Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2 alpha

Abstract

To provide a compound that inhibits activity of a low hypoxia inducible factor (HIF) family of a transcription factor, in particular of HIF-2α.SOLUTION: A composition comprising an equation (II) as well as the compound (one or more) and a method for synthesizing the compound are described. It also describes the use of such compounds and compositions for the treatment of a wide variety of diseases, disorders, and conditions, such as cancer and immune-related disorders mediated at least in part by HIF-2α.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Application No. 62 / 991,952, filed March 19, 2020, and U.S. Provisional Application No. 63 / 120,875, filed December 3, 2020, each of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Hypoxia-inducible factor (HIF) transcription factors play a key role in the cellular response to low oxygen availability [Immunity. 2014 Oct 16;41(4):518-528]. HIFs are heterodimeric transcription factors consisting of a common constituent subunit called the aryl hydrocarbon receptor nuclear translocator (ARNT, or HIF-β) and one of three HIF-α subunits [J. Med. Chem. 2015, 58, 5930-5941]. Under normal conditions, this α-subunit is hydroxylated at a conserved proline residue by prolyl-4-hydroxylase (PHD) and subsequently targeted for degradation by the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex [Cancer Res 2006;66(12):6264-70]. However, under hypoxic conditions, HIF-α accumulates and enters the nucleus, where it activates the expression of genes that regulate metabolism, angiogenesis, cell proliferation and survival, immune evasion, and inflammatory responses [J. Med. Chem. 2018, 61, 9691-9721.]

[0003] Among the three distinct α-subunit isoforms, HIF-1α, HIF-2α, and the less well-characterized HIF-3α, overexpression of HIF-1α and HIF-2α has been associated with poor clinical outcomes in patients with various cancers. Specifically, HIF-2α has been found to be a marker of poor prognosis in glioblastoma, neuroblastoma, head and neck squamous cell carcinoma, and non-small cell lung cancer. Hypoxia is also common in numerous acute and chronic inflammatory disorders, such as inflammatory bowel disease and rheumatoid arthritis [J. Clin Invest. 2016;126(10):3661-3671]. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Immunity. 2014 Oct 16;41(4):518-528 [Non-patent document 2] J. Med. Chem. 2015, 58, 5930-5941 [Non-patent document 3] Cancer Res 2006;66(12):6264-70 [Non-patent document 4] J. Med. Chem. 2018, 61, 9691-9721 [Non-Patent Document 5] J. Clin Invest. 2016;126(10):3661-3671 Summary of the Invention

[0005] Given the important role of HIF-2α in cancer, inflammation, and other disorders, there is a need in the art for HIF-2α inhibitors. The present invention addresses this need and further provides related advantages.

[0006] The present invention relates to compounds that inhibit the activity of the hypoxia inducible factor (HIF) family of transcription factors, particularly HIF-2α. The compounds have the formula (I):

[0007] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein W 1 , W 2 , W 3 , Y 1 , Y 2 , Y 3 , Y 4 , and R 1 has the meaning defined herein below.

[0008] In a related aspect, provided herein are methods for treating a disease or disorder mediated by HIF-2α in a subject (e.g., a human), comprising administering to the subject a therapeutically effective amount of at least one HIF-2α inhibitor described herein. HIF-2α-mediated diseases and disorders include cancer, inflammation, autoimmune disorders, and metabolic disorders, as described hereinafter. Other diseases, disorders, and conditions that can be treated or prevented, in whole or in part, by modulation of HIF-2α activity are candidate indications for the HIF-2α inhibitor compounds provided herein.

[0009] Also provided herein is the use of a HIF-2α inhibitor as described herein in combination with one or more additional agents as described hereinafter. DETAILED DESCRIPTION OF THE INVENTION

[0010] Before the present invention is further described, it is to be understood that the invention is not limited to particular embodiments described herein and that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0011] Where a range of values ​​is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range, and any other stated value or intervening value within that stated range, is encompassed within the invention unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, subject to any specifically excluded limit in the stated range, and are also encompassed within the invention. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0012] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to serve as a predicate for use of such exclusive terminology, such as "solely," "only," and the like, or for use of a "negative" limitation in connection with the recitation of claim elements.

[0013] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0014] definition Unless otherwise indicated, the following terms are intended to have the meanings indicated below. Other terms are defined elsewhere throughout the specification.

[0015] The term “alkyl,” by itself or as part of another substituent, has the specified number of carbon atoms (i.e., C 1-8means a straight or branched chain hydrocarbon group of 1 to 8 carbons. 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0016] The term "hydroxyalkyl" refers to a group having the indicated number of carbon atoms (e.g., C 1-6 or C 1-8 ) and substituted with one or two hydroxy (OH) groups.

[0017] The term "hydroxyhaloalkyl" refers to a group having the indicated number of carbon atoms (e.g., C 1-6 or C 1-8 ) and is substituted with 1 or 2 hydroxy (OH) groups and 1 to 6 halogen atoms (eg, F, Cl).

[0018] The term "alkylene" refers to a straight-chain or branched-chain saturated aliphatic group, i.e., a divalent hydrocarbon group, having the specified number of carbon atoms and linking at least two other groups. The two moieties linked to the alkylene can be attached to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) n-, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. In some embodiments, alkylene groups can be substituted or unsubstituted. It is understood that when a group containing alkylene is optionally substituted, the optional substitution can be present on the alkylene portion of the moiety.

[0019] The terms "cycloalkyl," "carbocycle," or "carbocyclic ring" refer to a ring having a specified number of ring atoms (e.g., C 3-6 "Cycloalkyl" refers to a hydrocarbon ring that is either fully saturated or has one or fewer double bonds between ring vertices. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. In some embodiments, the cycloalkyl compounds of the present disclosure are monocyclic C 3-6 It is a cycloalkyl moiety.

[0020] The terms "heterocycloalkyl," "heterocycle," or "heterocyclic ring" refer to a cycloalkyl ring having a specified number of ring vertices (or ring members) and having from 1 to 5 heteroatoms selected from N, O, and S replacing from 1 to 5 carbon vertices, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. The heterocycloalkyl may be a monocyclic, bicyclic, or polycyclic ring system and may have one or two double bonds connecting the ring vertices. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. Heterocycloheteroalkyl groups can be attached to the remainder of the molecule through a ring carbon or heteroatom. In some embodiments, the heterocycle is a 5- to 6-membered heterocycle.

[0021] As used herein, a wavy line crossing a single bond, double bond, or triple bond in any chemical structure shown herein

[0022] [ka] represents the point of attachment of a single, double, or triple bond to the rest of the molecule. Additionally, a bond extending into the center of a ring (e.g., a phenyl ring) is intended to indicate attachment at any of the available ring vertices. One of ordinary skill in the art will understand that multiple substituents shown attached to a ring will occupy any ring vertex that results in a stable compound or is sterically compatible. For divalent moieties, the representation is meant to include either orientation (forward or reverse). For example, the group "-C(O)NH-" is intended to include either the -C(O)NH- or -NHC(O)- attachment orientation; similarly, "-O-CHCH-" is meant to include both -O-CHCH- and -CHCH-O-.

[0023] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, "C 1-4 The term "haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0024] The term "aryl," unless otherwise specified, refers to a polyvalent unsaturated hydrocarbon group, typically an aromatic hydrocarbon group, which may be monocyclic or polycyclic (up to three rings), fused or covalently linked together. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl. The term is also intended to include fused cycloalkylphenyl and heterocycloalkylphenyl ring systems, such as, for example, indane, tetrahydronaphthalene, chroman, and isochroman rings. As a substituent, the point of attachment to the remainder of the molecule can be through a carbon atom of the aromatic portion, a carbon atom of the cycloalkyl portion, or an atom of the heterocycloalkyl portion for fused ring systems.

[0025] The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. Substituents for the heteroaryl ring can be selected from the group of acceptable substituents described below.

[0026] The above terms (e.g., "alkyl," "aryl," and "heteroaryl") are, in some embodiments, optionally substituted. Selected substituents for each type of radical are provided below.

[0027] Optional substituents for alkyl groups (including groups often referred to as alkylene, alkenyl, and alkynyl) can include a variety of groups, such as halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′-C(O)NR″R′, in a number ranging from zero to (2m′+1). R', R'', and R''' can each independently be a group selected from hydrogen, unsubstituted C(NH), ... 1-8 Alkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, C 1-8 Alkoxy or C 1-8 Thioalkoxy group, or unsubstituted aryl-C 1-4 refers to an alkyl group. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl.

[0028] Optional substituents on the cycloalkyl and heterocycloalkyl groups can be selected from a variety of groups, such as, for example, —C(O)OR′, halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)R′, —NH—C(NH)═NH, —NR′C(NH)═NH, —NH—C(NH)═NR′, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NR′S(O)R″, —CN(cyano), —NO, aryl, aryloxy, and alkyl optionally substituted with oxo (═O). R', R'' and R''' are each independently hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, C 1-8 Alkoxy group or C 1-8 Thioalkoxy group, or unsubstituted aryl-C 1-4 Refers to an alkyl group.

[0029] Optional substituents on the cycloalkyl and heterocycloalkyl groups can also include olefins (=CR'R''), where R' and R'' are each independently hydrogen, an unsubstituted C alkyl group, an unsubstituted aryl group, an aryl group substituted with 1 to 3 halogens, C 1-8 Alkoxy group or C 1-8 Thioalkoxy group, or unsubstituted aryl-C 1-4 It refers to an alkyl group. For example, the olefin can be an unsubstituted olefin (=CH2).

[0030] Similarly, the optional substituents for aryl and heteroaryl groups vary and can range from zero to open valences on the aromatic ring system. and R', R'' and R'' are selected from -halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -C02R', -CONR'R'', -C(O)R', -OC(O)NR'R'', -NR''C(O)R', -NR''C(O)2R', -NR'-C(O)NR''R'''', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -N3, perfluoro(C1-4)alkoxy, and perfluoro(C1-4)alkyl; 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl and C 2-8 and alkynyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of 1 to 6 carbon atoms.

[0031] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring are of the formula -TC(O)-(CH2) q Each of the aryl or heteroaryl rings may be optionally substituted with a substituent of the formula -U-, where T and U are independently -NH-, -O-, -CH2-, or a single bond, and q is an integer of 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be a group of the formula -A-(CR f R g ) r A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond; r is an integer from 1 to 3; and R f and R gare each independently H or halogen. One of the single bonds of the new ring thus formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be a group of the formula -(CH2) s -X-(CH2) t where s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C1-6 alkyl.

[0032] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[0033] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted, cyclic, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids, such as arginate, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0034] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms of the compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but are otherwise equivalent to the parent forms of the compounds for purposes of this invention.

[0035] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0036] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses envisioned by the present invention and are intended to be within the scope of the present invention.

[0037] Certain compounds of the present invention may exist as polymorphs under certain conditions.Polymorphism refers to the ability of a solid substance to exist in two or more crystalline structure forms or phases, where molecules in a crystal lattice have various arrangements or conformations.When these types of differences exist due to packing, they are called "packing polymorphs", and when these differences exist due to conformational differences, they are called "conformational polymorphs".Different polymorphs of the same compound often exhibit different physical properties, such as packing properties, spectroscopic properties, thermodynamic properties, solubility, and melting point; different kinetic properties, such as dissolution rate and stability; and different mechanical properties, such as hardness and tensile strength.

[0038] Polymorphs can be classified into one of two types according to their stability in different ranges of temperature and pressure.In monotropic system, only one polymorph (i.e., monotrope) is stable, which shows relatively low free energy content and solubility at all temperatures and pressures below the melting point.In enantiotropic system, one polymorph is stable at a specific temperature and pressure, while other polymorph(s) are stable at various temperatures and pressures.

[0039] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separate enantiomers) thereof are all intended to be encompassed within the scope of the present invention.

[0040] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. An unnatural proportion of an isotope may be defined as the amount found in nature to the amount that is made up of 100% of that atom. For example, a compound may contain an isotope of, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon-13 ( 13Non-radioactive isotopes, such as C, may be incorporated. Such isotopic variations may provide additional uses to those described elsewhere in this application. For example, isotopic variants of the compounds of the present invention may find additional uses, for example, but not limited to, as diagnostic and / or imaging reagents, or cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic properties that can contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0041] The terms "patient" and "subject" are used interchangeably to refer to a human or non-human animal (e.g., a mammal).

[0042] The terms "administration," "administering," and the like, when applied to, e.g., a subject, cell, tissue, organ, or biological fluid, refer to the contact of, e.g., an inhibitor of HIF-2α, a pharmaceutical composition comprising same, or a diagnostic agent, with the subject, cell, tissue, organ, or biological fluid. In the context of a cell, administration encompasses contact of a reagent with the cell (e.g., in vitro or ex vivo), as well as contact of a reagent with a fluid (where the fluid is in contact with the cell).

[0043] The terms "treat," "treating," "treatment," and the like refer to a course of action (e.g., administering an inhibitor of HIF-2α or a pharmaceutical composition comprising same) initiated after a disease, disorder, or condition, or a symptom thereof, has been diagnosed, observed, etc., to temporarily or permanently eliminate, reduce, suppress, alleviate, or ameliorate at least one of the underlying causes of the disease, disorder, or condition afflicting a subject, or at least one of the symptoms associated with the disease, disorder, or condition afflicting a subject. Thus, treatment encompasses inhibiting active disease (e.g., preventing the onset or further progression of the disease, disorder, or condition, or clinical symptoms associated therewith).

[0044] As used herein, the term "in need of treatment" refers to a judgment made by a physician or other caregiver that a subject needs or would benefit from treatment. This judgment is made based on a variety of factors within the physician's or caregiver's expertise.

[0045] The terms "prevent," "preventing," "prevention," and the like generally refer to a course of action (e.g., administering a HIF-2α inhibitor or a pharmaceutical composition comprising same) initiated (e.g., prior to the onset of the disease, disorder, condition, or symptoms thereof) in a manner that temporarily or permanently prevents, suppresses, arrests, or reduces the risk (e.g., as determined by the absence of clinical symptoms) of a subject developing a disease, disorder, condition, or the like, or delays its onset, generally with respect to a subject predisposed to a particular disease, disorder, or condition. In certain instances, these terms also refer to slowing the progression of a disease, disorder, or condition, or preventing its progression to a harmful or undesirable state.

[0046] As used herein, the term "in need of prevention" refers to a judgment made by a physician or other caregiver that a subject needs or would benefit from preventative care. This judgment is made based on a variety of factors within the physician's or caregiver's expertise.

[0047] The phrase "therapeutically effective amount" refers to the administration of an agent to a subject, alone or as part of a pharmaceutical composition, in an amount that, when administered to a subject, is capable of producing any detectable positive effect on any symptom, aspect, or characteristic of a disease, disorder, or condition, either as a single dose or as part of a series of doses. A therapeutically effective amount can be determined by measuring the relevant physiological effect and can be adjusted with respect to dosing regimens, diagnostic analysis of the subject's condition, and the like. For example, measuring serum levels of a HIF-2α inhibitor (or, for example, its metabolite) at a particular time after administration can indicate whether a therapeutically effective amount has been used.

[0048] The phrase "in an amount sufficient to effect a change" means that there is a detectable difference between the level of an indicator measured before administration of a particular therapy (e.g., baseline level) and the level of the indicator measured after administration, including any objective parameter (e.g., serum concentration) or subjective parameter (e.g., subject's sense of well-being).

[0049] The term "small molecule" refers to a compound having a molecular weight of less than about 10 kDa, less than about 2 kDa, or less than about 1 kDa. Small molecules include, but are not limited to, inorganic molecules, organic molecules, organic molecules containing inorganic components, molecules containing radioactive atoms, and synthetic molecules. Therapeutically, small molecules are more permeable to cells, less susceptible to degradation, and less likely to elicit an immune response than larger molecules.

[0050] The terms "inhibitor" and "antagonist" or "activator" and "agonist" refer to inhibitory or activating molecules, respectively, for the activation of, for example, a ligand, receptor, cofactor, gene, cell, tissue, or organ. An inhibitor is a molecule that decreases, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor can also be defined as a molecule that reduces, blocks, or inactivates constitutive activity. An "agonist" is a molecule that interacts with a target to cause or promote increased activation of the target. An "antagonist" is a molecule that opposes the action(s) of an agonist. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist; furthermore, an antagonist can also prevent, inhibit, or reduce the constitutive activity of a target, e.g., a target receptor, even in the absence of the same agonist.

[0051] The terms "modulate," "modulation," and the like refer to the ability of a molecule (e.g., an activator or inhibitor) to directly or indirectly increase or decrease the function or activity of HIF-2α. Modulators can act alone or can use cofactors, such as proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds and other bioorganic molecules.

[0052] The "activity" of a molecule may describe or refer to the binding of the molecule to a ligand or receptor; catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation or maturation; antigenic activity; modulation of the activity of other molecules, etc. The term "proliferative activity" includes, for example, activity that promotes, is required for, or is specifically associated with normal cell division, as well as cancer, tumors, metaplasia, cell transformation, metastasis, and angiogenesis.

[0053] As used herein, "comparable," "comparable activity," "activity comparable to," "comparable effect," "effect comparable to," and the like are relative terms that can be considered quantitatively and / or qualitatively. The meaning of the terms often depends on the context in which they are used. As an example, two agents that both activate a receptor may be considered to have comparable effects from a qualitative standpoint, but if one agent achieves only 20% of the activity of the other agent as determined in an art-recognized assay (e.g., a dose-response assay) or an art-recognized animal model, the two agents may not be considered to have comparable effects from a quantitative standpoint. When comparing one result to another (e.g., comparing one result to a reference standard), "comparable" often (but not always) means that one result deviates from the reference standard by less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%. In certain embodiments, a result is equivalent to the reference standard if it deviates from the reference standard by less than 15%, less than 10%, or less than 5%. By way of example, and not limitation, activity or effect may refer to efficacy, stability, solubility, or immunogenicity.

[0054] "Substantially pure" indicates that a component constitutes more than about 50% of the total content of the composition, typically more than about 60% of the total polypeptide content. More typically, "substantially pure" refers to a composition in which the component of interest constitutes at least 75%, at least 85%, at least 90%, or more of the total composition. In some instances, the polypeptide constitutes more than about 90%, or more than about 95%, of the total content of the composition.

[0055] Selective compounds may be particularly useful in treating certain disorders or may provide a reduced likelihood of unwanted side effects. In one embodiment, the compounds of the present disclosure are selective over other HIF isoforms. In yet another embodiment, the compounds of the present disclosure are selective over other kinases and targets in the HIF signaling pathway. Specific examples include HIF-1α and cytochrome P450 enzymes. Selectivity can be determined, for example, by comparing the inhibition of HIF-2α by a compound described herein to the inhibition of another protein by a compound described herein. In one embodiment, the selective inhibition of HIF-2α is at least 1000-fold, 500-fold, 100-fold, or 20-fold greater than the inhibition of another protein or isoform.

[0056] The compounds provided herein can have advantageous pharmacokinetic profiles, such as, for example, hepatocellular stability, clearance, and inhibition of CYPs.

[0057] The term "response," e.g., of a cell, tissue, organ, or organism, encompasses a change in biochemical or physiological behavior, e.g., a change in concentration, density, adhesion, or migration within a biological compartment, a rate of gene expression, or a state of differentiation, where the change correlates with activation, stimulation, or treatment, or correlates with internal mechanisms such as genetic programming. In certain contexts, terms such as "activation," "stimulation," and the like refer to cellular activation regulated by internal mechanisms as well as by external or environmental factors; whereas terms such as "inhibition," "downregulation," and the like refer to the opposite effect.

[0058] Disclosed Compounds In one particular embodiment, the compound of formula (I) is provided herein:

[0059] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: Y1 , Y 2 , Y 3 and Y 4 is CR 2 R 3 , N.R. 4 , C.R. 6 R 7 , N.R. 7 , O, SO, and a bond; Y 1 , Y 2 , Y 3 and Y 4 One of them is CR 6 R 7 or NR 7 and;Y 1 , Y 2 , Y 3 and Y 4 0 or 1 (not more than 1) of the W 1 , W 2 and W 3 is CR 5 and N; R 1 is H, halogen, hydroxy, CN, NO2, -NR a R b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , -S(O)(=NH)R a , and -S(O)NR a R b selected from the group consisting of: Each R 2 and R 3 H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)NR a R b , -S(O)(=NH)R a , and -NR a R b each independently selected from the group consisting of: Each R 4 is H, C 1-4 Alkyl, C 3-8 Cycloalkyl and -C(O)R a are independently selected from Each R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)NR a R b , -S(O)(=NH)R a , and -NR a R b independently selected from the group consisting of: R 6 is H, C 1-4 selected from the group consisting of alkyl, OH, F, and CN; R 7 is the following formula:

[0060] [ka] is a group having the formula: X 1 is N or CR 8a and; X 2 is N or CR 8b and; R 8a and R 8b H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b , -S(O)NR a R b , and -S(O)R a independently selected from the group consisting of: R 9 and R 10 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)NR a R b , and -S(O)R a independently selected from the group consisting of: R 11 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b , -S(O)NR c R b , -S(O)(=NH)R c , -S(O)2R c and a 5- or 6-membered heterocyclic or heteroaryl ring having 1 to 3 heteroatoms selected from N, O and S as ring vertices; wherein the heterocyclic or heteroaryl ring is selected from halogen, CN, NO, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl and C 1-4 Alkoxy C 1-4 optionally substituted with 1 to 3 members independently selected from alkyl; Or R 9 and R 10 is combined with R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 forming a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic, or heteroaryl ring optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from: Or R 10 and R 11 is combined with R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R18 and R 19 forming a 5- or 6-membered carbocyclic, heterocyclic, or heteroaryl ring optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each of these is H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b or two R on the same carbon atom are independently selected from the group consisting of 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 The moieties are linked to form an oxo group; Each R a and R b is H, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, and C 1-8 hydroxyalkyl; R c If present, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein the heterocycloalkyl ring or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices; However, R a , R b , and R c When bonded to a group to which is attached, N-oxide and peroxide bonds are not formed. The above compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided.

[0061] In some selected embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is Y 2 , Y 3 and Y 4 Each of these is CR 2 R 3 It is a compound in which

[0062] In some selected embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is Y 2 and Y 3 Each of these is CR 2 R 3 and Y 4 is a bond.

[0063] In some selected embodiments, the compound of formula (I) has formula (II):

[0064] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Z is N or CR 6 and the remaining groups have the meanings given for formula (I).

[0065] In some selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, has the formula (II):

[0066] [ka] wherein Z is N or CR 6 and; Y 2 , Y 3 and Y 4 is CR 2 R 3 , N.R. 4 , O, SO, and a bond; Y 2 , Y 3 and Y 4 0 or 1 of is a bond; W 1 , W 2 and W 3 is CR 5 and N; R 1 is H, halogen, hydroxy, CN, NO2, -NR a R b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , -S(O)(=NH)R a , and -S(O)NR a R b selected from the group consisting of: Each R 2 and R 3 H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)NR a R b , -S(O)(=NH)R a , and -NR a R b each independently selected from the group consisting of: Each R 4 is H, C 1-4 Alkyl, C 3-8 Cycloalkyl and -C(O)R a are independently selected from Each R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)NR a R b , -S(O)(=NH)R a , and -NR a R b independently selected from the group consisting of: X 1 is N or CR 8a and; X 2 is N or CR 8b and; R 8a and R 8b H, halogen, CN, NH2, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b , -S(O)NR a R b , and -S(O)R a independently selected from the group consisting of: R 9 and R 10 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)NR a R b , and -S(O)R a independently selected from the group consisting of: R 11 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -NR c R b , -C(O)NR c R b , -C(O)OH, -S(O)NR c R b , -S(O)(=NH)R c , -S(O)2R c, phenyl, a 5- to 6-membered heterocyclic ring, or a 5- to 10-membered heteroaryl ring, wherein the heterocyclic ring and heteroaryl ring have 1 to 3 heteroatoms selected from N, O, and S as ring vertices; the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; the phenyl, heterocyclic ring, or heteroaryl ring is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl, heterocyclic ring, or heteroaryl ring is optionally fused to a 5- or 6-membered heterocyclic ring having halogen, CN, NO, NH, C(O)NH, S(O)CH, —CHNH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl and C 1-4 Alkoxy C 1-4 optionally substituted with 1 to 3 members independently selected from alkyl; optionally, two members attached to the same carbon of said heterocyclic ring taken together form a =CH2 or oxo (=O) group; Or R 9 and R 10 is combined with R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 forming a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaryl ring optionally substituted with one or more substituents independently selected from: Or R 10 and R 11 is combined with R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19forming a 5- or 6-membered carbocyclic, heterocyclic, or heteroaryl ring optionally substituted with one or more substituents independently selected from: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each of these is H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b or two R on the same carbon atom are independently selected from the group consisting of 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 The moieties are linked to form an oxo group; Each R a and R b is H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, and C 1-8 hydroxyalkyl; R c If present, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6It is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein the heterocycloalkyl ring or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices.

[0067] In some embodiments, the compound of formula (II) is Y 2 is CR 2 R 3 where each R 2 and R 3 is H;Y 3 and Y 4 are CR 2 R 3 where each R 2 and R 3 is a compound independently selected from H and F, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0068] In some embodiments, the compound of formula (II) is R 11 SO2R c or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, R c is C 1-8 Alkyl or C 1-8 It is haloalkyl.

[0069] In some embodiments, the compound of formula (II) is R 11 But the following:

[0070] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0071] In some selected embodiments, the compound of formula (I) has formula (III):

[0072] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, Y 2 , Y 3 and Y 4 is CR 2 R 3 , N.R. 4 , SO2, O, and a bond; Y 2 , Y 3 and Y 4 0 or 1 of is a bond; W 1 and W 3 are each independently selected from CH and N; Z is N or CR 6 and; R 1 is selected from the group consisting of halogen and CN; Each R 2 and R 3 H, halogen, CN, NO2, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -S(O)R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)NR a R b , -S(O)(=NH)R a , and -NR a R b each independently selected from the group consisting of: Each R 4 is H, C 1-3 Alkyl, C 3-6 Cycloalkyl and -C(O)R a are independently selected from; R 5a is selected from the group consisting of hydrogen, halogen, and CN; R 6 is H; X 1 is N or CR 8a and; X 2 is N or CR 8b and; R 8a and R 8b H, halogen, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-3 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b , -S(O)NR a R b , and -S(O)R a independently selected from the group consisting of: R 9 and R 10 H, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 1-3 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)NR a R b , and -S(O)R a independently selected from the group consisting of: R 11 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b , -C(O)OH, -S(O)NR c R b , -S(O)(=NH)R c , -S(O)2R c , phenyl, and a 5- or 6-membered heterocyclic ring or a 5- to 10-membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring has 1 to 3 heteroatoms selected from N, O, and S as ring vertices; the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; the phenyl, heterocyclic ring, or heteroaryl ring is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl, heterocyclic ring, or heteroaryl ring is optionally fused to a 5- or 6-membered heterocyclic ring having halogen, CN, NO, NH, C(O)NH, S(O)CH, —CHNH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 1-3 Hydroxyhaloalkyl and C 1-3 Alkoxy C 1-4 optionally substituted with 1 to 3 members independently selected from alkyl; optionally, two members attached to the same carbon of said heterocyclic ring taken together form a =CH2 or oxo (=O) group; Or R 9 and R 10 is combined with R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19forming a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaryl ring optionally substituted with one or more substituents independently selected from: Or R 10 and R 11 is combined with R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 forming a 5- or 6-membered carbocyclic, heterocyclic, or heteroaryl ring optionally substituted with one or more substituents independently selected from: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each of these is H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b or two R on the same carbon atom are independently selected from the group consisting of 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 The moieties are linked to form an oxo group; Each R a and R b is H, C 1-3 Alkyl, C 1-3Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, and C 1-3 independently selected from the group consisting of hydroxyalkyl; R c If present, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6 It is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, and the heterocycloalkyl ring or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices.

[0073] In some selected embodiments, the compound of formula (I) has formula (III):

[0074] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Y 2 , Y 3 and Y 4 is CR 2 R 3 , N.R. 4 , SO2, O, and a bond; Y 2 , Y 3 and Y 4 0 or 1 of is a bond; W 1 and W 3 are each independently selected from CH and N; Z is N or CR 6 and; R 1 is selected from the group consisting of halogen and CN; Each R 2 and R 3 H, halogen, CN, NO2, OH, C 1-3 Alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -S(O)R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)NR a R b , -S(O)(=NH)R a , and -NR a R b are each independently selected from the group consisting of: Each R 4 is H, C 1-3 Alkyl, C 3-6 Cycloalkyl and -C(O)R a are independently selected from; R 5a is selected from the group consisting of hydrogen, halogen, and CN; R 6 is H; X 1 is N or CR 8a and; X 2 is N or CR 8b and; R 8a and R 8b H, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-3 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b , -S(O)NR a R b , and -S(O)R a independently selected from the group consisting of: R9 and R 10 H, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 1-3 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)NR a R b , and -S(O)R a independently selected from the group consisting of: R 11 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Harolkill, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b , -S(O)NR c R b , -S(O)(=NH)R c , -S(O)2R c and a 5- or 6-membered heterocyclic or heteroaryl ring having 1 to 3 heteroatoms selected from N, O and S as ring vertices; wherein the heterocyclic or heteroaryl ring is selected from halogen, CN, NO, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 1-3 Hydroxyhaloalkyl and C 1-3 Alkoxy C1-4 optionally substituted with 1 to 3 members independently selected from alkyl; Or R 9 and R 10 is combined with R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 forming a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaryl ring optionally substituted with, each of said heterocyclic or heteroaryl rings having 1 to 4 heteroatoms selected from N, O and S as ring vertices; Or R 10 and R 11 is combined with R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 forming a 5- or 6-membered carbocyclic, heterocyclic, or heteroaryl ring optionally substituted with, each of said heterocyclic or heteroaryl rings having 1 to 4 heteroatoms selected from N, O, and S as ring vertices; R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each of these is H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b or two R on the same carbon atom are independently selected from the group consisting of 12 , R 13 , R14 , R 15 , R 16 , R 17 , R 18 and R 19 The moieties are linked to form an oxo group; Each R a and R b is H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, and C 1-3 independently selected from the group consisting of hydroxyalkyl; R c If present, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6 It is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, and the heterocycloalkyl ring or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices.

[0075] In some embodiments, the compound of formula (III) is Y 2 is CR 2 R 3 where each R 2 and R 3 is H;Y 3 and Y 4 are CR 2 R 3 where each R 2 and R 3 is a compound independently selected from H and F, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0076] In some embodiments, the compound of Formula (III) is 5a is a halogen and R 4 is CR 2 R 3 and R 2and R 3 is selected from H, F, and OCH3, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0077] In some embodiments, the compound of formula (III) is R 11 is phenyl, a 5- or 6-membered heterocyclic ring, or a 5- to 10-membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring has 1 to 3 heteroatoms selected from N, O, and S as ring vertices; the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; the phenyl ring, heterocyclic ring, or heteroaryl ring is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl ring, heterocyclic ring, or heteroaryl ring is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl and C 1-4 Alkoxy C 1-4 and optionally substituted with 1 to 3 members independently selected from alkyl; and optionally, two members attached to the same carbon of the heterocyclic ring taken together form a =CH2 or oxo (=O) group, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0078] In some selected embodiments, the compound of formula (I) has formula (IV-a):

[0079] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Y 2 , Y 3 and Y 4 is CR 2 R 3 , N.R. 4Y is independently selected from the group consisting of , SO2, and a bond; 2 , Y 3 and Y 4 0 or 1 of is a bond; R 1 are halogens, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)R a and -C(O)NR a R b selected from the group consisting of: Each R 2 and R 3 H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a and -C(O)NR a R b each independently selected from the group consisting of: Each R 4 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl and -C(O)R a independently selected from the group consisting of: Each R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -S(O)NR a R b are independently selected from the group consisting of The remaining groups have the meanings given for Formula (I). In some embodiments of compounds of Formula (IV-a), the remaining groups have the meanings given for Formula (II).

[0080] In some embodiments, the compound of formula (IV-a) is X 1 and X 2 is a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

[0081] In some selected embodiments, the compound of formula (I) has formula (IV-b):

[0082] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein The subscript m is 1, 2, 3, 4, 5, 6, 7, or 8; The subscript n is 1 or 2; R z is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 represents one or more of; Y 2 , Y 3 and Y 4 is CR 2 R 3 , N.R. 4 Y is independently selected from the group consisting of , SO2, and a bond; 2 , Y 3 and Y 4 0 or 1 of is a bond; R 1 are halogens, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)R aand -C(O)NR a R b selected from the group consisting of: Each R 2 and R 3 H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a and -C(O)NR a R b each independently selected from the group consisting of: Each R 4 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl and -C(O)R a are independently selected from; R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -S(O)NR a R b selected from the group consisting of: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each of these is H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NRa R b or two R on the same carbon atom are independently selected from the group consisting of 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 The moieties are linked to form an oxo group, The remaining groups have the meanings given for formula (I). In some embodiments of compounds of formula (IV-b), the remaining groups have the meanings given for formula (II).

[0083] In some embodiments, the compound of formula (IV-b) is Y 4 is a member selected from the group consisting of O and NH, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0084] In some selected embodiments, the compound of formula (I) has formula (IV-c):

[0085] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein A 1 is O or CHR 13 and; Y 2 , Y 3 and Y 4 is CR 2 R 3 , N.R. 4 Y is independently selected from the group consisting of , SO2, and a bond; 2 , Y 3 and Y 4 0 or 1 of is a bond; R 1 are halogens, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Haloalkoxy, -S(O)R a and -C(O)NR a R b selected from the group consisting of: R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -S(O)NR a R b selected from the group consisting of: R 11 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b , -S(O)NR c R b , -S(O)(=NH)R c , and -S(O)R c selected from the group consisting of: R 13 , R 14 and R 15 Each of these is H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b independently selected from the group consisting of: R 16 is H, C1-4 Alkyl and C 1-4 fluoroalkyl; The remaining groups have the meanings given for Formula (I). In some embodiments of compounds of Formula (IV-c), the remaining groups have the meanings given for Formula (II).

[0086] In some selected embodiments, the compound of formula (IV-c) is R 8b is H, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0087] In some embodiments, the compound of formula (IV-c) is Y 2 is CR 2 R 3 where each R 2 and R 3 is H;Y 3 and Y 4 are CR 2 R 3 where each R 2 and R 3 is a compound independently selected from H and F, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0088] In some selected embodiments, the compound of formula (I) has formula (IV-d):

[0089] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R 1 are halogens, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)R a and -C(O)NR a R b selected from the group consisting of: R 2 and R 3H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b each independently selected from the group consisting of: R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -S(O)NR a R b selected from the group consisting of: R 11 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-6 Hydroxyfluoroalkyl, C 3-8 Cycloalkyl, -C(O)NR c R b , -S(O)NR c R b , -S(O)(=NH)R c , and -S(O)R c selected from the group consisting of: R 12 , R 13 , R 14 and R 15 Each of these is H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy and -NR a R b are independently selected from the group consisting of The remaining groups have the meanings given for Formula (I). In some embodiments of compounds of Formula (IV-d), the remaining groups have the meanings given for Formula (II).

[0090] In some selected embodiments, the compound of formula (I) has formula (IV-e):

[0091] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 are halogens, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)R a and -C(O)NR a R b selected from the group consisting of: R 2 and R 3 H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b each independently selected from the group consisting of: R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -S(O)NR a R b selected from the group consisting of: R 13 and R15 are H, F and C 1-4 independently selected from the group consisting of alkyl; R 20 is C 1-6 Alkyl and C 1-6 fluoroalkyl; The remaining groups have the meanings given for formula (I).

[0092] In some embodiments, the compound of formula (IV-e) is R 20 is selected from the group consisting of methyl, fluoromethyl, difluoromethyl and trifluoromethyl, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0093] In some selected embodiments, the compound of formula (II) has the formula (IV-f):

[0094] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the groups have the meanings given for formula (II). In some embodiments of the compound of formula (IV-f), R 8b is H.

[0095] In some selected embodiments, the compound of formula (I) has the formula (Va):

[0096] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the groups have the meanings given for Formula (I). In some embodiments of the compound of Formula (Va), the groups have the meanings given for Formula (II).

[0097] In some selected embodiments, the compound of formula (I) has the formula (Vb):

[0098] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Each R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)NR a R b , -S(O)(=NH)R a , and -NR a R b independently selected from the group consisting of: The remaining groups have the meanings given for Formula (I). In some embodiments of compounds of Formula (Vb), the remaining groups have the meanings given for Formula (II).

[0099] In some embodiments, the compound of Formula (Vb) is R 9 and R 10 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)NR a Rb , and -S(O)R a R 11 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b , -S(O)NR c R b , and -S(O)R c or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0100] In some selected embodiments, the compound of formula (I) has the formula (Vc):

[0101] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: Y 2 , Y 3 and Y 4 is CR 2 R 3 , N.R. 4 Y is independently selected from the group consisting of , SO2, and a bond; 2 , Y 3 and Y 4 0 or 1 of is a bond; R 1 are halogens, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)R a and -C(O)NR a R b selected from the group consisting of: R2 and R 3 H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -NR a R b each independently selected from the group consisting of: R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -S(O)NR a R b selected from the group consisting of: The remaining groups have the meanings given for formula (I). In some embodiments of compounds of formula (Vc), the remaining groups have the meanings given for formula (II).

[0102] In some selected embodiments, the compound of formula (I) has the formula (Vd):

[0103] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Y 2 , Y 3 and Y 4 is CR 2 R 3 and a bond; Y 2 , Y 3 and Y 4 0 or 1 of is a bond; R 1 are halogens, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)R a and -C(O)NR a R b selected from the group consisting of: R 2 and R 3 H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -NR a R b each independently selected from the group consisting of: R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -S(O)NR a R b selected from the group consisting of: The remaining groups have the meanings given for Formula (I). In some embodiments of compounds of Formula (Vd), the remaining groups have the meanings given for Formula (II).

[0104] In some selected embodiments, the compound of formula (I) has the formula (Ve):

[0105] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R 1 are halogens, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)R a and -C(O)NR a R b selected from the group consisting of: R 2 and R 3 H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -NR a R b each independently selected from the group consisting of: R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -S(O)NR a R b selected from the group consisting of: The remaining groups have the meanings given for formula (I). In some embodiments of compounds of formula (Vd), the remaining groups have the meanings given for formula (II).

[0106] In some embodiments, the compound of formula (Ve) is R 9 and R 10are combined to form R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which forms a 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with

[0107] In some embodiments, the compound of formula (Ve) is R 9 and R 10 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)NR a R b , and -S(O)R a or a pharmaceutically acceptable salt, hydrate, or solvate thereof, independently selected from the group consisting of:

[0108] In some selected embodiments, the compound of formula (I) has the formula (Vf):

[0109] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein The subscript m is 1, 2, 3, 4, 5, 6, 7, or 8; The subscript n is 1 or 2; R z is R 12, R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 represents one or more of; Y 2 , Y 3 and Y 4 is CR 2 R 3 , N.R. 4 Y is independently selected from the group consisting of , SO2, and a bond; 2 , Y 3 and Y 4 0 or 1 of is a bond; R 1 are halogens, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)R a and -C(O)NR a R b selected from the group consisting of: Each R 2 and R 3 H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)R a and -C(O)NR a R b each independently selected from the group consisting of: Each R 4 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl and -C(O)R a are independently selected from R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -S(O)NR a R b selected from the group consisting of: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each of these is H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b or two R on the same carbon atom are independently selected from the group consisting of 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 The moieties are linked to form an oxo group; The remaining groups have the meanings given for Formula (I). In some embodiments of compounds of Formula (Vf), the remaining groups have the meanings given for Formula (II).

[0110] In some selected embodiments, the compound of formula (I) has the formula (Vg):

[0111] [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R 1 are halogens, CN, C 1-4 Alkyl, C1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)R a and -C(O)NR a R b selected from the group consisting of: R 2 and R 3 H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b each independently selected from the group consisting of: R 5 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)R a , -C(O)NR a R b , and -S(O)NR a R b selected from the group consisting of: R 11 H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -C(O)NR c R b , -S(O)NR c R b , -S(O)(=NH)R c , and -S(O)R c selected from the group consisting of: R 12 , R 13 , R 14 and R 15 Each of these is H, halogen, CN, OH, C1-4 Alkyl, C 1-4 Alkoxy and -NR a R b independently selected from the group consisting of: The remaining groups have the meanings given for formula (I).

[0112] In some embodiments, the compound of Formula (Vg) is R 11 is phenyl, a 5- or 6-membered heterocyclic ring, or a 5- to 10-membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring has 1 to 3 heteroatoms selected from N, O, and S as ring vertices; the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; the phenyl ring, heterocyclic ring, or heteroaryl ring is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl ring, heterocyclic ring, or heteroaryl ring is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl and C 1-4 Alkoxy C 1-4 and optionally substituted with 1 to 3 members independently selected from alkyl; and optionally, two members attached to the same carbon of the heterocyclic ring taken together form a =CH2 or oxo (=O) group, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0113] In some selected embodiments, a compound of any one of Table 1, Table 2, or Table 3 is provided.

[0114] Identification of HIF-2α inhibitors with desirable properties The present invention relates, in part, to the identification of inhibitors of HIF-2α that have at least one therapeutically relevant property or characteristic. Candidate inhibitors can be identified, for example, by using art-recognized assays or models, examples of which are described herein.

[0115] After identification, candidate inhibitors can be further evaluated using techniques that provide data on the inhibitor's properties (e.g., means of determining pharmacokinetic parameters, solubility, or stability). Comparison of candidate inhibitors with a reference standard (which may be a "best in class" of current inhibitors) indicates the potential viability of such candidates.

[0116] Synthesis method General Methods for the Preparation of Claimed Compounds In order to ensure the most efficient preparation of any particular compound of the present invention, one of skill in the art will recognize that the timing and order of attachment of fragments, as well as the modification of functionality present on any of the fragments, may be varied in the preparation of any given compound. A variety of methods have been used to prepare the compounds of the present invention, some of which are illustrated in the Examples.

[0117] Prodrugs and other means of drug delivery and / or half-life extension In some aspects of the present invention, the compounds described herein are administered in prodrug form.

[0118] To provide extended therapeutic activity, drug molecules can be engineered to utilize carriers for delivery. Such carriers are used either in a non-covalent manner by physicochemically formulating the drug moiety in a solvent-carrier mixture, or by permanent covalent attachment of the carrier reagent to one of the functional groups of the drug moiety (see generally WO 2015 / 0202317).

[0119] Some noncovalent approaches are preferred. By way of example, and not limitation, certain embodiments utilize depot formulations involving noncovalent drug encapsulation in a polymeric carrier. In such formulations, drug molecules are combined with a carrier material and processed to disperse the drug molecules within the bulk carrier. Examples include microparticle polymer-drug aggregates administered as an injectable suspension (e.g., Degradex® Microspheres (Phosphorex, Inc.)); polymer-drug molecule aggregates formulated as a gel administered as a single bolus injection (e.g., Lupron Depot® (AbbVie Inc.)); and liposomal formulations (e.g., DepoCyt® (Pacira Pharmaceuticals)), in which the carrier can be a polymeric or non-polymeric substance capable of solubilizing the drug. In these formulations, release of the drug molecules can occur when the carrier swells or physically deteriorates. In other examples, chemical degradation allows the drug to diffuse into the biological environment; such chemical degradation processes can be autohydrolytic or enzyme-catalyzed. Among other limitations, non-covalent drug encapsulation requires prevention of uncontrolled drug release, and reliance on biodegradation as the drug release mechanism can lead to inter-patient variability.

[0120] In certain embodiments, drug molecules, including both small and large molecules, are conjugated to carriers through permanent covalent bonds. Certain small molecule therapeutic agents that exhibit low solubility in aqueous fluids can be solubilized by conjugation to hydrophilic polymers, examples of which are described elsewhere herein. For large protein molecules, half-life extension can be achieved by permanent covalent modification, for example, with a palmitoyl moiety and another protein (e.g., Albuferon®) that itself has an extended half-life. Generally, when a carrier is covalently conjugated to a drug, the drug molecule exhibits reduced biological activity.

[0121] In certain instances, limitations associated with either non-covalent polymer mixtures or drug molecules containing permanent covalent bonds can be successfully addressed by utilizing a prodrug approach for chemical conjugation of drugs to polymeric carriers. In this context, therapeutic agents that are inactive or less active than the drug moiety itself are predictably converted into active molecular entities. The reduced biological activity of the prodrug compared to the released drug is advantageous when sustained or controlled release of the drug is desired. In such instances, drug release occurs over time, thereby reducing the need for repeated and frequent drug administration. The prodrug approach can also be advantageous when the drug moiety itself is not absorbed or has suboptimal absorption in the gastrointestinal tract; in these instances, the prodrug facilitates absorption of the drug moiety and is subsequently cleaved (e.g., by first-pass metabolism) some time later. Biologically active drug molecules are typically attached to the polymeric carrier moiety via temporary bonds formed between the carrier moiety and a hydroxy, amino, or carboxy group on the drug molecule.

[0122] The above approaches are associated with several limitations. Prodrug activation can occur by enzymatic or non-enzymatic cleavage of the temporary bond between the carrier and drug molecule, or by a sequential combination of both (e.g., an enzymatic step followed by a non-enzymatic modification). In an enzyme-free in vitro environment (e.g., a buffered aqueous solution), temporary bonds such as esters or amides can undergo hydrolysis, but the associated hydrolysis rate can be outside the therapeutically useful range. In contrast, in vivo environments typically involve esterases or amidases, which can cause significant catalytic acceleration of the hydrolysis rate, ranging from two-fold to several orders of magnitude (see, e.g., Greenwald et al., (1999) J Med Chem 42(18):3857-67).

[0123] As described herein, prodrugs can be classified into i) bioprecursors and ii) carrier-linked prodrugs. Bioprecursors do not contain a carrier group and are activated by metabolic generation of a functional group. In contrast, in carrier-linked prodrugs, the active substance is conjugated to the carrier moiety via a temporary bond at a functional group on the bioactive substance. Preferred functional groups are hydroxyl or amino groups. Both the attachment chemistry and hydrolysis conditions depend on the type of functional group utilized. The carrier can be biologically inert (e.g., PEG) or can have targeting properties (e.g., antibodies). Cleavage of the carrier moiety of a carrier-linked prodrug yields the bioactive substance of interest, and the nature of the deprotected functional group on the bioactive substance often contributes to its bioactivity.

[0124] The patent and scientific literature describes many polymeric prodrugs in which the temporary bond is a labile ester bond. In these examples, the functional group of the bioactive substance is either a hydroxyl group or a carboxylic acid (see, e.g., Cheng et al. (2003) Bioconjugate Chem 14:1007-17). Furthermore, for biopolymers and certain small molecule drugs, it is often advantageous to attach the carrier to one or more amino groups of the bioactive substance (e.g., the N-terminus or lysine amino groups of proteins). During the preparation of prodrugs, these amino groups can be addressed more chemoselectively due to their greater nucleophilicity compared to hydroxyl or phenol groups. This is particularly relevant for proteins and peptides, which contain a wide variety of different reactive functional groups, where nonselective conjugation reactions result in undesirable product mixtures that require extensive characterization or purification, thereby reducing the reaction yield and therapeutic efficacy of the active moiety.

[0125] Generally, amide bonds are more stable to hydrolysis than ester bonds, and the cleavage rate of the amide bond may be too slow for the therapeutic use of carrier-linked prodrugs. As a result, it may be advantageous to add a structural chemical moiety to exert control over the cleavage of the prodrug amide bond. These additional cleavage-controlling chemical moieties, not provided by either the carrier substance or the drug, are generally referred to as "linkers." Prodrug linkers can significantly affect the hydrolysis rate of the temporary bond, and changes in the chemical nature of the linker often result in specific properties. Prodrug activation of amine-containing biologically active moieties by specific enzymes for targeted release requires that the linker structure present a structural motif recognized as a substrate by the corresponding endogenous enzyme. In these examples, cleavage of the temporary bond occurs in a single-step process catalyzed by the enzyme. For example, the enzymatic release of cytarabine is affected by the protease plasmin, the concentration of which is relatively high in various types of tumor masses.

[0126] Inter-patient variability is a major drawback of primary enzyme cleavage. Enzyme levels can vary significantly between subjects, resulting in biological variability in prodrug activation by enzymatic cleavage. Enzyme levels can also vary depending on the administration site (e.g., for subcutaneous injection, certain areas of the body produce more predictable therapeutic effects than others). Furthermore, it is difficult to establish in vivo-in vitro correlations of pharmacokinetic properties for enzyme-dependent carrier-bound prodrugs.

[0127] Other carrier prodrugs that utilize a temporary bond to the amino group of a drug moiety are based on a cascade mechanism. Cascade cleavage is made possible by a linker compound consisting of the structural combination of a masking group and an activating group. The masking group is attached to the activating group through a first temporary bond, such as an ester or carbamate. The activating group is attached to the amino group of the drug molecule through a second temporary bond (e.g., a carbamate). The hydrolytic stability or susceptibility of the second temporary bond depends on the presence or absence of the masking group. In the presence of the masking group, the second temporary bond is highly stable and unlikely to release the drug molecule at therapeutically useful kinetics, whereas in the absence of the masking group, this bond is highly unstable, resulting in rapid cleavage and release of the drug moiety.

[0128] The cleavage of the first temporary bond is the rate-limiting step in the cascade mechanism. The first step can induce intramolecular rearrangement of the activating group (e.g., 1,6-elimination as described in Greenwald et al. (1999) J Med Chem 42:3657-67), which makes the second temporary bond even more unstable so that its cleavage can be induced. Ideally, the cleavage rate of the first temporary bond is identical to the desired release rate for the drug molecule in a given therapeutic scenario. Furthermore, it is desirable that the cleavage of the second temporary bond occurs substantially immediately after its instability is induced by the cleavage of the first temporary bond.

[0129] Another embodiment includes polymeric amino-containing prodrugs based on trimethyl lock lactonization (see, e.g., Greenwald et al. (2000) J Med Chem 43(3):457-87). In this prodrug system, a substituted o-hydroxyphenyl-dimethylpropionic acid is attached to PEG through an ester, carbonate, or carbamate group as the first temporary bond and to the amino group of the drug molecule through an amide bond as the second temporary bond. The rate-limiting step in drug release is enzymatic cleavage of the first bond, followed by rapid amide cleavage via lactonization, releasing an aromatic lactone by-product. The major disadvantage of the prodrug system described by Greenwald et al. is the release of highly reactive and potentially toxic small aromatic molecule by-products, such as quinone methides or aromatic lactones, after temporary bond cleavage. The potentially toxic substances are released in a 1:1 stoichiometry with the drug, and high in vivo concentrations can be expected.

[0130] In certain embodiments of cascade prodrugs containing aromatic activating groups based on 1,6-elimination, the masking group is structurally separated from the carrier. This can be achieved by using a stable bond between the polymer carrier and the activating group, where the stable bond does not participate in the cascade cleavage mechanism. When the carrier does not serve as a masking group and the activating group is attached to the carrier by a stable bond, the release of potentially toxic by-products (such as the activating group) is avoided. The stable bond between the activating group and the polymer also suppresses the release of drug-linker intermediates with undefined pharmacology.

[0131] A first example of the approach described in the previous paragraph involves a polymer prodrug system based on a mandelic acid activating group (see, for example, Shabat et al. (2004) Chem Eur J 10:2626-34). In this approach, the masking group is linked to the activating group via a carbamate bond. The activating group is permanently conjugated to a polyacrylamide polymer via an amide bond. After enzymatic activation of the masking group by a catalytic antibody, the masking group is cleaved by cyclization to release the drug; the activating group remains attached to the polyacrylamide polymer after drug release. A similar prodrug system is based on a mandelic acid activating group and an enzymatically cleavable ester-linked masking group (see, for example, Lee et al. (2004) Angew Chem 116:1707-10).

[0132] When using the above-mentioned linkers, the 1,6-elimination step still generates highly reactive aromatic intermediates. Even if the aromatic moiety remains permanently attached to the polymeric carrier, side reactions with potentially toxic by-products or immunogenic effects may occur. Therefore, it would be advantageous to develop linker technology for forming polymeric prodrugs of amine-containing active agents using aliphatic prodrug linkers that are not enzyme-dependent and do not generate reactive aromatic intermediates during cleavage. One such example uses PEG5000-maleic anhydride for the reversible modification of amino groups in tissue-type plasminogen activator and urokinase (see, e.g., (1987) Garman et al. FEBS Lett 223(2):361-65). Regeneration of functional enzyme from PEG-uPA conjugates upon incubation in pH 7.4 buffer via cleavage of the maleamic acid bond follows first-order kinetics with a half-life of approximately 6 hours. A disadvantage of the maleamic acid bond is the lack of stability of the conjugate at relatively low pH values.

[0133] A further approach involves a PEG cascade prodrug system based on an N,N-bis-(2-hydroxyethyl)glycinamide (bicine) linker (see, e.g., (2004) J Med Chem 47:726-34). In this system, two PEG carrier molecules are attached via temporary bonds to a bicine molecule, which is attached to an amino group on a drug molecule. The first step in prodrug activation involves enzymatic cleavage of the first temporary bond connecting both PEG carrier molecules to the hydroxy groups of the bicine activating groups. Different linkages between PEG and bicine result in different prodrug activation rates. The second step in prodrug activation involves cleavage of the second temporary bond connecting the bicine activating group to the amino group on the drug molecule. A disadvantage of this system is the slow hydrolysis rate of this second temporary bicine amide bond, which results in the release of a bicine-modified prodrug intermediate, which may exhibit different pharmacokinetic, immunological, toxicological, and pharmacodynamic properties compared to the native parent drug molecule.

[0134] In certain embodiments, dipeptides are utilized for the development of prodrugs for targeted or targeted delivery because they are substrates for enzymes or biotransport systems. Nonenzymatic pathways for dipeptide prodrug formation, i.e., their ability to undergo intramolecular cyclization to form the corresponding diketopiperazine (DKP) and release the active drug, are not well defined.

[0135] In some embodiments, the dipeptide is attached to the drug moiety via an ester bond, as described for the dipeptide ester of the drug paracetamol (Gomes et al. (2005) Bio & Med Chem Lett. In this example, the cyclization reaction consists of nucleophilic attack of the N-terminal amine of the peptide on the ester carbon atom to form a tetrahedral intermediate, followed by proton transfer from the amine to the leaving group oxyanion with concomitant peptide bond formation to yield the cyclic DKP product and the free drug. This method is applicable to hydroxyl-containing drugs in vitro, but has been found to compete with enzymatic hydrolysis of the ester bond in vivo, as the corresponding dipeptide ester released paracetamol at a much faster rate than in buffer (Gomes et al. (Molecules 12(2007) 2484-2506)). The susceptibility of dipeptide-based prodrugs to peptidases can be addressed by incorporating at least one unnatural amino acid into the dipeptide motif. However, endogenous enzymes capable of cleaving the ester bond are not limited to peptidases, and the enzyme-dependence of such prodrug cleavage still leads to unpredictable in vivo performance.

[0136] In some embodiments, enzyme dependency is intentionally incorporated into DKP prodrugs; for example, a dipeptide ester prodrug is formylated at the amino terminus of the dipeptide, and enzymatic deformylation is used to initiate diketopiperazine formation, followed by cleavage of the ester-dipeptide bond and subsequent release of the drug molecule (see, e.g., USP 7,163,923). As a further example, an octapeptide is attached to the 4-hydroxyl group of vinblastine via an ester bond, and after removal of the N-terminal hexapeptide by a specific enzyme, undergoes ester bond cleavage resulting in DKP formation (see Brady et al. (2002) J Med Chem 45:4706-15).

[0137] The scope of DKP formation reactions extends to amide prodrugs. For example, U.S. Patent No. 5,952,294 describes the prodrug activation of a dipeptidyl amide prodrug of cytarabine using diketopiperazine formation. In this example, a temporary bond is formed between the carbonyl of the dipeptide and the aromatic amino group of cytarabine. However, with such conjugates, it is unlikely that a sustained release effect can be achieved due to the absence of a carrier or other half-life extending moiety or functional group.

[0138] Dipeptide prodrugs containing bioactive peptides, such as GLP-1, that can release the peptide via diketopiperazine formation of the dipeptide extension have also been described (see, e.g., WO 2009 / 099763). The bioactive peptide moiety can contain an additional PEG chain on one of its amino acid side chain residues to achieve extended circulation of the bioactive peptide. However, this approach has several significant disadvantages. First, the PEG chain must be attached to the peptide without impairing its bioactivity, which can be difficult to achieve for many peptide-based bioactive agents. Second, because PEGylated peptides are themselves bioactive, the dipeptide promoiety can affect the peptide's bioactivity and adversely affect its receptor binding properties.

[0139] Specific exemplary technologies that may be used with the compounds of the invention include those developed by ProLynx (San Francisco, CA) and Ascendis Pharma (Palo Alto, CA). The ProLynx technology platform utilizes a set of novel linkers preprogrammed to cleave at different rates, enabling controlled and predictable sustained release of small molecules and peptides from circulating semi-solid polymeric conjugates. This technology allows for the maintenance of desired steady-state serum levels of therapeutic agents for weeks to months.

[0140] Ascendis' technology platform combines the advantages of prodrugs and sustained-release technology to enhance the properties of small molecules and peptides. In the circulation, proprietary prodrugs release the unmodified active parent therapeutic agent at a predetermined rate determined by physiological pH and temperature conditions. Because the therapeutic agent is released in its unmodified form, it retains its original mechanism of action.

[0141] Modifications to enhance inhibitor properties In many cases, it will be advantageous, and sometimes necessary, to improve one or more physical properties of the therapeutics disclosed herein and / or their methods of administration, including, for example, methods to increase aqueous solubility, bioavailability, serum half-life, and / or therapeutic half-life, and / or modulate biological activity.

[0142] Modifications known in the art include PEGylation, Fc fusion, and albumin fusion. While such modifications are generally associated with macromolecular agents (e.g., polypeptides), they have recently been evaluated for specific small molecules. For example, Chiang, M. et al. (J. Am. Chem. Soc., 2014, 136(9):3370-73) described a small molecule agonist of the adenosine 2a receptor conjugated to an immunoglobulin Fc domain. This small molecule Fc conjugate retained potent Fc receptor and adenosine 2a receptor interactions and exhibited superior properties compared to unconjugated small molecules. Covalent attachment of PEG molecules to small molecule therapeutic agents has also been described (Li, W. et al., Progress in Polymer Science, 2013, 38:421-44).

[0143] Other known modifications include deuteration to improve pharmacokinetic, pharmacodynamic, and toxicity profiles. Due to the large atomic mass of deuterium, breaking a carbon-deuterium bond requires more energy than breaking a carbon-hydrogen bond. Because these stronger bonds are more difficult to break, the rate of drug metabolism is slower than that of non-deuterated forms, which can reduce the frequency of dosing and further reduce toxicity (Charles Schmidt, Nature Biotechnology, 2017, 35(6):493-494; Harbeson, S. and Tung, R., Medchem News, 2014(2):8-22).

[0144] Therapeutic and prophylactic use The present invention contemplates the use of the HIF-2α inhibitors described herein in the treatment or prevention of a wide range of diseases, disorders, and / or conditions, and / or symptoms thereof. While particular uses are described in detail hereinafter, it should be understood that the present invention is not limited thereto. Furthermore, while general categories of certain diseases, disorders, and conditions are presented hereinafter, some of the diseases, disorders, and conditions described above may be members of more than one category, and other diseases, disorders, and conditions may not be members of any of the disclosed categories.

[0145] In some embodiments, the HIF-2α inhibitors described herein are administered in an amount effective to reverse, stop, or slow the progression of HIF-2α-mediated dysregulation.

[0146] In one embodiment, patients are selected for the treatments described herein based on the patient's HIF-2a expression level. In some embodiments, patients are selected for the treatments described herein based on HIF-2a expression in the patient's tumor. In yet another embodiment, patients are selected for the treatments described herein based on the presence or absence of a VHL mutation.

[0147] Oncology-Related Disorders The HIF-2α inhibitors described herein can be used to treat or prevent a proliferative condition or disorder, such as cancer, e.g., cancer of the uterus, cervix, breast, prostate (including metastatic castration-resistant prostate cancer), testis, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestine, colon or rectum), kidney, renal cell, bladder, bone, bone marrow, skin, head and neck, liver, gallbladder, bile duct, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., glioma), ganglion, central nervous system (CNS) and peripheral nervous system (PNS), and cancer of the hematopoietic and immune systems (e.g., spleen or thymus). The present invention also provides methods for treating or preventing other cancer-related diseases, disorders, or conditions, such as, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virus-induced cancers (e.g., epithelial cell carcinoma, endothelial cell carcinoma, squamous cell carcinoma, and papillomavirus), adenocarcinoma, lymphoma, carcinoma, melanoma, leukemia, myeloma, sarcoma, teratocarcinoma, chemically-induced cancer, metastasis, and angiogenesis. In certain embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia. The use of the term(s) cancer-related disease, disorder, and condition is meant to refer broadly to conditions directly or indirectly related to cancer, including, for example, precancerous conditions such as angiogenesis and dysplasia.

[0148] In certain embodiments, the cancer may be metastatic or may be at risk of becoming metastatic, or may arise in diffuse tissues, such as cancers of the blood or bone marrow (e.g., leukemia).

[0149] In some embodiments, the present invention provides methods for treating a proliferative condition, cancer, tumor, or precancerous condition with an HIF-α inhibitor and at least one additional therapeutic or diagnostic agent, examples of which are provided elsewhere herein.

[0150] In some embodiments, the disease or disorder is VHL-associated, for example, VHL-associated renal cell carcinoma.

[0151] Iron overloadIn one embodiment, the compounds described herein may be useful in treating iron overload. The iron overload may be primary or secondary iron overload. In one embodiment, the iron overload may be hemochromatosis. In other embodiments, the compounds described herein may be useful in treating polycythemia, such as polycythemia vera. In another embodiment, the compounds described herein may be useful in treating Pacak-Zhuang syndrome. In yet another embodiment, the compounds described herein may be useful for treating polycythemia.

[0152] Immune and Inflammatory Related Disorders A non-limiting list of immune and inflammation-related diseases, disorders, and conditions that can be treated or prevented with the compounds and compositions of the present invention includes arthritis (e.g., rheumatoid arthritis), renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., when inflammatory cytokines interfere with healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), chronic obstructive pulmonary disease (COPD), atherosclerosis, allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation, and multiple sclerosis.

[0153] In certain embodiments of the present disclosure, HIF-2α inhibitors are used to increase or enhance immune responses to antigens by providing adjuvant activity. In certain embodiments, at least one antigen or vaccine is administered to a subject in combination with at least one HIF-2α inhibitor of the present invention to prolong the immune response to the antigen or vaccine. Therapeutic compositions comprising at least one antigenic agent or vaccine component, such as, but not limited to, viruses, bacteria, fungi, or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines, in combination with at least one HIF-2α inhibitor of the present invention are also provided.

[0154] In some embodiments, the HIF-2α inhibitors described herein can be combined with immunosuppressants to reduce the number of immune effector cells.

[0155] Other disorders Embodiments of the present invention contemplate the administration of a HIF-2α inhibitor described herein to a subject for the treatment or prevention of any other disorder that may benefit from at least some degree of HIF-2α inhibition. Such diseases, disorders, and conditions include, for example, cardiovascular disorders (e.g., cardiac ischemia or pulmonary arterial hypertension) and metabolic disorders (e.g., diabetes, insulin resistance, obesity).

[0156] Pharmaceutical Composition The HIF-2α inhibitor of the present invention can be in the form of a composition suitable for administration to a subject. Generally, such a composition is a "pharmaceutical composition" comprising a HIF-2α inhibitor(s) and one or more pharmaceutically or physiologically acceptable diluents, carriers, or excipients. In certain embodiments, the HIF-2α inhibitor is present in a therapeutically acceptable amount. The pharmaceutical composition can be used in the methods of the present invention; thus, for example, the pharmaceutical composition can be administered to a subject ex vivo or in vivo to carry out the therapeutic and prophylactic methods and uses described herein.

[0157] The pharmaceutical compositions of the invention can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are provided herein. Furthermore, the pharmaceutical compositions can be used in combination with other therapeutically active agents or compounds described herein to treat or prevent the diseases, disorders, and conditions contemplated by the invention.

[0158] Pharmaceutical compositions containing an active ingredient (e.g., an inhibitor of HIF-2α function) can be in a form suitable for oral use, such as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide pharmaceutically elegant and palatable preparations. Tablets, capsules, etc. contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch, gelatin, or acacia, and lubricants, such as magnesium stearate, stearic acid, or talc.

[0159] Tablets, capsules, and the like suitable for oral administration can be uncoated, or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action. For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, can be used. They can also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or polymeric materials, such as polyesters, polyamic acids, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide / glycolide copolymers, polylactide / glycolide copolymers, or ethylene-vinyl acetate copolymers, to control delivery of the administered composition. For example, oral agents can be encapsulated in microcapsules prepared by coacervation techniques or interfacial polymerization, using hydroxymethylcellulose or gelatin microcapsules or poly(methyl methacrylate) microcapsules, respectively, or can be encapsulated in colloidal drug delivery systems. Colloidal dispersion systems include polymer complexes, nanocapsules, microspheres, microbeads, and lipid-based systems, such as oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the above formulations are readily apparent to those skilled in the art.

[0160] Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0161] Aqueous suspensions contain the active material in admixture with excipients suitable for their manufacture. Such excipients may be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as natural phosphatides (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0162] Oily suspensions can be formulated by suspending the active ingredient in vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oil such as liquid paraffin.Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol.In order to provide a palatable oral preparation, sweeteners and flavoring agents as mentioned above can be added.

[0163] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0164] The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion.The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof.Suitable emulsifiers may be natural gums, such as acacia gum or tragacanth gum; natural phosphatides, such as esters or partial esters derived from soybeans, lecithin, and fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0165] Pharmaceutical compositions typically contain a therapeutically effective amount of a HIF-2α inhibitor contemplated by the present invention and one or more pharmaceutically and physiologically acceptable formulations. Suitable pharmaceutically or physiologically acceptable diluents, carriers, or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethyl or n-propyl p-hydroxybenzoate), emulsifiers, suspending agents, dispersing agents, solvents, fillers, extenders, surfactants, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be saline solution or citrate-buffered saline, optionally supplemented with other materials commonly used in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize various buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, buffer components can be water-soluble substances such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0166] After the pharmaceutical composition has been formulated, it can be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dry or lyophilized powder. Such formulations can be stored in a ready-to-use form, a lyophilized form that requires reconstitution before use, a liquid form that requires dilution before use, or any other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, an ampoule, a syringe, or an autoinjector (e.g., similar to EpiPen®)), while in other embodiments, it is provided in a multi-use container (e.g., a multi-use vial).

[0167] The formulation can also contain carriers to protect the composition from rapid degradation or excretion from the body, such as controlled-release formulations, such as liposomes, hydrogels, prodrugs, and microencapsulated delivery systems.For example, time-delay materials such as glyceryl monostearate or glyceryl stearate can be used alone or in combination with wax.HIF-2α inhibitors can be delivered using any drug delivery device, including implants (e.g., implantable pumps) and catheter systems, slow infusion pumps and devices, etc., all of which are well known to those skilled in the art.

[0168] Depot injections, typically administered subcutaneously or intramuscularly, may also be utilized to release the HIF-2α inhibitors disclosed herein over a period of time. Depot injections are typically either solid-based or oil-based and typically contain at least one of the formulation components set forth herein.

[0169] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. These suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that may be employed include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media. Any sterile, fixed oil, such as synthetic mono- or diglycerides, may be employed for this purpose. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables. Prolonged absorption of certain injectable formulations can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0170] The present invention contemplates administration of HIF-2α inhibitors in the form of suppositories for rectal administration. Suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature, and thus will melt in the rectum and release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycols.

[0171] The HIF-2α inhibitors contemplated by the present invention may be in the form of any other suitable pharmaceutical composition (e.g., a spray for nasal or inhalation use) now known or developed in the future.

[0172] Administration route The present invention contemplates administration of HIF-2α inhibitors and compositions thereof in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracapsular, intraarticular, intraperitoneal, intracerebral (intraparenchymal and intraventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation. Depot injections, typically administered subcutaneously or intramuscularly, may also be utilized to release the HIF-2α inhibitors disclosed herein over a predetermined period of time.

[0173] Certain embodiments of the present invention contemplate oral administration.

[0174] Combination Therapy The present invention contemplates the use of HIF-2α inhibitors, alone or in combination with one or more active therapeutic agents. The additional active therapeutic agent may be a small chemical molecule; a macromolecule, such as a protein, antibody, peptibody, peptide, DNA, RNA, or fragment of such a macromolecule; or cell therapy or gene therapy. Combination therapy may target different but complementary mechanisms of action, thereby providing a synergistic therapeutic or preventative effect against the underlying disease, disorder, or condition. Additionally or alternatively, combination therapy may allow for a reduced dosage of one or more agents, thereby ameliorating, reducing, or eliminating adverse effects associated with one or more agents.

[0175] The active therapeutic agents in such combination therapy can be formulated as a single composition or as separate compositions. When administered separately, each therapeutic agent in the combination can be administered simultaneously or nearly simultaneously, or at different times. Furthermore, during the course of a patient's treatment, the therapeutic agents are administered "in combination" even if they are administered in different dosage forms (e.g., oral capsules and intravenous administration), they are administered at different dosage intervals, one therapeutic agent is administered according to a fixed dosing regimen while the other is titrated up, tapered, or discontinued, or each therapeutic agent in the combination is independently titrated up, tapered, increased or reduced in dose, or discontinued and / or resumed. When the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0176] In some embodiments, the additional therapeutic agent is an immunomodulator. Suitable immunomodulators that may be used in the present invention include CD40L, B7, and B7RP1; activating monoclonal antibodies (mAbs) against stimulatory receptors, such as anti-CD40, anti-CD38, anti-ICOS, and 4-IBB ligand; dendritic cell antigen loading (in vitro or in vivo); anti-cancer vaccines, such as dendritic cell cancer vaccines; cytokines / chemokines, such as IL1, IL2, IL12, IL18, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharide (LPS); indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and immunostimulatory oligonucleotides.

[0177] In certain embodiments, the present invention provides a method for tumor suppression of tumor growth, comprising administering a HIF-2α inhibitor described herein in combination with a signal transduction inhibitor (STI) to achieve additive or synergistic suppression of tumor growth. As used herein, the term "signal transduction inhibitor" refers to an agent that selectively inhibits one or more steps in a signal transduction pathway. Signal transduction inhibitors (STIs) of the present invention include, for example, (i) bcr / abl kinase inhibitors (e.g., GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors, such as kinase inhibitors and antibodies; (iii) her-2 / neu receptor inhibitors (e.g., HERCEPTIN®); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., Trop2 inhibitors or rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidylinositol kinase inhibitors. Agents involved in immune regulation can also be used in combination with the HIF-2α inhibitors described herein to suppress tumor growth in cancer patients.

[0178] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, mesuredopa, and uredopa; ethylenimines and methylameramines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; and nitrogen mustards. Antibiotics such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, potassium Caremicin, carabicin, kaminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, pomalidomide, potfilomycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinos tatins, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU) with or without leucovorin; folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU;Androgens, such as calsterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenal drugs, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; Bestravsil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformitin; acetic acid Elliptinium; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenameth; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitrite acetaminophen; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids such as paclitaxel, nab-paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitomycin C Examples of suitable anti-inflammatory drugs include xantrone, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunomycin, aminopterin, xeloda, ibandronate, CPT11, topoisomerase inhibitors, difluoromethylornithine (DMFO), retinoic acid, esperamicins, capecitabine, anthracyclines, arginase inhibitors (see PCT / US2019 / 020507), and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0179] Chemotherapeutic agents also include antihormonal agents that regulate or inhibit hormone action on tumors, such as antiestrogens, such as tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, ketoxifene, onapristone, and toremifene; and antiandrogens, such as abiraterone, enzalutamide, flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy includes a chemotherapy regimen comprising one or more chemotherapeutic agents. In certain embodiments, the combination therapy includes the administration of a hormone or related hormonal agent.

[0180] Additional therapies that can be used in combination with HIF-2α inhibitors include radiation therapy, monoclonal antibodies against tumor antigens, monoclonal antibody-toxin conjugates, T-cell adjuvants, bone marrow transplantation, or antigen-presenting cells (e.g., dendritic cell therapy), including TLR agonists used to stimulate such antigen-presenting cells.

[0181] In certain embodiments, the present invention contemplates the use of the compounds described herein in combination with adoptive cell therapy, a novel and promising form of personalized immunotherapy in which immune cells with anti-tumor activity are administered to cancer patients. Adoptive cell therapy has been explored, for example, using tumor-infiltrating lymphocytes (TILs) and T cells engineered to express chimeric antigen receptors (CARs) or T cell receptors (TCRs). Adoptive cell therapy generally involves collecting T cells from an individual, genetically modifying the T cells to target specific antigens or enhance their anti-tumor effects, expanding them to sufficient numbers, and infusing the genetically modified T cells into the cancer patient. T cells can be collected from the patient (e.g., autologous) where the expanded cells are later re-infused, or they can be collected from a donor patient (e.g., allogeneic).

[0182] In certain embodiments, the present invention contemplates the use of the compounds described herein in combination with RNA interference-based therapy for silencing gene expression.RNAi begins by the cleavage of relatively long double-stranded RNA into small interfering RNA (siRNA).One strand of siRNA is incorporated into a ribonucleoprotein complex known as RNA-induced silencing complex (RISC), and then this complex is used to identify the mRNA molecule that is at least partially complementary to the incorporated siRNA strand.RISC can bind to or cleave the mRNA, both of which inhibit translation.

[0183] In certain embodiments, the present invention contemplates the use of the compounds described herein in combination with agents that modulate adenosine levels. Such therapeutic agents can act on ectonucleotides, which catalyze the conversion of ATP to adenosine, such as ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​also known as CD39 or cluster of differentiation 39), which hydrolyzes ATP to ADP and ADP to AMP, and 5'-nucleotidase ecto (NT5E or 5NT, also known as CD73 or cluster of differentiation 73), which converts AMP to adenosine. The enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemistry of purinergic signals delivered to various cells (e.g., immune cells). Alterations in the activity of these enzymes can alter the course or determine the outcome of several pathophysiological events, such as cancer, autoimmune diseases, infectious diseases, atherosclerosis, and ischemia-reperfusion injury, suggesting that these ectoenzymes represent novel therapeutic targets for addressing a variety of disorders. In one embodiment, the CD73 inhibitor is one described in WO2017 / 120508, WO2018 / 067424, WO2018 / 094148, and WO2020 / 046813. In another embodiment, the CD73 inhibitor is AB680.

[0184] Alternatively, such a therapeutic agent may be an adenosine 2 receptor (A2R) antagonist. Adenosine binds to four different G protein-coupled receptors: A1R, A2R, and A3R. 2a R.A. 2b It can bind to and activate A3R and A3R. A3R is expressed on myeloid cells such as T cells, natural killer cells, and dendritic cells. 2a The binding of adenosine to the A R receptor leads to an increase in the intracellular level of cyclic AMP and impaired maturation and / or activation of such cells. This process significantly impairs the activation of the immune system against cancer cells. Furthermore, A R 2A A2R is involved in selectively enhancing anti-inflammatory cytokines, promoting the upregulation of PD-1 and CTLA-4, promoting the generation of LAG-3 and Foxp3+ regulatory T cells, and mediating the inhibition of regulatory T cells. PD-1, CTLA-4, and other immune checkpoints are further discussed herein. Combining the combinations described herein with an A2R antagonist can provide at least additive effects, given their different mechanisms of action. In one embodiment, the present invention contemplates a combination with an adenosine receptor antagonist described in WO2018 / 136700, WO2018 / 204661, WO2018 / 213377, or WO2020 / 023846. In another embodiment, the adenosine receptor antagonist is AB928.

[0185] In certain embodiments, the present invention contemplates the use of the compounds described herein in combination with inhibitors of phosphatidylinositol 3-kinase (PI3K), particularly the PI3Kγ isoform. PI3Kγ inhibitors can stimulate anti-cancer immune responses through modulation of myeloid cells, for example, by inhibiting suppressive myeloid cells and attenuating immunosuppressive tumor-infiltrating macrophages, or by stimulating macrophages and dendritic cells to produce cytokines that contribute to effective T-cell responses and suppress the development and spread of cancer. PI3Kγ inhibitors include those described in PCT / US2020 / 035920.

[0186] In certain embodiments, the present invention contemplates the use of the compounds described herein in combination with inhibitors of arginase, which has been shown to cause or contribute to pro-inflammatory immune dysfunction, tumor immune evasion, immunosuppression and immunopathology of infectious diseases. Exemplary arginase compounds can be found, for example, in PCT / US2019 / 020507 and WO / 2020 / 102646.

[0187] Immune checkpoint inhibitors The present invention contemplates the use of inhibitors of HIF-2α function described herein in combination with immune checkpoint inhibitors.

[0188] The enormous number of genetic and epigenetic alterations characteristic of all cancers provides a diverse array of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the maximum amplitude (e.g., level of cytokine production or proliferation) and quality (e.g., type of immune response generated, such as the pattern of cytokine production) of the response initiated through antigen recognition by the T cell receptor (TCR) are regulated by the balance between costimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are important for preventing autoimmunity (i.e., maintaining self-tolerance) and also for protecting tissues from damage when the immune system is responding to pathogenic infections. Expression of immune checkpoint proteins can be dysregulated by tumors as a critical immune resistance mechanism.

[0189] T cells have been a major focus of efforts to therapeutically manipulate endogenous antitumor immunity due to i) their capacity for selective recognition of peptides derived from proteins in all intracellular compartments; ii) their ability to directly recognize and kill antigen-expressing cells (by CD8+ effector T cells, also known as cytotoxic T lymphocytes (CTLs)); and iii) their ability to orchestrate diverse immune responses by CD4+ helper T cells integrating adaptive and innate effector mechanisms.

[0190] In the clinical setting, blockade of immune checkpoints leading to the amplification of antigen-specific T cell responses has been shown to be a promising approach in human cancer therapy.

[0191] T cell-mediated immunity involves multiple sequential steps, each of which is regulated by balancing stimulatory and inhibitory signals to optimize the response. Nearly all inhibitory signals in the immune response ultimately regulate intracellular signaling pathways, many of which are initiated through membrane receptors, and their ligands are either membrane-bound or membrane-soluble (cytokines). Costimulatory and inhibitory receptors and ligands that regulate T cell activation are often not overexpressed in cancer compared to normal tissues, whereas inhibitory ligands and receptors that regulate T cell effector function in tissues are commonly overexpressed on tumor cells or on non-transformed cells associated with the tumor microenvironment. The function of soluble and membrane-bound receptor-ligand immune checkpoints can be modulated using agonistic antibodies (in the case of costimulatory pathways) or antagonistic antibodies (in the case of inhibitory pathways). Thus, in contrast to most antibodies currently approved for cancer therapy, immune checkpoint-blocking antibodies do not directly target tumor cells but rather target lymphocyte receptors or their ligands to enhance intrinsic antitumor activity [see Pardoll, (April 2012) Nature Rev. Cancer 12:252-64].

[0192] Examples of immune checkpoints (ligands and receptors) selectively upregulated in various types of tumor cells, some of which are candidates for blocking, include PD1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA4 (cytotoxic T lymphocyte-associated antigen 4); TIM3 (T cell membrane protein 3); LAG3 (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); and killer inhibitory receptors, which can be divided into two classes based on structural features: i) killer cell immunoglobulin-like receptors (KIRs), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints have been described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)) [see Pardoll, (April 2012) Nature Rev. Cancer 12:252-64].

[0193] The present invention contemplates the use of inhibitors of HIF-2α function described herein in combination with inhibitors of the above-mentioned immune checkpoint receptors and ligands, as well as undescribed immune checkpoint receptors and ligands. Currently, certain modulators of immune checkpoints have been approved, and many others are in development. The fully humanized CTLA4 monoclonal antibody ipilimumab (YERVOY®; Bristol-Myers Squibb) became the first immune checkpoint inhibitor to receive regulatory approval in the United States when it was approved for the treatment of melanoma in 2011. Fusion proteins containing CTLA4 and an antibody (CTLA4-Ig; abatcept (ORENCIA®; Bristol-Myers Squibb)) have been used to treat rheumatoid arthritis, and other fusion proteins have been shown to be effective in kidney transplant patients sensitized to Epstein-Barr virus. The next class of immune checkpoint inhibitors to receive regulatory approval were inhibitors directed against PD-1 and its ligands, PD-L1 and PD-L2. Approved anti-PD1 antibodies include nivolumab (OPDIVO®; Bristol-Myers Squibb) and pembrolizumab (KEYTRUDA®; Merck) for various cancers, including squamous cell carcinoma, classical Hodgkin lymphoma, and urothelial carcinoma. Approved anti-PD-L1 antibodies include avelumab (BAVENCIO®, EMD Serono & Pfizer), atezolizumab (TECENTRIQ®; Roche / Genentech), and durvalumab (IMFINZI®; AstraZeneca) for certain cancers, such as urothelial carcinoma. There are no approved therapeutic agents targeting TIGIT or its ligands CD155 and CD112, but agents under development include BMS-986207 (Bristol-Myers Squibb), MTIG7192A / RG6058 (Roche / Genentech), domvanalimab (AB154), and OMP-31M32 (OncoMed).In some combinations provided herein, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, cemiplimab, and zimberelimab. In another embodiment, the immune checkpoint inhibitor is selected from sintilimab, camrelizumab, tislelizumab, toripalimab, dostallimab, retifanlimab, sasanlimab, budigalimab, BI-754091, cosibelimab, and spartalizumab.

[0194] In one aspect of the present invention, the claimed HIF-2α inhibitor is combined with a cancer immunotherapeutic agent that is either (i) an agonist of stimulatory (including costimulatory) receptors on T cells or (ii) an antagonist of inhibitory (including co-inhibitory) signals, both of which lead to the amplification of antigen-specific T cell responses. Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), B7-H6, and B7-H7 (HHLA2). Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which include CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD3OL, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, T RAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT13R, LIGHT, Dc R3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin a / TNF13, TNFR2, TNFa, LT13R, lymphotoxin a Includes 1132, FAS, FASL, RELT, DR6, TROY, NGFR.

[0195] In another embodiment, the cancer immunotherapeutic is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-B, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0196] In one aspect, the T cell response is enhanced by combining a disclosed HIF-2α inhibitor with (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin-9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and / or (ii) T cell activation can be stimulated by a combination of agonists of proteins that stimulate T cell activation, such as one or more of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2. Other drugs that can be combined with the HIF-2α inhibitors of the present invention for cancer treatment include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds described herein can be combined with KIR antagonists, such as lirilumab. As another example, the compounds described herein can be combined with lenvatinib or cabozantinib.

[0197] Still other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, such as, but not limited to, CSF-1R antagonists, e.g., CSF-1R antagonist antibodies, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0198] In another aspect, the disclosed HIF-2α inhibitors can be used with one or more of: an agonistic agent that ligates a positive costimulatory receptor; a blocking agent that attenuates signaling through an inhibitory receptor; and one or more agents that systemically increase the frequency of anti-tumor T cells; an agent that overcomes a distinct immunosuppressive pathway within the tumor microenvironment (e.g., blocks the engagement of inhibitory receptors (e.g., PD-L1 / PD-1 interactions); depletes or suppresses regulatory T cells (Tregs) (e.g., with an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion); or reverses / prevents T cell anergy or exhaustion); and an agent that causes innate immune activation and / or inflammation at the tumor site.

[0199] In one embodiment, the cancer immunotherapeutic is a CTLA-4 antagonist, e.g., an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0200] In another embodiment, the cancer immunotherapy is a PD-1 antagonist, e.g., an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO® (nivolumab), KEYTRUDA® (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). Cancer immunotherapy also includes pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach to targeting the PD-1 receptor is a recombinant protein called AMP-224, consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1. In another embodiment, the agent is zimberelimab.

[0201] In another embodiment, the cancer immunotherapeutic agent is a PD-L1 antagonist, e.g., an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ® (atezolizumab; MPDL3280A; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0202] In another embodiment, the cancer immunotherapeutic agent is a LAG-3 antagonist, e.g., an antagonistic LAG-3 antibody. Suitable LAG-3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0203] In another embodiment, the cancer immunotherapeutic agent is a CD137 (4-1BB) agonist, e.g., an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0204] In another embodiment, the cancer immunotherapeutic agent is a GITR agonist, e.g., an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683).

[0205] In another embodiment, the cancer immunotherapeutic is an OX40 agonist, e.g., an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0206] In another embodiment, the cancer immunotherapeutic agent is an OX40L antagonist, e.g., an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0207] In another aspect, the cancer immunotherapeutic is a CD40 agonist, e.g., an agonistic CD40 antibody. In yet another embodiment, the cancer immunotherapeutic is a CD40 antagonist, e.g., an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0208] In another embodiment, the cancer immunotherapeutic agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0209] In another embodiment, the cancer immunotherapeutic is MGA271 (against B7H3) (WO11 / 109400).

[0210] The present invention includes pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0211] Examples of therapeutic agents useful in combination therapy for the treatment of cardiovascular and / or metabolic related diseases, disorders and conditions include statins, which inhibit the enzymatic synthesis of cholesterol (e.g., CRESTOR®, LESCOL®, LIPITOR®, MEVACOR®, PRAVACOL®, and ZOCOR®); bile acid resins, which sequester cholesterol and prevent its absorption (e.g., COLESTID®, LO-CHOLEST®, PREVALITE®, QUESTRAN®, and WELCHOL®); ezetimibe, which blocks cholesterol absorption; fibric acids (e.g., TRICOR®), which may lower triglycerides and modestly increase HDL; niacin (e.g., NIACOR®), which modestly lowers LDL cholesterol and triglycerides; and / or combinations of the above (e.g., VYTORIN® (a combination of ezetimibe and simvastatin)). Alternative cholesterol therapeutic agents that may be candidates for use in combination with the HIF-2α inhibitors described herein include various nutritional supplements and herbs (e.g., garlic, policosanol, and guggul).

[0212] The present invention includes pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0213] Examples of therapeutic agents useful in combination therapy for immune and inflammation-related diseases, disorders and conditions include, but are not limited to, the following: nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and other propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pir ... phen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, filofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam, and tenoxicam), salicylates (acetylsalicylic acid, sulfasalazine), and pyrazolones (apazone, bezupiperylone, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone). Other combinations include cyclooxygenase-2 (COX-2) inhibitors.

[0214] Other active agents for combinations include, for example, steroid drugs such as prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone, or hydrocortisone. Such combinations can be particularly advantageous because they can reduce or even eliminate one or more adverse effects of steroids by tapering the required steroid dose.

[0215] Further examples of active agents that may be used in combinations, for example to treat rheumatoid arthritis, include cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies or antagonists to other human cytokines or growth factors, such as TNF, LT, IL-10, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, or PDGF.

[0216] Specific combinations of active agents can interfere at different points in the autoimmune and subsequent inflammatory cascade, including TNF antagonists such as chimeric, humanized, or human TNF antibodies, REMICADE®, HUMERA®, anti-TNF antibody fragments (e.g., CDP870), and soluble p55 or p75 TNF receptors, their derivatives, p75TNFRIgG (ENBREL®) or p55TNFR1gG (lenercept), soluble IL-13 receptors (sIL-13), and TNFα-converting enzyme (TACE) inhibitors; IL-1 inhibitors (e.g., interleukin-1-converting enzyme inhibitors) can also be effective. Other combinations include interleukin-11, anti-p7, and p-selectin glycoprotein ligand (PSGL). Other examples of agents useful in combination with the HIF-2α inhibitors described herein include interferon-131a (AVONEX®); interferon-131b (BETASERON®); copaxone; hyperbaric oxygen; intravenous immunoglobulin; clavulivin; and antibodies or antagonists to other human cytokines or growth factors (e.g., antibodies to CD40 ligand and CD80).

[0217] dosage The HIF-2α inhibitors of the present invention can be administered to a subject in an amount determined, for example, by the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to whom the formulation is administered; the route of administration; and the nature of the disease, disorder, condition, or symptoms thereof. The dosing regimen can also take into account the existence, nature, and extent of any adverse effects associated with the administered agent(s). Effective dosages and administration regimens can be readily determined, for example, from safety and dose escalation studies, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0218] Generally, dosing parameters indicate that the amount administered is less than the amount that would be irreversibly toxic to the subject (maximum tolerated dose (MTD)) and greater than or equal to the amount required to produce a measurable effect in the subject, as determined by, for example, pharmacokinetic and pharmacodynamic parameters relevant to ADME, taking into account the route of administration and other factors.

[0219] The effective dose (ED) is the dose or amount of a drug that produces a therapeutic response or desired effect in a proportion of subjects receiving the drug. The "median effective dose" or ED50 of a drug is the dose or amount of a drug that produces a therapeutic response or desired effect in 50% of the population to which the drug is administered. The ED50 is generally used as a measure of a reasonable prediction of the drug's effectiveness, but is not necessarily the dose that a clinician would consider appropriate given all relevant factors. Thus, in some situations, the effective amount exceeds the calculated ED50, in other situations, the effective amount is less than the calculated ED50, and in still other situations, the effective amount is the same as the calculated ED50.

[0220] Furthermore, an effective dose of a HIF-2α inhibitor of the present invention can be an amount that, when administered in one or more doses to a subject, produces a desirable result compared to a healthy subject. For example, for a subject suffering from a particular disorder, an effective dose is an amount that improves a diagnostic parameter, measurement, marker, etc. of the disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measurement, marker, etc. exhibited by a normal subject.

[0221] In certain embodiments, HIF-2α inhibitors contemplated by the present invention can be administered (e.g., orally) at dosage levels of about 0.01 mg to about 50 mg, or about 1 mg to about 25 mg per kg of subject body weight per day, one or more times per day to achieve the desired therapeutic effect.

[0222] For oral administration, the composition can be provided in the form of a tablet, capsule, or the like containing 1.0 to 1000 milligrams of active ingredient, more specifically 1 to 100 milligrams or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, or 40 milligrams once daily.

[0223] In certain embodiments, the desired dose of HIF-2α inhibitor is contained in a "unit dosage form." The term "unit dosage form" refers to a physically discrete unit, each unit containing a predetermined amount of HIF-2α inhibitor, alone or in combination with one or more additional agents, sufficient to produce a desired effect. It will be understood that the parameters of the unit dosage form depend on the specific agent and the effect to be achieved.

[0224] kit The present invention also contemplates kits comprising the compounds described herein, and pharmaceutical compositions thereof. The kits are generally in the form of physical structures housing various components, as described below, that can be utilized in the practice of the above-described methods.

[0225] The kit can include one or more compounds disclosed herein (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein can be provided in a ready-to-use form (e.g., tablet or capsule) or in a form that requires reconstitution or dilution, e.g., prior to administration (e.g., powder). If the compounds described herein are in a form that requires reconstitution or dilution by the user, the kit can also include a diluent (e.g., sterile water), buffer, pharmaceutically acceptable excipient, etc., packaged together with or separately from the compounds described herein. If combination therapy is envisioned, the kit may contain several agents separately, or the agents may be pre-combined in the kit. Each component of the kit can be enclosed in a separate container, and all of the various containers may be in a single package. The kits of the present invention can be designed for the conditions (refrigeration or freezing) necessary to properly maintain the components contained in the kit.

[0226] The kit may include a label or package insert containing the identity of the components therein and instructions for their use (e.g., administration parameters of the active ingredient(s), clinical pharmacology, e.g., mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or package insert may include manufacturer information, such as a lot number or expiration date. The label or package insert may, for example, be integral to the physical structure that houses the component, may be contained separately in the physical structure, or may be affixed to a component of the kit (e.g., an ampoule, tube, or vial).

[0227] The label or package insert may further comprise or be incorporated into a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk, e.g., CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape, or electrical storage media, e.g., RAM and ROM or hybrids thereof, e.g., magnetic / optical storage media, FLASH® media, or memory type cards. In some embodiments, the actual instructions are not present in the kit, but rather means are provided for obtaining the instructions from a remote source, e.g., via the internet. [Example]

[0228] experiment The following examples are put forth to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments have been performed or that they are all that may be performed. It is understood that exemplary descriptions written in the present tense have not necessarily been performed, but rather that the above descriptions can be performed to generate data of the nature described herein, etc. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0229] Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius (° C.), and pressure is at or near atmospheric. Standard abbreviations are used, including, for example: wt = wild type; bp = base pair(s); kb = kilobase(s); nt = nucleotide(s); aa = amino acid(s); s or sec = second(s); min = minute(s); h or hr = hour(s); ng = nanogram; μg = microgram; mg = milligram; g = gram; kg = kilogram; dl or dL = deciliter; μl or μL = microliter; ml or mL = milliliter; l or L = liter; μM = micromolar; mM = millimolar; M = molar; kDa = kilodalton; im = intramuscular; ip = intraperitoneal; SC or SQ = subcutaneous; QD = once daily; BID = twice daily; QW = once a week; QM = once a month; HPLC = high performance liquid chromatography; BW = body weight; U = units; ns = not statistically significant; PBS = phosphate-buffered saline; IHC = immunohistochemistry; DMEM = Dulbecco's modified Eagle's medium; EDTA = ethylenediaminetetraacetic acid.

[0230] Materials and Methods The following general materials and methods were used where indicated or can be used in the examples below.

[0231] Standard methods in molecular biology are described in the scientific literature (see, e.g., Sambrook and Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; and Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, NY, which describes cloning and DNA mutagenesis in bacterial cells (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), expression of glycoconjugates and proteins (Vol. 3), and bioinformatics (Vol. 4)).

[0232] The scientific literature describes methods for protein purification, such as immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization, as well as chemical analysis, chemical modification, post-translational modification, production of fusion proteins, and protein glycosylation (see, e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vols. 1-2, John Wiley and Sons, Inc., NY).

[0233] Where the literature contains assays or experimental procedures, such assays or procedures may serve as a surrogate standard for evaluating the compounds described herein.

[0234] All reactions were carried out at the indicated temperatures using Teflon-coated magnetic stir bars and, where specified, under an inert atmosphere. Reactions were monitored by TLC (silica gel 60 with fluorescent indicator F254, visualized with a short-wave / long-wave UV lamp) and / or LCMS (Agilent 1100 Series LCMS with UV detection at 254 nm using one of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm inner diameter (id) x 100 mm], a binary solvent system [MeCN with 0.1% TFA / HO with 0.1% TFA], and one with UV detection at 254 nm. Flash chromatography was performed on silica gel using an automated system (CombiFlash® RF+ manufactured by Teledyne ISCO) with detection wavelengths of 254 nm and 280 nm. Reverse-phase preparative HPLC was performed on an Agilent 1260 Infinity Series HPLC. Samples were eluted by gradient elution on a Gemini C18 110Å column (21.2 mm internal diameter (id) × 250 mm) using a binary solvent system (MeCN with 0.1% TFA / HO with 0.1% TFA) and detected at 254 nm. Final compounds obtained through preparative HPLC were concentrated. Unless otherwise noted, the reported yields are isolated yields. All assayed compounds were purified to ≥95% purity as determined by LCMS (Agilent 1100 Series LCMS with UV detection at 254 nm using the following column: Agilent Eclipse Plus C18 column [3.5 μm, 4.6 mm internal diameter (id) × 100 mm] using a binary solvent system [MeCN with 0.1% TFA / HO with 0.1% TFA]). 1 H NMR spectra were recorded on a Varian 400 MHz NMR spectrometer equipped with an Oxford AS400 magnet. Chemical shifts (δ) are reported as parts per million (ppm) relative to residual non-deuterated solvent as an internal standard.

[0235] Example Example 1: 2-chloro-3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-6-methanesulfonylbenzonitrile

[0236] [ka]

[0237] Step a: 6,8-Difluoro-1,2,3,4-tetrahydronaphthalen-1-one (500 mg, 2.74 mmol) was dissolved in CHCl (11 mL, 0.25 M), and the resulting solution was sparged with nitrogen gas for 5 minutes. Triethylamine (574 μL, 1.5 equiv.) was added, and the solution was cooled to 0 °C, followed by the addition of TfO (691 μL, 1.5 equiv.). The reaction was allowed to warm to room temperature and stirred overnight. The solution was quenched with water and extracted with CHCl. ​​The resulting organics were dried over NaSO and concentrated onto Celite. The crude material was flashed over silica gel (gradient, 0% to 20% ethyl acetate in hexanes) to afford the desired 5,7-difluoro-4-(trifluoromethylsulfonyloxy)-1,2-dihydronaphthalene (470 mg, 54% yield) as an oil.

[0238] Step b: A vial was charged with the alkenyl triflate from step a (2.50 g, 7.96 mmol, 1.0 equiv), PdCl(dppf) (872 mg, 1.19 mmol, 15 mol%), B2pin2 (2.82 g, 11.1 mmol, 1.4 equiv), KOAc (1.72 g, 17.5 mmol, 2.2 equiv), and 1,4-dioxane (20 mL). The vial was capped, and the reaction mixture was purged with N2 for 2 minutes. The reaction was heated at 80 °C and stirred for 30 minutes. The reaction was cooled, filtered, and concentrated onto Celite. Purification by flash chromatography (SiO2, hexane to 10% EtOAc) afforded the alkenyl pinacol boronic ester as a brown oil (1.16 g, 3.97 mmol, 50%).

[0239] Step c: To a vial containing the product from step b (100 mg, 0.342 mmol, 1.0 equiv.), 3-bromo-2-chloro-6-(methylsulfonyl)benzonitrile (100 mg, 0.342 mmol, 1.0 equiv.), PdCl(dppf) (25 mg, 0.034 mmol, 10 mol%), 1,4-dioxane (1 mL), and 1 M aqueous NaCO (0.7 mL) were added. The vial was capped and purged with N for 2 minutes. The reaction was heated at 80 °C and stirred for 1.5 hours. Upon completion, the reaction was cooled, diluted with saturated aqueous NHCl (20 mL), and extracted with DCM (20 mL). The aqueous layer was separated and back-extracted with additional DCM (2 × 20 mL). The organic layers were combined, washed with brine (40 mL), and dried over MgSO. Concentration under reduced pressure and purification by flash chromatography (SiO, gradient from hexane to 50% EtOAc) gave the cross-coupled product as a white solid, which was carried on to the next step (58.6 mg, 0.154 mmol, 45%, C 18 H 12 ESI MS of ClF2NO2S [M+H] + , calculated value 380.0, measured value 380.1).

[0240] Step d: To a vial containing the product from step c (58.6 mg, 0.154 mmol, 1.0 equiv.) was added Pd / C (10% Pd, 25 mg). The vial was evacuated and backfilled with N (×3). MeOH (1 mL) and EtOAc (1 mL) were added, and the reaction mixture was purged with H for 2 min and then stirred at room temperature under 1 atm of H for 16 h. The reaction vessel was flushed with N, and the mixture was filtered through Celite and rinsed with EtOAc. Concentration under reduced pressure and purification by preparative reverse-phase HPLC (20–100% gradient of acetonitrile and water containing 0.1% TFA) afforded the product as a white solid. 1H NMR(400 MHz, DMSO-d6) δ 7.95 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.10 - 6.98 (m, 2H), 4.79 - 4.72(m, 1H), 3.43 (s, 3H), C 18 H 14 ESI MS of ClF2NO2S [M+H] + , calculated value 382.0, measured value 382.1.

[0241] Example 2a / b: (1S,2R)-4-[R-6,8-difluoro-1,2,3,4-tetrahydronaphth-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol

[0242] [ka]

[0243] Step a: To a suspension of 7-fluoro-2,3-dihydro-1H-inden-1-one (10.0 g, 66.6 mmol) and aluminum trichloride (22.2 g, 166.5 mmol, 2.5 equiv.) in 1,2-dichloroethane (190 mL, 0.35 M), bromine (3.58 mL, 70 mmol, 1.05 equiv.) was added dropwise. The resulting solution was heated to 60 °C for 3 h, after which the reaction was cooled to room temperature and poured onto ice. The reaction was extracted with MTBE, dried over magnesium sulfate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in a 1:1 solution of CHCl:hexane) to give 4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one.

[0244] Step b: To a suspension of 4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one (17.0 g, 74.3 mmol) and CsCO (26.6 g, 81.7 mmol, 1.1 equiv.) in DMF (372 ml, 0.2 M) was added benzyl mercaptan (9.24 g, 8.71 ml, 1.0 equiv.). The reaction was stirred at room temperature for 90 minutes. The desired product was precipitated from the solution by adding 1.5 L of water and dried under high vacuum overnight. The resulting crude product (23.1 g, 93% yield) was used without further purification.

[0245] Step c: The crude thioether from step b (23.1 g, 69.2 mmol) was suspended in toluene (692 ml, 0.1 M). Aluminum trichloride (10.2 g, 1.1 equiv.) was added at room temperature. After 3 h, an additional portion of aluminum trichloride (3.6 g, 27 mmol, 0.4 equiv.) was added. After an additional 3 h, the reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in a 3:1 solution of CHCl in hexanes) to afford the desired thiophenol as a yellow solid (13.4 g, 80% yield).

[0246] Step d: A solution of the thiophenol product from step c (6.7 g, 27.6 mmol) and methyl viologen dichloride hydrate (710 mg, 0.1 equiv.) in DMF (55 ml, 0.5 M) was carefully degassed by three freeze-pump-thaw cycles under nitrogen. The resulting solution was cooled to −10°C to −5°C in a brine ice bath, and excess CF3I was sparged through the reaction mixture. The reaction was then stirred overnight under an atmosphere of CF3I. The reaction was carefully quenched with water at room temperature (use with caution as residual CF3I off-gassing occurs), extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexanes) to give the desired thioether (5.21 g, 61% yield).

[0247] Step e: To a solution of the product from step d (10.45 g, 33.6 mmol) in MeCN (129 mL, 0.26 M relative to starting material), CCl4 (129 mL, 0.26 M relative to starting material), and HO (258 mL, 0.13 M relative to starting material) was added ruthenium trichloride (697 mg, 3.36 mmol, 0.1 equiv.), followed by sodium periodate (29.6 g, 138.4 mmol, 4.12 equiv.). The reaction was stirred at room temperature for 1 h and, upon completion, extracted with CHCl2 (×2). The combined organics were washed with saturated NaSO3, washed with brine, dried over sodium sulfate, and then concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in a 3:1 solution of CHCl2 in hexanes) to give the product sulfone (10.53 g, 91% yield) as a white solid. 10 ESI MS of H6BrF3O3S [M+H] + ;Calculated value 342.9, measured value 342.9.

[0248] Step f: A solution of the product sulfone from step e (3.5 g, 10.2 mmol) and Selectfluor (4.32 g, 12.2 mmol, 1.2 equiv.) in methanol (102 mL, 0.1 M) was heated to 50 °C. Sulfuric acid (27 μL, 5 mol%) was added, and the reaction was stirred at 50 °C for 48 h. The solution was then diluted with diethyl ether, and the resulting white precipitate was filtered off and discarded. The organic solution was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in a 3:1 solution of CHCl in hexanes) to give the product dimethyl acetal as a white solid (3.57 g, 87% yield).

[0249] Step g: A solution of the product acetal from step f (3.18 g, 7.8 mmol) and wet Amberlyst 15 (4.77 g, 150 wt%) in dioxane (31 ml, 0.2 M) was heated to 90 °C overnight. Upon completion, the polymer beads were removed by filtration, and the concentrated crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in a 3:1 solution of CHCl in hexanes) to give the desired fluorinated ketone (2.33 g, 83% yield).

[0250] Step h: A solution of the indanone product from step g (2.5 g, 6.93 mmol) in dichloromethane (28 mL, 0.25 M) was sparged with nitrogen gas, after which formic acid (783 μL, 956 mg, 20.8 mmol, 3 equiv.) and triethylamine (1.94 mL, 1.41 g, 13.9 mmol, 2 equiv.) were added at 0 °C under nitrogen. RuCl(p-cymene)[(R,R)-Ts-DPEN] (44.5 mg, 0.07 mmol, 0.01 equiv.) was added, and the reaction was stirred at 0–5 °C for a minimum of 12 h. Upon complete conversion, the reaction was quenched with saturated NaHCO and extracted with CHCl. The combined organics were concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in 1:1 CHCl:hexane) to afford the desired indanol (2.0 g, 80% yield) as a single diastereomer. The enantiomeric excess of this material was found to be 98% relative to the racemic sample obtained via reduction of 2-fluoroindanone with sodium borohydride by chiral HPLC (Chiralpak AD-H, 20% iPrOH / hexane, isocratic, 20 min).

[0251] Step i: To a solution of the chiral indanol (1.01 g, 2.75 mmol) from step h in CHCl (11 mL, 0.25 M) was added 2,6-lutidine (800 μL, 6.9 mmol, 2.5 equiv) and TBSOTf (791 μL, 3.44 mmol, 1.25 equiv) at 0 °C. The reaction was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction was concentrated directly onto Celite and purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in hexanes) to give the TBS ether (1.35 g, 100% yield).

[0252] Step j: The TBS ether product from step i (674 mg, 1.41 mmol) was combined with B2Pin2 (457 mg, 1.8 mmol, 1.3 equiv), Pd(dppf)Cl2 (103 mg, 0.14 mmol, 0.1 equiv), and potassium acetate (213 mg, 3 mmol, 2.2 equiv) in dioxane (14 mL, 0.1 M), and the resulting solution was heated to 100 °C for 3 h. The reaction solution was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to give the desired boronic acid pinacol ester (638 mg, 86% yield) as a colorless oil.

[0253] Step k: The boronate ester product from step j (1.64 g, 3.13 mmol) was combined with 5,7-difluoro-4-(trifluoromethylsulfonyloxy)-1,2-dihydronaphthalene (1.18 g, 3.75 mmol, 1.2 equiv.), Pd(dppf)Cl (227 mg, 0.31 mmol, 0.1 equiv.), and sodium carbonate (2 M, aq., 3.13 mL, 2.0 equiv.) in dioxane (31 mL, 0.1 M) and heated to 75 °C for 3 h. Upon completion, the reaction was concentrated onto Celite and purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexanes) to give the desired alkene product (1.42 g, 86% yield) as a colorless resin.

[0254] Step 1: TBAF (0.1 M in THF, 0.3 mmol, 1.5 equiv.) was added to a cooled solution of the product of step k (113 mg, 0.2 mmol) at 0 °C, and the reaction was allowed to warm to ambient temperature. After 2 h, the reaction was concentrated onto Celite and purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexanes) to give the free indanol (1S,2R)-4-(6,8-difluoro-3,4-dihydronaphth-1-yl)-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol (33.7 mg, 37% yield). 1 H NMR (400 MHz, CDCl3): δ 7.92(d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.56 (ddd, J = 11.3, 8.7, 2.6 Hz, 1H), 6.15 (dd, J = 4.9, 4.9 Hz, 1H), 5.58-5.51 (br m, 1H), 5.28-5.08 (m, 1H), 3.14-3.00 (m, 2H), 2.92-2.79 (m, 2H), 2.48-2.37 (m, 2H). C 20 H 14 ESI MS of F6O3S [M+Na] + ;Calculated value 471.0, measured value 471.0.

[0255] Step m: The indanol product of step l was dissolved in methanol (700 μL, 0.1 M) and added to palladium on carbon (3 mg, 10 wt % Pd) under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere at 55 psi and stirred overnight in a Parr shaker. The resulting diastereomers were separated by column chromatography (silica gel, 100% toluene) to give (1S,2R)-4-[R-6,8-difluoro-1,2,3,4-tetrahydronaphth-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol (Example 2a) as the less polar diastereomer. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.1 Hz, 1H), 6.98 (d, J - 8.1 Hz, 1H), 6.75 (br d, J = 10.0 Hz, 1H), 6.58 (dd, J = 9.8 Hz, 1H), 5.59-5.55 (m, 1H), 5.41-5.23 (m, 1H), 4.41-4.36 (br m, 1H), 3.51-3.41 (m, 1H), 3.25-3.16 (m, 1H), 3.12(d, J = 4.1 Hz, 1H), 2.94-2.78 (m, 2H), 2.17-2.07 (m, 1H), 1.78-1.67 (m, 2H). C 20 H 16 ESI MS of F6O3S [M+Na] + calculated 473.1, found 473.1. (1S,2R)-4-[S-6,8-difluoro-1,2,3,4-tetrahydronaphth-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol (Example 2b) was isolated as the more polar diastereomer. 1 H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.3 Hz, 1H), 6.92(d, J = 8.3 Hz, 1H), 6.79-6.72(m, 1H), 6.62-6.54 (m, 1H), 5.60 (td, J = 5.0, 3.7 Hz, 1H), 5.47-5.24 (m, 1H), 4.38-4.34 (m, 1H), 3.50-3.27 (m, 2H), 3.08 (d, 1H), 2.98-2.75 (m, 2H), 2.16-2.07 (m, 1H), 1.86-1.62(m, 2H). C 20 H 16 ESI MS of F6O3S [M+Na] + ;Calculated value 473.1, measured value 473.1.

[0256] Example 3: (1S,2R)-4-[(1S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl]-2-fluoro-7-methanesulfonyl-2,3-dihydro-1H-inden-1-ol

[0257] [ka]

[0258] The title compound was synthesized in a similar manner to Example 2. 1 H NMR (400 MHz, chloroform-d) δ 7.71 - 7.67 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 9.1, Hz, 1H), 6.55 (ddd, J = 2.1, 9.2, 18.4 Hz, 1H), 5.67 (dt, J = 4.7, 12.4 Hz, 1H), 5.51 - 5.33 (dq, J = 4.7, 52.4 Hz, 1H), 4.32(m, 1H), 3.59 (dd, J = 4.4, 1.4 Hz, 1H), 3.31 (dd, J = 21.2, 4.9 Hz, 2H), 3.23 (s, 3H), 2.94 - 2.76 (m, 2H), 2.14 - 2.05 (m, 1H), 1.83 (m, 1H), 1.75 - 1.65 (m, 2H). C 20 H 19 ESI MS of F3O3S [M-H2O+H] + Calculated value 379.1, measured value 379.1.

[0259] Example 4: (1S,2R)-4-[(1R)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl]-2-fluoro-7-methanesulfonyl-2,3-dihydro-1H-inden-1-ol

[0260] [ka]

[0261] The title compound was synthesized in a similar manner to Example 2. 1 H NMR (400 MHz, chloroform-d) δ 7.70 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 9.1 Hz, 1H), 6.56 (ddd, J = 2.4, 9.1, 18.0 Hz, 1H), 5.65 (dt, J = 4.8, 14.4 Hz, 1H), 5.49 - 5.31 (m, 1H), 4.36 (m, 1H), 3.66 (dd, J = 5.1, 1.8 Hz, 1H), 3.40 (ddd, J = 21.6, 16.9, 3.2 Hz, 1H), 3.25 (s, 3H). 3.16 - 2.99 (m, 1H), 2.95-2.74 (m, 2H), 2.13 - 2.00 (m, 1H), 1.76-1.62(m, 3H). C 20 H 19 ESI MS of F3O3S [M-H2O+H] + Calculated value 379.1, measured value 379.1.

[0262] Example 5: (8R)-3-Fluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0263] [ka]

[0264] Step a: A solution of 6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-one (7 g, 38.4 mmol) and TMSONa (14.8 g, 115.3 mmol) in dioxane (128 mL) was refluxed for 20 min under a nitrogen atmosphere. Once the starting material had disappeared (TLC analysis, 30% EtOAc in hexanes as eluent, the desired product spot is the least polar), the mixture was cooled to room temperature and poured into a saturated aqueous solution of NH4Cl (200 mL). The product was extracted with EtOAc (3 x 70 mL). The combined extracts were washed with brine (200 mL). The organic phase was separated and dried over Na2SO4. After removing all solvents under reduced pressure, the crude product was purified by flash chromatography (SiO2, hexane / EtOAc gradient) to give 8-hydroxy-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one as a yellow solid (4.7 g, 26.1 mmol, 68% yield). 1 H NMR (400 MHz, CDCl3) δ 12.74 (d, J = 1.5 Hz, 1H), 6.45 (dd, J = 10.4, 2.5 Hz, 1H), 6.41 (ddd, J = 9.1, 2.3, 1.2 Hz, 1H), 2.93 - 2.82(m, 2H), 2.71 - 2.60 (m, 2H), 2.14 - 1.99 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ -98.95 (t, J = 9.7 Hz).

[0265] Step b: A mixture of 8-hydroxy-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (5.3 g, 29.4 mmol), triethylamine (5.3 mL, 38.2 mmol), and LiCl (1.6 g, 38.2 mmol) in dichloromethane (150 mL) was cooled to 0 °C. Trifluoromethanesulfonic anhydride (6.4 mL, 38.2 mmol) was added dropwise over 10 min. The mixture was stirred for an additional 30 min, after which complete disappearance of the starting material was observed by TLC analysis (30% EtOAc in hexanes as eluent). The reaction was then diluted with dichloromethane (50 mL) and washed successively with a saturated aqueous solution of NaHCO (150 mL), 1 M aqueous HCl (100 mL), and brine (150 mL). The organic phase was separated and dried over NaSO. After removing all solvents under reduced pressure, the crude product was purified by flash chromatography (SiO, hexane / EtOAc gradient) to give trifluoromethanesulfonic acid 8-oxo-6-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl ester as a yellow oil (8.1 g, 25.9 mmol, 88% yield). 1 H NMR (400 MHz, CDCl3) δ 7.03 (ddt, J = 8.3, 2.5, 0.9 Hz, 1H), 6.86 (dd, J = 8.3, 2.5 Hz, 1H), 3.10 - 2.87 (m, 2H), 2.84 - 2.58 (m, 2H), 2.30 - 2.07 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ -73.66, -100.52(t, J = 8.5 Hz).

[0266] Step c: A mixture of trifluoromethanesulfonic acid 8-oxo-6-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl ester (8.1 g, 25.9 mmol), zinc cyanide (2.4 g, 20.7 mmol), and Pd(PPh3)4 (3.0 g, 0.26 mmol) in DMF (65 mL) was heated at 100 °C for 3 h under a nitrogen atmosphere. Once complete disappearance of the starting material was observed by TLC analysis (30% EtOAc in hexanes as eluent), the solution was cooled to ambient temperature and poured into a mixture of EtOAc (100 mL) and water (150 mL). The resulting suspension was filtered through a plug of Celite. The organic phase was separated, and the aqueous solution was further extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with water (2 × 150 mL) and brine (100 mL), dried over Na2SO4, and concentrated to dryness. The dried residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to give 8-cyano-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (4.0 g, 21.1 mmol, 82% yield) as a white crystalline solid. 1 H NMR (400 MHz, CDCl3) δ 7.37 (ddt, J = 8.0, 2.6, 0.6 Hz, 1H), 7.19 (ddt, J = 8.3, 2.6, 0.9 Hz, 1H), 3.09 - 2.90 (m, 2H), 2.87 - 2.65 (m, 2H), 2.31 - 2.06 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ -103.48 (t, J = 8.2 Hz).

[0267] Step d: A solution of N-phenyl-bis(trifluoromethanesulfonimide) (11.3 g, 31.6 mmol) and 8-cyano-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (4.0 g, 21.1 mmol) in THF (105 mL) was cooled to −78 °C under a nitrogen atmosphere. A 1 M solution of LiHMDS in THF (21.1 mmol, 21.1 mL) was then added dropwise over 5 min. The resulting brown solution was stirred at −78 °C for an additional 5 min and transferred to an ice bath. After 30 min at 0 °C, TLC analysis indicated complete consumption of the starting material. The reaction was quenched by the addition of an aqueous solution of NH4Cl (10 mL), which was then diluted with water (150 mL) and EtOAc (150 mL). The organic phase was separated, and the aqueous phase was further extracted with EtOAc (2 × 80 mL). The combined organic extracts were washed with brine (100 mL), dried over NaSO, and concentrated to dryness. The dry residue was fractionated by column chromatography (SiO, hexane / EtOAc gradient) to afford 8-cyano-6-fluoro-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (6.74 g, 21.0 mmol, 99% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 8.0, 2.6 Hz, 1H), 7.17 (ddt, J = 8.1, 2.6, 0.9 Hz, 1H), 6.30 (dd, J = 5.4, 4.8 Hz, 1H), 2.94 - 2.80 (m, 2H), 2.61 - 2.40 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ -72.31, -109.26 (t, J = 8.0 Hz).

[0268] Step e: A solution of 2-[(1S,2R)-2-fluoro-1-(tertbutyldimethylsilyloxy)-7-(trifluoromethylsulfonyl)-4-indanyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.44 g, 0.84 mmol) and 8-cyano-6-fluoro-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (0.27 g, 0.84 mmol) in dioxane (4.2 mL) was placed in a 30 mL vial. Pd(dppf)Cl (62 mg, 0.084 mmol) and aqueous sodium carbonate (2 M solution, 0.84 mL, 1.68 mmol) were then added sequentially. The mixture was degassed under vacuum, backfilled with nitrogen, and heated at 90 °C for 1 h. Upon completion, the reaction was concentrated onto Celite and fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to afford the desired alkene product (0.401 g, 0.7 mmol, 84% yield) as a white foam. 1 H NMR (400 MHz, CDCl 3、 mixture of atropisomers) δ 7.98 - 7.86 (m, J = 17.7, 8.2 Hz, 1H), 7.63 - 7.57 (m, 0.3H), 7.43 - 7.33 (m, 0.7H), 7.22(dd, J = 8.5, 2.6 Hz, 1H), 7.18 - 7.08 (m, 1H), 6.44 - 6.36 (m, 1H), 5.64 - 5.56 (m, 1H), 5.09 - 4.71 (m, 1H), 3.34 - 3.19 (m, 0.7H), 3.01 - 2.71 (m, 3H), 2.61 - 2.25 (m, 2.3H), 0.84 (s, 9H), 0.28 - 0.07 (m, 6H). 19 F NMR (376 MHz, CDCl3) δ -78.81, -111.26 (t, J = 7.7 Hz), -111.52(t, J = 8.2 Hz), -195.20 (dd, J = 51.0, 11.8 Hz), -195.85 (dd, J = 50.9, 10.3 Hz).

[0269] Step f: The product from step e (0.25 g, 0.44 mmol) was dissolved in dry methanol (15 mL) and added to palladium on carbon (125 mg, 10 wt% Pd) under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere at 55 psi and stirred in a Parr shaker for 4 h. Excess hydrogen was vented, and the mixture was degassed under vacuum and backfilled with nitrogen to remove residual hydrogen gas. The resulting suspension was filtered through a Celite pad, and the filtrate was concentrated to dryness under reduced pressure to produce a crude mixture of epimers (1:2 dr). The crude mixture from step f was subjected to column chromatography (SiO2, hexane / EtOAc gradient) to produce both epimers of the desired product. (R)-epimer (more polar product, 70 mg, 0.12 mmol, 28% yield): 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.72(d, J = 8.3 Hz, 1H), 5.62(d, J = 4.3 Hz, 1H), 5.01 (dddd, J = 51.2, 8.8, 6.9, 4.3 Hz, 1H), 4.58 (dd, J = 6.3, 3.0 Hz, 1H), 3.61 (dddd, J = 14.8, 12.5, 8.8, 1.0 Hz, 1H), 3.18 (dd, J = 14.8, 6.9 Hz, 1H), 3.03 - 2.93 (m, 1H), 2.93 - 2.81 (m, 1H), 2.26 - 2.07 (m, 1H), 1.95 - 1.65 (m, 2H), 1.63 - 1.45 (m, 1H), 0.83 (s, 9H), 0.17 (d, J = 2.6 Hz, 3H), 0.13 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -78.71, -112.94 (t, J = 8.2 Hz), -196.32 (dd, J = 51.1, 12.8 Hz). (S)-Epimer (less polar product, 120 mg, 0.21 mmol, 48% yield): 1H NMR (400 MHz、CDCl3) δ 7.70 (d, J = 8.3 Hz, 1H), 7.21 - 7.07 (m, 2H), 6.69 (d, J = 8.3 Hz, 1H), 5.63 (d, J = 4.2 Hz, 1H), 5.03 (dddd, J = 51.2, 8.3, 6.8, 4.3 Hz, 1H), 4.55 (dd, J = 6.5, 3.3 Hz, 1H), 3.47 (ddd, J = 14.9, 7.0, 1.5 Hz, 1H), 3.37 - 3.20 (m, 1H), 3.09 - 2.94 (m, 1H), 2.93 - 2.78 (m, 1H), 2.25 - 2.12(m, 1H), 1.95 - 1.87 (m, 1H), 1.86 - 1.66 (m, 1H), 1.59 - 1.44 (m, 1H), 0.86 (s, 9H), 0.20 (d, J = 2.3 Hz, 3H), 0.15 (s, 3H)。 19 F NMR (376 MHz、CDCl3) δ -78.50, -112.92(t, J = 8.2 Hz), -194.99 (dd, J = 51.1, 12.6 Hz)。

[0270] Step h: A solution of the product from step f (8R-epimer, 70 mg, 0.122 mmol) in CHCN (2 mL) was placed in a 3 mL vial equipped with a magnetic stir bar, followed by the addition of HF·Py complex (approximately 70% hydrogen fluoride, approximately 30% pyridine, 0.2 mL). The resulting colorless solution was stirred overnight at ambient temperature. After TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (20 mL) and 1 M aqueous HCl (20 mL). The product was extracted with EtOAc (2 × 10 mL), and the combined organic extracts were washed with aqueous NaHCO (20 mL) and brine (20 mL), dried over NaSO, and concentrated to dryness. The residue was purified by column chromatography (SiO, hexane / EtOAc gradient) to give (8R)-3-fluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (52 mg, 0.114 mmol, 93% yield) as a white foam. 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.21 - 7.13 (m, 2H), 6.77 (d, J = 8.2 Hz, 1H), 5.56 (q, J = 5.1 Hz, 1H), 5.32(dtd, J = 51.2, 6.4, 5.2 Hz, 1H), 4.59 (dd, J = 6.3, 3.2 Hz, 1H), 3.62(dddd, J = 17.9, 16.1, 6.3, 1.0 Hz, 1H), 3.40 - 3.17 (m, 1H), 3.10 - 2.79 (m, 3H), 2.31 - 2.10 (m, 1H), 1.92 - 1.58 (m, 3H). 19 F NMR (376 MHz, CDCl3) δ -77.60, -112.71, -200.62(dddd, J = 51.2, 16.8, 10.9, 5.5 Hz). C 21 H 16 ESI MS of F5NO3S [M+Na] + ;Calculated value 480.1, measured value 480.1.

[0271] Example 6: (S)-3-Fluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0272] [ka]

[0273] This compound was prepared from the corresponding TBS-protected S-epimer of 1-indanol (150 mg, 0.262 mmol) and 0.4 mL of HF·Py complex according to the protocol described in Example 5. The title compound was isolated as a white foam (89 mg, 0.195 mmol, 74% yield). 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 1H), 7.23 - 7.05 (m, 2H), 6.70 (d, J = 8.2 Hz, 1H), 5.61 (ddd, J = 6.1, 5.1, 3.9 Hz, 1H), 5.37 (dddd, J = 51.4, 6.6, 6.0, 5.1 Hz, 1H), 4.56 (dd, J = 6.4, 3.1 Hz, 1H), 3.65 - 3.49 (m, 1H), 3.47 - 3.27 (m, 1H), 3.17 (dd, J = 3.9, 0.7 Hz, 1H), 3.08 - 2.69 (m, 2H), 2.30 - 2.09 (m, 1H), 1.98 - 1.86 (m, 1H), 1.83 - 1.64 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ -77.73, - 112.69, -200.05 (dddd, J = 51.2, 18.3, 12.2, 6.2 Hz). C 21 H 16 ESI MS of F5NO3S [M+Na] + ;Calculated value 480.1, measured value 480.1.

[0274] Example 7: (8S)-3-Fluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0275] [ka]

[0276] The title compound was synthesized in a similar manner to Example 5. 1 H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 8.1, 0.8 Hz, 1H), 7.21 - 7.11 (m, 2H), 6.60 (d, J = 8.1 Hz, 1H), 5.66 (dddd, J = 13.0, 5.5, 4.9, 0.5 Hz, 1H), 5.40 (dddd, J = 52.6, 5.7, 4.9, 3.6 Hz, 1H), 4.56 (dd, J = 6.2, 2.9 Hz, 1H), 3.72 - 3.40 (m, 2H), 3.26 (s, 3H), 3.15 (ddd, J = 23.3, 17.0, 5.8Hz, 1H), 3.03 - 2.90 (m, 1H), 2.91 - 2.77 (m, 1H), 2.19 - 2.04 (m, 1H), 1.85 - 1.57 (m, 3H). 19 F NMR (376 MHz, CDCl3) δ -113.22, -199.17. C 21 H 19 ESI MS of F2NO3S [M+Na] + ;Calculated value 426.1, measured value 426.1.

[0277] Example 8: (1S,2R)-4-[(4R)-5,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-yl]-2-fluoro-7-trifluoromethanesulfonyl-2,3-dihydro-1H-inden-1-ol

[0278] [ka]

[0279] Step a: To a solution of 5,7-difluorochroman-4-one (500 mg, 2.71 mmol) in CHCl (12 mL, 0.2 M) at 0 °C, 2,6-di-tert-butylmethylpyridine (1.17 g, 5.69 mmol, 2.1 equiv.) was added, followed by the dropwise addition of trifluoromethanesulfonic anhydride (860 μL, 5.14 mmol, 1.9 equiv.). The reaction was stirred at 0 °C for 1 h and then warmed to room temperature for an additional 1 h. At this point, hexanes (5 mL) were added to precipitate the pyridinium salt, and the reaction mixture was filtered over a pad of Celite. The solvent was removed in vacuo, and the crude residue was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexanes) to afford the desired vinyl triflate (754 mg, 88%) as a yellow oil. 10 ESI MS of H5F5O4S [M+H] + Calculated value: 316.9, measured value: 317.2.

[0280] Step b: The title compound was synthesized analogously to Example 1. 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.59 - 6.45 (m, 1H), 6.45 - 6.35 (m, 1H), 5.60 (dd, J = 6.6, 5.1 Hz, 1H), 5.51 - 5.22(m, 1H), 4.45 - 4.34 (m, 1H), 4.29 - 4.14 (m, 1H), 4.08 - 3.98 (m, 1H), 3.61 - 3.42 (m, 1H), 3.28 - 3.16 (m, 1H), 2.43 - 2.33 (m, 1H), 1.96 - 1.80 (m, 1H). C 19 H 14 ESI MS of F6O4SNa [M+Na] + Calculated value: 475.0, measured value: 475.0.

[0281] Example 9: 1-[2,2-difluoro-7-(methylsulfonyl)-4-indanyl]-6-fluoro-1,2,3,4-tetrahydronaphthalene

[0282] [ka]

[0283] The title compound was synthesized in a similar manner to Example 1. 1 H NMR (400 MHz, methanol d4) δ 7.78 (dt, J = 8.1, 1.7 Hz, 1H), 7.13 (dd, J = 15.1, 8.1 Hz, 1H), 6.89 (ddd, J = 9.8, 2.7, 1.1 Hz, 1H), 6.83 - 6.64 (m, 2H), 5.56 - 5.49 (m, 1H), 4.32 - 4.25 (m, 1H), 3.63 - 3.06 (m, 3H), 2.97 - 2.78 (m, 2H), 2.21 - 2.06 (m, 1H), 1.97 - 1.76 (m, 1H), 1.80 - 1.68 (m, 1H). C 20 H 19 F3O3 S ESI MS [M+H] + , calculated value 380.4, measured value 380.1.

[0284] Example 10: 1-(2-chloro-3-cyano-4-trifluoromethanesulfonylphenyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0285] [ka]

[0286] Step a: A suspension of 3-bromo-2-chloro-6-fluorobenzaldehyde (25 g, 105.3 mmol), NHOH×HCl (8.8 g, 126.4 mmol, 1.2 equiv.), and NaOAc (10.4 g, 126.4 mmol, 1.2 equiv.) in anhydrous EtOH (100 mL) was stirred under reflux overnight. The reaction was cooled to room temperature, evaporated, and the residue was diluted with HO (300 mL). The white solid was filtered off, washed with HO, and dried under vacuum (24.3 g, 91%). The crude product was used in the next step without further purification. ESI MS [M+H] for CHBrClFNO + , calculated value 251.9, measured value 251.9.

[0287] Step b: The oxime from step a was diluted with acetic anhydride (150 mL) and stirred at 120° C. overnight, then cooled and concentrated in vacuo to give a brown solid (22.5 g, 99%). The crude product was used in the next step without further purification.

[0288] Step c: The product from step b (20 g, 85.3 mmol) was dissolved in anhydrous DMF (100 mL), cooled to 0 °C, and anhydrous NaS (6.6 g, 85.3 mmol) was added in one portion. The reaction mixture was stirred at 0 °C for 2 h, then quenched with HO (500 mL) and extracted with CHCl (3 × 200 mL). The organics were discarded, and the aqueous layer was neutralized to pH ∼2 with 10% KHSO solution and extracted again with CHCl (3 × 150 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give a yellow solid (19.1 g, 90%), which was used in the next step without further purification. ESI MS [MH] for CHBrClNS - , calculated value 245.9, measured value 245.9.

[0289] Step d: The product from step c (33.6 g, 135.2 mmol) was dissolved in anhydrous DMF (300 mL) and paraquat dichloride hydrate (3.5 g, 13.5 mmol, 10% mol) was added. The mixture was cooled to 0 °C and trifluoroiodomethane x TMG reagent (33.6 mL, 162.2 mmol, 1.2 equiv) was added, followed by TEA (18.8 mL, 135.2 mmol). The reaction was stirred at 0 °C for 15 minutes, then warmed to room temperature and stirred overnight. It was quenched with HO (1500 mL) and extracted with EtOAc (3 × 300 mL). The combined organics were washed with brine (2 × 100 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product as a yellow solid (19.3 g, 45%).

[0290] Step e: The product from step d (18.5 g, 58.4 mmol) was dissolved in CHCl:CHCN:HO (1:1:2; 300 mL) and NaIO (50 g, 233.6 mmol, 4 equiv.) was added, followed by RuCl×HO (394 mg, 1.75 mmol, 3% mol). The reaction was stirred at room temperature for 1.5 h, then diluted with HO (1000 mL) and 10% NaSO solution (100 mL) and extracted with EtOAc (3×300 mL). The combined organics were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes (hex) → 40% EtOAc in hexanes) to give the product as a white solid (19.4 g, 95%). 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.6, 1H).

[0291] Step f: A mixture of 8-bromo-6-fluoroquinoline (15.7 g, 69.5 mmol), Zn(CN) (4.9 g, 41.7 mmol, 0.8 equiv.), and Pd(PPh) (8 g, 6.9 mmol, 10% mol) in anhydrous DMF (100 mL) was stirred at 100 °C overnight. The reaction was then cooled to room temperature and diluted with HO (500 mL). The yellow solid was filtered off, washed with HO, and dried under vacuum. The crude product was used in the next step without further purification.

[0292] Step g: The product from step f was placed in a Parr bottle and dissolved in MeOH (300 mL) and concentrated HCl (50 mL). The mixture was purged with N, and PtO (1.56 g, 6.9 mmol, 10% mol) was added. The reaction was shaken under an H atmosphere (50 psi) for 5 h, then filtered through Celite, washed with MeOH, and evaporated. The crude residue was purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product as a yellow solid (5.9 g, 48% over two steps). 1 H NMR (400 MHz, CDCl3) δ 6.90 - 6.81 (m, 2H), 4.63 (brs, 1H), 3.41 - 3.33 (m, 2H), 2.77 - 2.68 (m, 2H), 1.96 - 1.85 (m, 2H).

[0293] Step h: A mixture of the bromide from step g (200 mg, 0.57 mmol), the tetrahydroquinoline from step g (100 mg, 0.57 mmol), Pd(OAc) (25 mg, 0.22 mmol, 20% mol), rac-BINAP (87 mg, 0.14 mmol, 25% mol), and CsCO (372 mg, 1.14 mmol, 2 equiv.) in anhydrous, degassed toluene (2 mL) was stirred at 100 °C for 5 h. The entire reaction mixture was loaded onto a silica gel cartridge and purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product as a yellow solid (44 mg, 17%). 1H NMR (400 MHz, CDCl3) δ 8.02(d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.19 - 7.13 (m, 1H), 7.11 - 7.07 (m, 1H), 3.90 - 3.57 (m, 2H), 3.06 - 2.82(m, 2H), 2.20 - 1.78 (m, 2H). C 18 H 10 ESI MS of ClF4N3O2S [M+H] + , calculated value 444.0, measured value 444.0.

[0294] Example 11: 1-(2-chloro-3-cyano-4-methanesulfonylphenyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0295] [ka]

[0296] Step a: A solution of 3-bromo-2-chloro-6-fluorobenzonitrile (5 g, 21.3 mmol) in anhydrous CHCN (100 mL) was cooled to 0 °C, after which CHSNa (1.64 g, 23.4 mmol, 1.1 equiv) was added in one portion. The mixture was stirred at 0 °C for 15 min, then the cooled batch was removed and the reaction was stirred at room temperature overnight. After dilution with HO (300 mL), the product was filtered off (white solid, 4.6 g, 82%).

[0297] Step b was carried out in the same manner as in Example 10. 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 3.30 (s, 3H).

[0298] Step c was carried out similarly to Example 10 (brown solid, 3.5 mg, 1%). 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.08 - 7.03 (m, 1H), 3.72 - 3.57 (m, 2H), 3.31 (s, 3H), 3.00 - 2.81 (m, 2H), 2.10 - 1.79 (m, 2H). C 18 H 13 ESI MS of ClFN3O2S [M+H] + , calculated value 390.0, measured value 390.0.

[0299] Example 12: 2-chloro-3-(8-chloro-6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-6-trifluoromethanesulfonylbenzonitrile

[0300] [ka]

[0301] The title compound was synthesized similarly to Example 10. (yellow solid, 130 mg, 50%). 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.00 - 6.93 (m, 1H), 6.93 - 6.86 (m, 1H), 3.91 - 3.82(m, 1H), 3.66 - 3.53 (m, 1H), 3.02 - 2.86 (m, 2H), 2.06 - 1.93 (m, 1H), 1.89 - 1.75 (m, 1H). C 17 H 10 ESI MS of Cl2F4N2O2S [M+H] + , calculated value 453.0, measured value 453.0.

[0302] Example 13: 2-chloro-3-(6,8-difluoro-1,2,3,4-tetrahydroquinolin-1-yl)-6-trifluoromethanesulfonylbenzonitrile

[0303] [ka]

[0304] The title compound was synthesized in the same manner as in Example 10. (yellow solid, 172 mg, 69%) 1 H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 6.79 - 6.73 (m, 1H), 6.70 - 6.59 (m, 1H), 3.77 - 3.67 (m, 2H), 2.95 - 2.87 (m, 2H), 1.99 - 1.89 (m, 2H). C 17 H 10 ESI MS of ClF5N2O2S [M+H] + , calculated value 437.0, measured value 437.0.

[0305] Example 14: 1-[5-cyano-6-(trifluoromethyl)pyridin-3-yl]-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0306] [ka]

[0307] Step a: To a 40 mL vial was added 6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (61 mg, 0.344 mmol, 1.2 equiv.), 5-bromo-3-fluoro-2-(trifluoromethyl)-pyridine (70 mg, 0.287 mmol, 1.0 equiv.), Pd(OAc) (13 mg, 0.057 mmol, 20 mol%), rac-BINAP (45 mg, 0.072 mmol, 25 mol%), CsCO (190 mg, 0.574 mmol, 2.0 equiv.), and toluene (1.5 mL). The reaction vessel was capped, and the mixture was purged with N for 2 minutes. The reaction was stirred at 100 °C for 2 hours. The reaction mixture was cooled, concentrated onto Celite, and purified by flash column chromatography (SiO, hexanes → 40% EtOAc in hexanes) to give the product as a white solid (65 mg, 0.192 mmol, 55%, C 16 H 10 ESI MS of F5N3 [M+H] + , calculated value 340.3, measured value 340.0).

[0308] Step b: A vial was charged with the product from step a (30 mg, 0.088 mmol, 1.0 equiv), KCN (7.0 mg, 0.097 mmol, 1.1 equiv), and NMP (0.3 mL). The reaction mixture was stirred at 100 °C for 4 h. The reaction was diluted with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (10 mL). The aqueous layer was separated and back-extracted with additional EtOAc (15 mL). The organic layers were combined, washed with HO (2 × 20 mL), brine (20 mL), and dried over MgSO. Concentration under reduced pressure and purification by flash chromatography afforded the product as a yellow solid (4.0 mg, 0.012 mmol, 13%). 1 H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.63 (m, 1H), 8.31 - 8.25 (m, 1H), 7.70 - 7.64 (m, 1H), 7.61 - 7.54 (m, 1H), 3.86 - 3.80 (m, 2H), 2.80 (t, J = 6.4 Hz, 2H), 1.95 - 1.87 (m, 2H). C 17H 10 ESI MS of F4N4 [M+H] + , calculated value 347.1, measured value 347.0.

[0309] Example 15: 1-[2-chloro-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0310] [ka]

[0311] The title compound was synthesized in the same manner as in Example 14 using 1-bromo-2-chloro-3-fluoro-4-(trifluoromethyl)-benzene. 1 H NMR (400 MHz, DMSO-d6) δ 7.74 - 7.67 (m, 1H), 7.53 - 7.43 (m, 2H), 7.13 - 7.04 (m, 1H), 3.74 - 3.48 (m, 2H), 3.07 - 2.77 (m, 2H), 2.06 - 1.64 (m, 2H). C 17 H 10 ESI MS of ClF5N2 [M+H] + , calculated value 373.0, measured value 373.0.

[0312] Example 16: 6-Fluoro-1-[8-(trifluoromethylsulfonyl)-5-isoquinolyl]-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0313] [ka]

[0314] The title compound was synthesized in a similar manner to Example 10. 1H NMR (400 MHz, chloroform-d) δ 10.24 (s, 1H), 8.87 (d, J = 6.1 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.26 (dd, J = 6.2, 0.9 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.26 - 7.22(m, 1H), 7.15 - 7.11 (m, 1H), 3.87 - 3.76 (m, 2H), 3.16 - 2.94 (m, 2H), 2.08 - 1.85 (m, 2H). C 20 H 13 ESI MS of F4N3O2S [M+H] + , calculated value 436.1, measured value 436.1.

[0315] Example 17: (1S,2R)-4-[(S)-4-ethyl-6,8-difluoro-1,2,3,4-tetrahydroquinol-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol

[0316] [ka]

[0317] The title compound was synthesized in a similar manner to Example 19. 1 H NMR (400 MHz, chloroform-d) δ 7.77 (d, J = 8.4 Hz, 1H), 7.00 (s, 0H), 6.83 (d, J = 8.8 Hz, 1H), 6.70 (ddd, J = 11.0, 8.3, 2.6 Hz, 1H), 5.51 (s, 1H), 5.18 (d, J = 50.8 Hz, 1H), 3.69 (s, 2H), 3.00 (br m, 2H), 2.84 (p, J = 6.4 Hz, 1H), 2.12 - 1.99 (m, 1H), 1.81 (br m, 2H), 1.60 (dq, J = 14.5, 7.5 Hz, 1H), 0.98 (t, J = 7.4 Hz, 3H). C 21 H 19ESI MS of F6NO3S [M+H] + , calculated value 480.1, measured value 480.1.

[0318] Example 18: 2-chloro-3-(6-fluoro-8-methoxy-3,4-dihydroquinolin-1(2H)-yl)-6-((trifluoromethyl)sulfonyl)benzonitrile

[0319] [ka]

[0320] The title compound was synthesized in a similar manner to Example 10. 1 H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 8.8, 0.4 Hz, 1H), 7.13 (d, J = 8.9 Hz, 1H), 6.54 (dd, J = 8.6, 2.7 Hz, 1H), 6.43 (dd, J = 10.2, 2.8 Hz, 1H), 3.74 (br. s, 2H), 3.51 (s, 3H), 2.95 - 2.79 (m, 2H), 1.91 (br. s, 2H). 19 F NMR (376 MHz, CDCl3) δ -77.11, -115.53. C 18 H 13 ESI MS of ClF4N2O3S [M+H] + ;Calculated value 449.0, measured value 449.1.

[0321] Example 19: 7-Fluoro-4-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile

[0322] [ka]

[0323] Step a: At 0 °C, chloroacetyl chloride (8.3 mL, 110 mmol) was added dropwise to a stirred suspension of 2-amino-5-fluorophenol (9.5 g, 75 mmol) and potassium carbonate (41.4 g, 300 mmol) in THF (120 mL). The reaction was stirred at ambient temperature for 30 min, after which it was maintained at 66 °C for 48 h. The mixture was cooled and filtered through a Celite pad to remove inorganic solids, and the filtrate was concentrated to dryness. The residue was fractionated by column chromatography (SiO, hexane / EtOAc gradient) to afford 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (5.5 g, 32.9 mmol, 44% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 6.90 - 6.53 (m, 3H), 4.60 (s, 2H). 19 F NMR (376 MHz, CDCl3) δ -117.25.

[0324] Step b: At 0 °C, lithium aluminum hydride (1.2 g, 3.2 mmol) was carefully added portionwise to a solution of 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (3.5 g, 2.1 mmol) in THF (30 mL). Upon completion of the addition, the cooling bath was removed, and the mixture was stirred at ambient temperature for 4 h. After TLC analysis indicated complete reaction, the mixture was quenched using the Fieser protocol, and the product was extracted with diethyl ether. After removing all solvents under reduced pressure, the crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to afford 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (2.9 g, 18.9 mmol, 90% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ 6.63 - 6.22(m, 3H), 4.30 - 4.18 (m, 2H), 3.59 (s, 1H), 3.44 - 3.32(m, 2H). 19 F NMR (376 MHz, CDCl3) δ -124.56.

[0325] Step c: Bromine (0.4 mL, 7.5 mmol) was added dropwise to a solution of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1 g, 6.5 mmol) in acetic acid (26 mL), which was placed in a water bath to maintain the reaction temperature below 25 °C. Upon completion of the addition, the reaction was stirred at ambient temperature for 10 min and poured into 5% aqueous NaHSO (100 mL). The crude product was extracted with a mixture of EtOAc and hexane (v / v 1:1, 3 × 35 mL), and the combined extracts were then washed with water (3 × 100 mL), aqueous NaHCO (2 × 100 mL), and brine (50 mL). The solution was dried over NaSO, and the solvent was evaporated to dryness. The crude product was purified by column chromatography (SiO 2 , hexane / EtOAc gradient) to give 5-bromo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.05 g, 4.5 mmol, 70% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 6.79 (dd, J = 8.0, 2.8 Hz, 1H), 6.52(dd, J = 9.5, 2.8 Hz, 1H), 4.32 - 4.14 (m, 2H), 4.14 - 3.88 (br. s, 1H), 3.53 - 3.34 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ -124.82(d, J = 8.3 Hz).

[0326] Step d: A mixture of 5-bromo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.05 g, 4.5 mmol), zinc cyanide (0.43 g, 3.6 mmol), and Pd(PPh3)4 (0.52 g, 0.45 mmol) in DMF (11 mL) was heated at 100 °C for 4 h under a nitrogen atmosphere. Once complete disappearance of the starting material was observed by TLC analysis (30% EtOAc in hexanes as eluent), the solution was cooled to ambient temperature and poured into a mixture of EtOAc (50 mL) and water (50 mL). The resulting suspension was filtered through a plug of Celite. The organic phase was separated, and the aqueous solution was further extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with water (2 × 75 mL) and brine (75 mL), dried over Na2SO4, and concentrated to dryness. The dried residue was fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to give 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (0.75 g, 4.2 mmol, 94% yield) as a white powder. 1 H NMR (400 MHz, CDCl3) δ 6.78 - 6.54 (m, 2H), 4.51 (br. s, 1H), 4.33 - 4.17 (m, 2H), 3.60 - 3.40(m, 2H). 19 F NMR (376 MHz, CDCl3) δ -124.17. ESI MS of C9H7FN2O [M+Na] + ;Calculated value 179.1, measured value 179.1.

[0327] Step e: A mixture of (1S,2R)-4-bromo-2-fluoro-1-(tertbutyl-dimethylsilyl)-7-(trifluoromethylsulfonyl)indane (100 mg, 0.21 mmol), 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (38 mg, 0.21 mmol), Pd(OAc) (9.5 mg, 0.042 mmol), rac-BINAP (33 mg, 0.053 mmol), and CsCO (137 mg, 0.42 mmol) in anhydrous, degassed toluene (1 mL) was stirred at 100° C. for 6 h. The mixture was then cooled to ambient temperature, diluted with EtOAc, and filtered through a pad of Celite to remove inorganic solids. The filtrate was concentrated onto Celite and purified by column chromatography (SiO, hexane / EtOAc gradient) to give a mixture of the product and unreacted benzomorpholine (55 mg), which was subjected to step f without further purification.

[0328] Step f: The mixture of the TBS-protected indanol from the previous step and unreacted benzomorpholine was dissolved in CH3CN (1 mL) and placed in a 3 mL vial equipped with a magnetic stir bar, followed by the addition of HF·Py complex (approximately 70% hydrogen fluoride, approximately 30% pyridine, 0.1 mL). The resulting solution was stirred overnight at ambient temperature. After TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (20 mL) and 1 M aqueous HCl (20 mL). The product was extracted with EtOAc (2 × 10 mL), and the combined organic extracts were washed with aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated to dryness. The residue was fractionated by column chromatography (SiO, hexane / EtOAc gradient) to give 7-fluoro-4-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (25 mg, 0.054 mmol, 26% yield over two steps) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.6 Hz, 1H), 7.05 - 6.93 (m, 2H), 6.89 (dd, J = 7.5, 2.8 Hz, 1H), 5.59 (br. s, 1H), 5.28 (br. d, J = 49.6 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 4.10 (br. s, 1H), 3.76 - 3.57 (m, 2H), 3.34 (br. s, 2H), 3.03 (s, 1H). 19 F NMR (376 MHz, CDCl3) δ -78.08, -113.95, -199.41 (d, J = 51.0 Hz). C 19 H 13 ESI MS of F5N2O4S [M+Na] + ;Calculated value 483.0, measured value 483.1.

[0329] Example 20: 7-Fluoro-4-((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile

[0330] [ka]

[0331] The title compound was synthesized in a similar manner to Example 19. 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 1H), 6.99 - 6.79 (m, 3H), 5.68 - 5.61 (m, 1H), 5.37 (br. d, J = 52.1, 1H), 4.38 - 4.23 (m, 1H), 4.18 - 4.02(m, 1H), 3.72 - 3.48 (m, 3H), 3.43 - 2.93 (m, 5H). 19 F NMR (376 MHz, CDCl3) δ -115.26, -199.17. C 19 H16 ESI MS of F2N2O4S [M-OH] + ;Calculated value 389.1, measured value 389.1.

[0332] Example 21: 6,8-Difluoro-8'-trifluoromethanesulfonyl-3,4-dihydro-2H-1,5'-biquinoline

[0333] [ka]

[0334] The title compound was synthesized in a similar manner to Example 10. 1 H NMR (400 MHz, CDCl3) δ 9.15 (dd, J = 4.3, 1.7 Hz, 1H), 8.61 (dd, J = 8.6, 1.7 Hz, 1H), 8.44 (d, J = 8.3 Hz, 1H), 7.60 (dd, J = 8.6, 4.2 Hz, 1H), 7.08 (dd, J = 8.3, 0.9 Hz, 1H), 6.85 - 6.76 (m, 1H), 6.71 - 6.61 (m, 1H), 3.86 - 3.69 (m, 2H), 3.04 - 2.96 (m, 2H), 1.99 - 1.82(m, 2H). C 19 H 13 ESI MS of F5N2O2S [M+H] + Calculated value 429.1, measured value 429.1.

[0335] Example 22: 4-(6,8-difluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2,2-difluoro-7-methanesulfonyl-2,3-dihydro-1H-inden-1-ol

[0336] [ka]

[0337] The title compound was synthesized in a similar manner to Example 19. 1H NMR (400 MHz, methanol d4) δ 7.76 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.85 - 6.80 (m, 1H), 6.77 - 6.69 (m, 1H), 5.50 - 5.44 (m, 1H), 3.66 - 3.57 (m, 3H), 3.22(s, 3H), 3.18 - 3.03 (m, 1H), 2.93 - 2.84 (t, J = 6.6 Hz, 2H), 1.96 - 1.84 (m, 2H). C 19 H 17 ESI MS of F4NO3S [M+H] + Calculated value: 416.1, measured value: 416.0.

[0338] Example 23: 6,8-Difluoro-1-(2-nitro-4-trifluoromethanesulfonylphenyl)-1,2,3,4-tetrahydroquinoline

[0339] [ka]

[0340] The title compound was synthesized in a similar manner to Example 24. 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.2 Hz, 1H), 7.94 (dd, J = 8.9, 2.3 Hz, 1H), 7.33 (dd, J = 8.9, 1.7 Hz, 1H), 6.82 - 6.76 (m, 1H), 6.76 - 6.63 (m, 1H), 3.77 - 3.50 (m, 2H), 2.92 - 2.81 (m, 2H), 2.15 - 1.99 (m, 2H). C 16 H 11 ESI MS of F5N2O4S [M+H] + Calculated value: 423.0, measured value: 423.1.

[0341] Example 24: 6,8-Difluoro-1-[2-nitro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinoline.

[0342] [ka]

[0343] 4-Bromo-3-nitrobenotrifluoride (270 mg, 1 mmol), 6,8-difluoro-1,2,3,4-tetrahydroquinoline (324 mg, 1.2 mmol), Pd(OAc) (45 mg, 0.2 mmol), rac-BINAP (187 mg, 0.3 mmol), and CsCO (652 mg, 2 mmol) were suspended in PhMe (5 mL). The suspension was degassed with N at ambient temperature for 5 minutes and heated to 100 °C for 1.5 hours. The mixture was cooled to room temperature, diluted with EtOAc, filtered, and concentrated onto Celite®. Purification by column chromatography (0-10% EtOAc / hexanes) afforded the title compound as an orange oil (125 mg, 35% yield). 1 H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 2.2, 0.9 Hz, 1 H), 7.68 - 7.61 (m, 1 H), 7.26 - 7.22 (m, 1 H), 6.73 (dddt, J = 8.4, 2.6, 1.7, 0.9 Hz, 1 H), 6.63 (dddd, J = 11.3, 8.4, 2.8, 0.7 Hz, 1 H), 3.57 (s, 2 H), 2.88 (tt, J = 6.6, 0.8 Hz, 2 H), 2.00 (q, J = 6.2 Hz, 2 H). 19 F NMR (376 MHz, CDCl3) δ -62.3 (3 F), -117.3 (1 F), -116.7 (1 F). C 16 H 11 ESI MS of F5N2O2 [M+H] + , calculated value 359.1, measured value 359.1.

[0344] Example 25: 5-(6,8-difluoro-1,2,3,4-tetrahydronaphth-1-yl)-8-(trifluoromethylsulfonyl)isoquinoline

[0345] [ka]

[0346] Step a: 5-Bromo-8-isoquinolylamine (2.23 g, 10 mmol, 1 equiv.) was dissolved in a mixture of ethanol (3 mL) and aqueous HBF (48 wt %, 2.62 mL, 20 mmol, 2 equiv.), and the solution was cooled to 0 °C. t-BuONO (2.37 mL, 20 mmol, 2 equiv.) was added dropwise, after which the reaction was left stirring for 1 h. EtO (10 mL) was added to the reaction mixture, which was then filtered and washed with additional EtO (2 × 10 mL). The filtrate was dried under vacuum for 30 min to give the diazonium salt as an orange solid (3.06 g, 9.52 mmol, 95%). ESI MS [M] for CHBrN + Calculated value 234.0, actual value 234.0.

[0347] Step b: To a vigorously stirred solution of NaSOCF (4.68 g, 30 mmol, 3 equiv.) and CuO (143 mg, 1 mmol, 0.1 equiv.) in DMSO (10 mL) was added a solution of the product from step a in DMSO (10 mL) using a dropping funnel. After the addition was complete, the reaction was left stirring for 2 h or until LCMS indicated complete conversion of the starting material. The reaction mixture was then diluted with EtOAc (100 mL) and water (100 mL). After separation of the layers, the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organics were washed with water (2 × 100 mL) and brine (100 mL) and finally dried over NaSO. The crude material was purified by flash column chromatography (SiO, 0–100% EtOAc / hexanes) to give the product as a brown solid (716 mg, 2.94 mmol, 29%). 10 ESI MS of H5BrF3NO2S [M+H] + Calculated value 339.9, measured value 339.9.

[0348] Step c: A vial was charged with the product from step b (24 mg, 0.07 mmol, 1 equiv.), 2-(6,8-difluoro-3,4-dihydronaphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21 mg, 0.07 mmol, 1 equiv.), Pd(dppf)Cl (5 mg, 0.007 mmol, 0.1 equiv.), an aqueous solution of NaCO (1 M, 0.21 mL, 3 equiv.), and dioxane (1 mL). The vial was sparged with N for 10 minutes and then heated to 100 °C for 16 hours. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried over NaSO and concentrated. The crude material was purified by flash column chromatography (0-100% EtOAc / hexanes) to give the target product (7 mg, 0.016 mmol, 23%). 20 H 12 ESI MS of F5NO2S [M+H] + Calculated value 426.1, measured value 426.1.

[0349] Step d: The product from step c (7 mg, 0.016 mmol, 1 equiv.) was dissolved in i-PrOH (1 mL), and PhSiH (4 μL, 0.032 mmol, 2 equiv.) and tert-butyl hydroperoxide (5.5 M in decane, 8 μL, 0.032 mmol, 2 equiv.) were added under nitrogen. The solution was sparged with nitrogen for 10 min, after which Mn(dmp) (10 mg, 0.016 mmol, 1 equiv.) was added, and the resulting mixture was sparged for an additional 30 s. The reaction was then left stirring under nitrogen for 16 h. After concentration of the reaction mixture, the crude material was purified by flash column chromatography (SiO, 0–100% EtOAc / hexanes) to give the title compound (4 mg, 0.009 mmol, 57%). 1H NMR (400 MHz, chloroform-d) δ 10.23 (s, 1H), 8.85 (d, J = 6.0 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 6.0 Hz, 1H), 7.16 (m, 1H), 6.84 - 6.79 (m, 1H), 6.67 - 6.59 (m, 1H), 5.12(m, 1H), 3.02 - 2.78 (m, 2H), 2.33 - 2.19 (m, 1H), 2.05 - 1.97 (m, 1H), 1.84 - 1.70 (m, 1H), 1.57 (br m, J = 17.9 Hz, 1H). C 20 H 14 ESI MS of F5NO2S [M+H] + Calculated value 428.1, measured value 428.1.

[0350] Examples 26-120: Compound synthesis The following examples were prepared according to the general synthetic protocols described for the other examples, as detailed in Table A below. Each example provides characteristic physical data, such as mass spectral peaks indicated.

[0351] [Table 1] TIFF0007648828000049.tif210164TIFF0007648828000050.tif210164TIFF0007648828000051.tif222164 TIFF0007648828000052.tif201164TIFF0007648828000053.tif223164TIFF0007648828000054.tif223164 TIFF0007648828000055.tif223164TIFF0007648828000056.tif223164TIFF0007648828000057.tif209164 TIFF0007648828000058.tif225164TIFF0007648828000059.tif223164TIFF0007648828000060.tif139164

[0352] Example 121: (4S)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile.

[0353] [ka]

[0354] Step a: A flask was charged with 2-chloro-4-fluoroaniline (18.2 g, 15 mL, 1.0 mol equiv.) and excess acrylic acid (46 g, 5.0 mol equiv.), and the resulting mixture was stirred for 15 h at 45° C. During this time, the product solidified from the reaction mixture and was collected by filtration and rinsed with hexane to give the aniline product, which was used crude in the next step (25.4 g, 93%).

[0355] Step b: The product from step a (25.4 g) was then added portionwise to Eaton's reagent (100 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and then heated at 80° C. for 3 h. After this time, the reaction was cooled and carefully poured onto ice, after which the product precipitated from solution as a yellow solid (17.4 g, 75%).

[0356] Step c: A flask containing the product from the previous step (15 g, 75.3 mmol, 1.0 mol equiv.) in MeOH (250 mL) was cooled to 0 °C under N. NaBH (3.41 g, 90.4 mmol, 1.2 mol equiv.) was added slowly in portions, after which the reaction was stirred at room temperature for 30 minutes. At this time, the reaction was placed in an ice bath, quenched with HO, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with water, brine, and dried over MgSO. Concentration under reduced pressure provided the tetrahydroquinoline intermediate, which was carried on to the next step without further purification.

[0357] Step d: To the crude intermediate from step c was added DCM (250 mL) and imidazole (7.70 g, approximately 1.5 mol eq.). The resulting mixture was cooled to 0 °C, and TBSCl (17.0 g, approximately 1.5 eq.) was added. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was filtered to remove imidazole hydrochloride and concentrated onto Celite. Purification by flash column chromatography (SiO, hexane to 10% EtOAc / hexane) afforded the TBS-protected alcohol as a colorless oil (16.7 g, 70% over two steps).

[0358] Step e: A flask was charged with TBS alcohol (6.0 g, 19 mmol, 1.0 mol eq.) from the previous step, KFe(CN)6.3HO (5.61 g, 13.3 mmol, 0.7 mol eq.), Pd XPhos gen III (0.803 g, 0.95 mmol, 5 mol%), XPhos (0.452 g, 0.95 mmol, 5 mol%), KOAc (0.242 g, 2.47 mmol, 0.13 mol eq.), HO (40 mL), and 1,4-dioxane (40 mL). The resulting mixture was purged with N2, heated to 100 °C, and stirred vigorously under N2. After 3 h, the reaction was cooled and diluted with EtOAc and HO. The aqueous layer was separated and back-extracted with additional EtOAc. Filtration through Celite to remove solids can improve layer differentiation. The combined organic layers were dried over MgSO. Purification by flash column chromatography (SiO, hexane to 20% EtOAc) gave the benzonitrile product as a yellow solid (5.68 g, 98%).

[0359] Step f: To a flask containing 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (10 g, 34.8 mmol, 1.0 mol equiv.) was added DMF (70 mL), followed by EDC.HCl (9.98 g, 52.2 mmol, 1.5 mol equiv.), HOBt.HO (7.0 g, 52.2 mmol, 1.5 mol equiv.), ammonium carbonate (16.7 g, 174 mmol, 5.0 mol equiv.), and DIPEA (18 mL, 3.0 mol equiv.). The resulting mixture was stirred at 40 °C overnight. The reaction was partitioned between EtOAc and HO. The aqueous layer was separated and extracted with additional EtOAc. The organic layers were combined, washed with HO to remove DMF, and dried over MgSO. Concentration under reduced pressure gave the crude amide, which was carried on to the next step without purification.

[0360] Step g: To a flask containing the crude amide from the previous step was added DMF (100 mL) and cyanuric trichloride (2.55 g, 13.9 mmol, approximately 0.6 mol equivalents). The resulting mixture was stirred at room temperature under N for 16 h. The reaction was partitioned between EtOAc and H2O. The aqueous layer was separated and extracted with additional EtOAc. The organic layers were combined, washed with H2O to remove DMF, and dried over MgSO4. Concentration under reduced pressure and purification by flash column chromatography (SiO2, hexanes to 20% EtOAc) afforded the nitrile product as a white solid (2.68 g, 26% over two steps).

[0361] Step h: A vial was charged with benzonitrile (1.0 g, 3.73 mmol, 1.0 mol eq.) from the previous step, 4-[tert-butyl(dimethyl)silyl]oxy-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (1.10 g, 3.73 mmol, 1.0 mol eq.), Pd(OAc) (0.167 g, 0.746 mmol, 20 mol %), rac-BINAP (0.580 g, 0.925 mmol, 25 mol %), CsCO (2.42 g, 7.46 mmol, 2.0 mol eq.), and toluene (15 mL). N was bubbled through the reaction mixture for 3 min, then the vial was capped and heated at 100 °C for 15 h. The reaction was monitored by TLC and NMR analysis. The reaction was cooled, filtered, and concentrated onto Celite. Purification by flash column chromatography (SiO2, hexanes to 10-20% EtOAc) gave the coupled product as a yellow solid (1.00 g, 54%). 24 H 24 ESI MS [M+H] of F5N3OSi + , calculated value 494.2, measured value 494.2.

[0362] Step i: A flask containing the product from the previous step (1.0 g, 2.02 mmol, 1.0 mol eq) and THF (10 mL) was cooled to 0 °C, and TBAF (1 M in THF, 3.0 mL, 1.5 mol eq) was added. The reaction mixture was warmed to room temperature and stirred for 15 min. After this time, the reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with brine, and dried over MgSO4. Concentration under reduced pressure and purification by flash column chromatography (SiO2, hexanes to 20% to 50% to 80% EtOAc) afforded the alcohol product as a white solid (0.694 g, 91%).

[0363] Step j: A vial containing the alcohol product from the previous step (35 mg, 0.093 mmol, 1.0 mol equiv.) in DCM (1 mL) was cooled to -78 °C. DAST (20 μL, 0.149 mmol, 1.6 mol equiv.) was added, and the reaction was warmed to room temperature and stirred for 5 min. The reaction was quenched at 0 °C with saturated aqueous NaHCO3 and diluted with DCM. The aqueous layer was separated and back-extracted with additional DCM. The organic layers were combined and dried over MgSO4. Concentration under reduced pressure and purification by column chromatography (SiO2, hexanes to 20% EtOAc) afforded racemic 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile as a white solid (13 mg, 37%). The enantiomers were separated by preparative SFC chiral purification (2.0 x 25.0 cm ChromegaChiral CC4 from ES Industries, West Berlin, NJ, CO2 co-solvent isopropanol / hexane (1:9), 15% co-solvent at 100 mL / min) to afford the title compound (4S)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile as a white solid (98.8% ee, t R = 1.5 min). The absolute stereochemistry was confirmed by single crystal X-ray analysis. 1H NMR (400 MHz, DMSO-d6, appearing as a 2:1 mixture of rotamers) δ 8.11 (t, J = 8.6 Hz, 1H), 8.03 (t, J = 8.6 Hz, 2H), 7.94 - 7.79 (m, 6H), 7.43 (d, J = 8.8 Hz, 1H), 7.12(d, J = 8.7 Hz, 2H), 5.82(dt, J = 49.7, 2.9 Hz, 1H), 5.70 (dt, J = 49.8, 2.9 Hz, 2H), 4.08 - 3.67 (m, 6H), 2.38 - 2.02(m, 6H). C 18 ESI MS of H8F5N3 [(M-HF) + H] + , calculated value 362.0, measured value 362.0.

[0364] Example 122: 1-(3-chloro-2-cyano-4-methylsulfonylphenyl)-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile

[0365] [ka]

[0366] Step a: A solution of 3-amino-2-chloro-benzonitrile (1 g, 6.58 mmol) in DMF (20 mL) was cooled to −10° C., and NBS (1.17 g, 6.58 mmol, 1.0 equiv.) in DMF (10 mL) was added dropwise over 10 minutes. The mixture was stirred at −10° C. for 10 minutes, then the cooled batch was removed and the reaction stirred at room temperature for 1.5 hours. It was diluted with 10% NaSO (100 mL) and extracted with EtOAc (3×100 mL). The combined organics were washed with brine (50 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product (0.92 g, 60%).

[0367] Step b: The product from step a (0.5 g, 2.16 mmol) was dissolved in MeCN (8.5 mL). tBuONO (0.39 mL, 3.25 mmol, 1.5 equiv) and MeS-SMe (0.23 mL, 2.50 mmol, 1.2 equiv) were added. The mixture was stirred at room temperature for 15 minutes and then heated at 60° C. for 1 hour. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product (0.36 g, 64%).

[0368] Step c: A mixture of the bromide from step b (180 mg, 0.68 mmol, 1.5 equiv), 4-[tert-butyl(dimethyl)silyl]oxy-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (148 mg, 0.45 mmol), Pd(OAc) (10 mg, 0.045 mmol, 10% mol), Xantphos (52 mg, 0.09 mmol, 20% mol), and CsCO (440 mg, 1.35 mmol, 3 equiv) in anhydrous, degassed toluene (8 mL) was stirred at 100 °C for 15 h. The entire reaction mixture was loaded onto a silica gel cartridge and purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product (88 mg, 40%).

[0369] Step d: The product from step c (88 mg, 0.18 mmol) was dissolved in DCM (4 mL). mCPBA (254 mg, 1.1 mmol, 6.0 equiv) was added in one portion. The reaction mixture was stirred at room temperature for 2 h, then quenched with 10% NaSO (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organics were washed with saturated NaHCO (50 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product (quantitative yield).

[0370] Step e: The product from step d (0.18 mmol) was dissolved in THF (40 mL) and TBAF (1.0 M in THF, 0.54 mL, 3.0 equiv.) was added. The reaction was stirred at room temperature for 15 minutes. It was quenched with HO (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organics were washed with brine (10 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 80% EtOAc in hexane) to give the product as a yellow solid (58 mg, 80%).

[0371] Step f: The product from step e (25 mg, 0.05 mmol) in DCM (2 mL) was cooled to -10 °C, and DAST (16 mg, 0.1 mmol, 2.0 equiv.) was added. The mixture was stirred at -10 °C for 10 min, then the cooled batch was removed and the reaction stirred at room temperature for 0.5 h. It was quenched with HO (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organics were washed with brine (10 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 60% EtOAc in hexane) to give the product as a yellow solid (23 mg, 95%). 1 H NMR (400 MHz, DMSO-d6) δ 8.22(d, J = 8.8 Hz, 0.4 H), 8.11 (d, J = 8.8 Hz, 0.6 H), 7.92 - 7.74 (m, 2H), 7.54 (d, J = 8.8 Hz, 0.4 H), 7.25 (d, J = 8.8 Hz, 0.6 H), 5.89 - 5.59 (m, 1H), 4.04 - 3.90 (m, 1H), 3.84 - 3.63 (m, 1H), 3.38 (m, 3H), 2.30 - 1.97 (m, 2H). C 18 H 12 ESI MS of ClF2N3O2S [M+H] + , Calculated value 408.0, measured value 408.0.

[0372] Example 123: 1-[3-chloro-2-cyano-4-(trifluoromethyl)phenyl]-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile.

[0373] [ka]

[0374] This compound was prepared analogously to Example 121 from 6-bromo-2-chloro-3-(trifluoromethyl)benzoic acid. 1H NMR (400 MHz, DMSO-d6, appearing as a 2:1 mixture of rotamers) δ 8.15 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 2H), 7.93 - 7.86 (m, 4H), 7.86 - 7.77 (m, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.7 Hz, 2H), 5.82(dt, J = 49.7, 2.9 Hz, 1H), 5.70 (dt, J = 49.8 Hz, 2.9 Hz, 2H), 4.05 - 3.91 (m, 3H), 3.88 - 3.66 (m, 3H), 2.32 - 2.00 (m, 6H). C 18 ESI MS of H9ClF5N3 [M+H] + , calculated value 398.0, measured value 397.9.

[0375] Example 124: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-3,4-dihydro-2H-quinoline-4,8-dicarbonitrile

[0376] [ka]

[0377] Step a: A vial containing 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (110 mg, 0.290 mmol, 1.0 mol equiv.) in DCM (1.5 mL) was cooled to 0 °C, and DMP (150 mg, 0.348 mmol, 1.2 mol equiv.) was added. The reaction mixture was warmed to room temperature and stirred for 20 min. The reaction was quenched with saturated aqueous NaHCO3 and saturated aqueous Na2SO3 (1:1) and diluted with DCM. The mixture was stirred vigorously for 30 min. The organic layer was separated and washed with additional saturated aqueous NaHCO3 / Na2SO3. The organic layer was separated and dried over MgSO4. Concentration under reduced pressure afforded the ketone product as a yellow solid (110 mg, approximately quantitative), which was sufficiently pure for use in the subsequent step. C 18 ESI MS of H8F5N3O [M+H] + , calculated value 378.1, measured value 378.1.

[0378] Step b: A solution of KOtBu (1 M in THF, 520 μL, 2 equiv.) was added to a solution of 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-oxo-2,3-dihydroquinoline-8-carbonitrile (100 mg, 0.265 mmol) and tosMIC (83 mg, 0.42 mmol, 1.6 equiv.) in dichloromethane (1.3 mL) at room temperature. Ethanol (18 mg, 0.4 mmol, 1.5 equiv.) was added, and the reaction was stirred at room temperature for 48 hours. Upon completion, the reaction was quenched with 2N aqueous HCl, extracted with dichloromethane, and purified by flash chromatography on silica gel to give 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-3,4-dihydro-2H-quinoline-4,8-dicarbonitrile. 1H NMR (400 MHz, DMSO-d6):δ 8.11-7.95 (m, 1H), 7.88-7.68 (m, overlap, 2H), 7.24 (dd, J = 8.2, 8.2 Hz, 1H), 4.69-4.57 (m, 1H), 4.09-3.69 (m, 2H), 2.43-2.27 (m, 1H), 2.22-2.09 (m, 1H). C 19 ESI MS of H9F5N4 [M+H] + , Calculated value 389.0, measured value 389.0.

[0379] Example 125: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile

[0380] [ka]

[0381] Step a: A solution of 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-oxo-2,3-dihydroquinoline-8-carbonitrile (100 mg, 0.265 mmol) in 1 ml of a 50 wt% solution of Deoxo-Fluor® in toluene was heated to 70° C. overnight. Upon completion, the reaction was cooled to 0° C. in an ice bath and quenched with water. The resulting solution was extracted with ethyl acetate and methylene chloride, and the crude concentrate was purified by flash chromatography on silica gel (0% to 30% ethyl acetate in hexanes) to give 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile. 1H NMR (400 MHz, CDCl3): δ 7.75 (dd, J = 8.2, 8.2 Hz, 1H), 7.68 (dd, J = 7.8, 3.0 Hz, 1H), 7.27 (dd, J = 7.2, 3.0 Hz, 1H), 6.92(d, J = 8.6 Hz, 1H), 4.16-4.09 (m, 1H), 3.99-3.92(m, 1H), 2.53-2.39 (m, 2H). C 18 ESI MS of H8F7N3 [M+H] + , calculated value 400.1, measured value 400.0.

[0382] Example 126: 1-[6-(1,1-difluoroethyl)-5-fluoro-4-methylpyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile.

[0383] [ka]

[0384] Step a: A flask containing 2,5-dibromo-3-fluoropyridine (6.00 g, 23.6 mmol, 1.0 mol equiv.) in THF (100 mL) was cooled to −78 °C under N. A solution of LDA (2.0 M in heptane / THF / ethylbenzene, 17.7 mL, 1.5 mol equiv.) was slowly added, and the resulting mixture was stirred for 15 min. MeI (2.9 mL, 2.0 mol equiv.) was added, and the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction was cooled to 0 °C, quenched with saturated aqueous NH.sub.4Cl, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO. Concentration under reduced pressure and purification by flash column chromatography (SiO.sub.2, hexanes to 15% EtOAc) afforded the methylated product as a yellow oil (3.64 g, 57%).

[0385] Step b: A flask containing the product from the previous step (3.00 g, 11.2 mmol, 1.0 mol equiv.) in dry toluene (30 mL) was cooled to −78 °C under N. nBuLi (2.5 M in hexanes, 5.4 mL, 1.2 mol equiv.) was added, and the reaction was stirred for 30 min. After this time, the organolithium was trapped with anhydrous DMA (3.2 mL, 33.6 mmol, 2.0 mol equiv.), and the reaction was stirred for an additional 20 min. The reaction was quenched with saturated aqueous NH4Cl at −78 °C. After warming, the mixture was diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO4. Concentration under reduced pressure and purification by flash column chromatography (SiO2, hexanes to 30% EtOAc) gave the ketone product (906 mg, 35%).

[0386] Step c: To the ketone product from the previous step (400 mg, 1.72 mmol, 1.0 mol equiv.) was added Deoxo-Fluor (2.7 M in toluene, 3.0 mL, 4.0 mol equiv.), and the resulting mixture was stirred at 70 °C for 9 h. The reaction mixture was poured onto ice, quenched with saturated aqueous NaHCO3, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO4. Concentration under reduced pressure and purification by flash column chromatography (SiO2, hexane to 20% EtOAc) afforded the difluorinated product as a yellow oil (342 mg, 78%). ESI MS [M+H] for CHBrF3N + , calculated value 253.9, measured value 253.8.

[0387] The title compound 1-[6-(1,1-difluoroethyl)-5-fluoro-4-methylpyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile was prepared from 5-bromo-2-(1,1-difluoroethyl)-3-fluoro-4-methylpyridine in four additional steps, similar to Example 125. 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J = 0.6 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.31 - 7.27 (m, 1H), 3.90 - 3.79 (m, 1H), 3.55 - 3.46 (m, 1H), 2.59 - 2.40 (m, 2H), 2.38 (d, J = 2.3 Hz, 3H), 2.05 (td, J = 18.8, 0.7 Hz, 3H). 18 H 13 ESI MS of F6N3 [M+H] + , calculated value 386.1, measured value 386.0.

[0388] Example 127: 1-[4-chloro-5-fluoro-6-(trifluoromethyl)pyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile.

[0389] [ka]

[0390] Step a: A flask containing 5-bromo-3-fluoro-2-(trifluoromethyl)pyridine (1.00 g, 4.09 mmol, 1.0 mol eq) in THF (10 mL) was cooled to -78 °C under N. A solution of LDA (2.0 M in heptane / THF / ethylbenzene, 17.7 mL, 1.5 mol eq) was slowly added, and the resulting mixture was stirred for 15 min. A solution of hexachloroethane (1.93 g, 8.18 mmol, 2.0 mol eq) in THF (3 mL) was added, and the reaction mixture was warmed to room temperature and stirred for 15 min. The reaction was cooled to 0 °C, quenched with saturated aqueous NH4Cl, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO4. Concentration under reduced pressure and purification by flash column chromatography (SiO.sub.2, hexanes to 15% EtOAc) gave the chlorinated product as a yellow oil (824 mg, 72%).

[0391] The title compound 1-[4-chloro-5-fluoro-6-(trifluoromethyl)pyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile was prepared from 5-bromo-4-chloro-3-fluoro-2-(trifluoromethyl)pyridine in four additional steps, similar to Example 125. 1 H NMR (400 MHz, chloroform-d) δ 8.18 (s, 1H), 7.69 (ddt, J = 7.7, 3.0, 0.8 Hz, 1H), 7.34 (ddt, J = 7.2, 3.1, 0.9 Hz, 1H), 4.07 - 3.90 (m, 1H), 3.83 - 3.70 (m, 1H), 2.63 - 2.41 (m, 2H). 16 ESI MS of H7F7N3 [M+H] + , calculated value 410.0, measured value 409.9.

[0392] Example 128: 4,4,6-trifluoro-1-[5-fluoro-4-methyl-6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydroquinoline-8-carbonitrile

[0393] [ka]

[0394] Step a: A flask containing 5-bromo-3-fluoro-2-(trifluoromethyl)pyridine (1.00 g, 4.10 mmol, 1.0 mol equiv.) in THF (10 mL) was cooled to −78 °C under N. A solution of LDA (2.0 M in heptane / THF / ethylbenzene, 3.0 mL, 1.5 mol equiv.) was slowly added, and the resulting mixture was stirred for 15 min. MeI (0.55 mL, 2.0 mol equiv.) was added, and the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction was cooled to 0 °C, quenched with saturated aqueous NH.sub.4Cl, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO. Concentration under reduced pressure and purification by flash column chromatography (SiO.sub.2, hexanes to 15% EtOAc) afforded the methylated product as a yellow oil (970 mg, 92%).

[0395] Step b: A vial was charged with pyridine bromide (350 mg, 1.36 mmol, 1.3 mol eq.) from the previous step, 4-[tert-butyl(dimethyl)silyl]oxy-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (320 mg, 1.04 mmol, 1.0 mol eq.), Pd(OAc) (46 mg, 0.20 mmol, 20 mol %), Xantphos (150 mg, 0.26 mmol, 25 mol %), CsCO (468 mg, 2.08 mmol, 2.0 mol eq.), and toluene (3.5 mL). N was bubbled through the reaction mixture for 3 min, and the vial was capped and heated at 100 °C for 24 h. The reaction was monitored by TLC and NMR analysis. The reaction was cooled, filtered, and concentrated onto Celite. Purification by flash column chromatography (SiO 2 , hexanes to 20% EtOAc) gave the coupled product as a yellow solid (240 mg, 47%).

[0396] Step c: A vial was charged with the product from step b (90 mg, 0.186 mmol, 1.0 mol equiv.) and NMP (1.0 mL). KCN (18 mg, 0.28 mmol, 1.5 mol equiv.) was added, and the reaction was stirred at 110 °C. An additional portion of KCN (18 mg, 0.28 mmol, 1.5 mol equiv.) was added after 40 min, and the reaction was continued at 110 °C for 15 h. During this time, the TBS group was also cleaved. The reaction was cooled and diluted with saturated aqueous NaHCO3 and EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO4. Concentration under reduced pressure and purification by flash column chromatography (SiO2, hexanes to 60% EtOAc) gave the benzonitrile alcohol (18 mg, 0.048 mmol, 26%). C 18 H 12 ESI MS of F4NO [M+H] + , calculated value 377.1, measured value 377.0.

[0397] The title compound 1-[5-cyano-4-methyl-6-(trifluoromethyl)pyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile was prepared in two additional steps analogously to Examples 124 and 125. 1 H NMR (400 MHz, chloroform-d) δ 8.33 (s, 1H), 7.72 - 7.67 (m, 1H), 7.36 - 7.31 (m, 1H), 3.97 - 3.86 (m, 1H), 3.55 - 3.46 (m, 1H), 2.71 (s, 3H), 2.56 - 2.44 (m, 2H). 18 H 10 ESI MS of F6N4 [M+H] + , calculated value 397.1, measured value 397.0.

[0398] Example 129: 4,4,6-trifluoro-1-[5-fluoro-4-methyl-6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydroquinoline-8-carbonitrile.

[0399] [ka]

[0400] The title compound 4,4,6-trifluoro-1-[5-fluoro-4-methyl-6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydroquinoline-8-carbonitrile was prepared analogously to Example 125 in three additional steps. 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.96 - 7.90 (m, 1H), 7.87 (dd, J = 8.0, 2.9 Hz, 1H), 3.95 - 3.80 (m, 1H), 3.78 - 3.65 (m, 1H), 2.70 - 2.52(m, 2H), 2.33 (d, J = 2.1 Hz, 3H). C 17 H 10 ESI MS of F7N3 [M+H] + , calculated value 390.0, measured value 390.0.

[0401] Example 130: (3S,4R)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile.

[0402] [ka]

[0403] Step a: To a solution of 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-oxo-2,3-dihydroquinoline-8-carbonitrile (1.20 g, 3.71 mmol, 1.0 equiv.) in MeOH (18 mL) was added N-fluorobenzenesulfonimide (1.29 g, 4.08 mmol, 1.1 equiv.). The reaction mixture was stirred at 65° C. for 16 h. The reaction was quenched with saturated aqueous NaHCO3 and partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The resulting residue was dissolved in 1,4-dioxane (18 mL) and wet Amberlyst 15 (0.5 g, 150 wt%) was added. The reaction was stirred at 90° C. for 16 h. Upon completion, the polymer beads were removed by filtration and the concentrated crude material was purified by chromatography on silica gel (0-25% gradient EtOAc in hexanes) to give 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,6-difluoro-4-oxo-2,3-dihydroquinoline-8-carbonitrile as a yellow solid (1.28 g, 87% over two steps). 18 ESI MS of H8F6N3O1 [M+H] + , calculated value 396.0, measured value 395.9.

[0404] Step b: The product from step a (250 mg, 0.63 mmol, 1.0 equiv) was dissolved in CHCl (1.60 mL) and sparged with nitrogen gas, followed by the addition of formic acid (70 μL, 1.90 mmol, 3.0 equiv) and triethylamine (180 μL, 1.26 mmol, 2.0 equiv) at 0° C. RuCl(p-cymene)[(S,S)-Ts-DPEN] (6 mg, 0.01 mmol, 1.5 mol%) was added, and the reaction was stirred at 5° C. for 16 h. Upon complete conversion, the reaction was quenched with saturated aqueous NaHCO and extracted with CHCl. The combined organics were concentrated and the crude material was purified by flash chromatography on silica gel (0-35% gradient EtOAc in hexanes) to afford (3S,4R)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,6-difluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (160 mg, 64%) as a single diastereomer. 18 H 11 ESI MS of F6N3O2 [M+H2O] + , calculated value 415.0, measured value 415.0.

[0405] Step c: The product of step b (100 mg, 0.25 mmol, 1.0 equiv) was dissolved in CHCl (2.5 mL) and the solution was cooled to −40° C. Diethylaminosulfur trifluoride (0.17 mL, 1.26 mmol, 5.0 equiv) was added dropwise, and the reaction mixture was allowed to warm slowly to 0° C. with stirring over 2 h. The mixture was then diluted with CHCl and poured into a saturated aqueous solution of NaHCO, and the layers were separated. The organic phase was washed with brine, dried over NaSO, and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-18% gradient EtOAc in hexanes) to afford a 4:1 mixture of diastereoisomers with (3S,4S)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (64 mg, 64%) and (3S,4R)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (17 mg, 17%) as a white solid (combined yield 81%). The properties of (3S,4R)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile were reported. The enantiomeric excess of this material was 97% by chiral HPLC (Chiralpak AD-H, 15% iPrOH / hexane, isocratic, 20 min), R T minor = 7.18 min and R T major = 7.70 minutes. 1 H NMR (400 MHz, DMSO-d6) δ:8.11 - 7.99 (m, 1H), 7.85 (dd, J = 8.2, 3.0 Hz, 1H), 7.80 - 7.70 (m, 1H), 7.28 (d, J = 9.0 Hz, 1H), 5.97 (dd, J = 47.5, 3.0 Hz, 1H), 5.52(d, J = 51.5 Hz, 1H), 4.43 - 4.05 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ: -59.6 (3F), -108.7 (q, J = 11.8, 11.2 Hz, 1F), - 116.4 (t, J = 8.6 Hz, 1F), -198.7 (m, 1F), -201.9 (m, 1F). C 18 H 10 ESI MS of F7N3O1 [M+H2O] + , calculated value 417.0, measured value 416.9.

[0406] Example 131: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-methoxy-3,4-dihydro-2H-quinoline-8-carbonitrile

[0407] [ka]

[0408] Step a: To a solution of 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (80 mg, 0.21 mmol) in methanol (2.1 mL, 0.1 M), concentrated sulfuric acid (120 μL) was added, and the resulting solution was heated to reflux. Upon completion, the reaction solution was quenched with saturated NaHCO, extracted with ethyl acetate, and dried over NaSO. After concentration of the organics onto Celite, the resulting crude material was purified by flash chromatography (SiO) using a gradient of 0% to 100% dichloromethane in hexanes to give 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-methoxy-3,4-dihydro-2H-quinoline-8-carbonitrile. 1H NMR (400 MHz, CDCl3): δ 7.69 (dd, J = 8.3, 8.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 7.6, 3.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.33 (s, 1H), 3.90 (br m, 2H), 4.36 (s, 3H), 2.18 (br m, 2H). C 19 H 12 ESI MS of F5N3O [M+H] + , calculated value 394.1, measured value 394.0.

[0409] Example 132: 1-[2-cyano-4-(1,1-difluoroethyl)-3-fluorophenyl]-6-fluoro-4-methoxy-3,4-dihydro-2H-quinoline-8-carbonitrile

[0410] [ka]

[0411] Step a: A solution of 1-(4-bromo-2-cyano-3-fluorophenyl)-6-fluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (400 mg, 1.0 mmol) in MeOH (4 mL) and concentrated HSO (0.02 mL) was heated at 70 °C for 8 h. The reaction was then cooled to room temperature, quenched with saturated NaHCO (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 40% EtOAc in hexane) to give the product (280 mg, 68%).

[0412] Step b: A mixture of the product from step a (280 mg, 0.69 mmol), tributyl(1-ethoxyvinyl)tin (0.5 g, 1.39 mmol, 2.0 equiv.), and PdCl(dppf) (51 mg, 0.069 mmol, 10% mol) in 1,4-dioxane (7 mL) was stirred overnight at 100 °C under N. The reaction was then cooled to room temperature and diluted with 1 N HCl (10 mL). It was stirred for 2 h. The mixture was quenched with water and extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 40% EtOAc in hexane) to give the product (0.26 g, quantitative yield).

[0413] Step c: A solution of the product from step b (130 mg, 0.35 mmol) and Deoxo-Fluor (50 wt % in toluene) (1.25 g, 2.83 mmol, 8.0 equiv) in CHCl (1 mL) was heated at 70 °C for 12 h. The reaction was then cooled to room temperature, quenched with saturated NaHCO (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes (hex) → 40% EtOAc in hexanes) to give the product (28 mg, 20%).

[0414] 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (m, 1H), 7.73 - 7.57 (m, 2H), 7.06 (m, 1H), 4.42(m, 1H), 3.85 (m, 1H), 3.70 - 3.56 (m, 1H), 3.35 (d, J = 8.4 Hz, 3H), 2.20 - 1.79 (m, 5H). C 20 H 15 ESI MS of F4N3O [M+H] + , calculated value 390.1, measured value 390.1.

[0415] Example 133: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-3,4-dihydro-2H-quinoline-4,8-dicarbonitrile

[0416] [ka]

[0417] Step a: A mixture of 1-(4-bromo-2-cyano-3-fluorophenyl)-6-fluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (500 mg, 1.28 mmol), isopropenylboronic acid pinacol ester (0.237 g, 1.41 mmol, 1.1 equiv.), and PdCl(dppf) (94 mg, 0.128 mmol, 10% mol) in 1,4-dioxane (6 mL) and 2.0 M NaCO (2 mL) was stirred at 90 °C overnight under N. The reaction was then quenched with water and extracted with EtOAc (3 × 50 mL). The combined organics were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) -> 50% EtOAc in hexane) to give the product (0.50 g, quantitative yield).

[0418] Step b: The product from step a (0.5 g, 1.28 mmol) was dissolved in THF / HO (2:1; 6 / 3 mL). 2,6-Lutidine (274 mg, 2.56 mmol, 2 equiv.) and NaIO (1.64 g, 7.68 mmol, 6 equiv.) were added, followed by KOsOHO (24 mg, 0.06 mmol, 5% mol.). The reaction was stirred at room temperature for 15 h, then diluted with 10% NaSO solution (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organics were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 50% EtOAc in hexane) to give the product (390 mg, 87%).

[0419] Step c: The product from step b (0.39 g, 1.11 mmol) was dissolved in DCM (10 mL). Dess-Martin periodinane (705 mg, 1.65 mmol, 1.5 equiv) was added. The reaction was stirred at room temperature for 0.5 h, then diluted with 10% NaSO solution (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organics were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 40% EtOAc in hexane) to give the product (240 mg, 62%).

[0420] Step d: A solution of the product from step c (120 mg, 0.34 mmol) and Deoxo-Fluor (50 wt % in toluene) (2.42 g, 5.48 mmol, 16 equiv) in CHCl (1 mL) was heated at 70 °C for 12 h. The reaction was then cooled to room temperature, quenched with saturated NaHCO (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes (hex) → 40% EtOAc in hexanes) to give the product (25 mg, 20%). 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.2 Hz, 2H), 7.83 (t, J = 8.7 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 4.07 - 3.97 (m, 1H), 3.97 - 3.86 (m, 1H), 2.52(m, 2H), 2.01 (t, J = 19.2 Hz, 3H). C 19 H 11 ESI MS of F6N3 [M+H] + , calculated value 396.0, measured value 396.1.

[0421] Example 134: (5S,8R)-3,5-difluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0422] [ka]

[0423] Step a: A solution of 4-bromo-7-methylsulfonyl-2,3-dihydroinden-1-one (25.0 g, 86.5 mmol) in 500 mL of dry methanol was loaded into a 1 L single-neck round-bottom flask equipped with a stir bar and a reflux condenser with a drying tube. SelectFluor (38.2 g, 104 mmol) and concentrated sulfuric acid (0.5 mL) were added sequentially, and the mixture was refluxed for 5 h. When TLC analysis showed the complete disappearance of the starting material, the reaction was cooled to ambient temperature. Aqueous sulfuric acid (0.3 M, 130 mL) was added, and the mixture was refluxed for 3 h, converting the corresponding dimethyl acetal to the desired α-fluoroketone. The resulting clear solution was cooled to ambient temperature, and the methanol was distilled off under reduced pressure. The remaining mixture was diluted with dichloromethane (1 L) and water (500 mL). The organic phase was separated, and the aqueous solution was extracted with dichloromethane (2 × 100 mL). The combined organic extracts were washed with brine (500 mL). The organic phase was separated, dried over Na2SO4, and concentrated to dryness to afford the α-fluoroketone (25.9 g, 84.3 mmol, 97% yield) as a white solid.

[0424] Step b: The product from step a (25.9 g, 84.3 mmol) was placed in a 1 L single-neck round-bottom flask equipped with a stir bar. This flask was charged with dichloromethane (700 mL), formic acid (20.0 mL, 0.50 mol), and triethylamine (47.0 mL, 0.34 mol). The resulting solution was cooled to 0 °C, and RuCl(p-cymene)[(R,R)-TsDPEN] (2.2 g, 3.4 mmol) was added. The resulting brown solution was stirred at 0 °C for 16 h. When TLC analysis indicated complete conversion of the starting material, the reaction was concentrated under reduced pressure to approximately half of its original volume. The remaining solution was washed successively with 1 M aqueous NaOH (400 mL) and brine (500 mL). The organic phase was separated, dried over Na2SO4, and concentrated to dryness to yield a crude product of sufficient purity for the next step.

[0425] The enantiomeric purity of this material (enantiomeric excess 96%) was determined using HPLC-UV chromatography [Chiralpak® AD-H (4.6 × 250 mm; 90% i-PrOH-hexane; flow rate = 1 mL / min; 10 μL injection of 1 mg / mL solution; detection at 254 nm; t = 4.89 min (minor), t = 5.26 min (major)].

[0426] Step c: The crude material from the previous step was dissolved in dichloromethane (700 mL) and placed in a 2 L, three-necked, round-bottom flask equipped with a thermometer, an addition funnel, a stir bar, and a reflux condenser with a drying tube. Triethylamine (105.0 mL, 0.81 mmol) was added to the mixture in one portion, and the addition funnel was charged with TBSOTf (96.4 g, 0.37 mmol). TBSOTf was then added dropwise, resulting in an exothermic reaction at a rate necessary to maintain continuous reflux. Upon completion of the addition, the reaction mixture was refluxed for an additional 15 min, at which time TLC analysis indicated complete conversion of the starting material to product. The solution was cooled to ambient temperature, transferred to a separatory funnel, and washed successively with saturated aqueous NH4Cl (500 mL) and brine (500 mL). The organic phase was separated, dried over Na2SO4, and concentrated to dryness. The resulting crude product was purified by flash chromatography (SiO 2 , hexane / EtOAc gradient) to give the TBS ether as a white solid (26.5 g, 62.6 mmol, 74% yield over two steps).

[0427] Step d: In a 500 mL single-neck round-bottom flask equipped with a magnetic stir bar and a reflux condenser with a nitrogen inlet adapter, the TBS ether product from the previous step (29.5 g, 70.0 mmol) was combined with B2Pin2 (23.0 g, 91.0 mmol, 1.3 equiv.), Pd(dppf)Cl2 (5.1 g, 7.0 mmol, 0.1 equiv.), and potassium acetate (13.8 g, 0.14 mmol, 2.0 equiv.) in dioxane (230 mL). The mixture was degassed under vacuum, backfilled with nitrogen, and heated to 100 °C for 2 h. An aliquot of 1 After H NMR analysis showed complete consumption of the starting material, the reaction mixture was cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue was partitioned between EtOAc (500 mL) and water (300 mL). The organic layer was separated, and the aqueous phase was further extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over NaSO, and the solvent was evaporated under reduced pressure to give the crude boronic acid pinacol ester, which was used in the next step without further purification.

[0428] Step e: A solution of the crude product from step d (70 mmol) and 8-cyano-6-fluoro-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (22.5 g, 70.0 mmol) in dioxane (230 mL) was placed in a 500 mL single-neck round-bottom flask equipped with a magnetic stir bar and a reflux condenser with a nitrogen inlet. Pd(dppf)Cl2 (5.1 g, 7.0 mmol) and aqueous sodium carbonate (2 M solution, 70.0 mL, 40.0 mmol) were then added sequentially. The mixture was degassed under vacuum, backfilled with nitrogen, and heated to 100 °C for 1 h. Upon completion of the reaction, dioxane was removed under reduced pressure. The residue was partitioned between EtOAc (500 mL) and water (500 mL). The organic layer was separated, and the aqueous phase was further extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine (500 mL), dried over NaSO, and concentrated to dryness. The crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to give the desired alkene (28.5 g, 55.3 mmol, 79% yield) as a white foam.

[0429] Step f: The alkene from step e (28.0 g, 54.0 mmol) was dissolved in dry methanol (540 mL) and added to palladium on carbon (5.0 g, 10 wt% Pd) under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere at 50 psi and stirred in a Parr shaker for 4 h. The excess hydrogen was vented, and the mixture was sparged with nitrogen to remove residual hydrogen gas. The resulting suspension was filtered through a Celite pad, and the filtrate was concentrated to dryness under reduced pressure to produce a crude mixture of epimers (1:1 dr). To isolate the more polar (S)-epimer, the crude mixture was subjected to column chromatography (SiO2, hexane / EtOAc gradient) to produce the desired tetralin derivative (9.6 g, 18.5 mmol, 34% yield) as a white foam.

[0430] Step g: To a solution of the TBS ether from step f in THF (93 mL) was added TBAF (37.2 mL, 37.2 mmol, 1 M solution in THF) dropwise at ambient temperature. The resulting brown solution was stirred for 20 min, after which TLC analysis indicated complete conversion of the starting material. The mixture was diluted with EtOAc (200 mL) and washed successively with water (200 mL) and brine (150 mL). The organic extract was dried over Na2SO4 and concentrated to dryness, and the crude product was subjected to the acylation reaction without purification.

[0431] The dried material from the previous conversion was dissolved in dichloromethane (50 mL), followed by the addition of DMAP (0.7 g, 5.8 mmol) and EtN (8.0 mL, 77.0 mmol). The reaction mixture was cooled to 0 °C, and acetic anhydride (7.3 mL, 77.0 mmol) was added dropwise over 1 min. The cooling bath was removed, and the reaction was stirred at room temperature for 30 min. When TLC and LCMS analysis indicated complete conversion, the solution was diluted with dichloromethane (150 mL) and washed successively with water (200 mL), saturated aqueous NaHCO (100 mL), and brine (100 mL). The crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the desired acetate (8.3 g, 18.5 mmol, 100% yield) as a white powder.

[0432] Step h: The acetate ester from step g (8.3 g, 18.6 mmol), MnO (6.5 g, 75 mmol), and dichloromethane (93 mL) were loaded into a 500 mL, single-neck, round-bottom flask equipped with a magnetic stir bar and a reflux condenser. The mixture was cooled to 0 °C, and tBuOH (34 mL, 186 mmol, 5.5 M solution in decane) was added dropwise over 5 min. The reaction was stirred at 0 °C for 10 min, then it was warmed to ambient temperature and stirred until gas formation ceased. The resulting black suspension was refluxed for 24 h, after which it was cooled to room temperature, and additional amounts of MnO (6.5 g, 75 mmol) and tBuOH (34 mL, 186 mmol, 5.5 M solution in decane) were added successively. The mixture was refluxed for an additional 48 h and cooled to room temperature. The inorganic solids were removed by filtration. The filtrate was passed through a plug of Celite, washed with water (100 mL), dried over NaSO, and concentrated to dryness. The crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the corresponding α-tetralone (6.2 g, 13.5 mmol, 72% yield) as a white powder.

[0433] Step i: A solution of α-tetralone (1.5 g, 3.3 mmol) from step h in dichloromethane (33 mL) was placed in a 100 mL single-neck round-bottom flask equipped with a magnetic stir bar and a drying tube. To this mixture, formic acid (0.37 mL, 9.8 mmol), EtN (0.91 mL, 6.5 mmol), and RuCl(p-cymene) [(R,R)-Ts-DPEN) (62 mg, 0.1 mmol) were added at ambient temperature and stirred for 1 h. The resulting brown solution was diluted with dichloromethane (70 mL) and washed with saturated aqueous NaHCO. The organic extract was dried over NaSO and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO 2 , dichloromethane / EtOAc gradient) to afford the corresponding 1,2,3,4-tetrahydro-1-naphthol (1.43 g, 3.1 mmol, 95% yield, single epimer) as a white powder.

[0434] Step j: A solution of Deoxo-Fluor (3.4 mL, 9.1 mmol, 2.7 M in toluene) in dichloromethane (52 mL) was placed in a 100 mL single-neck round-bottom flask equipped with a magnetic stir bar and nitrogen inlet and cooled to −78 °C, followed by the dropwise addition of TMS-morpholine (1.65 mL, 9.2 mmol). The reaction was stirred at −78 °C for 5 minutes, and then the mixture was warmed to room temperature and stirred for 2 hours. The resulting clear solution was cooled to −78 °C, and the solid 1,2,3,4-tetrahydro-1-naphthol (1.2 g, 2.6 mmol) from step i was added in one portion. The cooling bath was removed, and the reaction was stirred at room temperature for 30 minutes. When TLC analysis indicated complete consumption of the starting material, the mixture was diluted with DCM (50 mL) and quenched with saturated aqueous NaHCO (50 mL). The organic phase was separated, dried over NaSO, and concentrated to dryness. The dry residue was dissolved in 1,2-dimethoxyethane (60 mL) and AgClOxHO (0.20 g) was added. The mixture was heated at 70 °C for 1 h, concentrated to dryness, and the crude product was purified by column chromatography (SiO, dichloromethane / EtOAc gradient) followed by trituration with 30 mL of MTBE and filtration to give the desired α-fluorotetralin (1.1 g, 2.4 mmol, 92% yield, single epimer) as a white solid.

[0435] Step k: α-Fluorotetralin (1.1 g, 2.4 mmol) from step j was suspended in a 7 M solution of NH in MeOH (90 mL), and the mixture was stirred at ambient temperature for 36 h. The resulting clear solution was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (SiO, dichloromethane / EtOAc gradient), followed by trituration with 30 mL of hexane and filtration to give the desired product (0.85 g, 2.0 mmol, 85% yield). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 8.4, 1H), 7.39 (d, J = 7.5 Hz, 1H), 6.43 (d, J = 8.1 Hz, 1H), 5.69 (dt, J = 13.5, 5.1 Hz, 1H), 5.65 - 5.33 (m, 2H), 4.67 - 4.60 (m, 1H), 3.58 (ddd, J = 20.8, 16.8, 3.4 Hz, 1H), 3.44 (dd, J = 5.7, 2.9 Hz, 1H), 3.28 (s, 3H), 3.28 - 3.10 (m, 1H), 2.56 - 2.38 (m, 1H), 2.24 - 2.04 (m, 1H), 2.02 - 1.79 (m, 1H), 1.76 - 1.65 (m, 1H). 19 F NMR (376 MHz, CDCl3) δ -110.92(m), -157.06 (m), -199.18 (m). C 21 H 18 ESI MS of F3NO3SNa [M+Na] + , calculated value 444.1, measured value 444.0).

[0436] Example 135: (8R)-3,5,5-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]-7,8-dihydro-6H-naphthalene-1-carbonitrile

[0437] [ka]

[0438] Step a: A mixture of [(1S,2R)-4-[(1R)-8-cyano-6-fluoro-4-oxo-2,3-dihydro-1H-naphthalen-1-yl]-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (145 mg, 0.31 mmol), 1,2-ethanedithiol (0.38 mL, 4.6 mmol), and p-toluenesulfonic acid monohydrate (12.0 mg, 0.06 mmol) prepared by the protocol from Example 134 in benzene (25 mL) was placed in a single-neck round-bottom flask equipped with a Dean-Stark apparatus and a reflux condenser with a nitrogen inlet adapter. The reaction was refluxed for 16 hours, cooled to ambient temperature, and washed with 1 M NaOH (25 mL). The organic phase was separated, dried over Na2SO4, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO 2 , dichloromethane / EtOAc gradient) to yield the desired product (0.17 g, 0.31 mmol, 100% yield) as a colorless oil.

[0439] Step b: To a suspension of N-iodosuccinimide (71.0 mg, 0.32 mmol) in dichloromethane (1 mL) cooled to −78 °C was added HF Py (0.19 mL, 0.80 mmol). The resulting dark suspension was stirred for 5 min, after which a solution of the 1,3-dithiolane from step a (85 mg, 0.16 mmol) in dichloromethane (1 mL) was added dropwise over 1 min. The reaction mixture was stirred at −78 °C for 20 min and then at 0 °C for an additional 20 min. When TLC analysis indicated complete conversion of the 1,3-dithiolane, the reaction was diluted with dichloromethane (15 mL) and washed with a mixture of saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 (1:1, v / v). The organic phase was separated, dried over Na2SO4, and concentrated to dryness. The crude material was fractionated by column chromatography (SiO 2 , dichloromethane / EtOAc gradient) to yield the desired product (33.0 mg, 0.07 mmol, 43% yield) as a white solid.

[0440] Step c: 1,1-Difluorotetralin (33.0 mg, 0.07 mmol) from step b was dissolved in THF (1 mL) and a solution of LiOH HO (8.5 mg, 0.2 mmol) in water (0.2 mL) was added at 0 °C. The reaction was stirred at room temperature for 3 h and monitored by LCMS analysis. Upon complete conversion, the reaction was diluted with EtOAc (20 mL) and washed with 1 M aqueous HCl (15 mL). The organic phase was separated, and the aqueous solution was further extracted with EtOAc (15 mL). The combined organic extracts were washed with brine, dried over NaSO, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO, dichloromethane / EtOAc gradient) to yield the desired product (27.0 mg, 0.06 mmol, 90% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.84 - 7.65 (m, 2H), 7.51 - 7.38 (m, 1H), 6.56 (d, J = 8.3 Hz, 1H), 5.68 (dt, J = 13.5, 5.0 Hz, 1H), 5.51 - 5.32(m, 1H), 4.64 (br. s, 1H), 3.68 - 3.42(m, 2H), 3.27 (s, 3H), 3.23 - 3.03 (m, 1H), 2.62 - 2.38 (m, 1H), 2.38 - 2.08 (m, 2H), 1.95 - 1.85 (m, 1H). 19 F NMR (376 MHz, CDCl3) δ -85.85 (d, J = 5260.8 Hz), -109.12(m), -199.20 (dtd, J = 52.8, 22.4, 13.5 Hz). C 21 H 17 ESI MS of F4NNaO3S [M+Na] + , calculated value 462.1, measured value 462.0).

[0441] Example 136: (5S,8R)-3,5-difluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-(trifluoromethylsulfonyl)-2,3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0442] [ka]

[0443] Step a: To a suspension of 7-fluoro-2,3-dihydro-1H-inden-1-one (10.0 g, 66.6 mmol) and aluminum trichloride (22.2 g, 166.5 mmol, 2.5 equiv.) in 1,2-dichloroethane (190 mL, 0.35 M), bromine (3.58 mL, 70 mmol, 1.05 equiv.) was added dropwise. The resulting solution was heated to 60 °C for 3 h, after which the reaction was cooled to room temperature and poured onto ice. The reaction was extracted with MTBE, dried over magnesium sulfate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in a 1:1 solution of CHCl:hexane) to give 4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one.

[0444] Step b: To a suspension of 4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one (17.0 g, 74.3 mmol) and CsCO (26.6 g, 81.7 mmol, 1.1 equiv.) in DMF (372 ml, 0.2 M) was added benzyl mercaptan (9.24 g, 8.71 ml, 1.0 equiv.). The reaction was stirred at room temperature for 90 minutes. The desired product was precipitated from the solution by adding 1.5 L of water and dried under high vacuum overnight. The resulting crude product (23.1 g, 93% yield) was used without further purification.

[0445] Step c: The crude thioether from step b (23.1 g, 69.2 mmol) was suspended in toluene (692 ml, 0.1 M). Aluminum trichloride (10.2 g, 1.1 equiv.) was added at room temperature. An additional portion of aluminum trichloride (3.6 g, 27 mmol, 0.4 equiv.) was added after 3 h. Upon completion, the reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in a 3:1 solution of CHCl in hexanes) to afford the desired thiophenol as a yellow solid (13.4 g, 80% yield).

[0446] Step d: A solution of the thiophenol product from step c (6.7 g, 27.6 mmol) and methyl viologen dichloride hydrate (710 mg, 0.1 equiv.) in DMF (55 mL, 0.5 M) was carefully degassed via three freeze-pump-thaw cycles under nitrogen. The resulting solution was cooled to −10 to −5 °C in a brine-ice bath, and excess CF3I was sparged through the reaction mixture. The reaction was then stirred overnight under an atmosphere of CF3I. The reaction was carefully quenched with water at room temperature (use with caution as residual CF3I off-gassing occurs), extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexanes) to give the desired thioether (5.21 g, 61% yield).

[0447] Step e: To a solution of the product from step d (10.45 g, 33.6 mmol) in MeCN (129 mL, 0.26 M relative to starting material), CCl (129 mL, 0.26 M relative to starting material), and HO (258 mL, 0.13 M relative to starting material) was added ruthenium trichloride (697 mg, 3.36 mmol, 0.1 equiv.), followed by sodium periodate (29.6 g, 138.4 mmol, 4.12 equiv.). The reaction was stirred at room temperature for 1 h and, upon completion, extracted with CHCl (x2). The combined organics were washed with saturated NaSO, washed with brine, dried over sodium sulfate, and then concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in a 3:1 solution of CHCl in hexanes) to give the product sulfone as a white solid (10.53 g, 91% yield). 10 ESI MS of H6BrF3O3S [M+H] + ;Calculated value 342.9, measured value 342.9.

[0448] Step f: A solution of the product sulfone from step e (3.5 g, 10.2 mmol) and Selectfluor (4.32 g, 12.2 mmol, 1.2 equiv.) in methanol (102 mL, 0.1 M) was heated to 50 °C. Sulfuric acid (27 μL, 5 mol%) was added, and the reaction was stirred at 50 °C for 48 h. The solution was then diluted with diethyl ether, and the resulting white precipitate was filtered off and discarded. The organic solution was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in a 3:1 solution of CHCl in hexanes) to give the product dimethyl acetal as a white solid (3.57 g, 87% yield).

[0449] Step g: A solution of the acetal of the product from step f (3.18 g, 7.8 mmol) and wet Amberlyst 15 (4.77 g, 150 wt%) in dioxane (31 ml, 0.2 M) was heated to 90 °C overnight. Upon completion, the polymer beads were removed by filtration, and the concentrated crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in a 3:1 solution of CHCl in hexanes) to give the desired fluorinated ketone (2.33 g, 83% yield).

[0450] Step h: A solution of the indanone product from step g (2.5 g, 6.93 mmol) in dichloromethane (28 mL, 0.25 M) was sparged with nitrogen gas, followed by the addition of formic acid (783 μL, 956 mg, 20.8 mmol, 3 equiv.) and triethylamine (1.94 mL, 1.41 g, 13.9 mmol, 2 equiv.) under nitrogen at 0 °C. RuCl(p-cymene)[(R,R)-Ts-DPEN] (44.5 mg, 0.07 mmol, 0.01 equiv.) was added, and the reaction was stirred at 0–5 °C for a minimum of 12 h. Upon complete conversion, the reaction was quenched with saturated NaHCO and extracted with CHCl. The combined organics were concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in 1:1 CHCl:hexane) to afford the desired indanol (2.0 g, 80% yield) as a single diastereomer. The enantiomeric excess of this material was found to be 98% by chiral HPLC (Chiralpak AD-H, 20% iPrOH / hexane, isocratic, 20 min) compared to a racemic sample obtained via reduction of 2-fluoroindanone with sodium borohydride.

[0451] Step i: To a solution of the chiral indanol from step h (1.01 g, 2.75 mmol) in CHCl (11 mL, 0.25 M) was added 2,6-lutidine (800 μL, 6.9 mmol, 2.5 equiv) and TBSOTf (791 μL, 3.44 mmol, 1.25 equiv) at 0 °C. The reaction was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction was concentrated directly onto Celite and purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in hexanes) to give the TBS ether (1.35 g, 100% yield).

[0452] Step j: The TBS ether product from step i (674 mg, 1.41 mmol) was combined with B2Pin2 (457 mg, 1.8 mmol, 1.3 equiv), Pd(dppf)Cl2 (103 mg, 0.14 mmol, 0.1 equiv), and potassium acetate (213 mg, 3 mmol, 2.2 equiv) in dioxane (14 mL, 0.1 M), and the resulting solution was heated to 100 °C for 3 h. The reaction solution was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to give the desired boronic acid pinacol ester (638 mg, 86% yield) as a colorless oil.

[0453] The protocol for the following steps was the same as in Example 134. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.52(ddd, J = 8.3, 2.8, 1.4 Hz, 1H), 7.40 (ddd, J = 7.5, 2.7, 1.7 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 5.73 - 5.50 (m, 2H), 5.46 - 5.23 (m, 1H), 4.74 - 4.60 (m, 1H), 3.79 - 3.51 (m, 1H), 3.36 - 3.20 (m, 1H), 3.02(d, J = 4.2Hz, 1H), 2.61 - 2.43 (m, 1H), 2.22 - 2.09 (m, 1H), 1.97 - 1.86 (m, 1H), 1.81 - 1.73 (m, 1H). 19 F NMR (376 MHz, CDCl3) δ -77.43, -110.37 (d, J = 1.6 Hz), -157.81 (d, J = 45.0 Hz), -197.41 - -202.71 (m). C 21 H 15 ESI MS of F6NNaO3S [M+Na] + , calculated value 498.1, measured value 498.0.

[0454] Example 137: (5S,8R)-8-[3-chloro-2-cyano-4-(trifluoromethyl)phenyl]-3,5-difluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0455] [ka]

[0456] Step a: A solution of 4-bromo-2-chloro-1-(trifluoromethyl)benzene (15.0 g, 57.8 mmol) in tetrahydrofuran (600 mL) was placed in a 1 L single-neck round-bottom flask equipped with a nitrogen inlet adapter with a rubber septum. The solution was cooled to -78 °C, and LDA solution (43 mL, 87.0 mmol, 2 M solution in THF / heptane / ethylbenzene) was added dropwise via syringe over 10 min. The reaction mixture was stirred at -78 °C for 1 h, after which dry CO gas was bubbled through the mixture at -78 °C for 30 min. The cooling bath was replaced with an ice / water mixture, and CO bubbling was continued for an additional 30 min. The reaction mixture was carefully poured into 3 M aqueous HCl (700 mL) under vigorous stirring, and the product was extracted with EtOAc (3 × 300 mL). The combined organic extracts were washed with brine and dried over Na SO . The solvent was distilled off under reduced pressure, and the residue was partitioned between 3M aqueous NaOH (400 mL) and MTBE (250 mL). The organic phase was separated, and the aqueous phase was further extracted with MTBE (200 mL). The separated aqueous solution was acidified to pH ∼3 with 3M aqueous HCl, and the product was extracted with dichloromethane (3 × 200 mL). The combined extracts were dried over NaSO and concentrated to dryness to give the corresponding benzoic acid (17.5 g, 57.6 mmol, 99% yield) as an orange oil.

[0457] Step b: A mixture of benzoic acid (17.5 g, 57.6 mmol) from step a, thionyl chloride (12.6 mL, 173.0 mmol), and N,N-dimethylformamide (0.3 mL) in dry benzene (290 mL) was placed in a 500 mL single-neck round-bottom flask equipped with a reflux condenser and a drying tube. The reaction was refluxed for 6 h, then cooled to ambient temperature, and excess thionyl chloride and benzene were distilled off under reduced pressure. The oily residue was dissolved in THF (150 mL) and added dropwise over 30 min to 30% aqueous ammonium hydroxide solution (150 mL) cooled to 0 °C. Upon completion of the addition, the reaction was stirred vigorously for 20 min. The product was extracted with dichloromethane (3 × 200 mL). The combined extracts were dried over Na2SO4 and concentrated to dryness under reduced pressure. The oily residue was triturated with hexane (200 mL) and the gray precipitate that formed was collected by filtration to give the corresponding benzamide (15.0 g, 49.7 mmol, 86% yield) as a gray solid.

[0458] Step c: A mixture of the benzamide from step b (30.1 g, 99.5 mmol) and cyanuric chloride (25.6 g, 139.4 mmol) in N,N-dimethylformamide (170 mL) was heated at 70 °C for 2 h. The mixture was then cooled to room temperature and poured into 500 mL of water. The product was extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with water (2 × 300 mL) and brine (300 mL), dried over NaSO, and concentrated to dryness under reduced pressure. The resulting residue was fractionated by flash chromatography (silica gel, 0% to 25% ethyl acetate in hexanes) to afford the desired benzonitrile (15.1 g, 53.0 mmol, 53% yield) as a white crystalline solid.

[0459] Step d: In a 40 mL vial with a magnetic stir bar, the benzonitrile from step c (0.5 g, 1.8 mmol) was combined with B2Pin2 (0.58 g, 2.3 mmol, 1.3 equiv.), Pd(dppf)Cl2 (0.13 g, 0.18 mmol, 0.1 equiv.), and potassium acetate (0.35 g, 3.5 mmol, 2.0 equiv.) in dioxane (9 mL, 0.2 M). The mixture was degassed under vacuum, backfilled with nitrogen, and heated to 90 °C for 1 h. After TLC analysis indicated complete consumption of the starting material, the reaction mixture was cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue was partitioned between EtOAc (30 mL) and water (20 mL). The organic layer was separated, and the aqueous phase was further extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over Na2SO4 and the solvent was evaporated under reduced pressure to give the crude boronic acid pinacol ester, which was used without further purification.

[0460] 8-Cyano-6-fluoro-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (0.57 g, 1.8 mmol) was added to the crude boronic acid pinacol ester along with dioxane (9 mL, 0.2 M), and the mixture was loaded into a 40 mL vial. Pd(dppf)Cl (0.13 g, 0.18 mmol) and 2 M aqueous sodium carbonate (1.8 mL, 3.6 mmol) were then added sequentially. The mixture was degassed under vacuum, backfilled with nitrogen, and heated to 100 °C for 1 h. Upon completion, the dioxane was removed under reduced pressure. The residue was partitioned between EtOAc (30 mL) and water (20 mL). The organic layer was separated, and the aqueous phase was further extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, and concentrated to dryness. The crude product was purified by column chromatography (SiO 2 , hexane / EtOAc gradient) to give the desired alkene (0.27 g, 0.7 mmol, 41% yield) as a brown solid.

[0461] Step e: The alkene from step d (0.27 g, 0.7 mmol) was dissolved in dry methanol (10 mL) and triethylamine (0.5 mL, 3.6 mmol), and then palladium on carbon (80.0 mg, 10 wt% Pd) was added under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere at 50 psi and stirred in a Parr shaker for 1 h. Excess hydrogen was vented, and the mixture was sparged with nitrogen to remove residual hydrogen gas. The resulting suspension was filtered through a Celite pad, and the filtrate was concentrated to dryness under reduced pressure to yield a crude mixture of the desired product and the corresponding dechlorinated compound. To isolate the desired product, the crude mixture was subjected to column chromatography (SiO2, hexane / EtOAc gradient) to yield the tetralin derivative (0.1 g, 0.26 mmol, 37% yield) as a white solid.

[0462] Step f: The tetralin derivative from step e (0.3 g, 0.8 mmol), MnO (0.28 g, 3.2 mmol), and dichloromethane (4 mL, 0.2 M) were loaded into a 40 mL vial equipped with a magnetic stir bar. The mixture was cooled to 0 °C, and tBuOH (1.5 mL, 8 mmol, 5.5 M solution in decane) was added dropwise over 5 min. The reaction was stirred at 0 °C for 10 min, then warmed to ambient temperature and stirred until gas formation ceased. The vial was sealed, and the resulting black suspension was maintained at 40 °C for 24 h. It was then cooled to room temperature, and additional amounts of MnO (0.28 g, 3.2 mmol) and tBuOH (1.5 mL, 8 mmol, 5.5 M solution in decane) were added successively. The mixture was refluxed for an additional 48 h and cooled to room temperature. The inorganic solids were removed by filtration. The filtrate was diluted with dichloromethane (30 mL), passed through a plug of Celite, washed with water (20 mL), dried over NaSO, and concentrated to dryness. The crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the corresponding α-tetralone (0.14 g, 0.36 mmol, 45% yield) as a white solid.

[0463] Step g: To a 0 °C-cooled solution of the α-tetralone from step f (70.0 mg, 0.18 mmol) in a mixture of MeOH (2 mL) and THF (3 mL) was added NaBH (14.0 mg, 0.36 mmol) in one portion. The reaction was stirred for 10 min and poured into 1 M aqueous HCl (10 mL). The crude product was extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine, dried over NaSO, and concentrated to dryness to yield a mixture of racemic cis and trans diastereomers. To separate the diastereomers, the crude mixture was fractionated by column chromatography (SiO, hexane / EtOAc gradient) to afford the more cis diastereomer (52.0 mg, 0.13 mmol, 74% yield, less polar product) along with the less trans diastereomer (8.0 mg, 0.02 mmol, 11% yield, more polar product). Both compounds were obtained in the form of a white solid.

[0464] Step f: A solution of Deoxo-Fluor (0.17 ml, 0.45 mmol, 2.7 M in toluene) in toluene (2.6 mL) was cooled to 0 °C under nitrogen, and then TMS-morpholine (81 μL, 0.46 mmol) was added. The reaction was stirred at 0 °C for 5 minutes, then it was warmed to room temperature and stirred for 2 hours. The resulting solution was cooled to 0 °C, and solid 1,2,3,4-tetrahydro-1-naphthol (51.0 mg, 0.13 mmol) from step e was added in one portion. The cooling bath was removed, and the reaction was stirred at room temperature for 30 minutes. When TLC analysis showed complete consumption of the starting material, the mixture was diluted with EtOAc (20 mL) and quenched with saturated aqueous NaHCO (10 mL). The organic phase was separated, dried over NaSO, and concentrated to dryness. The dry residue was purified by column chromatography (SiO 2 , dichloromethane / EtOAc gradient) to give the title compound as a white foam (44.0 mg, 0.11 mmol, 86% yield, single epimer). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 8.5, 2.7 Hz, 1H), 7.41 (ddd, J = 7.5, 2.7, 1.6 Hz, 1H), 6.54 (d, J = 8.3 Hz, 1H), 5.58 (dt, J = 49.9, 4.0 Hz, 1H), 4.95 (s, 1H), 2.75 - 2.50 (m, 1H), 2.26 - 2.10 (m, 1H), 2.07 - 1.78 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ -63.06, -109.85, -159.45. C 19 H 10 ESI MS of ClF5N2Na [M+Na] + , calculated value 419.0, measured value 419.2).

[0465] Example 138: (5R,8R)-8-[3-chloro-2-cyano-4-(trifluoromethyl)phenyl]-3,5-difluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0466] [ka]

[0467] Step a: A solution of Deoxo-Fluor (26.0 μL, 0.07 mmol, 2.7 M in toluene) in toluene (0.25 mL) was cooled to 0° C. under nitrogen, followed by the addition of TMS-morpholine (13.0 μL, 0.072 mmol). The reaction was stirred at 0° C. for 5 minutes, after which it was warmed to room temperature and stirred for 2 hours. The resulting solution was cooled back to 0° C., and a suspension of 1,2,3,4-tetrahydro-1-naphthol (8.0 mg, 0.02 mmol, prepared as in Example 134) in dry toluene (0.5 mL) was added. The cooling bath was removed, and the reaction was stirred at room temperature for 30 minutes. When TLC analysis indicated complete consumption of the starting material, the mixture was diluted with EtOAc (10 mL) and quenched with saturated aqueous NaHCO (3 mL). The organic phase was separated, dried over NaSO, and concentrated to dryness. The dry residue was purified by column chromatography (SiO 2 , dichloromethane / EtOAc gradient) to give the title compound (7.0 mg, 0.018 mmol, 87% yield, single epimer) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 8.5, 2.8 Hz, 1H), 7.37 (dd, J = 7.6, 2.5 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 5.62(ddd, J = 49.8, 8.4, 4.7 Hz, 1H), 4.89 (s, 1H), 2.51 - 2.31 (m, 1H), 2.34 - 2.07 (m, 2H), 2.03 - 1.86 (m, 1H). 19 F NMR (376 MHz, CDCl3) δ -63.03, -109.89, -169.86 (d, J = 50.8 Hz). C 19 H 10 ESI MS of ClF5N2Na [M+Na] + , calculated value 419.0, measured value 419.0).

[0468] Example 139: (5S,8S)-8-[6-(1,1-difluoroethyl)-5-fluoro-4-methylpyridin-3-yl]-3,5-difluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0469] [ka]

[0470] Step a: A mixture of LDA (30 mL, 59.3 ml, 2 M solution in THF / heptane / ethylbenzene) and dry THF (240 mL) was placed in a 500 mL single-neck round-bottom flask equipped with a magnetic stir bar and a nitrogen inlet adapter with a rubber septum under a nitrogen atmosphere. The solution was cooled to −78 °C under nitrogen, and a solution of 2,5-dibromo-3-fluoropyridine (12.1 g, 47.4 mmol) in dry THF (40 mL) was added dropwise via syringe over 20 min. The resulting mixture was stirred for 30 min, and MeI (5 mL, 81 mmol) was added dropwise over 5 min at −78 °C. The cooling bath was then removed, and the reaction was allowed to warm to ambient temperature and stirred for 1 h before being quenched with saturated aqueous NH4Cl (200 mL). The mixture was transferred to a separatory funnel and diluted with water (100 mL) and EtOAc (200 mL). The organic phase was separated, the aqueous phase was further extracted with EtOAc (2 × 100 mL), the combined organic extracts were washed with brine, dried over NaSO, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to afford 2,5-dibromo-3-fluoro-4-methyl-pyridine (12.0 g, 44.6 mmol, 94% yield) as a colorless crystallizing oil.

[0471] Step b: A solution of 2,5-dibromo-3-fluoro-4-methyl-pyridine (6.0 g, 22.3 mmol) in toluene (110 mL) was placed in a 250 mL single-neck round-bottom flask equipped with a magnetic stir bar and a nitrogen inlet adapter with a rubber septum. The solution was cooled to −78 °C, and nBuLi (9.8 mL, 24.5 mmol) was added dropwise via syringe over 10 min. The resulting heterogeneous solution was stirred at −78 °C for 20 min, after which N,N-dimethylacetamide (3.2 mL) was added dropwise over 1 min. The reaction mixture was stirred for 30 min and quenched at −78 °C with saturated aqueous NH4Cl (50 mL). The resulting biphasic mixture was diluted with water (50 mL) and EtOAc (100 mL). The organic phase was separated, and the aqueous phase was further extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine, dried over NaSO, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (silica gel, 0% to 40% ethyl acetate in hexanes) to give the corresponding 2-acetylpyridine (2.8 g, 12.1 mmol, 54% yield) as a colorless crystallizing oil.

[0472] Step c: A mixture of 2-acetylpyridine (2.8 g, 12.0 mmol) from step b and deoxo-fluor (6.7 mL, 36 mmol) in toluene (60 mL) was placed in a 250 mL single-neck round-bottom flask equipped with a stir bar and a reflux condenser with a drying tube. The mixture was maintained at 70 °C for 24 h. Although conversion was incomplete, the biphasic reaction was cooled to ambient temperature and poured into saturated aqueous NaHCO (200 mL) under vigorous stirring. The mixture was then diluted with EtOAc (200 mL) and filtered through a pad of Celite. The organic phase was separated, and the aqueous phase was further extracted with EtOAc (2 × 70 mL). The combined organic extracts were washed with brine, dried over NaSO, and concentrated to dryness. The crude material was fractionated by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to give 5-bromo-2-(1,1-difluoroethyl)-3-fluoro-4-methylpyridine (1.9 g, 7.5 mmol, 63% yield) as a yellowish liquid.

[0473] The protocol for the following steps was the same as in Example 134. Characterization data for the title compound: 1 H NMR (400 MHz, CDCl3) δ 7.53 - 7.42(m, 1H), 7.42 - 7.32(m, 1H), 7.22(s, 1H), 5.56 (dt, J = 49.9, 3.3 Hz, 1H), 4.69 (br. s, 1H), 2.64 - 2.36 (m, 4H), 2.27 - 2.09 (m, 1H), 2.08 - 1.85 (m, 4H), 1.83 - 1.67 (m, 1H). 19 F NMR (376 MHz, CDCl3) δ -89.77 (m), -110.97 (m), -125.45, -156.81 (m). C 19 H 16 ESI MS of F5N2 [M+H] + , calculated value 367.1, measured value 367.2).

[0474] Example 140: (8R)-8-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]-3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile.

[0475] [ka]

[0476] Step a: To an ice-cold solution of (1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-ol (11.5 g, 37.3 mmol) in dichloromethane (190 mL, 0.2 M) was added DMAP (1.4 g, 11.2 mmol) and triethylamine (10.4 mL, 75 mmol, 2 equiv.), followed by the dropwise addition of acetic anhydride (7.1 mL, 75 mmol, 2 equiv.). The solution was allowed to warm to room temperature and stirred for 1 hour. Upon completion, the reaction was quenched with saturated aqueous NaHCO3, and the resulting solution was extracted with dichloromethane (2x), dried over Na2SO4, and concentrated onto Celite. The crude material was purified by flash chromatography on silica gel (0-10% ethyl acetate in hexanes) to give [(1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (13.1 g, 100% yield). 12 H 12 ESI MS of BrFO4S [M+H] + , calculated value 351.0, measured value 351.0.

[0477] Step b: A solution of [(1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (13.5 g, 38.5 mmol), 2,2'-azobis(2-methylpropionitrile) (40 mg, 1 mol%), and N-bromosuccinimide (7.54 g, 1.1 equiv.) in dichloroethane (0.2 M, 190 mL) was heated to reflux for 90 minutes. Upon completion, the reaction was cooled and partitioned between ethyl acetate and saturated NaHCO. The organics were collected, washed with dilute NaSO, dried over NaSO, and concentrated onto Celite. The crude material was purified by flash chromatography on silica gel (5% ethyl acetate in a 1:3 ratio of CHCl:hexanes) to give two brominated diastereomers, [(1S,2S,3R)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (6.83 g, 41% yield) and [(1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (2.5 g, 15% yield). The diastereomeric products eluted in the order listed above.

[0478] Step c: To a solution of [(1S,2S,3R)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (6.73 g, 15.6 mmol) in THF (0.08 M, 195 ml) at 0 °C, a 0.5 M aqueous solution of LiOH (5.93 ml, 1.5 equiv.) was added and the reaction was allowed to stir at 0 °C for 3 h, at which time the reaction was quenched with 1 N HCl at 0 °C. The resulting solution was extracted three times with methylene chloride, the organics dried over NaSO, and flushed with 0–20% ethyl acetate in [1:1 hexane:dichloromethane] to give (1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-ol (3.68 g, 61% yield).

[0479] Step d: Sodium hydride (60% dispersion in mineral oil, 440 mg, 10.5 mmol, 1.1 equiv.) was slowly added to a solution of (1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-ol (3.68 g, 9.5 mmol) and benzyl bromide (6.77 mL, 9.75 g, 57 mmol, 6 equiv.) in THF (38 mL, 0.25 M relative to indanol) and DMF (9.5 mL, 1 M relative to indanol) at 0 °C. The reaction was allowed to warm to room temperature and stirred overnight. The next day, 3 additional equivalents of BnBr and 0.55 equivalents of NaH were added, and the reaction was complete within 2 h. The solution was quenched with 1 N HCl, extracted with ethyl acetate, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography on silica gel (0 to 20% ethyl acetate in hexanes) to give (1S,2S,3S)-1,7-dibromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene as a white foam (2.46 g, 54% yield).

[0480] Step e: To a solution of (1S,2S,3S)-1,7-dibromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (2.46 g, 5.1 mmol) in sulfolane (28.4 mL) and water (5.6 mL) was added silver perchlorate hydrate (unknown hydrate stoichiometry) (2.13 g, approximately 10.3 mmol), and the reaction was heated to 75 °C overnight, protected from light. After 23 h, the starting material was nearly completely consumed, and the reaction was quenched with HO. Dilution with MTBE allowed the silver salts to be filtered from the biphasic mixture, and the organics were collected and dried over sodium sulfate. Purification by flash chromatography (0-5%-50% ethyl acetate in dichloromethane) afforded the diastereomeric alcohol products (1R,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-inden-1-ol (750 mg, 35% yield) and (1S,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-inden-1-ol (470 mg, 22% yield). The diastereomeric products eluted in the order listed above, and the latter was used in further steps. 17 H 16 ESI MS of BrFO4S [M+Na] + , calculated value 437.0, measured value 437.0.

[0481] Step f: To an ice-cold solution of (1S,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-inden-1-ol (386 mg, 0.93 mmol) in dichloromethane (0.1 M, 9.3 ml), (diethylamino)sulfur trifluoride (492 μL, 600 mg, 3.7 mmol, 4 equiv.) was added and the resulting solution was stirred at a temperature of 0-10 °C for 3 h, at which time it was quenched with saturated NaHCO. The organics were extracted with ethyl acetate, dried over Na2SO4, and purified by flash chromatography on silica gel (10% ethyl acetate in hexanes, isocratic) to give two fluorinated products: (1S,2S,3S)-7-bromo-1,2-difluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (undesired product, less polar, 158 mg, 40% yield) and (1R,2S,3S)-7-bromo-1,2-difluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (desired product, more polar, 234 mg, 60% yield).

[0482] Step g: (1R,2S,3S)-7-Bromo-1,2-difluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (234 mg, 0.56 mmol), B2Pin2 (185 mg, 0.73 mmol, 1.3 equiv), KOAc (121 mg, 1.23 mmol, 2.2 equiv), and PdCl2(dppf) (44 mg, 0.06 mmol, 10 mol%) were combined in dioxane (5.6 mL, 0.1 M). The resulting solution was sparged with nitrogen and heated to 100 °C until all starting material was consumed (2.5 h). The crude reaction mixture was filtered over Celite, concentrated, taken up in ethyl acetate, and washed with water to remove residual KOAc. The resulting solid was subjected to the Suzuki cross-coupling step without further purification.

[0483] The title compound was prepared similarly to Example 134. 1H NMR (400 MHz, CDCl3): δ 7.96 (dd, J = 8.1, 2.0 Hz, 1H), 7.23-7.17 (m, 2H), 6.86 (d, J = 8.1 Hz, 1H), 5.91-5.75 (m, overlap, 2H), 5.20-5.02(m, 1H), 4.95-4.91 (m, 1H), 3.02-2.84 (m, 3H), 2.28-2.19 (m, 1H), 1.93-1.85 (m, 1H), 1.79-1.58 (m, 2H).

[0484] Example 141: 8-[(1S)-7-cyano-2,2-difluoro-1-hydroxy-1,3-dihydroinden-4-yl]-3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0485] [ka]

[0486] Step a: Carried out in the same manner as in step a of Example 134.

[0487] Step b: To a solution of the product from step a (10 g, 38 mmol, 1 equiv) in CHCl (190 mL, 0.2 M) at 0 °C, EtN (32 mL, 228 mmol, 6 equiv) was added, followed by TBSOTf (17.5 mL, 76 mmol, 2 equiv). The reaction was allowed to warm to room temperature overnight. The reaction mixture was concentrated and then dried under vacuum for 45 min. The crude silyl enol ether was dissolved in MeCN (190 mL, 0.2 M), followed by the addition of Selectfluor (20.2 g, 57 mmol, 1.5 equiv), and the reaction was stirred at room temperature for 2 h or until complete as determined by TLC. The reaction mixture was diluted with EtOAc and washed with 0.2 M aqueous HCl, followed by brine. The organic layer was dried over MgSO and concentrated. The crude product was purified by flash column chromatography (SiO 2 , 0-50% EtOAc / hexanes) to give the difluoroketone as a pale yellow solid (7.0 g, 24.9 mmol, 66%).1 H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 8.4 Hz, 1H), 7.36 (dt, J = 8.4, 0.9 Hz, 1H), 3.48 (td, J = 12.6, 0.8 Hz, 2H).

[0488] Step c: Performed in the same manner as in Example 134, step b. 1 H NMR (400 MHz, chloroform-d) δ 7.45 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 5.22 (d, J = 12.4 Hz, 1H), 3.61–3.33 (m, 2H), 1.11 (t, J = 7.1 Hz, 2H).

[0489] Step d: Carried out in the same manner as in step c of Example 134. 15 H 20 ESI MS [M+H] of BrClF2OSi + , calculated value 397.0, measured value 397.0.

[0490] Step e: Performed as in step d of Example 134. The crude product was used in step f without column chromatography purification.

[0491] Step f: Carried out in the same manner as step e of Example 134. 26 H 27 ESI MS of ClF3NOSi [M+H] + , calculated value 490.2, measured value 490.2.

[0492] Step g: 5 equivalents of EtN was added to the reaction mixture and the procedure was the same as in step f of Example 134. At this stage, the diastereomers were not separated. 26 H 29 ESI MS of ClF3NOSi [M+H] + , calculated value 492.2, measured value 492.2.

[0493] Step h: The aryl chloride (100 mg, 0.20 mmol, 1 equiv.), KFe(CN)HO (59 mg, 0.14 mmol, 0.7 equiv.), XPhos Pd G3 (17 mg, 0.02 mmol, 0.1 equiv.), XPhos (10 mg, 0.02 mmol, 0.1 equiv.), and KOAc (4 mg, 0.04 mmol, 0.2 equiv.) were dissolved in 1:1 water / dioxane (2 mL, 0.1 M). The reaction mixture was sparged with nitrogen for 10 minutes and then heated to 100 °C. After 2 hours, the reaction was judged complete by LCMS. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organics were dried over NaSO and concentrated. The crude product was purified by flash column chromatography (SiO2, 0-50% EtOAc / hexanes) to give the aryl nitrile product. 27 H 29 ESI MS [M+H] of F3N2OSi + , calculated value 483.2, measured value 483.2.

[0494] Step i: The product from step h was treated with excess HF-pyridine in acetonitrile. After stirring overnight, the mixture was quenched with saturated NaHCO3 and extracted with EtOAc. The product was purified by flash column chromatography. The final product was isolated as a 1:1 mixture of diastereomers (40 mg, 0.11 mmol, 54% over two steps). C 21 H 15 ESI MS of F3N2O [M] + , calculated value 369.1, measured value 369.1. 1H NMR (400 MHz, chloroform-d) δ 7.47 (dd, J = 8.0, 2.9 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.60 (dd, J = 14.3, 8.0 Hz, 1H), 5.33 (m, 1H), 4.45 (dt, J = 9.0, 4.1 Hz, 1H), 3.88 - 3.27 (m, 2H), 3.10 - 2.80 (m, 3H), 2.23 - 2.08 (m, 1H), 1.89 - 1.70 (m, 2H).

[0495] Example 142: (5S,8R)-3,5-difluoro-8-[3-oxo-7-(trifluoromethyl)-1,3-dihydro-2-benzofuran-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0496] [ka]

[0497] Step a: To a solution of 3-bromo-4-chlorobenzotrifluoride (3.5 mL, 23 mmol, 1.0 equiv.) in THF (75 mL) in a 250 mL round-bottom flask, LDA solution (2.0 M in THF / heptane / ethylbenzene, 17 mL, 1.5 equiv.) was added dropwise at −78° C. under N. After stirring at this temperature for 15 min, DMF (3.6 mL, 46 mmol, 2.0 equiv.) was added dropwise at −78° C., and the resulting mixture was continued to stir at this temperature for an additional 1.5 h, at which time TLC indicated the reaction was complete. The reaction mixture was then quenched with saturated aqueous NH4Cl (60 mL), warmed to room temperature, and then extracted with EtOAc (100 mL × 3). The organic layers were combined, washed with brine (60 mL), and dried over Na2SO4. Concentration under reduced pressure gave the crude desired aldehyde product and its isomer, which was taken directly to the next step without purification (6.52 g).

[0498] Step b: The crude product from step a (together with another batch, a total of 8.45 g) in a 250 mL round-bottom flask was dissolved in MeOH (100 mL) and cooled to 0 °C. NaBH (1.67 g, 1.5 equiv.) was added portionwise, and the resulting mixture was stirred at 0 °C for 30 min, at which time TLC indicated the reaction was complete. The reaction mixture was quenched with HO and then concentrated under reduced pressure to remove most of the MeOH. The residue was extracted with EtOAc (100 mL × 3). The organic layers were combined, washed with brine (60 mL), and dried over NaSO. Concentration under reduced pressure and purification by flash chromatography (SiO, 0–30% EtOAc / Hexane (Hex)) afforded the product as a white powder (2.75 g, 9.50 mmol, 41% yield over two steps). 1 H NMR (400 MHz, chloroform-d) δ 7.60 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 5.09 (d, J = 6.8 Hz, 2H), 2.20 (t, J = 7.0 Hz, 1H).

[0499] Step c: To a solution of the product from step b (2.30 g, 8.0 mmol, 1.0 equiv) and i-PrNEt (2.8 mL, 16.0 mmol, 2.0 equiv) in DCM (40 mL) was added chloromethyl methyl ether (1.2 mL, 16.0 mmol, 2.0 equiv) dropwise at room temperature. The resulting mixture was stirred at this temperature for 22 h and then quenched with saturated aqueous NaHCO (20 mL). The aqueous phase was extracted with DCM (30 mL). The organic layers were combined, washed with brine (20 mL), and dried over NaSO. Concentration under reduced pressure gave the crude product (1.84 g), which was used directly in the next step.

[0500] Step d: A 40 mL vial was charged with the crude product from step c (1.06 g) and DMF (20 mL). CuCN (1.43 g, 16 mmol, 2.0 equiv) was added, and the resulting mixture was heated at 150 °C for 2 h, then cooled to room temperature and diluted with EtOAc (50 mL). The organic phase was then washed with HO (20 mL × 2) and brine (20 mL) and dried over NaSO. Concentration under reduced pressure and purification by flash chromatography (SiO, 10–40% EtOAc / hexane (Hex)) afforded the product as a yellow solid (1.00 g, 3.6 mmol, 45% yield over two steps). 1 H NMR (400 MHz, chloroform-d) δ 7.77 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 4.94 (s, 2H), 4.81 (s, 2H), 3.45 (s, 3H).

[0501] Step e: A 40 mL vial was charged with the product from step d (1.00 g, 3.6 mmol, 1.0 equiv), B2Pin2 (1.17 g, 4.6 mmol, 1.3 equiv), PCy3-Pd-G2 (0.213 g, 0.36 mmol, 10 mol%), KOAc (0.707 g, 7.2 mmol, 2.0 equiv), and 1,4-dioxane (10 mL). The reaction mixture was degassed by bubbling N2 for 10 min and then heated. After stirring at 100 °C for 2 h, the reaction mixture was cooled, diluted with EtOAc (20 mL), washed with HO (10 mL), dried over Na2SO4, and concentrated to give the crude product (1.84 g), which was used in the next step.

[0502] Step f: A 40 mL vial was charged with the crude product from step e (1.84 g), alkenyl triflate (1.16 g, 3.6 mmol, 1.0 equiv), Pd(dppf)Cl (0.263 g, 0.36 mmol, 10 mol%), NaCO (0.763 g, 7.2 mmol, 2.0 equiv), 1,4-dioxane (10 mL), and HO (2 mL). The reaction mixture was degassed by bubbling N for 10 min and then heated. After stirring at 100 °C for 1 h, the reaction mixture was cooled, filtered, concentrated, and purified by flash chromatography (SiO, 10–30% EtOAc / hexane (Hex)) to give the product (0.743 g, 1.78 mmol, 50% yield over two steps). 1 H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 8. Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.23 (dd, J = 8.2, 2.8 Hz, 1H), 7.14 (dd, J = 8.0, 2.8 Hz, 1H), 6.35 (t, J = 4.9 Hz, 1H), 4.61 - 4.52(m, 3H), 4.50 (d, J = 6.7 Hz, 1H), 3.29 (s, 3H), 2.92(t, J = 7.8 Hz, 2H), 2.57 - 2.39 (m, 2H).

[0503] Step g: A mixture of the product from step f (0.535 g, 1.3 mmol, 1.0 equiv.), Pd / C (10 wt% Pd, 0.600 g) in MeOH (10 mL) was shaken in a Parr hydrogenation apparatus under H (50 psi) for 3 h, at which time TLC indicated the reaction was complete. The reaction mixture was then filtered through Celite and concentrated to give the product, which was used directly in the next step.

[0504] Step h: To the vial containing the product from step g, DCM (13 mL), MnO (0.452 g, 5.2 mmol, 4.0 equiv.), and a solution of t-BuOOH (5.5 M in decane, 2.4 mL, 13 mmol, 10 equiv.) were added. The resulting mixture was heated at 40 °C overnight, and another 4.0 equiv. of MnO and 10 equiv. of t-BuOOH solution were added to the reaction mixture. After reacting overnight, the reaction mixture was filtered through Celite, concentrated, and purified by flash chromatography (SiO, 10–20% EtOAc / hexane (Hex)) to give the desired product (0.272 g, 0.629 mmol, 48% yield over two steps). 1 H NMR (400 MHz, chloroform-d) δ 8.11 (dd, J = 8.2, 2.7 Hz, 1H), 7.62(d, J = 8.3 Hz, 1H), 7.58 (dd, J = 7.2, 2.9 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.23 - 5.13 (m, 3H), 4.87 (s, 2H), 3.51 (s, 3H), 2.75 - 2.64 (m, 2H), 2.63 - 2.55 (m, 1H), 2.49 - 2.41 (m, 1H).

[0505] Step i: A 40 mL vial was charged with the product from step h (78.1 mg, 0.18 mmol, 1.0 equiv.), RuCl(p-cymene) [(R,R)-TsDPEN] (11.5 mg, 18 μmol, 10 mol%), HCOH (41.4 mg, 0.90 mmol, 5.0 equiv.), EtN (54.6 mg, 0.54 mmol, 3.0 equiv.), and DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The crude material was purified by flash chromatography (SiO, 30–50% EtOAc / hexane (Hex)) to give the desired product (27.2 mg, 62.6 μmol, 35% yield). 1H NMR (400 MHz, chloroform-d) δ 7.70 (dd, J = 9.2, 2.7 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.31 - 7.23 (m, 1H), 6.92(d, J = 8.3 Hz, 1H), 5.20 - 5.06 (m, 2H), 4.92 - 4.81(m, 4H), 3.50 (s, 3H), 2.40 - 2.26 (m, 2H), 2.18 - 1.99 (m, 2H), 1.84 - 1.70 (m, 1H).

[0506] Step j: To a solution of Deoxo-Fluor (2.7 M in toluene, 0.219 mmol, 80 μL, 3.5 equiv) in DCM (2 mL) was added TMS-morpholine (0.222 mmol, 35.4 mg, 3.55 equiv) dropwise over 1 min at −78 °C. The resulting solution was stirred at this temperature for 5 min, then warmed to room temperature for 2 h, and then cooled back down to −78 °C. A solution of the product from step i (27.2 mg, 62.6 μmol, 1.0 equiv) in DCM (1 mL) was then added to the reaction mixture. The resulting mixture was then stirred at room temperature for an additional 15 min, at which time TLC indicated the reaction was complete. The reaction mixture was then diluted with DCM (10 mL), washed with saturated aqueous NaHCO (5 mL), dried over NaSO, and concentrated. The residue was then purified by flash chromatography (SiO 2 , 25% EtOAc / Hexanes (Hex)) to give the fluorinated product (25.1 mg, 57.5 μmol, 92% yield). 1H NMR (400 MHz, chloroform-d) δ 7.62 - 7.51 (m, 2H), 7.40 (ddd, J = 7.5, 2.7, 1.6 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 5.61 (dt, J = 49.9, 3.8 Hz, 1H), 5.21 - 5.07 (m, 2H), 4.99 - 4.92(m, 1H), 4.89 - 4.83 (m, 2H), 3.51 (s, 3H), 2.65 - 2.51 (m, 1H), 2.23 - 2.08 (m, 1H), 2.04 - 1.90 (m, 2H).

[0507] Step k: A solution of the product from step j (23.0 mg, 52.7 μmol, 1.0 equiv) in MeOH (0.5 mL) and 6 M HCl (0.5 mL aq.) was heated at 60° C. for 1 h and then concentrated. The residue was purified by flash chromatography (SiO, 30% EtOAc / Hexanes (Hex)) to afford the title compound as a white solid (17.3 mg, 44.0 μmol, 84% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.66 (d, J = 7.9 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.43 (ddd, J = 7.4, 2.7, 1.8 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.73 - 5.55 (m, 2H), 5.37 (d, J = 15.6 Hz, 1H), ...

Claims

1. Formula (II): 【Chemistry 1】 or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, wherein Z is N or CR 6 and Y 2 , Y 3 and Y 4 are each independently CR 2 R 3 and W 1 , W 2 and W 3 are each independently CR 5 and R 1 is halogen, hydroxy, CN, NO 2 , -NR a R b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O) 2 R a , -C(O)NR a R b , -S(O)(=NH)R a , and -S(O) 2 NR a R b selected from the group consisting of: Each R 2 and R 3 H, halogen, CN, NO 2 , O.H., C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O) 2 R a , -CO 2 R a , -C(O)R a , -C(O)NR a R b , -S(O) 2 NR a R b , -S(O)(=NH)R a , and -NR a R b are each independently selected from the group consisting of: Each R 4 , H, C 1-4 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a are independently selected from Each R 5 H, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O) 2 R a , -CO 2 R a , -C(O)R a , -C(O)NR a R b , -S(O) 2 NR a R b , -S(O)(=NH)R a , and -NR a R b are independently selected from the group consisting of: R 6 , H, C 1-4 selected from the group consisting of alkyl, OH, F, and CN; X 1 is N or CR 8a and X 2 is N or CR 8b and R 8a and R 8b H, halogen, CN, NH 2 , NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b , -S(O) 2 NR a R b , and -S(O) 2 R a are independently selected from the group consisting of: R 9 and R 10 H, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O) 2 NR a R b , and -S(O) 2 R a are independently selected from the group consisting of: R 11 is halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -NR c R b , -C(O)NR c R b , -C(O)OH, -S(O) 2 NR c R b , -S(O)(=NH)R c , -S(O) 2 R c , phenyl, a 5- to 6-membered heterocyclic ring, and a 5- to 10-membered heteroaryl ring, wherein the heterocyclic ring and the heteroaryl ring have 1 to 3 heteroatoms selected from N, O, and S as ring vertices; the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl, heterocyclic ring, or heteroaryl ring .... 2 , N.H. 2 , C(O)NH 2 , S(O) 2 CH 3 , -CH 2 NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl and C 1-4 Alkoxy C 1-4 optionally substituted with 1 to 3 members independently selected from alkyl; and optionally, two members attached to the same carbon of said heterocyclic ring taken together form =CH 2 or forms an oxo (=O) group; Or R 9 and R 10 is combined with R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 、 and R 19 forming a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaryl ring optionally substituted with one or more substituents independently selected from Or R 10 and R 11 is combined with R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 、 and R 19 and forming a 5- or 6-membered carbocyclic, heterocyclic or heteroaryl ring optionally substituted with one or more substituents independently selected from 、 and S; R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 、 and R 19 are H, halogen, CN, OH, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b or two R on the same carbon atom are independently selected from the group consisting of 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 、 and R 19 The moieties are linked to form an oxo group; Each R a and R b , H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy and C 1-8 hydroxyalkyl; R c If present, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6 and wherein the heterocycloalkyl or heteroaryl ring each has N, O, or NH as a ring vertex. 、 and S, The compound, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

2. Formula (IV-a): 【Chemistry 2】 10. The compound of claim 1 having the structure: Y 2 , Y 3 and Y 4 are each independently CR 2 R 3 and R 1 is halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 2 R a , and -C(O)NR a R b selected from the group consisting of: Each R 2 and R 3 H, halogen, CN, NO 2 , O.H., C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O) 2 R a 、 and -C(O)NR a R b are each independently selected from the group consisting of: Each R 4 , H, C 1-4 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a are independently selected from the group consisting of: Each R 5 H, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, -S(O) 2 R a , -C(O)NR a R b , and -S(O) 2 NR a R b Independently selected from the group consisting of: The compound, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

3. X 1 and X 2 is independently selected from the group consisting of CH and N.

4. Formula (IV-b): 【Chemistry 3】 10. The compound of claim 1 having the structure: The subscript m is 1, 2, 3, 4, 5, 6, 7, or 8; The subscript n is 1 or 2; R z is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 represents one or more of: Y 2 , Y 3 and Y 4 are each independently CR 2 R 3 and R 1 is halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 2 R a 、 and -C(O)NR a R b selected from the group consisting of: Each R 2 and R 3 H, halogen, CN, NO 2 , O.H., C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O) 2 R a 、 and -C(O)NR a R b are each independently selected from the group consisting of: Each R 4 , H, C 1-6 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a are independently selected from; R 5 H, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, -S(O) 2 R a , -C(O)NR a R b , and -S(O) 2 NR a R b selected from the group consisting of: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 、 and R 19 are H, halogen, CN, OH, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl 、 and -NR a R b or two R on the same carbon atom are independently selected from the group consisting of 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 、 and R 19 The moieties are linked to form an oxo group, The compound, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

5. R 11 is a phenyl, a 5- or 6-membered heterocyclic ring, or a 5- to 10-membered heteroaryl ring, wherein said heterocyclic ring or heteroaryl ring has 1 to 3 heteroatoms selected from N, O, and S as ring vertices; said phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; said phenyl, heterocyclic ring, or heteroaryl ring is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and said phenyl, heterocyclic ring, or heteroaryl ring is optionally fused to a halogen, CN, NO 2 , N.H. 2 , C(O)NH 2 , S(O) 2 CH 3 , -CH 2 NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl 、 and C 1-4 Alkoxy C 1-4 optionally substituted with 1 to 3 members independently selected from alkyl; and optionally, two members attached to the same carbon of said heterocyclic ring taken together form =CH 2 or an oxo (=O) group.

6. Formula (IV-c): 【Chemistry 4】 10. The compound of claim 1 having the structure: A 1 is O or CHR 13 and Y 2 , Y 3 and Y 4 are each independently CR 2 R 3 and R 1 is halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 2 R a 、 and -C(O)NR a R b selected from the group consisting of: R 5 H, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, -S(O) 2 R a , -C(O)NR a R b , and -S(O) 2 NR a R b selected from the group consisting of: R 11 is halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b , -S(O) 2 NR c R b , -S(O)(=NH)R c , and -S(O) 2 R c selected from the group consisting of: R 13 , R 14 and R 15 are H, halogen, CN, OH, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl 、 and -NR a R b are independently selected from the group consisting of: R 16 , H, C 1-4 Alkyl 、 and C 1-4 fluoroalkyl, The compound, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

7. Y 2 CR 2 R 3 where each R 2 and R 3 is H; Y 3 and Y 4 are CR 2 R 3 where each R 2 and R 3 is independently selected from H and F, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

8. Formula (IV-f): 【Chemistry 5】 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

9. Formula (Vb): 【Chemistry 6】 10. The compound of claim 1 having the structure: Each R 5 H, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O) 2 R a , -CO 2 R a , -C(O)R a , -C(O)NR a R b , -S(O) 2 NR a R b , -S(O)(=NH)R a , and -NR a R b Independently selected from the group consisting of: The compound, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

10. R 9 and R 10 H, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O) 2 NR a R b , and -S(O) 2 R a are each independently selected from the group consisting of: R 11 But halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b , -S(O) 2 NR c R b , and -S(O) 2 R c Selected from the group consisting of:

10. The compound of claim 9, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

11. Formula (Vd): 【Chemistry 7】 10. The compound of claim 1 having the structure: Y 2 , Y 3 and Y 4 are each independently CR 2 R 3 and R 1 is halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O) 2 R a 、 and -C(O)NR a R b selected from the group consisting of: R 2 and R 3 H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O) 2 R a , -C(O)NR a R b , and -NR a R b are each independently selected from the group consisting of: R 5 H, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O) 2 R a , -C(O)NR a R b , and -S(O) 2 NR a R b Selected from the group consisting of: The compound, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

12. Formula (Vf): 【Chemistry 8】 10. The compound of claim 1 having the structure: The subscript m is 1, 2, 3, 4, 5, 6, 7, or 8; The subscript n is 1 or 2; R z is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 represents one or more of; Y 2 , Y 3 and Y 4 are each independently CR 2 R 3 and R 1 is halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 2 R a 、 and -C(O)NR a R b selected from the group consisting of: Each R 2 and R 3 H, halogen, CN, NO 2 , O.H., C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O) 2 R a 、 and -C(O)NR a R b are each independently selected from the group consisting of: Each R 4 , H, C 1-6 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a are independently selected from; R 5 H, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, -S(O) 2 R a , -C(O)NR a R b , and -S(O) 2 NR a R b selected from the group consisting of: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 、 and R 19 are H, halogen, CN, OH, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b or two R on the same carbon atom are independently selected from the group consisting of 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 、 and R 19 The moieties are linked to form an oxo group, The compound, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

13. 【Table 1】 or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

14. formula 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof.

15. formula 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof.

16. formula 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

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