Tetraline and tetrahydroquinoline compounds as inhibitors of HIF-2alpha

Abstract

Compounds that inhibit HIF-2α, compositions containing the compound(s), and methods for synthesizing the compounds are described herein. Additionally, the use of these compounds and compositions for the treatment of various diseases, disorders, and conditions, including cancer- and immune-related disorders mediated at least partially by HIF-2α, is described herein.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims 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 in its entirety for all purposes. Background Technology

[0003] Hypoxia-inducible factor (HIF) transcription factors play an essential role in the cellular response to low oxygen availability. [Immunity. 2014 Oct 16; 41(4): 518-528.] HIF is a heterodimeric transcription factor composed 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, the 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, activating the expression of genes that regulate metabolism, angiogenesis, cell proliferation and survival, immune evasion, and inflammatory responses. [J. Med. Chem. 2018, 61, 9691-9721.]

[0004] Among the three distinct α-subunit isoforms of HIF-1α, HIF-2α, and the less characteristic HIF-3α, overexpression of HIF-1α and HIF-2α is associated with poor clinical outcomes in patients with various cancers. Specifically, HIF-2α has been identified as 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 many acute and chronic inflammatory disorders, such as inflammatory bowel disease and rheumatoid arthritis. [J. Clin Invest. 2016;126(10):3661-3671.]

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

[0006] The present invention relates to a compound that inhibits the activity of the hypoxia-inducible factor (HIF) family among transcription factors, particularly HIF-2α. The said compound or its pharmaceutically acceptable salts, hydrates, or solvates are represented by the following chemical formula (I):

[0007]

[0008] Here, W 1 , W 2 , W 3 , Y 1 , Y 2 , Y 3 , Y 4 , and R 1 It has the meaning defined in the following text.

[0009] In a related aspect, a method for treating a disease or disorder mediated by HIF-2α in a subject is provided herein, comprising administering a therapeutically effective amount of at least one of the HIF-2α inhibitors described herein to a subject (e.g., a human). Diseases and disorders mediated by HIF-2α include cancer, inflammation, autoimmune disorders, and metabolic disorders as described below. Other diseases, disorders, and conditions that can be treated or prevented wholly or partially by modulating HIF-2α activity are candidate indications for the HIF-2α inhibitor compounds provided herein.

[0010] In addition, the use of the described HIF-2α inhibitor in combination with one or more additional agents as described below is provided herein. Specific details for implementing the invention

[0011] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments specified herein, and that the terms used herein are intended only to describe specific embodiments and are not intended to be limiting.

[0012] Where a range of values ​​is provided, the upper and lower limits of such range and any other value within the mentioned range or any value between them are understood to be included in the present invention up to 1 / 10 of the lower limit unit, unless the context otherwise clearly indicates. The upper and lower limits of a range smaller than these may be independently included in the smaller range and are also included in the present invention, except for any specifically excluded limits within the mentioned range. If the mentioned range includes one or both of the limits, the range excluding one or both of the included limits is also included in the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains.

[0013] The singular form used herein includes plural references unless the context clearly indicates otherwise. It should also be noted that claims may be drafted to exclude any optional elements. As such, this specification is intended to serve as a precedent for the use of exclusive terms such as "only," "only," etc., in connection with the enumeration or "negative" limitation of claim elements.

[0014] The publications discussed herein are provided only for their disclosures prior to the filing date of this application. Additionally, the provided disclosure dates may differ from the actual disclosure dates and may need to be verified independently.

[0015] definition

[0016] Unless otherwise indicated, the following terms are intended to have the meanings specified below. Other terms are defined elsewhere throughout the specification.

[0017] The term "alkyl" means a straight-chain or branched-chain hydrocarbon radical having a specified number of carbon atoms, either itself or as part of another substituent, unless otherwise noted (i.e., C1-8 means 1 to 8 carbons). Alkyl can have any number of carbons, for example, C 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 It may include. 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, etc.

[0018] The term "hydroxyalkyl" refers to a specified number of carbon atoms (e.g., C 1-6 or C 1-8 It refers to an alkyl group having ) and substituted with one or two hydroxy (OH) groups.

[0019] The term "hydroxyhaloalkyl" refers to a specified number of carbon atoms (e.g., C 1-6 or C 1-8 It refers to an alkyl group having ) and substituted with 1 or 2 hydroxy (OH) groups and 1 to 6 halogen atoms (e.g., F, Cl).

[0020] The term "alkylene" refers to a straight-chain or branched, saturated, aliphatic radical—that is, a divalent hydrocarbon radical—that has a specified number of carbon atoms and connects at least two other groups. The two moiety connected to the alkylene can be connected to the same or different atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) n - may be a divalent radical, 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, the alkylene group may be substituted or unsubstituted. Where the alkylene-containing group is optionally substituted, it is understood that the optional substitution may be on the alkylene portion of the moiety.

[0021] 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 fully saturated or has one or fewer double bonds between the ring vertices. "Cycloalkyl" is also intended to refer to non-cyclic and polycyclic hydrocarbon rings, e.g., bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. In some embodiments, the cycloalkyl compounds of this disclosure are monocyclic C 3-6 It is a cycloalkyl moiety.

[0022] The terms “cycloheteroalkyl,” “heterocycle,” or “heterocyclic ring” refer to a cycloalkyl ring having a specified number of ring vertices (or members) and having 1 to 5 heteroatoms selected from N, O, and S replacing 1 to 5 of the carbon vertices, wherein 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 1 or 2 double bonds connecting the ring vertices. Non-limiting examples of cycloheteroalkyl 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, quinuclideine, etc. The heterocycloalkyl group may be attached to the rest of the molecule through a ring carbon or a heteroatom. In some embodiments, the heterocycle is a 5- to 6-membered heterocycle.

[0023] Wavy lines crossing single, double, or triple bonds in any chemical structure illustrated herein as used herein " indicates the attachment point of a single, double, or triple bond to the rest of the molecule. Additionally, a bond extending to the center of a ring (e.g., a phenyl ring) is intended to indicate attachment at any available ring vertex. A person skilled in the art will understand that multiple substituents indicated as being attached to the ring will occupy ring vertices that provide a stable compound and, otherwise, are stereocompatible. In the case of a divalent component, the designation is intended to include either an orientation (forward or reverse). For example, the group "-C(O)NH-" means that it includes a linkage of either -C(O)NH- or -NHC(O)- in either orientation, and similarly, "-O-CH2CH2-" is intended to include both -O-CH2CH2- and -CH2CH2-O-.

[0024] The terms "halo" or "halogen," either as themselves or as part of another substituent, refer to fluorine, chlorine, bromine, or iodine atoms unless otherwise noted. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-4 haloalkyl" refers to those including trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0025] The term “aryl” means a polyunsaturated, typically aromatic hydrocarbon group that, unless otherwise noted, may be a single ring or a polycyclic group (up to three rings) that are fused to one another or connected by covalent bonds. 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 indan, tetrahydronaphthalene, chroman, and isochroman rings. As a substituent, the attachment point to the rest of the molecule for the fused ring system may be through a carbon atom on the aromatic portion, a carbon atom on the cycloalkyl portion, or an atom on the heterocycloalkyl portion.

[0026] The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. The heteroaryl group may be attached to the rest of the molecule through the heteroatoms. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinil, pyrazinil, pyrimidinil, triazinil, quinolinil, quinoxalinil, quinazolinil, cinnolinil, phthalazinil, benzotriazinil, furinil, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinil, benzotriazinil, thienopyridinil, thienopyrimidinil, pyrazolopyrimidinil, imidazopyridine, benzothiasolyl, benzofuranil, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazollyl, pyrazolyl, indazollyl, pteridinil, imidazollyl, triazolyl, tetrazollyl, oxazolyl, Includes isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, etc. Substituents for the heteroaryl ring may be selected from the group of acceptable substituents listed below.

[0027] The above terms (e.g., "alkyl," "aryl," and "heteroaryl") will be optionally substituted in some embodiments. Selected substituents for each type of radical are provided below.

[0028] Optional substituents for alkyl radicals (including groups often referred to as alkylene, alkenyl, and alkynyl) are, for example, halogens in a number ranging from 0 to (2 m'+1) (where m' is the total number of carbon atoms in these radicals), -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -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", -CN (cyano), -NO2, aryl, aryloxy, oxo (=O), cycloalkyl, and heterocycloalkyl may be various groups selected from. R', R" and R"' are each independently hydrogen, unsubstituted C1-8 alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C1-8 alkoxy or C1-8 thioalkoxy groups, or unsubstituted aryl-C 1-4 It refers to an alkyl group. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is intended to include 1-pyrrolidinyl and 4-morpholinyl.

[0029] Optional substituents for cycloalkyl and heterocycloalkyl radicals are, for example, various groups selected from alkyl, halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -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", -CN (cyano), -NO2, aryl, aryloxy, and oxo (=O). R', R" and R"' are each independently hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C 1-8 Alkoxy or C 1-8 Thioalkoxy groups, or unsubstituted aryl-C 1-4 It refers to an alkyl group.

[0030] Optional substituents for cycloalkyl and heterocycloalkyl radicals may also include olefins (=CR'R"), where R' and R" are each independently hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C 1-8 Alkoxy or C 1-8 Thioalkoxy groups, or unsubstituted aryl-C 1-4 It refers to an alkyl group. For example, the olefin can be an unsubstituted olefin (=CH2).

[0031] Similarly, arbitrary substituents for aryl and heteroaryl groups are diverse, for example, a number of -halogens, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -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(C 1-4 )alkoxy, and perfluoro(C 1-4 )can be selected from alkyls; where R', R" and R"' are independently hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl and C 2-8 It is selected from alkynyl. Other suitable substituents include each of the above aryl substituents attached to the ring atom by an alkylene tether of 1 to 6 carbon atoms.

[0032] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring are in the chemical formula -TC(O)-(CH2) q It can be optionally replaced with a substituent of -U-, where T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring are of the formula -A-(CR f R g ) r -B- can be optionally substituted with a substituent, where 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 gEach is independently H or a halogen. One of the single bonds of the new ring thus formed can be arbitrarily substituted with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring are of the chemical formula -(CH2) s -X-(CH2) t - can be optionally replaced with a substituent, 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 alkyls.

[0033] The term "heteroatom" as used herein is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0034] The term “pharmaceutical acceptable salt” is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on specific substituents found on the compounds described herein. Where the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting a neutral form of such compounds with a sufficient amount of the desired base in a pure state or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferrous iron, ferric iron, lithium, magnesium, manganese i.e., manganese i.e., potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include primary, secondary, and tertiary amines, such as substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the 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 compound with a sufficient amount of the desired acid in a pure state or in a suitable inert solvent.Examples of pharmaceutically permissible acid addition salts include salts derived from inorganic acids, such as hydrochloric acid, hydrobromide, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphate, dihydrophosphate, sulfuric acid, monohydrosulfuric acid, hydroiodide, or phosphoric 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, souveric acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. In addition, salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galactunoric acid are included (see, for example, the literature [Berge, SM, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19]). Specific compounds of the present invention contain both basic and acidic functional groups that cause the compound to be converted into a base or an acid addition salt.

[0035] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. Although the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, the salt is equivalent to the parent form of the compound for the purposes of the present invention except for this.

[0036] In addition to the salt form, the present invention provides a compound in the form of a prodrug. The prodrug of the compound described herein is a compound that readily undergoes chemical change under physiological conditions to provide the compound of the present invention. Additionally, the prodrug can be converted into the compound of the present invention through chemical or biochemical methods in an in vitro environment. For example, the prodrug can be gradually converted into the compound of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0037] Some compounds of the present invention may exist in solvated forms, including hydrated forms, as well as in nonsolved forms. Generally, solvated forms are equivalent to nonsolved forms and are intended to be encompassed within the scope of the present invention. Specific compounds of the present invention may exist in various crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses considered by the present invention and are intended to be within the scope of the present invention.

[0038] Certain compounds of the present invention may exist as polymorphs under specific conditions. Polymorphism refers to the ability of a solid material to exist in more than one crystal structure form or phase, wherein molecules within the crystal lattice have different arrangements or stereomorphs. When such differences exist due to packing, they are referred to as "packing polymorphism," and when they exist due to differences in stereomorphism, they are referred to as "stereomorphic polymorphism." Different polymorphs of the same compound often exhibit different physical properties, e.g., packing properties, spectroscopic properties, thermodynamic properties, solubility, and melting point; kinetic properties, e.g., dissolution rate and stability; and mechanical properties, e.g., hardness and tensile strength.

[0039] Polymorphs can be classified into one of two types based on their stability over different ranges of temperature and pressure. In a monomorphic system, only one type of polymorph (i.e., a monomorph) is stable and exhibits lower free energy content and solubility at all temperatures and pressures below the melting point. In a tautomorphic system, one polymorph is stable at a specific temperature and pressure, while the other polymorph(s) are stable at various temperatures and pressures.

[0040] Certain compounds of the present invention possess an asymmetric carbon atom (optical center) or a double bond; racemics, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., individual enantiomers) are all intended to be encompassed within the scope of the present invention.

[0041] The compounds of the present invention may also contain atomic isotopes in non-natural proportions in one or more atoms constituting the compounds. The non-natural proportion of isotopes may be defined as a range of amounts consisting of 100% of the corresponding atom from the amounts found in nature. For example, the compounds may contain radioactive isotopes, such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium ( 2 H) or carbon-13 ( 13 C) may be included. Such isotopic modifications may provide additional utility to those described elsewhere in this application. For example, isotopic modifications of the compounds of the present invention may find additional utility, including but not limited to utility as diagnostic and / or imaging reagents or as cytotoxic / radiotoxic therapeutic agents. Additionally, isotopic modifications of the compounds of the present invention may have modified pharmacokinetic and pharmacodynamic characteristics that may contribute to enhanced safety, tolerability, or efficacy during treatment. Whether radioactive or not, all isotopic modifications of the compounds of the present invention are intended to be encompassed within the scope of the present invention.

[0042] The terms "patient" or "subject" are used interchangeably to refer to humans or non-human animals (e.g., mammals).

[0043] The terms "administration," "to administer," etc. refer to contact with a subject, cell, tissue, organ, or biological fluid, for example, where they are applied to such a subject, cell, tissue, organ, or biological fluid, for example, an inhibitor of HIF-2α, a pharmaceutical composition containing the same, or a diagnostic agent. With respect to cells, administration includes contact of a reagent with the cell (e.g., in vitro or in vitro), as well as contact of a reagent with the fluid when the fluid comes into contact with the cell.

[0044] The terms "treat," "treating," "treatment," etc. refer to a process of action initiated after diagnosing or observing a disease, disorder, or condition or its symptoms in order to temporarily or permanently eliminate, reduce, suppress, alleviate, or improve at least one of the underlying causes of the disease, disorder, or condition afflicted by the subject, or at least one of the symptoms associated with the disease, disorder, or condition afflicted by the subject (e.g., administration of an HIF-2α inhibitor or a pharmaceutical composition containing it). Accordingly, treatment includes suppressing the active disease (e.g., stopping the occurrence or further occurrence of the disease, disorder, or condition or associated clinical symptoms).

[0045] As used herein, the term "in need of treatment" refers to a situation where a subject is judged by a physician or other guardian to require treatment or to benefit from it. Such judgment is made based on various factors within the scope of the physician's or guardian's professional knowledge.

[0046] The terms “prevent,” “preventing,” “prevention,” etc. refer to a course of action (e.g., administration of an HIF-2α inhibitor or a pharmaceutical composition containing it) initiated in such a manner as to temporarily or permanently prevent, limit, suppress, or reduce the risk of a subject developing a disease, disorder, condition, etc. (e.g., before the onset of the disease, disorder, condition, or its symptoms) (e.g., determined by the absence of clinical symptoms), or to delay the onset of such disease, disorder, or condition in relation to a subject who is generally predisposed to having a specific disease, disorder, or condition. In certain cases, the term also refers to slowing the progression of a disease, disorder, or condition or inhibiting its progression to a harmful or otherwise undesirable state.

[0047] As used herein, the term "requiring prevention" refers to a judgment made by a physician or other guardian that the subject requires preventive care or will benefit from it. Such judgment is based on various factors within the scope of the physician's or guardian's professional knowledge.

[0048] The term "therapeutic effective dose" refers to the administration of an agent to a subject, either alone or as part of a pharmaceutical composition, as a single dose or as part of a series of doses, in an amount capable of producing any detectable positive effect on any symptom, aspect, or characteristic of the disease, disorder, or condition upon administration to the subject. The therapeutic effective dose may be identified by measuring relevant physiological effects and may be adjusted in relation to the administration regimen and diagnostic analysis of the subject's condition. For example, measurement of serum levels of an HIF-2α inhibitor (or, e.g., its metabolites) at a specific time after administration may indicate whether the therapeutic effective dose has been used.

[0049] The phrase "amount sufficient to cause a change" means that there is a detectable difference between the levels of an indicator measured before (e.g., baseline level) and after the administration of a specific therapy. The indicator includes any objective parameter (e.g., serum concentration) or subjective parameter (e.g., subject's comfort).

[0050] The term “small molecule” refers to chemical compounds 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 may be more permeable to cells than macromolecules, less sensitive to degradation, and less likely to induce an immune response.

[0051] The terms "inhibitor" and "antagonist," or "activator" and "agonist," respectively refer to molecules that activate or inhibit the activation of, for example, ligands, receptors, cofactors, genes, cells, tissues, or organs. An inhibitor is a molecule that reduces, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, genes, proteins, ligands, receptors, or cells. An activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or upregulates, for example, genes, proteins, ligands, receptors, or cells. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates constitutive activity. An "agonist" is a molecule that interacts with a target to induce or promote an increase in the target's activation. An "antagonist" is a molecule that counteracts the action(s) of an agonist. Antagonists prevent, reduce, inhibit, or neutralize the activity of agonists, and antagonists can also prevent, inhibit, or reduce the constitutive activity of targets, e.g., target receptors, even in the absence of an identified agonist.

[0052] The terms "modulate," "modulation," etc. refer to the ability of a molecule (e.g., activator or inhibitor) to directly or indirectly increase or decrease the function or activity of HIF-2α. Modulators may act alone or may use cofactors, e.g., proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds and other bio-organic molecules.

[0053] 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; and the modulation of the activity of other molecules. The term “proliferative activity” encompasses, for example, activities that promote normal cell division as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis—that is, activities necessary for or specifically associated with these processes.

[0054] As used herein, terms such as “comparable,” “comparable activity,” “activity comparable to,” “comparable effect,” and “effect comparable to” are relative terms that can be judged quantitatively and / or qualitatively. The meaning of these terms depends on the context in which they are frequently used. For example, if both agents activate the receptor, they may be judged to have comparable effects from a qualitative perspective, but if one agent achieves only 20% of the activity of the other agent when measured in a test accepted in the relevant art (e.g., dose-response test) or in an animal model accepted in the relevant art, they may be judged to lack comparable effects from a quantitative perspective. When comparing one result to another result (e.g., one result to a reference standard), “comparable” 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% (if it deviates from the reference standard by less than 15%, less than 10%, or less than 5%). For example, the activity or effect may refer to, but is not limited to, efficacy, stability, solubility, or immunogenicity.

[0055] "Substantially pure" indicates that the 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%, or at least 90% of the total composition. In some cases, the polypeptide will constitute more than about 90% or more than about 95% of the total content of the composition.

[0056] Selective compounds may be particularly useful for the treatment of specific disorders or may reduce the likelihood of undesirable side effects. In one embodiment, the compounds of the present disclosure are selective relative to other HIF isoforms. In another embodiment, the compounds of the present disclosure are selective relative to 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 a compound as described herein for HIF-2α with the inhibition of another protein by a compound as described herein. In one embodiment, the selective inhibition of HIF-2α is at least 1,000 times, 500 times, 100 times, or 20 times greater than the inhibition of another protein or isoform.

[0057] The compounds provided herein may have favorable pharmacokinetic profiles, including, for example, hepatocyte stability, clearance, and inhibition of CYP.

[0058] For example, the term “response” of a cell, tissue, organ, or organism encompasses biochemical or physiological behaviors, e.g., concentration, density, attachment, or migration within a biological compartment, gene expression rates, or changes in differentiation status, where changes are correlated with activation, stimulation, or treatment, or internal mechanisms such as gene programming. In specific contexts, terms such as “activation” and “stimulation” refer to cellular activation regulated by external or environmental factors as well as internal mechanisms; whereas terms such as “inhibition” and “down-regulation” refer to the opposite effects.

[0059] Compounds of the present disclosure

[0060] In one particular aspect, a compound having the formula (I) or a salt, hydrate, or solvate thereof that is restrictively permissible is provided herein:

[0061]

[0062] Here:

[0063] Y 1 , Y 2 , Y 3 and Y 4 CR each independently 2 R 3 , NR 4 , CR 6 R 7 , NR 7 Selected from the group consisting of , O, SO2 and bonds; Y 1 , Y 2 , Y 3 and Y 4 One of them is CR 6 R 7 or NR 7 Igo; Y 1 , Y 2 , Y 3 and Y 4 One or fewer of them are combinations;

[0064] W 1 , W 2 and W 3 CR each independently 5 Selected from a group consisting of and N;

[0065] R 1 Silver, 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)2R a , -C(O)NR a R b , -S(O)(=NH)R a , and -S(O)2NR a R b Selected from a group consisting of;

[0066] Each R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of;

[0067] Each R 4 is independently H, C 1-4 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a Selected from,

[0068] Each R 5 is independently 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of;

[0069] R 6 H, C 1-4 Selected from the group consisting of alkyl, OH, F, and CN;

[0070] R 7 is a group having the following chemical formula:

[0071]

[0072] Here:

[0073] X 1 is N or CR 8a And;

[0074] X 2 is N or CR 8b And;

[0075] R 8a and R 8b is independently 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;

[0076] R 9 and R 10 It independently contains H, halogen, CN, NO2, and 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;

[0077] R 11 Silver, 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)2NR c R b , -S(O)(=NH)R c , -S(O)2R c , and selected from the group consisting of a 5- or 6-membered heterocyclic or heteroaryl ring having 1-3 heteroatoms selected from N, O, and S as ring vertices; wherein the heterocyclic or heteroaryl ring is a 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 and C 1-4 Alkoxy C 1-4 Optionally substituted with 1 to 3 members independently selected from alkyl;

[0078] or R 9 and R 10 It combines to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R16 , R 17 , R 18 and R 19 Optionally substituted with one or more independently selected from, e.g., 1, 2, 3, or 4 substituents, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices;

[0079] or R 10 and R 11 It combines to form a 5- or 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Optionally substituted with one or more independently selected from, e.g., 1, 2, 3, or 4 substituents, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices;

[0080] Each R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 is independently 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 Selected from the group consisting of; or two Rs on the same carbon atom 12 , R 13 , R 14 , R 15 , R16 , R 17 , R 18 and R 19 Moiety combines to form an iodine group;

[0081] Each R a and R b is independently H, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, and C 1-8 Selected from the group consisting of hydroxyalkyl,

[0082] R c is, in the case where, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6 Selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices, and

[0083] However, R a , R b and R c When combined with a group to which it is attached, N-oxide and peroxide links are not formed.

[0084] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is, respectively, Y 2 , Y 3 and Y 4 Ga CR 2 R 3 It is a phosphorus compound.

[0085] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is, respectively, Y 2 and Y 3 This CR 2 R 3and, Y 4 It is a compound in which bonds.

[0086] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (II):

[0087]

[0088] Here, Z is N or CR 6 and the remaining groups have the meanings provided for chemical formula (I).

[0089] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate has formula (II):

[0090]

[0091] Here

[0092] Z is N or CR 6 And;

[0093] Y 2 , Y 3 and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of , O, SO2 and bonds; Y 2 , Y 3 and Y 4 One or fewer of them are combinations;

[0094] W 1 , W 2 and W 3 CR each independently 5 Selected from a group consisting of and N;

[0095] R 1 Silver, 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, C1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a , -C(O)NR a R b , -S(O)(=NH)R a , and -S(O)2NR a R b Selected from a group consisting of;

[0096] Each R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of;

[0097] Each R 4 is independently H, C 1-4 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a Selected from,

[0098] Each R 5 is independently 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 1-4Alkyl, C 3-8 Cycloalkyl, -S(O)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of;

[0099] X 1 is N or CR 8a And;

[0100] X 2 is N or CR 8b And;

[0101] R 8a and R 8b is independently H, halogen, CN, NH2, 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;

[0102] R 9 and R 10 It independently contains H, halogen, CN, NO2, and 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;

[0103] R 11 Silver, 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)2NR c R b , -S(O)(=NH)R c , -S(O)2R c , selected from the group consisting of phenyl, 5- to 6-membered heterocyclic or 5- to 10-membered heteroaryl rings, wherein the heterocyclic and heteroaryl rings have 1-3 heteroatoms selected from N, O, and S as ring vertices; phenyl is optionally fused to a 5- or 6-membered heterocycle having 1-2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl, heterocyclic or heteroaryl ring is halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, 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 1-4Optionally substituted with 1 to 3 members independently selected from alkyls; optionally, two members attached to the same carbon of the heterocyclic ring together form a =CH2 or oxo (=O) group;

[0104] or R 9 and R 10 It combines to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Optionally substituted with one or more substituents independently selected from, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices;

[0105] or R 10 and R 11 It combines to form a 5- or 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Optionally substituted with one or more substituents independently selected from, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices;

[0106] Each R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 is independently H, halogen, CN, OH, C 1-4Alkyl, 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 Selected from the group consisting of; or two Rs on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Moiety combines to form an iodine group;

[0107] Each R a and R b is independently H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, and C 1-8 Selected from the group consisting of hydroxyalkyl,

[0108] R c is, in the case where, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6 Selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O and S as ring vertices.

[0109] In some embodiments, the compound of formula (II) is Y 2 Ga CR 2 R 3 and, where each R 2 and R 3 is H and; Y 3 and Y4 Each CR 2 R 3 and, where each R 2 and R 3 is a compound independently selected from H and F, or a salt, hydrate, or solvate thereof that is permitted under the constraints.

[0110] In some embodiments, the compound of formula (II) is R 11 This SO2R c It is a phosphorus compound or its pharmaceutically acceptable salt, hydrate, or solvate. In some embodiments, R c is C 1-8 alkyl, or C 1-8 It is a haloalkyl.

[0111] In some embodiments, the compound of formula (II) is R 11 This is a compound selected from the group consisting of the following, or its pharmaceutically permissible salt, hydrate, or solvate:

[0112] .

[0113] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (III):

[0114]

[0115] Y 2 , Y 3 and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of , SO2, O and bonds; Y 2 , Y 3 and Y 4 One or fewer of them are combinations;

[0116] W 1 and W 3 Each is independently selected from CH and N;

[0117] Z is N or CR6 And;

[0118] R 1 It is selected from the group consisting of halogens and CN;

[0119] Each R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of,

[0120] Each R 4 is independently H, C 1-3 Alkyl, C 3-6 Cycloalkyl, and -C(O)R a Selected from;

[0121] R 5a is selected from the group consisting of hydrogen, halogen, and CN;

[0122] R 6 is H, and

[0123] X 1 is N or CR 8a And;

[0124] X 2 is N or CR 8b And;

[0125] R 8a and R 8bis independently 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;

[0126] R 9 and R 10 It independently contains H, halogen, CN, NO2, and 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;

[0127] R 11 Silver, 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, -C(O)OH, -S(O)2NR c R b , -S(O)(=NH)R c , -S(O)2R c , phenyl, and is selected from the group consisting of a 5- or 6-membered heterocyclic or 5- to 10-membered heteroaryl ring, wherein the heterocyclic 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 heterocycle having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl, heterocyclic or heteroaryl ring is halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, 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 alkyls; optionally, two members attached to the same carbon of the heterocyclic ring together form a =CH2 or oxo (=O) group;

[0128] or R 9 and R 10 It combines to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Optionally substituted with one or more substituents independently selected from, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices;

[0129] or R 10 and R 11 It combines to form a 5- or 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Optionally substituted with one or more substituents independently selected from, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices;

[0130] Each R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 is independently 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 Selected from the group consisting of; or two Rs on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Moiety combines to form an iodine group;

[0131] Each R a and R b is independently H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C1-3 Haloalkoxy, and C 1-3 Selected from the group consisting of hydroxyalkyls;

[0132] R c is, in the case where, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6 Selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryls, and the heterocycloalkyl or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O and S as ring vertices.

[0133] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (III):

[0134]

[0135] Y 2 , Y 3 and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of , SO2, O and bonds; Y 2 , Y 3 and Y 4 One or fewer of them are combinations;

[0136] W 1 and W 3 Each is independently selected from CH and N;

[0137] Z is N or CR 6 And;

[0138] R 1 It is selected from the group consisting of halogens and CN;

[0139] Each R 2 and R 3Each independently contains H, halogen, CN, NO2, OH, and 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of,

[0140] Each R 4 is independently H, C 1-3 Alkyl, C 3-6 Cycloalkyl, and -C(O)R a Selected from;

[0141] R 5a is selected from the group consisting of hydrogen, halogen, and CN;

[0142] R 6 is H, and

[0143] X 1 is N or CR 8a And;

[0144] X 2 is N or CR 8b And;

[0145] R 8a and R 8b is independently 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, C3-6 Cycloalkyl, -C(O)NR a R b , -S(O)2NR a R b , and -S(O)2R a Selected from a group consisting of;

[0146] R 9 and R 10 It independently contains H, halogen, CN, NO2, and 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;

[0147] R 11 Silver, 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)2NR c R b , -S(O)(=NH)R c , -S(O)2R c, and selected from the group consisting of a 5- or 6-membered heterocyclic or heteroaryl ring having 1-3 heteroatoms selected from N, O, and S as ring vertices; wherein the heterocyclic or heteroaryl ring is a 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 and C 1-3 Alkoxy C 1-4 Optionally substituted with 1 to 3 members independently selected from alkyl;

[0148] or R 9 and R 10 It combines to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 It is arbitrarily substituted with, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices;

[0149] or R 10 and R 11 It combines to form a 5- or 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 It is arbitrarily substituted with, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices;

[0150] Each R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 is independently 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 Selected from the group consisting of; or two Rs on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Moiety combines to form an iodine group;

[0151] Each R a and R b is independently H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, and C 1-3 Selected from the group consisting of hydroxyalkyls;

[0152] R c is, in the case where, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6Selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryls, and the heterocycloalkyl or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O and S as ring vertices.

[0153] In some embodiments, the compound of formula (III) is Y 2 Ga CR 2 R 3 and, where each R 2 and R 3 is H and; Y 3 and Y 4 Each CR 2 R 3 and, where each R 2 and R 3 is a compound independently selected from H and F, or a salt, hydrate, or solvate thereof that is permitted under the constraints.

[0154] In some embodiments, the compound of formula (III) is each R 5a ga is a halogen, and R 4 Ga CR 2 R 3 and R 2 and R 3 This is a compound selected from H, F, and OCH3, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0155] In some embodiments, the compound of formula (III) is R 11 This is a phenyl, 5- or 6-membered heterocyclic, or 5- to 10-membered heteroaryl ring, wherein the heterocyclic 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 heterocycle having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl, heterocyclic, or heteroaryl ring is a halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, C1-6 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 It is a compound or its constrainedly permissible salt, hydrate, or solvate that is optionally substituted with one to three members independently selected from alkyl; and two members attached to the same carbon of the heterocyclic ring together form a =CH2 or oxo (=O) group.

[0156] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (IV-a):

[0157]

[0158] Here

[0159] Y 2 , Y 3 and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of , SO2 and bonds; Y 2 , Y 3 and Y 4 One or fewer of them are combinations;

[0160] R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of;

[0161] Each R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and C 1-6 Alkyl, C1-6 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)2R a and -C(O)NR a R b Selected from a group consisting of;

[0162] Each R 4 is independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a Selected from a group consisting of;

[0163] Each R 5 is independently 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of,

[0164] The remaining group has the meaning provided for formula (I). In some embodiments of the compound of formula (IV-a), the remaining group has the meaning provided for formula (II).

[0165] In some embodiments, the compound of formula (IV-a) is X 1 and X 2 is a compound independently selected from the group consisting of CH and N, or a salt, hydrate, or solvate thereof that is permitted by the constraints.

[0166] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (IV-b):

[0167]

[0168] Here

[0169] The subscript m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0170] The subscript n is 1 or 2 and;

[0171] R z is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Indicate one or more of the following;

[0172] Y 2 , Y 3 and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of , SO2 and bonds; Y 2 , Y 3 and Y 4 One or fewer of them are combinations;

[0173] R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of;

[0174] Each R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of;

[0175] Each R 4 is independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a Selected from;

[0176] R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of;

[0177] Each R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is independently 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 Selected from the group consisting of; or two Rs on the same carbon atom 12 , R 13 , R 14 , R15 , R 16 , R 17 , R 18 and R 19 Moiety combines to form an iodine group, and

[0178] The remaining group has the meaning provided for formula (I). In some embodiments of the compound of formula (IV-b), the remaining group has the meaning provided for formula (II).

[0179] In some embodiments, the compound of formula (IV-b) is Y 4 It is a compound that is a member selected from the group consisting of O and NH, or a salt, hydrate, or solvate thereof that is permitted by the constraints.

[0180] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (IV-c):

[0181]

[0182] Here

[0183] A 1 is O or CHR 13 And;

[0184] Y 2 , Y 3 and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of , SO2 and bonds; Y 2 , Y 3 and Y 4 One or fewer of them are combinations;

[0185] R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R bSelected from a group consisting of;

[0186] R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of;

[0187] R 11 Silver, 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)2NR c R b , -S(O)(=NH)R c , and -S(O)2R c Selected from a group consisting of;

[0188] Each R 13 , R 14 and R 15 is independently 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 Selected from a group consisting of;

[0189] R 16 H, C1-4 Alkyl and C 1-4 Selected from the group consisting of fluoroalkyls, and

[0190] The remaining group has the meaning provided for formula (I). In some embodiments of the compound of formula (IV-c), the remaining group has the meaning provided for formula (II).

[0191] In some selected embodiments, the compound of formula (IV-c) is R 8b It is a compound that is H or a salt, hydrate, or solvate that is permitted under the constraints thereof.

[0192] In some embodiments, the compound of formula (IV-c) is Y 2 Ga CR 2 R 3 and, where each R 2 and R 3 is H and; Y 3 and Y 4 Each CR 2 R 3 and, where each R 2 and R 3 is a compound independently selected from H and F, or a salt, hydrate, or solvate thereof that is permitted under the constraints.

[0193] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (IV-d):

[0194]

[0195] Here

[0196] R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of;

[0197] R 2and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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 Selected from a group consisting of;

[0198] R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of;

[0199] R 11 Silver, 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)2NR c R b , -S(O)(=NH)R c , and -S(O)2R c Selected from a group consisting of;

[0200] Each R 12 , R 13 , R 14 and R 15 is independently H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy and -NRa R b Selected from a group consisting of,

[0201] The remaining group has the meaning provided for formula (I). In some embodiments of the compound of formula (IV-d), the remaining group has the meaning provided for formula (II).

[0202] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (IV-e):

[0203]

[0204] Here

[0205] R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of;

[0206] R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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 Selected from a group consisting of;

[0207] R 5 is 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)2R a , -C(O)NR aR b , and -S(O)2NR a R b Selected from a group consisting of;

[0208] Each R 13 and R 15 is independently H, F, and C 1-4 Selected from the group consisting of alkyls;

[0209] R 20 C 1-6 Alkyl and C 1-6 Selected from the group consisting of fluoroalkyls, and

[0210] The remaining group has the meaning provided for chemical formula (I).

[0211] In some embodiments, the compound of formula (IV-e) is R 20 It is a compound selected from the group consisting of methyl, fluoromethyl, difluoromethyl, and trifluoromethyl, or its pharmaceutically acceptable salt, hydrate, or solvate.

[0212] In some selected embodiments, the compound of formula (II), or its restrictively permissible salt, hydrate, or solvate, is represented by formula (IV-f):

[0213]

[0214] Here, the gi has the meaning provided for formula (II). In some embodiments of the compound of formula (IV-f), R 8b is H.

[0215] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (Va):

[0216]

[0217] Here, the group has the meaning provided for chemical formula (I). In some embodiments of the compound of chemical formula (Va), the group has the meaning provided for chemical formula (II).

[0218] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (Vb):

[0219]

[0220] Here

[0221] Each R 5 is independently 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of;

[0222] The remaining group has the meaning provided for chemical formula (I). In some embodiments of the compound of chemical formula (Vb), the remaining group has the meaning provided for chemical formula (II).

[0223] In some embodiments, the compound of formula (Vb) is R 9 and R 10 These are each independently H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Haloalkoxy, 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)2NR a R b , and -S(O)2R a Selected from a group consisting of; R 11 This 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)2NR c R b , and -S(O)2R c It is a compound selected from the group consisting of, or a salt, hydrate, or solvate that is permitted by the constraints thereof.

[0224] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (Vc):

[0225]

[0226] Here

[0227] Y 2 , Y 3 and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of , SO2 and bonds; Y 2 , Y 3 and Y4 One or fewer of them are combinations;

[0228] R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of;

[0229] R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)2R a , -C(O)NR a R b , and -NR a R b Selected from a group consisting of;

[0230] R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of;

[0231] The remaining group has the meaning provided for formula (I). In some embodiments of the compound of formula (Vc), the remaining group has the meaning provided for formula (II).

[0232] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (Vd):

[0233]

[0234] Here

[0235] Y 2 , Y 3 and Y 4 CR each independently 2 R 3 Selected from a group consisting of and combinations; Y 2 , Y 3 and Y 4 One or fewer of them are combinations;

[0236] R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of;

[0237] R 2 and R 3 Each independently consists of H, halogen, CN, OH, and 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)2R a , -C(O)NR a R b , and -NR a R b Selected from a group consisting of;

[0238] R 5 is H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of;

[0239] The remaining group has the meaning provided for formula (I). In some embodiments of the compound of formula (Vd), the remaining group has the meaning provided for formula (II).

[0240] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (Ve):

[0241]

[0242] Here

[0243] R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of;

[0244] R 2 and R 3 Each independently consists of H, halogen, CN, OH, and 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)2R a , -C(O)NR a R b , and -NR a R b Selected from a group consisting of;

[0245] R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of;

[0246] The remaining group has the meaning provided for formula (I). In some embodiments of the compound of formula (Vd), the remaining group has the meaning provided for formula (II).

[0247] In some embodiments, the compound of formula (Ve) is R 9 and R 10 These combine to form a 5- or 6-membered carbocyclic or heterocyclic ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 It is a compound that is arbitrarily substituted with, or a salt, hydrate, or solvate that is permitted under its constraints.

[0248] In some embodiments, the compound of formula (Ve) is R 9 and R 10 This independently contains H, halogen, CN, NO2, and 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)ORa , -C(O)NR a R b , -S(O)2NR a R b , and -S(O)2R a It is a compound selected from the group consisting of, or a salt, hydrate, or solvate that is permitted by the constraints thereof.

[0249] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (Vf):

[0250]

[0251] Here

[0252] The subscript m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0253] The subscript n is 1 or 2 and;

[0254] R z is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Indicate one or more of the following;

[0255] Y 2 , Y 3 and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of , SO2 and bonds; Y 2 , Y 3 and Y 4 One or fewer of them are combinations;

[0256] R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)2R aand -C(O)NR a R b Selected from a group consisting of;

[0257] Each R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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)2R a and -C(O)NR a R b Selected from a group consisting of;

[0258] Each R 4 is independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a Selected from;

[0259] R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of;

[0260] Each R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 is independently H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b Selected from the group consisting of; or two Rs on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Moiety combines to form an iodine group;

[0261] The remaining group has the meaning provided for formula (I). In some embodiments of the compound of formula (Vf), the remaining group has the meaning provided for formula (II).

[0262] In some selected embodiments, the compound of formula (I) or its restrictively permissible salt, hydrate, or solvate is represented by formula (Vg):

[0263]

[0264] Here

[0265] R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of;

[0266] R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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 1-4Alkyl and -NR a R b Selected from a group consisting of;

[0267] R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of;

[0268] R 11 Silver, 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)2NR c R b , -S(O)(=NH)R c , and -S(O)2R c Selected from a group consisting of;

[0269] Each R 12 , R 13 , R 14 and R 15 is independently H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy and -NR a R b Selected from a group consisting of;

[0270] The remaining group has the meaning provided for chemical formula (I).

[0271] In some embodiments, the compound of formula (Vg) is R 11This is a phenyl, 5- or 6-membered heterocyclic, or 5- to 10-membered heteroaryl ring, wherein the heterocyclic 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 heterocycle having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl, heterocyclic, or heteroaryl ring is a halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, 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 It is a compound or its constrainedly permissible salt, hydrate, or solvate that is optionally substituted with one to three members independently selected from alkyl; and two members attached to the same carbon of the heterocyclic ring together form a =CH2 or oxo (=O) group.

[0272] In some selected embodiments, any one of Table 1, Table 2, or Table 3 is provided.

[0273] Identification of HIF-2α inhibitors having desirable characteristics

[0274] The present invention relates, in part, to the identification of inhibitors of HIF-2α having at least one characteristic or feature having therapeutic relevance. Candidate inhibitors may be identified, for example, using the examples described herein, which are tests or models accepted in the relevant art.

[0275] After verification, candidate inhibitors may be further evaluated by using techniques that provide data regarding the characteristics of the inhibitor (e.g., means for determining pharmacokinetic parameters, solubility, or stability). Comparison of the candidate inhibitor with a reference standard (which may be the "best-of-class" of conventional inhibitors) indicates the potential viability of said candidate.

[0276] Synthesis method

[0277] General method for manufacturing the compound of the claim

[0278] For the most efficient preparation of any specific compound of the present invention, a person skilled in the art will recognize that the timing and order of linking of fragments and modifications of functional groups present in any fragment may be modified in the preparation of any given compound. Various methods have been used to prepare the compounds of the present invention, some of which are exemplified in the examples.

[0279] Prodrugs and other means of drug delivery and / or extension of half-life

[0280] In some aspects of the present invention, the compound described herein is administered in the form of a prodrug.

[0281] To achieve an extension of therapeutic activity, drug molecules may be engineered to utilize a carrier for delivery. Such carriers are used in a non-covalent manner with a drug moiety physicochemically formulated as a solvent-carrier mixture, or by the permanent covalent attachment of a carrier reagent to one of the functional groups of the drug moiety (generally refer to WO 2015 / 0202317).

[0282] Several non-covalent approaches are advantageous. For example, and to a non-limiting extent, depot formulations comprising non-covalent drug encapsulation into a polymer carrier in certain embodiments are used. In such formulations, the drug molecule is combined with the carrier material and processed so that the drug molecule is distributed within the bulk carrier. Examples include microparticle polymer-drug aggregates administered as an injectable suspension (e.g., Degradex® Microspheres (Phosphorex, Inc.)); and polymer-drug molecule aggregates formulated as a gel administered as a single bolus injection (e.g., Lupron Depot® (AbbVie Inc.)). This includes liposomal formulations (e.g., DepoCyt® (Pacira Pharmaceuticals)), wherein the carrier may be a polymeric or non-polymeric material capable of solubilizing the drug. In these formulations, release of the drug molecule may occur when the carrier swells or is physically degraded. In other cases, chemical degradation enables the diffusion of the drug into the biological environment; this chemical degradation process may be autohydrolytic or enzyme-catalyzed. Among other limitations, non-covalent drug encapsulation requires the prevention of uncontrolled drug release, and the dependence of the drug release mechanism on biodegradation may cause inter-patient variability.

[0283] In certain embodiments, drug molecules comprising both small and large molecules are conjugated to a carrier via permanent covalent bonds. Certain small molecule therapeutic agents exhibiting low solubility in aqueous fluids may be solubilized by conjugation to a hydrophilic polymer, examples of which are described elsewhere in this invention. With respect to large molecule proteins, half-life extension may be achieved, for example, by permanent covalent modification using a palmitoyl moiety, and by permanent covalent modification using another protein (e.g., Albuferon®) that itself has an extended half-life. Generally, drug molecules exhibit reduced biological activity when a carrier is covalently conjugated to the drug.

[0284] In certain cases, limitations associated with drug molecules containing non-covalent polymer mixtures or permanent covalent attachment can be successfully resolved by using a prodrug approach for the chemical conjugation of a drug to a polymer carrier. In this regard, a therapeutic agent that is inactive or less active than the drug moiety itself is predictably converted into an active molecular substance. The reduced biological activity of the prodrug compared to the released drug is advantageous when slow or controlled release of the drug is desired. In such cases, drug release occurs over time, thereby reducing the need for repeated and frequent administration of the drug. The prodrug approach may also be advantageous when the drug moiety itself is not absorbed in the gastrointestinal tract or has suboptimal absorption; in such cases, the prodrug facilitates the absorption of the drug moiety, which is then partially cleaved (e.g., via first-pass metabolism). The biologically active drug molecule is typically connected to the polymer carrier moiety by a transient bond formed between the carrier moiety and the hydroxyl, amino, or carboxyl groups of the drug molecule.

[0285] The approach described above is associated with several limitations. Prodrug activation can occur through the enzymatic or non-enzymatic cleavage of a transient binding between a carrier and a drug molecule, or a sequential combination of both (e.g., a non-enzymatic modification following an enzymatic step). In enzyme-free in vitro environments (e.g., aqueous buffered solutions), transient bindings, such as esters or amides, may undergo hydrolysis, but the corresponding hydrolysis rates may be outside the therapeutically useful range. In contrast, in vivo environments, esterases or imidases are typically present, and these can induce significant catalytic acceleration of hydrolysis kinetics by two to several orders of magnitude (e.g., see Greenwald et al., (1999) J Med Chem 42(18):3857-67).

[0286] As described herein, prodrugs can be classified into i) bioprodrugs and ii) carrier-linked prodrugs. Bioprodrugs do not contain a carrier group and are activated by the metabolic generation of functional groups. In contrast, in carrier-linked prodrugs, the active substance is conjugated to a carrier moiety through transient linkage at the functional groups of the bioactive substance. Preferred functional groups are hydroxyl or amino groups. Both attachment chemistry and hydrolysis conditions depend on the type of functional group used. The carrier may be biologically inactive (e.g., PEG) or may have targeting properties (e.g., antibodies). Cleavage of the carrier moiety of a carrier-linked prodrug produces the bioactive substance of interest, and the properties of the deprotected functional groups of the bioactive substance often contribute to its bioactivity.

[0287] Patent and scientific literature describe numerous macromolecular prodrugs in which the transient linkage is an unstable ester bond. In these cases, the functional group of the bioactive substance is a hydroxyl group or a carboxylic acid (e.g., see Cheng et al. (2003) Bioconjugate Chem 14:1007-17). Additionally, for biomacromolecules and certain small molecule drugs, it is often advantageous to link the carrier to the amino group(s) of the bioactive substance (e.g., the N-terminal or lysine amino group of a protein). During the preparation of prodrugs, amino groups can be processed more chemoselectively due to their greater nucleophilicity compared to hydroxyl or phenolic groups. This is particularly relevant to proteins and peptides containing a wide variety of different reactive functional groups, where non-selective conjugation reactions lead to undesirable product mixtures requiring extensive characterization or purification, thereby reducing the reaction yield and therapeutic efficiency of the active moiety.

[0288] Generally, amide bonds are more stable against hydrolysis than ester bonds, and the cleavage rate of amide bonds may be too slow for therapeutic utility in carrier-linked prodrugs. Consequently, it may be advantageous to add structural chemical components to control the cleavage of prodrug amide bonds. These additional cleavage-controlling chemical components, which are not provided by the carrier material or the drug, are generally referred to as "linkers." Prodrug linkers can have a major effect on the hydrolysis rate of transient bonds, and changes in the chemical properties of the linker often induce specific characteristics. For the activation of amine-containing biologically active moiety prodrugs by specific enzymes for targeted release, it is necessary for the structure of the linker to exhibit a structural motif recognized as a substrate by the corresponding endogenous enzyme. In these cases, the cleavage of transient bonds occurs as a one-step process catalyzed by the enzyme. For example, the enzymatic release of cytarabine is carried out by the protease plasmin, which is present in relatively high concentrations in various types of tumor masses.

[0289] Inter-patient variability is a major drawback of dominant enzymatic cleavage. Enzyme levels differ significantly among subjects, which can lead to biological variations in prodrug activation by enzymatic cleavage. Enzyme levels can also vary depending on the administration site (e.g., in the case of subcutaneous injection, certain areas of the body provide more predictable therapeutic effects than others). Furthermore, it is difficult to establish in vivo-in vitro correlations of pharmacokinetic properties for enzyme-dependent carrier-linked prodrugs.

[0290] Other carrier prodrugs that utilize transient linkage to amino groups within the drug moiety are based on a cascade mechanism. Cascade cleavage is enabled by a linker compound composed of a structural combination of a shielding group and an activating group. The shielding group is attached to the activating group by a first transient linkage, e.g., an ester or a carbamate. The activating group is attached to the amino group of the drug molecule through a second transient linkage (e.g., a carbamate). The stability or susceptibility of the second transient linkage to hydrolysis depends on the presence or absence of the shielding group. In the presence of the shielding group, the second transient linkage is highly stable and unlikely to release the drug molecule with therapeutically useful kinetics, whereas in the absence of the shielding group, this linkage becomes highly unstable, leading to rapid cleavage and release of the drug moiety.

[0291] The cleavage of the first transient linkage is the rate-limiting step in the cascade mechanism. The first step can induce molecular rearrangement of the activating group (e.g., 1,6-elimination as described in the literature [Greenwald et al. (1999) J Med Chem 42:3657-67]), and this rearrangement makes the second transient linkage much more unstable, thereby inducing its cleavage. Ideally, the rate of cleavage of the first transient linkage is equal to the desired release rate of the drug molecule in a given therapeutic scenario. Furthermore, it is desirable that the cleavage of the second transient linkage occur substantially immediately after its instability is induced by the cleavage of the first transient linkage.

[0292] Another embodiment includes a polymeric amino-containing prodrug based on trimethyl lock lactonization (see, e.g., [Greenwald et al. (2000) J Med Chem 43(3):457-87]). In this prodrug system, substituted o-hydroxyphenyl-dimethylpropionic acid is linked to PEG by an ester, carbonate, or carbamate group as a first transient linkage and to the amino group of the drug molecule by an amide bond as a second transient linkage. The rate-determining step of drug release is the enzymatic cleavage of the first linkage, followed by the release of aromatic lactone byproducts through rapid amide cleavage by lactonization. A major disadvantage of the prodrug system described by Greenwald et al. is that highly reactive and potentially toxic aromatic small molecule byproducts, such as quinone methide or aromatic lactone, are released after the cleavage of the transient linkage. Potentially toxic substances are released in a 1:1 stoichiometry with the drug, and high in vivo concentrations can be expected.

[0293] In certain embodiments of a cascade prodrug comprising an aromatic activating group based on 1,6-removal, the shielding group is structurally separated from the carrier. This can be accomplished by using a stable bond between the polymer carrier and the activating group, wherein the stable bond does not participate in the cascade cleavage mechanism. When the carrier does not act as a shielding group and the activating group is coupled to the carrier by a stable bond, the release of potentially toxic byproducts (e.g., the activating group) is avoided. The stable attachment of the activating group and the polymer also inhibits the release of drug-linker intermediates having unspecified pharmacology.

[0294] A first example of the approach described in the above paragraph includes a polymeric prodrug system based on a mandelic acid activating group (e.g., see [Shabat et al. (2004) Chem Eur J 10:2626-34]). In this approach, the shielding group is connected to the activating group by a carbamate bond. The activating group is permanently conjugated to the polyacrylamide polymer via an amide bond. After enzymatic activation of the shielding group by a catalytic antibody, the shielding group is cleaved by cyclization, and the drug is released; the activating group remains connected 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 shielding group (e.g., see [Lee et al. (2004) Angew Chem 116:1707-10]).

[0295] When the aforementioned linker is used, the 1,6-elimination step still produces a highly reactive aromatic intermediate. Even if the aromatic moiety remains permanently attached to the polymer carrier, potentially toxic byproducts or side reactions with immunogenic effects may occur. Therefore, it is advantageous to develop linker techniques for forming polymeric prodrugs of amine-containing activators using aliphatic prodrug linkers that are not enzyme-dependent and do not produce reactive aromatic intermediates during cleavage. One such example uses PEG5000-maleic anhydride for the reversible modification of amino groups in tissue-type plasminogen activators and urokinases (see, e.g., *(1987) Garman et al. FEBS Lett 223(2):361-65*). The regeneration of the functional enzyme from the PEG-uPA conjugate by cleavage of the maleic acid linkage during incubation in pH 7.4 buffer follows first-order kinetics with a half-life of approximately 6 hours. A disadvantage of the maleic acid linkage is the lack of stability of the conjugate at lower pH values.

[0296] Further approaches include PEG cascade prodrug systems based on N,N-bis-(2-hydroxyethyl)glycinamide (bisin) linkers (see, e.g., literature [(2004) J Med Chem 47:726-34]). In these systems, two PEG carrier molecules are connected to a bisin molecule coupled to the amino group of the drug molecule via transient binding. The first step of prodrug activation involves the enzymatic cleavage of a first transient link connecting both PEG carrier molecules to the hydroxyl group of the bisin activator. Different linkages between PEG and bisin result in different prodrug activation kinetics. The second step of prodrug activation involves the cleavage of a second transient link connecting the bisin activator to the amino group of the drug molecule. A disadvantage of this system is the slow hydrolysis rate of these second transient visin amide linkages, which leads to the release of visin-modified prodrug intermediates that may exhibit different pharmacokinetic, immunogenic, toxic, and pharmacodynamic properties compared to the natural parent drug molecule.

[0297] In certain embodiments, dipeptides are used in the development of prodrugs for targeting or targeted transport because they are substrates for enzymes or biological transport systems. The ability of non-enzymatic pathways for dipeptide prodrug formation—namely, the ability to form the corresponding diketopiperazine (DKP) and release the active drug via intramolecular cyclization—is not well defined.

[0298] 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 case, the cyclization reaction consists of forming a tetrahedral intermediate by nucleophilic attack of the peptide's N-terminal amine on the ester carbon atom, followed by proton transfer from the amine to the leaving group oxyanion and simultaneous formation of a peptide bond, thereby providing a cyclic DKP product and a free drug. This method is applicable to hydroxyl-containing drugs in vitro, but it was found to compete with enzymatic hydrolysis of ester bonds in vivo because the corresponding dipeptide ester released paracetamol at a much faster rate than in the buffer (Gomes et al. (Molecules 12 (2007) 2484-2506). The sensitivity of dipeptide-based prodrugs to peptidases can be resolved by incorporating at least one non-natural amino acid into the dipeptide motif. However, endogenous enzymes capable of cleaving ester bonds are not limited to peptidases, and the enzyme-dependent nature of this prodrug cleavage still leads to unpredictable in vivo performance.

[0299] In some embodiments, enzyme-dependent processes are intentionally manipulated into DKP prodrugs, for example, wherein the dipeptide ester prodrug is formylated at the amino terminus of the dipeptide, and enzymatic deformylation is used for the formation of diketopiperazine and the initiation of subsequent cleavage of the ester-dipeptide bond, followed by the release of the drug molecule (see, e.g., USP 7,163,923). As an additional example, an octapeptide is attached to the 4-hydroxyl group of vinblastine by an ester linkage and undergoes ester bond cleavage by DKP formation following specific enzymatic removal of the N-terminal hexapeptide (see [Brady et al. (2002) J Med Chem 45:4706-15]).

[0300] The category of DKP-forming reactions has also been extended to amide prodrugs. As an example, USP 5,952,294 describes the activation of a cytarabine dipeptidyl amide prodrug using diketopiperazine formation. In this case, a transient link is formed between the carbonyl of the dipeptide and the aromatic amino group of cytarabine. However, a slow-release effect cannot be achieved for such conjugates because there is no carrier or other half-life-extending moiety or functional group present.

[0301] Dipeptide prodrugs, including bioactive peptides such as GLP-1, capable of releasing peptides through the formation of diketopiperazines via dipeptide extension, are also described (see, e.g., WO 2009 / 099763). A bioactive peptide moiety may include an additional PEG chain on one of its amino acid side chain residues to achieve extended circulation of the bioactive peptide. However, this approach is associated with several significant disadvantages. First, the PEG chain must be attached to the peptide without impairing its bioactivity, which may be difficult to achieve for many peptide-based bioactive agents. Second, since the PEGylated peptide itself is bioactive, the dipeptide promoiety affects the bioactivity of the peptide and may have a negative effect on its receptor binding properties.

[0302] Specific exemplary technologies that can be used with the compounds of the present invention include those developed by ProLynx (San Francisco, California) and Ascendis Pharma (Palo Alto, California). The ProLynx technology platform utilizes a set of novel linkers pre-programmed to cleave at different rates, enabling the controlled, predictable, and sustained release of small molecules and peptides from circulating semi-solid macromolecular conjugates. This technology enables the maintenance of desired steady-state serum levels of the therapeutic agent for weeks to months.

[0303] The Ascendis technology platform enhances the properties of small molecules and peptides by combining the advantages of prodrugs and sustained-release technologies. During circulation, the proprietary prodrug releases an unmodified active parent therapeutic agent at a predetermined rate governed by physiological pH and temperature conditions. Because the therapeutic agent is released in its unmodified form, it retains its original mechanism of action.

[0304] Modifications to enhance inhibitor characteristics

[0305] Improving one or more physical properties of the therapeutic techniques disclosed herein and / or the manner in which they are administered is frequently beneficial and sometimes essential. Improvements to physical properties include, for example, methods to increase bioavailability, serum half-life and / or therapeutic half-life and / or methods to adjust biological activity.

[0306] Modifications known in the relevant art include PEGylation, Fc-fusion, and albumin fusion. While generally associated with macromolecular agents (e.g., polypeptides), these modifications have recently been evaluated for specific small molecules. For example, the literature [Chiang, M. et al. (J. Am. Chem. Soc., 2014, 136(9):3370-73)] describes a small molecule agonist of an adenosine 2a receptor conjugated to an immunoglobulin Fc domain. The small molecule-Fc conjugate possesses potent Fc receptor-adenosine 2a receptor interactions and exhibited superior properties compared to the unconjugated small molecule. Covalent attachment of PEG molecules to small molecule therapeutics has also been described (Li, W. et al., Progress in Polymer Science, 2013 38:421-44).

[0307] Other known modifications include deuteration to improve pharmacokinetics, pharmacodynamics, and toxicity profiles. Due to the larger atomic mass of deuterium, the cleavage of carbon-deuterium bonds requires more energy than carbon-hydrogen bonds. Because these stronger bonds are more difficult to break, the rate of drug metabolism is slower compared to the non-deuterated form, which allows for less frequent administration and can further reduce toxicity. (Charles Schmidt, Nature Biotechnology, 2017, 35(6): 493-494; Harbeson, S. and Tung, R., Medchem News, 2014(2): 8-22).

[0308] Treatment and preventive use

[0309] The present invention takes into account 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. Specific uses are described in detail below, but it should be understood that the present invention is not limited thereto. Furthermore, while general categories of specific diseases, disorders, and conditions are specified below, some diseases, disorders, and conditions may be members of more than one category, and others may not be members of any disclosed category.

[0310] In some embodiments, the HIF-2α inhibitor described herein is administered in an amount effective in reversing, stopping, or slowing the progression of HIF-2α-mediated dysregulation.

[0311] In one embodiment, a patient is selected for treatment as described herein based on the patient's HIF-2α expression level. In some embodiments, a patient is selected for treatment as described herein based on HIF-2α expression in the patient's tumor. In another embodiment, a patient is selected for treatment as described herein based on the presence or absence of a VHL mutation.

[0312] Oncology-related disorders The HIF-2α inhibitors described herein may be used to treat or prevent proliferative conditions or disorders, such as cancer, e.g., uterine cancer, cervical cancer, breast cancer, prostate cancer (e.g., metastatic castration-resistant prostate cancer), testicular cancer, gastrointestinal cancer (e.g., esophageal cancer, oropharyngeal cancer, gastric cancer, small intestine cancer or colorectal cancer, colon cancer or rectal cancer), kidney cancer, renal cell carcinoma, bladder cancer, bone cancer, bone marrow cancer, skin cancer, head and neck cancer, liver cancer, gallbladder cancer, bile duct cancer, heart cancer, lung cancer, pancreatic cancer, salivary gland cancer, adrenal cancer, thyroid cancer, brain cancer (e.g., glioma), ganglion cancer, central nervous system (CNS) and peripheral nervous system (PNS) cancers, and hematopoietic and immune system cancers (e.g., splenic cancer or thymic cancer). The present invention also provides a method for treating or preventing other cancer-related diseases, disorders, or conditions, including, 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, multiple myeloma, sarcoma, teratoma, 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 diseases, disorders, and conditions is intended to broadly refer to conditions directly or indirectly associated with cancer, including, for example, angiogenesis and precancerous conditions, such as dysplasia.

[0313] In certain embodiments, the cancer may be metastatic or at risk of becoming metastatic, or may occur in diffuse tissues including cancer of the blood or bone marrow (e.g., leukemia).

[0314] In some embodiments, the present invention provides a method for treating a proliferative condition, cancer, tumor, or precancerous condition using an HIF-2α inhibitor and at least one additional therapeutic agent or diagnostic agent, examples thereof are presented elsewhere in the present invention.

[0315] In some embodiments, the disease or disorder is VHL-associated, e.g., VHL-associated renal cell carcinoma.

[0316] Iron overload disorder. In one embodiment, the compound described herein may be useful for treating iron overload disorders. Iron overload disorders may be primary or secondary. In one embodiment, the iron overload disorder may be hemochromatosis. In another embodiment, the compound described herein may be useful for treating polycythemia, e.g., polycythemia vera. In yet another embodiment, the compound described herein may be useful for treating Pacak-Zhuang syndrome. In yet another embodiment, the compound described herein may be useful for treating polycythemia.

[0317] Immune- and inflammation-related disordersA non-limiting list of immune- and inflammatory-related diseases, disorders, and conditions that may be treated or prevented by 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 valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), chronic obstructive pulmonary disease (COPD), atherosclerosis, allergic contact dermatitis and other eczema, systemic sclerosis, transplantation, and multiple sclerosis.

[0318] In a specific embodiment of the present disclosure, an HIF-2α inhibitor is used to increase or enhance an immune response to an antigen by providing ajuvant activity. In a specific embodiment, 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. A therapeutic composition is also provided comprising at least one antigen agonist or vaccine component, including but not limited to viruses, bacteria and fungi or parts thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines, in combination with at least one HIF-2α inhibitor of the present invention.

[0319] In some embodiments, the HIF-2α inhibitor described herein may be combined with an immunosuppressant to reduce the number of immune effector cells.

[0320] Other disabilitiesEmbodiments of the present invention consider administering the HIF-2α inhibitor described herein to a subject for the treatment or prevention of any other disorder that may benefit from at least some level of HIF-2α inhibition. Such diseases, disorders, and conditions include, for example, cardiovascular (e.g., cardiac ischemia or pulmonary hypertension) and metabolic (e.g., diabetes, insulin resistance, obesity) disorders.

[0321] Pharmaceutical composition

[0322] The HIF-2α inhibitor of the present invention may be in the form of a composition suitable for administration to a subject. Generally, such a composition is a “pharmaceutical composition” comprising the 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 may be used in the method of the present invention; thus, for example, the pharmaceutical composition may be administered to a subject in vitro or in vivo to carry out the therapeutic and prophylactic methods and uses described herein.

[0323] The pharmaceutical compositions of the present invention may be formulated to suit the intended method and route of administration, and exemplary routes of administration are specified herein. Additionally, the pharmaceutical compositions may be used in combination with other therapeutic active agents or compounds as described herein to treat or prevent diseases, disorders, and conditions considered by the present invention.

[0324] A pharmaceutical composition containing an active ingredient (e.g., an inhibitor of HIF-2α function) may be in a form suitable for oral use, e.g., tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, micro beads, or elixirs. A pharmaceutical composition for oral use may be produced according to any method known in the relevant art for the manufacture of the pharmaceutical composition, and such composition may contain one or more agents, e.g., sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically elegant and taste-good formulation. Tablets, capsules, etc. contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets. These excipients include, e.g., diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrating agents, e.g., corn starch, or alginate; A binder, for example, starch, gelatin, or acacia, and a lubricant, for example, magnesium stearate, stearic acid, or talc.

[0325] Tablets, capsules, etc. suitable for oral administration may be coated or uncoated by known techniques to delay disintegration and absorption in the gastrointestinal tract in order to provide a delayed action. For example, time-delaying materials, such as glyceryl monostearate or glyceryl distearate, may be used. These may 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, polyhydric anhydrides, polyglycolic acids, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfates, or lactide / glycolide copolymers, polylactide / glycolide copolymers, or ethylene vinyl acetate copolymers, to control the delivery of the administered composition. For example, oral agents may be encapsulated within microcapsules prepared by coacervation technology or interfacial polymerization, respectively, by the use of hydroxymethylcellulose or gelatin-microcapsules or poly(methyl methacrolate) microcapsules, or within colloidal drug delivery systems. Colloidal dispersion systems include oil-in-water emulsions, micelles, mixed micelles and macromolecular complexes including liposomes, nanocapsules, microspheres, microbeads, and lipid-based systems. Methods for preparing the aforementioned formulations will be obvious to a person skilled in the art.

[0326] A formulation for oral use may also be provided as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or as a soft gelatin capsule in which the active ingredient is mixed with a water or oil medium, e.g., peanut oil, liquid paraffin, or olive oil.

[0327] An aqueous suspension contains an active substance mixed with an excipient suitable for its preparation. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth gum, and acacia gum; A dispersant or wetting agent may be, for example, a naturally occurring phosphatid (e.g., lecithin), or a condensation product of an alkylene oxide and a fatty acid (e.g., polyoxy-ethylene stearate), or a condensation product of an ethylene oxide and a long-chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), or a condensation product of a partial ester derived from an ethylene oxide, a fatty acid, and hexitol (e.g., polyoxyethylene sorbitol monooleate), or a condensation product of a partial ester derived from an ethylene oxide, a fatty acid, and hexitol anhydride (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives.

[0328] Oily suspensions can be formulated by suspending the active ingredient in vegetable oil, e.g., peanut oil, olive oil, sesame oil, or coconut oil, or mineral oil, e.g., liquid paraffin. Oily suspensions may contain thickeners, e.g., beeswax, hard paraffin, or cetyl alcohol. Sweeteners, e.g. those presented above, and flavoring agents may be added to provide an oral formulation with excellent taste.

[0329] Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide an active ingredient mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified herein.

[0330] The pharmaceutical composition of the present invention may also exist in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example, olive oil or arrakis oil, or a mineral oil, for example, liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, for example, acacia gum or tragacanth gum; naturally occurring phosphatides, for example, esters or partial esters derived from soybeans, lecithin, and fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters and ethylene oxide, for example, polyoxyethylene sorbitan monooleate.

[0331] The pharmaceutical composition typically comprises a therapeutically effective amount of the HIF-2α inhibitor considered by the present invention and one or more pharmaceutically and physiologically acceptable formulation agents. 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, methyl paraben, ethyl or n-propyl, p-hydroxybenzoate), emulsifiers, suspending agents, dispersants, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and / or ajuvants. For example, a suitable vehicle may be a physiological saline solution or citrate-buffered saline, possibly supplemented with other substances conventional in pharmaceutical compositions for parenteral administration. A neutral buffered saline or saline mixed with serum albumin is also an exemplary vehicle. A person skilled in the art will readily recognize various buffers that may be used in the pharmaceutical compositions and dosage forms considered herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, buffer components may 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).

[0332] After formulation, the pharmaceutical composition may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored in a form ready for immediate use, a lyophilized form requiring reconstitution before use, a liquid form requiring dilution before use, or other acceptable forms. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or auto-syringe (e.g., similar to EpiPen®)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.

[0333] The formulation may also include controlled-release formulations, including carriers to protect the composition against rapid degradation or removal from the body, such as liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, time-delaying substances, such as glyceryl monostearate or glyceryl stearate, may be used alone or in combination with wax. Any drug delivery device, including implants (e.g., implantable pumps) and catheter systems, low-speed injection pumps and devices, may be used to deliver HIF-2α inhibitors, all of which are widely known to those skilled in the art.

[0334] Depot injections, generally administered subcutaneously or intramuscularly, may also be used to release the HIF-2α inhibitor disclosed herein over a prescribed period. Depot injections are typically solid- or oil-based and generally contain at least one of the formulation components specified herein.

[0335] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. Such suspensions may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents mentioned herein. The sterile injectable formulation may also be a sterile injectable solution or suspension in a diluent or solvent acceptable for non-toxic parenteral administration, for example, a solution in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, and Cremophor EL. TM (BASF, Parsippany, NJ) or comprises phosphate buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile fixing oils are typically used as solvents or suspension media. For the purposes of this invention, any non-irritating fixing oil may be used, which comprises synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable formulations. Sustained absorption of a particular injectable formulation may be achieved by including an absorption-delaying agent (e.g., aluminum monostearate or gelatin).

[0336] The present invention considers the administration of an HIF-2α inhibitor in the form of a suppository for rectal administration. The suppository may be produced by mixing the drug with a non-irritating excipient suitable for melting in the rectum and releasing the drug, which is solid at normal temperatures but exists as a liquid at rectal temperatures. Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0337] The HIF-2α inhibitor considered by the present invention may be in the form of any other suitable pharmaceutical composition currently known or to be developed in the future (e.g., a spray for nasal or inhalation use).

[0338] Administration route

[0339] The present invention considers the administration of HIF-2α inhibitors and their compositions in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intra-fracture, intra-articular, intraperitoneal, intracerebral (parenchymal), and intraventricular), nasal, vaginal, sublingual, intraocular, rectal, local (e.g., transdermal), buccal, and inhalation. Depot injections, generally administered subcutaneously or intramuscularly, may also be used to release the HIF-2α inhibitors disclosed herein over a prescribed period.

[0340] A specific embodiment of the present invention considers oral administration.

[0341] Combination therapy

[0342] The present invention considers the use of an HIF-2α inhibitor alone or in combination with one or more active therapeutic agents. Additional active therapeutic agents may be small chemical molecules; macromolecules, such as proteins, antibodies, peptibos, peptides, DNA, RNA, or fragments of such macromolecules; or cell or gene therapy. Combination therapy may target different but complementary mechanisms of action and thereby have synergistic therapeutic or prophylactic effects for underlying diseases, disorders, or conditions. Additionally, or alternatively, combination therapy may enable dose reduction of one or more of the agents, thereby improving, reducing, or eliminating adverse effects associated with one or more of the agents.

[0343] The active therapeutic agent in such combination therapy may be formulated as a single composition or as individual compositions. When administered individually, each therapeutic agent in the combination may be provided simultaneously, approximately simultaneously, or at different times. Additionally, the therapeutic agents may be administered "in combination" even if they have different dosage forms (e.g., oral capsules and intravenous), or given at different dosing intervals, or one therapeutic agent may be given as a constant dosage regimen while another is up-titrated, down-titrated, or discontinued, or each therapeutic agent in the combination may be independently up-titrated, down-titrated, increased or decreased in dosage, or discontinued and / or resumed during the patient's course of therapy. When the combination is formulated as individual compositions, in some embodiments, the individual compositions are provided together in a kit.

[0344] In some embodiments, additional therapeutic agents are immunomodulators. Suitable immunomodulators that may be used in the present invention include CD40L, B7, and B7RP1; activating monoclonal antibodies (mAbs) against stimulating receptors, such as anti-CD40, anti-CD38, anti-ICOS, and 4-IBB ligands; dendritic cell antigen loadings (in vitro or in vivo); anticancer 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 lipopolysaccharides (LPS); indoleamine 2,3-deoxygenase 1 (IDO1) inhibitors and immunostimulating oligonucleotides.

[0345] In certain embodiments, the present invention provides a method for suppressing tumor growth, comprising administering the HIF-2α inhibitor described herein in combination with a signaling inhibitor (STI) to achieve additive or synergistic inhibition of tumor growth. As used herein, the term “signaling inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway. The signaling inhibitors (STIs) of the present invention include (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) Akt family kinases or inhibitors of the Akt pathway (e.g., Trop2 inhibitors or rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopyridol); and (vi) phosphatidylinositol kinase inhibitors. Immunomodulatory agents may also be used in combination with the HIF-2α inhibitors described herein to inhibit tumor growth in cancer patients.

[0346] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents are alkylating agents, e.g., thiotepa and cyclophosphamide; alkyl sulfonates, e.g., busulfan, improsulfan and piposulfan; aziridines, e.g., benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylamelamines, e.g., altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethyloloramine; nitrogen mustards, e.g., chlorambucil, chlornafazine, colophamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, novelvikin, phenesterin, prednimustine, trophosphamide, uracil mustard; Nitroureas, for example, carmustine, chlorosotocin, potemustine, lomustine, nimustine, ranimustine; Antibiotics such as aclaxinomycin, actinomycin, autramycin, azacerin, bleomycin, cactinomycin, caliceamycin, carrabicin, kaminomycin, carcinophilin, cromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olibomycin, peplomycin, pomalidomide, portpyromycin, puromycin, quellamycin, rodorubicin, streptonigreen, streptozosin, tubercidin, uvenimex, genostatin, rhodorubicin; Anmetamines, e.g., methotrexate and 5-fluorouracil (5-FU) (with or without leucovorin); folic acid analogs, e.g., denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, e.g., fludarabine, 6-mercaptopurine, thiamiphrine, thioguanine; pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enositabine, floxuridine, 5-FU; androgens, e.g., calosterone, dromostanolone propionate, epithiostanol, mepitiostan, testolactone;Antiadrenal agents e.g., aminoglutethimide, mitothane, trilostan; folic acid supplements e.g., folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestabucil; arsentren; edatlaxate; depopamine; demecolsin; diaziquone; L-formitin; elliptinium acetate; ethoglucid; gallium nitrate; hydroxyurea; lentinan; ronidamine; mithoguazone; mitoxantrone; mophidamol; nitracrine; pentostatin; phenamet; pyrarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; lazoxic acid; sizopyran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethane; vindecin; dacarbazine; mannomustine; mitobronitol; mitolactol; pipovoromin; acitosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel, nab-paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, e.g., cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novelron; tenifoside; daunomycin; aminopterin; Xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine; anthracyclines inhibitors (see PCT / US2019 / 020507) and pharmaceutically acceptable salts, acids, or derivatives of any of the above, but not limited thereto.;

[0347] Chemotherapy agents also include anti-hormonal agents that act to modulate or inhibit hormonal action on a tumor, such as anti-estrogens, such as tamoxifen, raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxyfen, keoxyfen, onapriston, and toremifene; and anti-androgens 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, combination therapy comprises a chemotherapy regimen comprising one or more chemotherapy agents. In certain embodiments, combination therapy comprises the administration of a hormone or a related hormonal agonist.

[0348] Additional therapeutic modes that may be used in combination with HIF-2α inhibitors include radiotherapy, monoclonal antibodies against tumor antigens, complexes of monoclonal antibodies and toxins, T-cell ajuvants, bone marrow transplantation, or antigen-presenting cells (e.g., dendritic cell therapy), such as TLR agonists used to stimulate these antigen-presenting cells.

[0349] In certain embodiments, the present invention considers the use of the compounds described herein in combination with adoptive cell therapy, which is a novel and promising form of personalized immunotherapy in which immune cells having antitumor activity are administered to cancer patients. Adoptive cell therapy is being studied, 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 them to target specific antigens or enhance their antitumor effects, amplifying them to a sufficient number, and injecting the genetically modified T cells into a cancer patient. The T cells may be collected from the patient to whom the expanded cells are subsequently re-injected (e.g., autologous), or from a donor patient (e.g., allogeneic).

[0350] In certain embodiments, the present invention considers the use of the compounds described herein in combination with RNA interference-based therapies for silencing gene expression. RNAi begins with the cleavage of longer double-stranded RNA into small interfering RNA (siRNA). One strand of the siRNA is incorporated into a ribonucleoprotein complex known as an RNA-induced silencing complex (RISC), which is then used to identify mRNA molecules that are at least partially complementary to the incorporated siRNA strand. The RISC can bind to the mRNA or cleave it, both of which inhibit translation.

[0351] In certain embodiments, the present invention considers the use of the compounds described herein in combination with agents that regulate adenosine levels. Such therapeutic agents may act on ectonucleotides that catalyze the conversion from ATP to adenosine, including ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​also known as CD39 or differentiation cluster 39), which hydrolyzes ATP to ADP and ADP to AMP, and 5'-nucleotidase, ecto (NT5E or 5NT, also known as CD73 or differentiation cluster 73), which converts AMP to adenosine. The enzymatic activities of CD39 and CD73 play a strategic role in modulating the duration, magnitude, and chemical nature of purine signals delivered to various cells (e.g., immune cells). Alteration of these enzyme activities can alter the course or influence the outcome of various pathophysiological events, including cancer, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury, suggesting that these exoenzymes represent novel therapeutic targets for managing various disorders. In one embodiment, the CD73 inhibitor is that described in WO2017 / 120508, WO2018 / 067424, WO2018 / 094148, and WO2020 / 046813. In another embodiment, the CD73 inhibitor is AB680.

[0352] Alternatively, these therapeutic agents may be adenosine 2 receptor (A2R) antagonists. Adenosine has four different G-protein coupled receptors: A1R, A 2a R, A 2b It can bind to R, and A3R and be active. A expressed on T cells, natural killer cells, and bone marrow cells, e.g., dendritic cells. 2aThe binding of adenosine to R receptors leads to increased intracellular levels of cyclic AMP and impairs the maturation and / or activation of these cells. This process significantly impairs the activation of the immune system against cancer cells. In addition, A 2A R 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 suppression of regulatory T cells, PD-1, CTLA-4, and other immune checkpoints further discussed herein. Combining A2R antagonists in the combinations described herein may provide at least additive effects in terms of their different mechanisms of action. In one embodiment, the present invention considers 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.

[0353] In certain embodiments, the present invention considers the use of the compounds described herein in combination with inhibitors of phosphatidylinositol 3-kinase (PI3K), particularly the PI3Kγ isoform. PI3Kγ inhibitors can induce a reduction in cancer development and spread by stimulating an anticancer immune response through the modulation of bone marrow cells, for example, by suppressing suppressive bone marrow cells, by weakening immunosuppressive tumor-infiltrating macrophages, or by stimulating macrophages and dendritic cells to produce cytokines that contribute to an effective T-cell response. PI3Kγ inhibitors include those described in PCT / US2020 / 035920.

[0354] In certain embodiments, the present invention considers the use of the compounds described herein in combination with inhibitors of arginases found to be responsible for or involved in inflammation-triggered immune dysfunction, tumor immune evasion, immunosuppression, and immunopathological conditions of infectious diseases. Exemplary arginase compounds can be found, for example, in PCT / US2019 / 020507 and WO / 2020 / 102646.

[0355] immune checkpoint inhibitors The present invention considers the use of the inhibitor of HIF-2α function described herein in combination with an immune checkpoint inhibitor.

[0356] A significant number of genetic and epigenetic modifications characteristic of all cancers provide a diverse set of antigens that the immune system can use to distinguish tumor cells from its normal counterparts. In the case of T cells, the ultimate amplification (e.g., levels of cytokine production or proliferation) and characteristics (e.g., types of the generated immune response, such as patterns of cytokine production) of the response initiated by antigen recognition via the T-cell receptor (TCR) are regulated by a balance between co-stimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are important for the prevention of autoimmunity (i.e., the maintenance of self-tolerance) and also for the protection of tissues from damage when the immune system responds to pathogenic infections. The expression of immune checkpoint proteins can be dysregulated by tumors as an important immune tolerance mechanism.

[0357] T cells have become a major subject of interest in attempts to therapeutically manipulate endogenous anti-tumor immunity due to i) their ability to selectively recognize peptides derived from proteins within all cellular 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 organize various immune responses by CD4+ helper T cells incorporating adaptive and innate effector mechanisms.

[0358] In a clinical setting, blocking immune checkpoints—which induces amplification of antigen-specific T cell responses—has been found to be a promising approach in the treatment of human cancer.

[0359] T cell-mediated immunity involves multiple sequential steps, each of which is regulated by balancing stimulating and inhibitory signals to optimize the response. While almost all inhibitory signals in the immune response ultimately modulate intracellular signaling pathways, many are initiated via membrane receptors, and their ligands are either membrane-bound or soluble (cytokines). Co-stimulating and inhibitory receptors and ligands that regulate T cell activation are frequently 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 agonist antibodies (in the case of the co-stimulating pathway) or antagonist antibodies (in the case of the inhibitory pathway). Therefore, in contrast to most antibodies currently approved for cancer therapy, antibodies that block immune checkpoints do not directly target tumor cells, but rather target lymphocyte receptors or their ligands to enhance endogenous antitumor activity. [See Pardoll, (April 2012) Nature Rev. Cancer 12:252-64].

[0360] Examples of immune checkpoints (ligands and receptors) (some of which are selectively upregulated in various types of tumor cells that are candidates for blockade) include PD-1 (programmed apoptosis 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-activating gene 3); TIGIT (T-cell immune receptor with Ig and ITIM domains); and killer inhibitory receptors, which can be divided into two classes based on their structural characteristics: i) killer cell immunoglobulin-like receptors (KIRs), and ii) Type C lectin receptors (members of the Type II transmembrane receptor family). Other poorly defined immune checkpoints, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., specific B7 family inhibitory ligands such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)), have been described in the literature. [See Pardoll, (April 2012) Nature Rev. Cancer 12:252-64].

[0361] The present invention considers the use of inhibitors of HIF-2α function described herein in combination with the aforementioned immune-checkpoint receptors and ligands, as well as inhibitors of immune-checkpoint receptors and ligands not yet described. Certain modulators of immune checkpoints are currently approved, and many others are under development. When approved for the treatment of melanoma in 2011, 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. A fusion protein containing CTLA4 and an antibody (CTLA4-Ig; abatcept (ORENCIA®; Bristol-Myers Squibb)) is used for the treatment of rheumatoid arthritis, and other fusion proteins have been shown to be effective in kidney transplant patients sensitized to the Epstein-Barr virus. The next class of immune checkpoint inhibitors to receive regulatory approval were for 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, classic 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 including urothelial carcinoma.There are no approved therapies targeting TIGIT or its ligands CD155 and CD112, but those under development include BMS-986207 (Bristol-Myers Squibb), MTIG7192A / RG6058 (Roche / Genentech), dombanalimab (AB154), and OMP-31M32 (OncoMed). In some combinations provided herein, immune checkpoint inhibitors are selected from nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, cemiflimab, and zimberellimab. In another embodiment, the immune checkpoint inhibitor is selected from syntilimab, camrelizumab, tislellizumab, toripalimab, dostarlimab, retipanlimab, sasanlimab, budigalimab, BI-754091, cocibelimab, and spartalizumab.

[0362] In one aspect of the present invention, the claimed HIF-2α inhibitor is combined with an immuno-oncology agent that is an agonist of (i) a stimulating (including co-stimulating) receptor or (ii) an antagonist of an inhibiting (including co-inhibiting) signal to T cells, both of which amplify antigen-specific T cell responses. Specific stimulating and inhibiting molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulating or co-inhibiting 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 co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to members of the cognate TNF receptor family, 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, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT13R, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin a / TNF13, Includes TNFR2, TNFa, LT13R, lymphotoxin a 1132, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0363] In another aspect, immuno-oncology agents are cytokines that inhibit T cell activation (e.g., IL-6, IL-10, TGF-B, VEGF, and other immunosuppressive cytokines) or cytokines that stimulate T cell activation to stimulate an immune response.

[0364] In one aspect, the T cell response is initiated by a combination of one or more of the following: an HIF-2α inhibitor; and (i) antagonists of proteins that inhibit T cell activation, 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 (e.g., immune checkpoint inhibitors); and / or (ii) agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB(CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2. It may be stimulated. Other agents that may be combined with the HIF-2α inhibitor of the present invention for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds of the present invention may be combined with antagonists of KIR, such as lyrilumab. As another example, the compounds described herein may be combined with lenvatinib or cabozantinib.

[0365] Other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists, such as RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or CSF-1R antagonist antibodies including FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0366] In another aspect, the disclosed HIF-2α inhibitor may be used in combination with one or more of the following: an agonist that ligates positive co-stimulatory receptors; a blocker or antagonist that attenuates signal transduction through inhibitory receptors; one or more agonists that systemically increase the frequency of anti-tumor T cells; agonists that overcome distinct immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by in vitro depletion of anti-CD25 beads), or reversing / preventing T cell non-response or exhaustion); and agonists that trigger innate immune activation and / or inflammation at the tumor site.

[0367] In one aspect, an immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, Yervoy® (ipilimumab) or tremelimumab.

[0368] In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, Opdivo® (nivolumab), Keytruda® (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). The immuno-oncology agent may also include pidilizumab (CT-011), but its specificity for PD-1 binding has been questioned. Another approach to targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, designated as AMP-224. In another embodiment, the agent is zimberelimab.

[0369] In another aspect, immuno-oncology agents are PD-L1 antagonists, such as antagonistic PD-L1 antibodies. Suitable PD-L1 antibodies include, for example, TECENTRIQ® (atezolizumab; MPDL3280A; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0370] In another aspect, immuno-oncology agents are LAG-3 antagonists, such as antagonistic LAG-3 antibodies. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0371] In another aspect, immuno-oncology agents are CD137 (4-1BB) agonists, such as agonist CD137 antibodies. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0372] In another aspect, immuno-oncology agents are GITR agonists, such as agonist GITR antibodies. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683).

[0373] In another aspect, immuno-oncology agents are OX40 agonists, such as agonist OX40 antibodies. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0374] In another aspect, immuno-oncology agents are OX40L antagonists, such as antagonistic OX40 antibodies. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0375] In another aspect, the immuno-oncology agent is a CD40 agonist, e.g., an agonist-acting CD40 antibody. In another embodiment, the immuno-oncology agent is a CD40 antagonist, e.g., an antagonist-acting CD40 antibody. Suitable CD40 antibodies include, for example, rucatumumab or dasetuzumab.

[0376] In another aspect, immuno-oncology agents are CD27 agonists, such as agonist CD27 antibodies. Suitable CD27 antibodies include, for example, varlilumab.

[0377] In another aspect, the immuno-oncology agent is MGA271 (for B7H3) (WO11 / 109400).

[0378] The present invention includes any salt, acid, or derivative permitted under the above-mentioned constraints.

[0379] Examples of therapeutic agents useful for combination therapy for the treatment of cardiovascular and / or metabolic-related diseases, disorders, and conditions include statins that inhibit the enzymatic synthesis of cholesterol (e.g., Crestor®, Lescol®, Lipitor®, Mevacor®, Pravacol®, and Zocor®); bile acid resins that sequester cholesterol and prevent its absorption (e.g., Colestid®, Lo-Cholest®, Prevalite®, Questran®, and Welchol®); ezetimibe that blocks cholesterol absorption (Zetia®); and pyrivic acid that can reduce triglycerides and moderately increase HDL (e.g., Tricor®). Niacin that moderately lowers LDL cholesterol and triglycerides (e.g., NIACOR®); and / or combinations of the above (e.g., VYTORIN® (ezetimibe and simvastatin)). Alternative cholesterol treatments that may be candidates for use in combination with the HIF-2α inhibitors described herein include various supplements and herbs (e.g., garlic, policosanol, and guggul).

[0380] The present invention includes any salt, acid, or derivative permitted under the above-mentioned constraints.

[0381] Examples of therapeutic agents useful for combination therapy for immune- and inflammatory-related diseases, disorders, or conditions include, but are not limited to: non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and other propionic acid derivatives (alminoprofen, benoxaprofen, bucloxate, caprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozine, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and thioxaprofen), acetic acid derivatives (indomethacin, acemethacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozate, pentiazac, purirofenac, ibufenac, isoxepak, oxpinac, sulindac, thiopinac, tolmetine, zidomethacin, and Zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxycam (isoxicam, piroxicam, sudoxicam and tenoxycan), salicylates (acetylsalicylic acid, sulfasalazine) and pyrazolone (apazone, bezpiperilon, peprazone, mofebutazone, oxyfenbutazone, phenylbutazone). Other combinations include cyclooxygenase-2 (COX-2) inhibitors.

[0382] Other active agents for the combination include steroids, such as prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone, or hydrocortisone. This combination may be particularly beneficial because it can reduce or even eliminate one or more adverse effects of the steroid by gradually reducing the required dose of the steroid.

[0383] For example, additional examples of active agents that may be used in combination to treat rheumatoid arthritis include cytokine-inhibiting anti-inflammatory drug(s) (CSAIDs); antibodies or antagonists thereof against other human cytokines or growth factors, e.g., 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.

[0384] Specific combinations of activators can interfere with different points in the autoimmune and subsequent inflammatory cascades and include 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 (Renercept), soluble IL-13 receptors (sIL-13), and also TNFα-converting enzyme (TACE) inhibitors; similarly, IL-1 inhibitors (e.g., interleukin-1-converting enzyme inhibitors) may be effective. Other combinations include interleukin 11, anti-P7, and p-selectin glycoprotein ligands (PSGL). Other examples of agents useful in combination with the HIF-2α inhibitors described herein include interferon-131a (AVONEX®); interferon-13lb (BETASERON®); Copaxone; hyperbaric oxygen; intravenous immunoglobulin; clavribin; and antibodies or antagonists thereof against other human cytokines or growth factors (e.g., CD40 ligands and antibodies against CD80).

[0385] administration

[0386] The HIF-2α inhibitor of the present invention may be administered to a subject in an amount that varies depending, for example, the target of administration (e.g., the desired degree of elimination); the age, weight, sex, and health and physical condition of the subject to whom the agent is administered; the route of administration; and the nature of the disease, disorder, condition, or its symptoms. The administration regimen may also take into account the presence, nature, and degree of any adverse effects associated with the administered agent(s). The effective dose and administration regimen may 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.

[0387] Generally, administration parameters ensure that the dose is below the amount at which it may become irreversibly toxic to the subject (Maximum Tolerable Dose (MTD)) and below the amount required to produce a measurable effect on the subject. These amounts are determined by pharmacokinetic and pharmacodynamic parameters, for example, related to ADME, taking into account the route of administration and other factors.

[0388] The effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in a certain proportion of subjects upon ingestion. The "median effective dose" or ED50 of an agent is the dose or amount of an agent that produces a 50% therapeutic response or desired effect when administered to a population. While ED50 is commonly used as a measure of a reasonable expected effect of an agent, it does not need to be a dose that a clinician would consider appropriate after taking all relevant factors into account. Therefore, in some situations, the effective dose is greater than the calculated ED50, in other situations, the effective dose is less than the calculated ED50, and in yet other situations, the effective dose is equal to the calculated ED50.

[0389] In addition, the effective dose of the HIF-2α inhibitor of the present invention may be an amount that produces a desired result compared to a healthy subject when administered to a subject in one or more doses. For example, in the case of a subject suffering from a specific disorder, the effective dose may be a dose that improves the diagnostic parameters, measurements, markers, etc. of such 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 parameters, measurements, markers, etc. exhibited by a normal subject.

[0390] In certain embodiments, the HIF-2α inhibitor considered by the present invention may be administered at least once a day (e.g., orally) at a dose level of about 0.01 mg / kg to about 50 mg / kg or about 1 mg / kg to about 25 mg / kg per day to obtain the desired therapeutic effect.

[0391] In the case of administration of an oral agent, the composition may be provided in the form of tablets, capsules, etc. containing 1.0 to 1000 mg, more particularly 1 to 100 mg, 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 mg of an active ingredient once a day.

[0392] In certain embodiments, the desired dose of HIF-2α inhibitor is contained in “unit dosage forms.” The phrase “unit dosage form” refers to physical discrete units, each unit containing a predetermined amount of HIF-2α inhibitor, either alone or in combination with one or more additional agents, sufficient to produce the desired effect. The parameters of the unit dosage form will be recognized as depending on the specific agent and the effect to be achieved.

[0393] Kit

[0394] The present invention also considers a kit comprising the compounds and pharmaceutical compositions thereof described herein. The kit generally exists in the form of a physical structure accommodating various components as described below and can be used, for example, to carry out the method described above.

[0395] The kit may comprise one or more of the compounds disclosed herein (e.g., provided in sterile containers) that may be in the form of pharmaceutical compositions suitable for administration to a subject. The compounds described herein may be provided in a form ready for immediate use (e.g., tablets or capsules) or in a form requiring reconstitution or dilution prior to administration (e.g., powders). If the compounds described herein are in a form requiring reconstitution or dilution by the user, the kit may also include a diluent (e.g., sterile water), a buffer, pharmaceutically acceptable excipients, etc., packaged together with or separately from the compounds described herein. When considering combination therapy, the kit may contain several agents individually or they may already be combined within the kit. Each component of the kit may be enclosed in an individual container, and all various containers may be contained within a single package. The kit of the present invention may be designed for conditions necessary to properly maintain the components contained therein (e.g., refrigeration or freezing).

[0396] The kit may contain a label or packaging insert containing identification information for the components within it and instructions for their use (e.g., administration parameters, mechanism of action, clinical pharmacology of the active ingredient(s), including pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or packaging insert may include manufacturer information, such as a lot number and expiration date. The label or packaging insert may be incorporated, for example, into a physical structure containing the components, contained individually within a physical structure, or attached to the components of the kit (e.g., an ampoule, tube, or vial).

[0397] The label or insert may comprise or be incorporated therein a computer-readable medium, such as a disk (e.g., hard disk, card, memory disk), an optical disk, such as a CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape, or an electrical storage medium, such as RAM and ROM or a hybrid thereof, such as a magnetic / optical storage medium, a flash medium, or a memory-type card. In some embodiments, the actual instructions are not present in the kit, but means are provided for obtaining the instructions from a remote source, for example, via the Internet.

[0398] experiment

[0399] The following examples are provided to provide a complete disclosure and description of the methods for manufacturing and using the present invention to those skilled in the art, and are not intended to limit the scope of what the inventors consider to be the present invention, nor are they intended to indicate that the following experiments have been performed or that they represent all experiments that may be performed. The exemplary descriptions described in the present tense are not necessarily performed, but rather should be understood as being performed to generate data of the properties described herein. While efforts have been made to ensure accuracy regarding the numerical values ​​used (e.g., quantities, temperatures, etc.), some experimental error and deviation should be taken into account.

[0400] Unless otherwise indicated, parts are parts by weight, molecular weight is weight-average molecular weight, temperature is in degrees Celsius (°C), and pressure is atmospheric or near atmospheric pressure. Standard abbreviations including the following are used: wt = wild type; bp = base pair(s); kb = kilobase(s); nt = nucleotide(s); aa = amino acid(s); s or sec = second; min = minute; h or hr = hour; 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 = millimolear; M = mole; kDa = kilodalton; im = intramuscular; ip = intraperitoneal; SC or SQ = subcutaneous; QD = once daily; BID = twice daily; QW = weekly; QM = Monthly; HPLC = High Performance Liquid Chromatography; BW = Body Weight; U = Units; ns = Not Statistical; PBS = Phosphate-Buffered Saline; IHC = Immunohistochemistry; DMEM = Dulbecco's Modification of Eagle's Medium; EDTA = Ethylenediaminetetraacetic Acid.

[0401] Materials and Methods

[0402] The following general materials and methods have been used where specified or may be used in the following examples.

[0403] Standard methods in molecular biology are described in the scientific literature (see, for example, the literature [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 in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4)]).

[0404] The scientific literature describes protein purification methods, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization, as well as chemical analysis, chemical modification, post-translational modification, production of fusion proteins, and glycosylation of proteins (see, for example, the literature [Coligan, et al. (2000) Current Protocols in Protein Science, Vols. 1-2, John Wiley and Sons, Inc., NY]).

[0405] If the literature contains testing or experimental procedures, such testing or procedures may serve as an alternative basis for evaluating the compounds described herein.

[0406] All reactions were performed at specified temperatures using a Teflon-coated magnetic stirring bar and under an inert atmosphere where mentioned. Reactions were monitored by TLC (silica gel 60 with fluorescence F254, visualized with short / long wavelength UV lamps) and / or LCMS (UV detection at 254 nm using a binary solvent system [0.1% TFA in MeCN / 0.1% TFA in H2O] using either an Agilent 1100 Series LCMS, column below: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm id x 100 mm]). Flash chromatography was performed on silica gel using an automated system (CombiFlash RF+ manufactured by Teledyne ISCO) at detection wavelengths of 254 and 280 nm. Reverse-phase purification HPLC was performed on an Agilent 1260 Infinity Series HPLC. Samples were eluted using gradient elution on a Gemini C18 110 Å column (21.2 mm id x 250 mm) with a binary solvent system (0.1% TFA in MeCN / 0.1% TFA in H2O) and detected at 254 nm. The final compounds obtained from the purification HPLC were concentrated. Reported yields are isolated yields unless otherwise noted. All tested compounds were purified to a purity of ≥ 95% when determined by LCMS (Agilent 1100 Series LCMS, column below: Agilent Eclipse Plus C18 column [3.5 μm, 4.6 mm id x 100 mm] using a binary solvent system [0.1% TFA in MeCN / 0.1% TFA in H2O] with UV detection at 254 nm). 1H NMR spectra were recorded on a Varian 400 MHz NMR spectrometer equipped with an Oxford AS400 magnet. Chemical shift (δ) is reported as parts per million (ppm) relative to the residual specific dehydrogenated solvent as an internal reference.

[0407] Examples

[0408] Example 1: 2-chloro-3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalene-1-yl)-6-methanesulfonylbenzonitrile

[0409]

[0410] Step a: 6,8-difluoro-1,2,3,4-tetrahydronaphthalene-1-one (500 mg, 2.74 mmol) was dissolved in CH2Cl2 (11 ml, 0.25 M), and the resulting solution was aerated with nitrogen gas for 5 minutes. Triethylamine (574 μL, 1.5 equivalents) was added, and after cooling the solution to 0°C, Tf2O (691 μL, 1.5 equivalents) was added. The reaction mixture was heated to room temperature and stirred overnight. The solution was quenched with water, extracted with CH2Cl2, dried over Na2SO4, and concentrated over Celite. The crude material was flashed on silica gel (gradient, 0% to 20% ethyl acetate in hexane) to obtain the target 5,7-difluoro-4-(trifluoromethylsulfonyloxy)-1,2-dihydronaphthalene (470 mg, 54% yield) as oil.

[0411] Step b: Alkenyl trilate (2.50 g, 7.96 mmol, 1.0 equivalent), PdCl2 (dppf) (872 mg, 1.19 mmol, 15 mol%), B2pin2 (2.82 g, 11.1 mmol, 1.4 equivalent), KOAc (1.72 g, 17.5 mmol, 2.2 equivalent), and 1,4-dioxane (20 ml) from Step a were filled into a vial. The vial was stopped, and the reaction mixture was purged with N2 for 2 minutes. The reaction mixture was heated to 80°C and stirred for 30 minutes. The reaction mixture was cooled, filtered, and concentrated on Celite. Alkenyl pinacol boronate ester was obtained as brown oil (1.16 g, 3.97 mmol, 50%) by purification with flash chromatography (SiO2, hexane → 10% EtOAc).

[0412] Step c: To a vial containing the product from Step b (100 mg, 0.342 mmol, 1.0 equivalent), 3-bromo-2-chloro-6-(methylsulfonyl)benzonitrile (100 mg, 0.342 mmol, 1.0 equivalent), PdCl2(dppf) (25 mg, 0.034 mmol, 10 mol%), 1,4-dioxane (1 mL), and 1 M aqueous Na2CO3 solution (0.7 mL) were added. The vial was plugged and purged with N2 for 2 minutes. The reaction mixture was heated at 80°C and stirred for 1.5 hours. Upon completion, the reaction mixture was cooled, diluted with saturated aqueous NH4Cl solution (20 mL), and extracted with DCM (20 mL). The aqueous layer was separated and back-extracted with additional DCM (2 x 20 mL). The organic layers were combined, washed with brine (40 mL), and dried over MgSO4. The mixture was concentrated under reduced pressure and purified by flash chromatography (SiO2, hexane → 50% EtOAc gradient) to obtain a cross-coupled product as a white solid, which was used in subsequent steps (58.6 mg, 0.154 mmol, 45%, ESI MS [M+H] +- C 18 H 12 ClF2NO2S, calculated value 380.0, measured value 380.1).

[0413] Step d: Pd / C (10% Pd, 25 mg) was added to a vial containing the product from Step c (58.6 mg, 0.154 mmol, 1.0 equivalent). The vial was evacuated and refilled with N2 (x3). MeOH (1 mL) and EtOAc (1 mL) were added, and the reaction mixture was purged with H2 for 2 minutes, followed by stirring at room temperature under 1 atm H2 for 16 hours. The reaction vessel was flushed with N2, and the mixture was filtered through Celite while rinsing with EtOAc. The product was concentrated under reduced pressure and purified by reverse-phase HPLC (20 to 100% gradient of acetonitrile and water (containing 0.1% TFA) to obtain the product as a white solid. 1 H 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), 2.99 - 2.88 (m, 1H), 2.88 - 2.75 (m, 1H), 2.19 - 2.08 (m, 1H), 1.87 - 1.75 (m, 1H), 1.75 - 1.63 (m, 1H), 1.62 - 1.47 (m, 1H). ESI MS [M+H] + - C 18 H 14 ClF2NO2S, calculated value 382.0, measured value 382.1.

[0414] Examples 2a / b: (1S,2R)-4-[R-6,8-difluoro-1,2,3,4-tetrahydronaft-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol

[0415]

[0416] Step a: Bromine (3.58 ml, 70 mmol, 1.05 equivalents) was added dropwise to a suspension of 7-fluoro-2,3-dihydro-1H-indene-1-one (10.0 g, 66.6 mmol) and aluminum trichloride (22.2 g, 166.5 mmol, 2.5 equivalents) in 1,2-dichloroethane (190 ml, 0.35 M). The resulting solution was heated to 60°C for 3 hours, after which the reaction mixture was cooled to room temperature and poured over ice. The reaction mixture 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 CH2Cl2:hexane) to obtain 4-bromo-7-fluoro-2,3-dihydro-1H-indene-1-one.

[0417] Step b: Benzyl mercaptan (9.24 g, 8.71 ml, 1.0 equivalent) was added to a suspension of 4-bromo-7-fluoro-2,3-dihydro-1H-indene-1-one (17.0 g, 74.3 mmol) and Cs2CO3 (26.6 g, 81.7 mmol, 1.1 equivalent) in DMF (372 ml, 0.2 M). The reaction mixture was stirred at room temperature for 90 minutes. The target product was precipitated from the solution by adding 1.5 L of water and dried overnight under high vacuum. The resulting crude product (23.1 g, 93% yield) was used without further purification.

[0418] Step c: The crude thioether (23.1 g, 69.2 mmol) from Step b was suspended in toluene (692 ml, 0.1 M). Aluminum trichloride (10.2 g, 1.1 equivalents) was added at room temperature. An additional amount of aluminum trichloride (3.6 g, 27 mmol, 0.4 equivalents) was added after 3 hours. After an additional 3 hours, the reaction mixture 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 1:3 solution of CH2Cl2 in hexane) to obtain the target thiophenol as a yellow solid (13.4 g, 80% yield).

[0419] Step d: A solution of the thiophenol product (6.7 g, 27.6 mmol) from Step c and methyl viologen dichloride hydrate (710 mg, 0.1 equivalent) in DMF (55 ml, 0.5 M) was carefully degassed under nitrogen through three freeze-pump-thaw cycles. The resulting solution was cooled to -10 to -5°C in a brine ice bath and aerated through the reaction mixture with excess CF3I. The reaction mixture was then stirred overnight under an atmosphere of CF3I. The reaction mixture was carefully quenched with water at room temperature (use with caution as residual CF3I may be released), extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexane) to obtain the target thioether (5.21 g, 61% yield).

[0420] Step e: Ruthenium trichloride (697 mg, 3.36 mmol, 0.1 equivalent) was added to a solution of the product from Step d (10.45 g, 33.6 mmol) in MeCN (129 ml, 0.26 M relative to the starting material), CCl4 (129 ml, 0.26 M relative to the starting material), and H2O (258 ml, 0.13 M relative to the starting material), followed by sodium periodate (29.6 g, 138.4 mmol, 4.12 equivalents). The reaction mixture was stirred at room temperature for 1 hour and extracted with CH2Cl2 (x2) upon completion. The combined organic part was washed with saturated Na2S2O3, 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 1:3 solution of CH2Cl2 in hexane) to obtain the product sulfone as a white solid (10.53 g, 91% yield). ESI MS [M+H] + - C 10 H6BrF3O3S; calculated value 342.9, measured value 342.9.

[0421] Step f: A solution of the product sulfone (3.5 g, 10.2 mmol) and Selectfluor (4.32 g, 12.2 mmol, 1.2 equivalents) from Step e in methanol (102 ml, 0.1 M) was heated to 50°C. Sulfuric acid (27 μl, 5 mol%) was added, and the reaction mixture was stirred at 50°C for 48 hours. The solution was then diluted with diethyl ether, and the resulting white precipitate was filtered 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 1:3 solution of CH2Cl2 in hexane) to obtain the product dimethyl acetal as a white solid (3.57 g, 87% yield).

[0422] Step g: A solution of the product acetal (3.18 g, 7.8 mmol) from step f and wet Amberlist 15 (4.77 g, 150 wt%) in dioxane (31 ml, 0.2 M) was heated overnight at 90°C. After 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 1:3 solution of CH2Cl2 in hexane) to obtain the target fluorinated ketone (2.33 g, 83% yield).

[0423] Step h: A solution of the indanone product (2.5 g, 6.93 mmol) from step g in dichloromethane (28 ml, 0.25 M) was aerated with nitrogen gas, and then formic acid (783 μL, 956 mg, 20.8 mmol, 3 equivalents) and triethylamine (1.94 ml, 1.41 g, 13.9 mmol, 2 equivalents) were added under nitrogen at 0°C. RuCl(p-cymene)[(R,R)-Ts-DPEN] (44.5 mg, 0.07 mmol, 0.01 equivalents) was added, and the reaction mixture was stirred at 0 to 5°C for at least 12 hours. Upon complete conversion, the reaction mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2. The combined organic component was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in a 1:1 solution of CH2Cl2:hexane) to obtain the target indanol (2.0 g, 80% yield) as a single diastereomer. The enantiomer excess rate of this material was found to be 98% by chiral HPLC (ChiralPack AD-H, 20% iPrOH / hexane, isosolvent, 20 min) compared to a racemic sample obtained by the reduction of 2-fluoroindanone using sodium borohydride.

[0424] Step i: 2,6-lutidine (800 μL, 6.9 mmol, 2.5 equivalents) and TBSOTf (791 μL, 3.44 mmol, 1.25 equivalents) were added at 0°C to a solution of chiral indanol (1.01 g, 2.75 mmol) from Step h in CH2Cl2 (11 ml, 0.25 M). The reaction mixture was heated to room temperature and stirred overnight. After completion, the reaction mixture was concentrated directly over Celite and purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in hexane) to obtain TBS ether (1.35 g, 100% yield).

[0425] Step j: The TBS ether product of Step i (674 mg, 1.41 mmol) was combined with B2Pin2 (457 mg, 1.8 mmol, 1.3 equivalents), Pd(dppf)Cl2 (103 mg, 0.14 mmol, 0.1 equivalents), and potassium acetate (213 mg, 3 mmol, 2.2 equivalents) in dioxane (14 ml, 0.1 M), and the resulting solution was heated at 100°C for 3 hours. The reaction solution was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexane) to obtain the target boronic acid pinacol ester (638 mg, 86% yield) as a colorless oil.

[0426] Step k: The boronic acid ester product of 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 equivalents), Pd(dppf)Cl2 (227 mg, 0.31 mmol, 0.1 equivalents), and sodium carbonate (2 M, aqueous, 3.13 ml, 2.0 equivalents) in dioxane (31 ml, 0.1 M) and heated at 75°C for 3 hours. After completion, the reaction mixture was concentrated over Celite and purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexane) to obtain the target alkene product (1.42 g, 86% yield) as a colorless resin.

[0427] Step 1: TBAF (0.1 M in THF, 0.3 mmol, 1.5 equivalents) was added at 0°C to a cooled solution of the product of Step k (113 mg, 0.2 mmol), and the reaction mixture was heated to ambient temperature. After 2 hours, the reaction mixture was concentrated on Celite and purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexane) to obtain free indanol (1S,2R)-4-(6,8-difluoro-3,4-dihydronaft-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). ESI MS [M+Na] + - C20 H 14 F6O3S; Calculated value 471.0, Measured value 471.0.

[0428] Step m: The product indanol from Step l was dissolved in methanol (700 μL, 0.1 M) and added to carbon-phase palladium (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 shaker. The resulting diastereomers were separated by column chromatography (silica gel, 100% toluene) to obtain (1S,2R)-4-[R-6,8-difluoro-1,2,3,4-tetrahydronaft-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol (Example 2a) as a less polar diastereomer. 1 H 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). ESI MS [M+Na] + - C 20 H 16 F6O3S; calculated value 473.1, measured value 473.1. (1S,2R)-4-[S-6,8-difluoro-1,2,3,4-tetrahydronaft-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol (Example 2b) was isolated as a more polar diastereomer. 1H 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). ESI MS [M+Na] + - C 20 H 16 F6O3S; Calculated value 473.1, Measured value 473.1.

[0429] Example 3: (1S,2R)-4-[(1S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-1-yl]-2-fluoro-7-methanesulfonyl-2,3-dihydro-1H-indene-1-ol

[0430]

[0431] The title compound was synthesized in a manner similar 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). ESI MS [M-H2O+H]+ - C 20 H 19 F3O3S calculated value 379.1, measured value 379.1.

[0432] Example 4: (1S,2R)-4-[(1R)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-1-yl]-2-fluoro-7-methanesulfonyl-2,3-dihydro-1H-indene-1-ol

[0433]

[0434] The title compound was synthesized in a manner similar 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). ESI MS [M-H2O+H] + - C 20 H 19 F3O3S calculated value 379.1, measured value 379.1.

[0435] Example 5: (8R)-3-fluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-indene-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0436]

[0437] Step a: A solution of 6,8-difluoro-1,2,3,4-tetrahydronaphthalene-1-one (7 g, 38.4 mmol) and TMSONa (14.8 g, 115.3 mmol) in dioxane (128 mL) was refluxed under a nitrogen atmosphere for 20 minutes. Upon extinction of the starting material (TLC analysis, 30% EtOAc in hexane as eluent, target product spot is minimal 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 extract was washed with brine (200 mL). The organic phase was separated and dried on Na2SO4. After removing all solvent under reduced pressure, the crude product was purified by flash chromatography (SiO2, hexane / EtOAc gradient) to obtain 8-hydroxy-6-fluoro-1,2,3,4-tetrahydronaphthalene-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).

[0438] Step b: A mixture of 8-hydroxy-6-fluoro-1,2,3,4-tetrahydronaphthalene-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 acid anhydride (6.4 mL, 38.2 mmol) was added dropwise over 10 minutes. After stirring the mixture for an additional 30 minutes, the complete disappearance of the starting material was observed by TLC analysis (30% EtOAc in hexane as the eluent). The reaction mixture was then diluted with dichloromethane (50 mL) and washed sequentially with a saturated aqueous solution of NaHCO3 (150 mL), aqueous 1M HCl (100 mL), and brine (150 mL). The organic phase was separated and dried on Na2SO4. After removing all solvent under reduced pressure, the crude product was purified by flash chromatography (SiO2, hexane / EtOAc gradient) to obtain trifluoromethanesulfonic acid 8-oxo-6-fluoro-5,6,7,8-tetrahydro-naphthalene-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).

[0439] Step c: A mixture of trifluoromethanesulfonic acid 8-oxo-6-fluoro-5,6,7,8-tetrahydro-naphthalene-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 hours under a nitrogen atmosphere. Once the complete disappearance of the starting material was observed by TLC analysis (30% EtOAc in hexane as the 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 Celite plug. The organic phase was separated, and the aqueous solution was further extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with water (2 x 150 mL) and brine (100 mL), dried on Na2SO4, and concentrated and dried. The dried residue was fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to obtain 8-cyano-6-fluoro-1,2,3,4-tetrahydronaphthalene-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).

[0440] Step d: A solution of N-phenyl-bis(trifluoromethanesulfonimide) (11.3 g, 31.6 mmol) and 8-cyano-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (4.0 g, 21.1 mmol) in THF (105 mL) was cooled to -78°C under a nitrogen atmosphere. Subsequently, a 1 M solution of LiHMDS (21.1 mmol, 21.1 mL) in THF was added dropwise over 5 minutes. The resulting brownish solution was stirred at -78°C for an additional 5 minutes and transferred to an ice bath. After 30 minutes at 0°C, TLC analysis indicated the complete consumption of the starting material. The reaction mixture was quenched by the addition of an aqueous solution of NH4Cl (10 mL), and 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 x 80 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4, and concentrated and dried. The dried residue was fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to obtain 8-cyano-6-fluoro-3,4-dihydronaphthalene-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).

[0441] Step e: A solution of 2-[(1S,2R)-2-fluoro-1-(tert-butyldimethylsilyloxy)-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-dihydronaphthalene-1-yl trifluoromethanesulfonate (0.27 g, 0.84 mmol) in dioxane (4.2 mL) was placed in a 30 mL vial. Subsequently, Pd(dppf)Cl2 (62 mg, 0.084 mmol) and aqueous sodium carbonate (2 M solution, 0.84 mL, 1.68 mmol) were added sequentially. The mixture was degassed under vacuum, refilled with nitrogen, and heated at 90°C for 1 hour. After completion, the reaction mixture was concentrated on Celite and fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to obtain the target alkene product (0.401 g, 0.7 mmol, 84% yield) as a white foam. 1 ¹H NMR (400 MHz, CDCl₃, mixture of rotationally hindered isomers) 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).

[0442] Step f: The product of Step e (0.25 g, 0.44 mmol) was dissolved in anhydrous methanol (15 mL) and added to carbonaceous palladium (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 Par shaker for 4 hours. Excess hydrogen was evacuated, the mixture was degassed under vacuum, and refilled with nitrogen to remove residual hydrogen gas. The resulting suspension was filtered through a Celite pad, and the filtrate was concentrated and dried under reduced pressure to obtain a crude mixture of epimers (1:2 dr). The crude mixture from Step f was subjected to column chromatography (SiO2, hexane / EtOAc gradient) to obtain both epimers of the target 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). 19F 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): 1 H 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).

[0443] Step h: A solution of the product from step f (8R-epimer, 70 mg, 0.122 mmol) in CH3CN (2 mL) was placed in a 3 mL vial equipped with a magnetic stirrer, and then HF·Py complex (hydrofluoric acid ~70%, pyridine ~30%, 0.2 mL) was added. The resulting colorless solution was stirred overnight at ambient temperature. After TLC analysis indicated complete consumption of the starting material, the reaction mixture was diluted with EtOAc (20 mL) and 1 M aqueous HCl solution (20 mL). The product was extracted with EtOAc (2 x 10 mL), the combined organic extracts were washed with aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated dried. The residue was fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to obtain (8R)-3-fluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-indene-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). 19F NMR (376 MHz, CDCl3) δ -77.60, -112.71, -200.62 (dddd, J = 51.2, 16.8, 10.9, 5.5 Hz). ESI MS [M+Na] + - C 21 H 16 F5NO3S; Calculated value 480.1, Measured value 480.1

[0444] Example 6: (S)-3-fluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-indene-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0445]

[0446] This compound was prepared according to the protocol described in Example 5 from the corresponding TBS-protected 1-indanol S-epimer (150 mg, 0.262 mmol) and 0.4 mL of HF·Py complex. 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). 19F NMR (376 MHz, CDCl3) δ -77.73, -112.69, -200.05 (dddd, J = 51.2, 18.3, 12.2, 6.2 Hz). ESI MS [M+Na] + - C 21 H 16 F5NO3S; Calculated value 480.1, Measured value 480.1

[0447] Example 7: (8S)-3-fluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0448]

[0449] The title compound was synthesized in a manner similar 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, 5.8 Hz, 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. ESI MS [M+Na] + - C 21 H 19 F2NO3S; Calculated value 426.1, Measured value 426.1

[0450] 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-indene-1-ol

[0451]

[0452] Step a: 2,6-di-tert-butylmethylpyridine (1.17 g, 5.69 mmol, 2.1 equivalents) was added dropwise to a solution (12 mL, 0.2 M) of 5,7-difluorochroman-4-one (500 mg, 2.71 mmol) in CH2Cl2 at 0°C, followed by trifluoromethanesulfonic acid anhydride (860 μL, 5.14 mmol, 1.9 equivalents). The reaction mixture was stirred at 0°C for 1 hour, then heated to room temperature for an additional 1 hour. At this time, hexane (5 mL) was added to precipitate the pyridinium salt, and the reaction mixture was filtered over a Celite pad. The solvent was removed under vacuum, and the crude residue was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexane) to obtain the target vinyl trilate (754 mg, 88%) as a yellow oil. ESI MS [M+H] + - C 10 H5F5O4S calculated value 316.9, measured value 317.2.

[0453] Step b: The title compound was synthesized in a manner similar to Example 1. 1H 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). ESI MS [M+Na] + - C 19 H 14 F6O4SNa calculated value 475.0, measured value 475.0.

[0454] Example 9: 1-[2,2-difluoro-7-(methylsulfonyl)-4-indanyl]-6-fluoro-1,2,3,4-tetrahydronaphthalene

[0455]

[0456] The title compound was synthesized in a manner similar 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). ESI MS [M+H] + - C 20 H 19 F3O3 S , calculated value 380.4, measured value 380.1.

[0457] Example 10: 1-(2-chloro-3-cyano-4-trifluoromethanesulfonylphenyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0458]

[0459] Step a: A suspension of 3-bromo-2-chloro-6-fluorobenzaldehyde (25 g, 105.3 mmol), NH2OH x HCl (8.8 g, 126.4 mmol, 1.2 equivalents), and NaOAc (10.4 g, 126.4 mmol, 1.2 equivalents) in anhydrous EtOH (100 mL) was stirred overnight under reflux. The reaction mixture was cooled to room temperature, evaporated, and the residue was diluted with H2O (300 mL). The white solid was filtered, washed with H2O, and dried under vacuum (24.3 g, 91%). The crude product was used in subsequent steps without further purification. ESI MS [M+H] + - C7H4BrClFNO, calculated value 251.9, measured value 251.9.

[0460] Step b: The oxime from Step a was diluted with acetic anhydride (150 mL), stirred overnight at 120°C, cooled, and concentrated under vacuum to obtain a brown solid (22.5 g, 99%). The crude product was used in subsequent steps without further purification.

[0461] 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 Na2S (6.6 g, 85.3 mmol) was added all at once. The reaction mixture was stirred at 0°C for 2 hours, then quenched with H2O (500 mL) and extracted with CH2Cl2 (3 x 200 mL). The organic portion was discarded, the aqueous layer was neutralized to pH ~2 using a 10% KHSO4 solution, and extracted again with CH2Cl2 (3 x 150 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum to obtain a yellow solid, which was used in subsequent steps without further purification (19.1 g, 90%). ESI MS [MH] for C7H3BrClNS - , calculated value 245.9, measured value 245.9.

[0462] 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, trifluoroiodomethane x TMG reagent (33.6 mL, 162.2 mmol, 1.2 equivalents) was added, followed by the addition of TEA (18.8 mL, 135.2 mmol). The reaction mixture was stirred at 0°C for 15 minutes, then heated to room temperature and stirred overnight. It was quenched with H2O (1500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic part was washed with brine (2 x 100 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hex in hexane → 30% EtOAc) to obtain the product as a yellow solid (19.3 g, 45%).

[0463] Step e: The product from Step d (18.5 g, 58.4 mmol) was dissolved in CH2Cl2:CH3CN:H2O (1:1:2; 300 mL), NaIO4 (50 g, 233.6 mmol, 4 equivalents) was added, followed by the addition of RuCl3x H2O (394 mg, 1.75 mmol, 3% mol). The reaction mixture was stirred at room temperature for 1.5 hours, then diluted with H2O (1000 mL) and a 10% Na2S2O3 solution (100 mL), and extracted with EtOAc (3 x 300 mL). The combined organic part was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hex in hexane → 40% EtOAc) to obtain 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).

[0464] Step f: A mixture of 8-bromo-6-fluoroquinoline (15.7 g, 69.5 mmol), Zn(CN)2 (4.9 g, 41.7 mmol, 0.8 equivalents), and Pd(PPh3)4 (8 g, 6.9 mmol, 10% mol) in anhydrous DMF (100 mL) was stirred overnight at 100°C. The reaction mixture was then cooled to room temperature and diluted with H2O (500 mL). The yellow solid was filtered, washed with H2O, and dried under vacuum. The crude product was used in subsequent steps without further purification.

[0465] 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 N2, and PtO2 (1.56 g, 6.9 mmol, 10% mol) was added. The reaction mixture was shaken for 5 hours under an H2 atmosphere (50 psi), then filtered through Celite, washed with MeOH, and evaporated. The crude residue was purified by column chromatography (silica gel, hex in hexane → 30% EtOAc) to obtain 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).

[0466] Step h: A mixture of bromide (200 mg, 0.57 mmol) from step g, tetrahydroquinoline (100 mg, 0.57 mmol) from step g, Pd(OAc)2 (25 mg, 0.22 mmol, 20% mol), rac-BINAP (87 mg, 0.14 mmol, 25% mol.) and Cs2CO3 (372 mg, 1.14 mmol, 2 equivalents) from step g in anhydrous, degassed toluene (2 mL) was stirred at 100°C for 5 hours. The entire reaction mixture was loaded onto a silica gel cartridge and purified by column chromatography (silica gel, hex in hexane → 30% EtOAc) to obtain 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). ESI MS [M+H] + - C 18 H 10 ClF4N3O2S, calculated value 444.0, measured value 444.0.

[0467] Example 11: 1-(2-chloro-3-cyano-4-methanesulfonylphenyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0468]

[0469] Step a: A solution of 3-bromo-2-chloro-6-fluorobenzonitrile (5 g, 21.3 mmol) in anhydrous CH3CN (100 mL) was cooled to 0°C, and then CH3SNa (1.64 g, 23.4 mmol, 1.1 equivalents) was added all at once. The mixture was stirred at 0°C for 15 minutes. Subsequently, the cooling batch was removed, and the reaction mixture was stirred overnight at room temperature. It was diluted with H2O (300 mL), and the product was filtered (white solid, 4.6 g, 82%).

[0470] Step b was performed in a manner similar to 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).

[0471] Step c was performed in a manner similar 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). ESI MS [M+H] + - C 18 H 13 ClFN3O2S, calculated value 390.0, measured value 390.0.

[0472] Example 12: 2-chloro-3-(8-chloro-6-fluoro-1,2,3,4-tetrahydroquinoline-1-yl)-6-trifluoromethanesulfonylbenzonitrile

[0473]

[0474] The title compound was synthesized in a manner similar 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). ESI MS [M+H] + - C 17 H 10 Cl2F4N2O2S, calculated value 453.0, measured value 453.0.

[0475] Example 13: 2-chloro-3-(6,8-difluoro-1,2,3,4-tetrahydroquinoline-1-yl)-6-trifluoromethanesulfonylbenzonitrile

[0476]

[0477] The title compound was synthesized in a manner similar to 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). ESI MS [M+H] + - C 17 H 10 ClF5N2O2S, calculated value 437.0, measured value 437.0.

[0478] Example 14: 1-[5-cyano-6-(trifluoromethyl)pyridine-3-yl]-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0479]

[0480] Step a: 6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (61 mg, 0.344 mmol, 1.2 equivalents), 5-bromo-3-fluoro-2-(trifluoromethyl)-pyridine (70 mg, 0.287 mmol, 1.0 equivalent), Pd(OAc)2 (13 mg, 0.057 mmol, 20 mol%), rac-BINAP (45 mg, 0.072 mmol, 25 mol%), Cs2CO3 (190 mg, 0.574 mmol, 2.0 equivalents), and toluene (1.5 mL) were added to a 40 mL vial. The reaction vessel was plugged, and the mixture was purged with N2 for 2 minutes. The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled, concentrated on Celite, and purified by flash column chromatography (SiO2, hexane → 40% EtOAc in hexane) to obtain a white solid (65 mg, 0.192 mmol, 55%, ESI MS [M+H]). + - C 16 H10 F5N3 was obtained as calculated value 340.3, measured value 340.0).

[0481] Step b: A vial was filled with the product from Step a (30 mg, 0.088 mmol, 1.0 equivalent), KCN (7.0 mg, 0.097 mmol, 1.1 equivalent), and NMP (0.3 mL). The reaction mixture was stirred at 100°C for 4 hours. The reaction mixture was diluted with a saturated aqueous NaHCO3 solution (10 mL) and extracted with EtOAc (10 mL). The aqueous layer was separated and back-extracted with additional EtOAc (15 mL). The organic layer was combined, washed with H2O (2 x 20 mL) and brine (20 mL), and dried over MgSO4. The product was concentrated under reduced pressure and purified by flash chromatography to obtain 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). ESI MS [M+H] + - C 17 H 10 F4N4, calculated value 347.1, measured value 347.0.

[0482] Example 15: 1-[2-chloro-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0483]

[0484] The title compound was synthesized using 1-bromo-2-chloro-3-fluoro-4-(trifluoromethyl)-benzene in a manner similar to Example 14. 1H 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). ESI MS [M+H] + - C 17 H 10 ClF5N2, calculated value 373.0, measured value 373.0.

[0485] Example 16: 6-fluoro-1-[8-(trifluoromethylsulfonyl)-5-isoquinolyl]-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0486]

[0487] The title compound was synthesized in a manner similar to Example 10. 1 H 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). ESI MS [M+H] + - C 20 H 13 F4N3O2S calculated value 436.1, measured value 436.1.

[0488] Example 17: (1S,2R)-4-[(S)-4-ethyl-6,8-difluoro-1,2,3,4-tetrahydroquinoline-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol

[0489]

[0490] The title compound was synthesized in a manner similar 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). ESI MS [M+H] + - C 21 H 19 F6NO3S calculated value 480.1, measured value 480.1.

[0491] Example 18: 2-chloro-3-(6-fluoro-8-methoxy-3,4-dihydroquinoline-1 (2H)-yl)-6-((trifluoromethyl)sulfonyl)benzonitrile

[0492]

[0493] The title compound was synthesized in a manner similar 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. ESI MS [M+H] + - C 18 H 13 ClF4N2O3S; Calculated value 449.0, Measured value 449.1

[0494] Example 19: 7-fluoro-4-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-indene-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile

[0495]

[0496] Step a: Chloroacetyl chloride (8.3 mL, 110 mmol) was added dropwise at 0°C 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 mixture was stirred at ambient temperature for 30 minutes, then maintained at 66°C for 48 hours. The mixture was cooled, filtered through a Celite pad to remove inorganic solids, and the filtrate was concentrated and dried. The residue was fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to obtain 7-fluoro-2H-benzo[b][1,4]oxazine-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.

[0497] Step b: Lithium aluminum hydride (1.2 g, 3.2 mmol) was carefully added in small amounts at 0°C to a solution of 7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one (3.5 g, 2.1 mmol) in THF (30 mL). Once the addition was complete, the cooling bath was removed, and the mixture was stirred at ambient temperature for 4 hours. After TLC analysis indicated a complete reaction, the mixture was quenched using the Fieser protocol, and the product was extracted with diethyl ether. After removing all solvent under reduced pressure, the crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to obtain 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.

[0498] 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) placed in a water bath to maintain the reaction temperature below 25°C. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for 10 minutes and poured into 5% aqueous NaHSO₃ (100 mL). The crude product was extracted with a mixture of EtOAc and hexane (v / v 1:1, 3 x 35 mL), and the combined extract was washed with water (3 x 100 mL), aqueous NaHCO₃ (2 x 100 mL), and brine (50 mL). The solution was dried over Na₂SO₄, and the solvent was evaporated. The crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to obtain 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).

[0499] 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 hours under a nitrogen atmosphere. Once the complete disappearance of the starting material was observed by TLC analysis (30% EtOAc in hexane as the 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 Celite plug. The organic phase was separated, and the aqueous solution was further extracted with EtOAc (2 x 25 mL). The combined organic phase was washed with water (2 x 75 mL) and brine (75 mL), dried on Na2SO4, and concentrated and dried. The dried residue was fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to obtain 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 [M+Na] + - C9H7FN2O; Calculated value 179.1, Measured value 179.1.

[0500] Step e: A mixture of (1S,2R)-4-bromo-2-fluoro-1-(tert-butyl-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)2 (9.5 mg, 0.042 mmol), rac-BINAP (33 mg, 0.053 mmol), and Cs2CO3 (137 mg, 0.42 mmol) in degassed anhydrous toluene (1 mL) was stirred at 100°C for 6 hours. The mixture was then cooled to ambient temperature, diluted with EtOAc, and filtered through a Celite pad to remove inorganic solids. The filtrate was concentrated on Celite and purified into a mixture of product and unreacted benzomorpholine (55 mg) by column chromatography (SiO2, hexane / EtOAc gradient). This mixture was applied to step f without further purification.

[0501] Step f: A mixture of TBS-protected indanol and unreacted benzomorpholine from the previous step was dissolved in CH3CN (1 mL) and placed in a 3 mL vial equipped with a magnetic stirrer, and then HF·Py complex (hydrofluoric acid ~70%, pyridine ~30%, 0.1 mL) was added. The resulting solution was stirred overnight at ambient temperature. After TLC analysis indicated complete consumption of the starting material, the reaction mixture was diluted with EtOAc (20 mL) and 1 M aqueous HCl solution (20 mL). The product was extracted with EtOAc (2 x 10 mL), the combined organic extracts were washed with aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated and dried. The residue was fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to obtain 7-fluoro-4-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-indene-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (25 mg, 0.054 mmol, 26% yield over 2 steps) as a yellow oil. 1 H 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). ESI MS [M+Na] + - C 19 H 13 F5N2O4S; Calculated value 483.0, Measured value 483.1

[0502] Example 20: 7-fluoro-4-((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile

[0503]

[0504] The title compound was synthesized in a manner similar 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. ESI MS [M-OH] + - C 19 H 16 F2N2O4S; calculated value 389.1, measured value 389.1.

[0505] Example 21: 6,8-Difluoro-8'-Trifluoromethanesulfonyl-3,4-Dihydro-2H-1,5'-Biquinoline

[0506]

[0507] The title compound was synthesized in a manner similar to Example 10. 1H 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). ESI MS [M+H] + - C 19 H 13 F5N2O2S calculated value 429.1, measured value 429.1.

[0508] Example 22: 4-(6,8-difluoro-1,2,3,4-tetrahydroquinoline-1-yl)-2,2-difluoro-7-methanesulfonyl-2,3-dihydro-1H-indene-1-ol

[0509]

[0510] The title compound was synthesized in a manner similar to Example 19. 1 H 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). ESI MS [M+H] + - C 19 H 17 F4NO3S calculated value 416.1, measured value 416.0.

[0511] Example 23: 6,8-Difluoro-1-(2-nitro-4-trifluoromethanesulfonylphenyl)-1,2,3,4-tetrahydroquinoline

[0512]

[0513] The title compound was synthesized in a manner similar 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). ESI MS [M+H] + - C 16 H 11 F5N2O4S calculated value 423.0, measured value 423.1.

[0514] Example 24: 6,8-difluoro-1-[2-nitro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinoline.

[0515]

[0516] 4-bromo-3-nitrobenotrifluoride (270 mg, 1 mmol), 6,8-difluoro-1,2,3,4-tetrahydroquinoline (324 mg, 1.2 mmol), Pd(OAc)2 (45 mg, 0.2 mmol), rac-BINAP (187 mg, 0.3 mmol), and Cs2CO3 (652 mg, 2 mmol) were suspended in PhMe (5 mL). The suspension was degassed with N2 at ambient temperature for 5 minutes and heated at 100°C for 1.5 hours. The mixture was cooled to room temperature, diluted with EtOAc, filtered, and concentrated on Celite®. Purification by column chromatography (0-10% EtOAc / hexane) yielded 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). ESI MS [M+H] + - C 16 H 11 F5N2O2, calculated value 359.1, measured value 359.1.

[0517] Example 25: 5-(6,8-difluoro-1,2,3,4-tetrahydronaft-1-yl)-8-(trifluoromethylsulfonyl)isoquinoline

[0518]

[0519] Step a: 5-bromo-8-isoquinolylamine (2.23 g, 10 mmol, 1 equivalent) was dissolved in a mixture of ethanol (3 mL) and aqueous HBF4 (48 wt%, 2.62 mL, 20 mmol, 2 equivalents), and the solution was cooled to 0°C. After adding t-BuONO (2.37 mL, 20 mmol, 2 eq.), the reaction mixture was stirred for 1 hour. Et2O (10 mL) was added to the reaction mixture, which was then filtered and washed with additional Et2O (2 x 10 mL). The filtrate was dried under vacuum for 30 minutes to obtain the diazonium salt as an orange solid (3.06 g, 9.52 mmol, 95%). ESI MS [M] + - C9H5BrN3 Calculated value 234.0, Measured value 234.0

[0520] Step b: A solution of the product from Step a was added to a vigorously stirred solution of NaSO2CF3 (4.68 g, 30 mmol, 3 equivalents) and Cu2O (143 mg, 1 mmol, 0.1 equivalents) in DMSO (10 mL) using a dropping funnel. After the addition was complete, the reaction mixture was stirred for 2 hours, or until the LCMS indicated complete conversion of the starting material. The reaction mixture was then diluted with EtOAc (100 mL) and water (100 mL). After separating the layers, the aqueous portion was extracted with EtOAc (3 x 100 mL). The combined organic portion was washed with water (2 x 100 mL) and brine (100 mL) and finally dried over Na2SO4. The crude material was purified by flash column chromatography (SiO2, 0 to 100% EtOAc / hexane) to obtain the product as a brown solid (716 mg, 2.94 mmol, 29%). ESI MS [M+H] + - C 10 H5BrF3NO2S calculated value 339.9, measured value 339.9.

[0521] Step c: A vial was filled with the product from Step b (24 mg, 0.07 mmol, 1 equivalent), 2-(6,8-difluoro-3,4-dihydronaft-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21 mg, 0.07 mmol, 1 equivalent), Pd(dppf)Cl2 (5 mg, 0.007 mmol, 0.1 equivalent), an aqueous solution of Na2CO3 (1 M, 0.21 mL, 3 equivalents), and dioxane (1 mL). The vial was aerated with N2 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 and concentrated over Na2SO4. The crude material was purified by flash column chromatography (0 to 100% EtOAc / hexane) to obtain the target product (7 mg, 0.016 mmol, 23%). ESI MS [M+H] + - C 20 H 12 F5NO2S calculated value 426.1, measured value 426.1.

[0522] Step d: The product from Step c (7 mg, 0.016 mmol, 1 eq) was dissolved in i-PrOH (1 mL), and PhSiH3 (4 μL, 0.032 mmol, 2 eq) and tert-butyl hydroperoxide (5.5 M in decane, 8 μL, 0.032 mmol, 2 eq) were added under nitrogen. After aeration of this solution under nitrogen for 10 minutes, Mn(dmp)3 (10 mg, 0.016 mmol, 1 equivalent) was added, and the resulting mixture was aerated for an additional 30 seconds. The reaction mixture was then stirred under nitrogen for 16 hours. After concentrating the reaction mixture, the crude material was purified by flash column chromatography (SiO2, 0 to 100% EtOAc / hexane) to obtain 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). ESI MS [M+H] + - C 20 H 14 F5NO2S calculated value 428.1, measured value 428.1.

[0523] Examples 26-120: Compound Synthesis

[0524] The following examples were prepared according to the general synthesis protocol described for other examples as detailed in Table A below. Each example provided characteristic physical data, such as the presented mass spectrum peaks.

[0525] Table A: Synthesis of Examples 26-120

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539] Example 121: (4S)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile.

[0540]

[0541] Step a: 2-chloro-4-fluoroaniline (18.2 g, 15 mL, 1.0 molar equivalent) and an excess of acrylic acid (46 g, 5.0 molar equivalent) were placed in a flask, and the resulting mixture was stirred at 45°C for 15 hours. During this time, the product was solidified from the reaction mixture, collected by filtration, and rinsed with hexane to obtain the aniline product, which was used as is in the subsequent step (25.4 g, 93%).

[0542] Step b: Next, the product from Step a (25.4 g) was added little by little to Eaton's reagent (100 mL) at 0°C. The resulting mixture was heated to room temperature and then heated at 80°C for 3 hours. Afterward, the reaction mixture was cooled and carefully poured onto ice, after which the product precipitated from the solution as a yellow solid (17.4 g, 75%).

[0543] Step c: A flask containing the product from the previous step (15 g, 75.3 mmol, 1.0 molar equivalent) in MeOH (250 mL) was cooled to 0°C under N2. NaBH4 (3.41 g, 90.4 mmol, 1.2 molar equivalent) was slowly added, and the reaction mixture was stirred at room temperature for 30 minutes. At this point, the reaction mixture was placed in an ice bath, quenched with H2O, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layer was combined, washed with water and brine, and dried over MgSO4. The tetrahydroquinoline intermediate was obtained by concentration under reduced pressure and used in the subsequent step without further purification.

[0544] Step d: DCM (250 mL) and imidazole (7.70 g, ~1.5 molar equivalents) were added to the crude intermediate from Step c. The resulting mixture was cooled to 0°C, and TBSCl (17.0 g, ~1.5 equivalents) was added. The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was filtered to remove imidazole hydrochloride and concentrated on Celite. The TBS-protected alcohol was purified by flash column chromatography (SiO2, hexane → 10% EtOAc / hexane) to obtain a colorless oil (16.7 g, 70% over two steps).

[0545] Step e: A flask was filled with TBS alcohol (6.0 g, 19 mmol, 1.0 molar equivalent) from the previous step, K4Fe(CN)6.3H2O (5.61 g, 13.3 mmol, 0.7 mol), Pd XPhos generation 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 molar equivalent), H2O (40 mL), and 1,4-dioxane (40 mL). The resulting mixture was purged with N2, heated at 100°C, and vigorously stirred under N2. After 3 hours, the reaction mixture was cooled and diluted with EtOAc and H2O. The aqueous layer was separated and back-extracted with additional EtOAc. Filtration through Celite to remove solids can improve the separation of layers. The organic layers were combined and dried on MgSO4. The benzonitrile product was obtained as a yellow solid (5.68 g, 98%) by purification by flash column chromatography (SiO2, hexane → 20% EtOAc).

[0546] Step f: To a flask containing 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (10 g, 34.8 mmol, 1.0 molar equivalent), DMF (70 mL) was added, followed by EDC·HCl (9.98 g, 52.2 mmol, 1.5 molar equivalent), HOBt·H2O (7.0 g, 52.2 mmol, 1.5 molar equivalent), ammonium carbonate (16.7 g, 174 mmol, 5.0 molar equivalent), and DIPEA (18 mL, 3.0 molar equivalent). The resulting mixture was stirred overnight at 40°C. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was separated and extracted with additional EtOAc. The organic layer was combined, washed with H2O to remove DMF, and dried over MgSO4. The crude amide was obtained by concentrating under reduced pressure and used in a subsequent step without purification.

[0547] Step g: DMF (100 mL) and cyanuric acid trichloride (2.55 g, 13.9 mmol, ~0.6 molar equivalents) were added to a flask containing the crude amide from the previous step. The resulting mixture was stirred at room temperature under N2 for 16 hours. The reaction mixture was distributed between EtOAc and H2O. The aqueous layer was separated and extracted with additional EtOAc. The organic layer was combined, washed with H2O to remove DMF, and dried over MgSO4. It was concentrated under reduced pressure and purified by flash column chromatography (SiO2, hexane → 20% EtOAc) to obtain the nitrile product as a white solid (2.68 g, 26% over two steps).

[0548] Step h: Benzonitrile (1.0 g, 3.73 mmol, 1.0 molar equivalent), 4-[tert-butyl(dimethyl)silyl]oxy-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (1.10 g, 3.73 mmol, 1.0 molar equivalent), Pd(OAc)2 (0.167 g, 0.746 mmol, 20 mol%), rac-BINAP (0.580 g, 0.925 mmol, 25 mol%), Cs2CO3 (2.42 g, 7.46 mmol, 2.0 molar equivalent), and toluene (15 mL) were added to the vial from the previous step. N2 was bubbled through the reaction mixture for 3 minutes, the vial was plugged, and heated at 100°C for 15 hours. The reaction was monitored by TLC and NMR analysis. The reactants were cooled, filtered, and concentrated on Celite. The coupled product was purified by flash column chromatography (SiO2, hexane → 10 → 20% EtOAc) to obtain a yellow solid (1.00 g, 54%). ESI MS [M+H] + - C 24 H 24 F5N3OSi, calculated value 494.2, measured value 494.2.

[0549] Step i: A flask containing the product from the previous step (1.0 g, 2.02 mmol, 1.0 molar equivalent) and THF (10 mL) was cooled to 0°C, and TBAF (1 M in THF, 3.0 mL, 1.5 molar equivalent) was added. The reaction mixture was heated to room temperature and stirred for 15 minutes. Afterward, the reaction mixture was quenched with a saturated aqueous NH4Cl solution and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layer was combined, washed with brine, and dried over MgSO4. It was concentrated under reduced pressure and purified by flash column chromatography (SiO2, hexane → 20% → 50% → 80% EtOAc) to obtain the alcohol product as a white solid (0.694 g, 91%).

[0550] Step j: A vial containing the alcohol product from the previous step (35 mg, 0.093 mmol, 1.0 molar equivalent) in DCM (1 mL) was cooled to -78°C. DAST (20 μL, 0.149 mmol, 1.6 molar equivalent) was added, the reaction mixture was heated to room temperature, and stirred for 5 minutes. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution at 0°C and diluted with DCM. The aqueous layer was separated and back-extracted with additional DCM. The organic layer was combined and dried over MgSO4. The mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, hexane → 20% EtOAc) to obtain 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%). Enantiomers were separated by purification SFC chiral purification (2.0 x 25.0 cm ChromegaChiral CC4 from ES Industries (West Berlin, New Jersey), CO2 co-solvent isopropanol / hexane (1:9), 15% co-solvent, 100 mL / min) to obtain 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 RIt was obtained as = 1.5 min). The absolute stereochemistry was confirmed by single-crystal X-ray analysis. 1H NMR (400 MHz, DMSO-d6, appeared as a 2:1 mixture of rotational isomers) 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). ESI MS [ (M-HF)+ H] + - C 18 H8F5N3, calculated value 362.0, measured value 362.0.

[0551] Example 122: 1-(3-chloro-2-cyano-4-methylsulfonylphenyl)-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile

[0552]

[0553] 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 equivalent) 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 mixture was stirred at room temperature for 1.5 hours. It was diluted with 10% Na2S2O3 (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic part was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 30% EtOAc in hex → hexane) to obtain the product (0.92 g, 60%).

[0554] 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 equivalents) and MeS-SMe (0.23 mL, 2.50 mmol, 1.2 equivalents) were added. The mixture was stirred at room temperature for 15 minutes, followed by heating at 60°C for 1 hour. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 30% EtOAc in hex → hexane) to obtain the product (0.36 g, 64%).

[0555] Step c: A mixture of bromide (180 mg, 0.68 mmol, 1.5 equivalents), 4-[tert-butyl(dimethyl)silyl]oxy-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (148 mg, 0.45 mmol), Pd(OAc)2 (10 mg, 0.045 mmol, 10% mol.), Xantphos (52 mg, 0.09 mmol, 20% mol.), and Cs2CO3 (440 mg, 1.35 mmol, 3 equivalents) from Step b was stirred in anhydrous, degassed toluene (8 mL) at 100°C for 15 hours. The entire reaction mixture was loaded onto a silica gel cartridge and purified by column chromatography (silica gel, hex → hexane, 30% EtOAc) to obtain the product (88 mg, 40%).

[0556] 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 equivalents) was added all at once. The reaction mixture was stirred at room temperature for 2 hours, then quenched with 10% Na2S2O3 (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic matter was washed with saturated NaHCO3 (50 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 30% EtOAc in hex → hexane) to obtain the product (quantitative yield).

[0557] 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 equivalents) was added. The reaction mixture was stirred at room temperature for 15 minutes. It was quenched with H2O (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic part was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hex → hexane, 80% EtOAc) to obtain the product as a yellow solid (58 mg, 80%).

[0558] 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 equivalents) was added. The mixture was stirred at -10°C for 10 minutes, then the cooled batch was removed, and the reaction mixture was stirred at room temperature for 0.5 hours. It was quenched with H2O (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic part was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hex → hexane with 60% EtOAc) to obtain 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). ESI MS [M+H] + - C 18 H 12 ClF2N3O2S, calculated value 408.0, measured value 408.0.

[0559] Example 123: 1-[3-chloro-2-cyano-4-(trifluoromethyl)phenyl]-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile.

[0560]

[0561] This compound was prepared from 6-bromo-2-chloro-3-(trifluoromethyl)benzoic acid in a manner similar to Example 121. 1¹H NMR (400 MHz, DMSO-d6, appeared as a 2:1 mixture of rotational isomers) 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). ESI MS [M+H] + - C 18 H9ClF5N3, calculated value 398.0, measured value 397.9.

[0562] Example 124: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-3,4-dihydro-2H-quinoline-4,8-dicarbonitrile

[0563]

[0564] 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 equivalent) in DCM (1.5 mL) was cooled to 0°C, and DMP (150 mg, 0.348 mmol, 1.2 mol equivalent) was added. The reaction mixture was heated to room temperature and stirred for 20 minutes. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution and a saturated aqueous Na2S2O3 solution (1:1) and diluted with DCM. The mixture was vigorously stirred for 30 minutes. The organic layer was separated and washed with additional saturated aqueous NaHCO3 / Na2S2O3 solution. The organic layer was separated and dried over MgSO4. The ketone product was obtained as a yellow solid by concentration under reduced pressure, which was of sufficient purity for use in subsequent steps (110 mg, ~quantitative). ESI MS [M+H] + - C 18 H8F5N3O, calculated value 378.1, measured value 378.1.

[0565] Step b: A solution of KOtBu (1 M in THF, 520 μL, 2 equivalents) was added at room temperature 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 equivalents) in dichloromethane (1.3 ml). Ethanol (18 mg, 0.4 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred at room temperature for 48 hours. After completion, the reaction mixture was quenched with 2N aqueous HCl, extracted with dichloromethane, and purified by flash chromatography on silica gel to obtain 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). ESI MS [M+H] + - C 19 H9F5N4, calculated value 389.0, measured value 389.0.

[0566] Example 125: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile

[0567]

[0568] 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 overnight at 70°C. After completion, the reaction mixture 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 (0% to 30% ethyl acetate in hexane) on silica gel to obtain 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). ESI MS [M+H] + - C 18 H8F7N3, calculated value 400.1, measured value 400.0.

[0569] Example 126: 1-[6-(1,1-difluoroethyl)-5-fluoro-4-methylpyridine-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile.

[0570]

[0571] Step a: A flask containing 2,5-dibromo-3-fluoropyridine (6.00 g, 23.6 mmol, 1.0 mol equivalent) in THF (100 mL) was cooled to -78°C under N2. A solution of LDA (2.0 M in heptane / THF / ethylbenzene, 17.7 mL, 1.5 mol equivalent) was slowly added, and the resulting mixture was stirred for 15 minutes. MeI (2.9 mL, 2.0 mol equivalent) was added, the reaction mixture was allowed to warm to room temperature, and stirred for 30 minutes. The reaction mixture was cooled to 0°C, quenched with a saturated aqueous NH4Cl solution, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layer was combined and dried over MgSO4. The methylation product was concentrated under reduced pressure and purified by flash column chromatography (SiO2, hexane → 15% EtOAc) to obtain a yellow oil (3.64 g, 57%).

[0572] Step b: A flask containing the product from the previous step (3.00 g, 11.2 mmol, 1.0 mol equivalent) in dry toluene (30 mL) was cooled to -78 °C under N2. nBuLi (2.5 M, 5.4 mL, 1.2 mol equivalent) in hexane was added, and the reaction mixture was stirred for 30 minutes. Subsequently, the organolithium was trapped with anhydrous DMA (3.2 mL, 33.6 mmol, 2.0 mol equivalent), and the reaction mixture was stirred for an additional 20 minutes. The reaction mixture was quenched with a saturated aqueous NH4Cl solution at -78 °C. After heating, the mixture was diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layer was combined and dried over MgSO4. The product was concentrated under reduced pressure and purified by flash column chromatography (SiO2, hexane → 30% EtOAc) to obtain a ketone product (906 mg, 35%).

[0573] Step c: Deoxo-fluorine (2.7 M in toluene, 3.0 mL, 4.0 mol equivalents) was added to the ketone product from the previous step (400 mg, 1.72 mmol, 1.0 mol equivalent), and the resulting mixture was stirred at 70°C for 9 hours. The reaction mixture was placed on ice, quenched with a saturated aqueous NaHCO3 solution, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO4. The mixture was concentrated under reduced pressure and purified by flash column chromatography (SiO2, 20% EtOAc in hexane) to obtain the difluorinated product as a yellow oil (342 mg, 78%). ESI MS [M+H] + - C8H7BrF3N, calculated value 253.9, measured value 253.8.

[0574] The title compound 1-[6-(1,1-difluoroethyl)-5-fluoro-4-methylpyridine-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 in a manner similar to Example 125. 1 H 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). ESI MS [M+H] + - C 18 H 13 F6N3, calculated value 386.1, measured value 386.0.

[0575] Example 127: 1-[4-chloro-5-fluoro-6-(trifluoromethyl)pyridine-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile.

[0576]

[0577] Step a: A flask containing 5-bromo-3-fluoro-2-(trifluoromethyl)pyridine (1.00 g, 4.09 mmol, 1.0 mol equivalent) in THF (10 mL) was cooled to -78°C under N2. A solution of LDA (2.0 M in heptane / THF / ethylbenzene, 17.7 mL, 1.5 mol equivalent) was slowly added, and the resulting mixture was stirred for 15 minutes. A solution of hexachloroethane (1.93 g, 8.18 mmol, 2.0 mol equivalent) in THF (3 mL) was added, the reaction mixture was heated to room temperature, and stirred for 15 minutes. The reaction mixture was cooled to 0°C, quenched with a saturated aqueous NH4Cl solution, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layer was combined and dried over MgSO4. The product was concentrated under reduced pressure and purified by flash column chromatography (SiO2, hexane → 15% EtOAc) to obtain the chlorinated product as yellow oil (824 mg, 72%).

[0578] The title compound 1-[4-chloro-5-fluoro-6-(trifluoromethyl)pyridine-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 in a manner similar to Example 125. 1 ¹H 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). ESI MS [M+H] + - C 16 H7F7N3, calculated value 410.0, measured value 409.9.

[0579] Example 128: 1-[5-cyano-4-methyl-6-(trifluoromethyl)pyridine-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile

[0580]

[0581] Step a: A flask containing 5-bromo-3-fluoro-2-(trifluoromethyl)pyridine (1.00 g, 4.10 mmol, 1.0 mol equivalent) in THF (10 mL) was cooled to -78°C under N2. A solution of LDA (2.0 M in heptane / THF / ethylbenzene, 3.0 mL, 1.5 mol equivalent) was slowly added, and the resulting mixture was stirred for 15 minutes. MeI (0.55 mL, 2.0 mol equivalent) was added, the reaction mixture was heated to room temperature, and stirred for 30 minutes. The reaction mixture was cooled to 0°C, quenched with a saturated aqueous NH4Cl solution, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layer was combined and dried over MgSO4. The methylation product was concentrated under reduced pressure and purified by flash column chromatography (SiO2, hexane → 15% EtOAc) to obtain a yellow oil (970 mg, 92%).

[0582] Step b: Pyridine bromide (350 mg, 1.36 mmol, 1.3 mol equivalents), 4-[tert-butyl(dimethyl)silyl]oxy-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (320 mg, 1.04 mmol, 1.0 mol equivalents), Pd(OAc)2 (46 mg, 0.20 mmol, 20 mol%), Xantphos (150 mg, 0.26 mmol, 25 mol%), Cs2CO3 (468 mg, 2.08 mmol, 2.0 mol equivalents), and toluene (3.5 mL) from the previous step were filled into a vial. N2 was bubbled through the reaction mixture for 3 minutes, the vial was plugged, and heated at 100°C for 24 hours. The reaction was monitored by TLC and NMR analysis. The reactants were cooled, filtered, and concentrated on Celite. The coupled product was purified by flash column chromatography (SiO2, hexane → 20% EtOAc) to obtain a yellow solid (240 mg, 47%).

[0583] Step c: The product from Step b (90 mg, 0.186 mmol, 1.0 mol equivalent) and NMP (1.0 mL) were placed in a vial. KCN (18 mg, 0.28 mmol, 1.5 mol equivalent) was added, and the reaction mixture was stirred at 110°C. An additional portion of KCN (18 mg, 0.28 mmol, 1.5 mol equivalent) was added after 40 minutes, and the reaction was continued at 110°C for 15 hours. During this time, the TBS group was also cleaved. The reaction mixture was cooled and diluted with a saturated aqueous NaHCO3 solution and EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layer was combined and dried over MgSO4. Benzonitrile alcohol (18 mg, 0.048 mmol, 26%) was obtained by concentrating under reduced pressure and purifying by flash column chromatography (SiO2, 60% EtOAc in hexane). ESI MS [M+H] +- C 18 H 12 F4N4O, calculated value 377.1, measured value 377.0.

[0584] The title compound 1-[5-cyano-4-methyl-6-(trifluoromethyl)pyridine-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile was prepared in two additional steps in a manner similar to Examples 124 and 125. 1 ¹H 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). ESI MS [M+H] + - C 18 H 10 F6N4, calculated value 397.1, measured value 397.0.

[0585] Example 129: 4,4,6-trifluoro-1-[5-fluoro-4-methyl-6-(trifluoromethyl)pyridine-3-yl]-2,3-dihydroquinoline-8-carbonitrile.

[0586]

[0587] The title compound 4,4,6-trifluoro-1-[5-fluoro-4-methyl-6-(trifluoromethyl)pyridine-3-yl]-2,3-dihydroquinoline-8-carbonitrile was prepared in three additional steps in a manner similar to Example 125. 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). ESI MS [M+H] + - C 17 H 10F7N3, calculated value 390.0, measured value 390.0.

[0588] Example 130: (3S,4R)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile.

[0589]

[0590] Step a: N-fluorobenzenesulfonimide (1.29 g, 4.08 mmol, 1.1 equivalents) was added 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 equivalent) in MeOH (18 mL). The reaction mixture was stirred at 65°C for 16 hours. The reaction mixture was quenched with an aqueous saturated NaHCO3 solution 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 Amberlist 15 (0.5 g, 150 wt%) was added. The reaction mixture was stirred at 90°C for 16 hours. After completion, the polymer beads were removed by filtration, and the concentrated crude material was purified by chromatography on silica gel (EtOAc with a 0 to 25% gradient in hexane) to obtain 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). ESI MS [M+H] + - C 18 H8F6N3O1, calculated value 396.0, measured value 395.9.

[0591] Step b: The product from Step a (250 mg, 0.63 mmol, 1.0 equivalent) was dissolved in CH2Cl2 (1.60 ml) and aerated with nitrogen gas, after which formic acid (70 μL, 1.90 mmol, 3.0 equivalent) and triethylamine (180 μL, 1.26 mmol, 2.0 equivalent) were added at 0°C. RuCl(p-cymene)[(S,S)-Ts-DPEN] (6 mg, 0.01 mmol, 1.5 mol%) was added, and the reaction mixture was stirred at 5°C for 16 hours. Upon complete conversion, the reaction mixture was quenched with an aqueous saturated NaHCO3 solution and extracted with CH2Cl2. The combined organic component was concentrated, and the crude material was purified by flash chromatography (0 to 35% gradient EtOAc in hexane) on silica gel to obtain (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 monodiastereomer. ESI MS [M+H2O] + - C 18 H 11 F6N3O2, calculated value 415.0, measured value 415.0.

[0592] Step c: The product of Step b (100 mg, 0.25 mmol, 1.0 equivalent) was dissolved in CH2Cl2 (2.5 mL), and the solution was cooled to -40°C. Diethylaminosulfur trifluoride (0.17 mL, 1.26 mmol, 5.0 equivalent) was added dropwise, and the reaction mixture was slowly heated to 0°C over 2 hours while stirring. Subsequently, the mixture was [treated with] CH2Cl 2로 희석하고, NaHCO3The mixture was poured into a saturated aqueous solution and the layers were separated. The organic phase was washed with brine, dried on Na2SO4, and evaporated under reduced pressure. The resulting residue was purified by chromatography (0 to 18% gradient EtOAc in hexane) on silica gel to obtain a mixture of diastereomers (4:1) having (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 (81% combined yield). Characterization was reported for (3S,4R)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile. The enantiomer excess rate of this substance was 97% by chiral HPLC (ChiralPack AD-H, 15% iPrOH / hexane, isolytic solvent, 20 min), and R T Subdivision = 7.18 minutes and R T The main = 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). 19 F 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). ESI MS [M+H2O] + - C18 H 10 F7N3O1, calculated value 417.0, measured value 416.9.

[0593] Example 131: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-methoxy-3,4-dihydro-2H-quinoline-8-carbonitrile

[0594]

[0595] Step a: Concentrated sulfuric acid (120 μL) was added 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), and the resulting solution was heated under reflux. After completion, the reaction solution was quenched with saturated NaHCO3, extracted with ethyl acetate, and dried over Na2SO4. After concentrating the organic part on Celite, the resulting crude material was purified by flash chromatography (SiO2) using a gradient of 0% to 100% dichloromethane in hexane to obtain 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-methoxy-3,4-dihydro-2H-quinoline-8-carbonitrile. 1 H 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). ESI MS [M+H] + - C 19 H 12 F5N3O. Calculated value 394.1, measured value 394.0.

[0596] Example 132: 1-[2-cyano-4-(1,1-difluoroethyl)-3-fluorophenyl]-6-fluoro-4-methoxy-3,4-dihydro-2H-quinoline-8-carbonitrile

[0597]

[0598] 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 H2SO4 (0.02 mL) was heated at 70°C for 8 hours. The reaction mixture was then cooled to room temperature, quenched with saturated NaHCO3 (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic part was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 40% EtOAc in hex → hexane) to obtain the product (280 mg, 68%).

[0599] 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 equivalents), and PdCl2(dppf) (51 mg, 0.069 mmol, 10% mol) in 1,4-dioxane (7 mL) was stirred overnight at 100°C under N2. The reaction mixture was then cooled to room temperature and diluted with 1N HCl (10 mL). This was allowed to be stirred for 2 hours. The mixture was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic part was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hex → 40% EtOAc in hexane) to obtain a product (0.26 g, quantitative yield).

[0600] Step c: A solution of the product from step b (130 mg, 0.35 mmol) and deoxo-fluorine (50 wt% in toluene) (1.25 g, 2.83 mmol, 8.0 equivalents) in CHCl3 (1 mL) was heated at 70°C for 12 hours. The reaction mixture was then cooled to room temperature, quenched with saturated NaHCO3 (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic part was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 40% EtOAc in hex → hexane) to obtain the product (28 mg, 20%).

[0601] 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). ESI MS [M+H] + - C 20 H 15 F4N3O, calculated value 390.1, measured value 390.1.

[0602] Example 133: 1-[2-cyano-4-(1,1-difluoroethyl)-3-fluorophenyl]-4,4,6-trifluoro-1,2,3,4-tetrahydro-8-quinolinecarbonitrile

[0603]

[0604] 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), isopropenboronic acid pinacol ester (0.237 g, 1.41 mmol, 1.1 equivalents), and PdCl2 (dppf) (94 mg, 0.128 mmol, 10% mol) was stirred overnight at 90°C under N2 in 1,4-dioxane (6 mL) and 2.0 M Na2CO3 (2 mL). The reaction mixture was then quenched with water and extracted with EtOAc (3 x 50 mL). The combined organic part was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hex → 50% EtOAc in hexane) to obtain a product (0.50 g, quantitative yield).

[0605] Step b: The product from Step a (0.5 g, 1.28 mmol) was dissolved in THF / H2O (2:1; 6 / 3 mL). 2,6-Lutidine (274 mg, 2.56 mmol, 2 equivalents) and NaIO4 (1.64 g, 7.68 mmol, 6 equivalents) were added, followed by the addition of K2OsO42H2O (24 mg, 0.06 mmol, 5% mol). The reaction mixture was stirred at room temperature for 15 hours, then diluted with a 10% Na2S2O3 solution (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic part was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hex → 50% EtOAc in hexane) to obtain a product (390 mg, 87%).

[0606] Step c: The product from Step b (0.39 g, 1.11 mmol) was dissolved in DCM (10 mL). Des-martine periodinan (705 mg, 1.65 mmol, 1.5 equivalents) was added. The reaction mixture was stirred at room temperature for 0.5 hours, then diluted with 10% Na2S2O3 solution (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic part was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 40% EtOAc in hex → hexane) to obtain the product (240 mg, 62%).

[0607] Step d: A solution of the product from step c (120 mg, 0.34 mmol) and deoxo-fluorine (50 wt% in toluene) (2.42 g, 5.48 mmol, 16 equivalents) in CHCl3 (1 mL) was heated at 70°C for 12 hours. The reaction mixture was then cooled to room temperature, quenched with saturated NaHCO3 (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic part was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 40% EtOAc in hex → hexane) to obtain 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). ESI MS [M+H] + - C 19 H 11 F6N3, calculated value 396.0, measured value 396.1.

[0608] Example 134: (5S,8R)-3,5-difluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-indene-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0609]

[0610] Step a: A solution of 4-bromo-7-methylsulfonyl-2,3-dihydroindene-1-one (25.0 g, 86.5 mmol) in 500 mL of dry methanol was loaded into a 1 L one-neck round-bottom flask equipped with a reflux condenser having a stirring rod and a drying tube. Select fluoride (38.2 g, 104 mmol) and concentrated sulfuric acid (0.5 mL) were added sequentially, and the mixture was refluxed for 5 hours. When TLC analysis indicated the complete disappearance of the starting material, the reaction mixture was cooled to ambient temperature. Aqueous sulfuric acid (0.3 M, 130 mL) was added, and the mixture was refluxed for 3 hours to convert the corresponding dimethylacetal into the target α-fluoroketone. The resulting clear solution was cooled to ambient temperature, and the methanol was distilled 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 x 100 mL). The combined organic extract was washed with brine (500 mL). The organic phase was separated, dried on Na2SO4, and concentrated and dried to obtain α-fluoroketone (25.9 g, 84.3 mmol, 97% yield) as a white solid.

[0611] 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 stirring bar. The flask was filled 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 brownish solution was stirred at 0°C for 16 hours. When TLC analysis indicated complete conversion of the starting material, the reaction mixture was concentrated under reduced pressure to about half its original volume. The residual solution was washed sequentially with aqueous 1 M NaOH (400 mL) and brine (500 mL). The organic phase was separated, dried on Na2SO4, and concentrated dried to obtain the crude product with sufficient purity for the subsequent step.

[0612] The enantiomer purity (96% ee) of this substance was determined using HPLC-UV chromatography [Chiralpac®AD-H (4.6x250 mm; 90% i-PrOH-hexane; flow rate = 1 mL / min; injection of 10 μL of 1 mg / mL solution; detection at 254 nm; t1= 4.89 min (minor), t2= 5.26 min (major)].

[0613] 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 reflux condenser, a thermometer, an addition funnel, a stirring rod, and a drying tube. Triethylamine (105.0 mL, 0.81 mmol) was added to the mixture all at once, and TBSOTf (96.4 g, 0.37 mmol) was added to the addition funnel. Subsequently, TBSOTf was added dropwise to induce an exothermic reaction at a rate necessary to maintain continuous reflux. Once the addition was complete, the reaction mixture was refluxed for an additional 15 minutes, at which point TLC analysis indicated complete conversion of the starting material into the product. The solution was allowed to cool to ambient temperature, transferred to a separation funnel, and washed sequentially with saturated aqueous NH4Cl (500 mL) and brine (500 mL). The organic phase was separated, dried on Na2SO4, and concentrated and dried. The obtained crude product was purified by flash chromatography (SiO2, hexane / EtOAc gradient) to obtain TBS ether as a white solid (26.5 g, 62.6 mmol, 74% yield over two steps).

[0614] Step d: The TBS ether product (29.5 g, 70.0 mmol) from the previous step was combined with B2Pin2 (23.0 g, 91.0 mmol, 1.3 equivalents), Pd(dppf)Cl2 (5.1 g, 7.0 mmol, 0.1 equivalents), and potassium acetate (13.8 g, 0.14 mmol, 2.0 equivalents) in dioxane (230 ml) in a 500 mL single-neck round-bottom flask equipped with a reflux condenser with a nitrogen inlet adapter and a magnetic stirring bar. The mixture was degassed under vacuum, refilled with nitrogen, and heated at 100°C for 2 hours. The fraction 1After H NMR analysis indicated the complete consumption of the starting material, the reaction mixture was cooled to ambient temperature and concentrated and dried under reduced pressure. The residue was distributed between EtOAc (500 mL) and water (300 mL). The organic layer was separated, and the aqueous phase was further extracted with EtOAc (2 x 100 mL). The combined organic extract was dried over Na2SO4, and the solvent was evaporated under reduced pressure to obtain the crude boronic acid pinacol ester, which was used in subsequent steps without further purification.

[0615] Step e: A solution of the crude product from Step d (70 mmol) and 8-cyano-6-fluoro-3,4-dihydronaphthalene-1-yl trifluoromethanesulfonate (22.5 g, 70.0 mmol) in dioxane (230 mL) was placed in a 500 mL one-neck round-bottom flask equipped with a reflux condenser fitted with a magnetic stirring rod and a nitrogen inlet. Subsequently, Pd(dppf)Cl2 (5.1 g, 7.0 mmol) and aqueous sodium carbonate (2 M solution, 70.0 mL, 40.0 mmol) were added sequentially. The mixture was degassed under vacuum, refilled with nitrogen, and heated at 100°C for 1 hour. Upon completion of the reaction, the dioxane was removed under reduced pressure. The residue was distributed between EtOAc (500 mL) and water (500 mL). The organic layer was separated, and the aqueous phase was further extracted with EtOAc (2 x 100 mL). The combined organic extract was washed with brine (500 mL), dried over Na2SO4, and concentrated and dried. The crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to obtain the target alkene (28.5 g, 55.3 mmol, 79% yield) as a white foam.

[0616] Step f: The alkene (28.0 g, 54.0 mmol) from Step e was dissolved in dry methanol (540 mL) and added to carbon-phase palladium (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 shaker for 4 hours. Excess hydrogen was exhausted, and the mixture was aerated with nitrogen to remove residual hydrogen gas. The resulting suspension was filtered through a Celite pad, and the filtrate was concentrated and dried under reduced pressure to obtain 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 obtain the target tetralin derivative (9.6 g, 18.5 mmol, 34% yield) as a white foam.

[0617] Step g: TBAF (37.2 mL, 37.2 mmol, 1 M solution in THF) was added dropwise at ambient temperature to the solution of TBS ether from Step f in THF (93 mL). After stirring the resulting brown solution for 20 minutes, TLC analysis indicated complete conversion of the starting material. The mixture was diluted with EtOAc (200 mL) and washed sequentially with water (200 mL) and brine (150 mL). The organic extract was dried over Na2SO4, concentrated and dried, and the crude product was applied to the acylation reaction without purification.

[0618] The dry material obtained from the previous conversion was dissolved in dichloromethane (50 mL), and then DMAP (0.7 g, 5.8 mmol) and Et3N (8.0 mL, 77.0 mmol) were added. The reaction mixture was cooled to 0°C, and acetic anhydride (7.3 mL, 77.0 mmol) was added dropwise over a period of 1 minute. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 minutes. When TLC and LCMS analysis indicated complete conversion, the solution was diluted with dichloromethane (150 mL) and washed sequentially with water (200 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL). The crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to obtain the target acetate ester (8.3 g, 18.5 mmol, 100% yield) as a white powder.

[0619] Step h: Acetate ester (8.3 g, 18.6 mmol), MnO2 (6.5 g, 75 mmol), and dichloromethane (93 mL) from Step g were loaded into a 500 mL 1-neck round-bottom flask equipped with a magnetic stirring bar and a reflux condenser. The mixture was cooled to 0°C, and tBuO2H2 (34 mL, 186 mmol, 5.5 M solution in decane) was added dropwise over 5 minutes. The reaction mixture was stirred at 0°C for 10 minutes, then heated to ambient temperature and stirred until gas formation ceased. The resulting black suspension was refluxed for 24 hours, then cooled to room temperature, and additional amounts of MnO2 (6.5 g, 75 mmol) and tBuO2H2 (34 mL, 186 mmol, 5.5 M solution in decane) were added sequentially. The mixture was refluxed for an additional 48 hours and cooled to room temperature. Inorganic solids were removed by filtration. The filtrate was passed through a Celite plug, washed with water (100 mL), dried over Na2SO4, and concentrated dried. The crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to obtain the corresponding α-tetralon (6.2 g, 13.5 mmol, 72% yield) as a white powder.

[0620] Step i: A solution of α-tetralon (1.5 g, 3.3 mmol) from Step h in dichloromethane (33 mL) was placed in a 100 mL one-neck round-bottom flask equipped with a magnetic stirring rod and a drying tube. Formic acid (0.37 mL, 9.8 mmol), Et3N (0.91 mL, 6.5 mmol), and RuCl(p-cymene)[(R,R)-Ts-DPEN] (62 mg, 0.1 mmol) were added to the mixture at ambient temperature and stirred for 1 hour. The resulting brown solution was diluted with dichloromethane (70 mL) and washed with aqueous saturated NaHCO3. The organic extract was dried over Na2SO4 and concentrated and dried under reduced pressure. The crude product was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient) to obtain the corresponding 1,2,3,4-tetrahydro-1-naphthol (1.43 g, 3.1 mmol, 95% yield, single epimer) as a white powder.

[0621] Step j: A solution of deoxo-fluorine (3.4 ml, 9.1 mmol, 2.7 M in toluene) in dichloromethane (52 mL) was placed in a 100 ml one-neck round-bottom flask equipped with a magnetic stirring rod and a nitrogen inlet, cooled to -78°C, and then TMS-morpholine (1.65 mL, 9.2 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 5 minutes, then the mixture was allowed to warm 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 all at once. The cooling bath was removed, and the reaction mixture 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 aqueous saturated NaHCO3 (50 mL). The organic phase was separated, dried on Na2SO4, and concentrated and dried. The dried residue was dissolved in 1,2-dimethoxyethane (60 mL), and AgClO4xH2O (0.20 g) was added. The mixture was heated at 70°C for 1 hour, concentrated and dried, and the crude product was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient), then softened with 30 mL of MTBE, and filtered to obtain the target α-fluorotetralin (1.1 g, 2.4 mmol, 92% yield, single epimer) as a white solid.

[0622] Step k: α-fluorotetralin (1.1 g, 2.4 mmol) from Step j was suspended in a 7 M NH3 solution in 90 mL of MeOH, and the mixture was stirred at ambient temperature for 36 hours. The resulting clear solution was concentrated and dried under reduced pressure, and the crude product was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient), then softened with 30 mL of hexane, and filtered to obtain the target product (0.85 g, 2.0 mmol, 85% yield).1 H 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). ESI MS [M+Na] + - C 21 H 18 F3NO3SNa, calculated value 444.1, measured value 444.0).

[0623] Example 135: (8R)-3,5,5-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-indene-4-yl]-7,8-dihydro-6H-naphthalene-1-carbonitrile

[0624]

[0625] Step a: A mixture of [(1S,2R)-4-[(1R)-8-cyano-6-fluoro-4-oxo-2,3-dihydro-1H-naphthalene-1-yl]-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-indene-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 according to the protocol from Example 134 in benzene (25 mL), was placed in a 1-neck round-bottom flask equipped with a Dean-Stark apparatus and a reflux condenser with a nitrogen inlet adapter. The reaction mixture was refluxed for 16 hours, cooled to ambient temperature, and washed with 1 M NaOH (25 mL). The organic phase was separated, dried on Na2SO4, and concentrated and dried under reduced pressure. The crude product was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient) to obtain the target product (0.17 g, 0.31 mmol, 100% yield) as a colorless oil.

[0626] Step b: HF·Py (0.19 mL, 0.80 mmol) was added to a suspension of N-iodosuccinimide (71.0 mg, 0.32 mmol) cooled to -78°C in dichloromethane (1 mL). After stirring the resulting dark suspension for 5 minutes, a solution of 1,3-dithiolane (85 mg, 0.16 mmol) from Step a in dichloromethane (1 mL) was added dropwise over 1 minute. The reaction mixture was stirred at -78°C for 20 minutes, followed by an additional 20 minutes at 0°C. When TLC analysis indicated complete conversion of 1,3-dithiolane, the reaction mixture was diluted with dichloromethane (15 mL) and washed with a mixture of aqueous saturated NaHCO3 and Na2S2O3 (1:1, v / v). The organic phase was separated, dried on Na2SO4, and concentrated dried. The crude material was fractionated by column chromatography (SiO2, dichloromethane / EtOAc gradient) to obtain the target product (33.0 mg, 0.07 mmol, 43% yield) as a white solid.

[0627] Step c: 1,1-difluorotetraline (33.0 mg, 0.07 mmol) from Step b was dissolved in THF (1 mL), and a solution of LiOH·H2O (8.5 mg, 0.2 mmol) in water (0.2 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 3 hours and monitored by LCMS analysis. Once complete conversion was achieved, the reaction mixture 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 extract was washed with brine, dried over Na2SO4, and concentrated and dried under reduced pressure. The crude product was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient) to obtain the target product (27.0 mg, 0.06 mmol, 90% yield) as a white solid. 1H 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). ESI MS [M+Na] + - C 21 H 17 F4NNaO3S, calculated value 462.1, measured value 462.0).

[0628] Example 136: (5S,8R)-3,5-difluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-(trifluoromethylsulfonyl)-2,3-dihydro-1H-indene-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0629]

[0630] Step a: Bromine (3.58 ml, 70 mmol, 1.05 equivalents) was added dropwise to a suspension of 7-fluoro-2,3-dihydro-1H-indene-1-one (10.0 g, 66.6 mmol) and aluminum trichloride (22.2 g, 166.5 mmol, 2.5 equivalents) in 1,2-dichloroethane (190 ml, 0.35 M). The resulting solution was heated to 60°C for 3 hours, after which the reaction mixture was cooled to room temperature and poured over ice. The reaction mixture 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 CH2Cl2:hexane) to obtain 4-bromo-7-fluoro-2,3-dihydro-1H-indene-1-one.

[0631] Step b: Benzyl mercaptan (9.24 g, 8.71 ml, 1.0 equivalent) was added to a suspension of 4-bromo-7-fluoro-2,3-dihydro-1H-indene-1-one (17.0 g, 74.3 mmol) and Cs2CO3 (26.6 g, 81.7 mmol, 1.1 equivalent) in DMF (372 ml, 0.2 M). The reaction mixture was stirred at room temperature for 90 minutes. The target product was precipitated from the solution by adding 1.5 L of water and dried overnight under high vacuum. The resulting crude product (23.1 g, 93% yield) was used without further purification.

[0632] Step c: The crude thioether (23.1 g, 69.2 mmol) from Step b was suspended in toluene (692 ml, 0.1 M). Aluminum trichloride (10.2 g, 1.1 equivalents) was added at room temperature. An additional amount of aluminum trichloride (3.6 g, 27 mmol, 0.4 equivalents) was added after 3 hours. After completion, the reaction mixture 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 1:3 solution of CH2Cl2 in hexane) to obtain the target thiophenol as a yellow solid (13.4 g, 80% yield).

[0633] Step d: A solution of the thiophenol product (6.7 g, 27.6 mmol) from Step c and methyl viologen dichloride hydrate (710 mg, 0.1 equivalent) in DMF (55 ml, 0.5 M) was carefully degassed under nitrogen through three freeze-pump-thaw cycles. The resulting solution was cooled to -10 to -5°C in a brine ice bath and aerated through the reaction mixture with excess CF3I. The reaction mixture was then stirred overnight under an atmosphere of CF3I. The reaction mixture was carefully quenched with water at room temperature (use with caution as residual CF3I may be released), extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexane) to obtain the target thioether (5.21 g, 61% yield).

[0634] Step e: Ruthenium trichloride (697 mg, 3.36 mmol, 0.1 equivalent) was added to a solution of the product from Step d (10.45 g, 33.6 mmol) in MeCN (129 ml, 0.26 M relative to the starting material), CCl4 (129 ml, 0.26 M relative to the starting material), and H2O (258 ml, 0.13 M relative to the starting material), followed by sodium periodate (29.6 g, 138.4 mmol, 4.12 equivalents). The reaction mixture was stirred at room temperature for 1 hour and extracted with CH2Cl2 (x2) upon completion. The combined organic part was washed with saturated Na2S2O3, 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 1:3 solution of CH2Cl2 in hexane) to obtain the product sulfone as a white solid (10.53 g, 91% yield). ESI MS [M+H] + - C 10 H6BrF3O3S; calculated value 342.9, measured value 342.9.

[0635] Step f: A solution of the product sulfone (3.5 g, 10.2 mmol) and select fluoride (4.32 g, 12.2 mmol, 1.2 equivalents) from Step e in methanol (102 ml, 0.1 M) was heated to 50°C. Sulfuric acid (27 μl, 5 mol%) was added, and the reaction mixture was stirred at 50°C for 48 hours. The solution was then diluted with diethyl ether, and the resulting white precipitate was filtered 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 1:3 solution of CH2Cl2 in hexane) to obtain the product dimethyl acetal as a white solid (3.57 g, 87% yield).

[0636] Step g: A solution of the product acetal (3.18 g, 7.8 mmol) from step f and wet Amberlist 15 (4.77 g, 150 wt%) in dioxane (31 ml, 0.2 M) was heated overnight at 90°C. After 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 1:3 solution of CH2Cl2 in hexane) to obtain the target fluorinated ketone (2.33 g, 83% yield).

[0637] Step h: A solution of the indanone product (2.5 g, 6.93 mmol) from step g in dichloromethane (28 ml, 0.25 M) was aerated with nitrogen gas, and then formic acid (783 μL, 956 mg, 20.8 mmol, 3 equivalents) and triethylamine (1.94 ml, 1.41 g, 13.9 mmol, 2 equivalents) were added under nitrogen at 0°C. RuCl(p-cymene)[(R,R)-Ts-DPEN] (44.5 mg, 0.07 mmol, 0.01 equivalents) was added, and the reaction mixture was stirred at 0 to 5°C for at least 12 hours. Upon complete conversion, the reaction mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2. The combined organic component was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in a 1:1 solution of CH2Cl2:hexane) to obtain the target indanol (2.0 g, 80% yield) as a monodiastereomer. The enantiomer excess rate of this material was found to be 98% by chiral HPLC (ChiralPack AD-H, 20% iPrOH / hexane, isosolvent, 20 min) compared with a racemic sample obtained by the reduction of 2-fluoroindanone using sodium borohydride.

[0638] Step i: 2,6-lutidine (800 μL, 6.9 mmol, 2.5 equivalents) and TBSOTf (791 μL, 3.44 mmol, 1.25 equivalents) were added at 0°C to a solution of chiral indanol (1.01 g, 2.75 mmol) from Step h in CH2Cl2 (11 ml, 0.25 M). The reaction mixture was heated to room temperature and stirred overnight. After completion, the reaction mixture was concentrated directly over Celite and purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in hexane) to obtain TBS ether (1.35 g, 100% yield).

[0639] Step j: The TBS ether product of Step i (674 mg, 1.41 mmol) was combined with B2Pin2 (457 mg, 1.8 mmol, 1.3 equivalents), Pd(dppf)Cl2 (103 mg, 0.14 mmol, 0.1 equivalents), and potassium acetate (213 mg, 3 mmol, 2.2 equivalents) in dioxane (14 ml, 0.1 M), and the resulting solution was heated at 100°C for 3 hours. The reaction solution was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexane) to obtain the target boronic acid pinacol ester (638 mg, 86% yield) as a colorless oil.

[0640] 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 = 4.2 Hz, 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). ESI MS [M+Na] + - C 21 H 15 F6NNaO3S, calculated value 498.1, measured value 498.0.

[0641] Example 137: (5S,8R)-8-[3-chloro-2-cyano-4-(trifluoromethyl)phenyl]-3,5-difluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0642]

[0643] 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 diaphragm. 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 over 10 minutes using a syringe. The reaction mixture was stirred at -78°C for 1 hour, after which dry CO2 gas was bubbled through the mixture at -78°C for 30 minutes. The cooling bath was replaced with an ice / water mixture, and CO2 bubbling was continued for an additional 30 minutes. The reaction mixture was carefully poured into an aqueous 3 M HCl solution (700 mL) under vigorous stirring, and the product was extracted with EtOAc (3 x 300 mL). The combined organic extract was washed with brine and dried over Na2SO4. The solvent was distilled under reduced pressure, and the residue was distributed between aqueous 3 M 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 a pH of ~3 using aqueous 3 M HCl, and the product was extracted with dichloromethane (3 x 200 mL). The combined extract was dried over Na2SO4 and concentrated and dried to obtain the corresponding benzoic acid (17.5 g, 57.6 mmol, 99% yield) as an orange oil.

[0644] Step b: A mixture of benzoic acid (17.5 g, 57.6 mmol), thionyl chloride (12.6 mL, 173.0 mmol), and N,N-dimethylformamide (0.3 mL) from Step a in dry benzene (290 mL) was placed in a 500 mL one-neck round-bottom flask equipped with a reflux condenser having a drying tube. The reaction mixture was refluxed for 6 hours, then cooled to ambient temperature, and the excess thionyl chloride and benzene were distilled under reduced pressure. The oil residue was dissolved in THF (150 mL) and added dropwise over 30 minutes to aqueous 30% ammonium hydroxide (150 mL) cooled to 0°C. Once the addition was complete, the reaction mixture was vigorously stirred for 20 minutes. The product was extracted with dichloromethane (3 x 200 mL). The combined extract was dried over Na2SO4 and concentrated and dried under reduced pressure. The oily residue was softened with hexane (200 mL), and the formed gray precipitate was collected by filtration to obtain the corresponding benzamide (15.0 g, 49.7 mmol, 86% yield) as a gray solid.

[0645] Step c: A mixture of benzamide (30.1 g, 99.5 mmol) and cyanuric acid chloride (25.6 g, 139.4 mmol) from Step b in N,N-dimethylformamide (170 mL) was heated at 70°C for 2 hours. The mixture was then cooled to room temperature and poured into 500 mL of water. The product was extracted with EtOAc (3 x 200 mL). The combined organic extract was washed with water (2 x 300 mL) and brine (300 mL), dried over Na2SO4, and concentrated and dried under reduced pressure. The resulting residue was fractionated by flash chromatography (silica gel, 0% to 25% ethyl acetate in hexane) to obtain the target benzonitrile (15.1 g, 53.0 mmol, 53% yield) as a white crystalline solid.

[0646] Step d: Benzonitrile (0.5 g, 1.8 mmol) from Step c was combined with B2Pin2 (0.58 g, 2.3 mmol, 1.3 equivalents), Pd(dppf)Cl2 (0.13 g, 0.18 mmol, 0.1 equivalents), and potassium acetate (0.35 g, 3.5 mmol, 2.0 equivalents) in dioxane (9 ml, 0.2 M) in a 40 mL vial equipped with a magnetic stirring bar. The mixture was degassed under vacuum, refilled with nitrogen, and heated at 90°C for 1 hour. After TLC analysis indicated complete consumption of the starting material, the reaction mixture was allowed to cool to ambient temperature and concentrated and dried under reduced pressure. The residue was distributed between EtOAc (30 mL) and water (20 mL). The organic layer was separated, and the aqueous phase was further extracted with EtOAc (2 x 15 mL). The combined organic extract was dried over Na2SO4, and the solvent was evaporated under reduced pressure to obtain crude boronic acid pinacol ester, which was used without further purification.

[0647] 8-cyano-6-fluoro-3,4-dihydronaphthalene-1-yl trifluoromethanesulfonate (0.57 g, 1.8 mmol) was added to the crude pinacol ester of boronic acid together with dioxane (9 mL, 0.2 M), and the mixture was loaded into a 40 ml vial. Subsequently, Pd(dppf)Cl2 (0.13 g, 0.18 mmol) and an aqueous 2 M sodium carbonate solution (1.8 ml, 3.6 mmol) were added sequentially. The mixture was degassed under vacuum, refilled with nitrogen, and heated at 100°C for 1 hour. After completion, the dioxane was removed under reduced pressure. The residue was distributed between EtOAc (30 mL) and water (20 mL). The organic layer was separated, and the aqueous phase was further extracted with EtOAc (2 x 15 mL). The combined organic extract was washed with brine (30 mL), dried over Na2SO4, and concentrated and dried. The crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to obtain the target alkene (0.27 g, 0.7 mmol, 41% yield) as a brownish solid.

[0648] Step e: The alkene (0.27 g, 0.7 mmol) from Step d was dissolved in anhydrous methanol (10 mL) and triethylamine (0.5 mL, 3.6 mmol), and then carbonaceous palladium (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 Par shaker for 1 hour. Excess hydrogen was exhausted, and the mixture was aerated with nitrogen to remove residual hydrogen gas. The resulting suspension was filtered through a Celite pad, and the filtrate was concentrated and dried under reduced pressure to obtain a crude mixture of the target product and the corresponding dechlorinated compound. To isolate the target product, the crude mixture was subjected to column chromatography (SiO2, hexane / EtOAc gradient) to obtain a tetralin derivative (0.1 g, 0.26 mmol, 37% yield) as a white solid.

[0649] Step f: The tetralin derivative from Step e (0.3 g, 0.8 mmol), MnO2 (0.28 g, 3.2 mmol), and dichloromethane (4 mL, 0.2 M) were loaded into a 40 mL vial equipped with a magnetic stirring bar. The mixture was cooled to 0°C, and tBuO2H2 (1.5 mL, 8 mmol, 5.5 M solution in decane) was added dropwise over 5 minutes. The reaction mixture was stirred at 0°C for 10 minutes, then heated 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 hours, then cooled to room temperature, and additional amounts of MnO2 (0.28 g, 3.2 mmol) and tBuO2H2 (1.5 mL, 8 mmol, 5.5 M solution in decane) were added sequentially. The mixture was refluxed for an additional 48 hours and cooled to room temperature. Inorganic solids were removed by filtration. The filtrate was diluted with dichloromethane (30 mL), passed through a Celite plug, washed with water (20 mL), dried over Na2SO4, and concentrated dried. The crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to obtain the corresponding α-tetralon (0.14 g, 0.36 mmol, 45% yield) as a white solid.

[0650] Step g: NaBH4 (14.0 mg, 0.36 mmol) was added all at once to a solution of α-tetralon (70.0 mg, 0.18 mmol) from Step f cooled to 0°C in a mixture of MeOH (2 mL) and THF (3 mL). The reaction mixture was stirred for 10 minutes and poured into 1 M aqueous HCl (10 mL). The crude product was extracted with EtOAc (3 x 30 mL). The combined organic extract was washed with brine, dried over Na2SO4, and concentrated and dried to obtain a mixture of racemic cis and trans diastereomers. To separate the diastereomers, the crude mixture was fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to obtain the major cis diastereomer (52.0 mg, 0.13 mmol, 74% yield, less polar product) along with the secondary trans diastereomer (8.0 mg, 0.02 mmol, 11% yield, more polar product). Both compounds were obtained in the form of white solids.

[0651] Step f: A solution of deoxo-fluorine (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 mixture was stirred at 0°C for 5 minutes, then heated to room temperature and stirred for 2 hours. The resulting solution was cooled to 0°C, and the solid 1,2,3,4-tetrahydro-1-naphthol (51.0 mg, 0.13 mmol) from Step e was added all at once. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 minutes. When TLC analysis indicated complete consumption of the starting material, the mixture was diluted with EtOAc (20 mL) and quenched with aqueous saturated NaHCO3 (10 mL). The organic phase was separated, dried on Na2SO4, and concentrated dried. The dry residue was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient) to obtain the title compound (44.0 mg, 0.11 mmol, 86% yield, single epimer) as a white foam. 1 H 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. ESI MS [M+Na] + - C 19 H 10 ClF5N2Na, calculated value 419.0, measured value 419.2).

[0652] Example 138: (5R,8R)-8-[3-chloro-2-cyano-4-(trifluoromethyl)phenyl]-3,5-difluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0653]

[0654] Step a: A solution of deoxo-fluorine (26.0 μL, 0.07 mmol, 2.7 M in toluene) in toluene (0.25 mL) was cooled to 0°C under nitrogen, and then TMS-morpholine (13.0 μL, 0.072 mmol) was added. The reaction mixture was stirred at 0°C for 5 minutes, then heated 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 similarly to Example 134) in dry toluene (0.5 mL) was added. The cooling bath was removed, and the reaction mixture 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 aqueous saturated NaHCO3 (3 mL). The organic phase was separated, dried on the Na2SO4 phase, and concentrated and dried. The dried residue was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient) to obtain 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). 19F NMR (376 MHz, CDCl3) δ -63.03, -109.89, -169.86 (d, J = 50.8 Hz). ESI MS [M+Na] + - C 19 H 10 ClF5N2Na, calculated value 419.0, measured value 419.0).

[0655] Example 139: (5S,8S)-8-[6-(1,1-difluoroethyl)-5-fluoro-4-methylpyridine-3-yl]-3,5-difluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0656]

[0657] 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 one-neck round-bottom flask equipped with a nitrogen inlet adapter with a magnetic stirring rod and a rubber diaphragm 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 over 20 minutes using a syringe. The resulting mixture was stirred for 30 minutes, and MeI (5 mL, 81 mmol) was added dropwise over 5 minutes at -78°C. The cooling bath was then removed, the reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour, followed by quenching with saturated aqueous NH4Cl (200 mL). The mixture was transferred to a separating 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 x 100 mL), the combined organic extract was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexane) to obtain 2,5-dibromo-3-fluoro-4-methyl-pyridine (12.0 g, 44.6 mmol, 94% yield) as a colorless crystallized oil.

[0658] 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 one-neck round-bottom flask equipped with a magnetic stirring rod and a nitrogen inlet adapter with a rubber diaphragm. This solution was cooled to -78°C, and nBuLi (9.8 mL, 24.5 mmol) was added dropwise over 10 minutes using a syringe. The resulting heterogeneous solution was stirred at -78°C for 20 minutes, after which N,N-dimethylacetamide (3.2 mL) was added dropwise over 1 minute. The reaction mixture was stirred for 30 minutes and quenched at -78°C with aqueous saturated NH4Cl (50 mL). The resulting two-phase 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 x 100 mL). The combined organic extract was washed with brine, dried on Na2SO4, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (silica gel, 0% to 40% ethyl acetate in hexane) to obtain the corresponding 2-acetylpyridine (2.8 g, 12.1 mmol, 54% yield) as a colorless crystallized oil.

[0659] Step c: A mixture of 2-acetylpyridine (2.8 g, 12.0 mmol) and deoxo-fluorine (6.7 mL, 36 mmol) from Step b in toluene (60 mL) was placed in a 250 mL one-neck round-bottom flask equipped with a stirring rod and a reflux condenser, along with a drying tube. The mixture was maintained at 70°C for 24 hours. Despite incomplete conversion, the two-phase reaction mixture was cooled to ambient temperature and poured into saturated aqueous NaHCO3 (200 mL) under vigorous stirring. The mixture was then diluted with EtOAc (200 mL) and filtered through a Celite pad. The organic phase was separated, and the aqueous phase was further extracted with EtOAc (2 x 70 mL). The combined organic extract was washed with brine, dried over Na2SO4, and concentrated and dried. The crude material was fractionated by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexane) to obtain 5-bromo-2-(1,1-difluoroethyl)-3-fluoro-4-methylpyridine (1.9 g, 7.5 mmol, 63% yield) as a yellowish liquid.

[0660] The protocol for the following steps was the same as in Example 134. Title compound characterization data: 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). ESI MS [M+H] + - C 19 H 16F5N2, calculated value 367.1, measured value 367.2).

[0661] Example 140: (8R)-8-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-indene-4-yl]-3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile.

[0662]

[0663] Step a: DMAP (1.4 g, 11.2 mmol) and triethylamine (10.4 ml, 75 mmol, 2 equivalents) were added to an ice-cold solution of (1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-indene-1-ol (11.5 g, 37.3 mmol) in dichloromethane (190 ml, 0.2 M), followed by the dropwise addition of acetic anhydride (7.1 ml, 75 mmol, 2 equivalents). The solution was heated to room temperature and stirred for 1 hour. After completion, the reaction mixture was quenched with saturated aqueous NaHCO3, the resulting solution was extracted with dichloromethane (2x), dried over Na2SO4, and concentrated over Celite. The crude material was purified by flash chromatography (0-10% ethyl acetate in hexane) on silica gel to obtain [(1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-indene-1-yl]acetate (13.1 g, 100% yield). ESI MS [M+H] + - C 12 H 12 BrFO4S, calculated value 351.0, measured value 351.0.

[0664] Step b: A solution of dichloroethane (0.2 M, 190 ml) containing [ (1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-indene-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 equivalents) was heated under reflux for 90 minutes. After completion, the reaction mixture was cooled and partitioned between ethyl acetate and saturated NaHCO3. The organic part was collected, washed with dilute Na2S2O3, dried over Na2SO4, and concentrated over Celite. The crude material was purified by flash chromatography (5% ethyl acetate in a 1:3 ratio of CH2Cl2:hexane) on silica gel to obtain two brominated diastereomers, [(1S,2S,3R)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-indene-1-yl]acetate (6.83 g, 41% yield) and [(1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-indene-1-yl]acetate (2.5 g, 15% yield). The diastereomer products eluted in the order listed.

[0665] Step c: A 0.5 M aqueous solution of LiOH (5.93 ml, 1.5 equivalents) was added to a solution of [(1S,2S,3R)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-indene-1-yl]acetate (6.73 g, 15.6 mmol) in THF (0.08 M, 195 ml) at 0°C, and the reaction mixture was stirred at 0°C for 3 hours, at which time the reaction mixture was quenched with 1N HCl at 0°C. The resulting solution was extracted three times with methylene chloride, the organic matter was dried over Na2SO4, and flashed with 0 to 20% ethyl acetate in [1:1 hexane:dichloromethane] to obtain (1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-indene-1-ol (3.68 g, 61% yield).

[0666] Step d: Sodium hydride (60% dispersion in mineral oil, 440 mg, 10.5 mmol, 1.1 equivalents) was slowly added at 0°C to a solution of (1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-indene-1-ol (3.68 g, 9.5 mmol) and benzyl bromide (6.77 ml, 9.75 g, 57 mmol, 6 equivalents) in THF (38 ml, 0.25 M for indanol) and DMF (9.5 ml, 1 M for indanol). The reaction mixture was heated 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 completed within 2 hours. The solution was quenched with 1N HCl, extracted with ethyl acetate, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography (0 → 20% ethyl acetate in hexane) on silica gel to obtain (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).

[0667] Step e: Silver perchlorate hydrate (unknown hydrate stoichiometry) (2.13 g, ~10.3 mmol) was added 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), and the reaction mixture was heated overnight at 75°C while excluding light. After 23 hours, the starting material was almost completely consumed, and the reaction mixture was quenched with H2O. Upon dilution with MTBE, the silver salt could be filtered from the two-phase mixture, the organic part was collected, and dried over sodium sulfate. The diastereoisomer alcohol products (1R,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene-1-ol (750 mg, 35% yield) and (1S,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene-1-ol (470 mg, 22% yield) were obtained by purification by flash chromatography (0 → 5 → 5% ethyl acetate in dichloromethane). The diastereoisomer products were eluted in the order listed, and the latter were used through an additional step. ESI MS [M+Na] + - C 17 H 16 BrFO4S, calculated value 437.0, measured value 437.0.

[0668] Step f: (diethylamino)sulfur trifluoride (492 μl, 600 mg, 3.7 mmol, 4 equivalents) was added to an ice-cold solution of (1S,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene-1-ol (386 mg, 0.93 mmol) in dichloromethane (0.1 M, 9.3 ml), the resulting solution was stirred at a temperature of 0 to 10°C for 3 hours, and at this point, it was quenched with saturated NaHCO3. The organic part was extracted with ethyl acetate, dried over Na2SO4, and purified by flash chromatography (10% ethyl acetate in hexane, isolytic solvent) to obtain two fluorinated products: (1S,2S,3S)-7-bromo-1,2-difluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (unintended, less polar, 158 mg, 40% yield) and (1R,2S,3S)-7-bromo-1,2-difluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (intended, more polar, 234 mg, 60% yield).

[0669] 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 equivalents), KOAc (121 mg, 1.23 mmol, 2.2 equivalents), and PdCl2 (dppf) (44 mg, 0.06 mmol, 10 mol%) were combined in dioxane (5.6 ml, 0.1 M). The resulting solution was aerated with nitrogen and heated to 100°C until all starting materials were consumed (2.5 hours). The crude reaction mixture was filtered over Celite, concentrated, dissolved in ethyl acetate, and washed with water to remove residual KOAc. The resulting solid was used in the Suzuki cross-coupling step without further purification.

[0670] The title compound was completed in a manner similar to Example 134. 1 H 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).

[0671] Example 141: 8-[(1S)-7-cyano-2,2-difluoro-1-hydroxy-1,3-dihydroindene-4-yl]-3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0672]

[0673] Step a: Performed in a manner similar to Step a of Example 134.

[0674] Step b: TBSOTf (17.5 mL, 76 mmol, 2 equivalents) was added to a solution of the product from Step a (10 g, 38 mmol, 1 equivalent) in CH2Cl2 (190 mL, 0.2 M) at 0°C, followed by Et3N (32 mL, 228 mmol, 6 equivalents). The reaction mixture was allowed to be heated overnight at room temperature. The reaction mixture was concentrated and then dried under vacuum for 45 minutes. The crude silyl enol ether was dissolved in MeCN (190 mL, 0.2 M), followed by the addition of selectofluoride (20.2 g, 57 mmol, 1.5 equivalents), and the reaction mixture was stirred at room temperature for 2 hours or until determined to be complete 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 with MgSO4 and concentrated. The crude product was purified by flash column chromatography (SiO2, 0 → 50% EtOAc / hexane) to obtain difluoroketone as a pale yellow solid (7.0 g, 24.9 mmol, 66%). 1 ¹H 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).

[0675] Step c: Performed in a manner similar to Step b of Example 134. 1 ¹H 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).

[0676] Step d: Performed in a manner similar to Step c of Example 134. ESI MS [M+H] + - C 15 H 20BrClF2OSi calculated value 397.0, measured value 397.0.

[0677] Step e: Performed in a manner similar to Step d of Example 134. The crude product was used in Step f without column chromatography purification.

[0678] Step f: Performed in a manner similar to Step e of Example 134. ESI MS [M+H] + - C 26 H 27 ClF3NOSi calculated value 490.2, measured value 490.2.

[0679] Step g: 5 equivalents of Et3N were added to the reaction mixture and carried out in a manner similar to Step f of Example 134. The diastereomer was not separated at this step. ESI MS [M+H] + - C 26 H 29 ClF3NOSi calculated value 492.2, measured value 492.2.

[0680] Step h: Aryl chloride (100 mg, 0.20 mmol, 1 equivalent), K4Fe(CN)6·3H2O (59 mg, 0.14 mmol, 0.7 equivalents), XPhos Pd G3 (17 mg, 0.02 mmol, 0.1 equivalents), XPhos (10 mg, 0.02 mmol, 0.1 equivalents), and KOAc (4 mg, 0.04 mmol, 0.2 equivalents) were dissolved in a 1:1 water / dioxane mixture (2 mL, 0.1 M). The reaction mixture was aerated with nitrogen for 10 minutes and then heated to 100°C. After 2 hours, the reaction was determined to be complete by LCMS. The reaction mixture was allowed to cool 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 organic matter was dried and concentrated over Na2SO4. The crude product was purified by flash column chromatography (SiO2, 0 → 50% EtOAc / hexane) to obtain the aryl nitrile product. ESI MS [M+H]+ - C 27 H 29 F3N2OSi calculated value 483.2, measured value 483.2.

[0681] 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 diastereoisomers (40 mg, 0.11 mmol, 54% over two steps). ESI MS [M] + - C 21 H 15 F3N2O calculated value 369.1, measured value 369.1. 1 H 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).

[0682] 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

[0683]

[0684] Step a: LDA solution (2.0 M in THF / heptane / ethylbenzene, 17 mL, 1.5 equivalents) was added dropwise under N2 at -78°C to a solution of 3-bromo-4-chlorobenzotrifluoride (3.5 mL, 23 mmol, 1.0 equivalent) in THF (75 mL) in a 250-mL round-bottom flask. After stirring at this temperature for 15 minutes, DMF (3.6 mL, 46 mmol, 2.0 equivalents) was added dropwise at -78°C, and the resulting mixture was stirred at this temperature for an additional 1.5 hours when TLC indicated that the reaction was complete. The reaction mixture was then quenched with saturated aqueous NH4Cl solution (60 mL), heated to room temperature, and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with brine (60 mL), and dried over Na2SO4. The product was concentrated under reduced pressure to obtain the target crude aldehyde product and its isomers, which were used directly in the subsequent step without purification (6.52 g).

[0685] Step b: The crude product from Step a (another batch, total 8.45 g) in a 250-mL round-bottom flask was dissolved in MeOH (100 mL) and cooled to 0°C. NaBH4 (1.67 g, 1.5 equivalents) was added in small increments, and the resulting mixture was stirred at 0°C for 30 minutes until TLC indicated that the reaction was complete. The reaction mixture was quenched with H2O and then concentrated under reduced pressure to remove most of the MeOH. The residue was extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with brine (60 mL), and dried over Na2SO4. The product was concentrated under reduced pressure and purified by flash chromatography (SiO2, 0 → 30% EtOAc / Hex) to obtain a white powder (2.75 g, 9.50 mmol, 41% yield, over 2 steps). 1¹H 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).

[0686] Step c: Chloromethyl methyl ether (1.2 mL, 16.0 mmol, 2.0 equivalents) was added dropwise at room temperature to a solution of the product from step b (2.30 g, 8.0 mmol, 1.0 equivalents) and i-Pr2NEt (2.8 mL, 16.0 mmol, 2.0 equivalents) in DCM (40 mL). The resulting mixture was stirred at this temperature for 22 hours, then quenched with a saturated aqueous NaHCO3 solution (20 mL). The aqueous phase was extracted with DCM (30 mL). The organic layers were combined, washed with brine (20 mL), and dried over Na2SO4. The crude product (1.84 g) was obtained by concentrating under reduced pressure and used directly in the subsequent step.

[0687] Step d: The crude product from step c (1.06 g) and DMF (20 mL) were filled into a 40-mL vial. CuCN (1.43 g, 16 mmol, 2.0 equivalents) was added, and the resulting mixture was heated at 150°C for 2 hours, then cooled to room temperature and diluted with EtOAc (50 mL). The organic phase was then washed with H2O (20 mL x 2) and brine (20 mL) and dried over Na2SO4. The product was concentrated under reduced pressure and purified by flash chromatography (SiO2, 10 → 40% EtOAc / Hex) to obtain a yellow solid (1.00 g, 3.6 mmol, 45% yield, over 2 steps). 1¹H 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).

[0688] Step e: A 40-mL vial was filled with the product from Step d (1.00 g, 3.6 mmol, 1.0 equivalent), B2Pin2 (1.17 g, 4.6 mmol, 1.3 equivalent), PCy3-Pd-G2 (0.213 g, 0.36 mmol, 10 mol%), KOAc (0.707 g, 7.2 mmol, 2.0 equivalent), and 1,4-dioxane (10 mL). The reaction mixture was degassed by N2 bubbling for 10 minutes and then heated. After stirring at 100°C for 2 hours, the reaction mixture was cooled, diluted with EtOAc (20 mL), washed with H2O (10 mL), dried over Na2SO4, and concentrated to obtain a crude product (1.84 g), which was used in the subsequent step.

[0689] Step f: The crude product from Step e (1.84 g), alkenyl trilate (1.16 g, 3.6 mmol, 1.0 equivalent), Pd(dppf)Cl2 (0.263 g, 0.36 mmol, 10 mol%), Na2CO3 (0.763 g, 7.2 mmol, 2.0 equivalent), 1,4-dioxane (10 mL), and H2O (2 mL) were filled into a 40-mL vial. The reaction mixture was degassed by N2 bubbling for 10 minutes and then heated. After stirring at 100°C for 1 hour, the reaction mixture was cooled, filtered, concentrated, and purified by flash chromatography (SiO2, 10 → 30% EtOAc / Hex) to obtain the product (0.743 g, 1.78 mmol, 50% yield, over 2 steps). 1H 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 H...

Claims

Claim 1 A compound having the structure of the following chemical formula (II), or a salt, hydrate, or solvate thereof that is permitted by the constraints: Here, Z is N or CR 6 Igo;Y 2 and Y 3 CR each independently 2 R 3 , NR 4 Selected from the group consisting of , O and SO2; Y 4 is CR 2 R 3 , NR 4 Selected from the group consisting of and SO2; W 1 is CR 5 Selected from the group consisting of and N, where R 5 is H, halogen, CN, NO2, 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of;W 2 and W 3 CR each independently 5 Selected from the group consisting of and N, where each R 5 is independently 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of;R 1 Silver halogen, CN, NO2, -NR a R b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a , -C(O)NR a R b , -S(O)(=NH)R a , and -S(O)2NR a R b Selected from a group consisting of; each R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of; each R 4 is independently H, C 1-4 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a Selected from;R 6 H, C 1-4 Selected from the group consisting of alkyl, OH, F, and CN; X 1 is N or CR 8a Igo;X 2 is N or CR 8b Igo;R 8a is independently H, CN, NH2, 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;R 8b is H, halogen, CN, NH2, 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;R 9 and R 10 It independently contains H, halogen, CN, NO2, and 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;R 11 Silver halogen, CN, NO2, methyl, C 1-6 Haloalkyl, 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)2NR c R b , -S(O)(=NH)R c , -S(O)2R c , selected from the group consisting of phenyl, 5- to 6-membered heterocyclic rings and 5- to 10-membered heteroaryl rings, wherein the heterocyclic and heteroaryl rings have 1-3 heteroatoms selected from N, O, and S as ring vertices; phenyl is optionally fused to a 5- or 6-membered heterocycle having 1-2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl, heterocyclic or heteroaryl ring is halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, 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 alkyls; optionally, two members attached to the same carbon of the heterocyclic ring together form =CH2 or oxo (=O); or R 9 and R 10 It combines to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 Optionally substituted with one or more substituents independently selected from, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices; or R 10 and R 11 It combines to form a 5- or 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 Optionally substituted with one or more substituents independently selected from, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices; each R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 is independently 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 Selected from the group consisting of; or two Rs on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Moiety combines to form an oxo; each R a and R b is independently H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, and C 1-8 Selected from the group consisting of hydroxyalkyl; R c is, in the case where, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6 Selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O and S as ring vertices. Claim 2 In claim 1, a compound having the structure of the following chemical formula (III) or a salt thereof that is permitted by limitation: Here Y 2 and Y 3 CR each independently 2 R 3 , NR 4 Selected from the group consisting of , SO2 and O; Y 4 is CR 2 R 3 , NR 4 Selected from the group consisting of and SO2; W 1 and W 3 are each independently selected from CH and N; Z is N or CR 6 Igo;R 1 is selected from the group consisting of halogens and CN; each R 2 and R 3 Each independently contains H, halogen, CN, NH2, NO2, OH, and 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of; each R 4 is independently H, C 1-3 Alkyl, C 3-6 Cycloalkyl, and -C(O)R a Selected from;R 5a is selected from the group consisting of hydrogen, halogens, and CN; R 6 is H and;X 1 is N or CR 8a Igo;X 2 is N or CR 8b Igo;R 8a is H, 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;R 8b is 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;R 9 and R 10 It independently contains H, halogen, CN, NO2, and 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;R 11 Silver halogen, CN, NO2, methyl, C 1-6 Haloalkyl, 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 , -C(O)OH, -S(O)2NR c R b , -S(O)(=NH)R c , -S(O)2R c , selected from the group consisting of phenyl, a 5- or 6-membered heterocyclic ring and a 5- to 10-membered heteroaryl ring, wherein the heterocyclic or heteroaryl ring has 1 to 3 heteroatoms selected from N, O, and S as ring vertices; phenyl is optionally fused to a 5- or 6-membered heterocycle having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl, heterocyclic, or heteroaryl ring is halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, 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 alkyls; optionally, two members attached to the same carbon of the heterocyclic ring together form =CH2 or oxo (=O); or R 9 and R 10 It combines to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 Optionally substituted with one or more substituents independently selected from, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices; or R 10 and R 11 It combines to form a 5- or 6-membered carbocyclic, heterocyclic, or heteroaryl ring, which is R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 Optionally substituted with one or more substituents independently selected from, and the heterocyclic or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O, and S as ring vertices; each R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 is independently 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 Selected from the group consisting of; or two Rs on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 Moiety combines to form an oxo; each R a and R b is independently H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, and C 1-3 Selected from the group consisting of hydroxyalkyl; R c is, in the case where, H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-6 Selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryls, and each heterocycloalkyl or heteroaryl ring has 1 to 4 heteroatoms selected from N, O, and S as ring vertices. Claim 3 In claim 1, a compound having the structure of the following formula (IV-a), or a salt, hydrate, or solvate thereof that is financially permissible: Here Y 2 , Y 3 and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of and SO2; R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of; each R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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)2R a and -C(O)NR a R b Selected from a group consisting of; each R 4 is independently H, C 1-4 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a Selected from a group consisting of;R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b It is selected from a group consisting of. Claim 4 In Paragraph 3, X 1 and X 2 A compound that is independently selected from the group consisting of CH and N. Claim 5 In claim 1, a compound having the structure of the following formula (IV-b), or a salt, hydrate, or solvate thereof that is permitted by limitation: Here, subscript m is 1, 2, 3, 4, 5, 6, 7, or 8; 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 Indicate one or more of the following; Y 2 , Y 3 , and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of and SO2; R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -S(O)2R a , and -C(O)NR a R b Selected from a group consisting of; each R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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)2R a , and -C(O)NR a R b Selected from a group consisting of; each R 4 is independently H, C 1-4 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a Selected from;R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of; each R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 is independently 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 Selected from the group consisting of; or two Rs on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 Moiety combines to form iodine. Claim 6 In paragraph 5, R 11 This is a phenyl, 5- or 6-membered heterocyclic or 5- to 10-membered heteroaryl ring, wherein the heterocyclic 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 heterocycle having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; and the phenyl, heterocyclic or heteroaryl ring is a halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, 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 A compound optionally substituted with 1 to 3 members independently selected from alkyl; optionally, two members attached to the same carbon of a heterocyclic ring together forming =CH2 or oxo (=O). Claim 7 In claim 1, a compound having the structure of the following formula (IV-c), or a salt, hydrate, or solvate thereof that is permitted by limitation: Here A 1 is O or CHR 13 Igo;Y 2 , Y 3 , and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of and SO2; R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R b Selected from a group consisting of;R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of;R 11 Silver halogen, CN, NO2, methyl, C 1-6 Haloalkyl, 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)2NR c R b , -S(O)(=NH)R c , and -S(O)2R c Selected from a group consisting of; each R 13 , R 14 , and R 15 is independently 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 Selected from a group consisting of;R 16 H, C 1-4 Alkyl and C 1-4 It is selected from the group consisting of fluoroalkyls. Claim 8 In paragraph 1, Y 2 Ga CR 2 R 3 and, here, each R 2 and R 3 is H and; Y 3 and Y 4 Each CR 2 R 3 and, here, each R 2 and R 3 is a compound independently selected from H and F, or its constraint-allowable salt, hydrate, or solvate. Claim 9 In claim 1, a compound having the structure of the following formula (IV-f), or a salt, hydrate, or solvate thereof that is financially permissible: . Claim 10 In claim 1, a compound having the structure of the following formula (Va), or a salt, hydrate, or solvate thereof that is permitted by limitation: . Claim 11 In claim 1, a compound having the structure of the following formula (Vb), or a salt, hydrate, or solvate thereof that is permitted by limitation: Here W 1 Regarding, R 5 is H, halogen, CN, NO2, 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b Selected from a group consisting of;W 3 Regarding, R 5 is 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)2R a , -CO2R a , -C(O)R a , -C(O)NR a R b , -S(O)2NR a R b , -S(O)(=NH)R a , and -NR a R b It is selected from a group consisting of. Claim 12 In Paragraph 11, R 9 and R 10 These are each independently 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)2NR a R b , and -S(O)2R a Selected from a group consisting of;R 11 This halogen, CN, NO2, methyl, C 1-6 Haloalkyl, 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)2NR c R b , and -S(O)2R c A compound selected from the group consisting of, or a salt, hydrate, or solvate thereof that is permitted by the constraints thereof. Claim 13 In claim 1, a compound having the structure of the following chemical formula (Vd), or a salt, hydrate, or solvate thereof that is permitted by limitation: Here Y 2 , Y 3 , and Y 4 are respectively CR 2 R 3 Igo;R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, -S(O)2R a , and -C(O)NR a R b Selected from a group consisting of;R 2 and R 3 Each independently consists of H, halogen, CN, OH, and 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)2R a , -C(O)NR a R b , and -NR a R b Selected from a group consisting of;R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b It is selected from a group consisting of. Claim 14 In claim 1, a compound having the structure of the formula (Vf), or a salt, hydrate, or solvate thereof that is permitted by limitation: Here, subscript m is 1, 2, 3, 4, 5, 6, 7, or 8; 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 Indicate one or more of the following; Y 2 , Y 3 , and Y 4 CR each independently 2 R 3 , NR 4 Selected from the group consisting of and SO2; R 1 Silver halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -S(O)2R a , and -C(O)NR a R b Selected from a group consisting of; each R 2 and R 3 Each independently contains H, halogen, CN, NO2, OH, and 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)2R a and -C(O)NR a R b Selected from a group consisting of; each R 4 is independently H, C 1-4 Alkyl, C 3-8 Cycloalkyl, and -C(O)R a Selected from;R 5 is 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)2R a , -C(O)NR a R b , and -S(O)2NR a R b Selected from a group consisting of; each R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 is independently 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 Selected from the group consisting of; or two Rs on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 Moiety combines to form iodine. Claim 15 A compound selected from the group consisting of the following or a pharmaceutically permissible salt thereof: Claim 16 In paragraph 15, a compound selected from the group consisting of the following or a pharmaceutically permissible salt thereof: Claim 17 In paragraph 15, A compound having a structure. Claim 18 A pharmaceutical composition comprising a compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for use in a method for treating cancer, wherein the method comprises administering a therapeutically effective amount of the compound to a subject requiring treatment for cancer. Claim 19 A pharmaceutical composition according to claim 18, wherein the cancer is prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, gastric cancer, endometrial cancer, uterine cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, cervical cancer, skin cancer (including melanoma and basal carcinoma), mesothelioma, leukocyte cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, intestinal cancer, lung cancer (including small cell lung carcinoma and non-small cell lung carcinoma), adrenal cancer, thyroid cancer, kidney cancer, or bone cancer; or glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, cutaneous basal cell carcinoma, or testicular seminoma. Claim 20 A pharmaceutical composition according to claim 18, wherein the cancer is selected from the group consisting of melanoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, Kaposi's sarcoma, renal cell carcinoma, head and neck cancer, esophageal cancer, and urothelial carcinoma. Claim 21 A pharmaceutical composition in which the cancer in paragraph 18 is a renal cell carcinoma. Claim 22 A combination comprising a compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent. Claim 23 A combination according to claim 22, wherein at least one additional therapeutic agent comprises an immune checkpoint inhibitor. Claim 24 A combination according to claim 23, wherein the immune checkpoint inhibitor blocks the activity of at least one of PD-1, PD-L1, BTLA, LAG3, B7 family member, TIM3, TIGIT, or CTLA4. Claim 25 A combination according to claim 24, wherein the immune checkpoint inhibitor blocks the activity of PD-1 or PD-L1. Claim 26 In claim 25, the combination wherein the immune checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, cemiflimab, and zimberellimab. Claim 27 In paragraph 24, a combination in which the immune checkpoint inhibitor blocks the activity of TIGIT. Claim 28 A combination according to paragraph 22, wherein at least one additional therapeutic agent comprises a chemotherapy agent. Claim 29 In paragraph 22, the above at least one additional therapeutic agent A combination comprising an A2R antagonist, a CD73 inhibitor, and / or radiation. 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