Substituted benzoxazolylamino benzoxazoles

Abstract

Disclosed are substituted benzoxazolylamino benzoxazoles, methods for their preparation, and use thereof.

Description

Substituted Benzoxazolylamino BenzoxazolesCross-Reference to Related Applications

[0001] This application claims priority from U.S. Provisional Application No. 63 / 580,106, filed September 1, 2023, and U.S. Provisional Application No. 63 / 661 ,725, filed June 19, 2024, the disclosure of each of which is hereby incorporated by reference in its entirety.Field

[0002] This disclosure relates generally to substituted benzoxazolylamino benzoxazoles, and more particularly to such compounds there are useful in the treatment of hematological, inflammatory, or elevated oxidative stress conditions. The disclosure is directed to compounds and compositions that are useful in the treatment of hematological, inflammatory or elevated oxidative stress conditions, and methods of treating a hematological, inflammatory, or elevated oxidative stress condition.Background

[0003] Oxidative stress, characterized by elevated levels of reactive oxygen species (ROS) within the ceil, is counteracted by cellular anti-oxidant responses to maintain homeostasis. Aberrant ROS production, left unchecked, can result in damage to cellular components. Excessive and prolonged oxidative stress within the cell is linked to chronic diseases, including, but not limited to, autoimmune, pulmonary, neuroinflammatory, neurodegenerative, cardiovascular, hematological, renal, hepatic, metabolic, bone, and cancer. Hence, therapeutic strategies to restore a homeostatic oxidative state within the cell are of significant interest.

[0004] The Bach1 / Nrf2 axis is a master regulator of the cellular anti-oxidant response, and a proven clinical therapeutic target to counteract diseases driven by oxidative stress (FDA-approved Nrf2 activators Tecfidera for relapsing remitting multiple sclerosis and Skyclarys for Friedrich's ataxia). Under homeostatic conditions, Bachl occupies antioxidant response elements (AREs) in the promoters of diverse genes involved in cellular antioxidant responses, which prevents their transcription. In response to oxidative stress, Bachl dissociates from the AREs allowing binding by the transcription factor Nrf2. This drives the expression of anti-oxidant genes, including, but not limited to, Hmoxl (HO-1 protein), as well as other genes. Nrf2 activation also regulates various other pathways, such as NF-kB signaling and inflammasomes.

[0005] General activation of the Nrf2 pathway and consequent Hmoxl expression / HO-1 protein induction is associated with positive outcomes in numerous epidemiological association studies,genetic models, and anima! models of disease. Particularly with Nrf2 activation via Bachl repression, Bachl knockout mice and Bachl inhibitors have demonstrated protection in various preclinical models. The Bachl knockout mice have shown efficacy against various diseases, including in models for neuroinflammatory, neurological injury, autoimmune, hepatic, metabolic, cardiovascular, and inflammatory conditions. In many of these models, the protection against disease is dependent on HO-1 , as demonstrated with HO-1 inhibitors. Bachl inhibitors that repress its binding to the AREs (e.g., hemin / heme, other porphyrins, and small molecule compounds) have demonstrated similar protection in preclinical disease models for hematological, metabolic, hepatic, ocular, bone degeneration, and autoimmune conditions.

[0006] With the great potential demonstrated clinically with Nrf2 activators and preclinical with Bachl modulation, there is an untapped opportunity to develop new Nrf2 activators / Hmox 1 inducers via Bachl repression / inhibition for treating indications within the various therapeutic areas mentioned above.

[0007] Fetal hemoglobin (HbF, a2y2) induction is known to ameliorate the clinical complications of sickle cell disease (SCD). Several drugs are under investigation in clinical trials as HbF- inducing agents, but hydroxycarbamide remains the only widely used pharmacologic therapy for SCD. Autologous transplant of edited hematopoietic stem ceils holds promise as a cure for SCD, either through HbF induction or correction of the causative mutation, but there is limited access to this therapy and it is not appropriate for all patients. Thus, pharmacological therapies for SCD and related disorders are still needed.Summary

[0008] In one aspect, the present disclosure provides compounds of Formula (I):or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein:each of R1, R3, R4, and Rsis independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halo C1-C6 alkyl, or OR10, wherein R10is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halo C1-C6 alkyl;R2is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halo C1-C6 alkyl, OR10, hydroxy C1-C6 alkyl, or -C(O)NR11R12, wherein each of R11and R12is independently hydrogen, C1-C6 alkyl, C3-C0 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, or hydroxy C1-C6 alkoxy C1-C6 alkyl;R5is hydrogen, hydroxy C1-C6 alkyl, or carboxy C1-C6 alkyl;R6and R7are independently hydrogen, hydroxy C1-C6 alkyl, -X-C(O)R13, -Y- C(O)NR14R15, -Z-NR16R17, heteroaryl, or -S(O)2R18, whereinX is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino;R13is -OH or -OR10;Y is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C0 cycloalkyl, halogen, hydroxy, or amino; each of R14and R15is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl C3-C6 cycloalkylamino, C1-C6 amine, carboxy C1-C6 alkyl, -S(O)2R19, phenyl, heteroaryl, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group, whereinR19is C1-C6 alkyl; the phenyl is optionally substituted with C1-C6 alkyl; the heteroaryl is optionally substituted with C1-C6 alkyl; and the 3-8 membered monocyclic heterocyclyl group is optionally substituted with C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl;Z is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino; each of R1Sand R17is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, -(C1-C6 alkyl)-C(O)R20, -C(O)R2 i, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group, whereinR20is -OH, OR10, or NR22R23, wherein each R22and R23is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or hydroxy C1-C6 alkyl C3-C6 cycloalkylamino;R21is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or C1-C6 amine; and the 3-8 membered monocyclic heterocyclyl group is optionally substituted with C1-C6 alkyl, halogen, hydroxy, halo C1-C6 alkyl, Ci- Cs alkoxy, hydroxy C1-C6 alkyl, or amino- or mono- or di-C1-C6 alkyl amino C1-C6 alkyl;R18is C1-C6 alkyl or -NH-( C1-C6 alkyl); and R9is hydrogen, C1-C6 alkyl, or a N-protecting group.

[0009] in another aspect, the present disclosure provides for a pharmaceutical composition comprising a compound or salt as otherwise described herein together with a pharmaceutically acceptable carrier, excipient, or diluent

[0010] In another aspect, the present disclosure provides for a method of treating a hematological, inflammatory, or elevated oxidative stress condition, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound as otherwise described herein or a pharmaceutical composition as otherwise described herein.

[0011] Compared to existing, state of the art compounds, in certain aspects, the compounds of this disclosure have improved adsorption, distribution, metabolism, excretion, and pharmacokinetic (ADME-PK) properties, including improved thermodynamic stability and / or improved metabolic stability. Improved pharmacokinetics are realized with in certain aspects of this disclosure upon intravenous (IV) and oral (PO) administration. In certain aspects, the compounds of this disclosure have improved pharmacodynamic (PD) effects upon oral (PO) administration. In certain aspects, the compounds of this disclosure have improved potency as fetal hemoglobin inducing agents either in vitro, ex vivo, or upon oral (PO) administration in vivo.

[0012] Other aspects and embodiments of the disclosure are evident in view of the detailed description provided herein.DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention relates to benzoxazole derivatives. In particular, the present invention relates to compounds that are useful in the treatment of hematological, inflammatory, or elevated oxidative stress conditions, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of use therefor.DEFINITIONS

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference to the extent they are consistent with the present disclosure. Terms and ranges have their generally defined definition unless expressly defined otherwise.

[0015] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g., CH3-CH2-), in certain circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.” Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene. All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).

[0016] The term “amino” refers to -NH2.

[0017] The term “acetyl” refers to -C(O)CH3.

[0018] As herein employed, the term “acyl” refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.

[0019] The term “alkyl” as employed herein refers to saturated straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl" encompasses C1 , C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12 groups. Alkyl groups may be branched or unbranched. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0020] The term “C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino” in the definitions of X, Y and Z refers to groups such as:

[0021] The term “alkenyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12 groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0022] The term “alkynyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, “alkynyl” encompasses C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12 groups. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0023] An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.

[0024] The term “alkoxy” refers to -O( C1-C6 alkyl).

[0025] The term “cycloalkyl” as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. As such, “cycloalkyl” includes C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12 cyclic hydrocarbon groups. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0026] The term “C3-C6 cycloalkyloxy” refers to groups of the formula -O(C3-C6 cycloalkyl).

[0027] The term “heteroalkyl” refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced O, S, or NRX, wherein Rxis hydrogenor C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxy propyl.

[0028] An “aryl” group is a CS-CM aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes Ce, C10, C13, and C14 cyclic hydrocarbon groups. A representative aryl group is a C6-C10 aryl group. Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aryl” group also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic, such as indenyl.

[0029] An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group wherein the moiety is linked to another group via the alkyl moiety. An representative aralkyl group is - C1-C6 alkyl(C6-C10)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. For example, an arC1-C6alkyl is an aryl group covalently linked to a C1-C3 alkyl .

[0030] A “heterocyclyl” or “heterocyclic” or “heterocycloalkyl” group is a mono- or bicyclic (e.g., fused) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently N, O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons. Examples of heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl- morpholinyl, and morpholinyl. The heterocyclic groups can be attached to a parent group (i.e., the point of attachment) via any ring atom, including one of the heteroatoms or one of the carbon atoms, in the heterocyclic ring group. As chemically required, the heterocyclic ring may be attached to one or more other groups, for instance if operating as a bridging group. The term “heterocyclyl” also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is aromatic or non-aromatic, provided that at least one ring is non-aromatic contains an N, O, or S ring atom. Examples of such fused multicyclic ring systems are indolinyl, indolin-2-yl, 2,3-dihydrobenzofuran-2-yl, and 2,3,4,5-tetrahydrobenzo[d]oxazol-2-yl. Each of these examples is a 9-membered heterocyclyl.

[0031] As used herein, the term “heteroaryl” refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13, or 14 ring atoms; having 6, 10, or 14 TT electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S. “Heteroaryl” also includes fused multicyclic (e.g., bicyclic) ring systems in which one or moreof the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom. The heteroaryl groups can be attached to a parent group (i.e. , the point of attachment) via any ring atom, including one of the heteroatoms or one of the carbon atoms, in the heteroaryl ring group. As chemically required, the heteroaryl may be attached to one or more other groups, for instance if operating as a bridging group.

[0032] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1 ,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyi, benztriazolyl, benztetrazolyi, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyi, isoxazolyi, naphthyridinyl, octahydroisoquinolinyi, oxadiazolyl, 1 ,2,3- oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrroiyl, quinazolinyl, quinoiinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1 ,2,5-thiadiazinyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,5-triazolyl, 1 ,3,4-triazolyl, and xanthenyl.

[0033] Preferred heteroaryl groups have 5-10 members. Other preferred heteroaryl groups have from 5-6 members.

[0034] An “arylene,” “heteroarylene,” or “heterocyclylene” group is a bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.

[0035] As employed herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as “optionally substituted” without expressly stating the substituents, it is meant that the group optionally has multiple non-hydrogen substituents, for example, from one to five, or from one to four, or from one to three, or one, or two non-hydrogen substituents.

[0036] The term “halogen” or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine.

[0037] The term “haloalkyl” refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Representative haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0038] The term “hydroxyalkyl” refers to -alkylene-OH.

[0039] It is to be understood that each individual atom present in Formula (I) and the compounds within Formula (I), may be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in Formula (I), or in the formulae depicted hereinafter, may be present as a1H,2H (deuterium; D), or3H (tritium; T) atom, preferably1H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a12C,13C, or14C atom, preferably12C.

[0040] As used herein, “an effective amount” of a compound is an amount that is sufficient to treat an inflammatory condition.

[0041] As used herein, a “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate or in some manner reduce a symptom or stop or reverse progression of an inflammatory condition. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0042] As used herein, "treatment” means any manner in which the symptoms or pathology of a condition, disorder or disease in a patient are ameliorated or otherwise beneficially altered.

[0043] As used herein, “amelioration of the symptoms of an inflammatory condition by administration of a particular compound or pharmaceutical composition” refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.

[0044] As used herein, the terms “individual,” “patient,” or “subject” are used interchangeably, refers to any animal, including mammals, preferably humans.COMPOUNDS

[0045] In one aspect, the present disclosure provides compounds of Formula (I):or a pharmaceutically acceptable salt prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein: each of R1, R3, R4, and R8is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halo C1-C6 alkyl, or OR10, wherein R10is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halo C1-C6 alkyl;R2is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halo C1-C6 alkyl, OR10, hydroxy C1-C6 alkyl, or -C(O)NR11R12, wherein each of R11and R12is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, or hydroxy C1-C6 alkoxy C1-C6 alkyl;Rsis hydrogen, hydroxy C1-C6 alkyl, or carboxy C1-C6 alkyl;R6and R7are independently hydrogen, hydroxy C1-C6 alkyl, -X-C(O)R13, -Y- C(O)NR14R15, -Z-NR16R17, heteroaryl, or -S(O)2R18, whereinX is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino;R13is -OH or -OR10;Y is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino; each of R14and R15is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl C3-C6 cycloalkylamino, C1-C6 amine, carboxy C1-C6 alkyl, -S(O)2R19, phenyl, heteroaryl, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group, whereinR19is C1-C6 alkyl;the phenyl is optionally substituted with C1-C6 alkyl; the heteroaryl is optionally substituted with C1-C6 alkyl; and the 3-8 membered monocyclic heterocyclyl group is optionally substituted with C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl;Z is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino; each of R16and R17is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, -(C1-C6 alkyl)-C(O)R20, -C(O)R21, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group, whereinR2Gis -OH, OR10, or NR22R23, wherein each R22and R23is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or hydroxy C1-C6 alkyl C3-C6 cycloalkylamino;R21is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or C1-C6 amine; and the 3-8 membered monocyclic heterocyclyl group is optionally substituted with C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl;RiSis C1-C6 alkyl or -NH-(CrCsalkyl); andR9is hydrogen, C1-C6 alkyl, or a N-protecting group.

[0046] In certain embodiments of Formula (I) as otherwise described herein, R1is hydrogen.

[0047] In certain embodiments of Formula (I) as otherwise described herein, R1is methyl.

[0048] In certain embodiments of Formula (I) as otherwise described herein, R1is fluoro.

[0049] In certain embodiments of Formula (I) as otherwise described herein, R1is OR10, and wherein R10is methyl.

[0050] In certain embodiments of Formula (I) as otherwise described herein, R2is hydrogen.

[0051] In certain embodiments of Formula (I) as otherwise described herein, R2is methyl.

[0052] In certain embodiments of Formula (I) as otherwise described herein, R2is fluoro.

[0053] in certain embodiments of Formula (I) as otherwise described herein, R2is OR10, and wherein R10is methyl.

[0054] In certain embodiments of Formula (I) as otherwise described herein, R2is -C(O)NR11R12, and wherein R11is hydrogen, and R12is C1-C6 alkoxyC1-C6 alkyl.

[0055] In certain embodiments of Formula (I) as otherwise described herein, R2is -C(O)NR11R12, and wherein R11is hydrogen,

[0056] In certain embodiments of Formula (I) as otherwise described herein, R3is hydrogen.

[0057] In certain embodiments of Formula (I) as otherwise described herein, R3is methyl.

[0058] In certain embodiments of Formula (I) as otherwise described herein, R3is fluoro or chloro.

[0059] in certain embodiments of Formula (I) as otherwise described herein, R3is halo C1-C6 alkyl.

[0060] in certain embodiments of Formula (I) as otherwise described herein, R3is difluoromethyl or trifluoromethyl.

[0061] In certain embodiments of Formula (I) as otherwise described herein, R3is OR10, and wherein R10is methyl or difluoromethyl.

[0062] In certain embodiments of Formula (I) as otherwise described herein, R4is hydrogen.

[0063] In certain embodiments of Formula (I) as otherwise described herein, R4is methyl.

[0064] In certain embodiments of Formula (I) as otherwise described herein, R4is fluoro.

[0065] In certain embodiments of Formula (I) as otherwise described herein, Rsis hydrogen.

[0066] In certain embodiments of Formula (I) as otherwise described herein, R5is hydroxy CrCe alkyl and preferably

[0067] In certain embodiments of Formula (I) as otherwise described herein, R5is carboxyC1-C6 alkyl and preferably

[0068] in certain embodiments of Formula (I) as otherwise described herein, only one of R6and R7is hydrogen.

[0069] In certain embodiments of Formula (I) as otherwise described herein, each of R6and R7is hydrogen.

[0070] in certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is hydrogen and the other is hydroxy C1-C6 alkyl, preferably(embodiment 1-1).

[0071] In certain embodiments of Formula (I) as otherwise described herein, R6is -X-C(O)R13, wherein X is a bond (embodiment 1-2).

[0072] In certain embodiments of Formula (I) and embodiment 1-2 as otherwise described herein, R7is hydrogen (embodiment 1-3).

[0073] In certain embodiments of Formula (I) and embodiments 1-2 and 1-3 as otherwise described herein, R13is -OH.

[0074] In certain embodiments of Formula (I) and embodiments 1-2 and 1-3 as otherwise described herein, R13is -OR10, and wherein R10is methyl.

[0075] In certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is -X-C(O)R13, and wherein X is methyl or ethyl (embodiment 1-4).

[0076] In certain embodiments of Formula (I) and embodiment 1-4 as otherwise described herein, Rsis -X-C(O)R13, and wherein X is hydroxyethyl (embodiment 1-5).

[0077] in certain embodiments of Formula (I) as otherwise described herein, R6is -X-C(O)R13, and wherein X is cyclopropyl (embodiment 1-6).

[0078] In certain embodiments of Formula (I) and embodiments 1-4 to 1-6 as otherwise described herein, R13is -OH.

[0079] In certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is -Y-C(O)NR14R15, wherein Y is a bond (embodiment 1-7).

[0080] In certain embodiments of Formula (I) and embodiment 1-7 as otherwise described herein, R8is -Y-C(O)NR14R1S, wherein Y is a bond (embodiment 1-7-1).

[0081] in certain embodiments of Formula (I) and embodiment 1-7 as otherwise described herein, R7is -Y-C(O)NR14R15, wherein Y is a bond (embodiment 1-7-2).

[0082] References herein to embodiment 1-7 includes reference to embodiments 1-7-1 and 1-7- 2.

[0083] In certain embodiments of Formula (I) and embodiment 1-7 as otherwise described herein, R7is hydrogen (embodiment 1-8).

[0084] in certain embodiments of Formuia (i) and embodiment 1- / as otherwise described herein, R5is hydrogen (embodiment 1-8-1).

[0085] References herein to embodiment 1-8 includes reference to embodiment 1-8-1.

[0086] in certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and R1Sis hydrogen.

[0087] in certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and R1Sis C1-C6 alkyl,

[0088] in certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and R15is methyl.

[0089] In certain embodiments of Formuia (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and R15is C1-C6 alkoxy C1-C6 alkyl.

[0090] In certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and

[0091] in certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and R15is hydroxy C1-C6 alkoxy C1-C6 alkyl.

[0092] in certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and

[0093] in certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and R15is halo C1-C6 alkyl.

[0094] In certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and

[0095] in certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and R15is hydroxy C1-C6 alkyl C3-C6 cycloalkylamino.

[0096] in certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and

[0097] in certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and R15is C1-C6 amine.

[0098] in certain embodiments of Formula (I) and embodiments 1 -7 and 1-8 as otherwise described herein, R14is hydrogen, and

[0099] In certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is hydrogen, and R15is heteroaryi.

[0100] In certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise

[0101] In certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is C1-C6 alkyl, and R15is C1-C6 alkyl.

[0102] in certain embodiments of Formula (I) and embodiments 1-7 and 1-8 as otherwise described herein, R14is methyl, and R15is methyl.

[0103] In certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is -Y-C(O)NR14R15, wherein Y is

[0104] In certain embodiments of Formula (I) as otherwise described herein, Rsis -Y- C(O)NR14R1S, wherein Y is C1-C6 alkylene (embodiment 1-9-1). Reference herein to embodiment 1-9 includes reference to embodiment 1-9-1.

[0105] In certain embodiments of Formula (I) and embodiment 1-9 as otherwise described herein, R7is hydrogen (embodiment 1-10).

[0106] In certain embodiments of Formula (I) and embodiment 1-9 as otherwise described herein, R6is hydrogen (embodiment 1-10-1).

[0107] In certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is -Y-C(O)NR14R'i5, wherein Y is methylene (embodiment 1-11 ).

[0108] In certain embodiments of Formula (I) as otherwise described herein, R6is -Y- C(O)NR!4R15, wherein Y is methylene (embodiment 1-11-1). In certain embodiments, embodiment 1-11 includes embodiment 1-11-1.

[0109] in certain embodiments of Formula (I) and embodiment 1-11 as otherwise described herein, R7is hydrogen (embodiment 1-12).

[0110] In certain embodiments of Formula (I) and embodiment 1-11 as otherwise described herein, R6is hydrogen (embodiment 1-12-1 ).

[0111] References herein to embodiments 1-11 and 1-12 includes reference to embodiments 1- 11-1 and 1-12-1 , respectively.

[0112] In certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14is hydrogen, and R1Sis alkyl.C1-C6

[0113] In certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14is hydrogen, and R1Sis methyl.

[0114] in certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14is hydrogen, and R15is hydroxy C1-C6 alkyl.

[0115] In certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14is hydrogen, and.

[0116] In certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14is hydrogen, and R15is hydroxy C1-C6 alkoxy C1-C6 alkyl.

[0117] in certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14is hydrogen, and R15

[0118] In certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14is hydrogen, and R15is carboxy C1-C6 alkyl.

[0119] In certain embodiments of Formula (I) and embodiments 1-9 toas otherwise o described herein, R14is hydrogen, and

[0120] in certain embodiments of Formula (I) and embodimentsto 1-12 as otherwise described herein, R14is hydrogen, and R15is -S(O)2R19, and wherein R!9is methyl.

[0121] In certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14is hydrogen, and R15is heteroaryl. In various embodiments, the heteroaryl may be any heteroaromatic ring systems, including, but not limited to, isoxazole, pyrazole, and triazole.

[0122] In certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14is hydrogen, and R15is,

[0123] in certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14and R15together with the nitrogen to which they are attached form a 6- membered monocyclic heterocyciyl group (embodiment 1-13).

[0124] in certain embodiments of Formula (I) and embodiments 1-13 as otherwise described herein, the 6-membered monocyclic heterocyciyl group is

[0125] in certain embodiments of Formula (I) and embodiments 1-9 to 1-12 as otherwise described herein, R14is methyl, and R1Sis methyl.

[0126] in certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is -Y-C(O)NR14R1S, wherein Y is ethyl (embodiment 1-14).

[0127] in certain embodiments of Formula (I) as otherwise described herein, Rsis -Y- C(O)NR14R15, wherein Y is ethyl (embodiment 1-14-1). In certain embodiments, embodiment 1- 14 includes embodiment 1-14-1.

[0128] In certain embodiments of Formula (I) and embodiment 1-14 as otherwise described herein, R7is hydrogen (embodiment 1-15).

[0129] In certain embodiments of Formula (I) and embodiment 1-14 as otherwise described herein, R6is hydrogen (embodiment 1-15-1).

[0130] References herein to embodiment 1-15 includes reference to embodiment 1-15-1.

[0131] In certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is -Y-C(O)NR14R15, wherein Y is hydroxyethyl (embodiment 1-16).

[0132] in certain embodiments of Formula (I) as otherwise described herein, R6is -Y- C(O)NR14R15, wherein Y is hydroxyethyl (embodiment 1-16-1). In certain embodiments, embodiment 1-16 includes embodiment 1-16-1.

[0133] in certain embodiments of Formula (I) and embodiment 1-16 as otherwise described herein, R7is hydrogen (embodiment 1-17).

[0134] in certain embodiments of Formula (I) and embodiment 1-16 as otherwise described herein, R6is hydrogen (embodiment 1-17-1).

[0135] References herein to embodiment 1-17 includes reference to embodiment 1-17-1.

[0136] in certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is -Y-C(O)NR14R'i5, wherein Y is cyclopropylene (i.e. , a group having the formula(embodiment 1-18).

[0137] In certain embodiments of Formula (I) as otherwise described herein, Rsis -Y- C(O)NR14R1S, wherein Y is cyclopropylene (i.e, , a group having the formula

[0138] (embodiment 1-18-1). In certain embodiments, embodiment 1-18 includes embodiment 1-18-1.

[0139] in certain embodiments of Formula (I) and embodiment 1-18 as otherwise described herein, R7is hydrogen (embodiment 1-19).

[0140] in certain embodiments of Formula (I) and embodiment 1-18 as otherwise described herein, R6is hydrogen (embodiment 1-19-1).

[0141] References herein to embodiments 1-18 and 1-19 include reference to embodiments 1- 18-1 and 1-19-1 , respectively.

[0142] In certain embodiments of Formula (I) and embodiments 1-14 to 1-19 as otherwise described herein, R14is hydrogen, and R15is hydroxy C1-C6 alkoxy C1-C6 alkyl.

[0143] In certain embodiments of Formula (I) and embodiments 1-14 to 1-19 as otherwise described herein, R14is hydrogen, and R15is

[0144] In certain embodiments of Formula (I) and embodiments 1-14 to 1-19 as otherwise described herein, R14is hydrogen, and R15is C1-C6 alkyl.

[0145] In certain embodiments of Formula (I) and embodiments 1-14 to 1-19 as otherwise described herein, R14is hydrogen, and R1Sis methyl.

[0146] in certain embodiments of Formula (I) and embodiments 1-14 to 1-19 as otherwise described herein, R14is methyl, and R1Sis methyl.

[0147] in certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is -Z-NR18R17, wherein Z is a bond (embodiment 1-20).

[0148] in certain embodiments of Formula (I) as otherwise described herein, R6is -Z-NR16R17, wherein Z is a bond (embodiment 1-20-1 ). In certain embodiments, embodiment 1-20 includes embodiment 1-20-1.

[0149] in certain embodiments of Formula (i) and embodiment 1-20 as otherwise described herein, R7is hydrogen (embodiment 1-21).

[0150] in certain embodiments of Formula (I) and embodiment 1-20 as otherwise described herein, R6is hydrogen (embodiment 1-21-1).

[0151] References herein to embodiment 1-20 and 1-21 include reference to embodiments 1-20- 1 and 1-21 , respectively.

[0152] In certain embodiments of Formula (I) and embodiments 1-20 and 1-21 as otherwise described herein, R15is hydrogen, and R17is -C(O)R21, and wherein R21is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, CrC@ alkoxy, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or Ci-C6amine.

[0153] In certain embodiments of Formula (I) and embodiments 1-20 and 1-21 as otherwise described herein, R16is hydrogen, and R17is -C(O)R21, and wherein R21is methyl.

[0154] In certain embodiments of Formula (I) and embodiments 1-20 and 1-21 as otherwise described herein, R16is hydrogen, and R17is -C(O)R21, and wherein R21is methoxy.

[0155] In certain embodiments of Formula (I) and embodiments 1-20 and 1-21 as otherwiseI described herein, R16is hydrogen, and R17is -C(O)R21, and wherein R21is -NH2or

[0156] In certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is -Z-NRi6R17, wherein Z is methyl (embodiment 1-22).

[0157] In certain embodiments of Formula (I) as otherwise described herein, R6is -Z-NR16R17, wherein Z is methyl (embodiment 1-22-1). In certain embodiments, embodiment 1-22 includes embodiment 1-22-1.

[0158] in certain embodiments of Formula (i) and embodiment 1-22 as otherwise described herein, R7is hydrogen (embodiment 23).

[0159] in certain embodiments of Formula (i) and embodiment 1-22 as otherwise described herein, R6is hydrogen (embodiment 1-23-1).

[0160] References herein to embodiments 1-22 and 1-23 indude reference to embodiments 1- 22-1 and 1-23-1 , respectively.

[0161] In certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is hydrogen, and R17is methyl.

[0162] In certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is hydrogen, and R17is alkoxCy 1 C-C1-6C6 alkyl.

[0163] in certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is hydrogen, and

[0164] In certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is hydrogen, and R17is -(C1-C6 alkyl)-C(O)R20, and wherein R20is -OH, OR10, or NR22R23, and wherein each R22and R23is independently hydrogen, alkyl, C3-C6 C1-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or hydroxy C1-C6 alkyl C3-C6 cycloalkyl am I no.

[0165] In certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is hydrogen, and R17is -(C1-C6 alkyl)-C(O)R20, and wherein R20is -OH or

[0166] In certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R15is hydrogen, and R17is -C(O)R21, and wherein R21is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or C1-C6 amine.

[0167] In certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is hydrogen, and R17is -C(O)R21, and wherein R21is methyl.

[0168] In certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R1bis hydrogen, and R1' is -C(O)Rz1, and wherein R21is -NH2,

[0169] In certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is hydrogen, and R17is -C(O)R21, and wherein R21.

[0170] in certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is methyl, and R17is methyl.

[0171] in certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is methyl, and R17is hydroxy C1-C6 alkyl.

[0172] in certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is methyl, and

[0173] in certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is methyl, and R17is halo C1-C6 alkyl.

[0174] in certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is methyl, and

[0175] In certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R16is ethyl, and R17is ethyl.

[0176] in certain embodiments of Formula (I) and embodiments 1-22 and 1-23 as otherwise described herein, R1Sand R17together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group (embodiment 1-24).[017 / ] in certain embodiments of Formula (I) and embodiment 1-24 as otherwise described herein, the 3-8 membered monocyclic heterocyclyl group

[0178] in certain embodiments of Formula (I) as otherwise described herein, one of Rsand R7is

[0179] in certain embodiments of Formula (I) as otherwise described herein, R6is Hor H (embodiment 1-25-1). In certain embodiments, embodiment 1-25 includes embodiment 1-25-1.

[0180] in certain embodiments of Formula (I) and embodiment 1-25 as otherwise described herein, R7is hydrogen (embodiment 1-26).

[0181] In certain embodiments of Formula (I) as otherwise described herein, one of Rsand R7is -S(O)2R18, wherein R18is C1-C6 alkyl or -NH-(C1-C6 alkyl) (embodiment 1-27).

[0182] In certain embodiments of Formula (I) as otherwise described herein, R6is -S(O)2R18, wherein R1Sis C1-C6 alkyl or -NH-(C1-C6 alkyl) (embodiment 1-27-1). In certain embodiments, embodiment 1-27 includes embodiment 1-27-1.

[0183] In certain embodiments of Formula (I) and embodiment 1-27 as otherwise described herein, R7is hydrogen (embodiment 1-28).

[0184] In certain embodiments of Formula (I) as otherwise described herein, one of R6and R7is -S(O)2RiS, wherein R1Sis -NH2or -NHCH3(embodiment 1-29).

[0185] In certain embodiments of Formula (I) as otherwise described herein, R6is -S(O)2R1S, wherein R18is -NH2or -NHCH3(embodiment 1-29-1). In certain embodiments, embodiment 1-29 includes embodiment 1-29-1.

[0186] In certain embodiments of Formula (I) and embodiment 1-29 as otherwise described herein, R7is hydrogen (embodiment 1-30).

[0187] In certain embodiments of Formula (I) as otherwise described herein, R6is hydrogen, and R7is -C(O)NR2SR26, wherein each of R25and R25is independently hydrogen or hydroxy C1-C3 alkoxy C1-C3 alkyl (embodiment 1-31).

[0188] In certain embodiments of Formula (I) as otherwise described herein, R6is hydroxy C1-C6 alkyl, and R7is -OR24, wherein R24is C1-C3 alkyl (embodiment 1-32).

[0189] in certain embodiments of Formula (I) as otherwise described herein, R6is -X-C(O)R13, and R7is -OR24, wherein X is methyl, R13is -OH, and R24is C1-C3 alkyl (embodiment 1-33).

[0190] In certain embodiments of Formula (I) as otherwise described herein, R6is -Y- C(O)NR14R15, and R7is halogen, -OR24, or hydroxy C1-C6 alkyl, wherein Y is a bond, each of R14and R15is independently hydrogen, C1-C6 alkyl, or hydroxy C1-C6 alkoxy C1-C6 alkyl, and R24is C1-C3 alkyl (embodiment 1-34).

[0191] In certain embodiments of Formula (I) and embodiment 1-34 as otherwise described herein, R14is hydrogen, and R15is C1-C6 alkyl.

[0192] !n certain embodiments of Formula (I) and embodiment 1-34 as otherwise described herein, R14is hydrogen, and R15is methyl.

[0193] In certain embodiments of Formula (I) and embodiment 1-34 as otherwise described herein, R14is hydrogen, and R15is hydroxy alkoxCy 1 C-C1-6C6 alkyl.

[0194] In certain embodiments of Formula (I) and embodiment 1-34 as otherwise described herein, R14is hydrogen,

[0195] In certain embodiments of Formula (I) and embodiment 1-34 as otherwise described herein, R7is fluoro.

[0196] In certain embodiments of Formula (I) and embodiment 1-34 as otherwise described herein, R7is hydroxy C1-C6 alkyl, preferably, >OOH or ^OH .

[0197] In certain embodiments of Formula (I) as otherwise described herein, R6is -Y- C(O)NR14R15, and R7is -OR24or hydroxy C1-C6 alkyl, wherein Y is methyl, each of R14and R15is independently hydrogen or hydroxy C1-C6 alkoxy C1-C6 alkyl, and R24is C1-C3 alkyl (embodiment 1-35).

[0198] in certain embodiments of Formula (I) and embodiment 1-35 as otherwise described herein, R14is hydrogen, and R15is hydroxy C1-C6 alkoxy CrC@ alkyl.

[0199] in certain embodiments of Formula (I) and embodiment 1-35 as otherwise described herein, R14is hydrogen, and Ri5isZV^°''' / 'SOH .

[0200] In certain embodiments of Formula (I) and embodiment 1-35 as otherwise described herein, R7is hydroxy C1-C6 alkyl, preferably,.

[0201] In certain embodiments of Formula (I) as otherwise described herein, R6is -Z-NR16R17, and R7is -OR24, wherein each of R16and R17is C1-C6 alkyl, Z is methyl, and R24is C1-C3 alkyl (embodiment 1-36).

[0202] in certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, each of R16and R17is methyl (embodiment 1-37).

[0203] in certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R8is hydrogen (embodiment 1-37).

[0204] in certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R8is methyl (embodiment 1-38).

[0205] in certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R8is cyclopropyl (embodiment 1-39).

[0206] in certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R8is fluoro or chloro (embodiment 1-40).

[0207] in certain embodiments of Formula (!) and embodiments 1-1 to 1-36 as otherwise described herein, R8is OR10, and wherein R10is methyl (embodiment 1-41).

[0208] In certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R9is hydrogen (embodiment 1-42).

[0209] In certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R9is methyl (embodiment 1-43).

[0210] In certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R9is a N-protecting group (embodiment 1-44).

[0211] in certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R1-R4are all hydrogen (embodiment 1-45).

[0212] in certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R5and R8are hydrogen (embodiment 1-46).

[0213] in certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R2is halogen, preferably fluoro (embodiment 1-47).

[0214] in certain embodiments of of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R4is halogen, preferably fluoro (embodiment 1-48).

[0215] In certain embodiments of of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R2and R4are halogen, preferably fluoro (embodiment 1-49).

[0216] in certain embodiments of of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R1and R2are halogen, preferably fluoro (embodiment 1-50).

[0217] In certain embodiments of of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R2is halogen and R4is C1-C6 alkoxy, preferably methoxy or ethoxy(embodiment 1-51).

[0218] in certain embodiments of of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R1and R2are halogen, preferably fluoro (embodiment 1-52).

[0219] In certain embodiments of of Formula (I) and embodiments 11-1 to -36 as otherwise described herein, R!is halogen, preferably fluoro, alkoxCy,1 p-Cre6ferably methoxy or ethoxy, or C1-C6 alkyl, preferably methyl; and R2is halogen, preferably fluoro (embodiment 1-53).

[0220] in certain embodiments of of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R2is hydrogen or halogen; and R3is trifluoromethyl (embodiment 1-54).

[0221] In certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R2is halogen, trifluoromethyl, C1-C3 alkyl or C1-C3 alkoxy; and R1, R3, R4, R5, R7and Rsare hydrogen (embodiment 1-55).

[0222] In certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R1-Rs, R7and R8are hydrogen (embodiment 1-56).

[0223] In certain embodiments of Formula (I) and embodiments 1-1 to 1-36 as otherwise described herein, R2is halogen, trifluoromethyl, C1-C3 alkyl or C1-C3 alkoxy; and R1, R3, R4, R5, R6and R8are hydrogen (embodiment 1-57).

[0224] In certain embodiments of Formula (I) as otherwise described herein, R '-R6and R8are hydrogen.

[0225] In one aspect, the present disclosure provides compounds of Formula (II):or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein: each of R1, R3, R4, and R8is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halo C1-C6 alkyl, or OR10, wherein R10is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halo C1-C6 alkyl;R5is hydrogen, hydroxy C1-C6 alkyl , or carboxy C1-C6 alkyl;R6is hydrogen, hydroxy C1-C6 alkyl, -X-C(O)R13, -Y-C(O)NR14R15, -Z-NR16R17, heteroaryl, or -S(O)2R18, whereinX is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino;R13is -OH or -OR10;Y is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino; each of R14and R15is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl C3-C6 cycloalkylamino, C1-C6 amine, carboxy C1-C6 alkyl, -S(O)2R19, phenyl, heteroaryl, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group, whereinR19is C1-C6 alkyl; the phenyl is optionally substituted with C1-C6 alkyl; the heteroaryl is optionally substituted with C1-C6 alkyl; and the 3-8 membered monocyclic heterocyclyl group is optionally substituted with C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl;Z is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino; each of RiSand R17is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, -(C1-C6 alkyl)-C(O)R20, -C(O)R21, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group, whereinR20is -OH, OR10, or NR22R23, wherein each R22and R23is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or hydroxy C1-C6 alkyl C3-C6 cycloalkylamino;R21is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or C1-C6 amine; andthe 3-8 membered monocyclic heterocyclyl group is optionally substituted with C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, hydroxyC1-C6 alkyl, amino C1-C6 alkyl;R18is C1-C6 alkyl or -NH-(C1-C6 alkyl);R7is hydrogen, halogen, -OR24, hydroxy C1-C6 alkyl, or -C(O)NR25R26, wherein:R24is C1-C3 alkyl, and each of R25and R2Sis independently hydrogen or hydroxy C1-C3 alkoxy C1-C3 alkyl;R9is hydrogen, C1-C6 alkyl, or a N-protecting group.

[0226] In one embodiment, the compound of Formula (I) is selected from:PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS

[0227] The compounds of Formula (!) may be formulated into pharmaceutical compositions.

[0228] in another aspect, the present disclosure provides pharmaceutical compositions comprising benzoxazole derivatives according to the invention, or salts of the pharmaceutical compositions together with a pharmaceutically acceptable carrier, excipient, or diluent.Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by the oral route.

[0229] The characteristics of the carrier will depend on the route of administration. As used herein, the term “pharmaceutically acceptable” means a non-toxic material that is compatible with a biological system such as a cell, a cell culture, a tissue, or an organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington’s Pharmaceutical Sciences, 18th Edition, A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0230] As used herein, the term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, without limitation, acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NFTZ', wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsuifonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0231] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A dose of the active compound for all of the above- mentioned conditions is in the range from about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3 % wt / wt in a suitable carrier. The effective dosagerange of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.

[0232] The pharmaceutical compositions comprising compounds of the present invention may be used in the methods described herein.

[0233] The pharmaceutical composition can be, for example, in the form of a tablet, a capsule, or a parenteral formulation, but the person of ordinary skill in the art will appreciate that the compound can be provided in a wide variety of pharmaceutical compositions.

[0234] The compounds of the disclosure can be administered, for example, orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing one or more pharmaceutically acceptable carriers, diluents or excipients. The term “parenteral” as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. A medicament including a compound of the disclosure can be provided in any appropriate of the formulations and dosage forms as described herein.

[0235] in the pharmaceutical compositions disclosed herein, one or more compounds of the disclosure may be present in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and, if desired, other active ingredients. The pharmaceutical compositions containing compounds of the disclosure may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

[0236] Compositions intended for oral use can be prepared according to any suitable method for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or coated by knowntechniques, in some cases such coatings can be prepared by suitable techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

[0237] Formulations for oral use can also be presented as hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

[0238] Formulations for oral use can also be presented as lozenges.

[0239] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitoi anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0240] Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0241] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

[0242] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.

[0243] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not water. In other embodiments, the water comprises less than 50% of the composition. In some embodiments, compositions comprising less than 50% water have at least 1 %, 2%, 3%, 4% or 5% water, in other embodiments, the water content is present in the composition in a trace amount.

[0244] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not alcohol. In other embodiments, the alcohol comprises less than 50% of the composition, in some embodiments, compositions comprising less than 50% alcohol have at least 1%, 2%, 3%, 4% or 5% alcohol. In other embodiments, the alcohol content is present in the composition in a trace amount.

[0245] Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative, flavoring, and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0246] Compounds of the disclosure can also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

[0247] Compounds of the disclosure can also be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

[0248] The compositions can be formulated in a unit dosage form of the active ingredient. 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.

[0249] The compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0250] 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 described herein. Wien referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein.

[0251] The tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. 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 which serves to resistdisintegration 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.

[0252] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

[0253] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0254] The therapeutic dosage of the compounds can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 1 pg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0255] The compounds described herein can also be formulated in combination with or administered sequentially with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.

[0256] The person of ordinary skill in the art will formulate a compound as described into pharmaceutical formulations herein. For example, based on the physicochemical properties of the compound, one of ordinary skill in the art will recognize a pharmaceutically effective amount of the compound, and the desired route of administration.Methods of Use

[0257] In another aspect, the present disclosure generally relates to methods for treating an inflammatory condition or oxidative stress. These methods comprise administering to a subject in need thereof a therapeutically effective amount of a benzoxazole derivative according to the invention.

[0258] In some embodiments, the benzoxazole derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof. In particular embodiments, the benzoxazole derivative comprises a compound selected from Table 1 as described herein.

[0259] in another aspect, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in the General Reaction Schemes).

[0260] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, and a pharmaceutically acceptable diluent or carrier.

[0261] In another aspect, the present disclosure provides a method of treating an inflammatory condition or oxidative stress, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof.

[0262] The compositions and methods provided herein may be used for the treatment of a wide variety of inflammatory conditions or oxidative stress. In some embodiments, the inflammatorycondition or oxidative stress is a biood disorder, including, but not limited to, a sickle cell related disorder, beta-thalassemia, hemoglobinopathies, or a myelodysplastic syndrome.

[0263] In some other embodiments, the inflammatory condition or oxidative stress is an inflammatory bowel disease, an arthritic disease, or a neurodegenerative disorder.

[0264] In some other embodiments, the inflammatory condition or oxidative stress is an autoinflammatory syndrome.

[0265] in some other embodiments, the inflammatory condition or oxidative stress is an inflammation-related condition, including, but not limited to, Adult-Onset Still’s Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Macrophage Activation Syndrome (MAS), Autoinflammation with Infantile Enterocolitic (AIFEC), Bullous Pemphigoid, Pemphigus Vulgaris, idiopathic Pulmonary Fibrosis (I PF), Non-Alcoholic Steatohepatitis (NASH), Systemic Lupus Erythematosus (SLE), Multiple Sclerosis, Alzheimer’s Disease, Parkinson’s Disease, Friedreich's ataxia, amyotrophic lateral sclerosis, cerebral nerve degenerative disease, Charcot-Marie-Tooth syndrome, Traumatic Brain Injury (TBI), Inflammatory Bowel Disease (IBD), Rheumatoid Arthritis (RA), Cryopyrin-Associated Periodic Syndromes (CAPS), Vitiligo, Multiple Self-Healing Palmoplantar Carcinoma (MSPC), Autoimmune Addison’s Disease, Familial Mediterranean Fever (FMF), Autoimmune Thyroiditis, Stroke, Type 2 Diabetes (T2D), Osteoarthritis, Gout, Atherosclerosis, Hidradenitis Suppurativa, Psoriasis, Pyrin Diseases, or Sickle Cell Disease.

[0266] In some other embodiments, the inflammatory condition or oxidative stress is an infectious disease, an autoimmune disease, a cancer, a metabolic disorder, an eye disease, a liver disease, a renal disease, a cardiovascular disease, a skin disease, a mitochondrial disease, a hematological disorder, a muscle disease, or a neurological disease.

[0267] In some other embodiments, the inflammatory condition or oxidative stress is a fibrotic disease. More particularly, the fibrotic disease is a chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, bronchitis, asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, pulmonary bronchitis, bronchiectasis, pulmonary edema, emphysema, or sarcoidosis. The fibrotic disease may also be a liver fibrotic disease caused by alcoholic cirrhosis, steatosis, cholestasis, a drug side effect, a viral infection, or combinations thereof. Additionally, the fibrotic disease may be a skin fibrotic disease, including, but not limited to an autoimmune disease; and the autoimmune disease may be scleroderma or psoriasis.

[0268] In some other embodiments, the inflammatory condition or oxidative stress is a diabetic condition, including, but not limited to, a Type 1 diabetes mellitus, a Type 2 diabetes mellitus,gestational diabetes, pre-diabetes, hyperglycemia, a metabolic syndrome, or a secondary condition resulting therefrom. In addition, the secondary condition may be congestive heart failure or nephropathy.

[0269] In some other embodiments, the inflammatory condition or oxidative stress is a cardiovascular disease, including, but not limited to, hypertension, heart failure, hypercholesterolemia, atherosclerosis, arteriosclerosis, thrombosis, acute coronary thrombosis, deep vein thrombosis, peripheral vascular disease, congestive heart failure, acute coronary syndrome, failure of arterial fistula for dialysis, ischemia reperfusion injury, primary pulmonary hypertension, primary pulmonary arterial hypertension, or secondary pulmonary arterial hypertension.

[0270] The inflammatory condition as described herein may cause cell death, or release of pro- inflammatory cytokines or other inflammatory mediators, resulting from a coronavirus (e.g., SARS-CoV 2, SARS-CoV, or MERS), viral, bacterial, fungal, parasitic, or other type of infection in a subject.

[0271] In other aspects, the present disclosure provides methods for treating diseases and disorders that respond to fetal hemoglobin induction. The compounds of this disclosure induce fetal hemoglobin and are therefore useful for treating diseases and disorders such as, for example, Sickle Cell Disease, beta-thalassemia, and pyruvate kinase deficiency.

[0272] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.GENERAL REACTION SCHEMES AND EXAMPLES

[0273] The compounds of the present invention may be prepared using commercially available reagents and conventional methods well known to those skilled in the art, for example, in General Reaction Schemes and Examples as described herein. One of skill in the art can adapt the reaction sequences of schemes as provided herein to fit the desired target molecule. Of course,in certain situations one of skill in the art will use different reagents to affect one or more of the individual steps or to use protected versions of certain of the substituents. Additionally, one skilled in the art would recognize that compounds of the disclosure can be synthesized using different routes altogether. For example, the person of ordinary skill in the art may adapt the procedures described herein and / or other procedures familiar to the person of ordinary skill in the art to make the compounds described herein.

[0274] Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available. For example, the compounds of the present invention can be prepared using the reagents and methods as described in U.S. Patent Application Publication No. 2022 / 0177460 A1 and U.S. Patent Application Publication No. 2017 / 0231967 A1 , the disclosure of each of which is hereby incorporated by its entirety.

[0275] Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as HPLC, preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and / or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, New York, 1969.

[0276] During any of the processes for preparation of the subject compounds, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry,” Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis,” Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , in "Methoden der organischen Chemie,” Houben-Weyl, 4. sup. th edition, Vol. 15 / 1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine,” Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and / or in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate,” Georg Thieme Verlag, Stuttgart 1974. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.[027 / ] General Reaction Scheme 1

[0278] General Reaction Scheme 2

[0280] Generai Reaction Scheme 4

[0281] General Reaction Scheme 5

[0282] General Reaction Scheme 6

[0285] General Reaction Scheme 929 30

[0286] intermediate Reaction SchemeSynthesis of methyl 2-iodo-1,3-benzoxazole-5-carboxylatet en - ,Step 1 Step 2

[0287] Step-1 : Synthesis of methyl 1 ,3-benzoxazole-5-carboxyiate

[0288] To a solution of methyl 3-amino-4-hydroxybenzoate (25 g, 150 mmol) in a RB flask, monohydrated p-toluenesulfonic acid (3,56 g, 0.13 eq., 18.7 mmol) and Triethylorthoformate (250 mL) are added at RT. The reaction mixture is stirred at 100 °C for 12 h. The progress of the reaction is monitored by TLC (30 % EtOAc in Hexane). Reaction mixture is evaporated under reduced pressure and the residue is dissolved with ethyl acetate (500 mL). Organic layer is ished with water (750 mL), saturated NaHCCh solution. Organic layer is separated and dried over anhydrous NazSCLs, filtered and evaporated under reduced pressure to get crude compound. Crude is further purified by column chromatography using 20% EtOAC in Hexane as eluent to obtain methyl 1,3-benzoxazole-5-carboxylate (26.1 g, 98.5 %) as an off -white solid. LC-MS (m / z) = 178.0 [M+H]+.

[0289] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.90 (s, 1 H), 8.34 (d, J = 12Hz, 1 H), 8.08 (d, J = 12Hz, 1 H), 8.06 (d, J = 12Hz, 1H), 3.72 (s, 3H).

[0290] Step-2: Synthesis of methyl 2-iodo-1 ,3-benzoxazoie-5-carboxylate

[0291] To a solution of methyl 1,3-benzoxazole-5-carboxylate (5 g, 28.2 mmol) in tetrahydrofuran (59.5 mL, 731 mmol) at -78 °C, lithium bis(trimethy!silyl)azanide (11.8 g, 2.5 eq., 70.6 mmol) is added and stirred at the same temperature for 3 h. A solution of iodine (6.4 g, 1 .8 eq., 50.4 mmol) in THF (15 mL) is added at -78 °C to the reaction mixture. Reaction is allowed to warm up to -20 °C and stirred for 1 h. Reaction mixture is quenched with sat. aqueous ammonium chloride solution (40 mL) and extracted with ethyl acetate (4 X 60 mL). Combined organic layer is dried over sodium sulfate, filtered and concentrated to afford the crude. Crude is further purified by combiflash chromatography using EtOAc in n-heptane (2:8) to afford methyl 2-iodo-1 ,3-benzoxazoie-5- carboxylate (3.5 g, 41%) as a white solid. LC-MS (m / z) = 304.0 [M+H]+.

[0292] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.34 (d, J = 12Hz, 1 H), 8.08 (d, 12Hz, 1 H), 8.06(d, 12Hz, 1 H), 3.72 (s, 3H).

[0293] Below intermediates are synthesized in an analogous manner to Intermediate Reaction Scheme

[0294] Example 1Synthesis of methyl 2-[(5-fluoro-1 ,3-benzoxazol-2-yl)amino]-1 ,3-benzoxazole-5-carboxylate

[0295] Step 1 : Synthesis of methyl 1 ,3-benzoxazole-5" carboxylate

[0296] To a solution of methyl 3-amino-4-hydroxybenzoate (25 g, 150 mmol) in p-toluenesulfonic acid:water (1 :1) (3.56 g, 18.7 mmol) is added triethylorthoformate (250 mL) at room temperature. The reaction mixture is heated to 100 °C and stirred for 12 h. The progress of the reaction is monitored by TLC. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate. The organic layer is ished with water, saturated aqueous NaHCO3, dried over Na2SO.s, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography using 20% EtOAC:hexane as eluent to obtain methyl 1 ,3-benzoxazole- 5-carboxylate (26.1 g, 98.5 %) as an off white solid. LCMS (ES) m / z = 178.0 [M+Hp .

[0297] Step 2: Synthesis of 5-fluoro-1 ,3-benzoxazol-2-amine

[0298] To a stirred solution of 2"amino-4-fluorophenoi (0.5 g, 3.93 mmol) in methanol (8 mL) at room temperature is added cyanogen bromide (833 mg, 7.87 mmol). The reaction mixture is stirred at room temperature for 16 h and monitored by TLC and LCMS. After the completion of reaction, the reaction mixture is concentrated. The residue is diluted with water (50 mL) andextracted with ethyl acetate (2 x 25 mL). The pH of the aqueous layer is adjusted to pH —10-12 using 1M sodium hydroxide solution (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer is dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford 5-fluoro-1,3-benzoxazol-2-amine (580 mg, 97%) as a brown solid. LCMS (ES) m / z ~ 153.0 [M+H]L

[0299] Step 3: Synthesis of methyl 2-[(5-fluoro-1!3-benzoxazol-2-yl)amino]-1!3-benzoxazole-5- carboxylate

[0300] To a stirred solution of methyl 1,3-benzoxazole-5-carboxylate (0.5 g, 2.82 mmol) in tetrahydrofuran (10 mL) is added lithium ferf-butoxide (565 mg, 7.06 mmol) and iodine (466 mg, 3.67 mmol) at 0 °C. After stirring for 10 min, 5-fluoro-1,3-benzoxazol-2-amine (429 mg, 2.82 mmol) in tetrahydrofuran (2 mL) is added, and the resulting reaction mixture is stirred at room temperature for additional 16 h. Progress of the reaction is monitored by TLC and LCMS. After completion of reaction, the reaction mixture is diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer is dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by flash column chromatography, eluting with 50-70% ethyl acetate in n-heptane, to afford the compound of Example 1 (methyl 2- [(5-fluoro-1,3-benzoxazol-2-yl)amino]-1 ,3-benzoxazole-5-carboxylate) (260 mg, 28.15%) as an off-white solid. LCMS (ES) m / z = 328.2 [M+H]T

[0301] Example 2Synthesis of {2-[(5-fluoro-1 ,3-benzoxazol-2~yl)amino]~1 ,3-benzoxazol-5~yl}methanol

[0302] Step 1 : Synthesis of {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,3-benzoxazol-5-yl}- methanol

[0303] To a stirred solution of methyl 2-[(5-fluoro-1,3-benzoxazo!-2-yl)amino]-1,3-benzoxazo!e-5- carboxylate (Example

[10739] , 250 mg, 764 μmol) in tetrahydrofuran (10 mL) under nitrogen atmosphere is added dropwise 1M lithium aluminium hydride in tetrahydrofuran (47.3 pL, 1.15 mmol) at 0 °C. The reaction mixture is stirred at room temperature for 2 h. The reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is quenchedwith saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer is dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford crude compound. The crude material is ished with diethyl ether (10 mL) and n-pentane (10 mL) to afford the compound of Example 2 ({2-[(5-fluoro-1,3-benzoxazol- 2-yl)amino]-1,3-benzoxazol-5-yl}methanol) (180 mg, 78.74%) as a brown solid. LCMS (ES) m / z = 300.1 [M+H]+.

[0304] Example 3Synthesis of A / -{5-[(dimethylamino)methyl]-1 ,3-benzoxazol-2-yl}-5~fluoro-1 ,3-benzoxazol~2- amine

[0305] Step 1 : Synthesis of / V-[5-(chloromethyl)-1 ,3-benzoxazol“2“yl]-5-fluoro-1 ,3-benzoxazoi-2- amine

[0306] To a stirred solution of {2-[(5-fluoro-1 ,3-benzoxazol-2-yl)amino]-1 ,3-benzoxazol-5- yl}methanol (Example 2; 170 mg, 568 μmol) in dichloromethane (8 mL) and dimethylformamide (0.1 mL) under nitrogen atmosphere is added dropwise thionyl chloride (82.5 pL, 1.14 mmol) at 0 °C. The reaction mixture is stirred at room temperature for 3 h, and the reaction is monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture is quenched with saturated sodium bicarbonate solution (20 mL) and extracted with 5% methanol in dichloromethane (2 x 20 mL). The organic layer is separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford crude A / -[5-(chloromethyl)-1 ,3-benzoxazol-2-yl]-5-fluoro-1,3- benzoxazol-2-amine (140 mg, 77.57%) as an off-white solid. LCMS (ES) m / z = 318.1 [M+H]+.

[0307] Step 2: Synthesis of A / -{5-[(dimethylamino)methyl]-1,3-benzoxazol-2-yl}-5-fluoro-1 ,3- benzoxazol-2-amine

[0308] To a stirred solution of A / -[5-(chloromethyl)-1 ,3-benzoxazol-2-yl]-5-fluoro-1,3-benzoxazol- 2-amine (140 mg, 441 μmol) in dimethylformamide (8 mL) at room temperature is added dimethylamine hydrochloride (59.6 mg, 1.32 mmol) and potassium carbonate (183 mg, 1.32 mmol). The reaction mixture is stirred at 80 °C for 2 h in a sealed tube, and the reaction is monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture is dilutedwith water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic is dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is ished with diethyl ether (10 mL) and n-pentane (10 mL) to afford the compound of Example 3 (A / -{5- [(dimethylamino)methyl]-1l3-benzoxazoi-2-yl}-5-fluoro-1,3-benzoxazol-2-amine) (11 mg, 7.65%) as an off-white solid. LCMS (ES) m / z = 327.17

[0309] Example 4Synthesis of 5-fluoro- / V-(5-((4-methylpiperazin-1-yl)rnethyl)benzo[d]oxazol-2-yl)benzo[d]oxazol- 2-amine

[0310] Example 4 is synthesized in an analogous manner to Example 3. LCMS (ES) m / z = 382.4 [M+H]+.

[0311] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.39 - 7.31 (m, 3H), 7.15 (d,8.0 Hz, 1 H), 7.02(d, J = 8.0 Hz, 1 H), 6.89 - 6.84 (m, 1 H), 3.53 (s, 2 H), 2.33 (s, 8 H), 2.26 (s, 3H).

[0312] Example 5Synthesis of ({[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl] methyl} amino)acetic acid

[0313] Step 1 : Synthesis of tert-butyl ({[2-(5-fluoro-1,3-benzoxazol-2-yiamino)-1,3-benzoxazol-5- yl]methyl}amino)acetate

[0314] This step is conducted in an analogous manner to Step 2 of Example 3. LC-MS (m / z) = 413.3 [M+H]\

[0315] Step 2: Synthesis of ({[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl] methyl} amino)acetic acid

[0316] To a stirred solution of tert-butyl ({[2-(5-fluoro-1 ,3-benzoxazol-2-y!amino)-1 ,3-benzoxazol- 5-yl]methyl}amino)acetate (130 mg, 158 μmol) in dichloromethane (5 mL, 78.1 mmol) is added trifluoroacetic acid (60.3 pL, 5 eq., 788 μmol) at 0 °C, and the reaction mixture stirred at ambient temperature for 6 h. The progress of the reaction mixture is monitored by TLC. After the completion of the reaction, the reaction mixture is concentrated under reduced pressure. The crude material is purified by prep-HPLC to afford ({[2-(5-f!uoro-1,3-benzoxazol-2-ylamino)-1,3- benzoxazol-5-yl]methyl}amino)acetic acid (13 mg, 23%) as an white solid. LCMS (ES) m / z = 313.3 [M+H]+.

[0317] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.52 - 7.48 (m, 3 H), 7.27 (t, J = 8.0 Hz, 2 H), 7.01 - 6.97 (m, 1 H), 4.05 (s, 2 H), 3.26 (s, 2 H).

[0318] Purification conditionsFlow rate: 0.5 mL / minColumn: Kinetex EVO C18 (100 mm x 2.1 mm x 2.6 pm)Mobile Phase A: 0.1 % Ammonia in waterMobile Phase B: Acetonitrile

[0319] Example 6Synthesis of {2-[(5-fluoro-1 ,3-benzoxazol-2-yi)-N-methylamino]-1 ,3-benzoxazol-5-yl}methanol

[0320] Step 1 : Synthesis of methyl 2-(methyiamino)-1 ,3-benzoxazole-5-carboxylate

[0321] To a stirred solution of methyl 2-iodo-1,3-benzoxazole-5-carboxyiate (3 g, 9.9 mmol) in ethanol (15 mL) cooled in an ice bath is added 33 % methylamine in ethanol (461 mg, 1.5 eq., 15 mL). The reaction mixture is stirred for 30 mins at RT. The progress of the reaction is monitored by TLC (50 % EtOAc : Hexane) and LCMS. When the starting material is consumed, the reaction mixture is concentrated to obtain methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate (3.6 g).

[0322] Step 2: Synthesis of [2-(methylamino)-1 ,3-benzoxazol-5-yl]methanol

[0323] To a stirred solution of methyl 2-(methylamino)-1 ,3-benzoxazole-5-carboxylate (3.6 g, 17.5 mmol) in tetrahydrofuran (20 mL, 246 mmol) under nitrogen atmosphere at 0 °C is added lithiumaluminum hydride (1.33 g, 2 eq., 17.5 mL) dropwise. The reaction mixture is stirred for 2 h at 0 °C and monitored by TLC (5 % MeOH: 95% DCM) and LCMS. After the starting material is consumed, 1 .4 mL of water is added, and the resulting mixture is stirred for 5 min followed by the addition of 1.4 mL of 15% NaOH and an additional 4.2 mL of water. The solid formed is removed by filtration through a bed of celite, rinsing with 10 % MeOH:EtO.Ac. The filtrate is concentrated under reduced pressure to provide the crude material. Purification by column chromatography using 4-5 % MeOH in DCM as an eluent provides [2-(methylamino)-1,3-benzoxazol-5-yl]methanol (2 g, 64 %) as a yellow solid.

[0324] Step 3: Synthesis of A / -methyi(5-{[(tert-butyl)bis(methyl)siioxy]methyl}-1,3-benzoxazoi-2- yljamine

[0325] To a stirred solution of [2-(methyiamino)-1,3-benzoxazol-5-yl]methanol (2 g, 11.2 mmol) in dimethylformamide (20 mL, 258 mmol) under under nitrogen atmosphere is added imidazole (1 .91 g, 2.5 eq., 28.1 mmol) followed by (fe / t-butyi)(chloro)bis(methyl)silane (3.05 g, 1.8 eq., 20.2 mmol), and the reaction mixture is stirred for 2 h at RT. The progress of the reaction is monitored by TLC (5 % MeOH: 95% DCM) and LCMS. The reaction mixture is diluted with water and extracted with ethyl acetate (3 x 30 mL). The combined organic layers are ished with water, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography using 30-40 % EtOAc: n-heptane as the eluent provides N-methyl(5-{[(tert- butyl)bis(methyl)siioxy]methyl}-1 ,3-benzoxazoi-2-yl)amine (2 g, 60 %) as a yellow solid.

[0326] Step 4: Synthesis of (5-{[(fert-butyl)bis(methyl)siloxy]methyl}-1 ,3-benzoxazol-2-yl)-A / - methyl(5-fluoro-1,3-benzoxazol-2-yl)amine

[0327] To a solution of A / -methyl(5-{[(fert-butyl)bis(methyl)siloxy]methyl}-1,3-benzoxazol-2- yl)amine (2 g, 6.84 mmol), 2-chloro-5-fluoro-1,3-benzoxazole (1.69 g, 1.3 eq., 8.89 mmol) in 1 ,4- dioxane (20 mL, 234 mmol) is added cesium carbonate (6.68 g, 3 eq., 20.5 mmol), 2,2‘- bis(diphenylphosphino)-1 ,T-binaphthyl (426 mg, 0.1 eq., 684 μmol) and palladium bis(acetate) (76.8 mg, 0.05 eq., 342 pmol). The reaction mixture is irradiated at 120 °C in a microwave reactor for 45 min. The reaction mixture is filtered through a celite bed, and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography, eluting with 10-30 % EtOAC in n-heptane to provide (5-{[(fert-butyl)bis(methyl)siloxy]methyl}-1 ,3-benzoxazol-2-yl)- N-methyl(5-fluoro-1 ,3-benzoxazol-2-yl)amine (1.5 g, 51 %) as a light orange solid.

[0328] Step 5: Synthesis of {2-[(5-fluoro-1,3-benzoxazol-2-yl)-A / -methylamino]-1 ,3-benzoxazol-5- yl}methanol

[0329] To a stirred solution of (5-{[(tert-butyl)bis(methyl)siloxy]methy!}-1,3-benzoxazol-2-yl)-A / - methyl(5-fluoro-1,3-benzoxazol-2-yl)amine (1.5 g, 3.51 mmol) in oxolane (15 mL) is added tetrabutylazanium fluoride (8.26 g, 9 eq., 31.5 mL) at 0 °C, and the reaction mixture is stirred for 2 h at room temperature. The progress of the reaction is monitored by TLC. After the starting material is consumed, water is added to the reaction mixture followed extraction with ethyl acetate (2 x 50 mL). The organic layer is ished with brine and concentrated under reduced pressure. The residue is purified by column chromatography, eluting with 0-50 % EtOAC in hexane to afford {2- [(5-fluoro-1 ,3-benzoxazol-2-yl)- / V-methylamino]-1 ,3-benzoxazol-5-yl}methanol (0.5 g, 45 %) as an an off-white solid. LCMS (m / z) = 314.1 [M+H]L

[0330] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.76 - 7.72 (m, 1 H), 7.64 (d, J = 8 Hz, 1 H), 7.56 - 7.51 (m, 2H), 7.26 (dd, J = 1.6 Hz, 1.6 Hz, 1 H), 7.16 - 7.11 (m, 1 H), 5.30 (br, 1 H), 4.59 (s, 2H), 3.83 (s, 3H).

[0331] Example 7Synthesis of 5-((dimethy!amino)methyl)-A / -(5-fluorobenzo[d]oxazol-2-yl)-N- methylbenzo[d]oxazol-2-amine

[0332] Example 7 is synthesized in an analogous manner to Example 3. LCMS (ES) m / z = 341.3 [M+H]T

[0333] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.74 - 7.71 (m, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.53 - 7.51 (m, 2 H), 7.23 (d, J = 8.4 Hz, 1 H), 7.15 - 7.10 (m, 1 H), 3.82 (s, 3 H), 3.47 (s, 2 H), 2.16 (s, 6 H).

[0334] Example 8Synthesis of A / -(5-((dimethylamino)methyl)benzo[d]oxazol-2-yl)-5-fluoro-4- methoxybenzo[d]oxazol-2-amine

[0335] Example 8 is synthesized in an analogous manner to Example 3. LCMS (ES) m / z = 357.3 [M+H]T

[0336] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.36 - 7.28 (m, 3H), 7.24 - 7.21 (m, 1 H), 7.00 - 6.98 (d, 8.0 Hz, 1 H), 3.84 (s, 3H), 3.55 (s, 2H), 2.24 (s, 6H).

[0337] Example 9Synthesis of (2-((6-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methanol

[0338] Example 9 is synthesized in an analogous manner to Example 2. LCMS (ES) m / z ~ 300.2 [M+H]T

[0339] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.50 (bs, 1 H), 7.51-7.56 (m, 2H), 7.48 (d,8.0Hz, 2H), 7.18 (d, J = 8.8 Hz, 1 H), 7.12 (d, J - 2.4 Hz, 1 H), 5.31 (s, 1 H), 4.56 (s, 2H).

[0340] Example 10Synthesis5-((dimethylamino)methyl)-N-(5-fluorobenzo[d]oxazol-2-yl)-6- methoxybenzo[d]oxazol-2-amine

[0341] Step 1 : Synthesis of methyl 2,4-dihydroxybenzoate

[0342] To a solution of 2,4-dihydroxybenzoic acid (5 g, 32.4 mmol) in methanol (35 mL), cooled to 0 °C, is added sulfuric acid (7 mL). The reaction mixture is stirred at 73 °C for 16 h, and thenconcentrated under reduced pressure. The residue is treated with a saturated solution of sodium bicarbonate (100 mL), and the solid that precipitates is collected by vacuum filtration, ished with water (300 mL) and n-heptane (100 mL), and dried under vacuum to afford methyl 2,4- dihydroxybenzoate (5 g, 91 %) as an off-white solid.

[0343] Step 2: Synthesis of methyl 2-hydroxy-4-(methoxymethoxy)benzoate

[0344] To a solution of methyl 2, 4-di hydroxy benzoate (1 g, 5.95 mmol) in tetrahydrofuran (30 mL, 369 mmol), cooled to 0 °C, sodium hydride (178 mg, 1.3 eq., 7.43 mmol) is added, and the reaction mixture is stirred at ambient temperature for 30 min. Then chloromethoxymethane (497 pL, 1.1 eq., 6.54 mmol) is added dropwise to the mixture at 0 °C, and the resulting suspension is stirred for 0.5 h at 0 °C, gradually heated to 80 °C. After 2 h, the reaction solution is treated with ice water (50 mL), and extracted with ethyl acetate three times. The combined organic layers are ished with brine, dried with anhydrous Na2SO4, and concentrated under reduced pressure in to provide the product, which is directly used as a reactant in the next step without any further purification (1 g, crude).

[0345] Step 3: Synthesis of methyl 2-methoxy-4-(methoxymethoxy)benzoate

[0346] A mixture of methyl 2-hydroxy-4-methoxyanisate (1 g, 4.71 mmol) and anhydrous dipotassium carbonate (2.61 g, 4 eq., 18.9 mmol) in dimethylformamide (10 mL, 129 mmol) is stirred at 80 °C for 5 min. lodomethane (587 pL, 2 eq., 9.43 mmol) is added dropwise, and the reaction mixture is kept stirring at 80 °C for 1 h and monitored by TLC. The reaction mixture is then cooled to room temperature, and the solids are removed by filtration. The filtrate is treated with ice water (50 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers are ished with brine, dried over anhydrous NazSCu, filtered, and concentrated under reduced pressure to give methyl 2-methoxy-4-(methoxymethoxy)benzoate (1 g, crude). The product is directly used as a raw material in the next step without any purification.

[0347] Step 4: Synthesis of 4-hydroxy-2-methoxybenzoic acid

[0348] To a solution of methyl 2-methoxy-4-(methoxymethoxy)benzoate (1 g, 4.42 mmol) in methanol (10 mL, 247 mmol), cooled to 0 °C, is added 1 N HCI (3 mL), and the reaction mixture is stirred at room temperature for 16 h. The pH of the reaction mixture is adjusted to pH ~7 with sat. sodium carbonate solution and extracted with ethyl acetate (3 X 20 mL). The combined organic layers are ished with brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography, eluting with ethyl acetate in n-heptane, to provide 4-hydroxy-2-methoxybenzoic acid (350 mg, 43%) as a white solid.

[0349] Step 5: Synthesis of methyl 4"hydroxy-2-methoxy-5-nitrobenzoate

[0350] To a solution of methyl 4-hydroxy-2-anisate (350 mg, 1.92 mmol) in chloroform (14 mL), cooled to 0 °C, is added nitric acid (96.2 pL, 1.2 eq., 2.31 mmol). The reaction mixture is stirred at ambient temperature for 30 min, treated with ice water and extracted with DCM (2 X 50 mL). The combined organic layers are ished with brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography, eluting with ethyl acetate in n- heptane, to provide methyl 4-hydroxy-2-methoxy-5-nitrobenzoate (210 mg, 48 %) as a white solid.

[0351] Step 6: Synthesis of methyl 5-amino-4-hydroxy-2-methoxybenzoate

[0352] Nitrogen gas is bubbled for 5 min through a solution of methyl 4-hydroxy-2-methoxy~5- nitrobenzoate (0.2 g, 880 μmol) in methanol (15 mL), then palladium on carbon (50 % wet) (70 mg) is added, and the reaction mixture is stirred at room temperature under 60 psi of hydrogen gas for 16 h. After purging with nitrogen, the reaction mixture is filtered through a celite bed and the filtrate is concentrated to afford methyl 5-amino~4-hydroxy-2-methoxybenzoate (150 mg, 86 %) as an off-white solid.

[0353] Treating methyl 5-amino-4-hydroxy-2-methoxybenzoate in a manner analogous to the synthesis of Example 3 to provide 5-((dimethylamino)methyl)-N-(5-fluorobenzo[d]oxazol-2-yl)-6- methoxybenzo[d]oxazol-2-amine. LCMS (m / z) = 357.3 [M+H]+.

[0354] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.33 (br, 2H), 7.24 (s, 1 H), 7.10 (d, J = 8 Hz, 1 H), 6.82 (t, J - 8.4 Hz, 1 H), 3.82 (s, 3H), 3.81 (s, 2H), 2.43 (s, 6H).

[0355] Example 11

[0356] Synthesis of 2-((5-((dimethylamino)methyl)benzo[d]oxazol-2-yl)amino)-N-(2- methoxyethyl)benzo[d]oxazole-5-carboxamide

[0357] Step 1 : Synthesis of methyl 2-aminobenzo[d]oxazole-5-carboxylate

[0358] To a stirred solution of methyl 3-amino-4-hydroxybenzoate (5 g, 29.9 mmol, 1 eq) in methanol (100 mL) is added bromocarbonitrile (9.5 g, 89.7 mmol, 3 eq). The reaction mixture is stirred at room temperature for 16 h and monitored by TLC. The reaction mixture is concentratedunder reduced pressure, and the residue is treated with saturated aq Na2CO3 solution (80 mL). The resulting solids are removed by filtration, and the filtrate is concentrated under reduced pressure to afford methyl 2-amino-1 ,3~benzoxazole-5-carboxylate (4 g, 70 % yield ) as a white solid.

[0359] Step 2: Synthesis of methyl 2-((tert‘-butoxycarbonyl)amino)benzo[d]oxazole-5-carboxylate

[0360] To a stirred solution of methyl 2-amino-1 ,3-benzoxazole-5-carboxylate (4.6 g, 23.9 mmol, 1 eq) in THF (60 mL) is added triethylamine (10.1 mL, 71.8 mmol, 3 eq) and DMAP (0.29 g, 2.39 mmol, 0.1 eq). The reaction mixture is cooled to 0 °C, treated with fert-butoxycarbonyloxy-tert- butylformylate (8.25 mL, 38.9 mmol, 1.5 eq), stirred at room temperature for 5 h and monitored by TLC. The reaction mixture is then concentrated under reduced pressure, diluted with water and extracted with EtOAc (2 X 100 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography, eluting with ethyl acetate in n-heptane, to provide methyl 2-(ferf-butoxycarbonylamino)-1,3-benzoxazole-5- carboxylate (6 g, 86 % yield) as a white solid.

[0361] Step 3: Synthesis of 2-((tert-butoxycarbonyl)amino)benzo[d]oxazole-5-carboxylic acid

[0362] To a stirred solution of methyl 2-(ferf-butoxycarbonylamino)-1 ,3-benzoxazole-5- carboxylate (2.4 g, 8.21 mmol, 1 eq) in methanol (5 mL), THF (10 mL) and water (10 mL) is added lithium hydroxide (0.059 g, 24.6 mmol, 3 eq). The reaction mixture is stirred at 60 °C for 3 h, and monitored by TLC. The reaction mixture is concentrated under reduced pressure and treated with citric acid solution (30 mL). The solids are removed by filtration, and the filtrate is concentrated under reduced pressure to provide crude 2-(tert-butoxycarbonylamino)-1,3-benzoxazole-5- carboxylic acid (1.5 g).

[0363] Step 4: Synthesis of tert-butyl (5-((2-methoxyethyl)carbamoyl)benzo[d]oxazol-2- yl)carbamate

[0364] To a stirred solution of 2-(tert-butoxycarbonylamino)-1,3-benzoxazole-5-carboxylic acid (2.5 g, 8.98 mmol, 1 eq) in DMF (25 mL) are added HATU (5.12 g, 13.5 mmol, 1.5 eq) and 2- methoxyethylamine (1.56 mL, 18 mmol, 2 eq). The reaction mixture is cooled to 0 °C, treated with DI PEA (4.71 mL, 27 mmol, 3 eq) and stirred at room temperature for 5 h. The reaction mixture is diluted with ice cold water (30 mL), extracted with EtOAc (2x100 mL), and the combined organic layers are concentrated under reduced pressure. The residue is purified by column chromatography, eluting with ethyl acetate in n-heptane, to provide A / -2-methoxyethyl-2-(terf- butoxycarbonylamino)-1 ,3-benzoxazole-5-carboxamide (3 g, 99% yield) as a yellow gum.

[0365] Step 5: Synthesis of 2-arnino- / V-(2-methoxyethy!)benzo[d]oxazole-5-carboxamide

[0366] To a stirred solution of A / -2-methoxyethyl-2-(tert-butoxycarbonylamino)-1!3-benzoxazole- 5-carboxamide (3 g, 8.95 mmol, 1eq) in DCM (40 mL) is added dropwise 4N HCI in 1 ,4-dioxane (30 mL), and the reaction mixture is stirred at 0 °C for 12 h. The reaction mixture is concentrated under reduced pressure, and the crude material is triturated with n-pentane and diethyl ether, and dried to afford A / -2-methoxyethyl-2-amino-1,3-benzoxazole-5-carboxamide (2 g, 95 % yield) as a white solid.

[0367] Step 6: Synthesis of methyl 2-((5-((2-methoxyethyl)carbamoyl)benzo[d]oxazol-2- yl)amino)benzo[d]oxazole-5-carboxylate

[0368] To a solution of A / -2-methoxyethyl-2-amino-1 ,3~benzoxazole~5-carboxamide (1 g, 4.25 mmol, 1 eq) in THF (15 mL) are added lithium 2-methyl-2-propanolate (0.68 g, 8.5 mmol, 2 eq) and methyl 2-iodo-1 ,3-benzoxazole-5-carboxylate (1.16 g, 3.83 mmol, 0.9 eq). The reaction mixture is heated to 70 °C for 16 h, concentrated under reduced pressure, resuspended in ethyl acetate (10 mL), filtered and concentrated under reduced pressure. The residue is purified by column chromatography, eluting with MeOH and DCM to provide methyl 2-[5-( / V-2- methoxyethylcarbamoyl)-1,3-benzoxazol-2-ylamino]-1 ,3-benzoxazole-5-carboxylate (0.2 g, 11 % yield) as an white solid.

[0369] Treating methyl 2-[5-( / V-2-methoxyethylcarbarnoyl)-1!3-benzoxazol-2-ylamino]-1!3- benzoxazole-5-carboxylate in a manner analogous to the synthesis of Example 3 to provide 2- ((5-((dimethylamino)methyl)benzo[d]oxazol-2-yl)amino)-A / ~(2~methoxyethyl)benzo[d]oxazole-5- carboxamide. LCMS (m / z) = 410.4 [M+H]\

[0370] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.51 - 8.43 (m, 1 H), 7.85 (s, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.65 (s, 1 H), 7.46 - 7.39 (m, 3 H), 7.09 (d, J = 7.6 Hz, 1 H), 3.79 (bs, 2 H), 3.48 - 3.34 (m, 4 H), 3.26 (s, 3 H), 2.40 (s, 6 H).

[0371] Example 12Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)urea

[0372] Step 1 : Synthesis of 2-iodo-5-nitro-1 ,3-benzoxazole

[0373] To a solution of 5-nitro-1 ,3-benzoxazole (3 g, 18.3 mmol) in THF (25 mL), cooled to -78 °C, is added lithium bis(trimethylsilyl)azanide (7.74 g, 2.5 eq., 46.3 mmol), and the reaction mixture is stirred at -78 °C for 3 h. Iodine (3.48 g, 1.5 eq., 27.4 mmol) in THF (5 mL) is added, and the temperature is maintained at -20 °C for 1 h. The reaction mixture is then treated with a saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (2 X 40 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography, eluting with ethyl acetate in n- heptane, to provide 2-iodo-5-nitro-1 ,3-benzoxazole (1.1 g, 21%) as a brown solid.

[0374] Step 2: Synthesis of 2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-5-nitro-1 ,3-benzoxazole

[0375] To a solution of 5-fluoro-1 ,3-benzoxazol-2-ylamine (0.53 g, 3.45 mmol) in THF (15 mL) are added lithium fert-butoxide (0.55 g, 2 eq., 6.9 mmol) and 2-iodo-5-nitro-1 ,3-benzoxazole (1 g, 3.45 mmol). The reaction vessel is sealed and heated at 70 °C for 4 h, then concentrated under reduced pressure, dissolved in ethyl acetate (40 mL) and ished with water (20 mL) and brine (20 mL). The organic layer is concentrated, and the residue purified by column chromatography, eluting with ethyl acetate in n-heptane, to provide 2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-5-nitro- 1 ,3-benzoxazole (0.55 g, 51%) as an off-white solid.

[0376] Step 3: Synthesis of 5-amino-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazole

[0377] Nitrogen gas is bubbled through a solution of 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-5- nitro-1 ,3-benzoxazole (0.55 g, 1.75 mmol, 1 eq) in of MeOH (30 mL) for 5 min, then palladium on carbon (10 % wet; 0.3 g) is added, and the reaction mixture is stirred at room temperature under 50 psi of hydrogen for 16 h. The reaction mixture is filtered through a celite bed, and the filtrate is concentrated to afford 5-amino-2-(5-f!uoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole (0.38 g, 76%) as a brown solid.

[0378] Step 4: Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)urea

[0379] To a stirred solution of 5-amino-2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1,3-benzoxazole (0.1 g, 0.35 mmol) in THF (1 mL) is added ditrichloromethyl carbonate (0.10 g, 0.35 mmol) at 0 °C under nitrogen. The reaction mixture is stirred at ambient temperature for 2 h, then cooled to 0 °C. Ammonia gas is bubbled through the reaction mixture for 15 min, and the reaction mixture is stirred at room temperature for 2 h, concentrated under reduced pressure, diluted with water and extracted with EtOAc (3 X 10 mL). The combined organic extracts are dried over Na2SO4, filtered and concentrated under reduce pressure. The residue is purified by columnchromatography, eluting with methanol in DCM to provide the desired compound (0.10 g) which is further purified by prep HPLC to provide 1-(2-((5-fluorobenzo[d]oxazol-2- yl)amino)benzo[d]oxazol-5-yl)urea (0.018 g, 16%) as a pale yellow solid. LCMS (m / z) = 328.1 [M+Hp.

[0380] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.70 (s, 1 H), 7.80 (s, 1 H), 7.53 (q, 4 4 Hz, 1 H),7.39 (d, J = 8.8 Hz, 1 H), 7.31 (dd, J = 8.4 & 2 Hz, 1 H), 7.13 (dd, . / ~ 8.8 & 2 Hz, 1 H), 5.85 (s, 2H)

[0381] Example 13Synthesis of 3-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-1,1-dimethylurea

[0382] Example 13 is synthesized in an analogous manner to Example 12. LCMS (ES) m / z = 356.3 [M+H]L

[0383] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.41 (s, 1 H), 7.75 (s, 1 H), 7.53 (q, J = 4.4 Hz, 1 H), 7.39 (d, 8.8 Hz, 1 H), 7.31 (d, .. / = 8 4 Hz, 1 H), 7.24 (d, 8.8 Hz, 1 H), 7.02 (t,8.4 Hz, 1 H),2.94 (s, 6H).

[0384] Example 14Synthesis of methyl (2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)carbamate

[0385] Example 14 is synthesized in an analogous manner to Example 12. LCMS (ES) m / z = 343.3 [M+H]+.

[0386] 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.80 (s, 1 H), 7.79 (s, 1 H), 7.56 - 7.53 (m, 1 H), 7.45 (d, J = 8.8 Hz, 1 H), 7.33 - 7.30 (dd, J = 2 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 7.07 - 7.02 (m, 1 H), 3.69 (s, 3 H).

[0387] Example 15Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)propan-2-ol

[0388] To a stirred solution of methyl 2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-5~ carboxylate (Example 1, 240 mg, 0.732 mmol) in THE (6 ml) is added magnesium bromide methanide (437 mg, 5 eq., 3.66 mmol) at 0 °C under nitrogen. The reaction mixture is stirred at room temperature for 4 h, treated with water (15 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers are dried over sodium sulphate, filtered and concentrated under reduced pressure to provide the crude material (140 mg, 58%). From the crude, purification of 50 mg of material by prep-HPLC provides 2-[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1,3- benzoxazol-5-yl]-2-propanol (20 mg). LCMS (m / z) = 328.0 [M+H]+.

[0389] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.56 (s, 0.5H), 7.65 (d, J=1.2 Hz, 1 H), 7.56 - 7.53 (m, 1 H), 7.45 (s, 1 H), 7.35-7.31 (m, 2H), 7.07 - 7.01 (m, 1 H), 1.46 (s, 6H).

[0390] Purification conditionsColumn: Xbridge C-18 (250 mm x 4.6 mm x 5 pm )Mobile phase (A): 0.1 % Formic acid in WaterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / min

[0391] Example 16Synthesis of 2-(benzo[d]oxazol-2-ylamino)- / V-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazole-5- carboxamide

[0392] Step 1 : Synthesis of methyl 2-(benzo[d]oxazol-2-yiamino)benzo[d]oxazoie-5-carboxylate

[0393] Methyl 2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazole-5-carboxylate is prepared in a manner analogous to the synthesis described in Example 1 , except that 2-aminophenol is used in place of 2-amino-4-fluorophenol.

[0394] Step 2: Synthesis of 2-(benzo[d]oxazo!-2-ylamino)benzo[d]oxazole-5-carboxylic acid

[0395] To a stirred solution of methyl 2-(benzo[d]oxazol-2-y!amino)benzo[d]oxazo!e-5- carboxylate (0.36 g, 1.16 mmol, 1 eq) in methanol (1 mL), THF (2 mL) and water (2 mL) is added lithium hydroxide (0.083 g, 3.49 mmol, 3 eq), and the resultant mixture is heated at 70 °C for 4 h. Progress of reaction is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated under reduced pressure. The residue is acidified with dilute HCI solution (20 mL), and the resultant solid is filtered and dried to afford crude 2-(benzo[d]oxazol-2- ylamino)benzo[d]oxazole-5-carboxylic acid (0.25 g) as a white solid.

[0396] Step 3: Synthesis of 2-(benzo[d]oxazol-2-ylamino)- / V-(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole-5-carboxamide

[0397] To a solution of 2-(benzo[d]oxazol-2~ylamino)benzo[d]oxazoie-5-carboxylic acid (0.42 g, 1.42 mmol, 1 eq) in DMF (4 mL) are added HATU (1.08 g, 2.85 mmol, 2 eq) and 2-(2- aminoethoxy)ethanol (0.17 mL, 1 .71 mmol, 1 .2 eq). The reaction mixture is cooled to 0 °C, treated with DI PEA (0.74 mL, 4.27 mmol, 3 eq) and stirred at room temperature for 4 h. The reaction mixture is diluted with ice cold water (5 mL) and extracted with EtOAc (2x20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep HPLC to afford 24benzo[d]ox8zol--2-wimethylHT (2- (2-' hydroxyethoxy)ethyl)benzo[d]oxazole-5-carboxamide (96 mg, 18 % yield) as a white solid. LCMS (ES) m / z = 383.3 [M+H]+.

[0398] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.57 (s, 1 H), 8.54 (t, J = 5.6 Hz, 1 H), 7.95 (s, 1 H), 7.72 - 7.69 (dd, J = 1.6 Hz & J = 10.0 Hz, 1 H), 7.57 • 7.50 (m, 3 H), 7.30 - 7.19 (m, 2 H), 4.62 (s, 1 H), 3.73 - 3.12 (m, 8 H).

[0399] Purification conditionsColumn: Xselect CSH C18(250x19)mm;5uFlow: 19.0 mL / minMobile phase A: 0.1 % Ammonia in WaterMobile phase B: Acetonitrile

[0400] Example 17Synthesis of A / W-dimethyl-2~(5~fluoro-1 ,3-benzoxazol~2~ylamino)-1 ,3-benzoxazoie-5- carboxamide

[0401] Example 17 is synthesized in an analogous manner to Example 16. LCMS (ES) m / z = 341.3 [M+H]’.

[0402] 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.02 (s, 1 H), 8.06 (d, J=1.2 Hz, 1 H), 7.89 - 7.87 (dd, 1 H), 7.65 (s, 1 H), 7.60-7.57 (m, 1 H), 7.37 - 7.34 (dd, 1 H), 7.21 (bs, 0.5H), 7.11-7.06 (m, 1 H), 6.95 (bs, 0.5H).

[0403] Purification conditionsColumn: Inertsil C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1%Ammonia in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / min

[0404] Example 18Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazole-5-carboxamide

[0405] Example 18 is synthesized in an analogous manner to Example 16. LCMS (ES) m / z = 313.3 [M+H]+.

[0406] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.05 (s, 1 H), 7.98 (s, 1 H), 7.80 • 7.78 (m, 1 H), 7.61 - 7.56 (m, 2 H), 7.42 (s, 1 H), 7.37 - 7.34 (dd, J - 2.4 Hz, J = 2.8 Hz, 1 H), 7.10 - 7.05 (m, 1 H).

[0407] Purification conditionsColumn: X-Bridge C18(19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1% Ammonia in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / min

[0408] Example 19Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-A / -(2-methoxyethyi)benzo[d]oxazoie-5- carboxamide

[0409] Example 19 is synthesized in an analogous manner to Example 16. LCMS (ES) m / z = 371.3 [M+H]4.

[0410] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.61 - 8.59 (m, 1 H), 7.97 (d, J = 1.2 Hz, 1 H), 7.78 - 7.75 (dd, J = 1.6 Hz, J = 1.6 Hz, 1 H), 7.63 - 7.57 (m, 2 H), 7.37 - 7.35 (dd, J = 2.8 Hz, J = 2.4 Hz, 1 H), 7.11 - 7.06 (m, 1 H), 3.50 - 3.42 (m, 4 H), 3.28 (s, 3 H).

[0411] Purification conditionsColumn: Xselect CSH C18(250x19)mm;5uFlow: 19.0 mL / mlnMobile phase: EtOAc:Hex (7:3).

[0412] Example 20Synthesis of A / -[2-(2-hydroxyethoxy)ethyl]-A / -methy!-2-(1 ,3-benzoxazol-2-ylamino)-1 ,3- benzoxazole-5-carboxamide

[0413] Example 20 is synthesized in an analogous manner to Example 16. LCMS (ES) m / z = 397.4 [M+H]+.

[0414] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.58 - 7.54 (m, 3H), 7.51 (s, 1H), 7.33 - 7.23 (m, 3H), 4.60 (bs, 1 H), 3.64 - 3.35(m, 8H), 3.00 (s, 3H).

[0415] Purification conditionsColumn: SUNFIRE C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 5Mm Ammonium bicarbonate in WaterMobile phase (B): AcetonitrileFlow rate: 19 mUminDesired product RT at 12.49 min

[0416] Example 21Synthesis of A / -[2-(2-hydroxy-2-methylpropoxy)ethyl]-2-(1 ,3-benzoxazol-2-yiamino)~1 ,3- benzoxazole-5-carboxamide[041 / ] Example 21 is synthesized in an analogous manner to Example 16. LCMS (ES) m / z = 411.4 [M+H]+.

[0418] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.51 (t, J = 8.0 Hz, 1 H), 7.97 (s, 1 H), 7.73 - 7.71 (dd, J = 1.2 Hz, J = 0.8 Hz, 1 H), 7.60 - 7.53 (m, 3H), 7.31 (t, J = 8.0 Hz, 1 H). 7.25 (t, J = 8.0 Hz, 1 H), 4.33 (s, 1 H), 4.57 (t, J = 8.0 Hz, 2H), 3.47 - 3.43 (m, 2H), 3.20 (s, 2H), 1.07 (s, 6H).

[0419] Example 22Synthesis of 2-(benzo[d]oxazol-2-ylamino)-A / -(1-(2-hydroxyethyl)piperidin-4-yi)benzo[d]oxazole-5-carboxamide

[0420] Example 22 is synthesized in an analogous manner to Example 16. LCMS (ES) m / z = 422.5 [M+H]’.

[0421] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.27 (d, J = 7.2 Hz, 1 H), 7.86 (s, 1 H), 7.62 (d, J = 2.8 Hz, J = 8.0 Hz, 1 H), 7.47 - 7.40 (m, 3 H), 7.22 - 7.09 (m, 2 H), 4.71 (s, 1 H), 3.85 (d, J = 6.0 Hz, 1 H), 3.59 - 3.57 (m, 2 H), 3.10 (d, J = 10.4 Hz, 2 H), 2.67 • 2.66 (m, 2 H), 2.50 • 2.32 (m, 2 H), 1.88 - 1.67 (m, 4 H).

[0422] Example 23Synthesis of 2-(benzo[d]oxazol-2-yiamino)-N-(2-(2-hydroxyethoxy)ethyi)benzo[d]oxazole-6- carboxamide

[0423] Step-1 : Synthesis of methyl 1 ,3-benzoxazole-6-carboxylate

[0424] To a solution of methyl 4-amino-3-hydroxybenzoate (8 g, 47.9 mmol) in triethylorthoformate (80 mL) is added mono hydrate p-toluene sulfonic acid (1.14 g, 0.13 eq., 5.98 mmol) at rt. The reaction mixture is heated at 100 °C and stirred for 16 h. The progress of the reaction is monitored by TLC (30% ethyl acetate in heptane). After the starting material is consumed, the reaction mixture is concentrated under reduced pressure and the resultant residue re-suspended in ethyl acetate (200 mL). The organic layer is washed with water, saturated aqueous NaHCCh and concentrated under reduced pressure to obtain thecrude product. This material is further triturated by n-pentane to obtain the title compound (7.2 g, 64.54%) as brown colored solid.

[0425] Step-2: Synthesis of methyl 2-iodo-1 ,3-benzoxazole-6-carboxylate

[0426] To a solution of methyl 1 ,3-benzoxazole-6-carboxylate (5 g, 28.2 mmol) in tetrahydrofuran (0.1 L) at -78 °C, lithium bis(trimethylsilyl)azanide (5.9 g, 1.3 eq., 35.3 mmol, 1 N solution in THF 35.3 mL) is added and the reaction mixture is stirred at -78 °C for 3 h. A solution of iodine (7.16 g, 2 eq., 56.4 mmol) in THF (20 mL) is then added at -78 °C and the reaction mixture is gradually warmed to -20 °C, thenstirrred for 1 h. The progress of reaction is monitored by TLC (30% ethyl acetate in heptane). After the starting material is consumed, the reaction mixture is treated with sat. ammonium chloride solution (35 mL) and extracted with ethyl acetate (3 X 60 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford the crude product. This material is purified by flash chromatography, using 10%-20% EtOAc in n- heptane as mobile phase to afford methyl 2-iodo-1 ,3-benzoxazole-6-carboxylate (2.8 g, 21.28 %) as a white solid. LC-MS (m / z) = 303.9 [M+Hp.

[0427] Step-3: Synthesis of methyl 2-(1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-6-carboxylate

[0428] To a solution of 1 ,3-benzoxazol-2-ylamine (1.23 g, 9.17 mmol) in tetrahydrofuran (17.6 mL, 216 mmol), lithium 2-methyi-2-propanolate (1.47 g, 2 eq., 18.3 mmol) and methyl 2-iodo-1,3- benzoxazole-6-carboxylate (2.5 g, 0.9 eq., 8.25 mmol) are added, and the reaction mixture isstirred at 70 °C for 16 h. Progress of the reaction is monitored by TLC (40% ethyl acetate in heptane). After consumption of the starting materials, the reaction mixture is concentrated and the residue is re-suspended in water (50 mL). The resulting solid is filtered and dried under vacuum to provide the crude product. This material is further washed with DCM (50 mL) to provide methyl 2-(1 ,3-benzoxazo!-2-ylamino)-1 ,3-benzoxazole-6-carboxylate (2.2 g, 78 % yield) as off- white solid. LC-MS (m / z) = 310.0 [M + H]+.

[0429] Step-4: Synthesis of 2-(1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-6-carboxylic acid

[0430] To a stirred solution of methyl 2-(1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-6- carboxylate (2.2 g, 7.11 mmol) in methanol (8 mL, 197 mmol), tetrahydrofuran (15 mL, 184 mmol) and water (15 mL, 833 mmol) is added lithium hydroxide (852 mg, 5 eq., 35.6 mmol). The reaction mixture is stirred at 70 °C for 5 h and the reaction progress is monitored by TLC (30% ethyl acetate in heptane). After consumption of the starting materials, the reaction mixture is concentrated under reduced pressure to provide the crude residue. The residue is treated with 1 N HCI solution (20 mL) and the resultant solid is filtered and dried to afford crude 2-(1 ,3-benzoxazol-2-ylamino)- 1 ,3-benzoxazole-6-carboxylic acid (1.9 g, Yield: 90%) as purple solid. LC-MS (m / z) = 295.9 [M + Hf.

[0431] Step-5: Synthesis of 2-(benzo[d]oxazo!-2-ylamino)-N-(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole-6-carboxamide

[0432] To a stirred solution of 2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazole-6-carboxylic acid (0.5 g, 1.69 mmol) in dimethylformamide (20 mL), TSP (1.29 g, 2 eq., 3.39 mmol) and 2-(2- aminoethoxy)ethanol (257 pL, 1.5 eq., 2.54 mmol) are added and the reaction mixture is stirred for 10 min. The reaction mixture is then cooled to 0 °C, ethylbis(propan-2-yl)amine (885 pL 3 eq., 5.08 mmol) is added and the reaction mixture is stirred for 5 min. The reaction mixture is allowed to warm to room temperature and stirred for 2 h. Progress of the reaction is monitored by TLC (5% methanol in DCM). After consumption of the starting material, the reaction mixture is diluted with ice cold water (5 mL) and extracted with EtOAc (2x20 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure to get the crude product. This material is dissolved in DCM (30 mL) then treated with pentane dropwise at 0 °C. The resultant solid is filtered to afford 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole-6-carboxamide (64 mg, Yield: 9.59%) as pale pink solid. LC-MS (m / z) = 383.4 [M+H]+.

[0433] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.70 (s, 1 H), 8.51 (s, 1H), 7.99 (s, 1 H), 7.83 (m, 1 H), 7.57 - 7.55 (m, 3H), 7.32 • 7.25 (m, 2H), 4.60 (s, 1 H), 3.54 - 3.45 (m, 8H).

[0434] Example 24Synthesis of A / -[2-(2-hydroxyethoxy)ethyl]2-[2-(1 ,3-benzoxazol~2-ylamino)-1 ,3-benzoxazol-5- yljpropionamide

[0435] Step 1 : Synthesis of methyl 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)acetate

[0436] To a stirred solution of methyl (p-hydroxyphenyl)acetate (5 g, 30.1 mmol, 1 eq) in DMF (50 mL), is added imidazole (6.15 g, 90.3 mmol, 3 eq), after that reaction mixture is cooled to 0 °C is added (tert-butyl)(chloro)bis(methyl)silane (9.07 g, 60.2 mmol) and reaction mixture is allowed to stir at room temperature for 3 h. Progress of reaction is checked by TLC. After completion of the reaction, reaction mixture is diluted with ice cold water (20 mL), extracted with EtOAc (2x50 mL), concentrated under reduced pressure to get the crude. The crude is purified by flash column chromatography eluted on 5% EtOAc - Heptane to afford methyl {p-[(tert- butyl)bis(methyl)siloxy]phenyl}acetate (7 g, 83 % yield) as colorless liquid. LCMS m / z = 281.2 [M+Hr.

[0437] Step 2: Synthesis of methyl 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)propanoate

[0438] A solution of methyl {p-[(tert-butyl)bis(methyl)siloxy]phenyl}acetate (7 g, 25 mmol) in THF (70 mL) is cooled to -78 °C and then lithium bis(isopropyl)azanide (18.7 mL, 37.4 mmol, 1.5 eq) is added at same temperature. Reaction mixture is stirred at same temperature for 1 h. To above mixture lodomethane (3.11 mL, 49.9 mmol, 2 eq) is added and then reaction mass is slowly allowed to warm upto -20 °C and again stirred for 1 h. Reaction mass is quenched with sat. ammonium chloride solution (20 mL) and aqeious layer is extracted with ethyl acetate (2 X 50 mL). Combined organic layer is dried over sodium sulfate, filtered and concentrated to get crude product. Crude is further purified by flash column chromatography using 2.5% EtOAc - Heptane to afford methyl 2-{p-[(tert-butyl)bis(methyl)siloxy]phenyl}propionate (7.1 g, 96% yield) as colorless liquid. LCMS m / z = 295.2 [M+H]+.

[0439] Step 3: Synthesis of methyl 2-(4-hydroxyphenyl)propanoate

[0440] To a solution of methyl 2“{p“[(tert"butyl)bis(methyl)siloxy]phenyl}propionate (3 g, 10.2 mmol, 1 eq) in THF (30 mL) is cooled to 0 °C and then TBAF (10.2 mL, 10.2 mmol, 1 eq) is added at the same temperature. Reaction mass is allowed to warm upto room temperature and stirred for 3 h. Reaction mixture is quenched with H2O (30 mL) and extracted with ethyl acetate (2 X 100 mL), dried over sodium sulfate, filtered and concentrated to get crude methyl 2-(p- hydroxyphenyl)propionate (1.8 g). LCMS m / z = 181.1 [M+H]L

[0441] Step 4: Synthesis of methyl 2-(4-hydroxy-3-nitrophenyl)propanoate

[0442] To a solution of methyl 2-(p-hydroxyphenyl)propionate (2.6 g, 14.4 mmol, 1 eq) in acetic acid (10 mL) cooled to 0 °C, nitric acid (602 pL, 14.4 mmol) in 0.5 ml acetic acid is added drop wise to the reaction mixture and stirred for 10 min at the same temperature and continued stirring at RT for 1h . TLC, LCMS, monitored reaction. To the reaction mixture, water (30 ml) is added at 0 °C and extracted with EtOAc (50 mL), brine ish is given. Organic layer dried over sodium sulphate and concentrated to get crude product which is purified by flash column chromatography eluted on 8% EtOAc-Heptane to afford methyl 2-(4-hydroxy-3- nitrophenyl)propionate (2 g, 62 %) as yellow liquid. LCMS m / z = 224.0 [M-H],

[0443] Step 5: Synthesis of methyl 2-(3-amino-4-hydroxyphenyl)propanoate

[0444] To a solution of methyl 2-(4-hydroxy-3-nitrophenyl)propionate (1 g, 4.44 mmol, 1 eq) in ethanol (10 mL) and water (8 mL), iron (496 mg, 2 eq., 8.88 mmol) and ammonium chloride (713 mg, 3 eq., 13.3 mmol) is added and stirred at 70°C for 16 h. Progress of the reaction is monitored by TLC. Reaction mixture is filtered through celite bed, filtrate is diluted with water (10 mL), and aqueous layer is extracted with ethyl acetate. Organic layer is dried over NaSO4 and concentrated to afford methyl 2-(3-amino-4-hydroxyphenyl)propionate (0.6 g, Yield: 70%) as brown solid. LCMS m / z = 196.1 [M+H]+.

[0445] Step 6: Synthesis of methyl 2-(2-aminobenzo[d]oxazol-5-yl)propanoate

[0446] To a stirred solution of methyl 2-(3-amino-4-hydroxyphenyl)propionate (2 g, 10.2 mmol, 1 eq) methanol (20 mL) is added bromocarbonitrile (1.3 g, 12.3 mmol, 1.2 eq). After that reaction mixture is stirred at room temperature for 16 h, TLC monitoring, after completion of the reaction, checked reaction progress reaction mixture is concentrated under reduced pressure to get the crude residue. The residue is basified with saturated aq Na2CO3 solution (30 mL) solid formed, filtered and dried to afford methyl 2-(2-amino-1,3-benzoxazol-5-yl)propionate (2.1 g, 93 % yield ) as brown color solid. LCMS m / z = 221.2 [M+H]+.[044 / ] Step / : Synthesis of methyl 2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5- yl]propionate

[0448] To a solution of methyl 2-(2-amino-1 ,3-benzoxazol~5-yl)propionate (5.5 g, 25 mmol) in DMF (55 mL), is added 2-(methylthio)-1 ,3-benzoxazole (4.95 g, 30 mmol, 1.2 eq) and dicaesium carbonate (20.3 g, 62.4 mmol) and the reaction mixture is heated at 85 °C for 16 h. Progress of the reaction is monitored by TLC and LCMS. Once the reaction is completed, the reaction mixture is diluted with ice-cold water (50 ml) and extracted with EtOAc (2X 100 mL). Combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to get crude compound, which is purified by column chromatography using 50 % - 60 % Ethylacetate in n - Heptane as an eluent to give the title compound (3 g, 35.61 %). LCMS m / z = 338.0 [M+H]+.

[0449] Step 8: Synthesis of 2-[2-(1,3-benzoxazo!-2-ylamino)-1,3-benzoxazol-5-yl]propionic acid

[0450] To a stirred solution of methyl 2-[2-(1,3-benzoxazol-2-y!amino)-1 ,3-benzoxazol-5- yl]propionate (3 g, 8.89 mmol), methanol (25.3 mL), THF (25.3 mL) and water (25.3 mL) mixture, lithium hydroxide (1.06 g, 44.5 mmol) is added and reaction mixture is stirred at RT for 16 h. Progress of reaction is monitored by TLC. After completion of the reaction, reaction mixture is concentrated under reduced pressure to get crude residue. Residue is acidified with dilute HCI (10 mL) and resultant solid formed is filtered and dried under vacuum to afford title compound (1.5 g, 52.17 %). LCMS m / z = 324 [M+H]T

[0451] Step 9: Synthesis of A / -[2-(2-hydroxyethoxy)ethyl]2-[2-(1,3-benzoxazol-2-ylamino)-1 ,3- benzoxazol-5-yl]propionamide

[0452] To a solution of 2-[2~(1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl]propionic acid (1.5 g, 4.64 mmol) in DCM (15.8 mL) are added 2-(2-aminoethoxy)ethanol (0.976 g, 9.28 mmol) and 2,4,6-tripropyl-1 ,3,5,2A5,4As,6A5-trioxatriphosphinane-2,4,6-trione (5.52 mL, 9.28 mmol). To the above mixture at 0°C is added triethylamine (1.94 mL, 13.9 mmol) and the reaction mixture is stirred at room temperature for 5 h. Progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, reaction mixture is quenched with water (15 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The crude is further purified by below mentioned prep condition, collected fractions are concentrated to afford of N-[2-(2- hydroxyethoxy)ethyl]2-[2-(1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl]propionamide (0.9 g, 47.26 % yield) as white solid. Note: both isomer are collected together and concentrated to afford racemic compound. LCMS m / z = 411.4 [M+H]4.

[0453] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.05 (f, J = 5.6 Hz, 1 H), 7.55 - 7.51 (m,3 H), 7.45 ••• 7.43 (m,1 H), 7.31 ~ 7.28 (m, 1 H), 7.25 - 7.21 (m, 1 H), 7.19 - 7.16 (m, 1 H), 3.74 - 3.69 (m, 1 H), 3.47 - 3.37 (m, 8 H), 1 .36 (d, J = 6.8 Hz, 3 H).

[0454] Purification conditionsColumn: CHIRALCEL OJ H (250 mm x 4.6 mm x 5 pm)Mobile phase: n-Hexane: Ethanoi with 0.1% FA (70:30)Flow rate: 1.0 mL / min

[0455] Example 25 and Example 26Synthesis of A / -[2-(2-hydroxyethoxy)ethyi]( / :?)-2-[2-(1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5- yl]propionamide and A / -[2-(2-hydroxyethoxy)ethyl](S)-2-[2-(1 ,3-benzoxazol-2-ylamino)-1 ,3- benzoxazol-5-yl]propionamide

[0456] Chiral purification of Example 24

[0457] Purification conditionsColumn: CHIRALCEL OJ H (250 mm x 4.6 mm x 5 pm)Mobile phase: n-Hexane: Ethanol with 0.1% FA (70:30)Flow rate: 1.0 mL / min

[0458] After chiral purification compound containg fractions (peak 1) are concetrated under reduced pressure to get the A / -[2-(2-hydroxyethoxy)ethyl](F?)-2-[2-(1,3-benzoxazol-2-ylam!no)- 1,3-benzoxazol-5-yl]propionamide (0.195 g, 21.67 %). LCMS m / z = 411.4 [M+H]L

[0459] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.07 - 8.04 (m, 1 H), 7.55 - 7.51 (m, 3H), 7.46 - 7.44 (m, 1 H), 7.32 - 7.11 (m, 1 H), 7.30 (t, J = 7.4 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 3.79 (s, 1 H), 2.33 (s, 6H), 1.43 (d, J = 6.4 Hz, 3H).

[0460] After chiral purification compound containg fractions (peak 1) are concetrated under reduced pressure to get the A / -[2-(2-hydroxyethoxy)ethy!](S)-2-[2-(1,3-benzoxazok2-ylam!no)- 1,3-benzoxazo!-5-y!]propionamide (0.220 g, 24.44 %). LCMS m / z = 411.4 [M+H]’.

[0461] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.07 - 8.04 (m, 1 H), 7.55 - 7.51 (m, 3H), 7.46 - 7.44 (m, 1 H), 7.32 - 7.11 (m, 1 H), 7.30 (t, J = 7.4 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 3.79 (s, 1 H), 2.33 (s, 6H), 1.43 (d, J = 6.4 Hz, 3H).

[0462] Example 27Synthesis of 2-(2-(benzo[d]oxazol~2-ylamino)benzo[d]oxazol-5-yi)- / V-(2-(2-hydroxyethoxy)ethyl)-A / -methylpropanamide

[0463] Example 27 is synthesized following Step 9 of Example 24. Note: both isomer are collected together and concentrated to afford racemic compound. LCMS (ES) m / z = 425 [M+H]+.

[0464] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 - 7.52 (m, 2 H), 7.47 - 7.44 (m, 2 H), 7.31 - 7.28 (m, 1 H), 7.25 - 7.21 (m, 1 H), 7.17 - 7.13 (m, 1 H), 4.25 - 4.14 (m, 1 H), 3.65 - 3.60 (m, 1 H), 3.47 - 3.43 (m, 8 H), 2.92 - 2.85 ( m, 3 H), 1.31 ( t, J = 6.4 Hz, 3 H).

[0465] Purification conditionsColumn: CHIRALCEL OJ H (250 mm x 4.6 mm x 5 pm)Mobile phase A: Hexane: Ethanol with 0.1% DEA (50:50)Flow rate: 1.0 mL / min

[0466] Example 28 and Example 29Synthesis of (F?)-2-(2-(benzo[d]oxazo!-2-ylamino)benzo[d]oxazol-5-yl)-A / -(2-(2- hydroxyethoxy)ethyl)- / V-methylpropanamide and (S)-2-(2-(benzo[d]oxazol-2- ylamino)benzo[d]oxazol-5-yl)- / V-(2-(2-hydroxyethoxy)ethyl)-A / -methylpropanamide

[0467] Chiral purification of Example 27

[0468] Purification conditionsColumn: CHIRALCEL OJ H (250 mm x 4.6 mm x 5 pm)Mobile phase: n-Hexane: Ethanol with 0.1% DEA (50:50)Flow rate: 1.0 mL / min

[0469] After chiral purification compound containing fractions (peak 1) are concentrated under reduced pressure to get the 2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yi)-A / -(2-(2- hydroxyethoxy)ethyi)"A / “methylpropanamide (0.06 g, 7.5 %). LCMS (ES) m / z = 425 [M+H]+.

[0470] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 - 7.52 (m, 2 H), 7.47 - 7.44 (m, 2 H), 7.31 - 7.28 (m, 1 H), 7.25 - 7.21 (m, 1 H), 7.17 - 7.13 (m, 1 H), 4.25 - 4.14 (m, 1 H), 3.65 - 3.60 (m, 1 H), 3.47 - 3.43 (m, 8 H), 2.92 - 2.85 ( m, 3 H), 1.31 ( f, J = 6.4 Hz, 3 H).

[0471] After chiral purification compound containing fractions (peak 1) are concentrated under reduced pressure to get the 2-(2-(benzo[d]oxazo!-2-ylamino)benzo[d]oxazol-5-yl)- / V-(2-(2- hydroxyethoxy)ethyl)- / V-methylpropanamide (0.220 g, 27.5 %). LCMS (ES) m / z = 425 [M+H]’ .

[0472] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 - 7.52 (m, 2 H), 7.47 - 7.44 (m, 2 H), 7.31 - 7.28 (m, 1 H), 7.25 - 7.21 (m, 1 H), 7.17 - 7.13 (m, 1 H), 4.25 - 4.14 (m, 1 H), 3.65 - 3.60 (m, 1 H), 3.47 - 3.43 (m, 8 H), 2.92 - 2.85 ( m, 3 H), 1.31 ( t, J = 6.4 Hz, 3 H).

[0473] Example 30Synthesis of 2-{5-[(diethylamino)methyl]-1 ,3-benzoxazol-2-ylamino}-5-fluoro-1 ,3-benzoxazole

[0474] Step 1 : Synthesis of 5-fluoro-1 ,3-benzoxazol-2-ylamine

[0475] To a stirred solution of 2-amino-4-fiuoropheno! (15 g, 118 mmo!) in methanol (300 mL) is added cynogen bromide (31.2 g, 295 mmol) at room temperature and reaction mixture is allowed to stir for 16 h at room temperature. The progress of the reaction is monitor by TLC (40% ethylacetate / n-hexane) and LC-MS. The reaction mixture is evaporated under reduced pressure to obtain brown solid residue. Residue is re-suspended in water (100 mL) and extracted with ethyl acetate (2 * 50 mL). Combined organic layers is dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get the crude product. Crude is futher purified by column chromatography using 40 % ethyl acetate in n - Heptane as an eluent to give the 5- fluoro-1 ,3-benzoxazol-2-amine (12 g, 66.85 %) as a brown solid. LCMS (ES) m / z = 153 [M+H]L

[0476] Step 2: Synthesis of methyl 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazole-5- carboxylate

[0477] To a solution of 5-fluoro-1,3-benzoxazol-2-ylamine (0.8 g, 5.26 mmol) in THF (10 mL), methyl 2-iodo-1 ,3-benzoxazole-5-carboxylate (1.59 g, 5.26 mmol) is added and heated at 70 °C for 4 h. Reaction mixture is concentrated and residue is quenched with water (20 mL) and extracted with ethyl acetate (2 x 50 mL). Combined organic layers is dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get the crude product. Crude is further re-suspended in DCM (20 mL) and resultant precipitate is filtered and dried under vacuum to afford methyl 2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-5-carboxylate (1 g, 41 %) as brown color solid. LCMS (ES) m / z = 328.2 [M+H]h.

[0478] Step 3: Synthesis of [2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazo!-5-yl]methanol

[0479] To a stirred solution of methyl 2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-5- carboxylate (1 g, 2.14 mmol) in tetrahydrofuran (10 mL, 123 mmol) under inert condition at 0-5°C is added L1AIH4 (162 mg, 2 eq., 4.28 mmol). The reaction mixture stirred for 2 h at 0-5°C. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction the reaction mass is quenched with aq. NH4CI solution (10 mL) and extracted with ethylacetate (2 x 100 mL). Combined organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude. The crude material is purified using MPLC using 75% EtOAcin n-heptane to afford [2-(5-fluoro-1 ,3-benzoxazol-2-y!amino)-1 ,3-benzoxazol-5-y!]methanol (450 mg, 70%) as a light brown solid. LCMS (ES) m / z = 300.2 [M+H]+.

[0480] Step 4: Synthesis of [5-(chloromethyl)-1,3-benzoxazol-2-yl](5-f!uoro-1 ,3-benzoxazol-2- yl)amine

[0481] To a stirred solution of [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5- yl]methanol (350 mg, 1.17 mmol) in dichloromethane (10 mL), is added thionyl dichioride (0.13 mL, 1 .75 mmol) at 0°C. The reaction mixture is stirred at RT for 1 hr. After completion of reaction, reaction mass is concentrated under reduced pressure under nitrogen condition to get crude residue. The crude is directly taken for the next step. LCMS (ES) m / z = 318.1 [M+H]+.

[0482] Step 5: Synthesis of 2-{5-[(diethylamino)methyl]-1 ,3-benzoxazol-2-ylamino}-5-fluoro-1 ,3- benzoxazole

[0483] To a stirred solution of [5-(chloromethyl)-1,3-benzoxazo!-2-y!](5-fluoro-1 ,3-benzoxazol-2- yl)amine (0.2 g, 0.630 mmol) in dimethylformamide (5 mL) dipotassium carbonate (261 mg, 1.89 mmol) and diethylamine (0.130 mL, 1.26 mmol) are added at RT. The reaction mixture is stirred at 60 °C for 2 h The progress of the reaction is monitored by TLC [70% EA in Heptane] and LCMS. The reaction mixture is quenched with ice cold water and extracted with ethyl acetate (10 mL X 3). The combined organic layer is dried over sodium sulfate, filtered and evaporated under reduced pressure to afford crude compound. Crude is further purified using preparative HPLC using below mentioned condition to afford 2-{5-[(diethylamino)methyl]-1 ,3-benzoxazol-2- ylamino}-5-fluoro-1 ,3-benzoxazole (89 mg, 39.9 %) as pale yellow liquid. LCMS (ES) m / z = 355.29 [M+H]+.

[0484] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.38 - 7.34 (m, 3H) 7.130 (d, 7.2Hz, 1 H), 7.074(d, J = 7.2Hz, 1 H), 6.84 (t, J = 8.0Hz, 1 H), 3.81 (s, 2H), 2.67 (s, 4H), 1.09 - 1 .05 (t, J = 7.2Hz, 6H).

[0485] Preparative HPLC conditionsColumn: Xselect C18 (250x19) mm;5uFlow: 19.0 mL / minMobile phase A: 0.1 % Ammonia in WaterMobile phase B: AcetonitrileDesired product at 12.57 min

[0486] Example 31Synthesis of 2-(((2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5- yl)methyl)(methyl)amino)ethan-1-ol

[0487] Example 31 is synthesized following Step 5 of Example 30. LCMS (ES) m / z = 357.25 [M+H]\

[0488] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.57 - 7.53 (m, 1H) 7.50 (t, J = 4.0Hz, 2H), 7.33 (d, J = 2.8Hz, 1 H), 7.19 (m, 1 H), 7.05 (m, 1 H), 3.79 (s, 2H), 3.29 (m, 2H), 2.34 (s, 2H).

[0489] Purification conditionsColumn: Xbridge C18(250x19)mm;5uFlow: 19.0 mL / minMobile phase A: 0.1% Ammonia in WaterMobile phase B: Acetonitrile

[0490] Example 32Synthesis of 5-fluoro-A / -(5-((methyl(2,2,2-trifluoroethyl)amino)methyl)benzo[d]oxazol-2- yl)benzo[d]oxazo!-2-amlne

[0491] Example 32 is synthesized following Step 5 of Example 30. LCMS (ES) m / z = 395.2 [M+H]+.

[0492] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.57 - 7.55 (t, 1 H), 7.518.8Hz, 2H), 7.32 (d,J = 2.8Hz, 2H), 7.20 (s, 1 H), 3.79 (s, 2H), 3.33 - 3.26 (m, 2H) 2.34 (s, 3H).

[0493] Purification conditionsColumn: Xbridge C18(19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1 % Ammonia in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / min

[0494] Example 33Synthesis of 5-fluoro- / V-(5-(morpholinomethyl)benzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0495] Example 33 is synthesized following Step 5 of Example 30. LCMS (ES) m / z = 369.3 [M+H]\

[0496] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.16 - 7.13 (m, 3 H), 6.97 - 6.94 (dd, J = 2.4 Hz, 2.4 Hz, 1 H), 6.84 - 6.82 (dd, J = 1.2 Hz, 1.2 Hz, 1 H), 6.82 (m, 1 H), 3.58 (t, J = 8.0 Hz, 4 H), 3.46 (s, 2 H), 2.36 - 2.33 (m, 4 H).

[0497] Purification conditionsColumn: Xterra RP C18(19 mm X 250 mm X 10 mic)Mobile phase (A): 0.1 % Ammonia in waterMobile phase (B): AcetonitrileFlow'- rate: 19 mL / min

[0498] Example 34Synthesis of 5-(azetidin-1-ylmethyl)-A / -(5-fluorobenzo[d]oxazol-2-yl)benzo[d]oxazoi-2-amine

[0499] Example 34 is synthesized following Step 5 of Example 30. LCMS (ES) m / z = 339.3 [M+H]+.

[0500] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.30 - 7.25 (m, 3 H), 7.06 ■ 7.03 (dd, J = 2.4 Hz, 2.8 Hz 1 H), 6.99 - 6.97 (dd, J = 1.6 Hz, 1.6 Hz 1 H), 6.78 - 6.73 (m, 1 H), 3.99 (s, 2 H), 3.64 (t, J = 8.0 Hz, 4 H), 2.22 - 2.07 (s, 2 H).

[0501] Purification conditionsColumn: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic)Mobile phase (A): 0.1% Ammonia in waterMobile phase (B): Acetonitriie

[0502] Exampie 35Synthesis of 5-fluoro-A / -(5-((4-methylpiperazin-1-y!)methyl)benzo[d]oxazol-2-yl)benzo[d]oxazol- 2-amine

[0503] Exampie 35 is synthesized following Step 5 of Example 30. LCMS (ES) m / z = 382.4 [M+H]4.

[0504] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.39 - 7.31 (m, 3H), 7.15 (d,8.0 Hz, 1 H), 7.02(d, J = 8.0 Hz, 1 H), 6.89 - 6.84 (m, 1 H), 3.53 (s, 2 H), 2.33 (s, 8 H), 2.26 (s, 3H).

[0505] Purification conditionsColumn: X-Select CSH C18 (250x19)mm;5uFlow: 19.0 mL / minMobile phase A: 0.1 % Ammonia in WaterMobile phase B: Acetonitrile

[0506] Exampie 36Synthesis of 5-fluoro-A / -(5-(((2-methoxyethyl)amino)methyl)benzo[d]oxazol-2-yl)benzo[d]oxazol- 2-amine

[0507] Example 36 is synthesized following Step 5 of Example 30. LCMS (ES) m / z = 357.35 [M+H]4.

[0508] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.20 - 7.14 (m, 3H), 6.97 (dd, J = 2.4Hz, 2.4Hz, 1 H), 6.66 - 6.61 (m, 1 H), 3.81 (s, 2H), 3.44 (t, J = 5.2Hz, 2H), 3.25 (s, 3H), 2.75 (t, J = 5.2Hz, 2H).

[0509] Purification conditionsColumn: X-Select CSH C18(250x19)mm;5uFlow: 19.0 mL / minMobile phase A: 0.1 % Ammonia in WaterMobile phase B: Acetonitrile

[0510] Example 37Synthesis of 5-fluoro- / V-(5-((methylamino)methyl)benzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0511] Example 37 is synthesized following Step 5 of Example 30. LCMS (ES) m / z = 313.3 [M+H]\

[0512] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.27 (s, 2H), 7.185 (m, 1 H), 6.97 (t, J = 7.6Hz, 2H), 6.66 (t, J = 9.6Hz, 1 H), 4.08 (s, 2H), 2.54 (s, 3H).

[0513] Purification conditionsColumn: X-Seiect CSH C18(250x19)mm;5uFlow: 19.0 mL / minMobile phase A: 0.1% Ammonia in WaterMobile phase B: Acetonitrile

[0514] Example 38Synthesis of 5-fluoro-A / -(5-(((2,2,2"trifluoroethyl)amino)methyl)benzo[d]oxazoi"2" yl)benzo[d]oxazol-2-amine

[0515] Example 38 is synthesized following Step 5 of Example 30. LCMS (ES) m / z = 379.2 [M+Hp.

[0516] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 - 7.46 (m, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.06 - 6.78 (m, 5H), 3.54 (s, 2H), 2.67 (s, 2H).

[0517] Purification conditionsColumn: Sunfire C18 (250x19)mm;5uFlow: 19.0 mL / minMobile phase A: 5mM Ammonium Acetate in WaterMobile phase B: Acetonitrile

[0518] Example 39Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazole-5-carboxyiic acid

[0519] To a stirred solution of methyl 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazole-5- carboxylate (1 g, 3.06 mmol) in THF (10 mL), MeOH (10 mL) and water (10 mL) is added lithiumhydroxide monohydrate (641 mg, 15.3 mmol) and stirred at RT for 12 h. The progress of the reaction mixture is monitored by TLC. After the completion of the reaction, the reaction mixture is concentrated under reduced pressure to get the crude. The crude material is acidified with dil. HCI (15 mL) and filetred. The obtained solid is first ished with Heptane (3 mL) and then with DCM (3 mL), decanted and dried to get 2-(5-fluoro-1,3-benzoxazo!-2-ylamino)-1 ,3-benzoxazole-5- carboxylic acid (250 mg, 26%) as light brown solid. LCMS (ES) m / z = 314.1 [M+Hp .

[0520] 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.02 (s, 1 H), 8.06 (d, J=1.2 Hz, 1 H), 7.89 - 7.87 (dd, 1H), 7.65 (s, 1 H), 7.60-7.57 (m, 1 H), 7.37 - 7.34 (dd, 1H), 7.21 (bs, 0.5H), 7.11-7.06 (m, 1 H), 6.95 (bs, 0.5H).

[0521] Purification conditionsColumn: Inertsil C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1 % Ammonia in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / min

[0522] Example 40Synthesis of 2-((5-fluorobenzo[d]oxazol~2~yl)amino)- / V-methylbenzo[d]oxazole-5-carboxamide

[0523] Example 40 is synthesized in an analogous manner to Example 16. LCMS (ES) m / z = 327.3 [M+H]+.

[0524] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.5 (s, 1 H), 7.95 (d, J = 1.2 Hz, 1 H), 7.74 - 7.72 (dd, J = 1.6 Hz, J = 1 .6 Hz, 1 H), 7.62 - 7.56 (m, 2 H), 7.37 - 7.34 (dd, J = 2.4 Hz, J = 2.4 Hz, 1 H), 7.10 - 7.05 (m, 1 H), 2.81 - 2.80 (m, 3 H).

[0525] Purification conditionsColumn: Xselect CSH C18 (250x19)mm;5uFlow: 19.0 mL / minMobile phase: EtOAc:Hex ( / :3).

[0526] Example 41Synthesis of A / -(2-(dimethylamino)ethyl)-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazole- 5-carboxamide

[0527] Example 41 is synthesized in an analogous manner to Example 16. LCMS (ES) m / z = 356.3 [M+Hp.

[0528] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.50 (t, J = 8.0 Hz, 1 H), 7.92 (bs, 2 H), 7.75 (s, 1 H), 7.54 - 7.47 (dd, J = 1.2 Hz, 1.6 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.21 - 7.17 (m, 1 H), 7.04 • 7.01 (dd, J = 2.4 Hz, 2.4 Hz, 1 H), 6.71 • 6.65 (m, 1 H), 3.56 - 3.51 (m, 2 H), 3.07 (t, J = 8.0 Hz, 2 H).

[0529] Purification conditionsColumn: Sunfire C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 5mM Ammonium acetate in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / min

[0530] Example 42Synthesis of 2-((5-fiuorobenzo[d]oxazoi~2-yl)amino)- / V-(2,2,2-trifluoroethyl)benzo[d]oxazole~5~ carboxamide

[0531] Example 42 is synthesized in an analogous manner to Example 16. LCMS (ES) m / z = 395.3 [M+H]+.

[0532] 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.18 (L J = 8.0 Hz, 1 H), 8.01 (d, J = 1.2 Hz, 1 H), 7.82 - 7.79 (dd, J = 1.6 Hz, 2.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.60 - 7.57 (m, 1 H), 7.37 - 7.34 (dd, J = 2.4 Hz, 2.8 Hz, 1 H), 7.11 - 7.06 (m, 1 H), 4.16 - 4.07 (m, 2 H).

[0533] Purification conditionsColumn: X-Seiect CSH C18 (250x19)mm;5uFlow: 19.0 mL / minMobile phase A: 0.1 % Ammonia in WaterMobile phase B: Acetonitrile

[0534] Example 43Synthesis of A / -(2-aminoethyl)-2-((5-fiuorobenzo[d]oxazoi-2-yi)amino)benzo[d]oxazoie-5- carboxamide

[0535] Example 43 is synthesized in an analogous manner to Example 16. LCMS (ES) m / z = 384.1 [M+H]4.

[0536] 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.52 (bs, 1 H), 8.48 (t, J = 8.0 Hz, 1 H), 7.78 (s, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.32 - 7.29 (m, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 6.81 (t, J = 8.0 Hz, 1 H), 3.52 - 3.48 (m, 2 H), 2.91 - 2.86 (m, 2 H), 2.58 (s, 6 H).

[0537] Purification conditionsColumn: Sunfire C18 (250 mm x 4.6 mm x 5 pm)Mobile phase (A): 0.1% Ammonia in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / min

[0538] Example 44Synthesis of 2-((5-fluorobenzo[d]oxazol-2-y!)amino)- / V-(isoxazo!-4-yl)benzo[d]oxazo!e-5- carboxamide

[0539] Example 44 is synthesized in an analogous manner to Example 16, LCMS (ES) m / z = 380,3 [M+H]+.

[0540] 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.81 (s, 1 H), 9.28 (s, 1 H), 8,75 (s, 1 H), 8.06 (s, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.58 - 7.55 (m, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.07 (t, J = 2.4 Hz, 1 H).

[0541] Purification conditionsColumn: Sunfire C18 (250 mm x 4.6 mm x 5 pm)Mobile phase: MEOH:DCM (1 :9)

[0542] Example 45Synthesis of A / -(2-(2-hydroxyethoxy)ethy!)-2-((6-methylbenzo[d]oxazol-2- yl)amino)benzo[d]oxazole-5-carboxamide

[0543] To a solution of 2-(6~methyl-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-5-carboxylic acid (0.9 g, 2.91 mmol) in , cooled to 0°C, is added N-ethylbis(isopropyl)amine (1.52 mL, 3 eq., 8.73 mmol), 2,4,6-T3P (3.46 mL, 2 eq., 5.82 mmol) and 2-(2-aminoethoxy)ethanol (367 mg, 1.2 eq., 3.49 mmol). The reaction mixture is stirred at room temperature for 2 h. Progress of the reaction is monitored by TLC and LCMs data. After, the reaction mixture is quenched with water (80 mL) and extracted with DCM (2 x 100 mL). The combined organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The crude material is purified by prep HPLC method to afford N“[2-(2-hydroxyethoxy)ethyl]-2“(6-methyl“1 ,3"benzoxazol"2"ylamino)-1,3-benzoxazole-5-carboxamide (210 mg, 18% yield) as off-white solid. LCMS (ES) m / z = 397.4 [M+H]+.

[0544] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.55(t, J = 5.2 Hz, 1 H), 7.98(s, 1 H), 7.73(dd, J = 1.2Hz, 1 H), 7.58(d, J = 8.4Hz, 1 H), 7.43 - 7.39(01, 2H), 7.13(d, J = 8Hz, 1 H), 4.61(s, 1 H), 3.57 - 3.35(m, 8H), 2.40(s,3H).

[0545] Purification conditionsColumn: X-Bridge C18 (250 mm x 4.6 mm x 5 pm)Mobile phase (A): 0.1% Ammonia in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / min

[0546] Example 46Synthesis2-((6-fluorobenzo[d]oxazol-2-yl)amino)- / V-(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole-5-carboxamide

[0547] Example 46 is synthesized in an analogous manner to Example 45. LCMS (ES) m / z = 401.4 [M+H]+.

[0548] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.56(t, J = 5.6 Hz, 1 H), 7.96 (s, 1 H), 7.74 (dd, J = 8.4Hz, 1 H), 7.61 - 7.51(m, 3H), 7.19 - 7.14(m, 1H), 4.60(s, 1 H), 3.57 - 3.42(m, 8H)

[0549] Purification conditionsColumn: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic)Mobile phase (A): 0.1% Ammonia in waterMobile phase (B): AcetonitrileFlow'- rate: 1.0 mL / min

[0550] Example 47Synthesis of 2-((6-chlorobenzo[d]oxazol-2-yl)amino)- / V-(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole-5-carboxamide

[0551] Example 47 is synthesized in an analogous manner to Example 45. LCMS (ES) m / z = 417.4 [M+H]\

[0552] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.56 - 8.55 (m, 1 H), 7.94 (s, 1 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 4.60 (s, 1 H), 3.71 - 3.32 (m, 8 H).

[0553] Purification conditionsColumn: Kinetex EVO C18 (100 mm x 2.1 mm x 2.6 pm)Mobile Phase A: 0.1% Ammonia in waterMobile Phase B: AcetonitrileFlow rate: 0.5 mL / min

[0554] Example 48Synthesis of A / -(2-(2-hydroxyethoxy)ethyl)-2-((6-methoxybenzo[d]oxazol-2- yl)amino)benzo[d]oxazole-5-carboxamide

[0555] Example 48 is synthesized in an analogous manner to Example 45. LCMS (ES) m / z = 413.4 [M+H]’.

[0556] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.32 (s, 1H), 7.64 (d, J = 8.00 Hz, 1 H), 7.57 (d, J = 8.40 Hz, 1 H), 7.44 (s, 1 H), 7.21 (s, 1 H), 6.81 (d, J = 8.40 Hz, 1 H), 6.60-6.57 (m, 1H), 4.54 (t, J = 5.60 Hz, 1 H), 3.71 (s, 3H), 3.45-3.36 (m, 8H).

[0557] Purification conditionsColumn: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic)Mobile phase (A): 0.1 % Ammonia in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / min

[0558] Example 49Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)ethan-1-ol

[0559] Step 1 : Synthesis of 2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-5-carboxylic acid

[0560] To a stirred solution of methyl 2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-5- carboxylate (1 g, 3.06 mmol) in THF (10 mL), MeOH (10 mL) and water (10 mL) is added lithium hydroxide monohydrate (641 mg, 5 eq., 15.3 mmol) and stirred at RT for 12 h. The progress of the reaction mixture is monitored by TLC. After the completion of the reaction, the reaction mixture is concentrated under reduced pressure to get the crude. The crude material is acidified with dil. HCI (15 mL) and filetred. The obtained solid is first ished with Heptane (5 mL) and then with DCM (5 mL), decanted and dried to get 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-5- carboxylic acid (0.9 g, 94%) as light brown solid. LCMS (ES) m / z = 314.1 [M+H]+.

[0561] Step 2: Synthesis of N-methoxy-N-methyl-2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1,3- benzoxazole-5-carboxamide

[0562] To a solution of 2-(5-fluoro-1 ,3-benzoxazol~2-ylamino)-1 ,3-benzoxazole-5-carboxylic acid (0.2 g, 638 μmol) in DCM (7 mL), is added N-ethylbis(isopropyl)amine (334 pL, 3 eq., 1.92 mmol) and 2, 4,6-tripropyl-1 , 3,5, 2A5,4A5,6As-trioxatriphosphinane-2,4, 6-trione (406 mg, 2 eq., 1.28 mmol) at 0°C. After stirring for 30 min, N-methyl-O-methylhydroxylamine (81 mg, 1.3 eq., 830 μmol) is added to the above mixture at 0°C. After the completion of the reaction, RM is quenched with water (25 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure using rota vapor to getthe crude. The crude material is purified by column chromatography using 80% EtOAc:Hex as eluent to afford pure product N-methoxy-N-methyl-2~(5~fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3- benzoxazole-5-carboxamide (80 mg, 35%) as brown solid. LCMS (ES) m / z = 357.1 [M+H]+.

[0563] Step 3: Synthesis of 1-[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)~1 ,3~benzoxazol-5-yl]-1- ethanone

[0564] To a solution of N-methoxy-N-methyl-2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1!3- benzoxazole-5-carboxamide (325 mg, 912 pmo!) in THF (7 mL), is added lithium methanide (60.1 mg, 3 eq., 2.74 mmol) at -78°C under nitrogen condition. Then the reaction mixture is stirred at 78°C for 5 h. Then the reaction is stirred at RT for 10 h. After 15 h, the reaction is quenched with sat. ammonium chloride solution (15 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer is dried over sodium sulphate, filtered and concetrated under reduced pressure using rota vapor to afford 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5- yl]-1 -ethanone (0.2 g, 70.44%) as brown solid. LCMS (ES) m / z = 312.1 [M+H]+.

[0565] Step 4: Synthesis of 1-[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)~1 ,3-benzoxazol-5-yl]-1- ethanol

[0566] To a stirred solution of 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1 ,3-benzoxazo!-5-yl]-1- ethanone (0.2 g, 0.643 mmol) in MeOH (6 mL), is added sodium boranuide (72.9 mg, 3 eq., 1.93 mmol) at 0°C and stirred at RT for 5 h. After the completion of the reaction, reaction mixture is concentrated. The residue is quenched with water (10 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude. The crude material is purified by combiflash chromatography MPLC, product eluted at 3% MeOH:DCM to afford 1-[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3- benzoxazol-5-yl]-1 -ethanol (160 mg, 79%). Then, 40 mg of the same is further purified by Prep- HPLC to get pure compound (15 mg). LCMS (ES) m / z = 314.2 [M+Hf .

[0567] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.41 (bs, 0.5H), 7.56 - 7.52 (m, 1 H), 7.51 (s, 1 H), 7.47 (s, 1 H), 7.34 - 7.31 (dd, 1 H), 7.22 - 7.20 (dd, 1 H), 7.07 - 7.01 (m, 1 H), 5.26 (s, 1 H), 4.83 - 4.78 (m, 1 H), 1.35 (d, J=6.4 Hz, 3H).

[0568] Purification conditionsColumn: Xselect CSH-C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 5 mM Ammonium acetate in waterMobile phase (B): AcetonitrileFlow rate: 19 mL / minChiral HPLC: Racemic mixture (44.76% + 55.24%)Optical rotation: 0.00

[0569] Example 50Synthesis of 5-(1-(dimethylamino)ethyl)-A / -(5-f!uorobenzo[d]oxazo!-2-yl)benzo[d]oxazo!-2-amine

[0570] Step 1: Synthesis of [5-(1-chloroethyl)-1 ,3-benzoxazol-2-yl](5-fluoro-1 ,3-benzoxazol-2- yl)amine

[0571] To a stirred solution of 142-(5-fluoro-1,3-benzoxazol-2-ylamino)-1 ,3-benzoxazo!-5-yl]-1- ethanol (0.2 g, 638 μmol) in dichloromethane (5 mL, 78.1 mmol), is added thionyl dichloride (69.5 pL, 1.5 eq., 958 μmol) at 0°C. The reaction mixture is stirred at RT for 30 min. After 30 min, RM is concentrated under reduced pressure under nitrogen condition to get crude residue. The crude is directly taken for the next step. LCMS (ES) m / z = 331.9 [M+Hp.

[0572] Step 2: Synthesis of 2-{5-[T(dimethylam:no)ethyij-1 ,3-benzoxazol-2-ylamino}-5-fiuorc- 1 ,3-benzoxazole

[0573] To a stirred solution of [5-(1-chloroethyl)-1,3-benzoxazol-2-yl](5-fluoro-1 ,3-benzoxazol-2- yl)amine (0.2 g, 603 μmol) in dimethylformamide (5 mL, 64.6 mmol) is added triethylamine (254 pL, 3 eq., 1.81 mmol) and dimethylamine (32.6 mg, 1.2 eq., 723 μmol) at RT. The reaction mixture is stirred at 90°C for 12 hour. The progress of the reaction is monitored by TLC and LCMS. The reaction mixture is concentrated under reduced pressure to get the crude (350 mg). The crude material is purified by prep-HPLC to get 2-{5-[1-(dimethylamino)ethyl]-1,3-benzoxazol-2-ylamino}- 5-fluoro-1 ,3-benzoxazole (9 mg, 4.39%).. LCMS (ES) m / z = 339.3 [M+H]+.

[0574] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.37 (s, 3H), 7.15 - 7.14 (m, 1 H), 7.07 (d, J = 8.0 Hz, 1 H), 7.86 (d, J - 8.0 Hz, 1 H), 3.79 (s, 1 H), 2.33 (s, 6H), 1.43 (d, 6.4 Hz, 3H).

[0575] Purification conditionsColumn: X-Bridge C18 (250 mm x 4.6 mm x 5pm)Mobile phase (A): 0.1% Ammonia in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / minChiral HPLC: Racemic mixture (59.89% + 40.11%)Optical rotation: 0.00

[0576] Example 51Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetic acid

[0577] Step 1 : Preparation of 5-fluoro-2,3-dihydro-1,3-benzoxazolidine-2-thione

[0578] To a solution of 2-amino-4-fluorophenol (1 g, 7.87 mmol) in ethanol (15 mL, 257 mmol) is added dipotassium carbonate (1.09 g, 7.87 mmol) dissolved in water (2 mL, 111 mmol) followed by the addition of methanedithione (475 pL, 7.87 mmol) and the reaction is refluxed at 50 °C for 2 h . The reaction mixture is stirred at 50 °C for 2 h. The progress of the reaction is monitored by TLC. Once the reaction is completed, the reaction mixture is quenched with water and the aqueous solution is neutralized with acetic acid (3.0 mL) and extracted with EtOAc (2X 25 mL). Combined organic extracts are ished with water, brine and dried over Na2SO4, concentrated under reduced pressure to afford crude residue. Crude is loaded in Flash column MPLC using 10%-12% EtOAc in Hepane as an eluent to afford 5-fiuoro-2,3-dihydro-1,3~benzoxazolidine~2~ thione (0.6 g, Yield: 45%) as brown solid.

[0579] Step 2: Preparation of 2-chloro-5-fluoro-1,3-benzoxazole

[0580] A stirred solution of 5-fluoro-2,3-dihydro-1 ,3-benzoxazolidine-2-thione — methane (1 / 1) (0.3 g, 1.62 mmol) in thionyl dichloride (5 mL) is refluxed at 70 °C for 2 h. The progress of the reaction is monitor by TLC and mass. After completion of the reaction the reaction mixture is concentrated under reduced pressure to afford 2-chloro-5-fluoro-1,3-benzoxazole (265 mg, Yield:26%) as Violet gum. Crude is carried for next step without further purification. LCMS (ES) m / z = 172.0 [M+H]L

[0581] Step 3: Preparation of methyl (3-amino-4-hydroxyphenyl)acetate

[0582] To a solution of methyl (4-hydroxy-3-nitropheny!)acetate (1.5 g, 7.1 mmol) in methanol (15 mL, 370 mmol) is added palladium (0.8 g, 1.1 eq., 7.52 mmol) under nitrogen atmosphere at room temperature and the reaction is stirred at room temperature under hydrogen atmosphere at 60 PSI for 6 h. Progress of the reaction is monitored by TLC. Once the reaction is completed, the reaction mixture is filtered through celite bed using ethyl acetate and the filtrate is concentrated under reduced pressure to afford methyl (3-amino-4-hydroxyphenyl)acetate (1.3 g, Yield: 98 %, purity: 97%) as brown solid. LCMS (ES) m / z = 182.0 [M+H]+.

[0583] Step 4: Preparation of methyl (2-amino-1 ,3~benzoxazol~5~yl)acetate

[0584] To a stirred solution of methyl (3-amino-4-hydroxyphenyl)acetate (1 g, 5.52 mmol) methanol (15 mL) is added bromocarbonitrile (1.75 g, 3 eq., 16.6 mmol) at 0 °C. After that, reaction mixture is stirred at room temperature for 16 h, reaction progress is checked by TLC monitoring, after completion of the reaction, reaction mixture is concentrated under reduced pressure to get the crude residue. The residue is basified with saturated aq Na2CO3 solution (40 mL) and the solid formed is filtered and dried to afford methyl (2-amino-1 ,3-benzoxazol-5-yi)acetate (0.9 g, 79 % yield ) as brown color solid.

[0585] Step 5: Preparation of methyl [2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5- yl]acetate

[0586] To a solution of methyl (2-amino-1 ,3-benzoxazol-5-yl)acetate (90 mg, 436 pmol) in THF (2.0 mL), lithium 2-methyl-2-propanolate (69.9 mg, 2 eq., 873 μmol) and 2-chloro-5-fluoro-1 ,3- benzoxazole (250 mg, 436 μmol) are added and heated at 70 °C for 4 h. Once the reaction is completed, the reaction mixture is concentrated. The residue is dissolved in water (8.0 mL) and extracted with ethyl acetate (3X 5.0 mL). Combine organic extracts are ished with water, brine and dried over anhy. Na2SO4, concentrated under reduced pressure to get crude. Crude is loaded in Flash column MPLC using EtOAc in heptane as mobile phase (compound eluted at 100% EtOAc due to solubility issue) to afford methyl [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3- benzoxazol-5-yl]acetate (40 mg, Yield: 27%) as Brown solid.

[0587] Step 6: Preparation of [2“(5“fluoro-1 ,3-benzoxazol“2-ylamino)-1 ,3-benzoxazol-5-yl]acetic acid

[0588] To a stirred solution of methyl [2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5~ yljacetate (40 mg, 117 μmol) in tetrahydrofuran (134 pL, 1.65 mmol), methanol (67.2 pL, 1.66 mmol) and water (134 pL, 7.46 mmol) is added lithium hydroxide (8.42 mg, 3 eq., 352 pmol) and the reaction is stirred at RT for 3 h. Progress of the reaction mixture is monitored by TLC. Aftercompletion of the reaction, the reaction mixture is concentrated under reduced pressure to get the crude. The crude material is acidified with dii. HCI (1 .0 mL) and extracted with EtOAc (2X 4.0 mL). Combined organic extracts are ished with water, brine, dried over anhy. Na2SO4 and concenteted under reduced presssure to obtain the crude. Crude is purified by below mentioned prep HPLC method to obtain the desired product [2-(5-f!uoro-1 ,3-benzoxazol-2-ylamino)-1,3- benzoxazol-5-yl]acetic acid (9 mg, Yield: 23.4%) as off white solid. LCMS (ES) m / z = 328.2 [M+H]\

[0589] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.40 (bs, 1 H), 7.52- 7.55 (m, 1 H), 7.46 (d, J - 8.0 Hz, 1 H), 7.41 (s, 1 H), 7.30- 7.33 (dd, J = 2.0 Hz, 10.8 Hz, 1 H), 7.12 (d, J = 7.6 Hz, 1 H), 7.00- 7.06 (m, 1H), 3.67 (s, 2 H).

[0590] Purification conditionsColumn: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic)Mobile phase (A): 0.1% Ammonia in waterMobile phase (B): MethanolFlow rate: 1.0 mL / min% of B: 0 / 2,1 / 2,18 / 98,25 / 98,27 / 2,30 / 2

[0591] Example 52Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-4-yl)acet!C acid

[0592] Example 52 is synthesized in an analogous manner to Example 51. LCMS (ES) m / z = 328.3 [M+H]+.

[0593] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.53 - 7.50 (m,1 H), 7.42 - 7.41(d, J = 4 Hz ,1 H), 7.32 - 7.29 (d, J = 12 Hz, 1 H), 7.16 (s, 2 H), 7.03- 6.99 (m, 1 H), 3.95 (s, 2 H).

[0594] Purification conditionsColumn: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic)Mobile phase (A): 0.1 % Ammonia in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / min% of B :0 / 2, 1 / 2, 18 / 98,25 / 98,27 / 2,30 / 2

[0595] Example 53Synthesis of 2-(2-((6-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetic acid

[0596] Example 53 is synthesized in an analogous manner to Example 51. LCMS (ES) m / z = 328.3 [M+H]+.

[0597] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.4 (s, 1 H), 7.54-7.41 (m, 4H), 7.15-7.10 (m, 2H), 3.66 (s. 2H).

[0598] Purification conditionsColumn: Xterra C18 (250x19)mm;1 OuFlow: 19.0 mL / minMobile phase A: 0.1% Formic acid in WaterMobile phase B: Acetonitrile

[0599] Example 542-(2~((6~methylbenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetic acid

[0600] Example 54 is synthesized in an analogous manner to Example 51. The crude material is acidified with 1 N HCI, pH (2-3) and the solid obtained is filtered using sintered funnel to obtain the desired product. LCMS (ES) m / z = 324.3 [M+H]\

[0601] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.44 (s, 1 H), 7.46-7.37 (m, 4H), 7.11 (d, J = 8.00 Hz, 2H), 3.67 (s, 2H), 2.40 (s, 3H).

[0602] Example 55Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-y!)amino)benzo[d]oxazo!-5-yl)-A / , / V- dimethylacetamide

[0603] To a solution of [2-(5-fluoro-1 ,3-benzoxazo!-2-ylam!no)-1,3-benzoxazol-5-yl]acetic acid (120 mg, 0.367 mmol) in DMF (5.0 mL), is added 1,1 ,3,34etramethyl-2-(3H-1 ,2,3,4-tetraazainden- 3-yl)-3-isoureaium hexafluoridophosphate(l-) (279 mg, 0.733 mmol) and dimethylamine (0.05 mL, 2 eq., 0.733 mmol) at 0°C. After stirring for 5 min, N-ethylbis(isopropyl)amine (0.192 mL, 3 eq., 1.1 mmol) is added and the reaction mixture is stirred at rt for 16 h. Progress of the reaction is monitored by TLC. After completion of the reaction, reaction mixture is quenched with water (15 mL) and extracted with ethyl acetate (2 x 8.0 mL). The combined organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The crude material is purified by below mentioned prep HPLC method to afford N!N-dimethy![2-(5-fluoro-1!3- benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl]acetamide (8 mg, Yield: 6%) as off white solid. LCMS (ES) m / z = 355.4 [M+H]+-

[0604] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.53- 7.56 (m, 1 H), 7.468.0 Hz, 1 H), 7.37(s, 1 H), 7.31- 7.34 (dd,2.0 Hz, 10.8 Hz, 1 H), 7.02- 7.11 (m, 2 H), 3.78 (s, 2 H), 3.03 (s, 3 H), 2.85 (s, 3 H).

[0605] Purification conditionsColumn: X-Bridge C18 (250 mm x 4.6 mm x 5 pm)Mobile phase (A): 0.1 % Ammonia in waterMobile phase (B): AcetonitrileGradient% B: 0 / 2,2 / 2,18 / 98,25 / 98,27 / 2,30 / 2Flow'- rate: 1.0 mL / min

[0606] Example 56Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-A / -methylacetamide

[0607] Example 56 is synthesized in an analogous manner to Example 55, LCMS (ES) m / z = 341 ,3 [M+H]+.

[0608] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.99 (d, J = 3.6 Hz, 1 H), 7.53- 7.62 (m, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.42 (s, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.03- 7.07 (m, 1 H ), 3.47 (s, 2 H), 2.58 (d, J = 4.8Hz, 3 H).

[0609] Purification conditionsColumn: X-Bridge C18 (250 mm x 4.6 mm x 5 pm)Mobile phase (A): 0.1 % Ammonia in waterMobile phase (B): AcetonitrileGradient% B: 0 / 2,2 / 2,20 / 98,25 / 98,28 / 2,30 / 2Flow rate: 1.0 mL / min

[0610] Example 572-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- / V-methylacetamide

[0611] Example 5 / is synthesized in an analogous manner to Example 55. LCMS (ES) m / z = 323.3 [M+H]+.

[0612] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.48 (bs, 1 H), 7.97- 7.96 (m, 1 H), 7.55- 7.52 (m, 2 H), 7.45- 7.43 (m, 2 H) 7.29 (t, J = 7.4 Hz, 1 H), 7.25- 7.21 (m, 1 H), 7.10 (d, J = 9.6 Hz, 1 H), 3.47 (s, 2 H), 2.58 (d, J = 4.4 Hz, 3 H).

[0613] Purification conditionsColumn: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic)Mobile phase (A): 0.1% Ammonia in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / min% of B :0 / 2, 15 / 50,25 / 98,27 / 2,30 / 2

[0614] Example 58Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- / V-(1-methyl-1H- pyrazol-4-yl)acetamide

[0615] Example 58 is synthesized in an analogous manner to Example 55. LCMS (ES) m / z = 407.1 [M+H]+.

[0616] 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.20 (s, 1 H), 7.85 (s, 1 H), 7.41- 7.53 (m, 4 H), 7.32 (d, J = 6.0 Hz, 1 H), 7.17 (d, J = 6.8 Hz, 1 H), 7.04 (s, 1 H), 3.77 (s, 2 H), 3.65 (s, 3 H).

[0617] Purification conditionsColumn: X-Terra C18 (250x19)mm;1 OuFlow: 19.0 mL / minMobile phase A: 0.1% Ammonia in WaterMobile phase B: Acetonitrile

[0618] Example 59Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-A / -(2-methyl-2H- 1 ,2,3-triazol-4-yl)acetamide

[0619] Example 59 is synthesized in an analogous manner to Example 55. LCMS (ES) m / z = 408.1 [M+H]+.

[0620] !H N MR (400 MHz, DMSO-d6) δ ppm: 11.08 (s, 1 H), 7.79 (s, 1 H), 7.55 -7.52 (m, 1 H), 7.49- 7.47(d, J = 8 Hz, 2H), 7.33-7.30 (d, J =12, 1 H), 7.06 - 7.05 (d, J = 4Hz,1 H),7.04 -7.01 (m, 1H),4.05(s, 3H), 3.74 (s, 2H).

[0621] Purification conditionsColumn: X-Seiect C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1 % Ammonia in Water.Mobile phase (B): AcetonitrileFlow rate: 19 mL / min%B / T: 0 / 5, 1 / 5,12 / 50, 13 / 100, 17 / 100

[0622] Example 60Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yi)amino)benzo[d]oxazoi-5-yi)- / V-(isoxazol-4- yi)acetamide

[0623] Example 60 is synthesized in an analogous manner to Example 55. LCMS (ES) m / z = 394.3 [M+H]+.

[0624] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.58(s, 1 H), 10.50(s, 1H),9.33 (s, 1 H), 9.10 (s, 1 H), 7.55-7.52 (m,1H), 7.50- 7.45 (m, 2H),7.33 -7.30 (dd, 7=4 Hz, J = 4 Hz, 1 H), 7.18 -7.16 (d, J=8 Hz,1 H), 7.06 - 7.01 (m, 1 H), 3.73 (s, 2H).

[0625] Purification conditionsColumn: Kinetex EVO C18 (100 mm x 2.1 mm x 2.6 pm)Mobile Phase A: 0.1 % Ammonia in waterMobile Phase B: AcetonitrileFlow rate: 0.5 mL / min% B / T: 0.10 / 10, 06 / 80, 08 / 98, 8.01 / 10,10 / 10

[0626] Example 61Synthesis of 2-(2-((6-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-A / -methylacetamide

[0627] Example 61 is synthesized in an analogous manner to Example 55. Crude is purified over combi-flash MPLC with 5% MeOH in DCM as mobile phase. LCMS (ES) m / z = 341.3 [M+H]+.

[0628] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.98 (d, J = 3.2 Hz, 1H), 7.55-7.50 (m, 2H), 7.45- 7.41 (m, 2H), 7.16-7.10 (m, 2H), 3.47 (s, 2H), 2.58 (d, J = 4.4 Hz, 3H).

[0629] Example 62Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-1-morpholinoethan~ 1-one

[0630] Example 62 is synthesized in an analogous manner to Example 55. LCMS (ES) m / z = 371.34 [M+H]+.

[0631] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.54-7.56 (m, 1 H), 7.48-7.46 (m, 1 H), 7.37 (s, 1 H), 7.32-7.33 (d, J=6.8, 1 H), 7.0-7.1 (m, 2 H), 3.81 (s, 2 H), 3.47-3.55 (m, 8 H).

[0632] Purification conditionsColumn: X-select CSH C-18 (250 mm X 4.6 mm X 5 mic)Mobile phase (A): 0.1% Ammonia in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / min

[0633] Example 63Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- / V-(2- hydroxyethyl)acetamide

[0634] Example 63 is synthesized in an analogous manner to Example 55. LCMS (ES) m / z = 371.4 [M+H]+.

[0635] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.05 (s,1 H), 7.421-7.421 (m, 1 H), 7.339-7.37 (m, 2 H), 7.221-7.241 (d, J=8.0 1 H), 7.024-7.044 (d, J=8, 1 H), 6.908-6.951 (m, 1 H), 4.686 (s, 1 H), 3.473 (s, 2 H), 3.328-3.387 (m, 2H), 3.103-3.147 (m, 2H).

[0636] Purification conditionsColumn: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic)Mobile phase (A): 0.1 % Formic acid in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / min

[0637] Example 64Synthesis of (2-(2-((5-fluorobenzo[d]oxazo!-2-yi)amino)benzo[d]oxazoi-5-yl)acetyi)glycine

[0638] Example 64 is synthesized in an analogous manner to Example 55. The crude material is acidified with dil. HCI (3.0 mL) and the solid obtained is filtered using sintered funnel, ished with water to obtain the desired product. LCMS (ES) m / z = 385.4 [M+H]+.

[0639] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.542 (s,1 H), 8.41 (t, 1 H), 7.538-7.571 (m, 1 H), 7.438-7.483 (m, 2H), 7.324-7.353-7.166 (dd, J^1.2, J2=1.2, 1 H), 7.028-7.081 (m, 1 H), 3.764-3.779 (d, J=6, 2H), 3.577 (s, 2H).

[0640] Example 65Synthesis of A / -methyl-2-(2-((6-methy!benzo[d]oxazo!-2-yl)amino)benzo[d]oxazo!-5-yl)acetamide

[0641] Example 65 is synthesized in an analogous manner to Example 55. LCMS (ES) m / z = 337.3 [M+H]+.

[0642] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.97 (d, J = 3.60 Hz, 1 H), 7.45-7.40 (m, 3H), 7.37 (s, 1 H), 7.12-7.09 (m, 2H), 3.47 (s, 2H), 2.59 (d, J = 4.40 Hz, 3H), 2.40 (s, 3H).

[0643] Purification conditionsColumn: Xbridge C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1 % Ammonia in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / min

[0644] Example 66Synthesis of A / ,A / -dimethyk2-(2-((6-methylbenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5- yl)acetamide

[0645] Example 66 is synthesized in an analogous manner to Example 55. LCMS (ES) m / z = 351.4 [M+H]+.

[0646] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.45-7.37 (m, 4H), 7.12-7.06 (m, 2H), 3.78 (s, 2H), 3.03 (s, 3H), 2.85 (s, 3H), 2.40 (s, 3H).

[0647] Purification conditionsColumn: X-Select CSH C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1 % Ammonia in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / min%B / T: 0 / 5, 1 / 5, 12 / 35, 13 / 100, 18 / 100, 19 / 5

[0648] Example 67Synthesis of 2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- / V-(2-(2- hy d roxy ethoxy) ethy I ) aceta m ide

[0649] Example 67 is synthesized in an analogous manner to Example 55. LCMS (ES) m / z = 426.3 [M+H]+.

[0650] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.14 (s, 1 H), 7.53 (t, J = 4.8 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.30 (t, J - 8.0 Hz, 1 H), 7.23 (t,8.0 Hz, 1 H), 7.11 (t, J = 8.0 Hz, 1 H), 3.49 (d, J= 5.6 Hz, 4H), 3.42 (d, J = 3.2 Hz, 4H), 3.22 (d, J = 5.6 Hz, 2H).

[0651] Purification conditionsColumn: Xterra Flow: 19.0 mL / minMobile phase A: 0.1 % Ammonia in WaterMobile phase B: AcetonitrileDesired product rt at 8.56 min

[0652] Example 68Synthesis of 2-(2-(benzo[d]oxazoi-2-ylamino)benzo[d]oxazol-5-yl)-A / ,A / -dimethylacetamide

[0653] Example 68 is synthesized in an analogous manner to Example 55. LCMS (ES) m / z = 337.3 [M+H]+.

[0654] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.52 (d, J =7.6 Hz, 2 H), 7.44 (d, J =8.0 Hz, 1 H), 7.37 (s, 1 H), 7.20 -7.30 (m, 2 H), 7.07 (d, J =8.0 Hz, 1 H), 3.78 (s, 2 H), 3.03 (s, 3 H), 2.84 (s, 3 H).

[0655] Purification conditionsColumn: Kinetex EVO C18 (100 mm x 2.1mm x 1.7 pm)Mobile Phase A: 0.1 % Ammonia in waterMobile Phase B: Acetonitrile%B / T: 0.10 / 10, 06 / 98, 08 / 98, 8.01 / 10, 10 / 10

[0656] Example 69Synthesis of 2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)-A / -(2-(2-hydroxyethoxy)ethyl)-AZ-methylacetamide

[0657] To a stirred solution of [2-(1,3-benzoxazo!-2-ylamino)-1 ,3-benzoxazoi-5-yl]acetic acid (0.3 g, 630 μmol) in DMF (4.0 mL), is added 2-methyl~2,6,8-triaza-6,7-decadiene — hydrogen chloride (1 / 1) (242 mg, 2 eq., 1.26 mmol) , 1H-1,2,3-benzotriazoi-4-ol (128 mg, 1.5 eq., 946 pmol) and 2- [2"(methylamino)ethoxy]ethanol (225 mg, 3 eq., 1.89 mmol) at 0°C. After that, at same temperature N-ethylbis(isopropyl)amine (329 pL, 3 eq., 1.89 mmol) is added to the above mixture and and allowed to stirred at 100 °C for 12 h. Progress of the reaction is monitored by TLC (10% MeOH in DCM) and LCMs data. After completion of the reaction, reaction mixture is quenched with water (10 mL) and extracted with ethyl acetate (2 x 8 mL). The combined organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The crude material is purified by Flash column MPLC using (1.5 %- 2.0 %) MeOH in DCM as an eluent to afford the desired compound (0.34 g) with 42% purity in LCMS. Then it is further purified by using below mentioned Prep HPLC method to afford N-[2-(2-hydroxyethoxy)ethyl]-N-methyl[2-(I .S-benzoxazol^-ylaminoJ-l ^-benzoxazoi-S-ynacetamide (49 mg, Yield: 19 %) as Brown gummy liquid. LC-MS (m / z) = 411.4 [M+Hp.

[0658] Purification conditionsFlow rate: 0.5 mL / minColumn: Kinetex EVO C18 (100 mm x 2.1mm x 1.7 pm)Mobile Phase A: 0.1% Formic acid in waterMobile Phase B: Acetonitrile%B / T: 0.10 / 10,06 / 98,08 / 98,8.01 / 10, 10 / 10

[0659] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.46-7.48 (m, 2 H), 7.38 (s, 2 H), 7.19- 7.26 (m, 2 H), 7.06 (d, , / = 8.0 Hz, 1 H), 3.78 (s, 2 H), 3.45- 3.54 (m, 11 H).

[0660] Example 70Synthesis of A / -(5-((d!methylamino)methyl)benzo[d]oxazol-2-yl)-5,7-d!fluorobenzo[d]oxazol-2- amine

[0661] Step-1 : Synthesis of 2-amino-4,6-difluorophenol

[0662] To a stirred solution of 2,4-difluoro-6-nitrophenoi (1 g, 5.71 mmol) in tetrahydrofuran (70 mL), ammonium chloride (917 mg, 3 eq., 17.1 mmol) dissolved in water (15 mL, 833 mmol) is added and stir for 5 min. To above mixture zinc (1.87 g, 5 eq., 28.6 mmol) is added and resultant mixture is stir at RT for 12h. The progress of the reaction is monitored by TLC [50%EA in Heptane] and LCMS. The reaction mixture is first filtered to celite bed setup and filtrate is diluted with water. Aqueous layer is extracted with ethyl acetate (25 mL X 3). Combined organic layer is dried over sodium sulfate, filtered and evaporated under reduced pressure to afford crude compound. Crude is further purified using MPLC using 42% EA in Heptane as mobile phase to afford 2-amino-4,6- difluorophenol (580 mg, 70 %) as white solid.

[0663] Step-2: Synthesis of 5,7-dif!uoro-1 ,3-benzoxazol-2-ylamine

[0664] To a stirred solution of 2-amino-4,6-difluorophenol (0.6 g, 4.13 mmol) in methanol (60 mL) is added bromocarbonitrile (1.09 g, 2.5 eq., 10.3 mmol) at room temperature. The reaction mixture is allowed to stir for 16 h at room temperature. The progress of the reaction is monitor by TLC (40% ethyl acetate / n-hexane) and LC-MS. The reaction mixture is evaporated under reduced pressure to obtain brown solid crude which is purified by MPLC using 40 % ethyl acetate in n ■ Heptane as an eluent to give the 5,7-difluoro-1 ,3-benzoxazol-2-ylamine (70 mg, 10%) as a pale brown solid.

[0665] Step-3: Synthesis of methyl 2-(5,7~difluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3~benzoxazole~5- carboxylate

[0666] To a solution of 5,7-difluoro-1 ,3-benzoxazol-2-ylamine (0.4 g, 2.35 mmol) in tetrahydrofuran (18 mL), lithium 2-methyl-2-propanolate (376 mg, 2 eq., 4.7 mmol) and methyl 2- iodo-1,3-benzoxazo!e-5-carboxylate (641 mg, 0.9 eq., 2.12 mmol) is added and heated at 70 °C for 9h. Reaction is monitored by TLC & LCMS. Reaction mixture is concentrated. The residue is dissolved in ethyl acetate (100 mL) and ished with water (40 mL). The organic layer is concentrated and purified using MPLC flash using 5% MeOH in DCM as mobile phase to afford methyl 2-(5,7-difluoro-1 ,3-benzoxazol-2-ylamino)-1,3-benzoxazole-5-carboxylate (347 mg, 42 %) as pure brown solid product.

[0667] Step-4: Synthesis of [2-(5,7-difluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl] methanol

[0668] To a stirred solution of methyl 2-(5,7-difluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole- 5-carboxylate (0.1 g, 0.290 mmol) in tetrahydrofuran (4.93 mL) under inert condition at 0-5°C lithium (1+) alumanuide (22 mg, 2 eq., 0.6 mmol) is added to the reaction mixture at 0-5°C dropwise. Allowed the reaction mixture stirred for 1 h at 0-5°C. The progress of the reaction is monitor by TLC (50% EtOAc in Heptane) and LCMS. After completion of the reaction the reaction mixture is quenched with aq. ammonium Chloride solution and extracted with ethyl acetate (3 x 25 mL), the organic layer is ished with water and dried over sodium sulfate and concentrated under reduced pressure to afford [2-(5,7-difluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl] methanol (55 mg) the crude brown solid.

[0669] Step-5: Synthesis of [5-(chloromethyl)-1 ,3-benzoxazol-2-yl] (5,7-difluoro-1 ,3-benzoxazol- 2-yl) amine

[0670] To a stirred solution of [2-(5,7-difluoro-1,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl] methanol (55 mg, 0.173 mmol) in dichloromethane (4 mL, 62.5 mmol), thionyl dichloride (0.025mL, 2 eq., 0.347 mmol) and 2 drops of N,N-di methylformamide are added at 0°C. The reaction mixture is stirred at RT for 2 hours. The progress of the reaction is monitored by TLC [70%EA in Heptane] and LCMS. The reaction mixture is evaporated under reduced pressure to get crude residue. The residue is quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (20mL X 3). The combined organic layer is dried over sodium sulfate, filtered and evaporated under reduced pressure to afford [5-(chloromethyl)-1 ,3-benzoxazol-2-yl] (5,7-difluoro- 1 ,3-benzoxazol-2-yl) amine (54 mg) as brown powder solid.

[0671] Step-6: Synthesis of 2-{5-[(dimethylamino)methyl]-1 ,3-benzoxazol-2-ylamino}-5!7- difluoro-1 ,3-benzoxazole

[0672] To a stirred solution of [5-(chioromethyl)-1,3-benzoxazol-2-yi] (5,7-difluoro-1 ,3- benzoxazol-2-yl) amine (75 mg, 0.223 mmol) in dimethylformamide (3.87 mL, 49.9 mmol), dipotassium carbonate (124 mg, 4 eq., 0.894 mmol) and dimethylamine (50.4 mg, 5 eq., 1.12 mmol) are added. The reaction mixture is stirred at 70°C for 4 hours. The progress of the reaction is monitored by TLC [10%MeOH in DCM] and LCMS. The reaction mixture is evaporated under reduced pressure to get crude residue. The residue is diluted with ethyl acetate and ished with water. Aqueous layer extracted with ethyl acetate (20mL X 3). The combined organic layer is dried over sodium sulfate, filtered and evaporated under reduced pressure and purified using HPLC to afford 2-{5-[(dimethylamino)methyl]-1 ,3-benzoxazol-2-ylamino}-5,7-difluoro-1 ,3-benzoxazole (15 mg, 19.5%) as off-white powder solid. LC-MS (m / z) = 355.29 [M+H]+.

[0673] Purification conditionsColumn: X-Bridge C18 (250 mm x 4.6 mm x 5pm)Mobile phase (A): 0.1%Ammonia in waterMobile phase (B): AcetonitrileGradient% B: 0 / 02,2 / 02,18 / 98,25 / 98,27 / 02,30 / 02Flow rate: 1.0 mL / min

[0674] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.29 (s, 2H), 6.96 (d, J = 7.6Hz, 1 H), 6.91 (s, 2H), 6.78 (t, J = 9.6Hz, 1 H), 3.83 (s, 2H), 2.43 (s, 6H).

[0675] Examples 71-77Below compounds are synthesized in an analogous manner to Example 70:

[0676] Examples 78-82Below compounds are synthesized in an analogous manner to Example 70 and using RHSIntermediate synthesized in Intermediate Reaction Scheme.

[0677] Exampie 83Synthesis of 6-fluoro-2-((5-fluorobenzo[d]oxazol-2-yl)am!no)-A / -methy!benzo[d]oxazole-5- carboxamide

[0678] Step-1 : Synthesis of methyl 2-fluoro-4-hydroxy-5-nitrobenzoate

[0679] Potassium nitrate (3.09 g, 1.3 eq., 30.6 mmol) is added to methyl 2-fluoro-4- hydroxybenzoate (4 g, 23.5 mmol) in sulfuric acid (40 mL) solution, the reaction is stirred at 0 °C and the reaction mixture is stirred at RT for 12 hours. The reaction solution is poured into ice water and quenched. After stirring for 5 mins, and extracted with EtOAc and water combined organic layer dried over sodium sulphate and concentrated to provide the crude material. The crude product is purified by flash silica chromatography (dry loaded), elution gradient 0 to 30% EtOAc in heptane. Pure fractions are concentrated to afford methyl 2-fluoro-4-hydroxy-5- nitrobenzoate (2.34 g, 10.9 mmol) as a pale-yellow solid. LC-MS (m / z) = 214.6 [M-H]’.

[0680] Step-2: Synthesis of methyl 5-amino-2-fluoro-4-hydroxybenzoate

[0681] To a stirred solution of methyl 2-fluoro-4-hydroxy-5-nitrobenzoate (2.34 g, 10.9 mmol) in 1,4-dioxane (30 mL, 352 mmol) and water (10 mL, 555 mmol) is added zinc (5.69 g, 8 eq., 87 mmol) and ammonium chloride (4.65 g, 8 eq., 87 mmol). The reaction mixture is stirred at RT for 2h. Progress of the reaction is monitored by TLC and LCMS. Once the reaction is completed, the mixture is filtered and diluted with EtOAc (5 mL), ished with water (3 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the crude of methyl 5-amino- 2-fluoro-4-hydroxybenzoate (2 g, 10.8 mmol) as a brown solid. LC-MS (m / z) = 186.0 [M+1H]+.

[0682] Step-3: Synthesis of methyl 6-fluorobenzo[d]oxazole-5-carboxylate

[0683] To a solution of methyl 5-amino-2-fluoro-4-hydroxybenzoate (2 g, 0.9 eq., 10.8 mmol) in diethoxymethoxyethane (20 mL) is added p-toluenesulfonic acid (309 mg, 0.15 eq., 1.79 mmol) at RT. The reaction mixture is stirred at 100 °C for 16 h. The progress of the reaction is monitored by TLC. The reaction mixture is evaporated under reduced pressure to get crude compound. Crude is loaded in Flash column MPLC using EtOAc in heptane as mobile phase (compound eluted at 30 % EtOAc in hexane) to afford methyl 6-fluoro-1 ,3-benzoxazole-5-carboxyiate (1.26 g, 6.46 mmol, white solid). LC-MS (m / z) = 196.0 [M+1 H]+.

[0684] Step-4: Synthesis of methyl 6-fluoro-2-iodobenzo[d]oxazole-5-carboxylate

[0685] To a solution of methyl 6-fluoro-1 ,3-benzoxazole-5-carboxylate (1.19 g, 6.1 mmol) in THF (25 mL), cooled to -78 °C, then lithium bis(trimethy!silyl)azanide (2.04 g, 2 eq., 12.2 mmol) is added and stirred at same temperature for 2 h. iodine (1.16 g, 1.5 eq., 9.15 mmol) in THF (5.0 mL) is added and the temperature is gradually cooled to -78 °C for 2 h. Reaction mixture is quenched with sat. ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 X 20 mL), dried over sodium sulfate, filtered and concentrated to get the crude. The crude product ispurified by flash silica chromatography (dry loaded), elution gradient 0 to 30% EtOAc in heptane. Pure fractions are concentrated to afford methyl 6-fluoro-2-iodo-1 ,3-benzoxazole-5-carboxylate (0.9 g, 2.8 mmol) as an off white solid. LC-MS (m / z) = 322.0 [M+H]T

[0686] Step-5: Synthesis of methyl 6-fluoro-2-((5-fluorobenzo[d]oxazol-2- yl)amino)benzo[d]oxazole-5-carboxylate

[0687] To a solution of 5-fluoro-1,3-benzoxazol-2-ylamine (330 mg, 2.17 mmol) in tetrahydrofuran (9.9 mL, 122 mmol), lithium 2-methyl-2-propanolate (347 mg, 2 eq., 4.34 mmol) and methyl 6- fluoro-2-iodo-1 ,3-benzoxazole-5-carboxylate (696 mg, 2.17 mmol) is added and heated at

[0688] 70 °C for 4 h. The reaction mixture is concentrated, the residue is dissolved in ethyl acetate (15 mL) and ished with water (6 mL). The organic layer is concentrated to provide the crude material. The crude product is purified by flash silica chromatography (dry loaded), elution gradient 0 to 60% EtOAc in heptane. The fractions are concentrated, and dichloromethane (5 mL) is added, solid is precipitated. The precipitate is filtered and ished with dichloromethane (10 mL) and the solid is dried under vacuum to afford methyl 6-fluoro-2-(5-fluoro-1 ,3-benzoxazol-2- ylamino)-1 ,3-benzoxazole-5-carboxylate (190 mg, 550 μmol) as a pale brown solid. LC-MS (m / z) = 346.0 [M+H]f.

[0689] Step-6: Synthesis of 6-fluoro-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazole-5- carboxylic acid

[0690] To a stirred solution of methyl 6-fluoro-2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1,3- benzoxazole-5-carboxylate (190 mg, 1.4 eq., 550 μmol) in tetrahydrofuran (2 mL, 24.6 mmol), methanol (2 mL, 49.4 mmol) and water (1 mL, 55.5 mmol) is added lithium hydroxide (36.5 mg, 4 eq., 1.52 mmol) and the reaction is stirred at RT for 3 h. Progress of the reaction mixture is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to get the crude. The crude material is acidified with 1 N HCI, pH (2-3) and the solid obtained is filtered using sintered funnel to obtain the desired product 6-fluoro-2-(5-fluoro- 1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-5-carboxylic acid (140 mg, 423 μmol) as a brown solid. The crude is carried for next step without further purification. LC-MS (m / z) = 332.0 [M+H]+.

[0691] Step-7: Synthesis of 6-fluoro-2-((5-fluorobenzo[d]oxazol-2-yl)amino)-N- methylbenzo[d]oxazole-5-carboxamide

[0692] To a solution of 6-fluoro-2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3~benzoxazole~5- carboxylic acid (140 mg, 423 μmol) in dichloromethane (6 mL, 93.7 mmol) is added 2 ,4,6-tripropyl- 1 ,3, 5, 2A5,4A5,6A5-trioxatriphosphinane-2, 4, 6-trione 50%v / v (498 pL, 2 eq., 845 pmol) andmethylamine (39.4 mg, 3 eq., 1.27 mmol). To the above mixture at 0°C is added N- ethylbis(isopropyl)amine (221 pL, 3 eq., 1.27 mmol) and the reaction mixture is stirred at room temperature for 12 h. Progress of the reaction is monitored by TLC and LCMS data. After completion of the reaction, reaction mixture is quenched with water (3.0 mL) and extracted with ethyl acetate (2 x 5.0 mL). The combined organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The crude product is purified by flash silica chromatography (dry loaded), elution gradient 0 to 15% MeOH in DCM and the fractions are concentrated under reduced pressure to get the impure product (140 mg) as a brown solid. The crude material is purified by below mentioned prep HPLC method to afford N-methyl-6-fluoro-2- (5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-5-carboxamide (21.8 mg, 63.3 pmol, Yield: 14.98%) as a white solid. LC-MS (m / z) = 345.3 [M+H] \

[0693] Purification conditionsColumn: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic)Mobile phase (A): 0.1% Ammonia in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / min

[0694] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.07 (s, 1 H), 7.50 (d, J = 6.40 Hz, 1 H), 7.28 (d, J = 10.00 Hz, 1 H), 7.23-7.20 (m, 1 H), 7.09 (d, J = 8.40 Hz, 1 H), 6.73-6.69 (m, 1 H), 2.78 (d, J = 4.40 Hz, 3H).

[0695] Example 84Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxy- / V-methylbenzo[d]oxazole-5- carboxamide

[0696] Step-1 : Synthesis of methyl 2,4-dihydroxybenzoate

[0697] To a solution of 2,4-dihydroxybenzoic acid (5 g, 32.4 mmol) in methanol (35 mL), cooled to 0 °C, sulfuric acid (7 mL) is added to the reaction mixture and stirred at 73 °C for 16 h. Reactionmixture is concentrated. The residue basified with sat. solution of sodium bicarbonate (100 mL), solid is precipitated. The solid is filtered through sintered funnel, ished with water (300 mL), then n-heptane (100 mL), dried over vacuum to afford methyl 2,4-dihydroxybenzoate (5 g, 91%) as off- white solid. LC-MS (m / z) = 169.0 [M+1H]T

[0698] Step-2: Synthesis of methyl 2,4-dihydroxy-5- nitrobenzoate

[0699] To a solution of methyl 2,4-dihydroxybenzoate (4 g, 23.8 mmol) in chloroform (40 mL, 502 mmol), cooled to 0 °C, nitric acid (1.29 mL, 1.3 eq., 30.9 mmol) is added to the reaction mixture and stirred at 0 °C for 30 mins. After the reaction time, reaction mixture is quenched with ice cold water and extracted with DCM (2 X 50 mL). The organic layer is ished with brine, dried over sodium sulfate, filtered and concentrated. The crude material is purified by combi-flash using ethyl acetate in n-heptane (1-20% product is eluted at 12%) to afford methyl 2,4-dihydroxy-5- nitrobenzoate (1.1 g, 22%) as white solid (Desired product) and methyl 2,4-dihydroxy-3- nitrobenzoate (1.4 g, 27%) as yellow solid (Undesired product). LC-MS (m / z) = 211.9 [M-H]’.

[0700] Step-3: Synthesis of methyl 5-amino-2,4-dihydroxybenzoate

[0701] To a stirred solution of methyl 2,4-dihydroxy-5-nitrobenzoate (1 g, 4.69 mmol) in 1 ,4- dioxane (15 mL, 176 mmol) and water (5 mL, 278 mmol) is added zinc (2.45 g, 8 eq., 37.5 mmol) and ammonium chloride (2.01 g, 8 eq., 37.5 mmol). The reaction mixture is stirred at RT for 2h. Progress of the reaction is monitored by TLC and LCMS. Once the reaction is completed, the mixture is filtered and diluted with EtOAc (5 mL), ished with water (3 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the crude of methyl 5-amino- 2,4-dihydroxybenzoate (620 mg, 3.38 mmol) as a black solid. LC-MS (m / z) = 184.1 [M+H]+.

[0702] Step-4: Synthesis of methyl 6-hydroxybenzo[d]oxazole-5-carboxylate

[0703] To a solution of methyl 5-amino-2,4-dihydroxybenzoate (620 mg, 3.38 mmol) in diethoxymethoxyethane (10 mL) is added p-toluenesulfonic acid (87.4 mg, 0.15 eq., 508 pmol) at RT. The reaction mixture is stirred at 100 °C for 16 h. The progress of the reaction is monitored by TLC. The reaction mixture is evaporated under reduced pressure to get crude compound. Crude is loaded in Flash column MPLC using EtOAc in heptane as mobile phase (compound eluted at 50 % EtOAc in hexane) to afford methyl 6-hydroxy-1 ,3-benzoxazole-5-carboxylate (240 mg, 1.24 mmol) as a pale brown solid. LC-MS (m / z) = 194.1 [M+H]T

[0704] Step-5: Synthesis of methyl 6-methoxybenzo[d]oxazole-5-carboxylate

[0705] To a solution of methyl 6-hydroxy- t3-benzoxazole-5-c8rboxylate (240 mg, 1.24 mmol) in dimethylformamide (3 mL, 38.7 mmol). Then dipotassium carbonate (687 mg, 4 eq., 4.97 mmol) and iodomethane (155 pL, 2 eq., 2.49 mmol) at 0 °C and the reaction mixture is stirred at 100°C for 12 hours. The reaction mixture is concentrated and diluted with ethyl acetate (10 mL), ished with water (5 mL), brine (5 mL), dried over sodium sulfate, filtered and concentrated to provide the crude material. The crude product is purified by flash silica chromatography (dry loaded), elution gradient 0 to 40% EtOAc in heptane. Pure fractions are concentrated to afford methyl 6- methoxy-1 ,3-benzoxazole-5-carboxylate (160 mg, 772 μmol) as a white solid. LC-MS (m / z) = 208.1 [M+H]+.

[0706] Step-6: Synthesis of methyl 2-iodo-6-methoxybenzo[d]oxazole-5-carboxylate

[0707] To a solution of methyl 6-methoxy-1 ,3-benzoxazole-5-carboxylate (160 mg, 772 pmol) in THF (3.0 mL), cooled to -78 °C, then lithium bis(trimethylsilyl)azanide (258 mg, 2 eq., 1 .54 mmol) is added and stirred at same temperature for 2 h. iodine (147 mg, 1.5 eq., 1.16 mmol) in THF (1.0 mL) is added and the temperature is gradually cooled to -78 °C for 2 h. Reaction mixture is quenched with sat. ammonium chloride solution (5.0 mL) and extracted with ethyl acetate (2 X 10 mL), dried over sodium sulfate, filtered and concentrated to get the crude. The crude product is purified by flash silica chromatography (dry loaded), elution gradient 0 to 40% EtOAc in heptane. Pure fractions are concentrated to afford methyl 2-iodo-6-methoxy~1 ,3~benzoxazole~5~ carboxylate (153 mg, 459 μmol) as a white solid. LC-MS (m / z) = 334.0 [M+H]+.

[0708] Step-7: Synthesis of methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6- methoxybenzo[d]oxazole-5-carboxylate

[0709] To a solution of 5-fluoro-1,3-benzoxazol-2-ylamine (70 mg, 460 μmol) in tetra hydrofuran (3 mL, 36.9 mmol), lithium 2-methyl-2-propanolate (73.7 mg, 2 eq., 920 μmol) and methyl 2-iodo- 6-methoxy-1 ,3-benzoxazole-5-carboxylate (153 mg, 460 μmol) is added and heated at 70 °C for 4 h. The reaction mixture is monitored by TLC. The reaction mixture is concentrated, the residue is dissolved in ethyl acetate (10 mL) and ished with water (5 mL) and combined organic layer dried over sodium sulphate and concentrated to provide the crude material methyl 2-(5-fluoro- 1 ,3-benzoxazoi-2-ylamino)-6-methoxy-1 ,3-benzoxazole-5-carboxylate (140 mg, 392 pmol) as a pale brown solid.

[0710] Step-8: Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazole- 5-carboxylic acid

[0711] To a stirred solution of methyl 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-6-methoxy-1 ,3- benzoxazole-5-carboxylate (140 mg, 392 μmol) in tetrahydrofuran (2 mL, 24.6 mmol), methanol (2 mL, 49.4 mmol) and water (1 mL, 55.5 mmol) is added lithium hydroxide (37.5 mg, 4 eq., 1.57 mmol) and the reaction is stirred at RT for 3 h. Progress of the reaction mixture is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to get the crude. The crude material is acidified with 1 N HCI, pH (2-3) and the solid obtained is filtered using sintered funnel to obtain the desired product 2-(5~fluoro-1 , 3-benzoxazol- 2-ylamino)-6-methoxy-1 ,3-benzoxazole-5-carboxylic acid (60 mg, 175 μmol) as a Pale-brown solid and impure compound 82 mg, black solid. The crude is carried for next step without further purification. LC-MS (m / z) = 344.1 [M+H]+.

[0712] Step-9: Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxy-N- methylbenzo[d]oxazole-5-carboxamide

[0713] To a solution of 2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-6-methoxy-1,3-benzoxazole-5- carboxylic acid (82 mg, 239 μmol) in dichloromethane (6 mL, 93.7 mmol) is added 2,4,6-tripropyl- 1 ,3, 5, 2A5,4A5,6As-trioxatriphosphinane-2, 4, 6-trione 50%v / v (282 pL, 2 eq., 478 pmol) and methylamine (22.3 mg, 3 eq., 717 pmol). To the above mixture at 0°C is added N- ethylbis(isopropyl)amine (125 pL, 3 eq., 717 μmol) and the reaction mixture is stirred at room temperature for 12 h. Progress of the reaction is monitored by TLC and LCMS data. After completion of the reaction, reaction mixture is quenched with water (3.0 mL) and extracted with ethyl acetate (2 x 5.0 mL). The combined organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude (94 mg). The crude material is purified by below mentioned prep HPLC method to afford N~methyl-2~(5~fluoro-1 ,3~benzoxazol~2~ylamino)- 6-methoxy-1 ,3-benzoxazole-5-carboxamide (25 mg, 70.2 pmol, Yield: 29.37%) as an off white solid. LC-MS (m / z) = 357.1 [M+H]+.

[0714] Purification conditionsColumn: Xterra 018(250x19) mm; 10uFlow: 19.0mL / minMobile phase A: 0.1 % Ammonia in WaterMobile phase B: AcetonitrileDesired Product Rt at 8.90 min

[0715] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.12 (d, J = 4.40 Hz, 1 H), 7.77 (s, 1 H), 7.19-7.15 (m, 2H), 7.07-7.05 (m, 1H), 6.69-6.65 (m, 1H), 3.89 (s, 3H), 2.81 (d, J = 4.80 Hz, 3H).

[0716] Example 85Synthesis of 7-cyclopropyl-2-((5-fluorobenzo[d]oxazo!-2-yl)amino)-A / -methylbenzo[d]oxazo!e-5- carboxamide[0 / 17] Step-1 : Synthesis of methyl 4-(benzyloxy)-3- bromobenzoate

[0718] To a stirred solution of methyl 3-bromo-4-hydroxybenzoate (5 g, 21.6 mmol) in acetonitrile (70 mL) is added dipotassium carbonate (8.97 g, 3 eq., 64.9 mmol) after that (bromomethy!) benzene (3.86 mL, 1.5 eq., 32.5 mmol) is added drop wise, Reaction mixture is stirred at 80 °C temperature for 5 h, reaction progress is checked by TLC monitoring. After completion of the reaction, reaction mixture is concentrated under reduced pressure to get the residue. Reaction mass is quenched with water (100 mL) extracted with ethyl acetate(100ml) combined organic layers are concentrated under reduced pressure to get methyl 4-(benzy!oxy)- 3-bromobenzoate (6.7 g, 80.97%) as off white solid. LC-MS (m / z) = 322 [M+H]+.

[0719] Step-2: Synthesis of methyl 4-(benzyloxy)~3~cyclopropylbenzoate

[0720] To a stirred solution of methyl 4-(benzyloxy)-3-bromobenzoate (6.78 g, 21.1 mmol) in toluene (60 mL) and water (15 mL) is added cyclopropylboranediol (2.72 g, 1.5 eq., 31.7 mmol), tripotassium phosphate (13.4 g, 3 eq., 63.3 mmol) is added reaction mixture is purged with nitrogen for 5 mins, after that palladium—triphenylphosphine (1 / 4) (2.44 g, 0.1 eq., 2.11 mmol) added rection mixture is stirred at 100 °C for 12 h, reaction progress is checked by TLC monitoring, after completion of the reaction mixture is cooled to room temperature and quenched with water (50 mL) extracted with ethyl acetate (2 x50 mL) combined organic layers are dried under reduced pressure to get the crude product. Crude is purified by combi flash at 10-20% EtOAC: Hexane as elutant to obtain methyl 4-(benzyloxy)-3-cyclopropylbenzoate (4.2 g,59.19%) as off white solid. LC-MS (m / z) = 283 [M+H]+.[07'21] Step-3: Synthesis of methyl 3-cyclopropyl-4-hydroxybenzoate

[0722] To a solution of methyl 4-(benzyloxy)-3-cyclopropylbenzoate (4.2 g, 1 eq., 14.9 mmol) in methanol (0.1 L), ethyl acetate (0.1 L) is added palladium (1.14 g, 0.74 eq., 10.7 mmol) under nitrogen atmosphere at room temperature and the reaction is stirred at room temperature under hydrogen atmosphere at 60 Psi for 12 h. Progress of the reaction is monitored by TLC.Once the reaction is completed, the reaction mixture is filtered through celite bed using methanol and the filtrate is concentrated under reduced pressure to afford methyl 3-cyciopropyl-4-hydroxybenzoate (2.7 g,93.1%) as off white solid. LC-MS (m / z) = 193.3 [M+HT

[0723] Step-4: Synthesis of methyl 3-cyclopropyl-4-hydroxy-5-nitrobenzoate

[0724] To a solution of methyl 3-cyclopropyl-4-hydroxybenzoate (2.7 g, 14 mmol) in acetic acid (10 mL) cooled to 0 °C, nitric acid (586 pL, 14 mmol) in 0.5 ml acetic acid is added drop wise to the reaction mixture and stirred for 10 min at the same temperature and thick precipitate is stirred at RT 1 h. Reaction is monitored by TLC, LCMS. To the reaction mixture water (10 ml) is added at 0 °C and stirred for 15 min .Precipitate is filtered, ished with water and dried over high vacuum to afford crude yellow solid methyl 3~cyclopropyl-4-hydroxy-5-nitrobenzoate (3.2 g, 57.62%). LCMS (m / z) = 237 [M + H]\

[0725] Step-5: Synthesis of methyl 3-amino-5-cyclopropyl-4-hydroxybenzoate

[0726] To a solution of methyl 3-cyclopropyl-4-hydroxy-5-nitrobenzoate (3.2 g, 13.5 mmol) in methanol (0.1 L) , ethyl acetate (50 mL) is added palladium (1.06 g, 0.74 eq., 9.99 mmol) under nitrogen atmosphere at room temperature and the reaction is stirred at room temperature under hydrogen atmosphere at 60 Psi for 12 h. Progress of the reaction is monitored by TLC.Once the reaction is completed, the reaction mixture is filtered through celite bed using methanol and the filtrate is concentrated under reduced pressure to afford methyl 3-amino-5-cyclopropyl-4- hydroxybenzoate (2.7 g,59.88%) as off white solid. LC-MS (m / z) = 208 [M+Hp.

[0727] Step-6: Synthesis of methyl 7-cyclopropylbenzo[d]oxazole-5-carboxylate

[0728] Triethylorthoformate (30 mL) is added to methyl 3-amino-5-cyclopropyl-4- hydroxybenzoate (2.4 g, 11.6 mmol) and the reaction is heated at I00 °C for 2 hours. The reaction is cooled to room temperature.Reaction mixture is concentrated and diluted with EtOAc (20 mL x 3), water ish 10ml Is given. The combined organic layers are concentrated under reduced pressure and the crude residue is purified by flash column chromatography 20-30 % Ethyl acetate in n - Heptane to give methyl 7-cyclopropylbenzo[d]oxazole-5-carboxylate (1.7 g,58.11%) as off white solid. LC-MS (m / z) = 218 [M+H]+.

[0729] Step- / : Synthesis of methyl 7-cyclopropyl-2-iodobenzo[d]oxazole-5-carboxylate

[0730] To a stirred solution of methyl 7-cyclopropy!benzo[d]oxazo!e-5-carboxy!ate (1.7 g, 7.83 mmol) in tetrahydrofuran (72 mL) added LiHMDS in THF (3.27 g, 2.5 eq.19.6 ml) at -78 °C Stirred for 2h at same temperature. Then iodine (1.49 g, 1.5 eq., 11.7 mmol) dissolved in THF (5 ml) is added at -78 °C gradually allow the reaction mixture to - 20 °C for 2h. The progress of the reaction is monitored by TLC (20% EtOAc : Hexane) and LCMS. Reaction mixture is quenched with NH4CI, and extracted by EtOAc .water ish is given. Organic layer dried over sodium sulphate and concentrated. Crude compound is purified by combi flash column chromatography at (0-10% EtOAC: Heptane as elutant to obtain methyl 7-cyciopropyl-2-iodobenzo[d]oxazole-5- carboxylate(1.1 g, 38.51%) as off white solid. LC-MS (m / z) = 344 [M+H]T

[0731] Step-8: Synthesis of methyl 7-cyclopropyl-2-((5-fluorobenzo[d]oxazol-2- yl)amino)benzo[d]oxazole-5-carboxylate

[0732] To a solution of methyl 7-cyclopropyl~2-iodobenzo[d]oxazole-5-carboxylate (1 g, 2.91 mmol) in tetrahydrofuran (20 mL), 5-fluoro-1 ,3-benzoxazol-2-ylamine (443 mg, 2.91 mmol) and lithium 2-methyl-2-propanolate (467 mg, 2 eq., 5.83 mmol) are added and heated at 70 °C for 3h. Progress of the reaction is monitored by LCMS, TLC. Reaction mixture is concentrated and diluted with EtOAc( 50 ml),water(50 ml) ish is given. Organic layer is dried over sodium sulphate and concentrated. Crude compound is purified by combi flash column chromatography using EtOAC: Petether (30-50%) to obtain methyl 7-cyclopropyl-2-((5-fiuorobenzo[d]oxazol-2- yl)amino)benzo[d]oxazole-5-carboxylate (470 mg, 31 .61 %) as brown solid. LC-MS (m / z) = 368 [M+H]+.

[0733] Step-9: Synthesis of 7-cyclopropyl-2-((5-fluorobenzo[d]oxazol-2- yl)amino)benzo[d]oxazole-5-carboxylic acid

[0734] To a stirred solution of methyl 7-cyclopropyl-2-((5-fluorobenzo[d]oxazol-2- yl)amino)benzo[d]oxazole-5-carboxylate (470 mg, 1.28 mmol) in tetrahydrofuran (5 mL, 61.4 mmol)) methanol (5 mL, 123 mmol)) and water (5 mL, 278 mmol)) is added lithium hydroxide monohydrate (215 mg, 4 eq., 5.12 mmol) and the reaction is stirred at RT for 12h. Progress of the reaction mixture is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to get the crude. The crude material is acidified with dil. HCI (3.0 mL) and the solid obtained is filtered using sintered funnel to obtain the desired 7-cyclopropyl- 2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazole-5-carboxylic acid (0.4 g, 85.83%). LCMS (m / z) = 354 [M+H]+.

[0735] Step- 10: Syntheses of 7-cyclopropyl-2-((5-fluorobenzo[d]oxazol-2-yl)amino)-N- methylbenzo[d]oxazole-5-carboxamide

[0736] To a solution of 7-cyclopropyl-2-(5-fluoro-1!3-benzoxazol-2-ylamino)-1,3-benzoxazo!e-5- carboxylic acid (350 mg, 991 μmol) in dichloromethane (10 mL) is added methylamine (36.9 mg, 1.2 eq. 0.5 ml) at 0°C , N-ethylbis(isopropyi)amine (518 pL, 3 eq., 2.97 mmol) followed by 2,4,6- tripropyl-1 ,3,5,2As,4As,6A5-trioxatriphosphinane-2,4,6-trione (1.18 mL, 2 eq., 1.98 mmol) and the reaction mixture is stirred at room temperature for 12 h. Progress of the reaction is monitored by TLC and LCMS data. Reaction mixture is diluted with DCM (10ml), water (5 ml) is added, exctracted organic layer is ished with brine solution(10 mi) and dried over sodium sulphate and concentrated. Crude compound is taken in saturated NaHCOa solution and stirred for 15 mins, solid is filtered, ished with water (20 ml) .dried over vacuum to obtain 7-cyclopropyl-2-((5- fluorobenzo[d]oxazol-2-yl)amino)-N-methylbenzo[d]oxazole-5-carboxamide (170 mg, 45.8%) as off white solid. LC-MS (m / z) = 367 [M+H]+.

[0737] 1H N MR (400 MHz, DMSO-d6) δ ppm: 8.32 (s, 1 H), 7.60 (s, 1 H),7.42 (s, 1 H),7.21 -7.15 (m, 2H), 6.90 (m,1 H), 2.75(s, 3H), 2.19 -2.12 (m ,1 H), 1.07 -1.04 (2H), 0.94 - 0.93 (m, 2H).

[0738] Example 86Synthesis of A / -(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetamide[0 / 39] Step-1 : Synthesis of A / -(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzoxazol-5-yl)acetamide

[0740] To a stirred solution of 5-amino-2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1,3-benzoxazole (0.12 g, 0.42 mmol) in DCM (8 mL) under inert condition at 0 °C triethylamine (0.15 mL, 2.5 eq., 1.06 mmol) followed by acetic anhydride (0.047 mL, 1.1 eq., 0.46 mmol) is added dropwise to the reaction mixture at 0 °C. Allowed the reaction mixture stirred for 2 h. The progress of the reaction is monitor by TLC (5% MeOH: 95% DCM) and LCMS. After completion of the reaction the reaction mixture is quenched with water and extracted with ethyl acetate (3 x 15 mL), the organic layer is ished with brine and dried over sodium sulfate and concentrated under reduced pressure to get the crude. The crude is purified by flash column chromatography using 10-12% Methanol in DCM to afford desired compound (80 mg) which is further submitted for prep HPLC purification affordedA / -[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1!3-benzoxazol-5-yl]acetamide (0.023 g, 17%) as pate yellow solid. LC-MS (m / z) = 327.3 [M+H]+.

[0741] Purification conditionsColumn: Xbridge C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1 % HCI in WaterMobile phase (B): AcetonitrileFlow rate: 18 mL / minRT: 19.43 min

[0742] 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.5 (s, 1 H), 7.92 (s, 1 H), 7.48 (s, 1 H), 7.41-7.39 (m, 1 H), 7.29-7.27 (m, 2H), 6.98 (m, 1 H), 2.07 (s, 3H).

[0743] Example 87Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-A / -(methylsulfonyl)acetamide[0 / 44] Step-1 : Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- / V- (methylsulfonyl)acetamide

[0745] To a stirred solution of [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazo!-5-yl]acetic acid (0.2 g, 0.611 mmol, 1 equiv), methanesulfonamide (0.069 g, 0.733 mmol, 1.2 equiv) in DCM (10 mL) is added DMAP (0.003 g, 0.030 mmol, 0.05 equiv), 2-ch!oro-1 -methyl- 1 -pyridylium iodide (0.187 g, 0.733 mmol, 1.2 equiv) poration wise , reaction mixture is stirred for 5 mins, after that triethyl amine (0.256 mL, 1.83 mmol, 3 equiv) is added reaction drop wise under room temeperature , then reaction mixture is stirred at room temeperature for 12 h, reaction progress is checked by TLC monitoring, after completion of the reaction, reaction mixture is concetrated under reduced pressure to get the crude residue, obtained residue is diluted in ethyl acetate and ished with 1 N HCI aq solution, seperate the organic layer , dried the organic layer, concetratedunder reduced pressure to get the crude product, which is further purified by Prep-HPLC purification using following analytical method. LC-MS (m / z) = 405.3 [M+H]+.

[0746] Purification conditionsColumn: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic)Mobile phase (A): 5 mM Ammonium acetate in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL / min% of B: 0 / 2,2 / 02,18 / 98,25 / 98,27 / 2,30 / 2

[0747] After prep-HPLC purification, fraction containing samples are concentrated under reduced pressure to get the desired product, recovery is (0.017 g, 6.88 %) as an off-white solid.

[0748] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.08 (bs, 1 H), 7.57 - 7.54 (m, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.43 (s, 1 H), 7.35 -7.32 (m, 1 H), 5.14 (d, J = 8.4 Hz, 1 H), 7.08 -7.03 (m, 1 H), 3.71 (s, 2 H), 3.24 (s, 3 H).

[0749] Example 88Synthesis of A / -(5-(1 H-pyrazol-4-yl)benzo[d]oxazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine[0 / 50] Step-1 : Synthesis of 5-bromo-1 ,3-benzoxazol-2- ylamine

[0751] To a stirred solution of 2-amino-4-bromophenol (2 g, 10.6 mmol) in methanol (20 mL, 494 mmol) is added cyanogen bromide (1.35 g, 1.2 eq., 12.8 mmol) at room temperature. The reaction mixture is allowed to stir at room temperature for 12 h. The progress of the reaction is monitor by TLC and LCMS. The reaction mixture is quenched with saturated Na2CO3 (70 mL). MeOH is evaporated under reduced pressure, residue is extracted with ethylacetate (100 mL*2). The combined organic layer is dried over sodium sulfate and concentrated under reduced pressure to obtain 5-bromo-1 ,3-benzoxazol-2-ylamine (1.9 g, 72%) as brown solid. LC-MS (m / z) = 214.9 [M+H]+.

[0752] Step-2: Synthesis of 5-(4-pyrazolyl)-1 ,3-benzoxazol-2-ylamine

[0753] To a solution of 5-bromo-1 ,3"benzoxazol"2"ylamine (1 g, 4.69 mmol) and 4, 4,5,5- tetramethyl-2-(4-pyrazolyl)-1 ,3,2-dioxaborolane (911 mg, 4.69 mmol) in 1 ,2-dimethoxy ethane (30 mL) in MW vial, degassed for 5 min. Added solution of caesium carbonate (4.59 g, 3 eq., 14.1 mmol) in water (14 mL, 777 mmol) and [1 ,T- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), Complex with Dichloromethane (383 mg, 0.1 eq., 469 μmol) heated at 110 °C for 1h in microwave reactor. Monitored by TLC and LCMS. The reaction mixture is quenched with water (50 mL) and extracted with ethyl acetate (70 ml * 2). The combined organic layer is dried over sodium sulfate and concentrated under reduced pressure. The crude is purified by column chromatography using MeOH and DCM (0-7%). The fractions are concentrated under reduced pressure to get 5-(4-pyrazolyl)-1 ,3-benzoxazol-2- ylamine (280 mg, 25%) as a brown solid. LC-MS (m / z) = 201.1 [M+H]+.

[0754] Step- 3: Synthesis of (5-fluoro-1 ,3-benzoxazol-2-yl)[5-(4-pyrazolyl)-1 ,3-benzoxazol-2- yljamine

[0755] To a solution of 5-(4-pyrazolyl)-1 ,3~benzoxazol~2~ylamine (0.2 g, 999 μmol) in tetrahydrofuran (5.15 mL, 63.3 mmol), lithium 2-methyl-2-propanolate (160 mg, 2 eq., 2 mmol) and 2-chloro-5-fluoro-1 ,3-benzoxazole (245 mg, 999 μmol) are added and heated at 70 °C for 2 h. After, the reaction mixture is diluted with water (20 mL) and extracted with ethyl acetate (3X 50 mL). Combine organic extracts are ished with water, brine and dried over anhy. Na2SO4, concentrated under reduced pressure to get crude. Crude is loaded in Flash column MPLC using MeOH in DCM as mobile phase (compound eluted at 5%-7%). It is then submitted to prep HPLC purification. Mobile phase (A): 0.1 % Ammonia in water, Mobile phase (B): Acetonitrile, the fractions are concentrated under reduced pressure to afford (5-fluoro~1 ,3~benzoxazol-2~yl)[5-(4- pyrazolyl)-1 ,3-benzoxazol-2-yl]amine (72 mg, 21%) as white solid. LC-MS (m / z) = 336.3 [M+H]+.

[0756] Purification conditionsColumn: Xselect C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1 % Ammonia in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / min

[0757] 1H NMR (400 MHz, DMSO-d6) δ ppm: 1 H NMR (400 MHz, DMSO d6) 6 ppm - 12.97(s,1 H), 8.17(s, 1 H), 8.13(s, 1H), 7.6-7.7 (s,1 H) 7.4-7.7 (m,3H) ,7.34 (d, j=8.8, 1 H), 7.0-7.1 (t,1 H).

[0758] M.P: 297.7°C

[0759] Examples 89-92Below compounds are synthesized in an analogous manner to Example 88:

[0760] Example 93Synthesis of 3-((2-((5-f!uorobenzo[d]oxazo!-2-yl)amino)benzo[d]oxazol-5-yl)methy!)-1!1- di methyl urea

[0761] Step-1 : Synthesis of 2-{5-[(3,3-dimethy!ureido)methyl]-1 ,3-benzoxazoi-2-ylamino}-5- fluoro-1 ,3-benzoxazole

[0762] To a stirred solution of [5-(chloromethyl)-1,3-benzoxazol-2-yl](5-f!uoro-1 ,3-benzoxazol-2- yl)amine (150 mg, 472 μmol) in dimethylformamide (20 mL, 258 mmol) & 1 ,1-dimethylurea (208 mg, 5 eq,, 2,36 mmol) are added at RT, The reaction mixture is stirred for 5 mins and cooled 0°C sodium hydride (34 mg, 3 eq., 1.42 mmol) is added at 0°C and then stirred at RT for 3 hours. The progress of the reaction is monitored by TLC [10%MeOH in DOM] and LCMS. The reaction mixture is evaporated under reduced pressure to get crude residue. The residue is purified in HPLC to afford 2-{5-[(3,3-d!methylureido)methyl]-1,3-benzoxazol-2-ylamino}-5-fluoro-1,3- benzoxazole (32 mg, 86.6 μmol) (Yield: 18%) as off white solid. LC-MS (m / z) = 370.3 [M+H]\

[0763] Purification conditionsColumn: Xselect C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1 % Formic acid in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / minDesired product RT: 14.13min

[0764] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.56 - 7.54 (m, 1 H), 7.47 (s, 1 H) 7.32 (d,8.4Hz,1 H), 7.12 (d, 8.0Hz, 1 H), 7.06 (t, 1 H), 6.97(s, 1 H) 4.29 (d, J = 5.2Hz, 2H), 2.83 (s, 6H).

[0765] Example 94Synthesis of 1-((2-((5-fluorobenzo[d]oxazo!-2-yl)amino)benzo[d]oxazol-5-yl)methy!)urea

[0766] Example 94 is synthesized in an analogous manner to Example 93. LC-MS (m / z) = 342.3 [M+HE

[0767] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.19 • 7.16 (m, 3 H), 7.01 (d, J = 8.8 Hz, 1 H), 6.83 (d, J = 7.6 Hz, 1 H), 6.68 - 6.64 (t, J = 8.4 Hz, 1 H), 6.35 - 6.32 (t, J = 5.6 Hz, 1 H), 5.47 (s, 2 H), 4.18 (d, J = 5.6 Hz, 2 H).

[0768] Purification conditionsColumn: Inertsil ODS C18(250x19)mm;5uFlow :19.0 mL / minMobile phase A: 0.1% Formic acid in WaterMobile phase B: Acetonitrile

[0769] Example 95Synthesis of 1-((2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methyl)-3- methylurea

[0770] To a solution of [2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetic acid (150 mg, 458 μmol) in toluene (2 mL) are added triethylamine (193 pL, 3 eq., 1.38 mmol) and DPPA (298 pL, 3 eq., 1.38 mmol). After stirring for 5 h at 110 °C, methylamine (71.2 mg, 5 eq., 2.29 mmol) (2.0 M THF solution 1.15 mL) is added at 0 °C. After stirring for 18 h at room temperature, saturated NaHCO3 is added. The mixture is extracted with CHCI3, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material is purified by silica gel column chromatography eluted with 5-10% MeOH in CHCI3 to afford the titled compound (11 mg, 6.62%) as an off white solid. LC-MS (m / z) = 356.5 [M+H]+.

[0771] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 (d, J = 4.4 Hz, 1 H), 7.48- 7.42 (m, 2H), 7.32 (d, 7.6 Hz, 1 H), 7.13 (d, J = 8 Hz, 1 H), 7.07-7.02 (t,8.4 Hz, 1 H), 6.47 (s, 1 H), 5.86 (s, 1 H),4.26 (d, J = 5.2 Hz, 2H), 2.58 (d, J = 4Hz, 3H).

[0772] Example 96Synthesis of A / -((2-((5-f!uorobenzo[d]oxazo!-2-yl)amino)benzo[d]oxazo!-5-yl)methy!)acetamide

[0773] Step-1 : Synthesis of 2-[5-(aminomethy!)-1 ,3-benzoxazol-2-ylamino]-5-f!uoro-1,3- benzoxazole

[0774] To a stirred solution of [5-(chloromethyl)-1,3-benzoxazol-2-yl](5-fluoro-1 ,3-benzoxazol-2- yl)amine (0.6 g, 1.89 mmol) in dimethylformamide (30 mL, 387 mmol) are added after 5 mins the reaction mixture is purged with ammonia (3 g, 93 eq., 176 mmol) gas for 10 mins. The reaction mixture is stirred at RT for 8hours. The progress of the reaction is monitored by and LCMS. The reaction mixture is evaporated under reduced pressure to get crude residue to afford 2-[5- (aminomethyl)-1 ,3-benzoxazol-2-ylamino]-5-fluoro-1 ,3-benzoxazole (0.6 g, 1.75 mmol) (Yield:92 %) as brown thick liquid. LC-MS (m / z) = 299.9 [M+H]T

[0775] Step-2: Synthesis of N-{[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl] methyl}acetamide

[0776] To a stirred solution of 2-[5-(aminomethy!)-1 ,3-benzoxazol-2-ylamino]-5-f!uoro-1,3- benzoxazole (0.2 g, 671 μmol) in dichloromethane (20 mL, 312 mmol) stirred at RT after 5 mins triethylamine (471 pL, 5 eq., 3.35 mmol) & acetyl acetate (228 pL, 3 eq., 2.01 mmol) are added. The reaction mixture is stirred at RT for 8 hours. The progress of the reaction is monitored by TLC [10%MeOH in DCM] and LCMS. The reaction mixture is evaporated under reduced pressure to get crude residue. The residue is purified using HPLC then evaporated under reduced pressure to afford N-{[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl]methyl}acetamide (42 mg, 123 μmol) (Yield: 18.41 %) as off-white powder solid. LC-MS (m / z) = 341.4 [M+H]+.

[0777] Purification conditionsColumn: Sunfire C18 (250x19)mm;5uFlow: 19.0 mL / minMobile phase A: 0.1% Formic acid in WaterMobile phase B: AcetonitrileGradient %B: 0 / 20, 1 / 30, 14 / 57, 15 / 100,20 / 100,21 / 20,22 / 20Desired product RT at 12.0 min

[0778] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.43 (s, 1 H), 7.54(m, 1 H) 7.48 (d, J = 8.0Hz, 1 H), 7.41 (s, 1 H) 7.32 (d,8.8Hz, 1 H), 7.13 (d, J = 8.0Hz, 1 H), 7.13 (t, J = 9.2Hz, 1 H), 4.31 (d, J =5.6Hz, 2H) 1.89 (s, 3H).

[0779] Example 97Synthesis of (2-((5-fluorobenzo[d]oxazo!-2-yl)amino)-6-methoxybenzo[d]oxazol-5-y!)methanol

[0780] Step-1 : Synthesis of methyl 2,4-dihydroxybenzoate

[0781] To a solution of 2,4-dihydroxybenzoic acid (5 g, 32.4 mmol) in methanol (35 mL), cooled to 0 °C, sulfuric acid (7 mL) is added to the reaction mixture and stirred at 73 °C for 16 h. Reaction mixture is concentrated. The residue basified with sat. solution of sodium bicarbonate (100 mL), solid is precipitated. The solid is filtered through sintered funnel, ished with water (300 mL), then n-heptane (100 mL), dried over vacuum to afford methyl 2,4-dihydroxybenzoate (5 g, 91%) as off- white solid. LC-MS (m / z) = 169.0 [M+H]+.

[0782] Step-2: Synthesis of methyl 2-hydroxy-4-(methoxymethoxy)benzoate

[0783] To a solution of methyl 2,4-dihydroxybenzoate (1 g, 5.95 mmol) in tetrahydrofuran (30 mL, 369 mmol), cooled to 0 °C, sodium hydride (178 mg, 1.3 eq., 7.43 mmol) is added to the reaction mixture and stirred at rt for 30 min. Then chloromethoxymethane (497 pL, 1.1 eq., 6.54 mmol) is added dropwise to the mixture at 0 °C. The suspension is stirred for 0.5 h at 0 °C, gradually raising the temperature to 80 °C and and allowed to react for 2 h to finish. The reaction solution is quenched by ice water (50 mL), and extracted with ethyl acetate for three times. Then, the combined organic layers are ished with brine, dried with anhydrous Na2SO4, and evaporated in vacuo to get the product, which is directly used as a reactant for the next step without any further purification (1 g, crude). LC-MS (m / z) = 213.1 [M-H]+.

[0784] Step-3: Synthesis of methyl 2-methoxy-4-(methoxymethoxy)benzoate

[0785] A mixture of methyl 2-hydroxy-4-methoxyanisate (1 g, 4.71 mmol) and anhydrous dipotassium carbonate (2.61 g, 4 eq., 18.9 mmol) in dimethylformamide (10 mL, 129 mmol) is stirred at 80 °C for 5 min. iodomethane (587 pL, 2 eq., 9.43 mmol) is added dropwise, and the reaction mixture is kept stirring at 80 °C for 1 h. TLC monitoring showed that the reaction completed. After being cooled to room temperature, the reaction mixture is filtered out the solids, then quenched with ice water (50 mL), and extracted with ethyl acetate (2 X 50 mL). Then the combined organic layers are ished with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give methyl 2-methoxy-4-(methoxymethoxy)benzoate (1g, crude). The product is directly used as raw material for the next step without any purification. LC-MS (m / z) = 227 [M+H]+.

[0786] Step-4: Synthesis of 4-hydroxy-2-methoxybenzoic acid

[0787] To a solution of methyl 2-methoxy-4-(methoxymethoxy)benzoate (1 g, 4.42 mmol) in methanol (10 mL, 247 mmol), cooled to 0 °C, 1 N HCI (3 mL) is added and stirred at rt for 16 h. Reaction mixture is neutralized with sat. sodium carbonate solution adjust pH -7, and extracted with ethyl acetate (3 X 20 mL). Reaction mixture is ished with brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by combiflash chromatography using 12 g cartridge, ethyl acetate in n-heptane as eluent. Product eluted at 20 - 29% ethyl acetate in n- heptane to afford 4-hydroxy-2-methoxybenzoic acid (350 mg, 43%) as white solid. LC-MS (m / z) = 183.1 [M+H]+.

[0788] Step-5: Synthesis of methyl 4-hydroxy-2-methoxy-5"nitrobenzoate

[0789] To a solution of methyl 4-hydroxy-2-anisate (350 mg, 1.92 mmol) in chloroform (14 mL), cooled to 0 °C, nitric acid (96.2 pL, 1.2 eq., 2.31 mmol) is added and stirred at rt for 30 min. Reaction mixture is quenched with ice water and extracted with DCM (2 X 50 mL). The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material is purified by combiflash using ethyl acetate in n-heptane (1-30%) to afford methyl 4- hydroxy-2-methoxy-5-nitrobenzoate (210 mg, 48%) as white solid. LC-MS (m / z) = 225.9 [M-H]'.

[0790] Step-6: Synthesis of methyl 5-amino-4-hydroxy-2-methoxybenzoate

[0791] To a solution of methyl 4-hydroxy-2-methoxy-5-nitrobenzoate (0.2 g, 880 pmol) in the mixture of methanol (15 mL), purged N2 for 5 min, then palladium on carbon (50% wet) (70 mg) is added and stirred at rt for 60 psi for 16 h. Reaction mixture is filtered through celite bed and the filtrate is concentrated to afford methyl 5-amino-4-hydroxy-2-methoxybenzoate (150 mg, 86%) as off-white solid. LC-MS (m / z) = 198.1 [M+H]L

[0792] Step-7: Synthesis of methyl 6-methoxybenzo[d]oxazole-5-carboxylate

[0793] To a solution of methyl 5-amino-4-hydroxy-2-methoxybenzoate (150 mg, 761 pmol) in diethoxymethoxyethane (5 mL) is added p-toluenesulfonic acid (19.6 mg, 0.15 eq., 114 pmol) at rt. The reaction mixture is stirred at 100 °C for 12 h. The progress of the reaction is monitored by TLC. The reaction mixture is evaporated under reduced pressure to get crude compound. The crude compound is purified by comiflash using ethyl acetate in n-heptane (1-40%, product elutedat 28%) to afford methyl 6-methoxybenzo[d]oxazole-5-carboxylate (130 mg, 82%) as off-white solid. LC-MS (m / z) = 208.1 [M+H]\

[0794] Step-8: Synthesis of methyl 2-iodo-6-methoxybenzo[d]oxazole-5-carboxylate

[0795] To a solution of methyl 6-methoxybenzo[d]oxazole-5-carboxylate (130 mg, 627 pmol) in THF (8 mL), cooled to -78 °C, then lithium bis(trimethylsilyl)azanide (262 mg, 2.5 eq., 1.57 mmol) is added and stirred at same temperature for 2 h. iodine (119 mg, 1.5 eq., 941 μmol) in THF (2 ml_)is added and the temperature is gradually cooled to -20 °C for 1.5 h. Reaction mixture is quenched with sat. ammonium chloride solution (20 mL) and extracted with ethyl acetate (4 X 30 mL), dried over sodium sulfate, filtered and concentrated. The crude material from is purified by combiflash chromatography, product eluted at 10% - 35% EtOAc in n-heptane to afford methyl 2- iodo-6-methoxybenzo[d]oxazole-5-carboxylate (0.1 g, impure) as an off- white solid. LC-MS (m / z) = 334.0 [M+HJT

[0796] Step-9: Synthesis of methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6- methoxybenzo[d]oxazole-5-carboxylate

[0797] To a solution of 5-fluoro-1 ,3-benzoxazol-2-ylamine (45 mg, 296 μmol) in THF (10 mL), lithium 2-methyl-2-propanolate (47.4 mg, 2 eq., 592 μmol) and methyl 2-iodo-6- methoxybenzo[d]oxazole-5-carboxylate (98.5 mg, 296 μmol) is added and heated at 70 °C for 16 h. Reaction mixture is concentrated. The residue is dissolved in ethyl acetate (50 mL) and ished with water (20 mL), dried over sodium sulfate, filtered and concentrated. Dichloromethane (40 mL) is added to the reaction mixture, solid is precipitated out. The solid is filtered and dried under vacuum to afford methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazole-5- carboxylate (65 mg, 61 %) as brown color solid. LC-MS (m / z) = 358.1 [M+H]+.

[0798] Step-10: Synthesis of (2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazol- 5-yl)methanol

[0799] To a stirred solution methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6- methoxybenzo[d]oxazole-5-carboxylate (65 mg, 196 μmol) in tetrahydrofuran (5 mL, 61.4 mmol) under inert condition at 0-5 °C. lithium alumanuide (14.9 mg, 2 eq., 392 μmol) is added to the reaction mixture and allowed the reaction mixture stirred for 2 h at 0-5 °C . The progress of the reaction is monitor by TLC (5% MeOH: 95 % DCM) and LCMS. After completion of the reaction the reaction mixture is quenched with aq. ammonium chloride solution (3 mL) and extracted with ethylacetate (3 x 15 mL), the organic layer is ished with water and dried over sodium sulfate andconcentrated under reduced pressure to get the (2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6- methoxybenzo[d]oxazol-5-yl)methanol (0.050 g, crude) as gummy. LC-MS (m / z) = 330.3 [M+H]+.

[0800] The crude compound is purified by prep-HPLC purification, using following analytical condition:Column: X-Bridge C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1% Ammonia in waterMobile phase (B): AcetonitrileFlow rate: 19 mUmin

[0801] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.55 - 7.51 (m, 2 H), 7.33 - 7.30 (m, 2 H), 7.06 - 7.00 (m, 1 H), 5.18 (s, 1 H), 4.53 (s, 2 H), 3.82 (s, 3 H).

[0802] Example 98Synthesis of 1 -(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- / V- methylcyclopropane- 1 -carboxamide

[0803] Step-1 : Synthesis of 1-(4-methoxyphenyl)cyclopropane-1 -carbonitrile

[0804] Add a dimethyl sulfoxide (75 mL, 1.05 mol) in dropwise with vigorous stirring to a sodium hydride (4.35 g, 3.2 eq., 109 mmol) at 0 °C under inert atmosphere. Add a solution of (p- methoxyphenyl)acetonitrile (5 g, 34 mmol), 1 ,2-dibromoethane (3.24 mL, 1.1 eq., 37.4 mmol) in diethyl ether (37.5 mL, 361 mmol) at 0 °C after warm the mixture up to room temperature and stirred for 2 h. The progress of the reaction is monitored by TLC. Cooled to 0 °C and quench the reaction mixture with water. Dilute with EtOAc, ish the organic layer with water and brine. Dried over sodium sulfate, filtered and concentrated. The crude material is purified by combi flash column chromatography using EtOAc: n-heptane (10-20%) as eluent to obtain 1-(4- methoxyphenyl)cyclopropane-1-carbonitrile (1.5 g, 24.22%) colour less liquid. LC-MS (m / z) = 173 [M+H]+.

[0805] Step-2: Synthesis of 1-(4-methoxyphenyl)cyclopropane-1 -carboxylic acid

[0806] To a solution of 1 -(4-methoxyphenyl)cyciopropane-1-carbonitrile (2.25 g, 13 mmol) in cone. HCI (20 mL) and heated at 100 °C for 12h. The progress of the reaction is monitored by TLC. Precipitated reaction mixture is filtered through sintered funnel, ished with water (200 mL) and dried to obtain crude 1-(4-methoxypheny!)cyclopropane-1-carboxylic acid (1.6 g, 53.19%) off white solid. LC-MS (m / z) = 193 [M+H]+.

[0807] Step-3: Synthesis of 1-(4-methoxyphenyl)-N-methy!cyciopropane-1-carboxamide

[0808] To a solution of 1-(4-methoxyphenyl)cyciopropane-1 -carboxylic acid (1 g, 4.71 mmol) in dichloromethane (12.5 mL, 195 mmol) is added methylamine (322 mg, 2.2 eq., 10.4 mmol, 4.15 mi) at O°C, N-ethyibis(isopropyl)amine (2.46 mL, 3 eq., 14.1 mmol) followed by Propylphosphonic anhydride (5.61 mL, 2 eq., 9.42 mmol) and the reaction mixture is stirred at room temperature for 12 h. Progress of the reaction is monitored by TLC and LCMS data. Reaction mixture is diluted with DCM (20 mL), water (10 mL) and the extracted organic layer is ished with brine solution (10 mL) and dried over sodium sulphate, filtered and concentrated. Crude compound is purified by combi flash chromatography at 20-50% EtOAc:n-heptane to obtain 1-(4-methoxyphenyl)-N- methylcyclopropane-1 -carboxamide (870 mg, 89.05%) as an off white solid. LC-MS (m / z) = 206 [M+H]T

[0809] Step-4: Synthesis of 1-(4-hydroxyphenyl)-N-methylcyclopropane-1 -carboxamide

[0810] To solution of 1-(4-methoxyphenyl)-N-methylcyclopropane-1-carboxamide (870 mg, 1 eq., 4.24 mmol) in dichloromethane (32 mL, 0.5 mol) is added tribromoborane (0.7 mL, 4 eq., 16.9 mmol) at 0°C. Reaction mixture is slowly allowed to stirred at RT for 3h. Reaction mixture is quenched with methanol and concentrated to obtain crude residue which is purified by column chromatography using EtOAc:n-heptane (0-60%) to obtain 1-(4-hydroxyphenyl)-N- methylcyclopropane-1 -carboxamide (0.4 g, 49%) as an off white solid. LC-MS (m / z) = 192 [M + H]+.

[0811] Step-5: Synthesis of 1-(4-hydroxy-3-nitrophenyi)-N-methylcyclopropane-1-carboxamide

[0812] To a solution of 1-(4-hydroxyphenyl)-N-methy!cyclopropane-1 -carboxamide (0.4 g, 2.09 mmol) in acetic acid (2 mL, 34.9 mmol) cooled to 0 °C, fuming nitric acid (87.3 pL, 2.09 mmol) in 0.5 ml acetic acid is added drop wise to the reaction mixture and stirred for 10 min at the same temperature and continued stirring at RT for 1h. Reaction is monitored by TLC, LCMS. To the reaction mixture water (10 mL) is added at 0 °C and extracted with EtOAc (50 mL), NaHCOs (50 mL), brine (25 mL). Organic layer is dried over sodium sulphate, fitered and concentrated to afford crude compound. Which is purified by combi flash column chromatography using EtOAc:n-heptane (40-50%) as elutant to obtain 1-(4-hydroxy-3-nitrophenyl)-N-methylcyclopropane-1- carboxamide (370 mg, 52.42%) yellow solid. LC-MS (m / z) = 237 [M+H]+.

[0813] Step-6: Synthesis of 1-(3-amino-4-hydroxyphenyl)-N-methylcyclopropane-1-carboxamide

[0814] To a solution of 1-(4-hydroxy-3-nitrophenyl)-N-methylcyclopropane-1-carboxamide (370 mg, 1.57 mmol) in methanol (12 mL), ethyl acetate (6 mL) is added palladium on carbon (123 mg, 0.74 eq., 1.16 mmol) under nitrogen atmosphere at room temperature and the reaction is stirred at room temperature under hydrogen atmosphere at 60 psi for 12 h. Progress of the reaction is monitored by TLC. Once the reaction is completed, the reaction mixture is filtered through celite bed and ished with methanol and the filtrate is concentrated under reduced pressure to afford 1- (3-amino-4-hydroxyphenyl)-N-methylcyclopropane-1 -carboxamide (270 mg, 77.73%) as an off white solid. LC-MS (m / z) = 207 [M+H]L

[0815] Step-7: Synthesis of 1-(benzo[d]oxazol-5-yl)-N-methylcyclopropane-1-carboxamide

[0816] Tri ethyl orthoformate (3.64 mL, 31 eq., 21.9 mmol) is added to 1-(3-amino-4- hydroxyphenyl)-N-methylcyclopropane-1-carboxamide (145 mg, 703 μmol) and the reaction is heated at 100 °C for 12 h. Reaction is monitored by LCMS, TLC. The reaction is cooled to room temperature, and concentrated under reduced pressure and the crude residue is purified by combi flash chromatography using MethanokDCM (0-5%) eluent to obtain 1-(benzo[d]oxazol-5-yi)-N- methylcyclopropane-1 -carboxamide (150 mg, 57.23%) as yellow solid. LC-MS (m / z) = 217 [MW-

[0817] Step-8: Synthesis of 1-(2-iodobenzo[d]oxazol-5-yl)-N-methylcyclopropane-1 -carboxamide

[0818] To a solution of N-methyl1-(1 ,3-benzoxazol-5-yl)cyclopropanecarboxamide (140 mg, 647 μmol) in THF (6 mL), cooled to -78 °C, then LIHMDS (1.62 mL, 2.5 eq., 1.62 mmol) is added and stirred at same temperature for 2 h. Then iodine (123 mg, 1.5 eq., 971 μmol) in THF (2.0 mL) is added and slowly brought into 0 °C for 1 h. Reaction mixture is quenched with sat. ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 X 50 mL), dried over sodium sulfate, filtered and concentrated. The crude material is purified by combiflash chromatography MPLC, product eluted at 6% - 8% methanol in dichloromethane to afford 1-(2-iodobenzo[d]oxazol-5-yi)- N-methylcyclopropane-1-carboxamide (0.1 g, impure) as an off-white solid. LC-MS (m / z) = 343.1 [MW.

[0819] Step-9: Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-N- methyicyclopropane- 1 -carboxamide

[0820] To a solution of 1-(2-iodobenzo[d]oxazol-5-y!)-N-methylcyclopropane-1 -carboxamide (0.1 g, 292 pmoi) in tetrahydrofuran (6 mL, 73.7 mmol). Then 5-fluoro-1 ,3-benzoxazo!-2-yiamine (31.1 mg, 0.7 eq., 205 μmol) and lithium 2-methyl-2-propanolate (46.8 mg, 2 eq., 585 μmol) are added and stirred at 70 °C for 12 h. Reaction mixture is concentrated. The residue is dissolved in ethyl acetate (30 mL) and ished with water (10 mL) and brine (10 mL). The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography using silica gel (4 g, cartridge), methanol in DCM as eluent to afford N-methyl1-[2-(5-fluoro-1,3- benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl]cyclopropanecarboxamide (26 mg, impure). This impure fraction submitted for prep.HPLC to afford N-methyi1-[2-(5-f!uoro-1,3-benzoxazoi-2- ylamino)-1 ,3-benzoxazol-5-y!]cyclopropanecarboxamide (15 mg, 14%) as an off-white solid. LC- MS (m / z) = 367.4 [M+H]+.

[0821] Purification conditionsColumn: Xselect C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 0.1 % Ammonia in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / min%B / T: 0 / 20, 15 / 70, 16 / 98, 19 / 98,20 / 20Desired product at 12.74 min

[0822] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.58 (br, 1 H), 7.53 - 7.46 (m, 2H), 7.41 (s, 1 H), 7.29 (d, 7.2 Hz, 1 H), 7.20 - 7.17 (dd, 1.2 Hz & J = 1.2 Hz, 1 H), 7.04 - 6.99 (m, 1 H), 6.69(d, 4.4 Hz, 1 H), 2.50 (s, 3H), 1.363.6 Hz, 2H), 0.98 (d, 3 6 Hz, 2H).

[0823] Example 99Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)cyclopropane-1- carboxylic acid

[0824] Step-1 : Synthesis of 1-(4-hydroxyphenyl)cyclopropane-1-carboxylic acid

[0825] To a solution of methyl 1-(p-bromopheny!)cyclopropanecarboxylate (1 g, 3.92 mmol) in 1,4-dioxane (10 mL, 117 mmol) and water (10 mL, 555 mmol) is added potassium hydroxide (550 mg, 2.5 eq., 9.8 mmol) and the reaction mixture is purged with nitrogen gas for 5 min. and is added (1 E,4E)-1 ,5-diphenyl-1 ,4-pentadien-3-one — 1 ,5-diphenyl- 1 ,4-pentadien-3-one-palladium (1 / 2 / 2) (179 mg, 0.05 eq., 196 μmol) & bis(tert-butyl)[2',4',6'-tris(isopropyl)-2-biphenylyl]phosphine (83.2 mg, 0.05 eq., 196 μmol) and the reaction mixture is stirred at 100 °C for 12 h. Progress of the reaction is monitored by TLC. After completion of the reaction, the crude is filter through the celite bed and the filtrated, concentrated under the reduced pressure to get the crude. The crude is acidified with 1 N. HCI (pH: 3-4) and filtered, then dried over vacuum to get the crude 1-(p- hydroxyphenyl)cyclopropanecarboxylic acid (1.62 g, 9.09 mmol) as a pale-yellow solid. LC-MS (m / z) = 179 1 [M+H]L

[0826] Step-2: Preparation of methyl 1-(4-hydroxyphenyl)cyclopropane-1-carboxylate

[0827] To a solution of 1-(p-hydroxyphenyl)cyclopropanecarboxylic acid (1.6 g, 8.98 mmol) in methanol (30 mL, 741 mmol), cooled to 0 °C, sulfuric acid (1.5 mL) is added to the reaction mixture and stirred at 73 °C for 16 h. Reaction mixture is concentrated. The residue basified with sat. solution of sodium bicarbonate (20 mL), solid is precipitated. The solid is filtered through sintered funnel and ished with water (50 mL), then n-heptane (30 mL), dried over vacuum to provide the crude material. The crude product is purified by flash silica chromatography (dry loaded), elution gradient 0 to 60% EtOAc in heptane. Pure fractions are concentrated to afford methyl 1-(p- hydroxyphenyl)cyclopropanecarboxylate (920 mg, 4.79 mmol, Yield: 53.3 %) as a yellow oil.

[0828] Step-3: Preparation of methyl 1-(4-hydroxy-3-nitrophenyl)cyclopropane-1-carboxylate.

[0829] To a solution of methyl 1-(p-hydroxyphenyl)cyclopropanecarboxylate (920 mg, 4.79 mmol) in acetic acid (7.5 mL, 140 mmol) cooled to 0 °C, nitric acid (0.2 mL, 4.79 mmol) in 0.5 ml acetic acid is added drop wise to the reaction mixture and stirred for 10 min at the same temperature and continued stirring at RT for 1 h. The reaction is monitored by TLC. To the reaction mixture water (10 ml) is added at 0 °C and extracted with EtOAc (15 ml), brine ish is given. Organic layer dried over sodium sulphate and concentrated to provide the crude material. The crude product is purified by flash silica chromatography (dry loaded), elution gradient 0 to 30% EtOAc in heptane. Pure fractions are concentrated to afford methyl 1 -(4- hydroxy- 3- nitrophenyl)cyclopropanecarboxylate (690 mg, 2.91 mmol, Crude) as a pale-yellow oil. LC-MS (m / z) = 236.0 [M-H]-.

[0830] Step-4: Preparation of methyl 1-(3-amino-4-hydroxyphenyl)cyclopropane-1-carboxylate.

[0831] To a stirred solution of methyl 1-(4-hydroxy-3-nitrophenyl)cyciopropanecarboxylate (640 mg, 2.7 mmol) in 1 ,4-dioxane (7 mL, 82.1 mmol) and water (3 mL, 167 mmol) is added zinc (1.41 g, 8 eq., 21.6 mmol) and ammonium chloride (1.15 g, 8 eq., 21.6 mmol). The reaction mixture is stirred at RT for 1h. Progress of the reaction is monitored by TLC. Once the reaction is completed, the mixture is filtered and diluted with EtOAc (5 mL), ished with water (3 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the crude of methyl 1-(3- amino-4-hydroxyphenyl)cyclopropanecarboxylate (620 mg, 2.99 mmol) as a pale green solid.

[0832] Step-5: Preparation of methyl 1-(2~aminobenzo[d]oxazol~5-yl)cyclopropane-1-carboxylate.

[0833] To a stirred solution of methyl 1-(3-amino-4~hydroxyphenyl)cyclopropanecarboxylate (570 mg, 2.75 mmol) in methanol (6 mL, 148 mmol) is added bromocarbonitrile (350 mg, 1.2 eq., 3.3 mmol) at room temperature. The reaction mixture is allowed to stir at room temperature for 16 h. The progress of the reaction is monitor by TLC. The reaction mixture is quenched with saturated NaHCO3 (3 mL). MeOH is evaporated under reduced pressure, residue is extracted with Ethyl acetate (10 mL * 2). The combined organic layer is dried over sodium sulfate and concentrated under reduced pressure to obtain methyl 1-(2-amino-1,3-benzoxazol-5- yl)cyclopropanecarboxylate (610 mg, 2.63 mmol, Yield: 95.49 %) as a black solid. LC-MS (m / z) = 233.1 [M+H]T

[0834] Step-6: Preparation of methyl 1-(2-((5-fluorobenzo[d]oxazol-2~yl)amino)benzo[d]oxazol~5- yl)cyclopropane-1 -carboxylate

[0835] To a solution of methyl 1-(2-amino-1 ,3-benzoxazol-5-yl)cyclopropanecarboxylate (0.6 g, 2.58 mmol) in dimethylformamide (8 mL, 103 mmol), dicaesium carbonate (1.68 g, 2 eq., 5.17 mmol) and 5-fluoro-2-(methylthio)-1 ,3-benzoxazole (473 mg, 2.58 mmol) is added and heated at 85 °C for 16 h. The reaction mixture is monitored by TLC. The reaction mixture is concentrated, the residue is dissolved in ethyl acetate (10 mL) and ished with water (5 mL) and combined organic layer dried over sodium sulphate and concentrated to provide the crude material. The crude product is purified by flash silica chromatography (dry loaded), elution gradient 0 to 60% EtOAc in heptane. Pure fractions are concentrated to afford methyl 1-[2-(5-fluoro-1,3-benzoxazol- 2-ylamino)-1 ,3-benzoxazol-5-yl]cyclopropanecarboxylate (240 mg, 653 pmol, Yield: 25.29%) as a pale-yellow solid. LC-MS (m / z) = 368.1 [M+H]+.

[0836] Step-7: Preparation of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5- yl)cyclopropane-1-carboxylic acid

[0837] To a stirred solution of methy! 1-[2-(5-fluoro-1,3-benzoxazol-2-y!amino)-1 ,3-benzoxazol-5- yl]cyclopropanecarboxylate (240 mg, 653 μmol) in tetra hydrofuran (1 mL, 12.3 mmol), methanol (1 mL, 24.7 mmol) and water (0.5 mL, 27.8 mmol) is added lithium hydroxide (62.6 mg, 4 eq., 2.61 mmol) and the reaction is stirred at RT for 16 h. Progress of the reaction mixture is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to get the crude. The crude material is acidified with 1 N HCI, pH (2-3) and the solid obtained is filtered using sintered funnel to obtain the desired product 1-[2~(5~fluoro-1 ,3- benzoxazol-2-ylamino)-1 ,3-benzoxazoi-5-yl]cyclopropanecarboxylic acid (218 mg, 617 pmol) as an off white solid. The product is taken 80 mg and neutralized with saturated NaOH solution, pH (8-9) and the liquid are concentrated under reduced pressure to get the sodium 1-[2-(5-fluoro-1 ,3- benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl]cyclopropanecarboxylate (95.5 mg) as an off white solid, the compound registered as sodium salt. LC-MS (m / z) = 354.3 [M+H]+.

[0838] 1H NMR (400 MHz, DMSO-d6) δ ppm: 6 7.35 (s, 1 H), 7.16-7.13 (m, 2H), 7.01 (d, J = 8.00 Hz, 1 H), 6.84 (d, J = 8.00 Hz, 1 H), 6.68-6.63 (m, 1 H), 1.21-1.21 (m, 2H), 0.69-0.69 (m, 2H).

[0839] Example 100Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-A / , / V- dimethyl cyclopropane-1 -carboxamide

[0840] To a solution of 1-[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5- yl]cyclopropanecarboxylic acid (0.2 g, 566 μmol) in dichloromethane (24 mL, 375 mmol) is added 2,4,6-tripropyl-1 ,3,5,2A5,4A5,6A5-trioxatriphosphinane-2,4,6-trione 50%v / v (667 pL, 2 eq., 1.13 mmol) and 2-(2-aminoethoxy)ethanol (71.4 mg, 1.2 eq., 679 pmol). To the above mixture at 0°C is added N-ethylbis(isopropyl)amine (296 pL, 3 eq., 1.7 mmol) and the reaction mixture is stirred at room temperature for 12 h. Progress of the reaction is monitored by TLC and LCMS data. After completion of the reaction, reaction mixture is quenched with water (3.0 mL) and extracted with ethyl acetate (2 x 5.0 mL). The combined organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude (315 mg). The crude material is purified by below mentioned prep HPLC method to afford N-[2-(2-hydroxyethoxy)ethyl]1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5-yl]cyclopropanecarboxamide (138 mg, 314 pmol, Yield: 55.51 %) as a white solid. LC- VIS (m / z) = 441.4 [ Xi H i .

[0841] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.57-7.51 (m, 2H), 7.45 (s, 1 H), 7.35-7.33 (m, 1 H), 7.23 (d, J = 8.40 Hz, 1 H), 7.08-7.03 (m, 1 H), 6.74-6.71 (m, 1 H), 3.42-3.40 (m, 2H), 3.35-3.33 (m, 4H), 3.18-3.13 (m, 2H), 1.39-1.38 (m, 2H), 1.01-1.01 (m, 2H).

[0842] Purification conditionsColumn: Xterra C18 (250x19)mm;1 OuFlow: 19.0 mL / minMobile phase A: 0.1 % Ammonia in WaterMobile phase B: AcetonitrileDesired Product Rt at 10.82 min

[0843] Example 101Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)propanoic acid

[0844] Step-1 : Synthesis of methyl 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)acetate

[0845] To a stirred solution of methyl (p-hydroxyphenyl)acetate (5 g, 30.1 mmol, 1 eq) in DMF (50 mL), is added imidazole (6.15 g, 90.3 mmol, 3 eq), after that reaction mixture is cooled to 0 °C is added (tert-butyl)(chloro)bis(methyl)silane (9.07 g, 60.2 mmol, 2 eq) and Reaction mixture is allowed to stirred at room temperature for 3 h, reaction progress is checked by TLC monitoring, after completion of the reaction, reaction mixture is diluted with ice cold water (20 mL), extracted with EtOAc (2x50 mL), concentrated under reduced pressure to get the crude. The crude is purified by flash column chromatography eluted on 5% EtOAc - Heptane to afford methyl {p-[(tert- butyl)bis(methyl)siloxy]phenyl}acetate (7 g, 83 % yield) as colorless liquid. LC-MS (m / z) = 281.2 [M + H]+.

[0846] Step-2: Synthesis of methyl 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)propanoate

[0847] To a solution of methyl {p-[(tert-butyl)bis(methyl)siloxy]phenyl}acetate (7 g, 25 mmol, 1 eq) in THF (70 mL), cooled to -78 °C, then lithium bis(isopropyl)azanide (18.7 mL, 37.4 mmol, 1.5 eq) is added and stirred at same temperature for 1 h. iodomethane (3.11 mL, 49.9 mmol, 2 eq) is added and the temperature is gradually cooled to -20 °C for 1h. Reaction mixture is quenched with sat. ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 X 50 mL), dried over sodium sulfate, filtered and concentrated. To get crude product. Which is purified by flash column chromatography eluted on 2.5% EtOAc - Heptane to afford methyl 2-{p-[(tert~ butyl)bis(methyl)siloxy]phenyl}propionate (7.1 g, 96% yield) as colorless liquid. LC-MS (m / z) = 295.2 [M+H]+.

[0848] Step-3: Synthesis of methyl 2-(4-hydroxyphenyl)propanoate

[0849] To a solution of methyl 2“{p“[(tert-butyl)bis(methyl)siloxy]phenyl}propionate (3 g, 10.2 mmol, 1 eq) in THF (30 mL), cooled to 0 °C, then TBAF (10.2 mL, 10.2 mmol, 1 eq) is added and stirred at RT for 3 h. Reaction mixture is quenched with H2O (30 mL) and extracted with ethyl acetate (2 X 100 mL), dried over sodium sulfate, filtered and concentrated. To get crude methyl 2-(p-hydroxyphenyl)propionate (1.8 g). LC-MS (m / z) = 181.1 [M+H]f.

[0850] Step-4: Synthesis of methyl 2-(4-hydroxy-3-nitrophenyl)propanoate

[0851] To a solution of methyl 2-(p-hydroxyphenyl)propionate (2.6 g, 14.4 mmol, 1 eq) in acetic acid (10 mL) cooled to 0 °C, nitric acid (602 pL, 14.4 mmol) in 0.5 ml acetic acid is added drop wise to the reaction mixture and stirred for 10 min at the same temperature and continued stirring at RT for 1 h . Reaction is monitored by TLC, LCMS. To the reaction mixture water (30 ml) is added at 0 °C and extracted with EtOAc (50 ml), brine ish is given. Organic layer dried over sodium sulphate and concentrated to get crude product which is purified by flash column chromatography eluted on 8% EtOAc - Heptane to afford methyl 2-(4-hydroxy-3- nitropheny!)propionate (2 g, 62 %) as yellow liquid. LC-MS (m / z) = 224.0 [M - H],

[0852] Step-5: Synthesis of methyl 2-(3-amino-4-hydroxyphenyl)propanoate

[0853] To a solution of methyl 2-(4-hydroxy-3-nitrophenyl)propionate (1 g, 4.44 mmol, 1 eq) in ethanol (10 mL) and water (8 mL), iron (496 mg, 2 eq., 8.88 mmol) and ammonium chloride (713 mg, 3 eq., 13.3 mmol) is added and stirred at 70°C for 16 h. Progress of the reaction is monitored by TLC. Reaction mixture is filtered through celite. Filtrate is taken in water and extracted to organic layer with ethyl acetate. Organic layer is dried over NaSO4 and concentrated to afford methyl 2-(3-amino-4-hydroxyphenyl)propionate (0.6 g, Yield: 70%) as brown solid. LC-MS (m / z) = 196.1 [M + H]+.

[0854] Step-6: Synthesis of methyl 2-(2-aminobenzo[d]oxazol-5-yl)propanoate

[0855] To a stirred solution of methyl 2-(3-amino-4-hydroxypheny!)propionate (2 g, 10.2 mmol, 1 eq) methanol (20 mL) is added bromocarbonitrile (1.3 g, 12.3 mmol, 1.2 eq). After that reaction mixture is stirred at room temperature for 16 h, reaction progress is checked by TLC monitoring, after completion of the reaction, reaction mixture is concentrated under reduced pressure to get the crude residue. The residue is basified with saturated aq Na2CO3 solution (30 mL) solid formed, filtered and dried to afford methyl 2-(2-amino-1 ,3-benzoxazol-5-yl)propionate (2.1 g, 93 % yield ) as brown color solid. LC-MS (m / z) = 221 .2 [M + H]+.

[0856] Step-7: Synthesis of methyl 2-(2-((5-fluorobenzo[d]oxazol~2~yl)amino)benzo[d]oxazol~5- yl)propanoate

[0857] To a solution of methyl 2-(2-amino-1 ,3-benzoxazol-5-yl)propionate (0.5 g, 2.27 mmol, 1 eq) in DMF (5 mL), is added 5-fluoro-2-(methylthio)-1!3-benzoxazole (0.41 g, 2.27 mmol, 1 eq) and dicaesium carbonate (1.11 g, 3.41 mmol, 1.5 eq) and the reaction mixture is heated at 85 °C for 16 h. Progress of the reaction is monitored by TLC and LCMS. Once the reaction is completed, the reaction mixture is diluted with ice cold water(30ml) and extracted with EtOAc (2X 50mL). Combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to get crude compound. Crude is loaded in Flash column MPLC using 15%-20% EtOAc in Heptane as an eluent to afford methyl 2-[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3- benzoxazoi-5-yl]propionate (0.3 g, Yield: 37%) as white solid. LC-MS (m / z) = 356.0 [M + HL.

[0858] Step-8: Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl) propanoic acid

[0859] To a stirred solution of methyl 2-[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5- yl]propionate (0.25 g, 0.70 mmol, 1 eq) methanol (2 mL), THF (2 mL) and water (2 mL) is added lithium hydroxide (0.084 g, 3.52 mmol, 5 eq), after that reaction mixture is stirred at RT for 16 h, reaction progress is checked by TLC monitoring, after completion of the reaction, reaction mixture is concentrated under reduced pressure to get the crude residue. The residue is acidified with dilute HCI (5 mL) solid formed, filtered and dried to grt crude, which is purified by prep, collected fractions are concentrated to get 2-[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol~5- yljpropionic acid (0.17 g, 83 %) as white gummy solid, (registered as sodium salt). LC-MS (m / z) = 342.3 [M + H]+.

[0860] Purification conditionsColumn: Sunfire C18 (19 mm X 250 mm X 5 mic)Mobile phase (A): 5mM Ammonium bicarbonate in WaterMobile phase (B): AcetonitrileFlow rate: 19 mL / min

[0861] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.32 (s, 1 H), 7.15 - 7.08 (m, 2 H), 7.02 (d, J = 8.0 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 6.64 (t, J = 8.4 Hz, 1 H), 3.31 - 3.27 (m, 1 H), 1 .27 (d, J = 6.8 Hz, 3 H).

[0862] Example 102Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-A / -(2-(2- hydroxyethoxy)ethyi)propanamide

[0863] Step-1 : Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-N-(2- (hydroxymethoxy)ethyl)propanamide

[0864] To a solution of 2-[2-(5-fluoro-1 ,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionic acid (0.3 g, 0.87 mmol, 1 eq) in DCM (3 mL) are added 2-(2-aminoethoxy)ethanol (0.18 g, 1.76 mmol, 2 eq) and 2,4,6-tripropyl-1 ,3,5,2A5,4As,6A5-trioxatriphosphinane-2,4,6-trione (1.05 mL, 1.76 mmol, 2 eq). To the above mixture at 0°C is added N-ethylbis(isopropyl)amine (0.45 mL, 2.64 mmol, 3 eq) and the reaction mixture is stirred at room temperature for 16 h. Progress of the reaction is monitored by TLC and LCMs data. After completion of the reaction, reaction mixture is quenched with water (8.0 mL) and extracted with ethyl acetate (2 x 5.0 mL). The combined organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The crude is purified by below mentioned prep condition, collected fractions are concentrated to afford N~[2-(2-hydroxyethoxy)ethyl]2-[2~(5~fluoro-1 ,3-benzoxazol-2-ylamino)-1 ,3- benzoxazol-5-yl]propionamide (14 mg, 3% yield) as white solid. LC-MS (m / z) = 429.4 [M+H]+.

[0865] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.08 (t, J = 5.6 Hz, 1 H), 7.56 - 7.45 (m, 3 H), 7.34 - 7.31 (dd, J = 2.8 Hz, J = 2.8 Hz, 1 H), 7.20 - 7.18 (dd, J = 1.6 Hz, J = 1.6 Hz, 1 H), 7.07 - 7.02 (m, 1 H), 3.74 - 3.69 (m, 1 H), 3.47 - 3.34 (m, 5 H), 3.26 - 3.13 (m, 3 H), 1.35 (d, J = 6.8 Hz, 3 H).

[0866] Example 103Synthesis of 2-(benzo[d]oxazol-2-ylamino)- / V-(1-(2-hydroxyethyl)pyrrolidin-3-yl)benzo[d]oxazole- 5-carboxamide

[0867] Example 103 is synthesized in an analogous manner to Example 22.

[0868] Example 104Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)am!no)benzo[d]oxazol-5-yl)-A / -(2-(2- hydroxyethoxy)ethyl)cyclopropane-1 -carboxamide

[0869] To a solution of 1-[2-(5-f!uoro-1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5- yljcyclopropanecarboxylic acid (0.2 g, 566 μmol) in dichloromethane (24 mL, 375 mmol) is added 2, 4, 6-tripropyl-1 , 3, 5,2A5,4A5,6A5-trioxatriphosphinane-2, 4,6-trione 50%v / v (667 pL, 2 eq., 1.13 mmol) and 2-(2-aminoethoxy)ethanol (71.4 mg, 1.2 eq., 679 pmol). To the above mixture at 0°C is added N-ethy!bis(isopropy!)amine (296 pL, 3 eq., 1.7 mmol) and the reaction mixture is stirred at room temperature for 12 h. Progress of the reaction is monitored by TLC and LCMS data. After completion of the reaction, reaction mixture is quenched with water (3.0 mL) and extracted with ethyl acetate (2 x 5.0 mL). The combined organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude (315 mg). The crude material is purified by below mentioned prep HPLC method to afford N-[2-(2-hydroxyethoxy)ethyl]1-[2~(5~fluoro-1 ,3- benzoxazol-2-ylamino)~1 ,3-benzoxazol-5-yl]cyclopropanecarboxamide (138 mg, 314 pmol, Yield: 55.51 %) as a white solid. LC-MS (m / z) = 441.4 [M+H]+.

[0870] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.57-7.51 (m, 2H), 7.45 (s, 1 H), 7.35-7.33 (m, 1 H), 7.23 (d, J = 8.40 Hz, 1 H), 7.08-7.03 (m, 1 H), 6.74-6.71 (m, 1 H), 3.42-3.40 (m, 2H), 3.35-3.33 (m, 4H), 3.18-3.13 (m, 2H), 1.39-1.38 (m, 2H), 1.01-1.01 (m, 2H).

[0871] Purification conditionsColumn: Xterra C18(250x19)mm;1 OuFlow: 19.0 mL / mlnMobile phase A: 0.1% Ammonia In WaterMobile phase B: AcetonitrileDesired Product Rt at 10.82 minEXAMPLE A

[0872] Cellular Target Engagement

[0873] HEK293 ARE luciferase reporter cells (Signosis) are maintained according to the manufacturer’s instructions. For assessment of target engagement, cells are seeded into 96-well plates and treated with varying concentrations of compounds or a DMSO vehicle. Cells are incubated for 6 hours at 37°C and 5% CO2. After this time, the cells are ished and lysed using a RIPA buffer containing a protease inhibitor cocktail. Luciferase activity is assessed using a substrate (Signosis) according to the manufacturer’s instructions. Table A shows the results of cellular target engagement of the compounds as described herein.Table A. The results of cellular target engagement* “+” indicates a mean EC50 value of at least 10 pM; “++” indicates a mean EC50 value between 5 and 10 pM; “+++” indicates a mean EC50 value between 2.5 and 5 μM; and “++++" indicates a mean EC50 value of less than 2.5 μM.EXAMPLE B

[0874] Cellular HO-1 Protein Induction

[0875] HepG2 cells (ATCC) are maintained according to the manufacturer’s instructions. For assessment of HO-1 protein induction, cells are seeded into 96-well plates and treated with varying concentrations of compounds or a DMSO vehicle for 18 hours at 37°C and 5% COs. After this time, the cells are ished and lysed using a RIPA buffer containing a protease inhibitor cocktail. HO-1 induction is measured by an ELISA (R&D Systems) according to the manufacturer’s instructions. Table B shows the results of cellular HO-1 protein induction of the compounds as described herein.Table B. The results of cellular HO-1 protein induction.* “+” indicates a mean EC50 value of at least 10 pM; “++” indicates a mean EC50 value between 5 and 10 pM; “+++” indicates a mean EC50 value between 2.5 and 5 pM; and “++++" indicates a mean EC50 value of less than 2.5 μM.EXAMPLE C

[0876] Cellular F-Cell (fetal hemoglobin (HbF)) Induction (Method 1)

[0877] Mobilized peripheral blood CD34+ cells from a normal human donor are thawed, washed, counted, and diluted in media. The cells are then plated at 10,000 cells per well in a 96-well plate. The cells are cultured for 7 days (37°C and 5% CO2) in X-Vivo 15 media containing 10 ng / mL recombinant human IL-3 (rhlL-3), 100 ng / mL recombinant human stem cell factor (rhSCF), and 100 ng / mL recombinant human Flt-3 (rhFlt-3) ligand. On Day 7, the plates are centrifuged, media removed, and cells are washed. The cells are then cultured for 7 days in X-Vivo-15 media containing 10 ng / mL rhlL-3, 100 ng / mL rhSCF and 3 U / mL erythropoietin. Cells are treated with varying concentrations of compounds as described herein or a DMSO vehicle from Day 7-14. On Day 14, flow cytometry is used to stain for CD71 , CD235, and HbF to confirm HbF induction.Alternatively, % of intact HbF via EUSA (Fortis Life Sciences, E88-134 and E88-136) or HPLC- UV (Ou and Rognerud, Clin. Chem., 1993) or subunits of Hb via HPLC-MS are determined. Table C shows the results of cellular CD71 brighTHbR induction of the compounds as described herein.Table C. The results of cellular CD71bright+HbF+induction* “+” indicates a fold of no more than 1 .0; “++” indicates a fold between 1.0 and 1.5; “+++” indicates a fold between 1.5 and 2; and “++++” indicates a fold of at least 2.0.

[0878] Cellular F-Cell (fetal hemoglobin (HbF)) Induction (Method 2)

[0879] Mobilized peripheral blood CD34+ cells from a normal human donor are thawed, washed, counted, and diluted in media. The cells are then plated at 10,000 cells per well in a 96-well plate. The cells are cultured for 7 days (37°C and 5% CO?) in X-Vivo-15 media containing 1 ng / mL recombinant human IL-3 (rhlL-3), 10 ng / mL recombinant human stem cell factor (rhSCF), 3 U / mL heparin, and 3 U / mL erythropoietin. On Day 4, the cells are diluted 1 :4 in the same media cocktail. On Day 7, the plates are centrifuged, media removed, and cells are washed. The cells are then cultured until Day 12 in X-Vivo-15 media containing 10 ng / mL rhSCF, 3 U / mL heparin, and 3 U / mL erythropoietin. Finally, the cells are cultured in media containing 200 ug / mL transferrin, 3 U / mL heparin, and 3 U / mL erythropoietin. Cells are treated with varying concentrations of compounds as described herein or a DMSO vehicle for the entire culture period (from Day 0-14). On Day 14, flow cytometry is used to stain for CD71 , CD235, and HbF to confirm HbF induction. Alternatively, % of intact HbF via ELISA (Fortis Life Sciences, E88-134 and E88-136) or HPLC-UV (Ou and Rognerud, Clin. Chem., 1993), or subunits of Hb via HPLC-MS are determined.EXAMPLE D

[0880] Thermodynamic Solubility

[0881] Assay sampies are prepared by adding 1 mg of compound to a centrifuge tube and adding 1 mL of buffer (phosphate buffered saline, fasted state simulated intestinal fluid, fasted state simulated gastric fluid, or fed state simulated intestinal fluid) to achieve a concentration of 1 mg / mL. The tubes containing the assay samples are then shaken for the desired time at the desired temperature followed by centrifugation to separate undissolved drug from dissolved drug. The supernatant is collected and filtered. A sample of filtrate is transferred to a 96-well plate and analyzed by HPLC or UPLC in comparison to compound calibration standards.EXAMPLE E

[0882] Metabolic Stability in Hepatocytes

[0883] Cryopreserved hepatocytes are thawed, washed, counted, diluted to the desired concentration in media and plated in a 96-well plate. Aliquots of test compounds and positive controls are added to the plate to start the reaction. The plate is incubated on an orbital shaker for the desired time, then an aliquot of the contents from each well is transferred and mixed with acetonitrile containing internal standards to terminate the reaction. Samples are centrifuged and the supernatant is transferred to a 96-well plate and diluted with distilled water for analysis by LC- MS / MS.EXAMPLE F

[0884] In Vivo Pharmacokinetics (PK)

[0885] Compounds are dosed either per os (p.o.) or intravenous (i.v.). For p.o. delivery, animals are fasted. Compounds are suspended in either 0.5% w / v methyicellulose or 0.5% w / v methylcellulose:Tween 80 (99.5:0.5, v / v) and then dosed to various species. For i.v. delivery, animals are fed. Compounds are dissolved in DMSO:Solutol+Ethanol(1 :1 , v / v):0.9% saline (10:10:80, v / v / v), DMSO:Kolliphor RH40+Ethanol(1:1, v / v):0.9% saline (10:10:80, v / v / v) or PEG400:water (1 :1 , v / v), and then dosed to one of various species according to Table D. At predetermined timepoints, whole blood is collected in EDTA-K2 tubes, and then after centrifuging at 2,000 x g for 10 minutes at 4° C, plasma is collected. Plasma concentration (ng / mL) isdetermined by a fit-for-purpose LC-MS method using a calibration curve. Exampies of such methods are provided below in Example I.Table D. Representative experimental design for in vivo PK studies.EXAMPLE G

[0886] In Vivo Pharmacokinetics (PK) / Pharmacodynamic (PD) Model

[0887] Compounds are suspended in either 0.5% w / v methylcellulose or 0.5% w / v methylcellulose:Tween 80 (99.5:0.5, v / v) and then dosed per os (p.o.) to mice (female or male, C57BL / 6) at various dose strengths and levels. Mice are dosed either once or twice daily for >1 day(s). At predetermined time points, one fraction of whole blood is collected in EDTA-K2 tubes, and then processed to plasma. Plasma concentration (ng / mL) is determined by a fit-for-purpose LC-MS method. Examples of such methods are provided below in Example I. Plasma levels of HO-1 are determined by ELISA per the manufacturer’s instructions (Abeam, ab204524). A second fraction of whole blood is collected into RNAIater® solution (or equivalent). RNA is extracted per standard procedures (e.g., using RNeasy® kits per manufacturer’s instructions) and mRNA levels of various genes are determined by qPCR. Finally, white blood cells (WBCs) may be collected in a third fraction of whole blood by lysing the red blood cells and then pelleting the WBCs by centrifugation. RNA is extracted by lysing the WBCs and mRNA levels of various genes are determined per above.EXAMPLE H

[0888] Townes Mouse Model of Sickle Cell Disease (SCD)

[0889] Compounds are suspended in either 0.5% w / v methylcellulose or 0.5% w / v methylcellulose:Tween 80 (99.5:0.5, v / v) and then dosed per os (p.o.) to mice (female or male, Townes, homo / homo) at various dose strengths and levels. Mice are dosed either q.d. or b.i.d. for >1 day(s). At predetermined timepoints, one fraction of whole blood is collected in EDTA-K2 tubes, and then processed to plasma. Plasma exposure (ng / mL) is determined per the PK or PK / PD methods. F-cell levels are determined by a standard flow cytometry procedure using an anti-HbF antibody. Levels of %HbF are determined by either HPLC-UV (Ou and Rognerud, Clin. Chem., 1993) or ELISA (Fortis Life Sciences, E88-134 and E88-136), and levels of Hb subunits (alpha, beta, gamma) are determined by LC-MS. Other analytes and / or biomarkers are determined per the PK / PD model description.EXAMPLE I

[0890] Plasma Sample Preparation and Tandem Mass Spectrometry Methods

[0891] Methods of preparing plasma samples for mass spectrometry and analysis thereof are well known to those of ordinary skill in the art. Furthermore, those of ordinary skill in the art will appreciate that developing an LC-MS / MS analysis method for a given compound requires some amount of parameter optimization for optimal results. Such parameters can include but are not limited to: mobile phase, LC gradient, injection volume, column, flow rate, ionization mode, dwell time, declustering potential, entrance potential, collision energy, collision ceil exit potential, and m / z transition, inter alia. Nonetheless, provided herein are two plasma sample preparation and LC-MS / MS analysis methods that can be used in the practice of the invention.

[0892] Plasma Sample Preparation (Method 1)

[0893] The desired serial concentrations of working solutions are achieved by diluting stock solutions of compound with 50% acetonitrile in water solution. 5 pL of working solutions (5, 10, 20, 50,100, 500, 1000, 5000, 10000 ng / mL) are added to 50 pL of blank Beagle dog plasma to achieve calibration standards of 0.5-1000 ng / mL (0.5, 1 , 2, 5, 10, 50, 100, 500, 1000 ng / mL) in a total volume of 55 pL. Six quality control (QC) samples at 1 ng / mL, 2 ng / mL, 5 ng / mL, 50 ng / mL,400 ng / mL and 800 ng / mL for plasma are prepared independently of those used for the calibration curves. These QC samples are prepared on the day of analysis in the same way as calibration standards. 55 pL standards, 55 pL QC samples and 55 pL unknown samples (50 pL plasma with 5 pL blank solution) are added to 200 pL of acetonitrile containing internal standard (IS) mixture to precipitate protein. Samples are vortexed for 30s and centrifuged at 4 °C at 3,900 rpm for 15 min. The supernatant is diluted 3 times with water, and 5 pL of diluted supernatant is injected into the LC / MS / MS system for quantitative analysis.

[0894] LC-MS / MS Analysis (Method 1)

[0895] LC-MS / MS analyses are carried out using a Shimadzu HPLC system coupled to a SCI EX Triple Quad 5500+ LC-MS / MS instrument. Samples are separated on a Raptor Biphenyl 2.7 pm (50 x 2.1 mm) column using an injection volume of 5 pL and mobile phases A (95:5 water: acetonitrile + 0.1% formic acid) and B (5:95 wateracetonitrile + 0.1% formic acid). The gradient used is: 0-0.3 min, 95% A; 1.9-2.2 min, 5% A; 2.2-2.5 min, 95% A at a flow rate of 0.6 mL / min. The gradient is presented below in Table E.Table E. LC gradient utilized in LC-MS / MS (Method 1).Time (min) A (%) B (%)0.01 95.0 5.000.30 95.0 5.001.90 5.00 95.02.20 5.00 95.02.21 95.0 5.002.50 95.0 5.00

[0896] Tandem mass spectra are acquired in multiple reaction monitoring (MRM) mode using electrospray ionization in positive mode. Gas temperature is 550°C. MS / MS parameters are set as in Table F. Dexamethasone is spiked into samples and used as an internal standard.Table F. MS / MS parameters for detection of dexamethasone using LC-MS / MS (Method 1).[089 / ] These parameters can be adjusted for optimal detection based on the characteristics of the compounds of interest.

[0898] Plasma Sample Preparation (Method 2)

[0899] To prepare quality control (QC) samples, an aliquot of 2.5 pL of working stock solution of compound is spiked into 22.5 pL of blank Beagle dog plasma blank to obtain the desired concentration. To prepare study samples, vials containing the study samples are retrieved from -20°C deep freeze and thawed to room temperature. A volume of 25 pL of sample is aliquoted into pre-labeled vials. Both QC and study samples are processed as follows. To an aliquot of 25 pL of sample, 400 pL of 100 % acetonitrile containing IS (100 ng / mL) is added to precipitate protein. Samples are vortexed for 5 min and centrifuged at 14,000 rpm for 5 min at 4°C. Then, an aliquot of supernatant is separated and 2 pL are injected to the LC-MS / MS system as described below.

[0900] LC-MS / MS Analysis (Method 2)

[0901] LC-MS / MS analyses are carried out using an HPLC system coupled to a SCIEX Triple Quad 5500+ LC-MS / MS instrument. Samples are separated on a Zorbax SB phenyl 3.5 pm (50 x 4.6 mm) column using an injection volume of 2 pL and an isocratic gradient (45% A, 55% B) lasting 2 min at a flow rate of 0.9 mL / min. Mobile phase A is 0.1 % formic acid + 5 mM ammonium formate in water; mobile phase B is acetonitrile. Tandem mass spectra are acquired in MRM mode using electrospray ionization in positive mode. MS / MS parameters are set as in Table G. Warfarin is spiked into samples and used as an internal standard.Table G. MS / MS parameters for detection of warfarin using LC-MS / MS (Method 2).

[0902] These parameters can be adjusted for optimal detection based on the characteristics of the compounds of interest

[0903] it is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be incorporated within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated herein by reference for all purposes.

Claims

What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein: each of R1, R3, R4, and R3is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halo C1-C6 alkyl, or OR10, wherein R10is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halo C1-C6 alkyl;R2is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halo C1-C6 alkyl, OR10, hydroxy C1-C6 alkyl, or -C(O)NR11R12, wherein each of R11and R12is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, or hydroxy C1-C6 alkoxy C1-C6 alkyl;R5is hydrogen, hydroxy C1-C6 alkyl, or carboxy C1-C6 alkyl;R6and R7is independently hydrogen, hydroxy C1-C6 alkyl, -X-C(O)R13, -Y- C(O)NR14R1S, -Z-NR16R17, heteroaryl, or -S(O)2R18, whereinX is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino;R13is -OH or -OR10;Y is a bond, C3-C0 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino; each of R14and R15is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl C3-C6 cycloalkylamino, C1-C6 amine, carboxy C1-C6 alkyl, -S(O)2R19, phenyl, heteroaryl, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group, whereinR19is C1-C6 alkyl;the phenyl is optionally substituted with C1-C6 alkyl; the heteroaryl is optionally substituted with C1-C6 alkyl; and the 3-8 membered monocyclic heterocyclyl group is optionally substituted with C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl;Z is a bond, Cg-Cs cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino; each of R16and R17is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy Ci-C6alkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C5 alkyl, halo C1-C6 alkyl, -(C1-C6 alkyl)-C(O)R20, -C(O)R21, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group, whereinR2Gis -OH, OR10, or NR22R23, wherein each R22and R23is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or hydroxy C1-C6 alkyl C3-C6 cycloalkylamino;R21is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, amino, or mono- or di-C1-C6 alkyl amino; and the 3-8 membered monocyclic heterocyclyl group is optionally substituted with C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl; andRiSis C1-C6 alkyl or -NH-(CrCsalkyl); andR9is hydrogen, C1-C6 alkyl, or a N-protecting group.

2. The compound of claim 1 , wherein R1is hydrogen.

3. The compound of claim 1 , wherein R1is methyl.

4. The compound of claim 1 , wherein R1is fluoro.

5. The compound of claim 1 , wherein R1is OR10, and wherein R10is methyl.

6. The compound of any of claims 1-5, wherein R2is hydrogen.

7. The compound of any of claims 1-5, wherein R2is methyl.

8. The compound of any of claims 1-5, wherein R2is fluoro.

9. The compound of any of claims 1-5, wherein R2is OR10, and wherein R10is methyl.

10. The compound of any of claims 1-5, wherein R2is -C(O)NR! !R12, and wherein R11is hydrogen, and R12is C1-C6 aikoxy C1-C6 alkyl.

11. The compound of any of claims 1-5, wherein R2is -C(O)NR11R12, and wherein R11is hydrogen,12. The compound of any of claims 1-11, wherein R3is hydrogen.

13. The compound of any of claims 1-11, wherein R3is methyl.

14. The compound of any of claims 1-11, wherein R3is fluoro or chloro.

15. The compound of any of claims 1-11, wherein R3is halo C1-C6 alkyl.

16. The compound of any of claims 1-11, wherein R3is difluoromethyl or trifluoromethyl.

17. The compound of any of claims 1-11, wherein R3is OR10, and wherein Ri0is methyl or difluoromethyl.

18. The compound of any of claims 1-17, wherein R4is hydrogen.

19. The compound of any of claims 1-17, wherein R4is methyl.

20. The compound of any of claims 1-17, wherein R4is fluoro.

21. The compound of any of claims 1-20, wherein R5is hydrogen.

22. The compound of any of claims 1-20, wherein R5is hydroxy C1-C6 alkyl, and wherein Rs23. The compound of any of claims 1-20, wherein R5is carboxy C1-C6 alkyl, and wherein Rs24. The compound of any of claims 1-23, wherein only one of R6and R7is hydrogen.

25. The compound of any of claims 1-23, wherein each of R6and R7is hydrogen.

26. The compound of any of claims 1-23, wherein one of R6and R7is hydrogen and the other is hydroxy C1-C6 alkyl.

27. The compound of claim 26, wherein the hydroxy C1-C6 alkyl is, or28. The compound of any of claims 1-23, wherein R6is -X-C(O)R13, and wherein X is a bond.

29. The compound of claim 28, wherein R7is hydrogen.

30. The compound of claim 28 or claim 29, wherein R13is -OH.

31. The compound of claim 28 or claim 29, wherein R13is -OR10, and wherein R10is methyl.

32. The compound of any of claims 1-23, wherein R6is -X-C(O)R13, and wherein X is methyl or ethyl.

33. The compound of any of claims 1-23, wherein R6is -X-C(O)R13, and wherein X is hydroxyethyl.

34. The compound of any of claims 1-23, wherein R6is -X-C(O)R13, and wherein X is cyclopropyl.

35. The compound of any of claims 32-34, wherein R13is -OH.

36. The compound of any of claims 1-23, wherein R6is -Y-C(O)NR14R15, and wherein Y is a bond.

37. The compound of claim 36, wherein R7is hydrogen.

38. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R15is hydrogen.

39. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R15is C1-C6 alkyl.

40. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R15is methyl.41 . The compound of claim 36 or claim 37, wherein R14is hydrogen, and R15is C1-C6 alkoxy CrC6alkyl.

42. The compound of claim 36 or claim 37, wherein R14is hydrogen, and RiSis43. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R15is hydroxy Ci- Cs alkoxy C1-C6 alkyl.

44. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R15is45. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R!Sis halo C1-C6 alkyl.

46. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R1Sis47. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R!Sis hydroxy Ci- Cg alkyl Cg-Cg cycloalkylamino.

48. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R!Sis49. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R15is C1-C6 amine.The compound of claim 36 or claim 37, wherein R14is hydrogen, and R15is51 . The compound of claim 36 or claim 37, wherein R14is hydrogen, and R15is heteroaryl.

52. The compound of claim 36 or claim 37, wherein R14is hydrogen, and R15is53. The compound of claim 36 or claim 3 / , wherein R14is C1-C6 alkyl, and R15is C1-C6 alkyl.

54. The compound of claim 36 or claim 37, wherein R14is methyl, and R15is methyl.

55. The compound of any of claims 1-23, wherein R6is -Y-C(O)NR14R15, and wherein Y is C1-C6 alkyl.

56. The compound of claim 55, wherein R7is hydrogen.

57. The compound of any of claims 1-23, wherein R6is -Y-C(O)NR'i4R15, and wherein Y is methyl.

58. The compound of claim 57, wherein R7is hydrogen.

59. The compound of any of claims 55-58, wherein R14is hydrogen, and R15is CrCo alkyl.

60. The compound of any of claims 55-58, wherein R14is hydrogen, and R15is methyl.

61. The compound of any of claims 55-58, wherein R!4is hydrogen, and R1Sis hydroxy CrCg alkyl.

62. The compound of any of claims 55-58, wherein R14is hydrogen, and R15is.

63. The compound of any of claims 55-58, wherein R!4is hydrogen, and R1Sis hydroxy CrCs alkoxy C1-C6 alkyl.

64. The compound of any of claims 55-58, wherein R!4is hydrogen, and R1Sis65. The compound of any of claims 55-58, wherein R14is hydrogen, and R15is carboxy Cr Csalkyl.O66. The compound of any of claims 55-58, wherein R14is hydrogen, and R1Sis6 / . The compound of any of claims 55-58, wherein R14is hydrogen, and R15is -S(O)2R19, and wherein R19is methyl.

68. The compound of any of claims 55-58, wherein R14is hydrogen, and R15is heteroaryl.

69. The compound of any of claims 55-58, wherein R14is hydrogen, and R15is70. The compound of any of claims 55-58, wherein R14and R15together with the nitrogen to which they are attached form a 6-membered monocyclic heterocyclyl group.

71. The compound of claim 70, wherein the 6-membered monocyclic heterocyclyl group is72. The compound of any of claims 55-58, wherein R14is methyl, and R15is methyl.

73. The compound of any of claims 1-23, wherein R6is -Y-C(O)NR14R15, and wherein Y is ethyl.

74. The compound of claim 73, wherein R7is hydrogen.

75. The compound of any of claims 1-23, wherein R6is -Y-C(O)NR14R1S, and wherein Y is hydroxyethyl.

76. The compound of claim 75, wherein R7is hydrogen.

77. The compound of any of claims 1-23, wherein R6is -Y-C(O)NRi4R15, and wherein Y is cyclopropyl.

78. The compound of claim 77, wherein R7is hydrogen.

79. The compound of any of claims 73-78, wherein R14is hydrogen, and R15is hydroxy Cr Cs alkoxy C1-C a6lkyl.

80. The compound of any of claims 73-78, wherein R14is hydrogen, and R15is81. The compound of any of claims 73-78, wherein R14is hydrogen, and R15is C1-C0 alkyl.

82. The compound of any of claims 73-78, wherein R14is hydrogen, and R15is methyl.

83. The compound of any of claims 73-78, wherein R14is methyi, and R15is methyl.

84. The compound of any of claims 1-23, wherein R6is -Z-NR16R17, and wherein Z is a bond.

85. The compound of claim 84, wherein R7is hydrogen.

86. The compound of claim 84 or claim 85, wherein R16is hydrogen, and R17is -C(O)R21, and wherein R2 iis hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or C1-C6 amine.

87. The compound of claim 84 or claim 85, wherein R16is hydrogen, and R17is -C(O)R21, and wherein R21is methyl.

88. The compound of claim 84 or claim 85, wherein R16is hydrogen, and R17is -C(O)R2 i, and wherein R21is methoxy.

89. The compound of claim 84 or claim 85, wherein R16is hydrogen, and R17is -C(O)R21, and wherein90. The compound of any of claims 1-23, wherein R6is -Z-NR16R17, and wherein Z is methyl.91 . The compound fo claim 90, wherein R7is hydrogen.

92. The compound of claim 90 or claim 91 , wherein R16is hydrogen, and R17is methyi.

93. The compound of claim 90 or claim 91 , wherein R16is hydrogen, and R!7is C1-C6 alkoxy C1-C6 alkyl.

94. The compound of claim 90 or claim 91 , wherein R16is hydrogen, and R17is,95. The compound of claim 90 or claim 91 , wherein R16is hydrogen, and R!7is -(C1-C6 alkyl)-C(O)R20, and wherein R20is -OH, OR10, or NR22R23, and wherein each R22and R23is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or hydroxy C1-C6 alkyl C3-C6 cycloalkylamino.

96. The compound of claim 90 or claim 91 , wherein R16is hydrogen, and R17is -(C1-C6 alkyl)-C(O)R20, and wherein97. The compound of claim 90 or claim 91 , wherein R16is hydrogen, and R17is -C(O)R21:and wherein R21is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or C1-C6 amine.

98. The compound of claim 90 or claim 91 , wherein R16is hydrogen, and R17is -C(O)R21, and wherein R21is methyl.

99. The compound of claim 90 or claim 91 , wherein R16is hydrogen, and R1' is -C(O)R2 i, and wherein100. The compound of claim 90 or claim 91 , wherein R16is hydrogen, and R1' is -C(O)R2 i, and wherein101. The compound of claim 90 or claim 91 , wherein R16is methyl, and R!7is methyl.

102. The compound of claim 90 or claim 91 , wherein R16is methyl, and R17is hydroxy C1-C6 alkyl.

103. The compound of claim 90 or claim 91 , wherein R16is methyl, and R!7is104. The compound of claim 90 or claim 91 , wherein R16is methyl, and R17is halo C1-C6 alkyl.

105. The compound of claim 90 or claim 91 , wherein R16is methyl, and R!7is106. The compound of claim 90 or claim 91 , wherein R16is ethyl, and R17is ethyl.

107. The compound of claim 90 or claim 91 , wherein R16and R17together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group.

108. The compound of claim 107, wherein the 3-8 membered monocyclic heterocyclyl group109. The compound of any of claims 1-23, wherein R° is110. The compound of claim 109, wherein R7is hydrogen.

111. The compound of any of claims 1-23, wherein R6is -S(O)2R18, and wherein R1Sis C1-C6 alkyl or -NH-(Ci-C6alkyl).

112. The compound of claim 111 , wherein R7is hydrogen.

113. The compound of any of claims 1-23, wherein R6is -S(O)2R18, and wherein R18is -NH2 or -NHCH3.

114. The compound of claim 113, wherein R7is hydrogen.

115. The compound of any of claims 1-23, wherein R6is hydroxy C-I-CB alkyl, and R7is -OR24, wherein R24is C1-C3 alkyl.

116. The compound of any of claims 1-23, wherein R6is -X-C(O)R13, and R7is -OR24, wherein X is methyl, R13is -OH, and R24is C1-C3 alkyl.

117. The compound of any of claims 1-23, wherein R6is -Y-C(O)NR14R1S, and R7is halogen, - OR24, or hydroxy C i-Ce alkyl, wherein Y is a bond, each of R14and R!Sis independently hydrogen, C1-C6 alkyl, or hydroxy aClk1o-Cxy6 C1-C6 alkyl, and R24is C1-C3 alkyl.

118. The compound of claim 117, wherein R14is hydrogen, and R15is C1-C6 alkyl.

119. The compound of claim 117, wherein R14is hydrogen, and R15is methyl.

120. The compound of claim 117, wherein R14is hydrogen, and R15is hydroxy C1-C6 alkoxyCrC6alkyl.

121. The compound of claim 117, wherein R14is hydrogen, and R15is122. The compound of claim 117, wherein R7is fluoro.

123. The compound of claim 11 / , wherein R7is hydroxy C1-C6 alkyl.

124. The compound of any of claims 1-23, wherein R6is -Y-C(O)NR14R15, and R7is -OR24or hydroxy C1-C6 alkyl, wherein Y is methyl, each of R14and R15is independently hydrogen or hydroxy C1-C6 alkoxy C1-C6 alkyl, and R24is C1-C3 alkyl.

125. The compound of ciaim 124, wherein R14is hydrogen, and R1Sis hydroxy C1-C6 alkoxy CrC6alkyl.

126. The compound of claim 124, wherein R14is hydrogen, and R15is.

127. The compound of claim 124, wherein R7is hydroxy C1-C6 alkyl, preferably, >OOH or128. The compound of any of claims 1-23, wherein R6is -Z-NRi6R17, and R7is -OR24, wherein each of RiSand Ri7is C1-C6 alkyl, Z is methyl, and R24is C1-C3 alkyl.

129. The compound of claim 128, wherein each of R16and R17is methyl.

130. The compound of any of claims 1-107, wherein R8is hydrogen.

131. The compound of any of claims 1-107, wherein R8is methyl.

132. The compound of any of claims 1-107, wherein R8is cyclopropyl.

133. The compound of any of claims 1-107, wherein R8is fluoro or chloro.

134. The compound of any of claims 1-107, wherein R8is OR10, and wherein R1Gis methyl.

135. The compound of any of claims 1-112, wherein R9is hydrogen.

136. The compound of any of claims 1-112, wherein Rsis methyl.

137. The compound of any of claims 1-112, wherein R9is a N-protecting group.

138. The compound of any of claims 1-23, wherein R1-R4are ail hydrogen.

139. The compound of any of claims 1-23, wherein R5and R8are hydrogen.

140. The compound of any of claims 1-23, wherein R2is halogen.

141. The compound of any of claims 1-23, wherein R4is halogen.

142. The compound of any of claims 1-23, wherein R2and R4are halogen.

143. The compound of any of claims 1-23, wherein R1and R2are halogen.

144. The compound of any of claims 1-23, wherein R2is halogen and R4is C1-C6 alkoxy.

145. The compound of any of claims 1-23, wherein R1and R2are halogen.

146. The compound of any of claims 1-23, wherein R1is halogen, Ch-Cs alkoxy, or Ch-Cs alkyl, and R2is halogen.

147. The compound of any of claims 1-23, wherein R2is hydrogen or halogen, and R3is trifluoromethyl.

148. The compound of any of claims 1-23, wherein R2is halogen, trifluoromethyl, C1-C3 alkyl or C1-C3 alkoxy, and R1, R3, R4, Rs, R7and R8are hydrogen.

149. The compound of any of claims 1-23, wherein R1-R5, R7and Rsare hydrogen.

150. The compound of any of claims 1-23, wherein R2is halogen, trifluoromethyl, C1-C3 alkyl or C1-C3 alkoxy, and R1, R3, R4, Rs, R6and Rsare hydrogen.

151. The compound of any of claims 1-23, R1-R6and Rsare hydrogen.

152. A compound of Formula (II):or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein:each of R1, R3, R4, and R8is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halo C1-C6 alkyl, or OR10, wherein R10is hydrogen, C1-C6 alkyl, Cs-Cs cycloalkyl, or halo C1-C6 alkyl;R5is hydrogen, hydroxy C1-C6 alkyl, or carboxy C1-C6 alkyl;R6Is hydrogen, hydroxy C1-C6 alkyl, -X-C(O)R13, -Y-C(O)NR14R15, -Z-NR16Ri7, heteroaryl, or -S(O)2R1s, whereinX is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloaikyi, halogen, hydroxy, or amino;R13is -OH or -OR10;Y is a bond, C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, halogen, hydroxy, or amino; each of R14and R1Sis independently hydrogen, C1-C6 alkyl, C3-C6 cycloaikyi, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl C3-C6 cycloalkylamino, C1-C6 amine, carboxy C1-C6 alkyl, -S(O)2R19, phenyl, heteroaryl ring structure, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyi group, whereinR19is C1-C6 alkyl; the phenyl is optionally substituted with C1-C6 alkyl; the heteroaryl is optionally substituted with C1-C6 alkyl; and the 3-8 membered monocyclic heterocyclyi group is optionally substituted with C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl;Z is a bond, C3-C6 cycloaikyi C1-C6 alkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloaikyi, halogen, hydroxy, or amino; each of R16and R17is independently hydrogen, C1-C6 alkyl, C3-C6 cycloaikyi, CrC3alkoxy CrCsalkyl, hydroxy C1-C6 alkyl, hydroxy CrC5alkoxy C1-C6 alkyl, halo C1-C6 alkyl, -(C1-C6 aikyi)-C(O)R20, -C(O)R21, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyi group, whereinR20is -OH, OR10, or NR22R23, wherein each R22and R23is independently hydrogen, C1-C6 alkyl, C3-C6 cycloaikyi, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or hydroxy C1-C6 alkyl C3-C6 cycloalkylamino;R21is hydrogen, C1-C6 alkyl, C3-C6 cycloalky!, C1-C6 alkoxy, C1-C6 aikoxy C1-C6 alkyl, hydroxy C1-C6 alkoxy C1-C6 alkyl, halo C1-C6 alkyl, or C1-C6 amine; and the 3-8 membered monocyclic heterocyclyl group is optionally substituted with C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C0 alkyl, amino C1-C6 alkyl; the heteroaryl is pyrazole or triazole, optionally substituted with C1-C6 alkyl; andR18is CrCsalkyl or -NH-(CrC6alkyl); andR7is hydrogen, halogen, -OR24, hydroxy C1-C6 alkyl, or -C(O)NR25R26, wherein: R24is C1-C6 alkyl, and each of R25and R2Sis independently hydrogen or hydroxy C1-C3 alkoxy C1-C3 alkyl;R9is hydrogen, C1-C6 alkyl, or a N-protecting group.

153. A compound of claim 1 , which is: methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazole-5-carboxylate; (2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methanol;5-((dimethylamino)methyl)-A / -(5-fluorobenzo[d]oxazo!-2-yl)benzo[d]oxazol-2- amine;5-((diethylamino)methyl)-A / -(5-fluorobenzo[d]oxazol-2-yl)benzo[d]oxazol-2- amine;2-(((2~((5~fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5- yl)methyl)(methyl)amino)ethan-1-ol;2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazole-5-carboxylic acid;2-((5-fluorobenzo[d]oxazol-2-yl)amino)- / V,A / -dimethylbenzo[d]oxazole-5- carboxamide;2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)propan-2-ol;5-fluoro- / V-(5-((rnethyl(2,2,2-trif!uoroethyl)amino)methyl)benzo[d]oxazol-2- yl)benzo[d]oxazol-2-amine;1-(2-((5~fluorobenzo[d]oxazol-2~yl)amino)benzo[d]oxazol~5~yl)ethan-1-ol;5-((dimethylamino)methyl)- / V-(5-fluorobenzo[d]oxazol-2-yl)-7- methoxybenzo[d]oxazol-2-amine;2-((5-((dimethySamino)methyl)benzo[d]oxazoi-2-y!)amino)-A / -(2- methoxyethyi)benzo[d]oxazole-5-carboxamide;5-((dimethylamino)methyl)-A / -(5-fluorobenzo[d]oxazol-2-yl)-7- methylbenzo[d]oxazoi-2-amine;5"((dimethyhmino)methy^)-7-fluoro-A / -(5”fluorobenzo[d]oxazob2- yi)benzo[d]oxazol-2-amine;A / -(5-((dimethylamino)methyl)benzo[d]oxazo!-2-yl)-5,7-difluorobenzo[d]oxazol-2- amine;A / -(5-((dimethySamino)methyl)benzo[d]oxazoi-2-y!)-5-fluoro-7- methoxybenzo[d]oxazol-2-amine;2-(2-((5-fluorobenzo[d]oxazo!-2-yi)amino)benzo[d]oxazok5-yl)acetic acid;A / -(5-((d!methyiamino)methyi)benzo[d]oxazol-2-yi)-5,7-d!fluorobenzo[d]oxazoi-2- mine;5"(1"(dimethyhmino)ethyl)-A / -(5”fluorobenzo[d]oxazoi-2-yi)benzo[d]oxazob2“ amine;2-(benzo[d]oxazol-2-ylamino)-A / -(2-(2-hydroxyethoxy)ethy!)benzo[d]oxazoie-5- carboxamide;5-((dimethySam!no)methyl)- / V-(5-fluorobenzo[d]oxazo!-2-yi)-6- methoxybenzo[d]oxazol-2-amine;A / -(5-((dimethylamino)methy!)benzo[d]oxazol-2-yl)-4,5-difluorobenzo[d]oxazol-2- amine;A / -(2-(2-hydroxyethoxy)ethyi)-2-((6-(trif!uoromethyS)benzo[d]oxazol-2- yl)amino)benzo[d]oxazole-5”Carboxamide;5-((dimethylamino)methyl)-A / -(5-methyibenzo[d]oxazol-2-y!)benzo[d]oxazoi-2- amine;541uoro- / V-(5-(morphoiinomethyl)benzo[d]oxazoi-2-y!)benzo[d]oxazoi-2-am!ne;A / -(5-((dimethylamino)methyl)benzo[d]oxazol-2-yi)-5-fluoro-4- methylbenzo[d]oxazol-2-amine;A / -(5-((d!methyiamino)methyi)benzo[d]oxazoi-2-yl)-5-fluoro-4- methoxybenzo[d]oxazoi-2-amine;(2-((5-f!uorobenzo[d]oxazo!-2-yi)(methyi)amino)benzo[d]oxazol-5-yS)methanol;(2-((5-f!uorobenzo[d]oxazo!-2-yi)amino)-6-methoxybenzo[d]oxazob5- yljmethanol;5-(azetidin-1-y!methyi)-A / -(5-fluorobenzo[d]oxazol-2-yi)benzo[d]oxazoi-2-amine;5-fluoro-A / -(5-((4-methySpiperazin-1-yl)methy!)benzo[d]oxazol-2- yl)benzo[d]oxazo!-2-amine;2-((5-fluorobenzo[d]oxazok2-yl)amino)-A / -(2-methoxyethyl)benzo[d]oxazo!e-5- carboxamide;2-((5-fluorobenzo[d]oxazoi-2-yl)am!no)-A / -methy!benzo[d]oxazo!e-5- carboxamide;2-((5-fluorobenzo[d]oxazol-2-y!)amino)benzo[d]oxazole-5-carboxamide;A / -(2-(d!methylamino)ethyi)-2-((5-fluorobenzo[d]oxazol-2- yi)amino)benzo[d]oxazoie-5-carboxamide;2-((5-fluorobenzo[d]oxazol-2-yi)amino)- / V-(2,2!2-trifluoroethyS)benzo[d]oxazole- 5-carboxamide;(2-((6-fluorobenzo[d]oxazol-2-yi)amino)benzo[d]oxazol-5-yi)methanoi;2-(2-((5-fluorobenzo[d]oxazo!-2-yi)amino)benzo[d]oxazoi-5-yl)- / V, / V- dimethylacetamide;A / -(2-aminoethy!)-2-((5-fluorobenzo[d]oxazol-2-yi)amino)benzo[d]oxazoie-5’ carboxamide;(2-((5-fluorobenzo[d]oxazo!-2-yi)amino)benzo[d]oxazo!-4-yi)methanoi;5-fluoro-A / -(5-(((2-methoxyethyi)amino)methyS)benzo[d]oxazol-2- yl)benzo[d]oxazo!-2-amine;(2-((5-methoxybenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methanoS;2-(2-((5-fluorobenzo[d]oxazol-2-yi)amino)benzo[d]oxazoi-5-yl)- / V- methyiacetamide;(2-((6-methy!benzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methanoi;5-fluoro-A / -(5-((methy!amino)methy0benzo[d]oxazol-2-y!)benzo[d]oxazok2- amine;5-fluoro-A / -(5-(((2!2,2-trifluoroethyi)amino)methyS)benzo[d]oxazol-2- yl)benzo[d]oxazo!-2-amine;5-((dimethylamino)methyl)-A / -(5-fluorobenzo[d]oxazol-2-y!)-A / - methyibenzo[d]oxazoi-2-amine;2-(2-((5-fluorobenzo[d]oxazo!-2-yi)amino)benzo[d]oxazoi-4-yl)acet!C acid;(7-chloro-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methanol;A / -((2-((5-fluorobenzo[d]oxazok2-y!)amino)benzo[d]oxazok5- yi)methyl)acetamide; / V-(5-(1H-pyrazoi-4-y!)benzo[d]oxazol-2-yl)-5-fluorobenzo[d]oxazoi-2-amine;A / -(2-((5-f!uorobenzo[d]oxazo!-2-yi)amino)benzo[d]oxazo!-5-yl)acetamide;1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)urea;A / -(5-(1H-pyrazol-5-y!)benzo[d]oxazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine;3-((2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methyl)-1!1- di methyl urea;3-(2-((5-fluorobenzo[d]oxazo!-2-yl)amino)benzo[d]oxazol-5-yl)-1 ,1-dimethylurea;2-((5-fluorobenzo[d]oxazol-2-yl)amino)-A / -(isoxazol-4-yl)benzo[d]oxazole-5- carboxamide;2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-y!)-A / -methylacetam!de;5-fluoro- / V-(5-(4-methyk4H-1,2!4-triazo!-3-yl)benzo[d]oxazol-2- yl)benzo[d]oxazol-2-amine;5-fluoro-A / -(5-(1-methyl-1H-1,2,4-triazo!-3-yi)benzo[d]oxazol-2- yl)benzo[d]oxazo!-2-amine;6-fluoro-2-((5-fluorobenzo[d]oxazol-2-y!)amino)-A / -methylbenzo[d]oxazole-5- carboxamide;A / -(5-(4H~1l2,4-triazol-3-yl)benzo[d]oxazol-2-yl)-5-fluorobenzo[d]oxazol-2-arriine;2-(2-((5-fluorobenzo[d]oxazo!-2-yi)amino)benzo[d]oxazoi-5-yl)- / V-(1-methy!-1H- pyrazo!-4-yl)acetamide;2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- / V-(2-methyl-2H-11213-triazol~4~yl)acetamide;2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- / V-(isoxazol-4- yl)acetamide; methyl (2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)carbamate;2-((5-fluorobenzo[d]oxazol-2-yl)am!no)-6-methoxy-A / -methylbenzo[d]oxazole-5- carboxamide;7-cyciopropyl-2-((5-fluorobenzo[d]oxazol-2-yl)am!no)-A / -methyibenzo[d]oxazole- 5-carboxamide;2-(2-((6-fluorobenzo[d]oxazo!-2-yl)amino)benzo[d]oxazol-5-yl)- / V- methylacetamide;2-(2-((6-fluorobenzo[d]oxazo!-2-yl)amino)benzo[d]oxazol-5-yl)acetic acid;2-(2-((5-fluorobenzo[d]oxazo!-2-yl)amino)benzo[d]oxazol-5-yl)-1- morpholinoethan-1-one;2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-A / -(2- hydroxyethyi)acetamide;(2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetyl)g!ycine;1-((2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methyl)-3- methylurea;2-(2-((6-methylbenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetic acid; / V-methyl-2-(2-((6-methylbenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5- yijacetamide;A / ,A / -d!methyl-2-(2-((6-methylbenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5- yl)acetamide;2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- / V- (methylsulfonyl)acetamide;1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- / V- methyicyclopropane- 1 -carboxamide;((2-((5-fluorobenzo[d]oxazol-2-y!)amino)benzo[d]oxazol-5-y!)methyl)glycine;1-((2-((5-f!uorobenzo[d]oxazo!-2-yl)amino)benzo[d]oxazo!-5-yl)methy!)urea;2-(2-((5-fluorobenzo[d]oxazo!-2-yi)amino)benzo[d]oxazoi-5-yl)propanoic acid;1-(2-((5-fluorobenzo[d]oxazoi-2-yl)amino)benzo[d]oxazol-5-yl)- / V, / V- dimethylcyciopropane-1 -carboxamide;1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)cyclopropane-1- carboxyiic acid;1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-A / -(2-(2- hydroxyethoxy)ethyl)cyciopropane-1-carboxamide;2-(benzo[d]oxazo!-2-yiamino)-N-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazo!e-5- carboxamide;2-(2-((5-fluorobenzo[d]oxazol-2-yi)amino)benzo[d]oxazoi-5-y!)-2- hydroxypropanoic acid;2-(2-((5-fluorobenzo[d]oxazoi-2-yi)amino)benzo[d]oxazoi-5-y!)-2-hydroxy- / V-(2- (2- h yd roxy ethoxy) ethyl ) propanam ide;2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazol-5-yl)acetic acid;2-(2-((5-fluorobenzo[d]oxazo!-2-yl)amino)-6-methoxybenzo[d]oxazol-5-y!)- / V-(2- (hydroxymethoxy)ethyl)acetamide; / V-((2-((5-fluorobenzo[d]oxazoi-2-y!)amino)benzo[d]oxazok5-y!)methyi)-2-(2- hydroxyethoxy)acetamide;2-(2-((5-fluorobenzo[d]oxazo!-2-yi)amino)benzo[d]oxazoi-5-y!)-A / -(2-(2- hydroxyethoxy)ethyl)propanamide;2-(benzo[d]oxazo!-2-ylamino)-A / -(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazole-6- carboxamide;2-(benzo[d]oxazo!-2-ylamino)- / V-(2-(2-hydroxypropoxy)ethy!)benzo[d]oxazole-5- carboxamide;2-(benzo[d]oxazol-2-ylamino)-A / -(1-(2-hydroxyethyl)pyrroiid!n-3- yl)benzo[d]oxazole-5-carboxamide;2-(benzo[d]oxazol-2-ylamino)-A / -(1-(2-hydroxyethy!)p!peridin-4- yl)benzo[d]oxazole-5”Carboxamide;A / -(2-(2-hydroxyethoxy)ethyi)-2-((6-methylbenzo[d]oxazol-2- yl)amino)benzo[d]oxazole-5-carboxamide;2-((6-fiuorobenzo[d]oxazoi-2-yl)amino)-A / -(2-(2- hydroxyethoxy)ethyi)benzo[d]oxazole-5-carboxamide;2-((6-chlorobenzo[d]oxazol-2-yl)amino)-A / -(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole-5-carboxamide; / V-(2-(2-hydroxyethoxy)ethyi)-2-((6-methoxybenzo[d]oxazoi-2- yi)amino)benzo[d]oxazoie-5-carboxamide;2-((6-(difluoromethyl)benzo[d]oxazol-2-yi)amino)- / V-(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole-5-carboxamide;2-((6-(dif!uoromethoxy)benzo[d]oxazol-2-yi)amino)-A / -(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole- 5- carboxamide;2-(((2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yi)methyl)amino)-A / -(2-(2- hydroxyethoxy)ethyl)acetamide;2-(((2-(benzo[d]oxazol-2-yiamino)benzo[d]oxazol-5-yi)methyi)(methyl)amino)-N- (2-(2-hydroxyethoxy)ethyl)acetamide;2-(2-(benzo[d]oxazol-2-ylamino)-6-(hydroxymethyi)benzo[d]oxazoi-5-yl)- / V-(2-(2- hy d roxy ethoxy) ethy I ) aceta m i de ;2-(2-(benzo[d]oxazoi-2-ylamino)-6-(2-hydroxypropan-2-yi)benzo[d]oxazol-5-yl)- A / -(2-(2-hydroxyethoxy)ethyi)acetamide;2-(benzo[d]oxazoi-2-yiamino)-A / -(2-(2-hydroxyethoxy)ethyl)-6- (hydroxymethyi)benzo[d]oxazole”5~carboxamide;2-(benzo[d]oxazoi-2-ylamino)- / V-(2-(2-hydroxyethoxy)ethyi)-6-(2-hydroxypropan- 2-yi)benzo[d]oxazoie-5-carboxamide;1-((2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)methyl)-3-hydroxy-N-(2-(2- hydroxyethoxy)ethyl)azetidine-3-carboxamide;2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)-N-(2-(2- hyd roxyethoxy)ethyl)acetami de;2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxyethoxy)ethyl)-N- methylbenzo[d]oxazole-5-carboxamide;2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxy-2- methylpropoxy)ethyl)benzo[d]oxazole-5-carboxamide;2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)-N,N-dimethyiacetamide;2-(2-(benzo[d]oxazoi-2-ylamino)benzo[d]oxazol-5-yl)-N-(2-(2- hydroxyethoxy)ethyl)-N-methylacetamide;N-[2-(2-hydroxyethoxy)ethyl]2-[2-(1 ,3-benzoxazol-2-ylamino)-1 ,3-benzoxazol-5- yl]propionamide;N-[2-(2-hydroxyethoxy)ethyl](R)-2-[2-(1!3-benzoxazol-2-ylamino)-1 ,3- benzoxazol-5-yl]propionamide;N-[2-(2-hydroxyethoxy)ethyl](S)-2-[2-(1 ,3-benzoxazol-2-ylamino)-1,3- benzoxazol-5-yi]propionamide;2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)-N-(2-(2- hydroxyethoxy)ethyl)-N-methylpropanamide;(R)-2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)-N-(2-(2- hydroxyethoxy)ethyl)-N-methylpropanamide;(S)-2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yi)-N-(2-(2- hydroxyethoxy)ethyl)-N-methylpropanamide;N-(5-((dimethylamino)methyl)benzo[d]oxazol-2-yl)-5-fluoro-7- methylbenzo[d]oxazol-2-amine; or a pharmaceutically acceptable salt thereof.

154. A pharmaceutical composition comprising a compound or salt of any of claims 1-153 together with a pharmaceutically acceptable carrier, excipient, or diluent.

155. A method of treating an inflammatory condition or oxidative stress, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-153 or a pharmaceutical composition of claim 154.

156. The method of claim 155, wherein the inflammatory condition or oxidative stress is aWood disorder.

157. The method of claim 156, wherein the blood disorder is a sickle cell related disorder, beta-thalassemia, hemoglobinopathies, or a myelodysplastic syndrome.

158. The method of claim 155, wherein the inflammatory condition or oxidative stress is an inflammatory bowel disease, an arthritic disease, or a neurodegenerative disorder.

159. The method of claim 155, wherein the inflammatory condition or oxidative stress is an autoinflammatory syndrome.

160. The method of claim 155, wherein the inflammatory condition or oxidative stress is an inflammation-related condition.

161. The method of claim 160, wherein the inflammation-related condition is Adult-Onset Still’s Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Macrophage Activation Syndrome (MAS), Autoinflammation with Infantile Enterocolitic (AIFEC), Bullous Pemphigoid, Pemphigus Vulgaris, Idiopathic Pulmonary Fibrosis (IPF), Non-Alcoholic Steatohepatitis (NASH), Systemic Lupus Erythematosus (SLE), Multiple Sclerosis, Alzheimer’s Disease, Parkinson’s Disease, Friedreich's ataxia, amyotrophic lateral sclerosis, cerebral nerve degenerative disease, Charcot-Marie-Tooth syndrome, Traumatic Brain Injury (TBI), inflammatory Bowel Disease (IBD), Rheumatoid Arthritis (RA), Cryopyrin-Associated Periodic Syndromes (CAPS), Vitiligo, Multiple Self-Healing Palmoplantar Carcinoma (MSPC), Autoimmune Addison’s Disease, Familial Mediterranean Fever (FMF), Autoimmune Thyroiditis, Stroke, Type 2 Diabetes (T2D), Osteoarthritis, Gout, Atherosclerosis, Hidradenitis Suppurativa, Psoriasis, Pyrin Diseases, or Sickle Ceil Disease.

162. The method of claim 155, wherein the inflammatory condition or oxidative stress is an infectious disease, an autoimmune disease, a cancer, a metabolic disorder, an eye disease, a liver disease, a renal disease, a cardiovascular disease, a skin disease, a mitochondrial disease, a hematological disorder, a muscle disease, or a neurological disease.

163. The method of claim 155, wherein the inflammatory condition or oxidative stress is a fibrotic disease.

164. The method of claim 163, wherein the fibrotic disease is a chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, bronchitis, asthma, chronic obstructivepulmonasy disease, idiopathic pulmonasy fibrosis, pulmonary bronchitis, bronchiectasis, pulmonary edema, emphysema, or sarcoidosis.

165. The method of claim 163, wherein the fibrotic disease is a liver fibrotic disease caused by alcoholic cirrhosis, steatosis, cholestasis, a drug side effect, a viral infection, or combinations thereof.

166. The method of claim 163, wherein the fibrotic disease is a skin fibrotic disease.

167. The method of claim 166, wherein the skin fibrotic disease is an autoimmune disease.

168. The method of claim 167, wherein the autoimmune disease is scleroderma or psoriasis.

169. The method of claim 155, wherein the inflammatory condition or oxidative stress is a diabetic condition.

170. The method of claim 169, wherein the diabetic condition is a Type 1 diabetes mellitus, a Type 2 diabetes mellitus, gestational diabetes, pre-diabetes, hyperglycemia, a metabolic syndrome, or a secondary condition resulting therefrom.

171. The method of claim 170, wherein the secondary condition is congestive heart failure or nephropathy.

172. The method of claim 155, wherein the inflammatory condition or oxidative stress is a cardiovascular disease.

173. The method of claim 172, wherein the cardiovascular disease is hypertension, heart failure, hypercholesterolaemia, atherosclerosis, arteriosclerosis, thrombosis, acute coronary thrombosis, deep vein thrombosis, peripheral vascular disease, congestive heart failure, acute coronary syndrome, failure of arterial fistula for dialysis, ischemia reperfusion injury, primary pulmonary hypertension, primary pulmonary arterial hypertension, or secondary pulmonary arterial hypertension.

174. The method of claim 155, wherein the inflammatory condition causes cell death, or release of pro-inflammatory cytokines or other inflammatory mediators, resulting from a coronavirus (e.g., SARS-CoV 2, SARS-CoV, or MERS), viral, bacterial, fungal, parasitic, or other type of infection in a subject.

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