Trifluorodimethyl sulfide molecule as HIF2a inhibitor

Abstract

The invention provides a trifluoromethyl sulfide molecule capable of being used as an HIF2a inhibitor. The trifluoromethyl sulfide molecule is a compound as shown in a formula (I), and an optical isomer or pharmaceutically acceptable salt of the trifluoromethyl sulfide molecule. The invention also provides a pharmaceutical composition containing the compound as shown in the formula (I), the optical isomer thereof or the pharmaceutically acceptable salt thereof. And uses thereof. The compound disclosed by the invention has a relatively strong HIF2a-ARNT binding inhibition effect and can play a role of an HIF2a inhibitor, so that the compound is used for preventing and / or treating related diseases caused by HIF2a overexpression. # imgabs0 #

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a trifluoromethyl sulfide molecule as a HIF2a inhibitor. Background Art

[0002] Hypoxia inducible factor (HIF) is a key factor that controls gene expression in cells under hypoxic conditions. HIF factors have two subunits, α (alfa) and β (beta), of which the beta subunit is the structural unit aromatic hydrocarbon receptor nuclear translocator (ANRT) protein, and the alfa subunit is the oxygen sensing unit. The alfa subunit of HIF is divided into three types: HIF1a, HIF2a and HIF3a. In terms of function, HIF-1a and HIF-2a promote vascular development under hypoxic conditions, and HIF-3a can limit the expression of HIF-1a and HIF-2a. Studies have shown that HIF1-a is easily activated under short-term, high-degree hypoxia conditions; while HIF-2a plays a dominant role under long-term, low-degree hypoxia conditions.

[0003] The VHL (Von Hippel-Lindau) gene is a member of the E3 ubiquitin ligase complex, responsible for regulating the degradation of the HIF2a factor. The protein expressed by the tumor suppressor gene VHL can induce the ubiquitination and degradation of the transcription factor HIF, and VHL mutations can lead to the continuous activation of HIF2a, which in turn leads to the upregulation of G1 / S-specific cyclin D1, type A vascular epidermal growth factor (VEGF-A), transforming growth factor a (TGF-a), etc., which promote tumor proliferation. VHL mutations or methylation can cause the accumulation of HIF2a in cells, triggering angiogenesis, and causing various benign and malignant tumors in the brain, eyes, spinal cord, pancreas, and kidneys.

[0004] The HIF2a inhibitor PT2977 developed by Peloton has been clinically approved for the treatment of VHL syndrome; the HIF2a inhibitor NKT2152 developed by NiKang Therapeutics and the HIF2a inhibitor BPI-452080 developed by Beda Pharmaceuticals have also entered the clinical trial stage for advanced solid tumors. New molecular structures still need to be developed clinically to obtain HIF2a inhibitors with better efficacy.

[0005] At present, many ophthalmic diseases related to neovascularization, such as corneal angiogenesis caused by long-term wearing of corneal contact lenses (contact lenses), age-related macular degeneration (dry or wet), diabetic retinopathy, retinal vein occlusion, diabetic macular edema, etc., are mainly caused by long-term hypoxia in local tissues (such as cornea or retina). Long-term low-grade hypoxia activates HIF2a and induces cells to express angiogenesis factors such as vascular epidermal growth factor (VEGF) and angiopoietin-2 (ANG2). Therefore, inhibiting HIF-2a may bring good therapeutic effects to patients with ophthalmic angiogenesis diseases.

[0006] HIF2a inhibitors can change the conformation of HIF2a, prevent HIF2a from binding to ARNT, and inhibit the overexpression of HIF2a caused by VHL gene deletion, so they can be used to treat VHL-related diseases and ophthalmic neovascularization-related diseases. Summary of the invention

[0007] The purpose of this application is to provide a trifluoromethyl sulfide molecule that can be used as a HIF2a inhibitor, which has a strong HIF2a-ARNT binding inhibitory effect and can play the role of a HIF2a inhibitor, thereby being used to prevent and / or treat related diseases induced by HIF2a overexpression. The specific technical solution is as follows:

[0008] In a first aspect, the present application provides a compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof,

[0009]

[0010] wherein X is selected from CH or N;

[0011] L is selected from -O-, -NH-, -S-, -CH2-, -CF2-, -CH(F)-, -(C1-C3 alkylene)O-, -CH(CN)O-;

[0012] A is selected from C1-C6 alkyl, C2-C6 alkenyl, C6-C12 aryl, C3-C8 cycloalkyl, C3-C10 cycloalkenyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl;

[0013] B, C are independently selected from -CH2-, -CHF-, -CF2-;

[0014] R 1 , R 2 , R 3Each is independently selected from hydrogen, halogen, cyano, isocyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C2-C6 alkenyl, -C1-C3 alkylene-OH, C1-C6 heteroalkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -NHCHO;

[0015] The C1-C6 heteroalkyl group is selected from -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -SCH3, -SCH2CH3, -SOCH3;

[0016] The 3-8 membered heterocycloalkyl group and the 5-10 membered heteroaryl group contain 1-3 heteroatoms or heteroatom groups independently selected from O and N.

[0017] In some embodiments of the first aspect, the compound is a compound represented by formula (II):

[0018]

[0019] In some embodiments of the first aspect, the compound is a compound represented by formula (IIa):

[0020]

[0021] In some embodiments of the first aspect, R 1 and R 2 Each is independently selected from H, CN, F, Cl, CH3, CF3.

[0022] In some embodiments of the first aspect, the compound is a compound represented by formula (IIb):

[0023]

[0024] Wherein, A2 is selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl.

[0025] In some embodiments of the first aspect, in the compound represented by formula (IIb), Selected from

[0026] In some embodiments of the first aspect, in the compound represented by formula (IIb), Selected from

[0027] In some embodiments of the first aspect, the compound is a compound represented by formula (IIc):

[0028]

[0029] In some embodiments of the first aspect, the compound is a compound represented by formula (III):

[0030]

[0031] In some embodiments of the first aspect, the compound is a compound represented by formula (IV):

[0032]

[0033] In some embodiments of the first aspect, the compound is a compound represented by formula (V):

[0034]

[0035] In some embodiments of the first aspect, the compound is selected from any one of the following compounds:

[0036]

[0037]

[0038] In some embodiments of the first aspect, the compound is selected from any one of the following compounds:

[0039]

[0040] The second aspect of the present application provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound described in the first aspect of the present application, its optical isomer or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments of the second aspect, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients.

[0042] The third aspect of the present application provides the use of the compound described in the first aspect of the present application, its optical isomer or its pharmaceutically acceptable salt, or the pharmaceutical composition described in the second aspect of the present application in the preparation of a drug for preventing and / or treating VHL-related diseases.

[0043] In some embodiments of the third aspect, the VHL-related disease is selected from at least one of renal cancer, brain glioma, lung cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, gastric cancer, liver cancer, thyroid cancer, multiple myeloma, pancreatic ductal carcinoma, squamous cell carcinoma of the lung, colon cancer, and hemangioma.

[0044] The fourth aspect of the present application provides the use of the compound described in the first aspect of the present application, its optical isomer or its pharmaceutically acceptable salt, or the pharmaceutical composition described in the second aspect of the present application in the preparation of a medicament for preventing and / or treating ophthalmic neovascularization-related diseases, wherein the ophthalmic neovascularization-related diseases are selected from at least one of corneal neovascularization, retinal neovascularization, diabetic retinopathy, diabetic macular edema, age-related macular degeneration, retinal vein occlusion, dry fundus macular degeneration, and wet fundus macular degeneration.

[0045] The fifth aspect of the present application provides use of the compound described in the first aspect of the present application, its optical isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second aspect of the present application in the preparation of a HIF2α inhibitor.

[0046] In some embodiments of the fifth aspect, the HIF2α inhibitor is used to prevent and / or treat related diseases induced by overexpression of HIF2a.

[0047] In some embodiments of the fifth aspect, the related diseases induced by overexpression of HIF2a are selected from at least one of renal cancer, brain glioma, lung cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, gastric cancer, liver cancer, thyroid cancer, multiple myeloma, liver cancer, pancreatic ductal carcinoma, lung squamous cell carcinoma, colon cancer, hemangioma, corneal vascular proliferation, diabetic retinopathy, retinal vein occlusion, diabetic macular edema, dry fundus macular degeneration, and wet fundus macular degeneration.

[0048] The sixth aspect of the present application provides a method for preventing and / or treating VHL-related diseases, comprising administering a therapeutically effective amount of a compound of formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0049] The seventh aspect of the present application provides a method for preventing and / or treating ophthalmic neovascularization-related diseases, comprising administering a therapeutically effective amount of a compound of formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a patient in need.

[0050] In an eighth aspect, the present application provides a method for preventing and / or treating diseases related to overexpression of HIF2a, comprising administering a therapeutically effective amount of a compound of formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0051] The ninth aspect of the present application provides a compound as described in the first aspect of the present application, an optical isomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in the second aspect of the present application for use as a medicine or for treatment.

[0052] Definition and Description

[0053] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0054] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0055] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention, prepared from the compounds discovered by the invention with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0056] The compounds of the present invention may exist in specific optical isomers. The present invention contemplates all optical isomers of such compounds, including cis-trans isomers, enantiomers, diastereomers, single configuration compounds, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may exist in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0057] Unless otherwise indicated, the term "enantiomer" refers to stereoisomers that are mirror images of one another.

[0058] Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers in which, when a molecule has more than one asymmetric carbon atom, some of the asymmetric carbon atoms have different configurations but are not mirror images of each other.

[0059] Unless otherwise indicated, the term "cis-trans isomers" arises from the inability of a double bond or a single bond of a ring carbon atom to rotate freely.

[0060] When the substituent is listed without indicating the atom through which it is connected to the substituted group, the substituent can be bonded through any atom thereof. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0061] When a substituent is listed without specifying which atom it is attached to in the substituted group, the substituent may be attached to any atom in the substituted group. For example, a pyridyl group as a substituted group may be substituted at any position.

[0062] When the listed linking group L does not specify its connection direction, its connection direction is arbitrary. For example, when L between the benzene ring and the cyclobutyl group A is selected from -CH2O-, it can be selected that the carbon atom is connected to the benzene ring and the oxygen atom is connected to the cyclobutyl group, or it can be selected that the oxygen atom is connected to the benzene ring and the carbon atom is connected to the cyclobutyl group.

[0063] Unless otherwise specified, the term "C1-C6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. Examples of the C1-C6 alkyl include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0064] Unless otherwise specified, the term "C2-C6 alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 1 to 6 carbon atoms and containing 1 to 3 double bonds. Examples of the C2-C6 alkenyl include, but are not limited to, ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, etc.

[0065] Unless otherwise specified, the term "C2-C6 alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 1 to 6 carbon atoms and containing 1 to 3 double bonds. Examples of the C2-C6 alkynyl group include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, pentynyl, hexynyl, etc.

[0066] Unless otherwise specified, "C3-C8 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, which is a monocyclic or bicyclic ring system, wherein the bicyclic ring system includes spiro, cyclo and bridged rings. Examples of the C3-C8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3,3]heptyl, etc.

[0067] Unless otherwise specified, "C3-C10 cycloalkenyl" means a cyclic hydrocarbon group consisting of 3 to 10 carbon atoms and containing 1 to 3 double bonds, which is a monocyclic or bicyclic ring system, wherein the bicyclic ring system includes spiro, fused and bridged rings. Examples of C3-C10 cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, etc.

[0068] Unless otherwise specified, "halogen" means fluorine, chlorine, bromine or iodine.

[0069] Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized. It includes monocyclic, bicyclic and tricyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. In addition, with respect to the "3-8 membered heterocycloalkyl", heteroatoms may occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. Examples of 3-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

[0070] Unless otherwise specified, the term "5-10 membered heteroaryl" by itself or in combination with other terms refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from oxygen, nitrogen or sulfur, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. The 5-10 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0071] Unless otherwise specified, the term "C1-C6 heteroalkyl" itself or in combination with another term, represents a stable straight or branched alkyl radical or its composition consisting of a certain number of carbon atoms and at least one heteroatom or heteroatomic group. In some embodiments, the heteroatom is selected from oxygen, nitrogen, phosphorus and sulfur, wherein nitrogen, phosphorus and sulfur atoms are optionally oxidized, and nitrogen, phosphorus heteroatoms are optionally quaternized. The heteroatom or heteroatomic group can be located at any internal position of the heteroalkyl, including the connection position of the alkyl group to the rest of the molecule. Examples of C1-C6 heteroalkyl include but are not limited to -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -SCH3, -SCH2CH3, -SOCH3, etc.

[0072] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-6 includes C1, C2, C3, C4, C5 and C6, and also includes any range from n to n+m, for example, C1-C6 includes C2-C6, etc.; similarly, n to n+m members means that the number of atoms in the ring is n to n+m, for example, 3-10 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, and also includes any range from n to n+m, for example, 3-10 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring,

[0073] The compounds of the present application, their optical isomers or pharmaceutically acceptable salts thereof, can be used in a suitable dosage form with one or more pharmaceutical carriers or excipients. These dosage forms are suitable for oral, rectal, topical, oral and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, intravitreal, subretinal, suprachoroidal, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules and syrups. The compounds of the present application contained in these preparations can be solid powders or particles; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or water-in-oil emulsions, etc. The above dosage forms can be made from active compounds and one or more carriers or excipients via a common pharmaceutical method. The above carriers need to be compatible with active compounds or other excipients. For solid preparations, commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc. Carriers for liquid preparations include water, saline, aqueous glucose solution, ethylene glycol and polyethylene glycol, etc. The active compound may be in the form of a solution or suspension with the above-mentioned carriers.

[0074] "Pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of excipient that is compatible with a patient, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to a target site without terminating the activity of the agent.

[0075] The "active substance of the present application" or "active compound of the present application" refers to the compound of formula (I) of the present application, or its optical isomer, or its pharmaceutically acceptable salt, which has a higher HIF2α selective inhibitory activity.

[0076] The compositions of the present application are formulated, dosed and administered in a manner consistent with medical practice. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

[0077] "Therapeutically effective amount" refers to the amount of the compound of the present invention that will induce a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0078] The therapeutically effective amount of the compound of the present application or its optical isomer, or its pharmaceutically acceptable salt contained in the pharmaceutical composition or the pharmaceutical composition of the present application is preferably 0.1 mg / kg to 5 g / kg (body weight).

[0079] "Patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.

[0080] "Treatment" means to lessen, slow the progression, attenuate, prevent, or maintain an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.

[0081] The "pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Pharmaceutically acceptable acid addition salts refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.

[0082] "Pharmaceutically acceptable base addition salts" include, but are not limited to, salts of inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts, etc., and include, but are not limited to, salts of organic bases such as ammonium salts, triethylamine salts, lysine salts, arginine salts, etc. These salts can be prepared by methods known in the art.

[0083] The present application provides a trifluoromethyl sulfide molecule that can be used as a HIF2a inhibitor, wherein the HIF2a inhibitor is a compound shown in formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof; the present application also provides a pharmaceutical composition comprising the compound shown in formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof; and uses thereof. The compound of the present application has a strong HIF2a-ARNT binding inhibitory effect, and can play the role of a HIF2a inhibitor, thereby being used to prevent and / or treat related diseases induced by overexpression of HIF2a. DETAILED DESCRIPTION

[0084] The technical solutions in the embodiments of the present application are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field based on the present application belong to the scope of protection of the present application.

[0085] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0086] Abbreviations:

[0087] MeCN, ACN: acetonitrile; Select-F: 1-chloromethyl-4-fluoro-1,4-diazobicyclo 2.2.2 octane bis(tetrafluoroborate); PhMe: toluene; 1,10-phen: 1,10-phenanthroline; KSAc: potassium thioacetate; THF: tetrahydrofuran; EtOH: ethanol; DMF: N,N-dimethylformamide; Et3N, TEA: triethylamine; Py: pyridine; Cy: cyclohexane; PivOH: pivalic acid; Me OH: methanol; CyOH: cyclohexanol; DIAD: diisopropyl azodicarboxylate; PPh3: triphenylphosphine; DCM: dichloromethane; MsCl: methanesulfonyl chloride; TsCl: p-toluenesulfonyl chloride; DMAP: 4-dimethylaminopyridine; LDA: lithium diisopropylamide; DAST: diethylaminosulfur trifluoride; NBS: N-bromosuccinimide; MeI: iodomethane; DEAD: diethyl azodicarboxylate; TBDPSCl: tert-butyldiphenylchlorosilane; DMP: Dess-Martin periodinane; Bestmann's reagent: dimethyl 1-diazo-2-oxopropylphosphonate; TBAF: tetrabutylammonium fluoride; EA: ethyl acetate; TsOH: p-toluenesulfonic acid; AIBN: azobisisobutyronitrile; DIPEA: diisopropylethylamine; MeSO3H: methanesulfonic acid; DME: ethylene glycol dimethyl ether; PBSF: perfluorobutylsulfonyl fluoride; DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene; mC PBA: meta-chloroperbenzoic acid; TMSOTf: trimethylsilyl trifluoromethanesulfonate; tBuXPhos-Pd-G3: methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II); Tf2O: trifluoromethanesulfonic anhydride; BAST: [bis(2-methoxyethyl)amine]sulfur trifluoride; Boc2O: di-tert-butyl dicarbonate; TFA: trifluoroacetic acid;

[0088] LC-MS: liquid chromatography-mass spectrometry; room temperature (RT) refers to 25±5°C; 1M or 1N is 1 mol / L; 1mM is 1 mmol / L; 1μM is 1μmol / L; 1nM is 1nmol / L. Yield or production rate = actual mass of synthetic product / theoretical mass of synthetic product × 100%.

[0089] Example 1: 3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

[0090] Step A. 7-iodo-4-methoxy-2,3-dihydro-1H-inden-1-one

[0091] A solution of iodine (29.3 g, 115.5 mmol) in acetonitrile was cooled to 0°C and Select-F (33.5 g, 94.4 mmol) was added. The resulting solution was stirred at 0°C for 0.5 h, then 4-methoxy-1-indanone (17.0 g, 105 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was spin-dried and ethyl acetate (500 mL) and sodium thiosulfate aqueous solution (10 wt%, 300 mL) were added. The organic phase was washed with saturated brine and dried over sodium sulfate. The concentrated product was separated by column chromatography to obtain the product (20.0 g, yield 66.1%).

[0092] Step BS-(7-methoxy-3-oxo-2,3-dihydro-1H-inden-4-yl)thiol acetate

[0093] To a toluene (400 mL) solution of 7-iodo-4-methoxy-2,3-dihydro-1H-inden-1-one (19.2 g, 66.7 mmol) were added cuprous iodide (1.26 g, 6.6 mmol), 1,10-phenanthroline (1,10-phen, 1.2 g, 6.7 mmol) and potassium thioacetate (15.2 g, 133.3 mmol). The reaction mixture was filled with nitrogen and heated at 110°C for 16 h. The reaction mixture was filtered and concentrated, and the residue was purified by column chromatography to obtain the product (12 g, yield 76.2%).

[0094] Step C. 7-Mercapto-4-methoxy-2,3-dihydro-1H-inden-1-one

[0095] To a tetrahydrofuran / ethanol solution (50 mL / 15 mL) of S-(7-methoxy-3-oxo-2,3-dihydro-1H-inden-4-yl)thiol acetate (5.0 g, 21.1 mmol) was added sodium hydroxide (0.85 g, 21.1 mmol). After stirring at room temperature for 0.5 h, a dioxane hydrochloride solution (4 mol / L, 6 mL) was added. The reaction solution was concentrated to obtain a crude product (5 g, yield 100%), which was used directly in the next step.

[0096] Step D. 4-Methoxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0097] 7-mercapto-4-methoxy-2,3-dihydro-1H-inden-1-one (5.0 g, 21.1 mmol), triethylamine (4.3, 42.5 mmol) and methylviologen (372 mg, 2 mmol) were added to a solution of trifluoroiodomethane in DMF (40%, 32 g, 65.3 mmol). The reaction was stirred at room temperature for 16 h. The reaction solution was filtered, concentrated and purified by column chromatography to obtain the product (3.0 g, yield 48%).

[0098] Step E. 4-Hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0099] A mixture of pyridine hydrochloride (200 g) and 4-methoxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (3.0 g, 11.4 mmol) was heated at 180°C for 6 h. After cooling, ice water was poured into the mixture, and the product was filtered and dried to obtain the product (2.0 g, yield 70.7%).

[0100] Step F. 2,2-Difluoro-4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0101] 3-methoxylproylamine (923 mg, 10.4 mmol), pivalic acid (10.2 mg, 0.1 mmol) and anhydrous sodium sulfate (2.0 g) were added to a toluene / cyclohexane (5 mL / 5 mL) solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (260 mg, 1.04 mmol). The reaction solution was filled with nitrogen and heated at 80 ° C for 16 h, then concentrated to remove the solvent, and anhydrous acetonitrile (10 mL) was added. Select-F (1.84 g, 5.2 mmol) was added to the reaction solution and heated at 65 ° C for 5 h. The reaction was adjusted to pH <7 with 1N hydrochloric acid, and then ethyl acetate (100 mL × 3) was added for extraction. The organic phases were combined, washed with saturated brine (100 mL × 3), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (180 mg, yield 61%).

[0102] Step G. 2,2-Difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol

[0103] Sodium borohydride (60 mg, 1.58 mmol) was added to a solution of 2,2-difluoro-4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (210 mg, 0.74 mmol) in tetrahydrofuran / methanol (5 mL / 5 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (50 mL) was then added and extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL×3) and dried over sodium sulfate. After concentration under reduced pressure, the product was purified by column chromatography (165 mg, yield 78%).

[0104] Step H. 3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

[0105] Add 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (10 mg, 0.035 mmol), 3,5-difluorobenzonitrile (6 mg, 0.042 mmol), potassium carbonate (8 mg, 0.053 mmol) and DMF (2 mL) into a sealed tube. Add the mixture in a sealed tube at 100°C for 0.5 h, then cool and filter. After the filtrate is concentrated, purify it with reverse phase high performance liquid chromatography to obtain the product (4 mg, yield 17%).

[0106] LC-MS ESI(-)m / z:404.1(MH) - .

[0107] 1 H NMR(400MHz, CDCl3) δ7.61(d,J=8.4Hz,1H),6.94(ddd,J=8.4,4.0,2.0Hz,2H),6.84(q,J=1.6Hz,1H ),6.66(dt,J=9.2,2.4Hz,1H),5.27(dd,J=12.0,3.6Hz,1H),3.56–3.33(m,2H),2.73–2.59(m,1H).

[0108] Example 2: 4-(cyclohexyloxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0109]

[0110] Step A. 4-(Cyclohexyloxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0111] DIAD (162 mg, 0.80 mmol) and triphenylphosphine (210 mg, 0.80 mmol) were added to a solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (100 mg, 0.40 mmol) and cyclohexanol (80 mg, 0.80 mmol) in tetrahydrofuran (10 mL). After reacting for 12 hours, the mixture was concentrated and purified by column chromatography to obtain the product (40 mg, yield 30.0%).

[0112] LC-MS: m / z 331 (M+H) + .

[0113] Step B. 4-(Cyclohexyloxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0114] To a toluene / cyclohexane (5mL / 5mL) solution of 4-(cyclohexyloxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (100mg, 0.3mmol), 3-methoxypropylamine (40mg, 0.45mmol), pivalic acid (5.1mg, 0.05mmol) and anhydrous Na2SO4 (2.0g) were added. The reaction solution was filled with nitrogen and heated at 80℃ for 16h, then concentrated to remove the solvent, and anhydrous acetonitrile (20mL) was added. Select-F (531mg, 1.5mmol) was added to the reaction solution, and heated at 80℃ for 4h. After the reaction solution was concentrated, it was purified by column chromatography to obtain the product (25mg, yield 23%).

[0115] LC-MS: m / z 367 (M+H) + .

[0116] Step C. 4-(Cyclohexyloxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0117] Sodium borohydride (60 mg, 1.58 mmol) was added to a solution of 4-(cyclohexyloxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (25 mg, 0.07 mmol) in tetrahydrofuran / methanol (2.5 mL / 2.5 mL). The reaction solution was stirred at room temperature for 3 h. Ice water (5 mL) was then added. After concentration under reduced pressure, the product was purified by column chromatography (10 mg, yield 45%).

[0118] LC-MS: m / z 369 (M+H) + .

[0119] Example 3: 4-(1-cyclobutylethoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0120] Step A. 4-(1-cyclobutylethoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0121] DIAD (162 mg, 0.80 mmol) and triphenylphosphine (210 mg, 0.80 mmol) were added to a solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (100 mg, 0.40 mmol) and 1-cyclobutylethanol (80 mg, 0.80 mmol) in tetrahydrofuran (10 mL). After reacting for 12 hours, the mixture was concentrated and purified by column chromatography to obtain the product (30 mg, yield 22.5%). LC-MS: m / z 331 (M+H) + .

[0122] Step B. 4-(1-cyclobutylethoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0123] To a toluene / cyclohexane (5mL / 5mL) solution of 4-(1-cyclobutylethoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (100mg, 0.3mmol), 3-methoxypropylamine (40mg, 0.45mmol), pivalic acid (5.1mg, 0.05mmol) and anhydrous Na2SO4 (2.0g) were added. The reaction solution was filled with nitrogen and heated at 80℃ for 16h, then concentrated to remove the solvent, and anhydrous acetonitrile (20mL) was added. Select-F (531mg, 1.5mmol) was added to the reaction solution, and heated at 80℃ for 4h. After the reaction solution was concentrated, it was purified by column chromatography to obtain the product (20mg, yield 18.2%).

[0124] LC-MS: m / z 367 (M+H) + .

[0125] Step C. 4-(1-cyclobutylethoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0126] Sodium borohydride (26 mg, 0.70 mmol) was added to a solution of 4-(1-cyclobutylethoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (25 mg, 0.07 mmol) in methanol (5 mL). The reaction solution was stirred at room temperature for 3 h. Ice water (5 mL) was then added. After concentration under reduced pressure, the product was purified by column chromatography (10 mg, yield 45%).

[0127] LC-MS: m / z 369 (M+H)+ .

[0128] Example 4: 2,2-difluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0129] Step A. (1-(Trifluoromethyl)cyclobutyl)methanol

[0130] To a solution of 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (100 mg, 0.56 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (100 mg, 2.62 mmol) at 0°C. The reaction solution was stirred at room temperature for 1 h, then sodium sulfate decahydrate was added to quench, filtered, and washed with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (50 mg, yield 54.6%).

[0131] Step B. (1-(Trifluoromethyl)cyclobutyl)methyl methanesulfonate

[0132] Triethylamine (100 mg, 0.99 mmol) and methanesulfonyl chloride (100 mg, 0.88 mmol) were added to a solution of (1-(trifluoromethyl)cyclobutyl)methanol (50 mg, 0.32 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched by adding ice water, and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over sodium sulfate, concentrated, and used directly in the next step.

[0133] Step C. 2,2-Difluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0134] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a solution of (1-(trifluoromethyl)cyclobutyl)methyl methanesulfonate (100 mg) in DMF (2 mL). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by column chromatography (10 mg, yield 33.9%).

[0135] LC-MS: m / z 421(MH) - .

[0136] 1H NMR (400MHz, CDCl3) δ7.62(d,J=8.6Hz,1H),6.92(d,J=8.6Hz,1H),5.25(dd,J=12.2,3.1Hz,1H),4.16(s,2H),3.5 8–3.29(m,2H),2.56(d,J=3.5Hz,1H),2.43(ddd,J=13.0,10.3,8.0Hz,2H),2.25–2.12(m,2H),2.12–1.97(m,2H).

[0137] Embodiment 5, embodiment 6:

[0138] (1s,3s)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylcyclobutane-1-carbonitrile

[0139] (1r,3r)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylcyclobutane-1-carbonitrile

[0140]

[0141] Step A. 3-Hydroxy-1-methylcyclobutane-1-carbonitrile

[0142] Sodium borohydride (73 mg, 1.82 mmol) was added to a solution of 1-methyl-3-oxocyclobutane-1-carbonitrile (100 mg, 0.91 mmol) in tetrahydrofuran / methanol (5 mL / 5 mL) at 0°C. The reaction solution was stirred at room temperature for 1 h, quenched with ammonium chloride, and extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was used directly in the next reaction.

[0143] Step B. 3-Cyano-3-methylcyclobutanol 4-methylbenzenesulfonate

[0144] Triethylamine (100 mg, 0.99 mmol) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of 3-hydroxy-1-methylcyclobutane-1-carbonitrile (80 mg, 0.72 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (61 mg, yield 31.4%).

[0145] Step C

[0146] (1s,3s)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylcyclobutane-1-carbonitrile

[0147] (1r,3r)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylcyclobutane-1-carbonitrile

[0148] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a DMF (2 mL) solution of 3-cyano-3-methylcyclobutanol 4-methylbenzenesulfonate (61 mg, 0.23 mmol). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. Cooled, filtered, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product:

[0149] Example 5: (1s,3s)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylcyclobutane-1-carbonitrile (10 mg).

[0150] LC-MS: m / z 378 (MH) - .

[0151] 1 HNMR(400MHz,Chloroform-d)δ7.60(d,J=8.6Hz,1H),6.71(d,J=8.6Hz,1H),5.25(d,J=12.1Hz,1H),4.94(t,J=7.0 Hz,1H),3.60–3.28(m,2H),3.22–3.07(m,2H),2.63(s,1H),2.31(dddt,J=12.1,6.7,3.5,1.7Hz,2H),1.65(s,3H).

[0152] Example 6: (1r,3r)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylcyclobutane-1-carbonitrile (8 mg).

[0153] LC-MS: m / z 378 (MH) - .

[0154] 1H NMR(400MHz,Chloroform-d)δ7.58(d,J=8.6Hz,1H),6.64(d,J=8.3Hz,1H),5.26(dd,J=12.1,3.2Hz,1H),4.8 4(t,J=6.6Hz,1H),3.60–3.33(m,2H),2.88–2.76(m,2H),2.76–2.66(m,2H),2.66–2.57(m,1H),1.65(s,3H).

[0155] Example 7: 3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylcyclohexyl-1-carbonitrile

[0156]

[0157] Step A. 3-Hydroxy-1-methylcyclohexyl-1-carbonitrile

[0158] Sodium borohydride (73 mg, 1.82 mmol) was added to a solution of 1-methyl-3-oxocyclohexyl-1-carbonitrile (100 mg, 0.91 mmol) in tetrahydrofuran / methanol (5 mL / 5 mL) at 0°C. The reaction solution was stirred at room temperature for 1 h, quenched with ammonium chloride, and extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was directly used for the next reaction.

[0159] Step B. 3-Cyano-3-methylcyclohexanol methanesulfonate

[0160] Triethylamine (100 mg, 0.99 mmol), methanesulfonyl chloride (100 mg, 0.88 mmol) and DMAP (10 mg, 0.08 mmol) were added to a solution of 3-hydroxy-1-methylcyclohexyl-1-carbonitrile (80 mg, 0.58 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched by adding ice water, and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over sodium sulfate, concentrated, and used directly in the next step.

[0161] Step C. 3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylcyclohexyl-1-carbonitrile

[0162] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a solution of 3-cyano-3-methylcyclohexanol methanesulfonate (50 mg, 0.23 mmol) in DMF (2 mL). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by column chromatography (12 mg, yield 19.7%).

[0163] LC-MS: m / z 406(MH) - .

[0164] 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.6Hz,1H),6.99(d,J=8.6Hz,1H),5.2 5(d,J=12.4Hz,1H),4.68–4.55(m,1H),3.51–3.27(m,2H),2.61(s,1H),2.50–2. 37(m,1H),2.26(d,J=15.3Hz,1H),2.04(d,J=15.8Hz,1H),1.97(dt,J=14.5,3. 4Hz,1H),1.92–1.73(m,1H),1.47(s,3H),1.44–1.38(m,2H),1.37–1.26(m,3H).

[0165] Example 8: 3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)cyclobutane-1-carbonitrile

[0166]

[0167] Step A. 3-Hydroxycyclobutane-1-carbonitrile

[0168] Sodium borohydride (73 mg, 1.82 mmol) was added to a solution of 3-oxocyclobutane-1-carbonitrile (100 mg, 1.05 mmol) in tetrahydrofuran / methanol (5 mL / 5 mL) at 0°C. The reaction solution was stirred at room temperature for 1 h, quenched with ammonium chloride, and extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was used directly in the next reaction.

[0169] Step B. 3-Cyanocyclobutanol 4-methylbenzenesulfonate

[0170] Triethylamine (100 mg, 0.99 mmol) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of 3-hydroxycyclobutane-1-carbonitrile (80 mg, 0.82 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (58 mg, yield 29.2%).

[0171] Step C. 3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)cyclobutane-1-carbonitrile

[0172] To a solution of 3-cyano-3-methylcyclobutanol 4-methylbenzenesulfonate (61 mg, 0.23 mmol) in DMF (2 mL) were added 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase HPLC (13 mg, yield 23.7%).

[0173] LC-MS: m / z 364 (MH) - .

[0174] 1 H NMR(400MHz,Chloroform-d)δ7.60(d,J=8.6Hz,1H),6.69(d,J=8.6Hz,1H),5.25(dd,J=12.0,3.6Hz,1H),5.12–5.00(m,1H),3.5 5–3.35(m,2H),3.28(ddd,J=9.9,5.0,1.3Hz,1H),2.93(dtd,J=14.0,4.7,2.4Hz,2H),2.68(dddd,J=17.5,9.1,4.6,1.5Hz,3H).

[0175] Example 9: 4-(cyclohex-3-ene-1-oxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0176] Step A. 3-Cyclohexenyl-1-yl 4-methylbenzenesulfonate

[0177] Triethylamine (100 mg, 0.99 mmol) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of 3-cyclohexenyl-1-ol (80 mg, 0.81 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (63 mg, yield 33.4%).

[0178] Step B. 4-(Cyclohex-3-ene-1-oxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0179] To a solution of 3-cyclohexenyl-1-yl 4-methylbenzenesulfonate (63 mg, 0.24 mmol) in DMF (2 mL) were added 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase HPLC (20 mg, yield 22.8%).

[0180] LC-MS: m / z 365 (MH) - .

[0181] 1 H NMR (400MHz, Chloroform-d) δ7.58(d,J=8.6Hz,1H),6.94(d,J=8.6Hz,1H),5.89–5.52(m,2H),5.25(ddd,J=12.4,4.6,1.6Hz,1H),4.65(tq,J=9.4,3. 0Hz,1H),3.60–3.17(m,2H),2.71–2.42(m,2H),2.40–2.15(m,3H),2.04(d dddd,J=8.6,7.0,5.4,3.6,1.5Hz,1H),1.87(ddt,J=12.6,5.6,3.2Hz,1H).

[0182] Example 10: 3-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)oxetane-3-carbonitrile

[0183]

[0184] Step A. 3-(Chloromethyl)oxetane-3-carbonitrile

[0185] A solution of oxetane-3-carbonitrile (100 mg, 0.83 mmol) in tetrahydrofuran (5 mL) was cooled to -70 °C. LDA (0.6 mL, 1.20 mmol) was added under nitrogen. Stir for 0.5 h, and chloroiodomethane (150 mg, 0.85 mmol) was added. The reaction solution was slowly warmed to room temperature, stirred for 16 hours, and then poured into saturated ammonium chloride to quench, and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine and dried over sodium sulfate. After concentration under reduced pressure, it was directly used in the next reaction.

[0186] Step B. 3-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)oxetane-3-carbonitrile

[0187] To a solution of 3-(chloromethyl)oxetane-3-carbonitrile (80 mg) in DMF (2 mL) were added 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase HPLC (10 mg, yield 17.5%).

[0188] LC-MS: m / z 380 (MH) - .

[0189] 1 H NMR(400MHz,Chloroform-d)δ7.68(d,J=8.3Hz,1H),6.97(d,J=8.6Hz,1H),5.27(dd,J=12.1,3.8Hz,1H), 5.10(d,J=6.7Hz,2H),4.68(d,J=6.7Hz,2H),4.57–4.45(m,2H),3.62–3.34(m,2H),2.69(d,J=5.4Hz,1H).

[0190] Example 11: 4-(cyclobutylmethoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0191] Step A. Cyclobutylmethanol 4-methylbenzenesulfonate

[0192] Triethylamine (100 mg, 0.99 mmol) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of cyclobutanemethanol (60 mg, 0.70 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (62 mg, yield 35.7%).

[0193] Step B. 4-(Cyclobutylmethoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0194] To a solution of cyclobutylmethanol 4-methylbenzenesulfonate (62 mg) in DMF (2 mL) were added 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase HPLC (20 mg, yield 32%).

[0195] LC-MS: m / z 353 (MH) - .

[0196] 1 H NMR (400MHz, Chloroform-d) δ7.60(d,J=8.6Hz,1H),6.90(d,J=8.6Hz,1H),5.26(d,J=12.4Hz,1H),4.01(dd,J=6. 4,2.1Hz,2H),3.60–3.27(m,2H),2.81(d,J=7.3Hz,1H),2.69–2.44(m,1H),2.32–2.09(m,2H),2.11–1.77(m,4H).

[0197] Example 12, Example 13: 2,2-difluoro-4-((3-fluorocyclohexanol)oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0198] Step A. 3-Hydroxycyclohexanol 4-methylbenzenesulfonate

[0199] Triethylamine (869 mg, 8.6 mmol) and p-toluenesulfonyl chloride (950 mg, 5.0 mmol) were added to a solution of cyclohexyl-1,3-diol (500 mg, 4.3 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (40 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (300 mg, yield 25.8%).

[0200] Step B. 3-Fluorocyclohexanol 4-methylbenzenesulfonate

[0201] DAST (1 mL) was added to a dichloromethane solution (10 mL) of 3-hydroxycyclohexanol 4-methylbenzenesulfonate (300 mg, 1.1 mmol). The reaction solution was stirred at room temperature for 5 h, poured into ice water, and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over sodium sulfate, concentrated, and separated by column chromatography to obtain the product (30 mg, yield 10%).

[0202] Step C. 2,2-Difluoro-4-((3-fluorocyclohexanol)oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0203] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (40 mg, 0.15 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a DMF (2 mL) solution of 3-fluorocyclohexanol 4-methylbenzenesulfonate (30 mg). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. The solution was cooled, filtered, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product.

[0204] Example 12, cis isomer: LC-MS: m / z 385 (MH) - .

[0205] 1 H NMR (400MHz, Chloroform-d) δ5.26 (ddd, J=12.1, 4.7, 1.7Hz, 1H), 4.63 (dddd, J= 47.5, 13.7, 9.5, 4.0Hz, 1H), 4.43–4.30 (m, 1H).

[0206] Example 13, trans isomer: LC-MS: m / z 385 (MH) - .

[0207] 1H NMR(400MHz,Chloroform-d)δ7.58(d,J=8.3Hz,1H),6.92(dd,J=18.3,8.6Hz,1H),5.33–5.19(m,1H),4.63(dddd,J=47.8,14.0,9.8,4.2Hz,1H),4 .44–4.28(m,1H),3.57–3.27(m,2H),2.58(td,J=5.1,1.9Hz,1H),2.47(d d,J=13.7,12.1Hz,1H),2.18–1.94(m,2H),1.80(dt,J=12.4,9.5Hz,1H).

[0208] Embodiment 14, embodiment 15:

[0209] (1r,3r)-3-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutane-1-carbonitrile (1s,3s)-3-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutane-1-carbonitrile

[0210] Step A. (3-Cyanocyclobutyl)methanol 4-methylbenzenesulfonate

[0211] Triethylamine (100 mg, 0.99 mmol), DMAP (1 mg) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of 3-(hydroxymethyl)cyclobutane-1-carbonitrile (100 mg, 0.90 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (80 mg, yield 33.5%).

[0212] Step B

[0213] (1r,3r)-3-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutane-1-carbonitrile (1s,3s)-3-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutane-1-carbonitrile

[0214] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a solution of (3-cyanocyclobutyl)methanol 4-methylbenzenesulfonate (80 mg) in DMF (2 mL). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase high performance liquid chromatography:

[0215] Example 14, trans isomer: (1r,3r)-3-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutane-1-carbonitrile, 12 mg.

[0216] LC-MS: m / z 378 (MH) - .

[0217] 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.6Hz,1H),6.90(d,J=8.6Hz,1H),5.26(d,J=12.1Hz,1H),4.12–3.98(m,2H), 3.59–3.30(m,2H),3.28–3.15(m,1H),3.15–3.01(m,1H),2.72–2.54(m,3H),2.43(dddd,J=13.7,8.9,5.5,2.6Hz,2H).

[0218] Example 15, cis isomer: (1s,3s)-3-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutane-1-carbonitrile, 8 mg.

[0219] 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.6Hz,1H),6.96–6.80(m,1H),5.26(d,J=12.1Hz,1H),4.13–3.95(m,2H), 3.61–3.34(m,2H),3.12(p,J=8.9Hz,1H),2.88(ddt,J=11.8,8.9,4.4Hz,1H),2.75–2.53(m,3H),2.49–2.35(m,2H).

[0220] Example 16: 2,2-difluoro-4-(2-fluorocyclohex-2-ene-1-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0221] Step A. 6-Chloro-1-fluorocyclohex-1-ene

[0222] DAST (0.5 mL) was added to a solution of 2-chlorocyclohexanone (100 mg, 0.75 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 h, poured into a saturated sodium bicarbonate solution to quench, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, concentrated, and used directly in the next step.

[0223] Step B. 2,2-Difluoro-4-(2-fluorocyclohex-2-ene-1-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0224] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (40 mg, 0.15 mmol) and K2CO3 (100 mg, 0.72 mmol) were added to a DMF (2 mL) solution of 6-chloro-1-fluorocyclohex-1-ene (60 mg). The reaction solution was stirred at 80°C for 16 h under nitrogen. The solution was cooled, filtered, concentrated, and purified by reverse phase HPLC to obtain the product (10 mg, yield 17.3%). LC-MS: m / z 383 (MH) - .

[0225] 1 H NMR(400MHz,Chloroform-d)δ7.56(d,J=8.3Hz,1H),7.03(d,J=8.3Hz,1H),4.88–4.67(m,1H),4.65–4 .37(m,2H),3.09–2.97(m,2H),2.79–2.68(m,2H),2.48(s,2H),2.16–1.97(m,3H),1.94–1.75(m,3H).

[0226] Example 17: 4-(4,4-difluorocyclohexyloxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0227] Step A. 4,4-Difluorocyclohexanol 4-methylbenzenesulfonate

[0228] Triethylamine (100 mg, 0.99 mmol), DMAP (2 mg) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of 4,4-difluorocyclohexan-1-ol (100 mg, 0.73 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (60 mg, yield 28.3%).

[0229] Step B. 4-(4,4-difluorocyclohexyloxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0230] To a solution of 4,4-difluorocyclohexanol 4-methylbenzenesulfonate (60 mg, 0.207 mmol) in DMF (2 mL) were added 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase HPLC (10 mg, yield 16.5%).

[0231] LC-MS: m / z 403(MH) - .

[0232] 1 H NMR(400MHz,Chloroform-d)δ7.58(d,J=8.5Hz,1H),6.89(d,J=8.7Hz,1H),5.24(dd,J=12.0,3. 9Hz,1H),4.68–4.55(m,1H),3.52–3.27(m,2H),2.60(dd,J=4.6,1.8Hz,1H),2.12–1.89(m,8H).

[0233] Example 18: 1-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-3,3-difluorocyclobutane-1-carbonitrile

[0234]

[0235] Step A. 3,3-Difluorocyclobutane-1-carbonitrile

[0236] DAST (0.5 mL) was added to 3-oxocyclobutane-1-carbonitrile (100 mg, 1.05 mmol) in dichloromethane (5 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 h and quenched by adding saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3), and the extract was washed with saturated brine (10 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (80 mg, yield 65.1%).

[0237] Step B. 3-(Chloromethyl)oxetane-3-carbonitrile

[0238] A solution of 3,3-difluorocyclobutane-1-carbonitrile (80 mg, 0.68 mmol) in tetrahydrofuran (5 mL) was cooled to -70 °C. LDA (0.6 mL, 1.20 mmol) was added under nitrogen. Stir for 0.5 h, and chloroiodomethane (150 mg, 0.85 mmol) was added. The reaction solution was slowly warmed to room temperature, stirred for 16 hours, and then poured into saturated ammonium chloride to quench, and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine and dried over sodium sulfate. After concentration under reduced pressure, it was directly used in the next reaction.

[0239] Step C. 1-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-3,3-difluorocyclobutane-1-carbonitrile

[0240] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a solution of 3-(chloromethyl)oxetane-3-carbonitrile (60 mg) in DMF (2 mL). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase high performance liquid chromatography (15 mg, yield 24.2%).

[0241] LC-MS: m / z 414 (MH) - .

[0242] 1 H NMR(400MHz,Chloroform-d)δ7.66(d,J=8.6Hz,1H),6.92(d,J=8.6Hz,1H),5.27(d,J=12.1Hz,1H),4.27( s,2H),3.60–3.36(m,2H),3.26(dt,J=15.6,12.4Hz,2H),3.03(tdd,J=12.4,8.9,3.5Hz,2H),2.68(s,1H).

[0243] Example 19: 1-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutane-1-carbonitrile

[0244]

[0245] Step A. 1-(Hydroxymethyl)cyclobutane-1-carbonitrile

[0246] At 0°C, sodium borohydride (73 mg, 1.82 mmol) was added to a solution of 1-cyanocyclobutane-1-carboxylic acid ethyl ester (100 mg, 0.65 mmol) in tetrahydrofuran / methanol (5 mL / 5 mL). The reaction solution was stirred at room temperature for 1 h, then quenched with saturated ammonium chloride and extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated. The product (60 mg) was used directly in the next step.

[0247] Step B. (1-Cyanocyclobutyl)methanol 4-methylbenzenesulfonate

[0248] Triethylamine (100 mg, 0.99 mmol), DMAP (5 mg) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of 1-(hydroxymethyl)cyclobutane-1-carbonitrile (60 mg, 0.54 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (60 mg, yield 42.6%).

[0249] Step C. 1-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutane-1-carbonitrile

[0250] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a solution of (1-cyanocyclobutyl)methanol 4-methylbenzenesulfonate (60 mg, 0.23 mmol) in DMF (2 mL). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase high performance liquid chromatography (12 mg, yield 21.1%).

[0251] LC-MS: m / z 378 (MH) - .

[0252] 1H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.5Hz,1H),6.90(d,J=8.5Hz,1H),5.24(ddd,J=12.3,4.8,1.4Hz ,1H),4.19(d,J=2.5Hz,2H),3.60–3.31(m,2H),2.75–2.57(m,3H),2.42–2.22(m,3H),2.22–2.06(m,1H).

[0253] Example 20: 3-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-3-fluorocyclobutane-1-carbonitrile

[0254]

[0255] Step A. 3-(Bromomethyl)-3-fluorocyclobutane-1-carbonitrile

[0256] To a solution of 3-methylenecyclobutane-1-carbonitrile (100 mg, 1.08 mmol) in tetrahydrofuran (5 mL) was added NBS (205 mg, 1.15 mmol) and Et3N.3HF (433 mg, 1.52 mmol) at 0°C. The reaction solution was stirred at room temperature for 4 h, quenched by adding saturated sodium bicarbonate, and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine and dried with sodium sulfate. After concentration, the product was purified by column chromatography (60 mg, yield 28.9%).

[0257] Step B. 3-(((2,2-Difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-3-fluorocyclobutane-1-carbonitrile

[0258] To a solution of 3-(bromomethyl)-3-fluorocyclobutane-1-carbonitrile (60 mg, 0.31 mmol) in DMF (2 mL) were added 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase HPLC (15 mg, yield 25.2%).

[0259] LC-MS: m / z 396(MH) - .

[0260] 1H NMR(400MHz,Chloroform-d)δ7.62(d,8.6Hz,1H),6.96(d,J=8.6Hz,1H),5.27(dd,J=12.2,3.9Hz,1H),4 .33–4.24(m,2H),3.61–3.42(m,2H),3.33(td,J=10.1,5.0Hz,1H),2.95–2.77(m,4H),2.70–2.59(m,1H).

[0261] Example 21: 4-(cyclohex-2-ene-1-oxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0262]

[0263] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a solution of 3-bromocyclohex-1-ene (32 mg, 0.30 mmol) in DMF (2 mL). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase HPLC (21 mg, yield 38.3%). LC-MS: m / z 365 (MH) - .

[0264] 1 H NMR (400 MHz, Chloroform-d) δ 7.64–7.53 (m, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.12–5.98 (m, 1H), 5.85 (dd, J = 10.1, 2.3 Hz, 1H), 5.25 (d, J = 11.6 Hz, 1H), 4.97–4.78 (m, 1H), 3.57–3.28 (m, 2H), 2.59 (s, 1H), 2.26–2.02 (m, 2H), 2.02–1.80 (m, 3H), 1.70 (tt, J = 9.7, 4.6 Hz, 1H). Example 22, Example 23:

[0265] (1S,3R)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)cyclohexyl-1-carbonitrile (1R,3R)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)cyclohexyl-1-carbonitrile

[0266] Step A. 3-Cyanocyclohexanol 4-methylbenzenesulfonate

[0267] Triethylamine (100 mg, 0.99 mmol), DMAP (5 mg) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of 3-hydroxycyclohexyl-1-carbonitrile (80 mg, 0.70 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (61 mg, yield 51.2%).

[0268] Step B

[0269] (1S,3R)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)cyclohexyl-1-carbonitrile (1R,3R)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)cyclohexyl-1-carbonitrile

[0270] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20 mg, 0.07 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a solution of 3-cyanocyclohexanol 4-methylbenzenesulfonate (60 mg) in DMF (2 mL). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase high performance liquid chromatography:

[0271] Example 22, cis isomer (5 mg): (1S, 3R)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)cyclohexyl-1-carbonitrile.

[0272] LC-MS: m / z 392(MH) - .

[0273] 1 H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.6Hz,1H),6.87(d,J=8.6Hz,1H),5.25(dd,J=13.3,6.6Hz,1H),4.42(t,J=4.2Hz,1H), 3.60–3.35(m,2H),2.82–2.70(m,1H),2.64(s,1H),2.32(dd,J=13.2,3.8Hz,1H),2.01(qt,J=8.1,2.8Hz,5H),1.84–1.69(m,2H).

[0274] Example 23, trans isomer (6 mg): (1R,3R)-3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)cyclohexyl-1-carbonitrile.

[0275] LC-MS: m / z 392(MH) - .

[0276] 1 H NMR(400MHz,Chloroform-d)δ7.61(d,J=8.6Hz,1H),6.92(d,J=8.6Hz,1H),5.26(ddd,J=12.4,3.8,1.5Hz,1H),4.79–4. 68(m,1H),3.55–3.29(m,2H),3.08–3.00(m,1H),2.12(td,J=5.1,1.9Hz,2H),1.96(d,J=12.1Hz,1H),1.87–1.73(m,6H).

[0277] Example 24: 4-(3,3-difluorocyclobutyloxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0278] Step A. 3,3-Difluorocyclobutanol 4-methylbenzenesulfonate

[0279] Triethylamine (100 mg, 0.99 mmol), DMAP (5 mg) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of 3,3-difluorocyclobutane-1-ol (60 mg, 0.56 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (60 mg, yield 40.9%).

[0280] Step B. 4-(3,3-difluorocyclobutyloxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0281] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (40 mg, 0.15 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a DMF (2 mL) solution of 3,3-difluorocyclobutanol 4-methylbenzenesulfonate (60 mg, 0.23 mmol). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product (16 mg, yield 28.4%) was purified by reverse phase high performance liquid chromatography.

[0282] LC-MS: m / z 375 (MH) - .

[0283] 1 H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.6Hz,1H),6.69(d,J=8.6Hz,1H),5.24(d,J=12.4Hz,1H),4.7 7–4.61(m,1H),3.57–3.29(m,2H),3.13(ddt,J=12.2,9.4,6.3Hz,2H),2.88–2.72(m,2H),2.58(s,1H).

[0284] Embodiment 25, Embodiment 26:

[0285] (2S)-2-Cyclopropyl-2-(((S)-2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)acetonitrile (2R)-2-Cyclopropyl-2-(((S)-2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)acetonitrile

[0286] Step A. Cyano(cyclopropyl)methanol 4-methylbenzenesulfonate

[0287] Triethylamine (100 mg, 0.99 mmol), DMAP (5 mg) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of 2-cyclopropyl-2-hydroxyacetonitrile (60 mg, 0.66 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (60 mg, yield 38.6%).

[0288] Step B

[0289] (2S)-2-Cyclopropyl-2-(((S)-2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)acetonitrile (2R)-2-Cyclopropyl-2-(((S)-2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)acetonitrile

[0290] Add 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (40 mg, 0.15 mmol) and potassium carbonate (100 mg, 0.72 mmol) to a solution of cyano(cyclopropyl)methanol 4-methylbenzenesulfonate (60 mg, 0.23 mmol) in DMF (2 mL). Stir the reaction solution at 80 ° C for 16 h under nitrogen. Cool, filter, concentrate, and purify by reverse phase high performance liquid chromatography to obtain the product: racemic

[0291] Example 25: Racemic (2S)-2-cyclopropyl-2-(((S)-2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)acetonitrile, 6 mg.

[0292] LC-MS: m / z 364 (MH) - .

[0293] 1 H NMR(400MHz,Chloroform-d)δ7.65(d,J=8.7Hz,1H),7.02(d,J=8.6Hz,1H),5.24(d,J=12.4Hz,1H),4.5 8(d,J=7.0Hz,1H),3.65–3.33(m,2H),2.61(s,1H),0.87(d,J=7.3Hz,3H),0.69(dd,J=8.3,4.6Hz,2H).

[0294] Example 26: Racemic (2R)-2-cyclopropyl-2-(((S)-2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)acetonitrile, 5 mg.

[0295] LC-MS: m / z 364 (MH) - .

[0296] 1H NMR(400MHz,Chloroform-d)δ7.65(d,J=8.5Hz,1H),7.02(d,J=8.6Hz,1H),5.26(d,J=12.1Hz,1H),4.59 (d,J=7.0Hz,1H),3.58–3.37(m,2H),2.63(s,1H),0.88(ddt,J=8.1,4.6,2.6Hz,3H),0.74–0.63(m,2H).

[0297] Example 27: 2,2-difluoro-4-((3-methoxycyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0298] Step A. 3-((Benzyloxy)methyl)cyclobutan-1-ol

[0299] Sodium borohydride (1.392 g, 36.796 mmol) was added to a solution of 3-((benzyloxy)methyl)cyclobutan-1-one (3.5 g, 18.398 mmol) in tetrahydrofuran / methanol (5 mL / 5 mL) at 0°C. The reaction solution was stirred at room temperature for 3 h, quenched with ammonium chloride, and extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (3.5 g, yield 98.9%).

[0300] Step B. (((3-methoxycyclobutyl)methoxy)methyl)benzene

[0301] Add sodium hydrogen (780.0 mg, 19.505 mmol) to a solution of 3-((benzyloxy)methyl)cyclobutan-1-ol (2.5 g, 13.003 mmol) in tetrahydrofuran (10 mL) at 0°C. Stir for 0.5 h, add iodomethane (2.215 g, 15.604 mmol), and stir at room temperature for 4 h. After the reaction is complete, add H2O (80 mL) and ethyl acetate (50 mL×3) for extraction. The organic phase is washed with saturated brine (50 mL×2), dried with sodium sulfate, concentrated, and purified by column chromatography to obtain the product (1.4 g, yield 52.2%).

[0302] Step C. (3-Methoxycyclobutyl)methanol

[0303] Palladium on carbon (400 mg) was added to a solution of (((3-methoxycyclobutyl)methoxy)methyl)benzene (400 mg, 1.939 mmol) in methanol (20 mL). The reaction solution was hydrogenated at room temperature and pressure for 2 hours, filtered, and concentrated to obtain the product (200 mg, yield 88.9%).

[0304] Step D. 4-((3-methoxycyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0305] Under nitrogen, (3-methoxycyclobutyl)methanol (140 mg, 1.206 mmol), triphenylphosphine (211 mg, 0.804 mmol) and DEAD (140 mg, 0.804 mmol) were added to a solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (100 mg, 0.402 mmol) in tetrahydrofuran (10 mL). After stirring at room temperature for 12 hours, the reaction solution was quenched with water and extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated brine, dried with sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (60.0 mg, yield 43.1%).

[0306] Step E. 2,2-Difluoro-4-((3-methoxycyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0307] 3-Methoxypropylamine (90 mg, 1.0 mmol), pivalic acid (1.0 mg, 0.01 mmol) and anhydrous sodium sulfate (1.0 g) were added to a toluene / cyclohexane (1 mL / 1 mL) solution of 4-((3-methoxycyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (60.0 mg, 0.173 mmol). The reaction solution was filled with nitrogen and heated at 80°C for 16 h, then concentrated to remove the solvent and anhydrous acetonitrile (10 mL) was added. Select-F (300 mg, 0.85 mmol) was added to the reaction solution and heated at 65°C for 5 h. The reaction was adjusted to pH <7 with 1N hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (31 mg, yield 46.9%).

[0308] Step F. 2,2-Difluoro-4-((3-methoxycyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0309] Sodium borohydride (6.1 mg, 0.161 mmol) was added to a solution of 2,2-difluoro-4-((3-methoxycyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (31.0 mg, 0.081 mmol) in methanol / tetrahydrofuran (1 mL / 1 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (10 mL) was then added, and then extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the product (20.0 mg, yield 64.2%). LC-MS: m / z 385.6 (M+H) + .

[0310] 1 H NMR (400MHz, CDCl3) δ7.57(d,J=8.4Hz,1H),6.85(d,J=8.4Hz,1H),5.23(ddd,J=12.4,4.4,1.2Hz,1H),4.05–3.95(m,2H),3.83(p,J =7.2Hz,1H),3.51–3.150(m,2H),3.25(s,3H),2.58(dd,J=4.8,2.0Hz,1H),2.48-2.40(m,2H),2.37-2.25(m,1H),1.84–1.76(m,2H). Example 28: 2-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

[0311] Step A. 5-Fluoro-2-((1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

[0312] 2,5-Difluorobenzonitrile (336 mg, 2.418 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a DMF (8 mL) solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (200 mg, 0.806 mmol). The reaction solution was stirred at 60°C for 16 h under nitrogen. The solution was cooled, filtered, concentrated, and purified by column chromatography to obtain the product (40.0 mg, yield 13.5%).

[0313] Step B. 2-((2,2-difluoro-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

[0314] To a solution of 5-fluoro-2-((1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (40.0 mg, 0.109 mmol) in toluene / cyclohexane (0.5 mL / 0.5 mL) were added 3-methoxypropylamine (90 mg, 1.0 mmol), pivalic acid (1.0 mg, 0.01 mmol) and anhydrous sodium sulfate (1.0 g). The reaction solution was filled with nitrogen and heated at 80°C for 16 h, then concentrated to remove the solvent and anhydrous acetonitrile (10 mL) was added. Select-F (300 mg, 0.85 mmol) was added to the reaction solution and heated at 65°C for 5 h. The reaction was adjusted to pH <7 with 1N hydrochloric acid and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (19.0 mg, yield 43.2%).

[0315] Step C. 2-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

[0316] Sodium borohydride (15.0 mg, 0.396 mmol) was added to a solution of 2-((2,2-difluoro-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (19.0 mg, 0.047 mmol) in methanol / tetrahydrofuran (1 mL / 1 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (5 mL) was then added, and then extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the product (5.5 mg, yield 28.8%). LC-MS: m / z 406.4 (M+H) + .

[0317] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=8.4Hz,1H),7.43(dd,J=7.2,3.2Hz,1H),7.33(ddd,J=10.4,7.6,3.2Hz,1H) ,7.03(dd,J=9.2,4.0Hz,1H),6.87(d,J=8.4Hz,1H),5.28(d,J=12.0Hz,1H),3.62–3.39(m,2H),2.72(s,1H).

[0318] Example 29: 4-(2,3-dihydro-1H-indene-1-oxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0319] Step A. 4-(2,3-dihydro-1H-inden-1-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0320] Under nitrogen, 2,3-dihydro-1H-indene-1-ol (178 mg, 1.326 mmol), triphenylphosphine (232 mg, 0.886 mmol) and DEAD (154 mg, 0.886 mmol) were added to a solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-one (110 mg, 0.443 mmol) in tetrahydrofuran (10 mL). After stirring at room temperature for 12 hours, the reaction solution was quenched with water and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine, dried with sodium sulfate, concentrated, and purified by column chromatography to obtain the product (120 mg, yield 74.5%).

[0321] Step B. 4-(2,3-dihydro-1H-inden-1-oxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0322] To a toluene / cyclohexane (1mL / 1mL) solution of 4-(2,3-dihydro-1H-inden-1-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (120mg, 0.329mmol), 3-methoxypropylamine (90mg, 1.0mmol), pivalic acid (1.0mg, 0.01mmol) and anhydrous sodium sulfate (1.0g) were added. The reaction solution was filled with nitrogen and heated at 80℃ for 16h, then concentrated to remove the solvent, and anhydrous acetonitrile (10mL) was added. Select-F (300mg, 0.85mmol) was added to the reaction solution, and heated at 65℃ for 5h. The reaction was adjusted to pH <7 with 1N hydrochloric acid, and then extracted with ethyl acetate (15mL×3). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (53.0 mg, yield 40.2%).

[0323] Step C. 4-(2,3-dihydro-1H-inden-1-oxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0324] Sodium borohydride (15.0 mg, 0.396 mmol) was added to a solution of 4-(2,3-dihydro-1H-inden-1-oxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (53.0 mg, 0.132 mmol) in methanol / tetrahydrofuran (1 mL / 1 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (5 mL) was then added, and then extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated under reduced pressure, and purified by reverse phase high performance liquid chromatography to obtain the product (5.0 mg, yield 9.4%).

[0325] LC-MS: m / z 403.4 (M+H) + .

[0326] 1 H NMR(400MHz, CDCl3)δ7.63(d,J=8.4Hz,1H),7.41–7.32(m,3H),7.29–7.22(m,1H) ),7.10(dd,J=8.4,2.4Hz,1H),5.81(dt,J=7.2,3.6Hz,1H),5.24(d,J=12.0Hz,1 H), 3.45–3.32 (m, 2H), 3.20–3.12 (m, 1H), 3.00–2.93 (m, 1H), 2.67–2.57 (m, 2H), 2.25–2.15 (m, 1H). Example 30: 2,2-difluoro-4-(tetrahydrofuran-3-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0327] Step A. 4-(Tetrahydrofuran-3-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0328] Under nitrogen, 3-hydroxy-tetrahydrofuran (178 mg, 1.326 mmol), triphenylphosphine (232 mg, 0.886 mmol) and DEAD (154 mg, 0.886 mmol) were added to a solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (108 mg, 0.435 mmol) in tetrahydrofuran (10 mL) . After stirring the reaction solution at room temperature for 12 hours, water was added to quench the mixture and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, concentrated and purified by column chromatography to obtain the product (100 mg, yield 72.2%).

[0329] Step B. 2,2-Difluoro-4-(tetrahydrofuran-3-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0330] To a solution of 4-(tetrahydrofuran-3-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (100 mg, 0.314 mmol) in toluene / cyclohexane (0.5 mL / 0.5 mL) were added 3-methoxypropylamine (90 mg, 1.0 mmol), pivalic acid (1.0 mg, 0.01 mmol) and anhydrous sodium sulfate (1.0 g). The reaction solution was filled with nitrogen and heated at 80°C for 16 h, then concentrated to remove the solvent and anhydrous acetonitrile (10 mL) was added. Select-F (300 mg, 0.85 mmol) was added to the reaction solution and heated at 65°C for 5 h. The reaction was adjusted to pH <7 with 1N hydrochloric acid and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (40.0 mg, yield 36.0%).

[0331] Step C. 2,2-Difluoro-4-(tetrahydrofuran-3-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0332] Sodium borohydride (15.0 mg, 0.396 mmol) was added to a solution of 2,2-difluoro-4-(tetrahydrofuran-3-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (40.0 mg, 0.113 mmol) in methanol / tetrahydrofuran (1 mL / 1 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (5 mL) was then added, and then extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated under reduced pressure, and purified by reverse phase high performance liquid chromatography to obtain the product (5.0 mg, yield 12.5%).

[0333] LC MS: m / z 357.4 (M+H) + .

[0334] 1 H NMR (400MHz, CDCl3) δ7.58(d,J=8.4Hz,1H),6.81(dd,J=8.6,2.4Hz,1H),5.23(dd,J=12.4,3.6Hz,1H),5.00–4 .96(m,1H),4.08–3.88(m,4H),3.51–3.29(m,2H),2.63(d,J=4.8Hz,1H),2.31–2.22(m,1H),2.18–2.11(m,1H).

[0335] Example 31: 4-Chloro-2-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-6-fluorobenzonitrile

[0336]

[0337] 4-Chloro-2,6-difluorobenzonitrile (63.5 mg, 0.366 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a DMF (2 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (35.0 mg, 0.122 mmol). The reaction solution was stirred at 60 ° C for 0.5 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, and the organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (12.0 mg, yield 22.3%).

[0338] LC-MS: m / z 440.2 (M+H) + .

[0339] 1 H NMR(40MHz, CDCl3)δ7.71(d,J=8.4Hz,1H),7.12–7.03(m,2H),6.71(t,J=1.6Hz,1 H),5.29(dd,J=12.0,4.0Hz,1H),3.59–3.33(m,2H),2.76(dd,J=4.8,2.0Hz,1H).

[0340] Example 32: 4-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)isophthalonitrile

[0341]

[0342] 4-Fluoroisophthalonitrile (53.0 mg, 0.366 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a DMF (2 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (35.0 mg, 0.122 mmol). The reaction solution was stirred at 60 ° C for 2 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, and the organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (11.5 mg, yield 23.0%).

[0343] LC-MS: m / z 411.2 (M+H) + .

[0344] 1 H NMR (400MHz, CDCl3) δ7.85(d,J=8.0Hz,1H),7.71(d,J=8.4Hz,1H),7.54(dd,J=8.0,1.2Hz,1H),7.21(d,J=1. 6Hz,1H),7.03(d,J=8.8Hz,1H),5.30(dd,J=12.0,4.4Hz,1H),3.59–3.34(m,2H),2.77(dd,J=4.8,2.0Hz,1H).

[0345] Example 33: 6-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-4-(trifluoromethyl)picolinonitrile

[0346]

[0347] Step A. 6-((2,2-difluoro-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-4-oxy)-4-(trifluoromethyl)picolinonitrile

[0348] Potassium carbonate (29 mg, 0.21 mmol) and 6-fluoro-4-(trifluoromethyl)pyridinecarbonitrile (14 mg, 0.07 mmol) were added to a DMF (2 mL) solution of 2,2-difluoro-4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (20 mg, 0.07 mmol). The mixture was heated at 100 °C for 1 h under nitrogen. The mixture was cooled, and water and ethyl acetate were added to separate the layers. The organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (10 mg, yield 31.2%).

[0349] Step B. 6-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-4-(trifluoromethyl)picolinonitrile

[0350] Sodium borohydride (4 mg, 0.12 mmol) was added to a solution of 6-((2,2-difluoro-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-4-(trifluoromethyl)picolinonitrile (10.0 mg, 0.022 mmol) in methanol / tetrahydrofuran (3 mL / 2 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (5 mL) was then added, and then extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated under reduced pressure, and purified by reverse phase high performance liquid chromatography to obtain the product (5.0 mg, yield 50.3%).

[0351] LC-MS: m / z 457.4 (M+H) + .

[0352] 1 H NMR (400MHz, CDCl3) δ7.73(d,J=8.4Hz,1H),7.67(s,1H),7.49(s,1H),7.29(d,J=8.4Hz,1H),5.32-5.28(dd,1H),3.44-3.28(m,2H),2.71(d,1H).

[0353] Example 34: 2-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluoroterephthalonitrile

[0354]

[0355] 2,5-Difluoroterephthalonitrile (18.0 mg, 0.110 mmol) and potassium carbonate (29.0 mg, 0.210 mmol) were added to a DMF (1 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20.0 mg, 0.070 mmol). The reaction solution was stirred at 60°C for 2 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, and the organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (4.0 mg, yield 13.3%).

[0356] LC-MS: m / z 431.24 (M+H) + .

[0357] 1 H NMR (400MHz, CDCl3) δ7.70(d,J=8.4Hz,1H),7.61(d,J=7.6Hz,1H),7.24(d,J=4.8Hz,1H),6. 96(d,J=8.4Hz,1H),5.30(dd,J=12.0,3.6Hz,1H),3.62–3.36(m,2H),2.76(d,J=4.4Hz,1H).

[0358] Example 35: 2,2-difluoro-4-(6-fluoropyridin-2-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0359] Step A. 4-(6-fluoropyridin-2-yl)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0360] Potassium carbonate (111 mg, 0.80 mmol) and 2,6-difluoropyridine (80 mg, 0.80 mmol) were added to a DMF (1 mL) solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (100 mg, 0.40 mmol). The mixture was heated at 100°C for 1 h under nitrogen. The mixture was cooled, and water and ethyl acetate were added to separate the layers. The organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by column chromatography to obtain the product (50 mg, yield 36.5%).

[0361] Step B. 2,2-Difluoro-4-(6-fluoropyridin-2-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0362] 3-Methoxypropylamine (90 mg, 1.0 mmol), pivalic acid (1.0 mg, 0.01 mmol) and anhydrous sodium sulfate (1.0 g) were added to a toluene / cyclohexane (0.5 mL / 0.5 mL) solution of 4-(6-fluoropyridine-2-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (20 mg, 0.058 mmol). The reaction solution was filled with nitrogen and heated at 80 ° C for 16 h, then concentrated to remove the solvent, and anhydrous acetonitrile (10 mL) was added. Select-F (300 mg, 0.85 mmol) was added to the reaction solution and heated at 65 ° C for 5 h. The reaction was adjusted to pH <7 with 1N hydrochloric acid and then extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated brine (10 mL × 3), dried over sodium sulfate, concentrated and purified by column chromatography to obtain the product (7.0 mg, yield 31.8%).

[0363] Step C. 2,2-Difluoro-4-(6-fluoropyridin-2-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0364] Sodium borohydride (2.1 mg, 0.054 mmol) was added to a solution of 2,2-difluoro-4-(6-fluoropyridine-2-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (7.0 mg, 0.018 mmol) in methanol / tetrahydrofuran (0.5 mL / 0.5 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (5 mL) was then added, and then extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated under reduced pressure, and purified by reverse phase high performance liquid chromatography to obtain the product (4 mg, yield 58.3%).

[0365] LC-MS: m / z 382.4 (M+H) + .

[0366] 1 H NMR (400MHz, CDCl3) δ7.85 (qd, J=8.0, 1.7Hz, 1H), 7.66 (d, J=8.5Hz, 1H), 7.23 (dd, J=8.5, 1.6Hz, 1H), 6.8 6(d,J=8.0Hz,1H),6.70(dt,J=8.0,2.0Hz,1H),5.33-5.21(d,1H),3.47-3.29(m,2H),2.81-2.71(d,1H).

[0367] Example 36: 2-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

[0368] Step A. 2-((1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

[0369] Potassium carbonate (111 mg, 0.80 mmol) and 2-difluorobenzonitrile (484 mg, 4.0 mmol) were added to a DMF (1 mL) solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (100 mg, 0.40 mmol). The mixture was heated at 100°C for 1 h under nitrogen. The mixture was cooled, and water and ethyl acetate were added to separate the layers. The organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by column chromatography to obtain the product (40 mg, yield 14.3%).

[0370] Step B. 2-((2,2-difluoro-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

[0371] To a solution of 2-((1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (40 mg, 0.11 mmol) in toluene / cyclohexane (0.5 mL / 0.5 mL) were added 3-methoxypropylamine (90 mg, 1.0 mmol), pivalic acid (1.0 mg, 0.01 mmol) and anhydrous sodium sulfate (1.0 g). The reaction solution was filled with nitrogen and heated at 80°C for 16 h, then concentrated to remove the solvent and anhydrous acetonitrile (10 mL) was added. Select-F (300 mg, 0.85 mmol) was added to the reaction solution and heated at 65°C for 5 h. The reaction was adjusted to pH <7 with 1N hydrochloric acid and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (15.0 mg, yield 35.4%).

[0372] Step C. 2-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

[0373] Sodium borohydride (4 mg, 0.12 mmol) was added to a solution of 2-((2,2-difluoro-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (15 mg, 0.039 mmol) in methanol / tetrahydrofuran (0.5 mL / 0.5 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (5 mL) was then added, and then extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated under reduced pressure, and purified by reverse phase high performance liquid chromatography to obtain the product (4 mg, yield 26.5%).

[0374] LC-MS: m / z 388.4 (M+H) + .

[0375] 1 H NMR (400MHz, CDCl3) δ7.75(dd,J=7.8,1.7Hz,1H),7.61(ddd,J=9.0,7.6,1.8Hz,1H),7.55(d,J=8.5Hz,1H),7.31(t, J=7.8Hz,1H),7.06(d,J=8.4Hz,1H),6.89(d,J=8.6Hz,1H),5.28(d,J=15.9Hz,1H),3.54-3.51(m,2H),2.83(d,1H).

[0376] Example 37, Example 38: 3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylpiperidin-2-one

[0377]

[0378] Step A. 1-Methyl-3-((1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)piperidin-2-one

[0379] 3-Bromo-1-methylpiperidin-2-one (122 mg, 0.64 mmol) and potassium carbonate (88 mg, 0.64 mmol) were added to a DMF (4 mL) solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (80 mg, 0.32 mmol). The reaction solution was stirred at 60 ° C for 2 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, and the organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by column chromatography to obtain the product (40 mg, yield 69.6%).

[0380] Step B. 3-((2,2-difluoro-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylpiperidin-2-one

[0381] To a solution of 1-methyl-3-((1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)piperidin-2-one (50 mg, 0.14 mmol) in toluene / cyclohexane (0.5 mL / 0.5 mL) were added 3-methoxypropylamine (19 mg, 0.21 mmol) and pivalic acid (3.0 mg, 0.03 mmol). The reaction solution was filled with nitrogen and heated at 100°C for 12 h, then concentrated to remove the solvent, and anhydrous acetonitrile (5 mL) was added. Select-F (212 mg, 0.6 mmol) was added to the reaction solution and heated at 60°C for 5 h. The reaction was quenched with 2N hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (10 mg, yield 18.1%).

[0382] Step C. 3-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylpiperidin-2-one

[0383] Sodium borohydride (3 mg, 0.03 mmol) was added to a solution of 3-((2,2-difluoro-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-1-methylpiperidin-2-one (6 mg, 0.015 mmol) in methanol / tetrahydrofuran (3 mL / 2 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (5 mL) was then added, and then extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated under reduced pressure, and purified by reverse phase high performance liquid chromatography to obtain the products: Isomer 1 and Isomer 2.

[0384] LCMS ESI (-) m / z: 396.1 (MH) - .

[0385] Example 37, Isomer 1: 2 mg.

[0386] 1 H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.7Hz,1H),7.25(d,J=8.7Hz,1H),5.30–5.23(m,1H),4.80(t,J=5.8Hz,1H),3.50–3.31(m,4H),3.01(s,3H),1.31 -1.27(m,4H).

[0387] 19 F NMR(376MHz,Chloroform-d)δ-42.72,-102.65,-103.28,-113.83,-114.46.

[0388] Example 38, Isomer 2: 2 mg.

[0389] 1 H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.7Hz,1H),7.25(d,J=8.7Hz,1H),5.22(d,J= 12.4Hz,1H),4.80(t,J=6.0Hz,1H),3.56–3.33(m,4H),3.00(s,3H),1.31–1.26(m,4H). 19 F NMR(376MHz,Chloroform-d)δ-42.89,-102.34,-102.98,-113.94,-114.57.

[0390] Example 39: 2,2-difluoro-4-(1-methoxyisopropoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0391] Step A. 1-Methoxyisopropanol 4-methylbenzenesulfonate

[0392] Triethylamine (1.74 g, 17 mmol) and p-toluenesulfonyl chloride (2.5 g, 13 mmol) were added to a solution of 1-methoxy-2-propanol (1 g, 11 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 12 h, concentrated under reduced pressure, and purified by column chromatography to obtain the product (1.2 g, yield 45%).

[0393] Step B. 4-(1-methoxyisopropoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0394] 2,5-difluoroterephthalonitrile (18.0 mg, 0.110 mmol) and potassium carbonate (96 mg, 0.72 mmol) were added to a DMF (2 mL) solution of 1-methoxyisopropanol 4-methylbenzenesulfonate (160 mg, 0.64 mmol). The reaction solution was stirred at 80 ° C for 2 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, and the organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (80 mg, yield 80%).

[0395] Step C. 2,2-Difluoro-4-(1-methoxyisopropoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0396] 3-Methoxypropylamine (22 mg, 0.24 mmol), pivalic acid (1.0 mg, 0.01 mmol) and anhydrous sodium sulfate (1.0 g) were added to a toluene / cyclohexane (5 mL / 5 mL) solution of 4-(1-methoxyisopropoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (50 mg, 0.16 mmol). The reaction solution was filled with nitrogen and heated at 100 ° C for 12 h, then concentrated to remove the solvent, and anhydrous acetonitrile (10 mL) was added. Select-F (283 mg, 0.8 mmol) was added to the reaction solution and heated at 65 ° C for 5 h. The reaction was adjusted to pH <7 with 1N hydrochloric acid and then extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated brine (10 mL × 3), dried over sodium sulfate, concentrated and purified by column chromatography to obtain the product (10 mg, yield 17.6%).

[0397] Step D. 2,2-Difluoro-4-(1-methoxyisopropoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0398] Sodium borohydride (3 mg, 0.03 mmol) was added to a solution of 2,2-difluoro-4-(1-methoxyisopropoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (5 mg, 0.014 mmol) in methanol / tetrahydrofuran (3 mL / 2 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (5 mL) was then added, and then extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated under reduced pressure, and purified by reverse phase high performance liquid chromatography to obtain the product (2 mg, yield 40%).

[0399] LC-MS ESI(-)m / z:357.1(MH) - .

[0400] 1H NMR(400MHz,Chloroform-d)δ7.58(d,J=8.6Hz,1H),6.97(d,J=8.6Hz,1H),5.25(d,J=12.3Hz,1H),4.70–4.59 (m,1H),3.60(dd,J=10.4,6.2Hz,1H),3.52(dd,J=10.4,4.2Hz,1H),3.47–3.35(m,4H),1.36(d,J=6.3Hz,3H).

[0401] 19 F NMR(376MHz,Chloroform-d)δ-42.93,-102.54,-103.18,-114.02,-114.65.

[0402] Example 40: 2,2-difluoro-4-(2-hydroxycyclohexyloxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0403] Step A: 4-(2-Hydroxycyclohexyloxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0404] To a DMF (4 mL) solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (20 mg, 0.08 mmol), epoxycyclohexene (16 mg, 0.16 mmol) and potassium carbonate (22 mg, 0.16 mmol) were added. The reaction solution was stirred at 80 ° C for 2 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, and the organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (10 mg, yield 36.1%).

[0405] Step B: 2,2-difluoro-4-((2-hydroxycyclohexanol)oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0406] 3-Methoxypropylamine (5 mg, 0.052 mmol) and pivalic acid (2.0 mg, 0.02 mmol) were added to a toluene (5 mL) solution of 4-(2-hydroxycyclohexyloxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (12 mg, 0.35 mmol). The reaction solution was filled with nitrogen and heated at 100°C for 12 h, then concentrated to remove the solvent and anhydrous acetonitrile (10 mL) was added. Sodium sulfate (25 mg, 0.175 mmol) and Select-F (SelectFluor, 62 mg, 0.175 mmol) were added to the reaction solution and heated at 60°C for 2 h. The reaction was quenched with 2N hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (2 mg, yield 35.4%).

[0407] Step C: 2,2-difluoro-4-(2-hydroxycyclohexyloxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0408] Sodium borohydride (2 mg, 0.052 mmol) was added to a solution of 2,2-difluoro-4-((2-hydroxycyclohexanol)oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (2 mg, 0.0052 mmol) in methanol (2 mL). The reaction solution was stirred at room temperature for 0.5 h and then quenched by adding saturated ammonium chloride. After concentration, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (1 mg, yield 50%).

[0409] LC-MS ESI(-)m / z:383.1(MH) - .

[0410] 1 H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.5Hz,1H),7.01(d,J=8.6Hz,1H),5.27(d,J=12.2Hz,1H),4.16(s,1H ),3.83–3.75(m,1H),3.51–3.36(m,2H),2.62(s,1H),2.14(d,J=11.2Hz,2H),1.81(s,2H),1.52–1.42(m,4H).

[0411] 19 F NMR(376MHz,Chloroform-d)δ-42.85,-102.50,-103.13,-113.98,-114.61.

[0412] Example 41: 4-((3,3-difluorocyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0413] Step A: (3,3-difluorocyclobutyl)methanol 4-methylbenzenesulfonate

[0414] Pyridine (650 mg, 8.2 mmol) and p-toluenesulfonyl chloride (200 mg, 1.05 mmol) were added to a solution of (3,3-difluorocyclobutyl)methanol (500 mg, 4.1 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 12 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (800 mg, yield 71%).

[0415] Step B: 4-((3,3-difluorocyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0416] To a DMF (1 mL) solution of (3,3-difluorocyclobutyl)methanol 4-methylbenzenesulfonate (66 mg, 0.24 mmol), 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (30 mg, 0.12 mmol) and potassium carbonate (33 mg, 0.24 mmol) were added. The reaction solution was stirred at 80°C for 2 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, and the organic phase was washed with saturated brine (10 mL), dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (20 mg, yield 47%).

[0417] Step C: 4-((3,3-difluorocyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0418] 3-Methoxypropylamine (16 mg, 0.18 mmol) and pivalic acid (3.0 mg, 0.03 mmol) were added to a toluene (5 mL) solution of 4-((3,3-difluorocyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (20 mg, 0.12 mmol). The reaction solution was filled with nitrogen and heated at 100°C for 12 h, then concentrated to remove the solvent, and then anhydrous acetonitrile (10 mL) was added. Sodium sulfate (110 mg, 0.6 mmol) and Select-F (210 mg, 0.6 mmol) were added to the reaction solution and heated at 60°C for 2 h. The reaction was quenched with 2N hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (8 mg, yield 17.2%).

[0419] Step D: 4-((3,3-difluorocyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0420] Sodium borohydride (3 mg, 0.09 mmol) was added to a solution of 4-((3,3-difluorocyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (8 mg, 0.021 mmol) in methanol (5 mL). The reaction solution was stirred at room temperature for 0.5 h. Ice water (5 mL) was then added, and then extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over sodium sulfate, concentrated under reduced pressure, and purified by reverse phase high performance liquid chromatography to obtain the product (5.0 mg, yield 62%).

[0421] LC-MS ESI (-) m / z: 389.1 (MH) - .

[0422] 1 H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.5Hz,1H),6.88(d,J=8.6Hz,1H),5.27–5.20(m,1H),4.08(dd,J=5 .9,2.2Hz,2H),3.49–3.30(m,2H),2.77(ddt,J=13.5,9.6,3.0Hz,2H),2.67–2.61(m,1H),2.56–2.45(m,2H).

[0423] 19F NMR(377MHz,Chloroform-d)δ-42.89,-84.04,-84.55,-92.55,-93.07,-102.59,-103.22,-114.01,-114.64.

[0424] Example 42: 4-(1-(3,3-difluorocyclobutyl)eth-1-oxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0425] Step A: 1-(3,3-difluorocyclobutyl)ethan-1-ol 4-methylbenzenesulfonate

[0426] Pyridine (650 mg, 8.2 mmol) and p-toluenesulfonyl chloride (950 mg, 5 mmol) were added to a solution of 1-(3,3-difluorocyclobutyl)ethan-1-ol (500 mg, 4.1 mmol) in dichloromethane (20 mL). The reaction solution was stirred at room temperature for 12 h, quenched with ice water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (800 mg, yield 71%).

[0427] Step B: 4-(1-(3,3-difluorocyclobutyl)eth-1-oxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0428] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (18.0 mg, 0.110 mmol) and potassium carbonate (33 mg, 0.24 mmol) were added to a DMF (2 mL) solution of 1-(3,3-difluorocyclobutyl)ethan-1-ol 4-methylbenzenesulfonate (66 mg, 0.24 mmol). The reaction solution was stirred at 60 ° C for 2 h under nitrogen. Cool, add water and ethyl acetate to separate the layers, wash the organic phase with saturated brine (10 mL × 3), dry with sodium sulfate, concentrate, and purify with thin layer chromatography to obtain the product (20 mg, yield 47%). LC-MS ESI (-) m / z: 403.1 (MH) - .

[0429] 1H NMR(400MHz,Chloroform-d)δ7.58(d,J=8.5Hz,1H),6.87(d,J=8.6Hz,1H),5.27–5.20(m,1H),4.08(m,1H),3.49– 3.30(m,2H),2.77(ddt,J=13.5,9.6,3.0Hz,2H),2.67–2.61(m,1H),2.56–2.45(m,2H),1.25-1.23(d,J=6Hz,2H).

[0430] 19 F NMR(376MHz,Chloroform-d)δ-42.86,-83.27,-83.78,-94.99,-95.50,-102.42,-103.05,-114.01,-114.65.

[0431] Example 43: 6-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)picolinonitrile

[0432]

[0433] 6-Fluoropyridinecarbonitrile (5 mg, 0.042 mmol) and potassium carbonate (8 mg, 0.053 mmol) were added to a DMF (2 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (10 mg, 0.035 mmol). The reaction solution was stirred at 100 °C for 1 h under nitrogen. After cooling, water and ethyl acetate were added to separate the layers. The organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (3 mg, yield 18%).

[0434] LC-MS ESI(-)m / z:387.1(MH) - .

[0435] 1 H NMR (400MHz, DMSO-d6) δ8.17(dd,J=8.5,7.4Hz,1H),7.88(dd,J=7.4,0.8Hz,1H),7.76(d,J=8.5Hz,1H),7.55(dd,J=8.5,0.8 Hz,1H),7.43(d,J=8.6Hz,1H),6.56(d,J=6.8Hz,1H),5.11–5.02(m,1H),3.40(dd,J=10.6,6.7Hz,1H),3.30(d,J=4.8Hz,1H).

[0436] 19 F NMR(376MHz,Chloroform-d)δ-41.83,-102.82,-103.46,-113.77,-114.40.

[0437] Example 44: 2-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-6-fluorobenzonitrile

[0438]

[0439] 2,6-Difluorobenzonitrile (6 mg, 0.042 mmol) and potassium carbonate (8 mg, 0.053 mmol) were added to a DMF (2 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (10 mg, 0.035 mmol). The reaction solution was stirred at 100 ° C for 1 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, and the organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (4 mg, yield 17%).

[0440] LC-MS ESI(-)m / z:404.1(MH) - .

[0441] 1 H NMR(400MHz,Chloroform-d)δ7.66(d,J=8.5Hz,1H),7.54(td,J=8.5,6.3Hz,1H),7.03(t,J=8 .5Hz,2H),6.73(d,J=8.5Hz,1H),5.33–5.22(m,1H),3.59–3.34(m,2H),2.77(d,J=4.6Hz,1H).

[0442] 19 F NMR(377MHz,Chloroform-d)δ-41.93,-102.70,-103.05,-103.34,-113.93,-114.57.

[0443] Example 45: 4-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)pyridine-2-carbonitrile

[0444]

[0445] 4-Fluoropyridine-2-carbonitrile (10 mg, 0.084 mmol) and potassium carbonate (15 mg, 0.105 mmol) were added to a DMF (1 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1ΔH-indene-1,4-diol (20.0 mg, 0.070 mmol). The reaction solution was stirred at 100°C for 1 h under nitrogen. After cooling, water and ethyl acetate were added to separate the layers. The organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (5 mg, yield 18%).

[0446] LC-MS ESI (+) m / z: 387.1 (MH) - .

[0447] 1 H NMR(400MHz,Chloroform-d)δ8.36–8.25(m,1H),7.69(d,J=8.5Hz,1H),7.29(d,J= 4.6Hz,2H),7.23(d,J=8.5Hz,1H),5.28(dd,J=12.0,1.4Hz,1H),3.48–3.20(m,2H).

[0448] 19 F NMR(377MHz,Chloroform-d)δ-41.84,-102.68,-103.32,-113.83,-114.46.

[0449] Example 46: 4-(2,6-difluoro-4-(trifluoromethyl)phenoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0450]

[0451] 1,2,3-Trifluoro-5-(trifluoromethyl)benzene (14 mg, 0.07 mmol) and potassium carbonate (10 mg, 0.07 mmol) were added to a DMF (1 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20.0 mg, 0.070 mmol). The reaction solution was stirred at 100°C for 1 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, and the organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (3 mg, yield 18%).

[0452] LC-MS ESI(-)m / z:465.1(MH) - .

[0453] 1 H NMR(400MHz,Chloroform-d)δ7.54(d,J=8.6Hz,1H),7.36(d,J=7.0Hz,2H),6.67(dt,J=8.6 ,1.2Hz,1H),5.29(dd,J=12.2,4.2Hz,1H),3.74–3.48(m,2H),2.66(dd,J=4.8,1.8Hz,1H).

[0454] 19 F NMR (376 MHz, Chloroform-d) δ -42.29, -62.82, -102.40, -103.03, -113.66, -114.30, -122.05. Example 47: 2,2-difluoro-4-((1-methoxycyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0455] Step A: (1-methoxycyclobutyl)methanol 4-methylbenzenesulfonate

[0456] Triethylamine (164 mg, 1.62 mmol) and p-toluenesulfonyl chloride (184 mg, 0.97 mmol) were added to a solution of (1-methoxycyclobutyl)methanol (70 mg, 0.81 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 12 h, concentrated, and purified by column chromatography to obtain the product (45 mg, yield 23%).

[0457] Step B: 2,2-difluoro-4-((1-methoxycyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0458] To a DMF (2mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20.0 mg, 0.070 mmol) was added (1-methoxycyclobutyl)methanol 4-methylbenzenesulfonate (22 mg, 0.09 mmol) and potassium carbonate (17 mg, 0.12 mmol). The reaction solution was stirred at 80°C for 2 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, the organic phase was washed with saturated brine, dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (6 mg, yield 17%).

[0459] LC-MS ESI(-)m / z:383.1(MH) - .

[0460] 1H NMR(400MHz,Chloroform-d)δ7.60(d,J=8.5Hz,1H),6.94(d,J=8.6Hz,1H),5.23(d,J=12.3Hz,1H),4.09(d,J=2.0Hz,2H),3.55–3.33(m,2H),3.28(s,3H) ,2.65(s,1H),2.26(dt,J=12.6,9.7Hz,2H),2.08(dddd,J=13.6,8.8,3.2,1. 5Hz,2H),1.85(dtt,J=11.6,10.2,3.3Hz,1H),1.65(dd,J=10.4,7.8Hz,1H).

[0461] 19 F NMR(377MHz,Chloroform-d)δ-42.93,-102.52,-103.15,-113.96,-114.59.

[0462] Example 48: 2,2-difluoro-4-((1-(hydroxymethyl)cyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0463] Step A: (1-(Hydroxymethyl)cyclobutyl)methanol 4-methylbenzenesulfonate

[0464] To a solution of cyclobutane-1,1-dimethylol (1 g, 8.6 mmol) in dichloromethane (40 mL) were added triethylamine (1.7 g, 17.2 mmol) and p-toluenesulfonyl chloride (1.8 g, 9.5 mmol). The reaction solution was stirred at room temperature for 12 h, concentrated, and purified by column chromatography to obtain the product (1 g, yield 43%).

[0465] Step B: 2,2-difluoro-4-((1-(hydroxymethyl)cyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0466] To a DMF (2mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20.0 mg, 0.06 mmol) was added (1-(hydroxymethyl)cyclobutyl)methanol 4-methylbenzenesulfonate (22 mg, 0.09 mmol) and potassium carbonate (17 mg, 0.12 mmol). The reaction solution was stirred at 80°C for 12 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, the organic phase was washed with saturated brine, dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (8 mg, yield 19%).

[0467] LC-MS ESI(-)m / z:383.1(MH) - .

[0468] 1 H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.6Hz,1H),6.95(d,J=8.6Hz,1H),5.24(dd,J=12 .4,1.4Hz,1H),4.06(d,J=1.3Hz,2H),3.76(s,2H),3.50–3.36(m,2H),2.01–1.92(m,6H).

[0469] 19 F NMR(377MHz,Chloroform-d)δ-42.95,-102.46,-103.09,-113.91,-114.54.

[0470] Example 49: 4-((1-ethynylcyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0471] Step A: (1-((tert-Butyldiphenylsilyloxy)methyl)cyclobutyl)methanol

[0472] Add sodium hydrogen (344 mg, 8.6 mmol) to a solution of cyclobutane-1,1-dimethanol (1 g, 8.6 mmol) in DMF (25 mL) at 0°C and stir for 1 hour. Add a solution of TBDPSCl (2.4 g, 8.6 mmol) in DMF (5 mL) within 5 minutes. After 1 hour, the reaction solution was quenched with saturated ammonium chloride, diluted with 50 mL of water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with sodium sulfate, concentrated, and subjected to column chromatography to obtain the product (1.8 g, yield 58%).

[0473] Step B: 1-((tert-Butyldiphenylsilyloxy)methyl)cyclobutane-1-carbaldehyde

[0474] DMP (1.2 g, 2.8 mmol) was added to a solution of (1-((tert-butyldiphenylsilyloxy)methyl)cyclobutyl)methanol (500 mg, 1.4 mmol) in dichloromethane (20 mL) at 0°C. The mixture was stirred at 0°C for 2 hours, then heated to room temperature and stirred for 4 hours. Saturated sodium bicarbonate (20 mL) was added to quench the mixture, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, concentrated, and the product (350 mg, yield 72%) was obtained by column chromatography.

[0475] Step C: tert-Butyl((1-ethynylcyclobutyl)methoxy)diphenylsilane

[0476] Potassium carbonate (390 mg, 2.8 mmol) and Bestmann's reagent (300 mg, 1.6 mmol) were added to a solution of 1-((tert-butyldiphenylsilyloxy)methyl)cyclobutane-1-carbaldehyde (350 mg, 1 mmol) in methanol (10 mL) at 0°C. The reaction solution was stirred at room temperature for 12 hours, filtered with celite, diluted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The crude product (330 mg, yield 90%) was directly used for the next step.

[0477] Step D: (1-ethynylcyclobutyl)methanol

[0478] TBAF (320 mg, 1.2 mmol) was added to a solution of tert-butyl((1-ethynylcyclobutyl)methoxy)diphenylsilane (330 mg, 0.95 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred for 2 hours and then concentrated and purified by column chromatography to obtain the product (100 mg, yield 90%).

[0479] Step E: (1-ethynylcyclobutyl)methanol 4-methylbenzenesulfonate

[0480] Triethylamine (153 mg, 1.5 mmol) and p-toluenesulfonyl chloride (167 mg, 0.88 mmol) were added to a solution of (1-ethynylcyclobutyl)methanol (80 mg, 0.73 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 12 h, concentrated under reduced pressure, and purified by column chromatography to obtain the product (80 mg, yield 41%).

[0481] Step F: 4-((1-ethynylcyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0482] To a DMF (1 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20.0 mg, 0.070 mmol) was added (1-ethynylcyclobutyl)methanol 4-methylbenzenesulfonate (64 mg, 0.28 mmol) and potassium carbonate (40 mg, 0.28 mmol). The reaction solution was stirred at 80 ° C for 12 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, the organic phase was washed with saturated brine, dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (411 mg, yield 42%).

[0483] LC-MS ESI (-) m / z: 377.1 (MH) - .

[0484] 1H NMR (400 MHz, Chloroform-d) δ7.60 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 5.24 (dd, J = 12.4, 4.3 Hz, 1H), 4.05 (d, J = 1.9 Hz,2H),3.57–3.35(m,2H),2.58(dd,J=4.7,1.8 Hz,1H),2.37(ddd,J=12.0,9.5,7.1 Hz,2H),2.27(ddd,J=11.7,7.5,4.3 Hz,2H),2.13(dddd,J=15.3,11.7,9.2,5.9 Hz,1H),1.99(dtt,J=11.6,9.1,7.1 Hz,1H).

[0485] 19 F NMR (376 MHz, Chloroform-d) delta -42.91, -102.50, -103.13, -113.91, -114.54.

[0486] Example 50: 4-((1-(2,2-difluorovinyl)cyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0487]

[0488] Step A: tert-Butyl((1-(Δ2,2-difluorovinyl)cyclobutyl)methoxy)diphenylsilane

[0489] Sodium chlorodifluoroacetate (390 mg, 2.6 mmol) and triphenylphosphine (675 mg, 2.6 mmol) were added to a DMF (10 mL) solution of 1-((tert-butyldiphenylsilyloxy)methyl)cyclobutane-1-carbaldehyde (450 mg, 1.3 mmol). The reaction solution was heated at 100°C for 2 h, cooled to room temperature, 30 mL of water was added, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, concentrated, and subjected to column chromatography to obtain the product (360 mg, yield 70%).

[0490] Step B: (1-(2,2-difluorovinyl)cyclobutyl)methanol

[0491] TBAF (320 mg, 1.2 mmol) was added to a solution of tert-butyl((1-(2,2-difluorovinyl)cyclobutyl)methoxy)diphenylsilane (358 mg, 0.93 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred for 2 hours and then concentrated and purified by column chromatography to obtain the product (120 mg, 87%).

[0492] Step C: (1-(2,2-difluorovinyl)cyclobutyl)methanol 4-methylbenzenesulfonate

[0493] Triethylamine (165 mg, 1.62 mmol) and p-toluenesulfonyl chloride (185 mg, 0.97 mmol) were added to a solution of (1-(2,2-difluorovinyl)cyclobutyl)methanol (120 mg, 0.81 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 12 h, concentrated, and purified by column chromatography to obtain the product (130 mg, yield 53%).

[0494] Step D: 4-((1-(2,2-difluorovinyl)cyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0495] To a DMF (1 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (20.0 mg, 0.070 mmol) was added (1-(2,2-difluorovinyl)cyclobutyl)methanol 4-methylbenzenesulfonate (86 mg, 0.28 mmol) and potassium carbonate (20 mg, 0.14 mmol). The reaction solution was stirred at 80°C for 2 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, the organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (4.0 mg, yield 14%). LC-MS ESI (-) m / z: 415.1 (MH) - .

[0496] 1 H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.6Hz,1H),6.90(d,J=8.5Hz,1H),5.24(dd,J=12.2,4.2Hz,1H),4.34(dd,J=26.9 ,4.1Hz,1H),3.99(s,2H),3.55–3.27(m,2H),2.63–2.53(m,1H),2.27–2.11(m,4H),2.00(dtd,J=8.3,6.7,6.0,1.9Hz,2H).

[0497] 19 F NMR(377MHz,Chloroform-d)δ-42.95,-86.00,-86.11,-86.36,-86.48,-102.49,-103.12,-113.92,-114.56.

[0498] Example 51: 4-((1-ethylcyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0499]

[0500] Palladium on carbon (Pd / C, 2 mg) was added to a solution of 4-((1-ethynylcyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol (5 mg, 0.013 mmol) in methanol (5 mL), and hydrogenation was carried out at room temperature and pressure for 1 hour. The reaction solution was filtered and purified by reverse phase high performance liquid chromatography to obtain the product (3 mg, 60%).

[0501] LC-MS ESI(-)m / z:381.2(MH) - .

[0502] 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.6Hz,1H),6.95(d,J=8.6Hz,1H),5.31–5.23(m,1H),3.92(s,2H),3.51–3.38( m,2H),2.58(dd,J=4.7,1.7Hz,1H),1.98–1.91(m,4H),1.89–1.81(m,2H),1.65(t,J=7.5Hz,2H),0.88(t,J=7.5Hz,3H).

[0503] 19 F NMR(376MHz,Chloroform-d)δ-43.01,-102.44,-103.07,-113.89,-114.52.

[0504] Example 52: 2,2-difluoro-4-((1-hydroxycyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0505] Step A: 1-(Hydroxymethyl)cyclobutan-1-ol

[0506] Add 1M borane dimethyl sulfide (BH3·DMS, 7mL, 6.9mmol) to a solution of 1-hydroxycyclobutane-1-carboxylic acid (400mg, 3.45mmol) in tetrahydrofuran (20mL) at 0℃. After reacting at room temperature for 1h, add 2N HCl to quench. Concentrate to remove the organic solvent, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine, concentrate and use directly in the next step.

[0507] Step B: (1-Hydroxycyclobutyl)methanol 4-methylbenzenesulfonate

[0508] Triethylamine (400 mg, 2.4 mmol) and p-toluenesulfonyl chloride (456 mg, 2.4 mmol) were added to a solution of 1-(hydroxymethyl)cyclobutan-1-ol (200 mg, 2.0 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 5 h, directly concentrated, and purified by column chromatography to obtain the product (100 mg, two-step yield 20%).

[0509] Step C: 2,2-difluoro-4-((1-hydroxycyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0510] To a DMF (2 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (30 mg, 0.11 mmol) was added (1-hydroxycyclobutyl)methanol 4-methylbenzenesulfonate (100 mg, 0.41 mmol) and potassium carbonate (30 mg, 0.21 mmol). The reaction solution was stirred at 80 ° C for 2 h under nitrogen. Cooled, water and ethyl acetate were added to separate the layers, and the organic phase was washed with saturated brine (10 mL × 3), dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (6.5 mg, yield 16%).

[0511] LC-MS ESI (-) m / z: 369.1 (MH) - .

[0512] 1 H NMR(400MHz,Chloroform-d)δ7.63(d,J=8.5Hz,1H),6.98(d,J=8.6Hz,1H),5.27(d,J=12.2Hz,1H),4.08(d,J =1.4Hz,2H),3.58–3.36(m,2H),2.28–2.15(m,4H),1.90(tdd,J=8.6,4.2,2.8Hz,1H),1.67(d,J=2.7Hz,1H).

[0513] 19 F NMR(376MHz,Chloroform-d)δ-42.87,-102.57,-103.20,-113.96,-114.60.

[0514] Example 53: 3-(((1S,2S,3R)-2,3-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

[0515]

[0516] Step A. 3-Fluoro-5-((7-(trifluoromethylthio)-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-4-oxy)benzonitrile

[0517] To a solution of 3-fluoro-5-((1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (1.0 g, 2.72 mmol) in ethylene glycol (10 mL) were added p-toluenesulfonic acid (93 mg, 0.54 mmol) and trimethyl orthoformate (5.8 g, 54.4 mmol). The reaction solution was heated at 80 °C for h, poured into a saturated sodium bicarbonate solution (40 mL), and extracted with ethyl acetate (40 mL×3). The organic phase was washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (0.4 g, yield 35.8%). Step B. 3-((3-bromo-7-(trifluoromethylthio)-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-4-oxy)-5-fluorobenzonitrile

[0518] NBS (178 mg, 1 mmol) and AIBN (16 mg, 0.1 mmol) were added to a solution of 3-fluoro-5-((7-(trifluoromethylthio)-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-4-oxy)benzonitrile (0.4 g, 0.97 mmol) in dichloromethane (10 mL). The reaction solution was heated at 45°C for 4 h, poured into ice water, and extracted with ethyl acetate (30 mL×3). The extract was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (0.2 g, yield 42.1%).

[0519] LC-MS: m / z 490 (M+H) + .

[0520] Step C. 3-Fluoro-5-((3-oxo-7-(trifluoromethylthio)-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-4-oxy)benzonitrile

[0521] 2-Methylpyridinium oxide (106 mg, 1 mmol) and diisopropylethylamine (961 mg, 4.6 mmol) were added to a solution of 3-((3-bromo-7-(trifluoromethylthio)-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-4-oxy)-5-fluorobenzonitrile (200 mg, 0.41 mmol) in acetonitrile (10 mL). The reaction solution was heated at 50°C for 2 h under nitrogen protection, and the product was purified by column chromatography after concentration (160 mg, yield 91.6%).

[0522] LC-MS: m / z 426 (M+H) + .

[0523] Step D. (R)-3-Fluoro-5-((3-hydroxy-7-(trifluoromethylthio)-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-4-oxy)benzonitrile

[0524] To a solution of 3-fluoro-5-((3-oxo-7-(trifluoromethylthio)-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-4-oxy)benzonitrile (160 mg, 0.38 mmol) in acetonitrile (5 mL) were added (1R,2R)-(-)-N-(4-methylbenzenesulfonyl)-1,2-diphenylethylenediamine ((R,R)-Ts-DPEN, 34 mg, 0.04 mmol), triethylamine (40 mg, 0.4 mmol) and formic acid (100 mg). The reaction was stirred at 30°C under nitrogen for 16 h. Saturated sodium bicarbonate solution (40 mL) was poured into the mixture and extracted with ethyl acetate (40 mL×3). The organic phase was washed with saturated brine, dried over sodium sulfate, concentrated and purified by column chromatography to give the product (130 mg, yield 81.3%).

[0525] LC-MS: m / z 428 (M+H) + .

[0526] Step E. (R)-3-Fluoro-5-((3-hydroxy-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

[0527] 4M hydrochloric acid (1 mL) was added to a solution of (R)-3-fluoro-5-((3-hydroxy-7-(trifluoromethylthio)-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-4-oxy)benzonitrile (130 mg, 0.30 mmol) in methanol (5 mL). The reaction solution was stirred at room temperature for 0.5 h, poured into ice water, and extracted with ethyl acetate (30 mL×3). The extract was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (70 mg, yield 60.9%).

[0528] LC-MS: m / z 384 (M+H) + .

[0529] Step F. 3-Fluoro-5-(((3S)-2-fluoro-3-hydroxy-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

[0530] Select-F (63 mg, 0.18 mmol) and methanesulfonic acid (17 mg, 0.18 mmol) were added to a solution of (R)-3-fluoro-5-((3-hydroxy-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (70 mg, 0.18 mmol) in acetonitrile / methanol (10 mL / 3 mL). The reaction solution was heated at 60°C for 2 h, poured into ice water, and extracted with ethyl acetate (30 mL×3). The extract was washed with saturated brine (20 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (20 mg, yield 27.6%).

[0531] LC-MS: m / z 402 (M+H) + .

[0532] Step G. 3-Fluoro-5-(((1S,2R,3S)-2-fluoro-1,3-dihydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

[0533] To a solution of 3-fluoro-5-(((3S)-2-fluoro-3-hydroxy-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (20 mg, 0.05 mmol) in acetonitrile / methanol (5 mL / 3 mL) was added (R,R)-Ts-DPEN (8.5 mg, 0.01 mmol), triethylamine (10 mg, 0.1 mmol) and formic acid (10 mg). The reaction solution was stirred at 30°C under nitrogen for 16 h. Saturated sodium bicarbonate (30 mL) was poured in and extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (10 mg, yield 49.5%).

[0534] LC-MS: m / z 404 (M+H) + .

[0535] Step H. 3-(((1S,2S,3R)-2,3-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

[0536] To a solution of 3-fluoro-5-(((1S,2R,3S)-2-fluoro-1,3-dihydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (10 mg, 0.025 mmol) in DME (5 mL) was added PBSF (9 mg, 0.03 mmol) and DBU (5 mg, 0.03 mmol) in DME (0.5 mL) at -25°C. The reaction solution was stirred at -25°C for 1 h, poured into ice water, and extracted with ethyl acetate (30 mL×3). The extract was washed with saturated brine (20 mL), dried over sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (4 mg, yield 3%).

[0537] LC-MS: m / z 406 (M+H) + .

[0538] 1 H NMR (400MHz, CDCl3) δ7.87(dd,J=8.6,2.4Hz,1H),7.28–7.24(m,1H),7.21(dt,J=2.1,1.1Hz,1H),7.11(dt,J=9.1,2.3Hz,1H) ,7.03(d,J=8.3Hz,1H),6.02(dd,J=55.3,4.3Hz,1H),5.44(s,1H),5.12(ddt,J=47.8,16.7,4.8Hz,1H),2.51(d,J=5.1Hz,1H).

[0539] Example 54: 3-Fluoro-5-((7-hydroxy-1-(trifluoromethylthio)-6,7-dihydro-5H-3-azaindene-4-oxy)benzonitrile

[0540] Step A. 4-Bromo-5,6-dihydro-7H-3-azaindene-7-one-N-oxide

[0541] mCPBA (3.4 g, 17.0 mmol) was added to a solution of 4-bromo-5,6-dihydro-7H-3-azaindene-7-one (3.0 g, 14.15 mmol) in dichloromethane (30 mL). The reaction solution was stirred at room temperature for 16 h, saturated sodium bicarbonate solution (40 mL) was added, and ethyl acetate (40 mL × 3) was used for extraction. The organic phase was washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (1.5 g, yield 46.3%).

[0542] LC-MS: m / z 229 (M+H) + .

[0543] Step B. 4-Bromo-1-(trifluoromethylthio)-5,6-dihydro-7H-3-azaindene-7-one

[0544] AgSCF3 (2.8 g, 13.1 mmol) was added to a solution of 4-bromo-5,6-dihydro-7H-3-azaindene-7-one-N-oxide (1.5 g, 6.55 mmol) in dichloromethane (20 mL). The reaction was stirred at room temperature for 8 hours, poured into ice water, extracted with ethyl acetate (40 mL × 3), the organic phase was washed with saturated brine, dried with sodium sulfate, concentrated and purified by column chromatography to obtain the product (1.0 g, yield 48.9%). LC-MS: m / z 313 (M+H) + .

[0545] Step C. 4-Bromo-1-(trifluoromethylthio)-5,6-dihydrospiro[3-azaindene-7,2'-[1,3]dioxolane]

[0546] 2,2,7,7-Tetramethyl-3,6-dioxa-2,7-disilaoctane (3.3 g, 16 mmol) and TMSOTf (2.2 g, 10 mmol) were added to a solution of 4-bromo-1-(trifluoromethylthio)-5,6-dihydro-7H-3-azaindene-7-one (1.0 g, 3.2 mmol) in dichloromethane (20 mL). The reaction solution was stirred at room temperature for 16 hours, concentrated, and separated by column chromatography to obtain the product (500 mg, yield 43.8%). LC-MS: m / z 357 (M+H) + .

[0547] Step D. 1-(Trifluoromethylthio)-5,6-dihydrospiro[3-azaindene-7,2'-[1,3]dioxolane]-4-ol

[0548] Potassium hydroxide (157 mg, 2.8 mmol) and tBuXPhos-Pd-G3 (111 mg, 0.14 mmol) were added to a solution of 4-bromo-1-(trifluoromethylthio)-5,6-dihydrospiro[3-azaindene-7,2'-[1,3]dioxolane] (500 mg, 1.4 mmol) in dioxane / H2O (4 mL / 1 mL). The reaction was heated in a microwave at 100°C for 1 h under nitrogen, and then 1N HCl was added to adjust the pH to 6.0. The aqueous phase was extracted with ethyl acetate (40 mL×3), and the organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated to obtain a crude product (300 mg, yield 72.9%).

[0549] LC-MS: m / z 294 (M+H) + .

[0550] Step E. 3-Fluoro-5-((1-(trifluoromethylthio)-5,6-dihydrospiro[3-azaindene-7,2'-[1,3]dioxolane]-4-oxy)benzonitrile

[0551] 3,5-Difluorobenzonitrile (167 mg, 1.2 mmol) and cesium carbonate (488 mg, 1.5 mmol) were added to a DMF (5 mL) solution of 1-(trifluoromethylthio)-5,6-dihydrospiro[3-azaindene-7,2'-[1,3]dioxolane]-4-ol (300 mg, 1.0 mmol). The reaction solution was heated at 150°C for 1 h in a microwave oven, poured into ice water, and extracted with ethyl acetate (40 mL×3). The extract was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (200 mg, yield 48.4%). LC-MS: m / z 413 (M+H) + .

[0552] Step F. 3-Fluoro-5-((7-oxo-1-(trifluoromethylthio)-6,7-dihydro-5H-3-azaindene-4-oxy)benzonitrile

[0553] To a solution of 3-fluoro-5-((1-(trifluoromethylthio)-5,6-dihydrospiro[3-azaindene-7,2'-[1,3]dioxolane]-4-oxy)benzonitrile (200 mg, 0.48 mmol) in acetonitrile / water (8 mL / 3 mL) was added p-toluenesulfonic acid (83 mg, 0.48 mmol). The reaction mixture was stirred at 60°C for 2 h, then poured into a saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (40 mL×3). The extract was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (150 mg, yield 40.7%).

[0554] LC-MS: m / z 369 (M+H) + .

[0555] Step G. 3-Fluoro-5-((7-hydroxy-1-(trifluoromethylthio)-6,7-dihydro-5H-3-azaindene-4-oxy)benzonitrile

[0556] Sodium borohydride (33 mg, 0.82 mmol) was added to a solution of 3-fluoro-5-((7-oxo-1-(trifluoromethylthio)-6,7-dihydro-5H-3-azaindene-4-oxy)benzonitrile (150 mg, 0.41 mmol) in methanol (10 mL). The reaction solution was stirred at room temperature for 2 h under nitrogen, poured into saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (40 mL×3). The extract was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (100 mg, yield 66.1%).

[0557] LC-MS: m / z 369 (M+H) + .

[0558] 1 H NMR (400MHz, CDCl3) δ8.29 (s, 1H), 7.17 (ddd, J=7.5, 2.4, 1.3Hz, 1H), 7.06 (dt, J=2 .3,1.1Hz,1H),6.96(dt,J=9.3,2.4Hz,1H),5.50(dd,J=7.3,3.8Hz,1H),3.03(ddd, J=17.7,8.7,6.2 Hz,1H), 2.77 (ddd, J=17.7,8.9,4.8 Hz,1H), 2.61–2.43 (m,2H), 2.27–2.09 (m,1H). Example 55: 3-Fluoro-5-(6-fluoro-7-hydroxy-1-(trifluoromethylthio)-6,7-dihydro-5H-3-azaindene-4-oxy)benzonitrile

[0559] Step A. 3-Fluoro-5-(6-fluoro-7-oxo-1-(trifluoromethylthio)-6,7-dihydro-5H-3-azaindene-4-oxy)benzonitrile

[0560] Select-F (64 mg, 0.18 mmol) and 0.1 mL of 98% sulfuric acid were added to a solution of 3-fluoro-5-(1-(trifluoromethylthio)-5,6-dihydrospiro[3-azaindene-7,2'-[1,3]dioxolane]-4-oxy)benzonitrile (50 mg, 0.12 mmol) in methanol (10 mL). The reaction solution was heated at 65°C for 3 h, then poured into a saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (40 mL×3). The extract was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (10 mg, yield 21.6%).

[0561] LC-MS: m / z 387 (M+H) + .

[0562] Step B. 3-Fluoro-5-(6-fluoro-7-hydroxy-1-(trifluoromethylthio)-6,7-dihydro-5H-3-azaindene-4-oxy)benzonitrile

[0563] Sodium borohydride (33 mg, 0.82 mmol) was added to a solution of 3-fluoro-5-(6-fluoro-7-oxo-1-(trifluoromethylthio)-6,7-dihydro-5H-3-azaindene-4-oxy)benzonitrile (10 mg, 0.03 mmol) in methanol (8 mL). The reaction solution was stirred at room temperature for 2 h under nitrogen, poured into saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (40 mL×3). The extract was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (3 mg, yield 25.7%). LC-MS: m / z 389 (M+H) + .

[0564] 1 H NMR (400MHz, CDCl3) δ8.29 (s, 1H), 7.18 (ddd, J=7.5, 2.3, 1.3Hz, 1H), 7.07 (dt, J=2.3, 1.1Hz, 1H),7.02–6.92(m,1H),5.46–5.28(m,2H),3.31–3.14(m,1H),3.14–2.96(m,1H),2.72(s,1H).

[0565] 19 F NMR(377MHz, CDCl3)δ-39.06,-105.55,-198.67.

[0566] Example 56: 4-(3,3-difluorospiro[3.3]heptane-1-methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0567]

[0568] Step A. 3-((Benzyloxy)methyl)spiro[3.3]heptan-1-one

[0569] To a solution of cyclobutyl (1-piperidinyl) ketone (500 mg, 3.00 mmol) in dichloromethane (2 ml) were added trifluoromethanesulfonic anhydride (1.02 g, 3.60 mmol), benzyl allyl ether (888 mg, 6.00 mmol) and 2,4,6-trimethylpyridine (2,4,6-colidine, 435 mg, 3.6 mmol). The reaction solution was heated at 45 ° C for 15 h. The reaction was quenched with saturated ammonium chloride and extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (10 mL × 3), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (150 mg, yield 21.7%).

[0570] Step B. 3-((Benzyloxy)methyl)-1,1-difluorospiro[3.3]heptan-1-one

[0571] Add BAST (1 mL) to a chloroform (5 mL) solution of 3-((benzyloxy)methyl)spiro[3.3]heptane-1-one (100 mg, 0.434 mmol) at 0°C. Heat the reaction mixture at 60°C for 15 h. Pour into saturated sodium bicarbonate solution (20 mL) and extract with ethyl acetate (40 mL×3). Wash the extract with saturated brine (30 mL), dry with sodium sulfate, concentrate, and purify with column chromatography to obtain the product (45 mg, yield 40.0%).

[0572] Step C. 3,3-Difluorospiro[3.3]heptane-1-methanol

[0573] Pd / C (5 mg, 10% w / w) was added to a solution of 3-((benzyloxy)methyl)-1,1-difluorospiro[3.3]heptane-1-one (45 mg, 0.178 mmol) in methanol (5 mL). The reaction mixture was stirred at room temperature for 15 h under a hydrogen atmosphere. After filtration, the mixture was washed with methanol and the filtrate was concentrated to obtain a crude product (30 mg). It was used directly in the next step.

[0574] Step D. 3,3-Difluorospiro[3.3]heptane-1-methanol 4-methylbenzenesulfonate

[0575] Triethylamine (0.5 ml) and p-toluenesulfonyl chloride (38 mg, 0.200 mmol) were added to a solution of 3,3-difluorospiro[3.3]heptane-1-methanol (30 mg, 0.185 mmol) in dichloromethane (5 ml). The reaction solution was stirred at room temperature for 15 h, concentrated, and purified by column chromatography to obtain the product (20 mg, yield 41.9%).

[0576] Step E. 4-(3,3-Difluorospiro[3.3]heptane-1-methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0577] Potassium carbonate (64 mg, 0.465 mmol) and 3,3-difluorospiro[3.3]heptane-1-methanol 4-methylbenzenesulfonate (40 mg, 0.155 mmol) were added to a DMF (3 mL) solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (22 mg, 0.077 mmol). The reaction solution was heated at 110°C for 15 h. After cooling, water was added and extracted with ethyl acetate (40 mL×3). The extract was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (7 mg, yield 21.1%).

[0578] LC-MS: m / z 431.4 (M+H) + .

[0579] 1 H NMR(400MHz, CDCl3) δ7.61(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),5.26(dd,J=4.8Hz),4.10-4.07(m ,2H),3.47-3.34(m,2H),2.63-2.55(m,2H),2.47-2.39(m,2H),2.28-2.18(m,2H),2.05-1.85(m,4H)

[0580] Example 57: N-(1-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutyl)formamide

[0581]

[0582] Step A. Ethyl 1-((tert-Butyloxycarbonyl)amino)cyclobutane-1-carboxylate

[0583] Triethylamine (1 ml) and di-tert-butyl dicarbonate (200 mg, 0.916 mmol) were added to a solution of 1-aminocyclobutane-1-carboxylic acid ethyl ester (hydrochloride, 150 mg, 0.833 mmol) in tetrahydrofuran (10 ml) at 0°C. The reaction was stirred at room temperature for 15 h, then concentrated and purified by column chromatography to obtain the product (250 mg).

[0584] Step B. tert-Butyl (1-(hydroxymethyl)cyclobutyl)carbonic acid amide

[0585] Add lithium aluminum hydride (152 mg, 4.04 mmol) to a solution of ethyl 1-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylate (250 mg, 1.01 mmol) in tetrahydrofuran (10 ml) at 0°C. The reaction solution was heated to room temperature and stirred for 5 hours, then quenched with water. The solid after quenching was filtered off with diatomaceous earth and washed with tetrahydrofuran. The filtrate was concentrated and purified by column chromatography to obtain the product (80 mg, yield 38.1%).

[0586] Step C. (1-((tert-Butyloxycarbonyl)amino)cyclobutyl)methanol 4-methylbenzenesulfonate

[0587] Triethylamine (30 mg, 0.30 mmol) and p-toluenesulfonyl chloride (28 mg, 0.15 mmol) were added to a solution of tert-butyl (1-(hydroxymethyl)cyclobutyl)carbonic acid amide (20 mg, 0.10 mmol) in dichloromethane (10 ml) at 0°C. The reaction mixture was stirred at room temperature for 15 h and then concentrated and purified by column chromatography to obtain the product (25 mg, yield 83.3%).

[0588] Step D. tert-Butyl (1-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutyl) carbonate

[0589] To a solution of 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (50 mg, 0.175 mmol) in DMF (5 mL) was added (1-((tert-butyloxycarbonyl)amino)cyclobutyl)methanol 4-methylbenzenesulfonate (160 mg, 0.538 mmol) and potassium carbonate (120 mg, 0.875 mmol). The reaction was heated at 100°C for 15 h. The reaction solution was quenched with water and extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (10 mg, yield 12.2%).

[0590] Step E. 4-((1-aminocyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0591] Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl (1-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutyl) carbonate (10 mg, 0.021 mmol) in dichloromethane (2 mL) at 0°C. The reaction solution was stirred at room temperature for 2 h, then poured into a sodium bicarbonate solution until pH>7, extracted with ethyl acetate (10 mL×3), and the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (4 mg, yield 50.9%).

[0592] LC-MS: m / z 370.4 (M+H) + .

[0593] 1H NMR (400MHz, CDCl3) δ7.63(d,J=8.4Hz,1H),6.96(d,J=8.4Hz,1H),5.27(d,J=11.6Hz,1H) ,4.01(s,2H),3.51-3.39(m,2H),2.22-2.19(m,2H),2.05-1.98(m,2H),1.91-1.74(m,2H).

[0594] Step F N-(1-(((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)cyclobutyl)formamide

[0595] A solution of 4-((1-aminocyclobutyl)methoxy)-2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol (10 mg, 0.027 mmol) in formic acid (2 mL) was heated at 60°C for 15 h. The reaction solution was concentrated and purified by reverse phase HPLC to obtain the product (5 mg, yield 46.7%).

[0596] LC-MS: m / z 398.4 (M+H) + .

[0597] 1 H NMR (400MHz, CDCl3) δ8.12(s,1H),7.64(d,J=8.4Hz,1H),6.97(d,J=8.4Hz,1H),5.26(d,J=11.6H z,1H),4.00(s,2H),3.50-3.40(m,2H),2.22-2.19(m,2H),2.05-1.97(m,2H),1.90-1.75(m,2H).

[0598] Example 58: 2,2-difluoro-4-(1,2,3,4-tetrahydronaphthalene-1-yl)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0599]

[0600] Step A. 4-(1,2,3,4-Tetrahydronaphthalen-1-yl)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0601] 1,2,3,4-tetrahydronaphthalen-1-ol (52 mg, 0.352 mmol), DEAD (61 mg, 0.352 mmol) and triphenylphosphine (92 mg, 0352 mmol) were added to a solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (50 mg, 0.176 mmol) in tetrahydrofuran (10 mL) at 0°C. The reaction solution was stirred under nitrogen for 15 h and quenched with water. The reaction solution was extracted with ethyl acetate (10 mL × 3), the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (36 mg, yield 50.5%).

[0602] Step B. 2,2-Difluoro-4-(1,2,3,4-tetrahydronaphthalen-1-yl)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0603] To a toluene / cyclohexane (5mL / 5mL) solution of 4-(1,2,3,4-tetrahydronaphthalene-1-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (50mg, 0.132mmol) under nitrogen, 3-methoxypropylamine (35mg, 0.397mmol), pivalic acid (2.0mg, 0.02mmol) and sodium sulfate (1.0g) were added. The reaction solution was heated at 80°C for 16h and then concentrated under reduced pressure. Anhydrous acetonitrile (10mL) and Select-F (467mg, 1.32mmol) were added and heated at 65°C for 5h. The reaction was quenched with 1N hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (20mg, yield 36.8%).

[0604] Step C. 2,2-Difluoro-4-(1,2,3,4-tetrahydronaphthalen-1-yl)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0605] Sodium borohydride (6 mg, 0.18 mmol) was added to a solution of 2,2-difluoro-4-(1,2,3,4-tetrahydronaphthalene-1-yl)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (15 mg, 0.036 mmol) in tetrahydrofuran / methanol (2 mL / 2 mL). The reaction solution was stirred at room temperature for 0.5 h, poured into ice water (10 mL), extracted with ethyl acetate (10 mL×3), and the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (10 mg, yield 66.7%).

[0606] LC-MS: m / z 417.4 (M+H) + .

[0607] 1 H NMR (400MHz, CDCl3) δ7.55(d,J=8.8Hz,1H),7.21-7.09(m,4H),7.03(d,J=8.8Hz,1H),5.38(t,J=4.6Hz,1 H),5.18(d,J=12Hz,1H),4.23(t,J=6.8Hz,1H),3.33-3.22(m,2H),2.86-2.68(m,2H).2.11-1.55(m,4H).

[0608] Example 59: 2-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluoroisophthalonitrile

[0609] Step A. 5-Fluoro-2-((1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)isophthalonitrile

[0610] Potassium carbonate (20 mg, 0.147 mmol) and 2,5-difluoroisophthalonitrile (9 mg, 0.056 mmol) were added to a DMF (2 mL) solution of 2,2-difluoro-4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (16 mg, 0.056 mmol) under nitrogen. The reaction solution was stirred at 50°C for 2 h, then ice water (10 mL) was added, and extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (15 mg, yield 57.7%).

[0611] Step B. 2-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluoroisophthalonitrile

[0612] Sodium borohydride (3.0 mg, 0.082 mmol) was added to a solution of 5-fluoro-2-((1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)isophthalonitrile (7.0 mg, 0.016 mmol) in tetrahydrofuran / methanol (4 mL / 2 mL). The reaction solution was stirred at room temperature for 0.5 h, then poured into ice water (5 mL), extracted with ethyl acetate (10 mL×3), and the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (8 mg, yield 57.1%).

[0613] LC-MS: m / z 431.4 (M+H) + .

[0614] 1 H NMR (400MHz, CDCl3) δ7.73(d,J=6.4Hz,2H),7.62(d,J=8.4Hz,1H),6.63(d,J=8.4Hz,1H),5.35-5.31(dd,1H),3.74-3.62(m,2H),2.76-2.75(m,1H).

[0615] Example 60: 2,2-difluoro-4-(3-fluorobicyclo[1.1.1]pentan-1-methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1-ol

[0616] Step A. 4-(3-Fluorobicyclo[1.1.1]pentan-1-methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0617] 3-Fluorobicyclo[1.1.1]pentane-1-methanol (52 mg, 0.352 mmol), DEAD (67 mg, 0.384 mmol) and triphenylphosphine (100 mg, 0.384 mmol) were added to a solution of 4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (47 mg, 0.192 mmol) in tetrahydrofuran (10 mL) at 0°C. The reaction solution was stirred under nitrogen for 15 h and quenched with water. The reaction solution was extracted with ethyl acetate (10 mL × 3), the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated and purified by thin layer chromatography to obtain the product (20 mg, yield 30.3%).

[0618] Step B. 2,2-Difluoro-4-(3-fluorobicyclo[1.1.1]pentan-1-methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one

[0619] To a toluene / cyclohexane (2mL / 2mL) solution of 4-(3-fluorobicyclo[1.1.1]pentane-1-methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (20mg, 0.058mmol) under nitrogen, 3-methoxypropylamine (15mg, 0.173mmol), pivalic acid (1.0mg, 0.01mmol) and sodium sulfate (1.0g) were added. The reaction solution was heated at 80°C for 16h and then concentrated under reduced pressure. Anhydrous acetonitrile (10mL) and Select-F (205mg, 0.58mmol) were added and heated at 65°C for 5h. The reaction was quenched with 1N hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried with sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (5.0mg, yield 22.7%).

[0620] Step C. 2,2-Difluoro-4-(3-fluorobicyclo[1.1.1]pentan-1-methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0621] Sodium borohydride (2.1 mg, 0.054 mmol) was added to a solution of 2,2-difluoro-4-(3-fluorobicyclo[1.1.1]pentan-1-methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (5.0 mg, 0.013 mmol) in tetrahydrofuran / methanol (4 mL / 2 mL). The reaction solution was stirred at room temperature for 0.5 h, then poured into ice water (5 mL), extracted with ethyl acetate (10 mL×3), and the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (1 mg, yield 19.9%).

[0622] LC-MS: m / z 385.4 (M+H) + .

[0623] 1 H NMR (400MHz, CDCl3) δ7.61 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 5.26-5.22 (dd, 1H), 3.80 (s, 2H), 2.77 (dd, 1H), 2.06-1.50 (m, 6H).

[0624] Example 61: 6-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-4-(trifluoromethyl)picolinonitrile

[0625]

[0626] Step A. 6-((2,2-difluoro-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-4-(trifluoromethyl)picolinonitrile

[0627] Potassium carbonate (29 mg, 0.21 mmol) and 6-chloro-4-(trifluoromethyl)picolinonitrile (14 mg, 0.07 mmol) were added to a DMF (2 mL) solution of 2,2-difluoro-4-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-one (20 mg, 0.07 mmol). The reaction liquid was heated in a microwave at 100 ° C for 1 h under nitrogen. The reaction was quenched with water and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by thin layer chromatography to obtain the product (10 mg, yield 31.2%).

[0628] Step B. 6-((2,2-difluoro-1-hydroxy-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-4-(trifluoromethyl)picolinonitrile

[0629] Sodium borohydride (4 mg, 0.12 mmol) was added to a solution of 6-((2,2-difluoro-1-oxo-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-4-yl)oxy)-4-(trifluoromethyl)picolinonitrile (10.0 mg, 0.022 mmol) in tetrahydrofuran / methanol (3 mL / 2 mL). The reaction solution was stirred at room temperature for 0.5 h, then poured into ice water (5 mL), extracted with ethyl acetate (10 mL×3), and the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (5 mg, yield 50.3%).

[0630] LC-MS: m / z 457.4 (M+H) + .

[0631] 1 H NMR (400MHz, CDCl3) δ7.73(d,J=8.4Hz,1H),7.67(s,1H),7.49(s,1H),7.29(d,J=8.4Hz,1H),5.32-5.28(dd,1H),3.44-3.28(m,2H),2.71(d,1H).

[0632] Example 62: 2,2-difluoro-4-((3-methylbut-2-en-1-oxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0633]

[0634] 2,2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (43 mg, 0.155 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to a solution of 1-chloro-3-methylbut-2-ene (60 mg, 0.577 mmol) in DMF (2 mL). The reaction solution was stirred at 80 ° C for 16 h under nitrogen. After cooling, filtration and concentration, the product was purified by reverse phase high performance liquid chromatography (15 mg, yield 28.2%).

[0635] LC-MS: m / z 353 (MH) - .

[0636] 1H NMR(400MHz,Chloroform-d)δ7.60(d,J=8.6Hz,1H),6.91(d,J=8.6Hz,1H),5.46(ddt,J=5.1,3.5,1.5Hz,1H),5.25(dd ,J=12.5,2.6Hz,1H),4.61(d,J=6.7Hz,2H),3.60–3.31(m,2H),2.61(d,J=3.8Hz,1H),1.89–1.79(m,3H),1.77(s,3H).

[0637] Example 63: 2,2-difluoro-4-((3-fluorocyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0638] Step A. Benzyl 3-hydroxycyclobutane-1-carboxylate

[0639] Sodium borohydride (1.392 g, 36.796 mmol) was added to a solution of 3-oxocyclobutane-1-carboxylic acid benzyl ester (4.5 g, 22.034 mmol) in tetrahydrofuran / methanol (5 mL / 5 mL) at 0°C. The reaction solution was stirred at room temperature for 3 h, quenched with ammonium chloride, and extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (3.5 g, yield 98.9%).

[0640] Step B. Benzyl 3-fluorocyclobutane-1-carboxylate

[0641] DAST (8.587 g, 53.335 mmol) was added to a solution of 3-hydroxycyclobutane-1-carboxylic acid benzyl ester (4.4 g, 21.334 mmol) in dichloromethane (60 mL) at 0°C. The reaction was stirred for 12 hours after warming to room temperature, quenched with ice water (100 mL), and the aqueous phase was extracted with dichloromethane (80 mL × 3). The organic phases were combined and washed with saturated brine (50 mL × 2), dried with sodium sulfate, concentrated, and purified by column chromatography to obtain the product (1.64 g, yield 36.9%).

[0642] Step C. 3-Fluorocyclobutane-1-carboxylic acid

[0643] Palladium on carbon (500 mg) was added to a solution of 3-fluorocyclobutane-1-carboxylic acid benzyl ester (1.64 g, 7.876 mmol) in tetrahydrofuran (20 mL). The reaction was hydrogenated at room temperature and atmospheric pressure for 3 hours. The reaction solution was filtered and concentrated to obtain the product (850 mg, yield 91.4%). Step D. (3-fluorocyclobutyl)methanol

[0644] Add lithium aluminum hydride (547.0 mg, 14.394 mmol) to a solution of 3-fluorocyclobutane-1-carboxylic acid (850 mg, 7.197 mmol) in tetrahydrofuran (20 mL) at 0°C. The reaction solution was heated to room temperature and stirred for 3 h before being quenched by adding ice water (100 mL). The mixture was extracted with ethyl acetate (80 mL × 3), and the combined organic phases were washed with saturated brine (50 mL × 2), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the product (550 mg, yield 73.3%).

[0645] Step E. 2,2-Difluoro-4-((3-fluorocyclobutyl)methoxy)-7-(trifluoromethylthio)-2,3-dihydro-1H-inden-1-ol

[0646] Under nitrogen, (3-fluorocyclobutyl)methanol (350.0 mg, 3.356 mmol), triphenylphosphine (550 mg, 2.098 mmol) and DEAD (365 mg, 2.098 mmol) were added to a solution of 2-difluoro-7-(trifluoromethylthio)-2,3-dihydro-1H-indene-1,4-diol (240 mg, 0.839 mmol) in tetrahydrofuran (10 mL) . After stirring at room temperature for 12 hours, the reaction solution was quenched with water and extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine, dried with sodium sulfate, concentrated, and purified by reverse phase high performance liquid chromatography to obtain the product (12.0 mg, yield 3.8%).

[0647] LC-MS: m / z 373.3 (M+H) + .

[0648] 1 H NMR (400MHz, CDCl3) δ7.59(d,J=8.4Hz,1H),6.87(d,J=8.4Hz,1H),5.24(dt,J=12.0,4.8Hz,1H),5.12(p,J=6.4Hz,1H),4.06–3.96(m,2H),3. 54–3.31(m,2H),2.80(dq,J=9.6,4.8Hz,1H),2.62(d,J=4.4Hz,1H),2.50(tdt,J=19.6,10.0,4.4Hz,2H),2.35(tdd,J=14.0,6.8,4.0Hz,2H).

[0649] Example 64: HIF2a protein binding test results of the compounds of the present application

[0650] The HIF2a protein binding experiment was used to evaluate the binding of the compound of the present application to the HIF2a protein, and the experimental steps were as follows:

[0651] Step A: Add 3-fold diluted compound solution (DMSO as solvent) to a 96-well plate for a total of ten doses, starting from a concentration of 2 mM, 4 μL per well;

[0652] Step B: Add 4 μL of HIF2a working solution (Pharmaron) and 4 μL of ARNT protein (Sino Biological) working solution to each compound well in a 96-well plate; isolate from air and equilibrate at room temperature for 30 min;

[0653] Step C: Add detection reagents Mab Anti-Flag Eu (Cisbio) and streptavidin (Cisbio) to the wells of compound and HIF2a / ARNT and equilibrate at room temperature for 16 hours;

[0654] Step D: Read the reading of each well with an ELISA reader (Envision 2105, PerkinElmer), and fit the reading to the concentration to obtain a concentration-effect curve. Find the reading of the ELISA reader corresponding to the highest inhibitory concentration, halve it and read the corresponding concentration from the concentration-effect curve to obtain the half inhibitory concentration (IC 50 ) values, and the results are shown in Table 1.

[0655] Table 1 Results of HIF2a protein binding experiment

[0656]

[0657] Note: “A” stands for IC 50 ≤50nM, "B" stands for 50nM <IC 50 ≤500nM, "C" represents 500nM <IC 50 ≤2μM; “ / ” indicates absence.

[0658] The IC of the positive control compound PT2977 was measured simultaneously 50 The result is A.

[0659] Example 65: Luciferase reporter gene detection experimental results of the compounds of the present application

[0660] The Luciferase reporter gene assay was used to measure the cell activity of the compounds of the present application. The experimental steps are as follows:

[0661] Step A: 786-O_HIF2a_Luciferase cells (786-O cells, Kanglong Chemical) were cultured in basal medium RPMI MEDIUM 1640 (Invitrogen) until the exponential growth phase, the culture medium was poured out, and the cells were washed with PBS buffer (Gibico); TrypLE solution (ThermoFisher) was added to separate the cells from the bottom of the bottle, and then washed once with basal medium and twice with PBS buffer to aggregate the cells and remove the phenol red stain in TrypLE; the cell viability was ensured to be greater than 90%;

[0662] Step B: Add 3-fold diluted compound solution (DMSO as solvent) to a 96-well plate for a total of ten doses, starting from a concentration of 2 mM, 4 μL per well;

[0663] Step C: Add approximately 5,000 786-O cells to each well and incubate at 37°C in a 5% carbon dioxide atmosphere for 18-20 h;

[0664] Step D: Add 25 μL of Britelite reagent (PerkinElmer) and Luciferase assay reagent (Promega) to each well;

[0665] Step E: Read the fluorescence value of each well with an ELISA reader (Envision 2105, PerkinElmer), and fit the fluorescence value and concentration to obtain a concentration-effect curve. Find the fluorescence value corresponding to the highest inhibitory concentration, halve it, and read the corresponding concentration from the concentration-effect curve to obtain the half inhibitory concentration IC of the compound. 50 The results are shown in Table 2.

[0666] Table 2 Luciferase reporter gene detection experimental results

[0667]

[0668] Note: “A” IC 50 ≤50nM, "B" stands for 50nM <IC 50 ≤500nM, "C" represents 500nM <IC 50 ≤2μM; “ / ” indicates absence.

[0669] The IC of the positive control compound PT2977 was measured simultaneously 50 The result is A.

[0670] According to Tables 1 and 2, the results of Example 64 show that the compounds of the present application can prevent HIF2a from binding to the ARNT enzyme, and the results of Example 65 show that the compounds of the present application can inhibit the growth of 786-O cells in which HIF2a is overexpressed due to VHL gene deletion; the results of the HIF2a protein binding experiment and the results of the Luciferase reporter gene detection show that the compounds of the present application have a strong HIF2a-ARNT binding inhibitory effect.

[0671] The above description is only a preferred embodiment of the present application and is not intended to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application are included in the protection scope of the present application.

Claims

1. A compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, in, X is selected from CH or N; L is selected from -O-, -NH-, -S-, -CH2-, -CF2-, -CH(F)-, -(C1-C3 alkylene)O-, -CH(CN)O-; A is selected from C1-C6 alkyl, C2-C6 alkenyl, C6-C12 aryl, C3-C8 cycloalkyl, C3-C10 cycloalkenyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl; B, C are independently selected from -CH2-, -CHF-, -CF2-; R 1 , R 2 , R 3 Each is independently selected from hydrogen, halogen, cyano, isocyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C2-C6 alkenyl, -C1-C3 alkylene-OH, C1-C6 heteroalkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -NHCHO; The C1-C6 heteroalkyl group is selected from -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -SCH3, -SCH2CH3, -SOCH3; The 3-8 membered heterocycloalkyl group and the 5-10 membered heteroaryl group contain 1-3 heteroatoms or heteroatom groups independently selected from O and N.

2. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: The compound is a compound represented by formula (II):

3. The compound according to claim 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: The compound is a compound represented by formula (IIa):

4. The compound according to claim 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 Each is independently selected from H, CN, F, Cl, CH3, CF3.

5. The compound according to claim 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: The compound is a compound represented by formula (IIb): Wherein, A2 is selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl.

6. The compound according to claim 5, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: In the compound represented by formula (IIb), Selected from 7. The compound according to claim 5, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: In the compound represented by formula (IIb), Selected from 8. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: The compound is a compound represented by formula (III):

9. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from any one of the following compounds:

10. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from any one of the following compounds:

11. A pharmaceutical composition, wherein: The pharmaceutical composition comprises the compound according to any one of claims 1 to 10, its optical isomer or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 11, wherein The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients.

13. Use of the compound according to any one of claims 1 to 10, its optical isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 11 to 12 in the preparation of a medicament for preventing and / or treating VHL-related diseases.

14. The use according to claim 13, wherein The VHL-related disease is selected from at least one of renal cancer, brain glioma, lung cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, gastric cancer, liver cancer, thyroid cancer, multiple myeloma, pancreatic ductal carcinoma, squamous cell carcinoma of the lung, colon cancer and hemangioma.

15. Use of the compound according to any one of claims 1 to 10, its optical isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 11 to 12, in the preparation of a medicament for preventing and / or treating an ophthalmic neovascularization-related disease, wherein the ophthalmic neovascularization-related disease is selected from at least one of corneal neovascularization, retinal neovascularization, diabetic retinopathy, diabetic macular edema, age-related macular degeneration, retinal vein occlusion, dry fundus macular degeneration, and wet fundus macular degeneration.

16. Use of the compound according to any one of claims 1 to 10, its optical isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 11 to 12 in the preparation of a HIF2α inhibitor.

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