Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2alpha

Abstract

To provide compounds that inhibit HIF-2α.SOLUTION: There are described compounds having formula (I): and compositions containing (one or more of) the compounds, and a method for synthesizing the compounds. There are also described the use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer- and immune-related disorders that are mediated, at least in part, by HIF-2α.SELECTED DRAWING: None

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of priority of U.S. Provisional Application No. 62 / 991,952, filed Mar. 19, 2020, and U.S. Provisional Application No. 63 / 120,875, filed Dec. 3, 2020, each of which is hereby incorporated by reference in its entirety for all purposes.

Background Art

[0002] Hypoxia - inducible factor (HIF) transcription factors play important roles in cellular responses to hypoxia availability [Immunity. 2014 Oct 16;41(4):518 - 528]. HIF is a heterodimeric transcription factor consisting of a common constitutive subunit called aryl hydrocarbon receptor nuclear transporter (ARNT, or HIF - β), and one of three HIF - α subunits [J. Med. Chem. 2015, 58, 5930 - 5941]. Under normal conditions, this α - subunit is hydroxylated by prolyl - 4 - hydroxylase (PHD) at conserved proline residues and then 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.].

[0003] Among three different α-subunit isoforms, HIF-1α, HIF-2α, and HIF-3α, which has not been characterized as well, overexpression of HIF-1α and HIF-2α has been associated with poor clinical outcomes in various cancer patients. Specifically, HIF-2α has been found to be a marker of poor prognosis in glioblastoma, neuroblastoma, head and neck squamous cell carcinoma, and non-small cell lung cancer. Hypoxia is also common in many acute and chronic inflammatory disorders such as inflammatory bowel disease and rheumatoid arthritis [J. Clin Invest. 2016;126(10):3661-3671].

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

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

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

[0007]

Chem.

[0008] In related aspects, provided herein is a method of treating a HIF-2α-mediated disease or disorder in a subject (e.g., a human) comprising administering to the subject a therapeutically effective amount of at least one HIF-2α inhibitor described herein. HIF-2α-mediated diseases and disorders include, but are not limited to, cancer, inflammation, autoimmune disorders, and metabolic disorders, as described hereinafter. Other diseases, disorders, and conditions that can be treated or prevented, in whole or in part, by modulating HIF-2α activity are candidate indications for the HIF-2α inhibitor compounds provided herein.

[0009] Also provided herein is the use of an HIF-2α inhibitor described herein in combination with one or more additional agents described hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

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

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

[0012] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Further, it is noted that the claims may be drafted to exclude any optional element. Accordingly, this description is intended to serve as a basis for use of such exclusive terms as "solely", "only", etc. in connection with the recitation of claim elements, or as a basis for use of "negative" limitations.

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

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

[0015] The term "alkyl", by itself or as part of another substituent, unless otherwise specified, has the number of carbon atoms designated (i.e., C 1-8represents a linear or branched hydrocarbon group having 1 to 8 carbons. Alkyl is 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 etc. may contain any number of carbons. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0016] The term "hydroxyalkyl" refers to an alkyl group having the indicated number of carbon atoms (e.g., C 1-6 or C 1-8 ) and substituted with 1 or 2 hydroxy (OH) groups.

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

[0018] The term "alkylene" refers to a linear or branched saturated aliphatic group having a specified number of carbon atoms and bonding at least two other groups, i.e., a divalent hydrocarbon group. The two moieties attached to the alkylene can be attached to the same atom of the alkylene group or to different atoms. For example, linear alkylene is -(CH 2 ) n- can be a divalent group, 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 can be substituted or unsubstituted. It should be understood that when a group containing alkylene is optionally substituted, the optional substitution can be present in the alkylene portion of the moiety.

[0019] The terms "cycloalkyl", "carbocyclic", or "carbocyclic ring" refer to a hydrocarbon ring having a specified number of ring atoms (e.g., C 3-6 cycloalkyl), and being completely saturated or having one or fewer double bonds between ring vertices. Also, "cycloalkyl" also means referring to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. In some embodiments, the cycloalkyl compound of the present disclosure is a monocyclic C 3-6 cycloalkyl moiety.

[0020] The term "heterocycloalkyl", "heterocycle", or "heterocyclic ring" refers to a cycloalkyl ring having a specified number of ring vertices (or ring members) and having 1 to 5 heteroatoms selected from N, O, and S that replace 1 to 5 carbon vertices, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) is 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 heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. The heterocycloheteroalkyl group can be attached to the remainder of the molecule via a ring carbon or a heteroatom. In some embodiments, the heterocycle is a 5- to 6-membered heterocycle.

[0021] A wavy line that intersects a single bond, double bond, or triple bond in any chemical structure shown herein, as used herein

[0022]

Chem.

[0023] The terms “halo” or “halogen,” alone or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom unless otherwise specified. Further, terms such as “haloalkyl” mean including mono-haloalkyl and poly-haloalkyl. For example, the term “C 1-4 haloalkyl” means including trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

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

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

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

[0027] Optional substituents for an alkyl group (often including groups referred to as alkylene, alkenyl, and alkynyl) can be various groups, e.g., a number of from zero to (2m'+1) of halogen, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -CO 2 R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O) 2 R', -NH-C(NH 2 )=NH, -NR'C(NH 2 )=NH, -NH-C(NH 2 )=NR', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R'', -NR'S(O) 2 R'', -CN (cyano), -NO 2 , and can be a group selected from aryl, aryloxy, oxo (=O), cycloalkyl and heterocycloalkyl, where m' is the total number of carbon atoms in such a group. R', R'' and R''' are each independently hydrogen, unsubstituted C 1-8 alkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, C 1-8 alkoxy or C 1-8 thioalkoxy group, or unsubstituted aryl-C 1-4 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'' means including 1-pyrrolidinyl and 4-morpholinyl.

[0028] Optional substituents for cycloalkyl and heterocycloalkyl groups are various groups such as -C(O)OR', halogen, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -CO 2 R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O) 2 R', -NH-C(NH 2 )=NH, -NR'C(NH 2 )=NH, -NH-C(NH 2 )=NR', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R'', -NR'S(O) 2 R'', -CN (cyano), -NO 2 , aryl, aryloxy, and oxo (=O) optionally substituted alkyl. R', R'' and R''' are each independently hydrogen, unsubstituted C 1-8 alkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, C 1-8 alkoxy group or C 1-8 thioalkoxy group, or unsubstituted aryl-C 1-4 alkyl group.

[0029] Optional substituents for cycloalkyl and heterocycloalkyl groups can also include olefin (=CR'R''), where R' and R'' are each independently hydrogen, unsubstituted C 1 - 8 alkyl group, unsubstituted aryl group, aryl group substituted with 1 to 3 halogens, C 1-8 alkoxy group or C 1-8 thioalkoxy group, or unsubstituted aryl-C 1-4 alkyl group. For example, the olefin can be an unsubstituted olefin (=CH 2 ).

[0030] Similarly, the optional substituents for aryl and heteroaryl groups are diverse and include, for example, a number in the range from zero to the total number of open valences on the aromatic ring system of, -halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO 2 , -CO 2 R', -CONR'R'', -C(O)R', -OC(O)NR'R'', -NR''C(O)R', -NR”C(O) 2 R', -NR'-C(O)NR''R''', -NH-C(NH 2 )=NH, -NR'C(NH 2 )=NH, -NH-C(NH 2 )=NR', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R'', -NR'S(O) 2 R'', -N 3 , perfluoro(C 1 -), 4 )alkoxy, and perfluoro(C 1 -), 4 )alkyl; where R', R'' and R''' are independently selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl. Other suitable substituents include each of the above aryl substituents attached to the ring atoms by an alkylene tether of 1 to 6 carbon atoms.

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

[0032] The term "heteroatom" as used herein means including oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

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

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

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

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

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

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

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

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

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

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

[0043] Terms such as "treat", "treating", and "treatment" refer to a course of action (e.g., administering an inhibitor of HIF-2α or a pharmaceutical composition containing the same) that is initiated to temporarily or permanently remove, reduce, suppress, alleviate, or improve at least one of the underlying causes of a disease, disorder, or condition, or at least one of the symptoms associated with the disease, disorder, or condition that is afflicting a subject after the disease, disorder, or condition, or its symptoms, have been diagnosed, observed, etc. Thus, treatment includes inhibiting an active disease (e.g., preventing the onset or further progression of a disease, disorder, or condition or its associated clinical symptoms).

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

[0045] Terms such as "prevent", "preventing", and "prevention" generally refer to a course of action (e.g., administering an inhibitor of HIF-2α or a pharmaceutical composition containing the same) that, with respect to a subject having a predisposition to a particular disease, disorder, or condition, prevents, suppresses, stops, or reduces the risk that the subject will develop the disease, disorder, condition, etc. (e.g., as determined by the absence of clinical symptoms), either primarily or permanently, or delays their onset (e.g., prior to the onset of the disease, disorder, condition, or their symptoms). In certain instances, these terms also refer to delaying the progression of a disease, disorder, or condition or preventing their progression to a harmful or undesirable state.

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

[0047] The expression "therapeutically effective amount" refers to the administration of a drug to a subject, either alone or as part of a pharmaceutical composition, and either as a single dose or as part of a series of doses, in an amount that, when administered to the subject, can provide any detectable beneficial effect on any symptom, aspect, or feature of a disease, disorder, or condition. A therapeutically effective amount can be determined by measuring the relevant physiological effect and can be adjusted with respect to the administration regimen and diagnostic analysis of the subject's condition. By way of example, measurement of the serum level of a HIF-2α inhibitor (or, for example, their metabolites) at a particular post-administration time can indicate whether a therapeutically effective amount has been used.

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

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

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

[0051] The terms "modulate", "modulation", etc. refer to the ability of a molecule (e.g., an activator or inhibitor) to directly or indirectly enhance or reduce the function or activity of HIF-2α. A modulator can act alone or can use cofactors, for example, proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds and other bioorganic molecules.

[0052] The "activity" of a molecule can be described or referred to in terms of 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; the modulation of the activity of other molecules, etc. The term "proliferative activity" includes, for example, normal cell division and activities that promote, are required for, or are particularly associated with cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.

[0053] As used herein, relative terms such as "comparable", "comparable activity", "activity comparable to", "comparable effect", "effect comparable to", etc. are terms that can be considered quantitatively and / or qualitatively. The meaning of this term is often determined by the context in which it is used. As an example, two agents that both activate a receptor can be considered to have comparable effects from a qualitative perspective, but if, when determined in an assay recognized in the art (e.g., a dose-response assay) or an animal model recognized in the art, one agent can only achieve 20% of the activity of the other agent, then these two agents can be considered not to have comparable effects from a quantitative perspective. When comparing one result to another (e.g., comparing one result to a reference standard), "comparable" often (but not always) means that one result deviates from the reference standard by less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%. In certain embodiments, if one result deviates from the reference standard by less than 15%, less than 10%, or less than 5%, then it is comparable to the reference standard. As an example, without limitation, activity or effect can refer to efficacy, stability, solubility, or immunogenicity.

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

[0055] Selective compounds may be particularly useful in the treatment of certain disorders or may provide a reduction in the likelihood of undesirable side effects. In one embodiment, the compounds of the present disclosure are more selective than other HIF isoforms. In yet another embodiment, the compounds of the present disclosure are more selective than 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 the compounds described herein against HIF-2α to the inhibition of the compounds described herein against another protein. In one embodiment, the selective inhibition of HIF-2α is at least 1000-fold, 500-fold, or 100-fold, or 20-fold greater than the inhibition of another protein or isoform.

[0056] The compounds provided herein may have advantageous pharmacokinetic profiles, such as, for example, hepatocyte stability, clearance, and inhibition of CYP.

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

[0058] Disclosed compounds In one particular aspect, herein, Formula (I):

[0059]

Chemical formula

[0060]

Chemical formula

[0061] In some selected embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is such that each of Y 2 , Y 3 and Y 4 is CR 2 R 3

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

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

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

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

[0066] [Chemical formula] having, wherein Z is N or CR 6 ; Y 2 Y 3 and Y 4 are each independently selected from the group consisting of CR 2 R 3 NR 4 O, SO 2 and a bond; and 0 or 1 of Y 2 Y 3 and Y 4 is a bond; W 1 W 2 and W 3 are each independently selected from the group consisting of CR 5 and N; R 1 is H, halogen, hydroxy, CN, NO 2 -NR a R b C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 1-4 alkoxyC 1-4 alkyl, C 3-8 cycloalkyl, -S(O) 2 R a -C(O)NRa R b 、 -S(O)(=NH)R a 、 and -S(O) 2 NR a R b selected from the group consisting of; each R 2 and R 3 is H, halogen, CN, NO 2 、 OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-4 alkoxyC 1-4 alkyl, C 3-8 cycloalkyl, -S(O) 2 R a 、 -CO 2 R a 、 -C(O)R a 、 -C(O)NR a R b 、 -S(O) 2 NR a R b 、 -S(O)(=NH)R a 、 and -NR a R b independently selected from the group consisting of; each R 4 is H, C 1-4 alkyl, C 3-8 cycloalkyl, and -C(O)R a independently selected from, each R 5 is H, halogen, CN, NO 2 、 C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-4 alkoxyC 1-4 alkyl, C 3-8 cycloalkyl, -S(O) 2 R a 、 -CO 2 R a 、 -C(O)R a, -C(O)NR a R b , -S(O) 2 NR a R b , -S(O)(=NH)R a , and -NR a R b is independently selected from the group consisting of; X 1 is N or CR 8a ; X 2 is N or CR 8b ; R 8a and R 8b are H, halogen, CN, NH 2 , NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-4 alkoxyC 1-4 alkyl, C 3-6 cycloalkyl, -C(O)NR a R b , -S(O) 2 NR a R b , and -S(O) 2 R a is independently selected from the group consisting of; R 9 and R 10 are H, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyhaloalkyl, C 1-4 alkoxyC 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) 2 R a independently selected from the group consisting of; R 11 is H, halogen, CN, NO 2 、 C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyhaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 3-8 cycloalkyl, -NR c R b 、 -C(O)NR c R b 、 -C(O)OH, -S(O) 2 NR c R b 、 -S(O)(=NH)R c 、 -S(O) 2 R c 、 phenyl, a 5- to 6-membered heterocyclic ring or a 5- to 10-membered heteroaryl ring, wherein said heterocyclic ring and heteroaryl ring have 1 to 3 heteroatoms selected from N, O, and S as ring vertices; said phenyl is optionally condensed to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; said phenyl, heterocyclic ring, or heteroaryl ring is halogen, CN, NO 2 、 NH 2 、 C(O)NH 2 、 S(O) 2 CH 3 、 -CH 2 NH 2 、 C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyhaloalkyl and C 1-4 alkoxyC 1-4Optionally substituted with one to three members independently selected from alkyl; optionally, two members attached to the same carbon of the above heterocyclic ring together form =CH 2 or an oxo (=O) group; or R 9 and R 10 are bonded to form a 5-membered carbocyclic ring, heterocyclic ring or 6-membered carbocyclic ring, heterocyclic ring or heteroaryl ring optionally substituted with one or more substituents independently selected from R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 ; the above heterocyclic ring or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O and S as ring vertices; or R 10 and R 11 are bonded to form a 5- or 6-membered carbocyclic ring, heterocyclic ring or heteroaryl ring optionally substituted with one or more substituents independently selected from R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 ; the above heterocyclic ring or heteroaryl ring each has 1 to 4 heteroatoms selected from N, O and S as ring vertices; R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 each is H, halogen, CN, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 1-4 alkoxyC 1-4Alkyl and -NR a R b is independently 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 moieties are joined to form an oxo group; each R a and R b is independently selected from the group consisting of H, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, and C 1-8 hydroxyalkyl, R c when present, is H, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 3-6 cycloalkyl, 3 - to 6 - membered heterocycloalkyl, and 5 - to 6 - membered heteroaryl, wherein each said heterocycloalkyl ring or heteroaryl ring has 1 to 4 heteroatoms selected from N, O, and S as ring vertices.

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

[0068] In some embodiments, the compound of formula (II) is R 11 is SO 2 R c or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, R c is C 1-8 alkyl, or C 1-8 haloalkyl.

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

[0070]

Chemical formula

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

[0072]

Chemical formula

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

[0074]

Chemical formula

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

[0076] In some embodiments, the compound of formula (III) has each R 5a being halogen, R 4 being CR 2 R 3 , and R 2 and R 3 being H, F, and OCH 3It is a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof selected from

[0077] In some embodiments, the compound of formula (III) has R 11 being phenyl, a 5- or 6-membered heterocyclic ring, or a 5- to 10-membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring has 1 to 3 heteroatoms selected from N, O, and S as ring vertices; the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; the phenyl ring, heterocyclic ring, or heteroaryl ring is halogen, CN, NO 2 , NH 2 , C(O)NH 2 , S(O) 2 CH 3 , -CH 2 NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyhaloalkyl and C 1-4 alkoxyC 1-4 alkyl and is optionally substituted with 1 to 3 members independently selected therefrom; optionally, two members bonded to the same carbon of the heterocyclic ring together form a =CH 2 or oxo (=O) group, and is a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

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

[0079]

Chemical formula

[0080] In some embodiments, the compound of formula (IV-a) is X 1 and X 2 are independently selected from the group consisting of CH and N, a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

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

[0082]

Chemical formula

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

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

[0085]

Chemical formula

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

[0087] is CR 2 R 2 R 3 and each R 2 and R 3 is H; Y 3 and Y 4 are each CR 2 R 3 and each R 2 and R 3 is independently selected from H and F, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

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

[0089]

Chemical formula

[0090] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein

[0091] [Chemical formula] R is selected from the group consisting of halogen, CN, C 1 alkyl, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, -S(O) 2 R a and -C(O)NR a R b ; and R 2 and R 3 are each independently selected from the group consisting of H, halogen, CN, NO 2 、 OH, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy, C 1-6 hydroxyalkyl, C 1-4 alkoxyC 1-4Alkyl and -NR a R b each independently selected from the group consisting of: R 5 H, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O) 2 R a , -C(O)NR a R b , and -S(O) 2 NR a R b selected from the group consisting of; R 13 and R 15 are H, F and C, respectively. 1-4 independently selected from the group consisting of alkyl; R 20 is C 1-6 Alkyl and C 1-6 fluoroalkyl; The remaining radicals have the meanings given for formula (I).

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

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

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

[0095] In some selected embodiments, the compound of formula (I) is of formula (V-a):

[0096]

Chemical formula

[0097] In some selected embodiments, the compound of formula (I) is of formula (V-b):

[0098]

Chemical formula

[0099] In some embodiments, the compound of formula (V-b) is R 9 and R 10 are each independently selected from the group consisting of H, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyhaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 3-8 cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O) 2 NR a R b , and -S(O) 2 R a ; and R 11 is selected from the group consisting of H, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyhaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 3-8 cycloalkyl, -C(O)NR c R b , -S(O) 2 NR c R b , and -S(O) 2 R c and is a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0100] In certain selected embodiments, the compound of formula (I) is of formula (V-c):

[0101]

Chemical formula

[0102] In some selected embodiments, the compound of formula (I) is of formula (V-d):

[0103]

Chemical formula

[0104] In some selected embodiments, the compound of formula (I) is of formula (V-e):

[0105]

Chemical formula

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

[0107] In some embodiments, the compound of formula (V-e) is R 9 and R 10 are each independently selected from the group consisting of H, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyhaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 3-8 cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O) 2 NR a R b , and -S(O) 2 R a and is a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0108] In some selected embodiments, the compound of formula (I) is of formula (V-f):

[0109]

Chemical formula

[0110] In some selected embodiments, the compound of formula (I) is of formula (V-g):

[0111]

Chemical formula

[0112] In some embodiments, the compound of formula (V-g) has R 11 which is phenyl, a 5- or 6-membered heterocyclic ring, or a 5- to 10-membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring has 1 to 3 heteroatoms selected from N, O, and S as ring vertices; the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O, and S as ring vertices; the phenyl ring, heterocyclic ring, or heteroaryl ring is halogen, CN, NO 2 , NH 2 , C(O)NH 2 , S(O) 2 CH 3 , -CH 2 NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyhaloalkyl, and C 1-4 alkoxyC 1-4 alkyl, and is optionally substituted with 1 to 3 members independently selected therefrom; optionally, two members attached to the same carbon of the heterocyclic ring together form a =CH 2 or oxo (=O) group, and is a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

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

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

[0115] Following identification, candidate inhibitors can be further evaluated by using techniques that provide data regarding the properties of the inhibitor (e.g., means for determining pharmacokinetic parameters, solubility or stability). Comparison of a candidate inhibitor to a reference standard, which may be the “best in class” of current inhibitors, indicates the potential viability of such a candidate.

[0116] Synthetic methods General methods for the preparation of the claimed compounds For the most efficient preparation of any particular compound of the invention, one of ordinary skill in the art will recognize that the timing and order of fragment coupling, as well as modifications to the functionality present in any of the fragments, can vary in the preparation of any given compound. A variety of methods are used to prepare the compounds of the invention, some of which are illustrated in the Examples.

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

[0118] To effect an extension of therapeutic activity, a drug molecule can be engineered to utilize a delivery vehicle. Such a vehicle can be used by physically formulating the drug moiety in a non-covalent manner in a solvent-vehicle mixture or by covalently attaching the vehicle reagent permanently to one of the functional groups of the drug moiety (see generally WO 2015 / 0202317).

[0119] Several non-covalent approaches are preferred. By way of example, and not limitation, in certain embodiments, depot formulations are utilized that include non-covalent drug encapsulation within a polymeric carrier. In such formulations, drug molecules are combined with a carrier material and processed such that the drug molecules are dispersed within the interior of the bulk carrier. Examples include particulate polymer-drug aggregates (e.g., Degradex® Microspheres (Phosphorex, Inc.)) administered as an injectable suspension; polymer-drug molecule aggregates formulated as a gel (e.g., Lupron Depot® (AbbVie Inc.)) administered as a single bolus injection; and liposomal formulations (e.g., DepoCyt® (Pacira Pharmaceuticals)) where the carrier can be a polymeric or non-polymeric substance that can solubilize the drug. In these formulations, release of the drug molecules can occur when the carrier swells or physically deteriorates. In other examples, chemical degradation enables diffusion of the drug into the biological environment; such chemical degradation processes can be autocatalytic or enzyme-catalyzed. Among other limitations, non-covalent drug encapsulation requires prevention of uncontrolled drug release, and reliance of the drug release mechanism on biodegradation can cause patient-to-patient variability.

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

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

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

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

[0124] Patents and scientific literature have described many polymeric prodrugs in which the temporary bond is an ester bond that is labile. In these examples, the functional group of the bioactive substance is either a hydroxyl group or a carboxylic acid (see, for example, Cheng et al. (2003) Bioconjugate Chem 14:1007-17). Furthermore, in many cases, for biopolymers and certain small molecule drugs, it is advantageous to attach the carrier to an amino group(s) of the bioactive substance (e.g., the N-terminus of a protein or a lysine amino group). During the preparation of the prodrug, the above amino groups can be dealt with more chemoselectively due to their greater nucleophilicity compared to their hydroxyl or phenol groups. This is particularly relevant to proteins and peptides containing a wide variety of different reactive functional groups, where non-selective conjugate reactions result in an undesirable product mixture that requires extensive characterization or purification, thus reducing the reaction yield and therapeutic efficiency of the active moiety.

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

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

[0127] Other carrier prodrugs that utilize a temporary bond to the amino group of the drug moiety are based on a cascade mechanism. Cascade cleavage is made possible by a linker compound consisting of a structural combination of a masking group and an activating group. The masking group is bonded to the activating group by a first temporary bond such as an ester or a carbamate. The activating group is bonded to the amino group of the drug molecule via a second temporary bond (e.g., a carbamate). The stability or sensitivity of the second temporary bond to hydrolysis is determined by the presence or absence of the masking group. In the presence of the masking group, the second temporary bond is extremely stable and there is a low likelihood of releasing the drug molecule at a therapeutically useful kinetics, while in the absence of the masking group this bond becomes extremely unstable, resulting in rapid cleavage and release of the drug moiety.

[0128] Cleavage of the first temporary bond is the rate-determining step in the cascade mechanism. The first step is capable of inducing an intramolecular rearrangement of the activating group (e.g., a 1,6-elimination as described in Greenwald et al. (1999) J Med Chem 42:3657-67), which makes the second temporary bond even more unstable such that its cleavage is induced. Ideally, the cleavage rate of the first temporary bond is the same as the desired release rate for the drug molecule in a given therapeutic scenario. Further, it is desirable that cleavage of the second temporary bond occurs substantially immediately after its instability has been induced by cleavage of the first temporary bond.

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

[0130] In a particular embodiment of a cascade prodrug comprising an aromatic activating group based on 1,6-elimination, the masking group is structurally separated from the carrier. This can be achieved by using a stable bond between the polymer carrier and the activating group, where the stable bond is not involved in the cascade cleavage mechanism. When the carrier does not serve as a masking group and the activating group is linked to the carrier by a stable bond, the release of potentially toxic byproducts (such as the activating group) is avoided. The stable bond between the activating group and the polymer also suppresses the release of drug-linker intermediates with undefined pharmacology.

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

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

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

[0134] In certain embodiments, dipeptides are utilized for prodrug development for targeted transport or transport to be targeted because they are substrates of enzymes or biological transport systems. The non-enzymatic pathway for dipeptide prodrug formation, i.e., the ability to undergo intramolecular cyclization to form the corresponding diketopiperazine (DKP) and release the active drug, is not clearly defined.

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

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

[0137] The scope of the DKP-forming reaction extends to amide prodrugs. As an example, U.S. Patent No. 5,952,294 describes prodrug activation using diketopiperazine formation for a dipeptidyl amide prodrug of cytarabine. In this example, a temporary bond is formed between the carbonyl of the dipeptide and the aromatic amino group of cytarabine. However, for such conjugates, since there is no carrier or other half-life extending moiety or functional group, the possibility of achieving a sustained release effect is low.

[0138] Dipeptide prodrugs containing bioactive peptides such as GLP-1 that can release the peptide via diketopiperazine formation of dipeptide extension are also described (see, for example, WO 2009 / 099763). The bioactive peptide moiety may contain an additional PEG chain on one of its amino acid side chain residues to achieve extended circulation of the bioactive peptide. However, this approach has several significant disadvantages. First, the PEG chain must be bound to the peptide without impairing its bioactivity, which can be difficult to achieve for many peptide-based bioactive agents. Second, since the pegylated peptide itself is bioactive, the pro portion of its dipeptide may affect the bioactivity of the peptide and may have an adverse effect on its receptor binding properties.

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

[0140] Ascendis' technology platform combines the advantages of prodrugs and sustained release technologies to enhance the properties of small molecules and peptides. In circulation, a proprietary prodrug releases the unmodified active parent therapeutic at a defined rate determined by physiological pH and temperature conditions. Since the therapeutic is released in its unmodified form, the original mechanism of action is retained.

[0141] Modifications to enhance inhibitor properties In many cases, it is advantageous, and in some cases essential, to improve one or more physical properties of the therapies disclosed herein and / or their methods of administration. Improvements in physical properties include, for example, methods to enhance water solubility, bioavailability, serum half-life, and / or therapeutic half-life, and / or methods to modulate biological activity.

[0142] Modifications known in the art include pegylation, Fc fusion, and albumin fusion. Such modifications are generally associated with macromolecular agents (e.g., polypeptides), but more recently have been evaluated for certain small molecules. As an example, Chiang, M. et al. (J. Am. Chem. Soc., 2014, 136(9):3370-73) describe a small molecule agonist of the adenosine 2a receptor conjugated to an immunoglobulin Fc domain. This small molecule Fc conjugate retained the strong interaction between the Fc receptor and the adenosine 2a receptor 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).

[0143] Other known modifications include deuteration to improve pharmacokinetic profiles, pharmacodynamic profiles, and toxicity profiles. Since deuterium has a higher atomic mass, the cleavage of carbon-deuterium bonds requires more energy than carbon-hydrogen bonds. These stronger bonds are more difficult to break, so the rate of drug metabolism is slower compared to the non-deuterated form, which can allow for a reduced dosing frequency and further reduced toxicity (Charles Schmidt, Nature Biotechnology, 2017, 35(6):493-494; Harbeson, S. and Tung, R., Medchem News, 2014(2):8-22).

[0144] Therapeutic and prophylactic uses The present invention contemplates the use of the HIF-2α inhibitors described herein in the treatment or prevention of a wide range of diseases, disorders and / or conditions, and / or their symptoms. It should be understood that specific uses are described in detail hereinafter, but the present invention is not limited thereto. Further, general categories of specific diseases, disorders and conditions are shown hereinafter, but some of the above diseases, disorders and conditions are members of two or more categories, and other diseases, disorders and conditions may not be members of any of the disclosed categories.

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

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

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

[0148] In certain embodiments, the cancer can be metastatic or may have a risk of becoming metastatic, or can occur in diffuse tissues, such as cancers of the blood or bone marrow (such as leukemia), etc.

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

[0150] In some embodiments, the disease or disorder is VHL-related, such as, for example, VHL-related renal cell cancer.

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

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

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

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

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

[0156] Pharmaceutical composition The HIF-2α inhibitors of the invention can 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 above pharmaceutical composition can be used in the methods of the invention; thus, for example, the above pharmaceutical composition can be administered to a subject ex vivo or in vivo for carrying out the treatment methods, prevention methods and uses described herein.

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

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

[0159] Tablets, capsules, etc. suitable for oral administration may or may not be coated, or may be coated by known techniques for delaying disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. These can also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Further agents include biodegradable or biocompatible particles or polymeric substances, such as polyesters, polyamino acids, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide / glycolide copolymers, polylactide / glycolide copolymers, or ethylene vinyl acetate copolymers, etc., for controlling the delivery of the administered composition. For example, oral formulations can be encapsulated in microcapsules prepared by coacervation techniques or interfacial polymerization or by the use of hydroxyethylmethylcellulose or gelatin-microcapsules or poly(methyl methacrylate) microcapsules, respectively, or can be encapsulated in a colloidal drug delivery system. Colloidal dispersion systems include polymer complexes, nanocapsules, microspheres, microbeads, and lipid-based systems such as oil-in-water emulsions, micelles, mixed micelles, and liposomes. The methods for preparing the above formulations will be apparent to those skilled in the art.

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

[0161] An aqueous suspension contains an active material mixed with excipients suitable for their production. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum; dispersants or wetting agents such as natural phosphatides (e.g., lecithin), or condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain fatty alcohols (e.g., in the case of heptadecaethyleneoxy cetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives.

[0162] An oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspension may contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents as shown above may be added to provide a palatable oral preparation.

[0163] Dispersible powders and granules suitable for the preparation of an aqueous suspension by adding water are provided by mixing the active ingredient 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.

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

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

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

[0167] The formulation may also include carriers for protecting the composition from rapid degradation or excretion from the body, such as controlled release formulations such as liposomes, hydrogels, prodrugs, and microencapsulation delivery systems. For example, time delay materials such as glyceryl monostearate or glyceryl stearate can be used alone or in combination with waxes. It is possible to deliver the HIF-2α inhibitor using any drug delivery device, such as an implant (e.g., an implantable pump) and catheter systems, low rate infusion pumps and devices, etc., all of which are well known to those skilled in the art.

[0168] To release the HIF-2α inhibitor disclosed herein over a predetermined period, depot injections that are generally administered subcutaneously or intramuscularly can also be utilized. Depot injections are usually either solid-based or oil-based and generally contain at least one of the formulation components shown herein.

[0169] The pharmaceutical composition can be in the form of a sterile injectable aqueous suspension or an oily suspension. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned herein. This sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol. Acceptable diluents, solvents, and dispersion media that can be utilized include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL (trademark) (BASF, Parsippany, New Jersey), or phosphate - buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Furthermore, sterile non - volatile oils have been conventionally used as solvents or suspending media. For this purpose, any sterile non - volatile oil such as synthetic monoglycerides or diglycerides can be utilized. Additionally, fatty acids such as oleic acid are used in the preparation of injectables. By including agents that delay absorption (e.g., aluminum monostearate or gelatin), sustained absorption of certain injectable formulations can be achieved.

[0170] The present invention contemplates the administration of the HIF - 2α inhibitor in the form of a suppository for rectal administration. Suppositories can be prepared by mixing the drug with a suitable non - irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the drug. Such substances include, but are not limited to, cocoa butter and polyethylene glycol.

[0171] The HIF - 2α inhibitor contemplated by the present invention can 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).

[0172] Route of administration The present invention contemplates administration of the HIF-2α inhibitor and its compositions in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracapsular, intra-articular, intraperitoneal, intracerebral (intraparenchymal and intraventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation, etc.). To release the HIF-2α inhibitor disclosed herein over a predetermined period, depot injections generally administered subcutaneously or intramuscularly may be utilized.

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

[0174] Combination Therapy The present invention contemplates the use of the HIF-2α inhibitor alone or in combination with one or more active therapeutic agents. Further active therapeutic agents can be small chemical molecules; macromolecules such as proteins, antibodies, peptibodies, peptides, DNA, RNA, or fragments of such macromolecules; or cell therapy or gene therapy. Combination therapies can target different but complementary mechanisms of action, thereby providing a synergistic therapeutic or prophylactic effect against the underlying disease, disorder, or condition. Additionally or alternatively, combination therapies can allow for a reduction in the dosage of one or more agents, thereby improving, reducing, or eliminating the adverse effects associated with one or more agents.

[0175] The active therapeutic agents in such combination therapies can be formulated as a single composition or as separate compositions. When administered separately, each therapeutic agent in the combination can be administered simultaneously or nearly simultaneously, or at different times. Further, during the course of a patient's treatment, the therapeutic agents can be administered "in combination" even if their modes of administration are different (e.g., oral capsule administration and intravenous administration), and these are administered at different dosing intervals, where one therapeutic agent is administered according to a fixed dosing regimen while the other is increased, decreased, or discontinued, or each therapeutic agent in the combination is independently increased, decreased, the dose is increased or decreased, or discontinued and / or restarted. When the above combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

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

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

[0178] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocone, meturedopa, and uredopa; ethyleneimines and methylamelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chloronaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobemycin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, pomalidomide, potfiromycin, puromycin, keramycin, rhodrubicin, streptozocin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU) with or without leucovorin; folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyruridine, doxifluridine, enocitabine, floxuridine, 5-FU;Androgens, for example, calusterone, drostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenal drugs, for example aminoglutethimide, mitotane, trilostane; folic acid supplements, for example folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demeclocycline; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, for example, paclitaxel, nab-paclitaxel and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, for example, cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; zeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; anthracyclines; arginase inhibitors (see PCT / US2019 / 020507) and pharmaceutically acceptable salts, acids or derivatives of any of the above, etc. can be mentioned.;

[0179] As chemotherapeutic agents, antihormonal agents that act to regulate or inhibit the hormonal action on tumors, such as antiestrogen drugs such as tamoxifen, raloxifene, aromatase inhibitory 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogen drugs such as abiraterone, enzalutamide, flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above may also be mentioned. In certain embodiments, the combination therapy includes a chemotherapy regimen comprising one or more chemotherapeutic agents. In certain embodiments, the combination therapy includes the administration of a hormone or related hormonal agent.

[0180] Further therapies that can be used in combination with the HIF-2α inhibitor include radiotherapy, monoclonal antibodies against tumor antigens, conjugates of monoclonal antibodies and toxins, T cell adjuvants, bone marrow transplantation, or antigen-presenting cells (e.g., dendritic cell therapy) (including TLR agonists used to stimulate such antigen-presenting cells).

[0181] In certain embodiments, the present invention contemplates the use of the compounds described herein in combination with adoptive cell therapy, a novel and promising form of personalized immunotherapy in which immune cells having antitumor activity are administered to a cancer patient. Adoptive cell therapy is being explored, for example, using tumor-infiltrating lymphocytes (TILs) and T cells engineered to express a chimeric antigen receptor (CAR) or a T cell receptor (TCR). Adoptive cell therapy generally involves collecting T cells from an individual, genetically engineering those T cells to target a specific antigen or enhance their antitumor effect, amplifying them to a sufficient number, and injecting the genetically engineered T cells into a cancer patient. The T cells can be collected from the patient (e.g., autologous) from whom the expanded cells will later be reinjected, or they can be collected from a donor patient (e.g., allogeneic).

[0182] In certain embodiments, the invention contemplates the use of the compounds described herein in combination with RNA interference-based therapies for silencing gene expression. RNAi is initiated by the cleavage of relatively long double-stranded RNAs into small interfering RNAs (siRNAs). One strand of the siRNA is incorporated into a ribonucleoprotein complex known as the 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 is capable of binding to or cleaving the mRNA, both of which inhibit translation.

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

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

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

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

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

[0188] The numerous genetic and epigenetic changes characteristic of all cancers provide diverse antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the maximum amplitude (e.g., levels of cytokine production or proliferation) and quality (e.g., type of immune response generated such as pattern of cytokine production) of the response initiated through antigen recognition by the T cell receptor (TCR) are regulated by the balance between co-stimulatory signals and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are important for the prevention of autoimmunity (i.e., maintenance of self-tolerance) and also for the protection of tissues from damage when the immune system is responding to a pathogenic infection. The expression of immune checkpoint proteins can be dysregulated by tumors as a major immune escape mechanism.

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

[0190] Clinically, blockade of immune checkpoints to boost antigen-specific T cell responses has been shown to be a promising approach in human cancer therapeutics.

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

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

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

[0194] In one aspect of the invention, the claimed HIF-2α inhibitor is combined with a cancer immunotherapy agent that is (i) an agonist of a stimulatory (including co-stimulatory) receptor on T cells or (ii) an antagonist of an inhibitory (including co-inhibitory) signal (both of which result in amplification of the antigen-specific T cell response). Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), B7-H6, and B7-H7 (HHLA2). Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to homologous TNF receptor family members, which includes 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, TNFR2, TNFa, LT13R, lymphotoxin a 1132, FAS, FASL, RELT, DR6, TROY, NGFR.

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

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

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

[0198] In another aspect, the disclosed HIF-2α inhibitor can be used in combination with one or more of an agonistic agent that ligates a positive co-stimulatory receptor, a blocking agent that attenuates signaling via an antagonist that is an inhibitory receptor, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome distinct immunosuppressive pathways within the tumor microenvironment (e.g., blocking the involvement of inhibitory receptors (e.g., PD-L1 / PD-1 interaction), depleting or suppressing regulatory T cells (Tregs) (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), or reversing / preventing T cell anergy or exhaustion), and agents that activate innate immunity and / or cause inflammation at the tumor site.

[0199] In one aspect, the cancer immunotherapy agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0200] In another aspect, the cancer immunotherapy 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 cancer immunotherapy agent also includes pidilizumab (CT-011), although its specificity for PD-1 binding is questioned. Another approach targeting the PD-1 receptor is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1. In another embodiment, the agent is zimberelimab.

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

[0202] In another aspect, the cancer immunotherapy agent is a LAG-3 antagonist, for example, an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273), among others.

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

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

[0205] In another aspect, the cancer immunotherapy agent is an OX40 agonist, for example, an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469, among others.

[0206] In another aspect, the cancer immunotherapy agent is an OX40L antagonist, for example, an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879), among others.

[0207] In another aspect, the cancer immunotherapy agent is a CD40 agonist, such as an activating CD40 antibody. In yet another embodiment, the cancer immunotherapy agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

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

[0209] In another aspect, the cancer immunotherapy agent is MGA271 (against B7H3) (WO11 / 109400).

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

[0211] Examples of therapeutic agents useful in combination therapies 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®); fibrates that can lower 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® (a combination of ezetimibe and simvastatin), etc. Alternative cholesterol therapeutic agents that may be candidates for use in combination with the HIF-2α inhibitors described herein can include various nutritional supplements and herbs (e.g., garlic, policosanol, and guggul), etc.

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

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

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

[0215] Further examples of active agents that can be used in a combination for treating, for example, rheumatoid arthritis include cytokine-suppressive anti-inflammatory drugs (one or more) (CSAIDs); antibodies or antagonists against other human cytokines or growth factors, such as TNF, LT, IL-10, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, or PDGF, and the like.

[0216] Certain combinations of active agents can interfere at different points in autoimmune and subsequent inflammatory cascades, including TNF antagonists such as chimeric, humanized or human TNF antibodies, REMICADE®, HUMERA®, anti-TNF antibody fragments (e.g., CDP870), and soluble p55 or p75 TNF receptors, their derivatives, p75TNFRIgG (ENBREL®) or p55TNFR1gG (renesept), soluble IL-13 receptor (sIL-13), and also TNFα-converting enzyme (TACE) inhibitors, and the like; similarly, IL-1 inhibitors (e.g., interleukin-1-converting enzyme inhibitors) may also be effective. Other combinations include interleukin 11, anti-P7, and p-selectin glycoprotein ligand (PSGL), and the like. Other examples of agents useful in combinations with the HIF-2α inhibitors described herein include interferon-β1a (AVONEX®); interferon-β1b (BETASERON®); copaxone; hyperbaric oxygen; intravenous immunoglobulin; cladribine; and antibodies or antagonists against other human cytokines or growth factors (e.g., antibodies against CD40 ligand and CD80), and the like.

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

[0218] Generally, dosing parameters indicate that the dosage is less than the amount at which the dosage can be toxic to the point of being non-recoverable for the subject (maximum tolerated dose (MTD)) and greater than the amount required to produce a measurable effect on the subject. Such amounts are determined by, for example, pharmacokinetic parameters and pharmacodynamic parameters related to ADME, taking into account the route of administration and other factors.

[0219] The effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in a portion of the subjects taking the agent. The "median effective dose" or ED50 of an agent is the dose or amount of the agent that produces a therapeutic response or desired effect in 50% of the population to which the agent is administered. The ED50 is generally used as a measure for a reasonable prediction of the effect of an agent, but is not necessarily a dose that a clinician can determine to be appropriate considering all relevant factors. Thus, in some situations, the effective amount is above the calculated ED50, in other situations, the effective amount is below the calculated ED50, and in still other situations, the effective amount is the same as the calculated ED50.

[0220] Furthermore, the effective dose of the HIF-2α inhibitor of the present invention can be an amount that produces a desirable result when administered to a subject in one or more doses, as compared to a healthy subject. For example, for a subject with a particular disorder, the effective dose is such that the diagnostic parameters, measurements, markers, etc. of that disorder are improved 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. shown by a normal subject.

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

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

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

[0224] Kit The present invention also contemplates kits containing the compounds described herein and their pharmaceutical compositions. The kits are generally in the form of a physical structure containing various components as described below and can be used in the practice of the above methods.

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

[0226] The kit can include a label or package insert containing identification information of the components therein and instructions for their use (e.g., administration parameters of the active ingredient(s), clinical pharmacology, e.g., mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or package insert can include manufacturer information such as lot number or expiration date. The label or package insert can be integrated into the physical structure containing the components, for example, or separately included in the physical structure, or attached to the components of the kit (e.g., ampoules, tubes, or vials).

[0227] The label or attached document may further include, or be incorporated into, 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 media such as RAM and ROM or a hybrid thereof such as a magnetic / optical storage media, FLASH (registered trademark) media, or a memory type card. In some embodiments, the actual instructions are not present in the kit and means are provided for obtaining the instructions from a remote source, e.g., via the Internet.

Examples

[0228] Experiment The following examples are presented to provide a complete disclosure and description of the method of making and using the invention to those skilled in the art and are not intended to limit the scope of the invention as regarded by the inventors as their invention, nor are they intended to represent that the following experiments were conducted or are all the experiments that could be conducted. The exemplary descriptions written in the present tense are not necessarily those that have been carried out. Rather, it should be understood that the above description can be carried out to generate data of the nature described herein, etc. Although efforts have been made to ensure the accuracy of the numerical values used (e.g., amounts, temperatures, etc.), some experimental errors and deviations should be taken into account.

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

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

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

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

[0233] If the literature includes an assay or experimental procedure, such an assay or procedure can serve as an alternative criterion for evaluating the compounds described herein.

[0234] All reactions were carried out at the indicated temperatures using a Teflon®-coated magnetic stir bar and, where specified, under an inert atmosphere. Reactions were monitored by TLC (silica gel 60 with fluorescent indicator F254, visualized with short-wave / long-wave UV lamps), and / or LCMS (using any of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm inner diameter (i.d.) x 100 mm] with a two-component solvent system [MeCN containing 0.1% TFA / H 2 O containing 0.1% TFA] for UV detection at 254 nm on an Agilent 1100 series LCMS). Flash chromatography was performed on silica gel using an automated system (CombiFlash® RF+ manufactured by Teledyne ISCO) with detection wavelengths of 254 nm and 280 nm. Reverse-phase preparative HPLC was performed on an Agilent 1260 Infinity series HPLC. A two-component solvent system (MeCN containing 0.1% TFA / H 2 O containing 0.1% TFA) was used to elute the samples by gradient elution on a Gemini C18 110 Å column (21.2 mm inner diameter (i.d.) x 250 mm) with detection at 254 nm. The final compounds obtained through preparative HPLC were concentrated. Unless otherwise stated, the reported yields are isolation yields. All compounds assayed were purified by LCMS (using the following column: Agilent Eclipse Plus C18 column [3.5 μm, 4.6 mm inner diameter (i.d.) x 100 mm] with a two-component solvent system [MeCN containing 0.1% TFA / H 2 O containing 0.1% TFA] for UV detection at 254 nm on an Agilent 1100 series LCMS) to a purity of ≧95%. 1 1H NMR spectra were recorded on a Varian 400 MHz NMR spectrometer equipped with an Oxford AS400 magnet. Chemical shifts (δ) are reported in parts per million (ppm) relative to the residual non-deuterated solvent as an internal standard.

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

[0236]

Chemical formula

[0237] Step a: Dissolve 6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-one (500 mg, 2.74 mmol) in CH 2 Cl 2 (11 mL, 0.25 M), and sparge the resulting solution with nitrogen gas for 5 minutes. Add triethylamine (574 μL, 1.5 equivalents), cool the solution to 0 °C, and then add Tf 2 O (691 μL, 1.5 equivalents). Warm the reaction mixture to room temperature and stir overnight. Quench the solution with water, extract with CH 2 Cl 2 , dry the resulting organic matter over Na 2 SO 4 , and concentrate it on celite. Flash the crude material on silica gel (gradient, 0% - 20% ethyl acetate in hexane) to obtain the desired 5,7-difluoro-4-(trifluoromethylsulfonyloxy)-1,2-dihydronaphthalene (470 mg, yield 54%) as an oil.

[0238] Step b: Place in a vial the alkenyl triflate from step a (2.50 g, 7.96 mmol, 1.0 equivalent), PdCl 2 (dppf) (872 mg, 1.19 mmol, 15 mol%), B 2 pin 2 (2.82 g, 11.1 mmol, 1.4 equivalents), KOAc (1.72 g, 17.5 mmol, 2.2 equivalents), and 1,4-dioxane (20 ml). Cap the vial and purge the reaction mixture with N 2 for 2 minutes. Heat the reaction at 80 °C and stir for 30 minutes. Cool the reaction, filter it, and concentrate it on celite. Flash chromatography (SiO 2Purified with hexane (10% EtOAc), the alkenylpinacol boronic acid ester was obtained as a brown oil (1.16 g, 3.97 mmol, 50%).

[0239] Step c: To a vial containing the product from step b (100 mg, 0.342 mmol, 1.0 equiv), 3-bromo-2-chloro-6-(methylsulfonyl)benzonitrile (100 mg, 0.342 mmol, 1.0 equiv), PdCl 2 (dppf) (25 mg, 0.034 mmol, 10 mol%), 1,4-dioxane (1 mL) and 1M Na 2 CO 3 aqueous solution (0.7 mL) were added. The vial was capped and purged with N 2 for 2 minutes. The reaction was heated at 80 °C and stirred for 1.5 h. When complete, the reaction was cooled, diluted with saturated NH 4 Cl aqueous solution (20 mL), and extracted with DCM (20 mL). The aqueous layer was separated and back-extracted with additional DCM (2 × 20 mL). The combined organic layers were washed with brine (40 mL), dried over MgSO 4 and concentrated under reduced pressure. Purified by flash chromatography (SiO 2 , gradient of 50% EtOAc from hexane), the cross-coupled product was obtained as a white solid and used in the next step (58.6 mg, 0.154 mmol, 45%, C 18 H 12 ClF 2 NO 2 S ESI MS [M+H] + , calcd 380.0, found 380.1).

[0240] Step d: To a vial containing the product from step c (58.6 mg, 0.154 mmol, 1.0 equiv), Pd / C (10% Pd, 25 mg) was added. The vial was evacuated and backfilled with N 2 (×3). MeOH (1 mL) and EtOAc (1 mL) were added, the reaction mixture was purged with H 2 for 2 minutes, then stirred at room temperature under 1 atm of H 2 for 16 h. The reaction vessel was filled with N2 Flash it, filter the mixture through celite, and rinse with EtOAc. Concentrate under reduced pressure and purify by preparative reverse-phase HPLC (gradient of 20 - 100% of acetonitrile and water containing 0.1% TFA) to obtain the product as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.10 - 6.98 (m, 2H), 4.79 - 4.72(m, 1H), 3.43 (s, 3H), 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). C 18 1H 14 ClF 2 NO 2 ESI MS of S [M+H] + , calculated value 382.0, measured value 382.1.

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

[0242]

Chemical Structure

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

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

[0245] Step c: The crude thioether from step b (23.1 g, 69.2 mmol) was suspended in toluene (692 ml, 0.1 M). Aluminum trichloride (10.2 g, 1.1 eq) was added at room temperature. After 3 h, an additional portion of aluminum trichloride (3.6 g, 27 mmol, 0.4 eq) was added. After a further 3 h, the reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, CH in hexane 2 Cl 2Purified with 0% - 20% ethyl acetate in a 3:1 solution to obtain the desired thiophenol as a yellow solid (13.4 g, 80% yield).

[0246] 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 equiv) in DMF (55 ml, 0.5 M) was carefully degassed by three freeze - pump - thaw cycles under nitrogen. The resulting solution was cooled to - 10 °C to - 5 °C in an ice bath of brine, and excess CF 3 I was sparged through the reaction mixture. The reaction was then stirred overnight under an atmosphere of CF 3 I. The reaction was carefully quenched with water at room temperature (due to off - gas generation of residual CF 3 I, use with care), extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% - 20% ethyl acetate in hexane) to obtain the desired thioether (5.21 g, 61% yield).

[0247] Step e: To a solution of the product (10.45 g, 33.6 mmol) from step d in MeCN (129 ml, 0.26 M with respect to the starting material), CCl 4 (129 ml, 0.26 M with respect to the starting material), and H 2 O (258 ml, 0.13 M with respect to the starting material), ruthenium(III) chloride (697 mg, 3.36 mmol, 0.1 equiv) was added, followed by sodium periodate (29.6 g, 138.4 mmol, 4.12 equiv). The reaction was stirred at room temperature for 1 hour, and when complete, extracted with CH 2 Cl 2 (×2). The combined organics were washed with saturated Na 2 S 2 O 3 then washed with brine, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (silica gel, CH in hexane 2 Cl 2Purified with 0% - 10% ethyl acetate in a 3:1 solution of [solvent not specified], and the resulting product, sulfone (10.53 g, 91% yield), was obtained as a white solid. C 10 H 6 BrF 3 O 3 ESI MS of S [M+H] + ; Calculated value 342.9, measured value 342.9.

[0248] Step f: A solution of sulfone (3.5 g, 10.2 mmol), the product from step e, and Selectfluor (4.32 g, 12.2 mmol, 1.2 equiv) in methanol (102 ml, 0.1 M) was heated to 50 °C. Sulfuric acid (27 μL, 5 mol%) was added, and the reaction mixture was stirred at 50 °C for 48 h. The solution was then diluted with diethyl ether, and the resulting white precipitate was removed by filtration and discarded. The organic solution was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% - 10% ethyl acetate in a 3:1 solution of CH 2 Cl 2 to obtain the product, dimethyl acetal, as a white solid (3.57 g, 87% yield).

[0249] Step g: A solution of acetal (3.18 g, 7.8 mmol), the product from step f, and wet Amberlyst 15 (4.77 g, 150 wt%) in dioxane (31 ml, 0.2 M) was heated at 90 °C overnight. Once complete, the polymer beads were removed by filtration, and the concentrated crude material was purified by flash chromatography (silica gel, 0% - 10% ethyl acetate in a 3:1 solution of CH 2 Cl 2 to obtain the desired fluorinated ketone (2.33 g, 83% yield).

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

[0251] Step i: To a solution of the chiral indanol from step h (1.01 g, 2.75 mmol) in CH 2 Cl 2 (11 ml, 0.25 M) were added 2,6-lutidine (800 μL, 6.9 mmol, 2.5 equiv) and TBSOTf (791 μL, 3.44 mmol, 1.25 equiv) at 0 °C. The reaction was warmed to room temperature and stirred overnight. Once complete, the reaction was concentrated directly onto celite and purified by flash chromatography (silica gel, 0% - 10% ethyl acetate in hexane) to afford the TBS ether (1.35 g, 100% yield).

[0252] Step j: The TBS ether product from step i (674 mg, 1.41 mmol) was taken up in B 2 Pin 2(457 mg, 1.8 mmol, 1.3 equiv), Pd(dppf)Cl 2 (103 mg, 0.14 mmol, 0.1 equiv) and potassium acetate (213 mg, 3 mmol, 2.2 equiv) were combined, and the resulting solution was heated to 100 °C for 3 h. The reaction solution was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% - 30% ethyl acetate in hexane) to afford the desired boronic acid pinacol ester (638 mg, 86% yield) as a colorless oil.

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

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

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

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

[0257]

Chem.

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

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

[0260]

Chem.

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

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

[0263]

Chemical Structure

[0264] Step a: A solution of 6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-one (7 g, 38.4 mmol) and TMSONa (14.8 g, 115.3 mmol) in dioxane (128 mL) was refluxed for 20 min under a nitrogen atmosphere. Once the starting material had disappeared (TLC analysis, 30% EtOAc in hexane as eluent, the desired product spot has the minimum polarity), the mixture was cooled to room temperature and poured into a saturated aqueous solution of NH 4 Cl (200 mL). The product was extracted with EtOAc (3 × 70 mL). The combined extracts were washed with brine (200 mL). The organic phase was separated and dried over Na 2 SO 4 . After removing all the solvents under reduced pressure, the crude product was purified by flash chromatography (SiO 2 , hexane / EtOAc gradient) to give 8-hydroxy-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one as a yellow solid (4.7 g, 26.1 mmol, 68% yield). 1 1H NMR (400 MHz, CDCl 3 ) 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 19F NMR (376 MHz, CDCl 3 ) δ -98.95 (t, J = 9.7 Hz).

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

[0266] Step c: 8-Oxo-6-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl trifluoromethanesulfonate (8.1 g, 25.9 mmol), zinc cyanide (2.4 g, 20.7 mmol), and Pd(PPh 3 ) 4A mixture of (3.0 g, 0.26 mmol) was heated at 100 °C for 3 h under a nitrogen atmosphere. When 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 × 50 mL). The combined organic phases were washed with water (2 × 150 mL) and brine (100 mL), dried over Na 2 SO 4 and concentrated in vacuo. The dry residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to afford 8-cyano-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (4.0 g, 21.1 mmol, 82% yield) as a white crystalline solid. 1 1H NMR (400 MHz, CDCl 3 ) 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 19F NMR (376 MHz, CDCl 3 ) δ -103.48 (t, J = 8.2 Hz).

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

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

[0269] Step f: The product of step e (0.25 g, 0.44 mmol) was dissolved in dry methanol (15 mL) and added to palladium on carbon (125 mg, 10 wt% Pd) under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere of 55 psi and stirred in a Parr shaker for 4 h. Excess hydrogen was vented, the mixture was degassed under vacuum and backfilled with nitrogen to remove residual hydrogen gas. The resulting suspension was filtered through a Celite pad and the filtrate was concentrated to dryness under reduced pressure to produce a crude mixture of epimers (1:2 dr). The crude mixture from step f was subjected to column chromatography (SiO 2 , hexane / EtOAc gradient) to produce both epimers of the desired product. (R)-Epimer (more polar product, 70 mg, 0.12 mmol, 28% yield): 11H NMR (400 MHz, CDCl 3 ) δ 7.70 (d, J = 8.2 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.72 (d, J = 8.3 Hz, 1H), 5.62 (d, J = 4.3 Hz, 1H), 5.01 (dddd, J = 51.2, 8.8, 6.9, 4.3 Hz, 1H), 4.58 (dd, J = 6.3, 3.0 Hz, 1H), 3.61 (dddd, J = 14.8, 12.5, 8.8, 1.0 Hz, 1H), 3.18 (dd, J = 14.8, 6.9 Hz, 1H), 3.03 - 2.93 (m, 1H), 2.93 - 2.81 (m, 1H), 2.26 - 2.07 (m, 1H), 1.95 - 1.65 (m, 2H), 1.63 - 1.45 (m, 1H), 0.83 (s, 9H), 0.17 (d, J = 2.6 Hz, 3H), 0.13 (s, 3H). 19 19F NMR (376 MHz, CDCl 3 ) 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 1H NMR (400 MHz, CDCl 3) 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, CDCl 3 ) δ -78.50, -112.92 (t, J = 8.2 Hz), -194.99 (dd, J = 51.1, 12.6 Hz).

[0270] Step h: A solution of the product from Step f (8R-epimer, 70 mg, 0.122 mmol) in CH 3 CN (2 mL) was placed in a 3 mL vial equipped with a magnetic stir bar, and then HF·Py complex (hydrogen fluoride approximately 70%, pyridine approximately 30%, 0.2 mL) was added. The resulting colorless solution was stirred at ambient temperature overnight. After TLC analysis indicated complete consumption of the starting material, the reaction mixture was diluted with EtOAc (20 mL) and 1 M aqueous HCl (20 mL). The product was extracted with EtOAc (2 × 10 mL), and the combined organic extracts were washed with NaHCO 3 aqueous solution (20 mL) and brine (20 mL), dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column chromatography (SiO 2, fractionated with a hexane / EtOAc gradient to give (8R)-3-fluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (52 mg, 0.114 mmol, 93% yield) as a white foam. 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (d, J = 8.2 Hz, 1H), 7.21 - 7.13 (m, 2H), 6.77 (d, J = 8.2 Hz, 1H), 5.56 (q, J = 5.1 Hz, 1H), 5.32(dtd, J = 51.2, 6.4, 5.2 Hz, 1H), 4.59 (dd, J = 6.3, 3.2 Hz, 1H), 3.62(dddd, J = 17.9, 16.1, 6.3, 1.0 Hz, 1H), 3.40 - 3.17 (m, 1H), 3.10 - 2.79 (m, 3H), 2.31 - 2.10 (m, 1H), 1.92 - 1.58 (m, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ -77.60, -112.71, -200.62(dddd, J = 51.2, 16.8, 10.9, 5.5 Hz). C 21 H 16 F 5 NO 3 S ESI MS [M+Na] + ; calculated value 480.1, measured value 480.1.

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

[0272]

Chemical formula

[0273] This compound was prepared from the corresponding TBS-protected S-epimer of 1-indanol (150 mg, 0.262 mmol) and 0.4 mL of HF·Py complex according to the protocol described in Example 5. The title compound was isolated as a white foam (89 mg, 0.195 mmol, 74% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (d, J = 8.2 Hz, 1H), 7.23 - 7.05 (m, 2H), 6.70 (d, J = 8.2 Hz, 1H), 5.61 (ddd, J = 6.1, 5.1, 3.9 Hz, 1H), 5.37 (dddd, J = 51.4, 6.6, 6.0, 5.1 Hz, 1H), 4.56 (dd, J = 6.4, 3.1 Hz, 1H), 3.65 - 3.49 (m, 1H), 3.47 - 3.27 (m, 1H), 3.17 (dd, J = 3.9, 0.7 Hz, 1H), 3.08 - 2.69 (m, 2H), 2.30 - 2.09 (m, 1H), 1.98 - 1.86 (m, 1H), 1.83 - 1.64 (m, 2H). 19 F NMR (376 MHz, CDCl 3 ) δ -77.73, - 112.69, -200.05 (dddd, J = 51.2, 18.3, 12.2, 6.2 Hz). C 21 H 16 F 5 NO 3 ESI MS of C + H

[0274]

[0275]

Chemical formula

[0276] The title compound was synthesized in the same manner as in Example 5. 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) δ -113.22, -199.17. C 21 H 19 F 2 NO 3 ESI MS of C H F NO S [M+Na] + ; calculated value 426.1, measured value 426.1.

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

[0278]

Chemical Structure

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

[0280] Step b: The title compound was synthesized in the same manner as in Example 1. 1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.59 - 6.45 (m, 1H), 6.45 - 6.35 (m, 1H), 5.60 (dd, J = 6.6, 5.1 Hz, 1H), 5.51 - 5.22(m, 1H), 4.45 - 4.34 (m, 1H), 4.29 - 4.14 (m, 1H), 4.08 - 3.98 (m, 1H), 3.61 - 3.42 (m, 1H), 3.28 - 3.16 (m, 1H), 2.43 - 2.33 (m, 1H), 1.96 - 1.80 (m, 1H). C 19 H 14 F 6 O 4 ESI MS of SNa [M+Na] + Calculated 475.0, found 475.0.

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

[0282]

Chemical formula

[0283] The title compound was synthesized in the same manner as in Example 1. 1 H NMR (400 MHz, methanol-d 4 ) δ 7.78 (dt, J = 8.1, 1.7 Hz, 1H), 7.13 (dd, J = 15.1, 8.1 Hz, 1H), 6.89 (ddd, J = 9.8, 2.7, 1.1 Hz, 1H), 6.83 - 6.64 (m, 2H), 5.56 - 5.49 (m, 1H), 4.32 - 4.25 (m, 1H), 3.63 - 3.06 (m, 3H), 2.97 - 2.78 (m, 2H), 2.21 - 2.06 (m, 1H), 1.97 - 1.76 (m, 1H), 1.80 - 1.68 (m, 1H). C 20 H 19 F 3 O3 S The ESI MS [M+H] + , calculated value 380.4, measured value 380.1.

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

[0285]

Chemical formula

[0286] Step a: 3-Bromo-2-chloro-6-fluorobenzaldehyde (25 g, 105.3 mmol) in anhydrous EtOH (100 mL), NH 2A suspension of OH×HCl (8.8 g, 126.4 mmol, 1.2 equiv) and NaOAc (10.4 g, 126.4 mmol, 1.2 equiv) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and evaporated, and the residue was diluted with H 2 O (300 mL). The white solid was removed by filtration, washed with H 2 O and dried under vacuum (24.3 g, 91%). The crude product was used in the next step without further purification. C 7 H 4 The ESI MS of BrClFNO [M+H] + , calculated 251.9, found 251.9.

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

[0288] Step c: The product from step b (20 g, 85.3 mmol) was dissolved in anhydrous DMF (100 mL), cooled to 0 °C, and anhydrous Na 2 S (6.6 g, 85.3 mmol) was added all at once. The reaction mixture was stirred at 0 °C for 2 h, then quenched with H 2 O (500 mL) and extracted with CH 2 Cl 2 (3 × 200 mL). The organics were discarded, the aqueous layer was neutralized to pH ~2 with 10% KHSO 4 solution and extracted again with CH 2 Cl 2 (3 × 150 mL). The combined organic layers were dried over MgSO 4 and filtered and concentrated in vacuo to give a yellow solid, which was used in the next step without further purification (19.1 g, 90%). C 7 H 3 The ESI MS of BrClNS [M-H] - , calculated 245.9, found 245.9.

[0289] Step d: The product from step c (33.6 g, 135.2 mmol) was dissolved in anhydrous DMF (300 mL), and paracort hydrate dichloride (3.5 g, 13.5 mmol, 10% mol) was added. The mixture was cooled to 0 °C, trifluoromethyl iodide × TMG reagent (33.6 mL, 162.2 mmol, 1.2 equiv) was added, and then TEA (18.8 mL, 135.2 mmol) was added. The reaction was stirred at 0 °C for 15 minutes, then warmed to room temperature and stirred overnight. H 2 O (1500 mL) was quenched and extracted with EtOAc (3 × 300 mL). The combined organics were washed with brine (2 × 100 mL), dried over MgSO 4 and filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product as a yellow solid (19.3 g, 45%).

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

[0291] Step f: 8-Bromo-6-fluoroquinoline (15.7 g, 69.5 mmol), Zn(CN) 2 (4.9 g, 41.7 mmol, 0.8 eq), and Pd(PPh 3 ) 4 (8 g, 6.9 mmol, 10% mol) in anhydrous DMF (100 mL) were stirred at 100 °C overnight. Then, the reaction was cooled to room temperature and diluted with H 2 O (500 mL). The yellow solid was filtered off, washed with H 2 O, and dried under vacuum. The crude product was used in the next step without further purification.

[0292] Step g: The product from step f was placed in a Parr bottle and dissolved in MeOH (300 mL) and concentrated HCl (50 mL). The mixture was purged with N 2 and PtO 2 (1.56 g, 6.9 mmol, 10% mol) was added. The reaction was shaken under H 2 atmosphere (50 psi) for 5 h, then filtered through Celite, washed with MeOH, and evaporated. The crude residue was purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product as a yellow solid (5.9 g, 48% over 2 steps). 1 H NMR (400 MHz, CDCl 3 ) δ 6.90 - 6.81 (m, 2H), 4.63 (brs, 1H), 3.41 - 3.33 (m, 2H), 2.77 - 2.68 (m, 2H), 1.96 - 1.85 (m, 2H).

[0293] Step h: The bromide (200 mg, 0.57 mmol) from step g, the tetrahydroquinoline (100 mg, 0.57 mmol) from step g, and Pd(OAc) 2(25 mg, 0.22 mmol, 20% mol.), rac-BINAP (87 mg, 0.14 mmol, 25% mol.), and Cs 2 CO 3 (372 mg, 1.14 mmol, 2 equiv.) were stirred at 100 °C for 5 h. The entire reaction mixture was loaded onto a silica gel cartridge and purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product as a yellow solid (44 mg, 17%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.19 - 7.13 (m, 1H), 7.11 - 7.07 (m, 1H), 3.90 - 3.57 (m, 2H), 3.06 - 2.82 (m, 2H), 2.20 - 1.78 (m, 2H). C 18 H 10 ClF 4 N 3 O 2 ESI MS of C + H

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

[0295]

Chemical Structure

[0296] Step a: A solution of 3-bromo-2-chloro-6-fluorobenzonitrile (5 g, 21.3 mmol) in anhydrous CH 3 CN (100 mL) was cooled to 0 °C, and then CH 3 SNa (1.64 g, 23.4 mmol, 1.1 equiv.) was added in one portion. The mixture was stirred at 0 °C for 15 min, then the cooling bath was removed and the reaction was stirred at room temperature overnight. H 2It was diluted with O (300 mL), and the product was removed by filtration (white solid, 4.6 g, 82%).

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

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

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

[0300]

Chemical formula

[0301] The title compound was synthesized in the same manner as in Example 10. (Yellow solid, 130 mg, 50%). 1 H NMR (400 MHz, CDCl 3) δ 7.90 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.00 - 6.93 (m, 1H), 6.93 - 6.86 (m, 1H), 3.91 - 3.82(m, 1H), 3.66 - 3.53 (m, 1H), 3.02 - 2.86 (m, 2H), 2.06 - 1.93 (m, 1H), 1.89 - 1.75 (m, 1H). C 17 H 10 Cl 2 F 4 N 2 O 2 ESI MS of S [M+H] + , calculated value 453.0, measured value 453.0.

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

[0303]

Chemical Structure

[0304] The title compound was synthesized in the same manner as in Example 10. (Yellow solid, 172 mg, 69%). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.93 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 6.79 - 6.73 (m, 1H), 6.70 - 6.59 (m, 1H), 3.77 - 3.67 (m, 2H), 2.95 - 2.87 (m, 2H), 1.99 - 1.89 (m, 2H). C 17 H 10 ClF 5 N 2 O 2 ESI MS of S [M+H] + , calculated value 437.0, measured value 437.0.

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

[0306] [Chemical formula]

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

[0308] Step b: In a vial, the product from step a (30 mg, 0.088 mmol, 1.0 equiv), KCN (7.0 mg, 0.097 mmol, 1.1 equiv) and NMP (0.3 mL) were placed. The reaction mixture was stirred at 100 °C for 4 hours. The reaction was diluted with saturated NaHCO 3 aqueous solution (10 mL) and extracted with EtOAc (10 mL). The aqueous layer was separated and back-extracted with additional EtOAc (15 mL). The organic layers were combined and H2 Washed with O(2×20 mL) and brine (20 mL), and dried over MgSO 4 It was concentrated under reduced pressure and purified by flash chromatography to obtain the product as a yellow solid (4.0 mg, 0.012 mmol, 13%). 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.63 (m, 1H), 8.31 - 8.25 (m, 1H), 7.70 - 7.64 (m, 1H), 7.61 - 7.54 (m, 1H), 3.86 - 3.80 (m, 2H), 2.80 (t, J = 6.4 Hz, 2H), 1.95 - 1.87 (m, 2H). C 17 1H 10 19F 4 15N 4 ESI MS [M+H] of + calculated value 347.1, measured value 347.0.

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

[0310]

Chemical Structure

[0311] The title compound was synthesized in the same manner as in Example 14 using 1-bromo-2-chloro-3-fluoro-4-(trifluoromethyl)-benzene. 1 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). C 17 1H 10 35Cl, 19F 5 15N 2 ESI MS [M+H] of + calculated value 373.0, measured value 373.0.

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

[0313]

Chemical Structure

[0314] The title compound was synthesized in the same manner as in 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). C 20 H 13 F 4 N 3 O 2 ESI MS [M+H] of S + , calculated value 436.1, measured value 436.1.

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

[0316]

Chemical Structure

[0317] The title compound was synthesized in the same manner as in Example 19. 11H NMR (400 MHz, chloroform-d) δ 7.77 (d, J = 8.4 Hz, 1H), 7.00 (s, 0H), 6.83 (d, J = 8.8 Hz, 1H), 6.70 (ddd, J = 11.0, 8.3, 2.6 Hz, 1H), 5.51 (s, 1H), 5.18 (d, J = 50.8 Hz, 1H), 3.69 (s, 2H), 3.00 (br m, 2H), 2.84 (p, J = 6.4 Hz, 1H), 2.12 - 1.99 (m, 1H), 1.81 (br m, 2H), 1.60 (dq, J = 14.5, 7.5 Hz, 1H), 0.98 (t, J = 7.4 Hz, 3H). C 21 H 19 F 6 NO 3 ESI MS of S [M+H] + , calculated value 480.1, measured value 480.1.

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

[0319]

Chemical Structure

[0320] The title compound was synthesized in the same manner as in Example 10. 1 1H NMR (400 MHz, CDCl 3 ) 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 19F NMR (376 MHz, CDCl 3) δ -77.11, -115.53. C 18 H 13 ClF 4 N 2 O 3 ESI MS of S [M+H] + ; Calculated value 449.0, measured value 449.1.

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

[0322]

Chemical Structure

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

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

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

[0326] Step d: A mixture of 5-bromo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.05 g, 4.5 mmol), zinc cyanide (0.43 g, 3.6 mmol) and Pd(PPh 3 ) 4 (0.52 g, 0.45 mmol) in DMF (11 mL) was heated at 100 °C for 4 h under a nitrogen atmosphere. When complete disappearance of the starting material was observed by TLC analysis (30% EtOAc in hexane as eluent), the solution was cooled to ambient temperature and poured into a mixture of EtOAc (50 mL) and water (50 mL). The resulting suspension was filtered through a celite plug. The organic phase was separated and the aqueous phase was further extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with water (2 × 75 mL) and brine (75 mL), dried over Na 2 SO 4 and concentrated to dryness. The dry residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to give 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (0.75 g, 4.2 mmol, 94% yield) as a white powder. 1 H NMR (400 MHz, CDCl 3) 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, CDCl 3 ) δ -124.17. C 9 H 7 FN 2 O's ESI MS [M+Na] + ; calculated value 179.1, measured value 179.1.

[0327] Step e: (1S,2R)-4-bromo-2-fluoro-1-(tert-butyldimethylsilyl)-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 Cs 2 CO 3 (137 mg, 0.42 mmol) in anhydrous degassed toluene (1 mL) was stirred at 100 °C for 6 h. Then the mixture was cooled to ambient temperature, diluted with EtOAc, filtered through a celite pad to remove inorganic solids. The filtrate was concentrated on celite and purified by column chromatography (SiO 2 , hexane / EtOAc gradient) to give a mixture of the product and unreacted benzomorpholine (55 mg). This mixture was subjected to step f without further purification.

[0328] Step f: A mixture of the TBS-protected indanol from the previous step and unreacted benzomorpholine in CH 3Dissolved in CN (1 mL), placed in a 3 mL vial equipped with a magnetic stir bar, and then HF·Py complex (about 70% hydrogen fluoride, about 30% pyridine, 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 (20 mL). The product was extracted with EtOAc (2 × 10 mL), and the combined organic extracts were washed with aqueous NaHCO 3 aqueous solution (20 mL) and brine (20 mL), dried over Na 2 SO 4 and concentrated to dryness. The residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to give 7-fluoro-4-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (25 mg, 0.054 mmol, 26% yield over 2 steps) as a yellowish oil. 1 1H NMR (400 MHz, CDCl 3 ) 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 19F NMR (376 MHz, CDCl 3 ) δ -78.08, -113.95, -199.41 (d, J = 51.0 Hz). C 19 1H 13 19F 5 15N 2 16O 4 13C NMR and ESI MS [M+Na] + ; calculated 483.0, found 483.1.

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

[0330]

Chemical Structure

[0331] The title compound was synthesized in the same manner as in Example 19. 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) δ -115.26, -199.17. C 19 H 16 F 2 N 2 O 4 ESI MS of C + H

[0332] S [M-OH]

[0333]

Chemical Structure

[0334] The title compound was synthesized in the same manner as in Example 10. 1 H NMR (400 MHz, CDCl 3) δ 9.15 (dd, J = 4.3, 1.7 Hz, 1H), 8.61 (dd, J = 8.6, 1.7 Hz, 1H), 8.44 (d, J = 8.3 Hz, 1H), 7.60 (dd, J = 8.6, 4.2 Hz, 1H), 7.08 (dd, J = 8.3, 0.9 Hz, 1H), 6.85 - 6.76 (m, 1H), 6.71 - 6.61 (m, 1H), 3.86 - 3.69 (m, 2H), 3.04 - 2.96 (m, 2H), 1.99 - 1.82(m, 2H). C 19 H 13 F 5 N 2 O 2 ESI MS of S [M+H] + Calculated value 429.1, measured value 429.1.

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

[0336]

Chemical Structure

[0337] The title compound was synthesized in the same manner as in Example 19. 1 H NMR (400 MHz, methanol-d 4 ) δ 7.76 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.85 - 6.80 (m, 1H), 6.77 - 6.69 (m, 1H), 5.50 - 5.44 (m, 1H), 3.66 - 3.57 (m, 3H), 3.22(s, 3H), 3.18 - 3.03 (m, 1H), 2.93 - 2.84 (t, J = 6.6 Hz, 2H), 1.96 - 1.84 (m, 2H). C 19 H 17 F 4 NO 3ESI MS of S [M+H] + Calculated value: 416.1, Measured value: 416.0.

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

[0339]

Chemical Structure

[0340] The title compound was synthesized in the same manner as in Example 24. 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (d, J = 2.2 Hz, 1H), 7.94 (dd, J = 8.9, 2.3 Hz, 1H), 7.33 (dd, J = 8.9, 1.7 Hz, 1H), 6.82 - 6.76 (m, 1H), 6.76 - 6.63 (m, 1H), 3.77 - 3.50 (m, 2H), 2.92 - 2.81 (m, 2H), 2.15 - 1.99 (m, 2H). C 16 H 11 F 5 N 2 O 4 ESI MS of S [M+H] + Calculated value: 423.0, Measured value: 423.1.

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

[0342]

Chemical Structure

[0343] 4-Bromo-3-nitrobenzotrifluoride (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 Cs 2 CO 3 (652 mg, 2 mmol) were suspended in PhMe (5 mL). The suspension was degassed with N 2 for 5 minutes at ambient temperature and heated at 100 °C for 1.5 hours. The mixture was cooled to room temperature, diluted with EtOAc, filtered and concentrated over Celite®. Purification by column chromatography (0 - 10% EtOAc / hexane) gave 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, CDCl 3 ) δ -62.3 (3 F), -117.3 (1 F), -116.7 (1 F). C 16 H 11 F 5 N 2 O 2 The ESI MS [M+H] + , calculated 359.1, found 359.1.

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

[0345]

Chemical Structure

[0346] Step a: 5-Bromo-8-isoquinolylamine (2.23 g, 10 mmol, 1 eq) was dissolved in a mixture of ethanol (3 mL) and HBF 4 aqueous solution (48 wt%, 2.62 mL, 20 mmol, 2 eq), and the solution was cooled to 0 °C. t-BuONO (2.37 mL, 20 mmol, 2 eq) was added dropwise, and then the reaction was stirred for 1 hour. Et 2 O (10 mL) was added to the reaction mixture, which was then filtered and washed with additional Et 2 O (2 × 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%). C 9 H 5 BrN 3 The ESI MS [M] + calculated value was 234.0, and the measured value was 234.0.

[0347] Step b: To a vigorously stirred solution of NaSO 2 CF 3 (4.68 g, 30 mmol, 3 eq) and Cu 2 O (143 mg, 1 mmol, 0.1 eq) in DMSO (10 mL), a solution of the product from step a in DMSO (10 mL) was added using a dropping funnel. After the addition was complete, the reaction was stirred for 2 hours or until LCMS indicated complete conversion of the starting material. The reaction mixture was then diluted with EtOAc (100 mL) and water (100 mL). After separation of the layers, the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organics were washed with water (2 × 100 mL) and brine (100 mL) and finally dried over Na 2 SO 4 . The crude material was purified by flash column chromatography (SiO 2 , 0 - 100% EtOAc / hexane) to obtain the product as a brown solid (716 mg, 2.94 mmol, 29%). C 10 H 5 BrF 3 NO 2 The ESI MS [M + H] + calculated value was 339.9, and the measured value was 339.9.

[0348] Step c: To the vial, the product from step b (24 mg, 0.07 mmol, 1 equiv), 2-(6,8-difluoro-3,4-dihydronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21 mg, 0.07 mmol, 1 equiv), Pd(dppf)Cl 2 (5 mg, 0.007 mmol, 0.1 equiv), Na 2 CO 3 aqueous solution (1 M, 0.21 mL, 3 equiv), and dioxane (1 mL) were added. The vial was sparged with N 2 for 10 minutes, and then heated at 100 °C for 16 hours. Then, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried over Na 2 SO 4 and concentrated. The crude material was purified by flash column chromatography (0 - 100% EtOAc / hexane) to give the target product (7 mg, 0.016 mmol, 23%). C 20 H 12 F 5 NO 2 S ESI MS [M + H] + Calculated value 426.1, measured value 426.1.

[0349] Step d: The product from step c (7 mg, 0.016 mmol, 1 equiv) was dissolved in i-PrOH (1 mL), and PhSiH 3 (4 μL, 0.032 mmol, 2 equiv) and tert-butyl hydroperoxide (5.5 M in decane, 8 μL, 0.032 mmol, 2 equiv) were added under nitrogen. The solution was sparged with nitrogen for 10 minutes, and then Mn(dmp) 3 (10 mg, 0.016 mmol, 1 equiv) was added, and the resulting mixture was sparged for an additional 30 seconds. Then, the reaction was stirred under nitrogen for 16 hours. After concentrating the reaction mixture, the crude material was purified by flash column chromatography (SiO 2 , 0 - 100% EtOAc / hexane) to give the title compound (4 mg, 0.009 mmol, 57%).1 1H NMR (400 MHz, chloroform-d) δ 10.23 (s, 1H), 8.85 (d, J = 6.0 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 6.0 Hz, 1H), 7.16 (m, 1H), 6.84 - 6.79 (m, 1H), 6.67 - 6.59 (m, 1H), 5.12(m, 1H), 3.02 - 2.78 (m, 2H), 2.33 - 2.19 (m, 1H), 2.05 - 1.97 (m, 1H), 1.84 - 1.70 (m, 1H), 1.57 (br m, J = 17.9 Hz, 1H). C 20 H 14 F 5 NO 2 ESI MS of + Calculated value 428.1, measured value 428.1.

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

[0351] [Table 1] JPEG2025087830000334.jpg210164JPEG2025087830000335.jpg210164JPEG2025087830000336.jpg222164JPEG2025087830000337.jpg201164JPEG2025087830000338.jpg223164JPEG2025087830000339.jpg223164JPEG2025087830000340.jpg223164JPEG2025087830000341.jpg223164JPEG2025087830000342.jpg209164JPEG2025087830000343.jpg225164JPEG2025087830000344.jpg223164JPEG2025087830000345.jpg139164

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

[0353]

Chemical formula

[0354] Step a: Into a flask, 2-chloro-4-fluoroaniline (18.2 g, 15 mL, 1.0 mol equivalent) and excess acrylic acid (46 g, 5.0 mol equivalent) were added, and the resulting mixture was stirred at 45 °C for 15 hours. During this time, the product was solidified from the reaction mixture, recovered by filtration, washed with hexane to obtain the aniline product, which was used as the crude product in the next step (25.4 g, 93%).

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

[0356] Step c: A flask containing the product from the previous step (15 g, 75.3 mmol, 1.0 mol equivalent) in MeOH (250 mL) was cooled to 0 °C under N 2 atmosphere. NaBH 4 (3.41 g, 90.4 mmol, 1.2 mol equivalent) was added slowly portionwise, and then the reaction mixture was stirred at room temperature for 30 minutes. At this time, the reaction mixture was placed in an ice bath, quenched with H 2 2O, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The combined organic layers were washed with water, brine, and dried over MgSO 4 4. The mixture was concentrated under reduced pressure to give the tetrahydroquinoline intermediate, which was used in the next step without further purification.

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

[0358] Step e: To a flask were added the TBS alcohol from the previous step (6.0 g, 19 mmol, 1.0 mol equivalent), K 4 3Fe(CN) 6 6.3H 2 2O (5.61 g, 13.3 mmol, 0.7 mol equivalent), Pd XPhos gen III (0.803 g, 0.95 mmol, 5 mol%), XPhos (0.452 g, 0.95 mmol, 5 mol%), KOAc (0.242 g, 2.47 mmol, 0.13 mol equivalent), H 2 2O (40 mL), and 1,4-dioxane (40 mL). The resulting mixture was placed under N2 Purge with N and heat at 100 °C, and stir vigorously under N. 2 After 3 hours, cool the reaction mixture and dilute with EtOAc and H 2 O. Separate the aqueous layer and back-extract with additional EtOAc. Filtration through Celite to remove solids can improve layer separation. Combine the organic layers and dry over MgSO 4 . Purify by flash column chromatography (SiO 2 , 20% EtOAc from hexane) to obtain the benzonitrile product as a yellow solid (5.68 g, 98%).

[0359] Step f: To a flask containing 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (10 g, 34.8 mmol, 1.0 mol equiv), add DMF (70 mL), then EDC·HCl (9.98 g, 52.2 mmol, 1.5 mol equiv), HOBt·H 2 O (7.0 g, 52.2 mmol, 1.5 mol equiv), ammonium carbonate (16.7 g, 174 mmol, 5.0 mol equiv) and DIPEA (18 mL, 3.0 mol equiv). Stir the resulting mixture at 40 °C overnight. Partition the reaction mixture between EtOAc and H 2 O. Separate the aqueous layer and extract with additional EtOAc. Combine the organic layers, wash with H 2 O to remove DMF, and dry over MgSO 4 . Concentrate under reduced pressure to obtain the crude amide, which was used in the next step without purification.

[0360] Step g: To a flask containing the crude amide from the previous step, add DMF (100 mL) and cyanuric chloride (2.55 g, 13.9 mmol, ~0.6 mol equiv). Stir the resulting mixture at room temperature under N 2 for 16 hours. Partition the reaction mixture between EtOAc and H 2 O. Separate the aqueous layer and extract with additional EtOAc. Combine the organic layers, wash with H 2 O to remove DMF, and dry over MgSO 4It was dried. It was concentrated under reduced pressure and purified by flash column chromatography (SiO 2 , from hexane to 20% EtOAc) to obtain the nitrile product as a white solid (2.68 g, 26% over 2 steps).

[0361] Step h: In a vial, benzonitrile (1.0 g, 3.73 mmol, 1.0 mol equivalent) from the previous step, 4-[tert-butyl(dimethyl)silyl]oxy-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (1.10 g, 3.73 mmol, 1.0 mol equivalent), Pd(OAc) 2 (0.167 g, 0.746 mmol, 20 mol%), rac-BINAP (0.580 g, 0.925 mmol, 25 mol%), Cs 2 CO 3 (2.42 g, 7.46 mmol, 2.0 mol equivalents) and toluene (15 mL) were added. N 2 was bubbled through the reaction mixture for 3 minutes, the vial was capped, and heated at 100 °C for 15 hours. The reaction was monitored by TLC analysis and NMR analysis. The reaction was cooled, filtered, and concentrated over celite. It was purified by flash column chromatography (SiO 2 , from hexane to 10 - 20% EtOAc) to obtain the coupled product as a yellow solid (1.00 g, 54%). C 24 H 24 F 5 N 3 OSi ESI MS [M + H] + , calculated value 494.2, measured value 494.2.

[0362] Step i: A flask containing the product (1.0 g, 2.02 mmol, 1.0 mol equivalent) from the previous step and THF (10 mL) was cooled to 0 °C, and TBAF (1 M in THF, 3.0 mL, 1.5 mol equivalents) was added. The reaction mixture was warmed to room temperature and stirred for 15 minutes. After this time, the reaction was quenched with saturated NH 4Quenched with aqueous Cl solution and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with brine, and dried over MgSO 4 . Concentrated under reduced pressure and purified by flash column chromatography (SiO 2 , 20% - 50% - 80% EtOAc from hexane) to give the alcohol product as a white solid (0.694 g, 91%).

[0363] Step j: A vial containing the alcohol product (35 mg, 0.093 mmol, 1.0 mol equiv) from the previous step in DCM (1 mL) was cooled to -78 °C. DAST (20 μL, 0.149 mmol, 1.6 mol equiv) was added and the reaction was warmed to room temperature and stirred for 5 minutes. The reaction was quenched with saturated aqueous NaHCO 3 and diluted with DCM. The aqueous layer was separated and back-extracted with additional DCM. The organic layers were combined and dried over MgSO 4 . Concentrated under reduced pressure and purified by column chromatography (SiO 2 , 20% EtOAc from hexane) to give 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%). These enantiomers were separated by preparative SFC chiral purification (2.0 x 25.0 cm ChromegaChiral CC4 from ES Industries (West Berlin, NJ), CO 2 co-solvent isopropanol / hexane (1:9), 15% co-solvent at 100 mL / min) to give the title compound (4S)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile as a white solid (98.8% ee, t R= 1.5 min). The absolute stereochemistry was confirmed by single crystal X-ray analysis. 1H NMR (400 MHz, DMSO-d6, appearing as a 2:1 mixture of 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). C 18 H 8 F 5 N 3 The ESI MS of [(M-HF) + H] + was calculated to be 362.0 and the measured value was 362.0.

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

[0365]

Chemical Structure

[0366] Step a: A solution of 3-amino-2-chloro-benzonitrile (1 g, 6.58 mmol) in DMF (20 mL) was cooled to -10 °C, and NBS (1.17 g, 6.58 mmol, 1.0 equiv) in DMF (10 mL) was added dropwise over 10 minutes. The mixture was stirred at -10 °C for 10 minutes, then the cooled batch was removed and the reaction was stirred at room temperature for 1.5 hours. Diluted with 10% Na 2 S 2 O 3 (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organics were washed with brine (50 mL) and MgSO 4It was dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product (0.92 g, 60%).

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

[0368] Step c: A mixture of the bromide from step b (180 mg, 0.68 mmol, 1.5 eq), 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 Cs 2 CO 3 (440 mg, 1.35 mmol, 3 eq) in anhydrous degassed toluene (8 mL) was stirred at 100 °C for 15 h. The entire reaction mixture was loaded onto a silica gel cartridge and purified by column chromatography (silica gel, hexane (hex) → 30% EtOAc in hexane) to give the product (88 mg, 40%).

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

[0370] Step e: The product from step d (0.18 mmol) was dissolved in THF (40 mL), and TBAF (1.0 M in THF, 0.54 mL, 3.0 equiv) was added. The reaction mixture was stirred at room temperature for 15 minutes. H 2 O (10 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 80% EtOAc in hexane) to give the product as a yellow solid (58 mg, 80%).

[0371] Step f: The product from step e (25 mg, 0.05 mmol) in DCM (2 mL) was cooled to -10 °C, and DAST (16 mg, 0.1 mmol, 2.0 equiv) was added. The mixture was stirred at -10 °C for 10 minutes, then the cooling bath was removed and the reaction mixture was stirred at room temperature for 0.5 hour. H 2 O (10 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 60% EtOAc in hexane) to give the product as a yellow solid (23 mg, 95%). 1 H NMR (400 MHz, DMSO-d 6) δ 8.22 (d, J = 8.8 Hz, 0.4 H), 8.11 (d, J = 8.8 Hz, 0.6 H), 7.92 - 7.74 (m, 2H), 7.54 (d, J = 8.8 Hz, 0.4 H), 7.25 (d, J = 8.8 Hz, 0.6 H), 5.89 - 5.59 (m, 1H), 4.04 - 3.90 (m, 1H), 3.84 - 3.63 (m, 1H), 3.38 (m, 3H), 2.30 - 1.97 (m, 2H). C 18 H 12 ClF 2 N 3 O 2 ESI MS of S [M+H] + , calculated value 408.0, measured value 408.0.

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

[0373]

Chemical Structure

[0374] This compound was prepared in the same manner as in Example 121 from 6-bromo-2-chloro-3-(trifluoromethyl)benzoic acid. 1 H NMR (400 MHz, DMSO-d6, appearing as a 2:1 mixture of rotamers) δ 8.15 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 2H), 7.93 - 7.86 (m, 4H), 7.86 - 7.77 (m, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.7 Hz, 2H), 5.82(dt, J = 49.7, 2.9 Hz, 1H), 5.70 (dt, J = 49.8 Hz, 2.9 Hz, 2H), 4.05 - 3.91 (m, 3H), 3.88 - 3.66 (m, 3H), 2.32 - 2.00 (m, 6H). C18 H 9 ClF 5 N 3 ESI MS [M+H] of + , calculated value 398.0, measured value 397.9.

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

[0376]

Chemical formula

[0377] Step a: A vial containing 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (110 mg, 0.290 mmol, 1.0 mol 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 warmed to room temperature and stirred for 20 minutes. The reaction was quenched with saturated NaHCO 3 aqueous solution and saturated Na 2 S 2 O 3 aqueous solution (1:1), and diluted with DCM. The mixture was stirred vigorously for 30 minutes. The organic layer was separated and further washed with saturated NaHCO 3 / Na 2 S 2 O 3 aqueous solution. The organic layer was separated and dried over MgSO 4 . It was concentrated under reduced pressure to obtain the ketone product as a yellow solid, which was pure enough to be used in the subsequent step (110 mg, approximate quantitative value). C 18 H 8 F 5 N 3 ESI MS [M+H] of + , calculated value 378.1, measured value 378.1.

[0378] Step b: A solution of KOtBu (1 M in THF, 520 μL, 2 equiv) was added to a solution of 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-oxo-2,3-dihydroquinoline-8-carbonitrile (100 mg, 0.265 mmol) and tosMIC (83 mg, 0.42 mmol, 1.6 equiv) in dichloromethane (1.3 ml) at room temperature. Ethanol (18 mg, 0.4 mmol, 1.5 equiv) was added and the reaction was stirred at room temperature for 48 h. Upon completion, the reaction was quenched with 2 N aqueous HCl and extracted with dichloromethane, and purified by flash chromatography on silica gel to afford 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-3,4-dihydro-2H-quinoline-4,8-dicarbonitrile. 1 H NMR (400 MHz, DMSO-d6): δ 8.11 - 7.95 (m, 1H), 7.88 - 7.68 (m, overlapping, 2H), 7.24 (dd, J = 8.2, 8.2 Hz, 1H), 4.69 - 4.57 (m, 1H), 4.09 - 3.69 (m, 2H), 2.43 - 2.27 (m, 1H), 2.22 - 2.09 (m, 1H). C 19 H 9 F 5 N 4 of ESI MS [M+H] + , calcd 389.0, found 389.0.

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

[0380]

Chem.

[0381] Step a: A solution of 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-oxo-2,3-dihydroquinoline-8-carbonitrile (100 mg, 0.265 mmol) in a 50 wt% solution of Deoxo-Fluor® in 1 mL of toluene was heated at 70 °C overnight. Upon completion, the reaction was cooled to 0 °C in an ice bath and quenched with water. The resulting solution was extracted with ethyl acetate and methylene chloride, and the crude concentrate was purified by flash chromatography on silica gel (0% - 30% ethyl acetate in hexanes) to afford 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile. 1 H NMR (400 MHz, CDCl 3 ): δ 7.75 (dd, J = 8.2, 8.2 Hz, 1H), 7.68 (dd, J = 7.8, 3.0 Hz, 1H), 7.27 (dd, J = 7.2, 3.0 Hz, 1H), 6.92(d, J = 8.6 Hz, 1H), 4.16 - 4.09 (m, 1H), 3.99 - 3.92(m, 1H), 2.53 - 2.39 (m, 2H). C 18 H 8 F 7 N 3 The ESI MS [M+H] + , calculated 400.1, found 400.0.

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

[0383]

Chemical Structure

[0384] Step a: A flask containing 2,5-dibromo-3-fluoropyridine (6.00 g, 23.6 mmol, 1.0 mol eq) in THF (100 mL) was purged with N2 It was cooled to -78 °C below. A solution of LDA (2.0 M in heptane / THF / ethylbenzene, 17.7 mL, 1.5 mol equiv) was slowly added, and the resulting mixture was stirred for 15 minutes. MeI (2.9 mL, 2.0 mol equiv) was added, the reaction mixture was warmed to room temperature, and stirred for 30 minutes. The reaction was cooled to 0 °C, quenched with saturated NH 4 Cl aqueous solution, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO 4 . It was concentrated under reduced pressure and purified by flash column chromatography (SiO 2 , 15% EtOAc from hexane) to give the methylation product as a yellow oil (3.64 g, 57%).

[0385] Step b: A flask containing the product from the previous step (3.00 g, 11.2 mmol, 1.0 mol equiv) in dry toluene (30 mL) was cooled to -78 °C under N 2 . nBuLi (2.5 M in hexane, 5.4 mL, 1.2 mol equiv) was added and the reaction was stirred for 30 minutes. After this time, the organolithium was quenched with anhydrous DMA (3.2 mL, 33.6 mmol, 2.0 mol equiv) and the reaction was stirred for an additional 20 minutes. The reaction was quenched with saturated NH 4 Cl aqueous solution at -78 °C. After warming, the mixture was diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO 4 . It was concentrated under reduced pressure and purified by flash column chromatography (SiO 2 , 30% EtOAc from hexane) to give the ketone product (906 mg, 35%).

[0386] Step c: To the ketone product from the previous step (400 mg, 1.72 mmol, 1.0 mol equiv) was added Deoxo-Fluor (2.7 M in toluene, 3.0 mL, 4.0 mol equiv), and the resulting mixture was stirred at 70 °C for 9 hours. The reaction mixture was poured onto ice and saturated NaHCO 3Quenched with aqueous solution and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO 4 and concentrated under reduced pressure and purified by flash column chromatography (SiO 2 , hexane to 20% EtOAc) to afford the difluorinated product as a yellow oil (342 mg, 78%). C 8 H 7 BrF 3 N ESI MS [M+H] + , calcd 253.9, found 253.8.

[0387] The title compound, 1-[6-(1,1-difluoroethyl)-5-fluoro-4-methylpyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile, was prepared from 5-bromo-2-(1,1-difluoroethyl)-3-fluoro-4-methylpyridine in four additional steps in the same manner as in 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). C 18 H 13 F 6 N 3 ESI MS [M+H] + , calcd 386.1, found 386.0.

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

[0389]

Chemical Structure

[0390] 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 N 2 2. 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 warmed to room temperature and stirred for 15 minutes. The reaction was cooled to 0 °C, quenched with saturated NH 4 4Cl aqueous solution and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, dried over MgSO 4 4, concentrated under reduced pressure and purified by flash column chromatography (SiO 2 2, 15% EtOAc from hexane) to give the chlorinated product as a yellow oil (824 mg, 72%).

[0391] The title compound 1-[4-chloro-5-fluoro-6-(trifluoromethyl)pyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile was prepared from 5-bromo-4-chloro-3-fluoro-2-(trifluoromethyl)pyridine in four further steps in a similar manner 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). C 16 1H 7 19F 7 15N 3 of the ESI MS [M+H] + , calculated 410.0, found 409.9.

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

[0393]

Chemical formula

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

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

[0396] Step c: To a vial was added the product from step b (90 mg, 0.186 mmol, 1.0 mol equivalent) and NMP (1.0 mL). KCN (18 mg, 0.28 mmol, 1.5 mol equivalent) was added and the reaction was stirred at 110 °C. A further 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 was cooled and diluted with saturated NaHCO 3 aqueous solution and EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO 4 . Concentration under reduced pressure and purification by flash column chromatography (SiO 2 , 60% EtOAc from hexane) gave benzonitrile alcohol (18 mg, 0.048 mmol, 26%). C 18 H 12 F 4 N 4 O ESI MS [M+H] + , calcd 377.1, found 377.0.

[0397] The title compound 1-[5-cyano-4-methyl-6-(trifluoromethyl)pyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile was prepared in two further steps as in Examples 124 and 125. 11H 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). C 18 H 10 F 6 N 4 The ESI MS [M+H] of + , calculated value 397.1, measured value 397.0.

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

[0399]

Chemical Structure

[0400] The title compound 4,4,6-trifluoro-1-[5-fluoro-4-methyl-6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydroquinoline-8-carbonitrile was prepared in three additional steps in the same manner as in Example 125. 1 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.96 - 7.90 (m, 1H), 7.87 (dd, J = 8.0, 2.9 Hz, 1H), 3.95 - 3.80 (m, 1H), 3.78 - 3.65 (m, 1H), 2.70 - 2.52(m, 2H), 2.33 (d, J = 2.1 Hz, 3H). C 17 H 10 F 7 N 3 The ESI MS [M+H] of + , calculated value 390.0, measured value 390.0.

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

[0402]

Chem.

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

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

[0405] Step c: The product of step b (100 mg, 0.25 mmol, 1.0 equiv) was dissolved in CH 2 Cl 2 (2.5 mL) and the solution was cooled to -40 °C. Diethylaminosulfur trifluoride (0.17 mL, 1.26 mmol, 5.0 equiv) was added dropwise and the reaction mixture was warmed slowly to 0 °C with stirring over 2 h. The mixture was then diluted with CH 2 Cl 2 and poured into saturated aqueous NaHCO 3 . The layers were separated. The organic phase was washed with brine and Na 2 SO 4It was dried and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0 - 18% gradient EtOAc in hexane), and a mixture of diastereoisomers (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%) was obtained as a white solid (combined yield 81%). The properties of (3S,4R)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile have been reported. This substance with enantiomeric excess was 97% by chiral HPLC (Chiralpak AD-H, 15% iPrOH / hexane, homogeneous solvent, 20 minutes), R T minor = 7.18 minutes and R T major = 7.70 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6 ) δ:-59.6 (3F), -108.7 (q, J = 11.8, 11.2 Hz, 1F), - 116.4 (t, J = 8.6 Hz, 1F), -198.7 (m, 1F), -201.9 (m, 1F). C 18 H 10 F 7 N 3 O1 ESI MS [M+H 2 O] + , calculated value 417.0, measured value 416.9.

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

[0407]

Chemical Structure

[0408] Step a: To a solution of 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (80 mg, 0.21 mmol) in methanol (2.1 ml, 0.1 M) was added concentrated sulfuric acid (120 μL), and the resulting solution was heated to reflux. When complete, the reaction solution was quenched with saturated NaHCO3, extracted with ethyl acetate, and dried over Na 2 SO 4 . After concentrating the organic matter on celite, the resulting crude material was purified by flash chromatography (SiO 2 ) using a gradient of 0% to 100% dichloromethane in hexane to give 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-methoxy-3,4-dihydro-2H-quinoline-8-carbonitrile. 1 1H NMR (400 MHz, CDCl 3 ): δ 7.69 (dd, J = 8.3, 8.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 7.6, 3.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.33 (s, 1H), 3.90 (br m, 2H), 4.36 (s, 3H), 2.18 (br m, 2H). C 19 H 12 F 5 N3 ESI MS of O [M+H] + Calculated value: 394.1, measured value: 394.0

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

[0410]

Chemical Structure

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

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

[0413] Step c: CHCl 3 (1 mL) of a solution of the product from step b (130 mg, 0.35 mmol) and Deoxo-Fluor (50 wt% in toluene) (1.25 g, 2.83 mmol, 8.0 equiv) was heated at 70 °C for 12 h. The reaction was then cooled to room temperature and quenched with saturated NaHCO 3 (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over MgSO 4 and filtered, then concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 40% EtOAc in hexane) to give the product (28 mg, 20%).

[0414] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.77 (m, 1H), 7.73 - 7.57 (m, 2H), 7.06 (m, 1H), 4.42(m, 1H), 3.85 (m, 1H), 3.70 - 3.56 (m, 1H), 3.35 (d, J = 8.4 Hz, 3H), 2.20 - 1.79 (m, 5H). C 20 H 15 F 4 N 3 O ESI MS [M+H] + , calcd 390.1, found 390.1.

[0415] Example 133: 1-[2-Cyano- 4-(1,1-Difluoroethyl)-3-fluorophenyl]-4,4,6-trifluoro-1,2,3,4-tetrahydro-8-quinoline carbonitrile

[0416]

Chemical Structure

[0417] Step a: 1,4-Dioxane (6 mL) and 2.0 M Na 2 CO 3 A mixture of 1-(4-bromo-2-cyano-3-fluorophenyl)-6-fluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (500 mg, 1.28 mmol), isopropenylboronic acid pinacol ester (0.237 g, 1.41 mmol, 1.1 eq), and PdCl 2 (dppf) (94 mg, 0.128 mmol, 10% mol) in 2 CO 4 (2 mL) was stirred at 90 °C overnight under N

[0418] Step b: The product from step a (0.5 g, 1.28 mmol) was dissolved in THF / H 2 O (2:1; 6 / 3 mL). 2,6-Lutidine (274 mg, 2.56 mmol, 2 eq) and NaIO 4 (1.64 g, 7.68 mmol, 6 eq) were added, followed by K 2 OsO 4 2H 2 O (24 mg, 0.06 mmol, 5% mol). The reaction mixture was stirred at room temperature for 15 h, then diluted with 10% Na 2 S 2 O 3 solution (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 50% EtOAc in hexane) to give the product (390 mg, 87%).

[0419] Step c: The product from step b (0.39 g, 1.11 mmol) was dissolved in DCM (10 mL). Dess-Martin periodinane (705 mg, 1.65 mmol, 1.5 equiv) was added. The reaction mixture was stirred at room temperature for 0.5 h and then diluted with 10% Na 2 S 2 O 3 solution (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organics were dried over MgSO 4 and filtered, then concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 40% EtOAc in hexane) to give the product (240 mg, 62%).

[0420] Step d: A solution of the product from step c (120 mg, 0.34 mmol) and Deoxo-Fluor (50 wt% in toluene) (2.42 g, 5.48 mmol, 16 equiv) in CHCl 3 (1 mL) was heated at 70 °C for 12 h. The reaction mixture was then cooled to room temperature, quenched with saturated NaHCO 3 (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over MgSO 4 and filtered, then concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane (hex) → 40% EtOAc in hexane) to give the product (25 mg, 20%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.97 (d, J = 8.2 Hz, 2H), 7.83 (t, J = 8.7 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 4.07 - 3.97 (m, 1H), 3.97 - 3.86 (m, 1H), 2.52(m, 2H), 2.01 (t, J = 19.2 Hz, 3H). C 19 H 11 F 6 N 3 of ESI MS [M+H] + , calcd 396.0, found 396.1.

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

[0422]

Chemical formula

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

[0424] Step b: The product from step a (25.9 g, 84.3 mmol) was placed in a 1 L single-neck round-bottom flask equipped with a stir bar. Dichloromethane (700 mL), formic acid (20.0 mL, 0.50 mol), and triethylamine (47.0 mL, 0.34 mol) were added to this flask. The resulting solution was cooled to 0 °C, and RuCl(p-cymene)[(R,R)-TsDPEN] (2.2 g, 3.4 mmol) was added. The resulting brown solution was stirred at 0 °C for 16 h. When TLC analysis indicated complete conversion of the starting material, the reaction mixture was concentrated under reduced pressure to approximately half its original volume. The residual solution was washed successively with 1 M aqueous NaOH (400 mL) and brine (500 mL). The organic phase was separated and dried over Na 2 SO 4 and concentrated to dryness to produce a crude product having sufficient purity for the next step.

[0425] The enantiopurity of this material (96% enantiomeric excess) was determined by HPLC-UV chromatography [Chiralpak® AD-H (4.6 × 250 mm; 90% i-PrOH-hexane; flow rate = 1 mL / min; injection of 10 μL of a 1 mg / mL solution; detection at 254 nm; t 1 = 4.89 min (minor), t 2 = 5.26 min (major)].

[0426] Step c: The crude material from the previous step was dissolved in dichloromethane (700 mL) and placed in a 2 L three-neck round-bottom flask equipped with a reflux condenser having a thermometer, addition funnel, stir bar, and 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 placed in the addition funnel. TBSOTf was then added dropwise, generating an exothermic reaction at a rate necessary to maintain continuous reflux. When the addition was complete, the reaction mixture was refluxed for an additional 15 min, at which time TLC analysis indicated complete conversion of the starting material to the product. The solution was cooled to ambient temperature and transferred to a separatory funnel, where it was washed with saturated NH 4It was washed successively with an aqueous NaCl solution (500 mL) and brine (500 mL). The organic phase was separated and dried over Na 2 SO 4 and concentrated to dryness. The resulting crude product was purified by flash chromatography (SiO 2 , hexane / EtOAc gradient) to afford the TBS ether as a white solid (26.5 g, 62.6 mmol, 74% yield over 2 steps).

[0427] Step d: In a 500 mL single-necked round-bottom flask equipped with a magnetic stir bar and a reflux condenser with a nitrogen inlet adapter, the TBS ether product (29.5 g, 70.0 mmol) from the previous step was combined with B 2 Pin 2 (23.0 g, 91.0 mmol, 1.3 equiv), Pd(dppf)Cl 2 (5.1 g, 7.0 mmol, 0.1 equiv) and potassium acetate (13.8 g, 0.14 mmol, 2.0 equiv) in dioxane (230 mL). The mixture was degassed under vacuum and backfilled with nitrogen and heated at 100 °C for 2 h. After an aliquot 1 1H NMR analysis indicated complete consumption of the starting material, the reaction mixture was cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue was partitioned between EtOAc (500 mL) and water (300 mL). The organic layer was separated and the aqueous phase was further extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure to give the crude boronic acid pinacol ester, which was used in the next step without further purification.

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

[0429] Step f: The alkene from step e (28.0 g, 54.0 mmol) was dissolved in dry methanol (540 mL) and added to palladium on carbon (5.0 g, 10 wt% Pd) under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere of 50 psi and stirred in a Parr shaker for 4 hours. Excess hydrogen was vented, and the mixture was sparged with nitrogen to remove residual hydrogen gas. The resulting suspension was filtered through a Celite pad, and the filtrate was concentrated to dryness under reduced pressure to produce a crude mixture of epimers (1:1 dr). To isolate the more polar (S)-epimer, the crude mixture was subjected to column chromatography (SiO 2 , hexane / EtOAc gradient) to produce the desired tetralin derivative (9.6 g, 18.5 mmol, 34% yield) as a white foam.

[0430] Step g: To a solution of the TBS ether from step f in THF (93 mL), TBAF (37.2 mL, 37.2 mmol, 1 M solution in THF) was added dropwise at ambient temperature. The resulting brown solution was stirred for 20 minutes, after which TLC analysis showed complete conversion of the starting material. The mixture was diluted with EtOAc (200 mL) and washed successively with water (200 mL) and brine (150 mL). The organic extract was dried over Na 2 SO 4It was dried, concentrated to dryness, and subjected to the acylation reaction without purifying the crude product.

[0431] The dried material obtained from the previous conversion was dissolved in dichloromethane (50 mL), and then DMAP (0.7 g, 5.8 mmol) and Et 3 N (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 1 minute. The cooling bath was removed, and the reaction was stirred at room temperature for 30 minutes. When TLC analysis and LCMS analysis indicated complete conversion, the solution was diluted with dichloromethane (150 mL) and washed successively with water (200 mL), saturated NaHCO 3 aqueous solution (100 mL), and brine (100 mL). The crude product was purified by column chromatography (SiO 2 , hexane / EtOAc gradient) to yield the desired acetate ester (8.3 g, 18.5 mmol, 100% yield) as a white powder.

[0432] Step h: The acetate ester (8.3 g, 18.6 mmol) from step g, MnO 2 (6.5 g, 75 mmol), and dichloromethane (93 mL) were loaded into a 500 mL single-neck round-bottom flask equipped with a magnetic stir bar and a reflux condenser. The mixture was cooled to 0 °C, and tBuO 2 H (34 mL, 186 mmol, 5.5 M solution in decane) was added dropwise over 5 minutes. The reaction was stirred at 0 °C for 10 minutes, then warmed to ambient temperature and stirred until gas evolution ceased. The resulting black suspension was refluxed for 24 hours, then cooled to room temperature, and additional amounts of MnO 2 (6.5 g, 75 mmol) and tBuO 2 H (34 mL, 186 mmol, 5.5 M solution in decane) were added successively. The mixture was refluxed for an additional 48 hours and cooled to room temperature. The inorganic solids were removed by filtration. The filtrate was passed through a plug of celite, washed with water (100 mL), dried over Na 2 SO 4 , and concentrated to dryness. The crude product was purified by column chromatography (SiO 2, purified by hexane / EtOAc gradient, to give the corresponding α-tetralone (6.2 g, 13.5 mmol, 72% yield) as a white powder.

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

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

[0435] Step k: α-Fluorotetralin (1.1 g, 2.4 mmol) from Step j was suspended in a 7 M NH 3 solution in MeOH (90 mL), and the mixture was stirred at ambient temperature for 36 hours. The resulting clear solution was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (SiO 2 , dichloromethane / EtOAc gradient), and then triturated with 30 mL of hexane and filtered to obtain the desired product (0.85 g, 2.0 mmol, 85% yield). 1 1H NMR (400 MHz, CDCl 3 ) 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 19F NMR (376 MHz, CDCl 3) δ -110.92(m), -157.06 (m), -199.18 (m). C 21 H 18 F 3 NO 3 ESI MS of SNa [M+Na] + , calculated value 444.1, measured value 444.0).

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

[0437] [Chemical formula]

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

[0439] 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). The resulting dark suspension was stirred for 5 minutes, and then 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 and then at 0 °C for an additional 20 minutes. When TLC analysis showed complete conversion of 1,3-dithiolane, the reaction was diluted with dichloromethane (15 mL) and washed with a mixture of saturated NaHCO 3 aqueous solution and saturated Na 2 S 2 O 3 aqueous solution (1:1, v / v). The organic phase was separated, dried over Na 2 SO 4 and concentrated to dryness. The crude material was fractionated by column chromatography (SiO 2 , dichloromethane / EtOAc gradient) to yield the desired product (33.0 mg, 0.07 mmol, 43% yield) as a white solid.

[0440] Step c: 1,1-Difluorotetralin (33.0 mg, 0.07 mmol) from Step b was dissolved in THF (1 mL), and a solution of LiOH H 2 O (8.5 mg, 0.2 mmol) in water (0.2 mL) was added at 0 °C. The reaction was stirred at room temperature for 3 hours and monitored by LCMS analysis. When complete conversion was achieved, the reaction was diluted with EtOAc (20 mL) and washed with 1 M aqueous HCl (15 mL). The organic phase was separated, and the aqueous phase was further extracted with EtOAc (15 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO 2 , dichloromethane / EtOAc gradient) to yield the desired product (27.0 mg, 0.06 mmol, 90% yield) as a white solid. 1 1H NMR (400 MHz, CDCl 3) 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, CDCl 3 ) δ -85.85 (d, J = 5260.8 Hz), -109.12(m), -199.20 (dtd, J = 52.8, 22.4, 13.5 Hz). C 21 H 17 F 4 NNaO 3 S ESI MS [M+Na] + , calculated value 462.1, measured value 462.0).

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

[0442]

Chemical Structure

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

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

[0445] Step c: The crude thioether from step b (23.1 g, 69.2 mmol) was suspended in toluene (692 ml, 0.1 M). Aluminum trichloride (10.2 g, 1.1 eq) was added at room temperature. A further portion of aluminum trichloride (3.6 g, 27 mmol, 0.4 eq) was added after 3 h. When complete, the reaction was quenched with water, extracted with ethyl acetate and concentrated. The crude material was purified by flash chromatography (silica gel, 0% - 20% ethyl acetate in a 3:1 solution of CH 2 Cl 2 in hexane) to give the desired thiophenol as a yellow solid (13.4 g, 80% yield).

[0446] 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 equiv) in DMF (55 ml, 0.5 M) was carefully degassed via three freeze-pump-thaw cycles under nitrogen. The resulting solution was cooled to -10 to -5 °C in a brine ice bath, and excess CF 3 I was sparged through the reaction mixture. The reaction was then stirred overnight under a CF 3 I atmosphere. The reaction was carefully quenched with water at room temperature (note the off-gas of residual CF 3 I is generated, use with care), extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% - 20% ethyl acetate in hexane) to give the desired thioether (5.21 g, 61% yield).

[0447] Step e: To a solution of the product from step d (10.45 g, 33.6 mmol) in MeCN (129 ml, 0.26 M with respect to the starting material), CCl 4 (129 ml, 0.26 M with respect to the starting material) and H 2 O (258 ml, 0.13 M with respect to the starting material), ruthenium(III) chloride (697 mg, 3.36 mmol, 0.1 equiv) was added, followed by sodium periodate (29.6 g, 138.4 mmol, 4.12 equiv). The reaction was stirred at room temperature for 1 hour and, upon completion, extracted with CH 2 Cl 2 (x2). The combined organics were washed with saturated Na 2 S 2 O 3 then with brine, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% - 10% ethyl acetate in a 3:1 solution of CH 2 Cl 2 in hexane) to give the product sulfone as a white solid (10.53 g, 91% yield). C 10 H 6 BrF 3 O3 ESI MS of S [M+H] + ; Calculated value 342.9, measured value 342.9.

[0448] Step f: A solution of the product sulfone (3.5 g, 10.2 mmol) from step e and Selectfluor (4.32 g, 12.2 mmol, 1.2 equiv) in methanol (102 ml, 0.1 M) was heated to 50 °C. Sulfuric acid (27 μL, 5 mol%) was added and the reaction mixture was stirred at 50 °C for 48 h. The solution was then diluted with diethyl ether and the resulting white precipitate was filtered off and discarded. The organic solution was concentrated and the crude material was purified by flash chromatography (silica gel, 0% - 10% ethyl acetate in a 3:1 solution of CH 2 Cl 2 in hexane) to give the dimethyl acetal of the product as a white solid (3.57 g, 87% yield).

[0449] Step g: A solution of the acetal of the product from step f (3.18 g, 7.8 mmol) and wet Amberlyst 15 (4.77 g, 150 wt%) in dioxane (31 ml, 0.2 M) was heated at 90 °C overnight. Once complete, the polymer beads were removed by filtration and the concentrated crude material was purified by flash chromatography (silica gel, 0% - 10% ethyl acetate in a 3:1 solution of CH 2 Cl 2 in hexane) to give the desired fluorinated ketone (2.33 g, 83% yield).

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

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

[0452] Step j: The TBS ether product from step i (674 mg, 1.41 mmol) was combined with B 2 Pin 2 (457 mg, 1.8 mmol, 1.3 equiv), Pd(dppf)Cl 2 (103 mg, 0.14 mmol, 0.1 equiv) and potassium acetate (213 mg, 3 mmol, 2.2 equiv) and the resulting solution was heated to 100 °C for 3 hours. The reaction solution was concentrated and the crude material was purified by flash chromatography (silica gel, 0% - 30% ethyl acetate in hexane) to give the desired boronic acid pinacol ester (638 mg, 86% yield) as a colorless oil.

[0453] The protocol for the following steps was the same as that of Example 134. 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) δ -77.43, -110.37 (d, J = 1.6 Hz), -157.81 (d, J = 45.0 Hz), -197.41 - -202.71 (m). C 21 H 15 F 6 NNaO 3 ESI MS of NNaO[S] [M+Na] + , calculated value 498.1, measured value 498.0.

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

[0455]

Chemical Structure

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

[0457] Step b: A mixture of benzoic acid (17.5 g, 57.6 mmol) from step a, thionyl chloride (12.6 mL, 173.0 mmol), and N,N-dimethylformamide (0.3 mL) in dry benzene (290 mL) was placed in a 500 mL single-neck round-bottom flask equipped with a reflux condenser having a drying tube. The reaction mixture was refluxed for 6 h, then cooled to ambient temperature, and the excess thionyl chloride and benzene were removed by distillation under reduced pressure. The oily residue was dissolved in THF (150 mL) and added dropwise over 30 min to 30% aqueous ammonium hydroxide solution (150 mL) cooled to 0 °C. After the addition was complete, the reaction mixture was stirred vigorously for 20 min. The product was extracted with dichloromethane (3 × 200 mL). The combined extracts were dried over Na 2 SO 4 and concentrated to dryness under reduced pressure. The oily residue was triturated with hexane (200 mL), and the resulting gray precipitate was collected by filtration to give the corresponding benzamide (15.0 g, 49.7 mmol, 86% yield) as a gray solid.

[0458] Step c: A mixture of benzamide (30.1 g, 99.5 mmol) from step b and cyanuric chloride (25.6 g, 139.4 mmol) in N,N-dimethylformamide (170 mL) was heated at 70 °C for 2 h. The mixture was then cooled to room temperature and poured into 500 mL of water. The product was extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with water (2 × 300 mL) and brine (300 mL), dried over Na 2 SO 4 and concentrated to dryness under reduced pressure. The resulting residue was fractionated by flash chromatography (silica gel, 0% - 25% ethyl acetate in hexane) to give the desired benzonitrile (15.1 g, 53.0 mmol, 53% yield) as a white crystalline solid.

[0459] Step d: In a 40 mL vial equipped with a magnetic stir bar, benzonitrile (0.5 g, 1.8 mmol) from step c was added to B 2 Pin 2 (0.58 g, 2.3 mmol, 1.3 equiv) in dioxane (9 ml, 0.2 M), Pd(dppf)Cl2 (0.13 g, 0.18 mmol, 0.1 equiv) was combined with potassium acetate (0.35 g, 3.5 mmol, 2.0 equiv). The mixture was degassed under vacuum and backfilled with nitrogen, then heated at 90 °C for 1 h. After TLC analysis indicated complete consumption of the starting material, the reaction mixture was cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue was partitioned between EtOAc (30 mL) and water (20 mL). The organic layer was separated, and the aqueous phase was further extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure to afford the crude boronic acid pinacol ester, which was used without further purification.

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

[0461] Step e: The alkene from step d (0.27 g, 0.7 mmol) was dissolved in dry methanol (10 mL) and triethylamine (0.5 mL, 3.6 mmol), and then palladium on carbon (80.0 mg, 10 wt% Pd) was added under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere of 50 psi and stirred in a Parr shaker for 1 hour. The excess hydrogen was vented, and the mixture was sparged with nitrogen to remove residual hydrogen gas. The resulting suspension was filtered through a Celite pad, and the filtrate was concentrated to dryness under reduced pressure to produce a crude mixture of the desired product and the corresponding dechlorinated compound. To isolate the desired product, the crude mixture was subjected to column chromatography (SiO 2 , hexane / EtOAc gradient), and the tetralin derivative (0.1 g, 0.26 mmol, 37% yield) was produced as a white solid.

[0462] Step f: The tetralin derivative from step e (0.3 g, 0.8 mmol), MnO 2 (0.28 g, 3.2 mmol) and dichloromethane (4 mL, 0.2 M) were loaded into a 40 mL vial equipped with a magnetic stir bar. The mixture was cooled to 0 °C, and tBuO 2 H (1.5 mL, 8 mmol, 5.5 M solution in decane) was added dropwise over 5 minutes. The reaction was stirred at 0 °C for 10 minutes, then warmed to ambient temperature and stirred until gas evolution 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 MnO 2 (0.28 g, 3.2 mmol) and tBuO 2 H (1.5 mL, 8 mmol, 5.5 M solution in decane) were added successively. The mixture was refluxed for a further 48 hours and cooled to room temperature. The inorganic solid was removed by filtration. The filtrate was diluted with dichloromethane (30 mL), passed through a plug of Celite, washed with water (20 mL), dried over Na 2 SO 4 and concentrated to dryness. The crude product was subjected to column chromatography (SiO 2, purified by hexane / EtOAc gradient, to give the corresponding α-tetralone (0.14 g, 0.36 mmol, 45% yield) as a white solid.

[0463] Step g: To a cooled to 0 °C solution of α-tetralone (70.0 mg, 0.18 mmol) from step f in a mixture of MeOH (2 mL) and THF (3 mL), NaBH 4 (14.0 mg, 0.36 mmol) was added in one portion. The reaction was stirred for 10 minutes and poured into 1 M aqueous HCl (10 mL). The crude product was extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine and dried over Na 2 SO 4 and concentrated in vacuo to give a mixture of racemic cis and trans diastereomers. To separate the diastereomers, the crude mixture was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to give the more cis diastereomer (52.0 mg, 0.13 mmol, 74% yield, less polar product) along with the less trans diastereomer (8.0 mg, 0.02 mmol, 11% yield, more polar product). Both compounds were obtained in the form of white solids.

[0464] Step f: A solution of Deoxo-Fluor (0.17 ml, 0.45 mmol, 2.7 M in toluene) in toluene (2.6 mL) was cooled to 0 °C under nitrogen and then TMS-morpholine (81 μL, 0.46 mmol) was added. The reaction was stirred at 0 °C for 5 minutes and then warmed 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 in one portion. The cooling bath was removed and the reaction was stirred at room temperature for 30 minutes. When TLC analysis showed complete consumption of the starting material, the mixture was diluted with EtOAc (20 mL) and quenched with saturated aqueous NaHCO 3 solution (10 mL). The organic phase was separated, dried over Na 2 SO 4 and concentrated in vacuo. The dry residue was subjected to column chromatography (SiO2 , purified by dichloromethane / EtOAc gradient to obtain the title compound as a white foam (44.0 mg, 0.11 mmol, yield 86%, single epimer). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) δ -63.06, -109.85, -159.45. C 19 H 10 ClF 5 N 2 Na ESI MS [M+Na] + , calculated value 419.0, measured value 419.2).

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

[0466]

Chemical Structure

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

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

[0469] [Chemical formula]

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

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

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

[0473] The protocol for the following steps was the same as that in Example 134. Characteristic data of the title compound: 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) δ -89.77 (m), -110.97 (m), -125.45, -156.81 (m). C 19 H 16 F 5 N 2 The ESI MS [M+H] + , calculated value 367.1, measured value 367.2).

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

[0475]

Chemical formula

[0476] Step a: To an ice-cooled solution of (1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-ol (11.5 g, 37.3 mmol) in dichloromethane (190 ml, 0.2 M) were added DMAP (1.4 g, 11.2 mmol) and triethylamine (10.4 ml, 75 mmol, 2 eq), followed by dropwise addition of acetic anhydride (7.1 ml, 75 mmol, 2 eq). The solution was warmed to room temperature and stirred for 1 hour. Upon completion, the reaction was quenched with saturated NaHCO 3 aqueous solution, and the resulting solution was extracted with dichloromethane (2x), dried over Na 2 SO 4 and concentrated over celite. The crude material was purified by flash chromatography on silica gel (0 - 10% ethyl acetate in hexane) to give [(1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl] acetate (13.1 g, 100% yield). C 12 H 12 BrFO 4 S ESI MS [M+H] + , calcd 351.0, found 351.0.

[0477] Step b: A solution of [(1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl] acetate (13.5 g, 38.5 mmol), 2,2'-azobis(2-methylpropionitrile) (40 mg, 1 mol%) and N-bromosuccinimide (7.54 g, 1.1 eq) in dichloroethane (0.2 M, 190 ml) was heated to reflux for 90 minutes. Upon completion, the reaction was cooled and partitioned between ethyl acetate and saturated NaHCO 3 . The organic layer was recovered, washed with dilute Na 2 S 2 O 3 , dried over Na 2 SO 4 and concentrated over celite. The crude material was purified by flash chromatography on silica gel (1:3 ratio of CH 2 Cl 2: Purified with 5% ethyl acetate in hexane to obtain two brominated diastereomers, [(1S,2S,3R)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (6.83 g, yield 41%) and [(1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (2.5 g, yield 15%). The diastereomer products eluted in the order listed above.

[0478] Step c: To a solution of [(1S,2S,3R)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (6.73 g, 15.6 mmol) in THF (0.08 M, 195 ml) at 0 °C was added a 0.5 M aqueous solution of LiOH (5.93 ml, 1.5 equivalents), and the reaction was kept stirring at 0 °C for 3 hours. At this time, the reaction was quenched with 1 N HCl at 0 °C. The resulting solution was extracted three times with methylene chloride, and the organic matter was dried over Na 2 SO 4 and flash chromatographed with 0 - 20% ethyl acetate in [1:1 hexane:dichloromethane] to obtain (1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-ol (3.68 g, yield 61%).

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

[0480] 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-inden (2.46 g, 5.1 mmol) in sulfolane (28.4 ml) and water (5.6 ml), and the reaction was heated at 75 °C overnight under light exclusion. After 23 h, the starting material was almost completely consumed and the reaction was quenched with H 2It was quenched with O. When diluted with MTBE, the silver salt could be filtered from the biphasic mixture, and the organic matter was recovered and dried with sodium sulfate. It was purified by flash chromatography (0 - 5% - 50% ethyl acetate in dichloromethane) to obtain the diastereomeric alcohol products (1R,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-inden-1-ol (750 mg, yield 35%) and (1S,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-inden-1-ol (470 mg, yield 22%). The diastereomeric products eluted in the order listed above, and the latter was used through further steps. C 17 H 16 BrFO 4 ESI MS of S [M+Na] + , calculated value 437.0, measured value 437.0.

[0481] Step f: To an ice-cooled solution of (1S,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-inden-1-ol (386 mg, 0.93 mmol) in dichloromethane (0.1 M, 9.3 ml), (diethylamino)sulfur trifluoride (492 μL, 600 mg, 3.7 mmol, 4 equivalents) was added, and the resulting solution was stirred at a temperature of 0 - 10 °C for 3 hours, at which time it was quenched with saturated NaHCO 3 It was quenched with. The organic matter was extracted with ethyl acetate and dried with Na 2 SO 4 and purified by flash chromatography on silica gel (10% ethyl acetate in hexane, homogeneous solvent) to obtain two fluorinated products: (1S,2S,3S)-7-bromo-1,2-difluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (undesired product, lower polarity, 158 mg, yield 40%) and (1R,2S,3S)-7-bromo-1,2-difluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (desired product, higher polarity, 234 mg, yield 60%).

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

[0483] The title compound was completed in the same manner as in Example 134. 1 H NMR (400 MHz, CDCl 3 ): 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, overlapping, 2H), 5.20 - 5.02 (m, 1H), 4.95 - 4.91 (m, 1H), 3.02 - 2.84 (m, 3H), 2.28 - 2.19 (m, 1H), 1.93 - 1.85 (m, 1H), 1.79 - 1.58 (m, 2H).

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

[0485]

Chemical formula

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

[0487] Step b: To a solution of the product (10 g, 38 mmol, 1 equivalent) derived from step a in CH 2 Cl 2 (190 mL, 0.2 M) at 0 °C, Et 3 N (32 mL, 228 mmol, 6 equivalents) was added, and then TBSOTf (17.5 mL, 76 mmol, 2 equivalents) was added. The reaction mixture was left to warm to room temperature overnight. 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), and then Selectfluor (20.2 g, 57 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred at room temperature for 2 hours or until completion was determined by TLC. The reaction mixture was diluted with EtOAc, washed with 0.2 M aqueous HCl, and then washed with brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by flash column chromatography (SiO 2 , 0 - 50% EtOAc / hexane) to give the 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).

[0488] Step c: It was carried out in the same manner as 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).

[0489] Step d: It was carried out in the same manner as step c of Example 134. C 15 H20 BrClF 2 ESI MS of OSi [M+H] + , calculated value 397.0, measured value 397.0.

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

[0491] Step f: Performed in the same manner as step e of Example 134. C 26 H 27 ClF 3 ESI MS of NOSi [M+H] + , calculated value 490.2, measured value 490.2.

[0492] Step g: 5 equivalents of Et 3 N was added to the reaction mixture and performed in the same manner as step f of Example 134. At this stage, the diastereomers were not separated. C 26 H 29 ClF 3 ESI MS of NOSi [M+H] + , calculated value 492.2, measured value 492.2.

[0493] Step h: Aryl chloride (100 mg, 0.20 mmol, 1 equivalent), K 4 Fe(CN) 6 3H 2 O (59 mg, 0.14 mmol, 0.7 equivalent), XPhos Pd G3 (17 mg, 0.02 mmol, 0.1 equivalent), XPhos (10 mg, 0.02 mmol, 0.1 equivalent) and KOAc (4 mg, 0.04 mmol, 0.2 equivalent) were dissolved in 1:1 water / dioxane (2 mL, 0.1 M). The reaction mixture was sparged with nitrogen for 10 minutes and then heated to 100 °C. After 2 hours, the reaction was determined to be complete by LCMS. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted 3 times with EtOAc. The combined organics were dried over Na 2 SO 4 and concentrated. The crude product was purified by flash column chromatography (SiO2 and purified with 0 - 50% EtOAc / hexane) to obtain the aryl nitrile product. C 27 H 29 F 3 N 2 ESI MS of OSi [M+H] + , calculated value 483.2, measured value 483.2.

[0494] Step i: The product from step h was treated with HF - pyridine in excess acetonitrile. After stirring overnight, the mixture was quenched with saturated NaHCO 3 and extracted with EtOAc. The product was purified by flash column chromatography. The final product was isolated as a 1:1 mixture of diastereomers (40 mg, 0.11 mmol, 54% over 2 steps). C 21 H 15 F 3 N 2 ESI MS of O [M] + , 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).

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

[0496]

Chemical Structure

[0497] Step a: To a solution of 3-bromo-4-chlorobenzotrifluoride (3.5 mL, 23 mmol, 1.0 equiv) in THF (75 mL) in a 250 mL round-bottom flask, an LDA solution (2.0 M in THF / heptane / ethylbenzene, 17 mL, 1.5 equiv) was added dropwise at N 2 -78 °C. After stirring at this temperature for 15 minutes, DMF (3.6 mL, 46 mmol, 2.0 equiv) was added dropwise at -78 °C, and the resulting mixture was stirred at this temperature for an additional 1.5 hours, at which point TLC indicated that the reaction was complete. The reaction mixture was then quenched with saturated NH 4 Cl aqueous solution (60 mL), warmed to room temperature, and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (60 mL) and dried over Na 2 SO 4 . Concentration under reduced pressure gave the desired crude aldehyde product and its isomers, which were used directly in the next step without purification (6.52 g).

[0498] Step b: The crude product from step a (total 8.45 g, together with another batch) in a 250 mL round-bottom flask was dissolved in MeOH (100 mL) and cooled to 0 °C. NaBH 4 (1.67 g, 1.5 equiv) was added portionwise, and the resulting mixture was stirred at 0 °C for 30 minutes, at which point TLC indicated that the reaction was complete. The reaction mixture was quenched with H 2 O and then concentrated under reduced pressure to remove most of the MeOH. The residue was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (60 mL) and dried over Na 2 SO 4 . Concentration under reduced pressure and purification by flash chromatography (SiO 2 , 0 - 30% EtOAc / hexane (Hex)) gave the product as 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).

[0499] Step c: To a solution of the product from step b (2.30 g, 8.0 mmol, 1.0 equiv) and i-Pr 2 NEt (2.8 mL, 16.0 mmol, 2.0 equiv) in DCM (40 mL) was added dropwise chloromethyl methyl ether (1.2 mL, 16.0 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at this temperature for 22 h and then quenched with saturated NaHCO 3 aqueous solution (20 mL). The aqueous phase was extracted with DCM (30 mL). The combined organic layers were washed with brine (20 mL) and dried over Na 2 SO 4 4. The mixture was concentrated under reduced pressure to give a crude product (1.84 g), which was used directly in the next step.

[0500] Step d: To a 40 mL vial were added the crude product from step c (1.06 g) and DMF (20 mL). CuCN (1.43 g, 16 mmol, 2.0 equiv) was added and the resulting mixture was heated at 150 °C for 2 h, then cooled to room temperature and diluted with EtOAc (50 mL). The organic phase was then washed wi...

Claims

[Claim 1] The invention described in the specification.

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