7-ol.

Example 3: Preparation of 4-|(/?)-5-[3-fluoro-4-(l-propylazetidin-3-yloxy)-phenyl1- l,5,6,7-tetrahvdro-8-oxa-l,2,5-triazacvclopenta[61naphthalen-6-yl|phenol (Compound No. 10).

Step I: 5-Bromo-l-(tetrahydropyran-2-yl)-6-(tetrahydropyan-2-yloxy)-/H-indazole.

To a stirred solution of 5-bromo-iH-indazol-6-ol (18.0 g, 0.084 mol) in (1 : 1) mixture of dichloromethane and tetrahydrofuran at 0-5 °C was added 3,4-dihydro-2H-pyran (38.26 mL, 0.42 mol) followed by methanesulphonic acid (1.11 mL, 0.017 mol). The mixture was stirred at room temperature for 30 mins. Reaction mixture was quenched with water and extracted with dichloromethane. Combined organic layer was washed with brine solution and dried over anhydrous sodium sulphate. Dichloromethane was removed under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh), ethylacetate: n-hexane (30: 70) to get 5-bromo-l-(tetrahydropyran-2-yl)-6-(tetrahydropyan-2- yloxy)-iH-indazole.

Step II: 5-Bromo-l- tetrahydropyran-2-yl)-/H-indazol-6-ol.

To a stirred solution of 5-bromo-l-(tetrahydropyran-2-yl)-6-(tetrahydropyan-2-yloxy)-iH- indazole (30.0 g, 0.78 mol) in 1,4-dioxane (60 mL) was added 4M HC1 in 1,4-dioxane (78 mL) at 0-5 °C. The mixture was stirred for 10 minutes at 0-5 °C. The mixture was diluted with ethylacetate (100 mL) and made alkaline (pH~9) with aqueous saturated sodium bicarbonate solution. Aqueous layer was extracted with ethylacetate. Combined organic layer was dried over anhydrous sodium sulphate. Ethylacetate was removed under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh), ethylacetate: n-hexane (20: 80) to get 5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6-ol.

Step III: {(/f)-l-(4-Benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-/H-indazol- 6- loxy]ethyl}carbamic acid tert butyl ester.

Z)z^'-isopropylazodicarboxylate (1.0 ml, 0.0048 mol) was added to a stirred mixture of [(R)-l- (4-benzyloxyphenyl)-2-hydroxyethyl]carbamic acid tert butyl ester (1.18 g, 0.0034 mol), 5- bromo- l-(tetrahydropyran-2-yl)-iH-indazol-6-ol (1.0 g, 0.0034 mol) and triphenylphosphine (1.17 g, 0.0044 mol) in a mixture of tetrahydrofuran (4 mL) and toluene (16 mL) under nitrogen atmosphere at room temperature and stirred for 1 hour. Reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure at 45 °C to give crude viscous liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 15:85) to get the title compound.

Step IV: (/f)-l-(4-Benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-/H-indazol-6- yloxy]eth lamine.

4M Hydrochloric acid in 1,4-dioxan (7.5 mL) was added to a stirred solution of { (R)- l-(4- benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6-yloxy]ethyl}carbamic acid tert butyl ester (1.5 g, 0.0024 mol) in 1,4-dioxane (3 mL) at 0-5 °C and stirred for 1 hr. Reaction mixture was basified with saturated sodium bicarbonate solution and extracted with dichloromethane. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get (R)- l-(4- benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6-yloxy]ethylamine, which was used for the next step without further purification.

Step V: (R)-6-(4-Benzyloxyphenyl)-l-(tetrahydropyran-2-yl)-l,5,6,7-tetrahydro-8- 1 ,2,5-triazac clopenta[Z> ] naphthalene.

Potassium ie/t-butoxide (0.36 g, 0.0032 mol) was added to a stirred solution of (R)-l-(4- benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6-yloxy]ethylamine (1.2 g, 0.0023 mol), tris(dibenzylideneacetone)dipalladium (0.11 g, 0.00011 mol) and 2,2'- bis(diphenylphosphino)- l, l '-binaphthyl (0.14 g, 0.00023 mol) in toluene (25 mL) under nitrogen atmosphere. Reaction mixture was heated at 100 °C for 1 hour 30 minutes. It was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n- hexane, 30:70) to get ( ?)-6-(4-benzyloxyphenyl)- l-(tetrahydropyran-2-yl)- l,5,6,7-tetrahydro- 8-oxa- 1 ,2,5-triazacyclopenta[ ]naphthalene.

Step VI: (/f)-6-(4-Benzyloxyphenyl)-5-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l- (tetrahydropyran-2-yl)-l,5,6,7-tetrahydro-8-oxa-l,2,5-triazacyclopenta[6]naphthalene.

Sodium ie/t-butoxide (0.11 g, 0.00115 mol) was added to a stirred mixture of (R)-6-(4- benzyloxyphenyl)- 1 -(tetrahydropyran-2-yl)- 1 ,5,6,7-tetrahydro-8-oxa- 1 ,2,5-triazacyclopenta

[b] naphthalene (0.38 g, 0.00086 mol), 3-(4-bromo-2-fluorophenoxy)-l-propylazetidine (0.237 g, 0.00082 mol), palladium acetate (0.009 g, 0.000041 mol) and tii-tert butylphosphine (0.033 mL, 0.000082 mol, 50 % solution in toluene) in toluene (10 mL) under nitrogen atmosphere and then heated at 105 °C for 2 hours. Reaction mixture was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude, which is purified by column chromatography (silica gel 230-400 mesh, ethylacetate: n-hexane, 30:70) to get (7?)- 6-(4-benzyloxyphenyl)-5-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l-(tetrahydropyran- 2-yl)- 1 ,5,6,7-tetrahydro-8-oxa- 1 ,2,5-triazacyclopenta[ ]naphthalene.

Step VII: 4-[(/f)-5-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l-(tetrahydropyran-2- l)-l,5,6,7-tetrahydro-8-oxa-l,2,5-triazacyclopenta[6]naphthalen-6-yl]-phenol.

5 % Palladium on charcoal (0.08 g, 50 % wet) followed by ammonium formate (0.265 g, 0.0036 mol) was added to a stirred solution of ( ?)-6-(4-benzyloxyphenyl)-5-[3-fluoro-4-(l- propylazetidin-3-yloxy)phenyl] - 1 -(tetrahydropyran-2-yl)- 1 ,5,6,7-tetrahydro-8-oxa- 1 ,2,5- triazacyclopenta[b] naphthalene (0.237 g, 0.00037 mol) in (1: 1) mixture of methanol (5 mL) and 1,4-dioxane (5 mL) at room temperature. The resultant reaction mixture was heated at 70 °C for 30 minutes. Reaction mixture was cooled to room temperature, filtered through celite bed and washed with a (1: 1) mixture of methanol and 1, 4-dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with ethyl acetate. Combined organic layer washed with water followed by brine solution and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to get 4-[( ?)-5-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l-(tetrahydropyran-2-yl)-l,5,6,7- tetrahydro-8-oxa-l,2,5-triazacyclopenta[^]naphthalen-6-yl]phenol, which was used for the next step without further purification.

Step VIII: 4-[(R)-5-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l,5,6,7-tetrahydro-8- oxa-l,2,5-triazacyclopenta[6]naphthalen-6-yl]-phenol.

4M Hydrochloric acid in 1,4-dioxane (1.0 niL) was added to a stirred solution of 4-[( ?)-5- [3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l-(tetrahydropyran-2-yl)-l,5,6,7-tetrahydro-8- oxa- l,2,5-triazacyclopenta[b]naphthalen-6-yl]phenol (0.2 g, 0.00035 mol) in ethanol (2 niL) at room temperature. Reaction mixture was heated at 70 °C for 1 hour. The reaction mixture was cooled to room temperature was basified with saturated sodium bicarbonate solution and extracted with ethylacetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude thus obtained was purified by column chromatography (silica gel 230-400 mesh, dichloromethane: methanol (95: 05) to get 4-[(R)-5-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]- l,5,6,7- tetrahydro-8-oxa-l,2,5-triazacyclopenta[^]naphthalen-6-yl]phenol (Compound No. 10).

Example 4: Preparation of (/?)-3-(4-Fluoromethoxyphenyl)-4-[5-(l-propylazetidin-3- yloxy)pyridin-3-yl1-3,4-dihvdro-2H-benzo[/,41oxazin-7-ol (Compound No. 15),

Step I: (R)-tert-Butoxycarbonylamino-(4-fluoromethoxyphenyl)acetic acid methyl ester.

Anhydrous potassium carbonate (7.86 g, 0.05686 mol) was added to a stirred solution of (R)- ieri-butoxycarbonylamino-(4-hydroxyphenyl)acetic acid methyl ester (8 g, 0.02846 mol) in N,N-dimethylformamide (80 niL) and stirred for 30 minutes. Bromofluoromethane (20 mL) was added to the reaction mixture and stirred for 4 hours at room temperature. Reaction mixture was then filtered and inorganic solids were washed with ethylacetate. Combined filtrate was concentrated at 50 °C under reduced pressure to give (R)-tert butoxycarbonylamino-(4-fluoromethoxyphenyl)acetic acid methyl ester, which was directly used for the next step without any further purification.

Step II: [(/f)-l-(4-Fluoromethoxyphenyl)-2-hydroxyethyl]carbamic acid tert butyl ester.

To a stirred solution of ( ?)-ieri-butoxycarbonylamino-(4-fluoromethoxyphenyl)acetic acid methyl ester (9.5 g, 0.0304 mol) in tetrahydrofuran (66.5 mL) was added sodium borohydride (3.45 g, 0.0912 mol) at 0-5 °C. Ethanol (142.5 mL) was added slowly to the reaction mixture. The mixture was then allowed to stir overnight at room temperature. Water was added and concentrated under reduced temperature at 40 °C, to the residue, water (150 mL) was added and stirred for 1 hour. Solid thus obtained was filtered and dried under reduced pressure to get [( ?)-l-(4-fluoromethoxyphenyl)-2-hydroxyethyl]carbamic acid tert butyl ester.

Step III: [(R)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluoromethoxyphenyl)- ethyl]carbamic acid tert butyl ester.

Z)z^'-isopropylazodicarboxylate ( 8.0 mL, 0.0407 mol) was added to a stirred mixture of [(R)- l-(4-fluoromethoxyphenyl)-2-hydroxyethyl]carbamic acid tert-butyl ester (8.3 g, 0.029 mol), 5-benzyloxy-2-bromophenol (7.72 g, 0.0276 mol) and triphenylphosphine (9.92 g, 0.0378 mol) in tetrahydrofuran (100 mL) under nitrogen atmosphere. Reaction mixture was stirred for further 2 hours and 30 minutes at ambient temperature. The mixture was concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, acetone: n-hexane, 10: 90) to get [( ?)-2-(5-benzyloxy-2-bromophenoxy)- l-(4-fluoromethoxyphenyl)ethyl]carbamic acid tert butyl ester.

Step IV: (R)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluoromethoxyphenyl) ethylamine.

Trifluoroacetic acid (15 mL) was added to a stirred solution of [( ?)-2-(5-benzyloxy-2- bromophenoxy)-l-(4-fluoromethoxyphenyl)-ethyl]carbamic acid tert-buty\ ester (7.7 g,

0.01409 mol) in dichloromethane (40 mL) at 0-5°C and then stirred at 0-5°C for 1 hour. Reaction mixture was diluted with dichloromethane and made alkaline (pH~9) with aqueous 5 % sodium hydroxide solution. Organic layer was separated, washed with brine solution and then dried over anhydrous sodium sulfate. Removal of dichloromethane under reduced pressure gave ( ?)-2-(5-benzyloxy-2-bromophenoxy)-l-(4-fluoromethoxyphenyl) ethylamine, which was directly used for the next step without any further purification.

Step V: (/?)-7-Benzyloxy-3-(4-fluoromethoxyphenyl)-3,4-dihydro-2H-benzo[/,4]oxazine.

Potassium ie/t-butoxide (2.21 g, 0.01977 mol) was added to a stirred mixture of (R)-2-(5- benzyloxy-2-bromophenoxy)-l-(4-fluoromethoxyphenyl)ethylamine (6.3 g, 0.014 mol), tris (dibenzylideneacetone)dipalladium (0.647 g, 0.0007 mol) and 2,2'-Ws(diphenylphosphino)- Ι, Γ-binaphthyl (0.88 g, 0.0014 mol) in toluene (70 mL). Reaction mixture was then heated at 105 °C for 1 hour under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulfate. Removal of ethyl acetate under reduced pressure gave residue, which was triturated with methanol (65 mL). Solid thus obtained was filtered, dried to get ( ?)-7-benzyloxy-3-(4-fluoromethoxyphenyl)- 3,4-dihydro-2H-benzo[i,4]oxazine. Step VI: 3-(5-Bromopyridin-3-yloxy)azetidine-l-carboxylic acid tert-butyl ester.

Z)z^'-isopropyl azodicarboxylate (1.3 niL, 0.00672 mol) was added dropwise to a stirred mixture of 3-hydroxyazetidine-l-carboxylic acid ieri-butyl ester (0.84 g, 0.0048 mol), 5- bromopyridin-3-ol (0.8 g, 0.031 mol) and triphenylphosphine (1.55 g, 0.00624 mol) in a mixture (1 : 1) of toluene (8 mL) and tetrahydrofuran (8 mL) under nitrogen atmosphere at 0-5 °C. The resultant reaction mixture was stirred at room temperature and then heated to reflux for 2 hour 30 minutes at 110 °C. The mixture was cooled to ambient temperature, concentrated and degassed under reduced pressure at 50 °C. The mixture (20 mL) of n- hexane: ethyl acetate (85: 15) was added to the residue and contents were stirred vigorously for 30 minutes. Solid thus obtained was filtered under vacuum and washed with same mixture. Combined filtrate was concentrated and degassed under reduced pressure at 50 °C to give residue, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 20: 80) to get 3-(5-bromopyridin-3-yloxy)azetidine- l-carboxylic acid tert butyl ester.

Step VII: 3-(Azetidin-3-yloxy)-5-bromopyridine.

Trifluoroacetic acid (1.4 mL) was added to a stirred solution of 3-(4-bromo-2- fluorophenoxy)azetidine- l-carboxylic acid tert-butyX ester (0.67 g, 0.002 mol) in dichloromethane (8 mL) at 0-5 °C and then stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (30 mL) and made alkaline (pH~9) with aqueous saturated sodium bicarbonate solution. Organic layer was separated, washed with water followed by brine solution and dried over anhydrous sodium sulfate. Dichloromethane was removed under reduced pressure to get 3-(azetidin-3-yloxy)-5-bromopyridine. Step VIII: 3-Bromo-5-(l-propylazetidin-3-yloxy)pyridine.

A mixture of 3-(azetidin-3-yloxy)-5-bromopyridine (0.325 g, 0.0014 mol) and n- propionaldehyde (0.12 mL, 0.0017 mol) in dichloromethane (5 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.131 g, 0.005mol) was then added to the reaction mixture at 0-5 °C and stirred for 30 minutes. Reaction mixture was quenched with water and extracted with dichloromethane. Combined organic layer was washed with brine solution and dried over anhydrous sodium sulfate. Dichloromethane was removed under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 2:98) to get 3-bromo-5-(l-propylazetidin-3- yloxy)pyridine.

Step IX: (/f)-7-Benzyloxy-3-(4-fluoromethoxyphenyl)-4-[5-(l-propylazetidin-3- yloxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[/,4]oxazine.

Sodium ie/t-butoxide (0.065 g, 0.00067 mol) was added to a stirred mixture of (R)-7- benzyloxy-3-(4-fluoromethoxyphenyl)-3,4-dihydro-2H-benzo[i,4]oxazine (0.179 g, 0.00049 mol), 3-bromo-5-(l-propylazetidin-3-yloxy)pyridine (0.13 g, 0.0004 mol), palladium(II)acetate (0.005g, 0.000024 mol ) and tri ieri-butylphosphine (0.019 mL, 0.000048 mol, 50 % solution in toluene) in toluene (5 mL). Reaction mixture was heated at 105 °C for 1 hour under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to give a residue, which was purified by column chromatography (silica gel, 230-400 mesh, ethyl acetate: n-hexane, 80: 20) to get (R)-7- benzyloxy-3-(4-fluoromethoxyphenyl)-4-[5-(l-propylazetidin-3-yloxy)pyridin-3-yl]-3,4- dihydro-2H-benzo [1 , 4] oxazine .

Step X: (R)-3-(4-Fluoromethoxyphenyl)-4-[5-(l-propylazetidin-3-yloxy)pyridin-3 3,4-dihydro-2H-benzo[/,4]oxazin-7-ol.

5 % Palladium on charcoal (0.03 g, 50 % wet) followed by ammonium formate (0.164 g, 0.0026 mol) were added to a stirred solution of ( ?)-7-benzyloxy-3-(4-fluoromethoxyphenyl)- 4-[5-(l-propylazetidin-3-yloxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[i,4]oxazine (0.075 g, 0.00013 mol) in a mixture (1: 1) of methanol (3 mL) and 1,4-dioxane (3 mL). The resultant reaction mixture was heated at 70 °C for two hours and 30 minutes. Reaction mixture was cooled to room temperature, filtered through celite bed and washed with 1: 1 mixture of methanol and 1,4-dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with dichloromethane. Combined organic layer was washed with brine solution and dried over anhydrous sodium sulphate. Dichloromethane was removed under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 04: 96) to get ( ?)-3-(4-fluoromethoxyphenyl)-4-[5-(l-propylazetidin-3-yloxy)pyridin-3-yl]-3,4-dihydro- 2H-benzo[J4]oxazin-7-ol.

Example 5: Preparation of (3/?)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl1-3-(4- hvdroxyphenyl)-2-methyl-3,4-dihvdro-2H-benzo|7,41oxazin-7-ol (Compound No. 20).

Step I: [(R)-(4-Benzyloxyphenyl)(methoxymethylcarbamoyl)methyl]carbamic acid tert butyl ester.

Sodium hydroxide (0.96 g, 0.024 mol) was added to a stirred solution of (R)-(4- benzyloxyphenyl)ieri-butoxycarbonylamino acetic acid methyl ester (6.0 g, 0.01615 mol) in methanol (42 mL) and water (18 mL) at ambient temperature. The mixture was heated at 65 °C for 1 hour. Reaction mixture was degassed under reduced pressure at 40 °C. Water was added and cooled to 0-5 °C and neutralised with 2N HC1 solution till pH~7 and extracted with ethylacetate. Combined organic layer was washed with water followed by brine solution. Ethylacetate was degassed under reduced pressure to get ( ?)-(4-benzyloxyphenyl)-ie/t- butoxycarbonylamino acetic acid.

To the above obtained acid derivative (6.4 g, 0.01795 mol) in dichloromethane (64 mL) was added Ν,Ο-dimethylhydroxylamine hydrochloride (2.15 g, 0.02208 mol), 1- hydroxybenztriazole (0.824 g, 0.00538 mol) and N-(3-dimethylaminopropyl)- V'- ethylcarbodiimide hydrochloride (4.23 g, 0.02208 mol) at ambient temperature. The mixture was cooled to 0-5 °C and N,N-diisopropylethylamine (11.03 mL, 0.0639 mol) was added slowly. Reaction mixture was stirred at room temperature for 2 hours. Reaction mixture was quenched with water and extracted with dichloromethane. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 °C to give crude, which was purified by column chromatography (silica gel 230-400 mesh, ethylacetate: n-hexane, 30:70) to get [(R)-(4- benzyloxyphenyl)(methoxymethylcarbamoyl)methyl]carbamic acid tert butyl ester.

Step II: [(R)-l-(4-Benzyloxyphenyl)-2-hydroxypropyl]carbamic acid tert butylester.

1M solution of methyl magnesium chloride in dichloromethane (11.2 mL, 0.01123 mol) was slowly added to a stirred solution of [( ?)-(4-benzyloxyphenyl)(methoxymethylcarbamoyl) methyl] carbamic acid ie/ -butyl ester (2.5 g, 0.00624 mol) in tetrahydrofuran at 0-5 °C. The mixture was allowed to stir at ambient temperature for 30 minutes. The mixture was cooled to 0-5 °C and quenched with saturated solution of ammonium chloride and then concentrated. Water was added and extracted with ethylacetate. Combined organic layer was washed with water followed by brine solution. Ethylacetate was degassed under reduced pressure to get [( ?)-l-(4-benzyloxyphenyl)-2-oxopropyl]carbamic acid tert butyl ester.

To the above obtained ketone derivative (2.4 g, 0.0067 mol) in methanol (25 mL) was added sodium borohydride (0.51 g, 0.0135 mol) slowly at -20 °C and stirred for 1 hour 30 minutes. The mixture was quenched with water and concentrated under reduced pressure at 35 °C. Aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, ethylacetate: n-hexane, 50:50) to get [(7?)-l-(4-benzyloxyphenyl)-2-hydroxypropyl]carbamic acid tert butylester.

Step III: [(/f)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-benzyloxyphenyl)propyl]carbamic acid tert butyl ester.

Z)z^'-ethylazodicarboxylate (1.29 mL, 0.0082 mol) was added to a stirred mixture of [(R)-l-(4- benzyloxyphenyl)-2-hydroxypropyl]carbamic acid tert-butyl ester (1.63g, 0.0045 mol), 5-benzyloxy-2-bromophenol (1.27 g, 0.0045 mol) and triphenylphosphine (1.67 g, 0.00638 mol) in tetrahydrofuran (20 mL) at 0-5 °C under nitrogen atmosphere. The mixture was stirred overnight for 16 hours at ambient temperature. Reaction mixture was degassed under reduced pressure at 40 °C and 10 % ethyl acetate in n-hexane solution (20 mL) was added to the residue, stirred and filtered. The filterate was concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 10:90) to get [( ?)-2-(5-benzyloxy-2-bromophenoxy)- l-(4- benzyloxyphenyl)propyl]carbamic acid tert butyl ester.

Step IV: (R)-7-Benzyloxy-3-(4-benzyloxyphenyl)-2-methyl-3,4-dihydro-2H- benzo[/,4]oxazine.

Trifluoroacetic acid (1.4 mL) was added to a stirred solution of [( ?)-2-(5-benzyloxy-2- bromophenoxy)-l-(4-benzyloxyphenyl)propyl]carbamic acid tert-buty\ ester (0.7 g, 0.0013 mol) in dichloromethane (7.0 mL) at 0-5 °C and then stirred at room temperature for 1 hour.

The mixture was diluted with dichloromethane (30 mL) and made alkaline (pH~9) with aqueous saturated sodium bicarbonate solution at 0-5 °C. Aqueous layer was extracted with dichloromethane and combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulfate. Dichloromethane was removed under reduced pressure to get ( ?)-2-(5-benzyloxy-2-bromophenoxy)-l-(4- benzyloxyphenyl)propylamine.

Potassium ie/t-butoxide (0.156 g, 0.00139 mol) was added to a stirred solution of (R)-2-(5- benzyloxy-2-bromophenoxy)-l-(4-benzyloxyphenyl)propylamine (0.516 g, 0.00099 mol), tris(dibenzylidineacetone)dipalladium (0.045 g, 0.000099 mol) and 2,2'- bis(diphenylphosphino)- l, l '-binaphthyl (0.062 g, 0.000099 mol) in toluene (5 mL) at room temperature under nitrogen atmosphere and then heated at 105 °C for two hour and thirty minutes. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to give crude liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 40: 60) to get (K)-7-benzyloxy-3-(4- benzyloxyphenyl)-2-methyl-3,4-dihydro-2H-benzo[i,4]oxazine. Step V: (R)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-[3-fluoro-4-(l-propylazetidin-3 ylox henyl]-2-methyl-3,4-dihydro-2H-benzo/7,4/oxazine.

Sodium ie/t-butoxide (0.084 g, 0.00088 mol) was added to a stirred mixture of (R)-7- benzyloxy-3-(4-benzyloxyphenyl)-2-methyl-3,4-dihydro-2H-benzo[i,4]oxazine (0.28 g, 0.000639 mol), 3-(4-bromo-2-fluorophenoxy)-l-propylazetidine (0.184 g, 0.000639 mol), palladium(II) acetate (0.007 g, 0.00003mol ) and tri-tert butylphosphine (0.025 mL, 50 % solution in toluene, 0.00006 mol) in toluene (8 mL). Reaction mixture was heated at 105 °C for 2 hours under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to give a residue, which was purified by column chromatography (silica gel 230-400 mesh, dichloromethane: methanol, 98:02) to get (R)-7- benzyloxy-3-(4-benzyloxyphenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-2- methyl-3,4-dihydro-2H-benzo[i,4]oxazine.

Step VI: (3/?)-4-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4-hydroxyphenyl)-2- methyl-3,4-dihydro-2H-benzoA/,4/oxazin-7-ol.

5 % Palladium on charcoal (0.126 g, 50 % wet) followed by ammonium formate (0.309 g, 0.0049 mol) were added to a solution of ( ?)-7-benzyloxy-3-(4-benzyloxyphenyl)-4-[3-fluoro- 4-(l-propylazetidin-3-yloxy)phenyl]-2-methyl-3,4-dihydro-2H-benzo[i,4]oxazine (0.317 g, 0.00049 mol) in a mixture (8 mL) of methanol: 1,4-dioxane (1 : 1) at room temperature. The resultant reaction mixture was heated at 70 °C for 30 minutes. It was allowed to cool, filtered through celite bed and washed with methanol: 1,4-dioxane (1 : 1) mixture. Combined filtrate was concentrated under reduced pressure to give a residue, to which water was added and extracted with ethyl acetate. Combined organic layer was washed with brine solution and then dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to give a residue at 40 °C, which was purified by column chromatography (silica gel 230-400 mesh, dichloromethane: methanol, 90: 10) to get (3 ?)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3-(4-hydroxyphenyl)-2-methyl-3,4-dihydro-2H-benzo i,47oxazin-7-ol (Compound No. 20).

Example 6 : Preparation of 4-|(/?)-6-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)-phenyl1- 3,6,7,8-tetrahvdro-9-oxa-2,3,6-triazacvclopenta[61naphthalen-6-yl|phenol (Compound No. 27).

Step I: 5-Bromo-/H-indazol-4-ol.

1M solution of boron tribromide in dichloromethane (36.5 mL, 0.0365 mol) was added to a stirred solution of 5-bromo-4-methoxy- lH-indazole (2.78 g, 0.012 mol) in dichloromethane (27.8 mL) at 0-5 °C. The mixture was stirred at room temperature for 16 hours. Reaction mixture was reverse quenched in ice-water and basified with sodium bicarbonate till alkaline (pH~9) and filtered through sintered funnel. Solid was dissolved in ethylacetate and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to get 5- bromo-iH-indazol-4-ol. Step II: 5-Bromo-l-(tetrahydropyran-2-yl)-4-(tetrahydropyan-2-yloxy)-/H-indazole.

To a stirred solution of 5-bromo-iH-indazol-4-ol (2.19.0 g, 0.01 mol) in (1 : 1) mixture of dichloromethane and tetrahydrofuran at 0-5 °C was added 3,4-dihydro-2H-pyran (4.65 mL, 0.0514 mol) followed by methanesulphonic acid (0.134 mL, 0.002 mol). The mixture was stirred at room temperature for 10 mins. Reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. Combined organic layer was washed with brine solution and dried over anhydrous sodium sulphate. Dichloromethane was removed under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh), ethylacetate: n-hexane (25:75) to get 5-bromo- l- (tetrahydropyran-2-yl)-4-(tetrahydropyan-2-yloxy)-iH-indazole.

Step III: 5-Bromo-l-(tetrahydropyran-2-yl)-/H-indazol-4-ol.

To a stirred solution of 5-bromo-l-(tetrahydropyran-2-yl)-4-(tetrahydropyan-2-yloxy)-iH- indazole (4.68 g, 0.0122 mol) in 1,4-dioxane (9.36 mL) was added 4M HC1 in 1,4-dioxane (12.16 mL) at 0-5 °C. The mixture was stirred for 10 min at 0-5 °C. The mixture was diluted with ethylacetate (100 mL) and made alkaline (pH~9) with aqueous saturated sodium bicarbonate solution. Aqueous layer was extracted with ethylacetate. Combined organic layer was dried over anhydrous sodium sulphate. Ethylacetate was removed under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh), ethylacetate: n-hexane (25: 75) to get 5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-4-ol. Step IV: [(/f)-2-[5-Bromo-l-(tetrahydropyran-2-yl)-/H-indazol-4-yloxy]-l-(4- fluoro henyl)ethyl]carbamic acid tert butyl ester.

Z)z^'-isopropylazodicarboxylate (1.064 ml, 0.0054 mol) was added to a stirred mixture of [(R)- l-(4-fluorophenyl)-2-hydroxyethyl]carbamic acid tert butyl ester (1.27 g, 0.00499 mol), 5- bromo- l-(tetrahydropyran-2-yl)-iH-indazol-4-ol (1.236 g, 0.00415 mol) and triphenylphosphine (1.309 g, 0.00499 mol) in tetrahydrofuran (30 mL) under nitrogen atmosphere at 0-5 °C and subsequently allowed to stir at room temperature for 2 hours. Reaction mixture was quenched with water and concentrated and then extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure at 50 °C to give crude viscous liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 20: 80) to get the title compound. Step V: (/f)-2-[5-Bromo-l-(tetrahydropyran-2-yl)-/H-indazol-4-yloxy]-l-(4- fluorophenyl)ethylamine.

Anhydrous zinc bromide (3.89 g, 0.0173 mol) was added to a stirred solution of [( ?)-2-[5- bromo- l-(tetrahydropyran-2-yl)- lH-indazol-4-yloxy]-l-(4-fluorophenyl)ethyl]carbamic acid tert butyl ester (1.85 g, 0.00346 mol) in dichloromethane (25 mL) at room temperature and stirred for 6 hours. Reaction mixture was cooled to 0-5 °C and basified with saturated sodium bicarbonate solution and extracted with dichloromethane. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get ( ?)-2-[5-bromo- l-(tetrahydropyran-2-yl)-iH- indazol-4-yloxy]- l-(4-fluorophenyl)ethylamine, which was used for the next step without further purification. Step VI: (R 7-(4-Fluorophenyl)-3-(tetrahydropyran-2-yl)-3,6,7,8-tetrahyd]

2,3,6-triazac clopenta[a]naphthalene.

Potassium ie/t-butoxide (0.614 g, 0.0054 mol) was added to a stirred solution of (R)-2-[5- bromo- l-(tetrahydropyran-2-yl)-iH-indazol-4-yloxy]-l-(4-fluorophenyl)ethylamine (1.7 g, 0.0039 mol), tris(dibenzylideneacetone)dipalladium (0.179 g, 0.000195 mol) and 2,2'- bis(diphenylphosphino)- l, -binaphthyl (0.244 g, 0.00039 mol) in toluene (17 mL) under nitrogen atmosphere. Reaction mixture was heated at 110 °C for 1 hour 40 minutes. It was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give viscous liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n- hexane, 20:80) to get ( ?)-7-(4-fluorophenyl)-3-(tetrahydropyran-2-yl)-3,6,7,8-tetrahydro-9- oxa-2,3,6-triazacyclopenta[a]naphthalene.

Step VII: (/?)-6-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(4-fluorophenyl)-3- (tetrahydropyran-2-yl)-3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[a]naphthalene.

Sodium ie/ -butoxide (0.131 g, 0.00136 mol) was added to a stirred mixture of (R)-7-(4- fluorophenyl)-3-(tetrahydropyran-2-yl)-3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[i3] naphthalene (0.35 g, 0.00099 mol), 3-(4-bromo-2,6-difluorophenoxy)-l-propylazetidine (0.318g, 0.001 mol), palladium acetate (0.011 g, 0.000049 mol) and tri-tert butylphosphine (0.040 mL, 0.000099 mol, 50 % solution in toluene) in toluene (8 mL) under nitrogen atmosphere and then heated at 105 °C for 1 hour 30 minutes. Reaction mixture was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 01:99) to get ( ?)-6-[3,5-difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(4-fluorophenyl)-3- (tetrahydropyran-2-yl)-3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[i3]naphthalene.

Step VIII: (R)-6-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(4-fluorophenyl)- 3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[a]naphthalene.

4M Hydrochloric acid in 1,4-dioxane (2.25 mL) was added to a stirred solution of ( ?)-6-[3,5- difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(4-fluorophenyl)-3-(tetrahydropyran-2-yl)- 3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[(3]naphthalene (0.45 g, 0.00077 mol) in ethanol (2.25 mL) at room temperature. Reaction mixture was heated at 70 °C for 30 minutes. The reaction mixture was cooled to 0-5 °C and was basified with saturated sodium bicarbonate solution and extracted with ethylacetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude thus obtained was purified by column chromatography (silica gel 230-400 mesh, dichloromethane: methanol (98: 2) to get ( ?)-6-[3,5-difluoro-4-(l-propylazetidin-3- yloxy)phenyl]-7-(4-fluorophenyl)-3,6,7,8-tetrahydro-9-oxa-2,3,6- triazacyclopenta[(3] naphthalene (Compound No. 27). The obtained product was dissolved in appropriate solvent and treated with hydrochloric acid to get hydrochloride salt of the compound No. 27.

Example 7: Preparation of (R)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[/,4]oxazin-7-ol (Compound No. 17).

Step I: [(/f)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethyl]carbamic acid tert-butyl ester.

Z)z^'-isopropyl azodicarboxylate (3.85 mL, 0.019 mol) was added dropwise to a stirred mixture of [(7?)-l-(4-fluorophenyl)-2-hydroxyethyl]carbamic acid tert butyl ester (3.5 g, 0.0136 mol), 5-benzyloxy-2-bromophenol (3.8 g, 0.0136 mol) and triphenylphosphine (4.64 g, 0.0177 mol) in tetrahydrofuran (40 mL) under nitrogen atmosphere at ambient temperature. The resultant reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated and degassed under reduced pressure at 40 °C. The mixture (90 mL) of n-hexane: ethyl acetate (90: 10) was added to the residue and contents were stirred vigorously for 30 minutes. Solid thus obtained was filtered under vacuum and washed with same mixture. Combined filtrate was concentrated and degassed under reduced pressure at 40 °C to give residue, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 10: 90) to get [( ?)-2-(5-benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethyl]carbamic acid ie/ -butyl ester.

Step II: (R)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethylamine.

Trifluoroacetic acid (5.2 niL) was added to a stirred solution of [( ?)-2-(5-benzyloxy-2- bromophenoxy)-l-(4-fluorophenyl)ethyl]carbamic acid ie/ -butyl ester (2.6 g, 0.0051 mol) in dichloromethane (13 niL) at 0-5 °C and then stirred at room temperature for 1 hour. Reaction mixture was cooled to 0-5 °C and diluted with dichloromethane and made alkaline (pH~9) with aqueous 10% sodium hydroxide solution. Organic layer was separated, washed with brine solution and then dried over anhydrous sodium sulfate. Removal of dichloromethane under reduced pressure gave ( ?)-2-(5-benzyloxy-2-bromophenoxy)- l-(4- fluorophenyl)ethylamine, which was directly used for the next step without any further purification.

Step III: (/?)-7-Benzyloxy-3-(4-fluorophenyl)-3,4-dihydro-2H-benzo[/,4]oxazine.

Potassium ie/t-butoxide (0.74 g, 0.0066 mol) was added to a stirred solution of (R)-2-(5- benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethylamine (2.0 g, 0.0048mol), tris(dibenzylidineacetone)dipalladium (0.22 g, 0.0002 mol) and 2,2'-bis(diphenylphosphino)- Ι, Γ-binaphthyl (0.3 g, 0.00048 mol) in toluene (20 mL) at room temperature under nitrogen atmosphere and then heated at 105 °C for half an hour. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to give crude liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethylacetate: n-hexane, 07: 93) to get (7?)- 7-benzyloxy-3-(4-fluorophenyl)-3,4-dihydro-2H-benzo[i,4]oxazine. Step IV: (/f)-7-Benzyloxy-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3

-yloxy)phenyl]-3,4-dihydro-2H-benzo[/,4]oxazine.

Sodium ie/t-butoxide (0.079 g, 0.00083 mol) was added to a stirred mixture of (R)-7- benzyloxy-3-(4-fluorophenyl)-3,4-dihydro-2H-benzo[i,4]oxazine (0.2 g, 0.00059 mol), 3-(4- bromo-2-fluorophenoxy)-l-propylazetidine (0.163 g, 0.00059 mol), palladium(II) acetate (0.007 g, 0.0000295 mol ) and tri ie/ -butylphosphine (0.024 mL, 0.000059 mol, 50 % solution in toluene) in toluene (6 mL). Reaction mixture was heated at 105 °C for 1 hour under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to give a residue, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 03: 97) to get ( ?)-7-benzyloxy-3-(4- fluorophenyl)-4- [3-fluoro-4-( 1 -propylazetidin-3-yloxy)phenyl] -3 ,4-dihydro-2H- benzo [1 , 4] oxazine . Step V: (/?)-3-(4-Fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4- dihydro-2H-benzo[/,4]oxazin-7-ol.

5% Palladium on charcoal (0.04 g, 50% wet) followed by ammonium formate (0.235 g, 0.00379 mol) were added to a stirred solution of ( ?)-7-benzyloxy-3-(4-fluorophenyl)-4-[3- fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazine (0.2 g, 0.000379 mol) in a mixture (1: 1) of methanol (3 mL) and 1,4-dioxane (3 mL). The resultant reaction mixture was heated at 70 °C for 1 hour. Reaction mixture was cooled to room temperature, filtered through celite bed and washed with an (1: 1) mixture of methanol and 1,4-dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with dichloromethane. Combined organic layer washed with brine solution and dried over anhydrous sodium sulphate. Dichloromethane was removed under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 05: 95) to get ( ?)-3- (4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H- benzo[i,4]oxazin-7-ol (Compound No. 17).

Example 8: Preparation of |(/?)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl1 -3,4-dihydro-2H-benzo|7,41oxazin-7- ylldihydrogen phosphate (Compound

No. 28).

Step I: Di-tert-butyl [(/f)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[/,4]oxazin-7yl]phosphite.

To a stirred solution of ( ?)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin- 3yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazin-7-ol (0.47 g, 0.0011 mol) in acetonitrile (5.0 mL) was added iH-tetrazole (0.154 g, 0.022 mol) and di-tert-butyl-N,N-diethyl phosphoramidite (0.45 mL, 0.0016 mol) sequentially at 0-5 °C. The mixture was then stirred at room temperature for 1 hour. Reaction mixture was degassed under reduced pressure at 40 °C to get di-ieri-butyl[( ?)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazin-7-yl]phosphite, which was used for the next step without any further purification. Step II: Di-tert-butyl [(R)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[/,4]oxazin-7yl]phosphate.

ie/t-Butyl hydroperoxide (2.5 mL, 70% solution in water) was added slowly to a stirred solution of di-ie/ -butyl [( ?)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazin-7-yl]phosphite (1.0 g, 0.00159 mol) in tetrahydrofuran at ambient temperature. The mixture was stirred at room temperature for 1 hour. Reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 06:94) to get di-ieri- butyl[( ?)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro- 2H-benzo [1 , 4] oxazin-7 -yl] pho sphate . Step III: {(R)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4- dihydro-2H-benzo[/,4]oxazin-7-yl}dihydrogen phosphate.

4M Hydrochloric acid in 1,4-dioxane (4.0 niL) was added to di-ie/ -butyl [( ?)-3-(4- fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4] oxazin-7-yl]phosphate (0.4 g, 0.00062 mol) at room temperature. The mixture was stirred for 2 hours. Reaction mixture was degassed under reduced pressure at 50 °C. To the residue, diethylether was added and stirred at room temperature for 1 hour. Solid thus obtained was filtered and dried under nitrogen to get { ( ?)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l- propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazin-7-yl}dihydrogen phosphate (compound No. 28). The obtained product was dissolved in appropriate solvent and treated with sodium hydroxide to get disodium salt of the compound No. 28.

Example 9: Preparation of (E)-4-(3-(2_<6-Difluoro-4-r(R)-7-(4-fluorophenyl)-7_<8- dihvdro-3H-9-oxa-2,3.i6-triazacvclopenta[a1naphthalen-6-yl1phenoxylazetidin-l-yl)but- 2-enoic acid dimethylamide (Compound No. 35).

Step-I: 3-(4-Bromo-2,6-difluorophenoxy)azetidine-l-carboxylic acid tert butyl ester.

To a stirred solution of 3-(4-bromo-2,6-difluorophenoxy)azetidine (0.45 g, 0.001704 mol) in dichloromethane (8.0 mL) was added triethylamine (0.355 mL, 0.00255 mol) and di-tert butyldicarbonate (0.45 mL, 0.00204 mol) sequentially at 0-5 °C. The mixture was stirred at room temperature for 30 minutes. Reaction mixture was quenched with water and extracted with dichloromethane. Combined organic layer was washed with brine solution and then dried over anhydrous sodium sulfate. Dichloromethane was removed under reduced pressure to give a residue, which was purified by column chromatography (silica gel 230-400 mesh, ethylacetate: n-hexane, 30:70) to get 3-(4-bromo-2,6-difluorophenoxy)azetidine-l-carboxylic acid tert butyl ester.

Step-II: 3-{2,6-Difluoro-4-[(R)-7-(4-fluorophenyl)-3-(tetrahydropyran-2-yl)-7,8-dihydro- 3H-9-oxa-2,3,6-triazacyclopenta[a]naphthalen-6-yl]phenoxy}azetidine-l-carboxylic acid tert-but l ester.

Sodium ie/t-butoxide (0.155 g, 0.0016 mol) was added to a stirred mixture of (R)-T-(4- fluorophenyl)-3-(tetrahydropyran-2-yl)-3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta

[a] naphthalene (0.412 g, 0.001166 mol), 3-(4-bromo-2,6-difluorophenoxy)azetidine- l- carboxylic acid tert-butyl ester (0.425 g, 0.001166 mol), palladium acetate (0.013 g, 0.000058 mol) and tri-tert butylphosphine (0.05 mL, 0.000116 mol, 50 % solution in toluene) in toluene (10 mL) under nitrogen atmosphere and then heated at 110 °C for 1 hour. Reaction mixture was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, ethylacetate: n- hexane, 20:80) to get 3-{2,6-difluoro-4-[( ?)-7-(4-fluorophenyl)-3-(tetrahydropyran-2-yl)- 7,8-dihydro-3H-9-oxa-2,3,6-triazacyclopenta[(3]naphthalen-6-yl]phenoxy}azetidine-l- carboxylic acid ieri-butyl ester.

Step-III: (R)-6-[4-(Azetidin-3-yloxy)-3,5-difluorophenyl]-7-(4-fluorophenyl)-3,6,7,8- tetrahydro-9-oxa-2 3,6-triazacyclopenta[a]naphthalene.

Trifluoroacetic acid (1.2 mL) was added slowly to a stirred solution of 3-{2,6-difluoro-4- [( ?)-7-(4-fluorophenyl)-3-(tetrahydropyran-2-yl)-7,8-dihydro-3H-9-oxa-2,3,6- triazacyclopenta[(3]naphthalen-6-yl]phenoxy}azetidine-l-carboxylic acid ie/ -butyl ester (0.6 g, 0.00094 mol) in dichloromethane (5.0 mL) at 0-5 °C and then stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane (30 mL) and made alkaline (pH~9) with aqueous saturated sodium bicarbonate solution at 0-5 °C. Aqueous layer was extracted with dichloromethane and combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulfate. Dichloromethane was removed under reduced pressure to get ( ?)-6-[4-(azetidin-3-yloxy)-3,5-difluorophenyl]-7-(4-fluorophenyl)- 3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[(3]naphthalene. Step-IV: (E)-4-(3-{2,6-Difluoro-4-[(R)-7-(4-fluorophenyl)-7,8-dihydro-3H-9-oxa-2,3,6- triazacyclopenta[a]naphthalen-6-yl]phenoxy}azetidin-l-yl)but-2-enoic acid dimethylamide.

To a stirred solution of ( ?)-6-[4-(azetidin-3-yloxy)-3,5-difluorophenyl]-7-(4-fluorophenyl)- 3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[(3]naphthalene (0.3 g, 0.00066 mol) in acetonitrile (5.0 mL) was added dz^'-isopropylethylamine (0.171mL, 0.00099 mol) and (E)-4- bromobut-2-enoic acid dimethylamide (0.124 g, 0.00065 mol) sequentially at 0-5 °C. The mixture was stirred for one hour at 0-5 °C and then stirred at room temperature for 30 minutes. To the reaction mixture, water was added and extracted with ethyl acetate. Combined organic layer was washed with brine solution and then dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to give a residue, which was purified by column chromatography (silica gel 230-400 mesh, dichloromethane: methanol, 96:04) to get (E)-4-(3-{2,6-difluoro-4-[( ?)-7-(4-fluorophenyl)-7,8-dihydro-3H-9- oxa-2,3,6-triazacyclopenta[a]naphthalen-6yl]phenoxy}azetidin- l-yl)but-2-enoic acid dimethylamide (Compound No. 35). The obtained product was dissolved in appropriate solvent and treated with hydrochloric acid to get the hydrochloride salt of the compound No. 35.

Example 10: Preparation of (/?)-8-dimethylaminomethyl-3-(4-fluorophenyl)-4-[3- fluoro-4-(l-propylazetidin-3-yloxy)phenyl1-3,4-dihvdro-2H-benzo[/,41oxazin-7-ol (Compound No. 36).

To a stirred solution of ( ?)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[J4]oxazin-7-ol (0.32 g, 0.000732 mol) in 1,4-dioxane (5 niL) was added aqueous formaldehyde solution (0.07 mL, 0.000879 mol, 37% in water), aqueous dimethylamine solution (0.1 mL, 0.000879 mol, 40% solution in water) and glacial acetic acid (0.03 mL, 0.0000732 mol) at ambient temperature. The mixture was heated at 75 °C for 15 minutes. Reaction mixture was cooled to room temperature and made alkaline (pH~9) with aqueous saturated sodium bicarbonate solution. Aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. Combined organic layer was washed with brine solution and then dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to give a residue, which was purified by column chromatography (silica gel, 240-400 mesh, methanol: dichloromethane, 05: 95) to get (R)-S- dimethylaminomethyl-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]- 3,4-dihydro-2H-benzo[i,4]oxazin-7-ol (Compound No. 36). The obtained product was dissolved in appropriate solvent and treated with hydrochloric acid to obtain its hydrochloride salt. Example 11; Preparation of 4-[(/?)-4-[3,5-difluoro-4-(l-propylazetidin-3-yloxy)phenyl1-

7-(lH-pyrazol-4-yl)-3,4-dihvdro-2H-benzo[/,41oxazin-3-yl1-phenol (Compound No. 38

Step I: (/f)-[(9H-Fluoren-9-ylmethoxycarbonylamino)]-(4-hydroxyphenyl)acetic acid methyl ester.

To a stirred solution of 4-hydroxy-(Z))-phenylglycine (50.0 g, 0.299 mol) in methanol (500 mL) was added thionyl chloride (32.66 mL, 0.499 mol) at 0-5 °C. The mixture was then allowed to stir overnight at room temperature. Reaction mixture was concentrated under reduced pressure at 50 °C to get hydrochloride salt of ( ?)-amino-(4-hydroxyphenyl)acetic acid methyl ester. To the above obtained compound (40.0 g, 0.184 mol) was added tetrahydrofuran (400.0 mL) and triethylamine (56.3 mL, 0.404 mol), followed by 9- fluorenmethylsuccimidyl carbonate (68.2 g, 0.202 mol) at 0-5 °C. The mixture was then stirred at room temperature for 2 hours. Reaction mixture was concentrated under reduced pressure at 35 °C to get crude which was purified by column chromatography (silica gel 230- 400 mesh, ethyl acetate: n-hexane, 50: 50) to get ( ?)-[(9H-fluoren-9- ylmethoxycarbonylamino)]-(4-hydroxyphenyl)acetic acid methyl ester.

Step II: (/f)-[(9H-Fluoren-9-ylmethoxycarbonylamino)]-[4-(tetrahydropyran-2-yloxy)- phenyl]acetic acid methyl ester.

To a stirred solution of ( ?)-[(9H-fluoren-9-ylmethoxycarbonylamino)]-(4- hydroxyphenyl) acetic acid methyl ester (58.46 g, 0.145 mol) in dichloromethane (584.6 mL) was added pyridinium para toluene sulphonate (3.64 g, 0.0145 mol) and 3,4-dihydro-2H- pyran (39.5 mL, 0.435 mol) sequentially at 0-5 °C. The mixture was then stirred at room temperature for 4 hours. Reaction mixture was quenched with water and extracted with dichloromethane. Combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulphate. Organic layer was removed under reduced pressure to give crude, to which, n-hexane (753 mL) was added and stirred for 1 hour. Solid thus obtained was filtered and dried under reduced pressure to get ( ?)-[(9H-fluoren-9- ylmethoxycarbonylamino)]-[4-(tetrahydropyran-2-yloxy)phenyl] acetic acid methyl ester.

Step III: (R)-2-Amino-2-(4-tetrahydropyran-2-yloxyphenyl)ethanol.

To a stirred solution of get ( ?)-[(9H-fluoren-9-ylmethoxycarbonylamino)]-[4- (tetrahydropyran-2-yloxy)phenyl]acetic acid methyl ester (63.0 g, 0.129 mol) in tetrahydrofuran (441 mL) was added sodium borohydride (12.23 g, 0.323 mol) at 0-5 °C. Ethanol (945.0 mL) was added slowly to the reaction mixture. The mixture was then allowed to stir overnight at room temperature. Water was added and concentrated under reduced temperature at 40 °C and extracted with dichloromethane. Combined organic layer was washed with brine solution and dried over anhydrous sodium sulphate. Dichloromethane was removed under reduced pressure to give crude, to which, n-hexane (250 mL) was added and stirred for 1 hour. Solid thus obtained was filtered and dried under reduced pressure to get ( ?)-2-amino-2-(4-tetrahydropyran-2-yloxyphenyl)ethanol.

Step IV: {(/?)-2-hydroxy-l-[4-(tetrahydropyran-2-yloxy)phenyl]ethyl}carbamic acid 9H- fluoren-9-ylmethyl ester.

To a stirred solution of ( ?)-2-amino-2-[4-(tetrahydropyran-2-yloxy)phenyl]ethanol (29.5 g, 0.124 mol) in tetrahydrofuran (295.0 mL) was added triethylamine (20.8 mL, 0.149 mol) and 9-fluorenmethylsuccimidyl carbonate (46.18 g, 0.137 mol) sequentially at 0-5 °C. The mixture was then stirred at room temperature for 1 hour. Reaction mixture was concentrated under reduced pressure at 35 °C to get crude, to which was added water (600.0 mL) and stirred for 1 hour and then filtered. Solid thus obtained was purified by adding a solution of 15% ethylacetate in n-hexane (1200 mL) and stirred for 1 hour. Solid obtained was filtered and dried under reduced pressure at 55 °C to get { ( ?)-2-hydroxy- l-[4-(tetrahydropyran-2- yloxy)phenyl] ethyl jcarbamic acid 9H-fluoren-9-ylmethyl ester.

Step V: {(R)-2-(5-Benzyloxy-2-bromophenoxy)-l-[4-(tetrahydropyran-2- loxy)phenyl]ethyl}carbamic acid 9H-fluoren-9-ylmethyl ester.

Z)z^'-isopropylazodicarboxylate (9.5 niL, 0.045 mol) was added to a stirred mixture of { (R)-2- hydroxy- l-[4-(tetrahydro-pyran-2-yloxy)phenyl]ethyl}carbamic acid 9H-fluoren-9- ylmethylester (15.0g, 0.032 mol), 5-benzyloxy-2-bromophenol (8.2 g, 0.029 mol) and triphenylphosphine (11.1 g, 0.094 mol) in tetrahydrofuran (225 mL) under nitrogen atmosphere. Reaction mixture was stirred for further 45 minutes at 0-5 °C. To the mixture, water was added and extracted with ethyl acetate. The combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gave residue, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 15:85) to get { (R)-2-(5- benzyloxy-2-bromophenoxy)-l-[4-(tetrahydropyran-2-yloxy)phenyl]ethyl}carbamic acid 9H- fluoren-9-ylmethyl ester.

Step VI: (R)-2-(5-benzyloxy-2-bromophenoxy)-l-(4-tetrahydropyran-2- yloxyphenyl)ethylamine.

Diethylamine (70.8 mL) was slowly added to a stirred solution of { ( ?)-2-(5-benzyloxy-2- bromophenoxy)- 1 - [4-(tetrahydropyran-2-yloxy)phenyl]ethyl } carbamic acid 9H-fluoren-9- ylmethyl ester (11.8 g, 0.016 mol) in tetrahydrofuran (118 niL) at ambient temperature for 2 hours. Reaction mixture was degassed under reduced pressure to get residue, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 3:97) to get ( ?)-2-(5-benzyloxy-2-bromophenoxy)- l-[4-(tetrahydropyran-2- yloxy)phenyl]ethylamine.

Step VII: (/f)-7-Benzyloxy-3-[4-(tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H- benzo[/,4]oxazine.

Potassium ie/t-butoxide (2.34 g, 0.0209 mol) was added to a stirred solution of (R)-2-(5- benzyloxy-2-bromo-phenoxy)- l-[4-(tetrahydropyran-2-yloxy)-phenyl]ethylamine (7.44 g, 0.0149 mol), tris(dibenzylidineacetone)dipalladium (0.684 g, 0.00074 mol) and 2,2'- bis(diphenylphosphino)- l, l '-binaphthyl (0.93 g, 0.00149 mol) in toluene (74.4 mL) at room temperature under nitrogen atmosphere and then heated at 105 °C for one hour. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to give crude liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 15:85) to get ( ?)-7-benzyloxy-3-[4-(tetrahydropyran-2-yloxy)phenyl]-3,4- dihydro-2H-benzo [1 , 4] oxazine .

Step VIII: (/f)-7-Benzyloxy-4-[3,5-difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-[4- (tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H-benzo[/,4]oxazine.

Sodium ie/t-butoxide (0.29 g, 0.003 mol) was added to a stirred mixture of ( ?)-7-benzyloxy- 3-[4-(tetrahydropyran-2-yloxy)-phenyl]-3,4-dihydro-2H-benzo[i,4]oxazine (0.9 g, 0.0021 mol), 3-(4-bromo-2,6-difluorophenoxy)-l-propylazetidine (0.66 g, 0.0021mol), palladium acetate (0.024 g, 0.0001 mol) and td-tert butylphosphine (0.087 mL, 0.0002 mol, 50 % solution in toluene) in toluene (8 mL) under nitrogen atmosphere and then heated at 105 °C for 1 hour 30 minutes. Reaction mixture was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 05:95) to get ( ?)-7-benzyloxy-4-[3,5-difluoro-4- (l-propylazetidin-3-yloxy)phenyl]-3-[4-(tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H- benzo [1 , 4] oxazine .

Step IX: (/?)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-[4-(tetrahydropyran- 2-yloxy)phenyl]-3,4-dihydro-2H-benzo[/,4]oxazin-7-ol.

5 % Palladium on charcoal (0.18 g, 50 % wet) followed by ammonium formate (0.88 g, 0.014 mol) was added to a stirred solution of ( ?)-7-benzyloxy-4-[3,5-difluoro-4-(l-propylazetidin- 3-yloxy)phenyl]-3-[4-(tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazine (0.9 g, 0.0014 mol) in (1: 1) mixture of methanol (5 mL) and 1,4-dioxane (5 mL) at room temperature. The resultant reaction mixture was heated at 65 °C for 30 minutes. Reaction mixture was cooled to room temperature, filtered through celite bed and washed with a (1: 1) mixture of methanol and 1, 4-dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with ethyl acetate. Combined organic layer washed with water followed by brine solution and dried over anhydrous sodium sulphate. Ethylacetate was removed under reduced pressure to get ( ?)-4-[3,5-difluoro-4-(l- propylazetidin-3-yloxy)phenyl]-3-[4-(tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H- benzo[i,4]oxazin-7-ol, which was used for the next step without further purification. Step X: (R)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-[4-(tetrahydropyran-

2-yloxy)phenyl]-7-[l-(tetrahydropyran-2-yl)-/H-pyrazol-4-yl]-3,4-dihydro-2H- benzo[/,4]oxazine.

Triflic anhydride (0.2 mL, 0.0012 mol) was added to a stirred solution of ( ?)-4-[3,5-difluoro- 4-(l-propylazetidin-3-yloxy)phenyl]-3-[4-(tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H- benzo[l,4]oxazin-7-ol (0.55 g, 0.000995 mol) in dichloromethane (10 mL) and pyridine (0.47 mL, 0.006 mol) at 0-5 °C. The mixture was allowed to stir at ambient temperature for 1 hour, and quenched with water and extracted with dichloromethane. Combined organic layer was washed with water followed by brine solution. Dichloromethane was degassed under reduced pressure to get trifluoromethanesulfonic acid ( ?)-4-[3,5-difluoro-4-(l-propylazetidin-3- yloxy)phenyl] -3 - [4-(tetrahydropyran-2-yloxy)phenyl] -3 ,4-dihydro-2H-benzo [ 1 ,4] oxazin-7-yl ester. To the above obtained triflate derivative (0.64 g, 0.00093 mol) in acetonitrile (7.0 mL) was added l-(tetrahydropyran-2-yl)-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-iH- pyrazole (0.416 g, 0.0015 mol) and bis(triphenylphosphine)palladium(II)dichloride (0.065 g, 0.000093 mol) under nitrogen atmosphere. An aqueous solution of sodium carbonate (0.297 g, 0.0028 mol) in water (3.0 mL) was added slowly at ambient temperature. The mixture was heated at 90 °C for half an hour. Reaction mixture was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 05: 95) to get (R)-4- [3,5-difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-[4-(tetrahydropyran-2-yloxy)phenyl]-7- [l-(tetrahydropyran-2-yl)-lH-pyrazol-4-yl]-3,4-dihydro-2H-benzo[i,4]oxazine. Step XI: 4-[(R)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(lH-pyrazol-4-yl)- 3,4-dihydro-2H-benzo[/,4]oxazin-3-yl]phenol.

4M Hydrochloric acid in 1,4-dioxane (1.25 niL) was added to a stirred solution of (R)-4-[3,5- difluoro-4-( 1 -propylazetidin-3-yloxy)phenyl] -3- [4-(tetrahydropyran-2-yloxy)phenyl] -7- [ 1 - (tetrahydropyran-2-yl)- lH-pyrazol-4-yl]-3,4-dihydro-2H-benzo[i,4]oxazine in ethanol (2.5 niL) at room temperature. The mixture was stirred for 1 hour. Reaction mixture was concentrated under reduced pressure at 40 °C. Residue was basified to pH~ 8 using saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 08: 92) to get 4-[(R)-4-[3,5-difluoro-4-(l- propylazetidin-3-yloxy)phenyl]-7-(iH-pyrazol-4-yl)-3,4-dihydro-2H-benzo[i,4]oxazin-3- yl]phenol (Compound No. 38). It was dissolved in appropriate solvent and treated with hydrochloric acid to obtain hydrochloride salt of compound no. 38.

Example 12: Preparation of (/?)-7-fluoro-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl1-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[/,41oxazine (Compound No,

51}.

Step I: [(/f)-2-(2-Bromo-5-fluorophenoxy)-l-(4-methoxyphenyl)ethyl]carbamic acid tert butyl ester.

Z)z^'-isopropylazodicarboxylate ( 1.52 mL, 0.00732 mol) was added to a stirred mixture of [( ?)-2-hydroxy-l-(4-methoxyphenyl)ethyl]carbamic acid ieri-butyl ester (1.4 g, 0.0052 mol), 2-bromo-5-fluorophenol (1 g, 0.0052 mol) and triphenylphosphine (1.78 g, 0.0068 mol) in tetrahydrofuran (15 mL) under nitrogen atmosphere. Reaction mixture was stirred for further 2 hours at ambient temperature. The mixture was concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel, acetone: n-hexane, 15: 85) to get [( ?)-2-(2-bromo-5-fluorophenoxy)-l-(4-methoxyphenyl)ethyl]carbamic acid tert- butyl ester.

Step II: (/?)-2-(2-Bromo-5-fluorophenoxy)-l-(4-methoxyphenyl)ethylamine.

Trifluoroacetic acid (2.2 mL) was added to a stirred solution of [(7?)-2-(2-bromo-5- fluorophenoxy)-l-(4-methoxyphenyl)ethyl]carbamic acid ie/ -butyl ester (1.1 g, 0.0025 mol) in dichloromethane (11 mL) at 0-5 °C and then stirred at ambient temperature for 1 hour. Reaction mixture was diluted with dichloromethane and made alkaline (pH~9) with aqueous saturated sodium bicarbonate solution. Organic layer was separated, washed with brine solution and then dried over anhydrous sodium sulfate. Removal of dichloromethane under reduced pressure gave ( ?)-2-(2-bromo-5-fluorophenoxy)-l-(4-methoxyphenyl)ethylamine, which was directly used for the next step without further purification. Step III: (/?)-7-Fluoro-3-(4-methoxphenyl)-3,4-dihydro-2H-benzo[/,4]oxazine.

Potassium ie/ -butoxide (0.4 g, 0.0035 mol) was added to a stirred mixture of (R)-2-(2- bromo-5-fluorophenoxy)-l-(4-methoxyphenyl)ethylamine (0.88 g, 0.00258 mol), ins(dibenzylideneacetone)dipalladium (0.118 g, 0.000129 mol) and 2,2'- Ws(diphenylphosphino)- l, l '-binaphthyl (0.16 g, 0.00025 mol) in toluene (10 mL). Reaction mixture was then heated at 105 °C for 2 hours under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulfate. Removal of ethyl acetate under reduced pressure gave residue, which was purified by column chromatography (silica gel, ethyl acetate: n-hexane, 15: 85) to get (R)-7- fluoro-3-(4-methoxphenyl)-3,4-dihydro-2H-benzo[i,4]oxazine.

Step IV: (/f)-7-Fluoro-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4- methoxyphenyl)-3,4-dihydro-2H-benzo[/,4]oxazine.

Sodium ie/t-butoxide (0.078 g, 0.0008 mol) was added to a stirred mixture of (R)-7-fluoro-3- (4-methoxphenyl)-3,4-dihydro-2H-benzo[J4]oxazine (0.15 g, 0.000578 mol), 3-(4-bromo-2- fluorophenoxy)- l-propylazetidine (0.183 g, 0.00063 mol), palladium(II) acetate (0.007 g, 0.0000289 mol ) and tri te/t-butylphosphine (0.017 mL, 0.0000578 mol, 50 % solution in toluene) in toluene (5 mL). Reaction mixture was heated at 105 °C for 25 minutes under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to give a residue, which was purified by column chromatography (silica gel, 240-400 mesh, acetone: n-hexane, 25: 75) to get (R)-7-fluoro-4-[3-fluoro-4-(l- propylazetidin-3-yloxy)phenyl]-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[i,4]oxazine (Compound No. 51). The obtained product was dissolved in appropriate solvent and treated with fumaric acid to get the fumarate salt of the compound No. 51.

Example 13: Preparation of 4-|3-fluoro-4-[(/?)-l-(3-fluoropropyl)pyrrolidin-3- yloxy1phenyl|-3-(3-fluoro-4-methoxyphenyl)-3,4-dihvdro-2H-benzo[/,41oxazin-7-ol (Compound No. 52).

Step I: (R )-3-(4-Bromo-2-fluorophenoxy)pyrrolidine-l-carboxylic acid tert butyl ester.

Z)z^'-isopropyl azodicarboxylate (3.04 mL, 0.0146 mol) was added dropwise to a stirred mixture of (S)-3-hydroxypyrrolidine-l-carboxylic acid ie/ -butyl ester (2.06 g, 0.0109 mol), 4-bromo-2-fluorophenol (2.0 g, 0.0104 mol) and triphenylphosphine (3.57 g, 0.0136 mol) in a mixture (1 : 1) of toluene (20 mL) and tetrahydrofuran (20 mL) under nitrogen atmosphere at ambient temperature. The resultant reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated and degassed under reduced pressure at 40 °C. The mixture (40 mL) of n-hexane: ethyl acetate (85: 15) was added to the residue and contents were stirred vigorously for 30 minutes. Solid thus obtained was filtered under vacuum and washed with same mixture. Combined filtrate was concentrated and degassed under reduced pressure at 40 °C to give residue, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 20: 80) to get (R)-3-(4-bromo-2- fluorophenoxy)pyrrolidine-l-carboxylic acid tert butyl ester.

Step II: (R)-3-(4-Bromo-2-fluorophenoxy)pyrrolidine hydrochloride.

4M Hydrochloric acid in 1,4-dioxane (17.15 mL) was added to a stirred solution of (R)-3-(4- bromo-2-fluorophenoxy)pyrrolidine-l-carboxylic acid ie/ -butyl ester (3.43 g, 0.00952 mol) in 1,4-dioxane (6.86 mL) at 0-5 °C and then stirred at room temperature for 1 hour. The mixture was degassed under reduced pressure at 50 °C to get crude which was triturated using diethylether to obtain ( ?)-3-(4-bromo-2-fluorophenoxy)pyrrolidine hydrchloride.

Step III: (R)-3-(4-Bromo-2-fluorophenoxy)-l-(3-fluoropropyl)pyrrolidine.

Mesyl chloride (1.09 mL, 0.014 mol) was added to a stirred solution of 3-fluoropropan-l-ol (1.0 g, 0.0128 mol) in dichloromethane (10 mL) and triethylamine (2.31 mL, 0.0166 mol) at 0-5 °C. The mixture was allowed to stir at ambient temperature for 2 hours, and quenched with water and extracted with dichloromethane. Combined organic layer was washed with brine solution. Dichloromethane was degassed under reduced pressure to get methanesulfonic acid 3-fluoropropyl ester. Above obtained mesylate derivative (1.0 g, 0.0065 mol) was added to a stirred solution of ( ?)-3-(4-bromo-2-fluorophenoxy)pyrrolidine hydrochloride (1.5 g, 0.005mol), potassium carbonate (2.45 g, 0.0177 mol) in acetonitrile (10 mL) at ambient temperature. Sodium iodide (0.076 g, 0.0005 mol) was added to the mixture and heated at 80 °C for 3 hour and 30 minutes. Reaction mixture was allowed to cool to room temperature, quenched with water, and degassed under reduced pressure. Aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 04: 96) to get ( ?)-3-(4-bromo-2-fluorophenoxy)- l-(3- fluoropropyl)pyrrolidine. Ste IV: 2-(5-Benzyloxy-2-bromophenoxy)-l-(3-fluoro-4-methoxyphenyl)ethanone.

Anhydrous potassium carbonate (3.71 g, 0.0268 mol) was added to a stirred solution of 5- benzyloxy-2-bromophenol (5.0 g, 0.0179 mol) in acetone (70 mL) and stirred for 15 minutes. 2-Bromo-l-(3-fluoro-4-methoxyphenyl)ethanone (4.9 g, 0.0198 mol) was added to the reaction mixture and stirred for 2 hours at room temperature. Reaction mixture was then filtered and inorganic solids were washed with acetone. Combined filtrate was concentrated at 50 °C under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh, ethylacetate: n-hexane, 20:80) to get 2-(5- benzyloxy-2-bromophenoxy)-l-(3-fluoro-4-methoxyphenyl)ethanone.

Step V: 2-(5-Benzyloxy-2-bromophenoxy)-l-(3-fluoro-4-methoxyphenyl)

eth lamine.

Ammonium acetate (8.65 g, 0.1123 mol) was added to a solution of 2-(5-benzyloxy-2- bromophenoxy)-l-(3-fluoro-4-methoxyphenyl)ethanone (5.0 g, 0.011 mol) in a mixture of methanol (50.0 mL) and dichloromethane (20.0 mL) at room temperature and stirred for 1 one hour at ambient temperature. Sodium cyanoborohydride (1.41 g, 0.022 mol) was added to reaction mixture and heated at 60 °C for 5 hours. Reaction mixture was concentrated under reduced pressure at 40 °C. Residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 03:97) to get 2-(5-benzyloxy-2-bromophenoxy)-l-(3-fluoro-4- methoxyphenyl)ethylamine.

Step VI: 7-Benzyloxy-3-(3-fluoro-4-methoxyphenyl)-3,4-dihydro-2H-benzo

[/,4]oxazine.

Potassium ie/t-butoxide (1.02 g, 0.0091 mol) was added to a stirred solution of 2-(5- benzyloxy-2-bromophenoxy)-l-(3-fluoro-4-methoxyphenyl)ethylamine (2.9 g, 0.0065mol), tris(dibenzylidineacetone)dipalladium (0.3 g, 0.000325 mol) and 2,2'- bis(diphenylphosphino)- l, -binaphthyl (0.41 g, 0.00065 mol) in toluene (29 mL) at room temperature under nitrogen atmosphere and then heated at 105 °C for one hour. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to give crude liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethylacetate: n-hexane, 15: 85) to get 7-benzylozy-3-pyridin-4-yl-3,4-dihydro-2H-benzo/7,4/oxazine.

Step VII: 7-Benzyloxy-4-{3-fluoro-4-[(/f)-l-(3-fluoropropyl)pyrrolidin-3-yloxy]phenyl}- 3-(3-fluoro-4-methox henyl)-3,4-dihydro-2H-benzo[/,4]oxazine.

Sodium ie/ -butoxide (0.11 g, 0.00114 mol) was added to a stirred mixture of 7-benzylozy-3- pyridin-4-yl-3,4-dihydro-2H-benzo/7,47oxazine (0.3 g, 0.00082 mol), (R)-3-(4-bromo-2- fluorophenoxy)- l-(3-fluoropropyl)pyrrolidine (0.287 g, 0.0009 mol), palladium(II) acetate (0.009 g, 0.000041 mol ) and tri ie/ -butylphosphine (0.033 mL, 0.000082 mol, 50 % solution in toluene) in toluene (6 mL). Reaction mixture was heated at 105 °C for 1 hour under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to give a residue, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 04: 96) to get 7-benzyloxy-4-{ 3- fluoro-4-[( ?)-l-(3-fluoropropyl)pyrrolidin-3-yloxy]phenyl}-3-(3-fluoro-4-methoxyphenyl)- 3,4-dihydro-2H-benzo[i,4]oxazine. Step VIII: 4-{3-Fluoro-4-[(/f)-l-(3-fluoropropyl)pyrrolidin-3-yloxy]phenyl}-3-(3-fluoro- 4-methoxyphenyl)-3,4-dihydro-2H-benzo[/,4]oxazin-7-ol.

5 % Palladium on charcoal (0.082 g, 50 % wet) followed by ammonium formate (0.427 g, 0.0067 mol) were added to a stirred solution of 7-benzyloxy-4-{ 3-fluoro-4-[( ?)- l-(3- fluoropropyl)pyrrolidin-3-yloxy]phenyl}-3-(3-fluoro-4-methoxyphenyl)-3,4-dihydro-2H- benzo[i,4]oxazine (0.41 g, 0.00067 mol) in a mixture (1 : 1) of methanol (4 mL) and 1,4- dioxane (4 mL). The resultant reaction mixture was heated at 70 °C for 1 hour. Reaction mixture was cooled to room temperature, filtered through celite bed and washed with an (1 : 1) mixture of methanol and 1,4-dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with dichloromethane. Combined organic layer washed with brine solution and dried over anhydrous sodium sulphate. Dichloromethane was removed under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 05: 95) to get 4-{ 3-fluoro-4-[( ?)-l-(3-fluoropropyl)pyrrolidin-3-yloxy]phenyl}-3-(3-fluoro- 4-methoxyphenyl)-3,4-dihydro-2H-benzo[i,4]oxazin-7-ol.

Some of the representative compounds of Formula I prepared as per the processes described above along with their proton NMR spectroscopy data are provided in Table-2 below.

Table 2.

of CD₃OD); 6.15 (dd, J, = 8.72 Hz, J₂ = 2.76 Hz, IH); 6.199 (d, J =

2.68 Hz, IH); 6.47 (t, J = 8.68 Hz, IH); 6.58 (d, J = 8.6 Hz, 2H); 6.68 (t, J = 8.8 Hz, IH); 6.72-6.76 (m, IH); 6.80 (dd, J, = 12.88 Hz, J₂ = 2.36 Hz, IH); 7.02 (d, J = 8.44 Hz, 2H); two exchangeable protons.

(R)-4-{ 3-Fluoro-4-[ 1 -(3-fluoro- (DMSO-Dj, 400 MHz): 1.72 (doublet of quintet, J, = 25.25 Hz, J₂ = propyl)-azetidin-3-yloxy]- 6.36 Hz, 2H); 2.5-2.7 ( merged with residual peak of CD₃SOCD₂H in phenyl } -3-(4-hydroxy-phenyl)- DMSO-¾ 2H) 3.01 (t, J = 6.76 Hz, 2H); 3.76 (t, J = 6.92 Hz, 2H); 4.2 3,4-dihydro-2//-benzo (dd, J, = 10.88 Hz, J₂ = 2.68 Hz, IH); 4.38 (dd, J, = 10.92 Hz, J₂ = [i,4]oxazin-7-ol. 4.56 Hz, IH); 4.5 (t of d, J, = 47.4 Hz, J₂ = 6.04 Hz, 2H); 4.75 - 7.84

(m, 2H); 6.24 -6.3 (m, 2H); 6.59 (dd, J, = 7.44 Hz, J₂ = 1.64 Hz, IH); 6.7 (d, J = 8.56 Hz, 2H); 6.84 - 6.95 (m, 2H); 7.02 (dd, J, = 13.00 Hz, J₂ = 2.36 Hz, IH); 7.15 (d, J = 8.52 Hz, 2H); 8.95 (s, IH); 9.37 (s,lH).

(#)-4-{ 3-Fluoro-4-[ 1 -(3-fluoro- (DMSO-Dj, 500 MHz): 1.66-1.18 (m, 2H); 2.5-2.6 (2H, merged with propyl)-azetidin-3-yloxy]- CD₃SOCD₂H of DMSO-Dj); 3.06(br s, 2H); 3.79 (br s, 2H); 4.23(dd, phenyl } -3-(4-fluoromethoxy- J, = 1 1.04 Hz, J₂ = 2.75 Hz, IH); 4.42-4.46 (m, merged with a triplet, phenyl)-3,4-dihydro-2//-benzo IH); 4.50 (t of d, J, = 47.41 Hz, J₂ = 6.05 Hz, 2H); 4.8 ( quintet, J = [i,4]oxazin-7-ol. 5.2 Hz, IH) ; 4.92 - 4.95 (m, IH); 5.87 (d, J = 54.56 Hz,2H); 6.25- 6.32(m, 2H); 6.66 (d, J = 8.50 Hz, IH); 6.85 -6.97 (m,2H); 7.03 -7.12 (m, 3H); 7.37 (d, J = 8.65 Hz, 2H); 8.99 (s, IH).

(,R)-3-(4-Fluoromethoxy (DMSO-Dj, 400 MHz): 0.89 (t, J = 7.44 Hz, 3H); 1.35 (sextet , J = phenyl)-4-[3-fluoro-4-(l- 7.16 Hz, 2H); 2.45 (t, J = 7.08 Hz, 2H); 3.0-3.06 (m, 2H); 3.76 (t, J = propylazetidin-3-yloxy) 6.28 Hz, 2H); 4.22 (dd, J_t = 10.92 Hz, J₂ = 2.64Hz, IH); 4.45 (dd, J_t = phenyl]-3,4-dihydro-2//- 1 1.0 Hz, J₂ = 3.96 Hz, IH); 4.8 (quintet, J = 5.72 Hz, IH); 4.94 (t, J = benzo[i,4]oxazin-7-ol. 3.16 Hz, IH); 5.87 (d, J = 54.5 Hz, 2H); 6.26 - 6.32(m, 2H); 6.66 (d, J

= 8.58 Hz, IH); 6.8 - 6.96 (m, 2H); 7.03 -7.1 (m, 3H); 7.37 (d, J = 13.12 Hz, 2H); 8.98 (s, IH).

(,R)-3-(4-Fluoromethoxy (DMSO-Dj, 500 MHz): 0.89 (t, J = 7.45 Hz, 3H); 1.34 (sextet , J = phenyl)-4-[3-fluoro-5-(l- 7.25 Hz, 2H); 2.42 (t, J = 7.00 Hz, 2H); 2.95 ( br m, 2H); 3.62 -3.76 propylazetidin-3-yloxy)phenyl]- (m, 2H); 4.24 (dd, Jj = 1 1.25 Hz, J₂ = 2.8Hz, IH); 4.62 (dd, Jj = 11.25

3,4-dihydro-2//-benzo Hz, J₂ = 2.5 Hz, IH); 4.77 (quintet, J = 5.60 Hz, IH); 5.13 (s, IH); 5.87

[i,4]oxazin-7-ol. (d, J = 54.51 Hz, 2H); 6.26 (d, J=2.7 Hz, IH); 6.3-6.4 (m, 3H); 6.54 (d,

J = 1 1.25Hz, IH); 7.02 (d, J = 8.75 Hz, IH); 7.1 (d, J = 8.65 Hz, 2H); 7.38 (d, J = 8.65 Hz, 2H); 9.14 (s, IH).

CR)-3-(4-Difluoromethoxy (DMSO-Dj, 400 MHz): 0.9 (t, J = 7.38 Hz, 3H) ; 1.35 (q, J = 7.28 Hz, phenyl)-4- { 3-fluoro-4-( 1 - 2H) ; 2.45 (t, J = 7.16 Hz, 2H) ; 3.01 (s, 2H) ; 3.76 (t, J = 6.88 Hz, 2H) propylazetidin-3-yloxy)phenyl]- ; 4.23 (dd, J_x = 1 1 Hz, J₂ =2.6 hz, IH ) 4.48 (dd, J_t = 11 Hz, J ₂ = 3.68 3,4-dihydro-2//-benzo Hz, 1 H) : 4.79 (t, J = 5.68 Hz, IH) ; 4.98 ( d, J = 2.96 Hz, IH) 6.27- [i,4]oxazin-7-ol. 6.33 ( m, 2H) 6.69 (d, J = 8.64 Hz, IH ) ; 6.86-6.97 (m, 2H) 7.06 (dd,

Ji = 10.56 Hz, J₂= 2.48 Hz, IH) ;7.15 (d, J = 8.64 Hz, 2H) 7.24 (t, J = 74.2 Hz, IH) ; 7.43 (d, J = 8.6 Hz, 2H) ; One exchangeable proton.

3-(4-Fluorophenyl)-4-[3-fluoro- (DMSO-Ds, 400 MHz): 0.88(t, J=7.44Hz, 3H), 1.28-1.38(m, 2H), 5 -( 1 -propylazetidin-3 - 2.38-2.46(m, 2H), 2.95(br s, 2H), 3.65-3.68(m, 2H), 4.24(dd, yloxy)phenyl] -3,4-dihydro-2//-

IH), 4.74- benzo[i,4]oxazin-7-ol. 4.79(m, IH), 5.16(s, IH), 6.26(d, J=2.68Hz, IH), 6.31-3.38(br m, 3H),

6.55(t of d, J=l 1.28Hz, IH), 7.02(d, J=8.76Hz, IH), 7.17-7.22(m, 2H), 7.41-7.45(m, 2H), 9.18(s, IH).

3- (4-Fluorophenyl)-4-[3-fluoro- (DMSO-Dj, 400 MHz): 0.9(t, J=7.44Hz, 3H), 1.3-1.39(m, 2H), 2.46(t,

4- ( 1 -propylazetidin-3 - J=7.12Hz, 2H), 3.02(br s, 2H), 3.77(t, J=6.08Hz, 2H), 4.23(dd, yloxy)phenyl] -3,4-dihydro-2//-

IH), 4.77- benzo[i,4]oxazin-7-ol. 4.82(m, IH), 4.97(s, IH), 6.27-6.31(m, 2H), 6.67(d, J=8.56Hz, IH),

6.85-6.95(m, 2H), 7.06(dd,

J₂=2.48Hz, IH), 7.17(t, J=8.84Hz, 2H), 7.39-7.43(m, 2H), 9.0(s, IH).

I 4-{ (#)-5-[3-Fluoro-4-(l- (DMSO-Ds, 400 MHz: 0.9 (t, J = 7.44 Hz, 3H); 1.36 (sextet, J = 7.20 propylazetidin-3-yloxy) Hz, 2H); 2.44 -2.55 (m, merged with residual CD3SOCD2H peak of phenyl] - 1 , 5 ,6 , 7 -tetra DMSO,2H); 3.07 (br m, 2H); 3.81 (br m, 2H); 4.37 (d, J = 3.5 Hz, 2H); hydro-8 -oxa- 1 ,2,5- 4.84 (quintet, J = 5.64 Hz, IH); 4.9 (t, J = 4.16 Hz, IH); 6.69 (d, J = triazacyclopenta 8.56 Hz, 2H); 6.83 (s, IH); 6.92 -7.03 (m, 3H); 7.12 - 7.22 (m, 3H); [£>]naphthalen-6-yl } -phenol. 7.78 (s, IH); 9.4 (s, IH); 12.58 (s, IH).

I (#)-4-[3,5-Difluoro-4-(l- (DMSO-Ds, 400 MHz): 0.9 (t, J = 7.44 Hz, 3H); 1.35 (sextet, J = 7.28 propylazetidin-3-yloxy)phenyl] Hz, 2H); 2.39 (t, J = 1.84Hz, 2H); 3.1(br m, 2H); 3.65(t, J = 6.16Hz, 3-(4-fluoromethoxyphenyl)-3,4- 2H); 4.23 (dd, Jj = 11.20 Hz, J₂ = 2.68Hz, 1H); 4.61 (dd, Jj = 11.08 dihydro-2//-benzo [1,4] oxazin- Hz, J₂ = 2.52Hz, 1H); 4.65 - 4.69 (m, 1H); 5.11( br s, 1H); 5.87(d, J = 7-ol. 54.54 Hz, 2H); 6.257(d, J = 2.68 Hz, 1H); 6.35 (dd, Jj = 8.76 Hz, J₂ =

2.72 Hz, 1H); 6.87 (dd, Jj = 14.92 Hz, J₂ = 4.2 Hz, 2H); 6.968 (d, J = 8.76 Hz, 1H); 7.09 (d, J = 8.72 Hz, 2H); 7.38 (d, J = 8.56 Hz, 2H); 9.17 (s, 1H).

(,R)-3-(4-Difluoromethoxy (DMSO-Dj, 400 MHz): 0.89 (t, J = 7.32 Hz, 3H); 1.25-1.45 (m, 2H); phenyl)-4-[3,5-difluoro-4-(l- 2.46 (t, J = 7.08Hz, 2H); 3.11(br s, 2H); 3.66 (t, J = 6.24Hz, 2H); 4.23 propylazetidin-3-yloxy)phenyl]- (dd, Ji = 11.16 Hz, J₂ = 2.60Hz, 1H); 4.6 - 4.7 (m, 2H); 5.15( br s,

3,4-dihydro-2//-benzo 1H); 6.26 (d, J = 2.68 Hz, 1H); 6.37 (dd, J_t = 8.76 Hz, J₂ = 2.72 Hz,

[i,4]oxazin-7-ol. 1H); 6.88 (dd, J_t = 15.21 Hz, J₂ = 4.56 Hz, 2H); 6.98 (d, J = 8.76 Hz,

1H); 7.17 (d, J = 8.64 Hz, 2H); 7.25 (t, J = 74.14 Hz, 1H); 7.44 (d, J = 8.52 Hz, 2H); 9.19 (s, 1H).

(fl)-4-[3-Fluoro-5-(l- (DMSO-Dj, 400 MHz): 0.88 (t, J=7.5 Hz, 3H), 1.25-1.33 (m, 2H), 2.43 propylazetidin-3-yloxy)phenyl]- (t, J=7.1 Hz, 2H), 2.88-3.05 (m, 2H), 3.58-3.63 (m, 2H), 3.76 (s, 3H),

3-(4-methoxyphenyl)-3,4- 4.23 (dd, ,

HZ, dihydro-2//-benzo 1H), 4.76 (quintet, J₁₌l 1.3 Hz, J₂=5.7 Hz, 1H), 5.04-5.12 (br s, 1H),

/7,4/oxazin-7-ol. 6.25 (d, J=2.7 Hz, 1H), 6.28-6.40 (m, 3H), 6.54 (d of t, J₁₌l 1.3 Hz,

J₂=2.04 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 9.13 (s, 1H).

(#)-4-[3-Fluoro-4-(l- (DMSO-Dj, 500 MHz): 0.81 (t, J=6.15Hz, 3H), 1.2 (br s, 18H), 1.27 propylazetidin-3-yloxy)phenyl]- (merge s, 2H), 1.57 (m, 2H), 2.9 (t, J=8Hz, 2H), 4.07 (d, J=4.9Hz, 2H),

3-(4-methoxyphenyl)-3,4- 4.2 (dd,

dihydro-2//-benzo 1H), 4.7 (s, 1H), 6.53-6.6 (m,4H), 6.76-6.71 (m, 3H), 6.8(d, J=8Hz,

/7,4/oxazin-7-ol. 1H), 7.0 (d, J=8.5Hz, 2H), 7.2 (t, J=7.95Hz, 1H), two exchangeable proton.

(,R)-3-(4-Fluoromethoxy (DMSO-Dj, 400 MHz): 0.88 (t, J = 6.72 Hz, 3H); 1.2-1.44 (br m, 2H); phenyl)-4-[5-( 1 -propylazetidin- 2.25 -2.63 (m, 2H); 2.95 3.1 (m, 2H); 3.2 - 3.3 (m, 2H); 4.32 (dd, Jj = 3 -yloxy)pyridin-3 -yl] -3 ,4- 11.04 Hz, J₂ = 2.92 Hz, 1H); 4.48 (dd, Jj = 10.80 Hz, J₂ = 3.24 Hz, dihydro-2//-benzo [1,4] oxazin- 1H); 4.72 (t, J = 5.44 Hz, 1H); 4.76 ( br s, 1H); 5.67 (d, J = 54.54 Hz, 7-ol. 2H); 6.36 (dd, Jj = 8.76 Hz, J₂ = 2.76 Hz, 1H); 6.41 (d, J = 2.72 Hz,

1H); 6.83 (br s, 1H); 6.88 (d, J = 8.68 Hz, 1H); 7.02 (d, J = 8.56 Hz, 2H); 7.2 - 7.4 (2H; merged with CDC13 residual solvent peak); 7.79 (d, J = 2.52 Hz, 1H); 8.13 (br s, 1H); one exchangeable proton

(#)-4-[3-Fluoro-4-(l- (DMSO-Dj, 400 MHz): 0.91 ( t, J= 6.64 Hz, 3H); 1.3 ( br s, 8H); ( 2H hexylazetidin-3-yloxy)phenyl]- merged with residual peak of CD₃OCD₂H of DMSO-D₆); 3.04 ( br s, 3-(4-hydroxyphenyl)-3,4- 2H); 3.78 ( br s, 2H); 4.19 (d, J=8.3 Hz, 2H); 4.38 ( dd, J_t= 10.92 Hz, dihydro-2//-benzo [1,4] oxazin- J₂= 4.56 Hz, 1H); 4.79 (s, 1H); 6.24-6.29 (m, 2H); 6.58 ( d, J= 9.08 Hz, 7-ol. 1H); 6.70 ( d, J= 8.60 Hz, 2H); 6.8-6.97 ( m, 2H); 7.02 ( dd,

13.08

Hz, J₂= 2.4 Hz, 1H); 7.15 ( d, J= 8.56 Hz, 2H); 8.95 ( s, 1H); 9.37 ( s, 1H).

(#)-3-(4-Fluorophenyl)-4-[3- (DMSO-Dj, 400 MHz): 0.91 ( t, J= 7.32 Hz, 3H); 1.39 ( sextet, J= 7.28 fluoro-4-( 1 -propylazetidin-3- Hz, 2H); 2.58 ( br s, merged with residual peak of CD30CD2H of yloxy)-phenyl] -3,4-dihydro-2//- DMSO-D6, 2H); 3.3 ( br s, 2H); 3.93 ( br s, 2H); 4.23 ( dd, Ji= 10.92 benzo[i,4]oxazin-7-ol. Hz, J2= 2.7 Hz, 1H); 4.47 ( dd, Ji= 11.12 Hz, J2= 4.0 Hz, 1H); 4.89 (s,

1H); 4.97 ( br s, 1H); 6.27-6.33 (m, 2H); 6.67 ( d, J= 8.76 Hz, 1H); 6.85-6.70 ( m, 2H); 7.07 ( dd, Ji= 13.08 Hz, J2= 2.4 Hz, 1H); 7.15 ( t, J= 8.56 Hz, 2H); 7.42 (dd, Ji= 8.64 Hz, J2= 5.6 Hz, 2H); 9.01 ( s, 1H).

Hydrochloride salt of (.R)-4-[4- (DMSO-Dj, 400 MHz): 0.91 (t, J= 7.0 Hz, 3H); 1.3 (br s, 14H); 1.5 (br ( 1 -Decylazetidin-3-yloxy)-3 - s, 2H); 3.19-3.27 (m, 2H); 4.1-4.32 ( m, 3H); 4.35- 4.52

fluorophenyl] -3-(4- (m, 2H); 4.63 (m, 1H); 4.95-5.15 (m, 2H); 5.87 (d, J=54.49, 2H); 6.27- fluoromethoxyphenyl)-3,4- 6.33 (m, 2H); 6.69 (d, J= 8.32 Hz, 1H); 6.89-7.04 (m, 2H); 7.04-7.15 dihydro-2//-benzo [1,4] oxazin- (m, 3H); 7.38 (d, J= 8.6 Hz, 2H); 9.06 (s, 1H); 10.8 (s, 1H).

7-ol.

Hydrochloride salt of (R)-6- (CDC1₃, 400 MHz): 1.05(t, J = 7.28 Hz, 3H); 1.7-1.9 (m, 2H); 3.18 (br [3,5-Difluoro-4-(l- s, 2H); 3.89(br s, 2H); 4.38 (d, J = 10.88 Hz, IH); 4.7-4.82(m, 3H); propylazetidin-3-yloxy)phenyl]- 4.87(s, IH); 4.94 (s, IH); 6.71 (d, J = 9.72Hz, 2H); 6.99 (t, J = 8.60 Hz, 7-(4-fluorophenyl)-3,6,7,8- 2H); 7.14 (d, J = 8.60Hz, IH); 7.2-7.35(m, 3H); 8.07 (s, IH); 12.5 (brs, tetrahydro-9 -oxa-2, 3 ,6- IH); one exchangeable proton.

triazacyclopenta/fl /naphthalene.

Phosphoric acid mono-{ (R)-3- (DMSO-Dj, 400 MHz): 0.83 (t, J=7.45 Hz, 3H), 1.31 (q, J=7.65 Hz, (4-fluorophenyl)-4-[3-fluoro-4- 2H), 2.41 (t, J=7.75 Hz, 2H), 3.1 1 (dd, J₁=9.1 Hz, J₂=5.25 Hz, 2H), (1 -propyl azetidin-3- 3.66 (dd,

yloxy)phenyl] -3,4-dihydro-2//- Hz, IH), 4.3 (dd, J₁₌10.9 Hz, J₂=3.85 Hz, IH), 4.64-4.72 (m, 2H), 6.56 benzo[i,4]oxazin-7-yl Jester (d, J=8.85 Hz, IH), 6.65-6.72 (m, 2H), 6.73-6.79 (m, 2H), 6.82 (dd, disodium salt.

Hz, IH), 6.89 (t, J=9.39 Hz, 2H), 7.25 (dd, J₁₌8.55

Hz, J₂=5.4 Hz, 2H).

Hydrochloride salt of (R)-5- (CD₃OD, 400 MHz): 0.93(m, 3H), 1.54 ( m, 2H), 3.12( merged m, [3,5-Difluoro-4-(l- 2H), 4.2(m, IH), 4.36- 4.47(m, 4H), 4.6(m, IH), 4.8(merged m, IH), propylazetidin-3-yloxy)phenyl]- 5.0(s, IH), 6.92-7.0(m, 5H), 7.13( s, IH), 7.3(m, 2H), 8.12(s, IH), 2 6-(4-fluorophenyl)- 1 ,5,6,7- exchangeable protons.

tetrahydro-8 -oxa- 1 ,2,5- triazacyclopenta[£>]naphthalene.

CRS)-3-(2-Chloro-4- (DMSO-Dj, 400 MHz): 0.89 (t, J = 7.32 Hz, 3H); 1.35 (sextet, J = 7.3 fluorophenyl)-4- [4-( 1 - Hz, 2H); 2.46 (t, J= 7.12 Hz, 2H); 2.95-3 (m, 2H); 3.78 (t, J= 7.08 Hz, propylazetidin-3-yloxy) 2H); 4.32 (d, J=3.68 Hz, IH); 4.76 (quintet, J = 5.72 Hz, IH); 5.15 (t, phenyl]-3,4-dihydro-2//- J=3.28 Hz, IH); 6.29 (dd, J_t = 1 1.44 Hz, J₂= 2.72 Hz, IH); 6.34 (d, J = benzo[i,4]oxazin-7-ol. 2.68 Hz, IH); 6.49 (d, J = 8.72 Hz, IH); 6.83 (dd, J_t = 6.8 Hz, J₂= 2.2

Hz, 2H); 7.1 1 (dd, J_t= 6.76 Hz, J₂= 2.16 Hz, 2H); 7.23(d of t, J_t= 8.6 Hz, J₂= 2.6 Hz, IH); 7.42-7.5( m, 2H); 8.94 (s, IH); One exchangeable proton.

Hydrochloride salt of (R)-4-[3- (DMSO-Dj, 400 MHz): 0.93 (t , J = 7.38 Hz, 3H); 1.5-1.63 (m, 2H); Fluoro-4-(l -propyl azetidine-3- 3.15-3.25(m, 2H); 4.15-4.34 (m, 4H); 4.4 - 4.5(m, IH); 4.6-4.71 (m, yloxy)phenyl] -3-(4- IH); 4.85 (t, J = 3.68 Hz, IH) ; 5.0-5.2 (m, IH) ;6.1-6.17(m, 2H); 6.65 hydroxyphenyl)-3,4-dihydro- (d, J = 8.44 Hz, IH); 6.71 (d, J= 8.56 Hz, 2H); 6.9-7.08 (m, 2H); 7.1 1 2H-benzo[i,4] oxazin-6-ol. (d, J = 8.56 Hz, 2H); 7.22 (d, J = 12.9 Hz, IH); 8.8 (s, IH) 9.45 (s, IH);

10.89 (s, IH); two exchangeable proton.

3-(2,4-Difluorophenyl)-4-{ 3- (CD₃OD, 400 MHz): 1.29(s,3H); 1.25 (s,3H); 2.59 (d, J = 21.33 Hz, fluoro-4- [ 1 -(2-fluoro-2- 2H); 3.17 9t, J = 1.6 Hz, 2H); 3.76 (t, J = 6.2 Hz, 2H); 4.14 (dd, J_t = methylpropyl)azetidine-3- 10.92 Hz,J₂ = 2.84 Ηζ,ΙΗ); 4.31 (dd,

3.12 Hz, IH); yloxyjphenyl} -3,4-dihydro-2//- 4.66-4.71(m, IH); 4.9-4.92 (brm, IH); 6.2-6.24 (m,2H) ; 6.57 (dd, J_t = benzo[i,4] oxazin-7-ol. 7.12 Hz, J₂= 2 Hz, IH); 6.67-6.8 (m, 3H); 6.8-6.9 (m, 2H) ; 7.2-7.29

(m, IH); One exchangeable proton.

Hydrochloride salt of (R)-3-(4- (CD₃OD, 400 MHz): 0.92(t, J=7.4Hz, 3H), 1.5-1.56(m, 2H), 3.15(t, Fluorophenyl)-4-[3-fluoro-4-( 1 - J=7.8Hz, 2H), 4.12-4.21(m, 4H), 4.5(br s, 2H), 4.74(m, IH), 5.0(m, propylazetidin-3-yloxy)phenyl]- IH), 6.06- 6.1 (m, 2H), 6.55(m, IH), 6.8(t, J=9.0Hz, 2H), 6.86- 3,4-dihydro-2//-benzo 6.93(m, 3H), 7.0(dd,

IH), 7.2-7.23(m, 2H), one [i,4]oxazin-6-ol. exchangeable proton.

Hydrochloride salt of (R)-3-(4- (DMSO-Dj, 400 MHz): 0.92 (t, J=7.24 Hz, 3H), 1.54 (quintet, J=7.64 Fluorophenyl)-4-[3-fluoro-4-( 1 - Hz, 2H), 3.13-3.25 (m, 2H), 4.15-4.23 (m, IH), 4.25-4.35 (m, 2H), 4.4- propyl azetidin-3- 4.5 (m, 2H), 4.53-4.61 (m, IH), 5.0-5.1 (m, IH), 5.1-5.18 (m, IH), 6.79 yloxy)phenyl] -7-(i//-pyrazol-4- (dd,

Hz, IH), 6.9-7.03 (m, 2H), 7.04-7.12 (m, 2H), yl)-3,4-dihydro-2//-benzo 7.13-7.25 (m, 3H), 7.39 (dd,

Hz, 2H), 7.98 (s, 2H), [i,4]oxazine. two exchangeable protons.

Hydrochloride salt of (E)-4-(3- (DMSO-Dj, 400 MHz): 2.9 (s, 3H); 3.08 (s, 3H); 3.17 (t, J = 6.04 Hz, {2,6-Difluoro-4-[(#)-7-(4- 2H); 3.29 (d, J = 2.12 Hz, 2H); 3.68 (dd, J_t = 8.52 Hz, J₂= 6.32 Hz, fluorophenyl) -7 , 8 -dihydro - 3 H- 2H); 4.35 (dd, J_t= 1 1.24 Hz, J₂=2.56 Hz, IH); 4.71 (q, J=5.8hz, IH); 9-oxa-2,3,6- 4.93(dd,

Hz, IH); 5.28 (s, IH); 6.55 (s, 2H); 6.90 triazacyclopenta[a]naphthalen- (d, J=10.56 Hz, 2H); 7.1 (d, J=8.80 Hz, IH); 7.12-7.22 (m,3H); 7.48

6-yl]-phenoxy} (dd,

2H); 7.92 (s, IH); 13.06(s, IH) azetidin- 1 -yl)but-2-enoicacid

dimethylamide.

Hydrochloride salt of (R)-8- (CD₃OD, 400 MHz): 0.92 (t, J = 7.4 Hz, 3H); 1.5-1.6 (m, 2H); 2.6 (s, Dimethylamino IH); 2.74 (s, 3H); 3.1-3.2 (m, 2H); 4.1-4.17(m, IH); 4.2(m, 2H); 4.23- methyl-3-(4-fluorophenyl)-4-[3- 4.3(m,2H); 4.36-4.42(m, lH) ; 4.52-4.56 (m, IH) ; 4.6-4.66 (m, IH); fluoro-4-( 1 -propylazetidin-3- 4.82-4.86 (m, IH); 4.95-5.02 (m, IH) ; 6.36 (d, J = 8.96 Hz, IH); 6.73- yloxy)phenyl] -3,4-dihydro-2//- 6.78 (m, lH) ; 6.81-6.86(m,2H); 6.9-6.96 (m, 3H); 7.25-7.31 (m, 2H); benzo[i,4]oxazin-7-ol. one exchangeable proton.

Hydrochloride salt of 6-[3,5- (CD₃OD, 400 MHz): 0.9-0.97 (m, 3H); 1.5-1.61 (m, 2H) ; 3.7 9s, 3H); Difluoro-4-( 1 -propylazetidin-3- 4.18 (dd, Ji = 12.4 Hz, J₂ = 5.6 Hz, IH); 4.26 (dd, J_t = 11.2 Hz, J₂= yloxy) -pheny 1] -7 - ( 3 -fluoro -4- 2.68 Hz, IH); 4.34-4.37 9m, 2H) ; 4.54-4.63 (m, IH); 4.63-4.67 (m, methoxyphenyl)-3, 6,7,8- IH); 4.85-4.88 (m, lH); 4.9-5 (m, 2H) ; 6.75 (dd, J_t= 10.56 Hz, J₂ = 2.6 tetrahydro-9 -oxa-2, 3 ,6- Hz, IH) ; 6.89 (t, J = 8.76 Hz, 2H) ; 7.02-7.08 (m, 3H) ; 7.20 (d, J = 9 triazacyclopenta[a]naphthalene. Hz, IH) ; 8.07 (s, IH); one exchangeable proton.

Hydrochloride salt of 4-[(.R)-4- (DMSO-Dj, 400 MHz): 0.96 (t, J=7.32 Hz, 3H), 1.5-1.66 (m, 2H),

[3,5-Difluoro-4-(l- 3.13-3.3 (m, 2H), 4.15-4.26 (m, IH), 4.27-4.45 (m, 3H), 4.47-4.6 (m, propylazetidin-3-yloxy) 2H), 4.86-5.1 (m, 2H), 6.74 (d, J=8.44 Hz, 2H), 7.0-7.08 (m, 3H), 7.1- phenyl] -7 -( i//-pyrazol-4-yl)- 7.2 (m, 4H), 8.08 (s, 2H), 10.9-1 1.15 (s, IH), two exchangeable

3,4-dihydro-2//-benzo protons.

[i,4]oxazin-3-yl]phenol.

Hydrochloride salt of (£)-4-(3- (CD₃OD, 400 MHz): 2.92 (s, 3H); 3.07 (s, 3H); 3.99 (d, J= 5.12 Hz, {2,6-Difluoro-4-[(#)-3-(4- IH); 4.08 (d, J=6.68 Hz, IH); 4.26 (dd,

Hz, J₂=2.72Hz, 2H); fluorophenyl)-7-( l//-pyrazol-4- 4.38-4.5 (m, 3H); 4.6-4.7 (m, IH); 4.9-5.0 (m, 2H); 6.43 -6.55 (m, IH); yi)-2,3- 6.79-6.9 (m, 3H); 6.91-7.0 (m, 3H); 7.08 (dd, J₁₌8.36 Hz, J₂=2.0 Hz, dihydrobenzo [ 1 ,4] oxazin-4-yl] - IH); 7.1 1 (d, J= 1.96 Hz, IH); 7.26 (dd,

5.24 Hz, 2H); phenoxy } azetidin- 1 -yl)but-2- 8.38 (s, 2H); two exchangeable protons

enoicacid dimethylamide.

Hydrochloride salt of (R)-4-[3- (DMSO-Dj, 400 MHz): 0.94 (t, J=7.4 Hz, 3H), 1.50-1.64 (m, 2H),

Fluoro-4-( 1 -propyl 3.16-3.29 (m, 2H), 3.75 (s, 3H), 4.15-4.75 (m, 6H), 4.95-5.10 (m, 2H), azetidin-3-yloxy) phenyl]-3-(4- 6.75 (d, J= 6.4 Hz, IH), 6.91 (d, J=8.8 Hz, 2H), 6.95-7.10 (m, 3H), methoxyphenyl) 7.12 (d, J=2.0 Hz, IH), 7.20-7.27 (m, IH), 7.29 (d, J=8.7 Hz, 2H), 7.99

-7-(ii/-pyrazol-4-yl)-3,4- (s, 2H), 10.60-10.80 (m, IH), one exchangeable proton.

dihydro-2//-benzo

[i,4]oxazine.

Hydrochloride salt of 4{ (R)-6- (CD₃OD, 400 MHz): 0.93(t, J=2.32Hz, 3H), 1.55(m, 2H), 3.11(t,

[3,5-Difluoro-4-(l- J=7.92Hz, IH), 4.1-4.3(m, 2H), 4.35(s, 2H), 4.6-4.7(m, 2H), propylazetidin-3-yloxy)phenyl]- 4.9(merged m, 3H), 6.6(d, J=8.7Hz, 2H), 6.73(d, J=8.44 Hz, 2H),

3,6,7,8-tetrahydro-9-oxa-2,3,6- 7.0(d, J=8.8Hz, IH), 7.14(dd,

3H), 7.95(s, lH), 3 triazacyclopenta[fl] exchangeable protons.

naphthalen-7-yl]phenol.

Hydrochloride salt of (R)-6- (CD₃OD, 500 MHz): 0.93 (t, J=6.6 Hz, 3H), 1.48-1.63 (m, 2H), 3.12 [3,5-Difluoro-4-(l- (t, J=7.8 Hz, 2H), 3.63 (s, 3H), 4.18 (dd, Jl=12.4 Hz, J2=5.6 Hz, IH), propylazetidin-3 -yloxy) - 4.27 (dd,

Hz, IH ), 4.30-4.40 (m, 2H), 4.54-4.64 phenyl] -7 -(4-methoxy (m, IH), 4.73 (dd, J₁₌l 1.1 Hz, J₂=2.5 Hz, IH), 4.80-4.89 (m, IH), phenyl) -3 , 6 ,7 , 8 -tetra 4.90-4.95 (brs, IH), 6.69-6.79 (m, 4H), 7.00 (d, J=9.0 Hz, IH), 7.14 (d, hydro-9-oxa-2,3,6-triaza J=9.0 Hz, IH), 7.21 (d, J=8.8 Hz, 2H), 7.98 (s, IH), two exchangeable cyclopenta [a] naphthalene. proton.

Hydrochloride salt of (R)-6- (CD₃OD, 500 MHz): 1.37 (d, J = 5.38 Hz, 3H); 1.41 (d, J = 5.39 Hz, { 3,5-Difluoro-4-[l- (2-fluoro-2- 3H); 3.56 (q, J = 19.93 Hz, 2H); 4.29 (dd, J_t= 1 1.19 Hz, J₂ = 2.69 Hz, methylpropyl)azetidin-3 - IH); 4.33-4.4(m, IH); 4.52 (d, J = 4.51 Hz, 2H); 4.66-4.73 (m,lH); yloxy]phenyl} -7-(4- 4.77 (d, J = 2.33 Hz, IH); 4.85-4.9 (m, IH) ; 5.02 (s, IH); 6.76 (d, J = fluorophenyl) -3 , 6 ,7 , 8 - 10.05 Hz, 2H); 6.91 (t, J = 6.7 Hz, 2H); 7.05 (d, 8.97 Hz, IH); 7.21 (d, tetrahydro-9 -oxa-2, 3 ,6- J = 8.99 Hz, IH); 7.33 (dd, Jj = 8.56 Hz, J₂=5.37Hz, 2H); 8.08(s, IH); triazacyclopenta[a]naphthalene. one exchangeable proton.

Hydrochloride salt of (CD₃OD, 400 MHz): 0.9-0.96 (m,3H); 1.5-1.61 (m, 2H); 3.13 (t, J =

6- [3,5-Difluoro-4-(l- 7.88 Hz, IH); 3.7 (s, 3H); 4.14-4.22 (m, IH); 4.27 (dd, Jj = 1 1.12 Hz, propylazetidin-3-yloxy)phenyl]- J₂= 2.64 Hz, IH); 4.34-4.38 (br m, 2H) ; 4.59 (dd, J_t = 12.44 Hz, J₂ =

7- (3-fluoro-4-methoxy 6.72 Ηζ,ΙΗ); 4.75-4.79 (m, IH); 4.85-4.9 (m, 2H) ; 6.89 (t, J = 8.48 phenyl)-3,6,7,8 -tetrahydro -9 - Hz, IH) ; 7.02-7.08 (m, 3H); 7.22 (d, J = 9 Hz, IH) ; 8.1 (s, IH); one oxa-2,3,6-triazacyclopenta exchangeable protons.

[a]naphthalene.

In-vitro cell line assay

MCF-7 Cell Growth Inhibition Assay

MCF-7 cells were plated in 96 well plate in the presence of estradiol (1 nM) and incubated overnight. After 24 hours test compound was added at various concentrations and incubated for five days. On the fifth day, cell viability was evaluated using Presto Blue^® Cell Viability Reagent. Percentage growth inhibition was calculated as follows: 100 - [(O.D. of sample)* 100/ O.D. of vehicle control] wherein O.D. is Optical Density.

Compounds of Formula I showed growth inhibition of about 50 % or more at 3 micromolar concentration.

Percentage inhibition at ΙμΜ in MCF-7 cell lines for some of the representative compounds is provided in Table-3 below.

Table 3:

SERD Assay:

ER-q Degradation Assay in MCF-7 WT Cell lines

MCF-7 WT cells were seeded at density of 40000 cells/well in 48-well plate. The cells were plated in phenol red free RPMI1640 medium supplemented with 5% CS-FBS and incubated overnight. Next day, the cells were treated with varying concentrations of test molecule in the range of 1000 nM to 0.01 nM and vehicle control (0.1 % DMSO) for 4 days. The cells were lysed and the lysate was analysed for detecting ER-a by Western blot. The compound of Formula I showed degradation of ER-a in the range of 90 % to 100 % when studied at a concentration of about 10 nM to 100 nM. Table 4 provides percentage of ER-a remained at 30 nM concentration of some of the representative compounds in ER-a degradation assay in MCF-7 WT cell lines. Table 4:

Compd. No. % ER-a Remaining at Drug Cone. (30 nM) Compd. No. % ER-a Remaining at Drug Cone. (30 nM)

2 19 42 77

14 16 43 116

17 26 44 179

34 78 45 110

36 115 46 89

38 91 52 55.6

41 100 53 20.1

Claims

Claims:

1 A compound of Formula I

and stereoisomers or pharmaceutically acceptable salts thereof, wherein

ring Z is a 5 to 10 membered mono- or bi-cyclic aromatic ring containing zero to 2 heteroatoms selected from nitrogen, oxygen and sulfur; m and n are integer independently selected from 1 or 2;

A is selected from a group consisting of -0-, -NH-, -S-, -N(Ci_₃alkyl)- and -N(C_3-6 cycloalkyl)-;

E is mono-, di- or tri- substitution and at each occurrence is independently selected from a group consisting of hydrogen, halogen, -COOH, -NH₂, -NH(C_1-3 alkyl), -N(C_1-3 alkyl)₂, - CN, -Ci-₃ haloalkyl, -Ci_₃ alkyl, -OCi_₃ haloalkyl and -OCi_₃ alkyl;

B is selected from a group consisting of -R_ls -C(0)R₂, -C(0)N(R₂)₂ and -C(=NH)NHR₂, wherein Ri is selected from hydrogen and Ci_₂o linear or branched alkyl chain optionally interrupted with one or more radicals selected from -0-, -NR₃-, -S-, -SO-,-S(0)₂-, - CR₃=CR₃-, -C≡C-, -NR₃CO-, -CONR₃-, -NR₃CONR₃-, -NR₃C(0)0-, -OC(0)0- and - C₆H₄-;

Ri is optionally further substituted with one or more groups selected from halogen, -C_3-6 cycloalkyl, -OR₄, -N(R₄)_2i -C(0)OCi_₆ alkyl and phenyl unsubstituted or substituted with one or more groups selected from halogen, -C_1-6 alkyl and -OCi_₆ alkyl; wherein, R₄, at each occurrence, is independently selected from a group consisting of hydrogen and Ci_₆ linear, branched or cyclic alkyl; R₂ at each occurrence, is independently selected from hydrogen, -C_1-6 alkyl, -C_1-6 haloalkyl, -C₃_6 cycloalkyl and -C₃_₆ halocycloalkyl;

R₃, at each occurrence is independently selected from hydrogen, -C_3-6 cycloalkyl and -Ci_ 6 alkyl;

Y is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting of -R₅, -OR₅, halogen, -CN, -NR5COR5, -NR₅S0₂R₅, -OS0₂R₅ - OC(0)R₅, -OC(0)N(R₅)₂ and -OC(0)OR₅; wherein R₅, at each occurrence is independently selected from a group consisting of hydrogen, Ci_₆ linear, branched or cyclic alkyl and C_1-6 linear, branched or cyclic haloalkyl;

L is selected from -0-, -NH-, -N(Ci_₆ alkyl)-, -N(C₃_₆ cycloalkyl)-, -N(Ci_₆ haloalkyl)- and -N(C₃_6 halocycloalkyl)-; ring X is a 5 to 10 membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms selected from oxygen, nitrogen and sulfur;

D is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting of -R₆, -OR₆, halogen, -CR₆=CR₆-COOH, -CN, -N(R₆)₂, -NR₆S0₂R₆, - NR₆CHO, -NR₆COR₆, -OC(0)R₆, -OC(0)N(R₆)₂, -NR₆CONR_{6 ,} -OC(0)OR_6, -Ci_₃ alkyl- N(R₆)₂ , -OP(0)(OH)₂ and 5 or 6 membered aryl or heteroaryl ring; wherein R₆ at each occurrence is independently selected from hydrogen or C_1-6 linear, branched or cyclic alkyl;

OR

The compound of Formula I of claim 1, wherein L is -O- and A is -O- The compound of Formula I as in claim 2, wherein Z is a 5 or 6 membered aromatic ring containing zero to 2 heteroatoms selected from nitrogen, oxygen and sulfur.

The compound of Formula I of claims 1, wherein

Z is a 5 or 6 membered aromatic ring containing zero to 2 heteroatoms selected from nitrogen, oxygen and sulfur; m and n are 1 ;

B is selected from hydrogen and Ci_io linear or branched alkyl chain optionally interrupted with one or more radicals selected from -CR₃=CR₃-, -NR₃CO- and -CONR₃-;

R₃, at each occurrence is independently selected from hydrogen or -Ci_₆ alkyl;

wherein, B is optionally further substituted with one or more groups selected from halogen or -C₃_6 cycloalkyl;

D is mono- or di-substitution and at each occurrence is independently selected from a group consisting of -R₆, -OR₆, halogen, -OC(0)R₆, -OC(0)N(R₆)₂, -Ci-₃ alkyl-N(R₆)₂ , - OP(0)(OH)₂ and 5 or 6 membered aryl or heteroaryl ring; wherein R₆ at each occurrence is independently selected from hydrogen and Ci_₆ linear, branched or cyclic alkyl; and

R₇ and R₈ are independently selected from hydrogen and C_1-3 alkyl.

The compound of Formula I of claim 1, wherein

ring Z is a 5 or 6 membered aromatic ring containing zero to 1 heteroatom selected from nitrogen, oxygen and sulfur; m and n are integer independently selected from 1 and 2;

A is -0-;

E is mono- or di- substitution and at each occurrence is independently selected from hydrogen or halogen; B is hydrogen or CM_O linear or branched alkyl chain optionally interrupted with one or more radicals selected from -CR₃=CR₃-, -NR CO- and -CONR -;

wherein, R₃, at each occurrence, is independently selected from hydrogen and -C_1-6 alkyl; and B is optionally further substituted with one or more groups selected from halogen and -C₃_₆ cycloalkyl;

Y is mono- or di-substitution and at each occurrence is independently selected from a group consisting of -OR5, halogen, -OC(0)Rs and -OC(0)N(R5)₂; wherein R5 at each occurrence is independently selected from a group consisting of hydrogen, Ci_₆ alkyl and Ci_₆ haloalkyl;

L is -0-; ring X is a 6 to 10 membered mono- or bi-cyclic ring containing zero to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

D is mono- or di-substitution and at each occurrence is independently selected from a group consisting of -R₆, -OR₆, halogen, -OC(0)R₆, -OC(0)N(R₆)₂, -Ci_₃ alkyl-N(R₆)₂, - OP(0)(OH)₂ and 5 or 6 membered aryl or heteroaryl ring; wherein R₆ at each occurrence is independently selected from hydrogen and C_1-6 alkyl;

R₇ and R₈ are independently selected from hydrogen and Ci_₃ alkyl.

The compound of Formula I of claim 1, wherein

ring Z is phenyl or pyridinyl;

m and n are integer independently selected from 1 and 2;

A is -0-;

E is mono- or di-substitution and at each occurrence, is independently selected from hydrogen and halogen;

Y is mono- or di-substitution and at each occurrence is independently selected from -OH, halogen, -OCi_₃ alkyl and -OCi_₃ haloalkyl;

L is -0-;

ring X is phenyl or

, wherein ')' indicates point of attachment to the nitrogen of the central ring and '] ' indicates the point of attachment to the L group of the central ring;

D is mono- or di-substitution and at each occurrence is independently selected from a group consisting of hydrogen, -OH, -C_1-3 alkyl-N(R6)2 and 5 or 6 membered heteroaryl ring; wherein R₆ at each occurrence is independently selected from hydrogen and Ci_₃ alkyl;

B is hydrogen or Ci_io linear or branched alkyl;

wherein B is optionally further substituted with one or more groups selected from halogen or -C₃_6 cycloalkyl; and

R₇ and R₈ are independently selected from hydrogen or C_1-3 alkyl. The compounds selected from the group consisting of

( ?)-4-[3-Fluoro-5-(l-propyl-azetidin-3-yloxy)-phenyl]-3-(4-hydroxy-phenyl)-3,4- dihydro-2H-benzo[J4]oxazin-7-ol;

3-(4-Fluorophenyl)-4-[3-fluoro-5-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H- benzo[l,4]oxazin-7-ol;

3-(4-Fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4-dihydro-2H- benzo[l,4]oxazin-7-ol; 4-{ ( ?)-5-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l,5,6,7-tetra ydro-8-oxa- 1,2,5- triazacyclopenta[b]naphthalen-6-yl}-phenol;

(R)-4- [3 -Fluoro-4-( 1 -propylazetidin-3 -yloxy)phenyl] -3 -(4-methoxyphenyl)-3 ,4-dihydro- 2H-benzo[l,4]oxazin-7-ol;

( ?)-4-[4-(l-Decylazetidin-3-yloxy)-3-fluorophenyl]-3-(4-fluoromethoxyphenyl)-3,4- dihydro-2H-benzo [J 4] oxazin-7-ol;

(3 ?)-4-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4-hydroxyphenyl)-2-methyl- 3,4-dihydro-2H-benzo[l,4]oxazin-7-ol;

4-[( ?)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(lH-pyrazol-4-yl)-3,4- dihydro-2H-benzo[l,4]oxazin-3-yl]phenol;

( ?)-6-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)-phenyl]-7-(4-methoxyphenyl)-3,6,7,8- tetrahydro-9-oxa-2,3,6-triazacyclopenta[a]naphthalene; ( ?)-6-{ 3,5-Difluoro-4-[l-(2-fluoro-2-methylpropyl)azetidin-3-yloxy]phenyl}-7-(4- fluorophenyl)-3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[a]naphthalene;

4-{ 3-Fluoro-4-[( ?)-l-(3-fluoropropyl)pyrrolidin-3-yloxy]phenyl}-3-(3-fluoro-4- methoxyphenyl)-3,4-dihydro-2H-benzo[l,4]oxazin-7-ol; and