Estrogen receptor modulators and uses thereof

Abstract

The present disclosure provides compounds that are estrogen receptor modulators (e.g., estrogen receptor agonists, estrogen receptor antagonists, and / or complete estrogen receptor antagonists), and uses thereof.

Description

ESTROGEN RECEPTOR MODULATORS AND USES THEREOFBACKGROUND

[0001] The estrogen receptor (ER) plays important roles in various diseases, disorders, and conditions, such as cancers, including breast cancers, menopause-related conditions or symptoms, and osteoporosis. An, K-C. Asian Spine J. 10(4);787-91 (2016 Aug). About 70% of human breast cancers arc hormone dependent and ER-positive. Lumachi, et al., Curr. Med. Chem., 20(5):596- 604 (2013). A variety of treatments have been developed to target the estrogen receptor and / or its activities.SUMMARY

[0002] Selective estrogen receptor modulators (SERMs) or degraders (SERDs) are particularly useful and promising tools for treating estrogen receptor-related diseases, disorders, and conditions. For example, an estrogen receptor modulator that acts as an agonist (or partial agonist) in bone tissue may be useful for treating osteoporosis, e.g., in post-menopausal women. Further, an estrogen receptor modulator that acts as an antagonist in breast tissue may be useful for treating breast cancer. In some instances, the same estrogen receptor modulator may be used in both scenarios.

[0003] In some embodiments, the present disclosure provides compounds that arc estrogen receptor modulators. In some embodiments, provided compounds are estrogen receptor agonists, e.g., as defined herein. In some embodiments, provided compounds are estrogen receptor antagonists, e.g., as defined herein.

[0004] Additionally, there remains a need for anti-estrogen agents that can completely inhibit estrogen receptors, including those coded for by both wild-type and mutant versions (e.g., those containing activating mutations) of the gene encoding Estrogen Receptor- alpha (ERa), Estrogen Receptor 1 (ESRI). The estrogen receptor is a tripartite protein comprising two distinct transcriptional activation functions (AF1 and AF2). Complete anti-estrogen activity requires inactivation of both AF1 and AF2. Activating mutations in the gene that codes for estrogen receptor 1 allows for activation of both AF1 and AF2 even in the absence of estrogen.

[0005] Many patients develop resistance to certain therapies that target the estrogen receptor (ER) over time. Certain first line therapies for treating ER-associated diseases, disorders, or conditions, are found to exhibit agonistic activity in conjunction with their antagonistic properties. Fulvestrant, in contrast, is the only approved therapy that exhibits complete anti-estrogenic activity, but is not orally bioavailable, and must be administered parenterally.

[0006] In some embodiments, the present disclosure provides certain compounds and compositions that are complete estrogen receptor antagonists, and therefore do not suffer from the deficiencies found in previous therapies.

[0007] Additionally, in some embodiments, provided compounds may be orally bioavailable.

[0008] In some embodiments, the present disclosure provides an estrogen receptor modulator (e.g., an estrogen receptor agonist, an estrogen receptor antagonist, and / or a complete estrogen receptor antagonist) that is a compound represented by Formula I:or a pharmaceutically acceptable salt thereof, wherein Ring A1, Ring A2, Ring B, Q, L1, p, R1, R2, r, Rb, m, and R3are as defined in classes and subclasses herein, both singly and in combination.

[0009] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with an estrogen receptor. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with a mutation of an estrogen receptor.

[0010] In some embodiments, the present disclosure provides methods of treating a cancer. In some embodiments, the present disclosure provides methods of treating a cancer comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in combination with an anti-cancer agent.

[0011] In some embodiments, the present disclosure provides methods of preventing recurrence of a cancer. In some embodiments, the present disclosure provides methods of preventing recurrence of a cancer comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in combination with an anti-cancer agent.

[0012] In some embodiments, the present disclosure provides methods of treating osteoporosis, e.g., in post-menopausal women. In some embodiments, the present disclosure provides methods of treating osteoporosis comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the present disclosure provides methods of treating one or more menopausal symptoms or conditions. In some embodiments, the present disclosure provides methods of treating one or more menopausal symptoms comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0014] The present disclosure provides compounds and compositions useful as estrogen receptor modulators (e.g., estrogen receptor agonists, estrogen receptor antagonists, and / or complete estrogen receptor antagonists). In some embodiments, such compounds include those of the formulae described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.Compounds and Definitions

[0015] Compounds of this disclosure include those described generally above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0016] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some cases, Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.

[0017] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0018] About or approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by “about” or “approximately” in that context. For example, in some embodiments, the term “approximately” or “about” may encompass a range of values that are within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0019] Administering: As used herein, the term “administering” or “administration” typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some particular embodiments, administration may be intravenous. In some particular embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In someembodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, administration may comprise a prime- and-boost protocol. A prime-and-boost protocol can include administration of a first dose of a pharmaceutical composition followed by, after an interval of time, administration of a second or subsequent dose of a pharmaceutical composition.

[0020] Agonist: As used herein, the term “agonist” generally refers to an agent whose presence or level correlates with elevated level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level). In some embodiments, an agonist is one whose presence or level correlates with a target level or activity that is comparable to or greater than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known agonist, e.g., a positive control). In some embodiments, an agonist may be a direct agonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an agonist may be an indirect agonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity.

[0021] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point or more than one points of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted orunsubstituted alkyl, alkenyl, or alkynyl groups and hybrids thereof. A preferred aliphatic group is C1-6alkyl.

[0022] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched chain hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0023] Alkylene: The term “alkylene” is refers to a bivalent alkyl group. In some embodiments, “alkylene” is a bivalent straight or branched alkyl group. In some embodiments, an “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms. The suffix “-ene” when appended to certain groups herein are intended to refer to a bifunctional moiety of said group. For example, “-ene”, when appended to “cyclopropyl” becomes “cyclopropylene” and is intended to refer to a bifunctional cyclopropyl group, e.g.,

[0024] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkcnyl rings include cyclopentenyl, cyclohcxenyl, and cyclopentenyl.

[0025] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12,C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pcntynyl, hexynyl, and heptynyl.

[0026] Antagonist'. As will be understood by those skilled in the art, the term “antagonist” generally refers to an agent whose presence or level correlates with decreased level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level). In some embodiments, an antagonist is one whose presence or level correlates with a target level or activity that is comparable to or less than a particular’ reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known antagonist, e.g., a positive control). In some embodiments, an antagonist may be a direct antagonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an antagonist may be an indirect antagonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity.

[0027] Aryl'. The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-C14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C6-C12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings that are fused include

[0028] Bicyclic: The term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “hctcrobicyclic” is a subset of “bicyclic” that requires that one or more hctcroatoms arc present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized formssuch as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 hctcroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:Exemplary bridged bicyclics include:

[0029] Biological sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0030] Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

[0031] Combination therapy: As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality(ies)). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0032] Comparable'. As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the ail will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or withdifferent sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that arc varied.

[0033] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e.g., gas, gel, liquid, solid, etc.

[0034] Cycloaliphatic. As used herein, the term “cycloaliphatic” refers to a monocyclic C3-8 hydrocarbon or a bicyclic C5-10 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.

[0035] Cycloalkyl-. As used herein, the term “cycloalkyl” refers to an optionally substituted saturated monocyclic or polycyclic ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0036] Dosage form or unit dosage form-. Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).

[0037] Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimenare of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0038] Effective Amount'. The term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.

[0039] Excipient: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0040] Halogen: The term “halogen” or “halo” means F, Cl, Br, or I.

[0041] Heteroaliphatic'. The term “heteroaliphatic” or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight-chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. The term “nitrogen” also includes a substituted nitrogen. Unless otherwise specified, heteroaliphatic groups contain 1-10 carbon atoms wherein 1-3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1-4 carbon atoms, wherein 1-2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen,nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, hctcroalkyl, hctcroalkcnyl, and hctcroalkynyl groups. For example, a 1- to 10 atom heteroaliphatic group includes the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3, -CH2-NH-CH3, and the like.

[0042] Heteroaryl-. The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 1471-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrolopyridyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / / -quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[0043] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0044] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 6- to 10-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclicmoiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, hctcroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic heterocyclic ring can also be a bridged ring system (e.g., 6- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms).

[0045] Modulator. The term “modulator,” as used herein, refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, a modulator can cause an increase or decrease in the magnitude of a certain activity of a type of molecule as compared to the magnitude of the activity in the absence of the modulator. For example, a modulator can be an agonist or an antagonist of a particular target, as those terms are defined herein. For example, in some embodiments, a modulator is an agonist. In some embodiments, a modulator is an antagonist.

[0046] Oral: The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.

[0047] Parenteral: The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other thanenteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrastemal injection and infusion.

[0048] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

[0049] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0050] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as apessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0051] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0052] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0053] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977, 66(1), 1-19; P. Gould, International J. of Pharmaceutics 1986, 33, 201-217; Anderson etal., The Practiceof Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures arc incorporated herein by reference.

[0054] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1 -4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0055] Prevent or prevention: As used herein, the terms "‘prevent” or “prevention”, when used in connection with the occurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0056] Substituted or optionally substituted: As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g.,refers to at least andrefers to at leastUnless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituentsenvisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that arc not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0057] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)0-4IRC; -(CH2)0-4OR°; -0(CH2)0-4R°, -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)0-4(CH2)0-1Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)0-40(CH2)0-1-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)O-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°;N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; - C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)0-4C(O)SR°; -(CH2)0-4.C(O)OsiR°3; -(CH2)0-4OC(O)R°; - OC(0)(CH2)0-4SR°; -(CH2)0-4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; - SC(S)SR°, -(CH2)0-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°: -(CH2)0-4OS(O)2R°; - S(O)2NR°2; -(CH2)0-4S(0)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; - P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; -SiR°3; -(C1-4straight or branched alkylene)O- N(R°)2; or -(C1-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o iPh, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0058] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)0-2R*, -(haloR*), -(CH2)0 -2H, -(CH2)0-2OR*, -(CH2)0-2CH(OR*)2, -O(haloR’), -CN, -N3, -(CH2)o-2C(O)R*, -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR*, -(CH2)0-2SR*, -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR*. -(CH2)0-2NR*2, -NO2, -SiR*3, -OsiR*3, -C(O)SR*-(CIM straight or branched alkylene)C(O)OR*, or -SSR*wherein each R*is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4aliphatic, - CH2Ph, -0(CH2)0-1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0059] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0 (“oxo”), =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*=NR*=NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R is selected from hydrogen, Ci 6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0060] Suitable substituents on the aliphatic group of R*include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R*is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently CIM aliphatic, -CH2Ph, 0(CH2)o iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0061] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R:, -NR:2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf,C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NRf2, -C(NH)NRt2, or -N(Rt)S(O)2Rt; wherein each R is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below,unsubstituted -Oph, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 hctcroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rf, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0062] Suitable substituents on the aliphatic group of R are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R*is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -0(CH2)0-1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0063] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and / or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer.

[0064] In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, a small molecule is not and / or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid.

[0065] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.

[0066] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0067] Those of ordinary skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more steroisomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.

[0068] Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.

[0069] Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g.,2H or3H for H;nC,13C or14C for12C;13N or15N for14N;17O or18O for16O;36C1 for35C1 or37C1;18F for19F;131I for127I; etc.). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0070] In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0071] In some embodiments, where a small molecule compound is one that exists or is found in nature, that compound may be provided and / or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature. Those of ordinary skill in the art will appreciate that, in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of thepreparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest (c.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.

[0072] Those skilled in the art will further appreciate that, in small molecule structures, the symbol , as used herein, refers to a point of attachment between two atoms. Additionally or alternatively, the symbol refers to a point of attachment ring in a spirocyclic manner.

[0073] Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.Estrogen Receptor Modulators

[0074] In some embodiments, the present disclosure provides compounds that are estrogen receptor modulators. In some embodiments, provided compounds are estrogen receptor agonists. As used herein, an “estrogen receptor agonist” refers to a compound or composition that produces an agonistic effect when contacting the estrogen receptor of a subject or biological sample. In some embodiments, an estrogen receptor agonist is characterized by having at least 15% increasein the E2-normalized signal in the AP assay (agonist mode) as described in Example 32. In some embodiments, an estrogen receptor agonist is characterized by having at least 50% increase in the E2-normalized signal in the AP assay (agonist mode) as described in Example 32.

[0075] In some embodiments, provided compounds are estrogen receptor antagonists. As used herein, an “estrogen receptor antagonist” refers to a compound or composition that produces an antagonistic effect when contacting the estrogen receptor of a subject or biological sample. In some embodiments, an estrogen receptor antagonist is characterized by having:1. measurable antagonist activity in the AP assay (antagonist mode) as described in Example 32; or2. a pIC50greater than 7.0 in the AP assay (antagonist mode) as described in Example 32;3. a pIC50greater than 8.0 in the AP assay (antagonist mode) of Example 32; or4. a pIC50greater than 9.0 in the AP assay (antagonist mode) as described in Example 32.

[0076] In some embodiments, the present disclosure provides compounds that are complete estrogen receptor (ER) antagonists. As used herein, a “complete estrogen receptor antagonist” refers to a compound or composition that produces an antagonistic effect when contacting the estrogen receptor of a subject or biological sample, with minimal agonistic effect (e.g., with no or substantially no agonistic effect). Complete estrogen receptor antagonism is determined according to methods described herein, for example in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 7.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no measurable agonist activity in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 8.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no measurable agonist activity in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 9.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no measurable agonist activity in the AP assay (agonist mode) as described in Example 32.

[0077] In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 7.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 10% increase in the E2-normalized signal in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist ischaracterized by having (i) a pIC50greater than 8.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 10% increase in the E2-normalizcd signal in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 9.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 10% increase in the E2-normalized signal in the AP assay (agonist mode) of Example 32.

[0078] In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 7.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 15% increase in the E2-normalized signal in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 8.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 15% increase in the E2-normalized signal in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 9.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 15% increase in the E2-normalized signal in the AP assay (agonist mode) of Example 32.

[0079] In some embodiments, a complete estrogen receptor antagonist is an agent (e.g., a small molecule compound) that shows ER antagonism and no or substantially no ER agonism in one or more of ERα protein level assays, MCF-7 cell line assays, Ishikawa cell line assays (measuring wild type ER and certain mutants including mutants lacking AF1 and / or AF2 domains), and rodent uterine weight gain assays. See, generally, WO 2017 / 059139. Alternatively or additionally, in some embodiments, a complete estrogen receptor antagonist has three characteristics: it (1) inhibits both activating function 1 (AF1) and activating function 2 (AF2), as complete anti-estrogen activity requires inactivation of both AF1 and AF2; (2) promotes ER degradation; and (3) lacks the partial ER agonist activity observed with certain other agents. Without being bound by theory, it is understood that complete inhibition of both AF1 and AF2 is required for complete estrogen receptor activity, activating mutations in the gene that codes for estrogen receptor 1 allows for activation of both AF1 and AF2 even in the absence of estrogen.

[0080] In some embodiments, the present disclosure provides a compound represented by Formula I:or a pharmaceutically acceptable salt thereof, wherein:Ring A1is optionally substituted 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted phenyl, or optionally substituted benzoxaborole;Ring A2is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 3- to 9-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C3-C9cycloaliphatic;Ring B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 6- to 10-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C6-C12aryl, wherein when Ring B is C6aryl, Ring A1is a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; p is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, 4, 5, or 6; each R1is independently selected from halogen, -ORa, -N(Ra)2, -C(O)ORa, -C(O)N(Ra)2, -C(O)N(ORa)(Ra), optionally substituted C1-6aliphatic, -B(ORa)2, - S(O)(Ra)N(Ra)2, -S(O)(NH)Ra, -P(O)(ORa)2, -C(NRa)-ORa, optionally substituted 3- to 7-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S;R2is -L2-R2a;R21is optionally substituted C1-C6aliphatic, optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted C3-C7cycloaliphatic, optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 5- to 12-mcmbcrcd hctcroaryl comprising 1-4 hctcroatoms selected from N, O, and S, optionally substituted C6-C12aryl, -ORa, or -C(O)ORa; L1is selected from -O-, -N(Ra)-, -S-, optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C1-C6aliphatic;L2is a bond, optionally substituted C1-C6aliphatic, or optionally substituted 2- to 10- atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S;Q is selected from optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 3- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C3-C6cycloaliphatic; each R3is independently selected from halogen and optionally substituted C1-C6aliphatic; each Rais independently selected from hydrogen, deuterium, halogen, and optionally substituted C1-C6aliphatic; each Rbis independently selected from hydrogen, deuterium, halogen, and optionally substituted C1-C6aliphatic; and mis 0, 1, 2, 3, 4, or 5.

[0081] As described generally above, Ring A1is optionally substituted 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted phenyl, or optionally substituted benzoxaborole.

[0082] In some embodiments, Ring A1is optionally substituted 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Ring A1is optionally substituted 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N and O. In some embodiments, Ring A1is optionally substituted 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N and O, wherein at least 1 heteroatom is N. In some embodiments, Ring A1is optionally substituted 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms, wherein each heteroatom is N. In some embodiments, Ring A1is 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, -(CH2)0-4R0, or -(CH2)0-40R°. In some embodiments, Ring A1is optionally substitutedmonocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Ring A1is optionally substituted pyridine, pyrrole, pyrazolc, or furan. In some embodiments, Ring A1is:

[0083] In some embodiments, Ring A1is optionally substituted 9-membered bicyclic heteroaryl. In some embodiments, Ring A1is indole, indoline, or indazole. In some embodiments, Ring A1is:

[0084] In some embodiments, Ring A1is optionally substituted phenyl. In some embodiments, Ring A1is phenyl optionally substituted with halogen, -(CH2)0-44R°. or -(CH2)0-4OR°. In some embodiments, Ring A1is:

[0085] In some embodiments, Ring A1is optionally substituted benzoxaborole. In some embodiments, Ring A1is benzoxaborazole optionally substituted with halogen, -(CH2)0-4R°, or - (CH2)0-4R°. In some embodiments, Ring A1is benzoxaborole optionally substituted with -OH.In some embodiments, Ring A1is:

[0086] In some embodiments, Ring A1is selected from:

[0087] In some embodiments, Ring A1is selected from:

[0088] As described generally above, Ring A2is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 3- to 8-mcmbcrcd heterocycle comprising 1 to 3 hctcroatoms selected from N, O, and S, or optionally substituted C3-C7cycloaliphatic.

[0089] In some embodiments, Ring A2is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Ring A2is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms, wherein each heteroatom is S. In some embodiments, Ring A2is 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with halogen, -(CH2)0-4R°, or -(CH2)0-40R°.

[0090] In some embodiments, Ring A2is optionally substituted 3- to 9-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Ring A2is optionally substituted 3- to 7-membered monocyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Ring A2is optionally substituted 3- to 8- membered heterocycle comprising 1 to 3 heteroatoms, wherein each heteroatom is N. In some embodiments, Ring A2is optionally substituted 3- to 8-membered heterocycle comprising 1 to 3heteroatoms, wherein each heteroatom is O. In some embodiments, Ring A2is 3- to 8-membered heterocycle comprising 1 to 3 hctcroatoms selected from N, O, and S optionally substituted with halogen, -(CH2)0-4R°, or -(CH2)0-4OR°.

[0091] In some embodiments, Ring A2is optionally substituted 8- to 9-membered bicyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Ring A2is 8- to 9-membered bicyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, -(CH2)0-4R°, or -(CH2)0-4OR°.

[0092] In some embodiments, Ring A2is optionally substituted C3-C9cycloaliphatic. In some embodiments, Ring A2is optionally substituted monocyclic C3-C7cycloaliphatic. In some embodiments, Ring A2is optionally substituted monocyclic C6 cycloaliphatic. In some embodiments, Ring A2is optionally substituted monocyclic C7cycloalophatic. In some embodiments, Ring A2is monocyclic C3-C7cycloaliphatic optionally substituted with halogen, - (CH2)0-4R°, or -(CH2)0-4OR°. In some embodiments, Ring A2is optionally substituted monocyclic C3-C7cycloalkyl. In some embodiments, Ring A2is monocyclic C3-C7cycloalkyl optionally substituted with halogen, -(CH2)0-4R°, or -(CH2)0-4OR°.

[0093] In some embodiments, Ring A2is optionally substituted bicyclic C7-C9cycloaliphatic. In some embodiments, Ring A2is bicyclic C7-C9cycloaliphatic optionally substituted with halogen, -(CH2)0-4R°, or -(CH2)0-4OR°.

[0094] In some embodiments, Ring A2is selected from:

[0095] In some embodiments, Ring A1is optionally substituted phenyl and Ring A2is optionally substituted 3- to 9-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C3-C9cycloaliphatic. In some embodiments, Ring A1is optionally substituted phenyl and Ring A2is optionally substituted C3-C9cycloaliphatic. In some embodiments, Ring A1is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and Ring A2is optionally substituted C3-C9- cycloaliphatic.

[0096] In some embodiments of formula I, a moiety:is selected from:

[0097] As described generally above, Ring B is optionally substituted 5- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C6- C12aryl, wherein when Ring B is C6aryl (e.g., phenyl), Ring A1is a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0098] In some embodiments, Ring B is optionally substituted 5- to 12-mcmbcrcd hctcroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Ring B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N and O. In some embodiments, Ring B is optionally substituted 5- to 12-membered hctcroaryl comprising 1 to 4 heteroatoms, wherein each heteroatom is N. In some embodiments, Ring B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms, wherein each heteroatom is O. In some embodiments, Ring B is optionally substituted 5- to 12-membered heteroaryl comprising 2 to 4 heteroatoms selected from N and O, wherein at least 1 heteroatom is N and at least 1 heteroatom is O. In some embodiments, Ring B is 5- to 12-membered heteroarylcomprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with deuterium, halogen, -(CH2)0-4R°, or -(CH2)0-4OR°.

[0099] In some embodiments, Ring B is optionally substituted monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodimetns, Ring B is optionally substituted pyridine. In some embodiments, Ring B is monocyclic 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with deuterium, halogen, -(CH2)0-4R°, or -(CH2)0-4OR°.

[0100] In some embodiments, Ring B is optionally substituted bicyclic 8- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0101] In some embodiments, Ring B is selected from:attachment to moiety L1.

[0102] In some embodiments, Ring B is selected from:wherein * represents a point of attachment to moiety L1.

[0103] In some embodiments, Ring B is selected from:

[0104] In some embodiments, Ring B is:, wherein * represents a point of attachment to moiety L1.

[0105] In some embodiments, Ring B is selected from:

[0106] In some embodiments, Ring B is selected from:represents a point of attachment to moiety L1.

[0107] In some embodiments, Ring B is optionally substituted C6-C12aryl. In some embodiments, Ring B is optionally substituted C6-C12aryl and Ring A1is a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Ring B is phenyl and Ring A1is a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0108] In some embodiments, Ring B is:, and Ring A1is a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0109] In some embodiments, Ring B is:Ring A1is a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0110] As described generally above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0111] As described generally above, r is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6.

[0112] As described generally above, each R1is independently selected from halogen, -ORa, - N(Ra)2, -C(O)ORa, -C(O)N(Ra)2, -C(O)N(ORa)(Ra), optionally substituted Ci-6aliphatic, -B(ORa)2, -S(O)(Ra)N(Ra)2, -S(O)(NH)Ra, -P(O)(ORa)2, -C(NRa)-ORa, optionally substituted 3- to 7- membered hctcroaryl comprising 1 to 3 hctcroatoms selected from N, O, and S, and optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.

[0113] In some embodiments, R1is halogen. In some embodiments R1is F.

[0114] In some embodiments, R1is -ORa. In some embodiments, R1is -OH. In some embodioments, R1is -OCH3.

[0115] In some embodiments, R1is N(Ra)2. In some embodiments, R1is -NH2. In some embodiments, R1is -NH(C1-C6aliphatic). In some embodiments, R1is -N(CH3)2.

[0116] In some embodiments, R1is -C(O)ORa. In some embodiments, R1is -C(O)OH. In some embodiments, R1is -C(O)OCH3.

[0117] In some embodiments, R1is -C(O)N(Ra)2. In some embodiments, R1is -C(O)NH2.

[0118] In some embodiments, R1is optionally substituted Ci-6 aliphatic. In some embodiments, R1is C1-C6aliphatic optionally substituted with -OR°. In some embodiments, R1is C1-C6aliphatic optionally substituted with -OH. In some embodiments, R1is -CH2-OH.

[0119] In some embodiments, R1is -C(NRa)-ORa. In some embodiments, R1is -C(NH)-OH.

[0120] In some embodiments, R1is -B(ORa)2. In some embodiments, R1is -B(OH)2.

[0121] In some embodiments, R1is -S(O)(Ra)N(Ra)2.

[0122] In some embodiments, R1is -S(O)(NH)Ra. In some embodiments, R1is -S(O)(NH)CH3.

[0123] In some embodiments, R1is -P(O)(ORa)2. In some embodiments, R1is -P(O)(OCH2CH3)2, -P(O)(OCH2CH3)(OH), or -P(O)(OH)2. In some embodiments, R1is - P(O)(OCH2CH3)2. In some embodiments, R1is -P(O)(OCH2CH3)(OH). In some embodiments, R1is -P(O)(OH)2.

[0124] In some embodiments, R1is optionally substituted 3- to 7-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R1is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R1is pyrazole.

[0125] In some embodiments, R1is optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S

[0126] In some embodiments, p is 2 and one instance of R1is -ORaand the other instance of R1is halogen. In some embodiments, p is 2 and one instance of R1is OH and the other instance of R1is F.

[0127] As described generally above, R2is -L2-R2a.

[0128] As described generally above, L2is a bond, optionally substituted C1-C6aliphatic, or optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S.

[0129] In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted C1-6 aliphatic. In some embodiments, L2is C1-6 aliphatic optionally substituted with oxo, halogen, -(CH2)0-4R°, or -(CH2)0-40R°. In some embodiments, L2is C1-C6alkylene. In some embodiments, L2is -CH2-.

[0130] In some embodiments, L2is optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2is optionallysubstituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N and O. In some embodiments, L2is optionally substituted 2- to 10-atom hetcroaliphatic comprising 1 to 4 heteroatoms, wherein each heteroatom is N. In some embodiments, L2is 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with halogen, -(CH2)0-44R°, or -(CH2)0-4OR°. In some embodiments, L2-R2ais

[0131] As described generally above, R2ais optionally substituted C1-C6aliphatic, optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted C3-C7cycloaliphatic, optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 5- to 12-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, optionally substituted aryl, - ORa, or -C(O)ORa.

[0132] In some embodiments, R2ais optionally substituted C1-C6aliphatic. In some embodiments, R2ais C1-C6aliphatic optionally substituted with halogen, -C(O)OR°, -(CH2)0-4R°, o -(CH2)0-4OR°. In some embodiments, R2ais C1-C6aliphatic substituted with halogen. In some embodiments, R2ais C1-C6aliphatic substituted with halogen or -OH. In some embodiments, R2a

[0133] In some embodiments, R2ais optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R2ais optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N and O. In some embodiments, R2ais optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms, wherein each heteroatom is N. In some embodiments, R2ais 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with halogen, -(CH2)0-44R°. or -(CH2)0-4OR°. In some embodiments, R2ais

[0134] In some embodiments, R2ais optionally substituted C3-C7cycloaliphatic. In some embodiments, R2ais optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Insome embodiments, R2ais cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with halogen, -(CH2)0-4R°, or -(CH2)0-4OR°. In some embodiments, R2ais cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with C1-C6aliphatic or-OH. In some embodiments, R2ais

[0135] In some embodiments, R2ais optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R2ais 3- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, oxo, -(CH2)0-4R°, or -(CH2)0-4OR°. In some embodiments, R2ais optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms, wherein each heteroatom is N. In some embodiments, R2ais optionally substituted 3-membered heterocycle comprising 1 to 2 heteroatoms, wherein each heteroatom is N. In some embodiments, R2ais optionally substituted 4-membered heterocycle comprising 1 to 2 heteroatoms, wherein each heteroatom is N. In some embodiments, R2ais optionally substituted 5-membered heterocycle comprising 1 to 3 heteroatoms, wherein each heteroatom is N. In some embodiments, R2ais optionally substituted 6-membered heterocycle comprising 1 to 3 heteroatoms, wherein each heteroatom is N. In some embodiments, R2ais optionally substituted 7-membered heterocycle comprising 1 to 3 heteroatoms, wherein each heteroatom is N. In some embodiments, R2aissome embodiments, R2ais optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms, wherein each heteroatom is O. In some embodiments, R2ais optionally substituted 3-membered heterocycle comprising 1 to 2 heteroatoms, wherein each heteroatom is O. In some embodiments, R2ais optionally substituted 4-membered heterocycle comprising 1 to 2 heteroatoms, wherein each heteroatom is O. In some embodiments, R2ais optionally substituted 5-membered heterocycle comprising 1 to 3 heteroatoms, wherein each heteroatom is O. In some embodiments, R2ais optionally substituted 6-membered heterocycle comprising 1 to 3heteroatoms, wherein each heteroatom is O. In some embodiments, R2ais optionally substituted 7-membered heterocycle comprising 1 to 3 hctcroatoms, wherein each hctcroatom is O. In some embodiments, R2ais selected fromIn some embodiments, R2ais selected fromIn some embodiments, R2aisIn some embodiments, R2ais. In some embodiments, R2aisIn some embodiments, R2aisIn some embodiments,R2ais

[0136] In some embodiments, R2ais optionally substituted 5- to 12-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S. In some embodiments, optionally substituted 5- to 12-membered heteroaryl comprising 1-4 heteroatoms selected from N and O. In some embodiments, R2ais 5- to 12-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S optionally substituted with halogen, -(CH2)0-4R°, or -(CH2)0-4OR°. In some embodiments, R2ais optionally substituted monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R2ais optionally substituted pyrazole, pyridine, or pyrimidine. In some embodiments, R2ais monocyclic 5- to 6-memberedheteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, -(CH2)0-4R°. or -(CH2)0-4OR°. In some embodiments, R2ais monocyclic 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with -CH3, -Cl. , or -OCH3.

[0137] In some embodiments, R2ais selected from:

[0138] In some embodiments, R2ais optionally substituted C6-C12aryl. In some embodiments, R2ais optionally substituted phenyl. In some embodiments, R2ais phenyl. In some embodiments, R2ais phenyl optionally substituted with -(CH2)0-4R°, or -(CH2)0-4OR°. In some embodiments, R2ais

[0139] In some embodiments, R2ais -ORa. In some embodiments, R2ais -OH. In some embodiments, R2ais -OCH3.

[0140] In some embodiments, R2ais -C(O)ORa. In some embodimetns, R2ais -C(O)OCH3.

[0141] In some embodiments, R2is selected from:

[0142] As described generally above, L1is selected from -O-, -N(Ra)-, -S-, optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, andS, and optionally substituted C1-C6aliphatic.

[0143] In some embodiments, L1is -O-.

[0144] In some embodiments, L1is -N(Ra)-. In some embodiments, L1is -N(H)-. In some embodiments, L1is -N(CH3)-.

[0145] In some embodiments, L1is -S-.

[0146] In some embodiments, L1is optionally substituted C1-C6aliphatic. In some embodiments, L1is C1-6 aliphatic optionally substituted with halogen, -(CH2)0-4R°, or -(CH2)o- 4OR°. In some embodiments, L1is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-,-CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and - CH2CH2CH2CH2CH2CH2-. In some embodiments, L1is -CH2-. In some emobdiments, L1is C1-C6aliphatic where one or more hydrogen atoms have been replaced with deueterium atoms. In some embodiments, L1is -CD2-.

[0147] In some embodiments, L1is optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L1is 2- to 6- atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with halogen, -(CH2)0-4R°, or -(CH2)0-40R°. In some embodiments, L1is 2- to 6-atom heteroaliphatic comprising 1 to 4 heteroatoms each N optionally substituted with halogen, - (CH2)0-4R°, or -(CH2)0-40R°. In some embodiments, L1is -CH2NH-.

[0148] As described generally above, Q is selected from optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 3- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C3-C6cycloaliphatic.

[0149] In some embodiments, Q is optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 hctcroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N and O. In some embodiments, Q is optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms, wherein each heteroatom is N. In some embodiments, Q is 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with halogen, (CH2)0-4R°, or (CH2)0-4OR°. In some embodiments, Q is selected from. In some embodiments, Q isIn some embodimentsQ is

[0150] In some embodiments, Q is optionally substituted 3- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted 6- to 12-mcmbcrcd spirocyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted 3- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N and O. In some embodiments, Q is optionally substituted 3- to 12-membered heterocycle comprising 1 to 4 heteroatoms, wherein each heteroatom is N. In some embodiments, Q is optionally substituted 3- to 12-membered heterocycle comprising 2 to 4 heteroatoms selected from N and O, wherein at least one heteroatom is N and at least one heteroatom is O. In some embodiments, Q is 3- to 12- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with halogen, deuterium, -(CH2)0-4R°. or -(CH2)0-4OR°.

[0151] In some embodiments, Q is optionally substituted monocyclic 4- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted azetidine or pyrrolidine. In some embodiments, Q is optionally substituted azetidine.

[0152] In some embodiments, Q is optionally substituted 7- to 12-membered bicyclic or spirocyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

[0153] In some embodiments, Q is selected from:In some embodiments, Q issome embodiments, Q isIn some embodiments, Q isIn some embodiments, Q isIn some embodiments, Q issome embodiments, Q isIn some embodiments, Q issome embodiments,

[0154] In some embodiments, Q is optionally substituted C3-C6cycloaliphatic. In some embodiments,

[0155] In some embodiments, Q is selected from:H embodiments, Q is. In some embodiments, Q is. In some embodiments,In some embodiments, Q isIn some embodiments, Q isIn some embodiments, Q is In some embodiments, Q isIn some embodiments, Q isIn some embodiments, Q issome embodiments, Q isIn some embodiments, Q isIn some embodiments,

[0156] As described generally above, each R3is independently selected from halogen and optionally substituted C1-C6aliphatic.

[0157] In some embodiments, each R3is independently selected from halogen and optionally substituted C1-C6aliphatic.

[0158] In some embodiments, R3is halogen. In some embodiments, each R3is fluoro.

[0159] In some embodiments, R3is an optionally substituted C1-C6aliphatic. In some embodiments, R3is C1-C6aliphatic optionally substituted with halogen. In some embodiments, R3is C1-C3alkyl optionally substituted with halogen. In some embodiments, R3is C1-C3alkyl optionally substituted with fluoro. In some embodiments, R3is C2-C4alkenyl optionally substituted with halogen. In some embodiments, R3is C2-C4alkenyl optionally substituted with fluoro. In some embodiments, R3is methyl, ethyl, propyl, butyl, pentyl, hexyl, -CH2F, -CH2CH2F, -CH2CHF2, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2F, or -CH2CH2CH(CH3)2.

[0160] As described generally above, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0161] In some embodiments of any one of formulae I, II, II- 1, III, III- 1 , III-2, III-3, III-4, IV- 1, IV-2, and IV-3, moiety:

[0162] As described generally above, each Rais independently selected from hydrogen, deuterium, halogen, and optionally substituted Ci-6 aliphatic.

[0163] In some embodiments, each Rais independently selected from hydrogen, deuterium, and optionally substituted C1-6aliphatic. In some embodiments, each Rais independently selected from hydrogen, and optionally substituted Ci-6 aliphatic.

[0164] As described generally above, each Rbis independently selected from hydrogen, deuterium, halogen, and optionally substituted C1-C6aliphatic.

[0165] In some embodiments, each Rbis independently selected from hydrogen, deuterium, halogen, and optionally substituted C1-C6aliphatic. In some embodiments, each Rbis independently selected from hydrogen, deuterium and optionally substituted C1-C6aliphatic. In some embodiments, each Rbis independently selected from hydrogen and deuterium.

[0166] In some embodiments, the present disclosure provides a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein:Ring A1, Ring B, R1, R2, R3, Rb, m, p, and r are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination;W is C, CRa, or N as valency permits;X is (-C(Ra)2-)n;Y is O, S, or C(Ra)2;Z is C or N, as valency permits; n is 0, 1, or 2, and— represents either a double or a single bond.

[0167] In some embodiments, the present disclosure provides a compound of Formula II- 1:or a pharmaceutically acceptable salt thereof, wherein Ring B, R1, R2, R3, Rb, m, p, r, n, and Y are as defined above for Formula I and / or Formula II and described in classes and subclasses herein, both singly and in combination.

[0168] In some embodiments, the present disclosure provides a compound of Formula III:or a pharmaceu tic ally acceptable salt thereof, wherein Ring A1, Ring B, R1, R2, R , Rb, m, p, r, X, and — are as defined above for Formula I and / or Formula II and described in classes and subclasses herein, both singly and in combination.

[0169] In some embodiments, the present disclosure provides a compound of Formula III- 1 :or a pharmaceutically acceptable salt thereof, wherein Ring B, R1, R2, R3, Rb, m, p, and r are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0170] In some embodiments, the present disclosure provides a compound of Formula III-2:111-2, or a pharmaceutically acceptable salt thereof, wherein Ring B, R1, R2, R3, Rb, m, p, and r are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0171] In some embodiments, the present disclosure provides a compound of Formula III-3 :III-3, or a pharmaceutically acceptable salt thereof, wherein Ring B, R1, R2, R3, Rb, m, p, and r are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0172] In some embodiments, the present disclosure provides a compound of Formula III-4:III-4, or a pharmaceutically acceptable salt thereof, wherein Ring B, R1, R2, R3, Rb, m, p, and r are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0173] In some embodiments, the present disclosure provides a compound of Formula IV- 1:or a pharmaceutically acceptable salt thereof, wherein Ring A1, Ring B, R1, R2, R3, Rb, m, p, r, and — are as defined above for Formula I or Formula II and described in classes and subclasses herein, both singly and in combination.

[0174] In some embodiments, the present disclosure provides a compound of Formula IV-2:or a pharmaceutically acceptable salt thereof, wherein Ring B, R1, R2, R3, Rb, m, p, and r are as defined above for Formula I or Formula II and described in classes and subclasses herein, both singly and in combination.

[0175] In some embodiments, the present disclosure provides a compound of Formula IV-3:or a pharmaceutically acceptable salt thereof, wherein Ring B, R1, R2, R3, Rb, m, p, and r are as defined above for Formula I or Formula II and described in classes and subclasses herein, both singly and in combination.

[0176] In some embodiments, the present disclosure provides a compound of Table 1.Table 1

[0177] In some embodiments, the present disclosure provides a compound selected from Table 2, or a pharmaceutically acceptable salt thereof:Table 2

[0178] In some embodiments, a compound provided herein is an estrogen receptor agonist, and is selected from Table 2.

[0179] In some embodiments, the present disclosure provides a compound selected from Table 3, or a pharmaceutically acceptable salt thereof:Table 3

[0180] In some embodiments, a compound provided herein is an estrogen receptor antagonist, and is selected from Table 3.

[0181] In some embodiments, the present disclosure provides a compound selected from Table 4, or a pharmaceutically acceptable salt thereof:Table 4

[0182] In some embodiments, a compound described herein is a complete estrogen receptor antagonist and is selected from Table 4.

[0183] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.

[0184] It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of Formula I is intended to also include Formulae I-IV-3, and compound species of such formulas disclosed herein.Uses, Formulation, and Administration

[0185] The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.Pharmaceutically Acceptable Compositions

[0186] According to another embodiment, the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of compound in compositions described herein is such that it is effective to measurably inducedegradation of a target in a biological sample or in a patient. In certain embodiments, a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient.

[0187] Compounds and compositions, according to method of the present disclosure, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.

[0188] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternallyor via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously.

[0189] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0190] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonlyused in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0191] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0192] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0193] In some embodiments, provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions described herein are administered with food. Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0194] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0195] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating ail. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0196] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate andmicrocrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain pail of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0197] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0198] Alternatively, pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0199] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0200] Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0201] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdcrmal patches may also be used.

[0202] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0203] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0204] Pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0205] Dosage forms for topical or transdermal administration of a compound disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, car drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.Estrogen Receptor-Associated Diseases and Disorders

[0206] The estrogen receptor (“ER”) is involved in a variety of biological processes, relating, for example, to development of the female reproductive system, maintenance of bone mass, protection of cardiovascular and / or central nervous system components, etc. (see, for example, Pearce & Jordan Crit. Rev. Onc / Hem 50:3, 2004; Heldring Phys. Rev. 87:905, 2007). The ER has been implicated in a variety of cancers. In many tumors that express the estrogen receptor (i.e., ER+tumors), active ERa signaling has been demonstrated to drive cell proliferation (although ER signaling has been reported to be able to achieve tumor suppressor effects; see, for example, Nilsson & Gustafson Clin. Pharmacol. Ther. 89:44, 2011). Typically, tumors (e.g., breast tumors) with as few as 1% of cells staining positive for ER are classified as “ER+”. Therapies targeting the ER are standard of care for many patients with ER+tumors (see, for example, Cardoso et al Annals One. <https: / / doi.org / 10.1093 / announc / mdmx036>, 2017; Rugo et al. J. Clin. Oncol. 34:3069, 2016; Senkus et e Annal One. 26:v8, 2015; Sareddy & Vadlamudi Clin. J Nat. Med, 13:801, 2015). For early stage breast cancer patients, for example, recommended therapy typically involves tumor resection, followed by ER-targeted therapy (e.g., as discussed below). For advanced breast cancer, including metastatic breast cancer, ER-targeted therapy is the mainstay.

[0207] Given the importance of ER signaling in many cancers, as well as in certain cardiovascular, inflammatory, and neurodegenerative diseases, significant effort has been invested in developing therapeutic agents and modalities that target the ER. There is some fluidity / flexibility in terminology that has been used to describe ER-targeting agents, but a variety of agents, with different mechanisms, have been developed and / or studied.

[0208] For example, some ER-targeting agents are designed and / or documented to reduce levels of estrogen (i.e., 17[3 estradiol) production. In other embodiments, some ER-targeting agents are designed and / or documented to increase levels of estrogen production.

[0209] Some ER-targeting agents are designed and / or documented to bind directly to the ER; in some cases, such agents compete with estrogen for binding to the ER and / or interfere with the allosteric changes that estrogen binding would naturally produce. Often, the term “antiestrogen”is used to refer to agents that bind to the ER, and sometimes is specifically used to indicate those agents that compete with estrogen for ER binding.

[0210] The term “selective estrogen receptor modulator, “SERM”, has been used to refer to compounds that are designed and / or documented to alter some aspect of ER activity. Some writings refer to “SERMs” as representing a particular type of anti-estrogens; other writings, however, use the term “SERM” more generally, to refer to a compound that specifically impacts some feature of ER (particularly ERa) expression and / or activity.

[0211] The term “selective estrogen receptor degrader” (“SERD”) has been used to refer to compounds that are designed and / or documented to trigger or enhance degradation of the ER. In many instances, if presence of a compound correlates with reduced level of ER, the compound may be referred to as a SERD. Some writings classify compounds either as SERMs or as SERDs; others refer to SERDs as a particular type, or species, of compounds that are SERMs.

[0212] Regardless of mechanism of action of a particular' agent, clinical experience thus far has revealed that incomplete effects (e.g., within an individual patient and / or across patient populations) and / or development of resistance remain a problem.

[0213] Among other things, presence or development of certain ER mutations has been reported to impact effectiveness of various ER-targeted therapies (see, for example, Jeselsohn et al Nature Rev. Clin. One. 12, 573, 2015; Gelsomino et al. Breast Cancer Res. Treat 157:253, 2016; Toy et al. 2013). Some particularly problematic mutations are those that “activate” one or more aspects of ER expression and / or function; some activating mutations have been reported that can render the ER ligand-independent (i.e., constitutively active). For example, particular mutations in the ER ligand binding domain, including D538G and Y537S, have been demonstrated to constitutively activate the ER; other mutations including deletions and / or fusions that remove the ligand binding domain, can have similar' effects (see, for example, Li et al. Cell Repts 4: 1116, 2013; Veeraraghavan et al Breast Cancer Research and Treatment 158, 219-232, 2016; Veeraraghavan, et al. Nature Comms 5:4577, 2014). Some reports have indicated that as many as 50% of women with metastatic breast cancer may have activating ER mutations detectible in circulating tumor DNA.Estrogen Receptor Antagonists

[0214] In some embodiments, compounds provided herein arc estrogen receptor antagonists. As used herein, an “estrogen receptor antagonist” refers to a compound or composition that produces an antagonistic effect when contacting the estrogen receptor of a subject or biological sample. In some embodiments, an estrogen receptor antagonist is characterized by having:1. measurable antagonist activity in the E2-normalized signal in the AP assay (antagonist mode) of Example 32;2. a pIC50greater than 7.0 in the AP assay (antagonist mode) of Example 32;3. a pIC50greater than 8.0 in the AP assay (antagonist mode) of Example 32; or4. a pIC50greeater than 9.0 in the AP assay (antagonist mode) of Example 32.

[0215] In some embodiments, compounds provided herein are complete estrogen receptor antagonists. As described herein, a complete estrogen receptor antagonist (a “CERAN”) is one that (1) inhibits both AF1 and AF2, and in particular inhibits AF1 activity that remains present in constitutively active ER mutants; (2) promotes ER degradation; and (3) lacks the partial ER agonist activity observed with certain other agents. The present disclosure further appreciates that many previous therapies, including for example, ARN-810, AZD9496, tamoxifen, and others, are less effective than CERANs at least in pail because they only partially antagonize ER, and specifically because they inhibit activation of AF2 but not AF1. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 7.0 in the AP assay (antagonist mode) of Example 32; and (ii) no measurable agonist activity in the AP assay (agonist mode) of Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 8.0 in the AP assay (antagonist mode) of Example 32; and (ii) no measurable agonist activity in the AP assay (agonist mode) of Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 9.0 in the AP assay (antagonist mode) of Example 32; and (ii) no measurable agonist activity in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 7.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 10% increase in the E2-normalized signal in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 8.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no morethan 10% increase in the E2-normalized signal in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 9.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 10% increase in the E2-normalized signal in the AP assay (agonist mode) as described in Example 32.

[0216] In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 7.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 15% increase in the E2-normalized signal in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 8.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 15% increase in the E2-normalized signal in the AP assay (agonist mode) as described in Example 32. In some embodiments, a complete estrogen receptor antagonist is characterized by having (i) a pIC50greater than 9.0 in the AP assay (antagonist mode) as described in Example 32; and (ii) no more than 15% increase in the E2-normalized signal in the AP assay (agonist mode) of Example 32.Estrogen Receptor Agonists

[0217] In some embodiments, compounds provided herein are estrogen receptor agonists. As used herein, an “estrogen receptor agonist” refers to a compound or composition that produces an agonistic effect when contacting the estrogen receptor of a subject or biological sample. In some embodiments, an estrogen receptor agonist is characterized by providing at least a 15% increase in the E2-normalized signal in the AP assay (agonist mode) as described in Example 32.Diseases, Disorders, and Conditions

[0218] The present disclosure encompasses the insight that provided compounds have a number of uses, including treatment of an ER-associated disorder (e.g., an ER-associated cancer, such as breast cancer, osteoporosis, or menopause symptoms), detection, and / or characterization of certain tumors. In some embodiments, a disease, disorder, or condition is a cancer. In some embodiments, a disease, disorder, or condition is associated with a mutation in an estrogen receptor.

[0219] In some embodiments, provided compounds are useful for treating a disorder associated with increased ER activity (e.g., an ER-associated cancer such as breast cancer). Insome embodiments, provided estrogen receptor antagonists (e.g., complete estrogen receptor antagonists) arc useful for treating such disorders.

[0220] In some embodiments, provided compounds are useful for treating a disorder associated with decreased ER activity (e.g., menopause-related conditions or symptoms, or osteoporosis). In some embodiments, provided estrogen receptor agonists are useful for treating such disorders. Other uses of estrogen receptor agonists exist; see, e.g., Harrison, R. F. and Bonnar, J., Pharmac. Ther., 1980, 11, 451-67.

[0221] In some embodiments, the present disclosure provides a method of treating a disorder mediated by an estrogen receptor in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein.

[0222] In some embodiments, a disorder is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, vaginal cancer, lung cancer, bone cancer, uterine cancer, and endometriosis. In some embodiments, a disorder is breast cancer. In some embodiments, a disorder is ovarian cancer. In some embodiments, a disorder is endometrial cancer. In some embodiments, a disorder is vaginal cancer. In some embodiments, a disorder is lung cancer. In some embodiments, a disorder is bone cancer. In some embodiments, a disorder is uterine cancer. In some embodiments, a disorder is endometriosis.

[0223] In some embodiments, the present disclosure provides a method of treating a disorder associated with a mutation of an estrogen receptor in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein. In some embodiments, a disorder is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, vaginal cancer, lung cancer, bone cancer, uterine cancer, and endometriosis. In some embodiments, a disorder is breast cancer. In some embodiments, a disorder is ovarian cancer. In some embodiments, a disorder is endometrial cancer. In some embodiments, a disorder is vaginal cancer. In some embodiments, a disorder is lung cancer. In some embodiments, a disorder is bone cancer. In some embodiments, a disorder is uterine cancer. In some embodiments, a disorder is endometriosis.

[0224] In some embodiments, a method of treating a disorder in a subject described herein comprises administering to the subject a compound described herein in combination with or alternation with an anti-cancer agent. In some embodiments, an anti-cancer agent is selected from an mTOR inhibitor, a CDK4 / 6 inhibitor, a CDK4-selective inhibitor, a PI3 kinase inhibitor, anaromatase inhibitor, an antibody to or inhibitor of PD-1 , PD-L1 or CTLA-4, or an antibody to or inhibitor of EGFR, PGFR, or IGFR.

[0225] In some embodiments, an anti-cancer agent is a HER2 inhibitor. In some embodiments, a HER2 inhibitor is selected from tucatinib, trastuzumab, pertuzumab, ado-trastuzumab, trastuzumab emtansine, ado-trastuzumab emtansine, trastuzumab deruxtecan pertuzumab, lapatinib, and neratinib.

[0226] In some embodiments, an anti-cancer agent is an mTOR inhibitor. In some embodiments, an mTOR inhibitor is selected from everolimus, sirolimus, temsirolimus, and LY3023414.

[0227] In some embodiments, an anti-cancer agent is a CDK4 / 6 inhibitor. In some embodiments, a CDK4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, lerociclib, trilaciclib, and SHR6390.

[0228] In some embodiments, an anti-cancer agent is a CDK4- selective inhibitor. In some embodiments, a CDK-4 selective inhibitor is PF-07220060.

[0229] In some embodiments, an anti-cancer agent is a PI3 kinase inhibitor. In some embodiments, a PI3 kinase inhibitor is selected from perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145.

[0230] In some embodiments, a PI3 kinase inhibitor is a PIK3CA inhibitor. In some embodiments, a PIK3CA inhibitor is selected from alpelisib, taselisib, LY3023414, Inavolisib, STX-478, RLY-2608, LOXO-783, and OKI-219.

[0231] In some embodiments, an anti-cancer agent is an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 4-hydroxyandrostenedione, 1, 4, 6-androstatrien-3, 17-dione, and 4-androstene-3, 6, 17-trione.

[0232] In some embodiments, an anti-cancer agent is an antibody to or inhibitor of PD-1, PD- L1 or CTLA-4.

[0233] In some embodiments, an anti-cancer agent is an antibody to or inhibitor of EGFR, PGFR, or IGFR. In some embodiments, an anti-cancer agent is erlotinib or gefitinib.

[0234] In some embodiments, a method described herein comprises administering a compound reported herein in combination or in alternation with an estrogen receptor antagonist or a partial estrogen receptor antagonist.

[0235] In some embodiments, the present disclosure provides a method of preventing recurrence of a cancer in a subject comprising administering to the subject a compound described herein. In some embodiments, a cancer is selected from breast cancer, ovarian cancer, endometrial cancer, vaginal cancer, lung cancer, bone cancer, and uterine cancer. In some embodiments, a compound described herein is administered as an adjunctive therapy after or instead of chemotherapy, radiation, or surgery. In some embodiments, a compound is administered after surgery. In some embodiments, a compound is administered prior to surgery. In some embodiments, a cancer is a breast cancer that has progressed in the presence of endocrine or aromatase therapy.

[0236] In some embodiments, the present disclosure provides a method of treating a cancer characterized by a mutation of Estrogen Receptor 1 (ESRI). In some embodiments, a mutation of ESRI is Y537C, Y537N, Y537S, S463P, D538G, or E380Q. In some embodiments, a mutation of ESRI is Y537S or D538 G.EXAMPLES

[0237] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0238] Certain abbreviations are used in this example section, as indicated by the table below:Example 1: Analytical Methods

[0239] All proton NMR experiments were recorded on a Bruker NEO Spectrometer equipped with a BBFO probe at 400 MHz. Deuterated solvents contained less than 0.05% v / v tetramethylsilane, which was used as the reference signal (set at 0.00 ppm). When deuterated solvents did not contain tetramethylsilane, the residual nondeuterated solvent peaks were used as a reference signal, as per published guidelines (J. Org. Chem. 1997, 62(21), 7512-7515). Chemical shifts are expressed in parts per million (ppm, 5 units). Coupling constants are in hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), qt (quintuplet), or bs (broad singlet).

[0240] LC / MS analyses were performed on an Agilent Technologies UHPLC 1290 Infinity II with a G6125 MS detector.

[0241] Microwave reactions were conducted using standard protocols with a Monowave 300 by Anton Paar GmbH.Example 2: Benzocycloheptanones (A)

[0242] The following aryl / heteroaryl ketones are either commercially available or were synthesized as described below.

[0243] Intermediate A3 was prepared as reported in US Publication No. US 2007-0249583 Al.

[0244] Intermediate A4 was prepared as reported in PCT Publication No.WO 2022 / 166879 Al.

[0245] Intermediate A6 was prepared as reported in US Publication No. US 2012-130129 Al.

[0246] Intermediate A7 was prepared as reported in PCT Publication No.WO 2021 / 087112 Al.

[0247] Intermediate A9 was prepared as reported in EP Publication No. EP 4019524 Al.

[0248] Intermediate A2 was prepared according to Scheme 1:Scheme 1Example 2.1: 2-((Dimethylamino)methylene)cycloheptane- 1,3 -dione (Intermediate 2)

[0249] A mixture of cycloheptane- 1,3-dione, Intermediate 1 (3.0 g, 23.78 mmol) in DMF- DMA (12.74 ml, 95 mmol) was stirred at 110 °C for 3 h. After the reaction was complete as monitored by TLC, the reaction mixture was concentrated under reduced pressure to yield the title product as an amber solid (4.22 g, 98% yield).1H NMR (400 MHz, DMSO-d6) δ = 7.66 (s, 1H), 3.29 (s, 3H), 2.68 (s, 3H), 2.43-2.47 (m, 4H), 1.70-1.75 (m, 4H); LCMS: 182.1 [M+H],Example 2.2: 2,5-Dioxo-2,5, 6, 7, 8, 9-hexahydro-lH-cyclohepta[b ]pyridine-3-carbonitrile )( Intermediate 3 )

[0250] To a stirred solution of 2-cyanoacetamide (3.90 g, 46.3 mmol) in DMF (15 mL) at 0 °C, NaH (60% in mineral oil, 2.039 g, 51.0 mmol) was added and stirred at 0 °C for 30 min. A solution of 2-((dimethylamino)methylene)cycloheptane- 1,3-dione, Intermediate 2 (4.2 g, 23.17 mmol) in DMF (15 mL) was then added at 0 °C and stirred at 25 °C for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with ice water (100 mL), extracted with EtOAc (100 mL x 3), the EtOAc layer was checked for the product and kept aside. The aqueous layer was acidified with aqueous HC1 (1.5N) (pH = 2-3) and extracted with 20% MeOH in DCM (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the crude product. The product was purified by silica gel (230-400 mesh) column chromatography using 100% EtOAc as the eluant to afford the title product as a yellow solid (2.56 g, 54.6 % yield). *H NMR (400 MHz, DMSO-d6) δ = 12.89 (bs, 1H), 8.29 (s, 1H), 3.02 (t, 7= 8.80 Hz, 2H), 2.68 (t, 7= 8.00 Hz, 2H), 1.72-1.86 (m, 4H); LCMS: 203.0 [M+H],Example 2.3: 2,5-Dioxo-2, 5, 6, 7, 8, 9-hexahydro-l H-cyclohepta[h ]pyridine-3 -carboxylic acid ( Intermediate 4 )

[0251] To a stirred solution of 2,5-dioxo-2,5,6,7,8,9-hexahydro-lH-cyclohepta[&]pyridine-3- carbonitrile, Intermediate 3 (2.56 g, 12.66 mmol) in ethanol (50 mL) at 25 °C, aqueous NaOH (20 N,100 mL) was added and stirred at 100 °C for 16 h. After completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to yield the residue. The residue was taken in water (2 mL), acidified to pH = Iwith cone. HC1, and was extracted with 20% MeOH in DCM (15 x 150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title as a yellow solid (2.8 g, crude). This material was taken to the next step without further purification.1H NMR (400 MHz, DMSO-de) <i = 12.07 (s, 1H), 8.35 (s, 1H), 2.96-2.98 (m, 2H), 2.68 (t, J = 7.60 Hz, 2H), 1.72-1.84 (m, 4H); LCMS: 222.0 [M+H],Example 2.4: 6,7,8,9-Tetrahydro-lH-cyclohepta[b]pyridine-2,5-dione (Intermediate 5)

[0252] To a stirred solution of 2,5-dioxo-2,5,6,7,8,9-hexahydro-lH-cyclohepta[&]pyridine-3- carboxylic acid, Intermediate 4 (1.4 g, 6.33 mmol) in quinoline (6 mL) at 25 °C, copper powder (2.011 g, 31.6 mmol) was added and subjected to microwave irradiation at 240 °C for 6 h. After completion of the reaction as monitored by LCMS, the reaction mixture was dried in a Genevac centrifugal evaporator to remove quinoline. The residue was taken in aqueous 1 .5 N HO ( 100 mL) and extracted with 20% MeOH in DCM (100 mL x 15). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. It was purified by silica gel (230-400 mesh) column chromatography using 100 % EtOAc as the eluant to afford the title product (0.49 g, 43.7% yield) as a brown solid. 'l l NMR (400 MHz, DMSO-de) d = 11.96 (bs, 1H), 7.76 (d, 7 = 9.20 Hz, 1H), 6.24 (d, J = 9.60 Hz, 1H), 2.94 (t, J = 6.80 Hz, 2H), 2.65 (t, J = 6.00 Hz, 2H), 1.70-1.82 (m, 4H); LCMS: 178.1 [M+H],Example 2.5: 2-Methoxy-6, 7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (Intermediate A2 )

[0253] To a stirred solution of 6,7,8,9-tetrahydro-lW-cyclohepta[7»]pyridine-2,5-dione, Intermediate 5 (0.98 g, 5.53 mmol) in CHCL (10 mL) at 0 °C, silver carbonate (2.303 g, 8.35 mmol) and iodomethane (3.44 ml, 55.3 mmol) were added and stirred at 25 °C for 24 h. After thereaction was completed as monitored by TLC, the reaction mixture was filtered through celite and washed with EtOAc (5 mL x 2). The filtrate was concentrated under reduced pressure to afford a residue. The residue was taken in EtOAc (25 mL), washed with ice water (5 mL x 2) and brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. It was purified by silica gel (230-400 mesh) column chromatography using 15% EtOAc in petroleum ether to afford the title product as brown liquid (0.93 g, 87.9% yield).1H NMR (400 MHz, DMSO-d6) δ = 7.95 (d, J - 8.40 Hz, 1H), 6.77 (d, J = 8.80 Hz, 1H), 3.92 (s, 3H), 3.08 (t, J = 6.80 Hz, 2H), 2.74 (t, J = 6.00 Hz, 2H), 1.75-1.86 (m, 4H); LCMS: 191.9 [M+H],Example 3: Aryl / heteroaryl Bromides (B)

[0254] The following aryl / heteroaryl bromides are either commercially available or were synthesized as described below.

[0255] Intermediate B5 was prepared as reported in PCT Publication No.WO 2017 / 060326 ALExample 4: Aryl / Heteroaryl Boronic Acids and Boronate Esters ( C)

[0256] The following aryl / heteroaryl boronic acids and boronate esters are either commercially available or were synthesized as described below.

[0257] Intermediate C 1 was prepared as reported in US Publication No. US 2012 / 302538 A 1 .

[0258] Intermediate C12 was prepared as reported in US Publication No. US 2020 / 247748 Al.

[0259] Intermediate C13 was [re[ared as reported in PCT Publication No.WO 2018 / 091153 Al.Example 5: Amines (D)

[0260] The following amines are either commercially available or were synthesized as described below.

[0261] Intermediate D9 was prepared as reported in PCT Publication No. US 2018-111931 Al.Example 6: Bicyclic Intermediates (E)

[0262] The following bicyclic intermediates arc either commercially available or were synthesized as described below.

[0264] Intermediate El 3 was prepared as reported in PCT Publication No.WO 2019 / 102494 Al.

[0265] Intermediate El 8 was prepared as reported in PCT Publication No.WO 2022 / 017338 Al.

[0266] Intermediate E21 was prepared as reported in PCT Publication No.WO 2006 / 077367 Al.Example 6.1: 1 -(Tert-butyl) 2-ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole- 1 ,2-dicarboxylate (Intermediate E2)

[0267] To a stirred solution of 1 -(tert-butyl) 2-ethyl 5-bromo-l / / -indole-l,2-dicarboxylate, Intermediate El (which was synthesized as reported in WO 2018 / 119395 Al) (1 g, 2.72 mmol) and bis(pinacolato)diboron (0.759 g, 2.99 mmol) in 1,4-dioxane (20 mL) at 25 °C, potassium acetate (0.800 g, 8.15 mmol) was added and purged with N2(g) for 10 minutes. Then, [1,1'- bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex (0.166 g, 0.204 mmol) was added and stirred at 100 °C for 6 h. After completion of the reaction as monitored by LCMS, the reaction mixture was filtered through a celite bed, washed with EtOAc (30 mL x 3), and the filtrate was evaporated under reduced pressure to afford the crude product. The crude product was triturated with MTBE and hexane (1:2) (20 mL), filtered off the solid, and the filtratewas concentrated under reduced pressure to the title product as a brown liquid (1g, crude). It was taken as such to the next step without further purification. LCMS: 360.1 |M+-( / -Butyl)|.Example 6.2: Tert-butyl 5-bromo-2-( ( 3 -(fluoromethyl )azetidin-l -yl )methyl)-lH-indole-l - carboxylate ( Intermediate E3 ).

[0268] Intermediate E3 was prepared according to the Scheme 2:Scheme 2

[0269] To a stirred solution of tert-butyl 5-bromo-2-formyl-lH-indole-l-carboxylate, Intermediate 6 (which was synthesized as reported in WO 2020 / 12422 Al) (0.931 g, 2.87 mmol) and 3-(fluoromethyl)azetidine hydrochloride, Intermediate DI (0.541 g, 4.31 mmol) in DCE (10 mL) at 0 °C, TEA (0.816 ml, 5.74 mmol) was added and stirred at 25 °C for an hour. Then, acetic acid was added (0.494 ml, 8.64 mmol) and the mixture stirred at 25 °C for 3 h. Sodium triacetoxyborohydride (1.826 g, 8.62 mmol) was added and stirred at 25 °C for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with ice water (30 mL), basified with aqueous NaHCO3(10%), and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (10 mL), dried over NaSO4, and filtered. The filtrate was then concentrated under reduced pressure to obtain the crude product. It was purified by silica gel (230-400 mesh) column chromatography using 4% MeOH in dichloromethane to afford the title product as a yellow gum (0.91 g, 79.7% yield).1H NMR (400 MHz, DMSO-de) 8 = 7.95 (d, J = 9.20 Hz, 1H), 7.75 (d, J = 2.00 Hz, 1H), 7.39 (dd, J = 2.00, 8.80 Hz, 1H), 6.56 (s, 1H), 4.62 (d, J = 6.40 Hz, 1H), 4.50 (d, J - 6.40 Hz, 1H), 3.88 (s, 2H), 3.37-3.39 (m, 2H), 3.06 (t, J = 6.80 Hz, 2H), 2.67-2.68 (m, 1H), 1.63 (s, 9H); LCMS: 397.1 [M+H],Example 6.3: 3-(Fluoromethyl)-l -((5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzofuran-2- yl)methyl)azetidine (Intermediate E4)

[0270] Intermediate E4 was prepared according to the Scheme 3:Scheme 3Step 1: l-((5-bromobenzofuran-2-yl)methyl)-3-(fluoromethyl)azetidine (Intermediate 8)

[0271] The title compound was prepared by following a similar procedure described for Intermediate E3, starting from 5-bromobenzofuran-2-carbaldehyde, 7 (0.500 g, 2.222 mmol) and 3-(fluoromethyl)azetidine hydrochloride, Intermediate DI (0.594 g, 4.73 mmol), and was obtained as a yellow gum (1.2 g, 83% yield). ^ NMR (300 MHz, DMSO-d6) δ = 7.79 (dj - 1.80 Hz, 1H), 7.52 (d, J = 8.70 Hz, 1H), 7.40 (dd, J = 2.10, 8.70 Hz, 1H), 6.71 (s, 1H), 4.60 (d, J = 6.00 Hz, 1H), 4.44 (d, J = 6.30 Hz, 1H), 3.70 (s, 2H), 3.36-3.39 (m, 2H), 3.06 (t, J = 6.90 Hz, 2H), 2.70-2.83 (m, 1H); LCMS: 298.0 [M+H],Step 2: 3-(Fluoromethyl)-l-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2- yl)methyl)azetidine (Intermediate E4)

[0272] The title compound was prepared by following a similar procedure described for Intermediate E2, starling from l-((5-bromobenzofuran-2-yl)methyl)-3-(fluoromethyl)azetidine, Intermediate 8 (110 mg, 0.369 mmol), bis(pinacolato)diboron (122 mg, 0.479 mmol), potassium acetate (108 mg, 1.107 mmol) and [l,T-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex (30 mg, 0.037 mmol) and was obtained as a yellow gum (120 mg, crude). LCMS: 346.1 [M+H],Example 6.4: Step 2: 2-((3-(Eluoromethyl)azetidin-l -yl)methyl)-5-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)benzo[d]oxazole (Intermediate E5)

[0273] Intermediate E5 was prepared according to the Scheme 4:Scheme 4Step 1: 5-Bromo-2-(chloromethyl)benzo[d]oxazole (Intermediate 10)

[0274] To a stirred solution of 2-amino-4-bromophenol, Intermediate 9 (5 g, 26.6 mmol) in chlorobenzene (75 ml) at 25 °C, pyridine (1.071 ml, 13.30 mmol) and 2-chloroacetyl chloride (2.115 ml, 26.6 mmol) were added at 0 °C and stirred at 25 °C for 2 h. Then, -tolucncsulfonic acid monohydrate (0.506 g, 2.66 mmol) was added at 25 °C and stirred at 130 °C for 6 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with water (50 mL) and EtOAc (50 mL). The reaction mixture was filtered through celite and the insoluble solids washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel (230-400 mesh) column chromatography using 20% EtOAc in petroleum ether to afford the title product as yellow solid (2.5g, 38.1% yield).1H NMR (400 MHz, CDCl3) δ = 7.91-7.92 (m, 1H), 7.53-7.55 (m, 1H), 7.45- 7.48 (m, 1H), 4.77 (s, 2H); LCMS: 245.8 [M+H],Step 2: 5-bromo-2-((3-(fluoromethyl)azetidin-l-yl)methyl)benzo[d]oxazole (Intermediate 11)

[0275] To a stirred solution of 3-(fluoromethyl)azetidine hydrochloride, Intermediate DI (397 mg, 3.16 mmol) and 5-bromo-2-(chloromethyl)benzo[d]oxazole, Intermediate 10 (650 mg, 2.64 mmol) in DMF (2 mL) at 0 °C, a solution of DBU (883 mg, 5.80 mmol) in DMF (0.65 mL) was added and stirred at 25 °C for 12 h. After completion of the reaction (as monitored by TLC), the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, and filtered. The combined organic layers were then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (230-400 mesh) column chromatographyusing 30% EtOAc in petroleum ether to afford the title product as brown gum (220 g, 27.9% yield).LCMS: 299.1 [M+H],2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzo[d] oxazole (Intermediate E5)

[0276] The title compound was prepared by following a similar procedure described for Intermediate E2, starting from 5-bromo-2-((3-(fluoromethyl)azetidin-l-yl)methyl)-3a,7a- dihydrobenzo[d] oxazole, Intermediate 11 (200 mg, 0.664 mmol), bis(pinacolato)diboron (253 mg, 0.996 mmol), potassium acetate (196 mg, 1.992 mmol) and [1,1'- bis(diphenylphosphino)ferrocene] -dichloropalladium (11) dichloromethane complex (54.2 mg, 0.066 mmol) and was obtained as a yellow gum (243 mg, crude). LCMS: 235.1 [M+H] (corresponds to boronic acid).Example 6.5: Ethyl 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-2- carboxylate (Intermediate E6)

[0277] Intermediate E6 was prepared according to the Scheme 5:Scheme 5

[0278] Intermediate E6 compound was prepared by following a similar procedure described for Intermediate E2, starting from ethyl 7-bromoimidazo[l,2-a]pyridine-2-carboxylate, Intermediate 12 (1 g, 3.72 mmol), bis(pinacolato)diboron (1.038 g, 4.09 mmol), potassium acetate (1.094 g, 11.15 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex (303 mg, 0.372 mmol) and was obtained as a black solid (1.25 g, crude). LCMS: 347.2 [M+H],Example 6.6: 2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-6-(4,4,5,5-lelramethyl-l,3,2- dioxaborolan-2-yl)-lH-indole (Intermediate E7)

[0279] Intermediate E7 was prepared according to the Scheme 6:Step 1: 6-Bromo-2-((3-(flnoromethyl)azetidin-l -yl)methyl)-l H-indole (Intermediate 14)

[0280] The title compound was prepared by following a similar procedure described for Intermediate E3, stalling from 6-bromo-lH-indole-2-carbaldehyde, Intermediate 13 (which was synthesized as reported in WO 2019 / 099402 Al) (0.95 g, 4.24 mmol) and 3- (fluoromethyl)azetidine hydrochloride, Intermediate DI (0.639 g, 4.73 mmol), and was obtained as a yellow gum (1.19 g, 93% yield).1H NMR (400 MHz, DMSO-d6) δ = 11.27 (bs, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.40 Hz, 1H), 7.11 (dd, J = 1.60, 8.40 Hz, 1H), 6.43 (s, 1H), 4.61 (d, J = 5.60 Hz, 1H), 4.49 (d, J = 5.60 Hz, 1H), 4.01-4.06 (m, 2H), 3.66 (s, 2H), 3.41 (bs, 2H), 2.85-2.93 (m, 1H); LCMS: 297.0 [M+H],Step 2: 2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-indole (Intermediate E7)

[0281] The title compound was prepared by following a similar procedure described for Intermediate E2, starting from 6-bromo-2-((3-(fluoromethyl)azetidin-l-yl)methyl)-lH-indole, Intermediate 14 (1.2 g, 4.04 mmol), bis(pinacolato)diboron (1.33 mg, 5.25 mmol), potassium acetate (1.189 g, 12.11 mmol) and [l,T-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex (0.330 g, 0.404 mmol) and was obtained as brown gum (600 mg, crude). LCMS: 345.2 [M+H],Example 6.7: 3-(Fluoromelhyl)-l -((6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzofuran-2- yl)methyl)azetidine (Intermediate E8)

[0282] Intermediate E8 was prepared according to the Scheme 7 :Intermediate 15 Intermediate 16 Intermediate 17Scheme 7Step 1: (6-Bromobenzofuran-2-yl)methanol (Intermediate 16)

[0283] To a stirred solution of ethyl 6-bromobenzofuran-2-carboxylate, Intermediate 15 (300 mg, 1.115 mmol) in EtOH (10 mL) at 0 °C, NaBH4 (129 mg, 3.40 mmol) was added and stirred at 80 °C for 3 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with saturated NH4CI (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL) solution, dried over Na2SO4, and filtered. The organic extracts were concentrated under reduced pressure to obtain the title product (220 mg, crude). The crude product was taken to the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ = 7.85 (s, 1H), 7.57 (d, J = 8.00 Hz, 1H), 7.40 (dd, J = 4.00, 8.00 Hz, 1H), 6.79 (s, 1H), 5.51-5.54 (m, 1H), 4.56-4.57 (m, 2H).Step 2: 6-Bromobenzofuran-2-carbaldehyde (Intermediate 17)

[0284] To a stirred solution of (6-bromobenzofuran-2-yl)methanol, Intermediate 16 (71 mg, 0.313 mmol) in DCM (5 mL) at 0 °C, was added Dess-Martin periodinane (159 mg, 0.375 mmol) and the mixture was stirred at 25 °C for 1 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with ice water (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, and filtered. The filtrate was then concentrated under reduced pressure to obtain the title product (60 mg, crude). The crude product was taken to the next step without further purification.1H NMR (400 MHz,DMSO-d6) δ = 9.88 (s, IH), 7.85 (s, 1H), 7.57 (d, J = 8.00 Hz, 1H), 7.40 (dd, J = 4.00, 8.00 Hz, 1H), 6.79 (s, IH).Step 3: Synthesis of l-((6-bromobenzofuran-2-yl)methyl)-3-(fluoromethyl)azetidine (Intermediate 18)

[0285] The title compound was prepared by following a similar procedure described for Intermediate E3, starting from 6-bromobenzofuran-2-carbaldehyde, Intermediate 17 (0.400 g, 1.777 mmol) and 3-(fluoromethyl)azetidine hydrochloride, Intermediate DI (0.270 g, 2.151 mmol), and was obtained as a yellow gum (0.190 g, 35.8% yield).1H NMR (400 MHz, DMSO- d6) δ = 7.83 (s, IH), 7.54 (d, J = 8.00 Hz, IH), 7.39 (dd, J = 4.00, 8.00 Hz, IH), 6.75 (s, IH), 4.58 (d, J = 8.00 Hz, IH), 4.46 (d, J = 8.00 Hz, IH), 3.68 (s, 2H), 3.37 (t, J = 8.00 Hz, 2H), 3.06 (t, J = 8.00 Hz, 2H), 2.71-2.79 (m, IH); LCMS: 299.5 [M+H],Step 3: 3-(Fluoromethyl)-l-((6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2- yl)methyl)az.etidine (Intermediate E8)

[0286] The title compound was prepared by following a similar procedure described for Intermediate E2, starting from l-((6-bromobenzofuran-2-yl)methyl)-3-(fluoromethyl)azetidine, Intermediate 18 (100 mg, 0.335 mmol), bis(pinacolato)diboron (1 11 mg, 0.436 mmol), potassium acetate (99 mg, 1.006 mmol) and [l,T-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex (30 mg, 0.037 mmol) and was obtained as a brown solid (160 mg, crude). LCMS: 345.3 [M],Example 6.8: 2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzo[d]oxazole (Intermediate E9)

[0287] Intermediate E8 was prepared according to the Scheme 8:Scheme 8Step 1: 6-bromo-2-(chloromethyl)benzo[d]oxazole (Intermediate 20)

[0288] The title compound was prepared by following a similar procedure described for Intermediate 10, starting from 2-amino-5-bromophenol, Intermediate 19 (1 g, 5.32 mmol), 2- chloroacetyl chloride (0.601 g, 5.32 mmol), pyridine (0.214 ml, 2.66 mmol) and p-toluenesulfonic acid monohydrate (0.101 g, 0.532 mmol). The title compound was obtained as yellow solid (630 mg, crude).1H NMR (400 MHz, CDCl3) δ = 7.76-7.77 (m, 1H), 7.62-7.65 (m, 1H), 7.51-7.54 (m, 1H), 4.76 (s, 2H); LCMS: 246.1 [M+H],Step 2: 6-bromo-2-((3-(fluoromethyl)azetidin-l-yl)methyl)benzo[d]oxazole (Intermediate 21)

[0289] To a stirred solution of 3-(fluoromethyl)azetidine hydrochloride, Intermediate DI (458 mg, 3.65 mmol) in DCM (10 mL) at 0 °C, DIPEA (1.060 mL, 6.09 mmol) was added at and stirred for 10 minutes. Then 6-bromo-2-(chloromethyl)benzo[d]oxazole, 20 (600 mg, 2.434 mmol) was added and stirred at 25 °C for 16 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, and filtered. The combined organic extracts were concentrated under reduced pressure to obtain the title product (700 mg, crude) as yellow gum. The crude product was taken to the next step without further purification. LCMS: 299.0 [M+H].Step 3: 2-((3-(Eluoromethyl)azetidin-l -yl)methyl)-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)benzo[d] oxazole (Intermediate E9)

[0290] The title compound was prepared by following a similar procedure described for Intermediate E2, starting from 6-bromo-2-((3-(fluoromethyl)azetidin-l- yl)methyl)benzo[d]oxazole, Intermediate 21 (550 mg, 1.838 mmol), bis(pinacolato)diboron (607 mg, 2.39 mmol), potassium acetate (541 mg, 5.514 mmol) and [1,1'- bis(diphenylphosphino)ferrocene] -dichloropalladium (II) dichloromethane complex (150 mg, 0.184 mmol) and was obtained as a brown gum (550 mg, crude). LCMS: 347.2 [M+H].Example 6.9: Tert-butyl 2-((3-(fluoromethyl)azetidin-l-yl)methyl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indole-l -carboxylate (Intermediate E10)

[0291] Intermediate E10 was prepared according to the Scheme 9:Scheme 9

[0292] The title compound was prepared by following a similar procedure described for Intermediate E2, starting from ethyl 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2- carboxylate, Intermediate 22 (which was synthesized as reported in WO 2015 / 086642 Al) (6.3 g, 15.81 mmol), bis(pinacolato)diboron (6.02 g, 23.72 mmol), potassium acetate (4.66 g, 47.4 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex (1.291 mg, 1.581 mmol) and was obtained as a brown gum (7.6 g, crude). GCMS: 445.20 [M].Example 6.10: Tert-butyl 2-((3-(fluoromethyl)azetidin-l-yl)methyl)-5-(4,4,5>5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indole-l -carboxylate (Intermediate Ell )

[0293] Intermediate El l was prepared according to the Scheme 10:Scheme 10

[0294] The title compound was prepared by following a similar procedure described for Intermediate E2, stalling from tert-butyl 5-bromo-2-((3-(fluoromethyl)azetidin-l-yl)methyl)-lH- indole-1 -carboxylate, Intermediate E3 (600 mg, 1.510 mmol), bis(pinacolato)diboron (460 mg, 1.812 mmol), potassium acetate (371 mg, 3.78 mmol) and [l,T-bis(diphenylphosphino)ferrocene]- dichloropalladium (II) dichloromethane complex (123 mg, 0.151 mmol) and was obtained as a brown gum (700 mg, crude). LCMS: 445.2 [M+H].Example 6.11: Methyl l-(tetrahydro-2EI-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indaz.ole-6-carboxylate (Intermediate E12)

[0295] Intermediate E12 was prepared according to the Scheme 11:Scheme 11

[0296] A solution of methyl l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-6-carboxylate, Intermediate 23 (which was synthesized as reported in WO 2023 / 287128 Al) (250 mg, 0.960 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (368 mg, 1.450 mmol) in THF (10 mL) was degassed with N2for 5 minutes. To the mixture, 4,4'-di-tert-butyl-2,2'-bipyridine (7.99 mg, 0.030 mmol) and [Ir(OMe)(COD)]2(9.55 mg, 0.014 mmol) were added, and the resulting mixture was stirred at 80 °C for 24 h. After completion of the reaction (as monitored by LCMS), the reaction mixture was filtered through celite, and washed with EtOAc (5 mL x 2). The filtrate was concentrated under reduced pressure to afford the title product (400 mg, crude). This was taken to the next step without further purification. LCMS: 305.1 [M+H] (corresponds to Boronic acid).Example 6.12: Ethyl 6-(4,4,5,5-tetramethyl-l ,3, 2-dioxaborolan-2-yl)pyrazolo[ 1 ,5-a] pyridine -2- carboxylate (Intermediate E14)

[0297] Intermediate E14 was prepared according to the Scheme 12:

[0298] The title compound was prepared by following a similar’ procedure described for Intermediate E2, starting from ethyl 6-bromopyrazolo[l,5-a]pyridine-2-carboxylate, Intermediate 24 (250 mg, 0.929 mmol), bis(pinacolato)diboron (283 mg, 1.115 mmol), potassium acetate (274 mg, 2.79 mmol) and [l,r-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex (76 mg, 0.093 mmol) and was obtained as a brown gum (310 mg, crude). LCMS: 235.1 [M+H] (corresponds to Boronic acid).Example 6.13: 7-Bromo-2-( (3-(jluoromelhyl)azelidin-l -yl)methyl)imidazo[ 1,2-a ] pyridine(Intermediate El 5) and 2-((3-(fluoromethyl)azetidin-l-yl)methyl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)imidazo[ 1,2-a Jpyridine ( Intermediate E16)

[0299] Intermediate E15 and Intermediate E16 was prepared according to the Scheme 13:Step 1 : 7-Bromoimidazo[ 1 ,2-a]pyridine-2-carbaldehyde (Intermediate 25)

[0300] Intermediate 25 was synthesized as reported in WO 2019 / 099311 Al and using the method described below.

[0301] To a stirred solution of 4-bromopyridin-2-amine, Intermediate D10 (3.0 g, 17.34 mmol) in DME (10 mL) at 0 °C, l,l,3-trichloropropan-2-one (3.70 mL, 34.7 mmol) was added and stirred at 65 °C for 4 h. After the disappearance of SM as determined by TLC, the reaction mixture was concentrated under reduced pressure to yield the residue. The residue was taken with 1,4-dioxane (10 mL) at 25 °C, and HO (g) in dioxane (4M, 110 mL) was added and stirred at 85 °C for 16 h. The reaction mixture was cooled to 0 °C, quenched with 3N NaOH to pH = 8. The solid thus obtained was filtered, washed with water, and dried to yield the crude product. The crude product was purified by silica gel (230-400 mesh) column chromatography using 10% MeOH in DCM to afford the title product (1.80 g, 44% yield) as a yellow solid.NMR (300 MHz, DMSO-de) <5 = 10.03 (s, 1H), 8.66-8.66 (m, 1H), 8.58-8.63 (m, 1H), 8.03-8.04 (m, 1H), 7.20-7.23 (m, 1H); LCMS: 225.0 [M+H],Step 2: 7-Bromo-2-( ( 3 -(fluoromethyl )az,etidin-l -yl jmethyl )imidazo[ 1 ,2-a J pyridine(Intermediate El 5)

[0302] The title compound was prepared by following a similar procedure described for Intermediate E3, starting from 7-bromoimidazo[l ,2-a]pyridine-2-carbaldehyde, Intermediate 25 (460 mg, 1.840 mmol) and 3 -(fluoromethyl) azetidine hydrochloride, Intermediate DI (349 mg, 2.78 mmol), and was obtained as a brown gum (400 mg, 72.8% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.49 (d, J = 6.80 Hz, 1H), 7.86 (s, 1H), 7.81 (d, J = 2.00 Hz, 1H), 7.04-7.06 (m, 1H), 4.60 (d, J = 6.00 Hz, 1H), 4.48 (d, J = 6.00 Hz, 1H), 3.82 (s, 2H), 3.51 (t, J = 7.60 Hz, 2H), 3.24 (t, J = 6.40 Hz, 2H), 2.79-2.84 (m, 1H); LCMS: 298.1 [M+H],Step 3: 2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)imidazo[l ,2-a]pyridine (Intermediate El 6)

[0303] The title compound was prepared by following a similar procedure described for Intermediate E2, starting from 7-bromo-2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2- a]pyridine, Intermediate E15 (600 mg, 2.012 mmol), bis(pinacolato)diboron (766 mg, 3.02 mmol),potassium acetate (592 mg, 6.04 mmol) and [l ,l'-bis(diphenylphosphino)ferrocene]- dichloropalladium (II) dichloromcthanc complex (164 mg, 0.2012 mmol) and was obtained as a brown gum (500 mg, crude). LCMS: 264.2 [M+H] (corresponds to Boronic acid) and 346.1 [M+H],Example 6.14: Ethyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolizine-2-carboxylate(Intermediate E17)

[0304] Intermediate E17 was prepared according to the Scheme 14:Scheme 14

[0305] The title compound was prepared by following a similar procedure described for Intermediate E2, starting from ethyl 6-bromoindolizine-2-carboxylate, Intermediate 26 (350 mg, 1.305 mmol), bis(pinacolato)diboron (398 mg, 1.567 mmol), potassium acetate (384 mg, 3.92 mmol) and [l,l'-bis(diphenylphosphino)ferrocene] -dichloropalladium (II) dichloromethane complex (107 mg, 0.131 mmol) and was obtained as a brown gum (400 mg, crude). LCMS: 234.1 [M+H] (corresponds to Boronic acid) and 316.2 [M+H].Example 6.15: 2-((3-(Eluoromethyl)azetidin-l -yl)methyl)-3-methyl-7-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)imidazo[l,2-a]pyridine (Intermediate El 9)

[0306] Intermediate E19 was prepared according to the Scheme 15:Step 1: Ethyl 7 -bromo-3-methylimidazo[ 1 ,2-a]pyridine-2-carboxylate (Intermediate 27)

[0307] To a stirred solution of ethyl 3-bromo-2-oxobutanoate (1 g, 4.78 mmol) in EtOH (20 mL) at 25 °C, 4-bromopyridin-2-amine, Intermediate D10 (0.993 g, 5.74 mmol) and 4 A molecular sieves (1 g) were added and stirred at 90 °C for 12 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was filtered through celite and washed with EtOH (5 mL x 2). The filtrate was concentrated under reduced pressure to yield the residue. The residue was taken in water (5 mL), basified with aqueous NaHCO? (10%), and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, and filtered. The combined organic extracts were concentrated under reduced pressure to yield the title product as a yellow solid (1 g, crude). This was taken to the next step without further purification. LCMS: 283.0 [M+H],Step 2: 7-Bromo-3-methylimidaz,o[I,2-a]pyridine-2-carbaldehyde (Intermediate 28)

[0308] To a stirred solution of ethyl 7-bromo-3-methylimidazo[l,2-a]pyridine-2-carboxylate, Intermediate 27 (500 mg, 1.766 mmol) in DCM (30 mL) at -78 °C, DIBAL-H (IM in toluene, 3.53 mL, 3.53 mmol) was added and stirred for 5 h. After completion of the reaction (as monitored by TLC and LCMS), the reaction mixture was cooled to 0 °C, was quenched with water (5 mL), aqueous NaOH (10%, 5 mL), and extracted with EtOAc (10 mL x 3). The combined organic extracts were dried over Na2SO4and filtered. The combined organic extracts were concentratedunder reduced pressure to yield the crude product. It was purified by silica gel (230-400 mesh) column chromatography using 60% EtOAc in petroleum ether to afford the title product (100 mg, 23.69%) as a yellow solid. LCMS: 239.0 [M+H],Step 3: 7-Bromo-2-( ( 3 -(fluoromethyl )azetidin-l-yl )methyl)-3 -methylimidazo[ 1,2-a ] pyridine(Intermediate 29)

[0309] The title compound was prepared by following a similar procedure described for Intermediate E3, starting from 7-bromo-3-methylimidazo[l,2-a]pyridine-2-carbaldehyde, Intermediate 28 (80 mg, 0.335 mmol) and 3-(fluoromethyl)azetidine hydrochloride, Intermediate DI (63 mg, 0.502 mmol), and was obtained as a yellow gum (80 mg, 76.9% yield). *H NMR (400 MHz, DMSO-d6) δ = 8.23 (d, J = 7.20 Hz, 1H), 7.81 (d, J = 1.60 Hz, 1H), 7.09 (dd, J = 2.00, 7.20 Hz, 1H), 4.58 (d, J = 6.00 Hz, 1H), 4.46 (d, J = 6.00 Hz, 1H), 3.84 (s, 2H), 3.50 (bs, 2H), 3.24 (bs, 2H), 2.75-2.83 (m, 1H), 2.46 (s, 3H); LCMS: 312.0 [M+H],Step 4: 2-((3-( Fluoromethyl )azetidin-l -yl )methyl)~ 3 -methyl- 7-( 4,4,5, 5-tetramethyl-l,3,2- dioxaborolan-2-yl)imidazo[ 1 ,2-a]pyridine (Intermediate El 9)

[0310] The title compound was prepared by following a similar procedure described for Intermediate E2, starting from 7-bromo-2-((3-(fluoromethyl)azetidin-l-yl)methyl)-3- methylimidazo[l,2-a]pyridine, Intermediate 29 (95 mg, 0.304 mmol), bis(pinacolato)diboron (116 mg, 0.456 mmol), potassium acetate (90 mg, 0.913 mmol) and [1,T- bis(diphenylphosphino)ferrocene] -dichloropalladium (II) dichloromethane complex (26 mg, 0.032 mmol) and was obtained as a brown gum (100 mg, crude). LCMS: 278.1 [M+H] (corresponds to Boronic acid) & 360.2 [M+H].Example 6.16: 2-( ( 3-(Fluoromethyl)azetidin-l -yl)methyl)-6-( 4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)imidazo[ 1 ,2-b]pyridazine (Intermediate E20)

[0311] Intermediate E20 was prepared according to the Scheme 16:Scheme 16Step 1: (6-Bromoimidazo[ l,2-b]pyridazin-2-yl)methanol (Intermediate 31)

[0312] To a stirred solution of ethyl 6-bromoimidazo[l,2-bJpyridazine-2-carboxylate, Intermediate 30 (500 mg, 1.851 mmol) in DCM (20 mL) at -78 °C, DIBAL-H (IM in toluene, 7.41 mL, 7.41 mmol) was added and stirred at 25 °C for 16 h. After completion of the reaction (as monitored by TLC & LCMS), the reaction mixture was cooled to 0 °C, quenched with water (10 mL) and saturated NH4CI (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic extracts were dried over Na2SO4and filtered. The combined organic extracts were concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel (230-400 mesh) column chromatography using 0.5% MeOH in dichloromethane to afford the title product (365 mg, 86.5%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.17 (d, J = 0.60 Hz, 1H), 8.04 (dd, I - 0.60, 9.60 Hz, 1H), 7.41 (d, J = 9.60 Hz, 1H), 5.35 (t, J = 5.70 Hz, 1H); LCMS: 227.9 [M+H],Step 2: 6-Bromoimidazo[l ,2-b]pyridazine-2-carbaldehyde (Intermediate 32)

[0313] To a stirred solution of (6-bromoimidazo[l,2-b]pyridazin-2-yl)methanol, Intermediate 31 (250 mg, 1.096 mmol) in DMSO (2 mL) at 0 °C, 2-iodoxybenzoic acid (IBX) (682 mg, 1.096 mmol) was added and stirred at 25 °C for 2 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with aqueous NaHCO3(5 mL) and extracted with EtOAc (5 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, and filtered. The combined organic extracts were concentrated under reduced pressure to yield the title product as an off-white solid (225 mg, 88% yield).1H NMR (400 MHz,DMSO-d6) δ = 10.07 (s, 1H), 9.04 (s, 1H), 8.24-8.27 (m, 1H), 7.61 (d, J = 9.60 Hz, 1H); LCMS:225.9 [M+H],Step 3: 6-bromo-2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-b]pyridazine(Intermediate 33)

[0314] The title compound was prepared by following a similar procedure described for Intermediate E3, starting from 6-bromoimidazo[l,2-b]pyridazine-2-carbaldehyde, Intermediate 32 (220 mg, 0.973 mmol), and 3-(fluoromethyl)azetidine hydrochloride, Intermediate DI (185 mg, 1.470 mmol), and was obtained as a yellow solid (155 mg, 53.2% yield). LCMS: 299.0 [M+H],Step 4: 2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)imidazo[l ,2-b]pyridazine (Intermediate E20)

[0315] The title compound was prepared by following a similar’ procedure described for Intermediate E2, starting from 6-bromo-2-((3-(fhioromethyl)azetidin-l-yl)methyl)imidazo[l,2- b]pyridazine, Intermediate 33 (50 mg, 0.167 mmol), bis(pinacolato)diboron (63.7 mg, 0.251 mmol), potassium acetate (41 mg, 0.418 mmol) and [l,l'-Bis(diphenylphosphino)ferrocene]- dichloropalladium (11) dichloromethane complex (13.65 mg, 0.017 mmol), and was obtained as a brown gum (50 mg, crude). LCMS: 347.2 [M+H],Example 7: a- Ary lated / Alkylated Ketones (F)

[0316] The following bicyclic intermediates are either commercially available or were synthesized as described below.

[0317] Intermediate F21 and Intermediate F22 were prepared as reported in PCT Publication No. WO 2019 / 144132 Al.Example 7.1 : 2-Methoxy-6-( o-tolyl)-6, 7, 8,9-tetrahydro-5H-benzo

[0007] annulen-5-one( Intermediate Fl )

[0318] Intermediate Fl was prepared according to the Scheme 17:Scheme 17

[0319] To a stirred solution of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate Al (2 g, 10.51 mmol) in toluene (30 mL) at 25 °C, cesium carbonate (8.60 g, 26.4 mmol) was added and degassed using N2for 15 minutes. Then l-bromo-2-methylbenzene, Intermediate B 1 (2.84 g, 16.61 mmol). XPhos (1.002 g, 2.103 mmol), and Pd(OAc)o (0.283 g, 1.262 mmol) were added under N2atmosphere and degassed for 5 min. The resulting reaction mixture was stirred at 115 °C (sealed tube) for 16 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was filtered through Celite and washed with EtOAc (5 mL x 2). The filtrate was evaporated under reduced pressure to yield the crude product. It was purified by silica gel (230-400 mesh) column chromatography using 2% EtOAc in petroleum ether to afford the title product as a brown liquid (1.9 g, 64.4% yield).1H NMR (400 MHz, CDCl3) δ = 7.74 (d, J = 8.80 Hz, 1H), 7.18-7.28 (m, 4H), 6.86 (dd, J = 2.40, 8.60 Hz, 1H), 6.79 (d, J = 2.40 Hz, 1H), 3.89 (s, 3H), 3.15-3.89 (m, 1H), 2.95-3.00 (m, 1H), 2.18-2.30 (m, 5H), 2.07-2.12 (m, 1H), 1.88-1.93 (m, 1H); LCMS: 281.2 [M+H],Example 7.2: 6-(o-Tolyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate F2)

[0320] Intermediate F2 was prepared according to the Scheme 18:Step 1: 6-bromo-6,7,8,9-tetrahydro-5H-benzo

[0007] annulen-5-one (Intermediate 34)

[0321] To a stirred solution of 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate A5 (500 mg, 3.12 mmol) in THF (15 mL) at -50 °C, a solution of pyridinium tribromide (998 mg, 3.12 mmol) in THF (5 mL) was added and the resulting reaction mixture was allowed to warm to -50 °C to 0 °C over 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with aqueous sodium thiosulphate (10%, 5 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, and filtered. The combined organic extracts were concentrated under reduced pressure to give the crude product. It was purified by silica gel (230-400 mesh) column chromatography using 3% EtOAc in petroleum ether to afford the title product (710 mg, 94% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 7.48-7.53 (m, 2H), 7.32-7.37 (m, 2H), 5.23-5.26 (m, 1H), 2.93-2.99 (m, 2H), 2.34-2.40 (m, 1H), 2.10-2.17 (m, 1H), 1.97-2.02 (m, 1H), 1.76-1.82 (m, 1H).Step 2: 8-Bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate (Intermediate 35)

[0322] To a stirred solution of 6-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate 34 (1.40 g, 5.85 mmol) in THF (20 mL) at -70 °C, LiHMDS (1.5M in THF, 5.07 ml, 7.61 mmol) was added and stirred for 25 minutes. Acetic anhydride (1.660 mL, 17.56 mmol) wasadded, and the resulting reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with aqueous NaHCO3(10 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, and filtered. The combined organic extracts were concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel (230-400 mesh) column chromatography using 2% EtOAc in petroleum ether to afford the title product (1.6 mg, 97% yield) as a colorless gum.1H NMR (400 MHz, DMSO-d6) δ = 7.18-7.33 (m, 4H), 2.83- 2.87 (m, 2H), 2.57-2.60 (m, 2H), 2.24-2.29 (m, 5H).Step 3: 8-(o-Tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate (Intermediate 36)

[0323] To a stirred solution of 8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 35 (500 mg, 1.778 mmol) and o-tolylboronic acid, Intermediate Cl (242 mg, 1.778 mmol) in 1,4-dioxane (9 mL) and water (1 mL) at 25 °C, CS2CO3(1449 mg, 4.45 mmol) was added and purged with N2for 10 minutes. Then PdCl2(dppf)-CH2Cl2(145 mg, 0.178 mmol) was added, and the resulting reaction mixture was stirred at 100 °C (sealed tube) for 12 h. After the reaction was completed as monitored by TLC, the reaction mixture was filtered through Celite and washed with EtOAc (10 mL). The filtrate was concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography using 2% EtOAc in petroleum ether to afford the title product as a colorless oil (430 mg, 82.7% yield).1H NMR (400 MHz, DMSO-d6) δ = 7.16-7.34 (m, 1H), 7.07-7.10 (m, 7H), 2.91-2.93 (m, 2H), 2.25 (s, 3H), 2.09-2.19 (m, 4H), 1.82 (s, 3H).Step 4: 6-(o-tolyl)-6,7,8,9-tetrahydro-5H-benzo[7]anmden-5-one (Intermediate F2)

[0324] To a stirred solution of 8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 36 (940 mg, 3.22 mmol) in methanol (13 mL) and DCM (2 mL) at 0 °C, aq HC1 (35%, 1 mL) was added and stirred at 70 °C overnight. After the reaction was completed as monitored by TLC, the reaction mixture was evaporated under reduced pressure to yield the crude residue. The residue was quenched with water (5 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4and filtered. The combined organic layers were concentrated under reduced pressure to give the crude product. Crude product was purified by silica gel (230-400 mesh) column chromatography using 3% EtOAc in petroleum ether to afford the title product (735 mg, 91.3% yield) as a colorless oil.1H NMR (400 MHz, DMSO-de) <5 = 7.49-7.53 (m, 2H), 7.35-7.38 (m, 2H), 7.14-7.22 (m, 4H), 4.25-4.29 (m, 1H), 3.16-3.24 (m, 1H), 2.95- 3.00 (m, 1H), 2.08-2.20 (m, 5H), 1.94-1.98 (m, 1H), 1.70-1.75 (m, 1H); LCMS: 251.2 [M+H],Example 7.3: 6-(2,4-Dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo

[0007] annulen-5-one( Intermediate F3 )

[0325] Intermediate F3 was prepared according to the Scheme 19:Step 1: 6-Bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate 37)

[0326] The title compound was prepared by following a similar procedure described for Intermediate 34, starting from 2-methoxy-6, 7,8, 9-tetrahydro-5H-benzo[7]annulen-5-one, Al (1 g, 5.26 mmol) and pyridinium tribromide (1.849 g, 5.78 mmol). It was obtained as a yellow gum (0.76 g, 53.7% yield).1H NMR (400 MHz, CD3OD) 3 = 7.62 (d, J = 8.80 Hz, 1H), 6.89 (dd, J = 2.40, 8.60 Hz, 1H), 6.83 (d, J = 2.40 Hz, 1H), 5.01-5.04 (m, 1H), 3.87 (s, 3H), 2.97-3.06 (m, 2H), 2.35-2.40 (m, 1H), 2.21-2.25 (m, 1H), 1.96-2.06 (m, 2H); LCMS: 270.9 [M+H],Step 2: 8-Bromo-3-methoxy-6 7-dihydro-5H-henzo[7]annulen-9-yl acetate (Intermediate 38)

[0327] The title compound was prepared by following a similar procedure described for Intermediate 35, starting from 6-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- one, Intermediate 37 (650 mg, 2.415 mmol), LiHMDS (1.5M in THF, 1.77 mL, 2.66 mmol) and acetic anhydride (0.685 mL, 7.25 mmol). The title compound was obtained as a yellow gum (420 mg, 55.9% yield).1H NMR (400 MHz, CD3OD) d = 7.24 (d, J = 9.20 Hz, 1H), 6.81-6.83 (m, 2H), 3.82 (s, 3H), 2.80 (t, J = 7.20 Hz, 2H), 2.55 (t, J = 7.20 Hz, 2H), 2.03-2.22 (m, 5H).Step 3: 8-(2,4-Dichlorophenyl)-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate (Intermediate 39)

[0328] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from 8-bromo-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 38 (200 mg, 0.643 mmol), 2-(2,4-dichlorophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane, Intermediate C5 (193 mg, 0.707 mmol), CS2CO3(628 mg, 1.928 mmol) and PdCl2(dppf)-CH2Cl2(52.5 mg, 0.064 mmol). The title compound was obtained as a yellow gum (200 mg, 82% yield).1H NMR (400 MHz, CDCl3) δ = 7.24-7.47 (m, 4H), 6.80-6.83 (m, 2H), 3.85 (s, 3H), 2.94 (s, 2H), 2.25 (s, 4H), 1.94 (s, 3H); LCMS: 335.1 [M+-(Acetyl)]Step 4: 6-( 2,4-Dichlorophenyl )-2-methoxy-6, 7, 8, 9-tetrahydro-5H-benzo

[0007] annulen-5-one(Intermediate F3 )

[0329] The title compound was prepared by following a similar procedure described in Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from 8-(2,4-dichlorophenyl)-3- methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 39 (200 mg, 0.530 mmol), aq HC1 (1.5 N, 1.8 mL) and was obtained as a colourless gum (150 mg, 84% yield).1H NMR (400 MHz, DMSO-d6) δ = 7.58-7.60 (m, 2H), 7.45-7.45 (m, 2H), 6.90-6.93 (m, 2H), 4.40-4.43 (m, 1H), 3.84 (s, 3H), 3.15-3.19 (m, 1H), 2.94-3.00 (m, 1H), 2.13-2.23 (m, 2H), 1.92-1.99 (m, 1H), 1.67- 1.73 (m, 1H); LCMS: 335.1 [M+H],Example 7.4: 2-Methoxy-6-(2-methylbenzo[ d ]oxazol-6-yl)-6, 7, 8,9-tetrahydro-5H- benzo[7]annulen-5-one (Intermediate F4)

[0330] Intermediate F4 was prepared according to the Scheme 20:Scheme 20

[0331] The title compound was prepared by following a similar procedure described for Intermediate Fl, starting from 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate Al (0.750 g, 3.94 mmol), 6-bromo-2-methylbenzo[d] oxazole, Intermediate B2 (1 g, 4.73 mmol), cesium carbonate (3.22 g, 9.90 mmol), XPhos (0.376 g, 0.788 mmol), and Pd(OAc)i (0.106 g, 0.473 mmol). It was obtained as a brown solid (1.015 g, 80.11% yield). LCMS: 322.2 [M+H],Example 7.5: 2-((Tert-butyldimethylsilyl)oxy)-6-(4-methoxy-2-methylphenyl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-one (Intermediate F5)

[0332] Intermediate F5 was prepared according to the Scheme 21:

[0333] The title compound was prepared by following a similar procedure described for Intermediate Fl, starting from 2-((tert-butyldimethylsilyl)oxy)-6,7,8,9-tetrahydro-5H- bcnzo[7]annulcn-5-onc, Intermediate A6 (150 mg, 0.516 mmol), l-bromo-4-mcthoxy-2-methylbenzene, Intermediate B3 (156 mg, 0.775 mmol), cesium carbonate (422 mg, 1 .296 mmol), XPhos (51.2 mg, 0.107 mmol), and Pd(OAc)2(23.19 mg, 0.103 mmol) and was obtained as a white solid (80 mg, 37.3% yield).NMR (300 MHz, DMSO-d6) δ = 7.48-7.51 (m, 1H), 7.08-7.11 (m, 1H), 6.80-6.83 (m, 2H), 6.71-6.74 (m, 2H), 4.13-4.17 (m, 1H), 3.75 (s, 3H), 3.12-3.17 (m, 1H), 2.03-2.17 (m, 5H), 1.88-1.94 (m, 1H), 1.65-1.69 (m, 1H), 1.00 (s, 9H), 0.26 (s, 6H); LCMS: 411.6 [M+H],Example 7.6: 22-Methoxy-6-(pyridin-4-yl)-677,8,9-tetrahydro-5H-benzo[7]annulen-5-one( Intermediate F6 )

[0334] Intermediate F6 was prepared according to the Scheme 22:Scheme 22Step 1: 3-methoxy-8-(pyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate(Intermediate 40)

[0335] The title compound was prepared by following a similar' procedure described for Intermediate 36, starting from 8-bromo-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 38 (350 mg, 1.125 mmol), pyridin-4-ylboronic acid, Intermediate C6 (173 mg, 1.406 mmol), CS2CO3(916 mg, 2.81 mmol), and PdCl2(dppf)-CH2Cl2(92 mg, 0.112 mmol). It was obtained as a yellow gum (185 mg, 53.2% yield) LCMS: 310.2 [M+H],Step 2: 2-Methoxy-6-(pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anmden-5-one( Intermediate F6 )

[0336] The title compound was prepared by following a similar procedure described Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from 3-methoxy-8-(pyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 40 (185 mg, 0.598 mmol), aq HC1 (35%, 0.5 mL), and was obtained as a colourless gum (150 mg, crude). LCMS: 268.1 [M+H].Example 7.7: 2-Methoxy-6-( 3-methylpyridin-4-yl)-6, 7,8,9-tetrahydro-5H-benzo[7]annulen-5-one( Intermediate F7 )

[0337] Intermediate F7 was prepared according to the Scheme 23:Scheme 23Step 1: 3-Methoxy-8-(3-methylpyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate (Intermediate 41 )

[0338] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from 8-bromo-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 38 (1 g, 3.21 mmol), (3-methylpyridin-4-yl)boronic acid, Intermediate C7 (0.44 g, 3.21 mmol), CS2CO3(2.62 g, 8.03 mmol) and PdCl2(dppf)-CH2Cl2(0.262 g, 0.321 mmol). It was obtained as a brown gum (0.499 g, 48% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.46 (s, 1H), 8.37 (d, J = 4.80 Hz, 1H), 7.24 (d, J = 8.80 Hz, 1H), 7.07 (d, J = 5.20 Hz, 1H), 6.93 (d, J = 2.40 Hz, 1H), 6.85 (dd, J = 2.40, 8.60 Hz, 1H), 3.80 (s, 3H), 2.22 (s, 3H), 2.11-2.18 (m, 4H), 1.84 (s, 3H); LCMS: 324.2 [M+H],Step 2: 2-Methoxy-6-(3-methylpyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate F7)

[0339] The title compound was prepared by following a similar procedure described Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from 3-methoxy-8-(3-methylpyridin-4- yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 41 (500 mg, 1.546 mmol), HC1 (35%, 0.8 mL), and was obtained as a colourless gum (400 mg, crude).1H NMR (400 MHz,DMSO-d6) δ = 8.34-8.37 (m, 2H), 7.60 (d, J = 8.40 Hz, 1H), 7.21 (d, J = 4.80 Hz, 1H), 6.91-6.95 (m, 2H), 4.28-4.32 (m, 1H), 3.84 (s, 3H), 3.22-3.29 (m, 1H), 2.08-2.20 (m, 5H), 1.93-1.97 (m, 1H), 1.67-1.72 (m, 1H); LCMS: 282.1 [M+H],Example 7.8: 2-Methoxy-6-(pyridin-3-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one( Intermediate F8 )

[0340] Intermediate F8 was prepared according to the Scheme 24:Scheme 24Step 1: 3-Methoxy-8-(pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate(Intermediate 42)

[0341] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from 8-bromo-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 38 (1 g, 3.21 mmol), pyridin-3-ylboronic acid, Intermediate C2 (0.494 g, 4.02 mmol), CS2CO3(2.62 g, 8.03 mmol) and PdCl2(dppf)-CH2C12(0.262 g, 0.321 mmol). The title compound was obtained as a brown gum (0.480 g, 48.3% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.57- 8.58 (m, 1H), 8.48-8.49 (m, 1H), 7.74-7.77 (m, 1H), 7.40-7.44 (m, 1H), 7.27 (d, I = 8.40 Hz, 1H), 6.92 (d, J = 2.40 Hz, 1H), 6.86 (dd, J = 2.80, 8.60 Hz, 1H), 3.80 (s, 3H), 2.80 (bs, 2H), 2.22 (bs, 4H), 2.01 (s, 3H); LCMS: 310.1 [M+H],Step 2: 2-Methoxy-6-(pyridin-3-yl)-6,7,8,9-tetrahydro-5H-benzo[7 Jannulen-5-one(Intermediate F8)

[0342] The title compound was prepared by following a similar procedure described Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from 3-methoxy-8-(pyridin-3-yl)-6,7- dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 42 (480 mg, 1.552 mmol), aq HCI (35%, 0.471 mL), and was obtained as a colourless gum (350 mg, 84.3% yield). LCMS: 268.2 [M+H].Example 7.9: 6-(3-Chloropyridin-4-yl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate F9)

[0343] Intermediate F6 was prepared according to the Scheme 25 :Scheme 25Step 1: 8-(3-Chloropyridin-4-yl)-3-methoxy-6, 7-dihydro-5H-benzo[7]annulen-9-yl acetate (Intermediate 43)

[0344] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from 8-bromo-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 38 (0.875 g, 2.81 mmol), (3-chloropyridin-4-yl)boronic acid, Intermediate C8 (0.531 g, 3.37 mmol), Cs2CO3(2.02 g, 6.19 mmol), and PdCl2(dppf)-CH2Cl2(0.230 g, 0.281 mmol). It was obtained as a yellow gum (0.445 g, 46% yield). LCMS: 344.1 [M+H].Step 2: 6-(3-Chloropyridin-4-yl)-2-methoxy-6, 7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate F9)

[0345] The title compound was prepared by following a similar procedure described Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from 8-(3-chloropyridin-4-yl)-3-methoxy- 6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, 43 (880 mg, 2.56 mmol), and aq HC1 (35%, 0.778 mL). It was obtained as a colourless gum (700 mg, 88.8% yield). LCMS: 302.2 [M+H].Example 7.10: 6-(3-Chloropyridin-4-yl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- one (Intermediate F10)

[0346] Intermediate F10 was prepared according to the Scheme 26:Scheme 26Step 1: 6-Bromo-l-fluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(Intermediate 44)

[0347] The title compound was prepared by following a similar procedure described for Intermediate 34, starting from l-fluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate A7 (529 mg, 2.54 mmol), and pyridinium tribromide (894 mg, 2.79 mmol). The title compound was obtained as a yellow gum (550 mg, 75.4% yield).1H NMR (400 MHz, DMSO-d6) δ = 7.42-7.45 (m, 1H), 7.13-7.19 (m, 1H), 5.24-5.29 (m, 1H), 3.90 (s, 3H), 3.06-3.13 (m, 1H), 2.84-2.92 (m, 1H), 2.32-2.44 (m, 1H), 2.07-2.18 (m, 2H), 1.67-1.76 (m, 1H).Step 2: 8-Bromo-4-fliioro-3-methoxy-6,7-dihydro-5H-benzo[7]anniden-9-yl acetate(Intermediate 45)

[0348] The title compound was prepared by following a similar procedure described for Intermediate 35, starting from 6-bromo-l-fluoro-2-methoxy-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-one, Intermediate 44 (710 mg, 2.415 mmol), LiHMDS (1.5M in THF, 2.14 mL, 3.21 mmol), and acetic anhydride (0.234 mL, 2.47 mmol). The title compound was obtained as a yellow gum (540 mg, 66.3% yield). LCMS: 287.0 [M+- (Acetyl)]Step 3: 4-Fluoro-3-methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate (Intermediate 46)

[0349] The title compound was prepared by following a similar procedure described for Intermediate 36, stalling from 8-bromo-4-fluoro-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9- yl acetate, Intermediate 45 (300 mg, 0.911 mmol), o-tolylboronic acid, Intermediate Cl (186 mg, 1.397 mmol), CS2CO3(742 mg, 2.278 mmol), and PdCl2(dppf)-CH2Cl2(74.4 mg, 0.091 mmol). The title compound was obtained as a brown gum (180 mg, 58% yield). LCMS: 299.2 [M+- (Acetyl)].Step 4: l-Fluoro-2-methoxy-6-(o-tolyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(Intermediate F10)

[0350] The title compound was prepared by following a similar procedure described Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from 4-fhioro-3-methoxy-8-(o-tolyl)-6,7- dihydro-5H-benzo[7]annulen-9-yl acetate, 46 (330 mg, 0.969 mmol), aq HC1 (35%, 0.59 mL), and was obtained as a brown gum (280 mg, 97% yield). LCMS: 299.1 [M+H].Example 7.11: 2 -Methoxy -6 -( 1 -(tetrahydro-2H-pyran-2-yl)-l H-indaz.ol-5-yl)-6,7,8,9-tetrah.ydro- 5H-benzo[7]annulen-5-one (Intermediate Fll)

[0351] Intermediate Fl l was prepared according to the Scheme 27:Scheme 27

[0352] The title compound was prepared by following a similar procedure described for Intermediate Fl, starting from 2-mcthoxy-6,7,8,9-tctrahydro-5H-bcnzo[7]annulcn-5-onc, Intermediate Al (800 mg, 4.21 mmol), 5-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole, Intermediate B 5 (1.182 g, 4.21 mmol), CS2CO3(4.11 g, 12.62 mmol), XPhos (401 mg, 0.841 mmol), Pd(OAc)2(0.094 g, 0.421 mmol), and was obtained as an off-white solid (1.2 g, 73% yield). LCMS: 391.2 [M+H],Example 7. 12: 2-Methoxy-6-( 1 -(tetrahydro-2H-pyran-2-yl)-lFI-indazol-5-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]anmden-5-one (Intermediate F12)

[0353] Intermediate F12 was prepared according to the Scheme 28:Scheme 28Step 1: 8-(Imidazo[l,2-a]pyridin-7-yl)-3miethoxy-6,7-dihydro-5FI-benzo[7]annulen-9-yl acetate (Intermediate 47):

[0354] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from 8-bromo-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, 38 (100 mg, 0.321 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine, C9 (78 mg, 0.321 mmol), Cs2CO3(314 mg, 0.964 mmol), and PdCl2(dppf)-CH2Cl2(26 mg, 0.032 mmol). It was obtained as a brown gum (100 mg, 89.3% yield). LCMS: 349.2 [M+H],Step 2: 6-(imidazo[l,2-a ]pyridin-7-yl)-2-methoxy-6, 7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate F12):

[0355] The title compound was prepared by following a similar procedure described Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from 8-(imidazo[l,2-a]pyridin-7-yl)-3- methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 47 (98 mg, 0.281 mmol), and aq HC1 (35%, 0.094 mL). The title compound was obtained as a brown gum (35 mg, 40.6% yield). LCMS: 307.2 [M+H],Example 7.13: 3-Chloro-4-(2-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6- yl)benzonitrile (Intermediate Fl 3)

[0356] Intermediate Fl 3 was prepared according to the Scheme 29:Scheme 29

[0357] To a stirred solution of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate Al (1.028 g, 5.41 mmol) in THF (50 mL) at 25 °C, 4-bromo-3-chlorobenzonitrile, Intermediate B8 (0.9 g, 4.16 mmol), and tripotassium phosphate (1.677 g, 7.90 mmol) were added under N2atmosphere. Then, Xantphos (0.060 g, 0.104 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.049 g, 0.054 mmol) were added under the N2atmosphere. The resulting reaction mixture was stirred at 80 °C for 16 h. Xantphos (0.060 g, 0.104 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.049 g, 0.054 mmol) were added again and stirred at the same temperature for an additional 20 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was filtered through Celite and washed with EtOAc (5 mL x 2). The filtrate was concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel (230-400 mesh) column chromatography using 5% EtOAc in petroleum ether to afford the title product as a pale yellow solid (0.45 g, 33.2% yield).NMR (400 MHz, CDCl3) 3 = 7.79 (d, J = 8.80 Hz, 1H), 7.70 (d, J = 1.60 Hz, 1H), 7.61 (dd, J = 1.60, 8.00 Hz, 1H), 7.47-7.53 (m, 1H), 6.87 (dd, J = 2.40, 8.80 Hz, 1H), 6.80 (d, J = 2.40 Hz, 1H), 4.54-4.58 (m, 1H), 3.89 (s, 3H), 3.18-3.25 (m, 1H), 2.98-3.04 (m, 1H), 2.20-2.30 (m, 2H), 2.04-2.10 (m, 1H), 1.88-1.93 (m, 1H). LCMS: 326.1 [M+H],Example 7.14: Methyl 6-(3-chloropyridin-4-yl)-5-oxo-6, 7,8, -lelrahydro-5H-ben~<)[7 jannulene- 2-carboxylate (Intermediate F14)

[0358] Intermediate F14 was prepared according to the Scheme 30:Scheme 30Step 1: Methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (Intermediate 48):

[0359] The title compound was prepared by following a similar procedure described for Intermediate 34, starling from methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2- carboxylate, Intermediate A4 (350 mg, 1.604 mmol), and pyridinium tribromide (564 mg, 1.764 mmol). The title compound was obtained as a yellow gum (435 mg, crude) and was taken to the next step without further purification.1H NMR (400 MHz, CDCl3) δ - 7.96 (dd, J = 1.20, 7.80 Hz, 1H), 7.91 (d, J = 1.20 Hz, 1H), 7.63 (d, J = 8.00 Hz, 1H), 4.85-4.88 (m, 1H), 3.97 (s, 3H), 2.90- 3.12 (m, 2H), 2.33-2.43 (m, 2H), 1.96-2.09 (m, 1H), 1.73-1.78 (m, 1H). LCMS: 297.1 [M+H]Step 2: Methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 49):

[0360] The title compound was prepared by following a similar procedure described for Intermediate 35, starting from methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2- carboxylate, Intermediate 48 (430 mg, 1.447 mmol), LiHMDS (IM in THF, 1.88 mL, 1.88 mmol), and acetic anhydride (0.410 mL, 4.34 mmol). The title compound was obtained as a yellow oil (410 mg, crude) and was taken to the next step without further purification. LCMS: 339.0 [M+H],Step 3: Methyl 9-acetoxy-8-(3-chloropyridin-4-yl)-6,7-dihydro-5H-benzol7]annulene-3- carboxylate (Intermediate 50):

[0361] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Intermediate 49 (400 mg, 1.179 mmol), (3-chloropyridin-4-yl)boronic acid, Intermediate C8 (186 mg, 1.397 mmol), CS2CO3(768 mg, 2.359 mmol), and PdCl2(dppf).CH2Cl2(96 mg, 0.118 mmol). The title compound was obtained as a brown gum (400 mg, 91% yield). LCMS: 372.2 [M+H].Step 4: Methyl 6-(3-chloropyridin-4-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2- carboxylate (Intermediate F14):

[0362] The title compound was prepared by following a similar’ procedure described Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from methyl 9-acetoxy-8-(3- chloropyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Intermediate 50 (360 mg, 0.968 mmol), HC1 (35%, 0.24 mL) and was obtained as a yellow solid (300 mg, 94% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.62 (s, 1H), 8.55 (d, J = 4.80 Hz, 1H), 7.93-7.98 (m, 2H), 7.68 (d, J = 7.80 Hz, 1H), 7.53 (d, J = 5.10 Hz, 1H), 4.51-4.56 (m, 1H), 3.90 (s, 3H), 3.08-3.25 (m, 2H), 2.18-2.29 (m, 2H), 2.00-2.09 (m, 1H), 1.76-1.83 (m, 1H). LCMS: 330.1 [M+H],Example 7.15: 6-(2-(Difluoromethyl)phenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-one (Intermediate Fl 5)

[0363] Intermediate Fl 5 was prepared according to the Scheme 31:Scheme 31

[0364] The title compound was prepared by following a similar’ procedure described for Intermediate Fl, starting from 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate Al (700 mg, 3.68 mmol), l-bromo-2-(difluoromethyl)benzene, Intermediate B9 (952 mg, 4.60 mmol), cesium carbonate (2650 mg, 8.13 mmol), XPhos (526 mg, 1.104 mmol), and Pd(OAc)2(124 mg, 0.552 mmol). The title compound was obtained as a colourless liquid (600 mg, 51.5% yield). LCMS: 317.3 [M+H],Example 7.16: 6-(2-(Difluoromethyl)phenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate F16)

[0365] Intermediate F16 was prepared according to the Scheme 32:Scheme 32Step 1: 6-Bromo-4-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate 51):

[0366] The title compound was prepared by following a similar procedure described for Intermediate 34, starting from 4-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate A9 (500 mg, 2.63 mmol), and pyridinium tribromide (925 mg, 2.89 mmol). The title compound was obtained as a yellow gum (320 mg, 45.2% yield) and was taken to the next step without further purification.Step 2: 8-Bromo-l-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate (Intermediate 52):

[0367] The title compound was prepared by following a similar procedure described for Intermediate 35, starting from 6-bromo-4-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- one, Intermediate 51 (320 mg, 1.189 mmol), LiHMDS (IM in THF, 1.55 mL, 1.55 mmol), and acetic anhydride (0.337 mL, 3.57 mmol). The title compound was obtained as a yellow oil (370 mg, crude) and was taken as such to the next step without further purification.Step 3: 1 -M ethoxy-8-(3-methylpyridin-4-yl)-6, 7-dihydro-5H-benzo[7]annulen-9-yl acetate(Intermediate 53):

[0368] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from 8-bromo-l-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 52 (366 mg, 1.176 mmol), (3-methylpyridin-4-yl)boronic acid, Intermediate C7 (193 mg, 1.411 mmol), CS2CO3(1150 mg, 3.53 mmol), and PdCl2(dppf)-CH2Cl2(96 mg, 0.118 mmol), and was obtained as a brown gum (240 mg, 63.2% yield). LCMS: 324.1 [M+H].Step 4: 4-Methoxy-6-( 3-methylpyridin-4-yl)-6, 7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(Intermediate F16):

[0369] The title compound was prepared by following a similar procedure described Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from l-methoxy-8-(3-methylpyridin-4- yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 53 (240 mg, 0.742 mmol), aq HC1 (35%, 0.23 mL), and was obtained as a brown solid (220 mg, 78.3% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.36-8.38 (m, 2H), 7.34-7.38 (m, 1H), 7.22 (d, J = 5.20 Hz, 1H), 7.01 (d, J = 8.40 Hz, 1H), 6.88 (d, J = 7.20 Hz, 1H), 4.18-4.21 (m, 1H), 3.72 (s, 3H), 2.76-2.85 (m, 2H), 2.24 (s, 3H), 2.08-2.15 (m, 1H), 1.90-1.99 (m, 3H); LCMS: 282.0 [M+H],Example 7.17: 2-(2-Methoxy-5-oxo-6, 7,8,9-tetrahydro-5H-benzo

[0007] annulen-6-yl)benzonitrile (Intermediate F17)

[0370] Intermediate F17 was prepared according to the Scheme 33:Scheme 33Step 1: 8-(2-Cyanophenyl)-3-methoxy-6,7-dihydro-5H-benzo

[0007] annulen-9-yl acetate(Intermediate 54):

[0371] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from 8-bromo-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 38 (100 mg, 0.321 mmol), (2-cyanophenyl)boronic acid, Intermediate C14 (56.7 mg, 0.386 mmol), CS2CO3(209 mg, 0.643 mmol), and PdCl2ldppfj-CtbCl2(26.2 mg, 0.032 mmol). The title compound was obtained as a yellow gum (100 mg, 93% yield).1H NMR (300 MHz, DMSO-d6) δ = 7.90-7.90 (m, 1H), 7.72-7.75 (m, 1H), 7.51-7.54 (m, 1H), 7.40 (d, J = 7.80 Hz, 1H), 7.25 (d, J = 8.40 Hz, 1H), 6.85-6.95 (m, 2H), 3.80 (s, 3H), 2.87-2.89 (m, 2H), 2.18-2.27 (m, 4H), 1.86 (s, 3H).Step 2: 2-(2-Methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)benzonitrile(Intermediate F17):

[0372] To a stirred solution of 8-(2-cyanophenyl)-3-methoxy-6,7-dihydro-5H- benzo[7]annulen-9-yl acetate , Intermediate 54 (100 mg, 0.300 mmol) in DCM (7 mL) and MeOH (2 mL) at 25 °C, lithium hydroxide (10.77 mg, 0.450 mmol) was added and stirred at 50 °C for 12 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was concentrated under reduced pressure to get the residue. The residue was taken in water (1 mL), neutralized with HC1 (1.5N), and extracted with DCM (5 mL x 3). The combined organic extracts were dried over Na2SO4and filtered. The combined organic extracts were concentrated under reduced pressure to give the title product (60 mg, crude), which was taken to the next step without further purification. LCMS: 292.3 [M+H],Example 7.18: 6-( 2-Chlorophenyl )-2-methoxy-6, 7, 8,9-tetrahydro-5H-benzo

[0007] annulen-5-one (Intermediate Fl 8)

[0373] Intermediate Fl 8 was prepared according to the Scheme 34:Scheme 34Step 1 : 8-( 2-Chlorophenyl)-3-methoxy-6, 7 -dihydro-5H-benzo

[0007] annulen-9-yl acetate(Intermediate 55):

[0374] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from 8-bromo-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 38 (100 mg, 0.321 mmol), (2-chlorophenyl)boronic acid, Intermediate C 15 (60.3 mg, 0.386 mmol), CS2CO3(209 mg, 0.643 mmol), and PdCl2(dppf -CH2Cl2(26.2 mg, 0.032 mmol). The title compound was obtained as a yellow gum (60 mg, 54.5% yield).1H NMR (400 MHz, DMSO-d6) δ = 7.42-7.46 (m, 1H), 7.22-7.32 (m, 4H), 6.80-6.84 (m, 2H), 3.86 (s, 3H), 2.94-3.01 (m, 2H), 2.22-2.32 (m, 4H), 1.92 (s, 3H); LCMS: 301.2 [M+- (Acetyl)].Step 2: 6-(2-Chlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(Intermediate F18):

[0375] The title compound was prepared by following a similar procedure described Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from 8-(2-chlorophenyl)-3-methoxy-6,7- dihydro-5H-benzo[7]annulen-9-yl acetate, Intermediate 55 (160 mg, 0.467 mmol), and aq HC1 (35%, 0.15 mL). The title compound was obtained as a colourless gum (140 mg, crude). LCMS: 301.2 [M+H],Example 7.19: Methyl 8-(o-tolyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H- benzo[7]annulene-3-carboxylate (Intermediate F19)

[0376] Intermediate Fl 9 was prepared according to the Scheme 35:Scheme 35Step 1: 2-Hydroxy-6-(o-tolyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate 56):

[0377] To a stirred solution of 2-methoxy-6-(o-tolyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-one, Intermediate Fl (600 mg, 2.140 mmol) in DCM (15 mL) at 0 °C, boron trifluoride dimethyl sulfide complex (2.78 mL, 21.40 mmol) was added under N2atmosphere and stirred at 25 °C for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was diluted with aqueous NaHCO3(10%, 30 mL) and extracted with DCM (25 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The title compound was purified by silica gel (230-400 mesh) column chromatography using 30% EtOAc in petroleum ether to afford the title product as a yellow solid (460 mg, 80.7% yield). ’l l NMR (400 MHz, DMSO-d6) d = 10.11 (s, 1H), 7.46-7.48 (m, 1H), 7.13-7.19 (m, 4H), 6.71-6.74 (m, 2H), 4.18-4.22 (m, 1H), 3.14-3.19 (m, 1H), 2.82-2.87 (m, 1H), 2.08-2.16 (m, 5H), 1.90-1.93 (m, 1H), 1.67-1.68 (m, 1H). LCMS: 265.1 [M-H],Step 2: 5-Oxo-6-(o-tolyl)-6,7,8,9-tetrah.ydro-5H-benz,ol7]annulen-2-yl trifluoromethanesulfonate (Intermediate 57):

[0378] To a stirred solution of 2-hydroxy-6-(o-tolyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-one and Intermediate 56 (100 mg, 0.375 mmol) in DCM (4 mL) at 0 °C, 2,6-lutidine (0.047 mL, 0.406 mmol) was added and stirred for 10 minutes. Then trifluoromethanesulfonic anhydride (0.074 mL, 0.441 mmol) was added at 0 °C and stirred for an hour. Then, the reaction mixture was warmed to 25 °C and stirred for an hour. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with ice-cold water (5 mL) and extracted with DCM (5 mL x3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. It was purified by silica gel (230- 400 mesh) column chromatography using 20% EtOAc in petroleum ether to afford the title product as a yellow oil (119 mg, 79.3% yield).1H NMR (400 MHz, CDCl3) δ = 7.75 (d, J = 8.40 Hz, 1H), 7.21-7.27 (m, 6H), 4.21-4.25 (m, 1H), 3.16-3.24 (m, 1H), 3.03-3.09 (m, 1H), 1.94-2.31 (m, 7H); GCMS: 398.10 [M],Step 3: Methyl 5-oxo-6-(o-tolyl)-6,7,8,9-tetrahyclro-5H-benzo[7]annulene-2-carboxylate (Intermediate F19):

[0379] To a stirred solution of 5-oxo-6-(o-tolyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate and Intermediate 57 (110 mg, 0.276 mmol) in DMF (2 mL) and MeOH (1 mL) at 25 °C, DIPEA (0.096 mL, 0.552 mmol) was added and degassed using N2for 10 minutes. PdCl2(dppf) (12.12 mg, 0.017 mmol) was added and stirred at 70 °C in a SS tinyclave under CO (10 bar) atmosphere for 6 h. After completion of the reaction as monitored by TLC, the reaction mixture was filtered through Celite and washed with MeOH (2 mL x 2), and the filtrate was concentrated under reduced pressure to yield the crude product. The title compound was purified by silica gel (230-400 mesh) column chromatography using 10% EtOAc in petroleum ether to afford the title product as a colorless gum (76 mg, 89.4% yield).1H NMR (400 MHz, DMSO-d6) δ = 7.92-7.96 (m, 2H), 7.61-7.63 (m, 1H), 7.16-7.19 (m, 4H), 4.28-4.32 (m, 1H), 3.90 (s, 3H), 3.11-3.27 (m, 1H), 3.05-3.11 (m, 1H), 2.07-2.22 (m, 5H), 1.95-1.99 (m, 1H), 1.73-1.80 (m, 1H); LCMS: 309.1 [M+H],Example 7.20: 4-(3-Chloropyridin-4-yl)-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one (Intermediate F20)

[0380] Intermediate E20 was prepared according to the Scheme 36:Step 1: 4-Bromo-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one (Intermediate 58):

[0381] The title compound was prepared by following a similar procedure described for Intermediate 34, starting from 8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, Intermediate A8 (250 mg, 1.301 mmol), and pyridinium tribromide (416 mg, 1.301 mmol). The title compound was obtained as a yellow oil (320 mg, 90% yield) and taken as such to the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ = 7.63 (d, J = 8.80 Hz, 1H), 6.75 (dd, J = 2.40, 8.40 Hz, 1H), 6.65 (d, J = 2.40 Hz, 1H), 5.18-5.21 (m, 1H), 4.37-4.42 (m, 1H), 4.16-4.19 (m, 1H), 3.81 (s, 3H), 2.83-2.91 (m, 1H), 2.41-2.48 (m, 1H).Step 2: 4-Bromo-8-methoxy-2,3-dihydrobenzo[b]oxepin-5-yl acetate (Intermediate 59):

[0382] The title compound was prepared by following a similar procedure described for Intermediate 35, starting from 4-bromo-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, Intermediate 58 (250 mg, 0.992 mmol), LiHMDS (IM in THF, 1.20 mL, 1.19 mmol), and acetic anhydride (0.261 mL, 2.77 mmol). The title compound was obtained as a yellow oil (270 mg, crude) and taken to the next step without further purification.1H NMR (300 MHz, DMSO-dp) <5 = 7.31 (d, J = 8.80 Hz, 1H), 6.64-6.68 (m, 1H), 6.61-6.62 (m, 1H), 4.18 (t, J = 5.20 Hz, 2H), 3.76 (s, 3H), 3.14 (t, J = 5.20 Hz, 2H), 2.32 (s, 3H); LCMS: 271.0 [M+- (Acetyl)].Step 3: 4-(3-Chloropyridin-4-yl)-8-methoxy-2,3-dihydrobenzo[b]oxepin-5-yl acetate (60):

[0383] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from 4-bromo-8-methoxy-2,3-dihydrobenzo[b]oxepin-5-yl acetate, Intermediate 59 (500 mg, 1.597 mmol), (3-chloropyridin-4-yl)boronic acid Intermediate C8 (251 mg, 1.597 mmol), CS2CO3(1145 mg, 3.51 mmol), and PdCl2(dppf)-CH2Cl2(130 mg, 3.51 mmol), was obtained as a brown gum (330 mg, 59.8% yield). LCMS: 346.1 [M+H].Step 4: 4-(3-Chloropyridin-4-yl)-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one(Intermediate F20):

[0384] The title compound was prepared by following a similar procedure described in Step 4 of the synthesis of Intermediate F4 (Example 7.2), stalling from 4-(3-chloropyridin-4-yl)-8- methoxy-2,3-dihydrobenzo[b]oxepin-5-yl acetate, Intermediate 60 (725 mg, 2.097 mmol), HC1 (35%, 0.7 mL), and was obtained as a brown solid (600 mg, 94% yield). LCMS: 304.1 [M+H].Example 7.21: 2-(3-Chloropyridm-4-yl)-6-methoxy-3,4-dihydronaphthalen-l(2H)-one( Intermediate F23 )

[0385] Intermediate F20 was prepared according to the Scheme 37 :

[0386] The title compound was prepared by following a similar procedure described for Intermediate F 1 , stalling from 6-methoxy-3,4-dihydronaphthalen-l(2H)-one, Intermediate A10 (1 g, 5.67 mmol), 4-bromo-3-chloropyridine, Intermediate B7 (1.42 g, 7.38 mmol), cesium carbonate (4.62 g, 14.19 mmol), XPhos (0.541 g, 1.135 mmol), and Pd(OAc)2(0.127 g, 0.567 mmol). The title compound was obtained as a brown solid (0.5 g, 30.6% yield). LCMS: 288.1 [M+H].Example 7.22: 7-Methoxy-2,2-dimethyl-3-(o-tolyl)chroman-4-one (Intermediate F24)

[0387] Intermediate F24 was prepared according to the Scheme 38:Step 1: 3-Bromo-7-methoxy-2,2-dimethylchroman-4-one (Intermediate 61):

[0388] The title compound was prepared by following a similar procedure described for Intermediate 34, starting from 7-methoxy-2,2-dimethylchroman-4-one, Intermediate Al l (100 mg, 0.485 mmol), and pyridinium tribromide (171 mg, 0.533 mmol). The title compound was obtained as a yellow gum (100 mg, Crude) and was taken as such to the next step without further purification. LCMS: 285.0 [M+H].Step 2: 3-Bromo-7-methoxy-2,2-dimethyl-2H-chromen-4-yl acetate (Intermediate 62):

[0389] The title compound was prepared by following a similar’ procedure described for Intermediate 35, starting from 3-bromo-7-methoxy-2,2-dimethylchroman-4-one, Intermediate 61 (100 mg, 0.351 mmol), LiHMDS (IM in THF, 0.386 mL, 0.386 mmol), and acetic anhydride (0.099 mL, 1.952 mmol). The title compound was obtained as a yellow oil (100 mg, Crude) and was taken as such to the next step without further purification. LCMS: 327.1 [M+H],Step 3: 7-Methoxy-2,2-dimethyl-3-(o-tolyl)-2H-chromen-4-yl acetate (Intermediate 63):

[0390] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from 3-bromo-7-mcthoxy-2,2-dimcthyl-2H-chromcn-4-yl acetate, Intermediate 62 (100 mg, 0.306 mmol), o-tolylboronic acid, Intermediate Cl (45.7 mg, 0.336mmol), CS2CO3(199 mg, 0.611 mmol), and PdCl2(dppfbCH2Cl2(25 mg, 0.031 mmol). The title compound was obtained as a brown gum (35 mg, 33.8% yield). LCMS: 339.1 [M+H].Step 4: 7-Methoxy-2,2-dimethyl-3-(o-tolyl)chroman-4-one (Intermediate F24):

[0391] The title compound was prepared by following a similar procedure described in Step 4 of the synthesis of Intermediate F4 (Example 7.2), starting from 7-methoxy-2,2-dimethyl-3-(o- tolyl)-2H-chromen-4-yl acetate, Intermediate 63 (30 mg, 0.089 mmol), aq HC1 (35%, 0.02 mL) and was obtained as a yellow solid (26 mg, crude). LCMS: 297.1 [M+H].Example 7.23: 3-(3-Chloropyridin-4-yl)-7-methoxy-2,2-dimethylchroman-4-one(Intermediate F25)

[0392] Intermediate F25 was prepared according to the Scheme 39:Step 1: 3-(3-chloropyridin-4-yl)-7-methoxy-2,2-dimethyl-2H-chromen-4-yl acetate(Intermediate 64):

[0393] To a stirred solution of 3-bromo-7-methoxy-2,2-dimethyl-2H-chromen-4-yl acetate, Intermediate 62 (100 mg, 0.306 mmol), (3-chloropyridin-4-yl)boronic acid, Intermediate C8, (72.1 mg, 0.458 mmol) in THF (4.5 mL) and water (0.5 mL) at 25 °C, potassium phosphate (83 mg, 0.611 mmol) was added and purged with N2for 10 minutes. Then SPhos Pd G3 (23.85 mg, 0.031 mmol) was added, and the resulting reaction mixture was stirred at 90 °C (sealed tube) for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was filtered through celite and washed with EtOAc (15 mL), and the filtrate was concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel (100-200 mesh) columnchromatography using 15% MeOH in dichloromethane to afford the title product as an off-white gum (15 mg, 13.2% yield). LCMS: 360.0 [M+H],Step 2: 3-(3-Chloropyridin-4-yl)-7-methoxy-2,2-dimethylchroman-4-one (Intermediate F25):

[0394] The title compound was prepared by following a similar procedure described in Step 4 of the synthesis of Intermediate F4 (Example 7.2), stalling from 3-(3-chloropyridin-4-yl)-7- methoxy-2,2-dimethyl-2H-chromen-4-yl acetate, Intermediate 64 (60 mg, 0.167 mmol), and aq HC1 (35%, 0.05 mL) and was obtained as a colourless gum (40 mg, crude). LCMS: 318.0 [M+H],Example 7.24: 3-(3-Chloropyridin-4-yl)-7miethoxy-2,2-dimethylchroman-4-one(Intermediate F26)

[0395] Intermediate F26 was prepared according to the Scheme 40:

[0396] To a stirred solution of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate Al (1 g, 5.26 mmol) in THF (30 mL) at -78 °C, lithium diisopropylamide (2M in THF, 2.63 mL, 5.26 mmol) was added and stirred for 30 minutes. Then, ethyl 2-bromoacetate (0.581 mL, 5.26 mmol) was added at -78 °C and stirred at 25 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with aqueous NH4CI (10%, 10 mL) and extracted with EtOAc (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The combined organic extracts were concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography using 10% EtOAc in petroleum ether to afford the title product as a yellowish liquid (500 mg, 34.5% yield). LCMS: 277.4 [M+H],Example 7.25: 6-((l-Fluorocyclopropyl)methyl)-2-methoxy-6,7,8,9-tetrahydro-5FI- benzo[7]annulen-5-one (Intermediate F27)

[0397] Intermediate F27 was prepared according to the Scheme 41:Scheme 41Step 1: 2-Methoxy-8,9-dihydro-7H-benzo[7]annulen-5-yl)oxy-trimethyl-silane (Int-a):

[0398] To a stirred solution of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate Al (800 mg, 4.21 mmol) and diisopropylamine (0.766 mL, 5.47 mmol) in THF (15 mL) at -78 °C, lithium diisopropylamide (2M in THF, 2.73 mL, 5.47 mmol) was added and stirred for 45 min. Then, chlorotrimethylsilane (0.802 mL, 6.31 mmol) was added dropwise and the mixture was stirred at 25 °C for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated under reduced pressure to give the residue. The residue was taken in water (25 mL) and extracted with petroleum ether (10 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4and filtered. The solvent was removed under reduced pressure to afford the title product as colourless gum (1.1 g, crude). The title compound was taken to the next step without further purification. LCMS: 263.1 [M+H].Step 2: 6-((l -Fluorocyclopropyl)(hydroxy )methyl )-2 -methoxy -6, 7, 8, 9-tetrahydro-5H- ben .o 7 ]anniden-5-one ( Int-c ) :

[0399] To a stirred solution of (3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9- yl)oxy)trimethylsilane, Int-a (1.5 g, 5.72 mmol) and 1 -fluorocyclopropane- 1-carbaldehy de, Int-b (which was synthesized as reported in WO 2020 / 146194 Al, 1.510 g, 17.15 mmol) in DCM (20 mL) at -78 °C, titanium (IV) chloride (IM in toluene, 7.43 mL, 7.43 mmol) was added dropwise and stirred at 25 °C for 16 h. After completion of the reaction (as monitored by LCMS),the reaction was quenched with saturated NaHCO3(20 mL) and extracted with DCM (25 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaiSO4, and filtered. The solvents were removed under reduced pressure to afford the crude product. The title compound was purified by RP-HPLC using 10 mM (NH4)HCO3in water:ACN to obtain the title product (0.342 g, 20.4% yield) as a brown solid. LCMS: 279.4 [M+H],Step 3: (E)-6-((l -Fluorocyclopropyl )methylene)-2-methoxy-6, 7, 8, 9-tetrahydro-5H- benz.o

[0007] annulen-5-one ( Int-d ) :

[0400] To a stirred solution of, 6-((l-fluorocyclopropyl)(hydroxy)methyl)-2-methoxy-6, 7,8,9- tetrahydro-5H-benzo[7]annulen-5-one, Int-c (320 mg, 1.150 mmol) in toluene (3 mL) at 25 °C, 4- methylbenzenesulfonic acid (29.7 mg, 0.172 mmol) was added and stirred at 80 °C for 5 h. After completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched with saturated NaHCO3(10 mL) and extracted with EtOAc (5 L x 3). The combined organic extracts were dried over anhydrous Na2SO4and filtered. The solvents were removed under reduced pressure to afford the title product as a yellow solid (290 mg, 95% yield), which was used in the next step without further purification. LCMS: 261.4 [M+HJ.Step 4: 6-((l -Fluorocyclopropyl )methyl)-2-methoxy-6, 7, 8, 9-tetrahydro-5H-benzo

[0007] annulen-5- one (Intermediate F27):

[0401] To a stirred solution of (E)-6-((l-fhiorocyclopropyl)methylene)-2-methoxy-6, 7,8,9- tetrahydro-5H-benzo[7]annulen-5-one (Int-d) (45 mg, 0.173 mmol) in EtOAc (5 mL) at 25 °C, Pd / C (10%, 18.40 mg, 0.017 mmol) was added and stirred under H2(bladder pressure) for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite, washed with EtOAc (5 mL x 2). The filtrate was concentrated under reduced pressure to afford the title product as pale-yellow gum (43 mg, crude), which was used in the next step without further purification. LCMS: 263.3 [M+H].Example 7.26: 2-Methoxy-6-(2-methylcyclohexyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(Intermediate F28)

[0402] Intermediate F28 was prepared according to the Scheme 42:Scheme 42Step 1: 6-(l-Hydroxy-2-methylcyclohexyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- one (Int-f):

[0403] The title compound was prepared by following a similar procedure described for Int-c in Step 2 of Example 7.24, stalling from (3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9- yl)oxy)trimethylsilane, Int-a (1.7 g, 6.48 mmol), 2-methylcyclohexan-l-one, Int-e (0.727 g, 6.48 mmol) and titanium (IV) chloride (IM in toluene, 7.13 ml, 7.13 mmol). The title compound obtained as a colourless gum (0.75 g, 38.3% yield). LCMS: 303.1 [M+H].Step 2: (E)-2-Methoxy-6-(2-methylcyclohexylidene)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- one (Inl-g):

[0404] To a stirred solution of 6-(l-hydroxy-2-methylcyclohexyl)-2-methoxy-6, 7,8,9- tetrahydro-5H-benzo[7]annulen-5-one, Int-f (765 mg, 2.53 mmol) in DCM (2 mL) at 0 °C, trifluoroacetic acid (0.292 mL, 3.79 mmol) was added stirred at 25 °C for 12 h. After completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to yield the residue. The residue was taken in DCM (5 mL), washed with aqueous NaHCO3(10%) (5 mL x 2), dried over anhydrous Na2SO4and filtered. The solvents were removed under reduced pressure to afford the title product as a yellow gum (700 mg, crude). LCMS: 285.2 [M+H],Step 3: 2-Methoxy-6-(2-methylcyclohexyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate F28):

[0405] To a stirred solution of (E)-2-methoxy-6-(2-methylcyclohexylidene)-6, 7,8,9- tetrahydro-5H-benzo[7]annulen-5-one (Int-f) (60 mg, 0.210 mmol) in EtOAc (10 mL) at 25 °C, Pd / C (10%, 30 mg, 0.028 mmol) was added and stirred under th (bladder pressure) for 3 h. After completion of the reaction (as monitored by LCMS), the reaction mixture was filtered throughcelite, and washed with EtOAc (5 mL x 2). The filtrate was concentrated under reduced pressure to afford the title product as pale yellow gum (30 mg, crude), which was used in the next step without further purification. LCMS: 287.1 [M+H].Example 7.27: 6-Cyclohexyl-2-methoxy-6,7,8,9-tetrahydrobenzo[7]annulen-5-one(Intermediate F29)

[0406] Intermediate F29 was prepared according to the Scheme 43:Scheme 43Step 1: 6-(l-Hydroxycyclohexyl)-2-methoxy-6,7,8,9-tetrahydrobenzo[7]annulen-5-one (Int-i):

[0407] The title compound was prepared by following a similar procedure described for Int-c, starting from (3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)oxy)trimethylsilane, Int-a (1.2 g, 4.57 mmol), cyclohexanone, Int-h (0.616 mL, 5.94 mmol) and titanium (IV) chloride (IM in toluene, 5.0 ml, 5.0 mmol). It was obtained as a colorless gum (0.78 g, 59% yield). LCMS: 289.1 [M+H],Step 2: 6-Cyclohexylidene-2-methoxy-8,9-dihydro-7H-benzo[7]anmden-5-one (Int-j):

[0408] To a stirred solution of 6-(l-Hydroxycyclohexyl)-2-methoxy-6, 7,8,9- tetrahydrobenzo[7]annulen-5-one, Int-i (765 mg, 2.65 mmol) in benzene (7.6 mL), p- toluenesulfonic acid monohydrate (50 mg, 0.27 mmol) was added stirred at 80 °C for 15 min. After completion of the reaction (as monitored by LCMS and TLC), the reaction mixture was allowed to cool to room temperature and was quenched with saturated NaHCO3(10 mL) and extracted with EtOAc (5 mL x 3). The combined organic extracts were washed with saturated brine solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography using 15% MTBE in petroleum ether to afford the title product as a clear oil (550 mg, 77% yield). LCMS: 271.1 [M+H],Step 3: 6-Cyclohexyl-2-methoxy-6,7,8,9-tetrahydrobenzo[7]annulen-5-one (Intermediate F29):

[0409] To a stirred solution of 6-cyclohcxylidcnc-2-mcthoxy-8,9-dihydro-7H- benzo[7]annulen-5-one (Int-j) (550 mg, 2.03 mmol) in ethanol (11 mL) at 25 °C, Pd / C (10%, 21 mg, 0.20 mmol) was added and stirred under H2 (balloon pressure) for 3 h. After completion of the reaction (as monitored by LCMS), the reaction mixture was filtered through Celite, and washed with MeOH (5 mL x 2). The filtrate was concentrated under reduced pressure to afford the title product as clear oil (550 mg, 99% yield), which was used in the next step without further purification. LCMS: 273.1 [M+H].Example 8: Triflate intermediates (G)General Procedure ( GP1 )

[0410] Method A: To a stirred solution of an a-Arylated / alkylated Ketone Intermediate, Intermediate F (see Example 7) (1 equiv.) in DCM (10 mL per g Intermediate F) at 0 °C, pyridine (1.5 equiv.) and trifluoromethanesulfonic anhydride (2.0 equiv.) were added and stirred at 25 °C for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with DCM (25 mL x 3). The combined organic extracts were washed with aqueous NaHCO3(10%, 10 mL) and brine (5 mL), dried over NaSO4, and filtered. The solvents were removed under reduced pressure to give the crude product. The crude product was taken as such to the next step or purified by column chromatography (neutral alumina column).

[0411] Method B: To a stirred suspension of a-Arylated / alkylated Ketone Intermediates F (1 equiv.) in THF (10 mF per g of Intermediate F) at -78 °C, NaHMDS (2M, 2.5 equiv.) was added and stirred at the same temperature for an hour. Then a solution of 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (2.3 equiv.) in THF (10 mF per g Intermediate F) was added and stirred at 25 °C for an hour. After the reaction was completed as monitored by TLC, the reaction mixture was quenched with aqueous NH4CI (10%) (5 mL) and extracted with EtOAc (10 mF x 3). The combined organic extracts were washed with aqueous NaHCO3(10%, 10 mF) and brine (5 mF), dried over NaSO4. and filtered. The solvents were removed under reduced pressure to give the crude product.

[0412] Method C: To a stirred suspension of a-Arylated / alkylated ketone Intermediates, Intermediate F (1 cquiv.) and l,l,l-trifluoro-A-(pyridin-2-yl)-A- ((trifluoromethyl)sulfonyl)methanesulfonamide (3 equiv.) in THF (10 mL per g Intermediate F) at -78 °C was added LiHMDS (IM, 1.5 equiv.). The reaction was stirred at the same temperature for three hours. After the reaction was completed as monitored by LCMS or TLC, the reaction mixture was quenched with aqueous NH4CI and extracted with EtOAC (10 mL x 3). The combined organic extracts were washed with aqueous NaHCO3(10 mL) and brine (5 mL), dried over anhydrous Na2SO4, and filtered. The solvents were removed under reduced pressure to give the crude product.

[0413] Method D: To a stirred suspension of a-Arylated / alkylated ketone Intermediates, Intermediate F (1 equiv.) and 1, 1, 1 -trifluoro- A- (pyridin-2-yl)-A- ( (trifhioromethyl)sulfonyl)methanesulfonamide (3 equiv.) in THF (10 mL per g Intermediate F) at -78 °C was added KHMDS (IM, 2.0 equiv.). The reaction was stirred at the same temperature for three hours. After the reaction was completed as monitored by LCMS or TLC, the reaction mixture was quenched with aqueous NH4CI and extracted with EtOAC (10 mL x 3). The combined organic extracts were washed with aqueous NaHCO3(10 mL) and brine (5 mL), dried over anhydrous Na2SO4, and filtered. The solvents were removed under reduced pressure to give the crude product.

[0414] Method E: To a stirred suspension of a-Arylated ketone Intermediates, Intermediate F (1 equiv.) in DMF (10 mL per g Intermediate) was added NaH (60% purity in mineral oil, 3.0 equiv.) at 0 °C. The reaction was stirred at the same temperature for 1 hour. Then 1, 1, 1-trifluoro- N- (pyridin-2-yl)-A- ( (trifluoromethyl)sulfonyl)methanesulfonamide (3 equiv.) was added in reaction mixture at room temperature. The reaction was stirred at the same temperature for 2 hours. After the reaction was completed as monitored by LCMS or TLC, the reaction mixture was quenched with aqueous NH4CI and extracted with EtOAC (10 mL x 3). The combined organic extracts were washed with aqueous NaHCO3(10 mL) and brine (5 mL), dried over anhydrous Na2SO4, and filtered. The solvents were removed under reduced pressure to give the crude product.

[0415] The following triflate intermediates were synthesized using GP1, Method A:

[0416] The following Triflate intermediates were synthesized using GP1, Method B:

[0417] The following Triflate intermediates were synthesized using GP1, Method C:

[0418] The following Triflate intermediates were synthesized using GP1 , Method D:

[0419] The following Triflate intermediates were synthesized using GP1, Method D:Example 8: Compound 1 to Compound 14

[0420] Compounds 1-15 were synthesized according to General Scheme 1:General Scheme 1Step 1: Syntheses of Intermediates H: General procedure 2 (GP2, Suzuki Coupling):

[0421] To a stirred solution of triflate intermediates, “G” (see Example 8) (1.0 equiv.) and bicyclic boronate intermediates, “E” (Example 6) (1.25 equiv.) in 1,4-dioxane: water (9:1) at 25 °C, CS2CO3(3.0 equiv.) was added and purged with N2for 10 minutes. Then PdCb(dppf)- CH2Cl2(0.1 equiv.) was added, and the resulting reaction mixture was stirred at 100 °C in a sealed tube for 12 h. After completion of the reaction as monitored by TLC, the reaction mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to yield the crude product. It was purified by silica gel column chromatography using 10% EtOAc in petroleum ether to afford the title products.

[0422] The following intermediates were synthesized using General Procedure 2.Step 2 (De-methylation): Syntheses of Examples 1 to 14: General procedure 3 (GP3):

[0423] To a stirred solution of a Compound H (1 equiv.) in DCM (10 mL per g Compound H) at 0 °C, trifluoroborane-methyl sulfide (10 to 20 equiv.) was added and stirring continued at 25 °C for 3 h to 12 h. After completion of the reaction as monitored by LCMS, the reaction mixture was cooled to 0 °C, quenched with water, neutralized using saturated aq NaHCO3(pH = 8), and extracted with DCM (5 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, and filtered. The solvents were removed under reduced pressure to afford the crude product. The crude product was purified by preparative HPLC (10 mM NH4HCO3in water:ACN or 10 mM NH4OAC in water:ACN) to afford the title compound as an off-white solid.The following compounds were synthesized by following General procedure 3 (GP3).Example 9: Compound 15 to Compound 19Example 9.1: 8-(3 -Chloropyridin-4-yl)-9-2-((3 -(fluoromethyl)azetidin-l -yl)methyl)imidazo[l ,2- a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (Compound 15)

[0424] Compound 15 was prepared according to the Scheme 44:Scheme 44

[0425] To a stirred solution of methyl 8-(3-chloropyridin-4-yl)-9-(2-((3- (fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridin-7-yl)-6,7-dihydro-5H- benzo[7]annulene-3-carboxylate, Compound H15 (20 mg, 0.038 mmol) in MeOH (2 mL) and water (0.100 mL) at 25 °C, NaOH (2.260 mg, 0.056 mmol) was added and stirred at 50 °C for an hour. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was concentrated under reduced pressure to yield the residue. The residue was taken in water (1 mL), neutralized with aq HC1 (1.5 N) and extracted with EtOAc (2 mL x 2). The combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure to afford the crude product. The crude product was purified by preparative HPLC (0.1% HCOOH in water: ACN) to afford the title compound as an off-white solid (10 mg, 51.4% yield).1H NMR (400 MHz,DMSO-d6) δ = 8.60 (bs, 1 H), 8.41 (d, J = 4.80 Hz, 1 H), 8.25 (d, J = 6.80 Hz, 1 H), 7.97 (d, J = 1 .60Hz, 1H), 7.77 (dd, J = 1.60, 8.00 Hz, 1H), 7.65 (bs, 1H), 7.42 (d, J = 5.20 Hz, 1H), 6.99 (d, J =8.00 Hz, 1H), 6.90 (bs, 1H), 6.29 (dd, J = 1.60, 7.20 Hz, 1H), 4.58 (d, J = 6.40 Hz, 1H), 4.46 (d, J= 6.40 Hz, 1H), 3.58 (bs, 2H), 3.39 (t, J = 7.60 Hz, 2H), 3.09 (t, J = 7.20 Hz, 2H), 2.97 (bs, 2H),2.67-2.68 (m, 1H), 2.20-2.34 (m, 4H); LCMS: 517.2 [M+H],Example 9.2: 7-(8-(3-Chloropyridin-4-yl)-3-(difluoromethyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-2-( ( 3 -(fluoromethyl )azetidin-l -yl )methyl )imidazo[l,2-a Jpyridine ( Compound 16)

[0426] Compound 16 was prepared according to the Scheme 45:Step 1 : ( 8-(3-Chloropyridin-4-yl)-9-(2-( (3 -(fluoromethyl )azetidin-l -yl )methyl )imidazo[l,2- a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanol (Intermediate 65):

[0427] To a solution of methyl 8-(3-chloropyridin-4-yl)-9-(2-((3-(fluoromethyl)azetidin-l- yl)methyl)imidazo[l,2-a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Compound H15 (50 mg, 0.094 mmol) in dry THF (5 mL) at 0 °C, lithium aluminium hydride (2M in THF, 0.059 mL, 0.118 mmol) was added and stirred at 25 °C for 2 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was quenched with aqueous NaOH, 10% and ammonium chloride (2 mL), filtered through celite, and washed with EtOAc (2 mL). Thefiltrate was concentrated under reduced pressure to yield the crude product. It was purified by silica gel (230-400 mesh) column chromatography using 10% McOH in DCM to afford the title product (40 mg, 84.4% yield) as a brown solid. LCMS: 503.2 [M+H].Step 2: 8-(3-Chloropyridin-4-yl)-9-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2- a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde (Intermediate 66):

[0428] To a stirred solution of (8-(3-chloropyridin-4-yl)-9-(2-((3-(fluoromethyl)azetidin-l- yl)methyl)imidazo[l,2-a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanol, Intermediate 65 (40 mg, 0.0795 mmol) in dry DMSO (2 mL) at 0 °C, was added 2-Iodoxybenzoic acid (45% w / w) (49.5 mg, 0.0795 mmol) and the mixture was stirred at 25 °C for 1 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was diluted with EtOAc (5 mL) and quenched with aqueous saturated NaHCO3(5 mL). The organic layer was collected, dried over anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure to obtain the title product as a brown gum (30 mg, crude). LCMS: 501.1 [M+H],Step 3: 7-( 8-( 3-Chloropyridin-4-yl)-3-( difluoromethyl)-6, 7-dihydro-5H-benzo[7]annulen-9-yl)-2- ((3-(fluoromethyl)azetidin-l -yl)methyl)imidazo[ 1 ,2-aJpyridine ( Compound 16):

[0429] To a stirred solution of, 8-(3-chloropyridin-4-yl)-9-(2-((3-(fluoromethyl)azetidin-l- yl)methyl)imidazo[l,2-a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde, Intermediate 66 (30 mg, 0.060 mmol) in dry DCM (5 mL) at 0 °C, diethylaminosulfur trifluoride (DAST) (0.021 mL, 0.160 mmol) was added and stirred at 25 °C for 2 h. After completion of the reaction (as monitored by LCMS), the reaction mixture was quenched with saturated bicarbonate solution (10 mL) and extracted with 5% MeOH in DCM (5 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure to obtain the crude product. The crude compound was purified by RP-HPLC using 10 mM NH4(HCO3) in water: ACN to afford the title product (2.1 mg, 5% yield) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.60 (bs, 1H), 8.41 (d, J = 4.80 Hz, 1H), 8.27 (d, J = 6.80 Hz, 1H), 7.71 (bs, 1H), 7.61 (bs, 1H), 7.42 (d, J = 5.20 Hz, 2H), 6.92- 7.21 (m, 3H), 6.32 (dd, J = 1.60, 6.80 Hz, 1H), 4.58 (d, J = 6.00 Hz, 1H), 4.46 (d, J = 6.00 Hz, 1H), 3.73 (bs, 2H), 3.14-3.19 (m, 4H), 2.99 (t, J = 5.60 Hz, 2H), 2.76-2.80 (m, 1H), 2.21-2.23 (m, 4H); LCMS: 523.2 [M+H],Example 9.3: (8-(3-Chloropyridin-4-yl)-9-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2- a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid ( Compound 17)

[0430] Compound 17 was prepared according to the Scheme 46:Step 1: Synthesis of 8-(3-chloropyridin-4-yl)-9-(2-((3-(fluoromethyl)azetidin-l- yl)methyl)imidazo[l,2-a]pyrielin-7-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethane sulfonate ( Intermediate 67 ):

[0431] To a solution of, 8-(3-chloropyridin-4-yl)-9-(2-((3-(fluoromethyl)azetidin-l- yl)methyl)imidazo[l,2-a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulen-3-ol, Compound 10 (50 mg, 0.102 mmol) in dry DCM (3 mL) 0 °C, pyridine (0.017 mL, 0.205 mmol) and trifluoromethanesulfonic anhydride (0.052 mL, 0.307 mmol) were added and stirred at 25 °C for 15 minutes. After completion of the reaction (as monitored by LCMS), the reaction mixture was quenched with ice water (15 mL) and extracted with DCM (5 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, and filtered. The solvents were removed under reduced pressure to obtain the title product (50 mg, crude) as a brown gum. LCMS: 621.1 [M+H],Step 2: 7-(8-(3-Chloropyridin-4-yl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridine(Intermediate 68):

[0432] To a stirred solution of 8-(3-chloropyridin-4-yl)-9-(2-((3-(fluoromethyl)azetidin-l- yl)methyl)imidazo[l,2-a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate, Intermediate 67 (50 mg, 0.081 mmol) in 1,4-dioxane (3 mL) at 25 °C, bis(pinacolato)diboron (40.9 mg, 0.161 mmol) and potassium acetate (15.80 mg, 0.161 mmol) were added. The resulting mixture was degassed with N2(g) for five minutes. Then, [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (6.57 mg, 8.05 μmol) was added and stirred at 100 °C for 16 h. After completion of the reaction as monitored by LCMS, the reaction mixture was filtered through celite and washed with EtOAc (5 mL x 2). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by RP-HPLC using 10 mM NH4(HCO3) in water:ACN to afford the title product as an off white solid (30 mg, 62.2% yield). LCMS: 599.2 [M+H].Step 3: ( 8-( 3-Chloropyridin-4-yl)-9-( 2-( ( 3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[ 1,2- a]pyridin-7-yl)-6,7 -dih.ydro-5H-benz.ol7 ]annulen-3-yl)boronic acid (Compound 17):

[0433] To a stirred solution of, 7-(8-(3-chloropyridin-4-yl)-3-(4,4,5,5-tetramethyLl,3,2- dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-2-((3-(fluoromethyl)azetidin-l- yl)methyl)imidazo[l ,2-a]pyridine, Intermediate 68 (25 mg, 0.042 mmol) in dry DCM (3 mL) at 0 °C, methylboronic acid (7.50 mg, 0.125 mmol) and trifluoroacetic acid (3 pL, 0.042 mmol) were added and stirred at 25 °C for 16 h. After completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by RP-HPLC using 0.1% TFA in water:ACN afford the title product as an off-white solid (3.3 mg, 15.3% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.60 (s, 1H), 8.38-8.41 (m, 2H), 8.10 (bs, 2H), 7.97 (bs, 1H), 7.81 (bs, 1H), 7.64 (dd, J - 1.20, 7.60 Hz, 1H), 7.42 (d, J = 4.80 Hz, 1H), 6.98-6.99 (m, 1H), 6.82 (d, J = 7.60 Hz, 1H), 6.42 (dd, J = 1.60, 7.00 Hz, 1H), 4.41- 4.60 (m, 4H), 3.95-4.16 (m, 4H), 3.09-3.15 (m, 1H), 2.91-2.95 (m, 2H), 2.18-2.23 (m, 4H); LCMS: 517.2 [M+H],Example 9.4: 9-(2-((3-( Fluoromethyl )azetidin- 1 -yl )methyl)imidazo[ 1 ,2-a ]pyridin-7-yl)-8-( 3 - methylpyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulen-l-ol ( Compound 18)

[0434] Compound 18 was prepared according to the Scheme 47:Step 1: 2-((3-(fluoromethyl)azetidin-l-yl)methyl)-7-(l-methoxy-8-(3-methylpyridin-4-yl)-6,7- dihydro-5H-benzo[7]annulen-9-yl)imidazo[l,2-a]pyridine (Compound H16):

[0435] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 483.2 [M+H],Step 2: 9-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridin-7-yl)-8-(3- methylpyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulen-l -ol ( Compound 18):

[0436] The title compound was synthesized using General procedure 3 (GP3).1H NMR (400 MHz, DMSO-d6) δ = 9.03 (bs, 1H), 8.48 (d, J = 7.20 Hz, 1H), 8.04-8.11 (m, 2H), 7.54 (d, J = 7.20 Hz, 1H), 7.11-7.15 (m, 1H), 6.83 (d, J = 5.20 Hz, 2H), 6.65-6.69 (m, 2H), 6.13 (d, J = 6.40 Hz, 1H), 4.57 (d, J = 6.40 Hz, 1H), 4.45 (d, J = 6.40 Hz, 1H), 3.53 (bs, 2H), 3.25-3.40 (m, 2H), 2.98 (t, J = 6.40 Hz, 2H), 2.71-2.88 (m, 3H), 2.41 (s, 3H), 1.91-2.08 (m, 4H); LCMS: 469.3 [M+H],Example 9.5: 9-(2-((3-(Fluoromelhyl)azetidin-l -yl)melhyl)imidazo[l,2-a]pyridin-7-yl)-8-(o- tolyl)-6,7-dihydro-5H-benz.o[7]annulene-3-carboxylic acid (Compound 19)

[0437] Compound 19 was prepared according to the Scheme 48:Scheme 48Step 1: Methyl 9-(2-aminopyridin-4-yl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulene-3- carboxylate (Intermediate 69):

[0438] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 385.3 [M+H],Step 2: Synthesis of methyl 9-(2-(chloromethyl)imidazo[l,2-a]pyridin-7-yl)-8-(o-tolyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 70):

[0439] A mixture of methyl 9-(2-aminopyridin-4-yl)-8-(o-tolyl)-6,7-dihydro-5H- benzo[7]annulene-3-carboxylate, Intermediate 69 (120 mg, 0.312 mmol) and 1,3-dichloropropan- 2-one (39.6 mg, 0.312 mmol) in acetonitrile (2 mL) was stirred at 80 °C (sealed tube) for 36 h. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated under reduced pressure to yield the crude product. The crude product was purified by RP-HPLC using 10 mM NfLlHCO3) in water: ACN to afford the title product as a brown gum (45 mg, 31.5% yield). LCMS: 457.4 [M+H],Step 3: Methyl 9-(2-(( 3 -(fluoromethyl )azetidin-l -yl )methyl)imidazo[l,2-a ]pyridin-7-yl)-8-( o- tolyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate ( Compound H17):

[0440] To a stirred solution of 3-(fluoromethyl)azetidine hydrochloride, Intermediate DI (21.98 mg, 0.175 mmol) in DCM (3 mL) at 0 °C, DIPEA (0.038 mL, 0.219 mmol) and methyl 9- (2-(chloromethyl)imidazo[l,2-a]pyridin-7-yl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulene-3- carboxylate, Intermediate 70 (40 mg, 0.088 mmol) were added and stirred at 25 °C for 16 h. Aftercompletion of the reaction as monitored by TLC and LCMS, the reaction mixture was quenched with water (5 mL) and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, and filtered. Solvent was removed under reduced pressure to yield the crude product. The crude product was purified by silica gel (230-400 mesh) column chromatography using 10% MeOH in DCM to afford the title compound as an off-white solid (30 mg, 67.3% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.17 (dd, J = 0.80, 7.20 Hz, 1H), 7.98 (d, J = 1.60 Hz, 1H), 7.79 (dd, J = 2.00, 8.00 Hz, 1H), 7.59 (bs, 1H), 7.07-7.18 (m, 4H), 7.01 (d, J = 8.00 Hz, 1H), 6.81 (bs, 1H), 6.23 (dd, J = 1.60, 7.00 Hz, 1H), 4.57 (d, J = 6.40 Hz, 1H), 4.45 (d, J = 6.40 Hz, 1H), 3.87 (s, 3H), 3.57 (s, 2H), 3.29-3.32 (m, 2H), 3.00 (t, J = 6.80 Hz, 2H), 2.67-2.94 (m, 3H), 2.20-2.25 (m, 7H); LCMS: 510.2 [M+H],Step 4: 9-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridin-7-yl)-8-(o-tolyl)-6,7- dihydro-5H-benzo[7 Jannulene-3-carboxylic acid (Compound 19):[04411 The title compound was prepared by following a similar procedure described for Compound 15, starting from methyl 9-(2-((3-(fhioromethyl)azetidin-l-yl)methyl)imidazo[l,2- a]pyridin-7-yl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Compound H17 (20 mg, 0.039 mmol), NaOH (1.73 mg, 0.043 mmol) and was obtained as an off-white solid (10 mg, 51.4% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.16 (d, J = 7.20 Hz, 1H), 7.94 (bs, 1H), 7.76 (d, J = 8.40 Hz, 1H), 7.59 (bs, 1H), 7.07-7.18 (m, 4H), 6.97 (d, J = 8.40 Hz, 1H), 6.80 (bs, 1H), 6.23 (d, J = 7.20 Hz, 1H), 4.57 (d, J = 6.00 Hz, 1H), 4.45 (d, J = 6.00 Hz, 1H), 3.56 (s, 2H), 3.46 (t, J = 8.00 Hz, 2H), 3.17 (t, J = 7.60 Hz, 2H), 2.68-2.93 (m, 3H), 2.21-2.25 (m, 7H); LCMS: 496.2 [M+H],Example 10: Compound 20 to Compound 46

[0442] Compounds 20-46 were synthesized according to General Scheme 2:General Scheme 2Step 1: Ester Intermediates (II):

[0443] Ester intermediates, II, were synthesized using General Procedure 2 (GP2).Step 2: Alcohol Intermediates (12) (Reduction of ester to alcohol, General Procedure 4 (GP4)):

[0444] To a stirred solution of ester intermediates, Intermediate II (1 equiv.) in THF (10 mL per g Intermediate II) at 0 °C, LAH (2M in THF, 2.0 equiv.) was added at 0 °C and stirred at 25 °C for 2 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with water, aqueous NaOH (15%) at 0 °C and stirred at 25 °C for 30 minutes. The reaction mixture was filtered through celite, washed with EtOAc, the filtrate was dried over Na2SO4, and filtered. The solvents were removed under reduced pressure to afford the alcohol intermediate, 12. The alcohol intermediate, 12, was taken to the next step without further purification.Step 3: Aldehyde Intermediates (13) (Oxidation of alcohol to aldehyde. General Procedure 5 (GP5)):

[0445] Method A: To a stirred solution of alcohol intermediates, Intermediate 12 (1.0 equiv.) in DMSO (10 mL per g Intermediate 12) at 0 °C, 2-Iodoxybenzoic acid (IBX) (45% w / w) (1.0 equiv.) was added and stirred at 25 °C for 2 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with aqueous NaHCO3(10%) and brine, dried over Na2SO4, and filtered. The solvents were removed under reduced pressure to yield the crude product. The aldehyde intermediate, 13, was taken to the next step without further purification.

[0446] Method B: To a stirred solution of alcohol intermediates, Intermediate 12 (1 .0 equiv.) in DCM (10 ml per g Intermediate 12) at 0 °C, Dess -Martin pcriodinanc (1.5 equiv.) was added and stirred at 25 °C for 1 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with aqueous NaHCO3, (10%) and brine, dried over Na2SO4, and filtered. The solvents were removed under reduced pressure to yield the crude product. The aldehyde intermediate, 12, was taken to the next step without further purification.Step 4: Methoxy Intermediates (H) (Reductive Amination, General Procedure 6 (GP6)):

[0447] Method A: To a stirred solution of an amine intermediate, Intermediate D (2.0 equiv.) in DCE or DMF (10 mL per g Intermediate D) at 0 °C, Et3N (2.0 equiv.) was added and stirred for 5 minutes. A solution of an aldehyde intermediate, Intermediate 13 (1.0 equiv.) in DMF or DCE (10 mL per g Intermediate D) and acetic acid (4.0 equiv.) was added and stirred at 25 °C for 30 minutes. Then, sodium triacetoxyborohydride (3.0 equiv.) was added at 25 °C and stirred for 2 h. After completion of the reaction as monitored by LCMS, the reaction mixture was quenched with saturated NaHCO ’, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and filtered. The solvents were removed under reduced pressure to afford the crude product. The methoxy compound, H, was taken to the next step without further purification.

[0448] Method B: To a stirred solution of an aldehyde intermediate, Intermediate 13 (1.0 equiv.) and an amine intermediate, Intermediate D (1.10 equiv.) in methanol (10 mL per g Intermediate 13), acetic acid (1 mL per g Intermediate 13) at 0 °C, 2-picoline borane complex (1.10 equiv.) was added and stirred at room temperature for 2 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was quenched with ice-cold water and extracted with DCM. The combine organic extracts were washed with saturated NaHCO3, and brine, dried over anhydrous sodium sulfate, and filtered. The solvents were removed under reduced pressure to afford the crude product. The methoxy compounds were taken to the next step without further purification.

[0449] The following intermediates were synthesized as described in this example.Step 5: Syntheses of Compounds 20 to 46:

[0450] The following compounds were synthesized from methoxy compounds, H, using General Procedure 3 (GP3).Example 11: Compound 47 to Compound 65 and Compound 79Example 11.1: 2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-7-(8-(o-tolyl)-6,7-dihydro-5H- benzo

[0007] annulen-9-yl)imidazo[l ,2-a]pyridine ( Compound 47)

[0451] Compound 47 was prepared according to the Scheme 50:Scheme 50Step 1: Ethyl 7-(8-(o-tolyl)-6,7-dihydro-5H-benzo

[0007] annulen-9-yl)imidazo[l ,2-a]pyridine-2- carboxylate (Intermediate 71):

[0452] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 423.2 [M+H],Step 2: (7-( 8-( o-Tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)imidazo[ 1,2-a ]pyridin-2- yl)methanol (Intermediate 72):

[0453] The title compound was synthesized using General procedure 4 (GP4). LCMS: 381.2 [M+H],Step 3: 7-( 8-(o-Tolyl )-6, 7-dihydro-5H-benzo[7]annulen-9-yl )imidazo[ 1,2-a ]pyridine-2- carbaldehyde (Intermediate 73):

[0454] The title compound was synthesized using General Procedure 5 (GP5) (Method A).LCMS: 379.2 [M+H],Step 4: 2-((3-(Fluoromethyl)azetidin-l -yl)methyl)-7-(8-(o-tolyl)-6,7 -dihydro-5H- benzo

[0007] annulen-9-yl)imidazo[ 1,2-a Jpyridine ( Intermediate 47):

[0455] The title compound was synthesized using General Procedure 6 (GP6) (Method A). H NMR (400 MHz, DMSO-d6) δ = 8.14 (dd, J = 0.80, 7.00 Hz, 1H), 7.57 (bs, 1H), 7.06-7.38 (m,7H), 6.86 (dd, J = 1.20, 7.40 Hz, 1H), 6.78 (s, 1H), 6.22 (dd, J = 1.60, 6.80 Hz, 1H), 4.57 (d, J = 6.40 Hz, 1H), 4.45 (d, J = 6.40 Hz, 1H), 3.54 (s, 2H), 3.28 (t, J = 6.40 Hz, 2H), 2.98 (t, J = 6.80 Hz, 2H), 2.66-2.94 (m, 3H), 2.13-2.25 (m, 7H);19F NMR (377 MHz, DMSO-dd) d = -219.51; LCMS: 452.3 [M+H].Example 11.2: 9-(2-((3-( Fluoromethyl )azetidin-l -yl )methyl)imidazo[l,2-a ]pyridin-7-yl)-8-(4- methoxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Compound 48)

[0456] Compound 48 was prepared according to the Scheme 51 :Scheme 51Step 1: Ethyl 7-(3-( ( tert-biityldimethylsilyl)oxy9-8-(4-methoxy-2-methylphenyl)-6, 7-dihydro-5H- benzo

[0007] annulen-9-yl)imidazo[ 1,2 -a ]pyridine-2 -carboxylate ( Intermediate 74 ):

[0457] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 583.0 [M+H],Step 2: (7-(3-((tert-Butyldimethylsilyl)oxy)-8-(4-methoxy-2-methylphenyl)-6,7-dihydro-5H- benzo[7]annulen-9-yl)imidazo[l,2-a]pyridin-2-yl)methanol (Intermediate 75):

[0458] The title compound was synthesized using General Procedure 4 (GP4). LCMS: 540.8[M],Step 3: 7-(3-((tert-Butyldimethylsilyl)oxy)-8-(4-methoxy-2-methylphenyl)-6,7-dihydro-5H- benzo[7]annulen-9-yl)imidazo[l,2-a]pyridine-2-carbaldehyde (Intermediate 76):

[0459] The title compound was synthesized using General Procedure 5 (GP5) (Method A). LCMS: 539.3 [M+H],Step 4: 7-(3-((tert-Butyldimethylsilyl)oxy)-8-(4-methoxy-2-methylphenyl)-6,7-dihydro-5H- benzo[7]annulen-9-yl)-2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridine ( Compound H45):

[0460] The title compound was synthesized using General Procedure 6 (GP6) (Method A). LCMS: 612.0 [M+H],Step 5: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridin-7-yl)-8-(4-methoxy-2- methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Compound 48):

[0461] To a stirred solution of 7-(3-((tert-butyldimethylsilyl)oxy)-8-(4-methoxy-2- methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-2-((3-(fluoromethyl)azetidin-l- yl)methyl)imidazo[l,2-a]pyridine, Compound H45 (70 mg, 0.069 mmol) in THF (2.5 mL) at 0 °C, TBAF (IM in THF, 0.343 mL, 0.343 mmol) was added and stirred at 25 °C for 4 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was quenched with aqueous sodium bicarbonate solution (10%, 5 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4and filtered. The combined organic layers were concentrated under reduced pressure to obtain the crude product. The crude product was purified by RP-HPLC using 10 mM NH4(HCO3) in H2O:ACN to afford the title compound as an off-white solid (7 mg, 19.5% yield).1H NMR (400 MHz, DMSO- d6) δ = 9.48 (s, 1H), 8.13 (d, J = 7.20 Hz, 1H), 7.56 (s, 1H), 6.98 (d, J = 8.40 Hz, 1H), 6.56-6.76 (m, 6H), 6.21 (dd, J = 1.60, 6.80 Hz, 1H), 4.57 (d, J = 6.00 Hz, 1H), 4.45 (d, J = 6.40 Hz, 1H), 3.68 (s, 3H), 3.55 (s, 2H), 3.29 (t, J - 7.60 Hz, 2H), 3.15-3.19 (m, 1H), 2.98 (t, J - 6.80 Hz, 2H), 2.67-2.82 (m, 2H), 2.07-2.20 (m, 7H);19F NMR (377 MHz, DMSO-d6) δ = -219.48; LCMS: 498.3 [M+H],Example 11.3: 4-Fluoro-9-(2-((3-(fluoromethyl)azetidin-l -yl)methyl)imidazo[l ,2-a]pyridin-7- yl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol ( Compound 49)

[0462] Compound 49 was prepared according to the Scheme 52:Scheme 52Step 1: Ethyl 7-(4-fluoro-3-meth.oxy-8-(o-tolyl)-6,7-dihydro-5H-benzo 7 Jannulen-9- yl)imidazo[l,2-a]pyridine-2-carboxylate (Intermediate 77):

[0463] The title compound was synthesized using General Procedure (GP2). LCMS: 471.2[M+H],Step 2: (7-(4-Fluoro-3-methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)imidazo[l,2- a]pyridin-2-yl)methanol (Intermediate 78):

[0464] The title compound was synthesized using General Procedure (GP4). LCMS: 429.2 [M+H],Step 3: 7-(4-Fluoro-3-melhoxy-8-(o-lolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)imidazo[l,2- a]pyridine-2-carbaldeh.yde (Intermediate 79):

[0465] The title compound was synthesized using General Procedure 5 (GP5) (Method A).LCMS: 426.9 [M+H],Step 4: 7-(4-Fluoro-3-methoxy-8-( o-tolyl )-6, 7-dihydro-5H-benzo[7]annulen-9-yl)-2-( ( 3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridine ( Compound H46):

[0466] The title compound was synthesized using General Procedure (GP6) (Method A).1H NMR (400 MHz, DMSO-d6) δ = 8.14 (dd, J = 0.80, 7.20 Hz, 1H), 7.57 (s, 1H), 6.95-7.17 (m, 5H),6.79 (d, J = 0.80 Hz, 1H), 6.65 (dd, J = 0.80, 8.60 Hz, 1H), 6.24 (dd, J = 1.60, 7.20 Hz, 1H), 4.57 (d, J = 6.40 Hz, 1H), 4.45 (d, J = 6.40 Hz, 1H), 3.84 (s, 3H), 3.54 (s, 2H), 3.28 (t, J = 6.40 Hz, 2H), 2.98 (t, J = 6.80 Hz, 2H), 2.66-2.95 (m, 3H), 2.12-2.50 (m, 7H);19F NMR (377 MHz, DMSO-d6) δ = -219.48, -142.287; LCMS: 500.5 [M+H].Step 5: 4-Fluoro-9-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridin-7-yl)-8-(o- tolyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Compound 49):

[0467] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, DMSO-d6) δ = 9.89 (s, 1H), 8.13 (dd, J = 0.80, 6.80 Hz, 1H), 7.56 (s, 1H), 7.05-7.14 (m, 4H), 6.73-6.78 (m, 2H), 6.50 (d, J = 8.40 Hz, 1H), 6.24 (dd, J = 2.00, 7.00 Hz, 1H), 4.57 (d, J = 6.40 Hz, 1H), 4.45 (d, J = 6.40 Hz, 1H), 3.54 (s, 2H), 3.28 (t, J = 7.60 Hz, 2H), 2.98 (t, J = 6.80 Hz, 2H), 2.67-2.91 (m, 3H), 2.09-2.24 (m, 7H); LCMS: 486.3 [M+H],Example 11.4: 9-(2-( (3-( Fluoromethyl )azetidin-l -yl )methyl)-lH-benzo[d ]imidazol-5-yl)-8-( o- tolyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Compound 50)

[0468] Compound 50 was prepared according to the Scheme 53:Scheme 53Step 1: Di-tert-butyl (4-(3miethoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l,2- phenylene)dicarbamate (Intermediate 80):

[0469] The title compound was synthesized using General Procedure (GP2). LCMS: 593.3 [M+Na].Step 2: 4-(3-Methoxy-8-(o-tolyl)-6f7-dihydro-5H-benzo[7]annulen-9-yl)benzene-l ,2 -diamine (Intermediate 81):

[0470] To a stirred solution of di-tert-butyl (4-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H- benzo[7]annulen-9-yl)-l,2-phenylene)dicarbamate, Intermediate 80 (0.49 g, 0.859 mmol) in DCM (10 mL) at 0 °C, TFA (1.321 mL, 17.26 mmol) was added and stirred at 25 °C for 12 h. After completion of the reaction as monitored by LCMS, the reaction mixture was quenched with saturated NaHCO3(50 mL) and extracted with 10% MeOH in DCM (50 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na SO4filtered and the solvents were concentrated under reduced pressure to obtain the title product as brown gum (0.36 g, 88% yield). LCMS: 371.2 [M+H],Step 3: 5-(3-Methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]anmden-9-yl)-2-(trichloromethyl)-lH- benzo[d] imidazole (Intermediate 82):

[0471] A mixture of 4-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9- yl)benzene-l,2-diamine, Intermediate 81 (0.36 g, 0.972 mmol) and methyl 2,2,2- trichloroacetimidate (0.241 mL, 1.943 mmol) in AcOH (10 mL) was stirred at 25 °C for 1 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with ice water (50 mL) and stirred at 25 °C for 30 minutes. The solid thus obtained was filtered and purified by silica gel (230-400 mesh) column chromatography using 10% EtOAc in petroleum ether to afford the title compound as yellow gummy solid (0.5 g, 81 % yield). LCMS: 497.1 [M+H],Step 4: Synthesis of ethyl 5-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-lH- benzo[d]imidazole-2-carboxylate (Intermediate 83):

[0472] To a stirred solution of 5-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9- yl)-2-(trichloromethyl)-lH-benzo[d]imidazole, Intermediate 82 (0.4 g, 0.803 mmol) in EtOH (10 mL) at 25 °C, NaaCO3(0.128 g, 1.205 mmol) was added and stirred at 80 °C for 1 h. After completion of the reaction as monitored by LCMS, the reaction mixture was evaporated under reduced pressure to yield the residue. The residue was quenched with ice water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel (230-400) column chromatography using30% EtOAc in petroleum ether to afford the title compound as a yellow solid (0.09 g, 20.3% yield).LCMS: 453.2 [M+H],Step 5: (5-(3-Methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-lH-benzo[d]imidazol- 2-yl)methanol (Intermediate 84):

[0473] The title compound was synthesized using General Procedure 4 (GP4). LCMS: 411.2 [M+H],Step 6: 5-(3-Methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-lH-benzo[d]imidazole- 2-carbaldehyde (Intermediate 85):

[0474] The title compound was synthesized using General Procedure 5 (GP5) (Method A). LCMS: 409.2 [M+H],Step 7: 2-((3-(Fluoromethyl)azetidin-l -yl)methyl)-5-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H- benzo[7]annulen-9-yl)-lH-benzo[d]imidazole (Compound H47):

[0475] The title compound was synthesized using General Procedure 6 (GP6) (Method A). LCMS: 482.3 [M+H],Step 8: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-benzo[d]imidazol-5-yl)-8-(o-tolyl)-6,7- dihydro-5H-benzo[7]annulen-3-ol (Compound 50):

[0476] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, DMSO-d6) δ = 11.93 (bs, 1H), 9.37 (bs, 1H), 6.59-7.22 (m, 10H), 4.59 (d, J = 6.40 Hz, 1H), 4.47 (d, J = 6.00 Hz, 1H), 3.67 (bs, 2H), 3.33 (t, J = 7.20 Hz, 2H), 3.03 (t, J = 6.80 Hz, 2H), 2.68- 2.83 (m, 3H), 2.09-2.22 (m, 7H); LCMS: 468.4 [M+H],Example 11.5: 9-(6-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indazol-3-yl)-8-(o-tolyl)-6,7- dihydro-5H-benzo[7]annulen-3-ol (Compound 51)

[0477] Compound 51 was prepared according to the Scheme 54:Scheme 54Step 1: Methyl 3-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]anniden-9-yl)-l-(tetrahydro- 2H-pyran-2-yl)-l H-indazole-6-carboxylate (Intermediate 86):

[0478] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 523.2 [M+H],Step 2: (3-(3-Methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-(tetrahydro-2H- pyran-2-yl)-lH-indazol-6-yl)methanol (Intermediate 87):

[0479] The title compound was synthesized using General Procedure 4 (GP4). LCMS: 495.4 [M+H],Step 3: 3-(3-Methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-(tetrahydro-2H- pyran-2-yl )-lH-indazole-6-carbaldehyde (Intermediate 88 ):

[0480] The title compound was synthesized using General Procedure 5 (GP5) (Method A). LCMS: 493.3 [M+H],Step 4: 6-((3-(Fluoromethyl)azetidin-l-yl)methyl)-3-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H- benzo[7]annulen-9-yl)- 1 -(tetrahydro-2H-pyran-2-yl)- ] H-indazole (Compound H48):

[0481] The title compound was synthesized using General Procedure 6 (GP6) (Method A). LCMS: 566.3 [M+H],Step 5: 6-( (3-(Fluoromethyl)azetidin-l -yl)methyl)-3-(3-methoxy-8-( o-tolyl)-6, 7 -dihydro- 5FI- benzo[7]annulen-9-yl)-lH-indazole (Compound J89):

[0482] To a stirred solution of 6-((3-(fhioromethyl)azetidin-Lyl)methyl)-3-(3-methoxy-8-(o- tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole,Compound H48 (50 mg, 0.053 mmol) in 1,4-dioxane (2 mL) at 0 °C, HC1 in dioxane, (4 M, 0.250 mL) was added and stirred at 25 °C for 16 h. After completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by RP-HPLC using 10 mM [ NH4]HCO3in water:ACN to afford the title product as an off-white solid (14 mg, 54.8% yield).1H NMR (400 MHz, DMSO-d6) δ = 12.60 (s, 1H), 6.76-7.18 (m, 10H), 4.57 (d, J = 6.00 Hz, 1H), 4.45 (d, J = 6.00 Hz, 1H), 3.77 (s, 3H), 3.55 (s, 2H), 3.24 (t, J = 7.20 Hz, 2H), 2.74-3.02 (m, 5H), 2.19-2.23 (m, 7H);19F NMR (377 MHz, DMSO-d6) δ = -219.70; LCMS: 482.2 [M+H],Step 6: Synthesis of9-(6-((3-(fluorometh.yl)azetidin-l-yl)methyl)-lH-indazol-3-yl)-8-(o-tolyl)-6,7- dihydro-5H-benzo[7]annulen-3-ol (Compound 51):

[0483] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, CD3OD) 3 = 7.33 (s, 1H), 6.81-7.10 (m, 7H), 6.61 (d, J = 8.40 Hz, 1H), 6.54 (dd, J = 2.80, 8.40 Hz, 1H), 4.56 (d, J = 4.80 Hz, 1H), 4.44 (d, J = 5.20 Hz, 1H), 3.86 (s, 2H), 3.60-3.64 (m, 2H), 3.37-3.40 (m, 2H), 2.91-3.04 (m, 3H), 2.39-2.47 (m, 2H), 2.18-2.30 (m, 5H);19F NMR (377 MHz, CD3OD) 3 = -227.05; LCMS: 468.2 [M+H],Example 11.6: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-8-(o-tolyl)-6,7- dihydro-5H-benzo[7]annulen-3-ol (Compound 52)

[0484] Compound 52 was prepared according to the Scheme 55:Scheme 55Step 1: 1 -(tert-Butyl) 2-ethyl 5-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)- IH-indole- 1 ,2-dicarboxylate (Intermediate 90):

[0485] The title compound was synthesized using General Procedure (GP2).1H NMR (400 MHz, DMSO-d6) δ = 7.63 (d, J = 8.80 Hz, 1H), 7.00-7.12 (m, 6H), 6.91-6.95 (m, 2H), 6.65-6.74 (m, 2H), 4.28 (q, J = 7.20 Hz, 2H), 3.78 (s, 3H), 2.84-2.91 (m, 2H), 2.14-2.25 (m, 7H), 1.53 (s, 9H), 1.28 (t, J = 7.20 Hz, 3H); LCMS: 496.1 [M+-(t-Butyl)].Step 2: Ethyl 5-(3-methoxy-8-(o-tolyl)-6,7 -dihydro-SH -benzo [7]annulen-9-yl)-l H-indole-2- carboxylate (Intermediate 91):

[0486] To a stirred solution of 1 -(tert-butyl) 2-ethyl 5-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H- benzo[7]annulen-9-yl)-lH-indole-l,2-dicarboxylate, Intermediate 90 (130 mg, 0.212 mmol) in 1,4-Dioxane (2 mL) at 0 °C, HC1 in dioxane (4M, 0.65 mL) was added and stirred at 60 °C for 12 h. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched with aqueous NaHCO3(10%, 10 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL) solution, dried over Na2SO4. filtered and evaporated under reduced pressure to afford the title compound as yellow solid (100 mg, crude). The title compound was taken to the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ = 11.70 (s, 1H), 6.99-7.10 (m, 6H), 6.91-6.93 (m, 2H), 6.68-6.73 (m, 3H), 4.03 (q, J = 7.20 Hz, 2H), 3.78 (s, 3H), 2.82-2.92 (m, 2H), 2.11-2.22 (m, 7H), 1.18 (t, J = 6.80 Hz, 3H); LCMS: 452.2 [M+H],Step 3: (5-(3-Methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-lH-indol-2- yl)methanol (Intermediate 92):

[0487] The title compound was synthesized using General Procedure 4 (GP4). LCMS: 410.1 [M+H],Step 4: 5-(3-Methoxy-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-lH-indole-2- carbaldehyde (Intermediate 93):

[0488] The title compound was synthesized using General Procedure 5 (GP5) (Method A).1H NMR (400 MHz, DMSO-d6) δ = 11.82 (s, 1H), 9.74 (s, 1H), 7.00-7.17 (m, 7H), 6.71-6.94 (m, 4H), 3.78 (s, 3H), 2.82-2.92 (m, 2H), 2.11-2.22 (m, 7H); LCMS: 408.1 [M+H],Step 5: 2-( (3-(Fluoromethyl)azetidin-l-yi)methyl)-5-(3-methoxy-8-( o-tolyl)-6, 7-dihydro-5H- benzo[7]annulen-9-yl)-lH-indole (Compound H49):

[0489] The title compound was synthesized using General Procedure 6 (GP6) (Method A). H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 6.86-7.05 (m, 7H), 6.66-6.71 (m, 2H), 6.50 (d, J = 1.60 Hz, 1H), 5.99 (s, 1H), 4.57 (d, J = 6.40 Hz, 1H), 4.45 (d, J = 6.00 Hz, 1H), 3.77 (s, 3H), 3.56 (s, 2H), 3.26 (t, J = 7.20 Hz, 2H), 2.95 (t, J = 6.80 Hz, 2H), 2.72-2.88 (m, 3H), 2.09-2.18 (m, 7H); LCMS: 481.2 [M+H],Step 6: 9-(2-((3-(Fluoromethyl)azetidin-l -yl)methyl)-l H-indol-5-yl)-8-(o-tolyl)-6,7-dihydro-5H - benzo[7]annulen-3-ol (Compound 52):

[0490] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, DMSO-d6) δ = 10.77 (s, 1H), 9.32 (s, 1H), 6.86-7.05 (m, 6H), 6.71 (d, J = 2.40 Hz, 1H), 6.47-6.57 (m, 3H), 5.99 (d, J = 1.20 Hz, 1H), 4.57 (d, J = 6.40 Hz, 1H), 4.45 (d, J = 6.40 Hz, 1H), 3.56 (s, 2H), 3.26 (t, J = 6.40 Hz, 2H), 2.95 (t, J= 6.80 Hz, 2H), 2.67-2.80 (m, 3H), 2.09-2.18 (m, 7H);19F NMR (377 MHz, DMSO-d6) δ = -219.78; LCMS: 467.2 [M+H],Example 11.7: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-8-(pyridin-3-yl)-6,7- dihydro-5H-benzo[7]annulen-3-ol (Compound 53)

[0491] Compound 53 was prepared according to the Scheme 56:Scheme 56Step 1: 3-Methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate (Intermediate 94):

[0492] To a stirred solution of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, Intermediate Al (1 g, 5.26 mmol) in THF (20 mL) at -78 °C, LiHMDS (IM in THF, 7.88 mL, 7.88 mmol) was added and stirred for 2 h. Then a solution of 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (2.82 g, 7.88 mmol) in THF (10 mL) was addeddropwise at -78 °C and the resulting reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with saturated NH4CI (50 mL), the insoluble materials were filtered through celite and washed with EtOAc (300 mL). The filtrate was washed with water (50 mL) and brine (25 mL), dried over anhydrous NaoSO i. and filtered. The combined organic extracts were concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel (100-200) column chromatography using 6% EtOAc in petroleum ether to afford the title compound as a colourless liquid (0.711 g, 39.4% yield). LCMS: 191.1 [M+-(Tf)].Step 2: Ethyl 5-( 3-methoxy-6, 7-dihydro-5H-benzo[7]anmden-9-yl)-lH-indole-2-carboxylate (Intermediate 95):

[0493] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 362.2 [M+H],Step 3: Ethyl 5-(3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylate (Intermediate 96):

[0494] To a stirred solution of ethyl 5-(3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)- lH-indole-2-carboxylate, Intermediate 95 (1.095 g, 3.03 mmol) in THE (20 mL) at 0 °C, NaH (0.182 g, 4.54 mmol) was added and stirred for 15 minutes. Then a solution of 2- (chloromethoxy)ethyltrimethylsilane (0.758 g, 4.54 mmol) in THF (10 mL) was added at 0 °C and stirred at 25 °C for 4 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with ice water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4and filtered. The combined organic extracts were concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel (100-200) column chromatography using 3% EtOAc in petroleum ether to afford the title compound as a yellow solid (0.79, 39.2% yield). LCMS: 374.2 [M+-(SEM)].Step 4: Ethyl 5-( 8-bromo-3-methoxy-6, 7-dihydro-5H-benzo[7]annulen-9-yl )-l-((2-( trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylate (Intermediate 97):

[0495] The title compound was prepared by following a similar procedure described for Intermediate 34, starting from ethyl 5-(3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylate, Intermediate 96 (0.78 g, 1.586 mmol) and pyridinium tribromidc (0.462 g, 1.444 mmol). The title compound was obtained as a pale yellow solid (0.71 g, crude) and was taken to the next step without further purification. LCMS: 452.0 [M+-(SEM)].Step 5: Ethyl 5-(3-methoxy-8-(pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylate (Intermediate 98):

[0496] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 569.3 [M+H],Step 6: (5-(3-Methoxy-8-(pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2-( trimethylsilyl)ethoxy )methyl)-lH-indol-2 -yl )methanol ( Intermediate 99 ) :

[0497] The title compound was synthesized using General Procedure 4 (GP4). LCMS: 527.4 [M+H],Step 7: 5-(3-Melhoxy-8-(pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2-( trimethylsilyl )ethoxy )methyl)-lH-indole-2 -carbaldehyde ( Intermediate 100):

[0498] The title compound was synthesized using Genral Procedure 5 (GP5) (Method B). LCMS: 525.3 [M+H],Step 8: 2-(( 3 -(fluoromethyl )azetidin-l -yl )methyl)-5-( 3-methoxy-8-(pyridin-3-yl)-6, 7-dihydro-5H- benzo[7]annulen-9-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole (Compound H50):

[0499] The title compound was synthesized using General Procedure 6 (GP6) (Method A). LCMS: 598.4 [M+H],Step 9: 2-((3-(fluoromethyl)azetidin-l-yl)methyl)-5-(3-methoxy-8-(pyridin-3-yl)-6,7-dihydro-5H- benzo[7]annulen-9-yl)-lH-indole (Compound J 101):

[0500] To a stirred solution of 2-((3-(fhroromethyl)azetidin-l-yl)methyl)-5-(3-methoxy-8- (pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indole, Compound H50 (0.11 g, 0.184 mmol) in THF (5 mL) at 25 °C, TBAF (IM in THF, 1.104 ml, 1.104 mmol) was added and heated to 70 °C for 16 h. After completion of the reaction as monitored by LCMS, the reaction mixture was quenched with aqueous NaHCO3(10%, 5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL),dried over anhydrous Na2SO4and filtered. The combined organic extracts were concentrated under reduced pressure to obtain crude product. The crude product was purified by RP-HPLC using lOmM NH4HCO3in water:ACN to afford the title compound as an off-white solid (3 mg, 3.5% yield).1H NMR (400 MHz, CD3OD) 3 = 8.23 (s, 1H), 8.15 (d, J = 3.60 Hz, 1H), 7.70-7.73 (m, 1H), 7.23-7.26 (m, 1H), 7.09 (d, J = 8.40 Hz, 1H), 7.02-7.03 (m, 1H), 6.89 (d, J = 2.80 Hz, 1H), 6.64-6.79 (m, 3H), 6.18 (s, 1H), 4.56 (d, J = 5.60 Hz, 1H), 4.44 (d, J = 5.20 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 2H), 3.49-3.53 (m, 2H), 3.24 (t, J - 7.60 Hz, 2H), 2.86-2.90 (m, 3H), 2.45 (t, J - 7.20 Hz, 2H), 2.21 (t, J = 7.20 Hz, 2H);19F NMR (377 MHz, CD3OD) 3 = -225.66; LCMS: 468.5 [M+H],Step 10: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-8-(pyridin-3-yl)-6,7- dihydro-5H-benzo[7]annulen-3-ol (Compound 53):

[0501] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, DMSO-d6) δ = 10.88 (s, 1H), 9.42 (s, 1H), 8.19-8.23 (m, 2H), 7.58 (d, J = 7.60 Hz, 1H), 7.16-7.19 (m, 1H), 7.01 (d, J = 8.40 Hz, 1H), 6.93 (s, 1H), 6.72 (d, J = 2.00 Hz, 1H), 6.51-6.58 (m, 3H), 6.05 (s, 1H), 4.57 (d, J = 6.00 Hz, 1H), 4.46 (d, J = 6.40 Hz, 1H), 3.58 (s, 2H), 3.26-3.28 (m, 2H), 2.96 (t, J = 6.40 Hz, 2H), 2.68-2.75 (m, 3H), 2.29-2.33 (m, 2H), 2.08 (t, J = 6.80 Hz, 2H);19F NMR (377 MHz, DMSO-d6) δ = -219.77; LCMS: 454.2 [M+H],Example 11.8: 9-(2-((3-(Fluoromethyl)azetidin-l -yl)methyl)-lll-indol-5-yl)-8-(pyrimidin-5-yl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Compound 54)

[0502] Compound 54 was prepared according to the Scheme 57:Scheme 57Step 1: Ethyl 5-(3-methoxy-8-(pyrimidin-5-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2- ( trimethylsilyl )ethoxy )methyl )-lH-indole-2 -carboxylate ( Intermediate 102):

[0503] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 570.3 [M+H],Step 2: (5-(3-Methoxy-8-(pyrimidin-5-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-2-yl)methanol (Intermediate 103 ):

[0504] The title compound was synthesized using General Procedure 4 (GP4).1H NMR (400 MHz, DMSO-d6) δ = 8.82 (s, 1H), 8.53 (s, 1H), 7.33 (d, J = 8.40 Hz, 1H), 7.04 (d, J = 1.20 Hz, 1H), 6.94 (d, J = 2.40 Hz, 1H), 6.67-6.71 (m, 3H), 6.27 (s, 1H), 5.51 (s, 2H), 5.24 (t, J = 5.60 Hz, 1H), 4.61 (d, J = 5.60 Hz, 2H), 3.78 (s, 3H), 3.45 (t, J = 8.00 Hz, 2H), 2.82-2.83 (m, 2H), 2.34- 2.35 (m, 2H), 2.15-2.17 (m, 2H), 0.79 (t, J = 7.60 Hz, 2H), -0.11 (s, 9H); LCMS: 528.0 [M+H],Step 3: 5-(3-Methoxy-8-(pyrimidin-5-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2-( trimethylsilyl )ethoxy )methyl)-l H-indole-2 -carbaldehyde ( Intermediate 104):

[0505] The title compound was synthesized using General Procedure 5 (GP5) (Method B). LCMS: 525.9 [M+H],Step 4: 2-((3-( Fluoromethyl )azetidin-l -yl )methyl)-5-( 3-methoxy-8-(pyrimidin-5-yl)-6, 7-dihydro- 5H-benzo[7]annulen-9-yl)-l-((2-( trimethylsilyl)ethoxy)methyl)-lH-indole ( Compound H51 ):

[0506] The title compound was synthesized using General Procedure 6 (GP6) (Method A). LCMS: 599.0 [M+H],Step 5: 2-((3-(Fluoromethyl)azetidin-l -yl)methyl)-5-(3-methoxy-8-(pyrimidin-5-yl)-6,7-dihydro- 5H-benzo[7]annulen-9-yl)-lH-indole (Intermediate 105):

[0507] To a stirred solution of 2-((3-(fluoromethyl)azetidin-l-yl)methyl)-5-(3-methoxy-8- (pyrimidin-5-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)- IH-indole, Compound H51 (38 mg, 0.064 mmol) in THF (5 mL) at 25 °C, TBAF (IM in THF, 635 pl, 0.635 mmol) was added and heated to 70 °C for 16 h. After completion of the reaction as monitored by LCMS, the reaction mixture was quenched with aqueous NaHCO3(10%, 5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL),dried over anhydrous Na2SO4and filtered. The organic extracts were concentrated under reduced pressure to obtain crude product. The crude product was purified by RP-HPLC using 0.1% TFA in water:ACN to afford the title compound as an off-white solid (3 mg, 10.1% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.95 (s, 1H), 8.82 (s, 1H), 8.52 (bs, 2H), 7.07 (d, J = 8.40 Hz, 1H), 6.93-6.97 (m, 2H), 6.68-6.74 (m, 2H), 6.56 (dd, J = 1.60, 8.20 Hz, 1H), 6.08 (s, 1H), 4.58 (d, J = 6.40 Hz, 1H), 4.46 (d, J = 6.00 Hz, 1H), 3.78 (s, 3H), 3.60 (s, 2H), 3.29 (t, J = 7.20 Hz, 2H), 2.97 (t, J - 6.80 Hz, 2H), 2.67-2.83 (m, 3H), 2.33-2.36 (m, 2H), 2.08-2.16 (m, 2H);19F NMR (377 MHz, DMSO-d6) δ = -219.79; LCMS: 469.5 [M+H],Step 6: 9-(2-( (3-( Fluoromethyl )azeticlin-l -yl )methyl)-lH-indol-5-yl)-8-(pyrimidin-5-yl)-6, 7- dihydro-5H-benzo[7]annulen-3-ol (Compound 54):

[0508] The title compound is synthesized using General Procedure 3 (GP3).Example 11.9: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-8-(lH-pyrazol-4-yl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Compound 55)

[0509] Compound 55 was prepared according to the Scheme 58:Scheme 58Step 1: Ethyl 5-(3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2-( trimethylsilyl)ethoxy )methyl)-lH-indole-2 -carboxylate ( Intermediate 106):

[0510] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 492.2 [M+H],Step 2: Ethyl 5-(8-bromo-3-methoxy-6,7-dihydro-5FI-benzo[7]annulen-9-yl)-l -((2-( trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylate (Intermediate 107):

[0511] The title compound was prepared by following a similar procedure described for Intermediate 34, starting from ethyl 5-(3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylate, Intermediate 106 (0.900 g, 1.830 mmol) and pyridinium tribromide (0.527 g, 1.647 mmol). It was obtained as a pale yellow solid (0.90 g, crude) and was taken to the next step without further purification. LCMS: 453.8 [M+-(SEM)].Step 3: Ethyl 5-(3-methoxy-8-(lH-pyrazol-4-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2- ( trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylate (Intermediate 108):

[0512] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 558.2 [M+H],Step 4: (5-(3-Methoxy-8-(lH-pyrazol-4-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indol-2-yl)methanol (Intermediate 109):

[0513] The title compound was synthesized using General Procedure 4 (GP4). LCMS: 516.4 [M+HJ.Step 5: 5-(3-Methoxy-8-(lH-pyrazol-4-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)- 1 H-indole-2-carbaldehyde (Intermediate 110):

[0514] The title compound was synthesized using General Procedure 5 (GP5) (Method A). LCMS: 514.3 [M+H],Step 6: 2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-5-(3-methoxy-8-(lEl-pyrazol-4-yl)-6,7- dihydro-5H-benzo

[0007] annulen-9-yl)-l -((2-( trimethylsilyl)ethoxy )methyl)-lH -indole ( Compound H52):

[0515] The title compound was synthesized using General Procedure 6 (GP6) (Method A). LCMS: 487.3 [M+H],Step 7: 2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-5-(3-methoxy-8-(lH-pyrazol-4-yl)-6,7- dihydro-5H-benzo[7]annulen-9-yl)-lH-indole ( Compound Jill):

[0516] To a stirred solution of 2-((3-(fluoromethyl)azetidin-l-yl)methyl)-5-(3-methoxy-8- (lH-pyrazol-4-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-IH-indole, Compound H52 (35 mg, 0.058 mmol) in THF (5 mL) at 25 °C, TBAF (IM in THF, 584 pl, 0.584 mmol) was added and heated to 70 °C for 16 h. After completion of the reaction as monitored by LCMS, the reaction mixture was quenched with aqueous NaHCO3(10%, 5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO4and filtered. The organic extracts were concentrated under reduced pressure to obtain crude product. The crude product was purified by RP-HPLC using 10 mM (NH4)HCO3in water:ACN to afford the title compound as an off-white solid (3.9 mg, 14.6% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.97 (s, 1H), 7.54 (s, 1H), 6.70-7.19 (m, 6H), 6.47 (dd, J = 1.20, 8.40 Hz, 1H), 6.04-6.12 (m, 2H), 4.59 (d, J = 6.00 Hz, 1H), 4.47 (d, J = 6.00 Hz, 1H), 3.79 (s, 3H), 3.67 (s, 2H), 3.05 (s, 2H), 2.67-2.86 (m, 3H), 2.17-2.22 (m, 2H); LCMS: 457.1 [M+H],Step 8: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-8-(lH-pyrazol-4-yl)-6,7- dihydro-5H-benzo[7]annulen-3-ol (Compound 55):

[0517] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, CD3OD) 3 = 7.27 (d, J = 8.40 Hz, 1H), 7.21 (d, J = 0.80 Hz, 1H), 7.06 (bs, 2H), 6.84 (dd, J = 1.60, 8.40 Hz, 1H), 6.67-6.70 (m, 2H), 6.52 (dd, J = 2.80, 8.40 Hz, 1H), 6.31 (s, 1H), 4.58 (d, J = 5.20 Hz, 1H), 4.46 (d, J = 5.60 Hz, 1H), 3.88 (s, 2H), 3.62 (t, J = 8.00 Hz, 2H), 3.33-3.36 (m, 2H), 2.70-2.94 (m, 3H), 2.40-2.44 (m, 2H), 2.20-2.25 (m, 2H); LCMS: 443.2 [M+H],Example 11.10: 9-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-8-(o-tolyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid (Compound 56)

[0518] Compound 56 was prepared according to the Scheme 59:Scheme 59Step 1: tert-Butyl 2-((3-(fluoromethyl)azetidin-l -yl)methyl)-5-(3-(methoxycarbonyl)-6, 7-dihydro- 5H-benzo[7]annulen-9-yl)-lH-indole-l-carboxylate (Intermediate 112 ):

[0519] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 519.2 [M+H],Step 2: tert-Butyl 5-( 8-bromo-3-( methoxycarbonyl)-6, 7-dihydro-5H-benzo[7]annulen-9-yl)-2-( ( 3- (fluoromethyl)azetidin-l -yl)methyl)-l H-indole-1 -carboxylate (Intermediate 113 ):

[0520] The title compound was prepared by following a similar procedure described for Intermediate 34, starting from tert-butyl 2-((3-(fluoromethyl)azetidin-l-yl)methyl)-5-(3- (methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-lH-indole-l-carboxylate, Intermediate 112 (250 mg, 0.313 mmol) and pyridinium tribromide (100 mg, 0.313 mmol). The title compound was obtained as a pale yellow solid (250 mg, Crude) and was taken to the next step without further purification. LCMS: 597.2 [M+H].Step 3: tert-Butyl 2-((3-(fluoromethyl)az.etidin-l -yl)methyl)-5-(3-(methoxycarbonyl)-8-(o-tolyl)- 6,7-dihydro-5H-benzo[7]annulen-9-yl)-lH-indole-l -carboxylate (Compound H53):

[0521] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 609.2 [M+H],Step 4: Methyl 9-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-8-(o-tolyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 114):

[0522] To a stirred solution of tert-butyl 2-((3-(fhioromethyl)azetidin-l-yl)methyl)-5-(3- (methoxycarbonyl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-lH-indole-l-carboxylate, Compound H53 (100 mg, 0.103 mmol) in 1,4-dioxane (3 mL) at 0 °C, HC1 (g) in dioxane, (4 M, 0.500 mL) was added and stirred at 60 °C for 12 h. After completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by RP-HPLC using 10 mM NH4HCO3in water:ACN to afford the title product (10 mg, 19% yield). LCMS: 509.4 [M+H].Step 5: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-8-(o-tolyl)-6,7-dihydro-5H- benzo[7]annulene-3 -carboxylic acid (Compound 56):

[0523] To a stirred solution of methyl 9-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)-lH-indol- 5-yl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Intermediate 114 (10 mg, 0.020 mmol) in MeOH (4 mL) at 25 °C, NaOH (5M in water, 0.079 ml, 0.393 mmol) was added and stirred at 60 °C for 2 h. After completion of the reaction as monitored by TLC, the reaction mixture was acidified with aqueous HC1 (2M) and concentrated under reduced pressure to give the crude product. It was purified by RP-HPLC using 10 mM NH4HCO3in water:ACN to afford the title product as an off-white solid (1.6 mg, 16.3 % yield).1H NMR (400 MHz, DMSO-d6) δ = 12.95 (bs, 1H), 10.84 (s, 1H), 7.91 (d, J = 1.60 Hz, 1H), 7.70 (dd, J = 1.60, 8.00 Hz, 1H), 7.01-7.06 (m, 4H), 6.99 (d, J = 14.80 Hz, 1H), 6.85-6.95 (m, 2H), 6.49 (dd, J = 1.60, 8.40 Hz, 1H), 6.01 (s, 1H), 4.57 (dd, J = 6.00, Hz, 1H), 4.45 (dd, I = 6.00, Hz, 1H), 3.56 (s, 2H), 3.25-3.29 (m, 2H), 2.94-2.97 (m, 5H), 2.17-2.23 (m, 7H);19F NMR (377 MHz, DMSO-d6) δ = -219.79; LCMS: 495.2 [M+H].Example 11.11: 5-(2-((3-(Fluoromethyl)azetidin-l-yl)meth.yl)-lH-indol-5-yl)-6-(o-tolyl)-8,9- dihydro-7FFcyclohepta[b]pyridin-2-ol ( Compound 57)

[0524] Compound 57 was prepared according to the Scheme 60:Scheme 60Step / : (E)-N'-(2-Methoxy-6, 7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylidene)-4- methylbenzenesulfonohydrazide (Intermediate 115):

[0525] To a stirred solution of 2-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one, Intermediate A2 (0.93 g, 4.86 mmol) in EtOH (10 mL) at 0 °C, tosylhydrazine (1.359 g, 7.29 mmol) was added and stirred at 100 °C for 12 h. After completion of the reaction (as monitored by TLC), the reaction mixture was concentrated under reduced pressure to yield the residue. The residue was taken in ice water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4and filtered. The combined organic extracts were concentrated under reduced pressure to yield the crude product. It was purified by silica gel (230-400 mesh) using 22% EtOAc in petroleum ether to afford the title product (2.2 g, 79% yield) as a yellow solid. LCMS: 360.1 [M+H].Step 2: 5-(2-(( 3 -(Fluoromethyl )azetidin-l -yl )methyl)-lH-indol-5-yl)-2-methoxy-8, 9-dihydro-7H- cyclohepta[ b ] pyridine (116):

[0526] To a stirred solution of (E)-N'-(2-methoxy-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridin-5-ylidene)-4-methylbenzenesulfonohydrazide, Intermediate 115 (101 mg, 0.281 mmol) and tert-butyl 5-bromo-2-((3-(fluoromethyl)azetidin-l-yl)methyl)-lH-indole-l- carboxylate, Intermediate E3 (112 mg, 0.281 mmol) in 1,4-dioxane (5 mL) at 25 °C, NaOtBu (81 mg, 0.846 mmol) was added and the mixture degassed with N2for 5 min. Then, XPhos (28 mg, 0.059 mmol) and Pd2(dba)3-CHC13 (29 mg, 0.028 mmol) were added and stirred at 110 °C in a sealed tube for 12 h. After completion of the reaction as monitored by LCMS, the reaction mixture was filtered through celite, washed with EtOAc (5 mL x 2). The filtrate was concentrated under reduced pressure to yield the title product as a yellow gum (0.14 g, crude) which was taken to the next step without further purification. LCMS: 392.2 [M+H].Step 3: tert-Butyl 2-( (3-(fluoromethyl)azetidin-l-yl )methyl)-5-(2-methoxy-8,9-dihydro-7H- cyclohepta[b]pyridin-5-yl)-lH-indole-l -carboxylate (Intermediate 117):

[0527] To a stirred solution of 5-(2-((3-(fhioromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-2- methoxy-8,9-dihydro-7H-cyclohepta[b]pyridine, Intermediate 116 (190 mg, 0.485 mmol) in DCM (10 mL) at 0 °C, triethylamine (0.203 mL, 1.456 mmol), Boc-anhydride (0.223 mL, 0.971 mmol) and 4-DMAP (30 mg, 0.243 mmol) were added and stirred at 25 °C for 3 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with ice water (10 mL) andextracted with DCM (IO mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product. It was purified by silica gel (230-400 mesh) column chromatography using 40% EtOAc in petroleum ether to afford the title product as a yellow liquid (210 mg, 63.4% yield). LCMS: 492.2 [M+H],Step 4: tert-Butyl 5-( 6-bromo-2-meth.oxy-8,9-dihydro-7H-cyclohepta[b]pyridin-5-yl)-2-((3- (fluoromethyl )azetidin-l -yl )methyl)-lH-indole-l -carboxylate ( Intermediate 118):

[0528] The title compound was prepared by following a similar procedure described for Intermediate 34, starting from tert-butyl 2-((3-(fhioromethyl)azetidin-l-yl)methyl)-5-(2-methoxy- 8,9-dihydro-7H-cyclohepta[b]pyridin-5-yl)-lH-indole-l-carboxylate, Intermediate 117 (210 mg, 0.308 mmol) and pyridinium tribromide (118 mg, 0.369 mmol). The title compound was obtained as a pale yellow solid (133 mg, 59.1% yield) and was taken to the next step without further purification. LCMS: 570.2 [M+H],Step 5: tert-Butyl 2-((3-(fluoromethyl)azetidin-l-yl)methyl)-5-(2-methoxy-6-(o-tolyl)-8,9-dihydro- 7H-cyclohepta[bJpyridin-5-yl)-l H-indole-1 -carboxylate ( Compound H54):

[0529] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 583.3 [M+H],Step 6: 5-(2-( ( 3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-2-methoxy-6-( o-tolyl)-8,9- dihydro-7H-cyclohepta[b]pyridine (Compound J 119):

[0530] To a stirred solution of tert-butyl 2-((3-(fluoromethyl)azetidin-l-yl)methyl)-5-(2- methoxy-6-(o-tolyl)-8,9-dihydro-7H-cyclohepta[b]pyridin-5-yl)-lH-indole-l-carboxylate,Compound H54 (45 mg, 0.077 mmol) in 1,4-dioxane (1 mL) at 0 °C, HC1 in dioxane (4M, 0.250 mL) was added and stirred at 25 °C for 24 h, then stirred at 60 °C for 3h. After completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to obtain crude product. The crude product was purified by RP-HPLC using 10 mM (NH4)HCO3in water:ACN to afford the title product as an off white solid (1 mg, 2.7% yield).1H NMR (400 MHz, CD3OD) δ = 7.14 (d, J = 8.40 Hz, 1H), 6.96-7.04 (m, 6H), 6.58-6.63 (m, 2H), 6.11 (s, 1H), 4.54 (d, J = 5.60 Hz, 1H), 4.43 (d, J = 5.60 Hz, 1H), 3.98 (s, 3H), 3.71 (s, 2H), 3.37-3.51 (m, 2H), 3.16-3.22 (m, 2H), 2.67-2.86 (m, 3H), 2.21-2.35 (m, 7H); LCMS: 482.3 [M+H],Example 11.12: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-8-(o-tolyl)-6,7- dihydro-5H-cyclohepta[c]pyridin-3-ol (Compound 58)

[0531] Compound 58 was prepared according to the Scheme 61:Scheme 61Step 1 : (E)-N'-( 3 -Methoxy-5, 6, 7, 8-tetrahydro-9H-cyclohepta[c ]pyridin-9-ylidene)-4- methylbenzenesulfonohydrazide (Intermediate 120):

[0532] The title compound was prepared by following a similar procedure described for Intermediate 115, starting from 3-methoxy-5,6,7,8-tetrahydro-9H-cyclohepta[c]pyridin-9-one, Intermediate A3 (0.56 g, 2.93 mmol) and tosylhydrazine (0.818 g, 4.39 mmol). The title compound was obtained as a yellow solid (1.08 g, 73.9% yield). LCMS: 360.6 [M+H].Step 2: Ethyl 5-(3-methoxy-6,7-dihydro-5H-cyclohepla[c]pyridin-9-yl)-lH-indole-2-carboxylale (Intermediate 121):

[0533] The title compound was prepared by following a similar procedure described for Intermediate 116, starting from (E)-N'-(3-methoxy-5,6,7,8-tetrahydro-9H-cyclohepta[c]pyridin-9- ylidene)-4-methylbenzenesulfonohydrazide, Intermediate 120 (0.71 g, 1.975 mmol), 1 -(tert-butyl) 2-ethyl 5-bromo-lH-indole-l,2-dicarboxylate, Intermediate El (0.735 g, 1.995 mmol), NaOtBu (0.571 g, 5.95 mmol), XPhos (0.188 g, 0.395 mmol) and Pd2(dba)3-CHCl3(0.204 g, 0.198 mmol). The title compound was obtained as a yellow gum (0.26 g, 36.3% yield). LCMS: 363.1 [M+H],Step 3: I -(tert-Butyl) 2-ethyl 5-(3-methoxy-6,7-dihydro-5H-cyclohepta[c]pyridin-9-yl)-l H- indole-l,2-dicarboxylate (Intermediate 122):

[0534] The title compound was prepared by following a similar procedure described for Intermediate 117, starting from ethyl 5-(3-methoxy-6,7-dihydro-5H-cyclohepta[c]pyridin-9-yl)- lH-indole-2-carboxylate, Intermediate 121 (0.26 g, 0.717 mmol), triethylamine (0.300 mL, 2.152 mmol). Boc-anhydride (0.249 ml, 1.083 mmol) and 4-DMAP (0.046 g, 0.373 mmol). The title compound was obtained as a yellow oil (0.22 g, 47.7% yield). LCMS: 463.2 [M+H],Step 4: 1 -(tert-Butyl) 2-ethyl 5-(8-bromo-3-methoxy-6,7-dihydro-5H-cyclohepta[c]pyridin-9-yl)- lH-indole-l,2-dicarboxylate (Intermediate 123):

[0535] The title compound was prepared by following a similar procedure described for Intermediate 34, starting from 1 -(tert-butyl) 2-ethyl 5-(3-methoxy-6,7-dihydro-5H- cyclohepta[c]pyridin-9-yl)-lH-indole-l,2-dicarboxylate, Intermediate 122 (220 mg, 0.476 mmol) and pyridinium tribromide (152 mg, 0.476 mmol). The title compound was obtained as a pale yellow solid (220 mg, 85.2% yield) and was taken to the next step without further purification. LCMS: 541.1 [M+H],Step 5: 1 -(tert-Butyl) 2-ethyl 5-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H-cyclohepta[c]pyridin-9- yl)-lH-indole-l,2-dicarboxylate (Intermediate 124):

[0536] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 553.2 [M+H],Step 6: Synthesis of ethyl 5-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H-cyclohepta[c]pyridin-9-yl)- lH-indole-2-carboxylate (Intermediate 125):

[0537] The title compound was prepared by following a similar procedure described for Compound JI 19, starting from 1 -(tert-butyl) 2-ethyl 5-(3-methoxy-8-(o-tolyl)-6,7-dihydro-5H- cyclohepta[c]pyridin-9-yl)-lH-indole-l,2-dicarboxylate, Intermediate 124 (130 mg, 0.198 mmol) and anhydrous HC1 in dioxane (4M, 1.5 mL). The title compound was obtained as a pale yellow solid (115 mg, crude) and was taken to the next step without further purification. LCMS: 453.2 [M+H],Step 7: (5-(3-Methoxy-8-(o-tolyl)-6,7-dihydro-5H-cyclohepta[c]pyridin-9-yl)-l H-indol-2- yl)methanol (Intermediate 126):

[0538] The title compound was synthesized using General Procedure 4 (GP4). LCMS: 411.2 [M+H],Step 8: 5-(3-Methoxy-8-(o-tolyl)-6,7-dihydro-5H-cyclohepta[c]pyridin-9-yl)-lH-indole-2- carbaldehyde (Intermediate 127):

[0539] The title compound was synthesized using General Procedure 5 (GP5) (Method A). LCMS: 409.1 [M+H],Step 9: 9-(2-((3-(Fluoromethyl)azetidin-l -yl)methyl)-l H-indol-5-yl)-3-methoxy-8-(o-tolyl)-6,7- dihydro-5H-cyclohepta[c]pyridine (Compound H55):

[0540] The title compound was synthesized using General Procedure 6 (GP6) (Method A).1H NMR (400 MHz, DMSO-d6) δ = 10.83 (s, 1H), 7.51 (s, 1H), 6.82-7.07 (m, 7H), 6.51 (dd, J = 1.60, 8.40 Hz, 1H), 6.01 (d, J = 1.20 Hz, 1H), 4.57 (d, J - 6.00 Hz, 1H), 4.45 (d, J - 6.00 Hz, 1H), 3.82 (s, 3H), 3.57 (s, 2H), 3.27 (t, J = 7.20 Hz, 2H), 2.96 (t, J = 6.40 Hz, 2H), 2.67-2.87 (m, 3H), 2.13- 2.22 (m, 7H);19F NMR (377 MHz, DMSO-d6) δ = -219.79; LCMS: 482.2 [M+HJ.Step 10: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-8-(o-tolyl)-6,7-dihydro-5H- cyclohepta[c]pyridin-3-ol (Compound 58):

[0541] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, DMSO-d6) δ = 11.34 (bs, 1H), 10.82 (s, 1H), 6.95-7.04 (m, 6H), 6.54-6.60 (m, 2H), 6.30 (s, 1H), 6.02 (s, 1H), 4.54 (d, J = 5.60 Hz, 1H), 4.43 (d, J = 5.60 Hz, 1H), 3.57 (s, 2H), 3.27-3.31 (m, 2H), 2.97 (t, J = 6.80 Hz, 2H), 2.67-2.83 (m, 3H), 2.15-2.34 (m, 5H), 1.97-2.04 (m, 2H);19F NMR (377 MHz, DMSO-d6) δ = -219.79; LCMS: 468.2 [M+H],Example 11.13: rel-(5R,6S)-5-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridin- 7-yl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (Compound 59) and rel-(5R,6S)-5-(2-((3- (Fluoromethyl )azetidin-l -yl )methyl )imidazo[l,2-a ]pyridin-7-yl)-6-phenyl-5, 6,7,8- tetrahydronaphthalen-2-ol (Compound 60)

[0542] Compound 59 and Compound 60 were prepared according to the Scheme 62:Scheme 62Step 1: Ethyl 7-( 6-Methoxy-2-phenyl-3,4-dihydronaphthalen-l-yl)imidaz.o[l,2-a ]pyridine-2- carboxylate (Intermediate 128):

[0543] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 425.2 [M+H],Step 2: (7-( 6-Methoxy-2-phenyl-3 ,4-dihydronaphthalen-l -yl)imidazo[ 1,2-a ]pyridin-2- yl)methanol (Intermediate 129):

[0544] The title compound was synthesized using General Procedure 4 (GP4). LCMS: 383.3 [M+H],Step 3: (7-(6-Methoxy-2-phenyl-l,2,3,4-tetrahydronaphthalen-l-yl)imidazo[l,2-a]pyridin-2- yl)methanol (Intermediate 130):

[0545] To a stirred solution of (7-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-l- yl)imidazo[l,2-a]pyridin-2-yl)methanol, Intermediate 129 (350 mg, 0.915 mmol) in MeOH (10 mL) at 25 °C, Pd / C (10%, 195 mg, 1.830 mmol) was added and stirred at 25 °C under H2 (bladder) pressure for 12 h. After completion of the reaction as monitored by LCMS, the reaction mixture was filtered through celite, washed with MeOH (5 mL x 2) and the filtrate was concentrated under reduced pressure to afford the title product as pale brown gum (270 mg, crude), which was taken to the next step without further purification. LCMS: 385.2[M+H].Step 4: 7-( 6-Methoxy-2-phenyl-l ,2,3,4-tetrahydronaphthalen-l -yl)imidazo[ 1 ,2-a ]pyridine-2- carbaldehyde (Intermediate 131 ):

[0546] The title compound was synthesized using General Procedure 5 (GP5) (Method A). LCMS: 383.0 [M+H],Step 5: rac-2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-7-((lR, 2S)-6-methoxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)imidazo[l,2-a]pyridine ( Compound H56):

[0547] The title compound was synthesized using General Procedure 6 (GP6) (Method B).1H NMR (400 MHz, CD3OD) δ = 7.94 (dd, J = 0.80, 7.00 Hz, 1H), 7.58 (d, J = 5.20 Hz, 1H), 7.14- 7.20 (m, 3H), 6.98 (dd, J = 1.20, 7.60 Hz, 2H), 6.85-6.87 (m, 2H), 6.71 (dd, J = 2.40, 8.80 Hz, 1H), 6.56 (s, 1H), 6.00 (dd, J = 1.60, 7.20 Hz, 1H), 4.61 (bs, 1H), 4.55 (d, J = 5.20 Hz, 1H), 4.43 (d, J = 5.20 Hz, 1H), 3.79-3.82 (m, 5H), 3.33-3.65 (m, 5H), 1.94-3.18 (m, 5H); LCMS: 456.3 [M+H].Step 6: rac-(5R,6S)-5-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridin-7-yl)-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol ( Compound J 132):

[0548] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, DMSO-d6) δ = 9.23 (s, 1H), 8.00 (d, J = 6.40 Hz, 1H), 7.51 (s, 1H), 7.12-7.20 (m, 3H), 6.85- 6.87 (m, 2H), 6.66-6.72 (m, 2H), 6.51 (dd, J = 2.40, 8.20 Hz, 1H), 6.39 (s, 1H), 5.82 (dd, J = 1.60, 7.20 Hz, 1H), 4.56 (d, J = 6.00 Hz, 1H), 4.44 (d, J = 6.00 Hz, 1H), 4.33 (d, J = 5.20 Hz, 1H), 3.52 (s, 2H), 3.41 -3.45 (m, 1H), 3.26-3.28 (m, 2H), 2.93-3.08 (m, 4H), 2.67-2.71 (m, 1H), 2.15-2.19 (m, 1H), 1.81-1.91 (m, 1H); LCMS: 442.3 [M+H],Step 7: rel-(5R,6S)-5-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridin-7-yl)-6- phenyl-5,6,7,8-tetrahydronaphthcden-2-ol (Compound (First Eluting peak)) and rel-(5R,6S)-5-(2- ((3-( Fluoromethyl )azetidin-l -yl )methyl )imidazo[l,2-a ]pyridin-7-yl)-6-phenyl-5, 6,7,8- tetrahydronaphthalen-2-ol (Compound 60 (Second Eluting peak)):

[0549] rac-(5R,6S)-5-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridin-7-yl)- 6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol, Compound J132 (7 mg, 0.016 mmol) was purified by SFC Chiral purification using CO2as primary solvent and 40% (0.5% isopropylamine in MeOH) as co-solvent to afford rel-(5R,6S)-5-(2-((3-(fhioromethyl)azetidin-l-yl)methyl)imidazo[l,2- a]pyridin-7-yl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (First eluting peak, Compound 59) (3 mg) as an off-white solid and rel-(5R,6S)-5-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidazo[l ,2-a]pyridin-7-yl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (Second eluting peak, Compound 60) (2 mg) as an off-white solid. Total yield = 71.5%.Spectral data (Compound 59 (First Eluting peak)): SFC Chiral purity = 90.95%; LCMS: 442.2 [M+H],Spectral data (Compound _60 (Second Eluting peak)): SEC Chiral purity = 92.87%; LCMS: 442.2[M+H],Example 11.14: rel-(5R,6R)-5-(2-((3-(Eluoromethyl)azetidin-l-yl)methyl)pyrazolo[l,5-a]pyridin-6-yl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (Compound 61) and rel-(5R,6R)-5-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)pyrazolo[l,5-a]pyridin-6-yl)-6-phenyl-5,6,7,8- tetrahydronaphthalen-2-ol (Compound 62)

[0550] Compound 61 and Compound 62 were prepared according to the Scheme 63:Scheme 63Step 1: Ethyl 6-( 6-methoxy-2-phenyl-3,4-dihydronaphthalen-l -yl)pyrazolo[l ,5-a ]pyridine-2- carboxylate (Intermediate 133):

[0551] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 425.1 [M+H],Step 2: rac-Ethyl 6-((lR,2R)-6-methoxy-2-phenyl-l ,2,3,4-tetrahydronaphthalen-l - yl )pyrazolo[l,5-a ]pyridine-2-carboxylate ( Intermediate 134):

[0552] The title compound was synthesized using the similar procedure described for the Intermediate 130. LCMS: 427.4 [M+H],Step 3: rac-(6-((lR,2R)-6-Methoxy-2-phenyl-l ,2,3,4-tetrahydronaphthalen- 1 -yl)pyrazolo[ 1 ,5- a]pyridin-2-yl)methanol (Intermediate 135):

[0553] The title compound was synthesized using General Procedure 4 (GP4). LCMS: 385.2 [M+H],Step 4: rac-6-((lR,2R)-6-Methoxy-2-phenyl- 1,2,3, 4-tetrahydronaphthalen-l-yl)pyrazolo[ 1,5- a]pyridine-2-carbaldehyde (Intermediate 136):

[0554] The title compound was synthesized using Genral Procedure 5 (GP5) (Method A). LCMS: 383.3 [M+H],Step 5: rac-2-( ( 3-(Fluoromethyl)azetidin-l-yl)melhyl)-6-( ( lR,2R)-6-methoxy-2-phenyl-l ,2,3 ,4- tetrahydronaphthalen-1 -yl)pyrazolo[ 1 ,5-a]pyridine ( Compound H57):

[0555] The title compound was synthesized using General Procedure 6 (GP6) (Method B).1H NMR (400 MHz, CD3OD) δ = 7.42 (bs, 1H), 7.14-7.18 (m, 4H), 6.97 (dd, J = 1.60, 7.40 Hz, 2H), 6.90 (d, J = 8.80 Hz, 1H), 6.85 (d, J = 2.80 Hz, 1H), 6.73 (d, J = 2.80 Hz, 1H), 6.35 (s, 1H), 6.29 (dd, J = 1.60, 9.20 Hz, 1H), 4.54 (d, J = 5.60 Hz, 1H), 4.42 (d, J = 5.60 Hz, 1H), 4.38 (d, J = 5.20 Hz, 1H), 3.82 (s, 3H), 3.73 (s, 2H), 3.45-3.51 (m, 3H), 3.09-3.21 (m, 4H), 2.80-2.85 (m, 1H), 2.22- 2.28 (m, 1H), 1.91-1.96 (m, 1H); LCMS: 456.3 [M+H],Step 6: rel-2-( (3-(Fluoromethyl)azetidin-l-yl)methyl)-6-( ( lR,2R)-6-methoxy-2-phenyl-l ,2,3,4- tetrahydronaphthalen-l-yl)pyrazolo[l,5-a]pyridine (Compound H58 (First Eluting peak)) and rel-2-((3-(fluoromethyl)azetidin-l-yl)methyl)-6-((lR,2R)-6-methoxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-1 -yl)pyrazolo[ 1 ,5 -a]pyridine (Compound H59 (Second Eluting peak)):

[0556] rac-2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-6-((lR,2R)-6-methoxy-2-phenyl- l,2,3,4-tetrahydronaphthalen-l-yl)pyrazolo[l,5-a]pyridine, Intermediate 57 (28 mg, 0.061 mmol) was purified by SFC Chiral purification using CO2as primary solvent and 40% (0.5% isopropylamine in MeOH) as co-solvent to afford rel-2-((3-(fhioromethyl)azetidin-l-yl)methyl)- 6-((lR,2R)-6-methoxy-2-phenyl-l,2,3,4-tetrahydronaphthalen-l-yl)pyrazolo[l,5-a]pyridine(Compound H58 (First Eluting peak)) (12 mg) as an off-white solid and rel-2-((3- (fluoromcthyl)azctidin-l-yl)mcthyl)-6-((lR,2R)-6-mcthoxy-2-phcnyl-l,2,3,4- tetrahydronaphthalen-l-yl)pyrazolo[l,5-a]pyridine (Compound H59 (Second Eluting peak)) (12 mg) as an off-white solid. Total yield = 85.7%.Spectral data (Compound H58 (First Eluting peak)): SFC Chiral purity = 100%; LCMS: 456.2 [M+H],Spectral data (Compound H59 (Second Eluting peak)): SFC Chiral purity = 100%; LCMS: 456.2 [M+H],Step 7: rel-( 5R, 6R )-5-(2-((3-( Fluoromethyl)azetidin-1 -yl )methyl )pyrazolo[ 1,5-a ]pyridin-6-yl)-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (Compound 61) and Step 7a: Synthesis of rel-(5R,6R)- 5-( 2-( ( 3 -(fluoromethyl )azetidin-l -yl )methyl )pyrazolo[ 1,5-a ]pyridin-6-yl)-6-phenyl-5, 6, 7, 8- tetrahydronaphthalen-2-ol (Compound 62)

[0557] The title compounds were synthesized using General Procedure 3 (GP3).Spectral data (Compound 61):1H NMR (400 MHz, CD3OD) δ = 7.42 (bs, 1H), 7.13-7.20 (m, 4H),6.95-6.98 (m, 2H), 6.81 (d, J = 8.40 Hz, 1H), 6.72 (d, J = 2.40 Hz, 1H), 6.59 (dd, J = 2.40, 8.40 Hz, 1H), 6.35 (s, 1H), 6.29 (dd, J = 1.60, 9.20 Hz, 1H), 4.54 (d, J = 5.60 Hz, 1H), 4.42 (d, J = 5.60 Hz, 1H), 4.35 (d, J = 4.80 Hz, 1H), 3.73 (s, 2H), 3.46-3.50 (m, 3H), 3.05-3.21 (m, 4H), 2.80-2.87 (m, 1H), 2.21-2.26 (m, 1H), 1.87-1.94 (m, 1H); SFC Chiral purity = 99.45%; LCMS: 442.3 [M+H],Spectral data (Compound 62):1H NMR (400 MHz, CD3OD) δ = 7.42 (bs, 1H), 7.13-7.21 (m, 4H),6.96-6.98 (m, 2H), 6.81 (d, J = 8.40 Hz, 1H), 6.72 (d, J = 2.80 Hz, 1H), 6.59 (dd, J = 2.80, 8.20 Hz, 1H), 6.35 (s, 1H), 6.30 (dd, J = 1.20, 9.20 Hz, 1H), 4.54 (d, J = 5.60 Hz, 1H), 4.42 (d, J = 5.60 Hz, 1H), 4.35 (d, J = 5.20 Hz, 1H), 3.74 (s, 2H), 3.46-3.51 (m, 3H), 3.20 (t, J - 7.60 Hz, 2H), 3.05- 3.16 (m, 2H), 2.81-2.86 (m, 1H), 2.07-2.26 (m, 1H), 1.91-1.94 (m, 1H); SFC Chiral purity = 99.39%; LCMS: 442.4 [M+H],Example 11. 15: 9-( 2 -(( 3 -( Fluoromethyl )azetidin- 1 -yl)methyl)imidazo[ 1 ,2-a]pyridin-7-yl)-8-(2- hydroxyethyl)-6, 7-dihydro-5H-benzo[7]annulen-3-ol ( Compound 63 )

[0558] Compound 63 was prepared according to the Scheme 64:Scheme 64Step 1 : Ethyl 2-(9-(2-(( 3 -(fluoromethyl )azetidin-l -yl )methyl )imidazo[ 1,2-a ]pyridin-7-yl)-3 - methoxy-6, 7-dihydro-5H-benzo[7]anmden-8-yl)acetate ( Compound H60):

[0559] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 478.3 [M+H],Step 2: Ethyl 2-(9-(2-((3-(fluoromethyl)azetidin-l-yl)methyl)imidaz.o[l,2-a]pyridin-7-yl)-3- hydroxy-6,7-dihydro-5EI-benzo[7]annulen-8-yl)acetate (Intermediate 137):

[0560] The title compound was synthesized using General Procedure 3 (GP3). LCMS: 464.3 [M+H],Step 3: 9-(2-((3-( Fluoromethyl )azetidin-l -yl )methyl)imidazo[l,2-a ]pyridin- 7-yl)-8-(2- hydroxyethyl)-6, 7-dihydro-5H-benzo[7]annulen-3-ol ( Compound 63 ):

[0561] The title compound was synthesized using General Procedure 4 (GP4).1H NMR (400 MHz, DMSO-d6) δ = 9.32 (s, 1H), 8.33 (dd, J = 0.80, 6.80 Hz, 1H), 7.69 (bs, 1H), 7.24 (bs, 1H), 6.67 (d, J - 2.40 Hz, 1H), 6.56 (d, J = 8.40 Hz, 1H), 6.49-6.51 (m, 1H), 4.57-4.61 (m, 2H), 4.49 (d, J = 6.40 Hz, 1H), 3.63 (s, 2H), 3.51-3.57 (m, 2H), 3.31-3.38 (m, 2H), 3.02-3.05 (m, 2H), 2.67- 2.71 (m, 1H), 2.50-2.53 (m, 2H), 2.33-2.42 (m, 2H), 2.09-2.13 (m, 2H), 1.92-1.96 (m, 2H);19F NMR (377 MHz, DMSO-d6) δ = -219.54; LCMS: 422.3 [M+H],Example 11.16: 8-((l-Fluorocyclopropyl)methyl)-9-(2-((3-(fluoromethyl)azetidin-l- yl)methyl)imidazo[l,2-a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Compound 64)

[0562] Compound 64 was prepared according to the Scheme 65:Scheme 65Step 1: 7-(8-((l -Fluorocyclopropyl)methyl)-3-methoxy-6,7-dihydro-5H-benzo

[0007] annulen-9-yl)-2- ((3 -(fluoromethyl )azetidin-l -yl)methyl)imiclazo[ 1 ,2-a]pyridine (Compound H61):

[0563] The title compound was synthesized using General Procedure 2 (GP2).1H NMR (400 MHz, DMSO-d6) δ = 8.36 (d, J = 6.80 Hz, 1H), 7.72 (s, 1H), 7.20 (s, 1H), 6.89 (s, 1H), 6.70-6.72 (m, 2H), 6.38 (dd, J = 1.60, 7.20 Hz, 1H), 4.61 (d, J = 6.00 Hz, 1H), 4.49 (d, J = 6.40 Hz, 1H), 3.75 (s, 3H), 3.67 (s, 2H), 3.36-3.40 (m, 2H), 3.08 (t, J = 6.40 Hz, 2H), 2.68-2.80 (m, 5H), 0.96- 1.05 (m, 2H), 0.65-0.69 (m, 2H); LCMS: 464.3 [M+H],Step 2: Synthesis of 8-((l-fluorocyclopropyl)methyl)-9-(2-((3-(fluorometh.yl)azetidin-l- yl)methyl)imidazo[l,2-a]pyridin-7-yl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Compound 64):

[0564] The title compound is synthesized using General Procedure 3 (GP3).Example 11.17: 9-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)imidazo[l,2-a]pyridin-7-yl)-8-(2- methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol ( Compound 65 )

[0565] Compound 65 was prepared according to the Scheme 66:Step 1 : 2-((3-( Fluoromethyl )azetidin- 1 -yl )methyl)-7-( 3 -methoxy-8-(2-methylcyclohexyl)-6, 7- dihydro-5H-benzo[7]annulen-9-yl)imidazo[ 1,2-a Jpyridine ( Compound H62 ):

[0566] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 488.3 [M+H],Step 1: 9-(2-((3-( Fluoromethyl )azetidin-l -yl )methyl)imidazojl,2-a ]pyridin-7-yl)-8-(2- methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Compound 65):

[0567] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, DMSO-d6) δ = 9.29 (s, 1H), 8.32-8.36 (m, 1H), 7.69 (s, 1H), 7.11-7.17 (m, 1H), 6.42-7.17 (m, 4H), 4.60 (d, J = 6.40 Hz, 1H), 4.48 (d, J = 6.40 Hz, 1H), 3.64 (s, 2H), 3.04 (t, J = 6.80 Hz, 2H), 2.67-2.72 (m, 3H), 1.66-2.12 (m, 8H), 0.83-1.44 (m, 11H);19F NMR (377 MHz, DMSO-d6) δ = -219.49;LCMS: 474.3 [M+H],Example 11.18: 6-Cyclohexyl-5 -[2-[[3-(fluoromethyl )azetidin-l -yl Jmethyl ]imidazo[l,2- a]pyridin-7-yl]-8,9-dihydro-7H-benzo[7]annulen-2-ol ( Compound 79)

[0568] Compound 65 was prepared according to the Scheme 67 :Step 1: 7-(6-Cyclohexyl-2-methoxy-8,9-dihydro-7H-benzo[7Jannulen-5-yl)-2-[J3-(fluoromethyl )azetidin- 1 -yl Jmethyl JimidazoJ 1 ,2 -a Jpyridine ( Compound H62 ):

[0569] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 474.1 [M+H],Step 2: 6-Cyclohexyl-5-[2-[[3 -(fluoromethyl)azetidin- 1 -yl Jmethyl ]imidazo[ 1,2-a ]pyridin-7-yl]- 8,9-dihydro-7H-benzo[7]anmden-2-ol (Compound 79):

[0570] The title compound was synthesized using General Procedure 3 (GP3). LCMS: 460.1 [M+H]1H NMR (400 MHz, CDC13) δ 8.45 (s, 1H), 7.83 (s, 1H), 7.72 (d, J = 6.9 Hz, 1H), 7.33 (s, 1H), 6.80 (s, 1H), 6.59 (s, 2H), 6.39 (d, J = 7.2 Hz, 1H), 4.55 (dd, J = 46.9, 3.9 Hz, 3H), 4.33 (s, 2H), 4.10 (dt, J = 101.5, 9.2 Hz, 5H), 2.64 (s, 2H), 2.52 (t, J = 11.5 Hz, 1H), 2.26 - 1.93 (m, 5H), 1.65 (d, J = 11.4 Hz, 3H), 1.46 (d, J - 12.4 Hz, 2H), 1.20 (s, 3H)Example 12: rac-(5R,6S)-5-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (Compound 81)

[0571] Compound 81 was prepared according to the Scheme 69:Scheme 69Step 1: 1 -(tert-Butyl) 2-ethyl 5-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-l-yl)-lH-indole-l,2- dicarboxylate (Intermediate 140):

[0572] The title compound was synthesized using General Procedure 2 (GP2). LCMS: 468.1 [M+-(t-butyl)].Step 2: Ethyl 5-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-l -yl)-lH-indole-2-carboxylate (Intermediate 141):

[0573] The title compound was synthesized using the similar procedure described for the Intermediate 91. LCMS: 424.5 [M+l],Step 3: rac-Ethyl 5-((lR,2S)-6-methoxy-2-phenyl-l,2,3,4-tetrahydronaphthalen-l-yl)-lH-indole- 2-carboxylate (Intermediate 142):

[0574] The title compound was synthesized using the similar procedure described for the Intermediate 130. LCMS: 426.5 [M+l],Step 4: rac-(5-(( lR,2S)-6-Methoxy-2-phenyl-l ,2,3 ,4-tetrahydronaphthalen- 1 -yl)- lH-indol-2- yl)methanol (Intermediate 143):

[0575] The title compound was synthesized using General Procedure 4 (GP4). LCMS: 384.5 [M+l],Step 5: rac-5-((lR, 2S)-6-Melhoxy-2-phenyl- 1,2,3, 4-lelrahydronaphthalen-l -yl)-lH-indole-2- carbaldehyde (Intermediate 144):

[0576] The title compound was synthesized using General Procedure 5 (GP5) (Method A). LCMS: 382.5 [M+l],Step 6: rac-2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-5-((lR,2S)-6-methoxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)-lH-indole (Compound H63):

[0577] The title compound was synthesized using General Procedure 6 (GP6) (Method B). LCMS: 455.5 [M+l],Step 7: rac-(5R,6S)-5-(2-((3-(Fluoromethyl)azetidin-l-yl)methyl)-lH-indol-5-yl)-6-phenyl- 5,6,7,8-tetrahydronaphthalen-2-ol (Compound 81):

[0578] The title compound is synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, CD3OD) δ = 7.06-7.08 (m, 3H), 6.89 (d, J = 8.40 Hz, 1H), 6.69-6.78 (m, 4H), 6.51-6.56 (m, 2H), 6.17 (dd, J = 1.60, 8.40 Hz, 1H), 6.10 (s, 1H), 4.59 (bs, 1H), 4.55 (d, J = 5.60 Hz, 1H), 4.43 (d, J = 5.20 Hz, 1H), 4.33 (d, I = 4.80 Hz, 1H), 3.75 (s, 2H), 3.50-3.54 (m, 2H), 3.33-3.37 (m, 1H), 3.01-3.08 (m, 2H), 2.79-2.91 (m, 1H), 2.32-2.40 (m, 1H), 1.73-1.78 (m, 1H); LCMS: 441.2 [M+H],Example 13: 5-[2-(2-Azaspiro[3.3]heptan-2-ylmethyl)-lH-indol-5-yl]-6-(o-tolyl)-8,9-dihydro- 7H-benzo[7]annulen-2-ol (Compound 82)

[0579] Compound 82 was prepared according to the Scheme 70:Step 1: 2-(2-Azaspiro[3.3 ]heptan-2-ylmethyl)-5-[2-methoxy-6-(o-tolyl)-8,9-dihydro-7H- benzo[7]annulen-5-yl]-lH-indole (Compound H64):

[0580] The title compound was synthesized using General Procedure 6 (GP6) (Method A).1H NMR (400 MHz, CDCl3) d 8.66 (s, 0.4H), 7.13 - 6.96 (m, 6H), 6.91 - 6.81 (m, 2H), 6.69 (ddd, J- 8.4, 6.2, 2.2 Hz, 2H), 6.14 (t, J - 1.4 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 2H), 3.41 (s, 4H), 2.90 (hept, J = 6.2 Hz, 2H), 2.34 (ddd, J = 8.0, 11.4, 6.4 Hz, 3H), 2.23 (s, 3H), 2.22 -2.12 (m, 6H), 1.89 - 1.74 (m, 3H). LCMS: 489.3 [M+H],Step 2: 5-[2-(2-Azaspiro[3.3]heptan-2-ylmethyl)-lH-indol-5-yl]-6-(o-tolyl)-8,9-dihydro-7H- benzo[7]anmden-2-ol (Compound 82):

[0581] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, CDCI3) d 10.81 (bs, 1H), 8.69 (s, 1H), 7.13 - 7.00 (m, 5H), 6.98 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 2.6 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.68 (dd, J = 8.5, 1.7 Hz, 1H), 6.62 (dd, J = 8.3, 2.7 Hz, 1H), 6.23 (dd, J = 1.8, 0.9 Hz, 1H), 4.10 (s, 2H), 3.73 (s, 4H), 2.85 (hept, J = 6.2 Hz, 2H), 2.41- 2.28 (m, 2H), 2.27 - 2.15 (m, 9H), 1.86 (p, J = 7.8 Hz, 2H). LCMS: 475.2 [M+H],Example 14: 5-[2-[(3-Methylazetidin-l-yl)methyl]-l H-indol-5-yl]-6-( o-tolyl)-8,9-dihydro-7H- benzo[7]annulen-2-ol (Compound 83)

[0582] Compound 83 was prepared according to the Scheme 71:Scheme 71Step 1 : 2-[(3-Fluoroazetidin-l -yl )methyl]-5-[2-methoxy-6-( o-tolyl)-8,9-dihydro-7H- benzo[7]annulen-5-yl]-lH-indole (Compound H65):

[0583] The title compound was synthesized using General Procedure 6 (GP6) (Method A).1H NMR (400 MHz, CDCl3) δ 8.68 (s, 0.5H), 7.17 - 6.95 (m, 6H), 6.94 - 6.82 (m, 2H), 6.69 (ddd, J = 8.4, 4.3, 2.1 Hz, 2H), 6.16 (s, 1H), 3.86 (s, 4H), 3.65 (t, J = 8.0 Hz, 2H), 3.03 (s, 2H), 2.92 (hept, J = 6.8 Hz, 2H), 2.72 (dt, J = 14.4, 7.2 Hz, 2H), 2.34 (ddd, J = 18.1, 11.5, 6.3 Hz, 2H), 2.23 (s, 3H), 2.21-2.17 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H). LCMS: 463.3 [M+H],Step 2: 5-[2-[(3-Methylazetidin-l-yl)methyl]-lH-indol-5-yl]-6-(o-tolyl)-8,9-dihydro-7H- benzo[7]annulen-2-ol (Compound 83)

[0584] The title compound was synthesized using General Procedure 3 (GP3).1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 7.13 - 6.97 (m, 6H), 6.81 (d, J = 2.7 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.68 (dd, J = 8.5, 1.6 Hz, 1H), 6.61 (dd, J = 8.3, 2.7 Hz, 1H), 6.21 (t, J = 1.3 Hz, 1H), 4.02 (s, 2H), 3.80 (t, J = 8.6 Hz, 2H), 3.22 (t, J = 8.6 Hz, 2H), 2.87 (h, J = 6.7 Hz, 3H), 2.31 (qd, J = 12.3, 5.5 Hz, 3H), 2.22 (s, 3H), 2.18 (d, J = 7.1 Hz, 1H), 1.26 (d, J = 6.8 Hz, 3H). LCMS: 449.3 [M+H],Example 15: 5-[2-[(3-Fluoroazetidin-l-yl)methyl]-lH-indol-5-yl]-6-( o-tolyl)-8,9-dihydro-7H- benzo[7]annulen-2-ol (Compound 84)

[0585] Compound 84 was prepared according to the Scheme 72:Scheme 72Step 1: Synthesis of 2-[(3-fluoroazetidin-l-yl)methyl]-5-[2-methoxy-6-(o-tolyl)-8,9-dihydro-7H- benzo[7]annulen-5-yl]-lH-indole (Compound H66):

[0586] The title compound was synthesized using General Procedure 6 (GP6) (Method A).NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.14 - 6.97 (m, 5H), 6.97 (dt, J = 8.4, 0.9 Hz, 1H), 6.91 - 6.84 (m, 2H), 6.69 (ddd, J = 8.5, 4.8, 2.2 Hz, 2H), 6.14 (dd, J = 2.1, 0.9 Hz, 1H), 5.16 (dp, J = 57.2, 5.1 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 2H), 3.75 - 3.59 (m, 2H), 3.29 (ddd, J = 23.6, 10.0, 4.7 Hz, 2H), 2.90 (tq, J - 12.7, 6.0 Hz, 2H), 2.32 (qt, J - 12.2, 5.9 Hz, 2H), 2.23 (s, 3H), 2.23-2.18 (m, 2H). LCMS: 467.2 [M+H],Step 2: 5-12-1(3 -fluoroazetidin- l-yl)methylj-l H-indol-5-ylJ -6-(o-tolyl)-8,9-dihydro-7 H- benzo[7]annulen-2-ol (Compound 84)

[0587] The title compound was synthesized using General Procedure 3 (GP3). LCMS: 453.0 [M+H],Example 16: 2-[[3-(Fluoromethyl)azetidin-l-yl]methyl]-5-[6-(o-tolyl)-2-(lH-pyrazol-3-yl)-8,9- dihydro-7H-benzo[7]annulen-5-yl]-lH-indole ( Compound 85)

[0588] Compound 85 was prepared according to the Scheme 73:Scheme 73Stepl: 5-[2-[[3-(Fhioromethyl)azetidin-l-y ]methyl]-lH-indol-5-yl]-6-(o-tolyl)-8,9-dihydro-7H- benzo[7]annulen-2-yl] trifluoromethanesulfonate (Intermediate 145)

[0589] The title compound was synthesized using GP1, Method A.Step 2: 2-[[3-(Fluoromethyl)azetidin-l -yl]methyl]-5-[6-(o-tolyl)-2-( 1 H-pyrazol-3-yl)-8,9- dihydro- 7H-benzo

[0007] annulen-5-yl ]-lH-indole ( Compound 85 )

[0590] The title compound was prepared by following a similar procedure described for Intermediate 36, starting from [5-[2-[[3-(fhioromethyl)azetidin-l-yl]methyl]-lH-indol-5-yl]-6-(o- tolyl)-8,9-dihydro-7H-benzo[7]annulen-2-yl] trifluoromethanesulfonate, Intermediate 145 (61 mg, 0.102 mmol), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole, Intermediate C 15 (50 mg, 0.258 mmol), CS2CO3(85 mg, 0.261 mmol) and PdCl2(dppf -CH2...

Claims

CLAIMS1. A compound of Formula I:I, or a pharmaceutically acceptable salt thereof, wherein:Ring A1is optionally substituted 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted phenyl, or optionally substituted benzoxaborole;Ring A2is optionally substituted 5- to 6-mcmbcrcd hctcroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 3- to 9-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C3-C9cycloaliphatic;Ring B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 6- to 10-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C6-C12aryl, wherein when Ring B is C6aryl, Ring A1is a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; p is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, 4, 5, or 6; each R1is independently selected from halogen, -ORa, -N(Ra)2, -C(O)ORa, -C(O)N(Ra)2, -C(O)N(ORa)(Ra), optionally substituted C1-6 aliphatic, -B(ORa)2, - S(O)(Ra)N(Ra)2, -S(O)(NH)Ra, -P(O)(ORa)2, -C(NRa)-ORa, optionally substituted 3- to 7-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S;R2is -L2-R2a;R2ais optionally substituted C1-C6aliphatic, optionally substituted 2- to 10-atom hctcroaliphatic comprising 1 to 4 hctcroatoms selected from N, O, and S, optionally substituted C3-C7cycloaliphatic, optionally substituted 3- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 5- to 12-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl, -ORa, or -C(O)ORa;L1is selected from -O-, -N(Ra)-, -S-, optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C1-C6aliphatic;L2is a bond, optionally substituted C1-C6aliphatic, or optionally substituted 2- to 10- atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S;Q is selected from optionally substituted 2- to 10-atom heteroaliphatic comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 3- to 12-membered heterocycle comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted C3-C6cycloaliphatic; each R3is independently selected from halogen and optionally substituted Ci-C& aliphatic; each Rais independently selected from hydrogen, deuterium, halogen, and optionally substituted C1-C6aliphatic; each Rbis independently selected from hydrogen, deuterium, halogen, and optionally substituted C1-C6aliphatic; and m is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1, wherein Ring A1is optionally substituted phenyl.

3. The compound of claim 1, wherein Ring A1is 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S.

4. The compound of claim 1, wherein Ring A1is:

5. The compound of claim 1, wherein moiety:

6. The compound of any one of claims 1-5, wherein Ring B is optionally substituted 5- to 12-mcmbcrcd hctcroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S.

7. The compound of claim 6, wherein Ring B is selected from:attachment to moiety L1.

8. The compound of claim 6, wherein Ring B is selected from:* represents a point of attachment to moiety L1.

9. The compound of any one of claims 1-5, wherein Ring B is optionally substituted bicyclic 8- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

10. The compound of claim 9, wherein Ring B is selected from:moiety L1.

11. The compound of claim 10, wherein Ring B is selected from:wherein * represents a point of attachment to moiety L1.

12. The compound of claim 11, wherein Ring B is; ,, wherein * represents a point of attachment to moiety L .

13. The compound of any one of claims 1-5, wherein Ring B is optionally substituted aryl.

14. The compound of claim 13, wherein Ring B is;, wherein * represents a point of attachment to moiety L1.

15. The compound of any one of claims 1-14, wherein L1is optionally substituted C1-C6aliphatic.

16. The compound of any one of claims 1-15, wherein Q is 4- to 6- membered monocyclic heterocycle comprising 1 to 3 heteroatoms selected from N ,0, and S.

17. The compound of claim 16, wherein Q is optionally substituted azetidine or pyrrolidine.

18. The compound of any one of claims 1-15, wherein Q is optionally substituted 6- to 12- membered spirocyclic heterocycle comprising 1- to 4 heteroatoms selected from N, O, and S.

19. The compound of claim any one of claims 1-15, wherein moietyis selected from:

20. The compound of claim 19, wherein moiety:is selected from:

21. The compound of any one of claims 1-15, wherein moiety:is selected from:

22. The compound of any of the claims 1-21, wherein R2is selected from optionally substituted phenyl, optionally substituted pyridine, and optionally substituted pyrimidine.

23. The compound of claim 22, wherein R2is selected from:

24. The compound of any one of claims 1-21, wherein R2is selected from:

25. The compound of any one of claims 1-4 and 6-24, wherein the compound is ofFormula II:or a pharmaceutically acceptable salt thereof, wherein:W is C, CRa, or N as valency pennits;X is (-C(Ra)2-)a;Y is O, S, or C(Ra)2;Z is C or N, as valency permits; n is 0, 1, or 2, and— represents either a double or a single bond.

26. The compound of claim 25, wherein the compound is of Formula II- 1:

27. The compound of claim 25, wherein the compound is of formula III:or a pharmaceutically acceptable salt thereof.

28. The compound of claim 25, wherein the compound is of formula III- 1 :or a pharmaceutically acceptable salt thereof.

29. The compound of claim 25, wherein the compound is of formula III-2:or a pharmaceutically acceptable salt thereof.

30. The compound of claim 25, wherein the compound is of formula III-3:or a pharmaceutically acceptable salt thereof.

31. The compound of claim 25, wherein the compound is of formula III-4:or a pharmaceutically acceptable salt thereof.

32. The compound of claim 25, wherein the compound is of formula IV- 1:or a pharmaceutically acceptable salt thereof.

33. The compound of claim 25, wherein the compound is of formula IV-2;or a pharmaceutically acceptable salt thereof.

34. The compound of claim 25, wherein the compound is of formula IV-3:or a pharmaceutically acceptable salt thereof.

35. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

36. A compound selected from Table 2, or a pharmaceutically acceptable salt thereof.

37. A compound selected from Table 3, or a pharmaceutically acceptable salt thereof.

38. A compound selected from Table 4, or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising the compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

40. A method for treating a disorder mediated by an estrogen receptor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, or the composition of claim 39.

41. The method of claim 40, wherein the disorder is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, vaginal cancer, lung cancer, bone cancer, uterine cancer, and endometriosis.

42. A method of treating a subject suffering from a cancer comprising administering the compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, or the composition of claim 39.

43. The method of claim 42, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, vaginal cancer, lung cancer, bone cancer, uterine cancer, and endometriosis.

44. The method of any one of claims 40-43, further comprising administering an additional anti-cancer agent.

45. The method of claim 44, wherein the additional anti-cancer agent is selected from an mTOR inhibitor, a CDK4 / 6 inhibitor, a CDK4-selective inhibitor, a PI3 kinase inhibitor, an aromatase inhibitor, an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4, or an antibody to or inhibitor of EGFR, PGFR, or IGFR.

46. The method of claim 45, wherein the anti-cancer agent is an mTOR inhibitor.

47. The method of claim 46, wherein the mTOR inhibitor is selected from everolimus, sirolimus, temsirolimus, and LY3023414.

48. The method of claim 45, wherein the anti-cancer agent is a CDK4 / 6 inhibitor.

49. The method of claim 48, wherein the CDK4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, lerociclib, trilaciclib, and SHR6390.

50. The method of claim 45, wherein the anti-cancer agent is a CDK4-selective inhibitor.

51. The method of claim 50, wherein the CDK4-selective inhibitor is PF-07220060.

52. The method of claim 45, wherein the anti-cancer agent is an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4.

53. The method of claim 45, wherein the anti-cancer agent is an antibody to or inhibitor of EGFR, PGFR, or IGFR.

54. The method of claim 45, wherein the anti-cancer agent is a HER2 inhibitor.

55. The method of claim 54, wherein the HER2 inhibitor is selected from tucatinib, trastuzumab, pertuzumab, ado-trastuzumab, trastuzumab emtansine, ado-trastuzumab emtansine, trastuzumab deruxtecan, pertuzumab, lapatinib, and neratinib.

56. The method of claim 45, wherein the anti-cancer agent is a PI3 kinase inhibitor.

57. The method of claim 56, wherein the PI3 kinase inhibitor is selected from perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145.

58. The method of claim 45, wherein the anti-cancer agent is a PIK3CA inhibitor.

59. The method of claim 58, wherein the PIK3CA inhibitor is selected from alpelisib, taselisib, LY3023414, Inavolisib, STX-478, RLY-2608, LOXO-783, and OKI-219.

60. The method of claim 45, wherein the anti-cancer agent is an aromatase inhibitor.

61. The method of claim 60, wherein the aromatase inhibitor is selected from aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 4-hydroxyandrostenedione, 1, 4, 6-androstatrien-3, 17-dione, and 4- androstene-3,6, 17-trione.

62. The method of claim 60, wherein the aromatase inhibitor is selected from anastrozole, letrozole, and exemestane.

63. A method of preventing recurrence of a cancer in a subject comprising administering to the subject the compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, or the composition of claim 39.

64. A method for inhibiting activation function 2 of the estrogen receptor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, or the composition of claim 39.

65. The method of claim 41, wherein the cancer is characterized by a mutation of Estrogen Receptor 1 (ESRI).

66. The method of claim 65, wherein the mutation is an activating mutation.

67. The method of claim 66, wherein the mutation is Y537C, Y537N, Y537S, S463P, D538G, or E38OQ.

68. The method of claim 66, wherein the mutation is Y537S or D538G.

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