Tetrahydronaphthalene and tetrahydroquinoline compounds as HIF-2 [alpha] inhibitors

Abstract

Described herein are compounds that inhibit HIF-2 [alpha] and compositions containing one or more of the compounds and methods of synthesizing the compounds. The use of such compounds and compositions for the treatment of a wide variety of diseases, disorders and conditions, including cancer and immune related conditions mediated at least in part by HIF-2 [alpha], is also described.

Description

[0001] This application is a divisional application based on the patent application with application date of March 18, 2021, application number 202180022951.7 (PCT / US2021 / 022912), and invention name: "Tetralin and tetrahydroquinoline compounds as HIF-2α inhibitors".

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 991,952, filed on March 19, 2020, and No. 63 / 120,875, filed on December 3, 2020, each of which is incorporated herein in its entirety for all purposes. Background Art

[0004] Hypoxia-inducible factor (HIF) transcription factors play an integral role in the cellular response to low oxygen availability. [Immunity. 2014 Oct 16;41(4):518–528.] HIF is a heterodimeric transcription factor composed of a common subunit called the aryl hydrocarbon receptor nuclear translocator (ARNT or HIF-β) and one of three HIF-α subunits. [J. Med. Chem. 2015, 58, 5930-5941.] Under normal circumstances, the α-subunit is hydroxylated on a conserved proline residue by prolyl-4-hydroxylases (PHDs) and subsequently targeted for degradation by the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex. [Cancer Res 2006;66(12):6264-70]. However, under hypoxic conditions, HIF-α accumulates and enters the cell nucleus to activate the expression of genes that regulate metabolism, angiogenesis, cell proliferation and survival, immune evasion, and inflammatory responses. [J. Med. Chem. 2018, 61, 9691-9721.]

[0005] Of the three different α-subunit isoforms, HIF-1α, HIF-2α, and the less characterized HIF-3α, overexpression of HIF-1α and HIF-2α has been associated with poor clinical outcomes in patients with various cancers. Specifically, HIF-2α has been found to be a marker of poor prognosis in glioblastoma, neuroblastoma, head and neck squamous cell carcinoma, and non-small cell lung cancer. Hypoxia is also prevalent in many acute and chronic inflammatory conditions, such as inflammatory bowel disease and rheumatoid arthritis. [J. Clin Invest. 2016; 126(10): 3661-3671.]

[0006] Given the important role of HIF-2α in cancer, inflammation, and other disorders, there is a need in the art for HIF-2α inhibitors. The present invention addresses this need and also provides related advantages. Summary of the Invention

[0007] The present invention relates to compounds that inhibit the activity of the hypoxia-inducible factor (HIF) transcription factor family, particularly HIF-2α. The compound is represented by formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof:

[0008]

[0009] Where W 1 、W 2 、W 3 、Y 1 、Y 2 、Y 3 、Y 4 and R 1 has the meaning defined below.

[0010] In a related aspect, provided herein is a method for treating a disease or condition mediated by HIF-2α in a subject (e.g., a human), comprising administering to the subject a therapeutically effective amount of at least one HIF-2α inhibitor as described herein. Diseases and conditions mediated by HIF-2α include cancer, inflammation, autoimmune disorders, and metabolic disorders, as described below. Other diseases, disorders, and conditions that can be treated or prevented in whole or in part by regulating HIF-2α activity are candidate indications for HIF-2α inhibitor compounds provided herein.

[0011] Also provided herein are uses of the described HIF-2α inhibitors in combination with one or more additional agents as described below. Detailed Description of the Invention

[0013] Before the present invention is further described, it is to be understood that the present invention is not limited to the particular embodiments described herein, and it is to be further understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0014] Where a numerical range is provided, it is understood that each intervening value between the upper and lower limits of the range to one-tenth of the lower limit (unless the context clearly dictates otherwise) and any other stated or intermediate values ​​within the stated range are encompassed within the present invention. The upper and lower limits of these smaller ranges may be independently included in smaller ranges and are also encompassed within the present invention, subject to any explicit exclusion of limits within the stated range. When a stated range includes one or two of the limits, ranges excluding one or two of those included limits are also encompassed within the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention pertains.

[0015] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should further be noted that the claims may be drafted to exclude any optional elements. Thus, this statement is intended to serve as antecedent basis for the use of such exclusive terminology (such as "solely," "only," etc.) in connection with the recitation of claim elements, or the use of a "negative" limitation.

[0016] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0017] definition

[0018] Unless otherwise stated, the following terms are intended to have the meanings set forth below. Other terms are defined elsewhere throughout the specification.

[0019] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight or branched chain hydrocarbon radical having the indicated number of carbon atoms (i.e., C 1-8 means one to eight carbons). Alkyl groups may include any number of carbons, such as 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 5-6Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0020] The term "hydroxyalkyl" refers to a group having the specified number of carbon atoms (e.g., C 1-6 or C 1-8 ) and substituted with one or two hydroxy (OH) groups.

[0021] The term "hydroxyhaloalkyl" refers to a group having the specified number of carbon atoms (e.g., C 1-6 or C 1-8 ) and an alkyl group substituted by one or two hydroxyl (OH) groups and one to six halogen atoms (e.g., F, Cl).

[0022] The term "alkylene" refers to a straight or branched saturated aliphatic group having the indicated number of carbon atoms and connecting at least two other groups, i.e., divalent hydrocarbon groups. The two moieties connected to the alkylene group can be connected to the same atom or different atoms of the alkylene group. For example, a straight chain alkylene group can be -(CH2) n -divalent radical, wherein n is 1, 2, 3, 4, 5 or 6.Representative alkylene groups include but are not limited to methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.In some embodiments, alkylene groups can be substituted or unsubstituted.When the group comprising alkylene is optionally substituted, it should be understood that the optional substitution can be on the alkylene part of this part.

[0023] The term "cycloalkyl," "carbocycle," or "carbocyclic ring" refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C 3-6 Cycloalkyl) and is fully saturated or has no more than one double bond between ring vertices. "Cycloalkyl" is also intended to refer 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 compounds of the present disclosure are monocyclic C 3-6 Cycloalkyl moiety.

[0024] The term "heterocycloalkyl", "heterocycle" or "heterocycle" refers to a cycloalkyl ring having an indicated number of ring vertices (or members) and having one to five heteroatoms selected from N, O and S, wherein the heteroatoms replace one to five carbon vertices and wherein the nitrogen and sulfur atoms are optionally oxidized and (one or more) nitrogen atoms are optionally quaternized. Heterocycloalkyl can be a monocyclic, bicyclic or polycyclic ring system and can have one or two double bonds connecting the ring vertices. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolinone, 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 etc. The heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or heteroatom.In some embodiments, the heterocycle is a 5- to 6-membered heterocycle.

[0025] As used herein, a wavy line that intersects a single, double, or triple bond in any chemical structure depicted herein Indicates the point of attachment of a single, double, or triple bond to the rest of the molecule. In addition, a bond extending to the center of a ring (such as a phenyl ring) is intended to indicate attachment at any available ring vertex. One skilled in the art will understand that multiple substituents shown as attached to a ring will occupy ring vertices that provide stable compounds and are otherwise sterically compatible. For divalent components, the representation is meant to include either orientation (forward or reverse). For example, the group "-C(O)NH-" is intended to include linkages in either orientation: -C(O)NH- or -NHC(O)-, and similarly,

[0026] “—O—CH 2 CH 2 —” is intended to include both —O—CH 2 CH 2 — and —CH 2 CH 2 —O—.

[0027] Unless otherwise stated, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0028] Unless otherwise indicated, the term "aryl" means a polyunsaturated, typically aromatic hydrocarbon group that can be a monocyclic or polycyclic (up to three rings) that are fused together or covalently linked. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl. The term is also intended to include fused cycloalkylphenyl and heterocycloalkylphenyl ring systems, such as, for example, indan, tetralin, chromane, and isochromane rings. As a substituent group, for fused ring systems, the point of attachment to the remainder of the molecule can be through a carbon atom on the aromatic moiety, a carbon atom on the cycloalkyl moiety, or an atom on the heterocycloalkyl moiety.

[0029] The term "heteroaryl" refers to an aryl group (or ring) containing one to five heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and one or more nitrogen atoms are optionally quaternized. The heteroaryl group can be attached to the rest of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like. Substituents for the heteroaryl ring may be selected from the group of acceptable substituents described below.

[0030] The above terms (eg, "alkyl," "aryl," and "heteroaryl") will, in some embodiments, be optionally substituted. Selected substituents for each type of group are provided below.

[0031] Optional substituents for alkyl groups (including those groups often referred to as alkylene, alkenyl, and alkynyl) can be, for example, a variety of groups selected from the group consisting of halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NH-C(NH 2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN(cyano), -NO2, aryl, aryloxy, oxo(=O), cycloalkyl and heterocycloalkyl, in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such groups. R', R" and R'"' each independently refer to hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C 1-8 Alkoxy or C 1-8 Thioalkoxy group, or unsubstituted aryl-C 1-4 Alkyl groups. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is intended to include 1-pyrrolidinyl and 4-morpholinyl.

[0032] Optional substituents for cycloalkyl and heterocycloalkyl groups may be, for example, various groups selected from the group consisting of alkyl optionally substituted with C(O)OR', halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R "', -NR"C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN(cyano), -NO2, aryl, aryloxy and oxo (=O). R', R" and R'"' each independently represent hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C 1-8 Alkoxy or C 1-8 Thioalkoxy, or unsubstituted aryl-C 1-4 Alkyl group.

[0033] Optional substituents for cycloalkyl and heterocycloalkyl groups may also include olefins (=CR'R"), wherein R' and R" are each independently hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted aryl, aryl substituted by 1-3 halogens, C 1-8 Alkoxy or C 1-8 Thioalkoxy, or unsubstituted aryl-C 1-4 Alkyl substitution. For example, the olefin can be an unsubstituted olefin (=CH2).

[0034] Similarly, optional substituents for aryl and heteroaryl groups are varied and can be selected, for example, from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -C02R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R"', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -N3, perfluoro(C(O) 1-4 ) alkoxy and perfluoro(C 1-4 ) alkyl, the number of which ranges from zero to the total number of open valences on the aromatic ring system; wherein R', R" and R"' are independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl and C 2-8 Other suitable substituents include each of the above aryl substituents attached to a ring atom via an alkylene tether of 1 to 6 carbon atoms.

[0035] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be replaced by a substituent of the formula -TC(O)-(CH2) q -U-, wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -A-(CR f R g ) r -B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, r is an integer from 1 to 3, and R f and R gEach independently represents H or halogen. One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a double bond of the formula -(CH2) s -X-(CH2) t -substituted by a substituent, wherein s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2- or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C 1-6 alkyl.

[0036] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0037] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, 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 aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganic salts, manganous salts, potassium, sodium, zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines (including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively nontoxic 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. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups that allow the compounds to be converted into base or acid addition salts.

[0038] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (such as solubility in polar solvents), but for purposes of the present invention, the salts are otherwise equivalent to the parent form of the compound.

[0039] In addition to salt forms, the present invention also provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present invention. Additionally, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted into a compound of the present invention.

[0040] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally speaking, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polymorphic or amorphous forms. Generally speaking, all physical forms are equivalent for the purposes contemplated by the present invention and are intended to be encompassed within the scope of the present invention.

[0041] Certain compounds of the present invention may exist as polymorphs under certain conditions. Polymorphism refers to the ability of a solid material to exist in more than one crystal structure form or phase, with different arrangements or conformations of the molecules in the crystal lattice. If this type of difference exists due to packing, it is referred to as a "packing polymorph," while if it exists due to conformational differences, it is referred to as a "conformational polymorph." Different polymorphs of the same compound often exhibit different physical properties, including packing properties, spectral properties, thermodynamic properties, solubility, and melting point; kinetic properties, such as dissolution rate and stability; and mechanical properties, such as hardness and tensile strength.

[0042] Polymorphs can be classified into one of two types based on their stability over different temperature and pressure ranges. In a monotropic system, only one polymorph (the monotrope) is stable, and it exhibits low free energy content and solubility at all temperatures and pressures below the melting point. In an enantiotropic system, one polymorph is stable at a certain temperature and pressure, while one or more other polymorphs are stable at a different temperature and pressure.

[0043] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (eg, individual enantiomers) are intended to be encompassed within the scope of the present invention.

[0044] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms comprising such compounds. Unnatural proportions of isotopes may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atoms in question. For example, the compounds may be doped with radioactive isotopes, such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes such as deuterium ( 2 H)) or carbon-13 ( 13 C). Such isotopic variations may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the present invention may have additional utility, including, but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics, which may help improve safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of this invention.

[0045] The terms "patient" or "subject" are used interchangeably to refer to a human or a non-human animal (eg, a mammal).

[0046] The terms "administration," "administer," and the like, as they apply to, for example, a subject, a cell, a tissue, an organ, or a biological fluid, refer to contacting, for example, a HIF-2α inhibitor, a pharmaceutical composition comprising a HIF-2α inhibitor, or a diagnostic agent with a subject, a cell, a tissue, an organ, or a biological fluid. In the context of cells, administration includes contacting an agent with a cell (e.g., in vitro or ex vivo), as well as contacting an agent with a fluid, wherein the fluid is in contact with the cell.

[0047] The terms "treat," "treating," "treatment," and the like refer to a course of action (such as administering a HIF-2α inhibitor or a pharmaceutical composition comprising a HIF-2α inhibitor) initiated after a disease, disorder, or condition, or its symptoms, has been diagnosed, observed, or the like, to temporarily or permanently eliminate, reduce, inhibit, alleviate, or ameliorate at least one of the underlying causes of the disease, disorder, or condition afflicting the subject, or at least one of the symptoms associated with the disease, disorder, or condition afflicting the subject. Thus, treatment includes inhibiting (e.g., arresting the development or further progression of) an active disease, disorder, or condition, or clinical symptoms associated therewith.

[0048] As used herein, the term "in need of treatment" refers to a judgment made by a physician or other health care provider that a subject requires treatment or will benefit from treatment. This judgment is made based on various factors within the physician's or health care provider's expertise.

[0049] The terms "prevent," "preventing," "prevention," and the like refer to a series of actions (such as the administration of a HIF-2α inhibitor or a pharmaceutical composition comprising a HIF-2α inhibitor) that are initiated in some manner (e.g., before the onset of the disease, disorder, condition, or its symptoms), usually in the context of a subject being susceptible to a particular disease, disorder, or condition, to temporarily or permanently prevent, suppress, inhibit, or reduce the subject's risk of developing the disease, disorder, condition, or the like (as determined by, for example, the absence of clinical symptoms) or to delay its onset. In some cases, the term also refers to slowing the progression of a disease, disorder, or condition or inhibiting its progression to a harmful or otherwise undesirable state.

[0050] As used herein, the term "in need of prevention" refers to a judgment made by a physician or other health care provider that a subject requires or will benefit from preventive care. This judgment is made based on various factors within the physician's or health care provider's expertise.

[0051] The phrase "therapeutically effective amount" refers to an amount that is administered to a subject, alone or as part of a pharmaceutical composition and in a single dose or as part of a series of doses, in an amount that is capable of having any detectable positive effect on any symptom, aspect or feature of a disease, disorder or condition when administered to a subject. A therapeutically effective amount can be determined by measuring relevant physiological effects, and it can be adjusted in conjunction with the dosing regimen and diagnostic analysis of the subject's condition, etc. For example, measuring serum levels of a HIF-2α inhibitor (or a metabolite thereof) at a specific time after administration can indicate whether a therapeutically effective amount has been used.

[0052] The phrase "in an amount sufficient to effect a change" means that there is a detectable difference between the level of the indicator measured before (e.g., baseline level) and after administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., a subject's sense of well-being).

[0053] The term "small molecule" refers to a chemical 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 may be more permeable to cells, less susceptible to degradation, and less likely to elicit an immune response than large molecules.

[0054] The terms "inhibitor" and "antagonist" or "activator" and "agonist" refer to inhibitory or activating molecules, respectively, that act to activate, for example, a ligand, receptor, cofactor, gene, cell, tissue, or organ. An inhibitor is a molecule that reduces, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor can also be defined as a molecule that reduces, blocks, or inactivates constitutive activity. An "agonist" is a molecule that interacts with a target to cause or promote increased activation of the target. An "antagonist" is a molecule that antagonizes one or more effects of an agonist. Antagonists prevent, reduce, inhibit, or neutralize the activity of an agonist, and antagonists can also prevent, inhibit, or reduce the constitutive activity of a target, such as a target receptor, even in the absence of an identified agonist.

[0055] The terms "modulate," "modulation," and the like refer to the ability of a molecule (e.g., an activator or inhibitor) to directly or indirectly increase or decrease the function or activity of HIF-2α. A modulator can act alone, or it can utilize cofactors such as proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds and other bioorganic molecules.

[0056] The "activity" of a molecule can describe or refer to binding of the molecule to a ligand or receptor; catalytic activity; ability to stimulate gene expression or cell signaling, differentiation or maturation; antigenic activity; modulation of the activity of other molecules; etc. The term "proliferative activity" encompasses activities that promote, are essential for, or are specifically associated with, e.g., normal cell division as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.

[0057] As used herein, "comparable," "comparable activity," "activity comparable to...", "comparable effect," "comparable effect to...", etc. are relative terms that can be viewed quantitatively and / or qualitatively. The meaning of the terms generally depends on the context in which they are used. For example, from a qualitative perspective, two agents that both activate a receptor can be considered to have comparable effects, but if one agent only achieves 20% of the activity of the other agent (as determined in an art-recognized assay (e.g., a dose-response assay) or in an art-recognized animal model), then the two agents can be considered to lack comparable effects. When comparing one result to another result (e.g., a result to a reference standard), "comparable" often (but not always) means that a 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 specific embodiments, a result is comparable to a reference standard if it deviates from the reference standard by less than 15%, less than 10%, or less than 5%. For example, but not limited to, activity or effect may refer to efficacy, stability, solubility, or immunogenicity.

[0058] "Substantially pure" indicates that the component comprises greater than about 50% of the total content of the composition, and typically comprises greater 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 total composition is the component of interest. In some cases, the polypeptide will comprise greater than about 90% or greater than about 95% of the total content of the composition.

[0059] Compounds with selectivity may be particularly useful in the treatment of certain conditions or may reduce the likelihood of undesirable side effects. In one embodiment, the compounds of the present disclosure are selective for other HIF isoforms. In another embodiment, the compounds of the present disclosure are selective for other kinases and targets in the HIF signaling pathway. Specific examples include HIF-1α and cytochrome P450 enzymes. Selectivity can be determined, for example, by comparing the inhibition of HIF-2α by a compound as described herein with the inhibition of another protein by a compound as described herein. In one embodiment, the selective inhibition of HIF-2α is at least 1000 times, 500 times, or 100 times, or 20 times greater than the inhibition of another protein or isoform.

[0060] The compounds provided herein can have favorable pharmacokinetic characteristics including, for example, hepatocellular stability, clearance, and inhibition of CYPs.

[0061] For example, the term "response" of a cell, tissue, organ, or organism encompasses biochemical or physiological behavior, such as concentration, density, adhesion, or migration within a biological compartment, a change in gene expression rate, or differentiation state, where the change is associated with activation, stimulation, or treatment, or with internal mechanisms such as genetic programming. In certain contexts, the terms "activate," "stimulate," and the like refer to cell activation, such as that regulated by internal mechanisms and by external or environmental factors; whereas the terms "inhibit," "downregulate," and the like refer to the opposite effect.

[0062] Compounds of the present disclosure

[0063] In a specific aspect, provided herein are compounds having formula (I):

[0064]

[0065] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

[0066] Y 1 、Y 2 、Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , CR 6 R 7 NR 7 , O, SO2 and bond; and Y 1 、Y 2 、Y 3 and Y 4 One of them is CR 6 R 7 or NR 7 ; Y 1 、Y 2 、Y 3 and Y 4 No more than one of them is a key;

[0067] W 1 、W 2 and W 3 Each independently selected from CR 5 and N;

[0068] R 1 Selected from H, halogen, hydroxyl, CN, NO2, -NR a R b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b 、-S(O)(=NH)R a and -S(O)2NR a R b ;

[0069] Each R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(=NH)R a and -NR a R b ;

[0070] Each R 4 Independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl and -C(O)R a ,

[0071] Each R 5 Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a Rb 、-S(O)(=NH)R a and -NR a R b ;

[0072] R 6 Selected from H, C 1-4 Alkyl, OH, F and CN;

[0073] R 7 is a group having the formula:

[0074]

[0075] in:

[0076] X 1 N or CR 8a ;

[0077] X 2 N or CR 8b ;

[0078] R 8a and R 8b Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ;

[0079] R 9 and R 10 Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b、-S(O)2NR a R b and -S(O)2R a ;

[0080] R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b 、-S(O)2NR c R b 、-S(O)(=NH)R c 、-S(O)2R c and a 5- or 6-membered heterocyclic or heteroaromatic ring having 1 to 3 heteroatoms selected from N, O and S as ring vertices; wherein the heterocyclic or heteroaromatic ring is optionally substituted with 1 to 3 members independently selected from the following: halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyl haloalkyl and C 1-4 Alkoxy C 1-4 alkyl;

[0081] or R 9 and R 10 are combined to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with one or more substituents, for example, 1, 2, 3 or 4 substituents independently selected from the group consisting of: R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 , the heterocyclic or heteroaromatic rings each have 1 to 4 heteroatoms selected from N, O and S as ring vertices;

[0082] or R 10 and R 11are combined to form a 5- or 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with one or more substituents, for example, 1, 2, 3 or 4 substituents independently selected from: R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 , the heterocyclic or heteroaromatic rings each have 1 to 4 heteroatoms selected from N, O and S as ring vertices;

[0083] R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ; or two R on the same carbon atom 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 The groups combine to form an oxo group;

[0084] Each R a and R b Independently selected from H, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy and C 1-8 hydroxyalkyl, and

[0085] R c , when present, is selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkyl, C 3-6cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl, each of the heterocycloalkyl or heteroaryl rings having 1 to 4 heteroatoms selected from N, O and S as ring vertices,

[0086] The condition is that when a 、R b and R c The attached groups do not form N-oxide and peroxide bonds when combined.

[0087] In some selected embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is the following compound, wherein Y 2 、Y 3 and Y 4 Each is CR 2 R 3 .

[0088] In some selected embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is the following compound, wherein Y 2 and Y 3 Each is CR 2 R 3 , and Y 4 is the key.

[0089] In some selected embodiments, the compound of formula (I) is represented by formula (II):

[0090]

[0091] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Z is N or CR 6 , and the remaining groups have the meanings provided for formula (I).

[0092] In some selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, has formula (II):

[0093]

[0094] in

[0095] Z is N or CR 6 ;

[0096] Y 2 、Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , O, SO2 and bond; and Y 2 、Y 3 and Y4 No more than one of them is a key;

[0097] W 1 、W 2 and W 3 Each independently selected from CR 5 and N;

[0098] R 1 Selected from H, halogen, hydroxyl, CN, NO2, -NR a R b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b 、-S(O)(=NH)R a and -S(O)2NR a R b ;

[0099] Each R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(=NH)R a and -NR a R b ;

[0100] Each R 4 Independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl and -C(O)R a ,

[0101] Each R 5 Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(=NH)R a and -NR a R b ;

[0102] X 1 N or CR 8a ;

[0103] X 2 N or CR 8b ;

[0104] R 8a and R 8b independently selected from H, halogen, CN, NH2, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ;

[0105] R 9 and R 10 Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ;

[0106] R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -NR c R b 、-C(O)NR c R b 、-C(O)OH、-S(O)2NR c R b 、-S(O)(=NH)R c 、-S(O)2R c , phenyl, 5- to 6-membered heterocyclic ring or 5- to 10-membered heteroaromatic ring, wherein the heterocyclic ring and heteroaromatic ring have 1-3 heteroatoms selected from N, O and S as ring vertices; wherein the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1-2 heteroatoms selected from N, O and S as ring vertices; and wherein the phenyl, heterocyclic ring or heteroaromatic ring is optionally substituted with 1 to 3 members independently selected from the following: halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyl haloalkyl and C 1-4 Alkoxy C 1-4 Alkyl; optionally wherein the two members attached to the same carbon of the heterocyclic ring together form a =CH2 or oxo (=O) group;

[0107] or R 9 and R 10are combined to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with one or more substituents independently selected from the group consisting of: R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 , the heterocyclic or heteroaromatic rings each have 1 to 4 heteroatoms selected from N, O and S as ring vertices;

[0108] or R 10 and R 11 are combined to form a 5- or 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with one or more substituents independently selected from the group consisting of: 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 , the heterocyclic or heteroaromatic rings each have 1 to 4 heteroatoms selected from N, O and S as ring vertices;

[0109] R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ; or two R on the same carbon atom 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 The groups combine to form an oxo group;

[0110] Each R a and R b Independently selected from H, C 1-8 Alkyl, C1-8 Alkoxy, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy and C 1-8 hydroxyalkyl, and

[0111] R c , when present, is selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl rings each have 1 to 4 heteroatoms selected from N, O, and S as ring vertices.

[0112] In some embodiments, the compound of formula (II) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Y 2 CR 2 R 3 , where each R 2 and R 3 is H; and Y 3 and Y 4 Each is CR 2 R 3 , where each R 2 and R 3 Independently selected from H and F.

[0113] In some embodiments, the compound of formula (II) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 11 SO2R c In some embodiments, R c C 1-8 Alkyl, or C 1-8 Halogenated alkyl.

[0114] In some embodiments, the compound of formula (II) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 11 Selected from:

[0115]

[0116] In some selected embodiments, the compound of formula (I) is represented by formula (III):

[0117]

[0118] or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0119] Y 2 、Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , SO2, O and bond; and Y 2 、Y 3 and Y 4 No more than one of them is a key;

[0120] W 1 and W 3 are each independently selected from CH and N;

[0121] Z is N or CR 6 ;

[0122] R 1 selected from halogen and CN;

[0123] Each R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(=NH)R a and -NR a R b

[0124] Each R 4 Independently selected from H, C 1-3 Alkyl, C 3-6 Cycloalkyl and -C(O)R a ;

[0125] R 5a is selected from hydrogen, halogen and CN;

[0126] R 6 H

[0127] X 1 N or CR 8a ;

[0128] X 2 N or CR 8b ;

[0129] R 8a and R 8b independently selected from H, halogen, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-3 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ;

[0130] R 9 and R 10 Independently selected from H, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ;

[0131] R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b、-C(O)OH、-S(O)2NR c R b 、-S(O)(=NH)R c 、-S(O)2R c , phenyl and a 5- or 6-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring has 1-3 heteroatoms selected from N, O and S as ring vertices; wherein the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1-2 heteroatoms selected from N, O and S as ring vertices; and wherein the phenyl, heterocyclic ring or heteroaromatic ring is optionally substituted with 1 to 3 members independently selected from the following: halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Hydroxyl haloalkyl and C 1-3 Alkoxy C 1-4 Alkyl; optionally wherein the two members attached to the same carbon of the heterocyclic ring together form a =CH2 or oxo (=O) group;

[0132] or R 9 and R 10 are combined to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with one or more substituents independently selected from the group consisting of: R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 , the heterocyclic or heteroaromatic rings each have 1 to 4 heteroatoms selected from N, O and S as ring vertices;

[0133] or R 10 and R 11 are combined to form a 5- or 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with one or more substituents independently selected from the group consisting of: R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 , the heterocyclic or heteroaromatic rings each have 1 to 4 heteroatoms selected from N, O and S as ring vertices;

[0134] R 12 、R13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ; or two R on the same carbon atom 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 The groups combine to form an oxo group;

[0135] Each R a and R b Independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy and C 1-3 hydroxyalkyl; and

[0136] R c , when present, is selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl, said heterocycloalkyl or heteroaryl ring each having 1 to 4 heteroatoms selected from N, O and S as ring vertices.

[0137] In some selected embodiments, the compound of formula (I) is represented by formula (III):

[0138]

[0139] or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0140] Y 2 、Y 3 and Y4 Each independently selected from CR 2 R 3 NR 4 , SO2, O and bond; and Y 2 、Y 3 and Y 4 No more than one of them is a key;

[0141] W 1 and W 3 are each independently selected from CH and N;

[0142] Z is N or CR 6 ;

[0143] R 1 selected from halogen and CN;

[0144] Each R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(=NH)R a and -NR a R b

[0145] Each R 4 Independently selected from H, C 1-3 Alkyl, C 3-6 Cycloalkyl and -C(O)R a ;

[0146] R 5a is selected from hydrogen, halogen and CN;

[0147] R 6 H

[0148] X 1 N or CR 8a ;

[0149] X 2 N or CR8b ;

[0150] R 8a and R 8b Independently selected from H, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-3 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ;

[0151] R 9 and R 10 Independently selected from H, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ;

[0152] R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b 、-S(O)2NR c R b 、-S(O)(=NH)Rc 、-S(O)2R c and a 5- or 6-membered heterocyclic or heteroaromatic ring having 1 to 3 heteroatoms selected from N, O and S as ring vertices; wherein the heterocyclic or heteroaromatic ring is optionally substituted with 1 to 3 members independently selected from the following: halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Hydroxyl haloalkyl and C 1-3 Alkoxy C 1-4 alkyl;

[0153] or R 9 and R 10 Combined to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 , the heterocyclic or heteroaromatic rings each have 1 to 4 heteroatoms selected from N, O and S as ring vertices;

[0154] or R 10 and R 11 Combined to form a 5- or 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 , the heterocyclic or heteroaromatic rings each have 1 to 4 heteroatoms selected from N, O and S as ring vertices;

[0155] R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C1-4 Alkoxy C 1-4 Alkyl and -NR a R b ; or two R on the same carbon atom 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 The groups combine to form an oxo group;

[0156] Each R a and R b Independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy and C 1-3 hydroxyalkyl; and

[0157] R c , when present, is selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl, the heterocycloalkyl or heteroaryl rings each having 1 to 4 heteroatoms selected from N, O and S as ring vertices.

[0158] In some embodiments, the compound of formula (III) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Y 2 CR 2 R 3 , where each R 2 and R 3 is H; and Y 3 and Y 4 Each is CR 2 R 3 , where each R 2 and R 3 Independently selected from H and F.

[0159] In some embodiments, the compound of formula (III) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R 5a for halogen and R 4 CR 2 R 3 And R 2 and R 3Selected from H, F and OCH3.

[0160] In some embodiments, the compound of formula (III) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 11 is phenyl, a 5- or 6-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring has 1-3 heteroatoms selected from N, O and S as ring vertices; wherein the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1-2 heteroatoms selected from N, O and S as ring vertices; and wherein the phenyl, heterocyclic ring or heteroaromatic ring is optionally substituted with 1 to 3 members independently selected from the following: halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyl haloalkyl and C 1-4 Alkoxy C 1-4 Alkyl; optionally wherein two members attached to the same carbon of the heterocycle are taken together to form a =CH2 or oxo (=O) group.

[0161] In some selected embodiments, the compound of formula (I) is represented by formula (IV-a):

[0162]

[0163] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0164] Y 2 、Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , SO2 and bond; and Y 2 、Y 3 and Y 4 No more than one of them is a key;

[0165] R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R b ;

[0166] Each R 2and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a and -C(O)NR a R b ;

[0167] Each R 4 Independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and -C(O)R a ;and

[0168] Each R 5 Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ,

[0169] and the remaining groups have the meanings provided for formula (I). In some embodiments of the compound of formula (IV-a), the remaining groups have the meanings provided for formula (II).

[0170] In some embodiments, the compound of formula (IV-a) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X 1 and X 2 are independently selected from CH and N.

[0171] In some selected embodiments, the compound of formula (I) is represented by formula (IV-b):

[0172]

[0173] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0174] The subscript m is 1, 2, 3, 4, 5, 6, 7 or 8;

[0175] The subscript n is 1 or 2;

[0176] R z Represents R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 One or more of;

[0177] Y 2 、Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , SO2 and bond; and Y 2 、Y 3 and Y 4 No more than one of them is a key;

[0178] R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R b ;

[0179] Each R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a and -C(O)NR a R b ;

[0180] Each R 4 Independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and -C(O)R a ;

[0181] R 5 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ;and

[0182] R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ; or two R on the same carbon atom 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 The groups combine to form oxo groups,

[0183] and the remaining groups have the meanings provided for formula (I).In some embodiments of the compound of formula (IV-b), the remaining groups have the meanings provided for formula (II).

[0184] In some embodiments, the compound of formula (IV-b) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Y 4 is a member selected from O and NH.

[0185] In some selected embodiments, the compound of formula (I) is represented by formula (IV-c):

[0186]

[0187] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0188] A 1 O or CHR 13 ;

[0189] Y 2 、Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , SO2 and bond; and Y 2 、Y 3 and Y 4 No more than one of them is a key;

[0190] R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R b ;

[0191] R 5 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ;

[0192] R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b 、-S(O)2NR c R b 、-S(O)(=NH)R c and -S(O)2R c ;

[0193] R 13 、R 14 and R15 Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ;and

[0194] R 16 Selected from H, C 1-4 Alkyl and C 1-4 Fluoroalkyl,

[0195] and the remaining groups have the meanings provided for formula (I).In some embodiments of the compound of formula (IV-c), the remaining groups have the meanings provided for formula (II).

[0196] In some selected embodiments, the compound of formula (IV-c) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 8b For H.

[0197] In some embodiments, the compound of formula (IV-c) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Y 2 CR 2 R 3 , where each R 2 and R 3 is H; and Y 3 and Y 4 Each is CR 2 R 3 , where each R 2 and R 3 Independently selected from H and F.

[0198] In some selected embodiments, the compound of formula (I) is represented by formula (IV-d):

[0199]

[0200] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0201] R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b;

[0202] R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ;

[0203] R 5 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ;

[0204] R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-6 Hydroxyfluoroalkyl, C 3-8 Cycloalkyl, -C(O)NR c R b 、-S(O)2NR c R b 、-S(O)(=NH)R c and -S(O)2R c ;

[0205] R 12 、R 13 、R 14 and R 15 Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy and -NR a R b ,

[0206] and the remaining groups have the meanings provided for formula (I). In some embodiments of the compound of formula (IV-d), the remaining groups have the meanings provided for formula (II).

[0207] In some selected embodiments, the compound of formula (I) is represented by formula (IV-e):

[0208]

[0209] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0210] R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b ;

[0211] R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ;

[0212] R 5 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ;

[0213] R 13 and R 15 Each independently selected from H, F and C 1-4 alkyl; and

[0214] R 20 Selected from C 1-6 Alkyl and C 1-6 Fluoroalkyl,

[0215] and the remaining groups have the meanings provided for formula (I).

[0216] In some embodiments, the compound of formula (IV-e) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 20 is selected from the group consisting of methyl, fluoromethyl, difluoromethyl and trifluoromethyl.

[0217] In some selected embodiments, the compound of formula (II) is represented by formula (IV-f):

[0218]

[0219] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein said group has the meaning provided for formula (II). In some embodiments of the compound of formula (IV-f), R 8b For H.

[0220] In some selected embodiments, the compound of formula (I) is represented by formula (Va):

[0221]

[0222] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein said group has the meaning provided for formula (I). In some embodiments of the compound of formula (Va), said group has the meaning provided for formula (II).

[0223] In some selected embodiments, the compound of formula (I) is represented by formula (Vb):

[0224]

[0225] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0226] Each R 5 Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a Rb 、-S(O)(=NH)R a and -NR a R b ;and

[0227] The remaining groups have the meanings provided for formula (I).In some embodiments of the compound of formula (Vb), the remaining groups have the meanings provided for formula (II).

[0228] In some embodiments, the compound of formula (Vb) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 9 and R 10 Each independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ; and R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b 、-S(O)2NR c R b and -S(O)2R c .

[0229] In some selected embodiments, the compound of formula (I) is represented by formula (Vc):

[0230]

[0231] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0232] Y 2 、Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , SO2 and bond; and Y 2 、Y 3 and Y 4 No more than one of them is a key;

[0233] R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b ;

[0234] R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -NR a R b ;

[0235] R 5 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ;and

[0236] The remaining groups have the meanings provided for formula (I).In some embodiments of the compound of formula (Vc), the remaining groups have the meanings provided for formula (II).

[0237] In some selected embodiments, the compound of formula (I) is represented by formula (Vd):

[0238]

[0239] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0240] Y 2 、Y 3 and Y 4 Each independently selected from CR 2 R 3 and key; and Y 2 、Y 3 and Y 4 No more than one of them is a key;

[0241] R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b ;

[0242] R 2 and R 3 Each independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -NR a R b ;and

[0243] R 5 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ;and

[0244] The remaining groups have the meanings provided for formula (I).In some embodiments of the compound of formula (Vd), the remaining groups have the meanings provided for formula (II).

[0245] In some selected embodiments, the compound of formula (I) is represented by formula (Ve):

[0246]

[0247] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0248] R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b ;

[0249] R 2 and R 3 Each independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -NR a R b ;and

[0250] R 5 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ;and

[0251] The remaining groups have the meanings provided for formula (I).In some embodiments of the compound of formula (Vd), the remaining groups have the meanings provided for formula (II).

[0252] In some embodiments, the compound of formula (Ve) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R9 and R 10 Combined to form a 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally substituted with R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 .

[0253] In some embodiments, the compound of formula (Ve) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 9 and R 10 Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a .

[0254] In some selected embodiments, the compound of formula (I) is represented by formula (Vf):

[0255]

[0256] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0257] The subscript m is 1, 2, 3, 4, 5, 6, 7 or 8;

[0258] The subscript n is 1 or 2;

[0259] R z Represents R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 One or more of;

[0260] Y 2 、Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , SO2 and bond; and Y 2 、Y 3 and Y 4 No more than one of them is a key;

[0261] R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R b ;

[0262] Each R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a and -C(O)NR a R b ;

[0263] Each R 4 Independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and -C(O)R a ;

[0264] R 5 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ;and

[0265] R12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ; or two R on the same carbon atom 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 groups to form an oxo group; and

[0266] The remaining groups have the meanings provided for formula (I).In some embodiments of the compound of formula (Vf), the remaining groups have the meanings provided for formula (II).

[0267] In some selected embodiments, the compound of formula (I) is represented by formula (Vg):

[0268]

[0269] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0270] R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, -S(O)2R a and -C(O)NR a R b ;

[0271] R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C1-4 Alkyl and -NR a R b ;

[0272] R 5 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ;

[0273] R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, -C(O)NR c R b 、-S(O)2NR c R b 、-S(O)(=NH)R c and -S(O)2R c ;

[0274] R 12 、R 13 、R 14 and R 15 Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy and -NR a R b ;and

[0275] The remaining radicals have the meanings given for formula (I).

[0276] In some embodiments, the compound of formula (Vg) is the following compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 11is phenyl, a 5- or 6-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring has 1-3 heteroatoms selected from N, O and S as ring vertices; wherein the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1-2 heteroatoms selected from N, O and S as ring vertices; and wherein the phenyl, heterocyclic ring or heteroaromatic ring is optionally substituted with 1 to 3 members independently selected from the following: halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyl haloalkyl and C 1-4 Alkoxy C 1-4 Alkyl; optionally wherein two members attached to the same carbon of the heterocycle are taken together to form a =CH2 or oxo (=O) group.

[0277] In some selected embodiments, a compound of any one of Table 1, Table 2, or Table 3 is provided.

[0278] Identification of HIF-2α inhibitors with desired characteristics

[0279] The present invention relates, in part, to identifying HIF-2α inhibitors having at least one therapeutically relevant property or characteristic.Candidate inhibitors can be identified by using, for example, art-recognized assays or models, examples of which are described herein.

[0280] After identification, candidate inhibitors can be further evaluated using techniques that provide data on the inhibitor's properties (e.g., pharmacokinetic parameters, ways to determine solubility or stability). Comparison of candidate inhibitors with a reference standard (which may be the "best in class" of the current inhibitor) indicates that such candidates have potential activity.

[0281] Synthesis method

[0282] General methods for preparing claimed compounds

[0283] For the most efficient preparation of any particular compound of the invention, those skilled in the art will recognize that the timing and order of fragment ligation and the modification of the functional groups present in any fragment can be varied in the preparation of any given compound. A variety of methods have been used to prepare the compounds of the invention, some of which are illustrated in the Examples.

[0284] Prodrugs and other drug delivery and / or half-life extension methods

[0285] In some aspects of the invention, the compounds described herein are administered in prodrug form.

[0286] To achieve prolonged therapeutic activity, drug molecules can be engineered to be delivered using carriers. Such carriers are used either non-covalently (where the drug moiety is formulated into a solvent-carrier mixture by physicochemical means) or by permanent covalent attachment of the carrier agent to one of the functional groups of the drug moiety (see generally WO 2015 / 0202317).

[0287] Several non-covalent approaches are favored. For example, but not limited to, in certain embodiments, depot formulations comprising non-covalent drugs encapsulated in polymeric carriers are used. In such formulations, the drug molecules are combined with the carrier material and processed so that the drug molecules are distributed in the bulk carrier. Examples include microparticle polymer-drug aggregates (e.g., Microspheres (Phosphorex, Inc.), which are administered as injectable suspensions; polymer-drug molecule aggregates formulated as gels (e.g., Lupron (AbbVie Inc.)), which are administered as a single bolus injection; and liposomal formulations (e.g., (Pacira Pharmaceuticals), where the carrier can be a polymeric or non-polymeric entity capable of dissolving the drug. In these formulations, release of drug molecules may occur when the carrier swells or physically deteriorates. In other cases, chemical degradation enables diffusion of the drug into the biological environment; such chemical degradation processes can be autohydrolytic or enzymatic. Among other limitations, non-covalent drug encapsulation needs to prevent uncontrolled drug release, and the reliance of the drug release mechanism on biodegradation may lead to interpatient variability.

[0288] In certain embodiments, drug molecules, including small molecules and macromolecules, are conjugated to the carrier via permanent covalent bonds. Certain small molecule therapeutics that exhibit low solubility in aqueous fluids can be solubilized by conjugation to hydrophilic polymers, examples of which are described elsewhere herein. With respect to macromolecular proteins, half-life extension can be achieved, for example, by permanent covalent modification with a palmitoyl moiety, as well as by conjugating the protein to another protein that itself has an extended half-life (e.g., Generally speaking, when a carrier is covalently conjugated to a drug, the drug molecule exhibits reduced biological activity.

[0289] In some cases, the limitations associated with drug molecules or permanent covalent attachments comprising non-covalent polymer mixtures can be successfully resolved by adopting a prodrug approach for chemically conjugating drugs to polymer carriers. In this context, therapeutic agents that are inactive or less active than the drug portion itself are predictably converted into active molecular entities. If slow or controlled release of the drug is required, it is advantageous for the prodrug to have reduced biological activity compared to the released drug. In such cases, the release of the drug occurs over time, thereby reducing the necessity for repeated and frequent administration of the drug. The prodrug approach may also be advantageous when the drug portion itself is not absorbed or poorly absorbed in the gastrointestinal tract; in these cases, the prodrug promotes the absorption of the drug portion and then cleaves at a later time (e.g., via first-pass metabolism). The bioactive drug molecule is typically connected to the polymer carrier portion via a temporary bond formed between the hydroxyl, amino, or carboxyl groups of the carrier portion and the drug molecule.

[0290] The approach described above is associated with several limitations. Prodrug activation can occur by enzymatic or non-enzymatic cleavage of the temporary bond between the carrier and the drug molecule, or a sequential combination of the two (e.g., an enzymatic step followed by non-enzymatic modification). In an enzyme-free in vitro environment (e.g., an aqueous buffer solution), temporary bonds such as esters or amides may hydrolyze, but the corresponding hydrolysis rate may be outside the therapeutically useful range. In contrast, in an in vivo environment, esterases or amidases are typically present, and esterases and amidases can lead to significant catalytic acceleration of hydrolysis kinetics, from two-fold to several orders of magnitude (see, e.g., Greenwald et al., (1999) J Med Chem 42(18):3857-67).

[0291] As described herein, prodrugs can be classified into i) bioprecursors and ii) carrier-connected prodrugs. Bioprecursors do not contain a carrier group and are activated by metabolic production of a functional group. In contrast, in carrier-connected prodrugs, the active substance is conjugated to the carrier portion via a temporary bond at the functional group of the biologically active entity. Preferred functional groups are hydroxyl or amino groups. Both attachment chemistry and hydrolysis conditions depend on the type of functional group used. The carrier can be biologically inert (e.g., PEG) or can have targeting properties (e.g., antibodies). The cleavage of the carrier portion of the carrier-connected prodrug produces the target biologically active entity, and the nature of the deprotection functional group of the biologically active entity generally contributes to its biological activity.

[0292] Patent and scientific literature describe many macromolecular prodrugs, wherein the temporary bond is an unstable ester bond. In these cases, the functional group of the bioactive entity is a hydroxyl group or a carboxylic acid (see, for example, Cheng et al. (2003) Bioconjugate Chem 14:1007-17). In addition, for biomacromolecules and some small molecule drugs, it is often advantageous to connect the carrier to one or more amino groups (such as the N-terminal or lysine amino group of a protein) of the bioactive entity. In the preparation process of prodrugs, due to compared with hydroxyl or phenolic groups, the amino group has larger nucleophilicity, so the amino group may be more chemoselectively processed. This is particularly applicable to proteins and peptides containing diverse different reactive functional groups, wherein non-selective conjugation reactions cause the need for extensive characterization or purification of the non-desired product mixture, thereby reducing reaction yield and the therapeutic efficacy of the active part.

[0293] In general, amide bonds are more stable against hydrolysis than ester bonds, and the cleavage rate of amide bonds may be too slow for therapeutic utility in carrier-linked prodrugs. As a result, it may be advantageous to add structural chemical components to achieve control over the cleavability of the prodrug amide bond. These additional cleavage-controlling chemical components, which are not provided by the carrier entity or the drug, are generally referred to as "linkers". Prodrug linkers can have a significant impact on the hydrolysis rate of the transient bond, and changes in the chemical nature of the linker often result in specific properties. Activation of prodrugs containing amine-containing bioactive moieties by specific enzymes for targeted release requires that the structure of the linker display a structural motif that is recognized as a substrate by the corresponding endogenous enzyme. In these cases, cleavage of the transient bond occurs in a one-step process catalyzed by the enzyme. For example, the enzymatic release of cytarabine is affected by the protease plasmin, which is present in relatively high concentrations in various types of tumor masses.

[0294] Interpatient variability is a major drawback of the dominant enzymatic cleavage. Enzyme levels may differ significantly between subjects, leading to biological variations in the activation of the prodrugs caused by enzymatic cleavage. Enzyme levels may also vary depending on the site of administration (e.g., for subcutaneous injection, certain areas of the body produce more predictable therapeutic effects than other areas). In addition, it is difficult to establish in vivo-in vitro correlations of the pharmacokinetic properties of enzyme-dependent carrier-linked prodrugs.

[0295] Other carrier prodrugs that adopt temporary linkage with the amino group in the drug part are based on cascade mechanism.The linker compound that is composed of the structural combination of masking group and activating group can realize cascade cracking.The masking group is attached to the activating group by means of the first temporary linkage (such as ester or carbamate).The activating group is attached to the amino group of the drug molecule by the second temporary linkage (such as carbamate).The stability of the second temporary linkage or the sensitivity to hydrolysis depends on the presence or absence of the masking group.In the presence of the masking group, the second temporary linkage is highly stable, and is unlikely to release the drug molecule with kinetics useful in treatment, and in the absence of the masking group, the linkage becomes highly unstable, resulting in rapid cracking and release of the drug part.

[0296] The cracking of the first temporary linkage is the rate-limiting step in the cascade mechanism. The first step can induce the molecular rearrangement of the activated group (such as, as Greenwald et al. (1999) J Med Chem 42:1,6-as described in 3657-67), and the rearrangement makes the second temporary linkage more unstable, thereby inducing its cracking. Ideally, the cracking rate of the first temporary linkage is identical with the release rate required for drug molecules in a given treatment regimen. In addition, it is desirable that the fracture of the second temporary linkage is substantially instantaneous after its instability has been induced by the first temporary bond cracking.

[0297] Another embodiment includes a polyamino-containing prodrug based on trimethyl lock lactonization (see, e.g., Greenwald et al. (2000) J Med Chem 43(3):457-87). In this prodrug system, a substituted o-hydroxyphenyl-dimethylpropionic acid is linked to PEG via an ester, carbonate, or carbamate group as a first temporary linkage and to the amino group of the drug molecule via an amide bond as a second temporary linkage. The rate-determining step in drug release is the enzymatic cleavage of the first linkage, followed by rapid amide cleavage by lactonization, thereby 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 quinone methides or aromatic lactones, after cleavage of the temporary linkage. The potentially toxic entity is released in a 1:1 stoichiometry with the drug and may present high in vivo concentrations.

[0298] In certain embodiments of cascade prodrugs comprising aromatic activating groups based on 1,6-elimination, the masking group is structurally separated from the carrier. This can be achieved by adopting a stable bond between the polymer carrier and the activating group, wherein the stable bond does not participate in the cascade cleavage mechanism. If the carrier does not serve as a masking group and the activating group is coupled to the carrier by means of a stable bond, the release of potential toxic by-products (such as activating groups) is avoided. The stable attachment of the activating group and the polymer also suppresses the release of drug-linker intermediates with uncertain pharmacology.

[0299] The first example of the approach described in the previous paragraph includes a polymer prodrug system based on a mandelic acid activating group (see, for example, Shabat et al. (2004) Chem Eur J 10: 2626-34). In this approach, the masking group is connected to the activating group via a carbamate bond. The activating group is permanently conjugated to the polyacrylamide polymer via an amide bond. After enzymatic activation of the masking group by a catalytic antibody, the masking group is cleaved by cyclization and releases the drug; the activating group is still connected to the polyacrylamide polymer after drug release. A similar prodrug system is a masking group based on a mandelic acid activating group and an enzymatically cleavable ester connection (see, for example, Lee et al. (2004) Angew Chem 116: 1707-10).

[0300] When using the above-mentioned linker, the 1,6-elimination step still produces highly reactive aromatic intermediates. Even if the aromatic portion remains permanently attached to the polymer carrier, side reactions or immunogenic effects with potential toxic byproducts may still occur. Therefore, it is advantageous to use an aliphatic prodrug linker that is enzyme-independent and does not produce reactive aromatic intermediates during cleavage to generate a linker technology for forming a polymer prodrug containing an amine-containing active agent. One such example uses PEG5000-maleic anhydride to reversibly modify the amino groups in tissue plasminogen activator and urokinase (see, e.g., (1987) Garman et al. FEBS Lett 223 (2): 361-65). The functional enzyme is incubated in a buffer solution at pH 7.4 and then regenerated from the PEG-uPA conjugate by cleavage of the maleamic acid linkage following first-order kinetics with a half-life of approximately 6 hours. The disadvantage of the maleic acid linkage is that the conjugate lacks stability at lower pH values.

[0301] A further approach includes a PEG cascade prodrug system based on an N,N-bis-(2-hydroxyethyl)glycine amide (bicine) linker (see, e.g., (2004) J Med Chem 47:726-34). In this system, two PEG carrier molecules are linked via a temporary bond to a bicine molecule coupled to an amino group of a drug molecule. The first step in prodrug activation involves enzymatic cleavage of the first temporary bond connecting the two PEG carrier molecules to the hydroxyl groups of the bicine activating group. Different bonds between PEG and bicine result in different prodrug activation kinetics. The second step in prodrug activation involves cleavage of the second temporary bond connecting the bicine activating group to the amino group of the drug molecule. A disadvantage of this system is the slow hydrolysis rate of the second temporary bicine amide bond, which results in the release of a bicine-modified prodrug intermediate that may exhibit different pharmacokinetic, immunogenic, toxic, and pharmacodynamic properties compared to the native parent drug molecule.

[0302] In certain embodiments, dipeptides are used for targeted or targeted transport prodrug development because they are substrates for 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) has not been well defined.

[0303] In some embodiments, the dipeptide is attached to the drug moiety via an ester bond, as described for the dipeptide ester of the drug paracetamol (Gomes et al. (2005) Bio & Med Chem Lett. In this case, the cyclization reaction consists of nucleophilic attack of the N-terminal amine of the peptide at the ester carbon atom, forming a tetrahedral intermediate, followed by proton transfer from the amine to the leaving group oxyanion, with simultaneous formation of the peptide bond to yield the cyclic DKP product and the free drug. This approach works well for hydroxyl-containing drugs in vitro, but has been found to compete with enzymatic hydrolysis of the ester bond in vivo, as the corresponding dipeptide ester releases paracetamol at a much faster rate than in buffer ((Gomes et al. (Molecules 12 (2007) 2484-2506)). The susceptibility of dipeptide-based prodrugs to peptidases can be addressed by incorporating at least one unnatural amino acid into the dipeptide motif. However, endogenous enzymes capable of cleaving ester bonds are not limited to peptidases, and the enzyme dependence of such prodrug cleavage still leads to unpredictable in vivo performance.

[0304] In some embodiments, enzyme dependency is intentionally engineered into a DKP prodrug, such as where a dipeptide ester prodrug is formylated at the amino terminus of the dipeptide, and enzymatic deformylation is used to initiate diketopiperazine formation and subsequent cleavage of the ester-dipeptide bond, followed by release of the drug molecule (see, e.g., USP 7,163,923). As a further example, an octapeptide is attached to the 4-hydroxyl group of vinblastine via an ester linkage, and ester bond cleavage is performed by DKP formation following specific enzymatic removal of the N-terminal hexapeptide (see Brady et al. (2002) J Med Chem 45:4706-15).

[0305] The scope of the DKP-forming reaction has also been extended to amide prodrugs. For example, USP 5,952,294 describes prodrug activation of the dipeptidylamide prodrug of cytarabine using diketopiperazine formation. In this case, a temporary linkage is formed between the carbonyl group of the dipeptide and the aromatic amino group of cytarabine. However, due to the absence of a carrier or other half-life-extending moiety or functional group, such conjugates are unlikely to achieve a slow-release effect.

[0306] Also described are dipeptide prodrugs comprising bioactive peptides such as GLP-1, which can form and release peptides through the diketopiperazines of dipeptide extension (see, e.g., WO 2009 / 099763). The bioactive peptide portion can comprise an extra PEG chain on one of its amino acid side chain residues to achieve a prolonged circulation of the bioactive peptide. However, this approach is associated with several significant shortcomings. First, the PEG chain must be connected to the peptide without damaging its biological activity, which may be difficult to achieve for many bioactivators based on peptides. Secondly, because the PEGylated peptide itself has biological activity, the dipeptide front portion has an impact on the biological activity of the peptide, and may have a negative impact on its receptor binding properties.

[0307] Specific exemplary technologies 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 ProLynx technology platform utilizes a novel set of linkers that are pre-programmed to cleave at different rates, thereby allowing controlled, predictable, and sustained release of small molecules and peptides from circulating semi-solid macromolecular conjugates. This technology allows the desired steady-state serum levels of therapeutic agents to be maintained for weeks to months.

[0308] The Ascendis technology platform combines the benefits of prodrug and sustained-release technologies to enhance the properties of small molecules and peptides. During circulation, the proprietary prodrug releases the unmodified active parent therapeutic agent at a predetermined rate controlled by physiological pH and temperature conditions. Because the therapeutic agent is released in its unmodified form, it retains its original mechanism of action.

[0309] Modifications to enhance inhibitor properties

[0310] It is often beneficial and sometimes necessary to improve one or more physical properties of the therapeutic modalities disclosed herein and / or the manner in which these therapeutic modalities are administered. Improvements in physical properties include, for example, increasing aqueous solubility, bioavailability, serum half-life, and / or therapeutic half-life; and / or methods of modulating biological activity.

[0311] Modifications known in the art include PEGylation, Fc-fusion, and albumin fusion. Although typically associated with macromolecular agents such as polypeptides, such modifications have recently been evaluated with specific small molecules. For example, Chiang, M. et al. demonstrated that small molecule-Fc conjugates retained potent Fc receptor and adenosine 2a receptor interactions and exhibited superior properties compared to unconjugated small molecules. Covalent attachment of PEG molecules to small molecule therapeutics has also been described (Li, W. et al., Progress in Polymer Science, 2013 38:421-44).

[0312] Other known modifications include deuteration to improve pharmacokinetics, pharmacodynamics, and toxicity profiles. Due to the larger atomic mass of deuterium, the cleavage of carbon-deuterium bonds requires more energy than carbon-hydrogen bonds. Because these stronger bonds are more difficult to break, the drug is metabolized more slowly than in the non-deuterated form, which allows for lower dosing frequencies and may further reduce toxicity. (Charles Schmidt, Nature Biotechnology, 2017, 35(6):493-494; Harbeson, S. and Tung, R., Medchem News, 2014(2):8-22).

[0313] Therapeutic and preventive uses

[0314] 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. Although specific uses are described in detail below, it should be understood that the present invention is not limited thereto. Furthermore, although general categories of specific diseases, disorders, and conditions are set forth below, some diseases, disorders, and conditions may be members of more than one category, while other diseases, disorders, and conditions may not be members of any disclosed category.

[0315] In some embodiments, a HIF-2α inhibitor described herein is administered in an amount effective to reverse, halt, or slow the progression of a HIF-2α-mediated disorder.

[0316] In one embodiment, patients are selected for treatment as described herein based on their HIF-2a expression levels. In some embodiments, patients are selected for treatment as described herein based on HIF-2a expression in their tumors. In yet another embodiment, patients are selected for treatment as described herein based on the presence or absence of VHL mutations.

[0317] Oncology-related conditions The HIF-2α inhibitors described herein can be used to treat or prevent proliferative disorders or conditions, including cancer, for example, uterine cancer, cervical cancer, breast cancer, prostate cancer (such as metastatic castration-resistant prostate cancer), testicular cancer, gastrointestinal cancer (e.g., esophageal, oropharyngeal, stomach, small or large intestine, colon or rectum cancer), kidney cancer, renal cell carcinoma, bladder cancer, bone cancer, bone marrow cancer, skin cancer, head or neck cancer, liver cancer, gallbladder cancer, bile duct cancer, heart cancer, lung cancer, pancreatic cancer, salivary gland cancer, adrenal cancer, thyroid cancer, brain cancer (e.g., glioma), ganglion cancer, central nervous system (CNS) cancer, and peripheral nervous system (PNS) cancer, as well as cancers of the hematopoietic system and immune system (e.g., spleen or thymus). The present invention also provides methods for treating or preventing other cancer-related diseases, disorders or conditions, including, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virally induced cancers (e.g., epithelial cell cancer, endothelial cell cancer, squamous cell carcinoma, and papillomavirus), adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically induced cancers, metastasis, and angiogenesis. In specific embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia. The use of the terms cancer-related diseases, disorders, and conditions is intended to broadly refer to conditions directly or indirectly related to cancer and includes, for example, angiogenesis and precancerous conditions such as dysplasia.

[0318] In certain embodiments, the cancer may be metastatic or at risk of becoming metastatic, or may have spread to other tissues, including cancers of the blood or bone marrow (eg, leukemia).

[0319] In some embodiments, the present invention provides methods of treating a proliferative disorder, cancer, tumor, or precancerous condition with a HIF-2α inhibitor and at least one additional therapeutic or diagnostic agent, examples of which are described elsewhere herein.

[0320] In some embodiments, the disease or disorder is VHL-associated, such as VHL-associated renal cell carcinoma.

[0321] Iron overload disease.In one embodiment, in one embodiment, the compounds as described herein can be used to treat iron overload conditions. Iron overload conditions may be primary or secondary. In one embodiment, the iron overload condition may be hemochromatosis. In other embodiments, the compounds as described herein can be used to treat polycythemia vera, such as, for example, polycythemia vera. In another embodiment, the compounds as described herein can be used to treat Pacak-Zhuang Syndrome. In yet another embodiment, the compounds as described herein can be used to treat polycythemia vera.

[0322] Immune and inflammation-related conditions. A non-limiting list of immune-related and inflammation-related diseases, disorders, and conditions that can be treated or prevented with the compounds and compositions of the present invention includes arthritis (e.g., rheumatoid arthritis), renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., where inflammatory cytokines prevent healing), anemia, and fibromyalgia. Other diseases and conditions that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), chronic obstructive pulmonary disease (COPD), atherosclerosis, allergic contact dermatitis and other eczema, systemic sclerosis, transplantation, and multiple sclerosis.

[0323] In certain embodiments of the present disclosure, HIF-2α inhibitors are 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 prolong the immune response to the antigen or vaccine. Also provided are therapeutic compositions comprising a combination of at least one antigenic agent or vaccine component (including but not limited to viruses, bacteria and fungi or parts thereof, proteins, peptides, tumor-specific antigens and nucleic acid vaccines) and at least one HIF-2α inhibitor of the present invention.

[0324] In some embodiments, a HIF-2α inhibitor as described herein can be combined with an immunosuppressive agent to reduce the number of immune effector cells.

[0325] Other conditionsEmbodiments of the present invention contemplate administering the HIF-2α inhibitors described herein to a subject to treat or prevent any other condition that may benefit from at least some level of HIF-2α inhibition. Such diseases, disorders, and conditions include, for example, cardiovascular (e.g., cardiac ischemia or pulmonary hypertension) and metabolic (e.g., diabetes, insulin resistance, obesity) conditions.

[0326] Pharmaceutical composition

[0327] The HIF-2α inhibitors of the present invention may be in the form of compositions suitable for administration to a subject. Generally, such compositions are "pharmaceutical compositions" comprising one or more HIF-2α inhibitors and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers, or excipients. In certain embodiments, the HIF-2α inhibitor is present in a therapeutically acceptable amount. The pharmaceutical compositions can be used in the methods of the present invention; thus, for example, the pharmaceutical compositions can be administered to a subject ex vivo or in vivo to implement the treatment and prevention methods and uses described herein.

[0328] The pharmaceutical compositions of the present invention can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are described herein. In addition, the pharmaceutical compositions can be used in combination with other therapeutically active agents or compounds as described herein to treat or prevent diseases, disorders, and conditions contemplated by the present invention.

[0329] Pharmaceutical compositions containing active ingredients (e.g., HIF-2α functional inhibitors) can be in a form suitable for oral use, for example, in the form of tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more agents, such as, for example, sweeteners, flavorings, colorants, and preservatives, in order to provide pharmaceutically refined and palatable products. Tablets, capsules, and the like contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for making tablets. These excipients can be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic, and lubricants such as magnesium stearate, stearic acid, or talc.

[0330] The tablets, capsules etc. that are applicable to oral administration can not be coated or be coated to postpone disintegration and absorption in the gastrointestinal tract by known technology, and thereby provide sustained action.For example, the time-delay material such as glyceryl monostearate or glyceryl distearate can be used.They also can be coated to form the osmotic therapeutic tablet for controlled release by technology known in the art.Extra agent comprises biodegradable or biocompatible particle or polymeric substance, such as polyester, polyamino acid, hydrogel, polyvinyl pyrrolidone, polyanhydride, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethyl cellulose, protamine sulfate or lactide / glycolide copolymer, polylactide / glycolide copolymer, or ethyl vinyl acetate copolymer is to control the sending of applied composition.For example, oral dosage form can be embedded in (carry out respectively by using hydroxymethyl cellulose or gelatin-microcapsule or poly (methyl methacrylate (methylmethacrolate)) microcapsule) by coacervation technique or by interfacial polymerization prepared microcapsule.Or it is embedded in colloidal drug delivery system. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microbeads and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles and liposomes. Methods for preparing the above-mentioned formulations will be apparent to those skilled in the art.

[0331] Formulations for oral use may also be presented as hard gelatin capsules wherein 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 wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0332] Aqueous suspensions contain active materials mixed with excipients suitable for their manufacture. Such excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents, such as naturally occurring phospholipids (such as lecithin), or condensation products of alkylene oxides and fatty acids (such as polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain fatty alcohols (such as, for heptadecaethyleneoxycetanol), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol (such as polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (such as polyethylene sorbitan monooleate). Aqueous suspensions can also contain one or more preservatives.

[0333] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil (such as liquid paraffin). Oily suspensions may contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those described above) and flavorings may be added to provide a palatable oral preparation.

[0334] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0335] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or gum tragacanth; naturally occurring phospholipids, such as soy, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0336] Pharmaceutical compositions typically comprise a therapeutically effective amount of the HIF-2α inhibitor contemplated by the present invention and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (such as ascorbic acid and sodium bisulfate), preservatives (such as benzyl alcohol, methyl parahydroxybenzoate, ethyl parahydroxybenzoate or n-propyl parahydroxybenzoate), emulsifiers, suspending agents, dispersants, solvents, fillers, expanders, detergents, buffers, vehicles, diluents and / or adjuvants. For example, a suitable vehicle may be a physiological saline solution or citrate buffered saline that may be supplemented with other substances commonly found in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin is a further exemplary vehicle. 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. As an example, the buffer component can be a water-soluble substance such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid and salts thereof. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS) and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0337] After the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations can be stored in a ready-to-use form, a lyophilized form that requires reconstitution before use, a liquid form that requires dilution before use, or other acceptable forms. In some embodiments, the pharmaceutical composition is in a disposable container (e.g., a disposable vial, ampoule, syringe, or autoinjector (similar to )), while in other embodiments multiple-use containers (e.g., multiple-use vials) are provided.

[0338] The preparation can also include a carrier to protect the composition from rapid degradation or elimination from the body, such as a controlled release formulation, which includes liposomes, hydrogels, prodrugs and microencapsulated delivery systems. For example, a time-delay material such as glyceryl monostearate or glyceryl stearate can be used in combination with wax alone. Any drug delivery device can be used to deliver HIF-2α inhibitors, including implants (such as implantable pumps) and catheter systems, slow injection pumps and equipment, all of which are well known to those skilled in the art.

[0339] Depot injections, typically administered subcutaneously or intramuscularly, can also be used to release the HIF-2α inhibitors disclosed herein over a defined period of time.Depot injections are typically solid-based or oil-based and typically contain at least one formulation component described herein.

[0340] The pharmaceutical composition may be in the form of a sterile injectable aqueous solution or oily suspension. The suspension may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents as mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Acceptable diluents, solvents and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL TM Injectable preparations can be prepared by mixing with a mixture of BASF, Parsippany, NJ or phosphate buffered saline (PBS), ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol) and suitable mixtures thereof. In addition, sterile, fixed oils are generally used as solvents or suspension media. For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used to prepare injectables. Prolonged absorption of specific injectable formulations can be achieved by comprising an agent that delays absorption (such as aluminum monostearate or gelatin).

[0341] The present invention contemplates the use of HIF-2α inhibitors in the form of suppositories for rectal administration. Suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0342] The HIF-2α inhibitors contemplated by the present invention may be in the form of any other suitable pharmaceutical composition (eg, a spray for nasal or inhalation use) currently known or later developed.

[0343] Route of administration

[0344] The present invention contemplates administering HIF-2α inhibitors and compositions thereof in any appropriate manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation. Depot injections, typically administered subcutaneously or intramuscularly, can also be used to release the HIF-2α inhibitors disclosed herein over a limited period of time.

[0345] Certain embodiments of the present invention contemplate oral administration.

[0346] Combination therapy

[0347] The present invention contemplates the use of HIF-2α inhibitors alone or in combination with one or more active therapeutic agents. The additional active therapeutic agent may be a small chemical molecule; a macromolecule such as a protein, antibody, peptibody, peptide, DNA, RNA, or a fragment of such a macromolecule; or a cell or gene therapy. Combination therapies may target different but complementary mechanisms of action and thereby have a synergistic therapeutic or preventive effect on the underlying disease, condition, or disorder. Additionally or alternatively, combination therapies may allow for a reduction in the dose of one or more agents, thereby ameliorating, reducing, or eliminating side effects associated with one or more agents.

[0348] The active therapeutic agent in this type of combination therapy can be formulated into a single composition or a separate composition. If used separately, each therapeutic agent in the combination can be given simultaneously or approximately simultaneously or at different times. In addition, even in the following cases, therapeutic agent is also used in "combination": therapeutic agent has different forms of administration (e.g., oral capsules and intravenous administration), which are given with different dosing intervals, a kind of therapeutic agent is given with a constant dosage regimen and the other is titrated upward, titrated downward or disabled, or each therapeutic agent in the combination is independently titrated upward, titrated downward, increased or decreased in dosage, or is disabled and / or resumed in the course of treatment of the patient. If the combination is formulated into a separate composition, in some embodiments, the separate composition is provided together in a kit.

[0349] In some embodiments, the additional therapeutic agent is an immunomodulator. Suitable immunomodulators 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-IBB ligands; 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.

[0350] In certain embodiments, the present invention provides a method for tumor suppression of tumor growth comprising administering a combination of a HIF-2α inhibitor as described herein and a signal transduction inhibitor (STI) to achieve additive or synergistic suppression of tumor growth. As used herein, the term "signal transduction inhibitor" refers to an agent that selectively inhibits one or more steps in a signal transduction pathway. The signal transduction inhibitors (STIs) of the present invention include: (i) bcr / abl kinase inhibitors (e.g., ); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) her-2 / neu receptor inhibitors (e.g., ); (iv) inhibitors of Akt family kinases or Akt pathways (e.g., Trop2 inhibitor orrapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidylinositol kinase inhibitors. Agents involved in immune regulation can also be used in combination with the HIF-2α inhibitors described herein to suppress tumor growth in cancer patients.

[0351] 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, carboquinone, metodopa, and urodopa; ethyleneimines and methylmelamines including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trishydroxymethylmelamine; nitrogen mustards such as chlorambucil, chlorambucil, chlorfosamide, estramustine, ifosfamide, methylchloroethylamine, methoxychlor hydrochloride, melphalan, novibacin, fenester, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, formosan, and chloramphenicol. aclarubicin, dactinomycin, anthramycin, azaserine, bleomycin, actinomycin C, calicheamicin, carbicin, carminomycin, carmophorin, chromomycin, dactinomycin, daunomycin, detoxib, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, erubicin, idarubicin, mesilomycin, mitomycin, mycophenolic acid, nogamycin, olivomycin, peplomycin, pomalidomide, porfiromycin, puromycin, triferon-adriamycin, rhodorubicin, streptozocin, streptozotocin, tuberculin, ubenimex, zoloft, daurubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU) , with or without folinic acid; folic acid analogs such as folinic acid, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as captestosterone, drostanolone propionate, cyclothiosteroid, melastane, testolactone; antiadreners such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; acetylglucosyl esters; aldophosphamide glycosides; aminolevulinic acid; amsacrine; betabucidin; bisantrene; edatrexate; dexfosfamide; demeclocycline; diazepam ; efamicin; elliptonium acetate; etogluconol; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguanidine; mitoxantrone; mopidamole; nitroacridine; pentostatin; methambucil; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; razoxane; sizolan; spirogermanium; tricholomanic acid; triazoline; 2,2',2"-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitropol; dibromodulcitol; pipobroman; gesetuxine; cytarabine (Ara-C); cyclophosphamide; thiotepa; paclitaxel, such as paclitaxel, albumin-paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;Platinum and platinum coordination complexes, such as cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; mitoxantrone; teniposide; daunorubicin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine; anthracyclines; arginase inhibitors (see PCT / US2019 / 020507), and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing.

[0352] Chemotherapeutic agents also include anti-hormonal agents that regulate or inhibit the hormonal effects on tumors, such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase inhibitory 4 (5) -imidazole, 4-hydroxytamoxifen, troxifen, raloxifene, onapristone and toremifene; and anti-androgens, such as abiraterone, enzalutamide, flutamide, nilutamide, bicalutamide, leuprorelin and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above substances. In certain embodiments, combination therapy includes a chemotherapy regimen comprising one or more chemotherapeutic agents. In certain embodiments, combination therapy includes administering hormones or related hormone agents.

[0353] Additional therapeutic modalities that may be used in combination with HIF-2α inhibitors include radiation therapy, monoclonal antibodies directed against tumor antigens, complexes of monoclonal antibodies and toxins, T cell adjuvants, bone marrow transplants, or antigen-presenting cells (e.g., dendritic cell therapy), including TLR agonists for stimulation of such antigen-presenting cells.

[0354] In certain embodiments, the present invention contemplates the use of compounds as described herein in combination with adoptive cell therapy, which is a novel and promising form of personalized immunotherapy in which immune cells with anti-tumor activity are administered to cancer patients. Tumor infiltrating lymphocytes (TIL) and T cells engineered to express, for example, chimeric antigen receptors (CAR) or T cell receptors (TCR) are being used to explore adoptive cell therapy. Adoptive cell therapy typically involves collecting T cells from an individual, genetically modifying them to target specific antigens or enhance their anti-tumor effects, amplifying them to a sufficient number, and infusing genetically modified T cells into cancer patients. T cells can be collected from subsequently amplified cells by being reinfused into the patient (such as autologous), or can be collected from a donor patient (such as an allogeneic).

[0355] In certain embodiments, the present invention contemplates the use of compounds described herein in combination with RNA interference-based therapies to silence gene expression. RNAi begins by cleaving longer double-stranded RNA into small interfering RNAs (siRNAs). One chain of siRNA is incorporated into a ribonucleoprotein complex known as RNA-induced silencing complex (RISC), which is then used to identify mRNA molecules that are at least partially complementary to the incorporated siRNA chain. RISC can bind to or cleave mRNA, both of which inhibit translation.

[0356] In certain embodiments, the present invention contemplates the use of the compounds described herein in combination with agents that modulate adenosine levels. Such therapeutic agents may act on extracellular nucleotides (ectonucleotides) that catalyze the conversion of ATP to adenosine, including ectonucleotide triphosphate diphosphohydrolase 1 (ENTPD1, ​​also known as CD39 or cluster of differentiation 39), which hydrolyzes ATP to ADP and ADP to AMP, and ecto5'-nucleotidase (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 key role in calibrating the duration, amplitude, and chemical nature of purinergic signals delivered to various cells, such as immune cells. Modification of these enzymatic activities can alter the course or determine the outcome of several pathophysiological events, including cancer, autoimmune diseases, infection, atherosclerosis, and ischemia-reperfusion injury, suggesting that these extracellular enzymes represent novel therapeutic targets for the management of various conditions. In one embodiment, the CD73 inhibitor is those described in WO2017 / 120508, WO2018 / 067424, WO2018 / 094148, and WO2020 / 046813. In another embodiment, the CD73 inhibitor is AB680.

[0357] Alternatively, such therapeutic agents may be adenosine 2 receptor (A2R) antagonists. Adenosine can bind to and activate four different G protein-coupled receptors: A1R, A2R, and A2R. 2a R, A 2b Adenosine binds to A3R expressed on T cells, natural killer cells, and myeloid cells such as dendritic cells. 2a Binding of A receptors results in elevated intracellular cyclic AMP levels and impaired maturation and / or activation of such cells. This process significantly impairs the activation of the immune system against cancer cells. 2AR is involved in selectively enhancing anti-inflammatory cytokines, promoting the upregulation of PD-1 and CTLA-4, promoting the generation of LAG-3 and Foxp3+ regulatory T cells, and mediating the inhibition of regulatory T cells. PD-1, CTLA-4 and other immune checkpoints are further discussed herein. In view of the different mechanisms of action of A2R antagonists, combining A2R antagonists in the combination described herein can provide at least one cumulative effect. In one embodiment, the present invention contemplates a combination with an adenosine receptor antagonist described in WO2018 / 136700, WO2018 / 204661, WO2018 / 213377 or WO2020 / 023846. In another embodiment, the adenosine receptor antagonist is AB928.

[0358] In certain embodiments, the present invention contemplates the use of compounds described herein in combination with inhibitors of phosphatidylinositol 3-kinase (PI3K), particularly PI3Kγ isoforms. PI3Kγ inhibitors can stimulate anti-cancer immune responses by regulating myeloid cells, such as by inhibiting suppressive myeloid cells, weakening immunosuppressive tumor-infiltrating macrophages, or by stimulating macrophages and dendritic cells to produce cytokines that contribute to effective T-cell responses, thereby leading to reduced cancer development and spread. PI3Kγ inhibitors include those described in PCT / US2020 / 035920.

[0359] In certain embodiments, the present invention contemplates the use of compounds described herein in combination with arginase inhibitors, which have been shown to be responsible for or involved in inflammation-triggered immune dysfunction, tumor immune escape, immune suppression, and the immunopathology of infectious diseases. Exemplary arginase compounds can be found, for example, in PCT / US2019 / 020507 and WO / 2020 / 102646.

[0360] Immune checkpoint inhibitors The present invention contemplates the use of the HIF-2α functional inhibitors described herein in combination with immune checkpoint inhibitors.

[0361] The large number of genetic and epigenetic changes that are characteristic of all cancers provide a variety of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the final amplitude (e.g., the level of cytokine production or proliferation) and quality (e.g., the type of immune response generated, such as the pattern of cytokine production) of the response initiated by antigen recognition of the T cell receptor (TCR) are regulated by the balance between co-stimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are crucial for the prevention of autoimmunity (i.e., maintaining self-tolerance) and for protecting tissues from damage when the immune system responds to pathogenic infections. The expression of immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism.

[0362] T cells have become a major focus of efforts to therapeutically manipulate endogenous antitumor immunity because: i) they are able to selectively recognize protein-derived peptides in all cellular compartments; ii) they are able to directly recognize and kill cells expressing antigens (via CD8+ effector T cells; also known as cytotoxic T lymphocytes (CTLs)); and iii) they are able to coordinate diverse immune responses through CD4+ helper T cells, which integrate adaptive and innate effector mechanisms.

[0363] In the clinical setting, blockade of immune checkpoints—which leads to the amplification of antigen-specific T cell responses—has proven to be a promising avenue in human cancer treatment.

[0364] T cell-mediated immunity includes multiple sequential steps, each of which is regulated by balancing stimulatory and inhibitory signals to optimize the response. Although almost all inhibitory signals in the immune response ultimately regulate intracellular signaling pathways, many are initiated through membrane receptors, whose ligands are either membrane-bound or soluble (cytokines). Although co-stimulatory and inhibitory receptors and ligands that regulate T-cell activation are generally not overexpressed in cancer relative to normal tissues, inhibitory ligands and receptors that regulate T cell effector functions in tissues are generally overexpressed on tumor cells or non-transformed cells associated with the tumor microenvironment. The function of soluble and membrane-bound receptor-ligand immune checkpoints can be regulated using agonist antibodies (for co-stimulatory pathways) or antagonist antibodies (for inhibitory pathways). Therefore, compared 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 anti-tumor activity. [See Pardoll, (April 2012) Nature Rev. Cancer 12: 252-64].

[0365] Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of tumor cells and are candidates for blockade, include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA4 (cytotoxic T lymphocyte-associated antigen 4); TIM3 (T cell membrane protein 3); LAG3 (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); and killer cell inhibitory receptors, which can be divided into two categories based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints are described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands, such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)). [See Pardoll, (April 2012) Nature Rev. Cancer 12:252-64].

[0366] The present invention contemplates the use of inhibitors of HIF-2α function as described herein in combination with inhibitors of the aforementioned immune checkpoint receptors and ligands, as well as inhibitors of immune checkpoint receptors and ligands not yet described. Certain immune checkpoint modulators are currently approved, and many others are in development. When ipilimumab ( Bristol-Myers Squibb became the first immune checkpoint inhibitor to receive regulatory approval in the United States. It includes CTLA4 and antibodies (CTLA4-Ig; Abatacept ( Fusion proteins developed by Bristol-Myers Squibb have been used to treat rheumatoid arthritis, and other fusion proteins have been shown to be effective in kidney transplant patients with Epstein-Barr virus sensitivity. The next class of immune checkpoint inhibitors to receive regulatory approval were those targeting PD-1 and its ligands PD-L1 and PD-L2. Approved anti-PD-1 antibodies include nivolumab ( nivolumab ) for various cancers, including squamous cell carcinoma, classical Hodgkin lymphoma, and urothelial carcinoma. Bristol-Myers Squibb) and pembrolizumab ( Approved anti-PD-L1 antibodies include avelumab ( EMD Serono & Pfizer), Atezolizumab ( Roche / Genentech) and durvalumab AstraZeneca). Although there are no approved therapeutics targeting TIGIT or its ligands CD155 and CD112, those under development include BMS-986207 (Bristol-Myers Squibb), MTIG7192A / RG6058 (Roche / Genentech), dunalimab (AB154) and OMP-31M32 (OncoMed). In some combinations provided herein, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, cemiplizumab and sepalizumab. In another embodiment, the immune checkpoint inhibitor is selected from cindilimab, carrelizumab, tislelizumab, toripalimab, dotalimab, rivulimab, santalizumab, burgalizumab, BI-754091, coxilimab and spartalizumab.

[0367] In one aspect of the present invention, the HIF-2α inhibitor claimed is combined with an immuno-oncology agent, which is an agonist of (i) stimulatory (including costimulatory) receptors or an antagonist of inhibition (including co-inhibition) signals on (ii) T cells, both of which can result in an amplification of antigen-specific T cell responses. Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands bound to costimulatory or co-inhibitory receptors is the B7 family, including 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 are the TNF family molecules that bind to cognate TNF receptor family members, including 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.

[0368] In another aspect, the immuno-oncology agent is a cytokine that inhibits T cell activation (eg, IL-6, IL-10, TGF-B, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0369] In one aspect, T cell responses can be stimulated by a combination of the disclosed HIF-2α inhibitors with one or more of the following: (i) antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin-9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and / or (ii) agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2. Other agents that can be used in combination with the HIF-2α inhibitors of the present invention for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds herein can be combined with KIR antagonists such as lirilumab. As another example, the compounds described herein can be combined with lenvatinib or cabozantinib.

[0370] Still other agents for use in combination therapy include agents that inhibit or deplete macrophages or monocytes, including 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; WO13 / 169264; WO14 / 036357).

[0371] In another aspect, the disclosed HIF-2α inhibitors can be used with one or more agonists that bind to positive co-stimulatory receptors, blockers that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, overcome different immune suppression pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), deplete or suppress Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), or reverse / prevent T cell anergy or exhaustion), and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0372] In one aspect, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example (ipilimumab) or tremelimumab.

[0373] In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example (nivolumab), (pembrolizumab) or MEDI-0680 (AMP-514; WO2012 / 145493). Immuno-oncology agents may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224. In another embodiment, the agent is zimberelimab.

[0374] In another aspect, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, (atezolizumab; MPDL3280A; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0375] In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonist 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).

[0376] In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0377] In another aspect, the immuno-oncology agent is a GITR agonist, such as 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).

[0378] In another aspect, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0379] In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonist OX40L antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0380] In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonist CD40 antibody. Suitable CD40 antibodies include, for example, lukatumomab or darcibinumab.

[0381] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varilutumab.

[0382] In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WO 11 / 109400).

[0383] The present invention encompasses pharmaceutically acceptable salts, acids, or derivatives of any of the above substances.

[0384] Examples of therapeutic agents that can be used in combination therapy to treat cardiovascular and / or metabolic related diseases, disorders and conditions include statins that inhibit the enzymatic synthesis of cholesterol (e.g., and ); bile acid resins that sequester cholesterol and prevent its absorption (such as LO- and ); Ezetimibe, which blocks cholesterol absorption Fibric acids that lower triglycerides and may modestly increase HDL (eg ); niacin, which modestly lowers LDL cholesterol and triglycerides (e.g., ); and / or a combination of the above (e.g., (ezetimibe with simvastatin.) Alternative cholesterol treatments that may be candidates for use in combination with the HIF-2α inhibitors described herein include various supplements and herbs (such as garlic, policosanol, and guggul).

[0385] The present invention encompasses pharmaceutically acceptable salts, acids, or derivatives of any of the above substances.

[0386] Examples of therapeutic agents that can be used in combination therapy for immune-related and inflammation-related diseases, disorders or conditions include, but are not limited to, the following: nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen and other propionic acid derivatives (amiprofen, fenoxysaprofen, buclofen, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, indoprofen, ketoprofen, miloprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and thiasaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclofenac, fentiazac, furofenic acid and fenfluramine), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclofenac, fenfluramine ... The following combinations include: oxfenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidomecin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenamic acid), oxicams (esoxicam, piroxicam, sudoxicam, and tenoxicam), salicylates (acetylsalicylic acid, sulfasalazine), and pyrazolones (azapropazone, bezpiperylon, feprazone, mofetil, oxyphenbutazone, and phenylbutazone). Other combinations include cyclooxygenase-2 (COX-2) inhibitors.

[0387] Other active agents for combination include steroids such as prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone or hydrocortisone. This combination may be particularly advantageous because one or more adverse effects of the steroid may be reduced or even eliminated by gradually reducing the required steroid dosage.

[0388] Additional examples of active agents that can be used in combination to treat, for example, rheumatoid arthritis include one or more cytokine suppressive anti-inflammatory drugs (CSAIDs); antibodies or antagonists to other human cytokines or growth factors, such as TNF, LT, IL-10, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, or PDGF.

[0389] Specific combinations of active agents may interfere at different points in the autoimmune and subsequent inflammatory cascade and include TNF antagonists, such as chimeric, humanized or human TNF antibodies, Anti-TNF antibody fragments (eg, CDP870) and soluble p55 or p75 TNF receptors, their derivatives, p75TNFRIgG or p55TNFR1gG Soluble IL-13 receptor (sIL-13), and also TNFa-converting enzyme (TACE) inhibitors; similarly, IL-1 inhibitors (e.g., interleukin-1-converting enzyme inhibitors) may be effective. Other combinations include interleukin 11, anti-P7s and p-selectin glycoprotein ligand (PSGL). Other examples of agents used in combination with the HIF-2α inhibitors described herein include interferon-131a Interferon-13lb Copaxone; hyperbaric oxygen; intravenous immunoglobulin; claribine; and antibodies or antagonists to other human cytokines or growth factors (such as antibodies to CD40 ligand and CD80).

[0390] Drug administration

[0391] The HIF-2α inhibitors of the present invention can be administered to a subject in an amount that depends on, for example, the goal of administration (e.g., the degree of resolution desired; the age, weight, sex, and health and physical condition of the subject to whom the formulation is administered; the route of administration; and the nature of the disease, condition, illness, or its symptoms). The dosing regimen can also take into account the presence, nature, and extent of any adverse effects associated with the administered agent or agents. The effective dose amount and dosing regimen can be readily determined from, for example, safety and dose escalation trials, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0392] In general, dosing parameters dictate that the dose amount should be less than the amount that may produce irreversible toxicity in the subject (maximum tolerated dose (MTD)) and not less than the amount required to produce a measurable effect in the subject. Such amounts are determined, for example, by pharmacokinetic and pharmacodynamic parameters related to ADME, taking into account the route of administration and other factors.

[0393] Effective dose (ED) is the dosage or amount of the agent that produces a therapeutic response or desired effect in a portion of the subjects using it. The "median effective dose" or ED50 of an agent is the dosage or amount of the agent that produces a therapeutic response or desired effect in 50% of the populations of the administered agent. Although ED50 is generally used as a measure of the reasonable expectation of the agent effect, it is not necessarily the dosage that a clinician may consider appropriate after considering all relevant factors. Therefore, in some cases, the effective dose is greater than the calculated ED50, in other cases, the effective dose is less than the calculated ED50, and in other cases, the effective dose is the same as the calculated ED50.

[0394] In addition, an effective dose of a HIF-2α inhibitor of the present invention can be an amount that produces a desired result relative to a healthy subject when administered to a subject in one or more doses. For example, for a subject experiencing a particular condition, an effective dose can be a dose that improves a diagnostic parameter, measurement result, marker, etc. of the condition 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 greater than 90%, where 100% is defined as the diagnostic parameter, measurement result, marker, etc. exhibited by a normal subject.

[0395] In certain embodiments, the HIF-2α inhibitors contemplated by the present invention can be administered (e.g., orally) at a dosage level of about 0.01 mg / kg of subject body weight / day to about 50 mg / kg of subject body weight / day, or about 1 mg / kg of subject body weight / day to about 25 mg / kg of subject body weight / day, once or more daily to achieve the desired therapeutic effect.

[0396] For oral administration, the composition can be provided in the form of tablets, capsules, etc., containing 1.0 to 1000 mg of active ingredient, more particularly 1 to 100 mg or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35 or 40 mg, once a day.

[0397] In certain embodiments, the desired dosage of the HIF-2α inhibitor is contained in a "unit dosage form." The phrase "unit dosage form" refers to physically discrete units, each unit containing a predetermined quantity of the HIF-2α inhibitor, alone or in combination with one or more additional agents, sufficient to produce the desired effect. It will be understood that the parameters of the unit dosage form will depend on the specific agent and the effect to be achieved.

[0398] Reagent test kit

[0399] The present invention also contemplates kits comprising the compounds described herein and pharmaceutical compositions thereof. A kit is generally in the form of a physical structure housing various components, as described below, and can be used, for example, to practice the methods described above.

[0400] The kit may include one or more of the compounds disclosed herein (provided in, for example, a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein may be provided in a ready-to-use form (e.g., tablets or capsules) or in a form (e.g., powder) that requires, for example, reconstitution or dilution prior to administration. When the compound described herein is in a form that requires reconstitution or dilution by the user, the kit may also include a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, etc. that is packaged together with the compound described herein or packaged separately from the compound described herein. When considering combination therapy, the kit may include several agents separately, or they may have been combined in a kit. Each component of the kit may be encapsulated in a separate container, and all the various containers may be in a single package. The kit of the present invention may be designed for appropriately maintaining the conditions necessary for the components contained therein (e.g., refrigeration or freezing).

[0401] The kit may contain a label or package insert that includes identification information of the components and their instructions for use (e.g., dosing parameters, clinical pharmacology of one or more active ingredients, including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or insert may include manufacturer information, such as batch number and expiration date. The label or package insert may, for example, be integrated into the physical structure that houses the components, be separately contained within the physical structure, or be affixed to a component of the kit (e.g., an ampoule, tube, or vial).

[0402] The label or insert may additionally include or be incorporated into a computer-readable medium such as a magnetic disk (e.g., hard disk, card, memory disk), an optical disk (e.g., CD- or DVD-ROM / RAM), a DVD, an MP3, a magnetic tape, or an electronic storage medium (e.g., RAM and ROM), or a mixture of these (e.g., magnetic / optical storage media, FLASH media, or memory-type cards). In some embodiments, the actual instructions are not present in the kit, but a means for obtaining the instructions from a remote source, e.g., via the Internet, is provided.

[0403] experiment

[0404] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the invention and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments were performed or that they are all that could be performed. It should be understood that the exemplary descriptions written in the present tense are not necessarily to be performed, but rather can be performed to generate data, etc., of the properties described therein. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be accounted for.

[0405] Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius (° C.), and pressure is at or near atmospheric. Standard abbreviations are used, including the following: wt = wild type; bp = base pair; kb = kilobase; nt = nucleotide; aa = amino acid; s or sec = second; min = minute; h or hr = hour; ng = nanogram; μg = microgram; mg = milligram; g = gram; kg = kilogram; dl or dL = deciliter; μl or μL = microliter; ml or mL = milliliter; l or L = liter; μM = micromolar; mM = millimolar; M = molar; kDa = kilodalton ; im = intramuscular (by injection into the muscle); ip = intraperitoneal (by injection into the peritoneum); SC or SQ = subcutaneous (by injection under the skin); QD = once a day; BID = twice a day; 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.

[0406] Materials and methods

[0407] Where indicated, the following general materials and methods were used in the examples below:

[0408] Standard methods in molecular biology are described in the scientific literature (see, e.g., Sambrook and Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; and Ausubel et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, NY, which describe cloning and DNA mutagenesis in bacterial cells (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4)).

[0409] The scientific literature describes methods for protein purification, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization, as well as chemical analysis, chemical modification, post-translational modification, production of fusion proteins, and glycosylation of proteins (see, e.g., Coligan et al. (2000) Current Protocols in Protein Science, Vols. 1-2, John Wiley and Sons, Inc., NY).

[0410] Where the literature contains assays or experimental procedures, such assays or procedures may be used as an alternative basis for evaluating the compounds described herein.

[0411] All reactions are carried out at the indicated temperature using a magnetic stirring bar coated with Teflon, and are carried out under an inert atmosphere when explained. By TLC (silica gel 60 with fluorescence F254, which is visualized with a shortwave / longwave UV lamp) and / or LCMS (Agilent 1100 series LCMS, using a binary solvent system [the MeCN / containing 0.1% TFA containing H2O] at 254nm using any one of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6mm idx 100mm] carries out UV detection) monitoring reaction. Use an automated system (CombiFlash RF+ manufactured by Teledyne ISCO) to carry out flash chromatography on silica gel, and the detection wavelength is 254 and 280nm. Reverse phase preparative HPLC is carried out on Agilent 1260 Infinity series HPLC. The samples were eluted using a binary solvent system (0.1% TFA in MeCN / 0.1% TFA in H2O) on a Gemini C18 The HPLC-MS / MS was used to determine the product. The HPLC-MS / MS was used to determine the product. The HPLC-MS / MS was used to determine the product. Gradient elution was performed on a column (21.2 mm idx 250 mm) and detected at 254 nm. The final compound obtained by preparative HPLC was concentrated. Unless otherwise noted, the yield reported is the yield of separation. As measured by LCMS (Agilent 1100 Series LCMS, using a binary solvent system [MeCN containing 0.1% TFA / H containing 0.1% TFA O] using the following column: Agilent Eclipse Plus C18 column [3.5 μm, 4.6 mm idx 100 mm]) with UV detection at 254 nm), all compounds measured were purified to >= 95% purity. 1 H 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 residual undeuterated solvent as an internal reference. Example

[0412] Example 1: 2-Chloro-3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-6-methanesulfonylbenzonitrile

[0413]

[0414] Step a: 6,8-difluoro-1,2,3,4-tetrahydronaphthalene-1-one (500mg, 2.74mmol) was dissolved in CHCl (11ml, 0.25M) and the resulting solution was sparged with nitrogen for 5 minutes. Triethylamine (574μL, 1.5 equivalents) was added, and the solution was cooled to 0°C, followed by the addition of TfO (691μL, 1.5 equivalents). The reaction was warmed to room temperature and stirred overnight. The solution was quenched with water, extracted with CHCl, and the resulting organic matter was dried over NaSO and concentrated onto celite. The crude material was flash chromatographed on silica gel (gradient, 0% to 20% ethyl acetate in hexane) to obtain the desired 5,7-difluoro-4-(trifluoromethylsulfonyloxy)-1,2-dihydronaphthalene (470mg, 54% yield), which was an oil.

[0415] Step b: A vial was filled with the alkenyl triflate (2.50 g, 7.96 mmol, 1.0 eq.) of step a, PdCl(dppf) (872 mg, 1.19 mmol, 15 mol%), Bpin (2.82 g, 11.1 mmol, 1.4 eq.), KOAc (1.72 g, 17.5 mmol, 2.2 eq.) and 1,4-dioxane (20 ml). The vial was capped and the reaction mixture was purged with N for 2 minutes. The reaction was heated at 80 ° C and stirred for 30 minutes. The reaction was cooled, filtered, and concentrated to celite. Alkenyl pinacol boronate was obtained by flash chromatography (SiO, hexane to 10% EtOAc) as a brown oil (1.16 g, 3.97 mmol, 50%).

[0416] Step c: To a vial containing the product of step b (100 mg, 0.342 mmol, 1.0 eq) was added 3-bromo-2-chloro-6-(methylsulfonyl)benzonitrile (100 mg, 0.342 mmol, 1.0 eq), PdCl2(dppf) (25 mg, 0.034 mmol, 10 mol%), 1,4-dioxane (1 mL) and 1 M Na2CO3 aqueous solution (0.7 mL). The vial was capped and purged with N2 for 2 minutes. The reaction was heated at 80 ° C and stirred for 1.5 h. Once complete, the reaction was cooled, diluted with saturated NH4Cl 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 organic layers were combined, washed with brine (40 mL), and dried over MgSO4. Concentration under reduced pressure and purification by flash chromatography (SiO2, hexanes to 50% EtOAc gradient) gave the cross-coupled product as a white solid which was carried to the next step (58.6 mg, 0.154 mmol, 45%, C 18 H 12 ESIMS of ClF2NO2S[M+H]+ , calculated value 380.0, measured value 380.1).

[0417] Step d: Pd / C (10%Pd, 25mg) is added to the bottle comprising the product (58.6mg, 0.154mmol, 1.0 equivalent) of step c. The bottle is evacuated and back-filled (× 3) with N. MeOH (1mL) and EtOAc (1mL) are added, and the reaction mixture is purged with H for 2 minutes, then stirred for 16h at room temperature at 1atm H. The reaction vessel is purged with N and the mixture is filtered through diatomite, cleaned with EtOAc. Under reduced pressure, concentrated and obtained by preparative reverse-phase HPLC purification (20 to 100% gradient of acetonitrile and water, with 0.1% TFA), it is a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.95 (d, J=8.2Hz, 1H), 7.31 (d, J=8.2Hz, 1H), 7.10–6.98 (m, 2H), 4.79–4.72 (m, 1H), 3.43 (s, 3 H), 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 H 14 ESIMS of ClF2NO2S[M+H] + , calculated value 382.0, measured value 382.1.

[0418] Example 2a / b: (1S,2R)-4-[R-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol

[0419]

[0420] Step a: bromine (3.58ml, 70mmol, 1.05 equivalents) was added dropwise to a suspension of 7-fluoro-2,3-dihydro-1H-indene-1-one (10.0g, 66.6mmol) and aluminum chloride (22.2g, 166.5mmol, 2.5 equivalents) in 1,2-dichloroethane (190ml, 0.35M). The resulting solution was heated to 60°C for three hours, 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% to 10% ethyl acetate in a 1:1 solution of hexane) to obtain 4-bromo-7-fluoro-2,3-dihydro-1H-indene-1-one.

[0421] Step b: To a suspension of 4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one (17.0 g, 74.3 mmol) and CsCO (26.6 g, 81.7 mmol, 1.1 equiv) in DMF (372 ml, 0.2 M) was added benzyl mercaptan (9.24 g, 8.71 ml, 1.0 equiv). The reaction was stirred at room temperature for 90 minutes. The desired product was precipitated from the solution by adding 1.5 L of water and dried under high vacuum overnight. The resulting crude product (23.1 g, 93% yield) was carried to the next step without further purification.

[0422] Step c: The crude thioether (23.1 g, 69.2 mmol) from step b was suspended in toluene (692 ml, 0.1 M). Aluminum chloride (10.2 g, 1.1 equivalents) was added at room temperature. An additional portion of aluminum chloride (3.6 g, 27 mmol, 0.4 equivalents) was added three hours later. After another 3 hours, the reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in a 1:3 solution of CH2Cl2 in hexane) to obtain the desired thiophenol as a yellow solid (13.4 g, 80% yield).

[0423] Step d: the solution of the thiophenol product (6.7g, 27.6mmol) and methyl viologen dichloride hydrate (710mg, 0.1 equivalent) in DMF (55ml, 0.5M) of step c is carefully degassed by three freeze-thaw pump cycles under nitrogen. The resulting solution is cooled to -10 to -5°C in a salt water ice bath, and excessive CF3I is bubbled through the reaction mixture. The reaction is then stirred in CF3I atmosphere overnight. The reaction is carefully quenched with water at room temperature (residual CF3I exhaust occurs, use caution), extracted with ethyl acetate, and concentrated. The crude material is purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexane) to obtain required thioether (5.21g, 61% yield).

[0424] Step e: to the product of step d (10.45g, 33.6mmol) in MeCN (129ml, 0.26M, relative to starting material), CCl4 (129ml, 0.26M, relative to starting material) and H2O (258ml, 0.13M, relative to starting material) solution in add ruthenium trichloride (697mg, 3.36mmol, 0.1 equivalent), then add sodium periodate (29.6g, 138.4mmol, 4.12 equivalent). The reaction was stirred at room temperature for 1 hour and extracted with CH2Cl2 (×2) after completion. The combined organics were washed with saturated Na2S2O3, washed with brine, dried over sodium sulfate, and then concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate, in CH2Cl2 in 1:3 solution in hexane) to obtain the product sulfone as a white solid (10.53g, 91% yield). 10 ESIMS of H6BrF3O3S[M+H] + ; Calculated value 342.9, measured value 342.9.

[0425] Step f: the product sulfone (3.5g, 10.2mmol) of step e and Selectfluor (4.32g, 12.2mmol, 1.2 equivalents) solution in methanol (102ml, 0.1M) is heated to 50 ℃.Add sulfuric acid (27 μ l, 5mol%), and react and stir 48 hours at 50 ℃.Then solution is diluted with ether, and gained white precipitate is filtered off and discarded.This organic solution is concentrated, and thick material passes through flash chromatography purification (silica gel, 0% to 10% ethyl acetate, at CH Cl In 1: 3 solution in hexane) to obtain product dimethyl acetal, it is white solid (3.57g, 87% productive rate).

[0426] Step g: A solution of the product acetal from step f (3.18 g, 7.8 mmol) and wet Amberlyst 15 (4.77 g, 150 wt%) in dioxane (31 ml, 0.2 M) was heated to 90° C. overnight. Upon completion, the polymeric beads were removed by filtration, and the concentrated crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in a 1:3 solution of CHCl in hexanes) to give the desired fluorinated ketone (2.33 g, 83% yield).

[0427] Step h: A solution of the 2,3-dihydro-1-indanone product of step g (2.5 g, 6.93 mmol) in dichloromethane (28 ml, 0.25 M) was sparged with nitrogen, and then formic acid (783 μL, 956 mg, 20.8 mmol, 3 eq) and triethylamine (1.94 ml, 1.41 g, 13.9 mmol, 2 eq) were added at 0° C. under nitrogen. RuCl(p-cymene)[(R,R)-Ts-DPEN] (44.5 mg, 0.07 mmol, 0.01 eq) was added and the reaction was stirred at 0 to 5° C. for a minimum of 12 hours. Upon complete conversion, the reaction was quenched with saturated NaHCO and extracted with CH Cl. The combined organics were concentrated and the crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in 1:1 solution of CHCl:hexanes) to give the desired indanol (2.0 g, 80% yield) as a single diastereomer. The enantiomeric excess of this material was determined to be 98% by chiral HPLC (Chiralpak AD-H, 20% iPrOH / hexanes, isocratic, 20 minutes) compared to the racemic sample. It was obtained by reduction of 2-fluoro-2,3-dihydro-1-indanone with sodium borohydride.

[0428] Step i: To a solution of the chiral indanol from step h (1.01 g, 2.75 mmol) in CHCl (11 ml, 0.25 M) was added 2,6-lutidine (800 μL, 6.9 mmol, 2.5 eq) and TBSOTf (791 μL, 3.44 mmol, 1.25 eq) at 0°C. The reaction was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction was concentrated directly onto celite and purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in hexanes) to afford TBS ether (1.35 g, 100% yield).

[0429] Step j: The TBS ether product of step i (674 mg, 1.41 mmol) was mixed with B2Pin2 (457 mg, 1.8 mmol, 1.3 eq), Pd(dppf)Cl2 (103 mg, 0.14 mmol, 0.1 eq) and potassium acetate (213 mg, 3 mmol, 2.2 eq) in dioxane (14 ml, 0.1 M) and the resulting solution was heated to 100° C. for three hours. The reaction solution was concentrated and the crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to give the desired boronic acid pinacol ester (638 mg, 86% yield) as a colorless oil.

[0430] Step k: The boronate product from step j (1.64 g, 3.13 mmol) was mixed with 5,7-difluoro-4-(trifluoromethylsulfonyloxy)-1,2-dihydronaphthalene (1.18 g, 3.75 mmol, 1.2 eq), Pd(dppf)Cl (227 mg, 0.31 mmol, 0.1 eq) and sodium carbonate (2 M, aq., 3.13 ml, 2.0 eq) in dioxane (31 ml, 0.1 M) and heated to 75° C. for three hours. Upon completion, the reaction was concentrated to celite and purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexanes) to give the desired olefin product (1.42 g, 86% yield) as a colorless resin.

[0431] Step 1: 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 allowed to warm to ambient temperature. After 2 hours, the reaction was concentrated onto celite and purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexanes) to give the free indanol (1S,2R)-4-(6,8-difluoro-3,4-dihydronaphthalen-1-yl)-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol (33.7 mg, 37% yield). 1 H NMR (400MHz, CDCl3): δ7.92 (d, J=8.1Hz, 1H), 7.49 (d, J=8.1Hz, 1H), 6.81 (d, J=8.3Hz , 1H), 6.56 (ddd, J=11.3, 8.7, 2.6Hz, 1H), 6.15 (dd, J=4.9, 4.9Hz, 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 ESIMS of F6O3S[M+Na] + ; Calculated value 471.0, measured value 471.0.

[0432] Step m: The product of step 1, indanol, was dissolved in methanol (700 μL, 0.1 M) and added to palladium on carbon (3 mg, 10% Pd by weight) under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere at 55 psi and stirred overnight in a Parr shaker. The resulting diastereomers were separated by column chromatography (silica gel, 100% toluene) to give (1S, 2R)-4-[R-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol (Example 2a), which is the less polar diastereomer.1 H NMR (400MHz, CDCl3): δ7.76 (d, J=8.1Hz, 1H), 6.98 (d, J-8.1Hz, 1H), 6.75 (br d, J=10.0Hz, 1H), 6.58 (dd, J=9.8Hz, 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=4.1Hz, 1H), 2.94-2.78 (m, 2H), 2.17-2.07 (m, 1H), 1.78-1.67 (m, 2H). C 20 H 16 ESIMS of F6O3S[M+Na] + ; Calculated value 473.1, found value 473.1. (1S,2R)-4-[S-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol (Example 2b) was separated as the more polar diastereomer. 1 H NMR (400MHz, CDCl3): δ7.75 (d, J=8.3Hz, 1H), 6.92 (d, J=8.3Hz, 1H), 6.79-6.72 (m, 1H), 6.62-6.54 (m, 1H), 5.60 (td, J=5.0, 3.7Hz, 1 H), 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 ESIMS of F6O3S[M+Na] + ; Calculated value 473.1, measured value 473.1.

[0433] Example 3: (1S,2R)-4-[(1S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl]-2-fluoro-7-methanesulfonyl-2,3-dihydro-1H-indene-1-ol

[0434]

[0435] The title compound was synthesized in a similar manner to Example 2. 1H 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, 52.4Hz, 1H), 4.32 (m, 1H), 3.59 (dd, J=4.4, 1.4Hz, 1H), 3.31 (dd, J=21.2, 4.9Hz, 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 ESIMS of F3O3S[M-H2O+H] + Calculated value 379.1, measured value 379.1.

[0436] Example 4: (1S,2R)-4-[(1R)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl]-2-fluoro-7-methanesulfonyl-2,3-dihydro-1H-indene-1-ol

[0437]

[0438] The title compound was synthesized in a similar manner to Example 2. 1 H NMR (400 MHz, chloroform-d) δ 7.70 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 9.1 Hz, 1H), 6.56 (ddd, J = 2.4, 9.1, 18.0 Hz, 1H), 5.65 (dt, J = 4.8, 14.4 Hz, 1H), 5.49–5.31 (m, 1H). ), 4.36 (m, 1H), 3.66 (dd, J=5.1, 1.8Hz, 1H), 3.40 (ddd, J=21.6, 16.9, 3.2Hz, 1H), 3.2 5(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 ESIMS of F3O3S[M-H2O+H] + Calculated value 379.1, measured value 379.1.

[0439] 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

[0440]

[0441] Step a: A solution of 6,8-difluoro-1,2,3,4-tetrahydronaphthalene-1-one (7 g, 38.4 mmol) and TMSONa (14.8 g, 115.3 mmol) in dioxane (128 mL) was refluxed under a nitrogen atmosphere for 20 minutes. After the starting material disappeared (TLC analysis, 30% EtOAc in hexane as eluent, the desired product point was the least polar), the mixture was cooled to room temperature and poured into a saturated aqueous solution of NH4Cl (200 mL). The product was extracted with EtOAc (3×70 mL). The combined extracts were washed with brine (200 mL). The organic phase was separated and dried over Na2SO4. After all solvents were removed under reduced pressure, the crude product was purified by flash chromatography (SiO 2 , hexane / EtOAc gradient) to afford 8-hydroxy-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one as a yellow solid (4.7 g, 26.1 mmol, 68% yield). 1 H NMR (400MHz, CDCl3) δ12.74 (d, J=1.5Hz, 1H), 6.45 (dd, J=10.4, 2.5Hz, 1H), 6.41 (dd d, J=9.1, 2.3, 1.2Hz, 1H), 2.93-2.82 (m, 2H), 2.71-2.60 (m, 2H), 2.14-1.99 (m, 2H). 19 F NMR (376MHz, CDCl3) δ-98.95 (t, J=9.7Hz).

[0442] Step b: 8-hydroxy-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (5.3g, 29.4mmol), triethylamine (5.3mL, 38.2mmol) and LiCl (1.6g, 38.2mmol) in dichloromethane (150mL) are cooled to 0 ℃.Trifluoromethanesulfonic anhydride (6.4mL, 38.2mmol) is added dropwise over 10 minutes.The mixture is stirred for 30 minutes, and then TLC analysis (30% EtOAc in hexane as eluent) observes that starting material disappears completely.Then the reaction is diluted with dichloromethane (50mL) and subsequently washed with NaHCO saturated aqueous solution (150mL), 1M HCl aqueous solution (100mL) and salt solution (150mL).The organic phase is separated and dried over Na SO Drying. After all solvents were removed under reduced pressure, the crude product was purified by flash chromatography (SiO 2 , hexanes / EtOAc gradient) to afford trifluoromethanesulfonic acid 8-oxo-6-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl ester as a yellow oil (8.1 g, 25.9 mmol, 88% yield). 1 H NMR (400MHz, CDCl3) δ7.03 (ddt, J=8.3, 2.5, 0.9Hz, 1H), 6.86 (dd, J=8.3, 2.5Hz, 1H), 3.10–2.87 (m, 2H), 2.84–2.58 (m, 2H), 2.30–2.07 (m, 2H). 19 FNMR (376MHz, CDCl3) δ -73.66, -100.52 (t, J=8.5Hz).

[0443] Step c: A mixture of 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 ) 4 (3.0 g, 0.26 mmol) in DMF (65 mL) was heated at 100 ° C under a nitrogen atmosphere for 3 hours. Once TLC analysis (30% EtOAc in hexane as eluent) observed complete disappearance of the starting material, 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 pad of celite. The organic phase was separated and the aqueous solution was further extracted with EtOAc (2×50 mL). The combined organic phases were washed with water (2×150 mL) and brine (100 mL), dried over Na 2 SO 4 and concentrated to dryness. The dried 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. 1H NMR (400MHz, CDCl3) δ7.37 (ddt, J=8.0, 2.6, 0.6Hz, 1H), 7.19 (ddt, J=8.3, 2.6, 0.9Hz, 1H), 3.09–2.90 (m, 2H), 2.87–2.65 (m, 2H), 2.31–2.06 (m, 2H). 19 F NMR (376MHz, CDCl3) δ-103.48 (t, J=8.2Hz).

[0444] Step d: A solution of N-phenyl-bis(trifluoromethanesulfonyl imide) (11.3 g, 31.6 mmol) and 8-cyano-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (4.0 g, 21.1 mmol) in THF (105 mL) was cooled to -78 ° C in a nitrogen atmosphere. A 1 M solution of LiHMDS in THF (21.1 mmol, 21.1 mL) was then added dropwise over 5 minutes. The resulting light brown solution was stirred at -78 ° C for another 5 minutes and transferred to an ice bath. After 30 minutes at 0 ° C, TLC analysis showed that the starting material was completely consumed. The reaction was quenched by adding NH4Cl aqueous solution (10 mL), which was then diluted with water (150 mL) and EtOAc (150 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 × 80 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated to dryness. The dried residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to afford 8-cyano-6-fluoro-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (6.74 g, 21.0 mmol, 99% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.28 (dd, J=8.0, 2.6Hz, 1H), 7.17 (ddt, J=8.1, 2.6, 0.9Hz, 1H), 6.30 (dd, J=5.4, 4.8Hz, 1H), 2.94–2.80 (m, 2H), 2.61–2.40 (m, 2H). 19 F NMR (376MHz, CDCl3) δ -72.31, -109.26 (t, J=8.0Hz).

[0445] 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. Pd(dppf)Cl (62 mg, 0.084 mmol) and aqueous sodium carbonate (2 M solution, 0.84 ml, 1.68 mmol) were then added sequentially. The mixture was degassed under vacuum, backfilled with nitrogen, and heated at 90° C. for 1 hour. Upon completion, the reaction was concentrated to celite and fractionated by column chromatography (SiO2, hexanes / EtOAc gradient) to give the desired olefin product (0.401 g, 0.7 mmol, 84% yield) as a white foam. 1 H NMR (400 MHz, CDCl 3， Mixture of atrop isomers) δ 7.98–7.86 (m, J = 17.7, 8.2 Hz, 1H), 7.63–7.57 (m, 0.3H), 7.43–7.33 (m, 0.7H), 7.22 (dd, J = 8.5, 2.6 Hz, 1H), 7.18–7.08 (m, 1H), 6.44–6.36 (m, 1H), 5.64–5.56 (m, 1H), 5.09–4.71 (m, 1H), 3.34–3.19 (m, 0.7H), 3.01–2.71 (m, 3H), 2.61–2.25 (m, 2.3H), 0.84 (s, 9H), 0.28–0.07 (m, 6H). 19 F NMR (376MHz, CDCl3) δ -78.81, -111.26 (t, J=7.7Hz), -111.52 (t, J=8.2Hz), -195.20 (dd, J=51.0, 11.8Hz), -195.85 (dd, J=50.9, 10.3Hz).

[0446] Step f: under nitrogen atmosphere, the product of step e (0.25g, 0.44mmol) was dissolved in anhydrous methanol (15mL) and added to palladium / carbon (125mg, 10% Pd weight). The reaction mixture was placed in a hydrogen atmosphere with 55psi and stirred in a Parr shaker for 4 hours. Excess hydrogen was discharged and the mixture was degassed in vacuo and backfilled with nitrogen to remove residual hydrogen. The gained suspension was filtered through a diatomaceous earth pad, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude epimer mixture (1:2dr). The crude mixture of step f was subjected to column chromatography (SiO , hexane / EtOAc gradient) to generate two epimers of the desired product. (R)-epimer (the more polar product, 70mg, 0.12mmol, 28% yield): 1 H NMR (400MHz, CDCl3) δ7.70 (d, J=8.2Hz, 1H), 7.20–7.11 (m, 2H), 6.72 (d, J=8.3Hz, 1H), 5.62 (d, J=4. 3Hz, 1H), 5.01 (dddd, J=51.2, 8.8, 6.9, 4.3Hz, 1H), 4.58 (dd, J=6.3, 3.0Hz, 1H), 3.61 (dddd, J=14.8 , 12.5, 8.8, 1.0Hz, 1H), 3.18 (dd, J=14.8, 6.9Hz, 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=2.6Hz, 3H), 0.13 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -78.71, -112.94 (t, J = 8.2 Hz), -196.32 (dd, J = 51.1, 12.8 Hz). (S)-epimer (less polar product, 120 mg, 0.21 mmol, 48% yield): 1H NMR (400MHz, CDCl3) δ7.70 (d, J=8.3Hz, 1H), 7.21–7.07 (m, 2H), 6.69 (d, J=8.3Hz, 1H), 5.63 (d, J=4. 2Hz, 1H), 5.03 (dddd, J=51.2, 8.3, 6.8, 4.3Hz, 1H), 4.55 (dd, J=6.5, 3.3Hz, 1H), 3.47 (dddd, J=14.9, 7.0, 1.5Hz, 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=2.3Hz, 3H), 0.15 (s, 3H). 19 F NMR (376MHz, CDCl3) δ -78.50, -112.92 (t, J=8.2Hz), -194.99 (dd, J=51.1, 12.6Hz).

[0447] Step h: A solution of the product of step f (8R-epimer, 70 mg, 0.122 mmol) in CH3CN (2 mL) was placed in a 3 mL vial equipped with a magnetic stirrer, and HF·Py complex (hydrogen fluoride 70%, pyridine 30%, 0.2 mL) was added. The resulting colorless solution was stirred overnight at ambient temperature. After TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (20 mL) and 1 M aqueous HCl (20 mL). The product was extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated to dryness. The residue was fractionated by column chromatography (SiO2, 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. 1H NMR (400MHz, CDCl3) δ7.75 (d, J=8.2Hz, 1H), 7.21–7.13 (m, 2H), 6.77 (d, J=8.2Hz, 1H), 5.56 (q, J=5.1Hz, 1H), 5.32 (dtd, J=51.2, 6.4, 5.2Hz, 1H), 4 .59 (dd, J=6.3, 3.2Hz, 1H), 3.62 (dddd, J=17.9, 16.1, 6.3, 1.0Hz, 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 (376MHz, CDCl3) δ -77.60, -112.71, -200.62 (dddd, J=51.2, 16.8, 10.9, 5.5Hz). C 21 H 16 ESIMS of F5NO3S[M+Na] + ; Calculated value 480.1, measured value 480.1

[0448] 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

[0449]

[0450] This compound was prepared from the corresponding TBS-protected S-epimer of 1-indanol (150 mg, 0.262 mmol) and 0.4 mL 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 (400MHz, CDCl3) δ7.74 (d, J=8.2Hz, 1H), 7.23–7.05 (m, 2H), 6.70 (d, J=8.2Hz, 1H ), 5.61 (dddd, J=6.1, 5.1, 3.9Hz, 1H), 5.37 (dddd, J=51.4, 6.6, 6.0, 5.1Hz, 1H), 4.56 (dd, J=6.4, 3.1Hz, 1H), 3.65–3.49 (m, 1H), 3.47–3.27 (m, 1H), 3.17 (dd, J=3.9, 0.7H z, 1H), 3.08–2.69 (m, 2H), 2.30–2.09 (m, 1H), 1.98–1.86 (m, 1H), 1.83–1.64 (m, 2H). 19F NMR (376MHz, CDCl3) δ -77.73, -112.69, -200.05 (dddd, J=51.2, 18.3, 12.2, 6.2Hz). C 21 H 16 ESIMS of F5NO3S[M+Na] + ; Calculated value 480.1, measured value 480.1

[0451] Example 7: (8S)-3-Fluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0452]

[0453] The title compound was synthesized in a similar manner to Example 5. 1 H NMR (400MHz, CDCl3) δ7.69 (dd, J=8.1, 0.8Hz, 1H), 7.21–7.11 (m, 2H), 6.60 (d, J=8.1Hz, 1H), 5.66 (dddd, J=13.0, 5.5, 4.9, 0.5Hz, 1H), 5.40 (dddd, J=52.6, 5.7, 4.9, 3.6Hz, 1H) , 4.56 (dd, J=6.2, 2.9Hz, 1H), 3.72–3.40 (m, 2H), 3.26 (s, 3H), 3.15 (ddd, J=23.3, 17.0, 5.8Hz, 1H), 3.03–2.90(m, 1H), 2.91–2.77(m, 1H), 2.19–2.04(m, 1H), 1.85–1.57(m, 3H). 19 F NMR(376MHz, CDCl3)δ-113.22, -199.17.C 21 H 19 ESIMS of F2NO3S[M+Na] + ; Calculated value 426.1, measured value 426.1

[0454] 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

[0455]

[0456] Step a: At 0 ° C, 2,6-di-tert-butylmethylpyridine (1.17 g, 5.69 mmol, 2.1 equivalents) was added dropwise to a solution of 5,7-difluorochroman-4-one (500 mg, 2.71 mmol) in CH2Cl2 (12 mL, 0.2 M), followed by trifluoromethanesulfonic anhydride (860 μL, 5.14 mmol, 1.9 equivalents). The reaction was stirred at 0 ° C for 1 h, then warmed to room temperature and kept for another 1 h. At this point, hexane (5 mL) was added to precipitate the pyridinium salt and the reaction mixture was filtered through a celite pad. The solvent was removed in vacuo and the crude residue was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexane) to obtain the desired trifluoromethanesulfonic acid vinyl ester (754 mg, 88%) as a yellow oil. 10 ESIMS of H5F5O4S[M+H] + Calculated value 316.9, measured value 317.2.

[0457] Step b: The title compound was synthesized in a manner similar to Example 1. 1 H NMR (400MHz, CDCl3) δ7.85 (d, J=8.2Hz, 1H), 7.17 (d, J=8.2Hz, 1H), 6.59–6.45 (m, 1H), 6.45–6.35 (m, 1H), 5.60 (dd, J=6.6, 5.1Hz, 1H), 5.51–5.2 2(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 ESIMS of F6O4SNa[M+Na] + Calculated value 475.0, measured value 475.0.

[0458] Example 9: 1-[2,2-difluoro-7-(methylsulfonyl)-4-indanyl]-6-fluoro-1,2,3,4-tetrahydronaphthalene

[0459]

[0460] The title compound was synthesized in a similar manner to Example 1. 1H NMR (400 MHz, methanol-d4) δ 7.78 (dt, J = 8.1, 1.7 Hz, 1H), 7.13 (dd, J = 15.1, 8.1 Hz, 1H), 6.89 (ddd, J = 9.8, 2.7, 1.1 Hz, 1H), 6.83–6.64 (m, 2H), 5.56–5.49 (m, 1H), 4.32–4.25 (m, 1H), 3.63–3.06 (m, 3H), 2.97–2.78 (m, 2H), 2.21–2.06 (m, 1H), 1.97–1.76 (m, 1H), 1.80–1.68 (m, 1H). 20 H 19 F3O3 S ESIMS[M+H] + , calculated value 380.4, measured value 380.1.

[0461] Example 10: 1-(2-chloro-3-cyano-4-trifluoromethanesulfonylphenyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0462]

[0463] Step a: A suspension of 3-bromo-2-chloro-6-fluorobenzaldehyde (25 g, 105.3 mmol), NH2OH×HCl (8.8 g, 126.4 mmol, 1.2 eq) and NaOAc (10.4 g, 126.4 mmol, 1.2 eq) in anhydrous EtOH (100 mL) was stirred at reflux overnight. The reaction was cooled to room temperature, evaporated and the residue diluted with H2O (300 mL). The white solid was filtered off, washed with H2O and dried under vacuum (24.3 g, 91%). The crude product was used in the next step without further purification. ESI MS [M+H] of C7H4BrClFNO + , calculated value 251.9, measured value 251.9.

[0464] Step b: The oxime from step a was diluted with acetic anhydride (150 mL) and stirred at 120°C overnight, then cooled and concentrated in vacuo to give a brown solid (22.5 g, 99%). The crude product was used in the next step without further purification.

[0465] Step c: The product of step b (20 g, 85.3 mmol) was dissolved in anhydrous DMF (100 mL), cooled to 0° C. and anhydrous Na2S (6.6 g, 85.3 mmol) was added in one portion. The reaction mixture was stirred at 0° C. for 2 h, then quenched with H2O (500 mL) and extracted with CH2Cl2 (3×200 mL). The organics were discarded and the aqueous layer was neutralized with 10% KHSO4 solution to pH~2 and extracted again with CH2Cl2 (3×150 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was used in the next step without further purification (19.1 g, 90%). ESIMS [MH] of C7H3BrClNS - , calculated value 245.9, measured value 245.9.

[0466] Step d: The product of step c (33.6 g, 135.2 mmol) was dissolved in anhydrous DMF (300 mL) and paraquat dichloride hydrate (3.5 g, 13.5 mmol, 10% mol.) was added. The mixture was cooled to 0 ° C and trifluoroiodomethane × TMG reagent (33.6 mL, 162.2 mmol, 1.2 equivalents) was added, followed by TEA (18.8 mL, 135.2 mmol). The reaction was stirred at 0 ° C for 15 minutes. It was then warmed to room temperature and stirred overnight. It was quenched with H2O (1500 mL) and extracted with EtOAc (3 × 300 mL). The combined organics were washed with brine (2 × 100 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex → 30% EtOAc in hexane) to obtain the product as a yellow solid (19.3 g, 45%).

[0467] Step e: The product of step d (18.5 g, 58.4 mmol) was dissolved in CH2Cl2:CH3CN:HO (1:1:2; 300 mL) and NaIO4 (50 g, 233.6 mmol, 4 equiv) was added followed by RuCl3×HO (394 mg, 1.75 mmol, 3% mol.). The reaction was stirred at room temperature for 1.5 h then diluted with HO (1000 mL) and 10% Na2S2O3 solution (100 mL) and extracted with EtOAc (3×300 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex→40% EtOAc in hexane) to give the product as a white solid (19.4 g, 95%). 1 H NMR (400MHz, CDCl3) δ8.17 (d, J=8.6Hz, 1H), 7.98 (d, J=8.6, 1H).

[0468] Step f: A mixture of 8-bromo-6-fluoroquinoline (15.7 g, 69.5 mmol), Zn(CN) (4.9 g, 41.7 mmol, 0.8 equiv) and Pd(PPh) (8 g, 6.9 mmol, 10% mol) in anhydrous DMF (100 mL) was stirred at 100° C. overnight. The reaction was then cooled to room temperature and diluted with H O (500 mL). The yellow solid was filtered off, washed with H O and dried in vacuo. The crude product was used in the next step without further purification.

[0469] Step g: the product of step f is placed in a Parr bottle and dissolved in MeOH (300mL) and concentrated HCl (50mL). The mixture is purged with N and PtO (1.56g, 6.9mmol, 10%mol) is added. The reaction is vibrated in H atmosphere (50psi) for 5h, then filtered through diatomite, washed with MeOH and evaporated. The crude residue is purified by column chromatography (silica gel, hex → 30% EtOAc in hexane) to obtain the product as a yellow solid (5.9g, 48% over 2 steps). 1 H NMR (400MHz, CDCl3) δ6.90–6.81(m, 2H), 4.63(brs, 1H), 3.41-3.33(m, 2H), 2.77–2.68(m, 2H), 1.96–1.85(m, 2H).

[0470] Step h: A mixture of the bromide from step g (200 mg, 0.57 mmol), tetrahydroquinoline from step g (100 mg, 0.57 mmol), Pd(OAc)2 (25 mg, 0.22 mmol, 20% mol.), rac-BINAP (87 mg, 0.14 mmol, 25% mol.) and Cs2CO3 (372 mg, 1.14 mmol, 2 eq.) in anhydrous degassed toluene (2 mL) was stirred at 100° C. for 5 h. The entire reaction mixture was loaded onto a silica gel column and purified by column chromatography (silica gel, hex→30% EtOAc in hexane) to give the product as a yellow solid (44 mg, 17%). 1 H NMR (400MHz, CDCl3) δ8.02 (d, J=8.7Hz, 1H), 7.34 (d, J=8.7Hz, 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 ESIMS of ClF4N3O2S[M+H] + , calculated value 444.0, measured value 444.0.

[0471] Example 11: 1-(2-chloro-3-cyano-4-methanesulfonylphenyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0472]

[0473] Step a: A solution of 3-bromo-2-chloro-6-fluorobenzonitrile (5 g, 21.3 mmol) in anhydrous CHCN (100 mL) was cooled to 0°C, and CHSNa (1.64 g, 23.4 mmol, 1.1 equiv) was added in one portion. The mixture was stirred at 0°C for 15 minutes. The cooling bath was then removed, and the reaction was stirred at room temperature overnight. The mixture was diluted with HO (300 mL) and the product was filtered off (white solid, 4.6 g, 82%).

[0474] Step b was carried out in a manner similar to Example 10. 1 H NMR (400MHz, CDCl3) δ 8.07 (d, J=8.5Hz, 1H), 7.95 (d, J=8.5Hz, 1H), 3.30 (s, 3H).

[0475] Step c was carried out in a similar manner to Example 10 (brown solid, 3.5 mg, 1%). 1 H NMR (400MHz, CDCl3) δ7.99 (d, J=8.5Hz, 1H), 7.29 (d, J=8.5Hz, 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 ESIMS of ClFN3O2S[M+H] + , calculated value 390.0, measured value 390.0.

[0476] Example 12: 2-Chloro-3-(8-chloro-6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-6-trifluoromethanesulfonylbenzonitrile

[0477]

[0478] The title compound was synthesized in a manner similar to Example 10. (yellow solid, 130 mg, 50%). 1H NMR (400MHz, CDCl3) δ7.90 (d, J=8.8Hz, 1H), 7.06 (d, J=8.8Hz, 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 ESIMS of Cl2F4N2O2S[M+H] + , calculated value 453.0, measured value 453.0.

[0479] Example 13: 2-Chloro-3-(6,8-difluoro-1,2,3,4-tetrahydroquinolin-1-yl)-6-trifluoromethanesulfonylbenzonitrile

[0480]

[0481] The title compound was synthesized in a manner similar to Example 10. (yellow solid, 172 mg, 69%). 1 H NMR (400MHz, CDCl3) δ7.93 (d, J=8.8Hz, 1H), 7.28 (d, J=8.8Hz, 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 ESIMS of ClF5N2O2S[M+H] + , calculated value 437.0, measured value 437.0.

[0482] Example 14: 1-[5-cyano-6-(trifluoromethyl)pyridin-3-yl]-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0483]

[0484] Step a: To a 40 mL vial was added 6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (61 mg, 0.344 mmol, 1.2 eq), 5-bromo-3-fluoro-2-(trifluoromethyl)-pyridine (70 mg, 0.287 mmol, 1.0 eq), Pd(OAc)2 (13 mg, 0.057 mmol, 20 mol%), rac-BINAP (45 mg, 0.072 mmol, 25 mol%), Cs2CO3 (190 mg, 0.574 mmol, 2.0 eq) and toluene (1.5 mL). The reaction vessel was capped and the mixture was sparged with N2 for 2 minutes. The reaction was stirred at 100°C for 2 hours. The reaction mixture was cooled, concentrated to celite and purified by flash column chromatography (SiO 2 , hexanes→40% EtOAc in hexanes) to give the product as a white solid (65 mg, 0.192 mmol, 55%, C 16 H 10 ESIMS of F5N3 [M+H] + , calculated value 340.3, measured value 340.0).

[0485] Step b: fill the bottle with the product (30 mg, 0.088 mmol, 1.0 equivalents), KCN (7.0 mg, 0.097 mmol, 1.1 equivalents) and NMP (0.3 mL) of step a. The reaction mixture was stirred at 100 ° C for 4 h. The reaction was diluted with saturated NaHCO 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, washed with H o (2 × 20 mL), salt water (20 mL), and dried over MgSO. 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 H NMR (400MHz, DMSO-d6) δ8.70-8.63(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=6.4Hz, 2H), 1.95-1.87 (m, 2H). C 17 H 10 ESIMS of F4N4[M+H] + , calculated value 347.1, measured value 347.0.

[0486] Example 15: 1-[2-Chloro-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0487]

[0488] The title compound was synthesized in a similar manner to Example 14 using 1-bromo-2-chloro-3-fluoro-4-(trifluoromethyl)-benzene. 1 H NMR (400MHz, DMSO-d6) δ7.74-7.67(m, 1H), 7.53-7.43(m, 2H), 7.13-7.04(m, 1H), 3.74-3.48(m, 2H), 3.07-2.77(m, 2H), 2.06-1.64(m, 2H). C 17 H 10 ESIMS of ClF5N2[M+H] + , calculated value 373.0, measured value 373.0.

[0489] Example 16: 6-Fluoro-1-[8-(trifluoromethylsulfonyl)-5-isoquinolinyl]-1,2,3,4-tetrahydroquinoline-8-carbonitrile

[0490]

[0491] The title compound was synthesized in a similar manner to Example 10. 1 H NMR (400 MHz, chloroform-d) δ 10.24 (s, 1H), 8.87 (d, J = 6.1 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.26 (dd, J = 6.2, 0.9 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.26–7.22 (m, 1H), 7.15–7.11 (m, 1H), 3.87–3.76 (m, 2H), 3.16–2.94 (m, 2H), 2.08–1.85 (m, 2H). 20 H 13 ESIMS of F4N3O2S[M+H] + Calculated value 436.1, measured value 436.1.

[0492] Example 17: (1S,2R)-4-[(S)-4-ethyl-6,8-difluoro-1,2,3,4-tetrahydroquinolin-1-yl]-2-fluoro-7-(trifluoromethylsulfonyl)-1-indanol

[0493]

[0494] The title compound was synthesized in a similar manner to Example 19. 1H NMR (400MHz, chloroform-d) δ7.77 (d, J=8.4Hz, 1H), 7.00 (s, 0H), 6.83 (d, J=8.8Hz, 1H), 6.70 (d dd, J=11.0, 8.3, 2.6Hz, 1H), 5.51 (s, 1H), 5.18 (d, J=50.8Hz, 1H), 3.69 (s, 2H), 3.00 (br m, 2H), 2.84 (p, J=6.4Hz, 1H), 2.12-1.99 (m, 1H), 1.81 (br m, 2H), 1.60 (dq, J=14.5, 7.5Hz, 1H), 0.98 (t, J=7.4Hz, 3H). C 21 H 19 ESIMS of F6NO3S[M+H] + Calculated value 480.1, measured value 480.1.

[0495] Example 18: 2-Chloro-3-(6-fluoro-8-methoxy-3,4-dihydroquinolin-1(2H)-yl)-6-((trifluoromethyl)sulfonyl)benzonitrile

[0496]

[0497] The title compound was synthesized in a similar manner to Example 10. 1 H NMR (400MHz, CDCl3) δ7.84 (dd, J=8.8, 0.4Hz, 1H), 7.13 (d, J=8.9Hz, 1H), 6.54 (dd, J=8.6, 2.7Hz, 1 H), 6.43 (dd, J=10.2, 2.8Hz, 1H), 3.74 (br.s, 2H), 3.51 (s, 3H), 2.95–2.79 (m, 2H), 1.91 (br.s, 2H). 19 F NMR (376MHz, CDCl3) δ-77.11, -115.53.C 18 H 13 ESIMS of ClF4N2O3S[M+H] + ; Calculated value 449.0, measured value 449.1

[0498] 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

[0499]

[0500] Step a: Chloroacetyl chloride (8.3mL, 110mmol) is added dropwise to a stirred suspension of 2-amino-5-fluorophenol (9.5g, 75mmol) and potassium carbonate (41.4g, 300mmol) in THF (120mL) at 0°C. The reaction is stirred at ambient temperature for 30 minutes and then maintained at 66°C for 48h. The mixture is cooled, filtered through a diatomaceous earth pad to remove inorganic solids and the filtrate is concentrated to dryness. The residue is classified by column chromatography (SiO2, hexane / EtOAc gradient) to obtain 7-fluoro-2H-benzo [b] [1,4] oxazine-3 (4H) -one (5.5g, 32.9mmol, 44% yield), which is a brown solid. 1 H NMR (400MHz, CDCl3) δ8.73 (s, 1H), 6.90-6.53 (m, 3H), 4.60 (s, 2H). 19 F NMR (376MHz, CDCl3) δ-117.25.

[0501] Step b: Lithium aluminum hydride (1.2 g, 3.2 mmol) was carefully added portionwise to a solution of 7-fluoro-2H-benzo [b] [1,4] oxazine-3 (4H) -one (3.5 g, 2.1 mmol) in THF (30 mL) at 0 ° C. Once the addition was complete, the cooling bath was removed and the mixture was stirred at ambient temperature for 4 h. After TLC analysis indicated the completion of the reaction, the mixture was quenched using a Fieser protocol and the product was extracted with ether. After all solvents were removed under reduced pressure, the crude product was purified by column chromatography (SiO , hexane / EtOAc gradient) to generate 7-fluoro-3,4-dihydro-2H-benzo [b] [1,4] oxazine (2.9 g, 18.9 mmol, 90% yield) as a brown solid. 1 H NMR (400MHz, CDCl3) δ6.63-6.22 (m, 3H), 4.30-4.18 (m, 2H), 3.59 (s, 1H), 3.44-3.32 (m, 2H). 19 F NMR(376MHz, CDCl3)δ-124.56.

[0502] 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) in a water bath to maintain the reaction temperature below 25°C. Once the addition was complete, the reaction was stirred at ambient temperature for 10 minutes and poured into a 5% aqueous NaHSO solution (100 mL). The crude product was extracted with a mixture of EtOAc and hexane (v / v 1:1, 3 x 35 mL), and the combined extracts were washed with water (3 x 100 mL), aqueous NaHCO solution (2 x 100 mL), and brine (50 mL). The solution was dried over NaSO and the solvent was evaporated to dryness. The crude product was purified by column chromatography (SiO 2 , hexane / EtOAc gradient) to give 5-bromo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.05 g, 4.5 mmol, 70% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ6.79 (dd, J=8.0, 2.8Hz, 1H), 6.52 (dd, J=9.5, 2.8Hz, 1H), 4.32–4.14 (m, 2H), 4.14–3.88 (br.s, 1H), 3.53–3.34 (m, 2H). 19 F NMR (376MHz, CDCl3) δ-124.82 (d, J=8.3Hz).

[0503] Step d: A mixture of 5-bromo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.05 g, 4.5 mmol), zinc cyanide (0.43 g, 3.6 mmol) and Pd(PPh3)4 (0.52 g, 0.45 mmol) in DMF (11 mL) was heated at 100 ° C under a nitrogen atmosphere for 4 hours. Once TLC analysis observed complete disappearance of the starting material (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 pad of celite. The organic phase was separated and the aqueous solution was further extracted with EtOAc (2×25 mL). The combined organic phases were washed with water (2×75 mL) and brine (75 mL), dried over Na2SO4 and concentrated to dryness. The dry residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to afford 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. 1H NMR (400MHz, CDCl3) δ6.78–6.54(m, 2H), 4.51(br.s, 1H), 4.33–4.17(m, 2H), 3.60–3.40(m, 2H). 19 ESIMS [M+Na] of F NMR(376MHz, CDCl3)δ-124.17.C9H7FN2O + ; Calculated value 179.1, measured value 179.1.

[0504] Step e: A mixture of (1S,2R)-4-bromo-2-fluoro-1-(tert-butyl-dimethylsilyl)-7-(trifluoromethylsulfonyl)indane (100 mg, 0.21 mmol), 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (38 mg, 0.21 mmol), Pd(OAc)2 (9.5 mg, 0.042 mmol), rac-BINAP (33 mg, 0.053 mmol) and Cs2CO3 (137 mg, 0.42 mmol) in anhydrous degassed toluene (1 mL) was stirred at 100° C. for 6 h. The mixture was then cooled to ambient temperature, diluted with EtOAc and filtered through a pad of celite to remove inorganic solids. The filtrate was concentrated onto celite and purified by column chromatography (SiO2, hexane / EtOAc gradient) to give a mixture of product and unreacted benzomorpholine (55 mg). This mixture was carried on to step f without further purification.

[0505] Step f: A mixture of TBS-protected indanol and the unreacted benzomorpholine from the previous step was dissolved in CH3CN (1 mL) and placed in a 3 mL vial equipped with a magnetic stirrer. HF·Py complex (hydrogen fluoride 70%, pyridine 30%, 0.1 mL) was then added. The resulting solution was stirred overnight at ambient temperature. After TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (20 mL) and 1 M aqueous HCl (20 mL). The product was extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated to dryness. The residue was fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to give 7-fluoro-4-((1S,2R)-2-fluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (25 mg, 0.054 mmol, 26% yield over two steps) as a light yellow oil. 1H NMR (400MHz, CDCl3) δ7.85 (d, J=8.6Hz, 1H), 7.05-6.93 (m, 2H), 6.89 (dd, J=7.5, 2.8Hz, 1H), 5.59 (br.s, 1H), 5.2 8 (br.d, J=49.6Hz, 1H), 4.39 (d, J=11.5Hz, 1H), 4.10 (br.s, 1H), 3.76–3.57 (m, 2H), 3.34 (br.s, 2H), 3.03 (s, 1H). 19 F NMR (376MHz, CDCl3) δ -78.08, -113.95, -199.41 (d, J=51.0Hz). C 19 H 13 ESIMS of F5N2O4S[M+Na] + ; Calculated value 483.0, measured value 483.1

[0506] 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

[0507]

[0508] The title compound was synthesized in a similar manner to Example 19. 1 H NMR (400MHz, CDCl3) δ7.80 (d, J=8.4Hz, 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(376MHz, CDCl3)δ-115.26, -199.17.C 19 H 16 ESIMS of F2N2O4S[M-OH] + ; Calculated value 389.1, measured value 389.1.

[0509] Example 21: 6,8-difluoro-8'-trifluoromethanesulfonyl-3,4-dihydro-2H-1,5'-bisquinoline

[0510]

[0511] The title compound was synthesized in a similar manner to Example 10. 1H NMR (400MHz, CDCl3) δ9.15 (dd, J=4.3, 1.7Hz, 1H), 8.61 (dd, J=8.6, 1.7Hz, 1H), 8.44 (d, J=8.3Hz, 1H), 7.60 (dd, J=8.6, 4.2Hz, 1 H), 7.08 (dd, J=8.3, 0.9Hz, 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 ESIMS of F5N2O2S[M+H] + Calculated value 429.1, measured value 429.1.

[0512] 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

[0513]

[0514] The title compound was synthesized in a similar manner to Example 19. 1 H NMR (400 MHz, methanol-d4) δ 7.76 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.85–6.80 (m, 1H), 6.77–6.69 (m, 1H), 5.50–5.44 (m, 1H), 3.66–3.57 (m, 3H), 3.22 (s, 3H), 3.18–3.03 (m, 1H), 2.93–2.84 (t, J = 6.6 Hz, 2H), 1.96–1.84 (m, 2H). 19 H 17 ESIMS of F4NO3S[M+H] + Calculated value 416.1, measured value 416.0.

[0515] Example 23: 6,8-difluoro-1-(2-nitro-4-trifluoromethanesulfonylphenyl)-1,2,3,4-tetrahydroquinoline

[0516]

[0517] The title compound was synthesized in a similar manner to Example 24. 1H NMR (400MHz, CDCl3) δ8.46 (d, J=2.2Hz, 1H), 7.94 (dd, J=8.9, 2.3Hz, 1H), 7.33 (dd, J=8.9, 1.7Hz, 1 H), 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 ESIMS of F5N2O4S[M+H] + Calculated value 423.0, measured value 423.1.

[0518] Example 24: 6,8-difluoro-1-[2-nitro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinoline.

[0519]

[0520] 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 Cs2CO3 (652 mg, 2 mmol) were suspended in PhMe (5 mL). The suspension was degassed with N2 at ambient temperature for 5 minutes and heated to 100°C for 1.5 hours. The mixture was cooled to room temperature, diluted with EtOAc, filtered, and concentrated to 40°C. Purification by column chromatography (0-10% EtOAc / hexanes) afforded the title compound as an orange oil (125 mg, 35% yield). 1 H NMR (400MHz, CDCl3) δ8.13 (dd, J=2.2, 0.9Hz, 1H), 7.68–7.61 (m, 1H), 7.26–7.22 (m, 1H), 6.73 (dddt, J=8.4, 2.6, 1.7, 0.9Hz, 1H), 6.63 (dddd, J=11.3, 8.4, 2.8, 0.7Hz, 1H), 3.57 (s, 2H), 2.88 (tt, J=6.6, 0.8Hz, 2H), 2.00 (q, J=6.2Hz, 2H). 19 F NMR (376MHz, CDCl3) δ-62.3(3F), -117.3(1F), -116.7(1F). C 16 H 11 ESIMS of F5N2O2[M+H] + , calculated value 359.1, measured value 359.1.

[0521] Example 25: 5-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-8-(trifluoromethylsulfonyl)isoquinoline

[0522]

[0523] Step a: 5-Bromo-8-isoquinolinylamine (2.23 g, 10 mmol, 1 eq.) was dissolved in a mixture of ethanol (3 mL) and aq. HBF4 (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 the reaction was stirred for 1 hour. Et2O (10 mL) was added to the reaction mixture, which was then filtered and washed with more Et2O (2 x 10 mL). The filtrate was dried under vacuum for 30 minutes to give the diazonium salt as an orange solid (3.06 g, 9.52 mmol, 95%). ESIMS [M] of C9H5BrN3 + Calculated value 234.0, measured value 234.0

[0524] Step b: A solution of the product of step a in DMSO (10 mL) was added to a vigorously stirred solution of NaSO2CF3 (4.68 g, 30 mmol, 3 eq.) and Cu2O (143 mg, 1 mmol, 0.1 eq.) in DMSO (10 mL) using a dropping funnel. After the addition was complete, the reaction was stirred for 2 hours, or until LCMS indicated that the starting material was completely converted. The reaction mixture was then diluted with EtOAc (100 mL) and water (100 mL). After separation, the aqueous solution 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 Na2SO4. The crude material was purified by flash column chromatography (SiO2, 0 to 100% EtOAc / hexane) to give the product as a brown solid (716 mg, 2.94 mmol, 29%). 10 ESIMS[M+H] of H5BrF3NO2S + Calculated value 339.9, measured value 339.9.

[0525] Step c: A vial was filled with the product of step b (24 mg, 0.07 mmol, 1 eq), 2-(6,8-difluoro-3,4-dihydronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21 mg, 0.07 mmol.1 eq.), Pd(dppf)Cl2 (5 mg, 0.007 mmol, 0.1 eq.), aqueous Na2CO3 solution (1 M, 0.21 mL, 3 eq.), and dioxane (1 mL). The vial was bubbled with N2 for 10 minutes and then heated to 100°C for 16 hours. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried over Na2SO4 and concentrated. The crude material was purified by flash column chromatography (0 to 100% EtOAc / hexane) to give the desired product (7 mg, 0.016 mmol, 23%). 20 H 12 ESI MS of F5NO2S[M+H] + Calculated value 426.1, measured value 426.1.

[0526] Step d: the product of step c (7 mg, 0.016 mmol, 1 eq) is dissolved in i-PrOH (1 mL), and PhSiH is added under nitrogen (4 μ L, 0.032 mmol, 2 eq) and tert-butyl hydroperoxide (5.5 M in decane, 8 μ L, 0.032 mmol, 2 eq). The solution is bubbled with nitrogen for 10 minutes, then Mn (dmp) is added (10 mg, 0.016 mmol, 1 eq) and the resulting mixture is bubbled for 30 seconds. The reaction is then stirred under nitrogen for 16 hours. After concentration of the reaction mixture, the crude material is purified by flash column chromatography (SiO , 0 to 100% EtOAc / hexane) to obtain the title compound (4 mg, 0.009 mmol, 57%). 1 H NMR (400MHz, chloroform-d) δ10.23 (s, 1H), 8.85 (d, J = 6.0Hz, 1H), 8.31 (d, J = 7.8Hz, 1H), 8.14 (d, J = 6.0Hz, 1H), 7.16 (m, 1H), 6.84-6.7 9(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=17.9Hz, 1H). C 20 H 14 ESIMS of F5NO2S[M+H] + Calculated value 428.1, measured value 428.1.

[0527] Example 26-120: Compound Synthesis

[0528] The following examples were prepared according to the general synthetic schemes described for the other examples, as detailed below in Table A. Characteristic physical data, such as mass spectral peaks as shown, are provided for each example.

[0529] Table A: Synthesis Examples 26-120

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542] Example 121: (4S)-1-[2-Cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile.

[0543]

[0544] Step a: A flask was charged with 2-chloro-4-fluoroaniline (18.2 g, 15 mL, 1.0 mol. eq) and excess acrylic acid (46 g, 5.0 mol. eq) and the resulting mixture was stirred at 45° C. for 15 h. During this time, the product solidified from the reaction mixture and was collected by filtration and washed with hexanes to give the aniline product, which was used as is in the next step (25.4 g, 93%).

[0545] Step b: The product of step a (25.4 g) was then added portionwise to Eaton's reagent (100 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and then heated at 80° C. for 3 h. The reaction was then cooled and carefully poured onto ice, whereupon the product precipitated from the solution as a yellow solid (17.4 g, 75%).

[0546] Step c: A flask containing a solution of the product from the previous step (15 g, 75.3 mmol, 1.0 mol. equiv.) in MeOH (250 mL) was cooled to 0° C. under N . NaBH 4 (3.41 g, 90.4 mmol, 1.2 mol. equiv.) was slowly added portionwise and the reaction was stirred at room temperature for 30 minutes. At this point, the reaction was placed in an ice bath, quenched with H 2 O, and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with water, brine, and dried over MgSO 4 . Concentrated under reduced pressure to give the tetrahydroquinoline intermediate, which was carried to the next step without further purification.

[0547] Step d: DCM (250 mL) and imidazole (7.70 g, ~1.5 mol equivalent) were added to the crude intermediate of step c. The resulting mixture was cooled to 0 ° C and TBSCl (17.0 g, ~1.5 equivalents) was added. The reaction was warmed to room temperature and stirred for 2 h. The reaction was filtered to remove imidazole hydrochloride and concentrated onto celite. The TBS-protected alcohol was purified by flash column chromatography (SiO , hexane to 10% EtOAc / hexane) as a colorless oil (16.7 g, 70% over 2 steps).

[0548] Step e: A flask was charged with TBS alcohol (6.0 g, 19 mmol, 1.0 mol. equiv.) from the previous step, K4Fe(CN)6.3H2O (5.61 g, 13.3 mmol, 0.7 mol. equiv.), PdXPhos 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. equiv.), H2O (40 mL), and 1,4-dioxane (40 mL). The resulting mixture was purged with N2, heated at 100°C, and stirred vigorously under N2. After 3 h, the reaction was cooled and diluted with EtOAc and H2O. The aqueous layer was separated and back-extracted with additional EtOAc. Filtration through celite to remove solids improved the layer partitioning. The organic layers were combined and dried over MgSO4. Purification by flash column chromatography (SiO2, hexanes to 20% EtOAc) gave the benzonitrile product as a yellow solid (5.68 g, 98%).

[0549] Step f: To a flask containing 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (10 g, 34.8 mmol, 1.0 mol equiv) was added DMF (70 mL) followed by EDC.HCl (9.98 g, 52.2 mmol, 1.5 mol equiv), HOBt.HO (7.0 g, 52.2 mmol, 1.5 mol equiv), ammonium carbonate (16.7 g, 174 mmol, 5.0 mol equiv) and DIPEA (18 mL, 3.0 mol equiv). The resulting mixture was stirred at 40°C overnight. The reaction was partitioned between EtOAc and HO. The aqueous layer was separated and extracted with additional EtOAc. The organic layers were combined, washed with HO to remove DMF, and dried over MgSO. Concentrated under reduced pressure to give the crude amide, which was carried to the next step without purification.

[0550] Step g: add DMF (100mL) and cyanuric chloride (2.55g, 13.9mmol,~0.6mol. equivalent) to the flask comprising the crude amide of the previous step. The resulting mixture is stirred at room temperature for 16h under N2. The reaction is distributed between EtOAc and H2O. The aqueous layer is separated and extracted with additional EtOAc. The organic layers are combined, washed with H2O to remove DMF, and dried with MgSO4. Concentrated under reduced pressure and purified by flash column chromatography (SiO2, hexane to 20% EtOAc) to obtain the nitrile product as a white solid (2.68g, 26% over 2 steps).

[0551] Step h: A vial was charged with benzonitrile from the previous step (1.0 g, 3.73 mmol, 1.0 mol. equiv), 4-[tert-butyl(dimethyl)silyl]oxy-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (1.10 g, 3.73 mmol, 1.0 mol. equiv), Pd(OAc)2 (0.167 g, 0.746 mmol, 20 mol%), rac-BINAP (0.580 g, 0.925 mmol, 25 mol%), Cs2CO3 (2.42 g, 7.46 mmol, 2.0 mol. equiv) and toluene (15 mL). N2 was bubbled through the reaction mixture for 3 minutes, the vial was capped, and heated at 100°C for 15 h. The reaction was monitored by TLC and NMR analysis. The reaction was cooled, filtered, and concentrated onto celite. Purification by flash column chromatography (SiO2, hexanes to 10 to 20% EtOAc) gave the coupled product as a yellow solid (1.00 g, 54%). 24 H 24 F5N3OSi's ESIMS[M+H] + , calculated value 494.2, measured value 494.2.

[0552] Step i: the flask comprising the product (1.0g, 2.02mmol, 1.0mol. equivalent) of the previous step and THF (10mL) is cooled to 0°C and TBAF (1M in THF, 3.0mL, 1.5mol. equivalent) is added. The reaction mixture is warmed to room temperature and stirred for 15 minutes. Then, the reaction is quenched with saturated NH4Cl aqueous solution and diluted with EtOAc. The separated aqueous layer is stripped with additional EtOAc. The organic layers are combined, washed with salt water, and dried with MgSO4. Under reduced pressure, concentrated and purified by flash column chromatography (SiO2, hexane to 20% to 50% to 80% EtOAc) to obtain the alcohol product as a white solid (0.694g, 91%).

[0553] Step j: the bottle containing the solution of the alcohol product (35mg, 0.093mmol, 1.0mol. equivalent) in DCM (1mL) of the previous step is cooled to -78 ° C. DAST (20 μ L, 0.149mmol, 1.6mol. equivalent) is added, and the reaction is warmed to room temperature and stirred for 5 minutes. The reaction is quenched with saturated aq.NaHCO solution at 0 ° C and diluted with DCM. The aqueous layer is separated and stripped with additional DCM. The organic layers are combined and dried with MgSO4. Concentrated under reduced pressure and purified by column chromatography (SiO2, hexane to 20% EtOAc) to obtain racemic 1- [2-cyano-3-fluoro-4- (trifluoromethyl) phenyl] -4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile as a white solid (13mg, 37%). The enantiomers were separated by preparative SFC chiral purification (2.0 x 25.0 cm Chromega Chiral CC4 from ES Industries (West Berlin, NJ), CO2 cosolvent isopropanol / hexane (1:9), 15% cosolvent at 100 mL / min) to afford the title compound (4S)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile as a white solid (98.8% ee, t R=1.5min). Absolute stereochemistry was confirmed by single crystal X-ray analysis. 1H NMR (400MHz, DMSO-d6, showing that it is a 2:1 mixture of rotamers) δ 8.11 (t, J = 8.6 Hz, 1H), 8.03 (t, J = 8.6 Hz, 2H), 7.94–7.79 (m, 6H), 7.43 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 5.82 (dt, J = 49.7, 2.9 Hz, 1H), 5.70 (dt, J = 49.8, 2.9 Hz, 2H), 4.08–3.67 (m, 6H), 2.38–2.02 (m, 6H). C 18 ESIMS of H8F5N3[(M-HF)+H] + , calculated value 362.0, measured value 362.0.

[0554] Example 122: 1-(3-chloro-2-cyano-4-methylsulfonylphenyl)-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile

[0555]

[0556] 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 a solution of NBS (1.17 g, 6.58 mmol, 1.0 equivalent) in DMF (10 mL) was added dropwise over 10 min. The mixture was stirred at -10 ° C for 10 minutes. The cooling bath was then removed and the reaction was stirred at room temperature for 1.5 h. It was diluted with 10% Na2S2O3 (100 mL) and extracted with EtOAc (3×100 mL). The combined organics were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex → 30% EtOAc in hexane) to give the product (0.92 g, 60%).

[0557] Step b: The product of step a (0.5 g, 2.16 mmol) was dissolved in MeCN (8.5 mL).

[0558] 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 minutes. It was then heated at 60 ° C for 1 hour. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex → 30% EtOAc in hexane) to give the product (0.36 g, 64%).

[0559] Step c: A mixture of the bromide of 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) (10 mg, 0.045 mmol, 10% mol.), Xantphos (52 mg, 0.09 mmol, 20% mol.) and CsCO (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 column and purified by column chromatography (silica gel, hex→30% EtOAc in hexane) to give the product (88 mg, 40%).

[0560] Step d: The product of step c (88 mg, 0.18 mmol) was dissolved in DCM (4 mL). mCPBA (254 mg, 1.1 mmol, 6.0 equivalents) was added in one go. The reaction mixture was stirred at room temperature for 2 h, then quenched with 10% Na2S2O3 (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with saturated NaHCO3 (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex→30% EtOAc in hexane) to obtain the product (quantitative yield).

[0561] Step e: The product of step d (0.18 mmol) was dissolved in THF (40 mL) and TBAF (1.0 M in THF, 0.54 mL, 3.0 equivalents) was added. The reaction was stirred at room temperature for 15 minutes. It was quenched with H2O (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organics were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex → 80% EtOAc in hexane) to give the product as a yellow solid (58 mg, 80%).

[0562] Step f: A solution of the product of step e (25 mg, 0.05 mmol) in DCM (2 mL) was cooled to -10 ° C and DAST (16 mg, 0.1 mmol, 2.0 equivalents) was added. The mixture was stirred at -10 ° C for 10 minutes. The cooling bath was then removed, and the reaction was stirred at room temperature for 0.5 h. It was quenched with H2O (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic matter was washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex → 60% EtOAc in hexane) to obtain the product as a yellow solid (23 mg, 95%). 1H NMR (400MHz, DMSO-d6) δ8.22 (d, J=8.8Hz, 0.4H), 8.11 (d, J=8.8Hz, 0.6H), 7.92–7.74 (m, 2H), 7.54 (d, J=8.8Hz, 0.4H) ), 7.25 (d, J=8.8Hz, 0.6H), 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 ESIMS of ClF2N3O2S[M+H] + , calculated value 408.0, measured value 408.0.

[0563] Example 123: 1-[3-Chloro-2-cyano-4-(trifluoromethyl)phenyl]-4,6-difluoro-3,4-dihydro-2H-quinoline-8-carbonitrile.

[0564]

[0565] This compound was prepared in a manner similar to 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). 18 ESIMS of H9ClF5N3[M+H] + , calculated value 398.0, measured value 397.9.

[0566] Example 124: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-3,4-dihydro-2H-quinoline-4,8-dicarbonitrile

[0567]

[0568] Step a: A vial containing a solution of 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (110 mg, 0.290 mmol, 1.0 mol. equiv.) in DCM (1.5 mL) was cooled to 0 ° C and DMP (150 mg, 0.348 mmol, 1.2 mol. equiv.) was added. The reaction mixture was warmed to room temperature and stirred for 20 minutes. The reaction was quenched with saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 (1:1) and diluted with DCM. The mixture was stirred vigorously for 30 minutes. The organic layer was separated and washed with additional saturated aq. NaHCO3 / Na2S2O3 solution. The organic layer was separated and dried with MgSO4. Concentration under reduced pressure gave the ketone product as a yellow solid, which was pure enough for subsequent steps (110 mg, ~quant.). 18 ESIMS of H8F5N3O[M+H] + , calculated value 378.1, measured value 378.1.

[0569] Step b: KOtBu solution (1M in THF, 520 μL, 2 equivalents) 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 equivalents) in dichloromethane (1.3 ml) at room temperature. Ethanol (18 mg, 0.4 mmol, 1.5 equivalents) was added and the reaction was stirred at room temperature for 48 h. After completion, the reaction was quenched with 2N HCl aqueous solution, extracted with dichloromethane, and purified by flash chromatography on silica gel to obtain 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-3,4-dihydro-2H-quinoline-4,8-dicarbonitrile. 1 H NMR (400MHz, DMSO-d6): δ8.11-7.95 (m, 1H), 7.88-7.68 (m, overlap, 2H), 7.24 (dd, J=8.2 , 8.2Hz, 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 ESIMS of H9F5N4[M+H] + , calculated value 389.0, measured value 389.0.

[0570] Example 125: 1-[2-Cyano-3-fluoro-4-(trifluoromethyl)phenyl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile

[0571]

[0572] Step a: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-oxo-2,3-dihydroquinoline-8-carbonitrile (100 mg, 0.265 mmol) was dissolved in 1 ml of 50 wt% Deoxo- The solution in toluene was heated to 70°C overnight. Upon completion, the reaction was cooled to 0°C in an ice bath and quenched with water. The resulting solution was extracted with ethyl acetate and dichloromethane, and the crude concentrate was purified by flash chromatography on silica gel (0% to 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, CDCl3): δ

[0573] 7.75 (dd, J=8.2, 8.2Hz, 1H), 7.68 (dd, J=7.8, 3.0Hz, 1H), 7.27 (dd, J=7.2, 3.0Hz, 1 H), 6.92 (d, J=8.6Hz, 1H), 4.16-4.09 (m, 1H), 3.99-3.92 (m, 1H), 2.53-2.39 (m, 2H). C 18 ESIMS of H8F7N3[M+H] + , calculated value 400.1, measured value 400.0.

[0574] Example 126: 1-[6-(1,1-difluoroethyl)-5-fluoro-4-methylpyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile.

[0575]

[0576] Step a: The flask containing 2,5-dibromo-3-fluoropyridine (6.00 g, 23.6 mmol, 1.0 mol. equivalent) in THF (100 mL) was cooled to -78 ° C under N . LDA solution (2.0 M in heptane / THF / ethylbenzene, 17.7 mL, 1.5 mol. equivalent) was slowly added, and the resulting mixture was stirred for 15 minutes. MeI (2.9 mL, 2.0 mol. equivalent) was added and the reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction was cooled to 0 ° C and quenched with saturated NH Cl aqueous solution and diluted with EtOAc. The aqueous layer was separated and stripped with additional EtOAc. The organic layers were combined and dried with MgSO . Concentrated under reduced pressure and purified by flash column chromatography (SiO , hexane to 15% EtOAc) to obtain the methylated product, which was a yellow oil (3.64 g, 57%).

[0577] Step b: Under N2, a flask containing a solution of the product of the previous step (3.00 g, 11.2 mmol, 1.0 mol. equivalent) in anhydrous toluene (30 mL) was cooled to -78 ° C. nBuLi (2.5 M in hexane, 5.4 mL, 1.2 mol. equivalent) was added, and the reaction was stirred for 30 minutes. Then, the organic lithium was imprisoned with anhydrous DMA (3.2 mL, 33.6 mmol, 2.0 mol. equivalent) and the reaction was stirred for another 20 minutes. The reaction was quenched with saturated NH4Cl aqueous solution at -78 ° C. After warming, the mixture was diluted with EtOAc. The aqueous layer was separated and stripped with additional EtOAc. The organic layers were combined and dried over MgSO4. The ketone product (906 mg, 35%) was obtained by flash column chromatography purification (SiO2, hexane to 30% EtOAc) under reduced pressure.

[0578] Step c: Deoxo-Fluor (2.7M in toluene, 3.0 mL, 4.0 mol. equivalents) was added to the ketone product of the previous step (400 mg, 1.72 mmol, 1.0 mol. equivalents) and the resulting mixture was stirred at 70 ° C for 9 h. The reaction mixture was poured onto ice, quenched with saturated aq. NaHCO solution and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried with MgSO4. Concentrated under reduced pressure and purified by flash column chromatography (SiO2, hexane to 20% EtOAc) to give the difluorinated product as a yellow oil (342 mg, 78%). ESIMS [M+H] of C8H7BrF3N + , calculated value 253.9, measured value 253.8.

[0579] 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 in a manner analogous to Example 125 in 4 additional steps from 5-bromo-2-(1,1-difluoroethyl)-3-fluoro-4-methylpyridine. 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). 18 H 13 ESIMS of F6N3 [M+H] + , calculated value 386.1, measured value 386.0.

[0580] Example 127: 1-[4-Chloro-5-fluoro-6-(trifluoromethyl)pyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile.

[0581]

[0582] Step a: Under N2, a flask containing a solution of 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. 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 and the reaction mixture was warmed to room temperature and stirred for 15 minutes. The reaction was cooled to 0°C and quenched with saturated NH4Cl 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 MgSO4. Concentration under reduced pressure and purification by flash column chromatography (SiO2, hexanes to 15% EtOAc) gave the chlorinated product as a yellow oil (824 mg, 72%).

[0583] The title compound, 1-[4-chloro-5-fluoro-6-(trifluoromethyl)pyridin-3-yl]-4,4,6-trifluoro-2,3-dihydroquinoline-8-carbonitrile, was prepared in a manner analogous to Example 125 in 4 additional steps from 5-bromo-4-chloro-3-fluoro-2-(trifluoromethyl)pyridine. 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). 16 ESIMS of H7F7N3[M+H] + , calculated value 410.0, measured value 409.9.

[0584] Example 128: 4,4,6-Trifluoro-1-[5-fluoro-4-methyl-6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydroquinoline-8-carbonitrile

[0585]

[0586] Step a: under N2, the flask containing the solution of 5-bromo-3-fluoro-2-(trifluoromethyl)pyridine (1.00g, 4.10mmol, 1.0mol.equivalent) in THF (10mL) is cooled to -78 ℃. Slowly add LDA solution (2.0M in heptane / THF / ethylbenzene, 3.0mL, 1.5mol.equivalent), and the resulting mixture is stirred for 15 minutes. Add MeI (0.55mL, 2.0mol.equivalent) and the reaction mixture is warmed to room temperature and stirred for 30 minutes. The reaction is cooled to 0 ℃ and quenched with saturated NH4Cl aqueous solution and diluted with EtOAc. The aqueous layer is separated and stripped with additional EtOAc. The organic layers are combined and dried with MgSO4. Concentrated under reduced pressure and purified by flash column chromatography (SiO2, hexane to 15% EtOAc) to obtain the methylated product, which is a yellow oil (970mg, 92%).

[0587] Step b: A vial was charged with the pyridinium bromide of the previous step (350 mg, 1.36 mmol, 1.3 mol. equiv), 4-[tert-butyl(dimethyl)silyl]oxy-6-fluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (320 mg, 1.04 mmol, 1.0 mol. equiv), Pd(OAc)2 (46 mg, 0.20 mmol, 20 mol%), Xantphos (150 mg, 0.26 mmol, 25 mol%), Cs2CO3 (468 mg, 2.08 mmol, 2.0 mol. equiv) and toluene (3.5 mL). N2 was bubbled through the reaction mixture for 3 minutes, the vial was capped, and heated at 100°C for 24 h. The reaction was monitored by TLC and NMR analysis. The reaction was cooled, filtered, and concentrated onto celite. Purification by flash column chromatography (SiO2, hexanes to 20% EtOAc) gave the coupled product as a yellow solid (240 mg, 47%).

[0588] Step c: A vial was charged with the product from step b (90 mg, 0.186 mmol, 1.0 mol eq) and NMP (1.0 mL). KCN (18 mg, 0.28 mmol, 1.5 mol eq) was added and the reaction was stirred at 110°C. After 40 minutes, an additional portion of KCN (18 mg, 0.28 mmol, 1.5 mol eq) was added and the reaction was continued at 110°C for 15 hours. The TBS group also cleaved during this process. The reaction was cooled and diluted with saturated aqueous NaHCO3 and EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined and dried over MgSO4. Concentrated under reduced pressure and purified by flash column chromatography (SiO2, hexane to 60% EtOAc) to give benzonitrile alcohol (18 mg, 0.048 mmol, 26%). 18 H 12 ESIMS of F4N4O[M+H] + , calculated value 377.1, measured value 377.0.

[0589] 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 a manner analogous to Examples 124 and 125 in 2 additional steps. 1 H NMR (400 MHz, chloroform-d) δ 8.33 (s, 1H), 7.72–7.67 (m, 1H), 7.36–7.31 (m, 1H), 3.97–3.86 (m, 1H), 3.55–3.46 (m, 1H), 2.71 (s, 3H), 2.56–2.44 (m, 2H). 18 H 10ESIMS of F6N4 [M+H] + , calculated value 397.1, measured value 397.0.

[0590] Example 129: 4,4,6-Trifluoro-1-[5-fluoro-4-methyl-6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydroquinoline-8-carbonitrile.

[0591]

[0592] 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 a manner analogous to Example 125 in 3 additional steps. 1 H NMR (400MHz, DMSO-d6) δ8.40 (s, 1H), 7.96–7.90 (m, 1H), 7.87 (dd, J=8.0, 2.9Hz, 1H ), 3.95–3.80 (m, 1H), 3.78–3.65 (m, 1H), 2.70–2.52 (m, 2H), 2.33 (d, J=2.1Hz, 3H). C 17 H 10 ESIMS of F7N3 [M+H] + , calculated value 390.0, measured value 390.0.

[0593] Example 130: (3S,4R)-1-[2-Cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile.

[0594]

[0595] Step a: To a solution of 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-oxo-2,3-dihydroquinoline-8-carbonitrile (1.20 g, 3.71 mmol, 1.0 equiv) in MeOH (18 mL) was added N-fluorobenzenesulfonimide (1.29 g, 4.08 mmol, 1.1 equiv). The reaction mixture was stirred at 65 ° C for 16 h. The reaction was quenched with saturated aqueous NaHCO 3 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 polymeric beads were removed by filtration, and the concentrated crude material was purified by chromatography on silica gel (0 to 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 two steps). 18 ESIMS[M+H] of H8F6N3O1 + , calculated value 396.0, measured value 395.9.

[0596] Step b: The product of step a (250 mg, 0.63 mmol, 1.0 eq) was dissolved in CHCl (1.60 ml) and sparged with nitrogen, then formic acid (70 μL, 1.90 mmol, 3.0 eq) and triethylamine (180 μL, 1.26 mmol, 2.0 eq) were added at 0° C. RuCl(p-cymene)[(S,S)-Ts-DPEN] (6 mg, 0.01 mmol, 1.5 mol%) was added, and the reaction was stirred at 5° C. for 16 hours. Upon complete conversion, the reaction was quenched with saturated aqueous NaHCO and extracted with CHCl. The combined organics were concentrated and the crude material was purified by flash chromatography on silica gel (0 to 35% gradient EtOAc in hexanes) to afford (3S,4R)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,6-difluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (160 mg, 64%) as a single diastereomer. 18 H 11 ESIMS of F6N3O2[M+H2O] + , calculated value 415.0, measured value 415.0.

[0597] Step c: The product of step b (100 mg, 0.25 mmol, 1.0 eq) was dissolved in CHCl (2.5 mL) and the solution was cooled to -40°C. Diethylaminosulfur trifluoride (0.17 mL, 1.26 mmol, 5.0 eq) was added dropwise and the reaction mixture was slowly warmed to 0°C over 2 h with stirring. The mixture was then diluted with CHCl. ​​Saturated aqueous NaHCO was poured into the solution and the layers were separated. The organic phase was washed with brine, dried over NaSO, and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0 to 18% gradient EtOAc in hexanes) to afford a diastereomeric mixture (4:1) with (3S,4S)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (64 mg, 64%) and (3S,4R)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile (17 mg, 17%) as a white solid (81% combined yield). Characterization is reported for (3S,4R)-1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-3,4,6-trifluoro-1,2,3,4-tetrahydroquinoline-8-carbonitrile. The enantiomeric excess of this material was 97% by chiral HPLC (Chiralpak AD-H, 15% iPrOH / hexanes, isocratic, 20 min), R T Secondary = 7.18 minutes and R T Main = 7.70 minutes. 1 H NMR (400MHz, DMSO-d6) δ: 8.11–7.99 (m, 1H), 7.85 (dd, J=8.2, 3.0Hz, 1H), 7.80–7.70 (m, 1H), 7 .28 (d, J=9.0Hz, 1H), 5.97 (dd, J=47.5, 3.0Hz, 1H), 5.52 (d, J=51.5Hz, 1H), 4.43–4.05 (m, 2H). 19 F NMR (376MHz, DMSO-d6) δ: –59.6 (3F), –108.7 (q, J=11.8, 11.2Hz, 1F), –116.4 (t, J=8.6Hz, 1F), –198.7 (m, 1F), –201.9 (m, 1F). C 18 H 10 ESIMS of F7N3O1[M+H2O] + , calculated value 417.0, measured value 416.9.

[0598] Example 131: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-methoxy-3,4-dihydro-2H-quinoline-8-carbonitrile

[0599]

[0600] 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. Upon completion, the reaction solution was quenched with saturated NaHCO 3 , extracted with ethyl acetate, and dried over Na 2 SO 4 . The organics were concentrated to celite and the resulting crude material was purified by flash chromatography (SiO 2 ) using a gradient of 0% to 100% dichloromethane in hexanes to give 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-4-methoxy-3,4-dihydro-2H-quinoline-8-carbonitrile. 1 H NMR (400MHz, CDCl3): δ7.69 (dd, J=8.3, 8.3Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.21 (dd, J=7.6, 3.0Hz, 1H), 6.88 (d, J=8.8Hz, 1H), 4.33 (s, 1H), 3.90 (br m, 2H), 4.36 (s, 3H), 2.18 (br m, 2H). C 19 H 12 ESIMS of F5N3O[M+H] + Calculated value 394.1, measured value 394.0.

[0601] Example 132: 1-[2-cyano-4-(1,1-difluoroethyl)-3-fluorophenyl]-6-fluoro-4-methoxy-3,4-dihydro-2H-quinoline-8-carbonitrile

[0602]

[0603] Step a: A solution of 1-(4-bromo-2-cyano-3-fluorophenyl)-6-fluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (400 mg, 1.0 mmol) in MeOH (4 mL) and concentrated H2SO4 (0.02 mL) was heated at 70 ° C for 8 h. The reaction was then cooled to room temperature and quenched with saturated NaHCO3 (20 mL) and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex→40% EtOAc in hexane) to give the product (280 mg, 68%).

[0604] Step b: A mixture of the product of step a (280 mg, 0.69 mmol), tributyl(1-ethoxyvinyl)tin (0.5 g, 1.39 mmol, 2.0 equiv) and PdCl2(dppf) (51 mg, 0.069 mmol, 10% mol) in 1,4-dioxane (7 mL) was stirred at 100 ° C under N2 overnight. The reaction was then cooled to room temperature and diluted with 1N HCl (10 mL). It was stirred for 2 h. The mixture was quenched with water and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex→40% EtOAc in hexane) to give the product (0.26 g, quantitative yield).

[0605] Step c: A solution of the product from step b (130 mg, 0.35 mmol) and Deoxo-Fluor (50% wt in toluene) (1.25 g, 2.83 mmol, 8.0 equivalents) in CHCl (1 mL) was heated at 70°C for 12 h. The reaction was then cooled to room temperature and quenched with saturated NaHCO (20 mL), extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex → 40% EtOAc in hexane) to obtain the product (28 mg, 20%).

[0606] 1 H NMR (400MHz, DMSO-d6) δ7.77(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=8.4Hz, 3H), 2.20–1.79(m, 5H). C 20 H 15 ESIMS of F4N3O[M+H]+ , calculated value 390.1, measured value 390.1.

[0607] Example 133: 1-[2-cyano-3-fluoro-4-(trifluoromethyl)phenyl]-6-fluoro-3,4-dihydro-2H-quinoline-4,8-dicarbonitrile

[0608]

[0609] Step a: A mixture of 1-(4-bromo-2-cyano-3-fluorophenyl)-6-fluoro-4-hydroxy-3,4-dihydro-2H-quinoline-8-carbonitrile (500 mg, 1.28 mmol), isopropenylboronic acid pinacol ester (0.237 g, 1.41 mmol, 1.1 equivalents) and PdCl2(dppf) (94 mg, 0.128 mmol, 10% mol) in 1,4-dioxane (6 mL) and 2.0 M Na2CO3 (2 mL) was stirred at 90 ° C under N2 overnight. The reaction was then quenched with water and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex→50% EtOAc in hexane) to give the product (0.50 g, quantitative yield).

[0610] Step b: The product of step a (0.5 g, 1.28 mmol) was dissolved in THF / H2O (2:1; 6 / 3 mL). 2,6-lutidine (274 mg, 2.56 mmol, 2 eq) and NaIO4 (1.64 g, 7.68 mmol, 6 eq) were added, followed by K2OsO4 2H2O (24 mg, 0.06 mmol, 5% mol.). The reaction was stirred at room temperature for 15 h, then diluted with 10% Na2S2O3 solution (50 mL) and extracted with EtOAc (3×30 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex→50% EtOAc in hexane) to give the product (390 mg, 87%).

[0611] Step c: The product of step b (0.39 g, 1.11 mmol) was dissolved in DCM (10 mL). Dess-Martin reagent (705 mg, 1.65 mmol, 1.5 equivalents) was added. The reaction was stirred at room temperature for 0.5 h, then diluted with 10% Na2S2O3 solution (50 mL) and extracted with EtOAc (3×30 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex→40% EtOAc in hexane) to give the product (240 mg, 62%).

[0612] Step d: A solution of the product of step c (120 mg, 0.34 mmol) and Deoxo-Fluor (50% wt in toluene) (2.42 g, 5.48 mmol, 16 equivalents) in CHCl (1 mL) was heated at 70 ° C for 12 h. The reaction was then cooled to room temperature and quenched with saturated NaHCO (20 mL), extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hex → 40% EtOAc in hexane) to obtain the product (25 mg, 20%). 1 H NMR (400MHz, DMSO-d6) δ7.97 (d, J=8.2Hz, 2H), 7.83 (t, J=8.7Hz, 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=19.2Hz, 3H). C 19 H 11 ESIMS of F6N3 [M+H] + , calculated value 396.0, measured value 396.1.

[0613] 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

[0614]

[0615] Step a: A solution of 4-bromo-7-methylsulfonyl-2,3-dihydroindan-1-one (25.0 g, 86.5 mmol) in 500 mL of anhydrous methanol was loaded into a 1 L single-necked round-bottom flask equipped with a stirring 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. Once 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 into the desired α-fluoroketone. The resulting clear solution was cooled to ambient temperature and methanol was distilled off under reduced pressure. The residual mixture was diluted with dichloromethane (1 L) and water (500 mL). The organic phase was separated, and the aqueous solution was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with brine (500 mL). The organic phase was separated, dried over Na2SO4 and concentrated to dryness to give the α-fluoroketone (25.9 g, 84.3 mmol, 97% yield) as a white solid.

[0616] Step b: The product of step a (25.9 g, 84.3 mmol) was placed in a 1 L single-necked round-bottom flask equipped with a stirring rod. The flask was filled with dichloromethane (700 mL), formic acid (20.0 mL, 0.50 mol) and triethylamine (47.0 mL, 0.34 mol). The resulting solution was cooled to 0 ° C and RuCl (p-isopropylphenylmethane) [(R, R)-TsDPEN] (2.2 g, 3.4 mmol) was added. The resulting light brown solution was stirred at 0 ° C for 16 h. Once TLC analysis showed that the starting material was fully converted, the reaction was concentrated to approximately half of its original volume under reduced pressure. The residual solution was washed with a 1 M NaOH aqueous solution (400 mL) and brine (500 ml) in succession. The organic phase was separated, dried with Na SO and concentrated to dryness to generate a crude product with sufficient purity for the next step.

[0617] The enantiomeric purity of the material (96% ee) was determined using HPLC-UV chromatography [ AD-H (4.6 x 250 mm; 90% i-PrOH-hexane; flow rate = 1 mL / min; 10 μL injection of a 1 mg / mL solution; detection at 254 nm; t1 = 4.89 min (minor), t2 = 5.26 min. (major)]

[0618] Step c: the thick material of previous step is dissolved in dichloromethane (700mL) and is placed in 2L three-necked round-bottom flasks, it is equipped with thermometer, addition funnel, stirring rod and the reflux exchanger with drying tube.Triethylamine (105.0mL, 0.81mmol) is disposable added into mixture and fills TBSOTf (96.4g, 0.37mmol) to addition funnel.Then drip TBSOTf to keep the required speed of continuous reflux and cause exothermic reaction.Once adding is completed, reaction mixture is refluxed 15 minutes more, now TLC analysis display parent material is converted into product completely.Solution is cooled to environment temperature, transferred to separating funnel and used saturated NH subsequently the Cl aqueous solution (500mL) and salt solution (500ml) washing.Separate organic phase, use Na sO dry and be concentrated into dry. 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 two steps).

[0619] Step d: The TBS ether product of the previous step (29.5 g, 70.0 mmol) was mixed with B2Pin2 (23.0 g, 91.0 mmol, 1.3 eq), Pd(dppf)Cl2 (5.1 g, 7.0 mmol, 0.1 eq) and potassium acetate (13.8 g, 0.14 mmol, 2.0 eq) in dioxane (230 ml) 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 mixture was degassed under vacuum, backfilled with nitrogen and heated to 100° C. for 2 h. An aliquot of 1 After H 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 extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over NaSO and the solvent was evaporated under reduced pressure to give crude boronic acid pinacol ester, which was used in the next step without further purification.

[0620] Step e: The crude product of step d (70mmol) and a solution of 8-cyano-6-fluoro-3,4-dihydronaphthalene-1-yl trifluoromethanesulfonate (22.5g, 70.0mmol) in dioxane (230mL) are placed in a 500mL single-necked round-bottom flask equipped with a magnetic stirring bar and a reflux condenser with a nitrogen inlet. Pd(dppf)Cl2 (5.1g, 7.0mmol) and aqueous sodium carbonate solution (2M solution, 70.0ml, 40.0mmol) are then added successively. The mixture is degassed in vacuo, backfilled with nitrogen and heated to 100°C for 1h. After completion of the reaction, dioxane is removed under reduced pressure. The residue is distributed between EtOAc (500mL) and water (500mL). The organic layer is separated, and the aqueous phase is extracted with EtOAc (2×100mL). The combined organic extracts were washed with brine (500 mL), dried over Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to give the desired olefin (28.5 g, 55.3 mmol, 79% yield) as a white foam.

[0621] Step f: the alkene (28.0g, 54.0mmol) of step e is dissolved in anhydrous methanol (540mL) and is added to palladium / carbon (5.0g, 10% Pd weight) in a nitrogen atmosphere. The reaction mixture is placed in a hydrogen atmosphere at 50psi and stirred 4 hours in a Parr oscillator. Excess hydrogen is discharged and the mixture is bubbled with nitrogen to remove residual hydrogen. The gained suspension is filtered through a diatomaceous earth pad, and the filtrate is concentrated under reduced pressure to dry and obtains a crude epimer mixture (1: 1dr). In order to separate the larger (S)-epimer of polarity, the crude mixture is subjected to column chromatography (SiO , hexane / EtOAc gradient) to generate required tetralin derivative (9.6g, 18.5mmol, 34% productive rate), which is a white foam.

[0622] Step g: TBAF (37.2 mL, 37.2 mmol, 1 M solution in THF) was added dropwise to a solution of TBS ether in THF (93 mL) of step f at ambient temperature. The brown solution was stirred for 20 minutes, and then TLC analysis indicated that the starting material was fully converted. The mixture was diluted with EtOAc (200 mL) and washed with water (200 mL) and salt solution (150 mL) subsequently. The organic extract was dried with Na2SO4, concentrated to dryness, and the crude product was subjected to acylation reaction without purification.

[0623] The dried material obtained by converting the obtained product was dissolved in dichloromethane (50 mL), and DMAP (0.7 g, 5.8 mmol) and EtN (8.0 mL, 77.0 mmol) were then 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. Once TLC and LCMS analysis indicated complete conversion, the solution was diluted with dichloromethane (150 mL) and subsequently washed with water (200 mL), saturated NaHCO aqueous solution (100 mL) and salt solution (100 mL). The crude product was purified by column chromatography (SiO , hexane / EtOAc gradient) to generate the required acetate (8.3 g, 18.5 mmol, 100% yield) as a white powder.

[0624] Step h: The acetate (8.3g, 18.6mmol), MnO2 (6.5g, 75mmol) and dichloromethane (93mL) of step g are loaded into a 500mL single-necked round-bottom flask equipped with a magnetic stirring bar and a reflux condenser. The mixture is cooled to 0°C and tBuO2H (34mL, 186mmol, 5.5M solution in decane) is added dropwise over 5 minutes. The reaction is stirred at 0°C for 10 minutes, then warmed to ambient temperature and stirred until gas formation stops. The gained black suspension is refluxed for 24h, then cooled to room temperature and an additional amount of MnO2 (6.5g, 75mmol) and tBuO2H (34mL, 186mmol, 5.5M solution in decane) are added in succession. The mixture is refluxed for another 48h and cooled to room temperature. The inorganic solid is removed by filtration. The filtrate is washed with water (100mL) by a celite pad, dried and concentrated to dryness using Na2SO4. The crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to give the corresponding α-tetralone (6.2 g, 13.5 mmol, 72% yield) as a white powder.

[0625] Step i: a solution of the α-tetralone (1.5 g, 3.3 mmol) of step h in dichloromethane (33 mL) was placed in a 100 mL single-necked round-bottom flask equipped with a magnetic stirring bar and a drying tube. The mixture was filled with formic acid (0.37 mL, 9.8 mmol), Et N (0.91 mL, 6.5 mmol) and RuCl (p-isopropylbenzyl methane) [(R, R)-Ts-DPEN) (62 mg, 0.1 mmol) and stirred for 1 h at ambient temperature. The gained brown solution was diluted with dichloromethane (70 mL) and washed with saturated NaHCO aqueous solution. The organic extract was dried and was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO 2 , dichloromethane / EtOAc gradient) to yield the corresponding 1,2,3,4-tetrahydro-1-naphthol (1.43 g, 3.1 mmol, 95% yield, single epimer) as a white powder.

[0626] 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-necked round-bottom flask equipped with a magnetic stirring bar and a nitrogen inlet and cooled to -78 ° C. TMS-morpholine (1.65 mL, 9.2 mmol) was then added dropwise. The reaction was stirred at -78 ° C. for 5 minutes, and then the mixture was warmed to room temperature and stirred for 2 h. The resulting transparent solution was cooled to -78 ° C. and the solid 1,2,3,4-tetrahydro-1-naphthol (1.2 g, 2.6 mmol) of step i was added in one go. The cooling bath was removed, and the reaction was stirred at room temperature for 30 minutes. Once TLC analysis indicated that the starting material was completely consumed, the mixture was diluted with DCM (50 mL) and quenched with a saturated NaHCO aqueous solution (50 mL). The organic phase was separated, dried over Na SO 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 h, concentrated to dryness and the crude product was purified by column chromatography (SiO 2 , dichloromethane / EtOAc gradient), then triturated with 30 mL of MTBE and filtered to give the desired α-fluorotetralin (1.1 g, 2.4 mmol, 92% yield, single epimer) as a white solid.

[0627] Step k: α-Fluorotetralin (1.1 g, 2.4 mmol) from step j was suspended in 7 M NH 3 in MeOH (90 mL) and the mixture was stirred at ambient temperature for 36 h. The resulting clear solution was concentrated to dryness under reduced pressure and the crude product was purified by column chromatography (SiO 2 , dichloromethane / EtOAc gradient), then triturated with 30 mL of hexanes and filtered to give the desired product (0.85 g, 2.0 mmol, 85% yield). 1H NMR (400MHz, CDCl3) δ7.69 (d, J=8.1Hz, 1H), 7.51 (d, J=8.4, 1H), 7.39 (d, J=7.5Hz, 1H), 6.43 (d, J=8.1Hz, 1H), 5.69 (dt, J=13.5, 5.1Hz, 1H), 5.65–5.33 (m, 2H), 4.67–4.60 (m, 1H ), 3.58 (ddd, J=20.8, 16.8, 3.4Hz, 1H), 3.44 (dd, J=5.7, 2.9Hz, 1H), 3.28 (s, 3H), 3.28–3 .10(m, 1H), 2.56–2.38(m, 1H), 2.24–2.04(m, 1H), 2.02–1.79(m, 1H), 1.76–1.65(m, 1H). 19 F NMR (376MHz, CDCl3) δ-110.92(m), -157.06(m), -199.18(m). C 21 H 18 ESIMS[M+Na] of F3NO3SNa + , calculated value 444.1, measured value 444.0).

[0628] 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

[0629]

[0630] 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 of Example 134 in benzene (25 mL) was placed in a single-necked round-bottom flask equipped with a Dean-Stark apparatus and a reflux condenser with a nitrogen inlet adapter. The reaction was refluxed for 16 h, cooled to ambient temperature and washed with 1 M NaOH (25 mL). The organic phase was separated, dried over NaSO and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient) to give the desired product (0.17 g, 0.31 mmol, 100% yield) as a colorless oil.

[0631] Step b: HF·Py (0.19 mL, 0.80 mmol) was added to a suspension of N-iodosuccinimide (71.0 mg, 0.32 mmol) in dichloromethane (1 mL) cooled to -78 ° C. The resulting dark suspension was stirred for 5 minutes, and then a solution of 1,3-dithiolane (85 mg, 0.16 mmol) in dichloromethane (1 mL) of step a was added dropwise over 1 minute. The reaction mixture was stirred at -78 ° C for 20 minutes and then stirred at 0 ° C for another 20 minutes. Once TLC analysis indicated that 1,3-dithiolane was completely converted, the reaction was diluted with dichloromethane (15 mL) and washed with a mixture of saturated NaHCO3 aqueous solution and Na2S2O3 (1: 1, v / v). The organic phase was separated, dried over Na2SO4 and concentrated to dryness. The crude material was fractionated by column chromatography (SiO2, dichloromethane / EtOAc gradient) to give the desired product (33.0 mg, 0.07 mmol, 43% yield) as a white solid.

[0632] Step c: 1,1-difluorotetralin (33.0 mg, 0.07 mmol) of step b was dissolved in THF (1 mL) and a solution of LiOH·H2O (8.5 mg, 0.2 mmol) in water (0.2 mL) was added at 0 ° C. The reaction was stirred at room temperature for 3 h and monitored by LCMS analysis. Once complete conversion was achieved, the reaction was diluted with EtOAc (20 mL) and washed with 1M HCl aqueous solution (15 mL). The organic phase was separated, and the aqueous solution was extracted with EtOAc (15 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient) to generate the desired product (27.0 mg, 0.06 mmol, 90% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.84–7.65 (m, 2H), 7.51–7.38 (m, 1H), 6.56 (d, J=8.3Hz, 1H), 5.68 (dt, J=13.5, 5.0Hz, 1H), 5.51–5.32 (m, 1 H), 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 (376MHz, CDCl3) δ -85.85 (d, J=5260.8Hz), -109.12 (m), -199.20 (dtd, J=52.8, 22.4, 13.5Hz). C 21 H 17ESIMS of F4NNaO3S[M+Na] + , calculated value 462.1, measured value 462.0).

[0633] 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

[0634]

[0635] Step a: bromine (3.58ml, 70mmol, 1.05 equivalents) was added dropwise to a suspension of 7-fluoro-2,3-dihydro-1H-indene-1-one (10.0g, 66.6mmol) and aluminum chloride (22.2g, 166.5mmol, 2.5 equivalents) in 1,2-dichloroethane (190ml, 0.35M). The resulting solution was heated to 60°C for three hours, 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% to 10% ethyl acetate in a 1:1 solution of hexane) to obtain 4-bromo-7-fluoro-2,3-dihydro-1H-indene-1-one.

[0636] Step b: To a suspension of 4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one (17.0 g, 74.3 mmol) and CsCO (26.6 g, 81.7 mmol, 1.1 equiv) in DMF (372 ml, 0.2 M) was added benzyl mercaptan (9.24 g, 8.71 ml, 1.0 equiv). The reaction was stirred at room temperature for 90 minutes. The desired product was precipitated from the solution by adding 1.5 L of water and dried under high vacuum overnight. The resulting crude product (23.1 g, 93% yield) was carried to the next step without further purification.

[0637] Step c: The crude thioether (23.1 g, 69.2 mmol) from step b was suspended in toluene (692 ml, 0.1 M). Aluminum chloride (10.2 g, 1.1 equivalents) was added at room temperature. An additional portion of aluminum chloride (3.6 g, 27 mmol, 0.4 equivalents) was added after 3 hours. Once complete, the reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in a 1:3 solution of CH2Cl2 in hexane) to obtain the desired thiophenol as a yellow solid (13.4 g, 80% yield).

[0638] Step d: the solution of the thiophenol product (6.7g, 27.6mmol) and methyl viologen dichloride hydrate (710mg, 0.1 equivalent) in DMF (55ml, 0.5M) of step c is carefully degassed by three freeze-thaw pump cycles under nitrogen. The resulting solution is cooled to -10 to -°C in a salt water ice bath, and excessive CF3I is bubbled through the reaction mixture. The reaction is then stirred in CF3I atmosphere overnight. The reaction is carefully quenched with water at room temperature (residual CF3I exhaust occurs, use with caution), extracted with ethyl acetate, and concentrated. The crude material is purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in hexane) to obtain the required thioether (5.21g, 61% yield).

[0639] Step e: to the product of step d (10.45g, 33.6mmol) in MeCN (129ml, 0.26M, relative to starting material), CCl (129ml, 0.26M, relative to starting material) and H o (258ml, 0.13M, relative to starting material) in solution add ruthenium trichloride (697mg, 3.36mmol, 0.1 equivalent), then add sodium periodate (29.6g, 138.4mmol, 4.12 equivalent). The reaction was stirred at room temperature for 1 hour, and after completing, use CH cl extraction (x2). The organic matter merged is saturated Na s o washing, washed with salt water, and dried over sodium sulfate, then concentrated. The crude material is purified by flash chromatography (silica gel, 0% to 10% ethyl acetate, in CH cl in 1: 3 solution in hexane) to obtain product sulfone, it is white solid (10.53g, 91% yield). 10 ESIMS of H6BrF3O3S[M+H] + ; Calculated value 342.9, measured value 342.9.

[0640] Step f: a solution of the product sulfone (3.5g, 10.2mmol) and Selectfluor (4.32g, 12.2mmol, 1.2 equivalents) of step e in methanol (102ml, 0.1M) was heated to 50°C. Sulfuric acid (27 μl, 5mol%) was added, and the reaction was stirred at 50°C for 48 hours. The solution was then diluted with ether, and the gained white precipitate was filtered off and discarded. The organic solution was concentrated, and the crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate, in CH2Cl2 in a 1:3 solution in hexane) to obtain the product dimethyl acetal as a white solid (3.57g, 87% yield).

[0641] Step g: A solution of the product acetal from step f (3.18 g, 7.8 mmol) and wet Amberlyst 15 (4.77 g, 150 wt%) in dioxane (31 ml, 0.2 M) was heated to 90° C. overnight. Upon completion, the polymeric beads were removed by filtration, and the concentrated crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in a 1:3 solution of CHCl in hexanes) to give the desired fluorinated ketone (2.33 g, 83% yield).

[0642] Step h: A solution of the 2,3-dihydro-1-indanone product of step g (2.5 g, 6.93 mmol) in dichloromethane (28 ml, 0.25 M) was sparged with nitrogen, and then formic acid (783 μL, 956 mg, 20.8 mmol, 3 eq) and triethylamine (1.94 ml, 1.41 g, 13.9 mmol, 2 eq) were added at 0° C. under nitrogen. RuCl(p-cymene)[(R,R)-Ts-DPEN] (44.5 mg, 0.07 mmol, 0.01 eq) was added and the reaction was stirred at 0 to 5° C. for a minimum of 12 hours. Upon complete conversion, the reaction was quenched with saturated NaHCO and extracted with CH Cl. The combined organics were concentrated and the crude material was purified by flash chromatography (silica gel, 0% to 20% ethyl acetate in 1:1 solution of CHCl:hexanes) to give the desired indanol (2.0 g, 80% yield) as a single diastereomer. The enantiomeric excess of this material was determined to be 98% by chiral HPLC (Chiralpak AD-H, 20% iPrOH / hexanes, isocratic, 20 minutes) compared to the racemic sample. It was obtained by reduction of 2-fluoro-2,3-dihydro-1-indanone with sodium borohydride.

[0643] Step i: To a solution of the chiral indanol from step h (1.01 g, 2.75 mmol) in CHCl (11 ml, 0.25 M) was added 2,6-lutidine (800 μL, 6.9 mmol, 2.5 eq) and TBSOTf (791 μL, 3.44 mmol, 1.25 eq) at 0°C. The reaction was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction was concentrated directly onto celite and purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in hexanes) to afford TBS ether (1.35 g, 100% yield).

[0644] Step j: The TBS ether product of step i (674 mg, 1.41 mmol) was mixed with B2Pin2 (457 mg, 1.8 mmol, 1.3 eq), Pd(dppf)Cl2 (103 mg, 0.14 mmol, 0.1 eq) and potassium acetate (213 mg, 3 mmol, 2.2 eq) in dioxane (14 ml, 0.1 M) and the resulting solution was heated to 100° C. for three hours. The reaction solution was concentrated and the crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to give the desired boronic acid pinacol ester (638 mg, 86% yield) as a colorless oil.

[0645] The protocol for the following steps is the same as that for Example 134. 1 H NMR (400MHz, CDCl3) δ7.75 (d, J=8.2Hz, 1H), 7.52 (ddd, J=8.3, 2.8, 1.4Hz, 1H), 7.4 0 (ddd, J=7.5, 2.7, 1.7Hz, 1H), 6.60 (d, J=8.2Hz, 1H), 5.73–5.50 (m, 2H), 5.46–5.2 3 (m, 1H), 4.74–4.60 (m, 1H), 3.79–3.51 (m, 1H), 3.36–3.20 (m, 1H), 3.02 (d, J=4.2H z, 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 (376MHz, CDCl3) δ -77.43, -110.37 (d, J=1.6Hz), -157.81 (d, J=45.0Hz), -197.41--202.71 (m). C 21 H 15 ESIMS of F6NNaO3S[M+Na] + , calculated value 498.1, measured value 498.0.

[0646] Example 137: (5S,8R)-8-[3-chloro-2-cyano-4-(trifluoromethyl)phenyl]-3,5-difluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0647]

[0648] Step a: A solution of 4-bromo-2-chloro-1-(trifluoromethyl)benzene (15.0 g, 57.8 mmol) in tetrahydrofuran (600 mL) is placed in a 1 L single-necked round-bottom flask equipped with a nitrogen inlet adapter with a rubber septum. The solution is cooled to -78 ° C and LDA solution (43 ml, 87.0 mmol, 2 M solution in THF / heptane / ethylbenzene) is added dropwise via a syringe over 10 minutes. The reaction mixture is stirred at -78 ° C for 1 h, then dried at -78 ° C for 30 minutes before CO gas is bubbled through the mixture. The cooling bath is replaced with an ice / water mixture, and CO bubbling continues for another 30 minutes. Under vigorous stirring, the reaction mixture is carefully poured into a 3M HCl aqueous solution (700 mL) and the product is extracted with EtOAc (3 × 300 mL). The combined organic extracts are washed with brine and dried over Na SO . The solvent was distilled off under reduced pressure, and the residue was partitioned between 3M aqueous NaOH solution (400 mL) and MTBE (250 mL). The organic phase was separated, and the aqueous phase was extracted with an additional MTBE (200 mL). The separated aqueous solution was acidified to pH ~ 3 with 3M aqueous HCl solution, and the product was extracted with dichloromethane (3 x 200 mL). The combined extracts were dried over Na2SO4 and concentrated to dryness to give the corresponding benzoic acid (17.5 g, 57.6 mmol, 99% yield) as an orange oil.

[0649] Step b: A mixture of benzoic acid (17.5 g, 57.6 mmol), thionyl chloride (12.6 mL, 173.0 mmol) and N,N-dimethylformamide (0.3 mL) in anhydrous benzene (290 mL) from step a was placed in a 500 mL single-necked round-bottom flask equipped with a reflux condenser with a drying tube. The reaction was refluxed for 6 h, then cooled to ambient temperature, and excess thionyl chloride and benzene were distilled off under reduced pressure. The oily residue was dissolved in THF (150 mL) and added dropwise to a 30% aqueous ammonium hydroxide solution (150 mL) cooled to 0° C. over 30 minutes. Once the addition was complete, the reaction was stirred vigorously for 20 minutes. 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 hexanes (200 mL) and the resulting grey precipitate was collected by filtration to give the corresponding benzamide (15.0 g, 49.7 mmol, 86% yield) as a grey solid.

[0650] Step c: a mixture of the benzamide (30.1 g, 99.5 mmol) and cyanuric chloride (25.6 g, 139.4 mmol) of step b 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 Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was fractionated by flash chromatography (silica gel, 0% to 25% ethyl acetate in hexane) to obtain the desired benzonitrile (15.1 g, 53.0 mmol, 53% yield) as a white crystalline solid.

[0651] Step d: Benzylnitrile from step c (0.5 g, 1.8 mmol) was mixed with B2Pin2 (0.58 g, 2.3 mmol, 1.3 equiv), Pd(dppf)Cl2 (0.13 g, 0.18 mmol, 0.1 equiv) and potassium acetate (0.35 g, 3.5 mmol, 2.0 equiv) in dioxane (9 ml, 0.2 M) in a 40 mL vial with a magnetic stir bar. The mixture was degassed under vacuum, backfilled with nitrogen and heated to 90° C. for 1 h. After TLC analysis indicated complete consumption of the starting material, the reaction mixture was cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue was partitioned between EtOAc (30 mL) and water (20 mL). The organic layer was separated and the aqueous phase was extracted with additional EtOAc (2×15 mL). The combined organic extracts were dried over Na2SO4 and the solvent was evaporated under reduced pressure to give crude pinacol boronic acid ester, which was used without further purification.

[0652] 8-cyano-6-fluoro-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (0.57 g, 1.8 mmol) was added to the crude pinacol borate together with dioxane (9 mL, 0.2 M) and the mixture was loaded into a 40 ml vial. Pd (dppf) Cl (0.13 g, 0.18 mmol) and 2 M aqueous sodium carbonate solution (1.8 ml, 3.6 mmol) were then added successively. The mixture was degassed under vacuum, backfilled with nitrogen and heated to 100 ° C for 1 h. Once complete, dioxane was removed under reduced pressure. The residue was distributed between EtOAc (30 mL) and water (20 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried over Na SO and concentrated to dryness. The crude product was purified by column chromatography (SiO2, hexane / EtOAc gradient) to give the desired olefin (0.27 g, 0.7 mmol, 41% yield) as a light brown solid.

[0653] Step e: the alkene (0.27g, 0.7mmol) of step d is dissolved in anhydrous methanol (10mL) and triethylamine (0.5mL, 3.6mmol), then palladium / carbon (80.0mg, 10%Pd weight) is added under nitrogen atmosphere. Reactant mixture is placed in hydrogen atmosphere with 50psi and stirred 1 hour in Parr oscillator. Excess hydrogen is discharged and this mixture is bubbled with nitrogen to remove residual hydrogen. The gained suspension is filtered through diatomite pad, and filtrate is concentrated under reduced pressure to the dry crude mixture that obtains required product and corresponding dechlorination compound. For separating required product, crude mixture is carried out column chromatography (SiO , hexane / EtOAc gradient) to generate tetralin derivative (0.1g, 0.26mmol, 37% productive rate), it is white solid.

[0654] Step f: the tetralin derivative (0.3g, 0.8mmol), MnO of step e (0.28g, 3.2mmol) and dichloromethane (4mL, 0.2M) are loaded into a 40mL bottle, which is equipped with a magnetic stirring bar. The mixture is cooled to 0°C and tBuO is added dropwise over 5 minutes. H (1.5mL, 8mmol, 5.5M solution in decane) is reacted and stirred at 0°C for 10 minutes, then warmed to ambient temperature and stirred until gas formation stops. The bottle is sealed and the gained black suspension is kept at 40°C for 24h, then cooled to room temperature and an additional amount of MnO (0.28g, 3.2mmol) and tBuO H (1.5mL, 8mmol, 5.5M solution in decane) are added in succession. The mixture is refluxed for 48h and cooled to room temperature. The inorganic solid is removed by filtration. The filtrate was diluted with dichloromethane (30 mL), passed through a celite pad, washed with water (20 mL), dried and concentrated to dryness using Na SO. The crude product was purified by column chromatography (SiO , hexane / EtOAc gradient) to generate the corresponding α-tetralone (0.14 g, 0.36 mmol, 45% yield) as a white solid.

[0655] Step g: To a solution of the α-tetralone (70.0 mg, 0.18 mmol) from step f in a mixture of MeOH (2 mL) and THF (3 mL) cooled to 0° C., NaBH 4 (14.0 mg, 0.36 mmol) was added in one portion. The reaction was stirred for 10 minutes and poured into a 1 M aqueous HCl solution (10 mL). The crude product was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated to dryness to produce a racemic mixture of cis and trans diastereomers. To separate the diastereomers, the crude mixture was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to give the major cis diastereomer (52.0 mg, 0.13 mmol, 74% yield, the less polar product) and the minor trans diastereomer (8.0 mg, 0.02 mmol, 11% yield, the more polar product). Both compounds were obtained as white solids.

[0656] 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, followed by the addition of TMS-morpholine (81 μL, 0.46 mmol). The reaction was stirred at 0 ° C for 5 minutes, then warmed to room temperature and stirred for 2 h. The resulting solution was cooled to 0 ° C and the solid 1,2,3,4-tetrahydro-1-naphthol (51.0 mg, 0.13 mmol) of step e was added once. The cooling bath was removed, and the reaction was stirred at room temperature for 30 minutes. Once TLC analysis indicated that the starting material was completely consumed, the mixture was diluted with EtOAc (20 mL) and quenched with saturated NaHCO aqueous solution (10 mL). The organic phase was separated, dried over Na SO and concentrated to dryness. The dry residue was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient) to give the title compound (44.0 mg, 0.11 mmol, 86% yield, single epimer) as a white foam. 1 HNMR (400MHz, CDCl3) δ7.70 (d, J=8.3Hz, 1H), 7.54 (dd, J=8.5, 2.7Hz, 1H), 7.41 (ddd, J=7.5, 2.7, 1.6Hz, 1H), 6.54 (d , J=8.3Hz, 1H), 5.58 (dt, J=49.9, 4.0Hz, 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 (376MHz, CDCl3) δ-63.06, -109.85, -159.45.C 19 H 10ESIMS of ClF5N2Na[M+Na] + , calculated value 419.0, measured value 419.2).

[0657] Example 138: (5R,8R)-8-[3-chloro-2-cyano-4-(trifluoromethyl)phenyl]-3,5-difluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0658]

[0659] Step a: Under nitrogen, 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., and then TMS-morpholine (13.0 μL, 0.072 mmol) was added. The reaction was stirred at 0 ° C. for 5 minutes, then warmed to room temperature and stirred for 2 h. The resulting solution was cooled back to 0 ° C. and a suspension of 1,2,3,4-tetrahydro-1-naphthol (8.0 mg, 0.02 mmol, prepared similarly to Example 134) in anhydrous toluene (0.5 mL) was added. The cooling bath was removed, and the reaction was stirred at room temperature for 30 minutes. Once TLC analysis indicated that the starting material was completely consumed, the mixture was diluted with EtOAc (10 mL) and quenched with saturated NaHCO3 aqueous solution (3 mL). The organic phase was separated, dried over Na2SO4 and concentrated to dryness. The dry residue was purified by column chromatography (SiO2, dichloromethane / EtOAc gradient) to give the title compound (7.0 mg, 0.018 mmol, 87% yield, single epimer) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.74 (d, J=8.3Hz, 1H), 7.58 (dd, J=8.5, 2.8Hz, 1H), 7.37 (dd, J=7.6, 2.5Hz, 1H), 6.68 (d, J=8. 3Hz, 1H), 5.62 (ddd, J=49.8, 8.4, 4.7Hz, 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 (376MHz, CDCl3) δ -63.03, -109.89, -169.86 (d, J=50.8Hz). C 19 H 10 ESIMS of ClF5N2Na[M+Na] + , calculated value 419.0, measured value 419.0).

[0660] 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

[0661]

[0662] Step a: A mixture of LDA (30mL, 59.3ml, 2M solution in THF / heptane / ethylbenzene) and anhydrous THF (240mL) is placed in a 500mL single-necked round-bottom flask under a nitrogen atmosphere, which is equipped with a magnetic stirring bar and a nitrogen inlet adapter with a rubber septum. The solution is cooled to -78 ° C under nitrogen and a solution of 2,5-dibromo-3-fluoropyridine (12.1g, 47.4mmol) in anhydrous THF (40mL) is added dropwise via a syringe over 20 minutes. The resulting mixture is stirred for 30 minutes and MeI (5mL, 81mmol) is added dropwise at -78 ° C over 5 minutes. The cooling bath is then removed and the reaction is warmed to ambient temperature and stirred for 1h, then quenched with saturated NH4Cl aqueous solution (200mL). The mixture is transferred to a separatory funnel, diluted with water (100mL) and EtOAc (200mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine, 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% to 30% ethyl acetate in hexanes) to give 2,5-dibromo-3-fluoro-4-methyl-pyridine (12.0 g, 44.6 mmol, 94% yield) as a colorless crystalline oil.

[0663] 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-necked round-bottom flask equipped with a magnetic stirring 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 a 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 with saturated NH4Cl aqueous solution (50 mL) at -78 ° C. The resulting two-phase mixture was diluted with water (50 mL) and EtOAc (100 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (silica gel, 0% to 40% ethyl acetate in hexanes) to give the corresponding 2-acetylpyridine (2.8 g, 12.1 mmol, 54% yield) as a colorless crystalline oil.

[0664] Step c: A mixture of the 2-acetylpyridine (2.8 g, 12.0 mmol) and deoxo-fluor (6.7 mL, 36 mmol) of step b in toluene (60 mL) was placed in a 250 mL single-necked round-bottom flask equipped with a stirring rod and a reflux condenser with a drying tube. The mixture was kept at 70 ° C for 24 h. Although the conversion was incomplete, the two phases were cooled to ambient temperature and poured into a saturated NaHCO aqueous solution (200 mL) under vigorous stirring. The mixture was then diluted with EtOAc (200 mL) and filtered through a diatomaceous earth pad. The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 × 70 mL) again. The combined organic extracts were washed with brine, dried over Na SO and concentrated to dryness. The crude material was fractionated by flash chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to give 5-bromo-2-(1,1-difluoroethyl)-3-fluoro-4-methylpyridine (1.9 g, 7.5 mmol, 63% yield) as a light yellow liquid.

[0665] The protocol for the following steps is the same as that for Example 134. Characterization data of the title compound: 1 H NMR (400MHz, CDCl3) δ7.53–7.42 (m, 1H), 7.42–7.32 (m, 1H), 7.22 (s, 1H), 5.56 (dt, J=49.9, 3.3Hz, 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 FNMR (376MHz, CDCl3) δ-89.77(m), -110.97(m), -125.45, -156.81(m). C 19 H 16 ESIMS of F5N2 [M+H] + , calculated value 367.1, measured value 367.2).

[0666] Example 140: (8R)-8-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]-3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile.

[0667]

[0668] 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) was added DMAP (1.4 g, 11.2 mmol) and triethylamine (10.4 ml, 75 mmol, 2 equivalents), followed by the dropwise addition of acetic anhydride (7.1 ml, 75 mmol, 2 equivalents). The solution was warmed to room temperature and stirred for 1 hour. After completion, the reaction was quenched with saturated aq. NaHCO 3 , and the resulting solution was extracted with dichloromethane (2x), dried over Na 2 SO 4 , and concentrated onto celite. The crude material was purified by flash chromatography on silica gel (0-10% ethyl acetate in hexanes) to give [(1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (13.1 g, 100% yield). 12 H 12 ESIMS of BrFO4S[M+H] + , calculated value 351.0, measured value 351.0.

[0669] Step b: A solution of [(1S,2R)-4-bromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl]acetate (13.5 g, 38.5 mmol), 2,2′-azobis(2-methylpropionitrile) (40 mg, 1 mol%), and N-bromosuccinimide (7.54 g, 1.1 equiv) in dichloroethane (0.2 M, 190 ml) was heated to reflux for 90 minutes. Upon completion, the reaction was cooled and partitioned between ethyl acetate and saturated NaHCO₃. The organics were collected, washed with dilute Na₂SO₃, dried over Na₂SO₄, and concentrated to celite. The crude material was purified by flash chromatography on silica gel (5% ethyl acetate in a 1:3 ratio of CH2Cl2:hexanes) to provide two brominated diastereomers, [(1S,2S,3R)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl] acetate (6.83 g, 41% yield) and [(1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-yl] acetate (2.5 g, 15% yield). The diastereomeric products eluted in the order listed.

[0670] 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) was added 0.5 M aqueous LiOH (5.93 ml, 1.5 equiv) at 0° C. and the reaction was stirred at 0° C. for three hours, at which time the reaction was quenched with 1N HCl at 0° C. The resulting solution was extracted three times with dichloromethane, the organics were dried over Na2SO4, and flash chromatographed by 0 to 20% ethyl acetate in [1:1 hexanes:dichloromethane] to give (1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-ol (3.68 g, 61% yield).

[0671] Step d: Sodium hydride (60% dispersion in mineral oil, 440 mg, 10.5 mmol, 1.1 equiv) was slowly added to a solution of (1S,2S,3S)-3,4-dibromo-2-fluoro-7-methylsulfonyl-2,3-dihydro-1H-inden-1-ol (3.68 g, 9.5 mmol) and benzyl bromide (6.77 ml, 9.75 g, 57 mmol, 6 equiv) in THF (38 ml, 0.25 M relative to indanol) and DMF (9.5 ml, 1 M relative to indanol) at 0°C. The reaction was warmed to room temperature and stirred overnight. The next day, 3 additional equivalents of BnBr and 0.55 equivalents of NaH were added, and the reaction was complete within 2 hours. The solution was quenched with 1N HCl, extracted with ethyl acetate, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography on silica gel, 0 to 20% ethyl acetate in hexanes to afford (1S,2S,3S)-1,7-dibromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene as a white foam (2.46 g, 54% yield).

[0672] Step e: To a solution of (1S,2S,3S)-1,7-dibromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (2.46 g, 5.1 mmol) in sulfolane (28.4 ml) and water (5.6 ml) was added silver perchlorate hydrate (unknown hydrate stoichiometry) (2.13 g, 10.3 mmol) and the reaction was heated to 7°C in the dark overnight. After 23 hours, the starting material was almost completely consumed and the reaction was quenched with H2O. After dilution with MTBE, the silver salts were filtered from the two-phase mixture and the organics were collected and dried over sodium sulfate. Purification by flash chromatography (0 to 5% to 50% ethyl acetate in dichloromethane) gave the diastereomeric alcohol products (1R,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-inden-1-ol (750 mg, 35% yield) and (1S,2R,3S)-7-bromo-2-fluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-inden-1-ol (470 mg, 22% yield). The diastereomeric products eluted in the order listed, and the latter was carried forward to the subsequent step. 17 H 16 ESIMS of BrFO4S[M+Na] + , calculated value 437.0, measured value 437.0.

[0673] 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) was added (diethylamino)sulfur trifluoride (492 μl, 600 mg, 3.7 mmol, 4 equiv) and the resulting solution was stirred at a temperature of 0 to 10°C for three hours, at which time it was quenched with saturated NaHCO3. The organics were extracted with ethyl acetate, dried over Na2SO4, and purified by flash chromatography on silica gel (10% ethyl acetate in hexanes, isocratic) to give two fluorinated products: (1S,2S,3S)-7-bromo-1,2-difluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (unwanted, less polar, 158 mg, 40% yield) and (1R,2S,3S)-7-bromo-1,2-difluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (desired, more polar, 234 mg, 60% yield).

[0674] Step g: (1R,2S,3S)-7-bromo-1,2-difluoro-4-methylsulfonyl-3-phenylmethoxy-2,3-dihydro-1H-indene (234 mg, 0.56 mmol), B2Pin2 (185 mg, 0.73 mmol, 1.3 eq), KOAc (121 mg, 1.23 mmol, 2.2 eq) and PdCl2(dppf) (44 mg, 0.06 mmol, 10 mol%) were mixed in dioxane (5.6 ml, 0.1 M). The resulting solution was sparged with nitrogen and heated to 100° C. until all the starting material was consumed (2.5 h). The crude reaction mixture was filtered through celite, concentrated, dissolved in ethyl acetate, and washed with water to remove residual KOAc. The resulting solid was subjected to the Suzuki cross-coupling step without further purification.

[0675] The title compound was prepared in a similar manner to Example 134. 1 H NMR (400MHz, CDCl3): δ7.96 (dd, J=8.1, 2.0Hz, 1H), 7.23-7.17 (m, 2H), 6.86 (d, J=8.1Hz, 1H), 5.91-5.75 (m, overlap, 2 H), 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).

[0676] Example 141: 8-[(1S)-7-Cyano-2,2-difluoro-1-hydroxy-1,3-dihydroindan-4-yl]-3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0677]

[0678] Step a: proceed in a similar manner to step a of Example 134,

[0679] Step b: at 0 ℃ to the product of step a (10g, 38mmol, 1 equivalent) in CH2Cl2 (190mL, 0.2M) in a solution of Et3N (32mL, 228mmol, 6 equivalents), then TBSOTf (17.5mL, 76mmol, 2 equivalents) was added. The reaction was warmed to room temperature overnight. The reaction mixture was concentrated and then vacuum dried for 45 minutes. The crude silyl enol ether was dissolved in MeCN (190mL, 0.2M), then Selectfluor (20.2g, 57mmol, 1.5 equivalents) was added and the reaction was stirred at room temperature for 2 hours or until TLC was determined to be complete. The reaction mixture was diluted with EtOAc, washed with a 0.2M HCl aqueous solution, and then washed with brine. The organic layer was dried and concentrated with MgSO4. The crude product was purified by flash column chromatography (SiO2, 0 to 50% EtOAc / hexanes) to afford the difluoroketone as a light yellow solid (7.0 g, 24.9 mmol, 66%). 1 H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 8.4 Hz, 1H), 7.36 (dt, J = 8.4, 0.9 Hz, 1H), 3.48 (td, J = 12.6, 0.8 Hz, 2H).

[0680] Step c: proceed in a similar manner to Example 134, step b. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.45 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 5.22 (d, J = 12.4 Hz, 1H), 3.61-3.33 (m, 2H), 1.11 (t, J = 7.1 Hz, 2H).

[0681] Step d: proceed in a similar manner to step c of Example 134. 15 H 20 ESI MS[M+H] of BrClF2OSi + Calculated value 397.0, measured value 397.0.

[0682] Step e: proceed in a similar manner to Example 134, step d. The crude product was used in step f without purification by column chromatography.

[0683] Step f: proceed in a similar manner to step e of Example 134. 26 H 27 ESI MS of ClF3NOSi[M+H] + Calculated value 490.2, measured value 490.2.

[0684] Step g: Proceed in a similar manner to Example 134, step f, where 5 equivalents of Et3N are added to the reaction mixture. The diastereomers are not separated at this stage. 26 H 29 ESIMS[M+H] of ClF3NOSi + Calculated value 492.2, measured value 492.2.

[0685] Step h: Aryl chloride (100 mg, 0.20 mmol, 1 eq), K4Fe(CN)6·3H2O (59 mg, 0.14 mmol, 0.7 eq), XPhosPdG3 (17 mg, 0.02 mmol, 0.1 eq), XPhos (10 mg, 0.02 mmol, 0.1 eq) and KOAc (4 mg, 0.04 mmol, 0.2 eq) were dissolved in 1:1 water / dioxane (2 mL, 0.1 M). The reaction mixture was sparged with nitrogen for 10 minutes and then heated to 100°C. After 2 hours, the reaction was judged complete by LCMS. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and water. The layers were separated and the aqueous solution was extracted three times with EtOAc. The combined organics were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (SiO2, 0 to 50% EtOAc / hexane) to give the aryl nitrile product. C 27 H 29 ESIMS of F3N2OSi[M+H] + Calculated value 483.2, measured value 483.2.

[0686] Step i: The product of step h was treated with excess HF-pyridine in acetonitrile. After stirring overnight, the mixture was quenched with saturated NaHCO3 and extracted with EtOAc. The product was purified by flash column chromatography. The final product was separated into a 1:1 mixture of diastereomers (40 mg, 0.11 mmol. 54% over two steps). 21 H 15 ESIMS of F3N2O[M] + Calculated value 369.1, measured value 369.1. 1 H NMR (400MHz, chloroform-d) δ7.47 (dd, J=8.0, 2.9Hz, 1H), 7.18 (d, J=8.6Hz, 2H), 6.60 (dd, J=14.3, 8.0Hz, 1H), 5.33 (m, 1H), 4.45 (dt, J=9.0, 4.1Hz, 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).

[0687] 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

[0688]

[0689] Step a: To a solution of 3-bromo-4-chlorobenzotrifluoride (3.5 mL, 23 mmol, 1.0 equivalent) in THF (75 mL) in a 250-mL round-bottom flask was added LDA solution (2.0 M in THF / heptane / ethylbenzene, 17 mL, 1.5 equivalents) dropwise at -78 ° C under N 2 . After stirring at this temperature for 15 minutes, DMF (3.6 mL, 46 mmol, 2.0 equivalents) was added dropwise at -78 ° C and the resulting mixture was stirred at this temperature for another 1.5 hours, at which time TLC showed 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 organic layers were combined, 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).

[0690] Step b: the crude product from step a (with another batch, 8.45g in total) in a 250-mL round-bottom flask was dissolved in MeOH (100mL) and cooled to 0°C. NaBH was added in batches (1.67g, 1.5 equivalents) and the resulting mixture was stirred at 0°C for 30 minutes, when TLC showed that the reaction was complete. The reaction mixture was quenched with H o, then concentrated under reduced pressure to remove most of MeOH. The residue was extracted with EtOAc (100mL×3). The organic layers were combined, washed with salt water (60mL), and dried over Na sO . The product was concentrated under reduced pressure and purified by flash chromatography (SiO , 0 to 30% EtOAc / Hex) to give a white powder (2.75g, 9.50mmol, 41% yield over 2 steps). 1 H NMR (400 MHz, chloroform-d) δ 7.60 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 5.09 (d, J = 6.8 Hz, 2H), 2.20 (t, J = 7.0 Hz, 1H).

[0691] Step c: at room temperature to the product of step b (2.30g, 8.0mmol, 1.0 equivalent) and i-Pr NEt (2.8mL, 16.0mmol, 2.0 equivalent) in DCM (40mL) solution, drip chloromethyl methyl ether (1.2mL, 16.0mmol, 2.0 equivalent). Gained mixture is stirred 22h in this temperature, then uses saturated aq.NaHCO solution cancellation (20mL). Aqueous phase is extracted with DCM (30mL). Combine organic layer, with salt water washing (20mL), and use Na SO Drying. Under reduced pressure, concentrate to obtain crude product (1.84g), it is directly used in next step.

[0692] Step d: fill the crude product (1.06g) and DMF (20mL) of step c into 40-mL bottle.Add CuCN (1.43g, 16mmol, 2.0 equivalents) and the gained mixture is heated at 150 ℃ for 2h, then cooled to room temperature and diluted with EtOAc (50mL).The organic phase is then washed with H o (20mL×2) and salt solution (20mL), and uses Na sO dry.Concentrate under reduced pressure and obtain product by purified by flash chromatography (SiO , 10 to 40% EtOAc / Hex) as yellow solid (1.00g, 3.6mmol, 45% yield, through 2 steps). 1 H NMR (400 MHz, chloroform-d) δ 7.77 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 4.94 (s, 2H), 4.81 (s, 2H), 3.45 (s, 3H).

[0693] Step e: A 40-mL vial was charged with the product of step d (1.00 g, 3.6 mmol, 1.0 eq), B2Pin2 (1.17 g, 4.6 mmol, 1.3 eq), PCy3-Pd-G2 (0.213 g, 0.36 mmol, 10 mol%), KOAc (0.707 g 7.2 mmol, 2.0 eq) and 1,4-dioxane (10 mL). The reaction mixture was degassed with N2 for 10 minutes and then heated. After stirring at 100 °C for 2 h, the reaction mixture was cooled, diluted with EtOAc (20 mL), washed with H2O (10 mL), dried over Na2SO4, and concentrated to give the crude product (1.84 g), which was used in the next step.

[0694] Step f: A 40-mL vial was charged with the crude product from step e (1.84 g), alkenyl triflate (1.16 g, 3.6 mmol, 1.0 eq), Pd(dppf)Cl (0.263 g, 0.36 mmol, 10 mol%), NaCO (0.763 g, 7.2 mmol, 2.0 eq), 1,4-dioxane (10 mL), and H0 (2 mL). The reaction mixture was degassed with N2 for 10 minutes and then heated. After stirring at 100°C for 1 h, the reaction mixture was cooled, filtered, concentrated, and purified by flash chromatography (SiO2, 10 to 30% EtOAc / Hex) to provide the product (0.743 g, 1.78 mmol, 50% yield over 2 steps). 1 H NMR (400MHz, chloroform-d) δ7.79 (d, J=8.Hz, 1H), 7.61 (d, J=8.2Hz, 1H), 7.23 (dd, J=8.2, 2.8Hz, 1H), 7.14 (dd, J=8.0, 2.8Hz, 1H) , 6.35 (t, J=4.9Hz, 1H), 4.61–4.52 (m, 3H), 4.50 (d, J=6.7Hz, 1H), 3.29 (s, 3H), 2.92 (t, J=7.8Hz, 2H), 2.57–2.39 (m, 2H).

[0695] Step g: A mixture of the product of step f (0.535 g, 1.3 mmol, 1.0 eq), Pd / C (10 wt% Pd, 0.600 g) in MeOH (10 mL) was shaken in a parr hydrogenator under H (50 psi) for 3 h when TLC showed completion of the reaction. The reaction mixture was then filtered through celite and concentrated to give the product, which was used directly in the next step.

[0696] Step h: To the vial containing the product of step g was added DCM (13 mL), MnO 2 (0.452 g, 5.2 mmol, 4.0 equiv) and t-BuOOH solution (5.5 M in decane, 2.4 mL, 13 mmol, 10 equiv). The resulting mixture was heated at 40° C. overnight and an additional 4.0 equiv of MnO 2 and 10 equiv of t-BuOOH solution were added to the reaction mixture. After an additional overnight reaction, the reaction mixture was filtered through celite, concentrated, and purified by flash chromatography (SiO 2, 10 to 20% EtOAc / Hex) to give the desired product (0.272 g, 0.629 mmol, 48% yield over 2 steps). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (dd, J = 8.2, 2.7 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 7.2, 2.9 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.23–5.13 (m, 3H), 4.87 (s, 2H), 3.51 (s, 3H), 2.75–2.64 (m, 2H), 2.63–2.55 (m, 1H), 2.49–2.41 (m, 1H).

[0697] Step i: A 40-mL bottle was filled with the product of step h (78.1 mg, 0.18 mmol, 1.0 equiv), RuCl(p-isopropylphenylmethane)[(R,R)-TsDPEN] (11.5 mg, 18 μmol, 10 mol%), HCO H (41.4 mg, 0.90 mmol, 5.0 equiv), Et N (54.6 mg, 0.54 mmol, 3.0 equiv) and DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The crude material was purified by flash chromatography (SiO , 30 to 50% EtOAc / Hex) to give the desired product (27.2 mg, 62.6 μmol, 35% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.70 (dd, J = 9.2, 2.7 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.31–7.23 (m, 1H), 6.92 (d, J = 8.3 Hz, 1H), 5.20–5.06 (m, 2H), 4.92–4.81 (m, 4H), 3.50 (s, 3H), 2.40–2.26 (m, 2H), 2.18–1.99 (m, 2H), 1.84–1.70 (m, 1H).

[0698] Step j: to Deoxo-Fluor (2.7M in toluene, 0.219mmol, 80 μ L, 3.5 equivalents) in DCM (2mL) solution, TMS-morpholine (0.222mmol, 35.4mg, 3.55 equivalents) was added dropwise at -78 ℃ over 1 minute. The resulting solution was stirred at this temperature for 5min, then warmed to room temperature and kept for 2h, then cooled back to -78 ℃. The product of step i (27.2mg, 62.6 μ mol, 1.0 equivalents) in DCM (1mL) was then added to the reaction mixture. The resulting mixture was then stirred at room temperature for another 15 minutes, and now TLC showed that the reaction was complete. The reaction mixture was then diluted with DCM (10mL), washed with saturated NaHCO 3 aqueous solution (5mL), washed with Na 2 SO 4 dried, and concentrated. The residue was then purified by flash chromatography (SiO2, 25% EtOAc / Hex) to afford the fluorinated product (25.1 mg, 57.5 μmol, 92% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.62–7.51 (m, 2H), 7.40 (ddd, J=7.5, 2.7, 1.6 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 5.61 (dt, J=49.9, 3.8 Hz, 1H), 5.21–5.07 (m, 2H), 4.99–4.92 (m, 1H), 4.89–4.83 (m, 2H), 3.51 (s, 3H), 2.65–2.51 (m, 1H), 2.23–2.08 (m, 1H), 2.04–1.90 (m, 2H).

[0699] Step k: A solution of the product of step j (23.0 mg, 52.7 μmol, 1.0 eq) in MeOH (0.5 mL) and 6M HCl (aq., 0.5 mL) was heated at 60° C. for 1 h, then concentrated. The residue was purified by flash chromatography (SiO , 30% EtOAc / Hex) to give the title compound as a white solid (17.3 mg, 44.0 μmol, 84% yield). 1H NMR (400 MHz, chloroform-d) δ 7.66 (d, J = 7.9 Hz, 1H), 7.59–7.55 (m, 1H), 7.43 (ddd, J = 7.4, 2.7, 1.8 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.73–5.55 (m, 2H), 5.37 (d, J = 15.6 Hz, 1H), 4.61–4.51 (m, 1H), 2.58 (tdd, J = 13.7, 6.3, 3.1 Hz, 1H), 2.29–2.19 (m, 1H), 2.13–1.90 (m, 1H), 1.84 (ddt, J = 14.0, 5.8, 3.2 Hz, 1H). 20 H 12 ESIMS of F5NO2[M+H] + , calculated value 394.1, measured value 394.0.

[0700] Example 143: (5S,8R)-8-[(1S)-2,2-difluoro-1-hydroxy-7-(2-methylpyrazol-3-yl)-1,3-dihydroindan-4-yl]-3,5-difluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0701]

[0702] Step a: From 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxy-7-chloro-2,2-difluoro-1,3-dihydroindan-4-yl]-3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, the compound 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxy-7-chloro-2,2-difluoro-1,3-dihydroindan-4-yl]-3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carbonitrile was prepared according to the same procedure as described in Example 134. 1 H NMR (400 MHz, chloroform-d) δ

[0703] 8.04 (dddd, J=8.4, 2.9, 1.6, 0.5Hz, 1H), 7.53 (dt, J=7.3, 2.9Hz, 1H), 7.09 (d, J=8.3Hz, 1H), 6.35 (dd, J=13.2, 8.3Hz, 1H), 5.29–

[0704] 5.01 (m, 1H), 4.62 (m, 1H), 3.80–3.33 (m, 2H), 2.80–2.30 (m, 2H), 2.20– 2.10 (m, 1H), 1.60–1.50 (m, 1H), 1.00–0.72 (m, 9H), 0.36–0.11 (m, 6H).

[0705] Step b: A vial was charged with 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxy-7-chloro-2,2-difluoro-1,3-dihydroindan-4-yl]-3-fluoro-5-oxo-7,8-dihydro-6H-naphthalene-1-carbonitrile (30 mg, 0.06 mmol, 1.0 eq) from step a and a mixture of solvents (MeOH 0.2 ml, THF 0.3 ml). The reaction mixture was cooled to 0° C. and NaBH 4 (2.2 mg, 0.06 mmol, 1.0 eq) was added. The reaction mixture was stirred at 0° C. for 30 minutes. Upon completion, purification by flash chromatography (SiO2, hexanes to 30% EtOAc) afforded (5R)-8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxy-7-chloro-2,2-difluoro-1,3-dihydroindan-4-yl]-3-fluoro-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (18 mg, 0.035 mmol, 59%).

[0706] C 26 H 29 ESIMS[M+H] of ClF3NO2Si + , calculated value 509.1, measured value 525.1.

[0707] Step c: To the...

Claims

1. Compounds represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: Y 1 , Y 2 , Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , CR 6 R 7 NR 7 , O, SO2 and bond; and Y 1 , Y 2 , Y 3 and Y 4 One of them is CR 6 R 7 or NR 7 ; and Y 1 , Y 2 , Y 3 and Y 4 No more than one of them is a key; W 1 , W 2 and W 3 Each independently selected from CR 5 and N; R 1 Selected from H, halogen, hydroxyl, CN, NO2, -NR a R b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b 、-S(O)(=NH)R a and -S(O)2NR a R b ; Each R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(=NH)R a and-NR a R b ; Each R 4 Independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl and -C(O)R a , Each R 5 independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(=NH)R a and-NR a R b ; R 6 Selected from H, C 1-4 Alkyl, OH, F and CN; R 7 is a group having the formula: in: X 1 N or CR 8a ; X 2 N or CR 8b ; R 8a and R 8b independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ; R 9 and R 10 independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ; R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b 、-S(O)2NR c R b 、-S(O)(=NH)R c 、-S(O)2R c and a 5- or 6-membered heterocyclic or heteroaromatic ring having 1-3 heteroatoms selected from N, O and S as ring vertices; wherein the heterocyclic or heteroaromatic ring is optionally substituted with 1 to 3 members independently selected from the following: halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyl haloalkyl and C 1-4 Alkoxy C 1-4 alkyl; or R 9 and R 10 Combined to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with one or more substituents independently selected from the following: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 , the heterocyclic ring or heteroaromatic ring each has 1 to 4 heteroatoms selected from N, O and S as ring vertices; or R 10 and R 11 are combined to form a 5- or 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is 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 heterocyclic ring or heteroaromatic 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 independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ; or two R on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 The groups combine to form an oxo group; Each R a and R b Independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy and C 1-8 hydroxyalkyl, and R c , when present, is selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl, the heterocycloalkyl or heteroaryl rings each having 1 to 4 heteroatoms selected from N, O and S as ring vertices.

2. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Y 2 , Y 3 and Y 4 Each is CR 2 R 3 .

3. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Y 2 and Y 3 Each is CR 2 R 3 , and Y 4 is the key.

4. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, having formula (II): in Z is N or CR 6 ; Y 2 , Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , O, SO2 and bond; and Y 2 , Y 3 and Y 4 No more than one of them is a key; W 1 , W 2 and W 3 Each independently selected from CR 5 and N; R 1 Selected from H, halogen, hydroxyl, CN, NO2, -NR a R b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b 、-S(O)(=NH)R a and -S(O)2NR a R b ; Each R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(=NH)R a and-NR a R b ; Each R 4 Independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl and -C(O)R a , Each R 5 independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(=NH)R a and-NR a R b ; X 1 N or CR 8a ; X 2 N or CR 8b ; R 8a and R 8b independently selected from H, halogen, CN, NH2, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ; R 9 and R 10 independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ; R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -NR c R b 、-C(O)NR c R b 、-C(O)OH、-S(O)2NR c R b 、-S(O)(=NH)R c 、-S(O)2R c , phenyl, 5- to 6-membered heterocyclic ring or 5- to 10-membered heteroaromatic ring, wherein the heterocyclic ring and heteroaromatic ring have 1-3 heteroatoms selected from N, O and S as ring vertices; wherein the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1-2 heteroatoms selected from N, O and S as ring vertices; and wherein the phenyl, heterocyclic ring or heteroaromatic ring is optionally substituted with 1 to 3 members independently selected from the following: halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyl haloalkyl and C 1-4 Alkoxy C 1-4 Alkyl; optionally wherein the two members attached to the same carbon of the heterocyclic ring together form a =CH2 or oxo (=O) group; or R 9 and R 10 Combined to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with one or more substituents independently selected from the following: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 , the heterocyclic ring or heteroaromatic ring each has 1 to 4 heteroatoms selected from N, O and S as ring vertices; or R 10 and R 11 are combined to form a 5- or 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with one or more substituents independently selected from the following: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 , the heterocyclic ring or heteroaromatic 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 independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ; or two R on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 The groups combine to form an oxo group; Each R a and R b Independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy and C 1-8 hydroxyalkyl, and R c , when present, is selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl rings each have 1 to 4 heteroatoms selected from N, O and S as ring vertices.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III): in Y 2 , Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , SO2, O and bond; and Y 2 , Y 3 and Y 4 No more than one of them is a key; W 1 and W 3 are each independently selected from CH and N; Z is N or CR 6 ; R 1 is selected from halogen and CN; Each R 2 and R 3 Each independently selected from H, halogen, CN, NH2, NO2, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -S(O)2R a 、-CO2R a 、-C(O)R a 、-C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(=NH)R a and-NR a R b Each R 4 Independently selected from H, C 1-3 Alkyl, C 3-6 Cycloalkyl and -C(O)R a ; R 5a is selected from hydrogen, halogen and CN; R 6 is H; X 1 N or CR 8a ; X 2 N or CR 8b ; R 8a and R 8b independently selected from H, halogen, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-3 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ; R 9 and R 10 independently selected from H, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-S(O)2NR a R b and -S(O)2R a ; R 11 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyhaloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -C(O)NR c R b 、-C(O)OH、-S(O)2NR c R b 、-S(O)(=NH)R c 、-S(O)2R c , phenyl and a 5- or 6-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring has 1-3 heteroatoms selected from N, O and S as ring vertices; wherein the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1-2 heteroatoms selected from N, O and S as ring vertices; and wherein the phenyl, heterocyclic ring or heteroaromatic ring is optionally substituted with 1 to 3 members independently selected from the following: halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Hydroxyl haloalkyl and C 1-3 Alkoxy C 1-4 Alkyl; optionally wherein the two members attached to the same carbon of the heterocyclic ring together form a =CH2 or oxo (=O) group; or R 9 and R 10 Combined to form a 5-membered carbocyclic or heterocyclic ring or a 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is optionally substituted with one or more substituents independently selected from the following: R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 , the heterocyclic ring or heteroaromatic ring each has 1 to 4 heteroatoms selected from N, O and S as ring vertices; or R 10 and R 11 are combined to form a 5- or 6-membered carbocyclic, heterocyclic or heteroaromatic ring, which is 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 heterocyclic ring or heteroaromatic 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 independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ; or two R on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 The groups combine to form an oxo group; Each R a and R b Independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy and C 1-3 hydroxyalkyl; and R c , when present, is selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl, the heterocycloalkyl or heteroaryl rings each having 1 to 4 heteroatoms selected from N, O and S as ring vertices.

6. The compound of claim 4, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has formula (IV-a): in Y 2 , Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , SO2 and bond; and Y 2 , Y 3 and Y 4 No more than one of them is a key; R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R b ; Each R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a and -C(O)NR a R b ; Each R 4 Independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and -C(O)R a , Each R 5 independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b .

7. The compound of claim 6, wherein X 1 and X 2 are independently selected from CH and N.

8. The compound of claim 4, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has formula (IV-b): in The subscript m is 1, 2, 3, 4, 5, 6, 7 or 8; The subscript n is 1 or 2; R z Represents R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 One or more of; Y 2 , Y 3 and Y 4 Each independently selected from CR 2 R 3 NR 4 , SO2 and bond; and Y 2 , Y 3 and Y 4 No more than one of them is a key; R 1 Selected from halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)2R a and -C(O)NR a R b ; Each R 2 and R 3 Each independently selected from H, halogen, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-8 Cycloalkyl, -S(O)2R a and -C(O)NR a R b ; Each R 4 Independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and -C(O)R a ; R 5 Selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -S(O)2R a 、-C(O)NR a R b and -S(O)2NR a R b ;and R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each is independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl and -NR a R b ; or two R on the same carbon atom 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 The groups combine to form an oxo group.

9. The compound of claim 8, wherein R 11 is phenyl, a 5- or 6-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring has 1-3 heteroatoms selected from N, O and S as ring vertices; wherein the phenyl is optionally fused to a 5- or 6-membered heterocyclic ring having 1-2 heteroatoms selected from N, O and S as ring vertices; and wherein the phenyl, heterocyclic ring or heteroaromatic ring is optionally substituted with 1 to 3 members independently selected from the following: halogen, CN, NO2, NH2, C(O)NH2, S(O)2CH3, -CH2NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyl haloalkyl and C 1-4 Alkoxy C 1-4 Alkyl; optionally wherein two members attached to the same carbon of the heterocyclic ring are taken together to form a =CH2 or oxo (=O) group.

10. The compound of claim 9, wherein R 11 Selected from:

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