Raf-mek protein complex modulators and methods of use thereof

Abstract

Described herein are compounds and compositions useful for preventing and / or treating a disease or condition, e.g., a disease or condition associated with MAPK signaling pathway, e.g., cancer. In one aspect, the present disclosure provides a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

Description

RAF-MEK PROTEIN COMPLEX MODULATORS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No.63 / 497149, filed on April 19, 2023, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION

[0002] The invention relates generally to compounds and compositions useful for preventing and / or treating a disease, disorder or condition associated with a MAPK signaling pathway, e.g., cancer. BACKGROUND

[0003] The mitogen-activated protein kinase (MAPK) pathway mediates the activity of a number of effector molecules (e.g., other cell cycle regulatory proteins) that coordinate the control of cellular proliferation, survival, differentiation, and migration (McCubrey J.A. et al. (2007) BIOCHEM. BIOPHYS. ACTA Aug;1773(8)). To activate the pathway, a cell signal, such as a growth factor, cytokine, or hormone, binds to a cell surface receptor, such as Rat sarcoma virus protein (RAS). Once bound, the RAS then binds a Guanosine-5’-triphosphate (GTP) molecule and activates rapidly accelerated fibrosarcoma protein (RAF). Once activated, RAF can directly phosphorylate mitogen / extracellular-signal-regulated kinase kinase (MEK, also known as Map Kinase Kinase (MKK)), and then MEK can phosphorylate the extracellular signal-related kinase (ERK). Activated ERK then phosphorylates a wide array of effector molecules, e.g., kinases, phosphatases, transcription factors, and cytoskeletal proteins, thereby effecting cell cycle changes (Bafico A. et al. (2003) Signaling Pathways of Tyrosine Kinase Receptors, Holland-Frei CANCER MEDICINE 6th edition. Hamilton (ON): BC Decker). As a result, the RAS-RAF-MEK-ERK signaling pathway can transmit signals from cell surface receptors to the nucleus, and is essential, e.g., in cell proliferation and survival (Barbosa R. et al. (2021) MOL. CANCER RES.19(3):361-374. doi: 10.1158 / 1541- 7786.MCR-20-0687). This signaling cascade is further regulated by the multiple isoforms of RAS (including KRAF, NRAS and HRAS), RAF (ARAF, BRAF, CRAF / RAF-1), MEK (MEK-1 and MEK-2) and ERK (ERK-1 and ERK-2).

[0004] Research continues to show this pathway regulates key cellular activities including proliferation, differentiation, survival, and angiogenesis (Zheng B. et al. (2003)BLOOD 102 (3): 1019–1027). Inappropriate activation of proteins in this pathway can lead to increased cell proliferation, a key characteristic of many cancers, such as melanoma, non- small cell lung, colorectal, and thyroid cancers. The MAPK / ERK signaling pathway plays an important role in tumor invasion and metastasis (McCubrey J.A. et al. (2007) supra).

[0005] Approximately 30% of all human cancers have been found to have a constitutively activated MAPK / ERK pathway, the most common mechanisms being a mutated KRAS or BRAF, and a constitutively activated MEK1, which results in uncontrolled cell growth. Despite the advances made to date in the treatment of cancers and other diseases and conditions mediated by MAPK / ERK pathway, there is an ongoing need for additional therapies for treating such cancers, diseases and conditions. SUMMARY

[0006] Described herein are compounds and compositions useful for preventing and / or treating a disease or condition associated with MAPK signaling pathway, e.g., cancer. The compounds described herein may act as a molecular glue and modulate the interaction of certain protein complexes within the MAPK signaling pathway. For example, the compounds disclosed herein may bind to the interface region between a RAF (rapidly accelerated fibrosarcoma) protein, e.g., BRAF protein, and a MEK (mitogen-activated protein kinase kinase) protein and modulate the activity and down signaling mediated by the RAF- MEK protein complex, e.g., a BRAF-MEK protein complex.

[0007] In one aspect, the present disclosure features a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0008] In some embodiments, the compound is a compound of formula (I-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0009] In certain embodiments, the compound is a compound of formula (IA):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0010] In other embodiments, the compound is a compound of formula (IA-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0011] In some embodiments, the compound is a compound of formula (IB):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0012] In certain embodiments, the compound is a compound of formula (IB-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0013] In some embodiments, the compound is a compound of Formula (IC):or a pharmaceutically acceptable salt thereof, wherein: R1and R2are taken together with the carbon atom to which they are attached to form C3-6cycloalkyl or 3-6 membered heterocyclyl ring, wherein the C3-6cycloalkyl or 3-6 membered heterocyclyl ring may be optionally substituted; and the remaining variables are as defined herein.

[0014] In some embodiments, the compound is a compound of Formula (IC-1):or a pharmaceutically acceptable salt thereof, wherein: R1and R2are taken together with the carbon atom to which they are attached to form C3-6cycloalkyl or 3-6 membered heterocyclyl ring, wherein the C3-6cycloalkyl or 3-6 membered heterocyclyl ring may be optionally substituted; and the remaining variables are as defined herein.

[0015] In some embodiments, the compound is a compound of Formula (IC-2):or a pharmaceutically acceptable salt thereof, wherein: R1and R2are taken together with the carbon atom to which they are attached to form C3-6cycloalkyl or 3-6 membered heterocyclyl ring, wherein the C3-6cycloalkyl or 3-6 membered heterocyclyl ring may be optionally substituted; and the remaining variables are as defined herein.

[0016] In certain embodiments, the compound is a compound of Formula (ID):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0017] In some embodiments, the compound is a compound of Formula (IE):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0018] In certain embodiments, the compound is a compound of Formula (IF):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0019] In some embodiments, the compound is a compound of Formula (IF-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0020] In some embodiments, the compound is a compound of Formula (IF-2):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0021] In some embodiments, the compound is a compound of Formula (IG):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0022] In some embodiments, the compound is a compound of Formula (IG-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0023] In some embodiments, the compound is a compound of Formula (IG-2):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0024] Also provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0025] In another aspect, the disclosure provides a method of modulating the interaction between RAF and MEK in a RAF-MEK complex, e.g., BRAF and MEK in a BRAF-MEK complex. The method comprises contacting BRAF, MEK or a combination of BRAF and MEK with an effective amount of a compound disclosed therein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein thereby to modulate the interaction between RAF (e.g., BRAF) and MEK. The modulation can involve stabilizing or destabilizing the interaction between RAF and MEK in a RAF-MEK complex, e.g., BRAF and MEK in a BRAF-MEK complex.

[0026] In another aspect, the present disclosure provides a method of treating a disease or condition associated with MAPK signaling pathway (e.g., cancer) in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0027] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Detailed Description, Examples, and Claims. DETAILED DESCRIPTION

[0028] As generally described herein, the present disclosure provides compounds and compositions useful for preventing and / or treating a disease or condition described herein, e.g., a disease, disorder, or condition associated with MAPK signaling pathway, e.g., cancer. I. DEFINITIONS Chemical Definitions

[0029] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0030] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw– Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0031] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight,more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0032] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S–compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0033] Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; F may be in any isotopic form, including18F and19F; and the like.

[0034] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an”may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0035] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C1–6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1-2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0036] As used herein, “alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). Examples of C1–6alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0037] As used herein, “alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon– carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C2–20alkenyl”).

[0038] As used herein, “alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds), and optionally one or more carbon– carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C2–20alkynyl”).

[0039] As used herein, “alkylene,” refers to a divalent radical of an alkyl. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene” group may be substituted or unsubstituted with one or more substituents as described herein.

[0040] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl).

[0041] As used herein, “heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).

[0042] In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatomsprovided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0043] Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6– bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0044] Examples of representative heteroaryls include the following:. wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, C1-C8alkyl, C3-C10carbocyclyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5- 10 membered heteroaryl.

[0045] As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non– aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3–10carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3–8carbocyclyl”).

[0046] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C4-8cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes. Unless specified otherwise, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, the cycloalkyl group is not substituted, i.e., it is unsubstituted.

[0047] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10– membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms,wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl or cycloalkyl groups wherein the point of attachment is either on the carbocyclyl, cycloalkyl, or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0048] In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0049] Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione. Exemplary 5– membered heterocyclyl groups containing two heteroatoms include, without limitation,dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0050] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g,. heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0051] As used herein, “halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0052] As used herein, “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms.

[0053] As used herein, “oxo” refers to -C=O.

[0054] In general, the term “substituted,” whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of thegroup, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0055] Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under this invention are preferably those that result in the formation of stable or chemically feasible compounds.

[0056] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group (such as an alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene or the carbon atom of a carbocyclyl, aryl, heterocyclyl or heteroaryl) are independently, for example, halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)0-4O(CH2)0-1Ph, which may be substituted with R°; -CH=CHPh, which may be substituted with -NO2; -CN; -N3; - (CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)0-4N(R°) C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)0-4C(O)SR°; -(CH2)0-4C(O)OSiR°3; -(CH2)0-4OC(O)R°; -OC(O)(CH2)0-4SR°-, SC(S)SR°; -(CH2)0-4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -(CH2)0-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NR°2; -(CH2)0-4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; -SiR3; -(C1-4straight or branched alkylene)O-N(R°)2; or -(C1-4straight or branched alkylene)C(O)O-N(R°)2, where each R° may be substituted as defined below and is independently hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0057] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently, for example, deuterium, halogen, -(CH2)0-2R●, -(haloR●), -(CH2)0-2OH, -(CH2)0-2OR●, -(CH2)0-2CH(OR●)2; -O(haloR●), -CN, -N3, -(CH2)0-2C(O)R●, -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR●, -(CH2)0-2SR●, -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR●, -(CH2)0-2NR●2, -NO2, -SiR●3, -OSiR●3, -C(O)SR●, -(C1-4straight or branched alkylene)C(O)OR●, or -SSR●, where each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4alkyl, C1-4alkenyl, C1-4alkynyl, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0058] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, where each independent occurrence of R*is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, and carbocyclyl, which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(C(R*)2)2-3O-, where each independent occurrence of R*is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, and carbocyclyl, which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0059] Suitable substituents on the alkyl, alkenyl, alkynyl, or carbocyclyl group of R*include halogen, -R●, -(haloR●), -OH, -OR●, -O(haloR●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, where each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-6alkyl, C1-6alkenyl, C1-6alkynyl, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0060] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R†, -NR†2, -C(O)R†, -C(O)OR†, -C(O)C(O)R†, -C(O)CH2C(O)R†,-S(O)2R†, -S(O)2NR†2, -C(S)NR†2, -C(NH)NR†2, or -N(R†)S(O)2R†; where each R†is independently hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, it should be understood that a substitutable nitrogen can be substituted with four substituents (or have four bonds to less than four substituents) such that the nitrogen atom will be positively charged or its cation, i.e., N+. Such substitution of a substitutable nitrogen can be of a ring nitrogen, for example, a ring nitrogen of a heterocyclic group containing nitrogen as a ring atom. In particular embodiments, where one of the substituents of a cationic nitrogen atom is a hydroxyl group, the hydroxyl group can be deprotonated and represented by a negatively charged oxygen atom, i.e., O-. In such cases, a general formula for the substitution can be represented by RN+(O-)(R’)R’’, where R, R’ and R’’ represent carbon or other atoms, groups and / or moieties to which the nitrogen atom is bound.

[0061] Suitable substituents on the alkyl, alkenyl, alkynyl, or carbocyclyl group of R†are independently, for example, halogen, -R●, -(haloR●), -OH, -OR●, -O(haloR●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, where each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-6alkyl, C1-6alkenyl, C1-6alkynyl, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0062] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other Definitions

[0063] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevantto a given product or process unless indicated to the contrary or otherwise evident from the context. Also contemplated are embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. Also contemplated are embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0064] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0065] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0066] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0067] The terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient” are used interchangeably herein and refer to buffers, carriers, and excipients suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable carriers include any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see e.g., Adeboye Adejare, Remington: The Science and Practice of Pharmacy (23d ed.2020).

[0068] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts indetail in J. Pharmaceutical Sciences (1977) 66:1–19, and Gould, Salt selection for basic drugs, International Journal of Pharmaceutics, 33 (1986) 201-217. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0069] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non- human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0070] Disease, disorder, and condition are used interchangeably herein.

[0071] As used herein, “treat”, “treating”, and “treatment” refer to the treatment of a disease, disorder, or symptom or manifestation of such in a subject, e.g., in a human. Thisincludes: (a) preventing a disease or disorder, (b) inhibiting the disease, disorder, etc., i.e., slowing or arresting its progress or development; and (b) relieving the disease, disorder, etc., i.e., causing regression of the disease state. As used herein, “prevent”, “preventing” and “prevention” refer to causing a disease, disorder, or symptom or manifestation of such not to occur for at least a period of time in at least some subjects.

[0072] The term “effective amount” as used herein refers to the amount of a compound, e.g., a compound or composition described herein, sufficient to elicit a beneficial or desired result or biological effect. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound or composition described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route. For example, an effective amount may be an amount of a compound or composition sufficient to achieve one or more of the following: (i) modulate an activity of MAPK signaling pathway, (ii) modulate an activity of a RAF protein (e.g., BRAF protein), (iii) modulate an activity of MEK, (iii) modulate an interaction of RAF and MEK protein complexes, or (iv) treat or prevent a disease or condition associated with MAPK signaling pathway, e.g., cancer, or a symptom or manifestation thereof.

[0073] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a disease or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. As will be appreciated by those of ordinary skill in this art, a therapeutically effective amount of a compound or composition described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. A therapeutically effective amount of a compound or composition can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route. A therapeutically effective amount of a compound or composition also includes an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. In addition, a therapeutically effective amount can encompass an amount of a compound orcomposition that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0074] At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0075] Throughout the description, where compounds or compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compounds or compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps. Similarly, throughout the description, where compounds or compositions are described as consisting essentially of specific components, or where processes and methods are described as consisting essentially of specific steps, it is contemplated that, additionally, there are compounds or compositions of the present invention that consist of the recited components, and that there are processes and methods according to the present invention that consist of the recited processing steps.

[0076] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0077] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and / or in methods of the presentinvention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0078] It should be understood that the expression “at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0079] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0080] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present invention remain operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0081] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

[0082] The claims encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.II. COMPOUNDS AND COMPOSITIONS

[0083] In one aspect, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: each G1is independently N or CH, wherein the H of CH may be substituted with R6; G2is N or CH, wherein the H of CH may be substituted with R3or R4; R1and R2are each independently selected from the group consisting of hydrogen, deuterium, halogen, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted, or R1and R2may be taken together with the carbon atom to which they are attached to form C3-6cycloalkyl or 3-6 membered heterocyclyl ring, wherein the C3-6cycloalkyl or 3-6 membered heterocyclyl ring may be optionally substituted; R3is selected from the group consisting of -ORa, -NRbRc, -C(O)N(Re)2, C1-6alkyl optionally substituted with one or more R7, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C3-10cycloalkyl, and phenyl, wherein the 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C3-10cycloalkyl, and phenyl are optionally substituted; each R4is independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, -CN, -N(Re)2, NO2, and C1-6alkoxy; Ra, Rb, Rcand Rdare each independently selected from the group consisting of hydrogen, C1-6alkyl optionally substituted with one or more R7, -C(O)-(3-10 membered heterocyclyl or 5-10 membered heteroaryl), -C(O)N(Re)2, -C(O)-(C1-6alkyl), -C(O)-(C3-10cycloalkyl), 5-10 membered heteroaryl, phenyl, 3-10 membered heterocyclyl, and C3-10cycloalkyl, wherein the 5-10 membered heteroaryl, phenyl, 3-10 membered heterocyclyl, and C3-10cycloalkyl are optionally substituted; R5is selected from the group consisting of -(C1-6alkylene)-S(O)pRh, -NReS(O)pRh, - NReC(O)Rh, -N(Re)2, NO2, -ORk, -S(O)qRh, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, (C1-6alkylene)-(3-10 membered heterocyclyl), and (C1-6alkylene)-5-10 memberedheteroaryl, wherein the 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted; each R6is independently selected from the group consisting of C1-6alkyl, halogen, C1-6haloalkyl, C1-6haloalkoxy, -CN, -N(Re)2, NO2, and C1-6alkoxy; each R7is selected from the group consisting of halogen, -C(O)N(Re)2, -C(O)ORp, 3- 10 membered heterocyclyl, and C3-10cycloalkyl, wherein the 3-10 membered heterocyclyl and C3-10cycloalkyl are optionally substituted; each Reis independently hydrogen or C1-6alkyl; each Rhis independently selected from the group consisting of -NRnRo, C1-6alkyl optionally substituted with one or more R8, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein the C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are optionally substituted; Rkis selected from the group consisting of C1-6alkyl optionally substituted with one or more R8, C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein the C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are optionally substituted; R8is selected from the group consisting of -N(Re)2, halogen, and C1-6alkoxy; each of Rnand Rois independently selected from hydrogen, and C1-6alkyl optionally substituted with one or more halogen or C1-6alkoxy; R11is hydrogen or C1-6alkyl; each Rpis independently hydrogen or C1-6alkyl; n is selected from 0, 1, 2, and 3; s is selected from 0, 1, 2, and 3; and m, p, and q are each independently selected from 0, 1, and 2; wherein when R1and R2are each independently hydrogen or optionally substituted C1-6alkyl, and R5is -NReS(O)pRh, then Rais selected from the group consisting of hydrogen, C1-6alkyl optionally substituted with one or more R7, -C(O)-(3-10 membered heterocyclyl or 5-10 membered heteroaryl), -C(O)-(C1-6alkyl), -C(O)-(C3-10cycloalkyl), 5-6 membered heteroaryl selected from the group consisting of pyridazinyl, oxazolyl, triazinyl, and pyrazinyl, phenyl,3-10 membered heterocyclyl, and C3-10cycloalkyl, wherein the 5-6 membered heteroaryl, phenyl, 3-10 membered heterocyclyl, and C3-10cycloalkyl are optionally substituted.

[0084] In some embodiments, G1is CH. In other embodiments, G1is N. In certain embodiments, both G1s are CH. In other embodiments, G2is CH. In some embodiments, G2is N.

[0085] In certain embodiments, R11is H. In other embodiments, R11is methyl.

[0086] In some embodiments, the compound is a compound of formula (I-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0087] In certain embodiments, the compound is a compound of formula (IA):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0088] In other embodiments, the compound is a compound of formula (IA-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0089] In some embodiments, the compound is a compound of formula (IB):or a pharmaceutically acceptable salt thereof, wherein: t is 0 or 1;is a 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted; and wherein the remaining variables are as defined herein.

[0090] In certain embodiments, the compound is a compound of formula (IB-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0091] In some embodiments, the compound is a compound of Formula (IC):or a pharmaceutically acceptable salt thereof, wherein: R1and R2are taken together with the carbon atom to which they are attached to form C3-6cycloalkyl or 3-6 membered heterocyclyl ring, wherein the C3-6cycloalkyl or 3-6 membered heterocyclyl ring may be optionally substituted; and the remaining variables are as defined herein.

[0092] In some embodiments, the compound is a compound of Formula (IC-1):or a pharmaceutically acceptable salt thereof, wherein: R1and R2are taken together with the carbon atom to which they are attached to form C3-6cycloalkyl or 3-6 membered heterocyclyl ring, wherein the C3-6cycloalkyl or 3-6 membered heterocyclyl ring may be optionally substituted; and the remaining variables are as defined herein.

[0093] In some embodiments, the compound is a compound of Formula (IC-2):or a pharmaceutically acceptable salt thereof, wherein: R1and R2are taken together with the carbon atom to which they are attached to form C3-6cycloalkyl or 3-6 membered heterocyclyl ring, wherein the C3-6cycloalkyl or 3-6 membered heterocyclyl ring may be optionally substituted; and the remaining variables are as defined herein.

[0094] In certain embodiments, the compound is a compound of Formula (ID):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0095] In some embodiments, the compound is a compound of Formula (IE):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0096] In certain embodiments, the compound is a compound of Formula (IF):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0097] In some embodiments, the compound is a compound of Formula (IF-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0098] In some embodiments, the compound is a compound of Formula (IF-2):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0099] In some embodiments, the compound is a compound of Formula (IG):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. [000100] In some embodiments, the compound is a compound of Formula (IG-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. [000101] In some embodiments, the compound is a compound of Formula (IG-2):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. [000102] In some embodiments, each G1is CH, wherein the H of CH may be substituted with R6. In some embodiments, one G1is N and the other G1is CH, wherein the H of CH may be substituted with R6. In some embodiments, G1is CH, wherein the H of CH may be substituted with R6. In some embodiments, G1is N. [000103] In some embodiments, G2is N. In some embodiments, G2is CH, wherein the H of CH may be substituted with R3or R4. [000104] In some embodiments, R1and R2are each independently selected from the group consisting of hydrogen, deuterium, halogen, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one, two, or three halogen(s). [000105] In certain embodiments, R1and R2may be taken together with the carbon atom to which they are attached to form C3-6cycloalkyl or 3-6 membered heterocyclyl ring, whereinthe C3-6cycloalkyl or 3-6 membered heterocyclyl ring may be optionally substituted with C1-6alkyl. [000106] In some embodiments, R1and R2are each independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, and -CF3. [000107] In certain embodiments, R1and R2are taken together with the carbon atom to which they are attached to form cyclobutyl ring, oxetanyl ring, or azetidinyl ring, wherein the cyclobutyl ring, oxetanyl ring, or azetidinyl ring is optionally substituted with C1-6alkyl. In some embodiments, R1and R2are taken together with the carbon atom to which they are attached to form cyclopropyl ring, cyclobutyl ring, oxetanyl ring, or azetidinyl ring, wherein the cyclopropyl ring, cyclobutyl ring, oxetanyl ring, or azetidinyl ring is optionally substituted with C1-6alkyl. [000108] In other embodiments, R3is selected from the group consisting of -ORa, - NRbRc, -S(O)mRd, -C(O)N(Re)2, C1-6alkyl optionally substituted with one or more R7, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C3-10cycloalkyl, and phenyl, wherein the 3-10 membered heterocyclyl and C3-10cycloalkyl are optionally substituted with one or two oxo. [000109] In some embodiments, R3is selected from the group consisting of -ORa, C1-6alkylene optionally substituted with one or more R7, -NRbRc, -C(O)N(Re)2, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl that is optionally substituted with one or two oxo. [000110] In other embodiments, Rbis selected from -C(O)-(3-10 membered heterocyclyl or 5-10 membered heteroaryl) and -C(O)N(Re)2, and Rcis selected from hydrogen and C1-6alkyl. [000111] In other embodiments, R3is -ORaor C1-6alkylene optionally substituted with one or more R7. [000112] In some embodiments, R3is -ORa. [000113] In other embodiments, each of Ra, Rb, Rcand Rdis selected from the group consisting of hydrogen, C1-6alkyl optionally substituted with one or more R7, -C(O)-(3-10 membered heterocyclyl or 5-10 membered heteroaryl), -C(O)N(Re)2, -C(O)-(C1-6alkyl), - C(O)-(C3-10cycloalkyl), 5-10 membered heteroaryl, phenyl, 3-10 membered heterocyclyl, andC3-10cycloalkyl, wherein the -10 membered heteroaryl, phenyl, 3-10 membered heterocyclyl, and C3-10cycloalkyl are optionally substituted with one, two, or three C1-6alkyl. [000114] In some embodiments, Rais selected from the group consisting of C(O)N(Re)2, 5- 10 membered heteroaryl, C1-6alkyl optionally substituted with one or more R7, C3-10cycloalkyl, -C(O)-(3-10 membered heterocyclyl), -C(O)-(C1-6alkyl), and -C(O)-(C3-10cycloalkyl). [000115] In some embodiments, Rais selected from the group consisting of C(O)N(Re)2, 5-6 membered heteroaryl optionally substituted with C1-6alkyl, C1-6alkyl optionally substituted with one or more R7, C3-10cycloalkyl, -C(O)-(3-10 membered heterocyclyl), -C(O)-(C1-6alkyl), and -C(O)-(C3-10cycloalkyl), wherein the 5-6 membered heteroaryl is selected from the group consisting of pyridazinyl, oxazolyl, triazinyl, and pyrazinyl. [000116] In other embodiments, Rais 5-6 membered heteroaryl selected from the group consisting of pyridazinyl, oxazolyl, triazinyl, and pyrazinyl, wherein the 5-6 membered heteroaryl is optionally substituted with C1-6alkyl. [000117] In certain embodiments, Rais C(O)N(Re)2or 5-10 membered heteroaryl. [000118] In other embodiments, Rais 5-6 membered heteroaryl. [000119] In some embodiments, Rais a 6-membered heteroaryl having two or three nitrogen. [000120] In certain embodiments, Rais selected from the group consisting of:[000121] In some embodiments, Rais selected from the group consisting of:[000122] In other embodiments, Rais selected from the group consisting of:[000123] In some embodiments, Rais selected from the group consisting of:[000124] In some embodiments, Rais selected from:[000125] In some embodiments, Rais[000126] In other embodiments, Rais:[000127] In certain embodiments, Rais:[000128] In some embodiments, Rais:[000129] In some embodiments, Rais:[000130] In some embodiments, Rais:[000131] In some embodiments, Rais:[000132] In some embodiments, each R7is independently selected from the group consisting of halogen, -C(O)N(Re)2, -C(O)ORp, 3-10 membered heterocyclyl, and C3-10cycloalkyl, wherein the 3-10 membered heterocyclyl and C3-10cycloalkyl are optionally substituted with one or two oxo. [000133] In certain embodiments, each R7is independently selected from the group consisting of halogen, -C(O)N(Re)2,3-10 membered heterocyclyl, and C3-10cycloalkyl. [000134] In other embodiments, each R7is independently halogen or -C(O)N(Re)2. [000135] In certain embodiments, each Reis hydrogen or C1-6alkyl. [000136] In some embodiments, each Reis C1-6alkyl. [000137] In certain embodiments, each R4is selected from the group consisting of halogen, C1-6alkyl, and C1-6haloalkyl.[000138] In certain embodiments, each R4is halogen. [000139] In some embodiments, R5is selected from the group consisting of -(C1-6alkylene)- S(O)pRh, -NReS(O)pRh, -NReC(O)Rh, -N(Re)2, NO2, -ORk, -S(O)qRh, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, (C1-6alkylene)-(3-10 membered heterocyclyl), and (C1-6alkylene)-5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or two oxo. [000140] In other embodiments, R5is selected from the group consisting of NReS(O)pRh, NReC(O)Rh, and -(C1-6alkylene)-S(O)pRh. [000141] In other embodiments, R5is NReS(O)pRh, for example, NHS(O)2Rh. [000142] In certain embodiments, each Rhis independently selected from the group consisting of -NRnRo, C1-6alkoxy, C1-6alkyl optionally substituted with one or more R8, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein the C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents (e.g., one, two, three, or four substituents) each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, and C(O)NRpRq, wherein Rpand Rqare independently hydrogen or C1-6alkyl. [000143] In some embodiments, Rhis selected from the group consisting of -NRnRo, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C3-10cycloalkyl, 3-10 membered heterocyclyl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents (e.g., one, two, three, or four substituents) each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, and C(O)NRpRq. [000144] In certain embodiments, Rhis -NRnRo. In some embodiments, Rhis -NHCH3. [000145] In some embodiments, each Rnand Roare independently selected from hydrogen, methy, and -C1-6alkylene-C1-6alkoxy. [000146] In other embodiments, each Rnand Roare independently selected from hydrogen and methyl. [000147] In some embodiments, Rhis 3-10 membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, and C(O)NRpRq.[000148] In other embodiments, Rkis selected from the group consisting of -NRnRo, C1-6alkyl optionally substituted with one or more R8, C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein the C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from halogen and C1-6alkyl. [000149] In certain embodiments, R5is selected from the group consisting of 3-10 membered heterocyclyl, 5-10 membered heteroaryl, (C1-6alkylene)-3-10 membered heterocyclyl, and (C1-6alkylene)-5-10 membered heteroaryl wherein the 3-10 membered heterocyclyl is optionally substituted with one or two oxo. [000150] In other embodiments, R5is selected from the group consisting of - 3-10 membered heterocyclyl and (C1-6alkylene)-3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with oxo. [000151] In some embodiments, each R6is halogen. In some embodiments, R6is chloro. In some embodiments, R6is fluoro. In some embodiments, R6is vicinal to the two substituents on the aryl group. [000152] In certain embodiments, n is 0. In other embodiments, n is 1. [000153] In some embodiments, s is 0. In certain embodiments, s is 1. In other embodiments, s is 2. [000154] In other embodiments, t is 0. In some embodiments, t is 1. [000155] In certain embodiments,is a 3-10 membered heterocyclyl wherein the 3-10 membered heterocyclyl is optionally substituted. [000156] In some embodiments,is selected from the group consisting ofand wherein R9is selected from the group consisting of O, NH, N-C1-6alkyl, N-C1-6alkoxy, and N-(C1-6alkylene)-C(O)N(Re)2. [000157] In some embodiments,[000158] In some embodiments, wherein R9is O.[000159] In some embodiments,wherein R9is NH. [000160] In certain embodiments, the compound is selected from the compound of Table 1 or a pharmaceutically acceptable salt thereof. Table 1. List of exemplified compounds[000161] In certain embodiments, the compound is selected from the compound of Table 2 or a pharmaceutically acceptable salt thereof.Table 2. List of exemplified compounds60III. COMPOUND SYNTHESIS General Synthetic Schemes [000162] Exemplary methods for preparing compounds described herein are illustrated in the following synthetic schemes. These schemes are given for the purpose of illustrating the scope of the disclosure, and should not be regarded in any manner as limiting the scope or the spirit of the claimed invention. [000163] The synthetic route illustrated in Scheme 1 depicts an exemplary procedure for preparing a compound of Formula (IA), where R1and R2are both hydrogen. SCHEME 1[000164] In the first step, optionally substituted 2,4-dihydroxybenzaldehyde A is reacted regioselectively with di-chloro agent Cl-Ra-Cl to give ether B. Alternatively, mono-chloro agent Ra-Cl may be used. This step may be modified depending on the particular Ragroup. In the second step, ether B is reacted under standard reductive amination conditions with a substituted amine (generally available commercially) to give compound C. In the third step, carbamate D is formed through reaction with carbonyl di-imdazole. In the fourth step, the chloride on Ragroup is removed via hydrogenolysis (if mono-chloro agent Ra-Cl is used in the first step, this step is omitted), and the Boc protecting group is removed under acidic conditions to provide compound E. In the last step, a reaction with a chlorosulfonamide agent yields a compound of Formula (IA). [000165] The synthetic route illustrated in Scheme 1A depicts an exemplary procedure for preparing a compound of Formula (IA), where at least one of R1and R2is not hydrogen. SCHEME 1A[000166] In the first step, an optionally substituted 2,4-dibenzyloxybenzene A is regioselectively reacted with dimethylbromohydantoin (DMDBH) to give the brominated compound B. In the second step, treatment of B with a n-butyllithium (or suitable lithiation reagent) provides the intermediate organolithium reagent, which is reacted with an appropriately substituted sulfenamide and then treated with aqueous HCl to provide the amine C. In the third step, standard reductive amination conditions with an appropriately substituted benzaldehyde provides D. In the fourth step, compound D is treated with carbonyl di-imadazole to form the carbamate E. In the fifth step, compound E is reacted with Ra-Cl or Cl-Ra-Cl agent to provide compound F. This step may be modified depending on the particular Ragroup. In the sixth step, if Cl-Ra-Cl agent is used in the previous step, the remaining chloride is removed via hydrogenolysis, and the Boc protecting group is removed under acidic conditions to provide compound G. In the last step, a reaction with a chlorosulfonamide agent yields a compound of Formula (IA). [000167] The synthetic route illustrated in Scheme 2 depicts an exemplary procedure for preparing a compound of Formula (IB), where R1and R2are both hydrogen and t is 1. SCHEME 2[000168] In the first step, optionally substituted 3-methylbenzonitrile A is reacted with N- bromosuccinimide to provide an intermediate bromide, which is reacted with ring A (which contains an amide, urea, or carbamate) to form compound B. This step may be modified if ring A does not have an amide, urea, or carbamate. In the second step, the nitrile moiety of compound B is reduced under standard hydrogenation conditions, and the resultant amine is reacted via reductive amination with 2,4-dihydroxybenzaldehyde derivative to yield amine C. In the third step, carbamate D is formed through reaction of the amine and phenol with carbonyl di-imdazole. In the last step, the remaining phenolic group is reacted with Ra-Cl or Cl-Ra-Cl agent. This step may be modified depending on the particular Ragroup. If Cl-Ra-Clagent is used, the remaining chloride is removed via hydrogenolysis to give a compound of Formula (IB). Ring A may be replaced with an acyclic amide, urea, or carbamate to prepare an acyclic analog. [000169] The synthetic route illustrated in Scheme 2A depicts an exemplary procedure for preparing a compound of Formula (IB), where R1and R2are both hydrogen and t is 0. SCHEME 2A[000170] In the first step, optionally substituted 3-aminobenzonitrile A is reacted with a bis- electrophile that forms ring A with the amine to provide compound B. This step may be modified based on the structure of ring A. In the second step, the nitrile moiety of compound B is reduced under standard hydrogenation conditions, and the resultant amine is reacted via reductive amination with 2,4-dihydroxybenzaldehyde derivative to yield amine C. In the third step, carbamate D is formed through reaction of the amine and phenol with carbonyl di- imdazole. In the last step, the remaining phenolic group is reacted with Ra-Cl or Cl-Ra-Cl agent. This step may be modified depending on the particular Ragroup. If Cl-Ra-Cl agent is used, the remaining chloride is removed via hydrogenolysis to give a compound of Formula (IB). [000171] The synthetic route illustrated in Scheme 2B depicts an exemplary procedure for preparing a compound of Formula (IB), where at least one of R1and R2are both hydrogen and t is 1.SCHEME 2B[000172] The preparation of compound C is as described in Scheme 1B. Standard reductive amination of compound C with an appropriately substituted benzaldehyde (prepared separately) provides compound D. Carbamate E is formed through reaction of the amine and phenol with carbonyl di-imdazole. Then carbamate E is reacted with Ra-Cl or Cl-Ra-Cl agent. This step may be modified depending on the particular Ragroup. Finally, if Cl-Ra-Cl agent is used in the previous step, the remaining chloride is removed via hydrogenolysis to yield a compound of Formula (IB). [000173] In addition to the general synthetic schemes, specific syntheses of the compounds disclosed herein are set forth in the various Examples. IV. PHARMACEUTICAL COMPOSITIONS AND ROUTES OF ADMINISTRATION Compounds provided in accordance with the present disclosure, e.g., a compound of Formula (I), (e.g., (I-1), (IA), (IA-1), (IB), (IB-1), (IC), (IC-1), (IC-2), (ID), (IE), (IF), (IF-1), (IF-2), (IG), (IG-1), or (IG-2)) are usually administered in the form of pharmaceutical compositions. Provided herein are pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Adeboye Adejare, Remington: The Science and Practice of Pharmacy (23d ed.2020)).[000174] In certain embodiments, a pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; and / or excipients (see Adeboye Adejare (2020) supra). [000175] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including, orally, topically, by rectal, buccal, intranasal or transdermal routes, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, or as an inhalant, or via an impregnated or coated device, e.g., a stent. [000176] One mode for administration is parenteral, particularly by injection. The forms in which the novel compounds or compositions described herein may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are alsoconventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. [000177] Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [000178] Oral administration is another route for administration of compounds in accordance with the invention. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. [000179] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents;preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents. [000180] The compounds or compositions described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos.3,845,770; 4,326,525; 4,902,514; and 5,616,345. Similarly, the compounds or compositions described herein can be delivered by transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., U.S. Pat. Nos.5,023,252, 4,992,445 and 5,001,139). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. [000181] The compositions are preferably formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. For oral administration, each dosage unit may contain from 1 mg to 2 g (e.g., 1 mg to 1 g, 1 mg to 500 mg, 1 mg to 100 mg) of a compound described herein, and for parenteral administration, from 0.1 to 700 mg (e.g., from 0.1 mg to 300 mg, from 0.1 mg to 100 mg, from 0.1 mg to 10 mg) of a compound described herein. The reference to compound includes the compound either alone or in combination with a pharmaceutically acceptable salt. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like. [000182] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [000183] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. [000184] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. [000185] In some embodiments, a pharmaceutical composition comprising a disclosed compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. V. METHODS OF TREATMENT [000186] The compounds and compositions herein can be used in a method of modulating the interaction between RAF and MEK in a RAF-MEK complex (e.g., BRAF and MEK in a BRAF-MEK complex). The method comprises contacting BRAF, MEK or a combination of BRAF and MEK with an effective amount of a compound disclosed therein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein thereby to modulate the interaction between BRAF and MEK. The modulation can involvestabilizing or destabilizing the interaction between RAF and MEK in a RAF-MEK complex, e.g., BRAF and MEK in a BRAF-MEK complex. [000187] The compounds and compositions described herein can be used to treat a disease or condition associated with MAPK signaling pathway in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In certain embodiments the disease or condition is cancer. [000188] The compounds and compositions described above and herein can be used to treat an abnormal cell growth in a subject in need thereof. Abnormal cell growth, as used herein and unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) whose growth is mediated, e.g., by aberrant MAPK Pathway Signaling; (2) benign and malignant cells of other proliferative diseases, e.g., in which aberrant RAF- MEK complex, e.g., BRAF-MEK, complex mediated signaling occurs; (3) any tumors that proliferate, e.g., by RAF-MEK complex, e.g., BRAF-MEK complex, signaling; (4) tumor proliferation, e.g., by aberrant upstream dysregulation of MAPK pathway including EGFR or RAS proteins; and (5) neoplastic disorders e.g., in which aberrant RAF-MEK complex, e.g., BRAF-MEK complex, signaling occurs. [000189] Abnormal cell growth can refer to cell growth of epithelial cells (e.g., carcinomas, adenocarcinomas), mesenchymal cells (e.g., sarcomas (e.g., Ewing’s sarcoma)), hematopoetic cells (e.g., lymphomas, leukemias, myelodysplasias) or other cells (e.g., melanoma, mesothelioma, and other tumors of unknown origin). A “neoplastic disorder” is a disease or disorder characterized by cells that have the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. An abnormal mass of tissue as a result of abnormal cell growth or division, or a neoplasm, can be benign, pre-malignant or malignant. Exemplary neoplastic disorders include: carcinoma, sarcoma, metastatic disorders (e.g., tumors arising from prostate, colon, lung, breast and liver origin), hematopoietic neoplastic disorders, e.g., leukemias, metastatic tumors. Treatment with the compound may be in an amount effective to ameliorate at least one symptom of the neoplastic disorder, e.g., reduced cell proliferation, reduced tumor mass, etc. [000190] The methods and compositions described herein may be useful in the prevention and treatment of a cancer, including, e.g., solid tumors, soft tissue tumors, and metastasesthereof. The disclosed methods are also useful in treating non-solid cancers. Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon, rectum, or colorectum), brain, pancreas, genitourinary tracts (e.g., renal, urothelial, or testicular tumors), pharynx, prostate, and ovary. Exemplary adenocarcinomas include colorectal cancers, renal-cell carcinoma, liver cancer (e.g.. hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer (NSCLC)), pancreatic (e.g., metastatic pancreatic adenocarcinoma) and cancer of the small intestine. In some embodiments, the cancer can be colorectal cancer, NSCLC, or pancreatic cancer. In certain embodiments, the cancer may include brain metastasis. [000191] The cancer can include mesothelioma; neurofibromatosis; e.g., neurofibromatosis type 2, neurofibromatosis type 1, renal cancer; lung cancer, non-small cell lung cancer; liver cancer; thyroid cancer; ovarian; breast cancer; a nervous system tumor; schwannoma; meningioma; schwannomatosis; neuroma acoustic; adenoid cystic carcinoma; ependymoma; ependymal tumors, or any other tumor which exhibits decreased merlin expression and / or mutation, and / or deletion and / or promotor hypermethylation of the NF-2 gene. In some embodiments, the cancer is renal cancer. [000192] The cancer can include cancers characterized as comprising cancer stem cells, cancer associated mesenchymal cells, or tumor initiating cancer cells. The cancer can include cancers that have been characterized as being enriched with cancer stem cells, cancer associated mesenchymal cells, or tumor initiating cancer cells (e.g., a tumor enriched with cells that have undergone an epithelial -to-mesenchymal transition or a metastatic tumor). [000193] The cancer can be a primary tumor, i.e., located at the anatomical site of tumor growth initiation. The cancer can also be metastatic, i.e., appearing at least a second anatomical site other than the anatomical site of tumor growth initiation. The cancer can be a recurrent cancer, i.e., cancer that returns following treatment, and after a period of time in which the cancer was undetectable. The recurrent cancer can be anatomically located locally to the original tumor, e.g., anatomically near the original tumor; regionally to the original tumor, e.g., in a lymph node located near the original tumor; or distantly to the original tumor, e.g., anatomically in a region remote from the original tumor. In some embodiments, the cancer can be brain or cerebrospinal fluid (CSF)-related metastasis.[000194] The cancer can also include for example, but is not limited to, epithelial cancers, breast, lung, pancreatic, colorectal (e.g., metastatic colorectal, e.g., metastatic KRAS mutated), prostate, head and neck, melanoma (e.g., NRAS mutated locally advanced or metastatic malignant cutaneous melanoma), acute myelogenous leukemia, and glioblastoma. Exemplary breast cancers include triple negative breast cancer, basal-like breast cancer, claudin-low breast cancer, invasive, inflammatory, metaplastic, and advanced HER-2 positive or ER-positive cancers resistant to therapy. [000195] In some embodiments, the cancer can also include a cancer characterized as having a RAF mutation. In some embodiments, the cancer can also include a cancer characterized as having a KRAS mutation, an NRAS mutation, or a HRAS mutation. In some embodiments, the cancer may also be characterized as having EGFR overexpression. [000196] The cancer can also include lung adenocarcinoma, colorectal cancer (CRC), uveal melanoma, ovarian cancer, uterine endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic type pleural mesothelioma, renal clear cell carcinoma, renal clear cell carcinoma, stomach adenocarcinoma, tubular stomach adenocarcinoma, head and neck squamous cell carcinoma, uterine carcinosarcoma, or uterine malignant mixed Mullerian tumor. [000197] In some embodiments, the cancer is unresectable or metastatic melanoma, melanoma with lymph node involvement or metastatic disease who have undergone complete resection, metastatic non-small cell lung cancer and progression on or after platinum-based chemotherapy, metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy, advanced renal cell carcinoma who have received prior anti angiogenic therapy, advanced renal cell carcinoma, classical Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy, locally advanced or metastatic urothelial carcinoma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, or hepatocellular carcinoma. [000198] In some embodiments, the cancer is melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability -highcancer, gastric cancer, esophageal cancer, cervical cancer, hepatocellular carcinoma, merkel cell carcinoma, renal cell carcinoma, or endometrial carcinoma. [000199] Other cancers include but are not limited to, uveal melanoma, brain, abdominal, esophagus, gastrointestinal, glioma, liver, tongue, neuroblastoma, osteosarcoma, ovarian, retinoblastoma, Wilm’s tumor, multiple myeloma, skin, lymphoma, blood and bone marrow cancers (e.g., advanced hematological malignancies, leukemia, e.g., acute myeloid leukemia (e.g., primary’ or secondary), acute lymphoblastic leukemia, acute lymphocytic leukemia, T cell leukemia, hematological malignancies, advanced myeloproliferative disorders, myelodysplastic syndrome, relapsed or refractory’ multiple myeloma, advanced myeloproliferative disorders), retinal, bladder, cervical, kidney, endometrial, meningioma, lymphoma, skin, uterine, lung, non small cell lung, nasopharyngeal carcinoma, neuroblastoma, solid tumor, hematologic malignancy, squamous cell carcinoma, testicular, thyroid, mesothelioma, brain vulval, sarcoma, intestine, oral, endocrine, salivary, spermatocyte seminoma, sporadic medullary thyroid carcinoma, non-proliferating testes cells, cancers related to malignant mast cells, non-Hodgkin’s lymphoma, and diffuse large B cell lymphoma. [000200] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is locally advanced or metastatic. In some embodiments, the solid tumor is refractory (e.g., resistant) after standard therapy. [000201] Methods described herein can reduce, ameliorate or altogether eliminate the disorder, and / or its associated symptoms, to keep it from becoming worse, to slow the rate of progression, or to minimize the rate of recurrence of the disorder once it has been initially eliminated (e.g., to avoid a relapse). A suitable dose and therapeutic regimen may vary depending upon the specific compounds, combinations, and / or pharmaceutical compositions used and the mode of delivery of the compounds, combinations, and / or pharmaceutical compositions. In some embodiments, the method increases the average length of survival, increases the average length of progression-free survival, and / or reduces the rate of recurrence, of subjects treated with the combinations described herein in a statistically significant manner. [000202] In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer CNSCLC), e.g., KRAS mutant NSCLC, metastatic cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer (e.g., unresectable low-grade ovarian, advanced or metastatic ovarian cancer), rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer (e.g., triple-negative breast cancer (e.g., breast cancer which does not express the genes for the estrogen receptor, progesterone receptor, and Her2 / neu)), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary’ adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgical resectable malignant pleural mesothelioma) or a combination of one or more of the foregoing cancers. EXAMPLES [000203] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope. [000204] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization. [000205] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are describedin T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. [000206] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography may either be performed manually or via an automated system. The compounds provided herein may be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in part per million (ppm) and are generated using methods well known to those of skill in the art. List of abbreviations ACN Acetonitrile AcOH Acetic acid ADP Adenosine diphosphate AIBN Azobisisobutyronitrile aq. Aqueous ATP Adenosine triphosphate BBr3Boron tribromide BF3·AcOH Boron trifluoride acetic acid complex BF3.Et2O Boron trifluoride etherate BnBr Benzyl bromide BnOH Benzyl alcohol B2Pin2Bis(pinacolato)diboron Boc-NH2tert-Butyl carbamate (Boc)2O Di-tert-butyl dicarbonate BRAF B-Raf proto-oncogene CBr4Carbon tetrabromide CBz-Cl Benzyl chloroformate CCl4Carbon tetrachloride ClCOOiBu Isobutyl chloroformate CDI 1,1’-Carbonyldiimidazole CHAPS 3-{Dimethyl[3-(3α,7α,12α-trihydroxy-5β-cholan-24- amido)propyl]azaniumyl}propane-1-sulfonateCO2Carbon dioxide (COCl)2Oxalyl chloride Cs2CO3Cesium carbonate C-term C-terminus Cu Copper CuCl Copper(I) chloride CuI Copper(I) iodide d Day(s) DBDMH 1,3-Dibromo-5,5-dimethylhydantoin (1,3-Dibromo-5,5- dimethylimidazolidine-2,4-dione) DMEDA N,N'-Dimethylethylenediamine DCE Dichloroethane DCM Dichloromethane DEA Diethylamine DIAD Diisopropyl azodicarboxylate DIBAL (or DIBAL- Diisobutylaluminum hydride H) DIPEA Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMEDA 1,2-Dimethylethylenediamine DMF N,N’-dimethylformamide DMF-d7Deuterated N,N’-dimethylformamide DMP Dess-Martin periodinane DMSO Dimethyl sulfoxide DMSO-d6Deuterated dimethyl sulfoxide DPPA Diphenylphosphoryl azide DTT Dithiothreitol EC50Half maximal effective concentration ERK Extracellular signal-regulated kinase ES Electrospray ionization EtMgBr Ethylmagnesium bromide EtOAc Ethyl acetate Ex / Em Excitation / emission ratio FeCl3Iron(III) chloride FRET Fluorescence energy transferGST Glutathione S-transferase h Hour; Hours H2Hydrogen H2O Water HATU Hexafluorophosphate azabenzotriazole tetramethyl uronium HCHO Formaldehyde HCl Hydrogen chloride HClO4Perchloric acid HEPES N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid His Histidine HPLC High-performance liquid chromatography IC50Half-maximal inhibitory concentration ICl Iodine chloride Im Imidazole K2CO3Potassium carbonate K3PO4Tripotassium phosphate KI Potassium iodide KOAc Potassium acetate LAH Lithium aluminum hydride LDA Lithium diisopropylamide LiAlH4Lithium aluminum hydride LiCl Lithium chloride LiOH Lithium hydroxide m / z Mass-to-charge ratio MeI Methyl iodide MEK Mitogen-activated protein kinase kinase MeMgBr Methyl magnesium bromide MeNH2Methylamine MeOH Methanol MgCl2Magnesium chloride min Minutes MOMCl Chloromethyl methyl ether N Normal (molarity) NaN3Sodium azide NaBH4Sodium borohydrideNaBH3CN Sodium cyanoborohydride NaCl Sodium chloride NaBD4Sodium borodeuteride NaH Sodium hydride NaHCO3Sodium bicarbonate NaIO4Sodium periodate NaOMe Sodium methoxide Na2SO4Sodium sulfate Na2S2O3Sodium thiosulfate NBS N-bromosuccinimide n-BuLi n-butyllithium NH3Ammonia NH4Cl Ammonium chloride NH(Me)2Dimethylamine NMP N-methyl-2-pyrrolidone N-term N-terminus OsO4Osmium tetroxide Pd / C Palladium on carbon PdCl2(PPh3)2Bis(triphenylphosphine)palladium(II) dichloride Pd2(dba)3Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2•DCM [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane Pd(dppf)Cl2·CH2Cl2[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane Pd(OAc)2Palladium acetate PMA Phorbol myristate acetate PMB-Cl para-Methoxybenzyl chloride POCl3Phosphoryl trichloride PPh3Triphenylphosphine PPTS Pyridinium p-toluenesulfonate Py Pyridine rt Room temperature SnCl2•2H2O Stannous chloride dihydrate SOCl2Thionyl chlorideSTAB Sodium triacetoxyborohydride TBAAc Tetrabutylammonium acetate TBAF Tetrabutylammonium fluouride TBDMS-Cl tert-Butyldimethylsilyl chloride TC Tissue culture TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran Ti(OiPr)4Titanium(IV) isopropoxide TLC Thin-layer chromatography TMSCF3Trimethyl(trifluoromethyl)silane TMSN3Trimethylsilyl azide T3P Propanephosphonic acid anhydride TR-FRET Time-resolved fluorescence energy transfer Tris Tris(hydroxymethyl)aminomethane Intermediate Preparation Intermediate 01: Preparation of 2-hydroxy-4-((4-methoxybenzyl)oxy)benzaldehyde (I- 01)[000207] Step-1: Synthesis of 2-hydroxy-4-((4-methoxybenzyl)oxy)benzaldehyde (I-01): To a stirred solution of 2,4-dihydroxybenzaldehyde (A1) (3 g, 21.7 mmol) in acetone (75 mL) was added K2CO3(3.3 g, 23.9 mmol) and potassium iodide (3.61 g, 21.7 mmol) followed by 1-(chloromethyl)-4-methoxybenzene (3.4 g, 21.7 mmol) at room temperature. The reaction mixture was stirred at 70 °C and the reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (2 h), it was cooled to room temperature and water (30 mL) was added to it. Extraction was carried out using EtOAc (30 mL x 3); the combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residuewas purified by Combi-Flash (using gradient elution of 0-10% of EtOAc in heptane) to afford desired compound I-01 (4.1 g) as an off white solid. LCMS (ES) m / z: 259.1 [M+H]+. Intermediate 02: Preparation of 2-(benzyloxy)-4-hydroxybenzaldehyde (I-02)[000208] Step-1: Synthesis of 2-hydroxy-4-(oxan-2-yloxy) benzaldehyde (A3): To a stirred solution of 2,4-dihydroxybenzaldehyde (A1) (10 g, 72.4 mmol) in DCM (100 mL) was added PPTS (728 mg, 2.9 mmol) and 3,4-dihydro-2H-pyran (A2) (13.4 g, 159 mmol) at 0 °C. The reaction mixture was stirred at room temperature and the reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (4 h), volatiles were removed under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford the desired compound A3 (15 g) as a colorless liquid. LCMS (ES) m / z: 221.2 [M-H]+. [000209] Step-2: Synthesis of 2-(benzyloxy)-4-(oxan-2-yloxy) benzaldehyde (A4): To a stirred solution of 2-hydroxy-4-(oxan-2-yloxy) benzaldehyde (A3) (15 g, 67.5 mmol) in DMF (150 mL) was added K2CO3(18.7 g, 135 mmol) and benzyl bromide (13.9 g, 81 mmol) at 0 °C. The reaction mixture was stirred at room temperature and the reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (3 h), water (200 mL) was added to it and extraction was carried out using EtOAc (3 x 100 mL). The combined organic extracts were washed with cold water (2 x 200 mL), brine solution (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford the desired compound A4 (16 g) as a viscous liquid. LCMS (ES) m / z: 313.3 [M+H]+.[000210] Step-3: Synthesis of 2-(benzyloxy)-4-hydroxybenzaldehyde (I-02): To a stirred solution of 2-(benzyloxy)-4-(oxan-2-yloxy)benzaldehyde (16 g, 51.2 mmol) in MeOH (211 mL) was added 1 M aqueous solution of HCl (2 mL) at 0 °C. The reaction mixture was stirred at room temperature and the reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (1 h), water (50 mL) was added to it and extraction was carried out using EtOAc (3 x 70 mL). The combined organic extracts were washed with brine solution (2 x 70 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the desired compound I-02 (12 g) as a pale yellow solid. LCMS (ES) m / z: 229.1 [M+H]+. [000211] Step-4: Synthesis of 2-(benzyloxy)-4-(cyclopropylmethoxy)benzaldehyde (I-02a): To a stirred solution of 2-(benzyloxy)-4-hydroxybenzaldehyde (I-02) (0.6 g, 2.63 mmol) in DMF (15 mL) was added K2CO3(545 mg, 3.94 mmol) and (bromomethyl)cyclopropane (461 mg, 3.42 mmol) at room temperature. The reaction mixture was stirred at 100 °C and the reaction progress was monitored by TLC / LCMS analysis. After completion of the reaction (16 h), the reaction mixture was cooled to room temperature and ice-cold water (20 mL) was added to it. Extraction was carried out with EtOAc (3 x 50 mL); the combined organic extracts were washed with brine solution (2 x 25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford desired compound I-02a (580 mg) as a pale-yellow solid. LCMS (ES) m / z: 283.2 [M+H]+. Intermediate 02b: Preparation of 2-(benzyloxy)-4-(oxetan-3-yloxy)benzaldehyde (I-02b)[000212] Step-1: Synthesis of 2-(benzyloxy)-4-(oxetan-3-yloxy)benzaldehyde (I-02b): To a stirred solution of 2-(benzyloxy)-4-hydroxybenzaldehyde (I-02) (0.8 g, 3.5 mmol) in DMF (13.3 mL) was added K2CO3(969 mg, 7.01 mmol) and oxetan-3-yl 4-methylbenzene-1- sulfonate (1.6 g, 7.01 mmol) in room temperature. The reaction mixture was stirred at 100°C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with addition of cold water (20 mL). Extraction was carried out using EtOAc (30 mL x 3); the combined organic extracts were washed with water (50 mL),brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% of EtOAc in heptane) to afford desired compound I-02b (0.8 g) as an off-white solid. LCMS (ES) m / z: 285.2 [M+H]+. Intermediate 03: Preparation of 3,5-difluoro-2,4-dihydroxybenzaldehyde (I-03)[000213] Step-1: Synthesis of 3,5-difluoro-2,4-dimethoxybenzaldehyde (A6): To a stirred solution of 2,3,4,5-tetrafluorobenzaldehyde (A5) (2 g, 11.2 mmol) in MeOH (8 mL) was added 25% of NaOMe in MeOH (8.0 mL, 34.81 mmol) at 0 °C and the reaction mixture was stirred at room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (16 h), the reaction mixture was quenched with addition of water (30 mL) and extraction was carried out using DCM (2 x 50 mL). The combined organic extracts were washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford the desired compound A6 as an off white solid (1.4 g). LCMS (ES) m / z: 202.9 [M+H]+. [000214] Step-2: Synthesis of 3,5-difluoro-2,4-dihydroxybenzaldehyde (I-03): To a stirred solution of 3,5-difluoro-2,4-dimethoxybenzaldehyde (A6) (1.4 g, 6.93 mmol) in anhydrous DCM (10 mL) was added BBr3(1.33 mL, 13.9 mmol) at 0 °C and the reaction mixture was allowed to stir at room temperature, while monitoring reaction progress by TLC / LCMS. After complete consumption of starting material (2 h), it was quenched by addition of ice water (20 mL) and extraction was carried out using EtOAc (2 x 40 mL), The combined organic extracts were washed with brine solution (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford desired I-03 as an off white solid (1 g). LCMS (ES) m / z: 175.0 [M+H]+. Intermediate 04: Preparation of 3-fluoro-2-hydroxy-4-((4-methoxybenzyl)oxy) benzaldehyde (I-04)[000215] Step-1: Synthesis of 3-fluoro-2-hydroxy-4-[(4- methoxyphenyl)methoxy]benzaldehyde (I-04): Intermediate I-04 (0.5 g) was synthesized by following procedure as described for the synthesis of I-01 (step-1) using 2-fluoro-4,6- dihydroxybenzaldehyde (A7) (0.7 g, 4.48 mmol) as the starting material. LCMS (ES) m / z: 275.0 [M-H]+. Intermediate 05: Preparation of 5-fluoro-2,4-dihydroxybenzaldehyde (I-05)[000216] Step-1: Synthesis of 5-fluoro-2,4-dihydroxybenzaldehyde (I-05): To a solution of Selectfluor (32.3 g, 91.2 mmol) in ACN (120 mL) was added 2,4-dihydroxybenzaldehyde (A1) (9.0 g, 65.2 mmol) portion wise and the reaction mixture was stirred at room temperature for 4 days. The reaction progress was monitored by TLC / LCMS. Water (300 mL) was then added to it and extraction was carried out using EtOAc (90 mL x 3). The combined organic extracts were washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-40% of EtOAc in heptane) followed by reverse phase preparative HPLC purification of the residue obtained [using XSelect CSH C-18 (250 mm x 4.6 mm, 5 µm particle size) column, 0.1% formic acid in water and acetonitrile as mobile phase with 1.0 mL / min flow rate] to afford desired I-05 (0.6 g) as a yellow solid. LCMS (ES) m / z: 155.1 (M-H)+.Intermediate 6: Preparation of 2-fluoro-6-hydroxy-4-((4- methoxybenzyl)oxy)benzaldehyde (I-06)[000217] Step-1: Synthesis of 2-fluoro-6-hydroxy-4-((4-methoxybenzyl)oxy)benzaldehyde (I-06): Intermediate I-06 (0.650 g) was synthesized by following procedure as described for the synthesis of I-01 (step-1) using 2-fluoro-4,6-dihydroxybenzaldehyde (A9) (0.5 g, 3.2 mmol) as the starting material. LCMS (ES) m / z: 277.1 [M+H]+. Intermediate 7: Preparation of 5-chloro-2-hydroxy-4-((4-methoxybenzyl)oxy) benzaldehyde (I-07)[000218] Step-1: Synthesis of 5-chloro-2-hydroxy-4-((4-methoxybenzyl)oxy)benzaldehyde (I-07): Intermediate I-07 (1.3 g) was synthesized by following procedure as described for the synthesis of I-01 (step-1) using 5-chloro-2,4-dihydroxybenzaldehyde (A10) (2 g, 11.6 mmol) as the starting material. LCMS (ES) m / z: 291.0 [M-H]+. Intermediate 8: Preparation of 2-hydroxy-4-((4-methoxybenzyl)oxy)-5-methyl benzaldehyde (I-08)[000219] Step-1: Synthesis of 2,4-dihydroxy-5-methylbenzaldehyde (A12): To the stirred solution of 4-methylbenzene-1,3-diol (A11) (2 g, 16.1 mmol) and DMF (2.49 mL, 32.2 mmol) in acetonitrile (28 mL) was added POCl3(1.81 mL, 19.3 mmol) dropwise over a period of 15 min at 0 °C. The resulting yellow colored solution was further stirred for 3 h atroom temperature. The yellow solid obtained was then filtered and washed with cold acetonitrile (3 x 15 mL). It was then dissolved in hot water (20 mL) and stirred at 50 °C for 30 min. The red colored liquid was then kept for overnight at room temperature and the precipitate obtained was then filtered, washed with water (5 mL x 2) and dried to afford desired compound A12 (1 g) as an off-white solid. LCMS (ES) m / z: 153.1 [M+H]+. [000220] Step-2: Synthesis of 2-hydroxy-4-[(4-methoxyphenyl)methoxy]-5- methylbenzaldehyde (I-08): Intermediate I-08 (1.2 g) was synthesized by following procedure as described for the synthesis of I-01 (step-1) using 2,4-dihydroxy-5- methylbenzaldehyde (A12) (1.2 g, 7.89 mmol) as the starting material. LCMS (ES) m / z: 273.1[M+H]+. Intermediate 9: Preparation of 2,4-dihydroxy-5-iodobenzaldehyde (I-09)[000221] Step-1: Synthesis of 2,4-dihydroxy-5-iodobenzaldehyde (I-09): A solution of ICl (3.22 mL, 61.5 mmol, in 35 mL DCM) was added dropwise to a stirred solution of 2,4- dihydroxybenzaldehyde (A1) (5 g, 36.2 mmol) in acetic acid (25 mL, 437 mmol) at 0 °C. The reaction mixture was then allowed to warm to room temperature and the reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (1 h), it was quenched with addition of an aqueous solution of Na2S2O3(50 mL) and stirred for 15 min. The resulting precipitates were filtered, washed with cold water (10 mL x 2) and dried to afford desired compound I-09 (3 g) as a grey solid. LCMS (ES) m / z: 262.87 [M-H]+. Intermediate 10: Preparation of 2-hydroxy-4-(pyrimidin-2-yloxy)benzaldehyde (I-10)[000222] Step-1: Synthesis of 2-hydroxy-4-(pyrimidin-2-yloxy)benzaldehyde (I-10): To a stirred solution of 2,4-dihydroxybenzaldehyde (A1) (1 g, 7.24 mmol) in DMF (30 mL) was added K2CO3(1.1 g, 7.96 mmol) and 2-bromopyrimidine (A14) (1.04 g, 6.52 mmol) undernitrogen atmosphere at room temperature. The reaction mixture was then stirred at 100 °C and the reaction progress was monitored by TLC. After complete consumption of starting material (6 h), it was cooled to room temperature and ice cold water (30 mL) was added to it. Extraction was carried out using EtOAc (2 x 30 mL); the combined organic extracts were washed with brine solution (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford the desired compound I-10 (0.4 g) as a pale yellow viscous liquid. LCMS m / z : 217.1 [M+H]+. Intermediate 11: Preparation of 3-fluoro-2-hydroxy-4-(pyrimidin-2-yloxy)benzaldehyde (I-11)[000223] Step-1: Synthesis of 3-fluoro-2-hydroxy-4-(pyrimidin-2-yloxy)benzaldehyde (I- 11): Intermediate I-11 (0.130 g) was synthesized by following procedure as described for the synthesis of I-10 (step-1) using 3-fluoro-2,4-dihydroxybenzaldehyde (A15) (650 mg, 4.16 mmol) as the starting material. LCMS (ES) m / z: 235.2 [M+H]+. Intermediate 12: Preparation of 2-(benzyloxy)-4-(2-oxopyridin-1(2H)-yl)benzaldehyde (I-12)[000224] Step-1: Synthesis of 2-(benzyloxy)-4-bromobenzaldehyde (A17): To a stirred solution of 4-bromo-2-hydroxybenzaldehyde (A16) (3 g, 14.9 mmol) in acetonitrile (40 mL) added K2CO3(3.09 g, 22.4 mmol) and benzyl bromide (2.66 mL, 22.4 mmol) at 0 °C. The reaction mixture was then stirred at 90 °C while monitoring reaction progress by TLC. Aftercomplete consumption of starting material (8 h), the reaction mixture was cooled to room temperature and diluted with water (60 mL). Extraction was carried out using EtOAc (4 x 50 ml); the combined organic extracts were washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-20% of EtOAc in heptane) to afford desired compound A17 (3.1 g) as a colorless solid. LCMS (ES) m / z: 291.0 [M+H]+. [000225] Step-2: Synthesis of 2-(benzyloxy)-4-(2-oxo-1,2-dihydropyridin-1- yl)benzaldehyde (I-12): Argon gas was purged through a stirred suspension of 2- (benzyloxy)-4-bromobenzaldehyde (A17) (0.64 g, 2.2 mmol); 1,2-dihydropyridin-2-one (A18) (0.41 g, 4.4 mmol) and K2CO3(0.6 g, 4.4 mmol) in toluene (6 mL) at room temperature for 10 min before addition of DMEDA (0.096 g, 1.1 mmol) and CuI (0.34 g, 1.1 mmol). It was then stirred at 110 °C in a sealed tube. After complete consumption of starting material (16 h), the reaction mixture was cooled to room temperature and water (15 mL) was added to it. Extraction was carried out using EtOAc (2 x 25 mL); the combined organic extracts were washed with brine solution (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure The residue was purified by Combi-Flash (using gradient elution of 0-60% of EtOAc in heptane) to afford the desired compound I-12 (0.4 g) as an off-white solid. LCMS (ES) m / z: 306.1 [M+H]+. Intermediate 13: Preparation of 2-hydroxy-4-(2-oxopyridin-1(2H)-yl)benzaldehyde (I- 13)[000226] Step-1: Synthesis of 4-bromo-2-[(4-methoxyphenyl) methoxy] benzaldehyde (A19): Compound A19 (1.5 g) was synthesized by following procedure as described for thesynthesis of I-11 (step-1) using 4-bromo-2-hydroxybenzaldehyde (A16) (1 g, 4.97 mmol) as the starting material. LCMS (ES) m / z: 321.2 [M+H]+. [000227] Step-2: Synthesis of 2-[(4-methoxyphenyl)methoxy]-4-(2-oxo-1,2- dihydropyridin-1-yl)benzaldehyde (A20): Compound A20 (0.6 g) was synthesized by following procedure as described for the synthesis of I-12 (step-2) using 4-bromo-2-[(4- methoxyphenyl)methoxy]benzaldehyde (A19) (0.5 g, 1.56 mmol) as the starting material. LCMS (ES) m / z: 336.2 [M+H]+. [000228] Step-3: Synthesis of 2-hydroxy-4-(2-oxo-1,2-dihydropyridin-1-yl)benzaldehyde (I-13): To a stirred solution of 2-[(4-methoxyphenyl)methoxy]-4-(2-oxo-1,2-dihydropyridin- 1-yl)benzaldehyde (A20) (0.3 g, 895 µmol) in anhydrous DCM (3 mL) was added trifluoroacetic acid (1.5 mL, 2.68 mmol) at 0 °C and the reaction mixture was then allowed to warm to room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (16 h), volatiles were removed under reduced pressure and water (15 mL) was added to the residue. Extraction was carried out using EtOAc (2 x 25 mL); the combined organic extracts were washed with saturated NaHCO3solution (25 mL), brine solution (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% MeOH in DCM) a to afford desired compound I-13 (0.3 g) as a pale yellow thick oil. LCMS (ES) m / z: 216.1 [M+H]+. Intermediate 14: Preparation of 2-hydroxy-4-((2-oxopyridin-1(2H)- yl)methyl)benzaldehyde (I-14)[000229] Step-1: Synthesis of methyl 2-methoxy-4-methylbenzoate (A22): To a stirred solution of 2-hydroxy-4-methylbenzoic acid (A21) (5 g, 32.9 mmol) in DMF (50 mL) was added methyl iodide (6.14 mL, 98.6 mmol) at 0 °C followed by portion wise addition of NaH(60% dispersion in mineral oil) (3.94 g, 98.6 mmol). The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was then quenched with addition of cold water (50 mL) and extraction was carried out using EtOAc (4 x 50 mL). The combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrate under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford the desired compound A22 (5 g) as a liquid. LCMS m / z: 181.0 [M+H]+. [000230] Step-2: Synthesis of methyl 4-(bromomethyl)-2-methoxybenzoate (A23): To a stirred solution of methyl 2-methoxy-4-methylbenzoate (A22) (5 g, 27.7 mmol) in CCl4(129 mL) was added NBS (4.94 g, 27.7 mmol) and benzoyl peroxide (33.6 mg, 139 µmol). The reaction mixture was then stirred at 100° C for 16 h. It was then cooled to room temperature and quenched water (50 mL). Extraction was carried out using DCM (2 x 50 mL); the combined organic extracts were washed with brine solution (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford desired compound A23 (6 g). LCMS m / z: 259.0 [M+H]+. [000231] Step-3: Synthesis of methyl 2-methoxy-4-[(2-oxo-1,2-dihydropyridin-1- yl)methyl]benzoate (A24): To a stirred solution of 1,2-dihydropyridin-2-one (A18) (1.1 g, 11.6 mmol) and methyl 4-(bromomethyl)-2-methoxybenzoate (A23) (3 g, 11.6 mmol) in DMF (32.4 mL) was added K2CO3(4.8 g, 34.7 mmol) at 0 °C and it was then stirred at room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (1.5 h), cold water (20 mL) was added to it and extraction was carried out using EtOAc (2 x 30 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-60% of EtOAc in heptane) to afford desired compound A24 (1.5 g). LCMS m / z: 273.9 [M+H]+. [000232] Step-4: Synthesis of 1-{[4-(hydroxymethyl)-3-methoxyphenyl]methyl}-1,2- dihydropyridin-2-one (A25): To a stirred solution of methyl 2-methoxy-4-[(2-oxo-1,2- dihydropyridin-1-yl)methyl]benzoate (A24) (1.5 g, 5.49 mmol) in THF (15 mL) was added 1 M solution of DIBAL in THF (13.7 mL, 13.7 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (1 h), it was quenched with addition of saturated NH4Cl solution (20 mL) and extraction was carried out using EtOAc (2 x 30 mL).The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-90% of EtOAc in heptane) to afford desired compound A25 (1.1 g) as an off-white semi-solid. LCMS m / z: 246.1 [M+H]+. [000233] Step-5: Synthesis of 2-methoxy-4-[(2-oxo-1,2-dihydropyridin-1- yl)methyl]benzaldehyde (A26): To a stirred solution of 1-{[4-(hydroxymethyl)-3- methoxyphenyl]methyl}-1,2-dihydropyridin-2-one (A25) (1.1 g, 4.48 mmol) in DCM (10 mL) was added DMP (3.8 g, 8.97 mmol) at 0 °C, and the reaction mixture was then allowed to warm to room temperature. The reaction progress was monitored by TLC / LCMS. After completion of the reaction (1 h), ice water (30 mL) was added to it and extraction was carried out using EtOAc (2 x 30 mL). The combined organic extracts were washed with brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-40% of EtOAc in heptane) to provide desired compound A26 (0.9 g) as an off-white solid. LCMS m / z: 244.1 [M+H]+. [000234] Step-6: Synthesis of 2-hydroxy-4-[(2-oxo-1,2-dihydropyridin-1- yl)methyl]benzaldehyde (I-14): To a stirred solution of 2-methoxy-4-[(2-oxo-1,2- dihydropyridin-1-yl)methyl]benzaldehyde (A26) (0.8 g, 3.29 mmol) in anhydrous DCM (8 mL) was added BBr3(624 µL, 6.58 mmol) at 0 °C and the reaction mixture was then allowed to warm to room temperature over 1 h. After complete consumption of starting material (1 h), the reaction mixture was quenched with addition of cold water (15 mL) and extraction was carried out using EtOAc (2 x 30 mL). The combined organic extracts were washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-90% of EtOAc in heptane) to afford the desired I-14 (0.5 g, 2.18 mmol) as a white solid. LCMS m / z: 230.1 [M+H]+. Intermediate 15: Preparation of 2-hydroxy-4-((2-oxopyrrolidin-1- yl)methyl)benzaldehyde (I-15)[000235] Step-1: Synthesis of methyl 2-methoxy-4-[(2-oxopyrrolidin-1-yl)methyl]benzoate (A28): To a stirred solution of A23 (6 g, 23.2 mmol) in DMF (60 mL, 775 mmol) was added pyrrolidin-2-one (A27) (1.97 g, 23.2 mmol) followed by portion wise addition of NaH (60% dispersion in mineral oil) (1.85 g, 46.3 mmol) at 0 °C. The reaction mixture was then allowed to warm to room temperature over 1 h. After complete consumption of starting material (1 h), it was quenched with addition of saturated NH4Cl solution (50 mL) and extraction was carried out using EtOAc (3 x 50 mL). The combined organic extracts were washed with brine solution (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-80% of EtOAc in heptane) to afford desired compound A28 (2.9 g) as an off-white solid. LCMS m / z: 264.1 [M+H]+. [000236] Step-2: Synthesis of 2-methoxy-4-[(2-oxopyrrolidin-1-yl)methyl]benzoic acid (A29): To a stirred solution of methyl 2-methoxy-4-[(2-oxopyrrolidin-1-yl)methyl]benzoate (A28) (2.6 g, 9.87 mmol) in THF (20 mL) was added an aqueous solution of LiOH (0.71 g, 29.6 mmol, in 6 mL water) and the reaction mixture was stirred at room temperature. After complete consumption of starting material (16 h), it was acidified to pH 6 using 1 N aqueous solution of HCl and extraction was carried out using EtOAc (2 x 40 mL). The combined organic extracts were washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford desired compound A29 (1.8 g) as an off white solid. LCMS m / z: 250.1 [M+H]+. [000237] Step-3: Synthesis of 1-{[4-(hydroxymethyl)-3-methoxyphenyl]methyl}pyrrolidin- 2-one (A30): To a stirred solution of 2-methoxy-4-[(2-oxopyrrolidin-1-yl)methyl]benzoic acid (A29) (1.8 g, 7.22 mmol) in THF (18 mL) was added TEA (2.03 mL, 14.4 mmol) and isobutyl chloroformate (1.88 mL, 14.4 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 30 min. It was then filtered through a pad of celite and washedwith THF (3 x 10 mL). The filtrate was then cooled to 0 °C and NaBH4(1.37 g, 36.1 mmol) in water (0.1 mL) was added to it. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (30 min), water (50 mL) was added to it and extraction was carried out using EtOAc (2 x 40 mL). The combined organic extracts were washed with saturated NaHCO3(20 mL), brine solution (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford desired compound A30 (1 g) as a yellow gum. LCMS m / z: 236.1 [M+H]+. [000238] Step-4: Synthesis of 2-methoxy-4-[(2-oxopyrrolidin-1-yl)methyl]benzaldehyde (A31): Compound A31 (0.9 g) was synthesized by following procedure as described for the synthesis of I-14 (step-5) using 1-{[4-(hydroxymethyl)-3-methoxyphenyl]methyl}pyrrolidin- 2-one (A30) (1 g, 4.25 mmol) as the starting material. LCMS (ES) m / z: 234.1 [M+H]+. [000239] Step-5: Synthesis of 2-hydroxy-4-[(2-oxopyrrolidin-1-yl)methyl]benzaldehyde (I- 15): Intermediate I-15 (0.62 g) was synthesized by following procedure as described for the synthesis of I-14 (step-6) using 2-methoxy-4-[(2-oxopyrrolidin-1-yl)methyl]benzaldehyde (A31) (0.9 g, 3.86 mmol) as the starting material. LCMS (ES) m / z: 220.2 [M+H]+. Intermediate 16: Preparation of (2,4-dihydroxyphenyl)(²H)formaldehyde (I-16)[000240] Step-1: Synthesis of 1-bromo-2,4-bis(methoxymethoxy)benzene (A33): To a stirred solution of NaH (381 mg, 15.9 mmol) in DMF (25 mL) was added 4-bromobenzene- 1,3-diol (A32) (2.5 g, 13.2 mmol) in DMF at 0 °C and stirred for 15 min, before dropwise addition of MOM-Cl (5.32 g, 66.1 mmol). After complete consumption of starting material (12 h), the reaction mixture was quenched with addition of cold water (50 mL) and extraction was carried out using EtOAc (2 x 50 mL). The combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated underreduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford the desired compound A33 (1.8 g) as a pale yellow liquid.1H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8.8 Hz, 1H); 6.86 (d, J = 2.8 Hz, 1H); 6.64-6.61 (m, 1H); 5.22 (s, 2H); 5.14 (s, 2H); 3.52 (s, 3H); 3.47 (s, 3H). [000241] Step-2: Synthesis of [2,4-bis(methoxymethoxy)phenyl](²H)formaldehyde (A34): To a stirred solution of 1-bromo-2,4-bis(methoxymethoxy)benzene (A33) (5 g, 18 mmol) in anhydrous THF (50 mL) was added n-BuLi (2.5 M in heptane) (10.8 mL, 27.1 mmol) dropwise at -78 °C and the reaction mixture was stirred at 30 min at the same temperature. To this was then added DMF-d7(2.81 mL, 36.1 mmol) and the reaction mixture was allowed to warm to room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (1 h), the reaction mixture was quenched with addition of saturated NH4Cl solution (50 mL) and extraction was carried out using EtOAc (2 x 50 mL). The combined organic extracts were washed with brine solution (2 x 25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-35% of EtOAc in heptane) to afford the desired compound A34 (2.4 g, 10.6 mmol) as a pale yellow solid. LCMS m / z: 228.1 [M+H]+. [000242] Step-3: Synthesis of (2,4-dihydroxyphenyl)(²H)formaldehyde (I-16): To a stirred solution of [2,4-bis(methoxymethoxy)phenyl](²H)formaldehyde (A34) (2.1 g, 9.24 mmol) in THF (20 mL) was added 6 N HCl solution (10 mL) at 0 °C. The reaction mixture was stirred at 50 °C while monitoring reaction progress by TLC. After complete consumption of starting material (2 h), the reaction mixture was cooled to room temperature and diluted with water (50 mL). Extraction was carried out using EtOAc (2 x 50 mL); the combined organic extracts were washed with brine solution (2 x 25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-40% of EtOAc in heptane) to afford the desired compound I-16 (0.9 g, 6.47 mmol) as a pale yellow viscous oil. LCMS m / z: 139.9 [M+H]+. Intermediate 17: Preparation of 3-(4-formyl-3-hydroxyphenyl)-1,1-dimethylurea (I-17)[000243] Step-1: Synthesis of 1-{4-formyl-3-[(4-methoxyphenyl)methoxy]phenyl}-3,3- dimethylurea (A36): Argon gas was purged through a stirred suspension of 4-bromo-2-{[4- (methylamino)phenyl]methoxy}benzaldehyde (A19) (1.3 g, 4.06 mmol), Cs2CO3(3.97 g, 12.2 mmol) and 1,1-dimethylurea (A35) (429 mg, 4.87 mmol) in 1,4-dioxane (26 mL) for 10 min, before addition of Pd(OAc)2(91.2 mg, 406 µmol) and Xantphos (235 mg, 406 µmol). The reaction mixture was stirred at 100 °C for 16 h. It was then cooled to room temperature and water (30 mL) was added to it. Extraction was carried out using EtOAc (30 mL x 3); the combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-25% of EtOAc in heptane) to afford the desired compound A36 (950 mg) as an off-white solid. LCMS m / z: 329.2 [M+H]+. [000244] Step-2: Synthesis of 1-(4-formyl-3-hydroxyphenyl)-3,3-dimethylurea (I-17): To a stirred solution of 1-{4-formyl-3-[(4-methoxyphenyl)methoxy]phenyl}-3,3-dimethylurea (A36) (0.8 g, 2.44 mmol) in DCM (12 mL) was added TFA (932 µL, 12.2 mmol) at 0 °C under nitrogen atmosphere and the reaction mixture was allowed to warm to room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (5 h), volatiles were removed under reduced pressure and the residue was dissolved in DCM (50 mL). The organic layer was washed with water (2 x 15 mL), saturated NaHCO3solution (2 x 15 mL), brine solution (2 x 10 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford the desired compound I-17 (420 mg) as an off-white solid. LCMS m / z: 209.0 [M+H]+. Intermediate 18: Preparation of 1-(4-formyl-3-hydroxyphenyl)-1,3,3-trimethylurea (I- 18)[000245] Step-1: Synthesis of methyl 4-[(dimethylcarbamoyl)amino]-2-methoxybenzoate (A39): To a stirred solution of methyl 4-amino-2-methoxybenzoate (A37) (5.0 g, 27.6 mmol) in DCM (20 mL) was added DMAP (3.4 g, 27.6 mmol), pyridine (8.91 mL, 110 mmol) and N,N-dimethylcarbamoyl chloride (5.12 mL, 55.2 mmol). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, water (20 mL) was added to it and extraction was carried out with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-40% of EtOAc in heptane) to afford the desired compound A39 (5.5 g) as an off white solid. LCMS (ES) m / z: 253.37 [M+H]+. [000246] Step-2: Synthesis of methyl 4-[(dimethylcarbamoyl)(methyl)amino]-2- methoxybenzoate (A40): To a stirred solution of NaH (60% dispersion in mineral oil) (547 mg, 23.8 mmol) in DMF (30 mL) was added methyl 4-[(dimethylcarbamoyl)amino]-2- methoxybenzoate (A39) (3 g, 11.9 mmol) at 0° C and stirred for 30 min. To this was then added iodomethane (2.22 mL, 35.7 mmol) and the reaction mixture was stirred at the same temperature, while monitoring reaction progress by TLC. After completion the reaction (0.5 h), the reaction mixture was quenched with water (15 mL) and extraction was carried out with EtOAc (3 x 40 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-5% of MeOH in DCM) to afford the desired compound A40 (2.8 g) as an off white solid. LCMS (ES) m / z: 267.37 [M+H]+. [000247] Step-3: Synthesis of 1-[4-(hydroxymethyl)-3-methoxyphenyl]-1,3,3-trimethylurea (A41): To a stirred solution of methyl 4-[(dimethylcarbamoyl)(methyl)amino]-2- methoxybenzoate (A40) (2.2 g, 8.26 mmol) in anhydrous THF (30 mL) was added lithiumaluminum hydride (470 mg, 12.4 mmol) portion wise at -20 °C. The reaction was stirred for 15 min at -20 °C and then allowed to warm to room temperature. After completion of the reaction (0.5 h), the reaction mixture was quenched with ice-cold water (10 mL) and extraction was carried out with EtOAc (3 x 40 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford desired compound A41 (1.3 g) as a white solid. LCMS (ES) m / z: 239.34 [M+H]+. [000248] Step-4: Synthesis of 1-(4-formyl-3-methoxyphenyl)-1,3,3-trimethylurea (A42): To a stirred solution of 1-[4-(hydroxymethyl)-3-methoxyphenyl]-1,3,3-trimethylurea (A41) (1.2 g, 5.04 mmol) in DCM (35 mL) was added DMP (3.84 g, 9.05 mmol) portion wise at 0 °C and the reaction mixture was stirred at room temperature. After completion of the reaction (2 h), ice-cold water (15 mL) was added to it and extraction was carried out using DCM (3 x 35 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-70% of EtOAc in heptane) to afford the desired compound A42 (0.75 g) as a dark red thick oil. LCMS (ES) m / z: 237.15 [M+H]+. [000249] Step-5: Synthesis of 1-(4-formyl-3-hydroxyphenyl)-1,3,3-trimethylurea (I-18): To a stirred solution of 1-(4-formyl-3-methoxyphenyl)-1,3,3-trimethylurea (A42) (650 mg, 2.75 mmol) in DCM (13 mL) was added BBr3(0.52 mL, 5.5 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature. The reaction progress was monitored by TLC / LCMS analysis. After completion of the reaction (0.5 h), the reaction mixture was quenched with ice-cold water (15 mL) and extraction was carried out with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford the desired I-18 (0.35 g) as white solid. LCMS (ES) m / z: 223.24 [M+H]+. Intermediate 19: Preparation of ethyl 2-(4-formyl-3-hydroxyphenyl)acetate (I-19)[000250] Step-1: Synthesis of 4-bromo-2-methoxybenzaldehyde (A43): To the stirred solution of 4-bromo-2-hydroxybenzaldehyde (A16) (10.0 g, 49.7 mmol) in DMF (90 mL) and was added K2CO3(20.6 g 149 mmol) and iodomethane (9.29 mL, 149 mmol) at room temperature. The reaction mixture was stirred at 50 °C, while monitoring reaction progress by TLC. After completion of the reaction (12 h), the reaction mixture was quenched with water (50 mL) and extraction was carried out with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford desired compound A43 (10.0 g) as yellow solid. LCMS (ES) m / z: 215 [M+H]+. [000251] Step-2: Synthesis of 1,3-diethyl 2-(4-formyl-3-methoxyphenyl)propanedioate (A44): To the stirred solution of 4-bromo-2-methoxybenzaldehyde (A43) (10.0 g, 46.5 mmol) in toluene (200 mL) was added Cs2CO3(30.3 g, 93 mmol) and diethylmalonate (7.09 mL, 46.5 mmol). The reaction mixture was purged with argon for 10 min, before addition of Pd(OAc)2(1.04 g, 4.65 mmol) and XPhos (1.11 g, 2.33 mmol). The reaction mixture was then stirred at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and water (100 mL) was added to it. Extraction was carried out using EtOAc (3 x 70 mL); the combined organic extracts were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-15% of EtOAc in heptane) to afford the desired compound A44 (9 g) as a white solid. LCMS (ES) m / z: 293.30 [M-H]+. [000252] Step-3: Synthesis of ethyl 2-(4-formyl-3-methoxyphenyl)acetate (A45): To a stirred solution of 1,3-diethyl 2-(4-formyl-3-methoxyphenyl)propanedioate (A44) (8.5 g, 28.9 mmol) in DMSO (35 mL) was added lithium chloride (3.67 g, 86.6 mmol) and the reaction mixture was stirred at 130 °C, while monitoring reaction progress by TLC. After completionof the reaction (36 h), it was cooled to room temperature and water (50 mL) was added to it. Extraction was carried out using EtOAc (3 x 60 mL); the combined organic extracts were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford desired compound A45 (1.2 g) as a white solid. LCMS (ES) m / z: 221.11 [M-H]+. [000253] Step-4: Synthesis of ethyl 2-(4-formyl-3-hydroxyphenyl)acetate (I-19): Intermediate I-19 (1.65 g) was synthesized by following procedure as described for the synthesis of I-18 (step-5) using ethyl 2-(4-formyl-3-methoxyphenyl)acetate (A45) (2.5 g, 11.2 mmol) as the starting material. LCMS (ES) m / z: 209.26 [M+H]+. Intermediate 20: Preparation of 5-chloro-2-hydroxy-4-iodobenzaldehyde (I-20)[000254] Step-1: Synthesis of 4-chloro-2-(hydroxymethyl)-5-iodophenol (A47): To stirred the solutions of methyl 5-chloro-2-hydroxy-4-iodobenzoate (A46) (6.0 g, 19.2 mmol) in THF (60 mL) was added a 1 M solution of DIBAL (in toluene) (57.6 mL, 57.6 mmol) at 0 °C. The reaction mixture was then stirred at 60 °C, while monitoring reaction progress by TLC / LCMS. After completion of the reaction (16 h), the reaction mixture was cooled to 0 °C and quenched with slow addition of aqueous 1 N HCl solution (20 mL). Extraction was carried out using EtOAc (3 x 70 mL); the combined organic extracts were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-60% of EtOAc in heptane) to afford desired compound A47 (5.8 g) as an off white solid. LCMS (ES) m / z: 284.90 [ M-H]+. [000255] Step-2: Synthesis of (5-chloro-4-iodo-2-methoxyphenyl)methanol (A48): To a stirred solution of 4-chloro-2-(hydroxymethyl)-5-iodophenol (A47) (5.8 g, 20.4 mmol) in DMF (25 mL) were added Cs2CO3(6.64 g, 20.4 mmol) and iodomethane (1.27 mL, 20.4mmol) and the reaction mixture was stirred at room temperature for 2 h. After completion, water (30 mL) was added to it and the precipitated solid was filtered, washed with ice cold water (3 x 40 mL) and dried to afford desired compound A48 (5.7 g) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 7.44 (s, 1H); 7.40 (s, 1H); 5.23 (t, J = 5.6 Hz, 1H); 4.40 (d, J = 5.6 Hz, 2H); 3.78 (s, 3H). [000256] Step-3: Synthesis of 5-chloro-4-iodo-2-methoxybenzaldehyde (A49): Compound A49 (4.1 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using (5-chloro-4-iodo-2-methoxyphenyl)methanol (A48) (5.7 g, 8.38 mmol) as the starting material.1H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H); 7.81 (s, 1H); 7.68 (s, 1H); 3.32 (s, 3H). [000257] Step-4: Synthesis of 5-chloro-2-hydroxy-4-iodobenzaldehyde (I-20): Intermediate (I-20) (3.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-5) using 5-chloro-4-iodo-2-methoxybenzaldehyde A49 (4.1 g, 13.8 mmol) as the starting material.1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H); 10.18 (s, 1H); 7.66 (s, 1H); 7.59 (s, 1H). Intermediate 21: Preparation of (2,4-bis(benzyloxy)phenyl)methanamine (I-21)[000258] Step-1: Synthesis of 2,4-bis(benzyloxy)benzaldehyde (A50): To a stirred solution of 2,4-dihydroxybenzaldehyde (A1) (3 g, 21.7 mmol) in DMF (30 mL) was added K2CO3(6 g, 43.4 mmol) and benzyl bromide (5.16 mL, 43.4 mmol); and the reaction mixture was stirred at room temperature for 16 h. Ice water (150 mL) was then added to it and extraction was carried out using EtOAc (3 x 50 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (30 mL), brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified byCombi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford the desired compound A50 (6.5 g) as an off white solid. LCMS m / z: 319.1 [M+H]+. [000259] Step-2: Synthesis of (E)-N-(2,4-bis(benzyloxy)benzylidene)-2-methylpropane-2- sulfinamide (A52): To a stirred solution of 2,4-bis(benzyloxy)benzaldehyde (A50) (4.0 g, 12.6 mmol) in THF (40 mL) was added 2-methylpropane-2-sulfinamide (A51) (1.52 g, 12.6 mmol) and Ti(OiPr)4(4.46 mL, 15.1 mmol) at room temperature. The reaction mixture was allowed to stir at 65 °C and the reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (16 h), it was cooled to room temperature and saturated NaHCO3solution (30 mL) was added to it. Extraction was carried out using EtOAc (2 x 40 mL); the combined organic extracts were washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-35% of EtOAc in heptane) to afford the desired compound A52 (4.4 g) as an off-white solid. LCMS m / z found 422.1 [M+H]+. [000260] Step-3: Synthesis of N-(2,4-bis(benzyloxy)benzyl)-2-methylpropane-2- sulfinamide (A53): To a stirred suspension of A52 (4.4 g, 10.4 mmol) in MeOH (20 mL) was added NaBH4(0.79 g, 20.9 mmol) at 0 °C and the reaction mixture was allowed to stir for 30 min at room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (30 min), the reaction mixture was quenched with addition of water (50 mL) and extraction was carried out using EtOAc (2 x 40 mL). The combined organic extracts were washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford the desired compound A53 (4.3 g) as an off white solid. LCMS m / z: 424.1 [M+H]+. [000261] Step-4: Synthesis of (2,4-bis(benzyloxy)phenyl)methanamine (I-21): To a stirred solution of N-{[2,4-bis(benzyloxy)phenyl]methyl}-2-methylpropane-2-sulfinamide (A53) (4.3 g, 10.2 mmol) in DCM (4 mL) was added a 4 M solution of HCl in dioxane (5.08 mL, 20.3 mmol) at 0 °C and the reaction mixture was allowed to stir at room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (2 h), volatiles were removed under reduced pressure and saturated NaHCO3solution (20 mL) was added to the residue. Extraction was carried out using DCM (30 mL x 3); the combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was washed with diethyl ether (2 x 10 mL) and dried to afford the desired compound I-21 (2.2 g) as an offwhite solid.1H NMR (400 MHz, DMSO-d6): δ 7.45-7.30 (m, 12H); 7.19 (d, J = 8.0 Hz, 1H); 6.70 (d, J = 2.0 Hz, 1H); 6.56-6.54 (m, 1H); 5.08 (d, J = 15.2 Hz, 4H); 3.63 (s, 2H). Intermediate 22: Preparation of 1-{2-hydroxy-4-[(4- methoxyphenyl)methoxy]phenyl}ethan-1-one (I-22)[000262] Step-1: Synthesis of 1-{2-hydroxy-4-[(4-methoxyphenyl)methoxy]phenyl}ethan- 1-one (I-22): Intermediate I-22 (4.0 g) was synthesized by following procedure as described for the synthesis of I-01 (step-1) using 1-(2,4-dihydroxyphenyl)ethan-1-one (A54) (2.5 g, 16.4 mmol) as the starting material. LCMS (ES) m / z: 273.1 [M+H]+. Intermediate 23: Preparation of 1-(3-fluoro-2-hydroxy-4-((4- methoxybenzyl)oxy)phenyl)ethan-1-one (I-23)[000263] Step-1: Synthesis of 1-(3-fluoro-2-hydroxy-4-methoxyphenyl)ethan-1-one (A56): A stirred solution of 2-fluoro-3-methoxyphenol (A55) (3 g, 21.1 mmol) in BF3·AcOH (12 mL) was slowly heated to 80 °C and the reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (4 h), the reaction mixture was cooled to room temperature and quenched with addition of water (50 mL). Extraction was carried out using EtOAc (2 x 50 mL); the combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford the desired compound A56 (3 g) as an off-white solid. LCMS (ES) m / z: 185.0 [M+H]+. [000264] Step-2: Synthesis of 1-(3-fluoro-2,4-dihydroxyphenyl)ethan-1-one (A57): To a stirred solution of 1-(3-fluoro-2-hydroxy-4-methoxyphenyl)ethan-1-one (A56) (3 g, 16.3 mmol) in DCM (30 mL) was added BBr3(3.14 mL, 32.6 mmol) dropwise at 0 °C and thereaction mixture was allowed to warm to room temperature over 2 h. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (16 h), the reaction mixture was quenched with addition of cold water (50 mL) and extraction was carried out using EtOAc (3 x 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford the desired compound A57 (2 g) as a colorless solid. LCMS (ES) m / z: 171.1 [M+H]+. [000265] Step-3: Synthesis of 1-{3-fluoro-2-hydroxy-4-[(4- methoxyphenyl)methoxy]phenyl}ethan-1-one (I-23): Intermediate I-23 (2.0 g) was synthesized by following procedure as described for the synthesis of I-01 (step-1) using 1-(3- fluoro-2,4-dihydroxyphenyl)ethan-1-one (A57) (2 g, 11.8 mmol) as the starting material. LCMS (ES) m / z: 291.0 [M+H]+. Intermediate 24: Preparation of 1-(5-fluoro-2-hydroxy-4-((4- methoxybenzyl)oxy)phenyl)ethan-1-one (I-24)[000266] Step-1: Synthesis of 1-(5-fluoro-2,4-dimethoxyphenyl)ethan-1-one (A59): Compound A59 (3.8 g) was synthesized by following procedure as described for the synthesis of I-23 (step-1) using 1-fluoro-2,4-dimethoxybenzene (A58) (2 g, 12.8 mmol) as the starting material. LCMS (ES) m / z: 199.0 [M+H]+. [000267] Step 2: Synthesis of 1-(5-fluoro-2,4-dihydroxyphenyl)ethan-1-one (A60): Compound A60 (3.2 g) was synthesized by following procedure as described for the synthesis of I-23 (step-2) using 1-(5-fluoro-2,4-dimethoxyphenyl)ethan-1-one (A59) (3.8 g, 19.2 mmol) as the starting material. LCMS (ES) m / z: 171 [M+H]+. [000268] Step 3: Synthesis of 1-{5-fluoro-2-hydroxy-4-[(4- methoxyphenyl)methoxy]phenyl}ethan-1-one (I-24): Intermediate I-24 (1.5 g) was synthesized by following procedure as described for the synthesis of I-01 (step-1) using 1-(2- fluoro-4,6-dihydroxyphenyl)ethan-1-one (A60) (1.5 g, 8.82 mmol) as the starting material. LCMS (ES) m / z: 290.9 [M+H]+.Intermediate 25: Preparation of 1-(2-fluoro-6-hydroxy-4-((4- methoxybenzyl)oxy)phenyl)ethan-1-one (I-25)[000269] Step 1: Synthesis of 1-(2-fluoro-6-hydroxy-4-methoxyphenyl)ethan-1-one (A62): Compound A62 (1.8 g) was synthesized by following procedure as described for the synthesis of I-23 (step-1) using 1-fluoro-3,5-dimethoxybenzene (A61) (2 g, 12.8 mmol) as the starting material. LCMS (ES) m / z: 184.9 [M+H]+. [000270] Step 2: Synthesis of 1-(2-fluoro-4,6-dihydroxyphenyl)ethan-1-one (A63): Compound A63 (1.5 g) was synthesized by following procedure as described for the synthesis of I-23 (step-2) using 1-(2-fluoro-6-hydroxy-4-methoxyphenyl)ethan-1-one (A62) (1.8 g, 9.77 mmol) as the starting material. LCMS (ES) m / z: 171.1 [M+H]+. [000271] Step 3: Synthesis of 1-{2-fluoro-6-hydroxy-4-[(4- methoxyphenyl)methoxy]phenyl}ethan-1-one (I-25): Intermediate I-25 (2.3 g) was synthesized by following procedure as described for the synthesis of I-01 (step-1) using 1-(2- fluoro-4,6-dihydroxyphenyl)ethan-1-one (A63) (1.5 g, 8.82 mmol) as the starting material. LCMS (ES) m / z: 290.9 [M+H]+. Intermediate 26: Preparation of 3-(2,4-bis(benzyloxy)phenyl)oxetan-3-amine (I-26)[000272] Step-1: Synthesis of 1,3-bis(benzyloxy)benzene (A65): To a stirred solution of benzene-1,3-diol (A64) (10 g, 90.8 mmol) in DMF (100 mL) was added K2CO3(37.7 g, 272mmol) and (bromomethyl)benzene (27.5 mL, 227 mmol); and the reaction mixture was stirred room temperature for 16 h. Water (100 mL) was then added to it and extraction was carried out using EtOAc (3 x 100 mL). The combined organic extracts were washed with brine solution (100 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford the desired compound A65 (18 g) as a colorless solid. LCMS m / z: 291.2 [M+H]+. [000273] Step-2: Synthesis of 2,4-bis(benzyloxy)-1-bromobenzene (A66): To a stirred solution of 1,3-bis(benzyloxy)benzene (A65) (19.3 g, 66.5 mmol) in THF (400 mL) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (9.5 g, 33.2 mmol) at 0 °C and the reaction mixture as allowed to warm to room temperature over 30 min. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (16 h), the reaction mixture was quenched with water (100 mL) and extraction was carried out using EtOAc (3 x 200 mL). The combined organic extracts were washed with brine solution (3 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford the desired A66 (24 g) as a pale yellow solid. LCMS m / z: 369.1 [M+H]+. [000274] Step-3: Synthesis of N-{3-[2,4-bis(benzyloxy)phenyl]oxetan-3-yl}-2- methylpropane-2-sulfinamide (A68): To a stirred solution of 2,4-bis(benzyloxy)-1- bromobenzene (A66) (12 g, 32.5 mmol) in anhydrous THF (120 mL) was added n-BuLi (2.5 M in hexane) (14.3 mL, 35.7 mmol) at -78 °C and the reaction was stirred for 10 min. To this was then added 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (A67) (5.7 g, 32.5 mmol, in 10 mL THF) and stirred at -78° C for additional 30 min. The reaction mixture was quenched with addition of saturated NH4Cl solution (100 mL) and extraction was carried out using EtOAc (3 x 70 mL). The combined organic extracts were washed with brine solution (3 x 70 mL), dried over Na2SO4and evaporated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford the desired compound A68 (4 g) as a pale yellow solid. LCMS m / z: 466.2 [M+H]+. [000275] Step-4: Synthesis of 3-[2,4-bis(benzyloxy)phenyl]oxetan-3-amine (I-26): To a stirred solution of N-{3-[2,4-bis(benzyloxy)phenyl]oxetan-3-yl}-2-methylpropane-2- sulfinamide (A68) (2 g, 4.3 mmol) in MeOH (20 mL) was added a 4 M solution of HCl in 1,4-dioxane (5.3 mL, 21.5 mmol) at 0 °C. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (5 min), the reaction mixturewas quenched with addition of a saturated NaHCO3solution (20 mL). Extraction was carried out using EtOAc (3 x 40 mL); the combined organic extracts were washed with brine solution (3 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford the desired compound I-26 (1.5 g) as a pale yellow solid. LCMS m / z: 360.1 [M-H]+. Intermediate 27: Preparation of 3-(2,4-bis(benzyloxy)-3-fluorophenyl)oxetan-3-amine (I-27)[000276] Step-1: Synthesis of 1-bromo-3-fluoro-2,4-dimethoxybenzene (A70): To a stirred solution of 2-fluoro-1,3-dimethoxybenzene (A69) (5 g, 32 mmol) in CCl4(25 mL) was added NBS (6.27 g, 35.2 mmol) and 60% of HClO4(134 mg, 0.8 mmol) at 0 °C. The reaction mixture was stirred at room temperature, while monitoring reaction progress by TLC / LCMS. After complete consumption of starting material (3 h), the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Combi- Flash (using gradient elution of 0-10% of EtOAc in heptane) to afford desired compound A70 (7.0 g) as a pale yellow oil.1H NMR (400 MHz, DMSO-d6): δ 7.34 (dd, J = 9.2 Hz, 2.0 Hz, 1H); 6.89 (t, J = 8.8 Hz, 1H); 3.83 (d, J = 7.6 Hz, 6H). [000277] Step-2: Synthesis of 4-bromo-2-fluorobenzene-1,3-diol (A71): Compound A71 (7.6 g) was synthesized by following procedure as described for the synthesis of I-03 (step-2) using 1-bromo-3-fluoro-2,4-dimethoxybenzene (A70) (10.0 g, 42.5 mmol) as the starting material. LCMS (ES) m / z: 207.0 [M+H]+. [000278] Step-3: Synthesis of 1,3-bis(benzyloxy)-4-bromo-2-fluorobenzene (A72): Compound A72 (18 g) was synthesized by following procedure as described for the synthesisof I-26 (step-1) using 4-bromo-2-fluorobenzene-1,3-diol (A71) (11.8 g, 57 mmol) as the starting material. LCMS (ES) m / z: 386.9 [M+H]+. [000279] Step-4: Synthesis of N-{3-[2,4-bis(benzyloxy)-3-fluorophenyl]oxetan-3-yl}-2- methylpropane-2-sulfinamide (A73): Compound A73 (1.4 g) was synthesized by following procedure as described for the synthesis of I-26 (step-3) using 1,3-bis(benzyloxy)-4-bromo-2- fluorobenzene (A72) (5.59 g, 14.4 mmol) as the starting material (toluene was used as the solvent). LCMS (ES) m / z: 484.2 [M+H]+. [000280] Step-5: Synthesis of 3-[2,4-bis(benzyloxy)-3-fluorophenyl]oxetan-3-amine (I-27): Intermediate I-27 (1.7 g) was synthesized by following procedure as described for the synthesis of I-26 (step-4) using N-{3-[2,4-bis(benzyloxy)-3-fluorophenyl]oxetan-3-yl}-2- methyl propane-2-sulfinamide (A73) (2.9 g, 6 mmol) as the starting material.1H NMR (400 MHz, DMSO-d6): δ 7.47-7.33 (m, 10H); 6.96-6.88 (m, 2H); 5.18 (d, J =11.6 Hz, 4H); 4.85 (d, J = 6 Hz, 2H); 4.40 (d, J = 6 Hz, 2H). Intermediate 28: Preparation of 3-(2,4-bis(benzyloxy)-5-fluorophenyl)oxetan-3-amine (I-28)[000281] Step-1: Synthesis of 2,4-bis(benzyloxy)-1-fluorobenzene (A75): Compound A75 (18 g) was synthesized by following procedure as described for the synthesis of I-26 (step-1) using 4-fluorobenzene-1,3-diol (A74) (4 g, 31.2 mmol) as the starting material. LCMS (ES) m / z: 309.1 [M+H]+. [000282] Step-2: Synthesis of 1,5-bis(benzyloxy)-2-bromo-4-fluorobenzene (A76): Compound A76 (1.8 g) was synthesized by following procedure as described for the synthesis of I-26 (step-2) using 2,4-bis(benzyloxy)-1-fluorobenzene (A75) (2 g, 6.49 mmol) as the starting material. LCMS (ES) m / z: 387.0 [M+H]+.[000283] Step-3: Synthesis of N-{3-[2,4-bis(benzyloxy)-5-fluorophenyl]oxetan-3-yl}-2- methylpropane-2-sulfinamide (A77): Compound A77 (1.1 g) was synthesized by following procedure as described for the synthesis of I-26 (step-3) using 1,5-bis(benzyloxy)-2-bromo-4- fluorobenzene (A76) (7.29 g, 18.8 mmol) as the starting material (toluene was used as the solvent). LCMS (ES) m / z: 484.2 [M+H]+. [000284] Step-4: Synthesis of 3-[2,4-bis(benzyloxy)-5-fluorophenyl]oxetan-3-amine (I-28): Intermediate I-28 (960 mg) was synthesized by following procedure as described for the synthesis of I-26 (step-4) using N-{3-[2,4-bis(benzyloxy)-5-fluorophenyl]oxetan-3-yl}-2- methylpropane-2-sulfinamide (A77) (1.6 g, 3.31 mmol) as the starting material. LCMS m / z: 363.1 [M-18H]+. Intermediate 29: Preparation of 3-(2,4-bis(benzyloxy)-6-fluorophenyl)oxetan-3-amine (I-29)[000285] Step-1: Synthesis of 4-bromo-5-fluorobenzene-1,3-diol (A79): Compound A79 (3.5 g) was synthesized by following procedure as described for the synthesis of I-03 (step-2) using 2-bromo-1-fluoro-3,5-dimethoxybenzene (A78) (4.5 g, 19.1 mmol) as the starting material. LCMS (ES) m / z: 206.9 [M+H]+. [000286] Step-2: Synthesis of 1,5-bis(benzyloxy)-2-bromo-3-fluorobenzene (A80): Compound A80 (6.8 g) was synthesized by following procedure as described for the synthesis of I-26 (step-1) using 4-bromo-5-fluorobenzene-1,3-diol (A79) (4 g, 19.3 mmol) as the starting material.1H NMR (400 MHz, CDCl3): δ 7.47-7.41 (m, 2H); 7.39-7.30 (m, 10H); 5.16 (s, 2H); 5.07 (s, 2H). [000287] Step-3: Synthesis of N-{3-[2,4-bis(benzyloxy)-6-fluorophenyl]oxetan-3-yl}-2- methylpropane-2-sulfinamide (A81): Compound A81 (1.5 g) was synthesized by followingprocedure as described for the synthesis of I-26 (step-3) using 1,5-bis(benzyloxy)-2-bromo-3- fluorobenzene (A80) (7.29 g, 18.8 mmol) as the starting material (toluene was used as the solvent). LCMS (ES) m / z: 484.1 [M+H]+. [000288] Step-4: Synthesis of 3-[2,4-bis(benzyloxy)-6-fluorophenyl]oxetan-3-amine (I-29): Intermediate I-29 (1.8 g) was synthesized by following procedure as described for the synthesis of I-26 (step-4) using N-{3-[2,4-bis(benzyloxy)-6-fluorophenyl]oxetan-3-yl}-2- methylpropane-2-sulfinamide (A81) (3 g, 6.2 mmol) as the starting material. LCMS m / z: 363.0 [(M-NH2)+H]+. Intermediate 30: Preparation of 1-(2,4-bis(methoxymethoxy)phenyl)cyclobutan-1-amine (I-30)[000289] Step-1: Synthesis of 1-(2,4-bis(methoxymethoxy)phenyl)cyclobutan-1-ol (A83): A 2.5 M solution of n-BuLi (12.1 mL, 30.3 mmol) in heptane was added to a stirred solution of 1-bromo-2,4-bis(methoxymethoxy)benzene (A33) (7 g, 25.3 mmol) in anhydrous THF (70 mL) at -78 °C. It was stirred for 5 min before addition of a solution of cyclobutanone (A82) (1.77 g, 25.3 mmol) in THF (10 mL). The reaction mixture was then allowed to warm to room temperature, while monitoring reaction progress by TLC. After completion of the reaction (2 h), the reaction mixture was quenched by addition of saturated NH4Cl solution (50 mL) and extraction was carried out using EtOAc (3 x 70 mL). The combined organic extracts were washed with brine solution (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford the desired compound A83 (4 g) as a pale yellow thick oil.1H NMR, (400 MHz, DMSO-d6): δ 7.18 (d, J = 8.4 Hz, 1H); 6.69 (d, J= 2.4 Hz, 1H); 6.61-6.58 (m, 1H); 5.20 (s, 2H); 5.14 (s, 2H); 4.87 (s, 1H); 3.42 (s, 3H); 3.40 (s, 3H); 2.22-2.14 (m, 2H); 2.01-1.90 (m, 2H); 1.63-1.55 (m, 2H). [000290] Step-2: Synthesis of 1-(1-azidocyclobutyl)-2,4-bis(methoxymethoxy)benzene (A84): To a stirred solution of 1-[2,4-bis(methoxymethoxy)phenyl]cyclobutan-1-ol (A83) (4 g, 14.9 mmol) in DCM (80 mL) was added azidotrimethylsilane (2.37 mL, 17.9 mmol) and FeCl3(242 mg, 1.49 mmol) at 0 °C and the reaction was allowed to warm to room temperature. After complete consumption of starting material (16 h), the reaction mixture was quenched with addition of saturated NH4Cl solution (50 mL) and extraction was carried out using EtOAc (3 x 50 mL). The combined organic extracts were washed with brine solution (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-100% of EtOAc in heptane) to afford desired compound A84 (3 g) as a pale yellow liquid.1H NMR, (400 MHz, CDCl3): δ 7.07 (d, J = 8.4 Hz 1H); 6.83 (d, J = 2 Hz, 1H); 6.68-6.66 (m, 1H); 5.23-5.16 (m, 4H); 3.65-3.44 (m, 6H); 2.64-2.57 (m, 2H); 2.51-2.44 (m, 2H); 2.26-2.15 (m, 1H); 1.85-1.79 (m, 1H). [000291] Step-3: Synthesis of 1-(2,4-bis(methoxymethoxy)phenyl)cyclobutan-1-amine (I- 30): To a stirred solution of 1-(1-azidocyclobutyl)-2,4-bis(methoxymethoxy)benzene (A84) (3 g, 10.2 mmol) in MeOH (30 mL) was added 10% Pd / C (1.5 g) and the reaction mixture was stirred under H2atmosphere, while monitoring reaction progress by TLC. After completion of the reaction (4 h), the catalyst was filtered off through a celite pad and washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure and the residue was triturated with diethyl ether (3 x 10 mL) to afford desired intermediate I-30 (2 g).1H NMR, (400 MHz, DMSO-d6): δ 7.02 (d, J = 8.4 Hz, 1H); 6.66 (s, 1H); 6.58-6.56 (m, 1H); 5.17 (s, 2H); 5.11 (s, 2H); 3.37 (s, 3H); 3.34 (s, 3H); 2.34-2.32 (m, 2H); 2.07-2.00 (m, 4H). Intermediate 31: Preparation of tert-butyl (3-(aminomethyl)-2-fluorophenyl)carbamate (I-31)[000292] Step-1: Synthesis of tert-butyl N-[(tert-butoxy) carbonyl]-N-(3-cyano-2- fluorophenyl) carbamate (A86): To a stirred solution of 3-amino-2-fluorobenzonitrile (A85)(10 g, 73.5 mmol) in THF (150 mL, 1.84 mol) was added (Boc)2O (42.2 mL, 184 mmol) and DMAP (2.26 g, 18.4 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was then cooled to room temperature and water (50 mL) was added to it. Extraction was carried out using EtOAc (3 x 70 mL); the combined organic extracts were washed with brine solution (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-16% of EtOAc in n-heptane) to afford desired compound A86 (20 g) as an off white solid. LCMS (ES) m / z: 237.0 [(M-Boc)+H]+. [000293] Step-2: Synthesis of tert-butyl N-[3-(amino methyl)-2-fluorophenyl]carbamate (I- 31): To a stirred solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-cyano-2- fluorophenyl)carbamate (A86) (10 g, 29.7 mmol) in anhydrous THF (0.2 L) was added a 2.0 M LAH solution in THF (2.26 g, 59.5 mmol) at 0 °C. The reaction mixture was then allowed to warm to room temperature while monitoring reaction progress by TLC. After complete consumption of starting material (2 h), the reaction mixture was quenched with addition of hydrated Na2SO4. The reaction mixture was then filtered through a pad of celite and washed with EtOAc (3 x 100 mL). The filtrate was concentrated under reduced pressure and the residue was purified by Combi-flash (using gradient elution of 0-80% of EtOAc in n-heptane) to afford desired compound I-31 (4.7 g) as a white solid. LCMS (ES) m / z: 241.0 [M+H]+. Intermediate 32: Preparation of tert-butyl (2-fluoro-3-formylphenyl)carbamate (I-32)[000294] Step-1: Synthesis of tert-butyl N-(2-fluoro-3-formylphenyl) carbamate (I-32): Argon gas was purged through a stirred suspension of 3-bromo-2-fluorobenzaldehyde (A87) (5 g, 24.6 mmol), tert-butyl carbamate (3.46 g, 29.6 mmol) and Cs2CO3(9.63 g, 29.6 mmol) in 1,4-dioxane (25 mL) for 10 min, before addition of Pd2(dba)3(564 mg, 616 µmol) and Xantphos (855 mg, 1.48 mmol). The reaction mixture was then stirred at 100 °C for 16 h. After complete consumption of starting material (16 h), the reaction mixture was cooled to room temperature and water (50 mL) was added to it. Extraction was carried out using EtOAc (2 x 40 mL); the combined organic extracts were washed with brine solution (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue waspurified by Combi-Flash (using gradient elution of 0-40% of EtOAc in heptane) to afford desired compound I-32 (1.75 g) as a white solid. LCMS (ES) m / z: 140.0 [(M-Boc)+H]+. Intermediate 33: Preparation of 1-(2-fluoro-3-formylphenyl)-N- methylmethanesulfonamide (I-33)[000295] Step-1: Synthesis of sodium (3-bromo-2-fluorophenyl)methanesulfonate (A89): To a stirred solution of 1-bromo-3-(bromomethyl)-2-fluorobenzene (A88) (6 g, 22.4 mmol) in EtOH (80 mL) and water (80 mL) was added sodium sulfite (2.77 g, 26.9 mmol); and the reaction mixture was allowed to stir at 90 °C, while monitoring reaction progress by TLC. After completion of reaction (5 h), it was concentrated under reduced pressure and dried to afford the desired compound A89 (6.7 g) as a colorless solid, which was carried forward for the next step. LCMS (ES) m / z: 268.7 [M+H]+(the corresponding acid mass). [000296] Step-2: Synthesis of 1-(3-bromo-2-fluorophenyl)-N-methylmethanesulfonamide (A90): To a stirred suspension of sodium (3-bromo-2-fluorophenyl)methanesulfonate (A89) (7.5 g, 25.8 mmol) in toluene (50 mL) was added SOCl2(8 mL) and the reaction mixture was allowed to stir at 85 °C for 5 h. It was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in THF (15 mL) and added to a solution of methylamine (8.6 mL, 17.2 mmol) in THF (10 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 h. Water (50 mL) was added to it and extraction was carried out using EtOAc (2 x 40 mL). The combined organic extracts were washed with brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-35% of EtOAc in heptane) to afford the desired compound A90 (4.5 g) as a white solid.1H NMR(400 MHz, DMSO-d6): δ 7.72-7.68 (m, 1H); 7.46-7.42 (m, 1H); 7.21-7.13 (m, 2H); 4.42 (s, 2H); 2.61 (d, J = 4.8 Hz, 3H). [000297] Step-3: Synthesis of 1-(3-ethenyl-2-fluorophenyl)-N-methylmethanesulfonamide (A91): Argon gas was purged through a stirred suspension of 1-(3-bromo-2-fluorophenyl)-N- methylmethanesulfonamide (A90) (3.5 g, 12.4 mmol), aqueous solution of Na2CO3(3.94 g, 37.2 mmol, in 7 mL water) and potassium ethenyltrifluoroboranuide (2.16 g, 16.1 mmol) in 1,4-dioxane (28 mL) for 10 min before addition of Pd(dppf)Cl2·CH2Cl2(1.01 g, 1.24 mmol). The reaction mixture was then stirred at 100 °C, while monitoring reaction progress by TLC. After complete consumption of starting material (2 h), the reaction mixture was cooled to room temperature, filtered through celite pad and washed with EtOAc (3 x 20 mL). The filtrate was diluted with water (30 mL) and extraction was carried out using EtOAc (2 x 30 mL). The combined organic extracts were washed with brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-40% of EtOAc in heptane) to afford desired compound A91 (2.8 g) as an off-white solid. LCMS (ES) m / z: 228.0 [M-H]+. [000298] Step-4: Synthesis of 1-(3-ethenyl-2-fluorophenyl)-N-methylmethanesulfonamide (I-33): To a stirred solution of 1-(3-ethenyl-2-fluorophenyl)-N-methylmethanesulfonamide (A91) (3.7 g, 16.1 mmol) in THF (37 mL) and water (18 mL) mixture was added OsO4(4% in water) (5 mL, 0.80 mmol) and the reaction mixture was allowed to stir at room temperature for 30 min. To this was then added NaIO4(6.9 g, 32.3 mmol) and the reaction mixture was allowed to stir at room temperature, while monitoring reaction progress by TLC / LCMS. After complete consumption of starting material (2 h), water (50 mL) was added to it and extraction was carried out using EtOAc (2 x 30 mL). The combined organic extracts were washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by Combi-flash (using gradient elution of 0-40% of EtOAc in n-heptane) to afford desired compound I-33 (1.7 g) as an off white solid. LCMS (ES) m / z: 230.1 [M-H]+. Intermediate 34: Preparation of benzyl (2-fluoro-3-formylphenyl)carbamate (I-34)[000299] Step-1: Synthesis of benzyl (3-cyano-2-fluorophenyl)carbamate (A92): To a stirred solution of 3-amino-2-fluorobenzonitrile (A85) (5 g, 36.7 mmol) in THF (50 mL) under nitrogen atmosphere was added K2CO3(15.2 g, 110 mmol) and benzyl chloroformate (15.8 mL, 110 mmol) at 0 °C. The reaction mixture was stirred at room temperature, while monitoring reaction progress by TLC / LCMS. After completion of the reaction (16 h), water (20 mL) was added to it and extraction was carried out using EtOAc (3 x 50 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (2 x 30 mL), brine solution (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash column (using gradient elution of 0-20% of EtOAc in heptane) to afford desired compound A92 (9.3 g) as an off- white solid. LCMS (ES) m / z: 271.1 [M+H]+. [000300] Step-2: Synthesis of benzyl (2-fluoro-3-formylphenyl)carbamate (I-34): To a stirred solution of benzyl N-(3-cyano-2-fluorophenyl)carbamate (A92) (1 g, 3.7 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere was added 1 M DIBAL-H in THF (18.5 mL, 18.5 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC / LCMS. After complete consumption of starting material (3 h), reaction mixture was quenched with addition of saturated NH4Cl solution (10 mL) and extraction was carried out using EtOAc (3 x 30 mL). the combined organic extracts were washed with water (2 x 30 mL), saturated NaHCO3solution (2 x 20 mL), brine solution (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated using DCM-n-heptane (1:4) followed by diethyl ether (2 x 10 mL) to afford desired compound I-34 (230 mg) as a white solid. LCMS (ES) m / z: 274.1 [M+H]+. Intermediate 35: Preparation of benzyl (2-fluoro-3-formylphenyl)carbamate (I-35)[000301] Step-1: Synthesis of (2-chloro-3-fluoropyridin-4-yl)methanol (A94): To a stirred solution of 2-chloro-3-fluoropyridine (A93) (8 g, 60.8 mmol) in THF (20 mL) was addedLDA (2.0 M in THF) (6.52 g, 30.4 mL, 60.8 mmol) at -78 °C and stirred for 2 h. To this was then DMF (44.5 g, 608 mmol) at -78 °C and the reaction mixture was allowed to warm to room temperature over 2 h. To this was then added NaBH4(2.99 g, 79.1 mmol) at 0 °C and stirred for 1 h. The reaction mixture was then quenched with water (50 mL) and extraction was carried out using EtOAc (3 x 70 mL). The combined organic extracts were washed with aqueous 1 M HCl solution (2 x 20 mL), saturated NaHCO3solution (3 x 30 mL), brine solution (2 x 25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-6% of MeOH in DCM) to afford the desired compound A94 (7.8 g) as a pale yellow solid. LCMS (ES) m / z: 162.1 [M+H]+. [000302] Step-2: Synthesis of 4-{[(tert-butyldimethylsilyl)oxy]methyl}-2-chloro-3- fluoropyridine (A95): To a stirred solution of (2-chloro-3-fluoropyridin-4-yl)methanol (A94) (8 g, 49.5 mmol) in DMF (80 mL) was added imidazole (10.1 g, 149 mmol) and TBDMS-Cl (14.9 g, 99 mmol) at 0 °C. The reaction mixture was stirred at room temperature, while monitoring reaction progress by TLC / LCMS analysis. After complete consumption of starting material (2 h), the reaction mixture was quenched with addition of water (50 mL) and extraction was carried out using DCM (3 x 50 mL). The combined organic extracts were washed with cold water (3 x 50 mL), brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-2% of EtOAc in DCM) to afford the desired compound A95 (10 g) as an off-white solid. LCMS (ES) m / z: 276.2 [M+H]+. [000303] Step-3: Synthesis of tert-butyl-4-{[(tert-butyl)bis(methyl)siloxy]methyl}-3-fluoro- 2-pyridylaminoformylate (A96): Argon gas was purged through a stirred suspension of 4- {[(tert-butyldimethylsilyl)oxy]methyl}-2-chloro-3-fluoropyridine (A95) (5 g, 18.1 mmol), Boc-NH2(3.4 g, 29 mmol) and K3PO4(12.3 g, 58 mmol) in THF (50 mL) for 10 min before addition of Xantphos (1.57 g, 2.72 mmol) and Pd(OAc)2(610 mg, 2.72 mmol). The reaction mixture was then stirred at 80 °C for 16 h. It was then cooled to room temperature and water (25 mL) was added to it. Extraction was carried out using EtOAc (3 x 50 mL); the combined organic extracts were washed with brine solution (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-70% of EtOAc in hexane) to afford the desired compound A96 (2.2 g, 6.16 mmol) as a pale yellow solid. LCMS (ES) m / z: 357.2 [M+H]+.[000304] Step-4: Synthesis of tert-butyl N-[3-fluoro-4-(hydroxymethyl)pyridin-2- yl]carbamate (A97): To a stirred solution of tert-butyl N-(4-{[(tert- butyldimethylsilyl)oxy]methyl}-3-fluoropyridin-2-yl)carbamate (A96) (8.5 g, 23.8 mmol) in THF (85 mL) was added 1.0 M TBAF in THF (9.35 g, 35.8 mmol) at 0 °C; and the reaction mixture was stirred at room temperature, while monitoring reaction progress by TLC / LCMS. After complete consumption of starting material (2 h), the reaction mixture was quenched with ice water (50 mL) and extraction was carried out using EtOAc (3 x 50 mL). The combined organic extracts were washed with brine solution (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-80% of EtOAc in heptane) to afford desired compound A97 (4.5 g, 18.6 mmol) as a pale yellow viscous oil. LCMS (ES) m / z: 243.1 [M+H]+. [000305] Step-5: Synthesis of tert-butyl N-(3-fluoro-4-formylpyridin-2-yl)carbamate (I- 35): To a stirred solution of tert-butyl N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]carbamate (A97) (4.5 g, 18.6 mmol) in DCM (150 mL) was added DMP (11.8 g, 27.9 mmol) at 0 °C and the reaction mixture was stirred at room temperature. The reaction progress was monitored by TLC / LCMS analysis. After complete consumption of starting material (2 h), cold water (50 mL) was added to it and extraction was carried out using DCM (3 x 70 mL). The combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-55% of EtOAc in hexane) to afford the desired compound I-35 (3.3 g) as an off-white solid. LCMS (ES) m / z: 185.1 [(M-tBu)+H]+. Intermediate 36: Preparation of 2-(cyclopropylsulfonylamino)-3- fluoroisonicotinaldehyde (I-36)[000306] Step-1: Synthesis of (cyclopropylsulfonyl)(4-{[(tert- butyl)bis(methyl)siloxy]methyl}-3-fluoro-2-pyridyl)amine (A98): Compound A98 (2.1 g) was synthesized by following procedure as described for the synthesis of I-35 (step-3) using (tert-butyl)[(2-chloro-3-fluoro-4-pyridyl)methoxy]bis(methyl)silane (A94) (10 g, 36.3 mmol) and cyclopropanesulfonamide (6.6 g, 54.4 mmol) as the starting materials. LCMS (ES) m / z: 361.1 [M+H]+. [000307] Step-2: Synthesis of [2-(cyclopropylsulfonylamino)-3-fluoro-4-pyridyl]methanol (A99): Compound A99 (2.0 g) was synthesized by following procedure as described for the synthesis of I-35 (step-4) using (cyclopropylsulfonyl)(4-{[(tert- butyl)bis(methyl)siloxy]methyl}-3-fluoro-2-pyridyl)amine (A98) (4.1 g, 11.4 mmol) as the starting material. LCMS (ES) m / z: 247.1 [M+H]+. [000308] Step-3: Synthesis of 2-(cyclopropylsulfonylamino)-3-fluoroisonicotinaldehyde (I- 36): Intermediate I-36 (1.4 g) was synthesized by following procedure as described for the synthesis of I-35 (step-5) using [2-(cyclopropylsulfonylamino)-3-fluoro-4-pyridyl]methanol (A99) as the starting material (2.0 g, 8.12 mmol). LCMS (ES) m / z: 245.1 [M+H]+. Intermediate 37: Preparation of 2-fluoro-3-[(2-oxo-1-imidazolidinyl)methyl] benzaldehyde (I-37)[000309] Step-1: Synthesis of 1-[(3-bromo-2-fluorophenyl)methyl]-2-imidazolidinone (A100): To a stirred solution of 2-imidazolidinone (5 g, 58.1 mmol) in DMF (125 mL) was added NaH (60% dispersion in mineral oil) (2.32 g, 58.1 mmol) at 0 °C and stirred for 10 min before addition of 1-bromo-3-(bromomethyl)-2-fluorobenzene (A88) (7.78 g, 29 mmol). The reaction mixture was allowed to warm to room temperature and the reaction progress was monitored by TLC / LCMS analysis. After completion of the reaction (3 h), it was quenched with water (20 mL) and extraction was carried out using DCM (3 x 50 mL). The combined organic extracts were washed with brine solution (2 x 25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-80% of EtOAc in heptane) to afford the desired compound A100 (4.5 g) as a colorless thick oil. LCMS (ES) m / z: 273.6 [M+H]+.[000310] Step-2: Synthesis of 1-(2-fluoro-3-vinylbenzyl)imidazolidin-2-one (A101): Argon gas was purged through a stirred solution of 1-[(3-bromo-2-fluorophenyl)methyl]-2- imidazolidinone (A100) (2.7 g, 9.89 mmol) and tributyl(vinyl)stannane (3.13 g, 9.89 mmol) in toluene (50.5 mL) for 5 min before addition of PdCl2(PPh3)2(27.7 mg, 39.5 µmol). The reaction mixture was then stirred at 100 °C, while monitoring reaction progress by TLC. After completion of the reaction (4 h), it was cooled to room temperature and volatiles were removed under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford desired compound A101 (2.4 g) as a pale yellow liquid. LCMS (ES) m / z: 221.6 [M+H]+. [000311] Step-3: Synthesis of 2-fluoro-3-[(2-oxo-1-imidazolidinyl)methyl]benzaldehyde (I- 37): To a stirred solution of 1-(2-fluoro-3-vinylbenzyl)imidazolidin-2-one (A101) (2.4 g, 10.9 mmol) in THF (30 mL) and water (10 mL) was added OsO4(4% in water) (3.5 mL, 545 µmol). To this was then added NaIO4(4.66 g, 21.8 mmol) and the reaction mixture was stirred at room temperature, while monitoring reaction progress by TLC. After completion of the reaction (2 h), water (30 mL) was added to it and extraction was carried out with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine solution (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-flash (using gradient elution of 0-40% of EtOAc in heptane) to afford the desired compound I-37 (2 g) as a pale yellow thick oil. LCMS (ES) m / z: 223.3 [M+H]+. Intermediate 38: Preparation of tert-butyl (4-(aminomethyl)-3-fluoropyridin-2- yl)carbamate (I-38)[000312] Step-1: Synthesis of 4-(bromomethyl)-3-fluoro-2-pyridylamino-tert- butylformylate (A102): To a stirred solution of tert-butyl-3-fluoro-4-(hydroxymethyl)-2- pyridylaminoformylate (A97) (2.4 g, 9.91 mmol) in DCM (100 mL) was added PPh3(3.9 g,14.9 mmol) and CBr4(4.6 g, 13.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature and the reaction progress was monitored by TLC / LCMS analysis. After complete consumption of starting material (2 h), water (50 mL) was added to it and extraction was carried out by using DCM (2 x 50 mL). The combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-40% of EtOAc in hexane) to afford the desired compound A102 (2.6 g) as a pale yellow viscous liquid. LCMS (ES) m / z: 305.0 [M+H]+. [000313] Step-2: Synthesis of 4-(azidomethyl)-3-fluoro-2-pyridylamino-tert-butylformylate (A103): To a stirred solution of 4-(bromomethyl)-3-fluoro-2-pyridylamino-tert- butylformylate (A102) (2.6 g, 8.52 mmol) in DMF (26 mL) was added sodium azide (665 mg, 10.2 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature over 16 h. After complete consumption of starting material (16 h), water (50 mL) was added to it and extraction was carried out with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine solution (2 x 25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford desired compound A103 (2.3 g) as a pale yellow viscous liquid. LCMS m / z: 268.0 [M+H]+. [000314] Step-3: Synthesis of tert-butyl (4-(aminomethyl)-3-fluoropyridin-2-yl) carbamate (I-38): To a stirred solution of 4-(azidomethyl)-3-fluoro-2-pyridylamino-tert-butylformylate (A103) (2.3 g, 8.61 mmol) in THF (24 mL) and water (6.1 mL) was added PPh3(3.39 g, 12.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After complete consumption of starting material, volatiles were removed under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-5% MeOH in DCM) to afford desired compound I-38 (1.5 g) as an off-white solid. LCMS m / z: 242.1 [M+H]+. Intermediate 39: Preparation of 4-(1-aminocyclobutyl)benzene-1,3-diol (I-39)[000315] Step-1: Synthesis of 4-(1-aminocyclobutyl)benzene-1,3-diol (I-39): To a stirred solution of 1-[2,4-bis(methoxymethoxy)phenyl]cyclobutylamine (I-30) (2.8 g, 10.5 mmol) in MeOH (20 mL) was added a 4 M solution of HCl in 1,4-dioxane (20 mL) at 0 °C. Thereaction mixture was then stirred at room temperature for 16 h. After completion of the reaction, volatiles were removed under reduced pressure and the residue was washed with diethyl ether (3 x 10 mL) to afford desired intermediate I-39 (1.8 g) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H); 9.49 (s, 1H); 8.08 (br s, 3H); 7.06 (d, J = 8.4 Hz, 1H); 6.45 (s, 1H); 6.27-6.25 (m, 1H); 3.63-3.56 (m, 2H); 2.09-1.98 (m, 2H); 1.70-1.68 (m, 2H). Intermediates 40 and 41: Preparations of 1-(5-fluoro-2,4- bis(methoxymethoxy)phenyl)cyclobutan-1-amine (I-40) and 4-(1-aminocyclobutyl)-6- fluorobenzene-1,3-diol (I-41)[000316] Step-1: Synthesis of 1-fluoro-2,4-bis(methoxymethoxy)benzene (A104): Compound A104 (10 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using 4-fluorobenzene-1,3-diol (A74) (10 g, 78.1 mmol) as the starting material.1H NMR (400 MHz, CDCl3): δ 7.03-6.98 (m, 1H); 6.93-6.90 (m, 1H); 6.68- 6.64 (m, 1H); 5.21 (s, 2H); 5.13 (s, 2H); 3.54 (s, 3H); 3.49 (s, 3H). [000317] Step-2: Synthesis of 1-bromo-5-fluoro-2,4-bis(methoxymethoxy)benzene (A105): Compound A105 (10 g) was synthesized by following procedure as described for the synthesis of I-26 (step-2) using 1-fluoro-2,4-bis(methoxymethoxy)benzene (A104) (10 g, 46.3 mmol) as the starting material. [000318] Step-3: Synthesis of 1-(5-fluoro-2,4-bis(methoxymethoxy)phenyl)cyclobutan-1-ol (A106): Compound A106 (1.75 g) was synthesized by following procedure as described for the synthesis of I-30 (step-1) using 1-bromo-5-fluoro-2,4-bis(methoxymethoxy)benzene (A105) (5 g, 16.9 mmol) as the starting material.1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 12.4 Hz, 1H); 6.94 (d, J = 7.6 Hz, 1H); 5.22-5.16 (m, 4H); 5.09 (s, 1H); 3.42-3.41 (m, 6H); 2.55-2.51 (m, 2H); 2.20-2.14 (m, 2H); 1.97-1.91 (m, 2H). [000319] Step-4: Synthesis of 1-(1-azidocyclobutyl)-5-fluoro-2,4- bis(methoxymethoxy)benzene (A107): Compound A107 (2.75 g) was synthesized byfollowing procedure as described for the synthesis of I-30 (step-2) using 1-[5-fluoro-2,4- bis(methoxymethoxy)phenyl]cyclobutanol (A106) (3.5 g, 12.2 mmol) as the starting material.1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 8.8 Hz, 1H); 6.73 (d, J = 2.8 Hz, 1H); 6.65-6.62 (m, 1H); 5.17-5.15 (m, 4H); 3.37-3.35 (m, 6H); 2.64-2.54 (m, 2H); 2.40-2.34 (m, 2H); 2.11- 2.04 (m, 1H); 1.76-1.69 (m, 1H). [000320] Step-5: Synthesis of 1-(5-fluoro-2,4-bis(methoxymethoxy)phenyl)cyclobutan-1- amine (I-40): Intermediate I-40 (4.5 g) was synthesized by following procedure as described for the synthesis of I-30 (step-3) using 1-(1-azidocyclobutyl)-5-fluoro-2,4- bis(methoxymethoxy)benzene (A107) (5.5 g, 17.7 mmol) as the starting material.1H NMR (400 MHz, DMSO-d6) δ 6.98-6.91 (m, 2H); 5.22-5.17 (m, 4H); 3.48-3.35 (m, 6H); 2.50-2.40 (m, 3H); 2.22-2.01 (m, 3H). [000321] Step-6: Synthesis of 4-(1-aminocyclobutyl)-6-fluorobenzene-1,3-diol (I-41): Intermediate I-41 (2.8 g) was synthesized by following procedure as described for the synthesis of I-39 (step-1) using 1-[5-fluoro-2,4- bis(methoxymethoxy)phenyl]cyclobutylamine (I-40) (4 g, 14 mmol) as the starting material.1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H); 9.96 (s, 1H); 8.12 (br s, 2H); 7.04 (d, J = 12.4 Hz, 1H); 6.65 (d, J = 8.0Hz, 1H); 3.56 (s, 2H); 2.46-2.40 (m, 2H); 2.10-2.06 (m, 1H); 1.74-1.68 (m, 1H). Intermediate 42: Preparation of 4-(2-aminopropan-2-yl)benzene-1,3-diol (I-42)[000322] Step-1: Synthesis of N-[(1Z)-1-(2,4-dihydroxyphenyl)ethylidene]-2- methylpropane-2-sulfinamide (A108): To a stirred solution of 1-(2,4-dihydroxyphenyl)ethan- 1-one (A54) (10 g, 65.7 mmol) and 2-methylpropane-2-sulfinamide (23.9 g, 197 mmol) in THF (120 mL) was added titanium (IV) isopropoxide (117 mL, 394 mmol) at room temperature and the reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction, it was cooled to room temperature and quenched with addition of ice-cold water (50 mL). It was then filtered through celite and washed with EtOAc (50 mL). The filtrate was extracted using EtOAc (3 x 50 mL); the combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reducedpressure. The residue was purified by Combi-Flash (using gradient elution of 0-40% of EtOAc in heptane) to afford the desired compound A108 (4.51 g) as a grey solid. LCMS (ES) m / z: 254.15 [M-H]+. [000323] Step-2: Synthesis of N-[2-(2,4-dihydroxyphenyl)propan-2-yl]-2-methylpropane-2- sulfinamide (A109): To a stirred solution of N-[(1Z)-1-(2,4-dihydroxyphenyl)ethylidene]-2- methylpropane-2-sulfinamide (A108) (4.5 g, 17.6 mmol) in THF (110 mL) was added MeMgBr (16.8 g, 141 mmol) at -10 °C and the reaction mixture was allowed to warm to room temperature. After completion of the reaction (6 h), the reaction mixture was quenched with addition of saturated ammonium chloride solution (30 mL) and extraction was carried out using EtOAc (3 x 40 mL). The combined organic extracts were washed with brine solution (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford the desired compound A109 (1.2 g) as a brown solid. LCMS (ES) m / z: 270.16 [M-H]+. [000324] Step-3: Synthesis of 4-(2-aminopropan-2-yl)benzene-1,3-diol (I-42): To a stirred solution of N-[2-(2,4-dihydroxyphenyl)propan-2-yl]-2-methylpropane-2-sulfinamide (A109) (1.2 g, 4.42 mmol) in MeOH (15 mL) was added a 4 M solution of HCl in 1,4-dioxane (5.2 mL, 22.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature and the reaction progress was monitored by TLC / LCMS analysis. After completion of the reaction (0.5 h), the reaction mixture was concentrated under reduced pressure and the residue was washed with diethyl ether (3 x 10 mL) to afford desired compound I-42 (0.37 g) as a yellow solid. LCMS (ES) m / z: 166.15 [M-H]+. Intermediate 43: Preparation of 4-(2-aminopropan-2-yl)benzene-1,3-diol (I-43)[000325] Step-1: Synthesis of tert-butyl 3-[2,4-bis(benzyloxy)phenyl]-3-hydroxyazetidine- 1-carboxylate (A110): To a stirred solution of 2,4-bis(benzyloxy)-1-bromobenzene (A66) (10 g, 27.1 mmol) in anhydrous THF (150 mL) was added a solution of n-BuLi (2.2 M in hexane, 14.8 mL, 32.5 mmol) at -78 °C under nitrogen atmosphere. The reaction was stirred for 60 min before addition of a solution of tert-butyl 3-oxoazetidine-1-carboxylate (6.95 g, 40.6mmol) in THF (21 mL). The reaction mixture was then allowed to warm to room temperature, while monitoring reaction progress by TLC. After completion of the reaction (2 h), it was quenched by addition of saturated ammonium chloride (50 mL) solution. Extraction was carried out using EtOAc (3 x 70 mL); the combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford desired compound A110 (3.2 g) as pale yellow solid. LCMS (ES) m / z: 462.20 [M+H]+. [000326] Step-2: Synthesis of tert-butyl 3-azido-3-[2,4-bis(benzyloxy)phenyl]azetidine-1- carboxylate (A111): The solution of tert-butyl 3-[2,4-bis(benzyloxy)phenyl]-3- hydroxyazetidine-1-carboxylate (A110) (7 g, 15.2 mmol) in THF (140 mL) was added PPh3(7.16 g, 27.3 mmol), DIAD (4.47 mL, 22.7 mmol) and diphenylphosphinoyl azide (5.19 mL, 27.3 mmol). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, ice water (50 mL) was added to it and extraction was carried out with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine solution (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-20% of EtOAc in heptane) to afford the desired compound A111 (4 g) as colorless sticky oil. LCMS (ES) m / z: 487.12 [M+H]+. [000327] Step-3: Synthesis of tert-butyl 3-amino-3-(2,4-dihydroxyphenyl)azetidine-1- carboxylate (I-43): The a solution of tert-butyl 3-azido-3-[2,4- bis(benzyloxy)phenyl]azetidine-1-carboxylate (A111) (4.1 g, 8.43 mmol) in MeOH (50 mL) was added 5% Pd / C (1.79 g) and the reaction mixture was allowed to stir at room temperature under hydrogen atmosphere. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (16 h), the catalyst was filtered off through a celite pad and washed with MeOH (2 x 5 mL). MeOH was then evaporated under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-80% of EtOAc in heptane) to afford the desired I-43 (1.8 g) as an off-white solid. LCMS (ES) m / z: 281.13 [M+H]+.Intermediate 44: Preparation of 2-(benzyloxy)-4-((1-methyl-1H-pyrazol-3- yl)oxy)benzaldehyde (I-44)[000328] Step-1: Synthesis of 2-(benzyloxy)-4-fluorobenzaldehyde (A113): To a stirred solution of 4-fluoro-2-hydroxybenzaldehyde (A112) (10.0 g, 71.4 mmol) in DMF (40 mL) was added K2CO3(29.6 g, 214 mmol) and (bromomethyl)benzene (12.7 mL, 107 mmol) at room temperature. The reaction progress was monitored by TLC / LCMS analysis. After complete consumption of starting material (16 h), cold water (50 mL) was added to it and extraction was carried out using EtOAc (3 x 70 mL). The combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford desired compound A113 (13.0 g) as a colorless liquid.1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H); 7.79 (t, J = 7.6 Hz, 1H); 7.53-7.52 (m, 2H); 7.43 (t, J = 7.6 Hz, 1H); 7.38-7.35 (m, 2H); 7.26 (d, J = 10.0 Hz, 1H); 6.94 (t, J = 8.4 Hz, 1H); 5.31 (s, 2H). [000329] Step-2: Synthesis of 2-(benzyloxy)-4-(1-methyl-3-pyrazolyloxy)benzaldehyde (I- 44): To a stirred solution of 1-methyl-3-pyrazolol (1.94 g, 19.8 mmol) and 2-(benzyloxy)-4- fluorobenzaldehyde (A113) (5.01 g, 21.8 mmol) in DMF (35 mL) was added Cs2CO3(12.9 g, 39.5 mmol) and the reaction mixture was stirred at 50 °C, while monitoring reaction progress by TLC. After complete consumption of starting material (3 h), the reaction mixture was cooled to room temperature and ice-cold water (30 mL) was added to it. Extraction was carried out using EtOAc (3 x 70 mL); the combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford desired compound I-44 (3.3 g) as a pale-yellow liquid.1H NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H); 7.72-7.69 (m, 2H); 7.49-7.47 (m, 2H); 7.41 (t, J = 7.2 Hz, 2H); 7.36-7.33 (m, 1H); 6.97 (d, J = 2.0 Hz, 1H); 6.66 (dd, J1= 2.0 Hz, J2= 8.4 Hz, 1H); 5.94 (d, J = 2.0 Hz, 1H); 5.25 (s, 2H); 3.78 (s, 3H). Intermediate 45: Preparation of 1-(2,4-bis(benzyloxy)phenyl)ethan-1-amine (I-45)[000330] Step-1: Synthesis of N-{1-[2,4-bis(benzyloxy)phenyl]ethyl}-2-methylpropane-2- sulfinamide (A114): To a stirred solution of 2,4-bis(benzyloxy)-1-bromobenzene (A66) (10.0 g, 27.1 mmol) in THF (120 mL) was added n-BuLi (2.08 g, 32.5 mmol) at -78 °C and stirred for 30 min, before addition of a solution of N-[(E)-ethylidene]-2-methylpropane-2- sulfinamide (5.98 g, 40.6 mmol) in THF (10 mL). The reaction mixture was stirred at the same temperature, while reaction progress was monitored by TLC / LCMS analysis. After complete consumption of starting material (1 h), the reaction mixture was quenched with addition of saturated NH4Cl solution (30 mL). Extraction was carried out using EtOAc (3 x 70 mL); the combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford desired compound A114 (8.00 g) as a thick oil. LCMS (ES) m / z: 438.2 [M+H]+. [000331] Step-2: Synthesis of 1-[2,4-bis(benzyloxy)phenyl]ethan-1-amine (I-45): To a stirred solution of N-{1-[2,4-bis(benzyloxy)phenyl]ethyl}-2-methylpropane-2-sulfinamide (A114) (4.0 g, 9.14 mmol) in MeOH (40 mL) was added a 4 M solution of HCl in 1,4- dioxane (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C, while monitoring reaction progress by TLC. After complete consumption of starting material (1 h), volatiles were removed under reduced pressure and saturated NaHCO3solution (30 mL) was added to the residue. Extraction was carried out using EtOAc (30 mL x 2); the combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford desired compound I-45 (1.75 g) as an off-white solid. LCMS (ES) m / z: 317.2 [(M-NH3)+H]+.Intermediate 46: Preparation of 1-(N-(3-(aminomethyl)-2- fluorophenyl)sulfamoyl)pyrrolidine-3-carboxamide (I-46)[000332] Step-1: Synthesis of methyl 1-[(3-cyano-2-fluorophenyl)sulfamoyl]pyrrolidine-3- carboxylate (A115): To a stirred solution of 3-amino-2-fluorobenzonitrile (A85) (2.69 g, 19.8 mmol) in pyridine (2 mL) was added DMAP (0.487 g, 3.95 mmol) and methyl 1- (chlorosulfonyl)pyrrolidine-3-carboxylate (4.5 g, 19.8 mmol) at room temperature. The reaction mixture was stirred at 45 °C and the reaction progress was monitored by TLC and LCMS analysis. After completion of the reaction (16 h), the reaction mixture was cooled to room temperature and then quenched with addition of water (30 mL). Extraction was carried out using EtOAc (3 x 70 mL); the combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-80% of EtOAc in heptane) to afford desired compound A115 (4.2 g) as brown solid. LCMS (ES) m / z: 328.1 [M+H]+. [000333] Step-2: Synthesis of 1-[(3-cyano-2-fluorophenyl)sulfamoyl]pyrrolidine-3- carboxylic acid (A116): To a stirred solution of methyl 1-[(3-cyano-2- fluorophenyl)sulfamoyl]pyrrolidine-3-carboxylate (A115) (4.2 g, 12.8 mmol) in THF (88 mL) was added an aqueous solution of lithium hydroxide (1.03 g, 25.7 mmol, in 18 mL water) at room temperature. The reaction progress was monitored by TLC / LCMS analysis. After complete consumption of starting material (4 h), the reaction mixture was acidified using 1 M HCL (15 mL) and extraction was carried out using DCM (3 x 70 mL). The combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue waspurified by Combi-Flash (using gradient elution of 0-5% of MeOH in DCM) to afford desired compound A116 (2.7 g) as a brown solid. LCMS (ES) m / z: 312.1 [M-H]+. [000334] Step-3: Synthesis of 1-[(3-cyano-2-fluorophenyl)sulfamoyl]pyrrolidine-3- carboxamide (A117): To a stirred solution of 1-[(3-cyano-2- fluorophenyl)sulfamoyl]pyrrolidine-3-carboxylic acid (A116) (2.7 g, 8.62 mmol) in DCM (50 mL) was added oxalylchloride (1.9 mL, 21.6 mmol) drop-wise under N2 atmosphere followed by addition of 5 drops of DMF at room temperature. After stirring for 1 h, the reaction mixture was cooled to -10 °C and ammonia gas was purged through it for 20 min. The reaction mixture was then stirred for additional 1 h. Water (15 mL) was then added to the reaction mixture and extraction was carried out using DCM (3 x 70 mL). The combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% of MeOH in DCM) to afford desired compound A117 (2.23 g) as an off-white solid. LCMS (ES) m / z: 313.0 [M+H]+. [000335] Step-4: Synthesis of 1-{[3-(aminomethyl)-2-fluorophenyl]sulfamoyl}pyrrolidine- 3-carboxamide (I-46): To a stirred solution of 1-[(3-cyano-2- fluorophenyl)sulfamoyl]pyrrolidine-3-carboxamide (A117) (2.23 g, 7.14 mmol) in MeOH (60 mL) was added 10% Pd / C (3.04 g) and the reaction mixture was stirred under hydrogen atmosphere (20 psi pressure) for 6 h at 40 °C. The reaction progress was monitored by TLC / LCMS analysis. After complete consumption of starting material (6 h), the catalyst was filtered off through a celite pad and washed with MeOH (5 mL x 2). MeOH was then evaporated under reduced pressure to afford the desired compound I-46 (1.20 g) as a pale yellow semi-solid. LCMS (ES) m / z: 315.2 [M-H]+. Intermediate 47: Preparation of 3-(3-(aminomethyl)-2-fluorophenyl)oxazolidin-2-one (I- 47)[000336] Step-1: Synthesis of 2-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzonitrile (A118): To a stirred solution of 3-amino-2-fluorobenzonitrile (A85) (8 g, 58.8 mmol) in acetonitrile(80 mL) was added K2CO3(24.4 g, 176 mmol) and 2-chloroethyl carbonochloridate (6.07 mL, 58.8 mmol) at room temperature. The reaction mixture was stirred at 80 °C and the reaction progress was monitored by TLC / LCMS analysis. After complete consumption of starting material (4 h), the reaction mixture was cooled to room temperature and then quenched with water (30 mL). Extraction was carried out using EtOAc (3 x 70 mL); the combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford desired compound A118 (6 g) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 7.95 (t, J = 7.6 Hz, 1H); 7.84 (t, J = 7.6 Hz, 1H); 7.64 (t, J = 8.0 Hz, 1H); 4.50 (t, J = 7.2 Hz, 2H); 4.07 (t, J = 8.0 Hz, 2H). [000337] Step-2: Synthesis of 3-[3-(aminomethyl)-2-fluorophenyl]-1,3-oxazolidin-2-one (I- 47): Intermediate I-47 (3.45 g) was synthesized by following procedure as described for the synthesis of I-46 (step-4) using 2-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzonitrile (A118) (4 g, 19.4 mmol) as the starting material. LCMS (ES) m / z: 211.2 [M+H]+. Intermediate 48: Preparation of 3-(3-(aminomethyl)-2-fluorobenzyl)oxazolidin-2-one (I- 48)[000338] Step-1: Synthesis of 3-(bromomethyl)-2-fluorobenzonitrile (A120): To a stirred solution of 2-fluoro-3-toluonitrile (A119) (5.0 g, 37 mmol) in DCE (30 mL) was added AIBN (0.608 g, 3.7 mmol) and NBS (6.59 g, 37 mmol) at room temperature. The reaction mixture was stirred at 80 °C, while monitoring reaction progress by TLC / LCMS analysis. After completion of the reaction (16 h), the reaction mixture was cooled to room temperature and quenched with addition of ice-cold water (50 mL). Extraction was carried out using EtOAc (3x 70 mL); the combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-20% of EtOAc in heptane) to afford desired compound A120 (4.2 g) as a colorless liquid.1H NMR (400 MHz, DMSO-d6): δ 7.95- 7.92 (m, 2H); 7.45-7.42 (m, 1H); 4.76 (s, 2H). [000339] Step-2: Synthesis of 2-fluoro-3-[(2-oxo-1,3-oxazolidin-3-yl)methyl]benzonitrile (A121): To a stirred solution of 1,3-oxazolidin-2-one (3.16 g, 36.3 mmol) in THF (60 mL) was added sodium hydride (60% dispersion in mineral oil) (1.52 g, 38.1 mmol) portion wise at 0 °C and stirred at 0 °C for 15 min. To this was then added a solution of 3-(bromomethyl)- 2-fluorobenzonitrile (A120) (3.7 g, 17.3 mmol, in 30 mL THF) dropwise. The reaction mixture was then allowed to stir at room temperature and the reaction progress was monitored by TLC / LCMS analysis. After completion of the reaction (1 h), the reaction mixture was quenched with addition of ice-cold water (20 ml) at 0 °C and extraction was carried out using EtOAc (3 x 70 mL). The combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford desired compound A121 (2.50 g) as a white solid, which is carried forward without any purification. LCMS (ES) m / z: 221.2 [M+H]+. [000340] Step-3: Synthesis of ({2-fluoro-3-[(2-oxo-1,3-oxazolidin-3- yl)methyl]phenyl}methyl)amine (I-48): Intermediate I-48 (2.2 g) was synthesized by following procedure as described for the synthesis of I-46 (step-4) using 2-fluoro-3-[(2-oxo- 1,3-oxazolidin-3-yl)methyl]benzonitrile (A121) (2.5 g, 11.4 mmol) as the starting material. LCMS (ES) m / z: 225.1 [M+H]+. Intermediate 49: Preparation of 1-(3-(aminomethyl)-2-fluorobenzyl)imidazolidin-2-one (I-49)[000341] Step-1: Synthesis of 2-fluoro-3-[(2-oxo-1-imidazolidinyl)methyl]benzonitrile (A122): Compound A122 (1.0 g) was synthesized by following procedure as described for the synthesis of I-48 (step-2) using 2-imidazolidinone (4.83 g, 56.1 mmol) and 3-(bromomethyl)-2-fluorobenzonitrile (A120) (3 g, 14 mmol) as the starting materials. LCMS (ES) m / z: 220.3 [M+H]+. [000342] Step-2: Synthesis of ({2-fluoro-3-[(2-oxo-1- imidazolidinyl)methyl]phenyl}methyl)amine (I-49): Intermediate I-49 (0.83 g) was synthesized by following procedure as described for the synthesis of I-46 (step-4) using 2- fluoro-3-[(2-oxo-1-imidazolidinyl)methyl]benzonitrile (A122) (1 g, 4.56 mmol) as the starting material. LCMS (ES) m / z: 224.1 [M+H]+. Intermediate 50: Preparation of 4-(3-(aminomethyl)-2-fluorobenzyl)morpholin-3-one (I- 50)[000343] Step-1: Synthesis of 2-fluoro-3-[(3-oxo-4-morpholinyl)methyl]benzonitrile (A123): Compound A123 (9.5 g) was synthesized by following procedure as described for the synthesis of I-48 (step-2) using 3-(bromomethyl)-2-fluorobenzonitrile (A120) (11 g, 51.4 mmol) and 3-morpholinone (10.9 g, 108 mmol) as the starting materials. LCMS (ES) m / z: 235.3 [M+H]+. [000344] Step-2: Synthesis of 4-{[3-(aminomethyl)-2-fluorophenyl]methyl}-3- morpholinone (I-50): Intermediate I-50 (3.5 g) was synthesized by following procedure as described for the synthesis of I-46 (step-4) using 2-fluoro-3-[(2-oxo-1,3-oxazolidin-3- yl)methyl]benzonitrile (A123) (8.5 g, 36.3 mmol) as the starting material. LCMS (ES) m / z: 239.2 [M+H]+. Intermediate 51: Preparation of 2-hydroxy-4-(pyridin-3-yloxy)benzaldehyde (I-51)[000345] Step-1: Synthesis of 2-hydroxy-4-(pyridin-3-yloxy)benzaldehyde (I-51): To a stirred solution of 4-bromo-2-hydroxybenzaldehyde (A16) (1 g, 4.97 mmol) in NMP (10 mL)was added Cs2CO3(3.24 g, 9.95 mmol), pyridin-3-ol (946 mg, 9.95 mmol), CuCl (246 mg, 2.49 mmol) and 2,2,6,6-tetramethylheptane-3,5-dione (229 mg, 1.24 mmol) at room temperature. The reaction mixture was stirred at 110 °C for 16 h. After completion of starting material, the reaction mixture was cooled to room temperature and then ice cold water (30 mL) was added to it. Extraction was carried out using EtOAc (30 mL x 3); the combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% of EtOAc in heptane) to afford desired compound I-51 (0.2 g) as a pale yellow solid. LCMS (ES) m / z: 216.1 [M+H]+. Intermediate 52: Preparation of 4-formyl-3-hydroxy-N,N-dimethylbenzamide (I-52)[000346] Step-1: Synthesis of 4-formyl-3-hydroxy-N-(propan-2-yl)benzamide (I-52): To a stirred solution of 4-formyl-3-hydroxybenzoic acid (A124) (1 g, 6.02 mmol) and dimethylamine (0.271 g, 6.02 mmol) in THF (10 mL) was added DIPEA (3.1 mL, 18 mmol) and a 50% solution of T3P in EtOAc (7.66 mL, 12 mmol). The reaction mixture was stirred at 60 °C in a sealed tube for 12 h. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with addition of ice water (20 mL). Extraction was carried out using EtOAc (30 mL x 3); the combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-5% of MeOH in DCM) to afford desired compound I-52 (0.8 g) as a colorless semi-solid.1H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H); 10.29 (s, 1H); 7.68 (d, J = 8.0 Hz, 1H); 6.95- 6.77 (m, 2H); 2.97 (s, 3H); 2.87 (s, 3H).Intermediate 53: Preparation of 1-(2,4-bis(benzyloxy)-5-fluorophenyl)ethan-1-amine (I- 53)[000347] Step-1: Synthesis of 1-(2,4-bis(benzyloxy)-5-fluorophenyl)ethan-1-one (A125): To a stirred solution of 1-(5-fluoro-2,4-dihydroxyphenyl)ethan-1-one (A60) (15 g, 88.2 mmol) in acetone (150 mL) was added K2CO3(36.6 g, 264 mmol), KI (29.3 g, 176 mmol) and benzyl bromide (26.2 mL, 220 mmol) at room temperature. The reaction mixture was stirred at 70 °C and the reaction progress was monitored by TLC / LCMS analysis. After completion of the reaction (2 h), the reaction mixture was cooled to room temperature and then water (100 mL) was added to it. Extraction was carried out using EtOAc (50 mL x 3); the combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford desired compound A125 (20 g) as an off-white solid. LCMS (ES) m / z: 351.2 [M+H]+. [000348] Step 2: Synthesis of 1-(2,4-bis(benzyloxy)-5-fluorophenyl)ethan-1-amine (I-53): To a stirred suspension of 1-[2,4-bis(benzyloxy)-5-fluorophenyl]-1-ethanone (A125) (15 g, 42.8 mmol) in DCM (50 mL) was added a solution of ammonia in MeOH (6 mL) and titanium (IV) isopropoxide (24.3 g, 85.6 mmol). The reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was then cooled to 0 °C and NaBH4(2.43 g, 64.2 mmol) was added to it. The reaction was slowly brought to room temperature and the reaction progress was monitored by TLC / LCMS analysis. After completion of the reaction (1 h), the reaction mixture was concentrated under reduced pressure and quenched with addition of water (50 mL). Extraction was carried out using EtOAc (50 mL x 3); the combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford desired compound I-53 (10 g) as an off-white solid. LCMS (ES) m / z: 352.1 [M+H]+. Intermediate-55: Preparation of 4-(1-aminocyclobutyl)-5-fluorobenzene-1,3-diol (I-55)[000349] Step-1: Synthesis of 1-(2-fluoro-4,6-bis(methoxymethoxy)phenyl)cyclobutan-1-ol (127): Compound A127 (6.2 g) was synthesized by following procedure as described for the synthesis of I-30 (step-1) using A33 (10 g, 33.8 mmol) and cyclobutanone (7.13 g, 102 mmol) as starting materials. LCMS (ES) m / z: 269.1 [(M-OH)+H]+. [000350] Step-2: Synthesis of 2-(1-azidocyclobutyl)-1-fluoro-3,5- bis(methoxymethoxy)benzene (A128): Compound A128 (6.5 g) was synthesized by following procedure as described for the synthesis of I-30 (step-2) using 1-(2-fluoro-4,6- bis(methoxymethoxy)phenyl)cyclobutan-1-ol (A127) (9.0 g, 31.4 mmol) as starting material. LCMS (ES) m / z: 269.1 [(M-N3)+H]+. [000351] Step-3: Synthesis of 1-(2-fluoro-4,6-bis(methoxymethoxy)phenyl)cyclobutan-1- amine (129): Compound A129 (5.2 g) was synthesized by following procedure as described for the synthesis of I-30 (step-3) using 2-(1-azidocyclobutyl)-1-fluoro-3,5- bis(methoxymethoxy)benzene (A128) (6.5 g) as starting material. LCMS (ES) m / z: 269.1 [(M-NH2)+H]+. [000352] Step-4: Synthesis of 4-(1-aminocyclobutyl)-5-fluorobenzene-1,3-diol (I-55): Intermediate (I-55) (4.0 g) was synthesized by following procedure as described for the synthesis of I-39 (step-1) using 1-(2-fluoro-4,6-bis(methoxymethoxy)phenyl)cyclobutan-1- amine (A129) (5.2 g, 18.2 mmol) as starting material. LCMS (ES) m / z: 181.1 [(M-NH2)+H]+. Intermediate-56: Preparation of 4-(1-aminocyclobutyl)-2-fluorobenzene-1,3-diol (I-56)[000353] Step-1: Synthesis of 2-fluoro-1,3-bis(methoxymethoxy)benzene (A131): Compound A131 (31 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using 2-fluorobenzene-1,3-diol (A130) (20 g, 156 mmol) as starting material.1H NMR (400 MHz, DMSO): δ 7.04-7.0 (m, 1H); 6.89 (t, J = 7.6 Hz, 2H); 5.22 (s, 4H); 3.43 (s, 6H). [000354] Step-2: Synthesis of 1-bromo-3-fluoro-2,4-bis(methoxymethoxy)benzene (A132): Compound A132 (25 g) was synthesized by following procedure as described for the synthesis of I-26 (step-2) using 2-fluoro-1,3-bis(methoxymethoxy)benzene (A131) (31 g, 143.5 mmol) as starting material.1H NMR (400 MHz, DMSO): δ 7.40 (d, J = 2.4 Hz, 1H); 7.03 (d, J = 2.0 Hz, 1H); 5.25 (s, 2H); 5.15 (s, 2H); 3.79 (s, 3H); 3.29 (s, 3H). [000355] Step-3: Synthesis of 1-(3-fluoro-2,4-bis(methoxymethoxy)phenyl)cyclobutan-1-ol (133): Compound A133 (15 g) was synthesized by following procedure as described for the synthesis of I-30 (step-1) using 1-bromo-3-fluoro-2,4-bis(methoxymethoxy)benzene (A132) (25 g, 85.3 mmol) as starting material.1H NMR (400 MHz, DMSO): δ 7.02-6.93 (m, 2H); 5.29 (s, 1H); 5.21-5.13 (m, 4H); 3.50 (s, 3H); 3.40 (s, 3H); 2.26-2.12 (m, 2H); 2.03-1.89 (m, 4H). [000356] Step-4: Synthesis of 1-(1-azidocyclobutyl)-3-fluoro-2,4- bis(methoxymethoxy)benzene (A134): Compound A134 (10 g) was synthesized by following procedure as described for the synthesis of I-30 (step-2) using 1-(3-fluoro-2,4- bis(methoxymethoxy)phenyl)cyclobutan-1-ol (A133) (15 g, 52.4 mmol) as starting material.1H NMR (400 MHz, CDCl3): δ 6.86-6.77 (m, 2H); 5.15-5.13 (m, 4H); 3.56 (s, 3H); 3.50 (s, 3H); 2.64-2.45 (m, 2H); 2.44-2.39 (m, 2H); 2.23-2.11 (m, 1H); 1.80-1.73 (m, 1H). [000357] Step-5: Synthesis of 1-(3-fluoro-2,4-bis(methoxymethoxy)phenyl)cyclobutan-1- amine (A135): Intermediate A135 (7 g) was synthesized by following procedure as described for the synthesis of I-30 (step-3) using 1-(1-azidocyclobutyl)-3-fluoro-2,4-bis(methoxymethoxy)benzene (A134) (10 g, 32.1 mmol) as the starting material.1H NMR (400 MHz, DMSO): δ 6.92-6.87 (m, 2H); 5.20-5.17 (m, 4H); 3.51 (s, 2H); 3.40 (s, 6H); 2.49- 2.37 (m, 2H); 2.10-2.06 (m, 2H); 1.91-1.90 (m, 2H). [000358] Step-6: Synthesis of 4-(1-aminocyclobutyl)-2-fluorobenzene-1,3-diol (I-56): Intermediate I-56 (4.5 g) was synthesized by following procedure as described for the synthesis of I-39 (step-1) using 1-(3-fluoro-2,4-bis(methoxymethoxy)phenyl)cyclobutan-1- amine (A135) (7 g, 24.5 mmol) as starting material.1H NMR (400 MHz, DMSO): δ 10.13 (s, 1H); 9.97 (s, 1H); 8.17 (s, 2H); 6.80 (d, J= 8.8 Hz, 1H); 6.42-6.38 (m, 1H); 2.51-2.42 (m, 2H); 2.11-2.00 (m, 2H); 1.68-1.60 (m, 2H). Intermediate-57: Preparation of 2-(dimethylaminosulfonylamino)-3- fluoroisonicotinaldehyde (I-57)[000359] Step-1: Synthesis of 4-{[(tert-butyl)bis(methyl)siloxy]methyl}-2- (dimethylaminosulfonylamino)-3-fluoropyridine (A136): Compound A136 (4.2 g) was synthesized by following procedure as described for the synthesis of I-35 (step-3) using (tert- butyl)[(2-chloro-3-fluoro-4-pyridyl)methoxy]bis(methyl)silane (A94) (10 g, 36.3 mmol) and N,N-dimethylaminosulfonylamine (18 g, 145 mmol) as starting materials. LCMS (ES) m / z: 364.1 [M+1]+. [000360] Step-2: Synthesis of [2-(dimethylaminosulfonylamino)-3-fluoro-4- pyridyl]methanol (A137): Compound A137 (3.7 g, crude) was synthesized by following procedure as described for the synthesis of I-35 (step-4) using 4-{[(tert- butyl)bis(methyl)siloxy]methyl}-2-(dimethylaminosulfonylamino)-3-fluoropyridine (A136) (4.2 g, 11.6 mmol) as starting material. LCMS (ES) m / z: 250.1 [M+H]+. [000361] Step-3: Synthesis of 2-(dimethylaminosulfonylamino)-3-fluoroisonicotinaldehyde (I-57): Intermediate I-57 (0.95 g) was synthesized by following procedure as described for the synthesis of I-35 (step-5) using [2-(dimethylaminosulfonylamino)-3-fluoro-4- pyridyl]methanol (A137) as starting material (3.1 g, 12.4 mmol). LCMS (ES) m / z: 248.1 [M+1]+.Intermediate-58: Preparation of 1-(2,4-bis(benzyloxy)-5-fluorophenyl)ethan-1-amine (I- 58)[000362] Step-1: Synthesis of 1-(2,4-bis(benzyloxy)-5-fluorophenyl)ethan-1-amine (A136): Compound A138 (27 g) was synthesized by following procedure as described for the synthesis of I-26 (step-1) using 1-(5-fluoro-2,4-dihydroxyphenyl)ethan-1-one (A60) (20 g, 118 mmol) as starting material. LCMS (ESI) m / z: 351.10 [M+H]+. [000363] Step-2: Synthesis of 1-(2,4-bis(benzyloxy)-5-fluorophenyl)ethan-1-amine (I-58): To a stirred solution of 1-(2,4-bis(benzyloxy)-5-fluorophenyl)ethan-1-one (A138) (13.0 g, 37.1 mmol) in DCM (100 mL) was added a 7N solution of ammonia in MeOH (8 mL) followed by titanium (IV) isopropoxide (22.5 mL, 74.2 mmol). The reaction mixture was allowed to stir at room temperature for 16 h. Then, the reaction mixture was cooled to 0 °C and NaBH4(2.11 g, 55.7 mmol) was added to it. The reaction mixture was stirred for 1 h at room temperature. The reaction progress was monitored by TLC / LCMS. After completion of the reaction (1 h), the reaction mixture was quenched with addition of ice water (30 mL) and extraction was carried out using EtOAc (3 x 30 mL). The combined organic extracts were washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% of MeOH in DCM) to afford the desired intermediate I-58 (8.0 g) as a brown oil. LCMS (ESI) m / z: 335.15 [M-NH2]+. Intermediate-59: Preparation of 1-(3,5-bis(benzyloxy)pyridin-2-yl)ethan-1-amine (I-59)[000364] Step-1: Synthesis of 3,5-bis(benzyloxy)picolinonitrile (A140): To a stirred solution of benzyl alcohol (74.2 mL, 714 mmol) in DMF (0.5 L, 6.46 mol) was added sodium hydride (60% in mineral oil, 17.1 g, 714 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 1 h. It was then cooled to 0 °C and 3,5-difluoro-2- pyridinecarbonitrile (A139) (50 g, 357 mmol) was added to it. After stirring at room temperature for 16 h, the reaction was quenched with addition of water (400 mL). The precipitate obtained was collected by vacuum filtration to afford the desired compound A140 (45.0 g) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 8.13 (d, J = 2 Hz, 1H); 7.56 (d, J = 2 Hz, 1H); 7.48-7.30 (m, 10H); 5.35 (s, 2H); 5.30 (s, 2H). [000365] Step-2: Synthesis of 1-(3,5-bis(benzyloxy)pyridin-2-yl)ethan-1-one (A141): To a stirred solution of 3,5-bis(benzyloxy)picolinonitrile (A140) (22.0 g, 69.5 mmol) in anhydrous THF (161 mL) was added a solution of MeMgBr (3.0 M in diethyl ether, 46.4 mL, 139 mmol) dropwise at -30 °C. The reaction mixture was then stirred at room temperature for 2 h under nitrogen atmosphere. The reaction progress was monitored by TLC. After complete consumption of starting material (2 h), the reaction mixture was quenched with addition of 2N HCl and then diluted with water (10 mL). Extraction was carried out using EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% EtOAc in heptane) to afford the desired compound (A141) (15.0 g) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 8.04 (d, J = 2.4 Hz, 1H); 7.45 (m, 2H), 7.40-7.30 (m, 8H); 6.90 (d, J = 2.0 Hz, 1H); 5.19 (s, 2H), 5.12 (s, 2H); 2.64 (s, 3H). [000366] Step-3: Synthesis of N-(1-(3,5-bis(benzyloxy)pyridin-2-yl)ethyl)-2- methylpropane-2-sulfinamide (A142): To a stirred solution of 1-(3,5-bis(benzyloxy)pyridin-2-yl)ethan-1-one (A141) (15 g, 45 mmol) in THF (0.3 L, 3.69 mol) was added 2- methylpropane-2-sulfinamide (5.45 g, 45 mmol) and Ti(OiPr)4(20 mL, 67.5 mmol) at room temperature. The reaction mixture was allowed to stir at 65 °C for 16 h. The reaction progress was monitored by TLC. After complete consumption of starting material, the reaction mixture was cooled to 0 °C and sodium borohydride (1.7 g, 45 mmol) was added portion wise. The reaction mixture was stirred at room temperature, while monitoring reaction by TLC. After complete consumption of starting material, the reaction mixture was quenched with water (50 mL) and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-35% of EtOAc in heptane) to afford the desired compound A142 (5.2 g). LCMS (ES) m / z: 439.20 [M+1]+. [000367] Step-4: Synthesis of 1-(3,5-bis(benzyloxy)pyridin-2-yl)ethan-1-amine (I-59): To a stirred solution of N-(1-(3,5-bis(benzyloxy)pyridin-2-yl)ethyl)-2-methylpropane-2- sulfinamide (A142) (5.2 g, 11.9 mmol) in MeOH (52 mL) was added a 4 M solution of HCl in 1,4- dioxane (7.4 mL, 29.6 mmol) at 0 °C and stirred at the same temperature for 1 h. Reaction was monitored by TLC and LCMS. After completion of the reaction, volatiles were removed under reduced pressure and saturated NaHCO3solution (30 mL) was added to the residue. Extraction was carried out using EtOAc (50 mL x 3), the combined organic extracts were washed with brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired compound (I-59) (3.0 g) as light brown semi solid. LCMS (ES) m / z: 335.30 [M+H]+. Intermediate-60: Preparation of tert-butyl (3-(bromomethyl)-2-fluorophenyl)carbamate (I-60)[000368] Step-1: Synthesis of methyl 3-((tert-butoxycarbonyl)amino)-2-fluorobenzoate (A144): Argon gas was purged through a stirred suspension of methyl 3-bromo-2- fluorobenzoate (A143) (50 g, 215 mmol), caesium carbonate (83.9 g, 257 mmol) and tert- butyl carbamate (30.2 g, 257 mmol) in toluene (0.5 L) for 10 min, before addition of Xantphos (7.45 g, 12.9 mmol) and Pd2(dba)3(4.91 g, 5.36 mmol). The reaction mixture was allowed to stir at 100 °C for 6 h. The reaction progress was monitored by TLC / LCMS. Aftercompletion of the reaction (6 h), the reaction mixture was cooled to room temperature and water (100 mL) was added to it. Extraction was carried out using EtOAc (3 x 3000 mL), the combined organic extracts were washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by Combi- Flash (using gradient elution of 0-40% EtOAc in heptane) to afford the desired compound A144 (42.0 g) as a yellow solid. LCMS (ES) m / z: 268.15 [M-H]+. [000369] Step-2: Synthesis of tert-butyl (2-fluoro-3-(hydroxymethyl)phenyl)carbamate (A145): To a stirred solution of methyl 3-((tert-butoxycarbonyl)amino)-2-fluorobenzoate (A144) (42 g, 156 mmol) in anhydrous THF (420 mL) was added a 2 M solution of LAH in THF (156 mL, 312 mmol) slowly at 0 °C. Then the reaction mixture was stirred at room temperature for 2 h, while monitoring reaction progress by TLC / LCMS. After completion, the reaction mixture was quenched with addition of saturated NH4Cl solution (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered and evaporated the solvent under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford desired compound A145 (32.0 g) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.89 (brs, 1H); 7.48-7.44 (m, 1H); 7.17-7.06 (m, 2H); 5.25 (t, J = 5.6 Hz, 1H); 4.52 (d, J = 5.6 Hz, 3H); 1.45 (s, 9H). [000370] Step-3: Synthesis of tert-butyl (3-(bromomethyl)-2-fluorophenyl)carbamate (I- 60): To a stirred solution of tert-butyl (2-fluoro-3-(hydroxymethyl)phenyl)carbamate (A145) (32.0 g, 133 mmol) in DCM (380 mL) was added PPh3(52.2 g, 199 mmol) and CBr4(66 g, 199 mmol) at 0 °C. The reaction mixture was then allowed to stir at room temperature for 2 h, while monitoring reaction progress by TLC / LCMS. After completion of the reaction, ice water (100 mL) was added to it and extracted with DCM (2 x 500 mL). The combined organic extracts were washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% of EtOAc in heptane) to afford the desired compound I-60 (15.0 g) as a white solid. LCMS (ES) m / z: 302.10 [M-H]+.1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H); 7.69 (t, J = 7.6 Hz, 1H); 7.31-7.27 (m, 1H); 7.107.69 (t, J = 8.0 Hz, 1H); 4.68 (s, 2H); 1.45 (s, 9H). Intermediate-61: Preparation of tert-butyl (tert-butoxycarbonyl)(2,5-difluoro-3- formylphenyl)carbamate (I-61)[000371] Step-1: Synthesis of 3-bromo-2,5-difluoroaniline (A147): To a stirred solution of 1-bromo-2,5-difluoro-3-nitrobenzene (A146) (15.0 g, 63 mmol) in EtOH (60 mL) was added iron (16.5 g, 295 mmol) and an aqueous solution of ammonium chloride (22.5 g, 421 mmol, in 20 mL water); and reaction mixture was stirred at 80 °C for 1 h. After complete consumption of starting material (1 h), the reaction mixture was cooled to room temperature and water (20 mL) was added to it. Extraction was carried out using EtOAc (2 x 30 mL); the combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford desired compound A147 (11.0 g) as a brown sticky liquid.1H NMR (400 MHz, DMSO-d6): δ 6.64-6.60 (m, 1H); 6.56-6.51 (m, 1H); 5.79 (s, 2H). [000372] Step-2: Synthesis of tert-butyl (3-bromo-2,5-difluorophenyl) (tert- butoxycarbonyl)carbamate (A148): To a stirred solution of 3-bromo-2,5-difluoroaniline (A147) (10 g, 48.1 mmol) in THF (100 mL) was added DMAP (0.587 g, 4.81 mmol) and (Boc)2O (33.1 mL, 144 mmol) at 0 °C; and then the reaction mixture was allowed to stir at 60 °C for 4 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and water (40 mL) was added to it. Extraction was carries out using EtOAc (2 x 45 mL); the combined organic extracts were washed with brine solution (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-20% of EtOAc in heptane) to afford desired compound A148 (16.0 g) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 7.81-7.77 (m, 1H); 7.61-7.56 (m, 1H); 1.38 (s, 18H). [000373] Step-3: Synthesis of tert-butyl (tert-butoxycarbonyl)(2,5-difluoro-3- vinylphenyl)carbamate (A149): Argon gas was purged through a stirred solution of tert-butyl(3-bromo-2,5-difluorophenyl)(tert-butoxycarbonyl)carbamate (A148) (16.0 g, 39.2 mmol) and tributyl(vinyl)stannane (12.4 g, 39.2 mmol) in toluene (0.1 L) for 10 min before addition of PdCl2(PPh3)2(2.75 g, 3.92 mmol). The reaction mixture was stirred at 110 °C for 4 h, before it was cooled to room temperature. Water (40 mL) was then added to it and extraction was carried out using EtOAc (3 x 40 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% of MeOH in DCM) to afford desired compound A149 (12.5 g) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 7.60-7.56 (m, 1H); 7.38-7.34 (m, 1H); 6.81 (dd, J = 17.6, 11.2 Hz, 1H); 6.04 (d, J = 17.6 Hz, 1H); 5.53 (d, J = 11.2 Hz, 1H); 1.38 (s, 18H). [000374] Step-4: Synthesis of tert-butyl (tert-butoxycarbonyl)(2,5-difluoro-3- formylphenyl)carbamate (I-61): To a stirred solution of tert-butyl (tert-butoxycarbonyl)(2,5- difluoro-3-vinylphenyl)carbamate (A149) (5.0 g, 14.1 mmol) in tetrahydrofuran (40 mL) and water (20 mL) was added OsO4(1.79 g, 7.03 mmol) at 0 °C and the reaction mixture was allowed to stir at room temperature for 10 min. Then sodium periodate (7.52 g, 35.2 mmol) was added to it at the same temperature and the reaction mixture was stirred at room temperature while monitoring reaction progress. After completion of the reaction (2 h), water (20 mL) was added to it and extraction was carried out using EtOAc (2 x 35 mL). The combined organic extracts were washed with brine solution (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-flash (using gradient elution of 0-40% of EtOAc in n-heptane) to afford desired compound I-61 (3.0 g) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 10.17 (d, J = 2.0 Hz, 1H); 7.93-7.89 (m, 1H); 7.69-7.67 (m, 1H); 1.39 (s, 18H). Intermediate-62: Preparation of tert-butyl (tert-butoxycarbonyl)(2,4-difluoro-3- formylphenyl)carbamate (I-62)[000375] Step-1: Synthesis of tert-butyl (3-bromo-2,4-difluorophenyl)(tert- butoxycarbonyl)carbamate (A151): Compound A151 (16.8 g) was synthesized by following procedure as described for the synthesis of I-61 (step-2) using 3-bromo-2,4-difluoroaniline (A150) (10.0 g, 48.1 mmol) and di-tert-butyl dicarbonate (22.1 mL, 96.2 mmol) as startingmaterials.1H NMR (400 MHz, DMSO-d6): δ 7.52-7.59 (m, 1H); 7.34-7.42 (m, 1H); 1.40 (s, 9H); 1.48 (s, 9H). [000376] Step-2: Synthesis of tert-butyl (tert-butoxycarbonyl)(2,4-difluoro-3- vinylphenyl)carbamate (A152): Compound A152 (4.5 g) was synthesized by following procedure as described for the synthesis of I-61 (step-3) using tert-butyl (3-bromo-2,4- difluorophenyl)(tert-butoxycarbonyl)carbamate (A151) (10.0 g, 24.5 mmol) and tributyl(vinyl)stannane (7.16 mL, 24.5 mmol) as starting materials.1H NMR (400 MHz, DMSO-d6): δ 7.34-7.43 (m, 1H); 7.15-7.25 (m, 1H); 6.70 (dd, J = 18.0, 11.6 Hz, 1H); 6.0 (d, J = 18.0 Hz, 1H); 5.69-5.76 (m, 1H); 1.39 (s, 18H). [000377] Step-3: Synthesis of tert-butyl (tert-butoxycarbonyl)(2,4-difluoro-3- formylphenyl)carbamate (I-62): Intermediate I-62 (4.5 g) was synthesized by following procedure as described for the synthesis of I-61 (step-4) using tert-butyl (tert- butoxycarbonyl)(2,4-difluoro-3-vinylphenyl)carbamate (A152) (4.50 g, 12.7 mmol) as starting material.1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H); 7.85 (dt, J = 5.6, 2.8 Hz, 1H); 7.33 (t, J = 6.0 Hz, 1H); 1.39 (s, 18H). Intermediate-64: Preparation of 1-[3,5-bis(benzyloxy)-2-pyridyl]cyclopropylamine (I- 64)[000378] Step-1: Synthesis of 1-[3,5-bis(benzyloxy)-2-pyridyl]cyclopropylamine (I-64): To a stirred solution of 3,5-bis(benzyloxy)-2-pyridinecarbonitrile (A140) (10 g, 31.6 mmol) in anhydrous THF (100 mL) under Argon atmosphere was added Ti(OiPr)4(10.8 g, 37.9 mmol) at ambient temperature. After stirring the reaction mixture for 15 min, EtMgBr (1.0 M, in THF) (79 mL, 79 mmol) was added slowly via syringe at room temperature, (during addition of EtMgBr, reaction mass becomes black). The reaction mixture was stirred for 1 h, before addition of BF3.Et2O (45%) (24.9 g, 79 mmol) at 0 °C. The reaction mixture was then allowed to warm to room temperature over 1 h. It was then quenched with addition of water (200 mL) and the reaction mass was filtered through Celite. The filtrate was then made alkaline using 10% NaOH solution (pH = 9) and extraction was carried out using DCM (3 x 150 mL). The combined organic extracts were washed with brine solution (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product 1-[3,5-bis(benzyloxy)-2-pyridyl]cyclopropylamine (I-64) (11 g), which was used in the next step without further purification. LCMS (ES) m / z: 347.2 [M+H]+. Example 1: Preparation of 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-3,4- dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-01; Compound 156)[000379] Step-1: Synthesis of tert-butyl (2-fluoro-3-(((2-hydroxy-4-((4- methoxybenzyl)oxy) benzyl)amino)methyl)phenyl)carbamate (E-01a): To a stirred solution of 2-hydroxy-4-[(4-methoxyphenyl)methoxy]benzaldehyde (I-01) (1 g, 3.87 mmol) in MeOH (30 mL) was added tert-butyl (3-(aminomethyl)-2-fluorophenyl)carbamate (I-31) (930 mg, 3.87 mmol) and the reaction mixture was stirred at room temperature for 16 h. To this was then added NaBH4(293 mg, 7.74 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature over 2 h. After complete consumption of starting material, it was quenched with water (30 mL) and MeOH was then removed under reduced pressure. Extraction was carried out using EtOAc (2 x 50 mL); the combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-40% of EtOAc in heptane) to afford the desired compound E-01a (1.1 g) as an off-white solid. LCMS m / z found 483.3 [M+H]+. [000380] Step-2: Synthesis of tert-butyl (2-fluoro-3-((7-((4-methoxybenzyl)oxy)-2-oxo-2H- benzo[e][1,3]oxazin-3(4H)-yl)methyl)phenyl)carbamate (E-01b): To a stirred solution of tert- butyl N-(2-fluoro-3-{[({2-hydroxy-4-[(4-methoxyphenyl) methoxy]phenyl}methyl)amino]methyl}phenyl) carbamate (E-01a) (550 mg, 1.14 mmol) inDCM (12 mL) was added CDI (370 mg, 2.28 mmol) at room temperature and the reaction mixture was stirred at room temperature for 16 h. Volatiles were then evaporated under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0- 5% of MeOH in DCM) to afford the desired compound E-01b (450 mg) as a pale yellow thick oil. LCMS (ES) m / z: 453.1 [(M-tBu)+H]+. [000381] Step-3: Synthesis of tert-butyl (2-fluoro-3-((7-hydroxy-2-oxo-2H- benzo[e][1,3]oxazin-3(4H)-yl)methyl)phenyl)carbamate (E-01c): To a stirred solution of tert- butyl N-[2-fluoro-3-({7-[(4-methoxyphenyl)methoxy]-2-oxo-3,4-dihydro-2H-1,3- benzoxazin-3-yl}methyl)phenyl] carbamate (E-01b) (450 mg, 885 µmol) in MeOH (10 mL) was added 10% Pd / C (150 mg, 1.41 mmol) and the reaction mixture was stirred under hydrogen atmosphere. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (2 h), the catalyst was filtered off through a celite pad and washed with MeOH (5 mL x 2). MeOH was then evaporated under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-70% of EtOAc in heptane) to afford the desired compound E-01c (310 mg) as an off-white solid. LCMS (ES) m / z: 387.1 [M-H]+. [000382] Step-4: Synthesis of 3-(3-((tert-butoxycarbonyl)amino)-2-fluorobenzyl)-2-oxo- 3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-01d): To a stirred solution of tert-butyl N-{2-fluoro-3-[(7-hydroxy-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3- yl)methyl]phenyl}carbamate (E-01c) (1 g, 2.57 mmol) in acetonitrile (20 mL, 383 mmol) was added K2CO3(712 mg, 5.15 mmol) and N,N-dimethylcarbamoyl chloride (356 µL, 3.86 mmol) at 0 °C. The reaction mixture was then stirred at 80 °C. The reaction progress was monitored by TLC / LCMS analysis. After completion of the reaction (4 h), it was cooled to room temperature and water (30 mL) was added to it. Extraction was carried out using EtOAc (2 x 30 mL); the combined organic extracts were washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrate under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-80% of EtOAc in heptane) to afford desired compound E-01d (1 g) as an off-white solid. LCMS (ES) m / z: 404.1 [(M-tBu)+H]+. [000383] Step-5: Synthesis of 3-(3-amino-2-fluorobenzyl)-2-oxo-3,4-dihydro-2H- benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-01e): To a stirred solution of 3-[(3-{[(tert- butoxy)carbonyl]amino}-2-fluorophenyl)methyl]-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl N,N-dimethylcarbamate (E-01d) (1 g, 2.18 mmol) in 1,4-dioxane (5 mL) was added a 4 M solution of HCl in 1,4-dioxane (1 mL) at 0 °C . The reaction mixture was stirred at roomtemperature, while monitoring reaction progress by TLC. After complete consumption of starting material (2 h), volatiles were removed under reduced pressure and saturated NaHCO3solution (10 mL) was added to the residue. Extraction was carried out using EtOAc (20 mL x 3); the combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether (10 mL), filtered and dried to provide desired compound E-01e (750 mg) as an off-white solid. LCMS (ES) m / z: 360.1 [M+H]+. [000384] Step-6: Synthesis of 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo- 3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-01): To a stirred solution of 3-[(3-amino-2-fluorophenyl)methyl]-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl N,N- dimethylcarbamate (E-01e) (172 mg, 479 µmol) in DCM (5 mL) was added pyridine (193 µL, 2.39 mmol) and N-methylsulfamoyl chloride (82.6 µL, 957 µmol) at 0 °C. The reaction mixture was then allowed to warm to room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (6 h), water (15 mL) was added to it and extraction was carried out using EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated under the vacuum. The residue was purified by Combi-Flash (using gradient elution of 0-7% of MeOH in DCM) followed by reverse phase preparative HPLC [using XBridge C18 (19 mm x 250 mm, 5 μm) particle size column, 0.1% ammonia in water and acetonitrile as mobile phase with 19 mL / min flow rate] to afford desired compound E-01 (22 mg) as an off-white solid. LCMS (ES) m / z: 453.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H); 7.41-7.37 (m, 1H); 7.26-7.12 (m, 4H); 6.92-6.88 (m, 2H); 4.67 (s, 2H); 4.48 (s, 2H); 3.03 (s, 3H); 2.91 (s, 3H); 2.51 (d, J = 4.4 Hz, 3H).Example 2: Preparation of 8-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2- oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-02; Compound 131)[000385] Step-1: Synthesis of 3-fluoro-2-hydroxy-4-[(4- methoxyphenyl)methoxy]benzaldehyde (13): Compound 13 (0.5 g) was synthesized by following procedure as described for the synthesis of E-01 (step-1) using 2-fluoro-4,6- dihydroxybenzaldehyde (12) (0.7 g, 4.48 mmol) as the starting material. LCMS (ES) m / z: 275.0 [M-H]+. [000386] Step-2: Synthesis of N-(2-fluoro-3-{[({3-fluoro-2-hydroxy-4-[(4- methoxyphenyl)methoxy] phenyl}methyl)amino]methyl}phenyl)carbamate (14): Compound 14 (0.48 g) was synthesized by following procedure as described for the synthesis of E-01 (step-2) using 2-fluoro-6-hydroxy-4-[(4-methoxyphenyl)methoxy]benzaldehyde (13) (0.3 g, 1.09 mmol) and tert-butyl N-[3-(aminomethyl)-2-fluorophenyl]carbamate (3) (0.26 g, 1.09 mmol) as the starting materials. LCMS (ES) m / z: 501.2 [M+H]+.[000387] Step-3: Synthesis of tert-butyl N-[2-fluoro-3-({8-fluoro-7-[(4- methoxyphenyl)methoxy]-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3- yl}methyl)phenyl]carbamate (15): Compound 15 (0.26 g) was synthesized by following procedure as described for the synthesis of E-01 (step-3) using N-(2-fluoro-3-{[({3-fluoro-2- hydroxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]methyl}phenyl)carbamate (14) (0.25 g, 499 µmol) as the starting material. LCMS (ES) m / z: 471.1 [(M-tBu)+H]+. [000388] Step-4: Synthesis of tert-butyl N-{2-fluoro-3-[(8-fluoro-7-hydroxy-2-oxo-3,4- dihydro-2H-1,3-benzoxazin-3-yl) methyl] phenyl} carbamate (16): To a stirred solution of tert-butyl N-[2-fluoro-3-({8-fluoro-7-[(4-methoxyphenyl)methoxy]-2-oxo-3,4-dihydro-2H- 1,3-benzoxazin-3-yl}methyl)phenyl] carbamate (15) (0.3 g, 570 µmol) in MeOH (10 mL) was added 10% palladium on carbon (0.12 g, 1.14 mmol) and the reaction mixture was allowed to stir at room temperature under hydrogen atmosphere. The reaction progress was monitored by TLC / LCMS analysis. After completion of the reaction (2 h), the catalyst was filtered off through a Celite pad and washed with MeOH (5 mL x 2). The filtrate was evaporated under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-5% of MeOH in DCM) to afford desired compound 16 (0.23 g) as an off-white solid. LCMS (ES) m / z: 351.1 [(M-tBu)+H]+. [000389] Step-5: Synthesis of 3-[(3-{[(tert-butoxy) carbonyl] amino}-2-fluorophenyl) methyl]-8-fluoro-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl N,N-dimethyl carbamate (17): Compound 17 (0.22 g) was synthesized by following procedure as described for the synthesis of E-01 (step-8) using tert-butyl N-{2-fluoro-3-[(8-fluoro-7-hydroxy-2-oxo-3,4-dihydro-2H- 1,3-benzoxazin-3-yl)methyl]phenyl}carbamate (16) (0.23 g, 492 µmol) as the starting material. LCMS (ES) m / z: 422.1 [(M-tBu)+H]+. [000390] Step-6: Synthesis of 3-[(3-amino-2-fluorophenyl) methyl]-8-fluoro-2-oxo-3,4- dihydro-2H-1,3-benzoxazin-7-yl N,N-dimethyl carbamate (18): To a stirred solution of 3-[(3- {[(tert-butoxy)carbonyl]amino}-2-fluorophenyl)methyl]-8-fluoro-2-oxo-3,4-dihydro-2H-1,3- benzoxazin-7-yl N,N-dimethyl carbamate (17) (0.22 g, 461 µmol) in 1,4-dioxane (1 mL) was added 4 M solution of HCl in 1,4-dioxane (64 µL, 1.84 mmol) at 0 °C . The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (as indicated by TLC), volatiles were concentrated under reduced pressure and saturated sodium bicarbonate solution (20 mL) was added to the residue. Extraction was carried out using EtOAc (30 mL x 2); the combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated withdiethyl ether (3 x 10 mL) and dried to obtain the desired compound 18 (0.130 g) as an off- white solid. LCMS (ES) m / z: 378.1 [M+H]+. [000391] Step-7: Synthesis of 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo- 3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-02): E-02 (0.05 g) was synthesized by following procedure as described for the synthesis of E-01 (step-6) using 3- [(3-amino-2-fluorophenyl)methyl]-8-fluoro-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl N,N- dimethyl carbamate (18) (0.13 g, 345 µmol) as the starting material. Reverse phase preparative HPLC purification method: XSelect C18 (20 mm x 250 mm, 5 μm particle size) column, 0.1% ammonia in water and acetonitrile as mobile phase with 18 mL / min flow rate. LCMS (ES) m / z: 471.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H); 7.42-7.37 (m, 1H); 7.23-7.13 (m, 3H); 7.07-7.02 (m, 2H); 4.68 (s, 2H); 4.53 (s, 2H); 3.06 (s, 3H); 2.92 (s, 3H); 2.52 (d, J = 4.8 Hz, 3H). Example 3: Preparation of 5-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2- oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-03; Compound 118)[000392] E-03 was synthesized by following synthesis sequence and experimental procedures as described for the synthesis of E-01, using key intermediates I-06 and I-31. LCMS (ES) m / z: 471.1 [M+H]+.1H NMR (400 MHz, DMSO-d6):  δ 9.41 (s, 1H); 7.42-7.38 (m, 1H); 7.22-7.12 (m, 3H); 6.94 (dd, J1= 2.0 Hz, J2= 10.0 Hz, 1H); 6.80 (s, 1H); 4.69 (s, 2H); 4.49 (s, 2H); 3.02 (s, 3H); 2.90 (s, 3H); 2.51 (d, J = 4.4 Hz, 3H). Example 4: Preparation of 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-6-methyl- 2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-04; Compound 112)[000393] E-04 was synthesized by following synthesis sequence and procedures as described for the synthesis of E-01, using key intermediates I-08 and I-31. LCMS (ES) m / z: 467.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H); 7.40-7.36 (m, 1H); 7.22-7.18(m, 1H); 7.16-7.10 (m, 3H); 6.83 (s, 1H); 4.66 (s, 2H); 4.44 (s, 2H); 3.05 (s, 3H); 2.91 (s, 3H); 2.51 (d, J = 4.4 Hz, 3H); 2.06 (s, 3H). Example 5: Preparation of 3-(3-(cyclopropanesulfonamido)-2-fluorobenzyl)-2-oxo-3,4- dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-05; Compound 125)[000394] E-05 was synthesized by following synthesis sequence and procedures as described for the synthesis of E-01, using intermediate E-01e and cyclopropylsulfonylchloride as the starting materials. LCMS (ES) m / z: 464.1 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H); 7.39-7.35 (m, 1H); 7.23-7.13 (m, 3H); 6.19-6.87 (m, 2H); 4.68 (s, 2H); 4.47 (s, 2H); 3.02 (s, 3H); 2.90 (s, 3H); 2.67-2.59 (m, 1H); 0.92-0.85 (m, 4H). Example 6: Preparation of 3-(3-(cyclopropanesulfonamido)-2-fluorobenzyl)-5-fluoro-2- oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-06; Compound 102)[000395] E-06 was synthesized by following synthesis sequence and experimental procedures as described for the synthesis of E-01, using key intermediates I-06 and I-31. (Note: cyclopropylsulfonyl chloride was used in final step). LCMS (ES) m / z: 482.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H); 7.40-7.36 (m, 1H); 7.31-7.24 (m, 1H); 7.19- 7.15 (m, 1H); 7.00-6.92 (m, 1H); 6.81-6.80 (m, 1H); 4.71 (s, 2H); 4.49 (s, 2H); 3.16 (s, 3H); 2.90 (s, 3H); 2.68-2.60 (m, 1H); 0.94-0.84 (m, 4H). Example 7: Preparation of 3-(2-fluoro-3-((3-fluoropyrrolidine)-1-sulfonamido)benzyl)- 2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-07; Compound 113)[000396] E-07 was synthesized by following synthesis sequence and procedures as described for the synthesis of E-01, using E-01e and 3-fluoropyrrolidine-1-sulfonyl chloride as the starting materials. LCMS (ES) m / z: 511.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H); 7.41 (td, J1= 1.6 Hz, J2= 8.0 Hz, 1H); 7.23-7.13 (m, 3H); 6.92-6.88 (m, 2H); 5.32-5.16 (m, 1H); 4.66 (s, 2H); 4.45 (s, 2H); 3.42 (d, J = 2.0 Hz, 1H); 3.38-3.35 (m, 2H); 3.28-3.23 (m, 1H); 3.02 (s, 3H); 2.90 (s, 3H); 2.06-1.90 (m, 2H). Example 8: E-08: Preparation of 3-(2-fluoro-3-(morpholine-4-sulfonamido)benzyl)-2- oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-08; Compound 110)[000397] E-08 was synthesized by following synthesis sequence and procedures as described for the synthesis of E-01, using intermediate E-01e and morpholine-4-sulfonyl chloride as the starting materials. LCMS (ES) m / z: 509.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H); 7.41 (td, J1= 1.6 Hz, J2= 7.6 Hz, 1H); 7.23-7.15 (m, 3H); 6.91- 6.88 (m, 2H); 4.68 (s, 2H); 4.47 (s, 2H); 3.54-3.52 (m, 4H); 3.05-3.02 (m, 4H); 3.02 (s, 3H); 2.90 (s, 3H). Example 9: Preparation of 3-(2-fluoro-3-(2-oxa-6-azaspiro[3.3]heptane-6- sulfonamido)benzyl)-2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-09; Compound 109)[000398] E-09 was synthesized by following synthesis sequence and procedures as described for the synthesis of E-01, using intermediate E-01e and 2-oxa-6- azaspiro[3.3]heptane-6-sulfonyl chloride as the starting materials. LCMS (ES) m / z: 521.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.75 (br s, 1H); 7.40-7.35 (m, 1H); 7.23 (d, J = 8.4 Hz, 1H); 7.20-7.12 (m, 2H); 6.92-6.88 (m, 2H); 4.66 (s, 2H); 4.60 (s, 4H); 4.49 (s, 2H); 3.95 (s, 4H); 3.02 (s, 3H); 2.90 (s, 3H).Example 10: Preparation of 3-(2-fluoro-3-((3-methoxypyrrolidine)-1- sulfonamido)benzyl)-2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-10; Compound 100)[000399] E-10 was synthesized by following synthesis sequence and procedures as described for the synthesis of E-01, using intermediate E-01e and 3-methoxypyrrolidine-1- sulfonyl chloride as the starting materials. LCMS (ES) m / z: 523.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H); 7.43 (td, J1= 2.0 Hz, J2= 8.0 Hz, 1H); 7.24-7.13 (m, 3H); 6.92-6.88 (m, 2H); 4.67 (s, 2H); 4.47 (s, 2H); 3.86-3.84 (m, 1H); 3.33-3.14 (m, 4H); 3.12 (s, 3H); 3.03 (s, 3H); 2.91 (s, 3H); 1.84-1.78 (m, 2H). Example 11: Preparation of 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo- 3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl cyclopropanecarboxylate (E-11; Compound 147)[000400] E-11 was synthesized by following synthesis sequence and procedures as described for the synthesis of E-01, using key intermediate E-01c and cyclopropylcarbonyl chloride as the starting materials. LCMS (ES) m / z: 448.2 [M-H]+.1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H); 7.41-7.37 (m, 1H); 7.27 (d, J = 8.8 Hz, 1H); 7.22 (d, J = 4.8 Hz, 1H); 7.15 (t, J = 3.2 Hz, 2H); 6.93 (t, J = 6.8 Hz, 2H); 4.67 (s, 2H); 4.48 (s, 2H); 2.52 (d, J = 4.4 Hz, 3H); 1.92-1.86 (m, 1H); 1.09-1.01 (m, 4H). Example 12: Preparation of 3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-6- methyl-7-(pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-12; Compound 111)[000401] E-12 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-01, using key intermediates I-08 and I-31. LCMS (ES) m / z: 474.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H); 8.64 (d, J = 4.8 Hz 2H); 7.41-7.37 (m, 1H); 7.27 (t, J = 4.8 Hz, 1H); 7.24-7.22 (m, 1H); 7.18-7.13 (m, 3H); 6.93 (s, 1H); 4.87 (s, 2H); 4.47 (s, 2H); 2.52 (d, J = 4.4 Hz, 3H); 1.98 (s, 3H). Example 13: Preparation of 5-fluoro-3-({2-fluoro-3- [(methylsulfamoyl)amino]phenyl}methyl)-7-(pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3- benzoxazin-2-one (E-13; Compound 117)[000402] E-13 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-01, using key intermediates I-06 and I-31. LCMS (ES) m / z: 478.3 [M+H]+.1H NMR (400 MHz, DMSO-d6):  δ 9.39 (s, 1H); 8.67 (d, J = 4.8 Hz, 2H); 7.42-7.38 (m, 1H); 7.33-7.30 (m, 1H); 7.22-7.13 (m, 3H); 7.08-7.05 (m, 1H); 6.92 (s, 1H); 4.70 (s, 2H); 4.53 (s, 2H); 2.52 (d, J = 4.8 Hz, 3H). Example 14: Preparation of 3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-7- (1,3-oxazol-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-14; Compound 80)[000403] E-14 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-01, using intermediate E-01c and 2- (methylsulfonyl)oxazole as the starting materials. LCMS (ES) m / z: 449.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H); 7.83 (d, J = 0.8 Hz 1H); 7.41-7.39 (m, 1H); 7.38-7.31 (m, 1H); 7.21-7.16 (m, 5H); 7.12 (s, 1H); 4.67(s, 2H); 4.50 (s, 2H); 2.52 (d, J = 4.8 Hz, 3H). Example 15: Preparation of 3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-7- (pyridin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-15; Compound 65)[000404] E-15 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-01, using key intermediate E-01c and 2- bromopyridine as the starting materials. LCMS (ES) m / z: 459.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H); 8.15-8.14 (m, 1H); 7.89-7.84 (m, 1H); 7.41-7.31 (m, 1H); 7.27-7.25 (m, 1H); 7.20 (s, 1H); 7.16-7.13 (m, 3H); 7.07-7.05 (m, 1H); 6.91-6.89 (m, 2H); 4.67 (s, 2H); 4.49 (s, 2H); 2.52 (d, J = 4.8 Hz, 3H). Example 16: Preparation of N-(2-fluoro-3-((2-oxo-7-(pyridin-2-yloxy)-2H- benzo[e][1,3]oxazin-3(4H)-yl)methyl)phenyl)cyclopropanesulfonamide (E-16; Compound 62)[000405] E-16 was synthesized by following synthesis sequence and procedures as described for the synthesis of E-01, using key intermediate E-01c and 2-bromopyridine as the starting materials. (note: cyclopropylsulfonyl chloride was used in last step). LCMS (ES) m / z: 470.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H); 8.16-8.14 (m, 1H); 7.89- 7.85 (m, 1H); 7.41-7.37 (m, 1H); 7.27 (d, J = 8.0 Hz, 2H); 7.20-7.14 (m, 2H); 7.06 (d, J = 8 Hz, 1H); 6.92-6.89 (m, 2H); 4.70 (s, 2H); 4.50 (s, 2H); 2.68-2.62 (m, 1H); 0.95-0.85 (m, 4H). Example 17: Preparation of 3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-7- (pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-17; Compound 157)[000406] Step-1: Synthesis of tert-butyl (2-fluoro-3-(((2-hydroxy-4-(pyrimidin-2- yloxy)benzyl)amino)methyl)phenyl)carbamate (E-17a): Compound E-17a (0.3 g) was synthesized by following procedure as described for the synthesis of E-01 (step-1) using 2- hydroxy-4-(pyrimidin-2-yloxy)benzaldehyde (I-10) (0.4 g, 1.85 mmol) and I-31 (0.533 g, 2.22 mmol) as the starting materials. LCMS (ES) m / z: 441.2 [M+H]+.[000407] Step-2: Synthesis of tert-butyl (2-fluoro-3-((2-oxo-7-(pyrimidin-2-yloxy)-2H- benzo[e][1,3]oxazin-3(4H)-yl)methyl)phenyl)carbamate (E-17b): Compound E-17b (0.150 g) was synthesized by following procedure as described for the synthesis of E-01 (step-2) using tert-butyl (2-fluoro-3-(((2-hydroxy-4-(pyrimidin-2- yloxy)benzyl)amino)methyl)phenyl)carbamate (E-17a) (0.250 g) as the starting material. LCMS (ES) m / z: 467.3 [M+H]+. [000408] Step-3: Synthesis of 3-(3-amino-2-fluorobenzyl)-7-(pyrimidin-2-yloxy)-3,4- dihydro-2H-benzo[e][1,3]oxazin-2-one (E-17c): To a stirred solution of tert-butyl N-(2- fluoro-3-{[2-oxo-7-(pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-3- yl]methyl}phenyl)carbamate (E-17b) (250 mg, 536 µmol) in 1,4-dioxane (2 mL) was added a 4 M solution of HCl in 1,4-dioxane (2.5 mL) at 0 °C and the reaction mixture was allowed to stir at room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (2 h), volatiles were removed under reduced pressure and saturated NaHCO3solution (10 mL) was added to the residue. Extraction was carried out using DCM (3 x 50 mL); the combined organic extracts were washed with brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) to afford the desire compound E-17c (0.1 g) as an off-white solid. LCMS (ES) m / z: 367.2 [M+H]+. [000409] Step-4: Synthesis of 3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-7- (pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-17): Example E-17 (0.055 g) was synthesized by following procedure as described for the synthesis of E-01 (step-6) using 3-(3-amino-2-fluorobenzyl)-7-(pyrimidin-2-yloxy)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2- one (E-17c) (0.2 g, 546 µmol) as the starting material. LCMS (ES) m / z: 460.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H); 8.63 (d, J = 4.8 Hz, 2H); 7.42-7.10 (m, 6H); 7.00-6.92 (m, 2H); 4.66 (s, 2H); 4.49 (s, 2H); 2.50 (d, J = 4.8 Hz, 3H). Example 18: Preparation of 8-fluoro-3-{[2-fluoro-3- (methylaminosulfonylamino)phenyl] methyl}-7-(2-pyrimidinyloxy)-3,4-dihydro-2H-1,3- benzoxazin-2-one (E-18; Compound 123)[000410] E-18 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-17, using key intermediates I-11 and I-31. LCMS (ES) m / z: 478.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.40 (s, 1H); 8.65 (d, J = 4.4 Hz, 2H); 7.39-7.29 (m, 2H); 7.20-7.08 (m, 5H); 4.65 (s, 2H); 4.53 (s, 2H); 2.50 (d, J = 4.8 Hz, 3H). Example 19: Preparation of 3-{[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl}- 7-(3-pyridyloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-19; Compound 61)[000411] E-19 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-17, using key intermediates I-51 and I-31. LCMS (ES) m / z: 459.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H); 8.39 (d, J = 2.0 Hz, 2H); 7.48-7.37 (m, 3H); 7.27 (d, J = 2 Hz, 1H); 7.21-7.19 (m, 1H); 7.17-7.13 (m, 2H); 6.84-6.80 (m, 2H); 4.66 (s, 2H); 4.47 (s, 2H); 2.50 (d, J = 4.8 Hz, 3H). Example 20: Preparation of (cyclopropylsulfonyl)(2-fluoro-3-{[2-oxo-7-(3-pyridyloxy)- 3,4-dihydro-2H-1,3-benzoxazin-3-yl]methyl}phenyl)amine (E-20; Compound 60)[000412] E-20 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-17, using key intermediates I-51 and I-31. (note: cyclopropylsulfonyl chloride was used in the last step). LCMS (ES) m / z: 470.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H); 8.38-8.37 (m, 2H); 7.47-7.34 (m, 3H); 7.27-7.22 (m, 2H); 7.18-7.14 (m, 1H); 6.83-6.80 (m, 2H); 4.66 (s, 2H); 4.45 (s, 2H); 2.65-2.61 (m, 1H); 0.90-0.84 (m, 4H).Example 21: Preparation of 7-(3,3-dimethylureido)-3-{[2-fluoro-3- (methylaminosulfonylamino) phenyl]methyl}-3,4-dihydro-2H-1,3-benzoxazin-2-one (E- 21; Compound 136)[000413] E-21 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-17, using key intermediates I-17 and I-31. LCMS (ES) m / z: 452.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H); 8.40 (s, 1H); 7.41-7.36 (m, 1H); 7.27-7.21 (m, 3H); 7.16-7.10 (m, 2H); 7.06 (d, J = 8.4 Hz, 1H); 4.66 (s, 2H); 4.40 (s, 2H); 2.92 (s, 6H); 2.50 (d, J = 4.8 Hz, 3H). Example 22: Preparation of 3-{[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl}- 7-(1,3,3-trimethylureido)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-22; Compound 135)[000414] E-22 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-17, using key intermediates I-18 and I-31. LCMS (ES) m / z: 466.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H); 7.40-7.36 (m, 1H); 7.23-7.22 (m, 1H); 7.17-7.11 (m, 3H); 6.78 (dd, J1= 2.4 Hz, J2= 8.0 Hz, 1H); 6.73 (d, J = 2.4 Hz, 1H); 4.65 (s, 2H); 4.42 (s, 2H); 3.05 (s, 3H); 2.66 (s, 6H); 2.50 (d, J = 4.4 Hz, 3H). Example 23: Preparation of N,N-dimethyl-3-{[2-fluoro-3- (methylaminosulfonylamino)phenyl] methyl}-2-oxo-3,4-dihydro-2H-1,3-benzoxazine-7- carboxamide (E-23; Compound 121)[000415] E-23 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-17, using key intermediates I-52 and I-31.LCMS (ES) m / z: 437.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H); 7.41-7.37 (m, 1H); 7.29 (d, J = 8.0 Hz, 1H); 7.24 (q, J = 4.8 Hz, 1H); 7.17-7.12 (m, 3H); 7.08 (d, J = 1.2 Hz, 1H); 4.67 (s, 2H); 4.52 (s, 2H); 2.97 (s, 3H); 2.89 (s, 3H); 2.50 (d, J = 4.4 Hz, 3H). Example 24: Preparation of 3-{[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl}- 7-[(2-oxo-1-pyridyl)methyl]-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-24; Compound 137)[000416] E-24 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-17, using key intermediates I-14 and I-31. LCMS (ES) m / z: 473.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.40 (s, 1H); 7.80 (dd, J1= 1.6 Hz, J2= 6.8 Hz, 1H); 7.45-7.35 (m, 2H); 7.21-7.04 (m, 5H); 6.98 (s, 1H); 6.42 (d, J = 8.8 Hz, 1H); 6.26 (t, J = 6.8 Hz, 1H); 5.07 (s, 2H); 4.66 (s, 2H); 4.46 (s, 2H); 2.50 (d, J = 4.4 Hz, 3H). Example 25: Preparation of 3-{[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl}- 7-[(2-oxo-1-pyrrolidinyl)methyl]-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-25; Compound 124)[000417] E-25 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-17, using key intermediates I-15 and I-31. LCMS (ES) m / z: 463.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H); 7.40-7.30 (m, 1H); 7.20-7.05 (m, 4H); 6.96 (d, J = 8.0, 1H); 6.86 (s, 1H); 4.63 (s, 2H); 4.43 (s, 2H); 4.31 (s, 2H); 3.20 (t, J = 6.8, 2H); 2.50 (d, J = 4.4 Hz, 3H); 2.25 (t, J = 7.6, 2H); 1.89 (t, J = 7.2 Hz, 2H).Example 26: Preparation of 3-{[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl}- 7-(2-oxo-1-pyridyl)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-26; Compound 139)[000418] E-26 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-17, using key intermediates I-13 and I-31. LCMS (ES) m / z: 459.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H); 7.63 (d, J = 4.0 Hz, 1H); 7.53-7.49 (m, 1H); 7.42-7.36 (m, 2H); 7.23-7.15 (m, 5H); 6.48 (d, J = 8.0 Hz, 1H); 6.34-6.30 (m, 1H); 4.70 (s, 2H); 4.56 (s, 2H); 2.50 (d, J = 4.4 Hz, 3H). Example 27: Preparation of 3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-7- (pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-27; Compound 99)[000419] Step-1: Synthesis of tert-butyl (3-(((2,4-dihydroxybenzyl)amino)methyl)-2- fluorophenyl)carbamate (E-27a): Compound E-27a (5.1 g) was synthesized by following procedure as described for the synthesis of E-01 (step-1) using 2,4-dihydroxybenzaldehyde (1) (2.0 g, 14.5 mmol) and I-31 (3.83 g, 15.9 mmol) as the starting materials. LCMS (ES) m / z: 363.2 [M+H]+. [000420] Step-2: Synthesis of tert-butyl (2-fluoro-3-((7-hydroxy-2-oxo-2H- benzo[e][1,3]oxazin-3(4H)-yl)methyl)phenyl)carbamate (E-27b): Compound E-27b (3.0 g) was synthesized by following procedure as described for the synthesis of E-01 (step-2) usingtert-butyl (3-(((2,4-dihydroxybenzyl)amino)methyl)-2-fluorophenyl)carbamate (E-27a) (5.0 g, 13.8 mmol) as the starting materials. LCMS (ES) m / z: 333.1 [(M-tBu)+H]+. [000421] Step-3: Synthesis of tert-butyl (2-fluoro-3-((7-(2-(methylamino)-2-oxoethoxy)-2- oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)methyl)phenyl)carbamate (E-27c): To a stirred solution of tert-butyl N-{2-fluoro-3-[(7-hydroxy-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3- yl)methyl]phenyl}carbamate (E-27b) (250 mg, 644 µmol) in ACN (5 mL) was added K2CO3(222 mg, 1.61 mmol) and 2-chloro-N-methylacetamide (138 mg, 1.29 mmol) at room temperature. The reaction mixture was then stirred at 80 °C, while monitoring reaction progress by TLC. After complete consumption of starting material (1 h), the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using gradient eluent of 0-50% of EtOAc in heptane) to afford desired compound E-27c (0.2 g) as an off-white solid. LCMS (ES) m / z: 458.3 [M-H]+. [000422] Step-4: Synthesis of 2-((3-(3-amino-2-fluorobenzyl)-2-oxo-3,4-dihydro-2H- benzo[e][1,3]oxazin-7-yl)oxy)-N-methylacetamide (E-27d): Compound E-27d (0.2 g) was synthesized by following procedure as described for the synthesis of E-17 (step-3) using tert- butyl (2-fluoro-3-((7-(2-(methylamino)-2-oxoethoxy)-2-oxo-2H-benzo[e][1,3]oxazin-3(4H)- yl)methyl)phenyl)carbamate (E-27c) (0.230 g, 501 µmol) as the starting material. LCMS (ES) m / z: 360.1 [M+H]+. [000423] Step-5: Synthesis of 2-((3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2- oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl)oxy)-N-methylacetamide (E-27): Example E- 27 (0.060 g) was synthesized by following procedure as described for the synthesis of E-17 (step-4) using 2-({3-[(3-amino-2-fluorophenyl)methyl]-2-oxo-3,4-dihydro-2H-1,3- benzoxazin-7-yl}oxy)-N-methylacetamide (E-27d) (0.2 g, 0.557 mmol) as the starting material. LCMS (ES) m / z: 451.2 [M-H]+.;1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H); 8.04 (s, 1H); 7.40-7.36 (m, 1H); 7.23 (br s, 1H); 7.16-7.13 (m, 3H); 6.75 (dd, J = 8.4, 2.4 Hz, 1H); 6.66 (d, J = 2.4 Hz, 1H); 4.65 (s, 2H); 4.47 (s, 2H); 4.41 (s, 2H); 2.64 (d, J = 4.8 Hz, 3H); 2.50 (d, J = 4.4 Hz, 3H).Example 28: Preparation of 6-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)- 2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-28; Compound 120)[000424] E-28 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-27, using key intermediate I-31 and I-05. LCMS (ES) m / z: 471.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H); 7.42-7.36 (m, 1H); 7.29 (d, J = 10.0 Hz, 1H); 7.22-7.08 (m, 4H); 4.66 (s, 2H); 4.46 (s, 2H); 3.04 (s, 3H); 2.91 (s, 3H); 2.53 (d, J = 4.4 Hz, 3H). Example 29: Preparation of 6,8-difluoro-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-29; Compound 96)[000425] E-29 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-27, using key intermediates I-03 and I-31. LCMS (ES) m / z: 489.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H); 7.44-7.34 (m, 1H); 7.22-7.14 (m, 4H); 4.67 (s, 2H); 4.52 (s, 2H); 3.08 (s, 3H); 2.94 (s, 3H); 2.50 (d, J = 4.4 Hz, 3H). Example 30: Preparation of 8-fluoro-3-{[2-fluoro-3- (methylaminosulfonylamino)phenyl] methyl}-7-(1,3-oxazol-2-yloxy)-3,4-dihydro-2H-1,3- benzoxazin-2-one (E-30; Compound 91)[000426] E-30 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-27, using key intermediates 4 and I-31. LCMS (ES) m / z: 467.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H); 7.86 (d, J = 0.8 Hz 1H); 7.41-7.33 (m, 2H); 7.24-7.13 (m, 4H); 6.99 (s, 1H); 4.68 (s, 2H); 4.56 (s, 2H); 2.52 (d, J = 4.4 Hz, 3H). Example 31: Preparation of 6-fluoro-3-{[2-fluoro-3- (methylaminosulfonylamino)phenyl] methyl}-7-(2-pyrimidinyloxy)-3,4-dihydro-2H-1,3- benzoxazin-2-one (E-31; Compound 83)[000427] E-31 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-27, using key intermediates I-05 and I-31. LCMS (ES) m / z: 478.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H); 8.68-8.66 (m, 2H); 7.42-7.32 (m, 3H); 7.25 (d, J = 6.8 Hz, 1H); 7.20-7.10 (m, 3H); 4.68 (s, 2H); 4.53 (s, 2H); 2.52 (d, J = 4.4 Hz, 3H). Example 32: Preparation of 3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-7- (1,2,4-triazin-3-yloxy)-3,4-dihydro(4,4-²H₂)-2H-1,3-benzoxazin-2-one (E-32; Compound 31)[000428] E-32 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-27, using key intermediates I-16 and I-31 (note: NaBD4 was used as reducing agent in step-1 while reductive amination). LCMS (ES) m / z: 463.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H); 9.27 (s, 1H); 8.74 (d, J = 2.4 Hz, 1H); 7.43-7.37 (m, 1H); 7.34 (d, J = 8.4 Hz, 1H); 7.24-7.08 (m, 5H); 4.68 (s, 2H); 2.52 (d, J = 4.4 Hz, 3H).Example 33: Preparation of 8-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)- 2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-02; Compound 14)[000429] E-33 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-27, using key intermediate E-01c and 3- (methylsulfonyl)-1,2,4-triazine as the starting materials. LCMS (ES) m / z: 461.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H); 9.27 (d, J = 2.4 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H); 7.42-7.36 (m, 1H); 7.34 (d, J = 8.0 Hz 1H); 7.14-7.04 (m, 5H); 4.68 (s, 2H), 4.52 (s, 2H); 2.66 (d, J = 4.4 Hz, 3H). Example 34: Preparation of 3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-7- (pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-34; Compound 105)[000430] Step-1: Synthesis of tert-butyl (3-((7-((6-chloropyridazin-3-yl)oxy)-2-oxo-2H- benzo[e][1,3]oxazin-3(4H)-yl)methyl)-2-fluorophenyl)carbamate (E-34a): To a stirred solution of tert-butyl N-{2-fluoro-3-[(7-hydroxy-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3- yl)methyl]phenyl}carbamate (E-27b) (3 g, 7.72 mmol) in DMF (30 mL) was added K2CO3(2.14 g, 15.4 mmol) and 3,6-dichloropyridazine (2.3 g, 15.4 mmol). The reaction mixture was then stirred at 100 °C, while monitoring reaction progress by TLC. After complete consumption of starting material (4 h), the reaction mixture was cooled to room temperature and cold water (30 mL) was added to it. Extraction was carried out using EtOAc (3 x 50 mL);the combined organic extracts were washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-70% of EtOAc in heptane) to afford the desired compound E-34a (2.3 g) as a pale yellow solid. LCMS (ES) m / z: 445.2 [(M-tBu)+H]+. [000431] Step-2: Synthesis of tert-butyl (2-fluoro-3-((2-oxo-7-(pyridazin-3-yloxy)-2H- benzo[e][1,3]oxazin-3(4H)-yl)methyl)phenyl)carbamate (E-34b): To a stirred solution of tert- butyl N-[3-({7-[(6-chloropyridazin-3-yl)oxy]-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3- yl}methyl)-2-fluorophenyl]carbamate (E-34a) (1.5 g, 2.99 mmol) in 1,4-dioxane (20 mL) was added KOAc (882 mg, 8.98 mmol) and bis(pinacolato)diboron (836 mg, 3.29 mmol). Argon gas was then purged through it for 5 min before addition of Pd(dppf)Cl2.DCM (245 mg, 299 µmol). The reaction mixture was then stirred at 100 °C, while monitoring reaction progress by TLC. After complete consumption of starting material (3 h), the reaction mixture was cooled to room temperature, filtered through celite pad and washed with EtOAc (2 x 30 mL). The filtrate was washed with water (2 x 50 mL), brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-70% of EtOAc in heptane) to afford desired compound E-34b (0.8 g) as a pale yellow solid. LCMS (ES) m / z: 467.1 [M+H]+. [000432] Step-3: Synthesis of 3-(3-amino-2-fluorobenzyl)-7-(pyridazin-3-yloxy)-3,4- dihydro-2H-benzo[e][1,3]oxazin-2-one (E-34c): Compound E-34c (0.76 g) was synthesized by following procedure as described for the synthesis of E-17 (step-3) using tert-butyl (2- fluoro-3-((2-oxo-7-(pyridazin-3-yloxy)-2H-benzo[e][1,3]oxazin-3(4H)- yl)methyl)phenyl)carbamate (E-34b) (1.2 g, 2.57 mmol) as the starting material. LCMS (ES) m / z: 367.3 [M+H]+. [000433] Step-4: 3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-7-(pyridazin-3- yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-42): Example 34 (0.940 g) was synthesized by following procedure as described for the synthesis of E-17 (step-4) using 3-(3-amino-2- fluorobenzyl)-7-(pyridazin-3-yloxy)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one (E-34c) (1.0 g, 2.73 mmol) as the starting material. The final compound was purified by reverse phase preparative HPLC purification [using Sunfire-C18 (19 mm x 250 mm, 5 μm particle size) column, water and acetonitrile as mobile phase with 19.0 mL / min flow rate]. LCMS (ES) m / z: 460.1 [M+H]+.1H NMR (400 MHz, DMSO d6): δ 9.42 (s, 1H); 9.03 (d, J = 1.2 Hz, 1H); 7.82-7.76 (m, 1H); 7.49 (dd, J1= 1.2 Hz, J2= 8.8 Hz, 1H); 7.44-7.36 (m, 1H); 7.31 (d, J = 8.4Hz, 1H); 7.24-7.16 (m, 3H); 7.04-6.98 (m, 2H); 4.69 (s, 2H); 4.52 (s, 1H); 2.53 (d, J = 4.8 Hz, 3H). Example 35: Preparation of 3-{[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl}- 7-(3-pyridazinyloxy)(4,4-²H₂)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-35; Compound 52)[000434] E-35 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-34, using key intermediates I-16 and I-31. LCMS (ES) m / z: 462.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H); 9.03-9.01 (m, 1H); 7.80-7.76 (m, 1H); 7.48 (dd, J1= 0.8 Hz, J2= 8.8 Hz, 1H); 7.41-7.37 (m, 1H); 7.31 (d, J = 8.0 Hz, 1H); 7.22-7.12 (m, 3H); 7.02-6.99 (m, 2H); 4.68 (s, 2H); 2.53 (d, J = 4.8 Hz, 3H). Example 36: Preparation of 3-{[3-(dimethylaminosulfonylamino)-2- fluorophenyl]methyl}-7-(3-pyridazinyloxy)(4,4-²H₂)-3,4-dihydro-2H-1,3-benzoxazin-2- one (E-36; Compound 39)[000435] E-36 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-34, using key intermediates I-16 and I-31. (note: dimethylsulfamoyl chloride was used in the last step). LCMS (ES) m / z: 476.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H); 9.02 (dd, J1= 1.2 Hz, J2= 4.4 Hz, 1H); 7.80- 7.76 (m, 1H); 7.48 (dd, J1= 1.2 Hz, J2= 9.2 Hz, 1H); 7.42-7.38 (m, 1H); 7.31 (d, J = 8.0 Hz, 1H); 7.22-7.12 (m, 2H); 7.02-6.98 (m, 2H); 4.69 (s, 2H); 2.68 (s, 6H).Example 37: Preparation of 3-{[3-(dimethylaminosulfonylamino)-2- fluorophenyl]methyl}-7-(3-pyridazinyloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-37; Compound 37)[000436] E-37 was synthesized by following synthesis sequence and procedures as described for the synthesis of E-34, using intermediate E-34c and dimethylsulfamoyl chloride as the starting materials. LCMS (ES) m / z: 474.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H); 9.01 (d, J = 4.4 Hz, 1H); 7.79-7.76 (m, 1H); 7.48 (d, J = 9.6 Hz, 1H); 7.40 (t, J = 8.0 Hz, 1H); 7.31 (d, J = 8.0 Hz, 1H); 7.23-7.14 (m, 2H); 6.99 (s, 2H); 4.51 (s, 2H); 4.72 (s, 2H); 2.72 (s, 6H). Example 38: Preparation of N-methoxycarbonyl(2-fluoro-3-{[2-oxo-7-(3- pyridazinyloxy)-3,4-dihydro-2H-1,3-benzoxazin-3-yl]methyl}phenyl)amine (E-38; Compound 11)[000437] E-38 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-34, using key intermediates E-34c and methylchloroformate as the starting materials. LCMS (ES) m / z: 425.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H); 9.02 (dd, J1= 1.2 Hz, J2= 4.8 Hz, 1H); 7.80-7.76 (m, 1H); 7.65-7.60 (m, 1H); 7.48 (dd, J1= 1.2 Hz, J2= 7.6 Hz, 1H); 7.31 (d, J = 8.4, 1H); 7.18- 7.12 (m, 2H); 7.02-6.98 (m, 2H); 4.69 (s, 2H), 4.51 (s, 2H); 3.67 (s, 3H). Example 39: Preparation of 3-{[3-fluoro-2-(methylaminosulfonylamino)-4- pyridyl]methyl}-7-(3-pyridazinyloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-39; Compound 1)[000438] E-39 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-34, using intermediate I-38 and 2,4- dihydroxybenzaldehyde as the starting materials. LCMS (ES) m / z: 461.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H); 9.02 (dd, J1= 1.2 Hz, J2= 4.4 Hz, 1H); 8.07 (d, J = 4.8 Hz, 1H); 7.81-7.77 (m, 1H); 7.50 (dd, J1= 1.2 Hz, J2= 9.2 Hz, 1H); 7.33 (d, J = 8.4 Hz, 1H); 7.10-7.00 (m, 4H); 4.71 (s, 2H); 4.59 (s, 2H); 2.53 (d, J = 4.8 Hz, 3H). Example 40: Preparation of 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-6- (trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-40; Compound 97)[000439] Step-1: Synthesis of tert-butyl (3-(((2,4-dihydroxy-5-iodobenzyl)amino)methyl)- 2-fluorophenyl)carbamate (E-40a): Compound E-40a (0.8 g) was synthesized by following procedure as described for the synthesis of E-01 (step-1) using 2,4-dihydroxy-5- iodobenzaldehyde (I-09) (1 g, 3.79 mmol) and tert-butyl N-[3-(aminomethyl)-2- fluorophenyl]carbamate (I-31) (0.910 g, 3.79 mmol) as the starting materials. LCMS (ES) m / z: 489.1 [M+H]+. [000440] Step-2: Synthesis of tert-butyl (2-fluoro-3-((7-hydroxy-6-iodo-2-oxo-2H- benzo[e][1,3]oxazin-3(4H)-yl)methyl)phenyl)carbamate (E-40b): Compound E-40b (0.2 g) was synthesized by following procedure as described for the synthesis of E-01 (step-2) using tert-butyl N-[3-({[(2,4-dihydroxy-5-iodophenyl)methyl]amino}methyl)-2-fluorophenyl]carbamate (E-40a) (0.8 g, 1.64 mmol) as the starting material. LCMS (ES) m / z: 513.1 [M-H]+. [000441] Step-3: Synthesis of 3-(3-((tert-butoxycarbonyl)amino)-2-fluorobenzyl)-6-iodo-2- oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-40c): Compound E-40c (0.190 g) was synthesized by following procedure as described for the synthesis of E-01 (step-4) using tert-butyl N-{2-fluoro-3-[(7-hydroxy-6-iodo-2-oxo-3,4-dihydro-2H-1,3- benzoxazin-3-yl)methyl]phenyl}carbamate (E-40b) (0.2 g, 389 µmol) as the starting material. LCMS (ES) m / z: 584.1 [M-H]+. [000442] Step-4: Synthesis of 3-(3-((tert-butoxycarbonyl)amino)-2-fluorobenzyl)-2-oxo-6- (trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-40d): To a stirred solution of 3-[(3-{[(tert-butoxy)carbonyl]amino}-2-fluorophenyl)methyl]-6-iodo-2- oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl N,N-dimethylcarbamate (E-40c) (150 mg, 256 µmol) in DMF (3 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (164 µL, 1.28 mmol) and CuI (146 mg, 769 µmol). The reaction mixture was then stirred at 100 °C, while monitoring reaction progress by TLC. After completion the reaction (16 h), the reaction mixture was cooled to room temperature and water (20 mL) was added to it. Extraction was carried out using EtOAc (30 mL x 2); the combined organic extracts were washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% EtOAc in heptane) to afford desired compound E-40d (120 mg) as a white solid. LCMS (ES) m / z: 526.37 [M-H]+. [000443] Step-5: Synthesis of 3-(3-amino-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)-3,4- dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-40e): Compound E-40e (0.1 g) was synthesized by following procedure as described for the synthesis of E-17 (step-3) using 3-[(3-{[(tert-butoxy)carbonyl]amino}-2-fluorophenyl)methyl]-2-oxo-6-(trifluoromethyl)-3,4- dihydro-2H-1,3-benzoxazin-7-yl N,N-dimethylcarbamate (E-40d) (120 mg, 227 µmol) as the starting material. LCMS (ES) m / z: 428.0 [M+H]+. [000444] Step-6: Synthesis of 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-6- (trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-40): Example E-40 (0.007 g) was synthesized by following procedure as described for the synthesis of E-17 (step-4) using 3-[(3-amino-2-fluorophenyl)methyl]-2-oxo-6- (trifluoromethyl)-3,4-dihydro-2H-1,3-benzoxazin-7-yl N,N-dimethylcarbamate (E-40e) (0.1g, 234 µmol) as the starting material. The final compound was purified by reverse phase preparative HPLC purification [using Xbridge C8 (19 mm x 250 mm, 5 μm particle size) column, ammonium bicarbonate in water and acetonitrile as mobile phase]. LCMS (ES) m / z: 519.15 [M-H]+.1H NMR (400 MHz, DMSO-d6): δ 9.41 (br s, 1H); 7.71 (s, 1H); 7.42-7.37 (m, 1H); 7.24-7.12 (m, 4H); 4.67 (s, 2H); 4.54 (s, 2H); 3.03 (s, 3H); 2.92 (s, 3H); 2.50 (d, J = 4.4 Hz, 3H). Example 41: Preparation of 3-({3-[(methylsulfamoyl)amino]phenyl}methyl)-7- (pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-41; Compound 159)[000445] Step-1: Synthesis of 2-(((3-nitrobenzyl)amino)methyl)-5-(pyrimidin-2- yloxy)phenol (E-41a): Compound E-41a (2.6 g) was synthesized by following procedure as described for the synthesis of E-01 (step-1) using 2-hydroxy-4-(pyrimidin-2- yloxy)benzaldehyde (I-10) (0.3 g, 1.39 mmol) and 1-(3-nitrophenyl)methanamine (211 mg, 1.39 mmol) as the starting materials. LCMS (ES) m / z: 353.1 [M+H]+. [000446] Step-2: Synthesis of 3-(3-nitrobenzyl)-7-(pyrimidin-2-yloxy)-3,4-dihydro-2H- benzo[e][1,3]oxazin-2-one (E-41b): Compound E-41b (0.386 g) was synthesized by following procedure as described for the synthesis of E-01 (step-2) using 2-({[(3- nitrophenyl)methyl]amino}methyl)-5-(pyrimidin-2-yloxy)phenol (E-41a) (0.4 g, 1.14 mmol) as the starting material. LCMS (ES) m / z: 379.1 [M+H]+. [000447] Step-3: Synthesis of 3-(3-aminobenzyl)-7-(pyrimidin-2-yloxy)-3,4-dihydro-2H- benzo[e][1,3]oxazin-2-one (E-41c): To a stirred solution of 3-[(3-nitrophenyl)methyl]-7- (pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-41b) (0.1 g, 264 µmol) in EtOAc (10 mL) was added SnCl2·2H2O (417 mg, 1.85 mmol) at room temperature and the reaction mixture was stirred at 80 °C, while monitoring reaction progress by TLC / LCMS. After complete consumption of starting material (6 h), the reaction mixture was cooled to room temperature and quenched with addition of saturated NaHCO3solution (15 mL).Extraction was carried out using EtOAc (2 x 20 mL); the combined organic extracts were washed with brine solution (2 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% of MeOH in DCM) to afford the desired compound E-41c (62 mg) as a pale yellow thick oil. LCMS (ES) m / z: 349.2 [M+H]+. [000448] Step-4: Synthesis of 3-({3-[(methylsulfamoyl)amino]phenyl}methyl)-7- (pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-41): To a stirred solution of 3- [(3-aminophenyl)methyl]-7-(pyrazin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-41c) (180 mg, 517 µmol) in ACN (15 mL) was added TEA (212 µL, 1.55 mmol) and N-methyl-2- oxo-1,3-oxazolidine-3-sulfonamide (186 mg, 1.03 mmol). The reaction mixture was then stirred at 90 °C, while monitoring reaction progress by TLC / LCMS. After complete consumption of starting material (16 h), the reaction mixture was cooled to room temperature and volatiles were removed under reduced pressure. The residue was purified by Combi- Flash (using gradient elution of 0-6% of MeOH in DCM) followed by reverse phase preparative HPLC purification [using X Terra C18 (250 mm x 19 mm, 5 μm particle size) column, 0.1% ammonia in water and acetonitrile as mobile phase with 19 mL / min flow rate] to afford desired compound E-41 (145 mg) as an off-white solid. LCMS (ES) m / z: 442.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H); 8.76 (d, J = 4.4 Hz, 2H); 7.42-7.37 (m, 4H); 7.26 (d, J = 7.6 Hz, 2H); 7.11-7.08 (m, 3H); 4.70 (s, 2H); 4.56 (s, 2H); 2.56 (d, J = 5.2 Hz, 3H).Example 42: Preparation of 3-(3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-3,4- dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-42; Compound 158)[000449] Step-1: Synthesis of 5-((4-methoxybenzyl)oxy)-2-(((3- nitrobenzyl)amino)methyl)phenol (E-42a): Compound E-42a (1.1 g) was synthesized by following procedure as described for the synthesis of E-01 (step-1) using 2-hydroxy-4-[(4- methoxyphenyl)methoxy]benzaldehyde (I-01) (1 g, 3.87 mmol) and 1-(3- nitrophenyl)methanamine (589 mg, 3.87 mmol) as the starting materials. LCMS (ES) m / z: 395 [M+H]+. [000450] Step-2: Synthesis of 7-((4-methoxybenzyl)oxy)-3-(3-nitrobenzyl)-3,4-dihydro- 2H-benzo[e][1,3]oxazin-2-one (E-42b): Compound E-42b (0.822 g) was synthesized by following procedure as described for the synthesis of E-01 (step-2) using 5-[(4- methoxyphenyl)methoxy]-2-({[(3-nitrophenyl)methyl]amino}methyl)phenol (E-42a) (1 g, 2.54 mmol) as the starting material. LCMS (ES) m / z: 421 [M+H]+. [000451] Step-3: Synthesis of 7-hydroxy-3-(3-nitrobenzyl)-3,4-dihydro-2H- benzo[e][1,3]oxazin-2-one (E-42c): To a stirred solution of 7-[(4-methoxyphenyl)methoxy]- 3-[(3-nitrophenyl)methyl]-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-42b) (0.9 g, 2.14 mmol) in DCM (30 mL) was added trifluoromethanesulfonic acid (379 µL, 4.28 mmol) at 0 °C and the reaction mixture was stirred at room temperature, while monitoring reaction progress by TLC / LCMS. After complete consumption of starting material (16 h), the reaction mixture was quenched with saturated NaHCO3solution (30 mL) at 0 °C and extraction was carried out using DCM (2 x 30 mL). The combined organic extracts were washed with water (2 x 20mL), brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-60% of EtOAc in heptane) to afford the desired E-42c (520 mg) as a pale yellow solid. LCMS (ES) m / z: 301.1 (M+H)+. [000452] Step-4: Synthesis of 3-(3-nitrobenzyl)-2-oxo-3,4-dihydro-2H- benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-42d): Compound E-42d (0.450 g) was synthesized by following procedure as described for the synthesis of E-01 (step-4) using tert- butyl N-[(4-aminophenyl)methyl]carbamate (E-42c) (0.5 g, 1.67 mmol) as the starting material. LCMS (ES) m / z: 372.2 [M+H]+. [000453] Step-5: Synthesis of 3-(3-aminobenzyl)-2-oxo-3,4-dihydro-2H- benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-42e): To a stirred solution of 3-[(3- nitrophenyl)methyl]-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl N,N-dimethylcarbamate (E- 42d) (450 mg, 1.21 mmol) in MeOH (10 mL) was added Pd / C (10%) (150 mg, 1.41 mmol) and the reaction mixture was allowed to stir under hydrogen atmosphere at room temperature. The reaction progress was monitored by TLC / LCMS analysis. After completion of the reaction (2 h), the catalyst was filtered off through a celite pad and washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-70% of EtOAc in heptane) to afforded desired compound E-42e (326 mg) as a pale yellow semi solid. LCMS (ES) m / z: 342.2 [M+H]+. [000454] Step-6: Synthesis of 3-(3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-3,4-dihydro- 2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-42): Example E-42 (34 mg) was synthesized by following procedure as described for the synthesis of E-17 (step-4) using 3- [(3-aminophenyl)methyl]-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl N,N- dimethylcarbamate (E-42e) (150 mg, 439 µmol) as the starting material. The final compound was purified by reverse phase preparative HPLC purification [using Eclipse C18 (150 mm x 21 mm, 7 μm particle size) column 0.1% ammonia in water and acetonitrile as mobile phase with 19 mL / min flow rate]. LCMS (ES) m / z: 435.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H); 7.30-7.21 (m, 3H); 7.13 (t, J = 1.6 Hz, 2H); 6.98 (d, J = 7.6 Hz, 1H); 6.91 (d, J = 2.4 Hz, 2H); 4.58 (s, 2H); 4.42 (s, 2H); 3.03 (s, 3H); 2.96 (s, 3H); 2.38 (d, J = 5.2 Hz, 3H).Example 43: Preparation of 7-(cyclopropylmethoxy)-3-({2-fluoro-3- [(methylsulfamoyl)amino]phenyl}methyl)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-43; Compound 106)[000455] Step-1: Synthesis of tert-butyl (3-(((2-(benzyloxy)-4- (cyclopropylmethoxy)benzyl)amino)methyl)-2-fluorophenyl)carbamate (E-43a): Compound E-39a (0.680 g) was synthesized by following procedure as described for the synthesis of E- 01 (step-1) using 2-(benzyloxy)-4-(cyclopropylmethoxy)benzaldehyde (I-02a) (580 mg, 2.05 mmol) and tert-butyl N-[3-(aminomethyl)-2-fluorophenyl]carbamate (I-31) (592 mg, 2.47 mmol) as the starting materials. LCMS (ES) m / z: 507.2 [M+H]+. [000456] Step-2: Synthesis of tert-butyl (3-(((4-(cyclopropylmethoxy)-2- hydroxybenzyl)amino)methyl)-2-fluorophenyl)carbamate (E-43b): To a stirred solution of tert-butyl N-{3-[({[2-(benzyloxy)-4-(cyclopropylmethoxy)phenyl] methyl}amino)methyl]-2- fluorophenyl}carbamate (E-43a) (680 mg, 1.34 mmol) in MeOH (10 mL) was added Pd / C (10%) (72 mg, 671 ∏mol) and the reaction mixture was allowed to stir at room temperature under hydrogen atmosphere. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (4 h), the catalyst was filtered off through a celite pad and washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-70% of EtOAc in heptane) to afforded desired compound E-43b (600 mg) as a pale yellow semi solid. LCMS (ES) m / z: 417.2 [M+H]+. [000457] Step-3: Synthesis of tert-butyl (3-((7-(cyclopropylmethoxy)-2-oxo-2H- benzo[e][1,3]oxazin-3(4H)-yl)methyl)-2-fluorophenyl)carbamate (E-43c): Compound E-43c (0.600 g) was synthesized by following procedure as described for the synthesis of E-17(step-3) using tert-butyl N-{3-[({[4-(cyclopropylmethoxy)-2- hydroxyphenyl]methyl}amino)methyl]-2-fluorophenyl}carbamate (E-43b) (680 mg, 1.63 mmol) as the starting material. LCMS (ES) m / z: 387.3 [(M-tBu)+H]+. [000458] Step-4: Synthesis of 3-(3-amino-2-fluorobenzyl)-7-(cyclopropylmethoxy)-3,4- dihydro-2H-benzo[e][1,3]oxazin-2-one (E-43d): To a stirred solution of tert-butyl N-(3-{[7- (cyclopropylmethoxy)-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl]methyl}-2-fluorophenyl) carbamate (E-43c) (0.6 g, 1.36 mmol) in DCM (5 mL) was added TFA (7 mL) at 0 °C and the reaction mixture was allowed to warm to room temperature over 1 h. The progress of the reaction was monitored by TLC / LCMS. After complete consumption of starting material (1 h), volatiles were removed under reduced pressure and saturated NaHCO3solution (15 mL) was added to the residue. Extraction was carried out using DCM (3 x 15 mL); the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% of EtOAc in heptane) afforded the desired compound E-43d (500 mg) as an off-white solid. LCMS (ES) m / z: 343.2 [M+H]+. [000459] Step-5: Synthesis of 7-(cyclopropylmethoxy)-3-({2-fluoro-3- [(methylsulfamoyl)amino]phenyl}methyl)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-43): Example E-43 (0.3 g) was synthesized by following procedure as described for the synthesis of E-17 (step-4) using 3-[(3-amino-2-fluorophenyl)methyl]-7-(cyclopropylmethoxy)-3,4- dihydro-2H-1,3-benzoxazin-2-one (E-43d) (0.5 g, 1.46 mmol) as the starting material. The final compound was purified by reverse phase preparative HPLC purification [using X- Bridge C-18 (250 mm x 4.6 mm, 5 μm particle size) column, 0.1% ammonia in water and acetonitrile as mobile phase with 1.0 mL / min flow rate]. LCMS (ES) m / z: 436.2 [M+H]+.1H NMR (400 MHz, DMSO d6): δ 9.41 (s, 1H); 7.42-7.36 (m, 1H); 7.20 (q, J = 4.8 Hz, 1H); 7.15-7.09 (m, 3H); 6.70 (dd, J1= 2.4 Hz, J2= 8.4 Hz, 1H); 6.62 (d, J = 2.4 Hz, 1H); 4.65 (s, 2H); 4.40 (s, 2H); 3.80 (d, J = 7.2 Hz, 2H); 2.50 (d, J = 5.2 Hz, 3H); 1.23-1.15 (m, 1H); 0.58- 0.52 (m, 2H); 0.32-0.28 (m, 2H). Example 44: Preparation of 3-{[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl}- 7-(3-oxetanyloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-44; Compound 98)[000460] E-44 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-43, using key intermediates I-02b and I-31. LCMS (ES) m / z: 438.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H); 7.40-7.35 (m, 1H); 7.22 (d, J = 5.2 Hz, 1H); 7.18-7.08 (m, 3H); 6.60 (dd, J1= 2.4 Hz, J2= 8.4 Hz, 1H); 6.50 (d, J = 2.4 Hz, 1H); 5.29 (q, J = 5.6 Hz, 1H); 4.92 (t, J = 7.2 Hz, 2H); 4.65 (s, 2H); 4.53- 4.48 (m, 2H); 4.40 (s, 2H); 2.50 (d, J = 5.2 Hz, 3H). Example 45: Preparation of 3-{[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl}- 7-(2-oxo-1-piperidyl)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-45; Compound 138)[000461] E-45 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-43, using key intermediates I-12 and I-31. (note: step-2 led to over-saturation of pyridone ring). LCMS (ES) m / z: 463.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H); 7.42-7.37 (m, 1H); 7.27-7.21 (m, 2H); 7.18-7.12 (m, 2H); 7.06 (dd, J1= 1.6 Hz, J2= 8.0 Hz, 1H); 7.02 (d, J = 2.0 Hz, 1H); 4.68 (s, 2H); 4.48 (s, 2H); 3.59 (t, J = 4.0 Hz, 2H); 2.50 (d, J = 5.2 Hz, 3H); 2.39 (t, J = 8.0 Hz, 2H); 1.90-1.82 (m, 4H). Example 46: Preparation of 3-{[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl}- 7-(1-methyl-3-pyrazolyloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-46; Compound 16)[000462] E-46 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-43, using key intermediates I-44 and I-31. LCMS (ES) m / z: 462.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 7.66 (d, J = 2.0 Hz, 1H); 7.40-7.36 (m, 1H); 7.20 (d, J = 8.8 Hz, 1H); 7.14-7.06 (m, 2H); 6.82 (dd, J1= 2.4 Hz, J2= 8.4 Hz, 1H); 6.70 (d, J = 2.4 Hz, 1H); 5.86 (d, J = 2.0 Hz, 1H); 4.65 (s, 2H), 4.44 (s, 2H); 3.74 (s, 3H); 2.53 (d, J = 4.8 Hz, 3H).Example 47: Preparation of 6-chloro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)- 2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-47; Compound 149)[000463] Step-1: Synthesis of tert-butyl (3-(((5-chloro-2-hydroxy-4-((4- methoxybenzyl)oxy)benzyl)amino)methyl)-2-fluorophenyl)carbamate (E-47a): Compound E-47a (2.6 g) was synthesized by following procedure as described for the synthesis of E-01 (step-1) using 5-chloro-2-hydroxy-4-[(4-methoxyphenyl)methoxy]benzaldehyde (I-07) (1.5 g, 5.12 mmol) and tert-butyl N-[3-(aminomethyl)-2-fluorophenyl]carbamate (I-31) (1.23 g, 5.12 mmol) as the starting materials. LCMS (ES) m / z: 517.2 [M+H]+. [000464] Step-2: Synthesis of tert-butyl (3-((6-chloro-7-((4-methoxybenzyl)oxy)-2-oxo- 2H-benzo[e][1,3]oxazin-3(4H)-yl)methyl)-2-fluorophenyl)carbamate (E-47b): Compound E- 47b (2.2 g) was synthesized by following procedure as described for the synthesis of E-01 (step-2) using tert-butyl N-(3-{[({5-chloro-2-hydroxy-4-[(4- methoxyphenyl)methoxy]phenyl}methyl)amino]methyl}-2-fluorophenyl)carbamate (E-47a) (2.6 g, 5.03 mmol) as the starting material.1H NMR (400 MHz, DMSO d6): δ 8.97 (s, 1H); 7.51 (d, J = 7.2 Hz, 1H); 7.35 (t, J = 8.4 Hz, 3H); 7.15-7.04 (m, 2H); 6.95 (t, J = 13.6 Hz, 3H); 5.16 (s, 2H); 4.79 (s, 2H); 4.61 (s, 2H); 3.73 (s, 3H); 1.42 (s, 9H). [000465] Step-3: Synthesis of 3-(3-amino-2-fluorobenzyl)-6-chloro-7-hydroxy-3,4-dihydro- 2H-benzo[e][1,3]oxazin-2-one (E-47c): To a stirred solution of tert-butyl N-[3-({6-chloro-7- [(4-methoxyphenyl)methoxy]-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl}methyl)-2- fluorophenyl]carbamate (E-47b) (1.3 g, 2.39 mmol) in DCM (4 mL) was added TFA (1.84 mL, 23.9 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of startingmaterial (1 h), volatiles were removed under reduced pressure and the residue was washed with diethyl ether (3 x 10 mL) to afford desired compound E-47c (0.9 g). LCMS (ES) m / z: 323.1 [M+H]+. [000466] Step-4: Synthesis of 3-(3-amino-2-fluorobenzyl)-6-chloro-2-oxo-3,4-dihydro-2H- benzo[e][1,3]oxazin-7-yl tert-butyl carbonate (E-47d): To a stirred solution of 3-[(3-amino-2- fluorophenyl)methyl]-6-chloro-7-hydroxy-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-47c) (0.5 g, 1.55 mmol) in THF (5 mL) and water (5 mL) was added NaHCO3(1.3 g, 15.5 mmol) at 0 °C and the reaction mixture was allowed to stir for 15 min. To this was then (Boc)2O (0.35 mL, 1.55 mmol) and reaction mixture was allowed to stir at room temperature for 16 h. Water (30 mL) was then added to it and extraction was carried out using EtOAc (2 x 30 mL). The combined organic extracts were washed with saturated NaHCO3solution (2 x 20 mL), brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-60% of EtOAc in heptane) to afford desired compound E-47d (0.35 g) as an off white solid. LCMS (ES) m / z: 423.1 [M+H]+. [000467] Step-5: Synthesis of tert-butyl (6-chloro-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl) carbonate (E-47e): Compound E-47e (0.3 g) was synthesized by following procedure as described for the synthesis of E-17 (step-4) using 3-[(3-amino-2-fluorophenyl)methyl]-6-chloro-2-oxo-3,4- dihydro-2H-1,3-benzoxazin-7-yl tert-butyl carbonate (E-47d) (0.3 g, 0.7 mmol) as the starting material. LCMS (ES) m / z: 513.9 [M-H]+. [000468] Step-6: Synthesis of 6-chloro-3-({2-fluoro-3- [(methylsulfamoyl)amino]phenyl}methyl)-7-hydroxy-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-47f): To a stirred solution of tert-butyl 6-chloro-3-({2-fluoro-3- [(methylsulfamoyl)amino]phenyl}methyl)-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl carbonate (E-47e) (0.25 g, 0.48 mmol) in DCM (2 mL) was added TFA (0.5 mL) at 0 °C and the reaction mixture was allowed to stir at room temperature. The reaction progress was monitored by TLC / LCMS. After complete consumption of starting material (1 h), volatiles were removed under reduced pressure and the residue was washed with diethyl ether (3 x 10 mL) to afford the desired compound E-47f (0.180 g). LCMS (ES) m / z: 416.1 [M+H]+. [000469] Step-7: Synthesis of 6-chloro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)- 2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl dimethylcarbamate (E-47): Example E-47(0.11 g) was synthesized by following procedure as described for the synthesis of E-01 (step- 4) using 6-chloro-3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-7-hydroxy-3,4- dihydro-2H-1,3-benzoxazin-2-one (E-47f) (0.2 g, 0.48 mmol) as the starting material. The final compound was purified by reverse phase preparative HPLC purification [using ODS C18 (250 mm x 20 mm, 5 μm particle size) column, 0.1% ammonia in water and acetonitrile as mobile phase with 19 mL / min flow rate]. LCMS (ES) m / z: 487.1 [M+H]+.1H NMR (400 MHz, DMSO d6): δ 9.45 (s, 1H); 7.49 (s, 1H); 7.42-7.37 (m, 1H); 7.22-7.13 (m, 4H); 4.66 (s, 2H); 4.48 (s, 2H); 3.07 (s, 3H); 2.92 (s, 3H); 2.50 (d, J = 5.2 Hz, 3H). Example 48: Preparation of 6-chloro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)- 2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl isobutyrate (E-48; Compound 129)[000470] E-48 was synthesized by following similar synthesis sequence and experimental procedures as described for the synthesis of E-47, using key intermediate E-47f and isobutyryl chloride as the starting materials. LCMS (ES) m / z: 486.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H); 7.53 (s, 1H); 7.42-7.37 (m, 1H); 7.25-7.13 (m, 4H); 4.67 (s, 2H); 4.49 (s, 2H); 2.88 (q, J = 7.2 Hz, 1H); 2.53 (d, J = 5.2 Hz, 3H); 1.26 (d, J = 7.2 Hz, 6H). Example 49: Preparation of 6-chloro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)- 2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl cyclopropanecarboxylate (E-49; Compound 130)[000471] E-49 was synthesized by following synthesis sequence and procedures as described for the synthesis of E-47, using key intermediate E-47f and cyclopropylcarbonyl chloride as the starting materials. LCMS (ES) m / z: 482.2 [M-H]+.1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H); 7.53 (s, 1H); 7.42-7.37 (m, 1H); 7.22-7.14 (m, 4H); 4.66 (s, 2H); 4.48 (s, 2H); 2.51 (d, J = 5.2 Hz, 3H); 1.97-1.93 (m, 1H); 1.14-1.06 (m, 4H).Example 50: Preparation of 6-chloro-3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl} methyl)-7-(pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-50; Compound 148)[000472] Step-1: Synthesis of 3-(3-amino-2-fluorobenzyl)-6-chloro-7-(pyrimidin-2-yloxy)- 3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one (E-50a): To a stirred solution of 3-[(3-amino-2- fluorophenyl)methyl]-6-chloro-7-hydroxy-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-47c) (0.25 g, 0.77 mmol) in DMF (4 mL) was added 2-bromopyrimidine (0.24 g, 1.55 mmol) and Cs2CO3(0.3 g, 0.93 mmol). The reaction mixture was allowed to stir at 100 °C, while monitoring reaction progress by TLC / LCMS. After complete consumption of stating material (4 h), the reaction mixture was cooled temperature and quenched with water (30 mL). Extraction was carried out using EtOAc (2 x 20 mL); the combined organic extracts were washed with brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-8% of MeOH in DCM) to afford the desired compound E-50a (0.2 g) as an off white solid. LCMS (ES) m / z: 401.0 [M+H]+. [000473] Step-2: Synthesis of 6-chloro-3-({2-fluoro-3- [(methylsulfamoyl)amino]phenyl}methyl)-7-(pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3- benzoxazin-2-one (E-50): Example E-50 (0.074 g) was synthesized by following procedure as described for the synthesis of E-17 (step-4) using 3-[(3-amino-2-fluorophenyl)methyl]-6- chloro-7-(pyrimidin-2-yloxy)-3,4-dihydro-2H-1,3-benzoxazin-2-one (E-50a) (0.3 g, 0.74 mmol) as the starting material. The final compound was purified by reverse phase preparative HPLC purification [using X-Bridge C18 (19 mm x 250 mm, 5 μm particle size) column, 0.1% ammonia in water and acetonitrile as mobile phase with 18 mL / min flow rate]. LCMS (ES) m / z: 494.2 [M+H]+.1H NMR (400 MHz, DMSO d6): δ 9.45 (s, 1H); 8.67 (d, J = 4.8 Hz, 2H); 7.55 (s, 1H); 7.42-7.38 (m, 1H); 7.32 (t, J = 4.8 Hz, 1H); 7.27 (s, 1H); 7.22 - 7.15 (m, 3H); 4.68 (s, 2H); 4.52 (s, 2H); 2.53 (d, J = 4.8 Hz, 3H).Example 51: Preparation of 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo- 3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl 3,3-difluoroazetidine-1-carboxylate (E-51; Compound 146)[000474] Step-1: Synthesis of 3-(3-((tert-butoxycarbonyl)amino)-2-fluorobenzyl)-2-oxo- 3,4-dihydro-2H-benzo[e][1,3]oxazin-7-yl 3,3-difluoroazetidine-1-carboxylate (E-51a): To a stirred solution of tert-butyl N-{2-fluoro-3-[(7-hydroxy-2-oxo-3,4-dihydro-2H-1,3- benzoxazin-3-yl)methyl]phenyl}carbamate (E-27b) (0.3 g, 772 µmol) in DCM (10 mL) was added TEA (434 µL, 3.09 mmol) and 4-nitrophenyl chloroformate (202 mg, 1 mmol) at 0 °C and the ...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: each G1is independently N or CH, wherein the H of CH may be substituted with R6; G2is N or CH, wherein the H of CH may be substituted with R3or R4; R1and R2are each independently selected from the group consisting of hydrogen, deuterium, halogen, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted, or R1and R2may be taken together with the carbon atom to which they are attached to form C3-6cycloalkyl or 3-6 membered heterocyclyl ring, wherein the C3-6cycloalkyl or 3-6 membered heterocyclyl ring may be optionally substituted; R3is selected from the group consisting of -ORa, -NRbRc, -C(O)N(Re)2, C1-6alkyl optionally substituted with one or more R7, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C3-10cycloalkyl, and phenyl, wherein the 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C3-10cycloalkyl, and phenyl are optionally substituted; each R4is independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, -CN, -N(Re)2, NO2, and C1-6alkoxy; Ra, Rb, Rcand Rdare each independently selected from the group consisting of hydrogen, C1-6alkyl optionally substituted with one or more R7, -C(O)-(3-10 membered heterocyclyl or 5-10 membered heteroaryl), -C(O)N(Re)2, -C(O)-(C1-6alkyl), -C(O)-(C3-10cycloalkyl), 5-10 membered heteroaryl, phenyl, 3-10 membered heterocyclyl, and C3-10cycloalkyl, wherein the 5-10 membered heteroaryl, phenyl, 3-10 membered heterocyclyl, and C3-10cycloalkyl are optionally substituted; R5is selected from the group consisting of -(C1-6alkylene)-S(O)pRh, -NReS(O)pRh, - NReC(O)Rh, -N(Re)2, NO2, -ORk, -S(O)qRh, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl, (C1-6alkylene)-(3-10 membered heterocyclyl), and (C1-6alkylene)-5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted; each R6is independently selected from the group consisting of C1-6alkyl, halogen, C1-6haloalkyl, C1-6haloalkoxy, -CN, -N(Re)2, NO2, and C1-6alkoxy; each R7is selected from the group consisting of halogen, -C(O)N(Re)2, -C(O)ORp, 3- 10 membered heterocyclyl, and C3-10cycloalkyl, wherein the 3-10 membered heterocyclyl and C3-10cycloalkyl are optionally substituted; each Reis independently hydrogen or C1-6alkyl; each Rhis independently selected from the group consisting of -NRnRo, C1-6alkyl optionally substituted with one or more R8, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein the C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are optionally substituted; Rkis selected from the group consisting of C1-6alkyl optionally substituted with one or more R8, C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein the C3-10cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are optionally substituted; R8is selected from the group consisting of -N(Re)2, halogen, and C1-6alkoxy; R11is hydrogen or C1-6alkyl; Rnand Roare each independently selected from hydrogen, and C1-6alkyl optionally substituted with one or more halogen or C1-6alkoxy; each Rpis independently hydrogen or C1-6alkyl; n is selected from 0, 1, 2, and 3; s is selected from 0, 1, 2, and 3; and m, p, and q are each independently selected from 0, 1, and 2; wherein: when R1and R2are each independently hydrogen or optionally substituted C1-6alkyl, and R5is -NReS(O)pRh, then Rais selected from the group consisting of hydrogen, C1-6alkyl optionally substituted with one or more R7, -C(O)-(3-10 membered heterocyclyl or 5-10 membered heteroaryl), -C(O)-(C1-6alkyl), -C(O)-(C3-10cycloalkyl), 5-6 membered heteroaryl selected from the group consisting of pyridazinyl, oxazolyl, triazinyl, and pyrazinyl, phenyl,3-10 membered heterocyclyl, and C3-10cycloalkyl, wherein the 5-6 membered heteroaryl, phenyl, 3-10 membered heterocyclyl, and C3-10cycloalkyl are optionally substituted.

2. The compound of claim 1, wherein the compound is a compound of formula (I-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

3. The compound of claim 1 or 2, wherein the compound is a compound of formula (IA):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

4. The compound of any one of claims 1-3, wherein the compound is a compound of formula (IA-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

5. The compound of claim 1 or 2, wherein the compound is a compound of formula (IB):or a pharmaceutically acceptable salt thereof, wherein:t is 0 or 1;is a 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted; and wherein the remainingvariables are as defined in claim 1.

6. The compound of claim 5, wherein the compound is a compound of formula (IB-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claims 1 and 5.

7. The compound of claim 1, wherein the compound is a compound of Formula (IC):or a pharmaceutically acceptable salt thereof, wherein: R1and R2are taken together with the carbon atom to which they are attached to form C3-6cycloalkyl or 3-6 membered heterocyclyl ring, wherein the C3-6cycloalkyl or 3-6 membered heterocyclyl ring may be optionally substituted; and the remaining variables are as defined in claim 1.

8. The compound of claim 7, wherein the compound is a compound of Formula (IC-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 7.

9. The compound of claim 7, wherein the compound is a compound of Formula (IC-2):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 7.

10. The compound of claim 1, wherein the compound is a compound of Formula (ID):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

11. The compound of claim 1, wherein the compound is a compound of Formula (IE):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

12. The compound of claim 1, wherein the compound is a compound of Formula (IF):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

13. The compound of claim 9, wherein the compound is a compound of Formula (IF-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

14. The compound of claim 9, wherein the compound is a compound of Formula (IF-2):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

15. The compound of claim 1, wherein the compound is a compound of Formula (IG):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

16. The compound of claim 15, wherein the compound is a compound of Formula (IG-1):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

17. The compound of claim 15, wherein the compound is a compound of Formula (IG-2):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

18. The compound of any one of claims 1, 7-17, wherein each G1is CH, wherein the H of CH may be substituted with R6.

19. The compound of any one of claims 1, 7-9, and 11-17, wherein one G1is N and the other G1is CH, wherein the H of CH may be substituted with R6.

20. The compound of any one of claims 1, 7-10, and 12-19, wherein G2is N.

21. The compound of any one of claims 1, 7-10, and 12-19, wherein G2is CH, wherein the H of CH may be substituted with R3or R4.

22. The compound of any one of claims 1-6 and 10-21, wherein R1and R2are each independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, and -CF3.

23. The compound of any one of claims 1-21, wherein R1and R2are taken together with the carbon atom to which they are attached to form cyclopropyl ring, cyclobutyl ring, oxetanyl ring, or azetidinyl ring, wherein the cyclopropyl ring, cyclobutyl ring, oxetanyl ring, or azetidinyl ring is optionally substituted with C1-6alkyl.

24. The compound of any one of claims 1, 2, 7, 10, 11, and 18-23, wherein R3is -ORaor C1-6alkylene optionally substituted with one or more R7.

25. The compound of claim 24, wherein R3is -ORa.

26. The compound of any one of claims 1-11 and 18-25, wherein Rais selected from the group consisting of C(O)N(Re)2, 5-10 membered heteroaryl, C1-6alkyl optionally substituted with one or more R7, C3-10cycloalkyl, -C(O)-(3-10 membered heterocyclyl), -C(O)-(C1-6alkyl), and -C(O)-(C3-10cycloalkyl).

27. The compound of any one of claims 1-11 and 18-26, wherein Rais 5-6 membered heteroaryl.

28. The compound of claim 27, wherein Rais selected from the group consisting of:

29. The compound of claim 28, wherein Rais selected from the group consisting of:

30. The compound of claim 28, wherein Rais selected from the group consisting of:

31. The compound of any one of claims 1-30, wherein each R7is independently selected from the group consisting of halogen, -C(O)N(Re)2, 3-10 membered heterocyclyl, and C3-10cycloalkyl.

32. The compound of claim 31, wherein each Reis hydrogen or C1-6alkyl.

33. The compound of any one of claims 1-32, wherein each R4is selected from the group consisting of halogen, C1-6alkyl, and C1-6haloalkyl.

34. The compound of any one of claims 1, 2, 7, 10-12, 15, and 18-33, wherein R5is selected from the group consisting of NReS(O)pRh, NReC(O)Rh, and -(C1-6alkylene)-S(O)pRh.

35. The compound of claim 34, wherein R5is NHS(O)2Rh.

36. The compound of any one of claims 1-4, 7, 8, 10-13, 15, 16, and 18-35, wherein Rhis selected from the group consisting of -NRnRo, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C3-10cycloalkyl, 3-10 membered heterocyclyl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, and C(O)NRpRq, wherein Rpand Rqare independently hydrogen or C1-6alkyl. NReC(O)Rh37. The compound of claim 36, wherein Rhis -NRnRo.

38. The compound of any one of claims 1-4, 7, 8, 10-13, 15, 16, and 18-37, wherein each Rnand Roare independently selected from hydrogen, methy, and -C1-6alkylene-C1-6alkoxy.

39. The compound of any one of claims 1-4, 7, 8, 10-13, 15, 16, and 18-35, wherein Rhis 3- 10 membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, and C(O)NRpRq.

40. The compound any one of claims 1, 2, 7, 10-12, 15, and 18-33, wherein R5is selected from the group consisting of 3-10 membered heterocyclyl, 5-10 membered heteroaryl, (C1-6alkylene)-3-10 membered heterocyclyl, and (C1-6alkylene)-5-10 membered heteroaryl wherein the 3-10 membered heterocyclyl, and 5-10 membered heteroaryl are optionally substituted.

41. The compound of claim 40, wherein R5is selected from 3-10 membered heterocyclyl and (C1-6alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl is optionally substituted with oxo.

42. The compound of any one of claims 1-41, wherein each R6is halogen.

43. The compound of any one of claims 1-42, wherein n is 0.

44. The compound of any one of claims 1-42, wherein n is 1.

45. The compound of any one of claims 1-3, 5, and 7-44, wherein s is 0.

46. The compound of any one of claims 1-3, 5, and 7-44, wherein s is 1.

47. The compound of any one of claims 1-3, 5 and 7-44, wherein s is 2.

48. The compound of any one of claims 5, 6, 9, 14, 17-33, 36-39, and 42-47, wherein t is 0.

49. The compound of any one of claims 5, 6, 9, 14, 17-33, 36-39, and 42-47, wherein t is 1.

50. The compound of any one of claims 5, 6, 9, 14, 17-33, 36-39, and 42-49, whereinis a 3-10 membered heterocyclyl wherein the 3-10 membered heterocyclyl is optionally substituted.

51. The compound of any one of claims 5, 6, 9, 14, 17-33, 36-39, and 42-50, whereinis selected from the group consisting ofand wherein R9is selected from the group consisting of O, NH, N-C1-6alkyl, N-C1-6alkoxy, and N-(C1-6alkylene)-C(O)N(Re)2.

52. The compound of claim 51, wherein53. The compound of claim 51, wherein where9in R is O.

54. The compound of claim 51, wherein where9in R is NH.

55. The compound of claim 1, wherein the compound is selected from Table 2.

56. A pharmaceutical composition comprising a compound of any one of claims 1-55 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

57. A method of modulating the interaction between RAF and MEK in a RAF-MEK complex, the method comprising contacting RAF, MEK or a combination of RAF and MEK with an effective amount of a compound of any one of claims 1-55 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 56 thereby to modulate the interaction between RAF and MEK.

58. The method of claim 57, wherein the modulation involves stabilizing or destabilizing the interaction between RAF and MEK in the RAF-MEK complex.

59. The method of claim 57 or 58, wherein the RAF is BRAF and the RAF-MEK complex is BRAF-MEK complex.

60. A method of treating a disease or condition associated with MAPK signaling pathway in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-55 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 56.

61. The method of claim 60, wherein the disease or condition associated with MAPK signaling pathway is cancer.

62. The method of claim 61, wherein the cancer is colorectal cancer, NSCLC, or pancreatic cancer.

63. The method of claim 62 or 63, wherein the cancer comprises brain metastasis.

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