Amp-activated protein kinase modulator compounds and uses thereof

Abstract

Compounds having activity as modulators of AMPK are provided. The compounds have Structure (I), (II), (III), or (IV): (I) (II) (III) (IV) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1a, R2, R3, W, X, Y, R4, R5, R6, X1, X2, X3, n, R8, R9, R10a, R10b, X4, ring A, R11, R12, R13a, R13b, and X5 are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of AMPK are also provided.

Description

[0001] AMP-ACTIVATED PROTEIN KINASE MODULATOR COMPOUNDS AND USES THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 662,310, filed June 20, 2024, entitled, “AMP-ACTIVATED PROTEIN KINASE MODULATOR COMPOUNDS AND USES THEREOF,” the entirety of which is hereby incorporated by reference.

[0004] BACKGROUND

[0005] Technical Field

[0006] Embodiments of the present disclosure are generally directed to compounds and methods for their preparation and use as therapeutic or prophylactic agents, for example for treatment of metabolic diseases and / or neurodegenerative diseases.

[0007] Description of Related Art

[0008] Adenosine monophosphate-activated protein kinase or AMP-activated protein kinase (AMPK) is a highly conserved serine / threonine protein kinase that acts as a central regulator of cellular energy homeostasis in eukaryotic cells. It is often referred to as a cellular energy sensor because its activation is triggered by a decrease in cellular ATP levels and an increase in the AMP to ATP ratio, indicating a state of cellular energy depletion. AMPK exists as a heterotrimeric protein complex composed of three subunits: a catalytic a subunit and regulatory P and y subunits. Each subunit has multiple isoforms encoded by distinct genes, resulting in a diverse array of AMPK complexes with tissue-specific functions.

[0009] When cellular energy levels are low, AMPK becomes activated through a two- step process. An increase in AMP levels allosterically activates AMPK by binding to its y subunit, promoting conformational changes that make the enzyme more sensitive to activation by upstream kinases, and phosphorylation of the a subunit at threonine- 172 (Thrl72) by upstream kinases, such as liver kinase Bl (LKB1) or calcium / calmodulin- dependent protein kinase kinase 2 (CaMKK2), further enhances AMPK activity.

[0010] Once activated, AMPK phosphorylates a wide range of downstream targets to restore cellular energy balance and promote energy conservation and production. Some of the key cellular processes regulated by AMPK include glucose uptake and glycolysis in skeletal muscle and other tissues while inhibiting glucose production in the liver. It promotes glucose transporter translocation to the cell membrane and phosphorylates enzymes involved in glycolysis and gluconeogenesis. AMPK stimulates fatty acid oxidation and inhibits lipogenesis, leading to reduced lipid accumulation in tissues. It phosphorylates and inactivates key enzymes involved in fatty acid synthesis and promotes the activation of enzymes involved in fatty acid oxidation and mitochondrial biogenesis.

[0011] AMPK inhibits protein synthesis by phosphorylating and inhibiting components of the mammalian target of rapamycin complex 1 (mTORCl) signaling pathway. This regulation helps conserve energy during times of cellular stress and nutrient deprivation. AMPK promotes mitochondrial biogenesis by phosphorylating transcriptional coactivators such as peroxisome proliferator-activated receptor gamma coactivator 1 -alpha (PGC-la), which in turn activates the transcription of genes involved in mitochondrial biogenesis and oxidative metabolism.

[0012] AMPK activation has implications for various physiological processes and diseases, including metabolism, cellular stress response, aging, obesity, type-2 diabetes, cardiometabolic, neurodegenerative diseases, and cancers. AMPK has emerged as an attractive target for the development of therapeutic interventions aimed at treating metabolic disorders and other related conditions.

[0013] Accordingly, there is a need to develop modulators (e.g., activators) that will directly target AMPK in several diseases, such as obesity, diabetes (e.g., type-2 diabetes), chronic inflammation, cardiometabolic diseases (e.g., cardiac energy homeostasis, ischemia-reperfusion injury, endothelial dysfunction, dyslipidemia, cardiac hypertrophy and remodeling), neuromuscular disorders (e.g., Duchenne muscular dystrophy), myotonic dystrophy type 1 (DM1), spinal muscular atrophy (SMA), non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases (e.g., Alzheimer’s disease), and / or cancer. Embodiments of the present disclosure fulfill this need and provide further related advantages.

[0014] BRIEF SUMMARY

[0015] In brief, embodiments of the present disclosure provide compounds, including pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, which are capable of modulating AMPK.

[0016] In one aspect, the disclosure provides compounds have Structure (I), (II), (III), or

[0017] (IV): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rla, R2, R3, W, X, Y, R4, R5, R6, X1, X2, X3, n, R8, R9, R10a, R10b, X4, ring A, R11, R12, R13a, R13b, and X5are as defined below.

[0018] In another aspect, pharmaceutical compositions comprising the disclosed compounds, and methods of use of the same for treatment of diseases (e.g., metabolic diseases, cancers, and / or neurodegenerative diseases) are also provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In the figures, identical reference numbers identify similar elements. The sizes and relative positions of elements in the figures are not necessarily drawn to scale. For example, the shapes of various elements and angles are not drawn to scale and some of these elements are enlarged and positioned to improve figure legibility. Further, the shapes of the elements as drawn, are not intended to convey any information regarding the actual shape of the elements and have been solely selected for ease of recognition in the figures.

[0020] FIGs. 1-4 show results for cells treated with differing doses of representative compounds of Structure (I) (z.e., compound 1-11 in FIG. 1 and compound 1-7 in FIG. 2) as well reference compounds (z.e., PF-06409577 in FIG. 3 and MK-8722 in FIG. 4). Compounds 1-11 and 1-7 show dose dependence for activation of insulin in human skeletal muscle cells (HSKM cells). Reference compounds show that AMPK activation that is highly variable when compared to compounds of Structure (I). Cells were starved for 3 hours in high glucose DMEM without FBS, then treated with indicated compounds in DMEM without FBS / glucose for 1 hour, and glucose uptake was detected using an uptake glucose kit (Promega). The bars show (from left to right) concentrations of 100 pM, 33 pM, 11 pM, 3.7 pM, 1.23 pM, 0.41 pM, 0.14 pM, 0.045 pM, 0.015 pM, 0.005 pM, 0 pM, and insulin.

[0021] FIGs. 5-8 show results for glucose update assays in Human white preadipocyte (HWP) cells (Promocell, cat. No. C-12735) when treated with compound 1-11 (FIG. 5), compound 1-7 (FIG. 6), MK-8722 (FIG. 7), and PF-06409577 (FIG. 8). HWP cells (subcutaneous upper arm of female Caucasian obese patient) were starved for 3 hours in DMEM without FBS, treated with the components noted above in high glucose DMEM without FBS / glucose for 1 hour, and glucose uptake was detected using a glucose uptake kit (Promega). It was unexpectedly discovered that compound 1-11 activates insulin in a dose dependent manner. The bars show (from left to right) concentrations of 100 pM, 33 pM, 11 pM, 3.7 pM, 1.23 pM, 0.41 pM, 0.14 pM, 0.045 pM, 0.015 pM, 0.005 pM, 0 pM, and insulin.

[0022] FIGs. 9-12 show results for glucose update assays in Human white preadipocyte (HWP) cells (Promocell, cat. No. C-12735) when treated with compound 1-11 (FIG. 9), compound 1-7 (FIG. 10), MK-8722 (FIG. 11), and PF-06409577 (FIG. 12). HWP cells (female abdomen cells) were starved for 3 hours in DMEM without FBS, treated with the components noted above in high glucose DMEM without FBS / glucose for 1 hour, and glucose uptake was detected using a glucose uptake kit (Promega). It was unexpectedly discovered that compound 1-7 activates insulin in a dose dependent manner. The bars show (from left to right) concentrations of 100 pM, 33 pM, 11 pM, 3.7 pM, 1.23 pM, 0.41 pM, 0.14 pM, 0.045 pM, 0.015 pM, 0.005 pM, 0 pM, and insulin.

[0023] FIGs. 13-16 show results for glucose update assays in THLE-2 cells (ATCC, cat. No. CRL-2706) when treated with compound 1-11 (FIG. 13), compound 1-7 (FIG. 14), MK-8722 (FIG. 15), and PF-06409577 (FIG. 16). The THLE-2 cells were starved for 3 hours in high glucose DMEM without FBS, treated with the components noted above in DMEM without FBS / glucose for 1 hour, and glucose uptake was detected using a glucose uptake kit (Promega). The bars show (from left to right) concentrations of 100 pM, 33 pM, 11 pM, 3.7 pM, 1.23 pM, 0.41 pM, 0.14 pM, 0.045 pM, 0.015 pM, 0.005 pM, 0 pM, and insulin.

[0024] FIGs. 17-19 show results for glucose update assays in human cardiomyocyte cells (“HCM” - healthy donor) (Promocell, cat. no. C-12810) when treated with compound 1-11 (FIG. 17), compound 1-7 (FIG. 18), and PF-06409577 (FIG. 19). After recovered HCM cells for 4 days, cells were starved for 3 hours in high glucose DMEM without FBS, treated with the components noted above in DMEM without FBS / glucose for 1 hour, and glucose uptake was detected using a glucose uptake kit (Promega). It was unexpectedly discovered that compounds of Structure (I) did not show AMPK activation activity in healthy donor cardiomyocyte cells, which indicates that activation activity is HSKM cell specific and indicates a good safety profile for healthy HCM cells. The reference compound (z.e., PF-06409577) demonstrated significant variability at the 10 doses that were tested. The bars show (from left to right) concentrations of 100 pM, 33 pM, 11 pM, 3.7 pM, 1.23 pM, 0.41 pM, 0.14 pM, 0.045 pM, 0.015 pM, 0.005 pM, 0 pM, and insulin.

[0025] FIGs. 20-22 show results for glucose update assays in human cardiomyocyte cells (“HCM” - diabetic donor) (Promocell, cat. no. C-12810) when treated with compound 1-11 (FIG. 20), compound 1-7 (FIG. 21), and PF-06409577 (FIG. 22). After recovered HCM cells for 4 days, cells were starved for 3 hours in high glucose DMEM without FBS, treated with the components noted above in DMEM without FBS / glucose for 1 hour, and glucose uptake was detected using a glucose uptake kit (Promega). It was unexpectedly discovered that compounds of Structure (I) did not show AMPK activation activity in healthy donor cardiomyocyte cells, which indicates that activation activity is HSKM cell specific and indicates a good safety profile for diabetic HCM cells. The reference compound (z.e., PF-06409577) demonstrated significant variability at the 10 doses that were tested. The bars show (from left to right) concentrations of 100 pM, 33 pM, 11 pM, 3.7 pM, 1.23 pM, 0.41 pM, 0.14 pM, 0.045 pM, 0.015 pM, 0.005 pM, 0 pM, and insulin.

[0026] FIG. 23 shows the effect compound 1-11 in db / db mice on fasted blood glucose at day 28. From left to right the columns show vehicle alone, group 2 (G2) treated with compound 1-11 at 30 mg / kg (po, QD) and group 3 (G3) treated with compound 1-11 at 50 mg (po, QD). Data is shown as Mean ± S.E.M. (n= 10), *P<0.5 and ***P<0.001, Significant difference as compared to vehicle Control (10 mL / kg); One-way ANOVA followed by Dunnett' s multiple comparisons test.

[0027] FIG. 24 shows animals fed blood glucose at day 14 when treated with (from left to right) 60% high fat diet (HFD) when treated with vehicle control (p.o.; q.d. - Group

[0028] 1 or Gl), 60% HFD when treated with compound 1-11 (at 30 mg / kg, p.o.; q.d. - Group

[0029] 2 or G2), and 60% HFD when treated with compound 1-11 (at 50 mg / kg, p.o.; q.d. - Group 3 or G3).

[0030] DETAILED DESCRIPTION

[0031] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details.

[0032] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is, as "including, but not limited to".

[0033] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ± 20%, ± 10%, ± 5% or ± 1% of the indicated range, value, or structure, unless otherwise indicated. The terms "a" and "an" as used herein refer to "one or more" of the enumerated components. The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0034] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0035] 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 disclosure belongs. As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

[0036] "Amino" refers to the -NH2 radical.

[0037] "Cyano" refers to the -CN radical.

[0038] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[0039] "Oxo" refers to the =0 substituent.

[0040] "Alkyl" refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (Ci-Cs alkyl) or one to six carbon atoms (Ci-Ce alkyl), or any value within these ranges, such as C4-C6 alkyl and the like, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, w-propyl,

[0041] 1 -methylethyl (Ao-propyl), / / -butyl, w-pentyl, 1,1 -dimethylethyl ( / -butyl), 3 -methylhexyl,

[0042] 2-methylhexyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted. "Alkoxy" refers to a radical of the formula -ORa where R is an alkyl radical as defined above containing one to twelve carbon atoms (C1-C12 alkoxy), one to eight carbon atoms (Ci-Cs alkoxy) or one to six carbon atoms (Ci-Ce alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0043] "Aromatic ring" refers to a cyclic planar molecule or portion of a molecule (z.e., a radical) with a ring of resonance bonds that exhibits increased stability relative to other connective arrangements with the same sets of atoms. Generally, aromatic rings contain a set of covalently bound co-planar atoms and comprises a number of 7t-electrons (for example, alternating double and single bonds) that is even but not a multiple of 4 (z.e., 4n + 2 ^-electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, pyrimidonyl. Unless stated otherwise specifically in the specification, an "aromatic ring" includes all radicals that are optionally substituted.

[0044] "Aryl" refers to a carbocyclic ring system radical comprising 6 to 18 carbon atoms, for example 6 to 10 carbon atoms (Ce-Cio aryl) and at least one carbocyclic aromatic ring. For purposes of embodiments of this disclosure, the aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, rz.s-indacene, -indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.

[0045] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C3-C15 cycloalkyl), from three to ten ring carbon atoms (C3-C10 cycloalkyl), or from three to eight ring carbon atoms (C3-C8 cycloalkyl), or any value within these ranges such as three to four carbon atoms (C3-C4 cycloalkyl), and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted.

[0046] "Fused" refers to any ring structure described herein which is fused to another ring structure.

[0047] "Halo" refers to bromo, chloro, fluoro, or iodo.

[0048] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0049] "Haloalkoxy" refers to a radical of the formula -ORa where R is an haloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a haloalkoxy group is optionally substituted.

[0050] "Hydroxy alkyl" refers to an alkyl radical, as defined above that is substituted by one or more hydroxyl radical. The hydroxyalkyl radical is joined to the remainder of the molecule through an alkyl carbon atom. Unless stated otherwise specifically in the specification, a hydroxyalkyl group is optionally substituted.

[0051] "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more -NH2 groups. The aminoalkyl radical is joined to the remainder of the molecule though an alkyl carbon atom. Unless stated otherwise specifically in the specification, an aminoalkyl group is optionally substituted.

[0052] "Heterocyclyl" refers to a 3- to 18-membered, for example 3- to 10-membered or 3- to 8-membered, non-aromatic ring radical having one to ten ring carbon atoms (e.g., two to ten) and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic and / or bridged ring systems. Nitrogen, carbon, and sulfur atoms in a heterocyclyl radical are optionally oxidized, and nitrogen atoms may be optionally quatemized. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro- 1H- pyrrolizine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and

[0053] 1,1-dioxo-thiomorpholinyl. The terms "O-heterocyclyl" and "N-heterocyclyl" refer to a heterocyclyl as defined above comprising at least one ring oxygen (e.g., oxirane, oxetane, tetrahydrofuran, dioxane, etc.) or at least one ring nitrogen (e.g., aziridine, pyrrolidine, morpholine, etc.), respectively. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted.

[0054] "Heteroaryl" refers to a 5- to 18-membered, for example 5- to 6-membered, ring system radical comprising one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl radicals may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (z.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[0055] The term "substituted" as used herein means any of the above groups (e.g., alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl, etc.) wherein at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxyalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents.

[0056] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to affect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and / or cell migration. The specific dose will vary depending on the compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0057] As used herein, "treatment" or "treating" refer to an approach for obtaining beneficial or desired results with respect to a disease, disorder or medical condition including but not limited to a therapeutic effect and / or a prophylactic effect. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0058] The term "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0059] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0060] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness of the free bases, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al.. "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-di sulfonic acid, ethanesulfonic acid, 2- hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo- glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2- sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, -toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0061] "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness of the free acids, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable base addition salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, Wethyl pi peri dine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0062] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts such as quaternary amine alkyl halide salts (e.g., methyl bromide). The term "inhibitor" refers to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein. Accordingly, the term "inhibitor" is defined in the context of the biological role of the target protein. In some embodiments, inhibitors specifically interact with (e.g., bind to) a target. In some embodiments, the biological activity inhibited is the development, growth, or spread of a tumor.

[0063] "Subject" refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0064] "Mammal" includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

[0065] "Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., compounds of Structure (I), (II), (III), or (IV)). Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergam on Press, 1987, both of which are incorporated in full by reference herein. The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or thiol group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.

[0066] The term "in vivo" refers to an event that takes place in a subject's body.

[0067] Embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of Structure (I), (II), (III), or (IV).

[0068] Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0069] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0070] Often crystallizations produce a solvate of the compounds disclosed herein. As used herein, the term "solvate" refers to an aggregate that comprises one or more compounds of the disclosure with one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. In some embodiments, the compounds of the disclosure are a true solvate, while in other cases, the compounds of the disclosure merely retain adventitious water or is a mixture of water plus some adventitious solvent.

[0071] "Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0072] A "pharmaceutical composition" refers to formulations of compounds of the disclosure and a medium generally accepted in the art for the delivery of compounds of the disclosure to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0073] "Pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.

[0074] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0075] The compounds of the disclosure (z.e., compounds of Structure (I), (II), (III), or (IV)) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and may thus give rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0076] Embodiments of the present disclosure include all manner of rotamers and conformationally restricted states of a compound of the disclosure. Atropisomers, which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included. As an example, certain compounds of the disclosure may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.

[0077] In some embodiments, the compounds of Structure (I), (II), (III), or (IV) are a mixture of enantiomers or diastereomers. In other embodiments, the compounds of Structure (I), (II), (III), or (IV) are substantially one enantiomer or diastereomer.

[0078] A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments thus include tautomers of the disclosed compounds.

[0079] The chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P. A.C. nomenclature system, using the ACD / Name Version 9.07 software program and / or ChemDraw Professional Version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.

[0080] “MK-8722” (or similar) is an AMPK activator catalogued under CAS Registry No. 1394371-71-1 and having the following structure:

[0081] “PF-06409577” (or similar) is an AMPK activator catalogued under CAS

[0082] Registry No. 1467057-23-3 and having the following structure: Compounds

[0083] The disclosure provides compounds including pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, which are capable of modulating AMPK.

[0084] Accordingly, one embodiment provides a compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

[0085] Y is N or CH;

[0086] X is N or CRlb; W is N or CRlc;

[0087] Rla, Rlb, and Rlcare each independently hydrogen or halo;

[0088] R2is 3-8 membered N-heterocyclyl, -NH-R2d, or has the following structure: Z is N or CR2b;

[0089] R2a, R2b, and R2care each independently hydrogen, optionally substituted C1-C4 alkoxy, -(CH2)niO(CH2)n2O(CH2)n3OH, -N=S(CH3)2=O, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3-8 membered heterocyclyl; R2dhas one of the following structures:

[0090] R2eis optionally substituted C3-C6 cycloalkyl;

[0091] R2fis halo or optionally substituted C3-C6 cycloalkyl; nl, n2, and n3 are each independently 1, 2, 3, or 4; and R3has one of the following structures:

[0092] One embodiment provides a compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Y is N or CH;

[0093] X is N or CRlb;

[0094] W is N or CR1C;

[0095] Rla, Rlb, and Rlcare each independently hydrogen or halo; R2is 3-8 membered N-heterocyclyl, -NH-R2d, or has the following structure:

[0096] R2® Z R2C

[0097] X T

[0098] Z is N or CR2b;

[0099] R2a, R2b, and R2care each independently hydrogen, optionally substituted C1-C4 alkoxy, -(CH2)niO(CH2)n2O(CH2)n3OH, -N=S(CH3)2=O, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3-8 membered heterocyclyl;

[0100] R2dhas one of the following structures:

[0101] R2eis optionally substituted C3-C6 cycloalkyl;

[0102] R2fis halo or optionally substituted C3-C6 cycloalkyl; nl, n2, and n3 are each independently 1, 2, 3, or 4; and

[0103] R3has one of the following structures: In some embodiments, Y is N. In certain embodiments, Y is CH. In some embodiments, X is N. In certain embodiments, X is CH, or CF. In some embodiments,

[0104] W is N or CH.

[0105] In certain embodiments, Rlais hydrogen, fluoro, or chloro.

[0106] In some embodiments, R2is a monocyclic 5-6 membered N-heterocyclyl. In some embodiments, R2is pyrrolidinyl. In certain embodiments, R2is optionally substituted with one or more -OH substituents. In certain embodiments, R2has one of the following structures:

[0107] In some embodiments, R2ais methoxy. In certain embodiments, R2cis C3-C6 cycloalkyl optionally substituted with one or more -OH substituents. In some embodiments, R2cis a 3-6 membered O-heterocyclyl or a 3-6 membered N-heterocyclyl each being optionally substituted with one or more -OH substituents. In some embodiments, R2a, R2c, or both are independently methoxy, -N=S(CH3)2=O, or have one of the following structures:

[0108] In some embodiments, R2has one of the following structures:

[0109] In certain embodiments, R2is -NH-R2d. In some embodiments, R2has one of the following structures: In some embodiments, R2has one of the following structures:

[0110] In certain embodiments, R3has one of the following structures:

[0111] In some embodiments, R3has one of the following structures: In some embodiments, R3has one of the following structures:

[0112] In certain embodiments, R3has one of the following structures: In certain embodiments, R3has one of the following structures:

[0113] In some embodiments, R3has one of the following structures:

[0114] In various embodiments, the compound has one of the structures set forth in Table 1A below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, isotopologue, hydrate, or prodrug thereof. Compounds in Table 1A were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or *HNMR.

[0115] Table 1A. Representative compounds of Structure (I)

[0116] One embodiment provides a compound of having the following Structure (II): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X1is N or CR7;

[0117] X2is N or CH;

[0118] X3is -NH-, -O-, or -S-;

[0119] R4is optionally substituted C3-C6 cycloalkyl or -N=S(R4a)2=O, wherein R4ais, at each occurrence, independently C1-C4 alkyl; R5is hydrogen or halo;

[0120] R6is, at each occurrence, independently optionally substituted C1-C4 alkyl, optionally substituted 5-membered heterocyclyl;

[0121] R7is hydrogen or halo; and n is 0, 1, or 2.

[0122] One embodiment provides a compound of having the following Structure (II): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

[0123] X1is N or CR7;

[0124] X2is N or CH;

[0125] X3is -NH-, -O-, or -S-;

[0126] R4is optionally substituted C3-C6 cycloalkyl, -N=S(R4a)2=O, or optionally substituted phenyl, wherein R4ais, at each occurrence, independently C1-C4 alkyl;

[0127] R5is hydrogen or halo;

[0128] R6is, at each occurrence, independently optionally substituted C1-C4 alkyl, optionally substituted 5-membered heterocyclyl, or two occurrences of R6join, together with the carbons to which they are attached to form a 4-6 membered heterocyclyl;

[0129] R7is hydrogen or halo; and n is 0, 1, 2, or 3.

[0130] In some embodiments, X1is N. In certain embodiments, X1is CF. In some embodiments, X1is N. In certain embodiments, X1is CF of CH. In some embodiments, X2is N. In certain embodiments, X2is CH. In some embodiments, X3is -NH-. In certain embodiments, X3is -O-. In certain embodiments, X3is -S-.

[0131] In some embodiments, R4is C3-C6 cycloalkyl optionally substituted with -OH. In certain embodiments, R4has the following structure: In certain embodiments, R4is -N=S(R4a)2=O and both occurrences of R4aare - CH3. In some embodiments, R4is unsubstituted phenyl.

[0132] In some embodiments, R5is fluoro. In some embodiments, R5is fluoro or chloro. In certain embodiments, one occurrence of R6is -CH3. In some embodiments, one occurrence of R6is 5-membered heterocyclyl optionally substituted with oxo. In certain embodiments, one occurrence of R6has the following structure:

[0133] In certain embodiments, one occurrence of R6has one of the following structures:

[0134] In some e , res: In certain embodiments, n is 1. In some embodiments, n is 2.

[0135] In various embodiments, the compound has one of the structures set forth in Table IB below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, isotopologue, hydrate, or prodrug thereof. Compounds in Table IB were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or 'H NMR.

[0136] Table IB: Representative compounds of Structure (II)

[0137] One embodiment provides a compound having the following Structure (III): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

[0138] X4is N or CH;

[0139] R8is optionally substituted C3-C6 cycloalkyl or -N=S(R8a)2=O wherein R8ais, at each occurrence, independently C1-C4 alkyl;

[0140] R9is optionally substituted 5-membered heterocyclyl; and R10aand R10bare each independently hydrogen or halo.

[0141] In some embodiments, R8is C3-C6 cycloalkyl optionally substituted with -OH.

[0142] In certain embodiments, R8has the following structure:

[0143] In certain embodiments, R8is -N=S(R8a)2=O and both occurrences of R8aare - CH3. In some embodiments, R9has the following structure:

[0144] In certain embodiments, R10aand R10bare both fluoro.

[0145] In various embodiments, the compound has one of the structures set forth in Table 1C below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, isotopologue, hydrate, or prodrug thereof. Compounds in Table 1C were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or 'H NMR. Table 1C: Representative compounds of Structure (III)

[0146] One embodiment provides a compound having the following Structure (IV): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: ring A is phenyl or dihyroindenyl;

[0147] X5is N or CH;

[0148] Rl lais optionally substituted C3-C6 cycloalkyl or -N=S(Rl la)2=O wherein Rl lais, at each occurrence, independently C1-C4 alkyl;

[0149] R12is optionally substituted 5-membered heterocyclyl; and

[0150] R13aand R13bare each independently hydrogen or halo.

[0151] In some embodiments, X5is N. In certain embodiments, R11is C3-C6 cycloalkyl optionally substituted with -OH. In certain embodiments, R11has the following structure:

[0152] In some embodiments, R11is -N=S(Rl la)2=O and both occurrences of Rllaare -

[0153] CH3.

[0154] In certain embodiments, has one of the following structures:

[0155] In some embodiments, R12has one of the following structures:

[0156] In certain embodiments, R13aand R13bare both fluoro.

[0157] In various embodiments, the compound has one of the structures set forth in Table ID below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, isotopologue, hydrate, or prodrug thereof. Compounds in Table ID were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or 'H NMR.

[0158] Table ID: Representative compounds of Structure (IV)

[0159] It is understood that in the present description, combinations of substituents and / or variables of the depicted formulae are permissible only if such contributions result in stable compounds.

[0160] In an additional embodiment, various compounds of the disclosure which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the disclosure can be converted to their free base or acid form by standard techniques.

[0161] Methods for producing the compounds described herein is provided below. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described herein.

[0162] It will also be appreciated by those skilled in the art that in the processes for preparing the compounds described herein the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include, but are not limited to, hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, Lbutyldimethylsilyl, Lbutyldiphenylsilyl or trimethyl silyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include Lbutoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or arylalkyl), / ?-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups are optionally added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.

[0163] It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this disclosure may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the disclosure which are pharmacologically active. Such derivatives may therefore be described as "prodrugs." Prodrugs of compounds of this disclosure are included within the scope of embodiments of the disclosure. Pharmaceutical Compositions

[0164] Other embodiments are directed to pharmaceutical compositions. The pharmaceutical composition comprises anyone (or more) of the foregoing compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent). Non-limiting examples of such therapeutic agents are described herein below.

[0165] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0166] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with and organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically.

[0167] In treatment methods according to embodiments of the disclosure, an effective amount of at least one compound of Structure (I), (II), (III), or (IV) is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. Effective amounts or doses may be ascertained by methods such as modeling, dose escalation studies or clinical trials, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.

[0168] The compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 10 to 5000 mg, from 100 to 5000 mg, from 1000 mg to 4000 mg per day, and from 1000 to 3000 mg per day are examples of dosages that are used in some embodiments. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0169] In some embodiments, compounds of the disclosure are administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, to introduce the agent quickly. However, other routes are used as appropriate. A single dose of a compound of the disclosure may also be used for treatment of an acute condition.

[0170] In some embodiments, compounds of the disclosure are administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment compounds of the disclosure and another agent (e.g., anti-cancer agent) are administered together about once per day to about 6 times per day. In another embodiment the administration of compounds of the disclosure and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0171] Administration of compounds of the disclosure may continue as long as necessary. In some embodiments, compounds of the disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, compounds of the disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, compounds of the disclosure are administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. In some embodiments, the compounds of the disclosure are administered in individual dosage forms. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy.

[0172] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the disclosed compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999).

[0173] Provided herein are pharmaceutical compositions comprising one or more compounds of Structure (I), (II), (III), or (IV), and a pharmaceutically acceptable carrier.

[0174] Provided herein are pharmaceutical compositions comprising one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of Structure (I), (II), (III), or (IV).

[0175] In a certain embodiment, pharmaceutical compositions of the compounds of Structure (I), (II), (III), or (IV) are modulators of AMPK. In some embodiments, pharmaceutical compositions of compounds of Structure (I), (II), (III), or (IV) are activators for AMPK.

[0176] A pharmaceutical composition, as used herein, refers to a mixture of one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, therapeutically effective amounts of one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0177] In one embodiment, one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) are formulated in aqueous solutions. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0178] In another embodiment, compounds described herein are formulated for oral administration. Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0179] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0180] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0181] In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0182] In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0183] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient, and one or more compounds selected from compounds of Structure (I), (II), (III), or (IV), described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0184] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semisolid compositions include, but are not limited to, gels, suspensions, and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[0185] In some embodiments, pharmaceutical compositions comprising one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically, when the composition is administered as a suspension, a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0186] In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0187] Pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of one or more compounds selected from compounds of Structure (I), (II), (III), or (IV). The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0188] Furthermore, pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[0189] Compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0190] Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride. Compositions may include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

[0191] Compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0192] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0193] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0194] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and / or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan poly sulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0195] In some embodiments, the concentration of one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) provided in the pharmaceutical compositions of the present disclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0196] In some embodiments, the concentration of one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) provided in the pharmaceutical compositions of the present disclosure is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v.

[0197] In some embodiments, the amount the one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) provided in the pharmaceutical compositions of the present disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[0198] In some embodiments, the amount of the one or more compounds selected from compounds of Structure (I), (II), (III), or (IV) provided in the pharmaceutical compositions of the present disclosure is in the range of 0.0001-10 g, 0.0005-9 g, 0.001- 8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0199] Packaging materials for use in packaging pharmaceutical compositions described herein include those found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0200] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.

[0201] For example, the pack may (1) contain metal or plastic foil (e.g., a blister pack), (2) be accompanied by instructions for administration, (3) be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound of Structure (I), (II), (III), or (IV) formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0202] Methods

[0203] Embodiments of the present disclosure provide compounds that are useful as AMPK modulators in a host species. Therefore, the compounds of Structure (I), (II), (III), or (IV) are also useful in the treatment of conditions mediated by AMPK.

[0204] The host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats, hamsters, rabbits, horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease.

[0205] In one embodiment, the present disclosure is useful as a modulator of AMPK. Therefore, the compounds of Structure (I), (II), (III), or (IV) are also useful in the treatment of conditions resulting from under expression of AMPK activity.

[0206] Embodiments also relate to the use of compounds according to Structure (I), (II), (III), or (IV) and / or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and / or monitoring of diseases that are caused, mediated, and / or modulated by AMPK. Furthermore, embodiments relate to the use of compounds according to Structure (I), (II), (III), or (IV) and / or physiologically acceptable salts thereof to produce a medicament for the prophylactic or therapeutic treatment and / or monitoring of diseases that are caused, mediated, and / or modulated by AMPK. In certain embodiments, the disclosure provides the use of a compound according to Structure (I), (II), (III), or (IV) or physiologically acceptable salts thereof, to produce a medicament for the prophylactic or therapeutic treatment of an AMPK-mediated disorder.

[0207] In another embodiment, the present disclosure relates to a method of treating diseases or conditions mediated by AMPK by administering to a patient in need thereof a therapeutically effective amount of the compound of Structure (I), (II), (III), or (IV).

[0208] One embodiment provides a method of treating an AMPK mediated disease, the method comprising administering the compound of Structure (I), (II), (III), or (IV), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof or a pharmaceutical composition comprising a compound of Structure (I), (II), (III), or (IV).

[0209] In some embodiments, the AMPK mediated disease is a cardiometabolic disease, a neuromuscular disorder, a cancer, a neurodegenerative disease, or combinations thereof. In certain embodiments, the AMPK mediated disease is obesity, diabetes, chronic inflammation, cardiac energy homeostasis, ischemia-reperfusion injury, endothelial dysfunction, dyslipidemia, cardiac hypertrophy and remodeling, Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), spinal muscular atrophy (SMA), Non-alcoholic Fatty Liver Disease (NAFLD), Alzheimer’s disease, or combinations thereof.

[0210] Also included herein are methods of treatment in which at least one compound of Structure (I), (II), (III), or (IV) is administered in combination with an anti-inflammatory or a therapeutic agent. Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) antagonists, immunosuppressants and methotrexate. Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Still other embodiments of the disclosure pertain to combinations in which at least one active agent is an immunosuppressant compound such as an immunosuppressant compound chosen from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and my cophenolate mofetil.

[0211] The disclosed compounds of Structure (I), (II), (III), or (IV) can be administered in combination with other known therapeutic agents, including anticancer agents. As used here, the term "anticancer agent" relates to any agent which is administered to a patient with cancer for the purposes of treating the cancer.

[0212] In some embodiments the anti-cancer agents belong to the following categories

[0213] Alkylating agents: such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH- 3024, VAL-0834;

[0214] Platinum Compounds: such as carboplatin, cisplatin, eptaplatin, miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;

[0215] DNA altering agents: such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, or laromustine;

[0216] Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, or voreloxin;

[0217] Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, or tesetaxel;

[0218] Antimetabolites: such as asparaginase3, azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur, or trimetrexate; Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin; aclarubicin, peplomycin, or pirarubicin;

[0219] Hormones / Antagonists: such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone fluoxy me sterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol, orteronel, or enzalutamide;

[0220] Aromatase inhibitors: such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, or formestane;

[0221] Small molecule kinase inhibitors: such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifamib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, or cediranib.

[0222] In some embodiments, medicaments which are administered in conjunction with the compounds described herein include any suitable drugs usefully delivered by inhalation for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti-infectives, e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine; antihistamines, e.g. methapyrilene; antiinflammatories, e.g. beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5-dichloro-a-[[[6-[2- (2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g., insulin. It will be clear to a person skilled in the art that, where appropriate, the medicaments are used in the form of salts (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and / or stability of the medicament.

[0223] The agents disclosed herein, or other suitable agents are administered depending on the condition being treated. Hence, in some embodiments the one or more compounds of the disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the disclosure and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of the disclosure and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

[0224] In some embodiments, the compounds of Structure (I), (II), (III), or (IV) are administered as a monotherapy.

[0225] In some embodiments, the methods of the disclosure can be performed either in vitro, in vivo, or as a combination thereof. The susceptibility of a particular cell to treatment with the compounds of Structure (I), (II), (III), or (IV) can be particularly determined by in vitro tests, whether during research or clinical application. Typically, a culture of the cell is combined with a compound at various concentrations for a period which is sufficient to allow the active agents to modulate AMPK activity, usually between about one hour and one week. In vitro treatment can be carried out using cultivated cells from a biopsy sample or cell line.

[0226] In some embodiments, the IC50 of the compounds of Structure (I), (II), (III), or (IV) to modulate AMPK was determined by the concentration of the compound required to modulate 50% of the activity of AMPK.

[0227] It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below, other compounds of Structure (I), (II), (III), or (IV) not specifically illustrated below by using the appropriate starting components and modifying the parameters of the synthesis as needed. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described in this disclosure.

[0228] The following examples are provided for purpose of illustration and not limitation.

[0229] Abbreviations'.

[0230] °C (degree Celsius);JH NMR (proton Nuclear Magnetic Resonance); DCM (dichloromethane); DMSO (dimethylsulfoxide); eq (equivalent); EtOAc (ethyl acetate); g (gram); h (hour); MeOH (methanol); mg (milligram); min (minute); mL (milliliter); mmol (millimole); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (Thin Layer Chromatography); LDA (lithium diisopropylamide); AcOH (acetic acid); mCPBA (3- chloroperbenzoic acid). SYNTHETIC EXAMPLE 1

[0231] SYNTHESIS OF 3-(6-CHLORO-5-(4-(1-HYDROXYCYCLOBUTYL) PHENYL)-1H-INDOL-3-YL)-

[0232] 1,2,4-OXADIAZOL- 5(4H) -ONE

[0233] Synthesis of l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl) cyclobutan-l-ol

[0234] In a sealed tube to a degassed solution of l-(4-bromophenyl)cyclobutan-l-ol (500 mg, 2.20 mmol, 1.0 eq) and B2(pin)2 (671 mg, 2.64 mmol, 1.2 eq) in tetrahydrofuran ("THF" - 10 mL) at room temperature, was added potassium acetate ("KOAc" - 647 mg, 6.60 mmol, 3.0 eq), Pd(dppf)C12 (80 mg, 0.11 mmol, 0.05 eq) and stirred at 80 °C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with ethyl acetate ("EtOAc" - 10 mL), collected filtrate was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 1 -(4, 4, 5, 5 -tetramethyl- 1,3,2- dioxaborolan-2-yl) phenyl) cyclobutan-l-ol as black gummy solid (500 mg, Yield: Crude).

[0235] TLC system: EtOAc / Hexane (30:70)

[0236] Rf value : ~0.5

[0237] 'H NMR (400 MHz, CDC ) 5: 7.83 (d, J= 8.0 Hz, 2H), 7.51 (d, J= 8.0 Hz, 2H), 2.57-2.53 (m, 2H), 2.41-2.34 (m, 2H), 2.08-1.98 (m, 2H), 1.35 (s, 12H)

[0238] Synthesis of 5-bromo-6-chloro-lH-indole-3-carbaldehyde

[0239] To a stirred solution of 5-bromo-6-chloro-lH-indole (3 g, 13.04 mmol, 1.0 eq) in DMF (3 mL) at room temperature, was added POCh (2.43 mL, 26.1 mmol, 2.0 eq) and stirred at 90°C for 1 h. After completion of reaction by TLC, reaction mixture was treated with IN NaOH solution (10 mL) and stirred at 95°C for 10 min. Solid precipitation observed, filtered, washed with diethyl ether (50 mL) and dried under vacuum to afford 5-bromo-6-chloro-lH-indole-3-carbaldehyde as pink solid (3.0 g, Yield: 92%).

[0240] TLC system: EtOAc / Hexane (30:70)

[0241] Rf value: ~0.4;

[0242] LCMS(m / z): 259.8 (M+H)+

[0243] 'HNMR (400 MHz, DMSO-dd) 5: 12.34 (s, 1H), 9.93 (s, 1H), 8.40 (s, 1H), 8.39 (s, 1H), 7.80 (s, 1H)

[0244] Synthesis of 5-bromo-6-chloro-lH-indole-3-carbonitrile

[0245] To a stirred solution of 5-bromo-6-chloro-lH-indole-3-carbaldehyde (3 g, 11.5 mmol, 1.0 eq) in Pyridine (15 mL) at room temperature, was added AC2O (2.2 mL, 23.1 mmol, 2.0 eq), NH2OH.HCI (888 mg, 12.7 mmol, 1.1 eq) and stirred at 90°C for 2 h. After completion of reaction by TLC, reaction mixture was quenched with 2 N HC1 solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude product was triturated with diethyl ether (10 mL), decanted, and dried under reduced pressure to afford 5-bromo-6-chloro-lH-indole-3-carbonitrile as an off white solid (2.2 g, Yield: Crude).

[0246] TLC system: EtOAc / Hexane (50:50)

[0247] Rf value: -0.4; LCMS(m / z): 253.0 (M-H)+ Synthesis of (Z)-5-bromo-6-chloro-N'-hydroxy-lH-indole-3-carboximidamide

[0248] To a stirred solution of 5-bromo-6-chloro-lH-indole-3-carbonitrile (1.1 g, 4.33 mmol, 1.0 eq) in EtOH (11 mL) at room temperature, was added triethyl amine ("EtsN" - 1.0 mL, 6.49 mmol, 1.5 eq) and NEEOH.HCl (451 mg, 6.49 mmol, 1.5 eq). The reaction mixture was stirred at 80°C for 4 h. After completion of reaction by TLC, reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200) column chromatography [elution with 60% EtOAc in Hexane] to afford (Z)-5-bromo-6-chloro-N'-hydroxy-lH-indole-3-carboximidamide as an off white solid (720 mg, Yield: 55%).

[0249] TLC system: EtOAc / Hexane (70:30)

[0250] Rf value : ~0.4

[0251] ‘HNMR (400MHz, DMSO-de) 5: 11.51 (s, 1H), 9.36 (s, 1H), 8.45 (s, 1H), 7.87 (d, J= 2.8 Hz, 1H), 7.65 (s, 1H), 5.69 (s, 2H).

[0252] Synthesis of 3-(5-bromo-6-chloro-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0253] To a stirred solution of (Z)-5-bromo-6-chloro-N'-hydroxy-lH-indole-3- (720 mg, 2.55 mmol, 1.0 eq) in dichloromethane ("DCM" - 21.6 mL, 30 Vol) at 0°C, was added EtsN (0.5 mL, 3.31 mmol, 1.3 eq) and Ethyl chloroformate (0.3 mL, 3.06 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, e reaction mixture was quenched with NaHCCh solution (20 mL) and extracted with DCM (2 x 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford crude. The crude was dissolved in DMSO (2.5 mL), treated with NaOH (96 mg, 2.40 mmol, 1.2 eq) and stirred for 3 h. Later, diluted with water (20 mL), quenched with 2N HC1 solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase column chromatography [elution with 30% acetonitrile ("ACN") in 0.1% formic acid ("FA") in FLO] to afford 3-(5-bromo-6- chloro-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as brick red solid (300 mg, Yield: 37%).

[0254] TLC system: EtOAc / Hexane (70:30) Rf value : ~0.3

[0255] LCMS(m / z): 314.0 (M+H)+

[0256] Synthesis of 3-(6-chloro-5-(4-(l-hydroxy cyclobutyl) phenyl)-lH-indol-3-yl)-l,2,4- oxadi azol - 5 (4H)-one

[0257] In a sealed tube to a degassed solution of 3-(5-bromo-6-chloro-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one (200 mg, 0.64 mmol, 1.0 eq) and l-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (262 mg, 0.95 mmol, 1.5 eq) in ACN:H2O (1 :1, 2 mL) at room temperature, was added K2CO3 (176 mg, 1.28 mmol, 2.0 eq), Pd(dppf)C12 (46 mg, 0.064 mmol, 0.1 eq) and stirred at 80°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase column chromatography [elution with 25% ACN in 0.1% FA in H2O] followed by Prep-HPLC and lyophilizing the fractions afforded 3-(6-chloro-5-(4-(l-hydroxy cyclobutyl) phenyl)-lH-indol-3-yl)-l,2,4- oxadiazol-5(4H)-one as white solid (31 mg, Yield: 25%).

[0258] TLC system: EtOAc / Hexane (70:30)

[0259] Rf value: ~0.4

[0260] LCMS(m / z): 380.0 (M-H)+

[0261] 'HNMR (400 MHz, DMSO-de) 5: 12.03 (s, 1H), 12.02 (s, 1H), 8.04 (d, J= 2.8 Hz, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.57 (d, J= 8.4 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 5.54 (s, 1H), 2.47-2.42 (m, 2H), 2.34-2.27 (m, 2H), 1.98-1.91 (m, 1H), 1.75-1.70 (m, 1H).

[0262] SYNTHETIC EXAMPLE 2

[0263] SYNTHESIS OF (S)-1-(6-CHLORO-5-(4-(1-HYDROXYCYCLOBUTYL) PHENYL)- 1H-INDOL-3- YL)-4-METH YL-4, 5 -DIH YDRO-3H- 1 L6,2, 5 -THIADIAZOL-3 -ONE 1 -OXIDE

[0264] Synthesis of 5-bromo-6-chloro-lH-indole-3-sulfonyl chloride

[0265] To a stirred solution of 5-bromo-6-chloro-lH-indole (6 g, 26.1 mmol, 1.0 eq) in MeCN (150 mL) at 0°C, was added CISO3H (17 mL, 31.3 mmol, 1.2 eq) and stirred at room temperature for 1 h. After observing conversion by TLC, reaction mixture was concentrated, diluted with water (70 mL) and extracted with EtOAc (2 * 70 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude product was triturated with n-pentane (50 mL), decanted, and dried under vacuum to afford 5-bromo-6-chloro-lH-indole-3-sulfonyl chloride as pale yellow solid (6 g, Yield: Crude).

[0266] TLC system: EtOAc / Hexane (20:80)

[0267] Rf value : ~ 0.4

[0268] LCMS (m / z): 308.5 (M-H of sulfonic acid)+

[0269] 'HNMR (400 MHz, CDC ) 5: 9.12 (s, 1H), 8.32 (s, 1H), 7.99 (d, J= 3.2 Hz, 1H), 7.66 (s, 1H).

[0270] Synthesis of 5-bromo-6-chloro-lH-indole-3-sulfonamide

[0271] To a stirred solution of 5-bromo-6-chloro-lH-indole-3-sulfonyl chloride (6.0 g, 18.2 mmol, 1.0 eq) in THF (120 mL) at 0°C, NH3 gas was purged for 30 min. Later, the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-pentane (50 mL), decanted, and dried under vacuum to afford 5-bromo-6-chloro-lH- indole-3 -sulfonamide as off white solid (4.5 g, Yield: 56%).

[0272] TLC system: EtOAc / Hexane (50:50)

[0273] Rf value: ~0.3

[0274] LCMS (m / z): 306.7 (M-H)+

[0275] 'HNMR (400 MHz, CDCls) 5: 12.01 (s, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.29 (s, 2H).

[0276] Synthesis of 5-bromo-N-(tert-butyldimethylsilyl)-6-chloro-lH-indole-3-sulfonamide To a stirred solution of 5-bromo-6-chloro-lH-indole-3-sulfonamide (4.5 g, 14.6 mmol, 1.0 eq) in THF (50 mL) at room temperature, was added EtiN (10.2 mL, 73.3 mmol, 5.0 eq) and TBDMS-C1 (8.8 g, 58.6 mmol, 4.0 eq). The reaction mixture was stirred at 50°C for 48 h. After completion of reaction by TLC, the reaction mixture was diluted with ice cold water (40 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200) column chromatography [elution with 20-25% EtOAc in Hexane] to afford 5-bromo-N-(tert-butyldimethylsilyl)-6-chloro-lH-indole-3-sulfonamide as pale yellow solid (1.0 g, Yield: 16%).

[0277] TLC system: EtOAc / Hexane (50:50)

[0278] Rf value: ~0.5

[0279] LCMS (m / z): 425.1 (M+H)+

[0280] 'HNMR (400 MHz, CDC ) 5: 8.63 (s, 1H), 8.19 (s, 1H), 7.70 (d, J= 2.8 Hz, 1H), 7.57 (s, 1H), 4.40 (s, 1H), 0.89 (s, 9H), 0.22 (s, 6H).

[0281] Synthesis of tert-butyl 5-bromo-3-(N-(tert-butyldimethylsilyl) sulfamoyl)-6-chloro-lH- indole- 1 -carboxylate

[0282] To a stirred solution of 5-bromo-N-(tert-butyldimethylsilyl)-6-chloro-lH- indole-3 -sulfonamide (1.0 g, 2.37 mmol, 1.0 eq) in DCM (5 mL) at 0°C, was added EtiN (0.8 mL, 5.92 mmol, 2.5 eq), (Boc)2O (0.6 mL, 4.74 mmol, 2.0 eq) followed by DMAP (86 mg, 0.71 mmol, 0.3 eq). The reaction mixture was stirred at room temperature for 3 h. After completion of reaction by TLC, e reaction mixture was diluted with ice cold water (30 mL) and extracted with DCM (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel (100 - 200) column chromatography [elution with 10 - 15% EtOAc in Hexane] to afford tert-butyl 5-bromo-3-(N-(tert-butyldimethylsilyl) sulfamoyl)-6-chloro-lH-indole-l-carboxylate as off white solid (1 g, Yield: 80%).

[0283] TLC system: EtOAc / Hexane (20:80)

[0284] Rf value: ~0.6

[0285] 'HNMR (400 MHz, CDC ) 5: 8.41 (s, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 4.54 (s, 1H), 1.72 (s, 9H), 0.96 (s, 9H), 0.30 (s, 6H).

[0286] Synthesis of tert-butyl (S)-5-bromo-3-(N'-(tert-butyldimethylsilyl)-N-(l-methoxy-l- oxopropan-2-yl) sulfamidimidoyl)-6-chloro-lH-indole-l-carboxylat

[0287] To a stirred solution of PPI13CI2 (953 mg, 2.86 mmol, 1.5 eq) in CHCI3 (20 mL) at 0°C, was added DIPEA (1.65 mL, 9.54 mmol, 5.0 eq), stirred for 1 h followed by addition of a solution of tert-butyl 5-bromo-3-(N-(tert-butyldimethylsilyl)sulfamoyl)-6- chloro-lH-indole-1 -carboxylate (1 g, 1.91 mmol, 1.0 eq) in CHCI3 (10 mL), continued stirring for 1 h at 0°C. Later, a solution of methyl L-alanine (801 mg, 5.72 mmol, 3.0 eq) in CHCI3 (10 mL) was added at 0°C and stirred for 24 h at room temperature. After completion of reaction by TLC, reaction mixture was quenched with ice cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200) column chromatography [elution with 10% EtOAc in Hexane] to afford tert-butyl (S)-5-bromo-3-(N'-(tert- butyldimethylsilyl)-N-(l-methoxy-l-oxopropan-2-yl) sulfamidimidoyl)-6-chloro-lH- indole-1 -carboxylate as a gummy liquid (700 mg, Yield: 63%).

[0288] TLC system: EtOAc / Hexane (10:90)

[0289] Rf value: -0.4

[0290] LCMS (m / z): 608.2 (M+H)+ Synthesis of (S)-l-(5-bromo-6-chloro-lH-indol-3-yl)-4-methyl-4,5-dihydro-3H-116,2,5- thiadiazol-3-one 1 -oxide

[0291] To a stirred solution of tert-butyl (S)-5-bromo-3-(N'-(tert-butyldimethylsilyl)-N- ( 1 -methoxy- 1 -oxopropan-2-yl)sulfamidimidoyl)-6-chloro- IH-indole- 1 -carboxylate (450 mg, 0.74 mmol, 1.0 eq) in THF (4.5 mL) at 0°C, was added TBAF (1.0 M in THF) (4.5 mL, 10 Vol) and stirred at 50°C for 48 h. After observing conversion by TLC, reaction mixture was quenched with NH4Q solution (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200) column chromatography [elution with 5 - 7% MeOH in DCM] to afford (S)-l-(5-bromo-6-chloro-lH-indol-3-yl)-4-methyl-4,5-dihydro-3H- 116,2,5-thiadiazol-3-one 1-oxide as an off white solid (350 mg, semi-pure).

[0292] TLC system: MeOH / DCM (10:90)

[0293] Rf value: ~0.2

[0294] LCMS (m / z): 364.0 (M+H)+

[0295] ‘HNMR (400 MHz, CDCls) 5: 8.30 (s, 1H), 7.87 (d, J= 2.8 Hz, 1H), 7.79-7.74 (m, 1H), 4.33-4.28 (m, 1H), methyl protons merged with impurity. Excess tetra butyl ammonium impurities observed by NMR. This material was taken forward to the next step without purification.

[0296] Synthesis of (S)-l-(6-chloro-5-(4-(l-hydroxy cyclobutyl) phenyl)-lH-indol-3-yl)-4- methyl-4,5-dihydro-3H-116,2,5-thiadiazol-3-one 1 -oxide

[0297] In a sealed tube, to a degassed solution of (S)-l-(5-bromo-6-chloro-lH-indol-3- yl)-4-methyl-4,5-dihydro-3H-116,2,5-thiadiazol-3-one 1-oxide (150 mg, 0.41 mmol, 1.0 eq) and l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (181 mg, 0.66 mmol, 1.6 eq) in ACNtlfcO (1 : 1, 3 mL) at room temperature, was added K2CO3 (115 mg, 0.83 mmol, 2.0 eq) followed by PdC12(dppf).DCM (33 mg, 0.04 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was diluted with water (10 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-Pentane (10 mL), dried under vacuum, and purified by Grace RP column and prep-HPLC. Collected fractions were lyophilized to afford (S)-l-(6-chloro- 5-(4-(l -hydroxy cyclobutyl) phenyl)- lH-indol-3-yl)-4-methyl-4,5-dihydro-3H- 116,2, 5- thiadiazol-3-one 1-oxide as white solid (15 mg, Yield: 8%).

[0298] TLC system: MeOH / DCM (10:90)

[0299] Rf value: ~0.3

[0300] LCMS(m / z): 428.1 (M+H)+

[0301] 'HNMR (400 MHz, DMSO-de) 5: 12.5 (br, 1H), 9.15 (br, 1H), 8.29 (d, J= 2.8 Hz, 1H), 7.76 (d, J= 2.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 2H), 7.43-7.35 (m, 3H), 5.54 (s, 1H), 4.29-4.20 (m, 1H), 2.49-2.42 (m, 2H), 2.33-2.26 (m, 2H), 2.00-1.90 (m, 1H), 1.73-1.68 (m, 1H), 1.36-1.30 (2 d, 3H).

[0302] (lS,4S)-l-(6-chloro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)-4- methyl-4,5-dihydro-3H-116,2,5-thiadiazol-3-one 1-oxide and (1R, 4S)-l-(6-chloro-5-(4-(l -hydroxy cy cl obutyl)phenyl)-lH-indol-3-yl)-4-

[0303] In a sealed tube, to a degassed solution of (S)-l-(5-bromo-6-chloro-lH-indol-3- yl)-4-methyl-4,5-dihydro-3H-116,2,5-thiadiazol-3-one 1-oxide (230 mg, 0.63 mmol, 1.0 eq) and l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (278 mg, 1.01 mmol, 1.6 eq) in ACN:H2O (1 : 1, 3 mL) at room temperature, was added K2CO3 (174 mg, 1.26 mmol, 2.0 eq) followed by PdC12(dppf).DCM (51 mg, 0.06 mmol, 0.1 eq) and stirred at 100 °C for 16 h. After completion of reaction by TLC, reaction mixture was diluted with water (10 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The Crude product was purified by reverse phase column chromatography [elution with 40% ACN with 0.1% FA in FLO] and pure fractions were lyophilized to afford (S)-l-(6-chloro-5-(4-(l- hydroxycyclobutyl)phenyl)-lH-indol-3-yl)-4-methyl-4,5-dihydro-3H-116,2,5- thiadiazol-3-one 1-oxide as a white solid (100 mg, Yield: 37%). TLC system: MeOH / DCM (10:90), Rfvalue:~0.3.

[0304] (S)- 1 -(6-chloro-5-(4-( 1 -hydroxycyclobutyl)phenyl)- lH-indol-3 -yl)-4-methyl- 4,5-dihydro-3H-116,2,5-thiadiazol-3-one 1-oxide (100 mg, Pure) was purified by SFC and recovered 41.5 mg of Peak 1 & 15.2 mg of Peak 2

[0305] Peak 1 : LCMS(m / z): 430.2 (M+H)+; 'HNMR (400 MHz, DMSO-de) 5: 12.57 (br, 1H), 9.22 (br, 1H), 8.29 (s, 1H), 7.76 (s, 1H), 7.57 (d, J= 8.4 Hz, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.35 (s, 1H), 5.54 (s, 1H), 4.24-4.20 (m, 1H), 2.49-2.43 (m, 2H), 2.33- 2.28 (m, 2H), 1.96-1.93 (m, 1H), 1.68-1.66 (m, 1H), 1.39 (d, J= 6.4 Hz, 3H).

[0306] Peak 2: LCMS(m / z): 428 (M-H)'; 'H NMR (400 MHz, DMSO-de) 5: 8.27 (s, 1H), 7.76 (s, 1H), 7.58 (d, J= 8.4 Hz, 2H), 7.43 (s, 1H), 7.36 (d, J= 8.4 Hz, 2H), 5.54 (s, 1H), 4.28-4.23 (m, 1H), 2.50-2.43 (m, 2H), 2.33-2.26 (m, 2H), 1.96-1.94 (m, 1H), 1.73-1.67 (m, 1H), 1.34-1.32 (d, J= 6.4 Hz, 3H). Exchangeable protons were not shown in the NMR

[0307] SYNTHETIC EXAMPLE 3

[0308] SYNTHESIS OF 3-(6-CHLORO-5-(4-(1-HYDROXYCYCLOBUTYL) PHENYL)- 1H-PYRROLO [2,3- B] PYRIDIN-3 - YL)- 1 ,2,4-OXADIAZOL-5(4H)-ONE

[0309] Synthesis of 5-bromo-6-chloro-lH-pyrrolo[2,3-b] pyridine-3-carbaldehyde

[0310] A solution of POCI3 (4.03 mL, 43.3 mmol, 2.0 eq) and DMF (3.5 mL, 45.4 mmol, 2.1 eq) was stirred at 0°C, later added 5-bromo-6-chloro-lH-pyrrolo[2,3-b] pyridine (5 g, 21.6 mmol, 1.0 eq) in DMF (5 mL) at room temperature. The reaction mixture was stirred at 90°C for 3 h. After completion of reaction by TLC, the reaction mixture was treated with IN NaOH solution (10 mL) and stirred at 95°C for 10 min, precipitated solid was filtered, washed with diethyl ether (50 mL) and dried under vacuum to afford 5-bromo-6-chloro-lH-pyrrolo[2,3-b] pyridine-3-carbaldehyde as pink solid (5.6 g, quantitative).

[0311] TLC system: EtOAc / Hexane (50:50)

[0312] Rf value: -0.25

[0313] LCMS(m / z): 259.1 (M+H)+ Synthesis of 5-bromo-6-chloro-lH-pyrrolo[2,3-b] pyridine-3 -carbonitrile

[0314] To a stirred solution of 5-bromo-6-chloro-lH-pyrrolo[2,3-b] pyridine-3- carbaldehyde (5.6 g, 21.6 mmol, 1.0 eq, Crude) in Pyridine (28 mL) at room temperature, was added AC2O (4.1 mL, 43.2 mmol, 2.0 eq) and NH2OH.HCl (1.65 g, 23.8 mmol, 1.1 eq). The reaction mixture was stirred at 90°C for 2 h. After completion of reaction by TLC, reaction mixture was quenched with 2 N HC1 solution (20 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with diethyl ether (50 mL), decanted, and dried under vacuum to afford 5-bromo-6-chloro-lH-pyrrolo[2,3-b] pyridine-3 -carbonitrile as off white solid (6 g, Crude, 72% purity).

[0315] TLC system: EtOAc / Hexane (50:50)

[0316] Rf value : ~0.35

[0317] LCMS(m / z): 256.1 (M+H)+

[0318] Synthesis of (Z)-5-bromo-6-chloro-N'-hydroxy-lH-pyrrolo[2,3-b] pyridine-3- carboximidamide

[0319] To a stirred solution of 5-bromo-6-chloro-lH-pyrrolo[2,3-b] pyridine-3- carbonitrile (3 g, 11.7 mmol, 1.0 eq) in EtOH (30 mL) at room temperature was added EtiN (2.44 mL, 17.6 mmol, 1.5 eq) and NH2OH.HCl (1.22 g, 17.6 mmol, 1.5 eq). The reaction mixture was stirred at 80°C for 5 h. After completion of reaction by TLC, reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Obtained crude was triturated with n-pentane, diethyl ether (50 mL), decanted and dried under vacuum to afford (Z)-5-bromo-6-chloro-N'-hydroxy-lH- pyrrolo[2,3-b] pyridine-3-carboximidamide as off white solid (1.4 g, yield: 23% in 2 steps).

[0320] TLC system: EtOAc / Hexane (70:30)

[0321] Rf value: ~0.1; LCMS(m / z): 289.0 (M+H)+

[0322] Synthesis of ethyl (Z)-5-bromo-6-chloro-3-(N'-((ethoxycarbonyl)oxy) carbamimidoyl)- 1 H-py rrol o [2, 3 -b ] py ri dine- 1 -carb oxy 1 ate

[0323] To a stirred solution of (Z)-5-bromo-6-chloro-N'-hydroxy-lH-pyrrolo[2,3-b] pyridine-3-carboximidamide (1.4 g, 4.84 mmol, 1.0 eq) in DCM (42 mL, 30 Vol) at 0°C, was added EtiN (0.9 mL, 6.29 mmol, 1.3 eq) and Ethyl chloroformate (0.55 mL, 5.81 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Obtained crude was triturated with n-pentane (20 mL), decanted, and dried under vacuum to afford ethyl (Z)-5-bromo-6-chloro-3-(N'- ((ethoxycarbonyl)oxy) carbamimidoyl)-lH-pyrrolo[2,3-b] pyridine- 1 -carboxylate as off white solid (1.2 g, Yield: 57%).

[0324] TLC system: EtOAc / Hexane (50:50)

[0325] Rf value : ~0.6

[0326] ‘HNMR (400 MHz, CDCls) 5: 8.86 (s, 1H), 8.71 (s, 1H), 7.00 (s, 2H), 4.48 (q, J = 7.2 Hz, 2H), 4.25 (q, J= 7.2 Hz, 2H), 1.40 (t, J= 7.2 Hz, 3H), 1.30 (t, J= 7.2 Hz, 3H). Synthesis of 3-(5-bromo-6-chloro-lH-pyrrolo[2,3-b] pyri din-3 -yl)- 1,2, 4-oxadiazol- 5(4H)-one

[0327] To a stirred solution of ethyl (Z)-5-bromo-6-chloro-3-(N'- ((ethoxycarbonyl)oxy)carbamimidoyl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (1.2 g, 2.76 mmol, 1.0 eq) in DMSO (4.5 mL, 3.5 Vol) at 0°C, was added NaOH (133 mg, 3.31 mmol, 1.2 eq) and stirred for 3 h at room temperature. After completion of reaction by TLC, reaction mixture was diluted with water (50 mL), quenched with 2N HC1 solution until reaching pH 2 and extracted with EtOAc (3 x 40 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Obtained crude was purified by silica gel (100-200 mesh) column chromatography [elution with 65 - 70% EtOAc in Hexane] to afford 3-(5-bromo-6-chloro-lH-pyrrolo[2,3-b] pyridin- 3-yl)-l,2,4-oxadiazol-5(4H)-one as yellow solid (0.5 g, mixture).

[0328] TLC system: EtOAc / Hexane (50:50)

[0329] Rf value : ~0.2 & 0.4

[0330] LCMS(m / z): 315.0 & 387.0 (M+H)

[0331] Synthesis of 3-(6-chloro-5-(4-(l-hydroxy cyclobutyl) phenyl)-lH-pyrrolo[2,3-b] pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one In a sealed tube to a degassed solution of 3-(5-bromo-6-chloro-lH-pyrrolo[2,3- b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one (200 mg, 0.69 mmol, 1.0 eq (Mixture)) and l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (276 mg, 1.10 mmol, 1.6 eq) in ACNtlfcO (1 : 1, 2 mL) at room temperature, was added K2CO3 (174 mg, 1.38 mmol, 2.0 eq) followed by Pd(dppf)C12-DCM (46 mg, 0.069 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was diluted with water (20 mL) and extracted with 10% MeOH in DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Obtained crude was purified by reverse phase column chromatography [elution with 35% ACN in 0.1% FA in FLO] followed by Prep-HPLC and lyophilized to afford 3-(6-chloro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH- pyrrolo[2,3-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (14 mg, Yield: 6%).

[0332] TLC system: MeOH / DCM (10:90), Rfvalue:~0.3;

[0333] LCMS(m / z): 381.1 (M-H)+;

[0334] 'HNMR (400 MHz, DMSO-de) 5: 12.79 (s, 2H), 8.17 (s, 1H), 8.14 (d, J= 2.8 Hz, 1H), 7.60 (d, J= 8.0 Hz, 2H), 7.47 (d, J= 8.4 Hz, 2H), 5.57 (s, 1H), 2.47-2.42 (m, 2H), 2.35-2.27 (m, 2H), 2.00-1.90 (m, 1H), 1.75-1.71 (m, 1H).

[0335] Prep Conditions:

[0336] Column Luna Cis (250 x 19) 5 MICRON Buffer,

[0337] Mobile Phase A: 0.1% TFA in water; Mobile Phase B: ACN Gradient (T / %B) 0.01 / 40,13 / 40,15 / 70,16 / 95, Flow Rate 15 mL / min Solubility ACN, WATER, THF

[0338] SYNTHETIC EXAMPLE 4

[0339] SYNTHESIS OF COMPOUND 1-7 Synthesis of 5-bromo-6-fluoro-lH-indole-3-carbaldehyde

[0340] To a stirred solution of 5-bromo-6-fluoro-lH-indole (2 g, 9.34 mmol, 1.0 eq) in DMF (3.5 mL) at room temperature, was added POCI3 (1.7 mL, 18.7 mmol, 2.0 eq). The reaction mixture was stirred at 90°C for 1 h. After completion of reaction by TLC, the reaction mixture was treated with IN NaOH solution (10 mL) and stirred at 90°C for 10 min. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-pentane (30 mL), decanted, and dried under reduced pressure to afford 5-bromo-6-fhioro-lH-indole-3-carbaldehyde as a brown solid (1.9 g, Yield: 90%).

[0341] TLC system: EtOAc / Hexane (50:50)

[0342] Rf value: ~0.3

[0343] LCMS(m / z): 242.31 (M+H)+; Bromo pattern observed.

[0344] Synthesis of 5-bromo-6-fluoro-lH-indole-3-carbonitrile

[0345] To a stirred solution of 5-bromo-6-fluoro-lH-indole-3-carbaldehyde (1.9 g, 7.85 mmol, 1.0 eq) in pyridine (14.5 mL) at room temperature, was added AC2O (1.6 mL, 15.7 mmol, 2.0 eq) and NH2OH HCI (600 mg, 8.63 mmol, 1.1 eq). The reaction mixture was stirred at 90°C for 2 h. After completion of reaction by TLC, the reaction mixture was quenched with 2 N HC1 solution (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 20% EtOAc in Hexane] to afford 5-bromo-6-fluoro-lH-indole-3-carbonitrile as a brown solid (1.6 g, Yield: 89%). TLC system: EtOAc / Hexane (50:50)

[0346] Rf value: ~0.6

[0347] LCMS(m / z): 239.43 (M+H)+

[0348] 'HNMR (400 MHz, CDC ) 5: 8.79 (br, 1H), 7.97 (d, J= 6.4 Hz, 1H), 7.73 (d, J = 3.2 Hz, 1H), 7.25 (s, 1H).

[0349] Synthesis of 5-bromo-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole- 3 -carbonitrile

[0350] To a stirred solution of 5-bromo-6-fluoro-lH-indole-3-carbonitrile (1.6 g, 6.69 mmol, 1.0 eq) in DMF (25.6 mL, 16 Vol) at 0°C, was added 60% NaH (323 mg, 13.4 mmol, 2.0 eq) and stirred for 30 min. After that SEM-C1 (1.4 mL, 8.03 mmol, 1.2 eq) was added to reaction mixture and stirred at room temperature for 3 h. After completion of reaction by TLC, the reaction mixture was diluted with ice cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (60 - 120 mesh) column chromatography [elution with 15% EtOAc in Hexane] to afford 5-bromo-6-fluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carbonitrile as a yellow solid (1.9 g, Yield: 73%).

[0351] TLC system: EtOAc / Hexane (50:50)

[0352] Rf value: -0.7

[0353] LCMS(m / z): 369.47 (M+H)+

[0354] 'HNMR (400 MHz, CDCls) 5: 7.94 (d, J= 6.4 Hz, 1H), 7.67 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 5.44 (s, 2H), 3.47 (t, J= 8.0 Hz, 2H), 0.90 (t, J= 8.0 Hz, 2H), -0.04 (s, 9H).

[0355] Synthesis of (E / Z)-5-bromo-6-fluoro-N'-hydroxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide

[0356] To a stirred solution of 5-bromo-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-indole-3-carbonitrile (1.9 g, 5.15 mmol, 1.0 eq) in EtOH (19 mL) at room temperature, was added EhN (1.1 mL, 7.72 mmol, 1.5 eq) and NELOEI HCI (393 mg, 7.72 mmol, 1.5 eq). The reaction mixture was stirred at 80°C for 4 h. After completion of reaction by TLC, the reaction mixture was diluted with water (35 mL) and extracted with EtOAc (2 x 35 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-pentane (50 mL), decanted and dried under vacuum to afford (E / Z)-5-bromo-6-fluoro-N'-hydroxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3- carboximidamide as brown solid (1.8 g, Crude).

[0357] TLC system: EtOAc / Hexane (50:50)

[0358] Rf value: ~0.3

[0359] LCMS(m / z): 402.51 (M+H)+

[0360] Synthesis of ethyl (E / Z)-((5-bromo-6-fluoro-l-((2-

[0361] (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)(hydroxyimino)methyl)carbamate

[0362] To a stirred solution of (E / Z)-5-bromo-6-fluoro-N'-hydroxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide (1.8 g, 4.48 mmol, 1.0 eq) in DCM (36 mL, 20 Vol) at 0°C, was added EtiN (0.8 mL, 5.82 mmol, 1.3 eq) and 2 -Ethylchloroformate (0.51 mL, 5.38 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with NaHCCh solution (30 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 20% EtOAc in Hexane] to afford ethyl (E / Z)-((5-bromo- 6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-3- yl)(hydroxyimino)methyl)carbamate as brown solid (1.4 g, Yield: 66%).

[0363] TLC system: EtOAc / Hexane (50:50)

[0364] Rf value: ~0.4

[0365] LCMS(m / z): 474.59 (M+H)+

[0366] 'HNMR (400 MHz, CDC ) 5: 8.26 (d, J= 6.8 Hz, 1H), 7.54 (s, 1H), 7.27-7.25 (m, 1H), 5.39 (s, 2H), 5.06 (s, 1H), 4.35 (q, J= 7.2 Hz, 2H), 3.45 (t, J= 8.0 Hz, 2H), 1.40 (t, J= 7.2 Hz, 2H), 0.88 (t, J= 8.0 Hz, 2H), -0.05 (s, 9H)

[0367] Synthesis of 3-(5-bromo-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0368] To a stirred solution of ethyl (E / Z)-((5-bromo-6-fluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)(hydroxyimino)methyl)carbamate (1.4 g, 2.95 mmol, 1.0 eq) in DMSO (3.5 mL) at 0°C, was added NaOH (142 mg, 3.54 mmol, 1.2 eq) and stirred for 3 h at room temperature. After completion of reaction by TLC, the reaction mixture was diluted with water (30 mL), quenched with 2N HC1 solution (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-pentane (30 mL), decanted and dried under vacuum to afford 3-(5-bromo-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol- 3-yl)-l,2,4-oxadiazol-5(4H)-one as brown solid (1.2 g, Yield: 87%).

[0369] TLC system: EtOAc / Hexane (50:50)

[0370] Rf value: -0.3 LCMS(m / z): 428.5 (M+H)+

[0371] 'HNMR (400 MHz, CDCls) 5: 11.90 (br, 1H), 8.28 (d, J= 6.4 Hz, 1H), 7.84 (s, 1H), 7.30 (d, J= 8.8 Hz, 1H), 5.47 (s, 2H), 3.51 (t, J= 8.0 Hz, 2H), 0.92 (t, J= 8.0 Hz, 2H), -0.03 (s, 9H).

[0372] Synthesis of 3-(5-bromo-6-fluoro-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0373] To a stirred solution of 3-(5-bromo-6-fluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one (200 mg, 0.47 mmol, 1.0 eq) in DCM (2 mL) at 0°C, was added TFA (4 mL, 10 Vol) and stirred for 3 h at room temperature. After completion of reaction by TLC, the reaction mixture was filtered, washed with ether (10 mL) and collected solid was dried under vacuum to afford 3-(5-bromo-6-fluoro-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as yellow solid (200 mg, crude).

[0374] TLC system: MeOH / DCM (10:90)

[0375] Rf value: ~0.2

[0376] LCMS(m / z): 296.41 (M-H)’.

[0377] Synthesis of 3-(6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one

[0378]

[0379] In a sealed tube to a degassed solution of 3-(5-bromo-6-fluoro-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one (200 mg, 0.67 mmol, 1.0 eq) and l-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (300 mg, 1.07 mmol, 1.6 eq) in ACN:H2O (1 :1, 4 mL) at room temperature, was added K2CO3 (185 mg, 1.34 mmol, 2.0 eq) followed by Pd(dppf)C12.DCM (54 mg, 0.067 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase column chromatography [elution with 35% ACN in 0.1% FA in H2O] to afford desired product. Obtained material was repurified by reverse phase column chromatography [elution with 35% ACN in 0.1% FA in H2O] and lyophilized to afford 3-(6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH- indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as white solid (38 mg, Yield: 16%).

[0380] TLC system: MeOH / DCM (10:90)

[0381] Rf value: ~0.3

[0382] LCMS(m / z): 364.0 (M-H)+

[0383] 'HNMR (400 MHz, DMSO-de) 5: 11.98 (s, 1H), 7.99 (d, J= 2.8 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.61-7.59 (m, 2H), 7.53-7.50 (m, 2H), 7.47 (d, J= 11.2 Hz, 1H), 5.54 (s, 1H), 2.42-2.40 (m, 2H), 2.30-2.27 (m, 2H), 1.99-1.90 (m, 1H), 1.74-1.71 (m, 1H). SYNTHETIC EXAMPLE 5

[0384] SYNTHESIS OF COMPOUND 1-8

[0385] Synthesis of 5-bromo-3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazolo[3,4-Z>]pyridine

[0386] To a stirred solution of 5-bromo-3-iodo-lH-pyrazolo[3,4-Z>]pyridine (5 g, 15.4 mmol, 1.0 eq) in DMF (50 mL, 10 Vol) at 0°C, was added 60% NaH (743 mg, 30.9 mmol, 2.0 eq) and stirred for 30 min. After that SEM-C1 (3.0 g, 18.5 mmol, 1.2 eq) was added to reaction mixture and stirred at room temperature for 5 h. After completion of reaction by TLC, the reaction mixture was diluted with ice cold water (100 mL) and extracted with DCM (2 x 200 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 15-20 % EtOAc in Hexane] to afford 5-bromo-3-iodo-l-((2-(trimethylsilyl)ethoxy) methyl)-lH-pyrazolo[3,4-Z>]pyridine as an off white solid (3.7 g, Yield: 53%).

[0387] TLC system: EtOAc / Hexane (20:80)

[0388] Ry value: -0.5

[0389] 'H NMR (400 MHz, CDC ) 5: 8.60 (d, J= 2.0 Hz, 1H), 7.96 (d, J= 2.4 Hz, 1H), 5.81 (s, 2H), 3.67-3.62 (m, 2H), 0.94-0.90 (m, 2H), -0.05 (s, 9H).

[0390] Synthesis of 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4- Z>]pyridine-3 -carbonitrile

[0391] To a stirred solution of 5-bromo-3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrazolo[3,4-Z>]pyridine (2.8 g, 6.2 mmol, 1.0 eq) in DMSO (56 mL, 20 Vol) at room tempearure, was added CuCN (1.1 g, 12.3 mmol, 2 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (60 - 120 mesh) column chromatography [elution with 5% EtOAc in Hexane] to afford 5 -bromo- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-Z>]pyridine-3-carbonitrile as white solid (1.8 g, Yield: 82%).

[0392] TLC system: EtOAc / Hexane (5:95)

[0393] R value: -0.3

[0394] LCMS: No proper ionization. Material was taken forward to next step.

[0395] Synthesis of (E / Z)-5-bromo-N'-hydroxy-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrazolo[3,4-Z>]pyridine-3-carboximidamide

[0396] To a stirred solution of 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazolo[3,4-Z>]pyridine-3 -carbonitrile (1.8 g, 5.1 mmol, 1.0 eq) in EtOH (18 mL, 10 Vol) at room temperature, was added EtiN (1.1 mL, 7.6 mmol, 1.5 eq) and NH2OH.HCI (390 mg, 5.6 mmol, 1.1 eq). The reaction mixture was stirred at 80°C for 4 h. After completion of reaction by TLC, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with / / -pentane (30 mL), decanted and dried under vacuum to afford (E / Z)-5-bromo-A'-hydroxy-l-((2-(trimethylsilyl)ethoxy) methyl)-lH- pyrazolo[3,4-Z>]pyridine-3-carboximidamide as off white solid (1.7 g, Crude).

[0397] TLC system: EtOAc / Hexane (10:90)

[0398] Ry value: -0.2

[0399] LCMS (m / z): 386.4 (M+H)+

[0400] ‘HNMR (400 MHz, CDC ) 5: 8.68 (s, 1H), 8.64 (s, 1H), 5.87 (m, 2H), 5.36 (s, 2H), 3.70-3.67 (m, 2H), 0.98 (t, J= 8.0 Hz, 2H), -0.01 (s, 9H).

[0401] Synthesis of (E / Z)-5-bromo-N'-((ethoxycarbonyl)oxy)-l-((2-

[0402] (trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide

[0403] To a stirred solution of (E / Z)-5-bromo-A'-hydroxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-3-carboximidamide (1.7 g, 4.4 mmol, 1.0 eq) in DCM (30 mL, 20 Vol) at 0°C, was added EtiN (0.8 mL, 5.7 mmol, 1.3 eq) and 2-Ethylchloroformate (0.5 mL, 5.3 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (75 mL) and extracted with DCM (3 * 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford crude product. The crude product was triturated with / / -pentane (20 mL), decanted and dried under vacuum to afford (E / Z)-5-bromo-N'-((ethoxycarbonyl)oxy)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide as an off white solid (2 g, Crude).

[0404] TLC system: EtOAc / Hexane (30:70)

[0405] Ry value: -0.3

[0406] LCMS (m / z): 458.7 (M+H)+ 'H NMR (400 MHz, CDCls) 5: 8.79 (d, J= 2.0 Hz, 1H), 8.61 (d, J= 2.4 Hz,

[0407] 1H), 5.84 (s, 2H), 5.56 (s, 2H), 4.37 (q, J= 7.2 Hz, 2H), 3.62 (t, J= 8.4 Hz, 2H), 1.41 (t, J= 6.8 Hz, 3H), 0.91 (t, J= 8.0 Hz, 2H), -0.06 (s, 9H).

[0408] Synthesis of 3-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4- Z>]pyri din-3 -yl)- 1 ,2,4-oxadi azol-5(4H)-one

[0409] To a stirred solution of (E / Z)-5-bromo-N'-((ethoxycarbonyl)oxy)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2 g, 4.6 mmol, 1.0 eq) in DMSO (7 mL) at 0°C, was added NaOH (223 mg, 5.57 mmol, 1.2 eq) and stirred for 3 h at room temperature. After completion of reaction by TLC, the reaction mixture was diluted with water (30 mL), quenched with 2N HC1 solution (8 mL) and extracted with 10% MeOH / DCM (3 x 40 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with / / -pentane (30 mL), decanted and dried under vacuum to afford 3-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazolo[3,4-Z>]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (1.5 g, Crude).

[0410] TLC system: EtOAc / Hexane (70:30)

[0411] R value :~0.1

[0412] LCMS (m / z): 410.3 (M-H)+

[0413] Synthesis of 3-(5-bromo-lH-pyrazolo[3,4-Z>]pyridin-3-yl)-l,2,4-oxadiazol- 5(4H)-one

[0414] To a stirred solution of 3-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazolo[3,4-Z>]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one (1 g, 2.3 mmol, 1.0 eq) in DCM (10 mL) at 0°C, was added TFA (10 mL, 10 Vol) and stirred for 3 h at room temperature. After completion of reaction by TLC, volatiles were removed, diluted with NaHCCh solution (35 mL) and extracted with 10% MeOH / DCM (2 ^ 35 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n- pentane (20 mL), decanted, and dried under vacuum to afford 3 -(5 -bromo- 1H- pyrazolo[3,4-Z>]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (650 mg of crude).

[0415] TLC system: MeOH / DCM (10:90)

[0416] R / value :~0.1

[0417] LCMS (ESI, m / z): 282.0 (M-H)+with 311.9 (M-H)+.

[0418] Synthesis of 3-(5-(4-(l-hydroxycyclobutyl)phenyl)-lH-pyrazolo[3,4-Z>]pyridin-

[0419] 3 -yl)- 1 ,2,4-oxadiazol-5(4H)-one

[0420] In a sealed tube to a degassed solution of 3-(5-bromo-lH-pyrazolo[3,4-

[0421] Z>]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one (300 mg, 1.0 mmol, 1.0 eq) and l-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (468 mg, 1.7 mmol, 1.6 eq) in ACNilfcO (1 : 1, 6 mL) at room temperature, was added K2CO3 (294 mg, 2.1 mmol, 2.0 eq) followed by Pd(dppf)C12.DCM (87 mg, 0.1 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography [elution with 35-40% ACN in 0.1% FA in H2O] to afford desired product along with impurity. This was dissolved in aq. NH3 (0.5 mL) in dioxane (0.5 mL) and stirred for 16 h. Reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography [elution with 35-40% ACN in 0.1% FA in H2O] to afford 3-(5-(4-(l-hydroxycyclobutyl)phenyl)-lH-pyrrolo[2,3- b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (18 mg, Yield: ~5%).

[0422] TLC system: MeOH / DCM (10:90) R value :~0.1

[0423] LCMS (m / z):348.0 [M-H]+

[0424] 'HNMR (400 MHz, DMSO-de) 5: 14.34 (s, 1H), 13.15 (s, 1H), 8.95 (d, J= 2.0 Hz, 1H), 8.57 (d, J= 2.0 Hz, 1H), 7.75 (d, J= 8.4 Hz, 2H), 7.63 (d, J= 8.4 Hz, 2H), 5.58 (s, 1H), 2.45-2.40 (m, 2H), 2.35-2.28 (m, 2H), 2.00-1.92 (m, 1H), 1.72-1.65 (m, 1H)

[0425] SYNTHETIC EXAMPLE 6

[0426] SYNTHESIS OF COMPOUND 1-9

[0427] Synthesis of 5-bromo-3-iodo-lH-pyrrolo[2,3-b]pyridine To a stirred solution of 5-bromo-lH-pyrrolo[2,3-b]pyridine (2 g, 10.2 mmol, 1.0 eq) in DMF (20 mL) at 0°C, was added N-iodosuccinimide (3.4 g, 15.2 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 2 h. After completion of reaction by TLC, reaction mixture was diluted with H2O (75 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Obtained crude product was triturated with n- pentane (30 mL), decanted and dried under vacuum to afford 5-bromo-3-iodo-lH- pyrrolo[2,3-b]pyridine as brown solid (2.8 g, Yield: 85%).

[0428] TLC system: EtOAc / Hexane (20:80)

[0429] Rf value: ~0.6

[0430] 'HNMR (400 MHz, CDC ) 5: 9.40 (br s, 1H), 8.35 (d, J= 2.0 Hz, 1H), 7.92 (d, J= 1.6 Hz, 1H), 7.43 (d, J= 2.4 Hz, 1H).

[0431] Synthesis of 5-bromo-3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridine

[0432] To a stirred solution of 5-bromo-3-iodo-lH-pyrrolo[2,3-b]pyridine (2.8 g, 8.72 mmol, 1.0 eq) in DMF (28 mL, 10 Vol) at 0°C, was added 60% NaH (418 mg, 17.4 mmol, 2.0 eq) and stirred for 30 min. After that SEM-CI (1.8 mL, 10.5 mmol, 1.2 eq) was added to reaction mixture and stirred at room temperature for 3 h. After completion of reaction by TLC, reaction mixture was diluted with ice cold water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 5-bromo-3-iodo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine as brown gummy liquid (3.7g, Crude).

[0433] TLC system: EtOAc / Hexane (20:80),

[0434] Rf value: -0.7;

[0435] LCMS (m / z): 453.37 (M+H)+; 'H NMR (400 MHz, CDCls) 5: 8.35 (d, J= 2.0 Hz, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.46 (s, 1H), 5.61 (s, 2H), 3.54-3.50 (m, 2H), 0.98-0.88 (m, 2H), -0.06 (s, 9H).

[0436] Synthesis of 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridine-3 -carbonitrile

[0437] To a stirred solution of 5-bromo-3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrrolo[2,3-b]pyridine (3.7 g, 8.22 mmol, 1.0 eq) in DMSO (75 mL, 20 Vol) at room temperature was added CuCN (1.47 g, 16.4 mmol, 2 eq) and stirred at 100°C for 16 h. Reaction mixture was diluted with ice cold water (70 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Obtained crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 15 - 20% EtOAc in Hexane] to afford 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-3- carbonitrile as off white solid (1.1 g, Yield: 48%).

[0438] TLC system: EtOAc / Hexane (30:70),

[0439] Rf value: ~0.3;

[0440] 'HNMR (400 MHz, CDC ) 5: 8.49 (d, J= 2.4 Hz, 1H), 8.23 (d, J= 2.0 Hz, 1H), 7.89 (s, 1H), 5.68 (s, 2H), 3.56 (t, J= 8.4 Hz, 2H), 0.92 (t, J= 8.4 Hz, 2H), -0.04 (s, 9H). (1 g S.M recoverd)

[0441] Synthesis of (E / Z)-5-bromo-N'-hydroxy-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrrolo[2,3-b]pyridine-3-carboximidamide To a stirred solution of 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridine-3 -carbonitrile (1.1 g, 3.13 mmol, 1.0 eq) in EtOH (11 mL) at room temperature was added EtiN (0.7 mL, 4.70 mmol, 1.5 eq) and NH2OH HCI (285 mg, 4.07 mmol, 1.3 eq). The reaction mixture was stirred at 80°C for 4 h. After completion of reaction by TLC, reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Obtained crude product was triturated with n-pentane (50 mL), decanted and dried under reduced pressure to afford (E / Z)-5- bromo-N'-hydroxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-3- carboximidamide as an off white solid (1 g, semi-pure).

[0442] TLC system: EtOAc / Hexane (30:70),

[0443] Rf value: ~0.2;

[0444] LCMS (m / z): 385.56 (M+H)+.

[0445] Synthesis of (E / Z)-5-bromo-N'-((ethoxycarbonyl)oxy)-l-((2- (trimethylsilyl)ethoxy)methyl)lH-pyrrolo[2,3-b]pyridine-3-carboximidamide

[0446] To a stirred solution of (E / Z)-5-bromo-N'-hydroxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-3-carboximidamide (1 g, 2.60 mmol, 1.0 eq) in DCM (20 mL, 20 Vol) at 0°C, was added EtsN (0.4 mL, 3.38 mmol, 1.3 eq) and 2-Ethylchloroformate (0.4 mL, 3.12 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was diluted with water (30 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 20 - 25% EtOAc in Hexane] to afford (E / Z)-5-bromo-N'- ((ethoxy carbonyl)oxy)-l-((2-(trimethylsilyl)ethoxy )methyl)-lH-pyrrolo[2, 3-b]pyridine- 3-carboximidamide off white solid (0.85 g, Yield: 72%).

[0447] TLC system: EtOAc / Hexane (30:70),

[0448] Rf value: ~0.5;

[0449] 'HNMR (400 MHz, CDC ) 5: 8.56 (d, J= 2.0 Hz, 1H), 8.39 (d, J= 2.0 Hz, 1H), 7.71 (s, 1H), 5.63 (s, 2H), 5.05 (s, 2H), 4.35 (q, J= 7.2 Hz, 2H), 3.52 (t, J= 8.4 Hz, 2H), 1.40 (t, J= 7.2 Hz, 2H), 0.92 (t, J= 8.4 Hz, 2H), -0.06 (s, 9H).

[0450] Synthesis of 3-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0451] To a stirred solution of (E / Z)-5-bromo-N'-((ethoxycarbonyl)oxy)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-3-carboximidamide (850 mg, 1.86 mmol, 1.0 eq) in DMSO (3 mL) at 0°C, was added NaOH (100 mg, 2.23 mmol, 1.2 eq) and stirred for 3 h at room temperature. After completion of reaction by TLC, the reaction mixture was diluted with water (30 mL), quenched with 2N HC1 solution (5 mL) and extracted with 10% MeOH / DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-pentane (30 mL), decanted and dried under vacuum to afford 3-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (900 mg, Crude).

[0452] TLC system: EtOAc / Hexane (50:50),

[0453] Rf value: -0.3;

[0454] LCMS (m / z): 411.71 (M+H)+; Synthesis of 3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)- one

[0455] To a stirred solution of 3-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one (400 mg, 0.97 mmol, 1.0 eq) in DCM (4 mL) at 0°C, was added TFA (4 mL, 10 Vol) and stirred for 3 h at room temperature. After completion of reaction by TLC, volatiles were removed, diluted with sat. NaHCCh solution (30 mL) and extracted with 10% MeOH / DCM (3x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-on as off white solid (250 mg of crude).

[0456] TLC system: MeOH / CH2Ch (10:90),

[0457] RfvalueLO.2;

[0458] LCMS (ESI, m / z): 280.50 (M+H)+; material was used in next step without further purification.

[0459] Synthesis of 3-(5-(4-(l-hydroxycyclobutyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-3- yl)-l,2,4-oxadiazol-5(4H)-one

[0460] In a sealed tube to a degassed solution of 3-(5-bromo-lH-pyrrolo[2,3-b]pyridin- 3-yl)-l,2,4-oxadiazol-5(4H)-one (250 mg, 0.89 mmol, 1.0 eq) and l-(4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (391 mg, 1.42 mmol, 1.6 eq) in ACN:H2O (1 : 1, 5 mL) at room temperature, was added K2CO3 (245 mg, 1.78 mmol, 2.0 eq) followed by Pd(dppf)C12.DCM (72 mg, 0.089 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase column chromatography [elution with 35-40% ACN in 0.1% FA in H2O] to afford 3-(5-(4-(l-hydroxycyclobutyl)phenyl)-lH-pyrrolo[2,3-b]pyridin- 3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (25 mg, Yield: 8%).

[0461] TLC system: MeOH / DCM (10:90),

[0462] Rf value: ~0.3;

[0463] LCMS (m / z): 349.1 (M+H)+;

[0464] 'HNMR (400 MHz, DMSO-de) 5: 12.73 (br s, 1H), 12.61 (s, 1H), 8.69 (d, J= 2.0 Hz, 1H), 8.41 (d, J= 2.0 Hz, 1H), 8.12 (d, J= 2.8 Hz, 1H), 7.70 (d, J= 8.4 Hz, 2H), 7.62 (d, J= 8.0 Hz, 2H), 5.55 (s, 1H), 2.45-2.40 (m, 2H), 2.34-2.27 (m, 2H), 1.98-1.90 (m, 1H), 1.68-1.62 (m, 1H).

[0465] SYNTHETIC EXAMPLE 7

[0466] SYNTHESIS OF COMPOUND 1-10

[0467] Synthesis of 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3- carbonitrile

[0468] To a stirred solution of 5-bromo-lH-indole-3-carbonitrile (2 g, 9.05 mmol, 1.0 eq) in DMF (20 mL, 20 Vol) at 0°C, was added 60% NaH (434 mg, 18.1 mmol, 2.0 eq) and stirred for 30 min. After that SEM-CI (1.36 mL, 10.8 mmol, 1.2 eq) was added and stirred at room temperature for 3 h. After completion of reaction by TLC, reaction mixture was diluted with ice cold water (40 mL) and extracted with DCM (2 x 40 mL). The combined organic layer was washed with ice cold water (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 5 -bromo- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carbonitrile as brown solid (3.1 g, Crude).

[0469] TLC system: EtOAc / Hexane (30:70),

[0470] Rf value: ~0.5;

[0471] 'HNMR (400 MHz, CDC ) 5: 7.91-7.90 (m, 1H), 7.67 (s, 1H), 7.46-7.44 (m, 2H), 5.48 (s, 2H), 3.47 (t, J= 8.4 Hz, 2H), 0.90-0.87 (m, 2H), -0.04 (s, 9H).

[0472] Synthesis of (Z)-5-bromo-N'-hydroxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indole-3-carboximidamide

[0473] To a stirred solution of 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indole-3 -carbonitrile (3.1 g, 8.83 mmol, 1.0 eq) in EtOH (31 mL) at room temperature, was added EtiN (1.9 mL, 13.2 mmol, 1.5 eq) and NH2OH.HCI (910 mg, 13.2 mmol, 1.5 eq). The reaction mixture was stirred at 80°C for 5 h. After completion of reaction by TLC, reaction mixture was diluted with water (60 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to. The crude product was triturated with n-pentane (50 mL), decanted and dried under reduced pressure to afford (Z)-5-bromo-N'-hydroxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide as a brown solid (1.6 g, Yield: 47%).

[0474] TLC system: EtOAc / Hexane (50:50),

[0475] Rf value: -0.4;

[0476] ‘HNMR (400 MHz, CDCls) 5: 8.20 (s, 1H), 7.45 (s, 1H), 7.36 (s, 2H), 5.46 (s, 2H), 4.86 (s, 2H), 3.46 (t, J= 8.0 Hz, 2H), 0.88 (t, J= 8.0 Hz, 2H), -0.06 (s, 9H). Synthesis of (Z)-5-bromo-N'-((ethoxycarbonyl)oxy)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide

[0477] To a stirred solution of (Z)-5-bromo-N'-hydroxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide (1.6 g, 4.17 mmol, 1.0 eq) in DCM (32 mL, 20 Vol) at 0°C, was added EtiN (0.8 mL, 5.42 mmol, 1.3 eq) and Ethyl chloroformate (0.5 mL, 5.00 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was diluted with ice cold water (70 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to afford crude product. The crude product was triturated with n-pentane (20 mL), decanted and dried under reduced pressure to afford (Z)-5-bromo-N'-((ethoxycarbonyl)oxy)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide as an off white solid (1.7 g, Yield: 89%).

[0478] TLC system: EtOAc / Hexane (40:60),

[0479] Rf value: ~0.5;

[0480] LCMS (m / z): 456.61 [M+H]+;

[0481] ‘HNMR (400 MHz, CDC ) 5: 8.17 (s, 1H), 7.58 (s, 1H), 7.38 (s, 2H), 5.44 (s, 2H), 5.09 (s, 2H), 4.35 (q, J= 6.8 Hz, 2H), 3.45 (t, J= 8.4 Hz, 2H), 1.40 (t, J= 7.2 Hz, 3H), 0.88 (t, J= 8.4 Hz, 2H), -0.06 (s, 9H).

[0482] Synthesis of 3-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one

[0483] To a stirred solution of (Z)-5-bromo-N'-((ethoxycarbonyl)oxy)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide (1.7 g, 3.73 mmol, 1.0 eq) in DMSO (6 mL) at 0°C, was added NaOH (180 mg, 4.48 mmol, 1.2 eq) and stirred for 3 h at room temperature. After completion of reaction by TLC, the reaction mixture was diluted with water (25 mL), quenched with 2N HC1 solution (5 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with n- pentane (30 mL), decanted and dried under reduced pressure to afford 3-(5-bromo-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (1.2 g, Yield: 80%).

[0484] TLC system: EtOAc / Hexane (50:50),

[0485] Rf value: ~0.3;

[0486] LCMS(m / z): 410.53 (M+H)+.

[0487] ‘HNMR (400 MHz, CDC ) 5: 8.10 (s, 1H), 8.05 (s, 1H), 7.70 (d, J= 8.8 Hz, 1H), 7.49 (dd, J = 8.8 & 2.0 Hz, 1H), 5.66 (s, 2H), 3.49-3.45 (m, 2H), 0.82 (t, J= 8.0 Hz, 2H), -0.10 (s, 9H).

[0488] Synthesis of 3-(5-bromo-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0489] To a stirred solution of 3-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indol-3-yl)-l,2,4-oxadiazol-5(4H)-one (400 mg, 0.97 mmol, 1.0 eq) in DCM (4 mL) at 0°C, was added TFA (4 mL, 10 Vol) and stirred for 3 h at room temperature. After completion of reaction by TLC, reaction mixture was concentrated, quenched with NaHCCh solution (20 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3-(5-bromo-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (250 mg, crude).

[0490] TLC system: MeOH / DCM (10:90),

[0491] Rf value: ~0.2;

[0492] LCMS(m / z): 277.9 (M-H)+.

[0493] Synthesis of 3-(5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)-l, 2,4- oxadi azol - 5 (4H)-one

[0494] In a sealed tube to a degassed solution of 3-(5-bromo-lH-indol-3-yl)-l,2,4- oxadiazol-5(4H)-one (200 mg, 0.71 mmol, 1.0 eq) and l-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (313 mg, 1.14 mmol, 1.6 eq) in ACN:H2O (1 : 1, 4 mL) at room temperature, was added K2CO3 (197 mg, 1.42 mmol, 2.0 eq) followed by Pd(dppf)C12.DCM (58 mg, 0.071 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 -200 mesh) column chromatography [elution with 35% ACN in 0.1% FA in FLO] and lyophilized to afford 3-(5-(4-(l- hydroxycyclobutyl)phenyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (38 mg, Yield: 15%).

[0495] TLC system: MeOH / DCM (10:90), Rf value: ~0.4;

[0496] LCMS(m / z): 348.2 (M+H)+;

[0497] 'HNMR (400 MHz, DMSO-de) 5: 12.54 (s, 1H), 11.99 (s, 1H), 8.13 (s, 1H), 8.01 (d, J= 2.8 Hz, 1H), 7.65-7.55 (m, 6H), 5.52 (s, 1H), 2.44-2.40 (m, 2H), 2.33-2.26 (m, 2H), 1.95-1.92 (m, 1H), 1.69-1.66 (m, 1H).

[0498] SYNTHETIC EXAMPLE 8

[0499] SYNTHESIS OF COMPOUND 1-11

[0500] Synthesis of 4,6-difluoroindoline

[0501] To a stirred solution of 4,6-difluoro-lH-indole (10 g, 64.5 mmol, 1.0 eq) in DCM (200 mL) at 0°C was added triethyl silane (27 mL, 167.7 mmol, 2.6 eq), TFA (100 mL, 10 vol) and stirred at RT for 4 h. After completion of reaction by TLC, the reaction mixture was concentrated and quenched with aq. NaHCCh solution (200 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (60 - 120 mesh) column chromatography [elution with 5-10% EtOAc in Hexane] to afford 4,6-difluoroindoline as a brown liquid (10 g, Crude).

[0502] TLC system: EtOAc / Hexane (15:85),

[0503] Rf value: -0.6;

[0504] 'HNMR (400 MHz, CDC ) 5: 6.14-6.09 (m, 2H), 3.63 (t, J= 8.4 Hz, 2H), 3.01 (t, J= 8.4 Hz, 2H). EtsSi impurities observed. Synthesis of 5-bromo-4,6-difluoroindoline

[0505] To a stirred solution of 4,6-difluoroindoline (10 g, 64.5 mmol, 1.0 eq) in ACN (200 mL) at 0°C, was added NBS (8 g, 45.2 mmol, 0.7 eq) and allowed to stir at RT for 2h. After completion of reaction by TLC, the reaction mixture was quenched with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (230- 400 mesh) column chromatography [elution with 10-15% EtOAc in Hexane] to afford 5-bromo- 4,6-difluoroindoline as a pink solid (5.1 g, Crude).

[0506] TLC system: EtOAc / Hexane (20:80),

[0507] Rf value: ~0.3;

[0508] 'HNMR (400 MHz, CDC ) 5: 6.23-6.20 (m, 1H), 3.66 (t, J= 8.4 Hz, 2H), 3.07 (t, J= 8.4 Hz, 2H). EtiSi impurities carried from the previous reaction step.

[0509] Synthesis of 5-bromo-4,6-difluoro-lH-indole

[0510] To a stirred solution of 5-bromo-4,6-difluoroindoline (5 g, 21.5 mmol, 1.0 eq) in 1,4-Dioxane (50 mL) at room temperature, was added DDQ (5.87 g, 25.8 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 1 h. After completion of reaction by TLC, reaction mixture was quenched with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100- 200 mesh) column chromatography [elution with 10-15% EtOAc in Hexane] to afford 5-bromo-4,6-difluoro-lH-indole as a gummy solid (5.5 g, Yield: 36% in 3-steps).

[0511] TLC system: EtOAc / Hexane (20:80), Rf value: ~0.6;

[0512] 'HNMR (400 MHz, CDC ) 5: 8.33 (s, 1H), 7.19-7.17 (m, 1H), 7.03-7.01 (m, 1H), 6.62-6.60 (m, 1H).

[0513] Synthesis of 5-bromo-4,6-difluoro-lH-indole-3-carbaldehyde

[0514] To a stirred solution of 5-bromo-4,6-difluoro-lH-indole (5.5 g, 23.7 mmol, 1.0 eq) in DMF (5.5 mL) at room temperature, was added POCh (4.42 mL, 47.4 mmol, 2.0 eq) and heated at 90°C for 1 h. After completion of reaction by TLC, reaction mixture was treated with IN NaOH solution (15 mL) and stirred at 90°C for 10 min. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-pentane (50 mL), decanted, and dried under vacuum to afford 5-bromo-4,6-difluoro- lH-indole-3-carbaldehyde as an off white solid (4.5 g, Crude).

[0515] TLC system: EtOAc / Hexane (50:50),

[0516] Rf value: -0.2;

[0517] LCMS(m / z): 257.0 (M+H+2)+.

[0518] Synthesis of 5-bromo-4,6-difluoro-lH-indole-3-carbonitrile

[0519] To a stirred solution of 5-bromo-4,6-difluoro-lH-indole-3-carbaldehyde (5 g, 19.2 mmol, 1.0 eq) in pyridine (25 mL) at room temperature, was added AC2O (3.9 mL, 38.5 mmol, 2.0 eq) and NH2OH.HCI (1.5 g, 21.2 mmol, 1.5 eq). The reaction mixture was stirred at 90°C for 2 h. After completion of reaction by TLC, the reaction mixture was quenched with 2 N HC1 solution (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n- pentane &diethyl ether (1 : 1) (20 mL) to afford 5-bromo-4,6-difluoro-lH-indole-3- carbonitrile as a brown solid (4.6 g, Crude).

[0520] TLC system: EtOAc / Hexane (50:50),

[0521] Rf value: ~0.5;

[0522] LCMS(m / z): 257.03 (M+H)+.

[0523] Synthesis of 5-bromo-4,6-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indole-3 -carbonitrile

[0524] To a stirred solution of 5-bromo-4,6-difluoro-lH-indole-3-carbonitrile (4.6 g, 17.9 mmol, 1.0 eq) in DMF (46 mL, 10 Vol) at 0°C, was added 60% NaH (0.86 g, 35.8 mmol, 2.0 eq) and stirred for 30 min. After that SEM-C1 (3.8 mL, 21.5 mmol, 1.2 eq) was added to reaction mixture and stirred at room temperature for 3 h. After completion of reaction by TLC, the reaction mixture was diluted with ice cold water (30 mL) and extracted with EtOAc (2 x 150mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (60 - 120 mesh) column chromatography [elution with 10-5% EtOAc in Hexane] to afford 5-bromo-4,6-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carbonitrile as brown liquid (4.6 g, Yield: 66%).

[0525] TLC system: EtOAc / Hexane (40:90),

[0526] Rf value: -0.6;

[0527] 'HNMR (400 MHz, CDCk) 5: 7.67 (s, 1H), 7.20-7.18 (m, 1H), 5.45 (s, 2H), 3.48 (t, J= 8.0 Hz, 2H), 0.90 (t, J= 8.0 Hz, 2H), -0.04 (s, 9H).

[0528] Synthesis of (Z)-5-bromo-4,6-difluoro-N'-hydroxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide

[0529] To a stirred solution of 5-bromo-4,6-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carbonitrile (4.6 g, 11.89 mmol, 1.0 eq) in EtOH (46 mL) at room temperature, was added EtiN (2.5 mL, 17.8 mmol, 1.5 eq) and NH2OH.HCI (0.9 g, 17.8 mmol, 1.5 eq). The reaction mixture was stirred at 80°C for 4 h. After completion of reaction by TLC, the reaction mixture was diluted with water (35 mL) and extracted with EtOAc (2 xlOO mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-pentane (30 mL), decanted and dried under vacuum to afford (Z)-5-bromo-4,6-difluoro-N'-hydroxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide as off white solid (4.28 g, Crude).

[0530] TLC system: EtOAc / Hexane (50:50),

[0531] Rf value: ~0.2;

[0532] LCMS(m / z): 420.23 (M+H+2)+

[0533] Synthesis of ethyl (Z)-((5-bromo-4,6-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)(hydroxyimino)methyl)carbamate

[0534] To a stirred solution of (Z)-5-bromo-4,6-difluoro-N'-hydroxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide (4.2 g, 10.0 mmol, 1.0 eq) in DCM (84 mL, 20 Vol) at 0°C, was added EtiN (1 mL, 13.0 mmol, 1.3 eq) and 2- ethylchloroformate (1.14 mL, 12.0 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with NaHCCh solution (30 mL) and extracted with EtOAc (2 x 75 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 30% EtOAc in Hexane] to afford ethyl (Z)-((5-bromo- 4,6-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-3- yl)(hydroxyimino)methyl)carbamate as a brown gummy solid (3.6 g, Yield:73%).

[0535] TLC system: EtOAc / Hexane (50:50),

[0536] Rf value: ~0.5;

[0537] LCMS(m / z): 492.32 (M+H)+;

[0538] 'HNMR (400 MHz, CDCh) 5: 7.80 (s, 1H), 7.25-7.23 (m, 1H), 5.44 (s, 4H), 4.37 (q, J= 7.2 Hz, 2H), 3.51 (t, J= 8.0 Hz, 2H), 1.41 (t, J= 7.2 Hz, 2H), 0.93 (t, J= 8.0 Hz, 2H), 0.01 (s, 9H).

[0539] Synthesis of 3-(5-bromo-4,6-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0540] To a stirred solution of ethyl (Z)-((5-bromo-4,6-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)(hydroxyimino)methyl)carbamate (3.6 g, 7.89 mmol, 1.0 eq) in DMSO (13 mL) at 0°C, was added NaOH (378 mg, 9.46 mmol, 1.2 eq) and stirred for 3 h at room temperature. After completion of reaction by TLC, the reaction mixture was diluted with water (30 mL), quenched with 2N HC1 solution (5 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with diethyl ether (20 mL), decanted and dried under vacuum to afford 3-(5- bromo-4,6-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)- 1,2,4- oxadiazol-5(4H)-one as a brown solid (3 g, Yield: 85%).

[0541] TLC system: EtOAc / Hexane (50:50), Rf value: ~0.3;

[0542] LCMS(m / z): 446.2 (M+H)+;

[0543] 'HNMR (400 MHz, CDCh) 5: 10.21 (br, 1H), 7.88 (s, 1H), 7.27-7.25 (m, 1H), 5.51 (s, 2H), 3.54 (t, J= 8.0 Hz, 2H), 0.95 (t, J= 8.0 Hz, 2H), -0.01 (s, 9H).

[0544] Synthesis of 3-(5-bromo-4,6-difluoro-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0545] To a stirred solution of 3-(5-bromo-4,6-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one (3 g, 6.74 mmol, 1.0 eq) in DCM (30 mL) at 0°C, was added TFA (15 mL, 5 Vol) and stirred at room temperature for 3h . Later, reaction mixture was filtered, washed with ether (10 mL) and collected solid was dissolved in aq. NH3 (17 mL), 1,4 Dioxane (17 mL) and stirred at room temperature for 16 h. Reaction mass was concentrated under reduced pressure, diluted with water (20 mL), solid was filtered, washed with ether (10 mL) and dried under vacuum to afford 3-(5-bromo-4,6-difluoro-lH-indol-3-yl)-l,2,4-oxadiazol- 5(4H)-one as off white solid (1 g, crude).

[0546] TLC system: EtOAc (100%),

[0547] Rf value: -0.3;

[0548] LCMS(m / z): 313.9 (M-H)+.

[0549] 'HNMR (400 MHz, DMSO-de) 5: 12.4 (s, 1H), 8.04 (s, 1H), 7.47-7.44 (m, 1H).

[0550] Synthesis of 3-(4,6-difluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one

[0551] In a sealed tube, to a degassed solution of 3-(5-bromo-4,6-difluoro-lH-indol-3- yl)-l,2,4-oxadiazol-5(4H)-one (150 mg, 0.47 mmol, 1.0 eq) and l-(4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (260 mg, 0.95 mmol, 2 eq) in ACN:H2O (1 : 1, 3 mL) at room temperature, was added K2CO3 (131 mg, 0.95 mmol, 2.0 eq) followed by Pd(dppf)C12.DCM (38 mg, 0.047 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with 10% MeOH / DCM (2 ^ 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by Prep-HPLC and lyophilized to afford 3-(4,6-difluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)-l,2,4- oxadiazol-5(4H)-one as a white solid (35 mg, Yield: 19%).

[0552] TLC system: EtOAc (100),

[0553] Rf value: ~0.4;

[0554] LCMS(m / z): 382.1 (M-H)+;

[0555] 'HNMR (400 MHz, DMSO-de) 5: 12.55 (s, 1H), 12.3 (s, 1H), 8.02 (s, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.43 (d, J= 8.0 Hz, 2H), 7.35 (d, J= 9.6 Hz, 1H), 5.56 (s, 1H), 2.46-2.41 (m, 2H), 2.34-2.27 (m, 2H), 1.99-1.95 (m, 1H), 1.75-1.72 (m, 1H).

[0556] Prep Conditions:

[0557] SAMPLE NAME:C0189-34-P

[0558] COLUMN NAME: X-BRIDGE (250 x 19) mm 5 MICRON Buffer MP- (A): 0.1% FA in WATER MP- (B):100% ACN Gradient (T / %B ): 0 / 30,15 / 60,25 / 95 Flow Rate : 13 mL / min Solubility: water, acetonitrile SYNTHETIC EXAMPLE 9

[0559] SYNTHESIS OF COMPOUND 1-12

[0560] Synthesis of 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3- ol

[0561] In a sealed tube, to a degassed solution of 3-(4-bromophenyl)oxetan-3-ol (1 g, 4.36 mmol, 1.0 eq) and B2(pin)2 (1.33 g, 5.23 mmol, 1.2 eq) in THF (20 mL) at room temperature, was added KOAc (1.28 g, 13.1 mmol, 3.0 eq), Pd(dppf)C12 DCM (178 mg, 0.21 mmol, 0.05 eq) and stirred at 80°C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with EtOAc (10 mL), collected filtrate was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol as off white solid (1 g, Yield: Crude).

[0562] TLC system: EtOAc / Hexane (50:50),

[0563] Rf value: ~0.2;

[0564] 'H NMR (400 MHz, CDC ) 5: 7.87 (d, J= 8.4 Hz, 2H), 7.61 (d, J= 8.4 Hz, 2H), 4.91 (s, 4H), 1.35 (s, 12H).

[0565] Synthesis of 3-(6-fluoro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one

[0566] In a sealed tube, to a degassed solution of 3-(5-bromo-6-fluoro-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one (250 mg, 0.84 mmol, 1.0 eq) and 3-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol (374 mg, 1.34 mmol, 1.6 eq) in ACN:H2O (1 : 1, 5 mL) at room temperature, was added K2CO3 (348 mg, 2.52 mmol, 3.0 eq), Pd(dppf)C12DCM (68 mg, 0.08 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was diluted with water (20 mL) and extracted with 20% MeOH / DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica column chromatography [elution with 10-15% MeOH / DCM ] followed by Prep-HPLC and lyophilizing the fractions afforded 3-(6- fluoro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as white solid (55 mg, Yield: 18%).

[0567] TLC system: EtOAc (100),

[0568] Rf value: ~0.4;

[0569] LCMS(m / z): 366.1 (M-H)+;

[0570] 'HNMR (400 MHz, DMSO-cE) 5: 12.66 (s, 1H), 12.02 (s, 1H), 8.02 (d, J= 2.8 Hz, 1H), 7.94 (d, J= 7.6 Hz, 1H), 7.72 (d, J= 8.4 Hz, 2H), 7.58 (dd, J= 1.6 Hz, 8.4 Hz, 2H), 7.48 (d, J= 11.2 Hz, 1H), 6.41 (s, 1H), 4.81 (d, J= 6.8 Hz, 2H), 4.74 (d, J= 6.8 Hz, 2H).

[0571] Prep Conditions

[0572] SUNFIRE C-18(250x l9mm) 5p

[0573] Buffer: MP- (A): 0.1%TFA IN WATER MP- (B): ACN Gradient: (T / %B ) 0.1 / 30,15 / 60,25 / 95..

[0574] Flow Rate: 13 mL / min Solubility: water, acetonitrile, THF

[0575] SYNTHETIC EXAMPLE 10

[0576] SYNTHESIS OF COMPOUND 1-13

[0577] Synthesis of 3-(4,6-difluoro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-lH-indol-3- yl)-l,2,4-oxadiazol-5(4H)-one

[0578] To a stirred solution of 3-(5-bromo-4,6-difluoro-lH-indol-3-yl)-l,2,4-oxadiazol- 5(4H)-one (150 mg, 0.47 mmol, 1.0 eq) in ACN: Water (20 vol, 1 : 1 ratio, 3 mL), was added 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol (265 mg, 0.95 mmol, 2 eq), K2CO3 (198 mg, 0.95 mmol, 2 eq). Reaction mixture was degassed with N2 for 10 min then added Pd(dppf)C12.DCM (39 mg, 0.047 mmol, O.leq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified reverse phase purification and further purified by Prep-HPLC to afford 3-(4,6-difhioro-5-(4-(3- hydroxyoxetan-3-yl)phenyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as Off-white solid (23 mg, Yield 12%),

[0579] TLC system: 10% MeOH in DCM,

[0580] Rf value: ~0.5;

[0581] LCMS (m / z):99.84%, 384.1 (M-H)’.

[0582] 'HNMR (400 MHz, DMSO-cbi) 5: 12.32 (s, 1H), 8.02 (s, 1H), 7.73 (d, J= 8.4 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.36 (d, J= 9.6 Hz, 1H), 6.45 (s, 1H), 4.81 (d, J= 6.8 Hz, 2H), 4.75 (d, J= 6.8 Hz, 2H)

[0583] Prep Conditions:

[0584] X-BRIDGE (250 x 19)mm 5 MICRON Buffer MP- (A): 0.1% FA in WATER MP- (B): 100% ACN Gradient (T / %B ) 0 / 20,15 / 40,25 / 95

[0585] Flow Rate 15 mL / min

[0586] Solubility: water, acetonitrile, THF

[0587] SYNTHETIC EXAMPLE 11

[0588] SYNTHESIS OF COMPOUND 1-14

[0589] Synthesi s of 3 -(5 -(2, 6-dimethoxypyri din-3 -yl)-6-fluoro- 1 H-indol-3 -yl)- 1,2,4- oxadi azol - 5 (4H)-one

[0590] In a sealed tube to a degassed solution of 3-(5-bromo-6-fluoro-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one (250 mg, 0.84 mmol, 1.0 eq) and (2, 6-dimethoxypyri din-3 - yl)boronic acid (308 mg, 1.68 mmol, 2 eq) in ACN / EEO (1 : 1, 5 mL) at room temperature, was added K2CO3 (232 mg, 1.68 mmol, 2.0 eq) followed by Pd(dppf)C12.DCM (68 mg, 0.084 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with 15% MeOH / DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase column chromatography [elution with 35% ACN in 0.1% FA in H2O] to3-(5-(2,6-dimethoxypyridin-3-yl)-6- fhioro-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as white solid (50 mg, Yield: 16%).

[0591] TLC system: EtOAc / Hexane (70:30),

[0592] Rfvalue:~0.25;

[0593] LCMS(m / z): 357.2 (M+H)+; 'H NMR (400 MHz, DMSO-cE) 5: 11.92 (s, 1H), 7.95 (d, J= 2.8 Hz, 1H), 7.78 (d, J= 7.6 Hz, 1H), 7.62 (d, J= 8.0 Hz, 1H), 7.38 (d, J= 10.4 Hz, 1H), 6.48 (d, J= 8.0 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H).

[0594] SYNTHETIC EXAMPLE 12

[0595] SYNTHESIS OF COMPOUND 1-15

[0596] Synthesi s of 3 -(6-fluoro-5 -(2-methoxypyridin-3 -yl)- 1 H-indol-3 -yl)- 1,2,4- oxadi azol - 5 (4H)-one

[0597] In a sealed tube to a degassed solution of 3-(5-bromo-6-fluoro-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one (250 mg, 0.84 mmol, 1.0 eq) and (2-methoxypyridin-3- yl)boronic acid (257 mg, 1.68 mmol, 2 eq) in ACN:H2O (1 : 1, 5 mL) at room temperature, was added K2CO3 (232 mg, 1.68 mmol, 2.0 eq) followed by Pd(dppf)C12.DCM (68 mg, 0.084 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with 15% MeOH / DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase column chromatography [elution with 35% ACN in 0.1% FA in H2O] to afford 37 mg of desired product (XH NMR aromatic impurities). This was re-purified by Prep-HPLC to afford 3-(6-fluoro-5- (2-methoxypyridin-3-yl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as white solid (20 mg, Yield: 7%).

[0598] TLC system: EtOAc / Hexane (70:30),

[0599] Rf value: ~0.3;

[0600] LCMS(m / z): 327.1 (M+H)+; 'H NMR (400 MHz, DMSO- E) 5: 12.66 (br s,lH), 12.01 (s, 1H), 8.33 (s,lH), 8.00 (s, 1H), 7.92- 7.87 (m, 2H), 7.49 (d, J=11.2 Hz, 1H), 6.94 (d, J= 8.4 Hz, 1H), 3.91 (s, 3H).

[0601] Prep Conditions:

[0602] Column :GEMINI Cis (250 x 21.2) mm 5mic

[0603] BuffeuMP- (A): lOmM ABC IN WATER, MP- (B): ACN

[0604] Gradient (T / %B ) : 0.1 / 5,5 / 5,15 / 65,25 / 95

[0605] Flow Rate : 14 mL / min

[0606] Solubility: water, acetonitrile, THF

[0607] SYNTHETIC EXAMPLE 13

[0608] SYNTHESIS OF COMPOUND 1-16

[0609] Synthesi s of 3 -(6-fluoro-5 -(6-methoxypyri din-3 -yl)- 1 H-indol-3 -yl)- 1,2,4- oxadi azol - 5 (4H)-one

[0610] In a sealed tube to a degassed solution of 3-(5-bromo-6-fluoro-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one (250 mg, 0.84 mmol, 1.0 eq) and (6-m ethoxypyri din-3 - yl)boronic acid (395 mg, 1.68 mmol, 2 eq) in ACN:H2O (1 : 1, 5 mL) at room temperature, was added K2CO3 (232 mg, 1.68 mmol, 2.0 eq) followed by Pd(dppf)C12.DCM (68 mg, 0.084 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mass was concentrated under reduced pressure and purified by reverse phase column chromatography [elution with 40% ACN in 0.1% FA in H2O] to afford 120 mg of desired product (LCMS:57% purity). This was repurified by Prep-HPLC to afford 3-(6-fluoro-5-(6-methoxypyridin-3-yl)-lH-indol-3- yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (40 mg, Yield: 14%).

[0611] TLC system: EtOAc (100%), Rf value: ~0.5;

[0612] LCMS(m / z): 327.1 (M+H)+;

[0613] 'HNMR (400 MHz, DMSO-de) 5: 12.65 (br s,lH), 12.04 (s, 1H), 8.24 (dd, J= 2 Hz, 5.2 Hz, 1H), 8.01 (d, J =2.8 Hz, 1H), 7.80 (d, J= 7.2 Hz, 1H), 7.71 (dd, J= 2 Hz, 7.2 Hz, 1H), 7.44 (d, J= 10.4 Hz, 1H),7.13-7.1O (m, 1H), 3.83 (s, 3H).

[0614] Prep Conditions:

[0615] Column: sunfire Cis (250 x 19)mm 5mic

[0616] Buffer: MP- (A): 0.1% TFA in water MP- (B): ACN

[0617] Gradient (T / %B ) : 0.1 / 40,13 / 55,14 / 95,18 / 95,18.20 / 40,22 / 40

[0618] Flow Rate : 12 mL / min

[0619] Solubility: ACN, Water, THF

[0620] SYNTHETIC EXAMPLE 14

[0621] SYNTHESIS OF COMPOUND 1-18

[0622] Synthesis of 3-(5-(tributylstannyl)pyridin-2-yl)oxetan-3-o

[0623] Pd2dba3, (Bu3Sn)2

[0624] In a sealed tube to a degassed solution of 3-(5-bromopyridin-2-yl)oxetan-3-ol (500 mg, 2.17 mmol, 1.0 eq) and (BusSn)2 (1.89 g, 3.26 mmol, 1.5 eq) in 1,4-dioxane (10 mL) at room temperature, was added PCys (60 mg, 0.21 mmol, 0.1 eq) followed by Pd2(dba)3 (99 mg, 0.11 mmol, 0.05 eq) and stirred at 90°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography [elution with 25 - 30% EtOAc in Hexane] to afford 3-(5-(tributylstannyl)pyridin-2-yl)oxetan-3-ol as a brown liquid (600 mg, Yield: 62%).

[0625] TLC system: EtOAc / Hexane (30:70),

[0626] Rf value: ~0.5;

[0627] 'HNMR (400 MHz, CDC ) 5: 8.49 (s, 1H), 7.96-7.92 (m, 2H), 5.09 (d, J= 7.2 Hz, 2H), 4.73 (d, .7= 7.2 Hz, 2H), 1.57-1.51 (m, 6H), 1.39-1.30 (m, 6H), 1.14-1.10 (m, 6H), 0.98-0.85 (m, 9H).

[0628] Synthesi s of 3 -(6-fluoro-5 -(6-(3 -hydroxy oxetan-3 -yl)pyri din-3 -yl)- 1 H-indol-3 - yl)-l,2,4-oxadiazol-5(4H)-one

[0629] In a sealed tube, to a degassed solution of 3-(5-bromo-6-fluoro-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one (200 mg, 0.67 mmol, 1.0 eq) and 3-(5- (tributylstannyl)pyridin-2-yl)oxetan-3-ol (445 mg, 1.01 mmol, 1.5 eq)) in DMF (4 mL) at room temperature, was added Pd(dppf)C12.DCM (28 mg, 0.033 mmol, 0.05 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (15 mL) and extracted with 10% MeOH in DCM (2 * 30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford 3-(6-fluoro- 5-(6-(3-hydroxyoxetan-3-yl)pyridin-3-yl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (60 mg, Yield: 24%).

[0630] TLC system: EtOAc (100%),

[0631] Rf value: -0.3;

[0632] LCMS(m / z): 369.3 (M+H)+; 'H NMR (400 MHz, DMSO-cE) 5: 12.69 (br s, 1H), 12.09 (s, 1H), 8.81 (s, 1H), 8.05-7.97 (m, 3H), 7.72 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 11.2 Hz, 1H), 6.63 (s, 1H), 4.98 (d, J= 6.0 Hz, 2H), 4.70 (d, J= 6.4 Hz, 2H).

[0633] SYNTHETIC EXAMPLE 15

[0634] SYNTHESIS OF COMPOUND 1-21

[0635] Synthesis of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-6-fluoro-l-

[0636] ((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3-carbonitrile

[0637] To a stirred solution of 5-bromo-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-indole-3-carbonitrile (2.0 g, 5.42 mmol, 1.0 eq) in Toluene (40 mL) at room temperature, was added (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (1.2 g, 5.96 mmol, 1.1 eq) and NaOtBu (1.04 g, 10.8 mmol, 2 eq) and Rac-BINAP (203 mg, 0.3 mmol, 0.06 eq), Reaction mixture was degassed with N2 for 10 min then added Pd2(dba)3 (149 mg, 0.1 mmol, 0.03 eq). The reaction mixture was stirred at 120 °C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (35 mL) and extracted with EtOAc (2x50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 30% EtOAc in Hexane] to afford (S)-5-(3-((tert- butyldimethylsilyl)oxy)pyrrolidin- 1 -yl)-6-fluoro- 1 -((2-(trimethylsilyl)ethoxy)methyl)- lH-indole-3-carbonitrile as a pale yellow liquid (1.0 g, Yield: 37%).

[0638] TLC system: EtOAc / Hexane (50:50), Rf value: ~0.8;

[0639] LCMS (m / z): 490.4 (M+H)+.

[0640] 'HNMR (400 MHz, CDC ) 5: 7.54 (s, 1H), 7.19 (d, J= 13.2 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H), 4.54-4.52 (m, 1H), 3.70-3.65 (m, 1H), 3.51-3.40 (m, 4H), 3.23-3.19 (m, 1H), 2.15-2.10 (m, 1H), 1.97-1.94 (m, 1H), 0.91 (s, 9H), 0.90-0.87 (m, 2H), 0.09 (s, 6H), -0.04 (s, 9H).

[0641] Synthesis of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-6-fluoro-N- hydroxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide

[0642] To a stirred solution of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-6- fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3-carbonitrile (1 g, 2.04 mmol, 1.0 eq) in EtOH (10 mL) at room temperature, was added EtiN (0.7 mL, 4.09 mmol, 2 eq) and NH2OH.HCI (284 mg, 4.09 mmol, 2 eq). The reaction mixture was stirred at 90 °C for 3 h. After completion of reaction by TLC, the reaction mixture was diluted with water (35 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-6-fluoro-N- hydroxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide as a color less liquid (950 mg, Crude).

[0643] TLC system: EtOAc / Hexane (30:70),

[0644] Rf value: -0.2;

[0645] LCMS (m / z): 523.4 (M+H)+.

[0646] 'HNMR (400 MHz, CDCt) 5: 7.36 (s, 1H), 7.31 (d, J= 8.8 Hz, 1H), 7.14 (d, J = 13.2 Hz, 1H), 5.35 (s, 2H), 4.54-4.52 (m, 1H), 3.68-3.65 (m, 1H), 3.50-3.38 (m, 4H), 3.19-3.16 (m, 1H), 2.16-1.89 (m, 2H), 0.91-0.86 (s, 11H), 0.09 (s, 3H), 0.08 (s, 3H), - 0.05 (s, 9H). Synthesis of ethyl (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-N- ((ethoxycarbonyl)oxy)-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3- carboximidamide

[0647] To a stirred solution of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-6- fluoro-N-hydroxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide (950 mg, 1.82 mmol, 1.0 eq) in DCM (9.5 mL, 10 Vol) at 0°C, was added EtiN (0.3 mL, 2.36 mmol, 1.3 eq) and 2-Ethylchloroformate (0.2 mL, 2.18 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with NaHCCh solution (10 mL) and extracted with EtOAc (2 x75 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford crude product. The crude product was purified by RP column afforded ethyl (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-N- ((ethoxycarbonyl)oxy)-6-fluoro-l-((2-(trimethylsilyl)ethoxy) methyl)- lH-indole-3- carboximidamide as a brown gummy solid (500 mg, Yield:46%).

[0648] TLC system: EtOAc / Hexane (50:50),

[0649] Rf value: ~0.8;

[0650] LCMS (m / z): 595.4 (M+H)+.

[0651] Synthesis of (S)-3-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-6-fluoro- l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one To a stirred solution of ethyl (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l- yl)-N-((ethoxycarbonyl)oxy)-6-fluoro- 1 -((2-(trimethylsilyl)ethoxy)methyl)- IH-indole- 3-carboximidamide (500 mg, 0.84 mmol, 1.0 eq) in DMSO (1.75 mL) at 0°C, was added NaOH (40 mg, 1.01 mmol, 1.2 eq) and stirred for 2 h at room temperature. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL), quenched with 2N HC1 solution (1 mL) resulting solid was filtered & dried to afford (S)-3 -(5-(3 -((tert-butyldimethylsilyl)oxy)pyrrolidin- 1 -yl)-6-fluoro- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as a brown solid (400 mg, Yield: 36%).

[0652] TLC system: EtOAc / Hexane (50:50),

[0653] Rf value: ~0.2;

[0654] LCMS(m / z):549.50 (M+H)+.

[0655] Synthesis of (S)-3-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-6-fluoro- l-(hydroxymethyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0656] To a stirred solution of (S)-3-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l- yl)-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol- 5(4H)-one (200 mg, 0.36 mmol, 1.0 eq) in DCM (2 M, 10 Vol) at 0°C, was added TFA (2 mL,10 Vol) and stirred at room temperature for 16h. After completion of reaction by TLC, the reaction mixture concentrated, triturated with pentane (10 mL) to afford (S)-3- (5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-6-fluoro-l-(hydroxymethyl)-lH- indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as brown solid (350 mg, crude).

[0657] TLC system: EtOAc (100%),

[0658] Rf value: -0.2;

[0659] LCMS (m / z): 335.23 (M+H)+ Synthesis of (S)-3-(6-fhroro-5-(3-hydroxypyrrolidin-l-yl)-lH-indol-3-yl)-l,2,4- oxadi azol - 5 (4H)-one

[0660] To a stirred solution of (S)-3-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l- yl)-6-fluoro- 1 -(hydroxymethyl)- lH-indol-3 -yl)- 1 ,2,4-oxadiazol-5(4H)-one (350 mg, 1.04 mmol, 1.0 eq) in Dioxane (3.5 mL) added aq. NH3 (3.5 mL) and stirred at room temperature for 16 h. Reaction mass was concentrated under reduced pressure, diluted with water (20 mL), solid filtered, washed with water & ether (10 mL) and lyophilized to afford (S)-3 -(6-fluoro-5-(3 -hydroxypyrrolidin- 1 -yl)- lH-indol-3 -yl)- 1 ,2,4-oxadiazol- 5(4H)-one as pale brown solid (82 mg, Yield: 26% ).

[0661] TLC system: EtOAc (100%),

[0662] Rf value: ~0.2;

[0663] LCMS (m / z): 305.1 [M+H]+.

[0664] 'HNMR (400 MHz, DMSO-cE) 5: 12.55 (br, s, 1H), 11.66 (s, 1H), 7.84 (d, J= 2.8 Hz, 1H), 7.28 (d, J= 13.6 Hz, 1H), 7.17 (d, J= 8.8 Hz, 1H), 4.91 (d, J= 4.0 Hz, 1H), 4.37 (brs, 1H), 3.54-3.50 (m, 1H), 3.43-3.34 (m, 1H), 3.25-3.21 (m, 1H), 3.09- 3.06 (m, 1H), 2.07-2.02 (m, 1H), 1.87-1.81 (m, 1H).

[0665] SYNTHETIC EXAMPLE 16

[0666] SYNTHESIS OF COMPOUND 1-23

[0667] Synthesis of l,2-bis(5-bromo-lH-indol-3-yl)disulfane Thio urea, KI,

[0668] To a stirred solution of 5-bromo-lH-indole (5 g, 25.5 mmol, 1.0 eq) in MeOH (80 mL) Water (20 mL) at room temperature, was added Thio urea (1.93 g, 25.5 mmol, 1.0 eq), I2 (6.32 g, 25.5 mmol, 1.0 eq) and KI (4.15 g, 25.5 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was treated with 2N aq. NaOH solution (10 mL) & THF (10 mL) (clear solution) and stirred at 100 °C for 30 min. RM was concentrated under reduced pressure. The reaction mixture was diluted with H2O (50 mL), resulting precipitate was filtered and dried under vacuum. The crude product was triturated with diethyl ether (20 mL), filtered and dried under reduced pressure to afford l,2-bis(5-bromo-lH-indol-3- yl)disulfane as an off white solid (2.2 g, Yield 38%).

[0669] TLC system: EtOAc / Hexane (50:50) or MeOH in DCM (10:90),

[0670] Rf value: ~0.3;

[0671] LCMS (m / z): 80%, 450.87 (M-H)’.

[0672] Synthesis of diethyl (((5-bromo-lH-indol-3-yl)thio)methyl)phosphonate To a stirred solution of l,2-bis(5 -bromo- lH-indol-3-yl)disulfane (1.5 g, 3.31 mmol, 1.0 eq) in THF (15 mL) at RT, was added 2,2',2"-phosphanetriyltriacetic acid (1.89 g, 6.62 mmol, 2.0 eq) and stirred for 16 h . After completion of reaction by TLC, & LC-MS. LC-MS indicated 75% m / z. Later, added diethyl (iodomethyl)phosphonate (2 g, 6.62 mmol, 2.0 eq) and TEA (2.3 mL, 16.5 mmol, 5 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 0.5-1% Me OH in DCM] to afford diethyl (((5-bromo-lH-indol-3- yl)thio)methyl)phosphonate as a pale brown oil (0.5 g, 67% pure).

[0673] TLC system: EtOAc / Hexane (50:50),

[0674] Rf value: ~0.3;

[0675] LCMS(m / z): 378.03 (M-H)+; 67% purity.

[0676] Synthesis of diethyl (S)-(((5-(4-(3-hydroxypyrrolidin-l-yl)phenyl)-lH-indol-3- yl)thio)methyl)phosphonate

[0677] To a stirred solution of diethyl (((5-bromo-lH-indol-3- yl)thio)methyl)phosphonate (500 mg, 1.32 mmol, 1.0 eq) in dioxane (8 mL, 20 Vol), water (2 mL,), was added (S)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrrolidin-3-ol (495 mg, 1.72 mmol, 1.3 eq), K2CO3 (538 mg, 3.96 mmol, 3 eq). Reaction mixture was degassed with N2 for 10 min then added Pd(dppf)C12-DCM (107 mg, 0.13 mmol, O.leq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 2-4% MeOH in DCM] to afford diethyl (S)-(((5-(4-(3-hydroxypyrrolidin-l-yl)phenyl)-lH- indol-3-yl)thio)methyl)phosphonate as a brown liquid (400 mg, semi-pure).

[0678] TLC system: EtOAc,

[0679] Rf value: ~0.3;

[0680] LCMS (m / z): 461.37 (M+H)+; 66% purity.

[0681] Synthesis of (S)-(((5-(4-(3-hydroxypyrrolidin-l-yl)phenyl)-lH-indol-3- yl)thio)methyl)phosphonic acid

[0682] To a stirred solution of diethyl (S)-(((5-(4-(3-hydroxypyrrolidin-l-yl)phenyl)- lH-indol-3-yl)thio)methyl)phosphonate (200 mg, 0.45 mmol, 1.0 eq) in DCM (10 mL), at 0°C, was added TMSBr (0.5 mL) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was concentrated, diluted with water (2 mL), basified with 2M NaOH solution, washed with EtOAc (2 x 10 mL). Aqueous layer was acidified with 2N aq. HC1 (pH - 2) and evaporated under reduced pressure. The crude product was purified by prep-HPLC to afford (S)-(((5-(4-(3- hydroxypyrrolidin-l-yl)phenyl)-lH-indol-3-yl)thio)methyl)phosphonic acid as a white solid (29.5 mg, Yield 15%).

[0683] TLC system: MeOH / DCM (10:90),

[0684] Rf value :0;

[0685] LCMS (m / z): 403.16 (M-H)+. 'H NMR (400 MHz, I)MS()-d6) 5: 11.31 (s, 1H), 7.80 (s, 1H), 7.54-7.51 (m, 3H), 7.43-7.36 (m, 2H), 6.60 (d, J= 8.8 Hz, 2H), 4.99 (br, s, 1H), 4.43-4.40 (m, 1H), 3.47-3.28 (m, 3H), 3.13-3.10 (m, 1H), 2.86 (d, J= 13.6 Hz, 2H), 2.09-2.04 (m, 1H). 1.93-1.91 (m, 1H).

[0686] Prep-HPLC Method:

[0687] Prep Conditions: Column YMC C-18 (250 x 19)mm 5mic

[0688] Buffer MP- (A): 0.1% FA IN WATER MP- (B): CAN Gradient (T / %B ) 0 / 25,12 / 40,12.5 / 95,17 / 95,18.1 / 25,22 / 95

[0689] Flow Rate 12 mL / min

[0690] Solubility: acetonitrile, water

[0691] SYNTHETIC EXAMPLE 17

[0692] SYNTHESIS OF COMPOUND 1-24

[0693] Synthesis of l,2-bis(5-bromo-6-fluoro-lH-indol-3-yl)disulfane

[0694] Thio urea, KI,

[0695] To a stirred solution of 5-bromo-6-fluoro-lH-indole (5 g, 23.5 mmol, 1.0 eq) in MeOH (80 mL), water (20 mL) at room temperature, was added Thio urea (1.75 g, 23.5 mmol, 1.0 eq), 12 (5.8 g, 23.5 mmol, 1.0 eq) and KI (3.8 g, 23.5 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was treated with 2N aq. NaOH solution (20 mL) & THF (20 mL) (clear solution) and stirred at 80 °C for 30 min. RM was concentrated under reduced pressure, diluted with H2O (50 mL), resulting precipitate was filtered, triturated with diethyl ether (20 mL) and dried under vacuum to afford l,2-bis(5-bromo-6-fluoro- lH-indol-3-yl)disulfane as off white solid (2.2 g, Yield 40%).

[0696] TLC system: MeOH in DCM (10:90),

[0697] Rf value: ~0.3;

[0698] LCMS (m / z): 486.90 (M-H)+. 'HNMR (400 MHz, DMSO-d6) 5: 11.86 (brs, 1H), 7.54 (s, 1H), 7.43 (d, J= 9.6 Hz, 1H), 7.16 (d, J = 6.8 Hz, 1H).

[0699] Synthesis of diethyl (((5-bromo-6-fluoro-lH-i yl)thio)methyl)phosphonate

[0700] To a stirred solution of l,2-bis(5-bromo-6-fluoro-lH-indol-3-yl)disulfane (1 g, 2.04 mmol, 1.0 eq) in THF (10 mL) was added 2,2',2"-phosphanetriyltriacetic acid (1.17 g, 4.09 mmol, 2.0 eq) at room temperature and stirred for 16 h. Later, added diethyl (iodomethyl)phosphonate (1.13 mL, 4.09 mmol, 2.0 eq) and TEA (1.1 mL, 10.2 mmol, 5 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 0.5-1% MeOH in DCM\ to afford diethyl (((5-bromo-6-fluoro-lH-indol-3- yl)thio)methyl)phosphonate as pale brown oil (0.5 g, Yield 61%).

[0701] TLC system: MeOH in DCM (10:90),

[0702] Rfvalue:~0.35;

[0703] LCMS(m / z): 396.16 (M+H)+; 'H NMR (400 MHz, CDCls) 5: 9.92 (s, 1H), 7.87 (d, J= 6.8 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H), 7.07 (d, J= 92 Hz, 1H), 4.20-4.11 (m, 4H), 2.95 (d, J= 12.4 Hz, 2H), 1.34 (t, J= 6.8 Hz, 6H).

[0704] Synthesis of (S)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrrolidin-3 -ol

[0705] To a stirred solution of 2-(4-iodophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (2 g, 6.06 mmol, 1.0 eq) in DMSO (20 mL) at room temperature, was added (S)-pyrrolidin-3-ol HC1 (2 g, 12.1 mmol, 2 eq), K2CO3 (1.6 g, 12.1 mmol, 2 eq). Cui (228 mg, 1.21 mmol, 0.2 eq) and L-proline (276 mg, 2.42 mmol, 0.4 eq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (2 x50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 15 % EtOAc in Hexane] to afford (S)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-ol as an off white solid (800 mg, Yield 45%).

[0706] TLC system: EtOAc / Hexane (30:70),

[0707] Rf value: ~0.2;

[0708] LCMS (m / z): 290.36 (M+H)+.

[0709] 'HNMR (400 MHz, CDC ) 5: 7.46 (d, J= 8.4 Hz, 2H), 6.47 (d, J= 8.8 Hz, 2H), 4.96 (d, J= 3.6 Hz, 1H), 4.39 (brs, 1H), 3.42-3.25 (m, 2H), 3.10-3.07 (m, 1H), 2.06-1.98 (m, 1H), 1.91-1.87 (m, 1H), 1.25 (s, 12H).

[0710] Synthesis of diethyl (S)-(((6-fhioro-5-(4-(3-hydroxypyrrolidin-l-yl)phenyl)-lH- indol-3-yl) thio)methyl)phosphonate

[0711] To a stirred solution of diethyl (((5-bromo-6-fluoro-lH-indol-3- yl)thio)methyl)phosphonate (200 mg, 0.51 mmol, 1.0 eq) in dioxane (3 mL), water (1 mL) was added (S)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrrolidin-3-ol (231 mg, 0.82 mmol, 1.6 eq), K2CO3 (331 mg, 1.53 mmol, 3 eq). Reaction mixture was degassed with N2 for 10 min then added Pd(dppf)C12.DCM (40 mg, 0.05 mmol, O.leq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 2-4% MeOH in DCM] to afford diethyl (S)-(((6-fluoro-5-(4-(3-hydroxypyrrolidin-l- yl)phenyl)-lH-indol-3-yl)thio)methyl)phosphonate as brown liquid (150 mg, Yield 61%).

[0712] TLC system: EtOAc,

[0713] Rf value: ~0.3;

[0714] LCMS (m / z): 479.38 (M+H)+.

[0715] 'HNMR (400 MHz, DMSO-d6) 5: 11.44 (s, 1H), 7.61-7.58 (m, 2H), 7.39 (d, J= 7.2 Hz, 2H), 7.25 (d, J= 11.6 Hz, 1H), 6.60 (d, J= 8.8 Hz, 2H), 4.98 (d, J= 3.6 Hz, 1H), 4.42 (brs, 1H), 3.99-3.93 (m, 4H), 3.47-3.45 (m, 1H), 3.38-3.32 (m, 1H), 3.10- 3.07 (m, 2H), 2.09-2.06 (m, 1H), 1.95-1.93 (m, 1H), 1.16 (t, J= 7.2 Hz, 6H).

[0716] Synthesis of diethyl (S)-(((6-fhioro-5-(4-(3-hydroxypyrrolidin-l-yl)phenyl)-lH- indol-3 -yl)thio)methyl)phosphonic acid

[0717] To a stirred solution of diethyl (S)-(((6-fluoro-5-(4-(3-hydroxypyrrolidin-l- yl)phenyl)-lH-indol-3-yl)thio)methyl)phosphonate (130 mg, 0.27 mmol, 1.0 eq) in DCM (3 mL) at 0 °C, was added TMSBr (0.13 mL) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was concentrated, diluted with water (2 mL), basified with 2M aq. NaOH solution, washed with EtOAc (2 xlO mL). Followed by acidification of aq. layer with 2N HC1 (pH ~ 2) and concentrated under reduced pressure. The crude product was purified by prep-HPLC to afford (S)- (((6-fluoro-5 -(4-(3 -hy droxypyrrolidin- 1 -yl)phenyl)- 1 H-indol-3 - yl)thio)methyl)phosphonic acid as a white solid (17 mg, Yield 15%).

[0718] TLC system: MeOH / DCM (10:90),

[0719] Rfvalue:0.1;

[0720] LCMS (m / z): 421.15 (M-H)’.

[0721] 'HNMR (400 MHz, DMSO-de) 5: 11.29 (s, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.48 (d, 1H), 7.35 (d, J= 7.2 Hz, 2H), 7.21 (d, J= 11.6 Hz, 1H), 6.55 (d, J= 8.8 Hz, 2H), 4.94 (br, 1H), 4.40 (brs, 1H), 3.45-3.26 (m, 3H), 3.10 (d, J= 9.2 Hz, 1H), 2.77 (d, J= 14 Hz, 2H), 2.09-2.03 (m, 1H), 1.95-1.90 (m, 1H).

[0722] Prep-HPLC Method:

[0723] COLUMN NAME: YMC TRIAT Cis (250 x 19) mm 5 MICRON

[0724] Buffer: MP- (A):0.1% FA IN WATER MP- (B):- ACN:WATER(85: 15) Gradient: (T / %B ) 0 / 30,12 / 60, 12.2 / 95,16 / 95,16.2 / 30,19 / 30

[0725] Flow Rate 12mL / min,

[0726] Solubility: water, acetonitrile, THF SYNTHETIC EXAMPLE 18

[0727] SYNTHESIS OF COMPOUND 1-25

[0728] Synthesi s of 1 ,2-bi s(5 -bromo-4, 6-difluoro- 1 H-indol-3 -yl)disulfane

[0729] To a stirred solution of 5-bromo-4,6-difluoro-lH-indole (2 g, 8.62 mmol, 1.0 eq) in MeOH (32 mL), water (8 mL) at room temperature, was added Thio urea (923 g, 12.9 mmol, 1.5 eq), I2 (3.2 g, 12.9 mmol, 1.5 eq) and KI (2.14 g, 12.9 mmol, 1.5 eq), The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was treated with 2N aq. NaOH solution (10 mL) & THF (10 mL) (clear solution) and stirred at 100 °C for 30 min. RM was concentrated, diluted with H2O (50 mL), resulting precipitate was filtered, triturated with diethyl ether (20 mL) & filtered and dried under reduced pressure to afford l,2-bis(5-bromo-4,6- difluoro-lH-indol-3-yl)disulfane as off white solid ( 480 mg, Yield 22%).

[0730] TLC system: MeOH in DCM (10:90),

[0731] Rf value: ~0.3;

[0732] LCMS (m / z): 486.90 (M+H)+.

[0733] Synthesis of diethyl (((5-bromo-4,6-difluoro-lH-indol-3- yl)thio)methyl)phosphonate

[0734] To a stirred solution of l,2-bis(5-bromo-4,6-difluoro-lH-indol-3-yl)disulfane (600 mg, 1.14 mmol, 1.0 eq) in THF (6 mL), was added PCy3 (641 mg, 2.28 mmol, 2.0 eq) and stirred at room temperature for 16 h . Later, added diethyl (iodomethyl)phosphonate (637 mg, 2.28 mmol, 2.0 eq) and TEA (0.33 mL, 2.28 mmol, 2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with water (40 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 0.5-1% MeOH in DCM] to afford diethyl (((5-bromo-4,6-difhioro-lH-indol-3- yl)thio)methyl)phosphonate as a pale brown oil (0.5 g, Yield 95%).

[0735] TLC system: MeOH in DCM (10:90),

[0736] Rf value: ~0.4; LCMS(m / z): 414 (M+H)+.

[0737] Synthesis of diethyl (diethyl (S)-(((4,6-difluoro-5-(4-(3-hydroxypyrrolidin-l- yl)phenyl)-lH-indol-3-yl)thio)methyl)phosphonate

[0738] To a stirred solution of diethyl (((5-bromo-4,6-difluoro-lH-indol-3- yl)thio)methyl)phosphonate (400 mg, 0.97 mmol, 1.0 eq) in dioxane (8 mL), water (3 mL), was added (S)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrrolidin-3-ol (447 mg, 1.54 mmol, 1.6 eq), K2CO3 (400 mg, 2.91 mmol, 3 eq). Reaction mixture was degassed with N2 for 10 min then added Pd(dppf)C12.DCM (78 mg, 0.096 mmol, O.leq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, diluted with water (50 mL) and extracted with EtOAc (2 x40 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 2-4% MeOH in DCM] to afford diethyl (S)-(((4,6-difluoro-5-(4-(3-hydroxypyrrolidin-l-yl)phenyl)-lH-indol-3- yl)thio)methyl)phosphonate as brown liquid (300 mg, Yield: 62%),

[0739] TLC system: EtOAc,

[0740] Rf value: ~0.2;

[0741] LCMS (m / z): 497.28 (M+H)+.

[0742] Synthesis of (S)-(((4,6-difhioro-5-(4-(3-hydroxypyrrolidin-l-yl)phenyl)-lH- indol-3 -yl)thio)methyl)phosphonic acid

[0743] To a stirred solution of diethyl (S)-(((4,6-difluoro-5-(4-(3-hydroxypyrrolidin-l- yl)phenyl)-lH-indol-3-yl)thio)methyl)phosphonate (130 mg, 0.26 mmol, 1.0 eq) in DCM (3 mL) at 0 °C was added TMSBr (0.13 mL) and stirred at room temperature for 16 h. After completion of reaction by TLC, volatiles removed under vacuum, diluted with water (10 mL), basified with 2M aq. NaOH solution, washed with EtOAc (2 x10 mL). Followed by acidification of aq. layer with 2N HC1 (pH ~ 2), evaporated and purified by prep-HPLC to afford (S)-(((4,6-difluoro-5-(4-(3-hydroxypyrrolidin-l- yl)phenyl)-lH-indol-3-yl)thio)methyl)phosphonic acid as a white solid (31 mg, Yield 26%).

[0744] TLC system: MeOH / DCM (10:90),

[0745] Rfvalue:0.1;

[0746] LCMS (m / z): 441.2 (M+H)+.

[0747] 'HNMR (400 MHz, DMSO-de) 5: 11.54 (s, 1H), 7.38 (s, 1H), 7.21 (d, J= 8.4 Hz, 2H), 7.07 (d, J= 10 Hz, 1H), 6.57 (d, J= 8.4 Hz, 2H), 5.03 (brs, 1H), 4.41 (m, 1H), 3.35-3.31 (m, 2H), 3.13-3.10 (m, 2H), 2.81 (d, J= 14 Hz, 2H), 2.08-2.04 (m, 1H), 1.95- 1.91 (m, 1H).

[0748] Prep-HPLC Method:

[0749] Column GEMINI C-18 (250 x 21.2)mm 5mic

[0750] Buffer MP- (A): 0.1% FA IN WATER MP- (B): ACN Gradient (T / %B ) 0 / 25,15 / 50,25 / 95

[0751] Flow Rate 13 mL / min

[0752] Solubility: acetonitrile, water

[0753] SYNTHETIC EXAMPLE 19

[0754] SYNTHESIS OF COMPOUND 1-27

[0755] Synthesis of 1,2-bis (5-bromo-lH-indol-3-yl)disulfane To a stirred solution of 5-bromo-lH-indole (5 g, 25.5 mmol, 1.0 eq) in MeOH (80 mL) & Water (20 mL) at room temperature, was added thio urea (1.93 g, 25.5 mmol, 1.0 eq), I2 (6.32 g, 25.5 mmol, 1.0 eq) and KI (4.15 g, 25.5 mmol, 1.0 eq), The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was treated with 2N NaOH solution (10 mL) & THF (10 mL) (clear solution) and stirred at 100 °C for 30 min. RM was concentrated under reduced pressure. The reaction mixture was diluted with H2O (50 mL), resulting precipitate was filtered, triturated with diethyl ether (20 mL) and dried under vacuum to afford l,2-bis(5-bromo-lH-indol-3-yl)disulfane as off white solid (2.2 g, Yield 38% ).

[0756] TLC system: EtOAc / Hexane (50:50) or MeOH in DCM (10:90),

[0757] Rf value: ~0.3;

[0758] LCMS (m / z): 80%, 450.87 (M-H)+.

[0759] Synthesis of (ethoxy(methyl)phosphoryl)methyl 4-methylbenzenesulfonate (Int-

[0760] To a stirred solution of (di ethoxyphosphoryl)m ethyl 4-methylbenzenesulfonate (500 mg, 1.55 mmol, 1.0 eq) in dry toluene (3 mL) at 0 °C was added PCI5 (484 mg, 2.32 mmol, 1.5 eq) and stirred for 20 min, later allowed to room temperature, stirred for 16h. The reaction mixture was concentrated, diluted with dry THF (3 mL), cooled to - 78° C and added 3M CHiMgBr (0.5 mL, 1.55 mmol, l.Oeq.). Reaction mixture was stirred at same temperature for 1 h. After completion of reaction by TLC, quenched with saturated ammonium chloride solution and extracted with EtOAc (2 x 20 mL). Organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 2-4% MeOH in DCM] to afford (ethoxy(methyl)phosphoryl)methyl 4-methylbenzenesulfonate as white solid (250 mg, Yield 55%).

[0761] TLC system: MeOH / DCM (10:90), Rfvalue:0.3;

[0762] LCMS (m / z): 293.10 (M+H)+.

[0763] ‘HNMR (400 MHz, DMSO-d6) 5: 7.84 (d, J= 8.0 Hz, 2H), 7.51 (d, J= 8.0 Hz, 2H), 4.36-4.27 (m, 2H), 3.98-3.82 (m, 2H), 2.44 (s, 3H), 1.43 (d, J= 14.8 Hz, 3H), 1.16 (t, .7= 7.2 Hz, 3H),

[0764] Synthesis of ethyl (((5-bromo-lH-indol-3-yl)thio)methyl)(methyl)phosphinate

[0765] To a stirred solution of 1 ,2-bis(5 -bromo- lH-indol-3-yl)disulfane (2 g, 4.42 mmol, 1.0 eq) in THF (20 mL), was added 2,2',2"-phosphanetriyltriacetic acid (3 g, 10.6 mmol, 2.4 eq) at room temperature, The reaction mixture was stirred at room temperature for 16 h . After completion of reaction by LC-MS, added (ethoxy(methyl)phosphoryl)methyl 4-methylbenzenesulfonate (2.4 g, 8.84 mmol, 2.0 eq) and TEA (3.18 mL, 22.1 mmol, 5 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 0.5-1% MeOH in DCM\ to afford ethyl (((5- bromo-lH-indol-3-yl)thio)methyl)(methyl)phosphinate as a pale brown oil (450 mg, Yield 30%).

[0766] TLC system: EtOAc / Hexane (50:50),

[0767] Rf value: ~0.4;

[0768] LCMS(m / z): 85%, 346.05 (M-H)'.

[0769] 'HNMR (400 MHz, CDC ) 5: 8.61 (brs, 1H), 7.87 (s, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.33 (dd, J= 8.4, 1.6 Hz, 1H), 7.19-7.17 (m, 1H), 4.08-4.03 (m, 1H), 3.96-3.88 (m, 1H), 3.04-2.91 (m, 2H), 1.26 (t, J= 7.2 Hz, 3H). P-CH3 protons might be merging with solevnts peak.

[0770] Synthesis of ethyl (((5-(4-((S)-3-hydroxypyrrolidin-l-yl)phenyl)-lH-indol-3- yl)thio)methyl)(methyl)phosphinate

[0771] To a stirred solution of ethyl (((5-bromo-lH-indol-3- yl)thio)methyl)(methyl)phosphinate (450 mg, 1.29 mmol, 1.0 eq) in Dioxane (7 mL), water (2 mL), was added (S)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrrolidin-3-ol (448 mg, 1.55 mmol, 1.2 eq), K2CO3 (356 mg, 2.58 mmol, 2 eq). Reaction mixture was degassed with N2 for 10 min then added Pd(dppf)C12.DCM (105 mg, 0.13 mmol, O.leq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 2-4% MeOH in DCM] to afford ethyl (((5-(4-((S)-3-hydroxypyrrolidin-l- yl)phenyl)-lH-indol-3-yl)thio)methyl)(methyl)phosphinate as a brown gummy solid (350 mg, Yield:63%).

[0772] TLC system: EtOAc Rf value: ~0.3;

[0773] LCMS (m / z):95%, 431.31 (M+H)+.

[0774] Synthesis of diethyl ((((5-(4-((S)-3-hydroxypyrrolidin-l-yl)phenyl)-lH-indol-3- yl)thio)methyl)(methyl)phosphinic acid

[0775] To a stirred solution of diethyl ethyl (((5-(4-((S)-3-hydroxypyrrolidin-l- yl)phenyl)-lH-indol-3-yl)thio)methyl)(methyl)phosphinate (350 mg, 5.4 mmol, 1.0 eq) in DCM (3 mL) at 0 °C was added TMSBr (0.35 mL) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was concentrated, diluted with water (10 mL), basified with 2M NaOH solution, washed with EtOAc (2 x 10 mL). Aqueous layer was acidified with 2N HC1 (pH - 2) and concentrated under reduced pressure to afford crude product. The crude product was purified by prep- HPLC provided (((5-(4-((S)-3-hydroxypyrrolidin-l-yl)phenyl)-lH-indol-3- yl)thio)methyl)(methyl)phosphinic acid as Off white solid (29 mg, Yield 8.5%).

[0776] TLC system: MeOH / DCM (10:90),

[0777] Rf value :0;

[0778] LCMS (m / z): 403.20 (M+H)+.

[0779] 'HNMR (400 MHz, DMSO-d6, D2O ex) 5: 11.33 (s, 1H), 7.75 (s, 1H), 7.54 (d, J= 2.4 Hz, 1H), 7.51 (d, J= 8.4 Hz, 2H), 7.41 (d, J= 8.4 Hz, 1H), 7.38-7.35 (m, 1H), 6.58 (d, J= 8.4 Hz, 2H), 4.97 (brs, 1H), 4.41 (brs, 1H), 3.46-3.37 (m, 3H), 3.11-3.09 (m, 1H), 2.89 (d, .7= 11.2 Hz, 2H), 2.07-2.01 (m, 1H), 1.92-1.88 (m, 1H), 1.32 (d, J = 14.4 Hz, 3H).

[0780] Prep Conditions:

[0781] Crude purity (HPLC / LCMS) 67

[0782] Column GEMINI (250 x 21.2) mm 5mic Buffer MP- (A): 0.1% FA IN WATER MP- (B): CAN Gradient (T / %B ) 0 / 20,15 / 55,25 / 95 Flow Rate 14 mL / min

[0783] Solubility: acetonitrile, THF

[0784] SYNTHETIC EXAMPLE 20

[0785] SYNTHESIS OF COMPOUND 1-28

[0786] Synthesis of ethyl (((5-bromo-6-fluoro-lH-indol-3- yl)thio)methyl)(methyl)phosphinate

[0787] To a stirred solution of l,2-bis(5-bromo-6-fluoro-lH-indol-3-yl)disulfane (550 mg, 1.12 mmol, 1.0 eq) in THF (10 mL), was added 2,2',2"-phosphanetriyltriacetic acid (644 mg, 2.25 mmol, 2.0 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, added (ethoxy(methyl)phosphoryl)methyl 4- methylbenzenesulfonate (658 mg, 2.25 mmol, 2.0 eq), TEA (0.8 mL, 5.56 mmol, 5 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with water (40 mL) and extracted with EtOAc (3x 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 2-5% MeOH in DCM] to afford ethyl (((5-bromo-6-fluoro-lH-indol-3- yl)thio)methyl)(methyl)phosphinate as a pale brown oil (0.5 g, Yield 49%).

[0788] TLC system: EtOAc / Hexane (50:50),

[0789] Rf value: ~0.3;

[0790] 'HNMR (400 MHz, CDC ) 5: 9.08 (s, 1H), 7.87 (d, J= 6.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.11 (d, J= 8.8 Hz, 1H), 4.11-3.94 (m, 2H), 2.95 (d, J= 10.4 Hz, 2H), 1.60 (d, 3H), 1.27 (t, J= 7.2 Hz, 3H).

[0791] Synthesis of ethyl (((6-fluoro-5-(4-((S)-3-hydroxypyrrolidin-l-yl)phenyl)-lH- indol-3-yl)thio)methyl)(methyl)phosphinate

[0792] To a stirred solution of ethyl (((5-bromo-6-fluoro-lH-indol-3- yl)thio)methyl)(methyl)phosphinate (500 mg, 1.37 mmol, 1.0 eq) in dioxane (8 mL), water (2 mL) was added (S)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrrolidin-3-ol (475 mg, 1.64 mmol, 1.2 eq), K2CO3 (378 mg, 2.74 mmol, 2 eq). Reaction mixture was degassed with N2 for 10 min then added Pd(dppf)C12.DCM (111 mg, 0.137 mmol, O.leq) and stirred at 100 °C for 16 h. After completion of reaction by TLC, diluted with water (20 mL) and extracted with EtOAc (2 x20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 2-4% MeOH in DCM] to afford ethyl (((6-fluoro-5-(4-((S)-3-hydroxypyrrolidin-l-yl)phenyl)-lH-indol-3- yl)thio)methyl)(methyl)phosphinate as brown solid (400 mg, Yield 65%).

[0793] TLC system: 10% MeOH in DCM, Rf value: ~0.4;

[0794] LCMS (m / z): 449.32 (M+H)+.

[0795] 'HNMR (400 MHz, CDC13) 5: 8.55 (brs, 1H), 7.68 (d, J= 7.6 Hz, 1H), 7.52- 7.48 (m, 2H), 7.42 (d, J= 2.4 Hz, 1H), 7.14 (d, J= 10.8 Hz, 1H), 6.72-6.70 (m, 2H), 4.65-4.64 (m, 1H), 4.10-4.02 (m, 1H), 3.93-3.89 (m, 1H), 3.62-3.55 (m, 2H), 3.44-3.35 (m, 2H), 3.05-2.96 (m, 2H), 2.24-2.12 (m, 2H), 1.56 (d, 3H), 1.28-1.26 (t, 3H).

[0796] Synthesis of (((6-fluoro-5-(4-((S)-3-hydroxypyrrolidin-l-yl)phenyl)-lH-indol-3- yl)thio)methyl)(methyl)phosphinic acid

[0797] To a stirred solution of ethyl (((6-fluoro-5-(4-((S)-3-hydroxypyrrolidin-l- yl)phenyl)-lH-indol-3-yl)thio)methyl)(methyl)phosphinate (200 mg, 0.44 mmol, 1.0 eq) in DCM (6 mL) at 0 °C was added TMSBr (0.2 mL) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was concentrated, diluted with water (10 mL), basified with 2M NaOH solution and washed with EtOAc (2 xlO mL). Aqueous layer was acidified with 2N HC1 (pH - 2) and concentrated under reduced pressure. The crude product was purified by prep-HPLC to afford (((6-fluoro- 5 -(4-((S)-3 -hy droxypyrrolidin- 1 -yl)phenyl)- 1 H-indol-3 - yl)thio)methyl)(methyl)phosphinic acid as white solid (27 mg, Yield 14%).

[0798] TLC system: MeOH / DCM (10:90),

[0799] Rf value :0;

[0800] LCMS (m / z): 421.1 (M+H)+.

[0801] 'HNMR (400 MHz, DMSO-de) 5: 11.39 (s, 1H), 7.59-7.56 (m, 2H), 7.38 (d, J= 7.2 Hz, 2H), 7.24 (d, J= 11.2 Hz, 1H), 6.59 (d, J= 8.8 Hz, 2H), 4.97 (brs, 1H), 4.42 (brs, 1H), 3.46-3.28 (m, 3H), 3.11 (d, J= 8.8 Hz, 1H), 2.89 (d, J= 11.2 Hz, 2H), 2.08- 2.04 (m, 1H), 1.93-1.88 (m, 1H), 1.32 (d, J= 14.4 Hz, 3H).

[0802] Prep-HPLC Method: Crude purity (HPLC / LCMS) 63%

[0803] Column GEMINI C-18 (250 x 21.2)mm 5mic

[0804] Buffer MP- (A): 0.1% FA IN WATER MP- (B): ACN Gradient (T / %B ) 0 / 20,15 / 55,25 / 95 Flow Rate 15 mL / min

[0805] Solubility: water, acetonitrile, THF

[0806] SYNTHETIC EXAMPLE 21

[0807] SYNTHESIS OF COMPOUND 1-29 Synthesis of ethyl (((5-bromo-4,6-difluoro-lH-indol-3- yl)thio)methyl)(methyl)phosphinate

[0808] To a stirred solution of l,2-bis(5-bromo-4,6-difluoro-lH-indol-3-yl)disulfane (1.5 g, 2.86 mmol, 1.0 eq) in THF (15 mL), was added 2,2',2"-phosphanetriyltriacetic acid (2 g, 6.87 mmol, 2.45 eq) and stirred at room temperature for 16 h . After completion of reaction by TLC, & LC-MS, LC-MS indicated 75% m / z, then added (ethoxy(methyl)phosphoryl)methyl 4-methylbenzenesulfonate (1.66 g, 5.72 mmol, 2.0 eq), TEA (3.06 mL, 21.5 mmol, 7.5 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with water (70 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 2-5% MeOH in DCM] to afford ethyl (((5-bromo-4,6-difluoro-lH-indol-3- yl)thio)methyl)(methyl)phosphinate as a pale brown gummy solid (0.5 g, Yield 45%).

[0809] TLC system: EtOAc / Hexane (50:50), Rf value: ~0.3;

[0810] LCMS(m / z): 384.06 (M+H)+.

[0811] Synthesis of ethyl (((4,6-difluoro-5-(4-((S)-3-hydroxypyrrolidin-l-yl)phenyl)- lH-indol-3-yl)thio)methyl)(methyl)phosphinate

[0812] To a stirred solution of ethyl (((5-bromo-lH-indol-3- yl)thio)methyl)(methyl)phosphinate (500 mg, 1.30 mmol, 1.0 eq) in Dioxane (8 mL), water (2 mL) was added (S)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrrolidin-3-ol (452 mg, 1.56 mmol, 1.2 eq), K2CO3 (360 mg, 2.61 mmol, 2 eq). Reaction mixture was degassed with N2 for 10 min then added Pd(dppf)C12.DCM (106 mg, 0.13 mmol, O.leq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 2-4% MeOH in DCM] to afford ethyl (((4,6-difluoro-5-(4-((S)-3- hydroxypyrrolidin-l-yl)phenyl)-lH-indol-3-yl)thio)methyl)(methyl)phosphinate as brick red solid (350 mg, Yield 57%),

[0813] TLC system: 10% MeOH in DCM,

[0814] Rf value: ~0.5;

[0815] LCMS (m / z): 467.37 (M+H)+.

[0816] 'HNMR (400 MHz, DMSO-cC) 5: 11.40 (s, 1H), 7.77 (s, 1H), 7.61 (d, J= 2.4 Hz, 1H), 7.55 (d, J= 8.8 Hz, 2H), 6.63 (d, J= 8.4 Hz, 2H), 4.98 (d, J= 3.6 Hz, 1H), 4.45 (brs, 1H), 3.97-3.81 (m, 2H), 3.50-3.46 (m, 1H), 3.40-3.37 (m, 1H), 3.15-3.08 (m, 3H), 2.10-2.06 (m, 1H), 1.98-1.90 (m, 1H), 1.49 (d, J= 14.4 Hz, 3H), 1.15 (t, J= 6.8 Hz, 3H).

[0817] Synthesi s of (((4, 6-difluoro-5 -(4-((S)-3 -hy droxypyrrolidin- 1 -yl)phenyl)- 1 H- indol-3 -yl)thio)methyl)(methyl)phosphinic acid

[0818] To a stirred solution of ethyl (((4,6-difluoro-5-(4-((S)-3-hydroxypyrrolidin-l- yl)phenyl)-lH-indol-3-yl)thio)methyl)(methyl)phosphinate (350 mg, 0.93 mmol, 1.0 eq) in DCM (10 mL) at 0 °C was added TMSBr (0.35 mL) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was concentrated, diluted with water (10 mL), basified with 2M NaOH solution and washed with EtOAc (2 x10 mL). Aqueous layer was acidified with 2N HC1 (pH - 2) and concentrated under reduced pressure to afford crude product. The crude product was purified by prep-HPLC to afford (((4,6-difluoro-5-(4-((S)-3-hydroxypyrrolidin-l- yl)phenyl)-lH-indol-3-yl)thio)methyl)(methyl)phosphinic acid as white solid (64 mg, Yield 18%).

[0819] TLC system: MeOH / DCM (10:90),

[0820] Rf value :0;

[0821] LCMS (m / z): 437.15 (M-H)’. 'HNMR (400 MHz, DMSO-d6) 5: 11.62 (s, 1H), 7.52 (d, J= 2.4 Hz, 1H), 7.24 (d, J= 8.4 Hz, 2H), 7.13 (d, J= 10 Hz, 1H), 6.60 (d, J= 8.8 Hz, 2H), 4.96 (br, 1H), 4.43 (brs, 1H), 3.47-3.27 (m, 3H), 3.13-3.05 (m, 1H), 2.95 (d, J= 12 Hz, 2H), 2.09- 2.02 (m, 1H), 1.94-1.89 (m, 1H), 1.34 (d, J= 14.4 Hz, 3H). Prep Conditions:

[0822] Crude purity (HPLC / LCMS) 55 % Column GEMINI C-18 (250 x 21.2)mm 5mic

[0823] Buffer MP- (A): 0.1% FA IN WATER MP- (B): ACN Gradient (T / %B) 0 / 30,15 / 55,25 / 95

[0824] Flow Rate 13 mL / min

[0825] Solubility: THF, water, acetonitrile

[0826] SYNTHETIC EXAMPLE 22

[0827] SYNTHESIS OF COMPOUND 1-35

[0828] Synthesis of 3-(5-(4-((2-(2-hydroxyethoxy)ethoxy)methyl)phenyl)-l-((2-

[0829] (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0830]

[0831] In a sealed tube, to a degassed solution of 3-(5-bromo-lH-indol-3-yl)-l,2,4- oxadiazol-5(4H)-one (300 mg, 0.73 mmol, 1.0 eq) and 2-(2-((4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzyl)oxy)ethoxy)ethan-l-ol (590 mg, 1.83 mmol, 2.5 eq) in ACN:H2O (1 :1, 6 mL) at room temperature, was added K2CO3 (303 mg, 2.20 mmol, 3 eq) followed by Pd(dppf)C12.DCM (30 mg, 0.036 mmol, 0.05 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and washed with 10% MeOH / DCM (2 x 20 mL). Aqueous layer concentrated and purified silica-gel column chromatography [elution with 30% Ethyl acetate in hexane] to afford 3-(5-(4-((2-(2-hydroxyethoxy)ethoxy)methyl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as an off white solid (150 mg, Yield: 39%).

[0832] TLC system: EtOAc (100%)

[0833] Rf value: ~0.2 LCMS (m / z): 524.27 (M-H)+ Synthesis of 3-(5-(4-((2-(2-hydroxyethoxy)ethoxy)methyl)phenyl)-lH-indol-3- yl)-l,2,4-oxadiazol-5(4H)-one

[0834] To a stirred solution of 3-(5-(4-((2-(2-hydroxyethoxy)ethoxy)methyl)phenyl)-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one (130 mg, 0.24 mmol, 1.0 eq) in THF (1.3 mL, 10 Vol) at 0°C, was added TBAF (4 mL) and stirred at 80 °C for 24h. After completion of reaction by TLC, volatiles removed, washed with pentane (10 mL) and purified by RP column [elution with 40-45% ACN: Water, (0.1%FA buffer)]. After evaporation, triturated with pentane, ether & acetonitrile followed by lyophilization afforded 3-(5-(4-((2-(2- hydroxyethoxy)ethoxy)methyl)phenyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (42 mg, 43%).

[0835] TLC system: 10% MeOH in DCM

[0836] Rf value: ~0.2 LCMS (m / z): 394.1 (M-H)’

[0837] 'HNMR (400 MHz, DMSO-cbi) 5: 12.56 (brs, 1H), 11.97 (s, 1H), 8.14 (s, 1H), 7.99 (d, J= 2.8 Hz, 1H), 7.66-7.55 (m, 4H), 7.42 (d, J= 8.0 Hz, 2H), 4.59 (br, s, 1H), 4.54 (s, 2H), 3.59 (s, 4H), 3.51-3.44 (m, 4H). SYNTHETIC EXAMPLE 23

[0838] SYNTHESIS OF COMPOUND 1-36

[0839] Synthesis of 3-(6-fluoro-5-(4-((2-(2 -hydroxy ethoxy)ethoxy)methyl)phenyl)-lH- indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0840] In a sealed tube, to a degassed solution of 3-(5-bromo-6-fluoro-lH-indol-3-yl)- l,2,4-oxadiazol-5(4H)-one (200 mg, 0.67 mmol, 1.0 eq) and 2-(2-((4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)oxy)ethoxy)ethan-l-ol (542 mg, 1.68 mmol, 2.5 eq) in ACN:H2O (1 : 1, 4 mL) at room temperature, was added K2CO3 (278 mg, 2.02 mmol, 3 eq) followed by Pd(dppf)C12.DCM (28 mg, 0.033 mmol, 0.05 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and washed with 10% MeOH / DCM (2 x 20 mL). Aqueous layer evaporated and purified by Cis reverse phase column chromatography [elution with40-45% ACN: Water, (0.1% FA Buffer)] to afford 3-(6-fluoro-5-(4-((2-(2- hydroxyethoxy)ethoxy)methyl)phenyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as an off white solid (66.7 mg, Yield: 24%).

[0841] TLC system: 10% MeOH in DCM,

[0842] Rfvalue:~0.1;

[0843] LCMS (m / z): 412.1 (M-H)’

[0844] 'H NMR (400 MHz, DMSO-d6) 5: 12.66 (brs, 1H), 12.00 (s, 1H), 8.00 (d, J= 2.8 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.55-7.53 (m, 2H), 7.49-7.43 (m, 3H), 4.60 (t, J = 4.8 Hz, 1H). 4.56 (s, 2H), 3.60 (s, 4H), 3.53-3.49 (m, 2H), 3.46-3.43 (m, 2H). SYNTHETIC EXAMPLE 24

[0845] SYNTHESIS OF COMPOUND 1-37

[0846] Synthesis of 2-(2-((4-bromobenzyl)oxy)ethoxy)ethan-l-ol

[0847] HO / ^°x / X'OH

[0848] To a stirred solution of 2,2'-oxybis(ethan-l-ol) (3.9 mL, 40.0 mmol, 5.0 eq) in THF (60 mL) at 0°C, was added 60% NaH (1.92 g, 80.0 mmol, 10 eq) and stirred for 30 min. After that l-bromo-4-(bromomethyl)benzene (1.92 g, 8.00 mmol, 1 eq) was added to reaction mixture and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with ice cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 50% to 70% EtOAc in Hexane] to afford 2-(2-((4-bromobenzyl)oxy)ethoxy)ethan- l-ol as light yellow liquid (2 g, Yield: 91%).

[0849] TLC system: EtOAc / Hexane (50:50),

[0850] Rfvalue:~0.1;

[0851] LCMS(m / z): 275.1 (M+H)+;

[0852] 'HNMR (400 MHz, CDC ) 5: 7.47 (d, J= 8.0 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 4.52 (s, 2H), 3.76 -3.68 (m, 4H), 3.65-3.61 (m, 4H).

[0853] Synthesis of 2-(2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)ethoxy)ethan- 1 -ol

[0854] In a sealed tube, to a degassed solution of 2-(2-((4- bromobenzyl)oxy)ethoxy)ethan-l-ol (2 g, 7.30 mmol, 1.0 eq) and B2(pin)2 (2.2 g, 8.75 mmol, 1.2 eq) in dioxane (20 mL) at room temperature, was added KOAc (1.43 g, 14.6 mmol, 2 eq), Pd(dppf)C12DCM (0.3 g, 0.36 mmol, 0.05 eq) and stirred at 80°C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with EtOAc (10 mL), and concentrated under reduced pressure to afford 2-(2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)ethoxy)ethan-l-ol as brown liquid (2 g, Yield: Crude). Material used as such without any modification.

[0855] Synthesis of 3-(4,6-difluoro-5-(4-((2-(2-hydroxyethoxy)ethoxy)methyl)phenyl)- lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0856]

[0857] In a sealed tube to a degassed solution of 3-(5-bromo-4,6-difluoro-lH-indol-3- yl)-l,2,4-oxadiazol-5(4H)-one (250 mg, 0.79 mmol, 1.0 eq) and 2-(2-((4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)oxy)ethoxy)ethan-l-ol (715 mg, 2.22 mmol, 2.8 eq) in ACbFFLO (1 : 1, 5 mL) at room temperature, was added K2CO3 (328 mg, 2.38 mmol, 3 eq) followed by Pd(dppf)C12.DCM (32 mg, 0.04 mmol, 0.05 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and washed with 10% MeOH / DCM (2 x 20 mL). Aqueous layer concentrated under reduced pressure and purified by reverse phase column chromatography [elution with 35% ACN in 0.1% FA in FLO] provided 150 mg semi pure compound. The semi pure product was purified by Prep-HPLC and lyophilized to afford 3-(4,6-difhioro-5-(4-((2-(2- hydroxyethoxy)ethoxy)methyl)phenyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as an off white solid (68 mg, Yield: 16%). TLC system: EtOAc (100%),

[0858] Rf value: ~0.2;

[0859] LCMS(m / z): 430.1 (M-H)’; 'H NMR (400 MHz, DMSO-d6) 5: 12.28 (s, 1H), 7.99 (s, 1H), 7.47-7.42 (m, 4H), 7.34 (d, J= 9.6 Hz, 1H), 4.61 (brs, 1H), 4.57 (s, 2H), 3.62-3.58 (m, 4H), 3.52- 3.48 (m, 2H), 3.46-3.43 (m, 2H).

[0860] Prep Conditions:

[0861] Column: X-B RIDGE C-18 (250 x 19)mm 5mic,

[0862] Buffer MP- (A): 0.1% FA IN WATER MP- (B): CAN,

[0863] Gradient (T / %B ): 0 / 25,12 / 50,15 / 95.

[0864] Flow Rate: 14 mL / min,

[0865] Solubility: THF, ACN, WATER.

[0866] SYNTHETIC EXAMPLE 25

[0867] SYNTHESIS OF COMPOUND 1-46

[0868] Synthesis of (((5-bromo-4,6-difluoro-lH-indol-3-yl)thio)methyl)phosphonic acid

[0869] To a stirred solution of diethyl (((5-bromo-4,6-difluoro-lH-indol-3- yl)thio)methyl)phosphonate (1.6 g, 3.87 mmol, 1.0 eq) in DCM (16 mL) at 0 °C, was added TMSBr (1.97 mL, 15.496 mmol, 4 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was concentrated, diluted with water (50 mL) and washed with DCM (2 x50 mL). Aqueous layer was concentrated under reduced pressure, purified by reverse phase Cis column chromatography [eluted with 20-25% ACN with 0.1% FA in H2O] and pure fractions were concentrated to afford (((5-bromo-4,6-difluoro-lH-indol-3-yl)thio)methyl)phosphonic acid as gummy liquid (330 mg, Yield: 24%).

[0870] TLC system: MeOH / DCM (10:90), Rfvalue:0.1,

[0871] LCMS (m / z): 358.08 (M+H)+.

[0872] Synthesis of (((4,6-difluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3- yl)thio)methyl)phosphonic acid

[0873] To a stirred solution of (((5-bromo-4,6-difluoro-lH-indol-3- yl)thio)methyl)phosphonic acid (250 mg, 0.70 mmol, 1.0 eq) in Dioxane:H2O (8:2) (25 mL, 20 Vol), was added l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclobutan-l-ol (288 mg, 1.05 mmol, 1.5 eq), CS2CO3 (682 mg, 2.10 mmol, 3 eq) and degassed with N2 for 10 min. Later added Xphos-Pd-G4 (60 mg, 0.070 mmol, 0.1 eq) and stirred at 100 °C for 16 h. After completion of reaction by TLC, the reaction mixture was concentrated and purified by reverse phase Cis column chromatography [eluted with 25-30% ACN with 0.1% ABC in H2O]. Collected fractions were lyophilized and re-purified by Prep-HPLC, lyophilized to afford (((4,6-difluoro-5-(4-(l- hydroxycyclobutyl)phenyl)-lH-indol-3-yl)thio)methyl)phosphonic acid as off white solid (23 mg, Yield: 7%).

[0874] TLC system: MeOH / DCM (10:90),

[0875] Rfvalue:~0.01;

[0876] LCMS (m / z): 424.13 (M-H)+.

[0877] 'HNMR (400 MHz, DMSO-de) 5: 11.88 (s, 1H), 7.58-7.55 (m, 2H), 7.41-7.39 (m, 3H), 7.14 (d, J= 10 Hz, 1H), 2.80 (d, J= 14 Hz, 2H), 2.49-2.41 (m, 2H), 2.33-2.26 (m, 2H), 1.96-1.91 (m, 1H), 1.71 -1.64 (m, 1H).

[0878] Prep-HPLC Method:

[0879] Column: YMC Cis (250 x 21.2)mm 5mic Buffer: MP- (A): lOmM ABC IN WATER MP- (B): Acetonitrile:

[0880] WATER(80:20)

[0881] Gradient: (T / %B ) 0 / 20,15 / 55,25 / 95

[0882] Flow Rate: 13 mL / min

[0883] Solubility: WATER, Acetonitrile, THF

[0884] SYNTHETIC EXAMPLE 26

[0885] SYNTHESIS OF COMPOUND 1-47

[0886] Synthesis of (((5-bromo-6-fluoro-lH-indol-3-yl)thio)methyl)phosphonic acid

[0887] To a stirred solution of diethyl (((5-bromo-6-fluoro-lH-indol-3- yl)thio)methyl)phosphonate (1.1 g, 2.78 mmol, 1.0 eq) in DCM (11 mL) at 0 °C, was added TMSBr (1.4 mL, 21.22 mmol, 4 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, volatiles removed, diluted with water (50 mL) and washed with DCM (2 x50 mL). Aqueous layer was concentrated under reduced pressure and purified by reverse phase Cis column chromatography [eluted with 20- 25% ACN with 0.1% FA in H2O], pure fractions were concentrated to afford (((5- bromo-6-fluoro-lH-indol-3-yl)thio)methyl)phosphonic acid as gummy liquid (300 mg, Yield: 31%).

[0888] TLC system: MeOH / DCM (10:90),

[0889] Rfvalue:0.1,

[0890] LCMS (m / z): 339.98 (M+H)+.

[0891] Synthesi s of (((6-fluoro-5 -(4-( 1 -hy droxy cy clobutyl)phenyl)- 1 H-indol-3 - yl)thio)methyl)phosphonic acid

[0892]

[0893] To a stirred solution of (((5-bromo-6-fluoro-lH-indol-3- yl)thio)methyl)phosphonic acid (250 mg, 0.73 mmol, 1.0 eq) in dioxane:H2O:ACN (3: 1 :1) (5 mL, 20 Vol), was added l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclobutan-l-ol (303 mg, 1.10 mmol, 1.5 eq), K2CO3 (305 mg, 2.21 mmol, 3 eq) and degassed with ISh for 10 min. Later added Pd(dppf)C12.DCM (60 mg, 0.073 mmol, 0.1 eq) and stirred at 100 °C for 16 h. After completion of reaction by TLC, reaction mixture was concentrated, purified by reverse phase Cis column chromatography [eluted with 25-30% ACN with 0.1% ABC in H2O]. Collected fractions were lyophilized and re-purified by prep-HPLC, lyophilized to afford (((6- fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)thio)methyl)phosphonic acid as off white solid (12 mg, Yield: 4%).

[0894] TLC system: MeOH / DCM (10:90),

[0895] Rfvalue:~0.01;

[0896] LCMS (m / z): 406.12 (M+H)+.

[0897] 'HNMR (400 MHz, DMSO-de) 5: 11.39 (s, 1H), 7.65 (d, J= 8.0 Hz, 1H), 7.56- 7.50 (m, 4H), 7.47 (d, J= 1.6 Hz, 1H), 7.27 (d, J= 11.6 Hz, 1H), 2.72 (d, J= 14.0 Hz, 2H), 2.46-2.39 (m, 2H), 2.33-2.25 (m, 2H), 1.97-1.88 (m, 1H), 1.70-1.63 (m, 1H).

[0898] Prep-HPLC Method:

[0899] Column: GEMINI NX Cis (250 x 21.2)mm 5mic,

[0900] Buffer: MP- (A): lOMm ABC IN WATER MP- (B): Acetonitrile:water (80:20), Gradient: (T / %B) 0 / 20,12 / 49,15 / 49,25 / 95,

[0901] Flow Rate: 14 mL / min,

[0902] Solubility: WATER, ACN, THF. SYNTHETIC EXAMPLE 27

[0903] SYNTHESIS OF COMPOUND 1-48

[0904] Synthesis of (((5-bromo-lH-indol-3-yl)thio)methyl)phosphonic acid

[0905] To a stirred solution of diethyl (((5-bromo-lH-indol-3- yl)thio)methyl)phosphonate (2 g, 5.30 mmol, 1.0 eq) in DCM (20 mL) at 0 °C, was added TMSBr (2.8 mL, 21.2 mmol, 4 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, volatiles removed under vacuum, diluted with water (50 mL) and washed with DCM (2 x50 mL). Aqueous layer was concentrated under reduced pressure and purified by reverse phase Cis column chromatography [eluted with 30% ACN with 0.1% FA in H2O], pure fractions were concentrated to afford (((5-bromo-lH-indol-3-yl)thio)methyl)phosphonic acid as gummy solid (1 g, Yield: 58%).

[0906] TLC system: MeOH / DCM (10:90),

[0907] Rfvalue:0.1,

[0908] LCMS (m / z): 322.0 (M+H)+.

[0909] Synthesis of (((5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3- yl)thio)methyl)phosphonic acid

[0910]

[0911] To a stirred solution of (((5-bromo-lH-indol-3-yl)thio)methyl)phosphonic acid (500 mg, 1.55 mmol, 1.0 eq) in Dioxane:H2O:ACN (3: 1 : 1) (10 mL, 20 Vol), was added l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (640 mg, 2.33 mmol, 1.5 eq), K2CO3 (645 mg, 4.67 mmol, 3 eq) and degassed with lSh for 10 min. Later, added Pd(dppf)C12.DCM (127 mg, 0.16 mmol, 0.1 eq) and stirred at 100 °C for 48 h. After completion of reaction by TLC, reaction mixture was concentrated and purified by reverse phase Cis column chromatography [eluted with 25-30% ACN with 0.1% ABC in H2O]. Collected fractions were lyophilized, re-purified by Prep-HPLC and lyophilized to afford (((5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3- yl)thio)methyl)phosphonic acid as off white solid (12 mg, Yield: 2%).

[0912] TLC system: MeOH / DCM (10:90),

[0913] Rfvalue:~0.01;

[0914] LCMS (m / z): 388.5 (M+H)+.

[0915] 'H NMR (400 MHz, DMSO-de) 5: 11.34 (s, 1H), 7.88 (s, 1H), 7.64 (d, J= 8.4 Hz, 2H), 7.53 (d, J= 8.4 Hz, 2H), 7.49 (d, J= 2.4 Hz, 1H), 7.44-7.40 (m, 2H), 2.76 (d, J= 14.0 Hz, 2H), 2.44-2.38 (m, 2H), 2.33-2.24 (m, 2H), 1.96-1.86 (m, 1H), 1.70-1.61 (m, 1H)

[0916] Prep-HPLC Method:

[0917] Column: GEMINI Cis (250 x 21.2)mm 5mic

[0918] Buffer: MP- (A): lOMm abc IN WATER MP- (B): Acetonotrile : WATER (80:20)

[0919] Gradient: (T / %B) 0 / 30,15 / 55,25 / 95

[0920] Flow Rate: 12 mL / min

[0921] Solubility: water, THF, acetonitrile SYNTHETIC EXAMPLE 28

[0922] SYNTHESIS OF COMPOUND 1-49

[0923] Synthesis of (5-bromo-4,6-difluoro-lH-indol-3-yl)phosphonic acid

[0924] To a stirred solution of 5-bromo-4,6-difluoro-lH-indole (500 mg, 2.16 mmol, 1.0 eq) and triethyl phosphite (1.1 mL, 6.49 mmol, 3 eq) in ACN (10 mL) at room temperature, was added K2S2O8 (1.1 g, 4.32 mmol, 2.0 eq), AIBN (533 mg, 3.25 mmol, 1.5 eq), Quinoline (0.12 mL, 1.08 mmol, 0.05 eq) and stirred at 120°C for 12 h. After completion of reaction by TLC, the reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography [elution with 16-18% ACN in 0.1% FA in H2O] to afford (5-bromo-4,6-difluoro-lH-indol-3-yl)phosphonic acid as off white solid (250 mg, Yield: 37%).

[0925] TLC system: MeOH / DCM (10:90),

[0926] Ry value: -0.2;

[0927] LCMS (m / z):309.95 [M-H]';

[0928] Synthesis of (4,6-difluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3- yl)phosphonic acid As bicarbonate salt

[0929] In a sealed tube, to a degassed solution of (5-bromo-4,6-difluoro-lH-indol-3- yl)phosphonic acid (450 mg, 1.456 mmol, 1.0 eq) and l-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (997 mg, 3.64 mmol, 2.5 eq) in Dioxane:H2O (2: 1, 15 mL) at room temperature, was added K2CO3 (602 mg, 4.37 mmol, 2.0 eq) followed by Pd(dppf)C12.DCM (118 mg, 0.145 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography [elution with 35-40% ACN in 0.1% FA in H2O] provided semi-pure material. Re-purified by Prep-HPLC and lyophilized to afford (4,6-difluoro-5-(4-(l- hydroxycyclobutyl)phenyl)-lH-indol-3-yl)phosphonic acid as bicarbonate salt as off white solid (37 mg, Yield: -6.7%).

[0930] TLC system: MeOH / DCM (10:90),

[0931] R / value:~0.1;

[0932] LCMS (m / z):378.11 [M-H]',

[0933] 'HNMR (400 MHz, DMSO-de) 5: 11.32 (s, 1H), 7.59-7.57 (m, 2H), 7.39-7.37 (m, 3H), 7.12-7.08 (m, 4H), 5.55 (s, 1H), 2.47-2.41 (m, 2H), 2.33-2.26 (m, 2H), 1.98- 1.91 (m, 1H), 1.73-1.66 (m, 1H).

[0934] Column name: Gemini NX Cis (250 x 21.2) mm 5 micron

[0935] Mobile phase (A): 10mm ABC in water, Mobile phase (B): ACN

[0936] Loading: 15 mg / inj ection

[0937] Method (%B): 0 / 20,15 / 43,20 / 95,25 / 95 Flow Rate : 13 mL / min Solubility: acetonitrile, water

[0938] SYNTHETIC EXAMPLE 29

[0939] SYNTHESIS OF COMPOUND 1-55

[0940] Synthesis of 5-(5-bromo-4,6-difluoro-lH-indol-3-yl)imidazolidine-2, 4-dione

[0941] To a stirred solution of 5-bromo-4,6-difluoro-lH-indole-3-carbaldehyde (1.5 g, 4.17 mmol, 1.0 eq) and (NH4)2CO3(1.2 g, 12.5 mmol, 3 eq) in EtOH:H2O (1 : 1, 21mL) at room temperature, was added NaCN (300 mg, 6.20 mmol, 1.5 eq) and stirred at 80°C for 16 h. After completion of reaction by TLC, reaction mixture was concentrated under reduced pressure and purified by silica gel (60 - 120 mesh) column chromatography [elution with 100% EtOAc] to afford 5-(5-bromo-4,6-difluoro-lH-indol-3- yl)imidazolidine-2, 4-dione as brown solid (800 mg, Yield: 42%).

[0942] TLC system: EtOAc (100%),

[0943] Ry value: -0.2;

[0944] LCMS (m / z):327.9 [M-H]';

[0945] Synthesis of 5-(4,6-difluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3- yl)imidazolidine-2, 4-dione

[0946] In a sealed tube, to a degassed solution of 5-(5-bromo-4,6-difluoro-lH-indol-3- yl)imidazolidine-2, 4-dione (800 mg, 2.43 mmol, 1.0 eq) and l-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (668 mg, 2.43 mmol, 1 eq) in Dioxane:H2O (8: 1, 20 mL) at room temperature, was added K3PO4 (1.5 g, 7.31 mmol, 3.0 eq), PCys (136 mg, 0.48 mmol, 0.2 eq), followed by Pd(OAc)2(54 mg, 0.24 mmol, 0.1 eq) and stirred at 100°C for 24 h. After completion of reaction by TLC, the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (60 - 120 mesh) column chromatography [elution with 100% EtOAc] followed by Prep-HPLC purification and lyophilization afforded. 5-(4,6-difluoro-5-(4- (l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)imidazolidine-2, 4-dione as off white solid (60 mg, Yield: -6%).

[0947] TLC system: EtOAc (100),

[0948] Ry value: -0.2;

[0949] LCMS (m / z):396.1 [M-H]+;

[0950] 'HNMR (400 MHz, DMSO-de) 5: 11.55 (s, 1H), 10.64 (s, 1H), 8.15 (s, 1H), 7.59-7.57 (m, 2H), 7.51 (d, J= 2.4 Hz, 1H), 7.35 (d, J= 8 Hz, 2H), 7.20 (d, J= 10 Hz, 1H), 5.52 (br s, 1H), 5.37 (s, 1H), 2.49-2.41 (m, 2H), 2.34-2.26 (m, 2H), 1.97-1.91 (m, 1H), 1.71-1.65 (m, 1H).

[0951] Column: GEMINI Cis (250 x 21.2)mm 5mic

[0952] Buffer: MP- (A): 0.1% TFA IN WATER MP- (B): ACN

[0953] Gradient: (T / %B) 0 / 25,15 / 50,25 / 95

[0954] Flow Rate: 13 mL / min

[0955] Solubility: water, THF, acetonitrile

[0956] SYNTHETIC EXAMPLE 30

[0957] SYNTHESIS OF COMPOUND 1-56 To a stirred solution of 5-bromo-4,6-difluoro-lH-indole (1 g, 4.32 mmol, 1 eq) in dioxane and water (2: 1) (10 mL), was added K2CO3 (1.8 g, 12.9 mmol, 3 eq), l-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol and degassed for 10 min later added Pd(dppf)C12DCM (350 mg, 0.43 mmol, 0.1 eq). RM degassed for 10 more min and the reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, reaction mixture filtered through a pad of diatomaceous earth (e.g., Celite®) and washed with ethyl acetate. Filtrate was washed with brine solution, dried over sodium sulfate and concentrated to afford crude compound. Purified by silica (100-200 mesh) column chromatography [eluted with 30% EtOAc / Hexane and pure fractions were concentrated under reduced pressure to afford l-(4-(4,6-difluoro-lH- indol-5-yl)phenyl)cyclobutan-l-ol as gummy liquid (800 mg, yield: 62%).

[0958] TLC system: EtOAC / Hexane (30:70)

[0959] Rf value: 0.3;

[0960] LCMS (m / z): 298.15 (M-H)+;

[0961] 'HNMR (400 MHz, CDCh) 5 8.31 (s, 1H), 7.62-7.59 (m, 2H), 7.54-7.52 (m, 2H), 7.20-7.18 (m, 1H), 7.04-7.02 (m, 1H), 6.66-6.64 (m, 1H), 2.67-2.61 (m, 2H), 2.45-2.38 (m, 2H), 2.07-2.04 (m, 1H), 1.79-1.70 (m, 1H).

[0962] Synthesis of 5-(4,6-difluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)- 5-hydroxypyrimidine-2,4,6(lH,3H,5H)-trione

[0963] To a stirred and solution of l-(4-(4,6-difluoro-lH-indol-5-yl)phenyl)cyclobutan- l-ol (800 mg, 2.67 mmol, 1.0 eq) in EtOH (8 mL, 10 Vol) at room temperature was added Alloxan (432 mg, 2.67 mmol, 1.0 eq) and IN aq. HC1 (6.4 mL, 8 Vol) drop-wise and reaction mixture was stirred at 80 °C, for 4 h. After completion of reaction by TLC, reaction mixture cooled to room temperature, evaporated under vacuum, washed with water provided 5-(4,6-difluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)-5- hydroxypyrimidine-2,4,6(lH,3H,5H)-trione as white color solid (800 mg, crude). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.1;

[0964] LCMS (m / z): 440.28 (M-H)+.

[0965] Synthesis of 5-(4,6-difluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3- yl)oxazolidine-2, 4-dione

[0966] To a stirred solution of 5-(4,6-difluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH- indol-3-yl)-5-hydroxypyrimidine-2,4,6(lH,3H,5H)-trione (800 mg, 1.8 mmol, 1.0 eq) at room temperature, was added IN aq. NaOH (12 mL) and stirred at RT for 3 h. After completion of reaction by TLC, reaction mixture was acidified with cone HC1 (8 mL) and extracted with ethyl acetate (2 x 100 mL). Organic layer was washed with aq. NaHCOs solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by reverse phase column chromatography (Grace) [elution with 30-35% of ACN in 0.1% FA in H2O], followed by Prep-HPLC and pure fraction were lyophilized to afford 5-(4,6-difhioro-5-(4-(l -hydroxy cy cl obutyl)phenyl)- lH-indol-3-yl)oxazolidine-2, 4-dione as white solid (62 mg, yield: 6%).

[0967] TLC system: EtOAc,

[0968] Rf value :~0.2;

[0969] LCMS: 397.4 [M-H]';

[0970] 1H NMR (400 MHz, DMSO-de) 5 11.9 (s, 1H), 11.85 (s, 1H), 7.76 (d, J= 2.8 Hz, 1H), 7.59 (dd, J= 4.8 & 1.6 Hz, 2H), 7.36 (d, J= 8.4 Hz, 2H), 7.27 (d, J= 10.0 Hz, 1H), 6.27 (s, 1H), 5.54 (s, 1H), 2.48-2.41 (m, 2H), 2.34-2.26 (m, 2H), 1.97-1.90 (m, 1H), 1.72-1.65 (m, 1H).

[0971] Column: GEMINI NX Cis (250 x 21.2)mm 5mic

[0972] Buffer: MP- (A): 0.1% FA IN WATER MP- (B): Acetonitrile : water (80:20) Gradient: (T / %B) 0 / 35,15 / 60,25 / 95 Flow Rate: 12 mL / min

[0973] Solubility: Water, Acetonitrile, THF

[0974] SYNTHETIC EXAMPLE 31

[0975] SYNTHESIS OF COMPOUND 1-5

[0976] Synthesis of 5-bromo-6-fluoro-lH-indole-3-sulfonyl chloride

[0977] To a stirred solution of 5-bromo-6-fluoro-lH-indole (5 g, 23.47 mmol, 1.0 eq) in MeCN (125 mL) at 0°C, was added CISO3H (1.8 mL, 28.16 mmol, 1.2 eq) and reaction mixture was stirred at room temperature for 1 h. After completion of reaction by TLC, the reaction mixture was concentrated, diluted with water (30 mL) and extracted with EtOAc (2 x 7 0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-Pentane (30 mL), decanted and dried under reduced pressure to afford 5-bromo-6-fluoro-lH-indole-3-sulfonyl chloride as a pale-yellow solid (5 g, Crude). TLC system: EtOAc / Hexane (20:80), Rfvalue:~0.4; LCMS (m / z): 292.10 sulfonic acid m / z

[0978] Synthesis of 5-bromo-6-fluoro-lH-indole-3-sulfonamide To a stirred solution of 5-bromo-6-fluoro-lH-indole-3-sulfonyl chloride (5 g, 16.08 mmol, 1.0 eq) (Crude) in THF (100 mL) at 0°C, NH3 gas was purged to the reaction mixture for 30 min. After completion of reaction by TLC, the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (2 * 70 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-pentane (50 mL), decanted and dried under reduced pressure to afford 5-bromo-6-fluoro-lH-indole-3- sulfonamide as an off white solid (5.2 g, Yield: Crude). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.3; LCMS (m / z): 292.9 (M-H)

[0979] Synthesis of 5-bromo-N-(tert-butyldimethylsilyl)-6-fluoro-lH-indole-3- sulfonamide

[0980] To a stirred solution of 5-bromo-6-fluoro-lH-indole-3-sulfonamide (5.2 g, 17.80 mmol, 1.0 eq) (Crude) in THF (52 mL) at room temperature, was added EtiN (12.5 mL, 89.00 mmol, 5.0 eq) and TBDMS-CI (10.68 g, 71.20 mmol, 4.0 eq). The reaction mixture was stirred at 50°C for 48 h. After completion of reaction by TLC, the reaction mixture was diluted with ice cold water (60 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200) column chromatography [elution with 20 - 25% EtOAc in Hexane] to afford 5-bromo-N-(tert-butyldimethylsilyl)-6-fluoro-lH-indole-3- sulfonamide as a pale-yellow solid (2.8 g, 3-Steps Yield: 29%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.5; 'HNMR (400 MHz, CDCls) 5: 8.59 (s, 1H), 8.12-8.07 (m, 1H), 7.72-7.70 (m, 1H), 7.23-7.21 (m, 1H), 4.36 (s, 1H), 0.89 (s, 9H), 0.22 (s, 6H). Synthesis of tert-butyl 5-bromo-3-(N-(tert-butyldimethylsilyl)sulfamoyl)-6- fluoro- IH-indole- 1 -carboxylate

[0981] To a stirred solution of 5-bromo-N-(tert-butyldimethylsilyl)-6-fluoro-lH-indole- 3-sulfonamide (2.8 g, 6.90 mmol, 1.0 eq) in DCM (30 mL) at 0°C, was added EtiN (2.42 mL, 17.25 mmol, 2.5 eq), (Boc)2O (3.15 mL, 13.80 mmol, 2.0 eq) followed by DMAP (253 mg, 2.07 mmol, 0.3 eq). The reaction mixture was stirred at room temperature for 3 h. After completion of reaction by TLC, the reaction mixture was diluted with ice cold water (40 mL) and extracted with DCM (2 x 60 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200) column chromatography [elution with 10 - 15% EtOAc in Hexane] to afford tertbutyl 5-bromo-3-(N-(tert-butyldimethylsilyl)sulfamoyl)-6-fluoro-lH-indole-l- carboxylate as off white solid (1.06 g, Yield: 30%). TLC system: EtOAc / Hexane (20:80), Rfvalue:~0.6; *HNMR (400 MHz, CDCls) 5: 8.07 (d, J= 6.4 Hz, 1H), 8.03 (s, 1H), 8.00 (d, J= 9.2 Hz, 1H), 4.49 (s, 1H), 1.69 (s, 9H), 0.92 (s, 9H), 0.26 (s, 6H).

[0982] Synthesis of tert-butyl (S)-5-bromo-3-(N'-(tert-butyldimethylsilyl)-N-(l- m ethoxy- 1 -oxopropan-2-yl)sulfamidimidoyl)-6-fluoro- IH-indole- 1 -carboxylate To a stirred solution of PPF13CI2 (787 mg, 2.37 mmol, 1.5 eq) in CHCI3 (20 mL) at 0°C, was added DIPEA (1.3 mL, 7.90 mmol, 5.0 eq) and stirred for 1 h. Later, a solution of tert-butyl 5-bromo-3-(N-(tert-butyldimethylsilyl)sulfamoyl)-6-fluoro-lH- indole-1 -carboxylate (800 mg, 1.58 mmol, 1.0 eq) in CHCI3 (10 mL) was added to reaction mixture and continued for 1 h. At same temperature, added solution of L- Alanine methyl ester HC1 (663 mg, 4.74 mmol, 3.0 eq) in CHCI3 (10 mL) and stirred for 24 h at room temperature. After completion of reaction by TLC, the reaction mixture was quenched with ice cold water (40 mL) and extracted with DCM (2 x 40 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200) column chromatography [elution with 10% EtOAc in Hexane] to afford tert-butyl (S)-5-bromo-3-(N'-(tert-butyldimethylsilyl)-N-(l-methoxy-l-oxopropan-2- yl)sulfamidimidoyl)-6-fluoro-lH-indole-l -carboxylate as a gummy liquid (500 mg, Yield: 53%). TLC system: EtOAc / Hexane (10:90), Rfvalue:~0.4; LCMS (m / z): 592.2 (M+H)+.

[0983] Synthesis of (S)-l-(5-bromo-6-fluoro-lH-indol-3-yl)-4-methyl-4,5-dihydro-3H- lX6,2,5-thiadiazol-3-one 1-oxide

[0984] To a stirred solution of tert-butyl (S)-5-bromo-3-(N'-(tert-butyldimethylsilyl)-N- ( 1 -methoxy- 1 -oxopropan-2-yl)sulfamidimidoyl)-6-fluoro- IH-indole- 1 -carboxylate (600 mg, 1.01 mmol, 1.0 eq) in THF (5 mL) at 0°C, was added TBAF (1.0 M in THF) (5 mL, 10 Vol). The reaction mixture was stirred at 50°C for 56 h. After completion of reaction by TLC, the reaction mixture was quenched with NH4Q solution (20 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase column chromatographyfelution 60% ACN in 0.1% FA in H2O] to afford (S)-l-(5-bromo-6-fluoro-lH-indol-3-yl)-4-methyl-4,5-dihydro-3H- lX6,2,5-thiadiazol-3-one 1-oxide as brown gummy solid (100 mg, Yield: 28%). TLC system: MeOH / DCM (10:90), Rfvalue:~0.4; LCMS (m / z): 346.0 (M+H)+.

[0985] Diastereomeric mixture

[0986] Synthesis of (S)-l-(6-chloro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)- 4-methyl-4,5-dihydro-3H-lX6,2,5-thiadiazol-3-one 1-oxide

[0987] In a sealed tube to a degassed solution of (S)-l-(5-bromo-6-fluoro-lH-indol-3- yl)-4-methyl-4,5-dihydro-3H-lX6,2,5-thiadiazol-3-one 1-oxide (100 mg, 0.28 mmol, 1.0 eq) and l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (127 mg, 0.45 mmol, 1.6 eq) in ACN:H2O (1 : 1, 2 mL) at room temperature, was added K2CO3 (77 mg, 0.56 mmol, 2.0 eq) followed by PdC12(dppf).DCM (23 mg, 0.028 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (15 mL) and extracted with 10% MeOH in DCM (2 x 15 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. Purified by Prep-HPLC and lyophilized to afford (S)-l-(6-chloro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol- 3-yl)-4-methyl-4,5-dihydro-3H-lX6,2,5-thiadiazol-3-one 1-oxide as off white solid (23 mg, Yield: 20%). TLC system: MeOH / DCM (10:90), Rfvalue:~0.2; LCMS(m / z): 414.32 (M+H)+; 'HNMR (400 MHz, DMSO-d / ) 5: 12.50 (br, 1H), 9.18-9.09 (m, 1H), 8.26-8.24 (m, 1H), 7.61-7.59 (m, 2H), 7.52-7.43 (m, 3H), 7.40 (d, J= 7.2 Hz, 1H), 5.56 (s, 1H), 4.30-4.27 (m, 1H), 2.45-2.42 (m, 2H), 2.33-2.30 (m, 2H), 1.95-1.92 (m, 1H), 1.70-1.66 (m, 1H), 1.39 (dd, J= 6.8 Hz, 13.6 Hz, 3H). (Diastereomeric mixture). SYNTHETIC EXAMPLE 32

[0988] SYNTHESIS OF COMPOUND 1-20

[0989] Synthesis of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-l-((2-

[0990] (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carbonitrile

[0991] To a stirred solution of 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indole-3 -carbonitrile (1.5 g, 4.27 mmol, 1.0 eq) in Toluene (45 mL) at room temperature, was added (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (1.03 g, 5.12 mmol, 1.2 eq) and NaOtBu (0.82 g, 8.54 mmol, 2 eq) and Rac-BINAP (160 mg, 0.25 mmol, 0.06 eq). Reaction mixture was degassed with N2 for 10 min then added Pd2(dba)3 (117 mg, 0.13 mmol, 0.03 eq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, reaction mixture was diluted with water (35 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography [elution with 70% ACN in 0.1% FA in H2O] to afford (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carbonitrile as a pale-yellow liquid (1.1 g, Yield: 54%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.8; LCMS (m / z): 472.55 (M+H)+.

[0992] Synthesis of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-N-hydroxy- l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide

[0993] To a stirred solution of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3-carbonitrile (0.9 g, 1.90 mmol, 1.0 eq) in EtOH (10 mL) at room temperature, was added EtiN (0.55 mL, 3.80 mmol, 2 eq) and NH2OH.HCI (0.21 g, 3.04 mmol, 1.6 eq). The reaction mixture was stirred at 90 °C for 32 h. After completion of reaction by TLC, the reaction mixture was diluted with water (35 mL) and extracted with EtOAc (2 *70 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 70% EtOAc / Hexane] to afford (S)-5-(3-((tert- butyldimethylsilyl)oxy)pyrrolidin-l -yl)-N-hydroxy- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide as a brown liquid (500 mg, Yield: 52%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.2; LCMS (m / z): 505.4 (M+H)+.

[0994] Synthesis of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-N- ((ethoxycarbonyl)oxy)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3- carboximidamide

[0995] To a stirred solution of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)- N-hydroxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3-carboximidamide (500 mg, 1.00 mmol, 1.0 eq) in DCM (5 mL, 10 Vol) at 0°C, was added EtiN (0.18 mL, 1.30 mmol, 1.3 eq) and ethylchloroformate (0.12 mL, 1.20 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with NaHCCh solution (10 mL) and extracted with EtOAc (2 *75 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)-N- ((ethoxycarbonyl)oxy)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3- carboximidamide as brown gummy solid (500 mg, Crude). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.8; LCMS (m / z): 577.5 (M+H)+.

[0996] Synthesi s of (S)-3 -(5 -(3 -((tert-butyl dimethyl silyl)oxy)pyrrolidin- 1 -yl)- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one

[0997] To a stirred solution of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)- N-((ethoxycarbonyl)oxy)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3- carboximidamide (500 mg, 0.86 mmol, 1.0 eq) in DMSO (5 mL) at 0°C, was added NaOH (103 mg, 2.58 mmol, 3 eq) and stirred for 5 h at room temperature. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL), quenched with 2NHC1 solution (2 mL), precipitated solid was filtered & dried to afford (S)-3 -(5-(3 -((tert-butyldimethylsilyl)oxy)pyrrolidin- 1 -yl)- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as brown solid (350 mg, Crude). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.2;

[0998] LCMS(m / z): 531.51 (M+H)+.

[0999] Synthesis of (S)-3-(l-(hydroxymethyl)-5-(3-hydroxypyrrolidin-l-yl)-lH-indol-

[1000] 3 -yl)- 1 ,2,4-oxadiazol-5(4H)-one

[1001] To a stirred solution of (S)-3-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l- yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one (300 mg, 0.56 mmol, 1.0 eq) in DCM (6 mL, 20 Vol) at 0°C, was added TFA (1.5 mL, 5 Vol) and stirred at room temperature for 16h. After completion of reaction by TLC, reaction mixture concentrated, triturated with pentane (10 mL) to afford (S)-3-(l- (hydroxymethyl)-5-(3 -hydroxypyrrolidin- 1 -yl)- lH-indol-3 -yl)- 1 ,2,4-oxadiazol-5(4H)- one as brown solid (300 mg, crude). TLC system: EtOAc (100%), Rfvalue:~0.2; LCMS (m / z): 317.2 (M+H).+

[1002] Synthesis of (S)-3-(5-(3-hydroxypyrrolidin-l-yl)-lH-indol-3-yl)-l,2,4- oxadi azol - 5 (4H)-one

[1003] To a stirred solution of (S)-3-(l-(hydroxymethyl)-5-(3-hydroxypyrrolidin-l-yl)- lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one (Crude 48%) (300 mg, 0.95 mmol, 1.0 eq) in 1,4-di oxane (3 mL) added aq NH3 (3 mL) and stirred at room temperature for 16 h. Reaction mass was concentrated under reduced pressure, diluted with water (20 mL), solid filtered, washed with water & ether (10 mL), dried to provide crude product. The crude product was purified by reverse phase column chromatography [elution with 35% ACN in 0.1% FA in FLO] and concentrated to afford semi pure compound. This was repurified by Prep-HPLC, collected fractions were frozen and lyophilized to afford (S)-3- (5-(3-hydroxypyrrolidin-l-yl)-lH-indol-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (20 mg, Yield: 3.6% -5 steps). TLC system: EtOAc (100%), Rfvalue:~0.2; LCMS (m / z): 287.23 [M+H]+. 'HNMR (400 MHz, DMSO-de) 5: 11.29 (s, 1H), 8.31 (s, 1H), 7.68 (d, J= 2.8 Hz, 1H), 7.28 (d, J= 8.8 Hz, 1H), 6.98 (d, J= 2 Hz, 1H), 6.58 (dd, J= 2.4 Hz, 8.8 Hz, 1H), 4.93 (br s, 1H), 4.42-4.40 (m, 1H), 3.51-3.40 (m, 1H), 3.37-3.31 (m, 1H), 3.28-3.23 (m, 1H), 3.09-3.06 (m, 1H), 2.10-2.05 (m, 1H), 1.92-1.89 (m, 1H).

[1004] Prep Conditions: COLUMN NAME: X-bridge C18 (250*19) mm 5 MICRON, Buffer MP- (A):0.1% FA IN WATER MP- (B): 100% ACN Gradient (T / %B ) 0 / 5,13 / 35, 15 / 60,20 / 95, Flow Rate 12ml / min, Solubility ACN, WATER.

[1005] SYNTHETIC EXAMPLE 33

[1006] SYNTHESIS OF COMPOUND 1-40

[1007] Synthesis of 2-(5-bromo-lH-indol-3-yl)-2-oxoacetamide

[1008] To a stirred solution of 5-bromo-lH-indole (5 g, 21.5 mmol, 1.0 eq) in diethyl ether (50 mL) at 0°C, added Oxalyl chloride (4.8 g, 38.2 mmol, 1.5 eq) and allowed to room temperature, stirred for 5 h. After completion of reaction by TLC, solid material was filtered, washed with n-pentane (50 mL) and dried under vacuum to afford 2-(5- bromo-lH-indol-3-yl)-2-oxoacetyl chloride as pale-yellow solid (6 g, Crude). TLC system: EtOAc / petroleum ether (20:80), Rfvalue:~0.8.

[1009] A solution of 2-(5-bromo-lH-indol-3-yl)-2-oxoacetyl chloride (6.0 g, 21.1 mmol, 1.0 eq) in THF (60 mL) at 0°C, NH3 gas purged to the reaction mixture for 20 min, and stirred at room temperature for 16 h. After completion of reaction by TLC, solid material was filtered, washed with n-pentane (50 mL) and dried under vacuum to afford 2-(5-bromo-lH-indol-3-yl)-2-oxoacetamide as off white solid (4.2 g, Crude).

[1010] TLC system: EtOAc / petroleum ether (50:50), Rfvalue:~0.5, LCMS(m / z): 267.06 (M+H)+.

[1011] Synthesis of 2-(5-bromo-l-tosyl-lH-indol-3-yl)-2-oxoacetamide

[1012] To a stirred solution of 2-(5-bromo-lH-indol-3-yl)-2-oxoacetamide (4.2 g, 15.8 mmol, 1 eq), in DMF (42 mL) at 0°C was added CS2CO3 (15.4 g, 47.4 mmol, 3 eq). After 5 min, Ts-Cl (6 g, 31.5 mmol, 3.0 eq) was added at 0°C and stirred at room temperature for 1 h. After completion of reaction by TLC, diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). Organic layer dried over anhydrous Na?SO4 and concentrated under reduced pressure to afford 2-(5-bromo-l-tosyl-lH-indol-3-yl)- 2-oxoacetamide as off white solid (6.2 g, yield: 93%). TLC system: EtOAc / petroleum ether (50:50), RrvalueCO.8; LCMS (m / z): 421.1 (M+H)+. 'HNMR (400 MHz, CDCls) 5: 9.36 (s, 1H), 8.53 (d, J= 2.0 Hz, 1H), 7.90-7.87 (m, 3H), 7.54-7.51 (m, 1H), 7.32 (d, J= 8.0 Hz, 2H), 7.20 (s, 1H), 5.59 (s, 1H), 2.41 (s, 3H).

[1013] Synthesis of 2-(5-bromo-l-tosyl-lH-indol-3-yl)-2-hydroxypropanamide

[1014] To a stirred solution of 2-(5-bromo-l-tosyl-lH-indol-3-yl)-2-oxoacetamide (3 g, 7.14 mmol, 1 eq) in THF (30 mL) at 0 °C, was added MeMgBr (3.0 M in Et2O) (3.6 mL, 10.7 mmol, 1.5 eq) and stirred at room temperature for 5 h. After completion of reaction by TLC, quenched with NH4Q solution (20 mL) and extracted with 10% MeOH / DCM (2 * 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was triturated with diethyl ether (20 mL) to afford 2-(5-bromo-l-tosyl-lH-indol-3-yl)-2- hydroxypropanamide as off white solid (1.5 g, yield: 48%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.3; LCMS (m / z): 419.16 (M-17)+:

[1015] Synthesis of 5-(5-bromo-l -tosyl- lH-indol-3-yl)-5-methyloxazolidine-2, 4-dione

[1016] To a stirred solution of 2-(5-bromo-l-tosyl-lH-indol-3-yl)-2- hydroxypropanamide (1.5 g, 3.44 mmol, 1.0 eq) in dioxane (15 mL, 10 Vol) at room temperature, was added DBU (1.02 mL, 6.80 mmol, 2 eq), CDI (1.1 g, 6.80 mmol, 2 eq) and stirred at 80 °C for 16 h. After completion of reaction by TLC, reaction mixture was diluted with ice cold water (20 mL) and acidified with 2N aq. HC1 (5 mL), stirred at room temperature for 20 min. Solid was filtered, washed with n-pentane (10 mL) and dried to afford 5-(5-bromo-l-tosyl-lH-indol-3-yl)-5-methyloxazolidine-2, 4-dione as brown solid (1 g, yield: 63%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.8; LCMS (m / z): 461.03 (M-H)’:

[1017] Synthesis of 5-(5-(4-(l-hydroxycyclobutyl)phenyl)-l-tosyl-lH-indol-3-yl)-5- methyloxazolidine-2, 4-dione

[1018]

[1019] In a sealed tube to a degassed solution of 5-(5-bromo-l-tosyl-lH-indol-3-yl)-5- methyloxazolidine-2, 4-dione (300 mg, 0.65 mmol, 1.0 eq) and l-(4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-l-ol (444 mg, 1.62 mmol, 2.5 eq) in EtOH ( 3 mL) at room temperature, was added K2CO3 (268 mg, 1.94 mmol, 3.0 eq) followed by Pd(dppf)C12 DCM (53 mg, 0.065 mmol, 0.1 eq) and stirred at 80°C for 16 h. After completion of reaction by TLC, reaction mixture was evaporated and purified by silica column chromatography [with a gradient elution of 5-10% MeOH / DCM] to afford 5-(5-(4-(l-hydroxycyclobutyl)phenyl)-l-tosyl-lH-indol-3-yl)- 5-methyloxazolidine-2, 4-dione as brown gummy (250 mg, semi pure). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.3; LCMS (m / z): 529.2 (M-H)

[1020] Synthesis of 5-(5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3-yl)-5- methyloxazolidine-2, 4-dione To a stirred solution of 5-(5-(4-(l-hydroxycyclobutyl)phenyl)-l-tosyl-lH-indol- 3-yl)-5-methyloxazolidine-2, 4-dione (210 mg, 0.40 mmol, 1 eq) (Crude) in THF:MeOH (1 : 1 ratio) (2 mL) at 0 °C was added CS2CO3 (776 mg, 2.40 mmol, 6 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mass was concentrated and purified by reverse phase column chromatography [elution with 35- 40% ACN in 0.1% FA in H2O], lyophilized to afford 5-(5-(4-(l - hydroxy cyclobutyl)phenyl)-lH-indol-3-yl)-5-methyloxazolidine-2, 4-dione as off white solid (14 mg, Yield: 5.7% (2-Steps). TLC system: EtOAc (100%), Rfvalue:~0.6; LCMS (m / z): 375.0 [M-H]’. 'HNMR (400 MHz, DMSO-cE) 5: 12.80-11.90 (br, 1H), 11.46 (s, 1H), 7.60-7.50 (m, 7H), 7.45-7.43 (m, 1H), 5.50 (s, 1H), 2.45-2.40 (m, 2H), 2.33-2.28 (m, 2H), 1.97 (s, 3H), 1.95-1.92 (m, 1H), 1.68-1.66 (m, 1H).

[1021] SYNTHETIC EXAMPLE 34

[1022] SYNTHESIS OF COMPOUND 1-43

[1023] Synthesi s of 5 -(5 -(4-(3 -hydroxy oxetan-3 -yl)phenyl)- 1 -tosyl- 1 H-indol-3 -y 1) - 5 - methyloxazolidine-2, 4-dione

[1024] In a sealed tube to a degassed solution of 5-(5-bromo-l-tosyl-lH-indol-3-yl)-5- methyloxazolidine-2, 4-dione (150 mg, 0.32 mmol, 1.0 eq) and 3-(4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol (224 mg, 0.80 mmol, 2.5 eq) in EtOH (2 mL, 10 Vol) at room temperature was added K2CO3 (134 mg, 0.98 mmol, 3.0 eq) followed by Pd(dppf)C12.DCM (26 mg, 0.03 mmol, 0.1 eq) and stirred at 80 °C for 16 h. After completion of reaction by TLC, reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography [elution with 40-46% ACN in 0.1% FA in H2O] to afford 5-(5-(4-(3-hydroxyoxetan-3-yl)phenyl)-l- tosyl-lH-indol-3-yl)-5-methyloxazolidine-2, 4-dione as a off brown solid (180 mg, semi-pure). TLC system: EtOAC / Hexane (50:50), Rfvalue:~0.1; LCMS (m / z) (>50% Purity): 531.22 (M+H)+

[1025] Synthesi s of 5 -(5 -(4-(3 -hydroxy oxetan-3 -yl)phenyl)- 1 H-indol-3 -y 1 ) - 5 - methyloxazolidine-2, 4-dione

[1026] To a stirred solution of 5 -(5 -(4-(3 -hydroxy oxetan-3-yl)phenyl)-l -tosyl- 1H- indol-3-yl)-5-methyloxazolidine-2, 4-dione (170 mg, 0.32 mmol, 1 eq) in THF:MeOH (1 : 1 ratio) (1.7 mL, 10 Vol ) at 0 °C was added CS2CO3 (620 mg, 1.92 mmol, 6 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was evaporated, diluted with water (20 mL) and extracted with Ethyl acetate (2 x 50 mL). Organic layer was dried over Na2SO4, evaporated and purified by reverse phase column chromatography [elution with 40-45% ACN in 0.1% FA in H2O] to afford 5-(5-(4-(3-hydroxyoxetan-3-yl)phenyl)-lH-indol-3-yl)-5-methyloxazolidine-2,4- dione as off white solid (15 mg, yield: 12% (2-steps)). TLC system: EtOAc (100), Rf valueCO.l; LCMS (m / z): 377.23 [M-H] 'HNMR (400 MHz, DMSO-de) 5: 12.24 (s, 1H), 11.49 (s, 1H), 7.69-7.60 (m, 6H), 7.53-7.45 (m, 2H), 6.36 (s, 1H), 4.80 (d, J= 6.6 Hz, 2H), 4.74 (d, J= 6.6 Hz, 2H), 1.98 (s, 3H). SYNTHETIC EXAMPLE 35

[1027] SYNTHESIS OF COMPOUND 1-44

[1028] Synthesis of 5-fluoro-2-((trimethylsilyl)ethynyl)pyridin-3-amine

[1029] To a stirred solution of 2-bromo-5-fluoropyridin-3-amine (5 g, 26.17 mmol, 1.0 eq) in EtiN (75 mL) at 0°C, was added Cui (250 mg, 1.31 mmol, 0.05 eq), Pd(PPh3)Ch (940 mg, 1.31 mmol, 0.05 eq), ethynyltrimethylsilane (3.0 g, 31.41 mmol, 1.2 eq) and stirred at room temperature for 2 h. After completion of reaction by TLC, volatiles removed under vacuum and purified by silica gel [60 - 120] column chromatography [elution with 10% EtOAc in petroleum ether] to afford 5-fluoro-2- ((trimethylsilyl)ethynyl)pyridin-3-amine as yellow solid (3.8 g, Yield: 70%). TLC system: EtOAc / Hexane (20:80), Rfvalue:~0.5; 'HNMR (400 MHz, CDCls) 5: 7.83 (d, J = 2.4 Hz, 1H), 6.73 (dd, J= 2.4 Hz, 9.6 Hz, 1H), 4.39 (bs, 2H), 0.28 (s, 9H).

[1030] Synthesis of 6-fluoro-lH-pyrrolo[3,2-b]pyridine

[1031] To a stirred solution of 5-fluoro-2-((trimethylsilyl)ethynyl)pyridin-3-amine (3.8 g, 18.3 mmol, 1.0 eq) in DMF (40 mL) at 0°C, was added NaH (1.75 g, 73.2 mmol, 4.0 eq) portion wise and stirred at room temperature for 2 h. After completion of reaction by TLC, quenched with ice cold water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Obtained crude was purified by silica gel (100-200) column chromatography [elution with 20% EtOAc in petroleum ether] to afford 6-fluoro-lH-pyrrolo[3,2-b]pyridine as yellow solid (1.7 g, Yield: 68%). TLC system: EtOAc / Hexane (30:70), Rfvalue:~0.3; LCMS(m / z): 137.2 (M+H)+; 'H NMR (400 MHz, CDCls) 5: 8.59 (bs,lH), 8.40-8.39 (m, 1H), 7.46-7.41 (m, 2H), 6.76-6.74 (m, 1H).

[1032] Synthesis of 6-fluoro-lH-pyrrolo[3,2-b]pyridine 4-oxide

[1033] To a stirred solution of 6-fluoro-lH-pyrrolo[3,2-b]pyridine (1.7 g, 12.4 mmol, 1.0 eq) in DCM (170 mL) at room temperature, was added m-CPBA (4.27 g, 24.8 mmol, 2.0 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was cooled to 0°C, precipitation observed. Precipitated solid was filtered, washed with DCM (500 mL) dried under vacuum to afford 6-fluoro-lH- pyrrolo[3,2-b]pyridine 4-oxide as pale brown solid (1.35 g, Yield: 72%). TLC system: MeOH / DCM ( Q-.9G), Rfvalue:~0.2; LCMS(m / z): 153.1 (M+H)+;XH NMR (400 MHz, CDCls) 5: 11.86 (s,lH), 8.32-8.30 (m, 1H), 7.58-7.56 (m, 1H), 7.47-7.45 (m, 1H), 6.66- 6.65 (m, 1H).

[1034] Synthesis of methyl 5-chloro-6-fluoro-lH-pyrrolo[3,2-b]pyridine-l-carboxylate

[1035] To a stirred solution of 6-fluoro-lH-pyrrolo[3,2-b]pyridine 4-oxide (2.7 g, 17.76 mmol, 1.0 eq) in THF (27 mL) at room temperature, was added HMDS (3.14 g, 19.54 mmol, 1.1 eq) followed by methyl carb onochlori date (27 mL, 10 Vol) and stirred at 65°C for 16 h. After completion of reaction by TLC, diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). Combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Obtained crude was purified by silica gel [100 - 200] column chromatography [elution with 10% EtOAc in petroleum ether] to afford methyl 5-chloro-6-fluoro-lH-pyrrolo[3,2-b]pyridine-l- carboxylate as white solid (1.9 g, Yield: 47%). TLC system: EtOAc / Hexane (20:80), Rf value:~0.5; LCMS(m / z): 229.0 (M+H)+; 'HNMR (400 MHz, CDC ) 5: 8.25 (brs, 1H), 7.85-7.84 (m, 1H), 6.75 (dd, J= 0.4 & 4 Hz, 1H), 4.09 (s, 3H).

[1036] Synthesis of 5-chloro-6-fluoro-lH-pyrrolo[3,2-b]pyridine

[1037] To a stirred solution of methyl 5-chloro-6-fluoro-lH-pyrrolo[3,2-b]pyridine-l- carboxylate (1.9 g, 8.29 mmol, 1.0 eq) in MeOH (19 mL) at 0°C, was added NaOMe (1.34 g, 24.89 mmol, 3.0 eq) and stirred at same temperature for 30 min. After completion of reaction by TLC, the reaction mixture was quenched with 2N HC1 solution (20 mL), diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was triturated with n-pentane (50 mL), decanted and dried under vacuum to afford 5-chloro-6-fluoro-lH-pyrrolo[3,2- b]pyridine as off white solid (1.25 g, Yield: 89%). TLC system: EtOAc / Hexane (30:70), Rfvalue:~0.3; LCMS(m / z): 171.0 (M+H)+.

[1038] Synthesis of 5-chloro-6-fluoro-lH-pyrrolo[3,2-b]pyridine-3-carbaldehyde

[1039] To a stirred solution of POCh (1.79 g, 11.7 mmol, 2.0 eq) in DMF (897 mg, 12.3 mmol, 2.1 eq) at room temperature, was added a solution of 5-chloro-6-fluoro-lH- pyrrolo[3,2-b]pyridine (1.0 g, 5.85 mmol, 1.0 eq) in DMF (1 mL). Reaction mixture was stirred at 90°C for 2 h. After completion of reaction by TLC, treated with IN NaOH solution (10 mL), diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL) followed by 10% MeOH in DCM (50 mL). Combined organic layer dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was triturated with n-pentane (30 mL), decanted and dried under vacuum to afford 5- chloro-6-fluoro-lH-pyrrolo[3,2-b]pyridine-3-carbaldehyde as off white solid (850 mg, Yield: 73%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.3; LCMS(m / z): 199.02 (M+H)+.

[1040] Synthesis of 5-chloro-6-fluoro-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile

[1041] To a stirred solution of 5-chloro-6-fluoro-lH-pyrrolo[3,2-b]pyridine-3- carbaldehyde (800 mg, 4.04 mmol, 1.0 eq) in pyridine (4 mL) at room temperature, was added NH2OH.HCI (307 g, 4.44 mmol, 1.1 eq) and stirred for 1 h. Then AC2O (824 mg, 8.08 mmol, 2.0 eq) was added to reaction mixture and stirred at 90°C for 2 h. After completion of reaction by TLC, diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with 2N HC1 solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 5-chloro-6-fluoro-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile as yellow solid (600 mg, Yield: 77%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.4; LCMS(m / z): 195.99 (M+H)+.

[1042] Synthesis of 5-chloro-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[3,2-b]pyridine-3 -carbonitrile To a stirred solution of 5-chloro-6-fluoro-lH-pyrrolo[3,2-b]pyridine-3- carbonitrile (550 mg, 2.82 mmol, 1.0 eq) in DMF (5.5 mL) at 0°C, was added NaH (226 mg, 5.64 mmol, 2.0 eq) and stirred for 30 min. Then SEM-C1 (1.17 g, 7.05 mmol, 2.5 eq) was added to reaction mixture and stirred at room temperature for 4 h. After completion of reaction by TLC, the reaction mixture was quenched with ice cold water (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with brine solution (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel [60 - 120] column chromatography [elution with 10% EtOAc in petroleum ether] to afford 5-chloro-6- fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile as yellow solid (650 mg, Yield: 76%). TLC system: EtOAc / Hexane (30:70), Rfvalue:~0.5; LCMS(m / z): 257.0 (M+H)+; 'HNMR (400 MHz, CDC ) 5: 7.91 (s, 1H), 7.73 (d, J= 8.0 Hz, 1H), 5.51 (s, 2H), 3.54-.349 (m, 2H), 0.96-0.91 (m, 2H), -0.01 (s, 9H).

[1043] Synthesis of 6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile

[1044] In a sealed tube, to a degassed solution of 5-chloro-6-fluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (450 mg, 1.38 mmol, 1.0 eq) and l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclobutan-l-ol (570 mg, 2.07 mmol, 1.5 eq) in ACN:H2O (1 :1, 5 mL) at room temperature, was added K2CO3 (1.32 g, 4.14 mmol, 3.0 eq), Pd(dppf)C12.DCM (113 mg, 0.14 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel [60- 120] column chromatography [elution with 25% EtOAc in petroleum ether] to afford 6- fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[3,2-b]pyridine-3 -carbonitrile as yellow gummy (550 mg, Yield: 74%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.3; LCMS(m / z): 438.31 (M+H)+; 'H NMR (400 MHz, CDCls) 5: 8.11-8.08 (m, 2H), 7.90 (s, 1H), 7.71-7.65 (m, 3H), 5.51 (s, 2H), 3.56-3.52 (m, 2H), 2.68-2.61 (m, 2H), 2.48-2.41 (m, 2H), 2.09-2.06 (m, 1H), 1.78-1.75 (m, 1H), 0.97-0.90 (m, 2H), 0.09 (s, 9H).

[1045] Synthesis of (Z)-6-fluoro-N'-hydroxy-5-(4-(l -hydroxy cyclobutyl)phenyl)- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carboximidamide

[1046] To a stirred solution of 6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (500 mg, 1.14 mmol, 1.0 eq) in EtOH (5 mL) at room temperature, was added EtiN (230 mg, 2.28 mmol, 2.0 eq) and NH2OH.HCI (157 mg, 2.28 mmol, 2.0 eq). The reaction mixture was stirred at 90°C for 3 h. After completion of reaction by TLC, the reaction mixture was diluted with water (10 mL) and extracted with 10% MeOH in DCM (2 ^ 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (Z)-6-fluoro-N'-hydroxy-5-(4-(l -hydroxy cy cl obutyl)phenyl)-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carboximidamide as yellow gum (500 mg, Yield: Crude). TLC system: EtOAc / Hexane (100:00), Rf value:~0.1; LCMS(m / z): 471.3 (M+H)+.

[1047] Synthesis of ethyl (Z)-((6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyri din-3 - yl)(hydroxyimino)methyl)carbamate

[1048] To a stirred solution of (Z)-6-fhioro-N'-hydroxy-5-(4-(l- hydroxycyclobutyl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2- b]pyridine-3-carboximidamide (500 mg, 1.06 mmol, 1.0 eq) in DCM (5 mL) at 0°C, was added EtiN (139 mg, 1.38 mmol, 1.3 eq) and ethylchloroformate (138 mg, 1.27 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 4 h. After completion of reaction by TLC, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product. The crude product was purified by silica gel [100 -200] column chromatography [elution with 20% EtOAc in petroleum ether] to afford ethyl (Z)-((6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3- yl)(hydroxyimino)methyl)carbamate as yellow gum (400 mg, Yield: 69%). TLC system: EtOAc / Hexane (30:70), Rfvalue:~0.4; LCMS(m / z): 543.48 (M+H)+; 'H NMR (400 MHz, CDCls) 5: 8.12 (s, 1H), 7.96-7.94 (m, 2H), 7.69-7.64 (m, 3H), 5.46 (s, 2H), 4.35 (q, J= 7.2 Hz, 2H), 3.49 (t, J= 8.0 Hz, 2H), 2.67-2.61 (m, 2H), 2.47-2.39 (m, 2H), 2.09-2.05 (m, 1H), 1.79-1.73 (m, 1H), 1.38 (t, J= 7.2 Hz, 3H), 0.93-0.86 (m, 2H), -0.03 (s, 9H).

[1049] Synthesis of 3-(6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)- one To a stirred solution of ethyl (Z)-((6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)- l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3- yl)(hydroxyimino)methyl)carbamate (400 mg, 0.74 mmol, 1.0 eq) in DMSO (1.5 mL) at room temperature, was added NaOH (36 mg, 0.88 mmol, 1.2 eq) and reaction mixture was stirred at room temperature for 4 h. After completion of reaction by TLC, the reaction mixture was quenched with 2N aq. HC1 solution (10 mL), precipitation observed. Solid filtered, washed with n-pentane (20 mL) and dried under vacuum to afford 3-(6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)- one as yellow gum (350 mg, Yield: Crude). TLC system: MeOH / DCM (10:90), Rf value:~0.3; LCMS(m / z): 497.27 (M+H)+.

[1050] Synthesis of 3-(6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-pyrrolo[3,2- b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one

[1051] To a stirred solution of 3-(6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)- one (350 mg, 0.70 mmol, 1.0 eq) in THF (3.5 mL) at 0°C, was added TBAF (1.0 M in THF) (7 mL, 7.00 mmol, 10 eq) and stirred at 80°C for 3 h. After completion of reaction by TLC, diluted with water (50 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was washed with NH4Q solution (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography [elution with 50% ACN in 0.1% FA in H2O] to afford product with TBAF impurities. Re-purified by prep-HPLC and pure fractions were lyophilized to afford 3-(6-fluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH- pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (31 mg, Yield: 12%). TLC system: MeOHZDC (10:90), Rfvalue:~0.2; LCMS(m / z): 367.1 (M+H)+; 'H NMR (400 MHz, DMSO-cE) 5: 12.46 (bs, 1H), 12.23 (s, 1H), 8.25 (s, 1H), 7.98-7.93 (m, 3H), 7.64 (d, J= 8.4 Hz, 2H), 5.59 (s, 1H), 2.51-2.41 (m, 2H), 2.36-2.28 (m, 2H), 1.99-1.93 (m, 1H), 1.73-1.67 (m, 1H).

[1052] Prep conditions: C0615-85-P1; Obtained Sample quantity 90mg; Column GEMINI C18 (250*21.2)mm 5mic; Buffer MP- (A): 0.1% TFA IN WATER; MP- (B): Acetonitrile; Gradient (T / %B); 0 / 30,15 / 60,16 / 60,16.50 / 95, 19 / 95,19.50 / 30,23 / 30; Flow Rate: 13ml / min; Solubility WATER : THF:ACN

[1053] SYNTHETIC EXAMPLE 36

[1054] SYNTHESIS OF COMPOUND 1-45

[1055] Synthesis of 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3- ol

[1056] In a sealed tube to a degassed solution of 3-(4-bromophenyl)oxetan-3-ol (1 g, 4.37 mmol, 1.0 eq) and B2Pin2 (1.66 g, 6.55 mmol, 1.5 eq) in Dioxane (20 Vol, 20 mL) at room temperature, was added KOAc (1.28 g, 13.1 mmol, 3.0 eq) followed by Pd(dppf)C12.DCM (357 mg, 0.43 mmol, 0.1 eq) and stirred at 80°C for 16 h. After completion of reaction by TLC, reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol as brown solid (1.2 g, Crude). TLC system: EtOAc / Hexane (30:70), Rfvalue:~0.4; 'HNMR (400 MHz, CDC ) 5: 7.87 (d, J= 8.4 Hz, 2H), 7.61 (d, J= 8.4 Hz, 2H), 4.92 (s, 4H), 1.35 (s, 12H). Synthesis of 6-fluoro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile

[1057] In a sealed tube, to a degassed solution of 5-chloro-6-fluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (350 mg, 1.07 mmol, 1.0 eq) and 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3- ol (443 mg, 1.6 mmol, 1.5 eq) in ACN:H2O (1 : 1, 3.5 mL) at room temperature, was added K2CO3 (443 mg, 3.21 mmol, 3.0 eq) Pd(dppf)C12.DCM (88 mg, 0.11 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel [100-200] column chromatography [elution with 30% EtOAc in petroleum ether] to afford 6- fluoro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[3,2-b]pyridine-3 -carbonitrile as an off white solid (400 mg, Yield: 51%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.3; LCMS(m / z): 440.22 (M+H)+; 'H NMR (400 MHz, CDCls) 5: 8.15 (d, J= 8.0 Hz, 2H), 7.91 (s, 1H), 7.77 (d, J= 8.0 Hz, 2H), 7.71 ((d, J= 10.8 Hz, 1H), 5.52 (s, 2H), 4.99 (s, 4H), 3.54 (t, J= 8.0 Hz, 2H), 0.95 (t, J = 8.4 Hz, 2H), 0.02 (s, 9H).

[1058] Synthesis of (Z)-6-fluoro-N'-hydroxy-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carboximidamide To a stirred solution of 6-fluoro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (400 mg, 0.91 mmol, 1.0 eq) in EtOH (4 mL) at room temperature, was added EtiN (276 mg, 2.73 mmol, 3.0 eq), NH2OH HCI (75 mg, 1.09 mmol, 1.2 eq) and stirred at 90°C for 3 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (Z)- 6-fluoro-N'-hydroxy-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carboximidamide as a yellow gum (400 mg, Yield: Crude). TLC system: MeOH / DCM (10:90), Rfvalue:~0.2; LCMS(m / z): 473.38 (M+H)+.

[1059] Synthesis of ethyl (Z)-((6-fluoro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyri din-3 - yl)(hydroxyimino)methyl)carbamate

[1060] To a stirred solution of (Z)-6-fluoro-N'-hydroxy-5-(4-(3-hydroxyoxetan-3- yl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3- carboximidamide (400 mg, 0.85 mmol, 1.0 eq) in DCM (4 mL) at 0°C, was added EtsN (112 mg, 1.1 mmol, 1.3 eq) and ethylchloroformate (110 mg, 1.02 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 4 h. After completion of reaction by TLC, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product. The crude product was purified by silica gel [100 -200] column chromatography [elution with 30% EtOAc in petroleum ether] to afford ethyl (Z)-((6-fluoro-5 -(4-(3 -hydroxy oxetan-3 -yl)phenyl)- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyri din-3 - yl)(hydroxyimino)methyl)carbamate as yellow gum (350 mg, Yield: 76%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.5; LCMS(m / z): 545.39 (M+H)+; *HNMR (400 MHz, CDC ) 5: 8.02-8.00 (m, 2H), 7.78-7.76 (m, 2H), 7.73-7.70 (m, 1H), 5.49 (s, 2H), 5.00-4.96 (m, 4H), 4.37 (q, J= 7.2 Hz, 2H), 3.53-3.49 (m, 2H), 1.41-1.37 (m, 3H), 0.94-0.86 (m, 2H), -0.02 (s, 9H).

[1061] Synthesis of 3-(6-fluoro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)- one

[1062] To a stirred solution of ethyl (Z)-((6-fluoro-5-(4-(3-hydroxyoxetan-3- yl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyri din-3- yl)(hydroxyimino)methyl)carbamate (350 mg, 0.64 mmol, 1.0 eq) in DMSO (1.3 mL) at room temperature, was added NaOH (31 mg, 0.77 mmol, 1.2 eq) and reaction mixture was stirred at room temperature for 6 h. After completion of reaction by TLC, the reaction mixture was quenched with 2N aq. HC1 solution (10 mL), precipitation observed. Solid filtered, washed with n-pentane (10 mL) and dried under vacuum to afford 3 -(6-fluoro-5 -(4-(3 -hydroxy oxetan-3 -yl)phenyl)- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)- one as yellow gum (300 mg, Crude). TLC system: MeOH / DCM (5:95), Rfvalue:~0.2; LCMS(m / z): 499.3 (M+H)+.

[1063] Synthesis of 3-(6-fluoro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-lH-pyrrolo[3,2- b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one

[1064] To a stirred solution of 3-(6-fluoro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)- one (300 mg, 0.6 mmol, 1.0 eq) in THF (3.0 mL) at 0°C, was added TBAF (1.0 M in THF) (6.0 mL, 6.02 mmol, 10 eq) and stirred at 80°C for 3 h. After completion of reaction by TLC, the reaction mixture was diluted with water (30 mL) and extracted with 10% MeOH in DCM (2 ^ 30 mL). The combined organic layer was dried over Na2SO4, filtered, concentrated and purified by Prep-HPLC. Collected fractions were frozen and lyophilized to afford 3 -(6-fluoro-5-(4-(3 -hydroxy oxetan-3 -yl)phenyl)-lH- pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one as white solid (15 mg, Yield: 7%). TLC system: MeOHZDC (10:90), Rfvalue:~0.2; LCMS(m / z): 369.32 (M+H)+; 'HNMR (400 MHz, DMSO-de) 5: 12.16 (s,lH), 8.23 (s, 1H), 8.02-7.95 (m, 3H), 7.77- 7.75 (m, 2H), 6.45 (s, 1H), 4.82 (d, J= 6.4 Hz, 2H), 4.75 (d, J= 6.4 Hz, 2H).

[1065] Prep-HPLC condition: Column X-Bridge,C18, (250*19.0mm)5p, Buffer A: 0.1% TFA IN IN WATER; B: A CN:H20(80:20) Gradient(T / %B) 0 / 35, 15 / 45, 25 / 95 / 98@13ML / MIN Flow Rate 13ml / min Solubility ACN+H20

[1066] SYNTHETIC EXAMPLE 37

[1067] SYNTHESIS OF COMPOUND 1-57

[1068] Synthesis of 5-bromothiazolidine-2, 4-dione

[1069] To a stirred solution of thiazolidine-2, 4-dione (3 g, 25.6 mmol, 1.0 eq) in acetic acid (4.5 mL, 1.5 Vol), was added Br2 (1.3 mL, 25.6 mmol, 1.0 eq) in acetic acid (0.7, 0.25 Vol) at 100 °C, continued stirring at 100 °C for 6 h. After completion of reaction by TLC, diluted with water and extracted with DCM (2x50 mL). Organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated. Obtained crude compound was purified by silica (100-200 mesh) column chromatography [eluted with 50% EtOAc / Hexane and pure fractions were concentrated under reduced pressure to afford 5-bromothiazolidine-2, 4-dione as a gummy liquid (3 g, yield: 61%). TLC system: EtOAC / Hexane (50:50) Revalue: ~0.5 (KMnO4 stain); 'H NMR (400 MHz, CDCh) 5 8.97 (br s, 1H), 5.89 (s, 1H).

[1070] Synthesis of 5-(5-bromo-4,6-difluoro-lH-indol-3-yl)thiazolidine-2, 4-dione

[1071] To a stirred and solution of AgOTf (1.10 g, 4.3 mmol, 2.0 eq) in DCM (5 mL, 10 Vol) at -78 °C was added 5-bromo-4,6-difluoro-lH-indole (500 mg, 2.2 mmol, 1.0 eq) followed by 5-bromothiazolidine-2, 4-dione (1.25 g, 6.5 mmol, 3.0 eq) slowly, and reaction mixture was stirred at -78°C for 4 h. After completion of reaction by TLC, the reaction mixture was diluted with water and extracted with DCM (2x 50 mL). Organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated. Obtained crude was purified by reverse phase Cl 8 column chromatography [eluted with 45% ACN with 0.1% FA in H2O], pure fractions was concentrated under reduced pressure to afford 5-(5-bromo-4,6-difluoro-lH-indol-3- yl)thiazolidine-2, 4-dione as white solid (180 mg, yield: 24%). TLC system: EtOAC / Hexane (50:50) RrvalueCO.3; LCMS (m / z): 344.98 (M-H)+;XH NMR (400 MHz, DMSO-tL) 5 12.24 (bs, 1H), 11.76 (s, 1H), 7.59 (d, J= 2.4 Hz, 1H), 7.32 (dd, J = 8.0 & 0.8 Hz, 1H), 6.14 (s, 1H).

[1072] Synthesis of 5-(4,6-difluoro-5-(4-(l-hydroxycyclobutyl)phenyl)-lH-indol-3- yl)thiazolidine-2, 4-dione

[1073] To a stirred solution of 5-(5-bromo-4,6-difluoro-lH-indol-3-yl)thiazolidine-2,4- dione (180 mg, 0.52 mmol, 1 eq) in Dioxane: Water (2: 1) (5.5 mL), was added CS2CO3 (507 mg, 1.56 mmol, 3 eq) followed by l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclobutan-l-ol (356 mg, 1.30 mmol, 2.5 eq) and degassed for 10 min, later added X-phos-Pd-G4 (45 mg, 0.05 mmol, 0.1 eq). RM was degassed for 10 min and the reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, reaction mixture filtered through a pad of diatomaceous earth (e.g., Celite®), and washed with ethyl acetate. Organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated. Obtained crude compound was purified by Prep-HPLC and pure fractions were lyophilized to afford 5-(4,6-difluoro-5-(4-(l- hydroxycyclobutyl)phenyl)-lH-indol-3-yl)thiazolidine-2, 4-dione as white solid (46 mg, yield: 21%). TLC system: EtOAC / Hexane (50:50) Revalue: ~0.1; LCMS (m / z): 413.19 (M+H)+; ‘H NMR (400 MHz, DMSO-de) 5 12.11 (s, 1H), 11.63 (s, 1H), 7.60-7.57 (m, 3H), 7.35 (d, J= 8.4 Hz, 2H), 7.22 (d, J= 10 Hz, 1H), 6.18 (s, 1H), 5.53 (s, 1H), 2.49- 2.41 (m, 2H), 2.33-2.26 (m, 2H), 1.98-1.88 (m, 1H), 1.74-1.65 (m, 1H).

[1074] Prep Conditions :Column GEMINI C18 (250*21.2)mm 5mic Buffer MP- (A): 0.1% FA IN WATER MP- (B): Acetonitrile : WATER(80:20), Gradient (T / %B ) 0 / 50,15 / 70,25 / 98,30 / 98, Flow Rate 13ml / min, Solubility WATER , Acetonitrile , THF SYNTHETIC EXAMPLE 38

[1075] SYNTHESIS OF COMPOUND 1-61

[1076] Synthesis of N-(4-bromophenyl)-2,2,2-trifluoroacetamide

[1077] To a stirred solution of 4-bromoaniline (10 g, 29.1 mmol, 1 eq), in DCM (100 mL), at 0 °C, was added EtiN (1.2 mL, 46.5 mmol, 1.6 eq), TFAA (11.2 mL, 84.3 mmol, 2.9 eq) and stirred for 16 h at room temperature. After completion of reaction by TLC, the reaction mixture was quenched with 1 N aq. NaOH solution (100 mL) and extracted with DCM (2 x lOOmL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel (60-120 mesh) column chromatography [eluted with 5-10% EtOAc in hexane] to afford N-(4-bromophenyl)-2,2,2-trifluoroacetamide as white solid (11 g, 83% yield), TLC system: EtOAc:hexane (20:80), Rfvalue:~0.5; LCMS (m / z): 265.97 (M-H).+ 1H NMR (400 MHz, CDCh). 5: 7.97 (brs, 1H), 7.54-7.46 (m, 4H).

[1078] Synthesis of N-(4-bromophenyl)-2,2,2-trifluoroacetamide

[1079] To a stirred solution of N-(4-bromophenyl)-2,2,2-trifluoroacetamide (5 g, 18.6 mmol, 1 eq), in THF (100 mL), cooled to -78 °C, added n-BuLi 1.6 M in THF (44.3 mL, 70.9 mmol, 3.8 eq) and stirred for 30 min. Later at same temperature, added cyclobutanone (1.95 g, 27.9 mmol, 1.5 eq) and allowed to room temperature, stirred for 16 h. After completion of reaction by TLC, quenched with NH4Q solution (lOOmL) and extracted with EtOAc (2x100 mL). Organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Obtained crude was purified by silica gel (100-200 mesh) column chromatography [eluted with 20% EtOAc in hexane to afford 2,2,2-trifluoro-N-(4-(l -hydroxy cyclobutyl)phenyl)acetamide as off white solid (2.3 g, 47% yield), TLC system: EtOAc:hexane (30:70), Rfvalue:~0.3;. LCMS (m / z): 258.16 (M-H)+.

[1080] Synthesis of l-(4-aminophenyl)cyclobutan-l-ol

[1081] To a stirred solution of 2,2,2-trifluoro-N-(4-(l- hydroxycyclobutyl)phenyl)acetamide 10.0 mmol, 1 eq), in MeOH (23 mL) at room temperature was added 1 N aq. NaOH (46 mL, 20 vol) and continued for 16h. After completion of reaction by TLC, quenched with water (50mL) and extracted with DCM (2x50 mL). Combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford l-(4-aminophenyl)cyclobutan-l-ol as brown gummy solid (1.5 g, crude), TLC system: EtOAc: hexane (50:50) , Rfvalue:~0.4;. LCMS (m / z): 164.11 (M+H)+. 'HNMR (400 MHz, CDC ) 5: 7.30 (dd, J= 2 & 6.4 Hz, 2H), 6.70 (dd, J= 2 & 6.4 Hz, 2H), 2.54-2.50 (m, 2H), 2.37-2.30 (m, 2H), 1.98-1.91 (m, 1H), 1.67- 1.57 (m, 1H).

[1082] Synthesis of 6-fluoro-5-((4-(l-hydroxycyclobutyl)phenyl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile

[1083] To a stirred solution off 5-chloro-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (900 mg, 2.77 mmol, 1 eq), in 1.4 dioxane (10 mL), was added l-(4-aminophenyl)cyclobutan-l-ol (681 mg, 4.15 mmol, 1.5 eq), CS2CO3 (1.80 g, 5.54 mmol, 2 eq) at room temperature, degassed with nitrogen for 5 min. Later added X-phos (527 mg, 1.10 mmol, 0.4 eq), Pd2(dba)3 (180 mg, 0.55 mmol, 0.2 eq) and degassed with nitrogen for additional 10 min, heated to 100 °C, stirred for 16 h. After completion of reaction by TLC, quenched with water (25 mL) and extracted with EtOAc (2 x 50 mL). Combined organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel (100-200 mesh) column chromatography [eluted with 40% EtOAc in hexane] to afford 6-fluoro-5-((4-(l- hydroxycyclobutyl)phenyl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[3,2-b]pyridine-3 -carbonitrile as off orange gummy (1.1 g, Yield: 88%). TLC system: EtOAc: hexane (50:50), Rfvalue:~0.3; LCMS (m / z): 453.2 (M+H)+.

[1084] Synthesis of ((Z)-6-fluoro-N'-hydroxy-5-((4-(l- hydroxycyclobutyl)phenyl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[3,2-b]pyridine-3-carboximidamide

[1085] To a stirred solution off 6-fluoro-5-((4-(l-hydroxycyclobutyl)phenyl)amino)-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (1.1 g, 2.43 mmol, 2 eq) in EtOH (11 mL) at room temperature was added EtiN (491 mg, 4.86 mmol, 2eq), NH2OH HCI (335 mg, 4.86 mmol, 2 eq) and stirred at 90 °C for 16h. After completion of reaction by TLC, diluted with ice water (20 mL) and extracted with 10% MeOH:DCM (2 x 50mL). Combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (Z)-6-fluoro-N'-hydroxy-5-((4-(l- hydroxycyclobutyl)phenyl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[3,2-b]pyridine-3-carboximidamide as black gummy (1.1 g, crude), TLC system: EtOAc , Rfvalue:~0.1; LCMS (m / z): 486.3 (M+H)+.

[1086] Synthesis of 3-(6-fluoro-5-((4-(l-hydroxycyclobutyl)phenyl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)- one

[1087] To a stirred solution of (Z)-6-fluoro-N'-hydroxy-5-((4-(l- hydroxycyclobutyl)phenyl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[3,2-b]pyridine-3-carboximidamide (1.1 g, 2.26 mmol, 1 eq) in 1,4 dioxane (11 mL) at room temperature was added CDI (734 mg, 4.53 mmol, 2 eq), DBU (1.37 g, 9.07 mmol, 4 eq) and heated at 80 °C for 16 h. After completion of reaction by TLC, diluted with ice cold water (30 mL) and extracted with 10% MeOH / DCM (3 x 50mL). Combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Obtained crude was purified by reverse phase Cl 8 column chromatography [eluted with 70% ACN with 0.1% FA in H2O] and pure fractions were concentrated to afford 3-(6-fluoro-5-((4-(l-hydroxycyclobutyl)phenyl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)- one (500 mg, Yield: 45%). TLC system: 10% MeOH / DCM (10:90), Rfvalue:~0.2; LCMS (m / z): 512.32 (M+H)+;

[1088] Synthesis of 3-(6-fluoro-5-((4-(l-hydroxycyclobutyl)phenyl)amino)-lH- pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one

[1089] To a stirred solution of 3-(6-fluoro-5-((4-(l-hydroxycyclobutyl)phenyl)amino)- l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol- 5(4H)-one (500 mg, 0.97 mmol, 1 eq), in THF (5 mL) at room temperature was added TBAF(l .OM) (9.7 mL, 9.78 mmol, 10 eq) and stirred for 3 h at 80 °C. After completion of reaction by TLC, quenched with saturated NH4Q solution (20mL) and extracted with 10% MeOH / DCM (2x50mL). Combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Obtained crude was purified by reverse phase C18 column chromatography [eluted with 50% ACN with 0.1% FA in H2O], followed by PREP-HPLC (ABC method) purification afforded 3-(6-fluoro-5-((4-(l- hydroxycyclobutyl)phenyl)amino)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol- 5(4H)-one as off white solid (80 mg, Yield: 21%). TLC system: MeOH / DCM (10:90), Rf value:~0.2; LCMS (m / z): 380.19 (M-H)’.1H NMR (400 MHz, DMSO-d / ) 5: 11.55 (brs, 1H), 8.66 (d, J= 2.0 Hz, 1H), 8.09 (d, J= 8.8 Hz, 2H), 7.91 (s, 1H), 7.77 (d, J= 12 Hz, 1H), 7.34 (d, J= 8.4 Hz, 2H), 5.33 (s, 1H), 2.42-2.40 (m, 2H), 2.39-2.20 (m, 2H), 1.94-1.84 (m, 1H), 1.66-1.57 (m, 1H).

[1090] Prep Conditions: Sample code: C0827-4-P ; Column: GEMINI NX C18 (250*21.2) mm 5mic; Buffer :MP- (A): lOMm ABC IN WATER MP- (B): Acetonitrile : WATER (80:20); Gradient :(T / %B ) 0 / 20,15 / 60,25 / 95; Flow Rate : 14ml / min; Solubility: WATER : ACN: THF. SYNTHETIC EXAMPLE 39

[1091] SYNTHESIS OF COMPOUND 1-62

[1092] Synthesis of 5-bromo-2,3-dihydro-lH-inden-2-ol

[1093] To a stirred solution of 2,3-dihydro-lH-inden-2-ol (5 g, 37.3 mmol, 1.0 eq) in ACN (30 mL, 6 Vol) at 0°C, was added 48% aq. HBr (150 mL, 30 Vol) followed by Br2 (11.9 g, 74.6 mmol, 2.0 eq) drop wise. The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with Na2COs solution (30 mL) (adjust PH=8) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to crude product. The crude product was triturated with n- pentane (30 mL), decanted and dried under vacuum to afford 5-bromo-2,3-dihydro-lH- inden-2-ol as white solid (6 g, Yield: Crude). TLC system: EtO Ac Hexane (20:80), Rf value:~0.4; 'HNMR (400 MHz, CDCls) 5: 7.37 (s, 1H), 7.30-7.28 (m, 1H), 7.10 (d, J= 8.0 Hz, 1H), 4.72-4.67 (m, 1H), 3.26-3.11 (m, 2H), 2.98-2.01 (m, 2H).

[1094] Synthesis of 5-bromo-2,3-dihydro-lH-inden-2-yl methanesulfonate

[1095] To a stirred solution of 5-bromo-2,3-dihydro-lH-inden-2-ol (6 g, 28.2 mmol, 1.0 eq) in DCM (60 mL) at 0°C, was added EtsN (5.6 g, 56.4 mmol, 2.0 eq), Ms-CI (3.9 g, 33.8 mmol, 1.2 eq) and stirred at room temperature for 2 h. After completion of reaction by TLC, the reaction mixture was quenched with water (40 mL) and extracted with DCM (2 x 40 mL). The combined organic layer was washed with NaHCCh solution (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 5-bromo-2,3-dihydro-lH-inden-2-yl methanesulfonate as yellow solid (8 g, Crude). TLC system: EtOAc / Hexane (20:80), Rfvalue:~0.5; 'H NMR (400

[1096] MHz, CDCti) 5: 7.39 (s, 1H), 7.35-7.33 (m, 1H), 7.12 (d, J= 8.0 Hz, 1H), 5.54-5.49 (m, 1H), 3.38-3.21 (m, 4H), 3.02 (s, 3H).

[1097] Synthesis of 2-azido-5-bromo-2,3-dihydro-lH-indene

[1098] To a stirred solution of 5-bromo-2,3-dihydro-lH-inden-2-yl methanesulfonate (8 g, 27.6 mmol, 1.0 eq) in EtOH (80 mL, 10 Vol) at room temperature, was added NaNs (2.7 g, 41.4 mmol, 1.5 eq) and stirred at 70°C for 16 h. After completion of reaction by TLC, reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-azido-5-bromo-2,3-dihydro-lH-indene as a pale-yellow gummy liquid (6 g, Yield: Crude). TLC system: EtOAc 7 / c.w / / c (30:70), Rfvalue:~0.5; *HNMR (400 MHz, CDCti) 5: 7.37 (s, 1H), 7.33-7.30 (m, 1H), 7.11-7.09 (m, 1H), 4.38-4.33 (m, 1H), 3.26-3.00 (m, 2H), 2.99-2.92 (m, 2H).

[1099] Synthesis of 5-bromo-2,3-dihydro-lH-inden-2-amine

[1100] PPh THF

[1101] To a stirred solution of 2-azido-5-bromo-2,3-dihydro-lH-indene (6 g, 25.3 mmol, 1.0 eq) in THF (120 mL, 20 Vol) at room temperature, was added PPhs (13 g, 50.6 mmol, 2.0 eq) followed by H2O (1 mL, 2.0 eq) and stirred at 80°C for 16 h. After completion of reaction by TLC, reaction mixture was acidified with 2N HC1 solution (20 mL), precipitated solid was discarded by filtration and collected aq. layer was concentrated under reduced pressure to afford 5-bromo-2,3-dihydro-lH-inden-2-amine as a pale-yellow solid (6 g, Yield: Crude). TLC system: EtOAc Hexane (100:00), Rf value:~0.1; LCMS(m / z): 212.08 (M+H)+.

[1102] Synthesis of N-(5-bromo-2,3-dihydro-lH-inden-2-yl)acetamide

[1103] To a stirred solution of 5-bromo-2,3-dihydro-lH-inden-2-amine (6 g, 28.3 mmol, 1.0 eq) in AC2O (30 mL, 5 Vol) at room temperature, was added EtiN (12 mL, 84.9 mmol, 3.0 eq) and stirred for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with NaHCOs solution (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (60-120) column chromatography [eluted 70% EtOAc in pet- ether] to afford N-(5-bromo-2,3-dihydro-lH-inden-2-yl)acetamide as off white solid (5.4 g, Yield: 75%). TLC system: EtOAc Hexane (100:00), Rfvalue:~0.4; *H NMR (400 MHz, CDCls) 5: 7.37 (s, 1H), 7.31-7.28 (m, 1H), 7.09 (d, J= 7.6 Hz, 1H), 5.73 (brs, 1H), 4.76-4.68 (m, 1H), 3.34-3.21 (m, 2H), 2.82-2.71 (m, 2H), 1.94 (s, 3H).

[1104] Synthesis of N-(5-(l-hydroxycyclobutyl)-2,3-dihydro-lH-inden-2-yl)acetamide

[1105] To a stirred solution of N-(5-bromo-2,3-dihydro-lH-inden-2-yl)acetamide (5.4 g, 21.3 mmol, 1 eq) in THF (55 mL) at -78 °C, was added n-BuLi (1.6 M in THF) (40 mL, 63.8 mmol, 3.0 eq) and stirred for 30 min. Later added cyclobutanone (2.2 g, 31.9 mmol, 1.5 eq) to reaction mixture and stirred for 2 h at -78°C. After completion of reaction by TLC, quenched with NH4Q solution (25 mL) and extracted with EtOAc (2 x 30 mL), The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100- 200 mesh) column chromatography [eluted with 50% EtOAc in Pet-ether] to afford N- (5-(l-hydroxycyclobutyl)-2,3-dihydro-lH-inden-2-yl)acetamide as off white solid (1.2 g, Yield: 23%), TLC system: EtO c Hexane (100:00), Rfvalue:~0.3; LCMS(m / z): 169.11 (M-OH)-;1H NMR (400 MHz, CDCls) 5: 7.38 (s, 1H), 7.32-7.28 (m, 2H), 5.73 (bs, 1H), 4.76-4.74 (m, 1H), 3.33-3.27 (m, 2H), 2.83-2.80 (m, 2H), 2.57-2.55 (m, 2H), 2.40-2.35 (m, 2H), 2.05-1.99 (m, 1H), 1.95 (s, 3H).

[1106] Synthesis of l-(2-amino-2,3-dihydro-lH-inden-5-yl)cyclobutan-l-ol

[1107] To a stirred solution of N-(5-(l-hydroxycyclobutyl)-2,3-dihydro-lH-inden-2- yl)acetamide (1.2 g, 4.89 mmol, 1 eq) in MeOH (12 mL) was added 10% aq. NaOH (26 mL, 20 vol) and stirred at room temperature for 24 h. After completion of reaction by TLC, quenched with water (20 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-pentane (20 mL), diethyl ether (20 mL), decanted and dried under reduced pressure to afford l-(2-amino-2,3-dihydro-lH-inden-5-yl)cyclobutan-l-ol as an off white solid (700 mg, yield: 71%); TLC system: MeOH DCM (10:90), Rfvalue:~0.1; LCMS (m / z): 204.1 (M+H)+.

[1108] Synthesis of 6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3-dihydro-lH-inden-2- yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3- carbonitrile

[1109]

[1110] In a sealed tube, to a degassed solution of 5-chloro-6-fluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (1 g, 3.07 mmol, 1.0 eq) and l-(2-amino-2,3-dihydro-lH-inden-5-yl)cyclobutan-l-ol (689 mg, 3.37 mmol, 1.1 eq) in Dioxane (10 mL) at room temperature, was added CS2CO3 (2.0 g, 6.14 mmol, 2.0 eq) followed by X-Phos (293 mg, 0.61 mmol, 0.2 eq) and Pd2(dba)3 (281 mg, 0.31 mmol, 0.1 eq). The reaction mixture was stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel [60-120] column chromatography [elution with 20% EtOAc in pet-ether] to afford 6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3-dihydro- lH-inden-2-yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine- 3 -carbonitrile as yellow gum (350 mg, Yield: 23%). TLC system: EtOAc / Hexane (30:70), Rfvalue:~0.3; LCMS(m / z): 493.46 (M+H)+; 'H NMR (400 MHz, CDC ) 5: 7.59 (s, 1H), 7.40-7.32 (m, 3H), 7.26-7.25 (m, 1H), 5.36 (s, 2H), 5.07-5.06 (m, 1H), 3.53-3.49 (m, 2H), 3.47-3.42 (m, 2H), 2.96-2.91 (m, 2H), 2.60-2.55 (m, 2H), 2.41-2.36 (m, 2H), 2.03-2.00 (m, 1H), 1.70-1.67 (m, 1H), 0.90-0.86 (m, 2H), -0.04 (s, 9H).

[1111] Synthesis of (E)-6-fluoro-N'-hydroxy-5-((5-(l-hydroxycyclobutyl)-2,3-dihydro- lH-inden-2-yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine- 3-carboximidamide

[1112]

[1113] To a stirred solution of 6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3-dihydro-lH- inden-2-yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridine-3- carbonitrile (350 mg, 0.71 mmol, 1.0 eq) in EtOH (3.5 mL) at room temperature, was added EtsN (215 mg, 2.13 mmol, 3.0 eq) and NH2OH HC1 (98 mg, 1.42 mmol, 2.0 eq). The reaction mixture was stirred at 90°C for 5 h. After completion of reaction by TLC, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (E)-6-fluoro-N'-hydroxy-5-((5-(l-hydroxycyclobutyl)- 2, 3 -dihydro- lH-inden-2-yl)amino)-l-((2-(trimethylsilyl)ethoxy)m ethyl)- 1H- pyrrolo[3,2-b]pyridine-3-carboximidamide as a brown solid (350 mg, Yield: Crude). TLC system: MeOHZDC (10:90), Rfvalue: ~0.4; LCMS(m / z): 526.49 (M+H)+.

[1114] Synthesis of ethyl (E)-((6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3-dihydro-lH- inden-2-yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyri din-3- yl)(hydroxyimino)methyl)carbamate

[1115] To a stirred solution of (E)-6-fluoro-N'-hydroxy-5-((5-(l-hydroxycyclobutyl)-

[1116] 2, 3 -dihydro- lH-inden-2-yl)amino)-l-((2-(trimethylsilyl)ethoxy)m ethyl)- 1 LI- pyrrolo[3,2-b]pyridine-3-carboximidamide (330 mg, 0.63 mmol, 1.0 eq) in DCM (3.3 mL) at 0°C, was added EtsN (83 mg, 0.82 mmol, 1.3 eq) and Ethyl chloroformate (82 mg, 0.76 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 2 h. After completion of reaction by TLC, the reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product. The crude product was purified by silica gel [60 -120] column chromatography [elution with 50% EtOAc in petroleum ether] to afford ethyl (E)-((6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3- dihydro-lH-inden-2-yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2- b]pyridin-3-yl)(hydroxyimino)methyl)carbamate as a yellow solid (300 mg, Yield: 81%). TLC system: EtOAc / Hexane (50:50), Rfvalue:~0.5; LCMS(m / z): 598.45 (M+H)+. 'H NMR (400 MHz, CDC ) 5: 7.98 (brs, 1H), 7.45 (d, J= 10.8 Hz, 1H), 7.40 (s, 1H), 7.36-7.31 (m, 1H), 5.37 (s, 2H), 4.98-4.97 (m, 1H), 4.34 (q, J= 7.2 Hz, 2H), 3.47-3.41 (m, 4H), 3.05-2.98 (m, 2H), 2.60-2.55 (m, 2H), 2.39-2.36 (m, 2H), 2.07-2.04 (m, 1H), 1.75-1.66 (m, 2H), 1.36 (t, J= 7.2 Hz, 3H), 0.89-0.85 (m, 2H), -0.05 (s, 9H).

[1117] Synthesis of 3-(6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3-dihydro-lH-inden-2- yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyri din-3-yl)- 1,2,4- oxadi azol - 5 (4H)-one

[1118] To a stirred solution of ethyl (E)-((6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3- dihydro-lH-inden-2-yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2- b]pyridin-3-yl)(hydroxyimino)methyl)carbamate (300 mg, 0.5 mmol, 1.0 eq) in DMSO (3.5 Vol, 1.0 mL) at room temperature, was added NaOH (24 mg, 0.6 mmol, 1.2 eq) and reaction mixture was stirred at room temperature for 3 h. After completion of reaction by TLC, the reaction mixture was quenched with 2N HC1 solution (5 mL), precipitated solid was filtered, washed with n-pentane (5 mL) and dried under vacuum to afford 3-(6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3-dihydro-lH-inden-2-yl)amino)-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol- 5(4H)-one as a pale brown solid (250 mg, Yield: Crude). TLC system: EtOAc 7 / C.YZ / / / C (100:00), Rfvalue: ~0.5; LCMS(m / z): 550.42 (M-H)’.

[1119] Synthesis of 3-(6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3-dihydro-lH-inden-2- yl)amino)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one

[1120] To a stirred solution of 3-(6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3-dihydro- lH-inden-2-yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin- 3-yl)-l,2,4-oxadiazol-5(4H)-one (250 mg, 0.45 mmol, 1.0 eq) in THF (2.5 mL) at 0°C, was added TBAF (1.0 M in THF) (4.53 mL, 4.53 mmol, 10 eq) and stirred at 80°C for 8 h. After completion of reaction by TLC, the reaction mixture was quenched with NH4Q solution (20 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Obtained crude was purified by reverse phase column chromatography [elution with 46% ACN in 0.1% FA in H2O] followed by Prep-HPLC and collected fractions were lyophilized to afford 3-(6-fluoro-5-((5-(l-hydroxycyclobutyl)-2,3-dihydro-lH-inden-2- yl)amino)-lH-pyrrolo[3,2-b]pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one as off white solid (33 mg, Yield: 17%). TLC system: MeOH / DC (10:90), Rfvalue:~0.4; LCMS(m / z): 420.19 (M-H)’; 'HNMR (400 MHz, DMSO-de) 5: 12.05 (s, 1H), 11.71 (s, 1H), 7.87 (d, J= 3.2 Hz, 1H), 7.61 (d, J= 11.6 Hz, 1H), 7.33 (s, 1H), 7.27-7.25 (m, 1H), 7.17 (d, J= 8.0 Hz, 1H), 6.60 (d, J= 6.0 Hz, 1H), 5.36 (s, 1H), 5.00-4.94 (m, 1H), 3.37-3.33 (m, 2H), 2.95-2.88 (m, 2H), 2.39-2.34 (m, 2H), 2.28-2.20 (m, 2H), 1.90-1.87 (m, 1H), 1.64- 1.59 (m, 1H).

[1121] Prep-HPLC condition: Column X-Bridge Cl 8, (250*19.0mm)5p Buffer A: 0.1% FA IN WATER; B: A CN:H20(80:20) Gradient(T / %B) 0 / 50,15 / 65,15.1 / 98 Flow Rate 12ml / min Solubility ACN+THF.

[1122] SYNTHETIC EXAMPLE 40

[1123] SYNTHESIS OF COMPOUND 1-66

[1124] Synthesis of ((4-bromophenyl)imino)dimethyl-X6-sulfanone

[1125] To a stirred solution iminodimethyl-X6-sulfanone (5 g, 53.7 mmol, 1 eq) and (4- bromophenyl) boronic acid (220 mL, 107.4 mmol, 1.6 eq) in MeOH (50 mL) at room temperature was added Cu(OAc)2 (0.98 g, 5.36 mmol, 0.1 eq) and stirred for 16 h under air atmosphere. After completion of reaction by TLC, reaction mixture was concentrated and purified by silica gel (100 - 200 mesh) column chromatography [elution with 30% EtOAc / Hexane] to afford ((4-b romophenyl)i mi no)di methyl -X6- sulfanone as off white solid (12 g, Yield: 90%), TLC system: EtOAc:hexane (50:50), Rf value:~0.3; LCMS (m / z): 248.04 (M+H).+'HNMR (400 MHz, CDCh). 7.34 (dd, J= 2.4 & 6.8 Hz, 2H), 6.98 (dd, J= 2.4 & 6.8 Hz, 2H), 3.18 (s, 6H).

[1126] Synthesis of dimethyl((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)imino)-X6-sulfanone Bispin KOAc

[1127] In a sealed tube, to a degassed solution of ((4-bromophenyl)imino)dimethyl-16- sulfanone (6 g, 24.3 mmol, 1.0 eq) and B2(pin)2 (9.3 g, 36.4 mmol, 1.5 eq) in DMSO (120 mL) at room temperature, was added KOAc (7 g, 72.9 mmol, 3.0 eq) followed by Pd(dppf)C12.DCM (2 g, 2.43 mmol, 0.1 eq) and stirred at 90 °C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with EtOAc (100 mL), collected filtrate was diluted with water (100 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Obtained crude was purified by silica gel (100 - 200 mesh) column chromatography [elution with 20% EtOAc / Hexane] to afford dimethyl((4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)imino)-X6-sulfanone as light brown solid (5 g, Yield:70%). TLC system: TLC system: EtOAc:hexane (50:50), Rfvalue:~0.25; 'H NMR (400 MHz, CDCls) 5: 7.69...

Claims

CLAIMS1. A compound having the following Structure (I):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:Y is N or CH;X is N or CRlb;W is N or CR1C;Rla, Rlb, and Rlcare each independently hydrogen or halo;R2is 3-8 membered N-heterocyclyl, -NH-R2d, or has the following structure:Z is N or CR2b;R2a, R2b, and R2care each independently hydrogen, optionally substituted C1-C4 alkoxy, -(CH2)niO(CH2)n2O(CH2)n3OH, -N=S(CH3)2=O, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3-8 membered heterocyclyl;R2dhas one of the following structures:R2eis optionally substituted C3-C6 cycloalkyl;R2fis halo or optionally substituted C3-C6 cycloalkyl; nl, n2, and n3 are each independently 1, 2, 3, or 4; andR3has one of the following structures:

2. The compound of claim 1, wherein Y is N.

3. The compound of claim 1, wherein Y is CH.

4. The compound of any one of claims 1-2, wherein X is N.

5. The compound of any one of claims 1-2, wherein X is CH, or CF.

6. The compound of any one of claims 1-3, wherein W is N or CH.

7. The compound of any one of claims 1-6, wherein Rlais hydrogen, fluoro, or chloro.

8. The compound of any one of claims 1-7, wherein R2is a monocyclic 5-6 membered N-heterocyclyl.

9. The compound of any one of claims 1-7, wherein R2is pyrrolidinyl.

10. The compound of claim 9, wherein R2is optionally substituted with one or more -OH substituents.

11. The compound of any one of claims 1-7, wherein R2has one of the following structures:

12. The compound of any one of claims 1-7, wherein R2ais methoxy.

13. The compound of any one of claims 1-7, wherein R2cis C3-C6 cycloalkyl optionally substituted with one or more -OH substituents.

14. The compound of any one of claims 1-7, wherein R2cis a 3-6 membered O- heterocyclyl or a 3-6 membered N-heterocyclyl each being optionally substituted with one or more -OH substituents.

15. The compound of any one of claim 1-7, wherein R2a, R2c, or both are independently methoxy, -N=S(CH3)2=O, or have one of the following structures:

16. The compound of any one of claims 1-15, wherein R2has one of the following structures:

17. The compound of any one of claims 1-16, wherein R2has one of the following structures:

18. The compound of any one of claims 1-7, wherein R2is -NH-R2d.

19. The compound of any one of claims 1-7, wherein R2has one of the following structures:

20. The compound of claim 19, wherein R2has one of the following structures:

21. The compound of any one of claims 1-20, wherein R3has one of the following structures:

22. The compound of any one of claims 1-20, wherein R3has one of the following structures:

23. The compound of any one of claims 1-20, wherein R3has one of the following structures:

24. The compound of any one of claims 1-20, wherein R3has one of the following structures:

25. The compound of claim 24, wherein R3has one of the following structures:

26. The compound of any one of claims 1-25, wherein the compound has one of the following structures:or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

27. A compound of having the following Structure (II):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:X1is N or CR7;X2is N or CH;X3is -NH-, -O-, or -S-;R4is optionally substituted C3-C6 cycloalkyl, -N=S(R4a)2=O, or optionally substituted phenyl, wherein R4ais, at each occurrence, independently C1-C4 alkyl;R5is hydrogen or halo;R6is, at each occurrence, independently optionally substituted C1-C4 alkyl, optionally substituted 5-membered heterocyclyl, or two occurrences of R6join, together with the carbons to which they are attached to form a 4-6 membered heterocyclyl;R7is hydrogen or halo; and n is 0, 1, 2, or 3.

28. The compound of claim 27, wherein X1is N.

29. The compound of claim 27, wherein X1is CF or CH.

30. The compound of any one of claims 27-29, wherein X2is N.

31. The compound of any one of claims 27-29, wherein X2is CH.

32. The compound of any one of claims 27-31, wherein X3is -NH-.

33. The compound of any one of claims 27-32, wherein X3is -O-.

34. The compound of any one of claims 27-32, wherein X3is -S-.

35. The compound of any one of claims 27-34, wherein R4is C3-C6 cycloalkyl optionally substituted with -OH.

36. The compound of any one of claims 27-34, wherein R4has the following structure:

37. The compound of any one of claims 27-34, wherein R4is -N=S(R4a)2=O and both occurrences of R4aare -CH3.

38. The compound of any one of claims 27-34, wherein R4is unsubstituted phenyl.

39. The compound of any one of claims 27-38, wherein R5is fluoro or chloro.

40. The compound of any one of claims 27-39, wherein one occurrence of R6is -CH3.

41. The compound of any one of claims 27-39, wherein one occurrence of R6is 5- membered heterocyclyl optionally substituted with oxo.

42. The compound of any one of claims 27-39, wherein one occurrence of R6has one of the following structures:

43. The compound of any one of claims 27-39, whereinhas one of the following structures:

44. The compound of any one of claims 27-42, wherein n is 1.

45. The compound of any one of claims 27-42, wherein n is 2 or 3.

46. The compound of any one of claims 27-45, wherein the compound has one of the following structures:

47. A compound having the following Structure (III):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:X4is N or CH;R8is optionally substituted C3-C6 cycloalkyl or -N=S(R8a)2=O wherein R8ais, at each occurrence, independently C1-C4 alkyl;R9is optionally substituted 5-membered heterocyclyl; andR10aand R10bare each independently hydrogen or halo.

48. The compound of claim 47, wherein R8is C3-C6 cycloalkyl optionally substituted with -OH.

49. The compound of any one of claims 47-48, wherein R8has the following structure:

50. The compound of claim 47, wherein R8is -N=S(R8a)2=O and both occurrences of R8aare -CH3.

51. The compound of any one of claims 47-50, wherein R9has the following structure:

52. The compound of any one of claims 47-51, wherein R10aand R10bare both fluoro.

53. The compound of any one of claims 47-52, wherein the compound has one of the following structures:or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

54. A compound having the following Structure (IV):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: ring A is phenyl or dihyroindenyl;X5is N or CH;Rl lais optionally substituted C3-C6 cycloalkyl or -N=S(Rl la)2=O wherein Rl lais, at each occurrence, independently C1-C4 alkyl;R12is optionally substituted 5-membered heterocyclyl; andR13aand R13bare each independently hydrogen or halo.

55. The compound of claim 54, wherein X5is N.

56. The compound of any one of claims 54-55, wherein R11is C3-C6 cycloalkyl optionally substituted with -OH.

57. The compound of any one of claims 54-56, wherein R11has the following structure:

58. The compound of any one of claims 54-57, wherein R11is -N=S(Rl la)2=O and both occurrences of Rl laare -CH3.

59. The compound of any one of claims 54-58, whereinhas one of the following structures:

60. The compound of any one of claims 54-59, wherein R12has one of the following structures:

61. The compound of any one of claims 54-60, wherein R13aand R13bare both fluoro.

62. The compound of any one of claims 54-61, wherein the compound has one of the following structures:or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

63. A salt form of the compound of any one of claims 1-62, wherein the salt form is a formic acid salt, a hydrochloric acid salt, or a trifluoroacetic acid salt.

64. A pharmaceutical composition comprising the compound of any one of claims 1-63, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.

65. A method of treating an AMPK mediated disease, the method comprising administering the compound of any one of claims 1-64, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof or the pharmaceutical composition of claim 64 to a subject in need thereof.

66. The method of claim 65, wherein the AMPK mediated disease is a cardiometabolic disease, a neuromuscular disorder, a cancer, a neurodegenerative disease, or combinations thereof.

67. The method of claim 65, wherein the AMPK mediated disease is obesity, diabetes, chronic inflammation, cardiac energy homeostasis, ischemia-reperfusion injury,endothelial dysfunction, dyslipidemia, cardiac hypertrophy and remodeling, Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), spinal muscular atrophy (SMA), Non-alcoholic Fatty Liver Disease (NAFLD), Alzheimer’s disease, or combinations thereof.

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