HIF-2 alpha inhibitors and methods of use thereof

Abstract

The present disclosure is directed to compounds that are inhibitors of HIF-2α, having a structure according to Formula I, and compositions containing those compounds. Methods of using the compounds for the treatment of a disease, disorder, or condition are also described. [Formula 1] JPEG2024541969000214.jpg3859

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Nos. 63 / 273,283, filed October 29, 2021, 63 / 345,120, filed May 24, 2022, and 63 / 380,221, filed October 19, 2022, the disclosures of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The following discussion is provided to aid the reader in understanding the present disclosure and is not admitted to describe or constitute prior art to the present disclosure.

[0003] Hypoxia-inducible factor (HIF) transcription factors play an essential role in the cellular response to low oxygen availability. HIFs are heterodimeric transcription factors composed of a common constituent subunit called the aryl hydrocarbon receptor nuclear translocator (ARNT, or HIF-β) and one of three HIF-α subunits. Under normal conditions, the α-subunit is hydroxylated at a conserved proline residue by prolyl-4-hydroxylase and then targeted for degradation by the von Hippel-Lindau ubiquitin E3 ligase complex. However, under hypoxic conditions, HIF-α accumulates and enters the nucleus, where it activates the expression of genes that regulate metabolism, angiogenesis, cell proliferation and survival, immune evasion, and inflammatory responses.

[0004] Among the three distinct α-subunit isoforms, HIF-1α, HIF-2α, and the less well-characterized HIF-3α, overexpression of HIF-1α and HIF-2α has been associated with poor clinical outcomes in patients with various cancers. Specifically, HIF-2α has been found to be a marker of poor prognosis in glioblastoma, neuroblastoma, head and neck squamous cell carcinoma, and non-small cell lung cancer. Hypoxia is also common in many acute and chronic inflammatory disorders, such as inflammatory bowel disease and rheumatoid arthritis.

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

[0006] In one aspect, the present disclosure relates to compounds that inhibit the activity of hypoxia-inducible factor (HIF) transcription factors, particularly HIF-2α. The compounds are represented by Formula I: [ka] (In the formula, n, m, R 1 , R 2 , and R 3 have the meanings provided herein below).

[0007] In another aspect, the present disclosure relates to a method of inhibiting HIF-2α function in a subject, comprising administering to the subject an effective amount of a compound described herein.

[0008] In yet another aspect, the present disclosure provides a method for treating a disease, disorder, or condition in a subject that is at least partially mediated by HIF-2α, comprising administering to the subject a therapeutically effective amount of a HIF-2α inhibitor described herein. HIF-2α-mediated diseases, disorders, and conditions include von Hippel-Lindau (VHL) disease, cancer, an immune-related disease, disorder, or condition, an inflammation-related disease, disorder, or condition, a cardiovascular disease, a renal disease, or a metabolic disease. Certain aspects of the present disclosure further comprise administering one or more additional therapeutic agents described herein below.

[0009] In another aspect, the present disclosure is directed to a combination of a HIF-2α inhibitor described herein with one or more additional therapeutic agents. DETAILED DESCRIPTION OF THE INVENTION

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

[0011] definition Unless otherwise defined, all technical terms, notation, and other scientific or technical terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0012] The term "about" as used herein has the inherent meaning of approximately and literally supports the exact number preceded by the term and numbers that are near or approximate to the number preceded by the term. When determining whether a number is near or approximate to a specifically recited number, the near or approximate unrecited number may be a number that provides a substantial equivalent to the specifically recited number in the context in which the number is presented. For example, if the degree of approximation is not clear from the context, "about" means within plus or minus 10% of the provided value, or rounded to the nearest significant figure, and in all cases includes the provided value. When a range is provided, the range includes the boundary values.

[0013] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a saturated monovalent hydrocarbon radical, in some embodiments, having 1 to 8 (e.g., C1-C8 alkyl), or 1 to 6 (e.g., C1-C6 alkyl), or 1 to 3 (e.g., C1-C3 alkyl), or 2 to 8 (e.g., C2-C8 alkyl), or 2 to 6 (e.g., C2-C6 alkyl), or 2 to 4 (e.g., C2-C4 alkyl), or 2 to 3 carbon atoms (e.g., C2-C3). The term "alkyl" encompasses straight-chain and branched-chain hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, sec-pentyl, 2-methylbutyl, isohexyl, sec-hexyl, tert-hexyl, and the like. In some embodiments, the alkyl group is a C1-C6 alkyl group. In some embodiments, the alkyl group is a C2-C6 alkyl group. In some embodiments, the alkyl group is a C1-C3 alkyl group.

[0014] The term "alkylene" in some embodiments refers to a group having 1 to 6 alkylene groups (e.g., C 1-6"(C-C alkylene)" refers to a straight-chain or branched saturated hydrocarbon radical, i.e., a divalent hydrocarbon radical, having 1 to 4 (e.g., C-C alkylene) or 1 to 3 (e.g., C-C alkylene) or 2 to 3 (e.g., C-C alkylene) carbon atoms and linking at least two other groups. When linked to an alkylene, the two moieties can be linked to the same carbon atom of the alkylene group or to different carbon atoms. For example, a straight-chain alkylene is -(CH) n -, where n is 1, 2, 3, 4, 5, or 6 (i.e., C1-C6 alkylene). Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, sec-pentylene, tert-pentylene, hexylene, and the like. In some embodiments, the alkylene group is a C1-C3 alkylene group (e.g., methylene, ethylene, propylene, and isopropylene).

[0015] As used herein, the term "alkoxy" refers to an alkyl group, as defined herein, attached to the remainder of the molecule through an oxygen atom (e.g., -O-(C-C 12 Alkoxy groups include -O-(C-C alkyl), -O-(C-C alkyl), -O-(C-C alkyl), or -O-(C-C alkyl). Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and the like. In some embodiments, the alkoxy is an -O-(C-C alkyl) group, e.g., methoxy, ethoxy, n-propoxy, isopropoxy.

[0016] The term "cycloalkyl" refers, in some embodiments, to alkyl groups having 3 to 14 carbon atoms (e.g., C3-C 14 cycloalkyl), or 3 to 10 carbon atoms (e.g., C3-C 10"Cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system having 3 to 8 carbon atoms (e.g., C3-C8 cycloalkyl), or 3 to 6 carbon atoms (e.g., C3-C6 cycloalkyl), or 4 to 6 carbon atoms (e.g., C4-C6 cycloalkyl), or 5 to 6 carbon atoms (e.g., C5-C6 cycloalkyl). Cycloalkyl groups can be saturated or characterized by one or more points of unsaturation (i.e., carbon-carbon double and / or triple bonds), provided that the points of unsaturation do not result in an aromatic system. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexynyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, and the like. The rings of bicyclic and polycyclic cycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting examples of bicyclic, spirocyclic, and polycyclic hydrocarbon groups include bicyclo[3.1.0]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, adamantyl, indanyl, spiro[5.5]undecane, spiro[2.2]pentane, spiro[2.2]pentadiene, spiro[2.3]hexane, spiro[3.3]heptane, spiro[2.5]octane, spiro[2.2]pentadiene, etc. In some embodiments, a cycloalkyl group of the present disclosure is a monocyclic C3-C6 cycloalkyl moiety (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or a bicyclic C6-C8 cycloalkyl moiety (e.g., spiro[2.3]hexane, spiro[3.3]heptane, or bicyclo[3.1.0]hexane).

[0017] The term "heterocycloalkyl," in some embodiments, refers to a non-aromatic monocyclic, bicyclic, or polycyclic cycloalkyl ring having 3 to 14 members (e.g., a 3-14 membered heterocycle), or 3 to 10 members (e.g., a 3-10 membered heterocycle), or 3 to 8 members (e.g., a 3-8 membered heterocycle), or 3 to 6 members (e.g., a 3-6 membered heterocycle), or 4 to 6 members (e.g., a 4-6 membered heterocycle), and having 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S). In some embodiments, the nitrogen and sulfur atoms of a heterocycloalkyl group are optionally oxidized (e.g., N-oxide (N)). + -O -), sulfoxide (S=O), or sulfone (S(=O)2), and the nitrogen atom(s) are optionally quaternized. Heterocycloalkyl groups are saturated or characterized by one or more points of unsaturation (e.g., one or more carbon-carbon double bonds, carbon-carbon triple bonds, carbon-nitrogen double bonds, and / or nitrogen-nitrogen double bonds), provided that these points of unsaturation do not result in an aromatic system. The rings of bicyclic and polycyclic heterocycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting examples of heterocycloalkyl groups include aziridine, oxirane, thiirane, thietane, sulfolane, isothiazolidine, isothiazolidine 1,1-dioxide, pyrrolidine, imidazolidine, pyrazolidine, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, 3,4,5, Examples include 6-tetrahydropyridazine, pyran, tetrahydropyran, decahydroisoquinoline, 3-pyrroline, thiopyran, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 1-oxaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 2-thiaspiro[3.3]heptane 2,2-dioxide, etc. Heterocycloalkyl groups can be attached to the remainder of the molecule through a ring carbon atom or a ring heteroatom, if chemically permissible. In some embodiments, heterocycloalkyl groups of the present disclosure are monocyclic 3- to 6-membered heterocycloalkyl moieties or bicyclic 6- to 8-membered heterocycloalkyl moieties having one or two heteroatoms or heteroatom groups selected from N, O, S, S═O, and S(═O)2 (e.g., aziridine, oxetane, piperidine, piperazine, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrofuran, tetrahydropyran, sulfolane, thietane, thietane 1-oxide, thietane 1,1-dioxide, 2-thiaspiro[3.3]heptane 2,2-dioxide).In some embodiments, the heterocycloalkyl group is a monocyclic 3- to 6-membered heterocycloalkyl moiety or a bicyclic 6- to 8-membered heterocycloalkyl moiety having one or two heteroatoms or heteroatom groups selected from O and S(═O)2 (e.g., oxetane, tetrahydrofuran, tetrahydropyran, sulfolane, thietane 1,1-dioxide, or 2-thiaspiro[3.3]heptane 2,2-dioxide).

[0018] The term "heteroaryl," in some embodiments, refers to a monocyclic or fused bicyclic aromatic group (or ring) having 5 to 14 (i.e., 5-14 membered heteroaryl), or 5 to 10 (i.e., 5-10 membered heteroaryl), or 5 to 6 (i.e., 5-6 membered heteroaryl) members (i.e., ring vertices) and containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S). In some embodiments, the nitrogen and sulfur atoms are optionally oxidized (e.g., N-oxide (N + -O - ), sulfoxide (S=O), or sulfone (S(=O)2), and the nitrogen atom(s) are optionally quaternized. Heteroaryl groups can be attached to the remainder of the molecule through a carbon atom or a heteroatom of the heteroaryl group, if chemically permissible. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, purinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. In some embodiments, heteroaryl groups of the present disclosure are monocyclic 5-6 membered heterocycloalkyl moieties having 1-3 heteroatoms selected from N, O, and S (e.g., pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl).

[0019] As used herein, a wavy line crossing a single bond, double bond, or triple bond in any chemical structure shown herein [ka] indicates that the point of attachment of a single, double, or triple bond to the rest of the molecule is through any of the atoms that make up the single, double, or triple bond. Additionally, a bond extending from a substituent to the center of a ring (e.g., a phenyl ring) is meant to indicate that the substituent is attached to the ring at any available ring vertex, i.e., the attachment of the substituent to the ring results in a chemically stable configuration.

[0020] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" refer to an alkyl group, as defined herein, that is substituted with one or more halogen(s). For example, the term "C-C haloalkyl" is meant to include trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. In some embodiments, a haloalkyl is a C-C alkyl or a C-C alkyl substituted with one to three halogens. In some embodiments, a haloalkyl is -CF.

[0021] The compounds of the present disclosure (e.g., compounds of Formula I, Formula II, Formula IIa, Formula IIa-1, Formula IIb, Formula IIb-1, Formula III, Formula IIIa, Formula IIIa-1, Formula IIIb, Formula IIIb-1, Formula IIIc, Formula IIIc-1, Formula IIId, Formula IIId-1, Formula IIIe, Formula IIIe-1, Formula IIIf, or Formula IIIf-1 described herein) can exist in their neutral form or as a pharmaceutically acceptable salt, isomer, polymorph, or solvate thereof.

[0022] As referred to herein, "pharmaceutically acceptable salts" is intended to include salts of compounds according to the present disclosure prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either directly or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid.Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids, such as arginate, and salts of organic acids, such as glucuronic acid or galactunolonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0023] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are identical to the parent form of the compound for purposes of this disclosure.

[0024] The present disclosure contemplates compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical transformation to provide the compounds of the present disclosure. Generally, prodrugs contain a moiety that is cleaved in vivo to yield the compounds of the present disclosure.

[0025] The present disclosure also contemplates isomers (e.g., stereoisomers) of the compounds described herein. For example, certain compounds of the present disclosure possess asymmetric carbon atoms (chiral centers); racemates, diastereomers, and enantiomers thereof are all intended to be encompassed within the scope of the present disclosure. Stereoisomers are defined in terms of absolute stereochemistry as (R) or (S) and / or indicated using a dash and / or a wedge. Stereochemical depictions (e.g., dashes, [ka] and / or wedge-shaped, [ka] When a stereochemical assignment (e.g., using (R) and (S) designations) is shown in a chemical structure, or when a stereochemical assignment (e.g., using (R) and (S) designations) is made in a chemical name, this is meant to indicate that the indicated stereoisomer is present and is substantially free of one or more other isomer(s) (e.g., enantiomers and diastereomers, if present), unless the context dictates otherwise. "Substantially free" of other isomers indicates that the ratio of the indicated isomer to the other isomer(s) is at least 70 / 30, more preferably 80 / 20, 90 / 10, or 95 / 5 or greater. In some embodiments, the indicated isomer will be present in an amount of at least 99%. Solid line [ka] A chemical bond to an asymmetric carbon indicated by indicates that all possible stereoisomers at that carbon atom are included (stereoisomers identified using a dash or wedge). In such cases, the compound may exist as a racemic mixture, a scalenemic mixture, or a mixture of diastereomers.

[0026] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. An unnatural proportion of an isotope can be defined as the range from the amount found in nature for that atom to the amount that constitutes 100%. For example, the compounds may contain radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C), or non-radioactive isotopes, e.g., deuterium ( 2 H) or carbon-13 ( 13 C). Such isotopic variations may provide additional utility to those described elsewhere herein. For example, isotopic variants of the disclosed compounds may find additional utility, including, but not limited to, as diagnostic and / or imaging reagents, or cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the disclosed compounds may have altered pharmacokinetic and pharmacodynamic properties that may contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variations of the disclosed compounds, whether radioactive or not, are intended to be encompassed within the scope of the present invention. In some embodiments, compounds according to the present disclosure are characterized by one or more deuterium atoms.

[0027] The terms "patient" or "subject" are used interchangeably and refer to a human or non-human animal (eg, a mammal).

[0028] The terms "treat," "treating," "treatment," and the like refer to a course of action that eliminates, alleviates, suppresses, alleviates, improves, or prevents the worsening of the disease, disorder, or condition to which the term applies, or at least one symptom associated therewith, either temporarily or permanently. Treatment includes alleviating symptoms, reducing the extent of disease, inhibiting active disease (e.g., preventing the onset or further development of the disease, disorder, or condition, or clinical symptoms associated therewith), delaying or slowing the progression of disease, improving quality of life, and / or prolonging the survival of a subject when compared to expected survival if not receiving treatment or when compared to the published standard of care for the particular disease.

[0029] As used herein, the term "in need of treatment" refers to a judgment made by a physician or other caregiver that a subject needs, will need, or will benefit from treatment. This judgment is made based on a variety of factors within the physician's or caregiver's area of ​​expertise.

[0030] The terms "prevent," "preventing," "prevention," "prophylaxis," and the like, generally refer to a course of action initiated in some manner (e.g., prior to the onset of a disease, disorder, condition, or symptoms thereof) in the context of a subject who is prone to having a particular disease, disorder, or condition, in order to temporarily or permanently prevent, suppress, inhibit, or reduce the subject's risk of developing the disease, disorder, condition, or the like (e.g., as determined by the absence of clinical symptoms) or delay its onset. In certain instances, these terms also refer to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or otherwise undesirable state. Prevention also refers to a course of action initiated in a subject after the subject has been treated for a disease, disorder, condition, or symptoms associated therewith, in order to prevent the recurrence of the disease, disorder, condition, or symptoms.

[0031] As used herein, the term "in need of prevention" refers to a judgment made by a physician or other caregiver that a subject needs or would benefit from preventive care. This judgment is made based on various factors within the physician's or caregiver's area of ​​expertise. In one embodiment, a person in need of prevention may be prone to having the disease, condition, or disorder to be prevented due to a genetic predisposition.

[0032] The phrase "therapeutically effective amount" or "effective amount" refers to an amount of an agent (e.g., a compound of Formula (I)) that, when administered to a subject, achieves a measurable and beneficial effect, such as ameliorating, eliminating, reducing, or alleviating one or more symptoms associated with a disease, disorder, or condition. A "therapeutically effective amount" also refers to an amount of an agent administered to a subject that can reduce, slow, or stop the progression and / or growth of a disease, disorder, or condition. A therapeutically effective amount can be ascertained by measuring the relevant physiological effect and can be adjusted in conjunction with dosing regimens, diagnostic analyses of the subject's condition, and the like. By way of example, measuring serum levels of a compound according to the present disclosure (or, for example, a metabolite thereof) at a particular time point after administration can indicate whether a therapeutically effective amount has been used.

[0033] The terms "inhibitor of HIF-2α" and "HIF-2α inhibitor" can be used interchangeably and refer to the ability of a molecule to directly or indirectly decrease the function or activity of HIF-2α. Inhibitors of HIF-2α may prevent protein dimerization, thereby decreasing the transcriptional activity of HIF-2α.

[0034] "Substantially pure" indicates that the component (e.g., a compound according to the present disclosure) constitutes more than about 50% of the total content of the composition, typically more than about 60% of the total content. More typically, "substantially pure" refers to a composition in which the component of interest constitutes at least 75%, at least 85%, at least 90% or more of the total composition. In some cases, the component of interest will constitute more than about 90%, or more than about 95% of the total content of the composition.

[0035] Compounds provided herein can have advantageous pharmacokinetic profiles, including, for example, hepatocyte stability, clearance, PXR agonism, and inhibition of CYPs.

[0036] The compounds provided herein may have a low serum fold shift value. The serum fold shift value reflects the ratio of the potency (i.e., IC50) against HIF-2α in 100% serum to the potency against HIF-2α in serum-free conditions. In one embodiment, the compounds described herein are characterized by a serum fold shift value of about 25 or less, about 24 or less, about 23 or less, about 22 or less, about 21 or less, or about 20 or less, for example, about 20 or less, about 19 or less, about 18 or less, about 17 or less, about 16 or less, about 15 or less, about 14 or less, about 13 or less, about 12 or less, about 11 or less, about 10 or less, about 9 or less, about 8 or less, about 7 or less, about 6 or less, about 5 or less, about 4 or less, about 3 or less, or about 2 or less. In one embodiment, the serum fold shift value is about 10 or less. In another embodiment, the serum fold shift value is about 5 or less. Compounds of the Disclosure

[0037] The present disclosure relates to compounds that inhibit the activity of hypoxia-inducible factor (HIF) transcription factors, particularly HIF-2α.

[0038] In one aspect, the disclosure is directed to a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, n is 1 or 2; m is 2, 3, 4, 5, 6, 7, or 8, except that if n is 1, then m is 2, 3, 4, 5, or 6; Each R 1 is independently selected from the group consisting of halo, —OH, and —O—(C1-C3 alkyl); R 2is selected from the group consisting of -C1-C6 alkyl, -CN, and -S(O)2-(C1-C3 alkyl), wherein -C1-C6 alkyl and -S(O)2-(C1-C3 alkyl) are substituted with 0-3 halo; R 3 is 1 to 3 R 4 -C1-C2 alkyl, -C3-C6 alkyl, -C3-C8 cycloalkyl, -3- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms or heteroatomic groups selected from N, O, S, S(=O), and S(=O)2, substituted with -Y-(C3-C6 cycloalkyl), -YO-(C3-C6 cycloalkyl), -Y-(3- to 6-membered heterocycloalkyl) having 1 to 3 heteroatoms or heteroatomic groups selected from N, O, S, S(=O), and S(=O)2; and -Y-(5-6 membered heteroaryl) having 1-3 heteroatoms selected from N, O, and S, wherein -C3-C6 alkyl, -C3-C6 cycloalkyl, -3- to 7-membered heterocycloalkyl, -Y-(C3-C6 cycloalkyl), -YO-(C3-C6 cycloalkyl), -Y-(3- to 6-membered heterocycloalkyl), -X-(phenyl), and -Y-(5- to 6-membered heteroaryl) are selected from the group consisting of 0-3 R 4 is replaced by; Each R 4 is independently selected from halo, -C1-C6 alkyl, -CN, -C1-C6 haloalkyl, -OH, -O-(C1-C6 alkyl), -YO-(C1-C6 alkyl), -S-(C1-C6 alkyl), -S(O)-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl), wherein -O-(C1-C6 alkyl), -YO-(C1-C6 alkyl), -S-(C1-C6 alkyl), -S(O)-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl) are substituted with 0-3 halo; X is -C2-C3 alkylene-; Y is -C1-C3 alkylene-.

[0039] In one aspect, the present disclosure is directed to a compound having the structure of Formula I, or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, n is 1 or 2; m is 2, 3, 4, 5, 6, 7, or 8, except that if n is 1, then m is 2, 3, 4, 5, or 6; Each R 1 is independently selected from the group consisting of halo, —OH, and —O—(C1-C3 alkyl); R 2 is selected from the group consisting of -C1-C6 alkyl, -CN, and -S(O)2-(C1-C3 alkyl), wherein -C1-C6 alkyl and -S(O)2-(C1-C3 alkyl) are substituted with 0-3 halo; R 3 is 1 to 3 R 4 -C1-C2 alkyl, -C3-C6 alkyl, -C3-C6 cycloalkyl, -Y-(C3-C6 cycloalkyl), -YO-(C3-C6 cycloalkyl), -Y-(3- to 6-membered heterocycloalkyl) having 1-3 heteroatoms or heteroatom groups selected from N, O, S, S(=O), and S(=O)2, and -Y-(5- to 6-membered heteroaryl) having 1-3 heteroatoms selected from N, O, and S, wherein -C3-C6 alkyl, -C3-C6 cycloalkyl, -Y-(C3-C6 cycloalkyl), -YO-(C3-C6 cycloalkyl), -Y-(3- to 6-membered heterocycloalkyl) and -Y-(5- to 6-membered heteroaryl) are each independently selected from 0 to 3 R 4 is replaced by; Each R 4is independently selected from halo, -C1-C6 alkyl, -CN, -C1-C6 haloalkyl, -OH, -O-(C1-C6 alkyl), -S-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl), wherein -O-(C1-C6 alkyl), -S-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl) are substituted with 0-3 halo; Y is -C1-C3 alkylene-.

[0040] In one or more embodiments, the present disclosure provides a compound according to formula I, wherein R 3 is 1 to 3 R 4 -3- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms or heteroatom groups selected from N, O, S, S(=O), and S(=O)2, -C1-C2 alkyl, -C3-C6 alkyl, -C3-C8 cycloalkyl, substituted with -Y-(C3-C6 cycloalkyl); -Y-(3- to 6-membered heterocycloalkyl) having 1-3 heteroatoms or heteroatom groups selected from N, O, S, S(═O), and S(═O)2, -X-(phenyl), and -Y-(5- to 6-membered heteroaryl) having 1-3 heteroatoms selected from N, O, and S, wherein -C3-C6 alkyl, -C3-C6 cycloalkyl, -3- to 7-membered heterocycloalkyl, -Y-(C3-C6 cycloalkyl), -Y-(C3-C6 cycloalkyl), -Y-(3- to 6-membered heterocycloalkyl), -X-(phenyl), and -Y-(5- to 6-membered heteroaryl) are selected from the group consisting of 0-3 R 4 The present invention relates to compounds substituted with

[0041] In some embodiments, m is 2, 3, or 4. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0042] In one or more embodiments, the compound according to Formula I has a structure according to Formula II: [ka] (In the formula, m, R 1 , R 2 , and R 3 has the meaning given in formula I).

[0043] In one or more embodiments, the compound according to Formula I or Formula II has a structure according to Formula IIa or Formula IIa-1: [ka] wherein p is 0 or 1; the remaining groups have the meanings given in formula I.

[0044] In some embodiments, the compound of Formula I, Formula II, or Formula IIa has a structure according to Formula IIb or Formula IIb-1: [ka] where p is 0 or 1; R' is H or -C1-C3 alkyl; and the remaining groups have the meanings given in formula I.

[0045] In some embodiments of the compound of Formula IIb or Formula IIb-1, R' is H.

[0046] In some embodiments of the compound of Formula IIb or Formula IIb-1, each R 1 is a halo.

[0047] In one or more embodiments, the compound according to Formula I has a structure according to Formula III: [ka] (In the formula, m, R 1 , R 2 , and R 3 has the meaning given in formula I).

[0048] In one or more embodiments, the compound according to Formula I or Formula III has a structure according to Formula IIIa or Formula IIIa-1: [ka] wherein p is 0 or 1, and the remaining groups have the meanings given in formula I.

[0049] In some embodiments, the compound of Formula I, Formula III, or Formula IIIa has a structure according to Formula IIIb or Formula IIIb-1: [ka] where p is 0 or 1; R' is H or -C1-C3 alkyl; and the remaining groups have the meanings given in formula I.

[0050] In some embodiments, the compound of Formula I or Formula III has a structure according to Formula IIIc or Formula IIIc-1: [ka] wherein p is 0 or 1, and the remaining groups have the meanings given in formula I.

[0051] In some embodiments, the compound of Formula I, Formula III, or Formula IIIc has a structure according to Formula IIId or Formula IIId-1: [ka] where p is 0 or 1; R' is H or -C1-C3 alkyl; and the remaining groups have the meanings given in formula I.

[0052] In some embodiments, the compound of Formula I or Formula III has a structure according to Formula IIIe or Formula IIIe-1: [ka] wherein p is 0 or 1, and the remaining groups have the meanings given in formula I.

[0053] In some embodiments, the compound of Formula I or Formula III has a structure according to Formula IIIf or Formula IIIf-1: [ka] where p is 0 or 1; R' is H or -C1-C3 alkyl; and the remaining groups have the meanings given in formula I.

[0054] In some embodiments of the compound of Formula IIIb, R' is H.

[0055] In some embodiments of the compound of Formula IIIb, each R 1 is a halo.

[0056] In some embodiments of the compound of Formula IIIb, Formula IIIb-1, Formula IIId, Formula IIId-1, Formula IIIf, or Formula IIIf-1, R′ is H.

[0057] In some embodiments of the compound of Formula IIIb, Formula IIIb-1, Formula IIId, Formula IIId-1, Formula IIIf, or Formula IIIf-1, each R 1 is a halo.

[0058] In some embodiments of the compound of Formula IIa, Formula IIa-1, Formula IIb, Formula IIb-1, Formula IIIa, Formula IIIa-1, Formula IIIb, Formula IIIb-1, Formula IIId, Formula IIId-1, Formula IIIf, or Formula IIIf-1, p is 1.

[0059] In one or more embodiments, the present disclosure is directed to compounds of formula I, wherein each R 1 are independently halo or -OH; R 2 is -C1-C6 alkyl substituted with 0 to 3 halo; R 3 is -C1-C6 alkyl, -C3-C6 cycloalkyl, or -Y-(C3-C6 cycloalkyl), each of which is selected from 1 to 3 R 4 and each R4 is independently halo, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -S-(C1-C6 alkyl), or -S(O)2-(C1-C6 alkyl), where -O-(C1-C6 alkyl), -S-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl) are substituted with 0-3 halo; and Y is -C1-C3 alkylene-. In some embodiments, R 2 is -C1-C6 alkyl substituted with 1 to 3 halo.

[0060] In one or more embodiments, the present disclosure is directed to compounds of formula I, wherein each R 1 are independently halo or -OH; R 2 is -C1-C6 alkyl substituted with 0 to 3 halo; R 3 is -C1-C6 alkyl, -C3-C8 cycloalkyl, oxygen-containing 6-membered heterocycloalkyl, or -Y-(C3-C6 cycloalkyl), each of which is selected from 1 to 3 R 4 and each R 4 is independently halo, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -YO-(C1-C6 alkyl), -S-(C1-C6 alkyl), or -S(O)2-(C1-C6 alkyl), where -O-(C1-C6 alkyl), -YO-(C1-C6 alkyl), -S-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl) are substituted with 0-3 halo; and Y is -C1-C3 alkylene-.

[0061] In some embodiments of the compound of Formula I, each R 4 is independently selected from the group consisting of halo, -CN, -O-(C-C alkyl), -S-(C-C alkyl), and -S(O)-(C-C alkyl), wherein -O-(C-C alkyl), -S-(C-C alkyl), and -S(O)-(C-C alkyl) are substituted with 0-3 halo. In some embodiments, each R 4is independently selected from the group consisting of halo, —O—(C1-C3 alkyl), —S—(C1-C3 alkyl), and —S(O)2-(C1-C3 alkyl), wherein —O—(C1-C3 alkyl), —S—(C1-C3 alkyl), and —S(O)2-(C1-C3 alkyl) are substituted with 0-3 halo, and the remaining groups have the meanings given in Formula I. In some embodiments, each R 4 is independently selected from -F, -CN, -OCH, -OCFH, -OCF, -SCF, and -S(O)CF. 4 is independently selected from -F, -OCH3, -OCF2H, -OCF3, -SCF3, and -S(O)2CF3. In some embodiments, the compound has a structure according to Formula II, Formula IIa, Formula IIa-1, Formula IIb, or Formula IIb-1.

[0062] In some embodiments of the compound of Formula I, each R 4 are independently halo, —C1-C6 haloalkyl, —O—(C1-C6 alkyl), or —YO—(C1-C6 alkyl), where —O—(C1-C6 alkyl) and —YO—(C1-C6 alkyl) are substituted with 0-3 halo, and the remaining groups have the meanings given in Formula I. In some embodiments, each R 4 is independently halo, —C1-C6 haloalkyl, or —O—(C1-C6 alkyl) substituted with 0-3 halo. In some embodiments, each R 4 is independently -F, -CF, -OCH, or -OCF, or -CH(CH)-O-CF. In some embodiments, each R 4 is independently -CF, -OCH, or -OCF. In some embodiments, the compound is of formula III, IIIa, IIIb, IIIb-1, IIIc, IIIc-1, IIId, IIId-1, IIIe, IIIe-1, IIIf, or IIIf-1.

[0063] In some embodiments of the compound of Formula I, R 3 is selected from the group consisting of: [ka] In some embodiments, the compound is of formula III, IIIa, IIIb, IIIb-1, IIIc, IIIc-1, IIId, IIId-1, IIIe, IIIe-1, IIIf, or IIIf-1.

[0064] In one or more embodiments, the present disclosure is directed to compounds of formula I, wherein each R 1 are independently halo or -OH; R 2 is -C1-C6 alkyl substituted with 0 to 3 halo; R 3 is -C1-C6 alkyl, -C3-C6 cycloalkyl, or -Y-(C3-C6 cycloalkyl), each of which is selected from 1 to 3 R 4 and each R 4 are independently halo, -CN, -C1-C6 haloalkyl, -OH, -O-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl), where -O-(C1-C6 alkyl) and -S(O)2-(C1-C6 alkyl) are substituted with 0-3 halo; and Y is -C1-C3 alkylene-. In some embodiments, R 2 is -C1-C6 alkyl substituted with 1-3 halo. In some embodiments, the compound is of Formula III, IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

[0065] In one or more embodiments, the present disclosure is directed to compounds of formula I, wherein each R 1 are independently halo or -OH; R 2 is —C1-C6 alkyl substituted with 0-3 halo, or —S(O)2-(C1-C3 alkyl); R 3is -C1-C6 alkyl, -C3-C8 cycloalkyl, -3- to 7-membered heterocycloalkyl substituted with 1-2 heteroatoms or heteroatom groups selected from O and S(=O)2, -Y-(C3-C6 cycloalkyl), -Y-(3- to 6-membered heterocycloalkyl) having 1 heteroatom or heteroatom group selected from O and S(=O)2, -X-(phenyl), or -Y-(5- to 6-membered heteroaryl) having 1-2 heteroatoms selected from N, O, and S, each of which is selected from 0-3 R 4 and each R 4 is independently selected from halo, -CN, -C1-C6 haloalkyl, -OH, -O-(C1-C6 alkyl), -YO-(C1-C6 alkyl), -S(O)-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl), where -O-(C1-C6 alkyl), -YO-(C1-C6 alkyl), -S(O)-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl) are substituted with 0-3 halo; X is -C2-C3 alkylene -; and Y is -C1-C3 alkylene-. In some embodiments, R 2 is -C1-C6 alkyl substituted with 1 to 3 halo. In some embodiments, the compound is of Formula III, IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

[0066] In one or more embodiments, the present disclosure is directed to compounds of formula I, wherein each R 1 are independently halo or -OH; R 2 is —C1-C6 alkyl substituted with 0-3 halo, or —S(O)2-(C1-C3 alkyl); R 3 is 1 to 3 R 4-C1-C6 alkyl substituted with, -C3-C6 cycloalkyl, 6- to 7-membered heterocycloalkyl having one heteroatom or heteroatom group selected from O and S(=O)2, -C1-C2 alkylene-(C3-C4 cycloalkyl), -C1-C2 alkylene-(4- to 5-membered heterocycloalkyl) having one heteroatom or heteroatom group selected from O and S(=O)2, -C2-C3 alkylene-(phenyl), and and -C1-C2 alkylene-(5-membered heteroaryl) having 1 to 2 heteroatoms selected from N, O, and S, wherein -C3-C6 cycloalkyl, -6- to 7-membered heterocycloalkyl, -C1-C2 alkylene-(C3-C4 cycloalkyl), -C1-C2 alkylene-(4- to 5-membered heterocycloalkyl), -C2-C3 alkylene-(phenyl), and -C1-C2 alkylene-(5-membered heteroaryl) are each independently selected from 0 to 3 R 4 and each R 4 is independently selected from halo, -CN, -C-C haloalkyl, -OH, -O-(C-C alkyl), -(C-C alkylene)-O-(C-C alkyl), -S(O)-(C-C alkyl), and -S(O)-(C-C alkyl); wherein -O-(C-C alkyl), -(C-C alkylene)-O-(C-C alkyl), -S(O)-(C-C alkyl), and -S(O)-(C-C alkyl) are substituted with 0 to 3 halo. In some embodiments, the compound is of Formula III, IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

[0067] In some embodiments of the compound of Formula I, R 3 is selected from the group consisting of: [ka] In some embodiments, the compound is of formula III, IIIa, IIIb, IIIb-1, IIIc, IIIc-1, IIId, IIId-1, IIIe, IIIe-1, IIIf, or IIIf-1.

[0068] In some embodiments of the compound of Formula I, R 3 is 1 to 3 R 4 -C1-C2 alkyl substituted with 0 to 3 R 4 In some embodiments, R 3 teeth, [ka] is selected from the group consisting of:

[0069] In some embodiments of the compound of Formula I, R 3 is 0 to 3 R 4 In some embodiments, R 3 is 0 to 3 R 4 is -C4-C7 cycloalkyl substituted with

[0070] In some embodiments, R 3 teeth, [ka] Selected from the group consisting of:

[0071] In some embodiments of the compound of Formula I, R 3 is a 3- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms or heteroatom groups selected from N, O, S, S(═O), and S(═O)2, wherein the heterocycloalkyl is selected from 0 to 3 R 4 In some embodiments, R 3 is a 6- to 7-membered heterocycloalkyl having one heteroatom or heteroatom group selected from O and S(=O)2, wherein the heterocycloalkyl is selected from 0 to 2 R 4 In some embodiments, R 3 is 0 to 2 R 4 In some embodiments, R3 teeth, [ka] and a 6- to 7-membered heterocycloalkyl selected from the group consisting of:

[0072] In some embodiments of the compound of Formula I, R 3 is 0 to 3 R 4 In some embodiments, R 3 is 0 to 3 R 4 In some embodiments, R 3 is 0 to 2 R 4 In some embodiments, R 3 teeth, [ka] is selected from the group consisting of:

[0073] In some embodiments of the compound of Formula I, R 3 is 0 to 3 R 4 and Y is -C1-C3 alkylene-. In some embodiments, R 3 is 0 to 2 R 4 In one embodiment, R 3 teeth [ka] is.

[0074] In some embodiments of the compound of Formula I, R 3is —Y-(3- to 6-membered heterocycloalkyl) having 1 to 3 heteroatoms or heteroatom groups selected from N, O, S, S(═O), and S(═O)2, wherein the heterocycloalkyl is selected from 0 to 3 R 4 and Y is -C1-C3 alkylene-. In some embodiments, R 3 is —C1-C2 alkylene-(4-5 membered heterocycloalkyl) having one heteroatom or heteroatom group selected from O and S(═O)2, wherein said —C1-C2 alkylene-(4-5 membered heterocycloalkyl) is substituted with 0-3 R4. In some embodiments, R 3 is —C1-C2 alkylene-(4- to 5-membered heterocycloalkyl) having one heteroatom or heteroatom group selected from O and S(═O)2, wherein the —C1-C2 alkylene-(4- to 5-membered heterocycloalkyl) is selected from 0 to 1 R 4 In some embodiments, R 3 teeth, [ka] is selected from the group consisting of:

[0075] In some embodiments of the compound of Formula I, R 3 is 0 to 3 R 4 In some embodiments, R is -X-(phenyl) substituted with -C-C alkylene-. 3 is 0 to 3 R 4 In some embodiments, R 3 is 0 to 1 R 4 In some embodiments, R 3 teeth, [ka]

[0076] In some embodiments of the compound of Formula I, R3 is —Y-(5- to 6-membered heteroaryl) having 1 to 3 heteroatoms selected from N, O, and S, wherein the —Y-(5- to 6-membered heteroaryl) is selected from 0 to 3 R 4 and Y is -C1-C3 alkylene. In some embodiments, R 3 is —C1-C2 alkylene-(5-membered heteroaryl) having 1-2 heteroatoms selected from N, O, and S, and the heteroaryl is selected from 0-3 R 4 In some embodiments, R 3 is —C1-C2 alkylene-(5-membered heteroaryl) having 1-2 heteroatoms selected from N, O, and S, and the heteroaryl is selected from 0-1 R 4 In some embodiments, R 3 teeth, [ka] is.

[0077] In some embodiments of the compound of Formula I, R 3 is phenyl or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms selected from N, O, and S, wherein said phenyl or 5- to 6-membered heteroaryl is selected from 0 to 3 R 4 In some embodiments, R 3 is 0 to 2 R 4 In some embodiments, R is phenyl or pyridyl substituted with 3 teeth, [ka] is.

[0078] In one or more embodiments of the compound of Formula I, R 2 is -CF3.

[0079] In one or more embodiments of the compound of Formula I, at least one R 1 is -F.

[0080] In one or more embodiments of the compound of Formula I, at least one R 1 is -OH.

[0081] In some embodiments, the compound of Formula I has a structure according to Formula II, Formula IIa, Formula IIa-1, Formula IIb, Formula IIb-1, Formula III, Formula IIIa, Formula IIIa-1, Formula IIIb, Formula IIIb-1, Formula IIIc, Formula IIIc-1, Formula IIId, Formula IIId-1, Formula IIIe, Formula IIIe-1, Formula IIIf, or Formula IIIf-1.

[0082] In some embodiments, the present disclosure is directed to a compound having a structure according to Formula I, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, n is an integer of 1 or 2; m is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, and 8, with the proviso that when n is 1, then m is not 7 or 8; Each R 1 is independently selected from the group consisting of halo, —OH, and —O—(C1-C3 alkyl); R 2 is selected from the group consisting of -C1-C6 alkyl, -CN, and -S(O)2-(C1-C3 alkyl), wherein -C1-C6 alkyl and -S(O)2-(C1-C3 alkyl) are substituted with 0-3 halo; R 3 is 1 to 3 R 4-C1-C2 alkyl, -C3-C6 alkyl, -C3-C8 cycloalkyl, -3- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms or heteroatomic groups selected from N, O, S, S(=O), and S(=O)2, substituted with -Y-(C3-C6 cycloalkyl), -YO-(C3-C6 cycloalkyl), -Y-(3- to 6-membered heterocycloalkyl) having 1 to 3 heteroatoms or heteroatomic groups selected from N, O, S, S(=O), and S(=O)2; and -Y-(5-6 membered heteroaryl) having 1-3 heteroatoms selected from N, O, and S, wherein -C3-C6 alkyl, -C3-C6 cycloalkyl, -3- to 7-membered heterocycloalkyl, -Y-(C3-C6 cycloalkyl), -YO-(C3-C6 cycloalkyl), -Y-(3- to 6-membered heterocycloalkyl), -X-(phenyl), and -Y-(5- to 6-membered heteroaryl) are selected from the group consisting of 0-3 R 4 is replaced by; Each R 4 is independently selected from halo, -C1-C6 alkyl, -CN, -C1-C6 haloalkyl, -OH, -O-(C1-C6 alkyl), -YO-(C1-C6 alkyl), -S-(C1-C6 alkyl), -S(O)-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl), wherein -O-(C1-C6 alkyl), -YO-(C1-C6 alkyl), -S-(C1-C6 alkyl), -S(O)-(C1-C6 alkyl), and -S(O)2-(C1-C6 alkyl) are optionally substituted with 1 to 3 halo; X is -C2-C3 alkylene-; Y is -C1-C3 alkylene-.

[0083] In one or more embodiments, the compound according to the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, is selected from the compounds provided in Table 1, or any stereoisomer thereof. In one or more embodiments, the compound according to the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, is selected from the compounds provided in Table 1.

[0084] In Table 1 below, when the absolute stereochemistry of a particular example / elution fraction has not yet been determined, the entry lists two example numbers. Examples with numbers ending in "a" or "b" refer to elution fractions with multiple isomers. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

[0085] Therapeutic and prophylactic use The present disclosure encompasses the use of a HIF-2α inhibitor as described herein in the preparation of a medicament for the treatment or prevention of a disease, disorder, and / or condition susceptible to inhibition of HIF-2α.

[0086] In some embodiments, the HIF-2α inhibitors described herein are administered to a subject in need thereof in an amount effective to prevent, reverse, stop or slow the progression of HIF-2α-mediated dysregulation, e.g., diseases, disorders, and / or conditions associated with overexpression and / or dysregulation of HIF-2α, and diseases, disorders, and / or conditions in which local or systemic HIF-2α-associated hypoxia is prevalent. For example, a disease, disorder, and / or condition responsive to HIF-2α inhibition may be characterized by (i) increased HIF-2α expression in one or more suitable samples compared to a healthy control or a similar sample from another disease, disorder, and / or condition that is not responsive to HIF-2α inhibition, (ii) increased HIF-2α expression compared to HIF-1α expression in one or more suitable samples compared to a healthy control or a similar sample from another disease, disorder, and / or condition that is not responsive to HIF-2α inhibition, (iii) increased expression of genes regulated by HIF-2α in one or more suitable samples compared to a healthy control or a similar sample from another disease, disorder, and / or condition that is not responsive to HIF-2α inhibition, or (iv) a combination thereof. Suitable samples may be tissue, blood, or lymph samples containing tumor cells, immune cells, etc., or enriched or purified samples of cells obtained from tissue, blood, lymph, etc. In various embodiments, the disease, disorder, and / or condition can be von Hippel-Lindau (VHL) disease, cancer, an immune-related disease, disorder or condition, an inflammation-related disease, disorder or condition, a cardiovascular disease, a renal disease, or a metabolic disease.

[0087] In some embodiments, the compounds described herein are useful for treating subjects with HIF-2α stabilizing defects. Under normoxic conditions, the α-subunit is hydroxylated at a conserved proline residue by prolyl-4-hydroxylase and then targeted for degradation by the von Hippel-Lindau ubiquitin E3 ligase complex. HIF-2α stabilization defects, caused by gene deletion(s), mutation(s), epigenetic silencing, post-translational modifications, etc., result in increased stabilization of HIF-2α and aberrant activation of the expression of genes regulating metabolism, angiogenesis, cell proliferation and survival, immune evasion, and inflammatory responses. For example, HIF-stabilizing mutations have been detected in the von Hippel-Lindau gene (VHL) and other genes, such as succinate dehydrogenase (SDHB, SDHC, SDHD), fumarate hydratase (FH), Egl9 homolog 1 (EGLN1), transcription elongation factor B subunit 1 (TCEB1), and the gene encoding HIF-2α itself: EPAS1. Subjects with HIF-2α stabilization defects may have a disease, disorder, or condition associated with HIF-2α dysregulation or may be at increased risk of developing said disease, disorder, or condition compared to subjects without HIF-2α stabilization defects.

[0088] In some embodiments, the HIF-2α inhibitors described herein are useful for treating subjects with von Hippel-Lindau (VHL) disease or subjects with a genetic mutation or deletion associated with VHL disease. In further embodiments, the subject also has cancer or a benign tumor or cyst. VHL-associated cancers include, but are not limited to, renal cancer (typically clear cell renal cell carcinoma), pancreatic neuroendocrine tumor, adrenal tumor, and pheochromocytoma. VHL-associated benign cysts and tumors include, but are not limited to, renal cysts, pancreatic cysts, epididymal cystadenoma, broad ligament cystadenoma, endolymphatic sac tumor, hemangioblastoma, and retinal hemangioma. In one embodiment, the subject has VHL disease and associated renal cell carcinoma, central nervous system hemangioblastoma, or pancreatic neuroendocrine tumor.

[0089] Tumor-related disorders. In one or more embodiments, the compounds described herein are useful for treating and / or preventing cancer (e.g., carcinoma, sarcoma, leukemia, lymphoma, and myeloma). In certain embodiments, the cancer is metastatic or at risk of becoming metastatic. Alternatively, or in addition, the cancer may recur or become unresponsive to treatment. Examples of types of cancer contemplated by the present disclosure include cancer of the genitourinary tract (e.g., bladder, kidney, renal cell, penis, prostate, testis, von Hippel-Lindau disease, etc.), cancer of the uterus, cancer of the cervix, cancer of the ovary, cancer of the peritoneum, cancer of the fallopian tubes, cancer of the breast, cancer of the gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestine, colon, or rectum), cancer of the bone, bone marrow, skin (e.g., melanoma), cancer of the head and neck, cancer of the liver, cancer of the gallbladder, cancer of the bile duct, cancer of the heart, cancer of the lung, cancer of the pancreas, cancer of the salivary gland, cancer of the adrenal gland, cancer of the thyroid gland, cancer of the brain (e.g., glioma), cancer of the ganglia, cancer of the central nervous system (CNS), cancer of the peripheral nervous system (PNS), cancer of the hematopoietic system (e.g., hematologic malignancies), and cancer of the immune system (e.g., spleen or thymus).

[0090] In some embodiments, compounds according to the present disclosure are useful for the treatment and / or prevention of hematological malignancies. Examples of cancer types that affect the hematopoietic system include leukemia, lymphoma, and myeloma, including acute myeloid leukemia, adult T-cell leukemia, T-cell large granular lymphocyte leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute monocytic leukemia, Hodgkin's and non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, and multiple myeloma.

[0091] In another embodiment, the compounds according to the present disclosure are useful for the treatment and / or prevention of solid tumors, such as ovarian cancer, endometrial cancer, breast cancer, lung cancer (small cell or non-small cell), colon cancer, prostate cancer, cervical cancer, biliary tract cancer, pancreatic cancer, gastric cancer, esophageal cancer, hepatocellular carcinoma (liver cancer), renal cell carcinoma (kidney cancer), head and neck tumors, mesothelioma, melanoma, sarcoma, and brain tumors (e.g., gliomas such as astrocytoma, oligodendroglioma, glioblastoma), etc. The solid tumor may also be an advanced solid tumor, e.g., a malignant solid tumor that has spread to other anatomical sites (metastatic), is recurrent, no longer responds to treatment, or a combination thereof.

[0092] In some embodiments, the cancer is colorectal cancer, bile duct cancer, gallbladder cancer, liver cancer, or pancreatic cancer.

[0093] In some embodiments, the cancer is cholangiocarcinoma, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, lung cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, or renal cell carcinoma.

[0094] In some embodiments, the cancer is lung cancer, genitourinary cancer, gastrointestinal cancer, or neuroendocrine cancer.

[0095] In some embodiments, the cancer is brain cancer, breast cancer, ovarian cancer, kidney cancer, liver cancer, lung cancer, neuroendocrine cancer, or pancreatic cancer.

[0096] In some embodiments, the cancer is breast cancer. In further embodiments, the breast cancer is ERα-positive breast cancer, HER2-positive breast cancer, HER2-overexpressing breast cancer, or any combination thereof.

[0097] In some embodiments, the cancer is renal cancer. In further embodiments, the renal cancer is renal cell carcinoma. In yet further embodiments, the renal cell carcinoma is clear cell renal cell carcinoma.

[0098] In some embodiments, the cancer is lung cancer. In further embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In yet further embodiments, the NSCLC is lung squamous cell carcinoma or lung adenocarcinoma.

[0099] In some embodiments, the cancer is pancreatic cancer. In further embodiments, the pancreatic cancer is pancreatic neuroendocrine tumor or pancreatic adenocarcinoma.

[0100] In some embodiments, the cancer is a neuroendocrine tumor. In further embodiments, the neuroendocrine tumor is a pancreatic neuroendocrine tumor, a pheochromocytoma, a paraganglioma, or a tumor of the adrenal gland.

[0101] In some embodiments, the cancer is a brain tumor. In further embodiments, the brain tumor is a glioma. In yet further embodiments, the glioma is an astrocytoma, oligodendroglioma, or glioblastoma.

[0102] In some embodiments, the cancer is biliary tract neoplasm, colon adenocarcinoma, colorectal neoplasm, glioblastoma, hepatocellular carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, paraganglioma, pheochromocytoma, or renal cell carcinoma.

[0103] The present disclosure also provides methods for treating or preventing other cancer-related diseases, disorders, or conditions. The use of the term cancer-related diseases, disorders, and conditions is meant to refer broadly to conditions directly or indirectly related to cancer, including, for example, precancerous conditions such as angiogenesis, dysplasia, and non-cancerous proliferative diseases, disorders, or conditions such as benign proliferative breast disease and papilloma. For clarity, the term(s) cancer-related diseases, disorders, and conditions do not include cancer itself.

[0104] The methods of the present disclosure can be practiced in an adjuvant setting. The term "adjuvant setting" refers to a clinical setting in which a subject has a history of a proliferative disease, particularly cancer, and has generally (but not necessarily) responded to therapy, including, but not limited to, surgery, radiation therapy, and / or chemotherapy. However, due to the history of a proliferative disease, these subjects are considered to be at risk for recurrence and / or disease progression. Treatment or administration in an "adjuvant setting" refers to a subsequent treatment modality. Generally, adjuvant therapy is administered in addition to primary treatment to reduce the risk of disease or symptom recurrence. In some embodiments, provided herein are methods for treating or achieving cancer prevention, comprising administering a therapeutically effective amount of any of the compounds disclosed herein in an adjuvant setting to a subject with or at risk of cancer.

[0105] The methods provided herein can also be practiced in a "neoadjuvant setting," i.e., the method can be performed before a primary treatment. In some aspects, the subject has previously been treated. In other aspects, the subject has not previously been treated. In some aspects, the primary treatment is a first-line therapy. In some embodiments, provided herein are methods for treating cancer or achieving cancer prevention, comprising administering to a subject having or at risk of having cancer a therapeutically effective amount of any of the compounds disclosed herein in a neoadjuvant setting.

[0106] The methods described herein may be referred to as first line, second line, third line, or higher line treatments.

[0107] In some embodiments, the present disclosure provides methods for treating a proliferative condition, cancer, tumor, or precancerous condition using a HIF-2α inhibitor according to the present disclosure and at least one additional therapeutic agent, examples of which are described elsewhere herein.

[0108] Immune-Related and Inflammation-Related Disorders. In one or more embodiments, the compounds described herein are useful for the treatment and / or prevention of immune-related or inflammation-related diseases, disorders, and conditions. In various embodiments, the immune-related or inflammation-related disease, disorder, or condition is arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergy, fibrosis, surgical complications (e.g., when inflammatory cytokines interfere with healing), anemia, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious disease, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), chronic obstructive pulmonary disease (COPD), atherosclerosis, allergic contact dermatitis, atopic dermatitis or other forms of eczema, systemic sclerosis, transplant, multiple sclerosis, reflux esophagitis, or gastroesophageal reflux disease.

[0109] In some embodiments, the subject has an acute inflammatory disease, disorder, or condition.

[0110] In some embodiments, the subject has a chronic inflammatory disease, disorder, or condition. In further embodiments, the chronic inflammatory disease, disorder, or condition is eosinophilic gastrointestinal disorder, arthritis, eczema, inflammatory bowel disease, lupus, psoriasis, or systemic sclerosis. In yet further embodiments, the chronic inflammatory disorder is Crohn's disease, ulcerative colitis, psoriasis, or rheumatoid arthritis. In yet further embodiments, the chronic inflammatory disorder is an allergic disease, disorder, or condition. In further embodiments, the allergic disease, disorder, or condition is antihistamine-resistant chronic idiopathic urticaria, allergic asthma, or atopic dermatitis.

[0111] In some embodiments, the compound described herein is useful for treating cardiovascular disease.In further embodiments, the cardiovascular disease is aortic stenosis, asthma, arteriosclerosis, atherosclerosis, cardiac ischemia, cardiac fibrosis, chronic obstructive pulmonary disease (COPD), congestive heart failure, pulmonary fibrosis, pulmonary hypertension or stroke.In yet another embodiment, the cardiovascular disease is pulmonary arterial hypertension.

[0112] In some embodiments, the compounds described herein are useful for treating a metabolic disease. In further embodiments, the metabolic disease is insulin resistance, diabetes, or obesity.

[0113] In some embodiments, the subject has kidney disease. In further embodiments, the kidney disease is chronic kidney disease. In yet further embodiments, the kidney disease is renal failure.

[0114] In certain embodiments of the present disclosure, the HIF-2α inhibitors described herein are used to increase or enhance the immune response to an antigen by providing adjuvant activity. In certain embodiments, at least one antigen or vaccine is administered to a subject in combination with at least one HIF-2α inhibitor of the present disclosure to prolong the immune response to the antigen or vaccine. Therapeutic compositions are also provided that include at least one antigenic agent or vaccine component, including, but not limited to, viruses, bacteria, and fungi, or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines, in combination with at least one HIF-2α inhibitor of the present disclosure.

[0115] Patient Selection. In some cases, the methods according to the present disclosure can be provided to selected patients, for example, subjects identified as having overexpression of genes associated with HIF-2α signaling, or having high microsatellite instability or high tumor mutation burden. In some cases, the subject is identified as having an oncogene-driven cancer with a mutation in at least one gene associated with cancer. In some embodiments, the patient is identified as having high expression of EPAS1 (the gene encoding HIF-2α) and / or a high HIF-2 / HIF-1 ratio. In another embodiment, the patient is identified as having a high hypoxia score. In one embodiment, the patient is identified as having high PD-1 and / or PD-L1 expression.

[0116] Route of administration In some embodiments, pharmaceutical compositions containing compounds according to the present disclosure may be in a form suitable for oral administration. Oral administration involves swallowing the formulation, thereby allowing the compound to be absorbed into the bloodstream from the gastrointestinal tract. Alternatively, oral administration may involve buccal, lingual, or sublingual administration, thereby allowing the compound to be absorbed into the bloodstream through the oral mucosa.

[0117] In some embodiments, pharmaceutical compositions containing compounds according to the present disclosure may be in a form suitable for oral administration.Forms of parenteral administration include, but are not limited to, intravenous, intraarterial, intramuscular, intradermal, intraperitoneal, intrathecal, intracisternal, intracerebral, intraventricular, intraventricular, and subcutaneous.Pharmaceutical compositions suitable for parenteral administration can be formulated using suitable aqueous or non-aqueous carriers.Depot injections, generally administered subcutaneously or intramuscularly, can also be used to release the compounds disclosed herein over a specified period of time.

[0118] Other routes of administration are also contemplated by the present disclosure, including, but not limited to, nasal, vaginal, ocular, rectal, topical (eg, transdermal), and inhalation.

[0119] Certain embodiments of the present disclosure contemplate oral or parenteral administration.

[0120] Pharmaceutical Composition The HIF-2α inhibitor of the present disclosure may be in the form of a composition suitable for administration to a subject. Generally, such a composition is a pharmaceutical composition comprising a HIF-2α inhibitor according to the present disclosure and one or more pharmaceutically acceptable excipients. In certain embodiments, the HIF-2α inhibitor can be present in a therapeutically effective amount. The pharmaceutical composition can be used in the methods of the present disclosure; thus, for example, a pharmaceutical composition comprising a HIF-2α inhibitor according to the present disclosure can be administered to a subject to practice the therapeutic and prophylactic methods and uses described herein.

[0121] Pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration. Routes of administration can include those known in the art. Exemplary routes of administration are oral and parenteral. Furthermore, pharmaceutical compositions can be used in combination with one or more other therapeutically active agents or compounds described herein to treat or prevent diseases, disorders, and conditions contemplated by the present disclosure. In one embodiment, one or more other therapeutically active agents or compounds contemplated by the present disclosure are included in the same pharmaceutical composition containing a HIF-2α inhibitor according to the present disclosure. In another embodiment, one or more other additional therapeutically active agents are in a separate composition from a pharmaceutical composition containing a HIF-2α inhibitor according to the present disclosure.

[0122] In one aspect, the compounds described herein can be administered orally. Oral administration can be carried out, for example, through capsules or tablets. In preparing pharmaceutical compositions comprising the compound of formula (I) or its pharmaceutically acceptable salt, tablets or capsules typically contain at least one pharmaceutically acceptable excipient, such as fillers, lubricants, wetting agents, emulsifiers, suspending agents, dispersing agents, preservatives, sweeteners, flavoring agents, coloring agents, etc. Oral dosage forms can be formulated as solutions or suspensions.

[0123] In another embodiment, the compounds described herein can be administered parenterally, for example, by intravenous injection. Pharmaceutical compositions suitable for parenteral administration can be formulated in a solution for injection or reconstituted for injection in a suitable system, such as a physiological solution. Such a solution can contain an appropriate amount of sterile water for injection, salts, buffers, and isotonic excipients to achieve isotonicity at the appropriate physiological level.

[0124] The pharmaceutical compositions described herein may be stored in one or more suitable sterile containers, hi some embodiments, the containers are designed to maintain the stability of the pharmaceutical composition for a given period of time.

[0125] Combination therapy The present disclosure contemplates the use of the HIF-2α inhibitors described herein alone or in combination with one or more additional therapeutically active agents, optionally in combination with other treatment modalities, for example, before or after surgery, bone marrow transplantation, etc. In embodiments including one or more additional therapeutically active agents, each agent can target a different but complementary mechanism of action. The additional therapeutically active agent can be a small chemical molecule; a macromolecule such as a protein, antibody, peptibody, peptide, DNA, RNA, or a fragment of such a macromolecule; or a cellular or gene therapy agent. The use of the HIF-2α inhibitors described herein in combination with one or more additional therapeutically active agents can have a synergistic therapeutic or preventative effect on the underlying disease, disorder, or condition. Additionally or alternatively, combination therapy can allow for a reduction in the dose of one or more agents, thereby ameliorating, alleviating, or eliminating adverse effects associated with one or more agents.

[0126] The therapeutically active agents used in such combination therapy can be formulated as a single composition or as separate compositions. When administered separately, each therapeutic agent in the combination can be given at the same time, about the same time, or at different times. Furthermore, therapeutic agents can be administered "in combination" even in different dosage forms (e.g., oral capsules and intravenous), given at different dosing intervals, one therapeutic agent given on a fixed dosing regimen while another is titrated up, tapered, or discontinued, or each therapeutic agent in the combination is independently titrated up, tapered, dose-increased or reduced, or discontinued and / or resumed during the course of a patient's treatment. When the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0127] Cancer treatment agents The present disclosure contemplates the use of HIF-2α inhibitors described herein in combination with one or more additional therapeutically active agents useful in the treatment of cancer.

[0128] In some embodiments, the therapeutic agent is a chemotherapeutic agent, examples of which include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; Nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, Examples include aclacinomycins, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, and olivomycin. cin, pomalidomide, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;Pyrimidine analogues, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and 5-FU; androgens, such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents, such as aminoglutethimide, mitotane, and trilostane; folic acid replenishers Replenishers, such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxant Lon; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triazicone; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside (Ara -C); cyclophosphamide; thiotepa; taxoids, such as paclitaxel, nab-paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, such as cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitors, such as irinotecan, topotecan, etoposide, mitoxantrone, and teniposide; difluoromethylornithine (DMFO); retinoic acid; esperamycin; capecitabine;Examples of suitable combination therapies include, but are not limited to, anthracyclines and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy comprises a chemotherapy regimen comprising one or more chemotherapeutic agents. In one embodiment, the combination therapy comprises a chemotherapy regimen comprising FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), taxanes (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), CAPOX (capecitabine and oxaliplatin), the platinum-based chemotherapy agent irinotecan, and / or gemcitabine.

[0129] In some embodiments, the one or more additional therapeutic agents are radiopharmaceuticals. Radiopharmaceuticals are a form of internal radiation therapy in which a radioactive source (i.e., one or more radionuclides) is placed inside the subject's body. The radioactive source may be in solid or liquid form. Non-limiting examples of radiopharmaceuticals include sodium iodide I-131, radium-223 dichloride, lobenguane iodine-131, radioactive iodide vesicles (e.g., saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles), various forms of brachytherapy, and various forms of targeted radionuclides. Targeted radionuclides include radionuclides associated (e.g., by covalent or ionic interactions) with a molecule (a "targeting agent") that specifically binds to a target on a cell, typically a cancer cell or immune cell. The targeting agent may be a small molecule, a sugar (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a sugar (including oligosaccharides and polysaccharides), lipid, protein, or peptide, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neo-antigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody, and the target is a tumor-associated antigen (i.e., an antigen enriched but not specific to cancer cells), a tumor-specific antigen (i.e., an antigen with minimal or no expression in normal tissues), or a neo-antigen (i.e., an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). Non-limiting examples of targeted radionuclides include radionuclides conjugated to somatostatin or its peptide analogs (e.g., 177Lu-Dotatate, etc.); prostate-specific membrane antigen or its peptide analogs (e.g., 177Lu-PSMA-617, 225Ac-PSMA-617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); cognate ligands of receptors, peptides derived from those ligands, or variants thereof (e.g., 188Re-labeled VEGF 125-136or variants thereof with higher affinity for the VEGF receptor; antibodies targeting tumor antigens (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-omburtamab, etc.).

[0130] In some embodiments, one or more additional therapeutic agents are hormonal therapeutic agents.Hormonal therapeutic agents act to regulate or inhibit hormone action on tumors.Examples of hormonal therapeutic agents include selective estrogen receptor degraders, such as fulvestrant, GDC-9545, SAR439859, RG6171, AZD9833, lindestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549; selective estrogen receptor modulators, such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, and toremifene; aromatase inhibitors, such as anastrozole and exemestane. , letrozole, and other aromatase inhibiting 4(5)-imidazoles; gonadotropin-releasing hormone agonists, such as nafarelin, triptorelin, and goserelin; gonadotropin-releasing hormone antagonists, such as degarelix; antiandrogens, such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide, and leuprolide; 5α-reductase inhibitors, such as finasteride and dutasteride; and the like. In certain embodiments, the combination therapy includes administration of a hormone or related hormone agent. In one embodiment, the combination therapy includes administration of enzalutamide.

[0131] In some embodiments, the one or more additional therapeutic agents are epigenetic modulators. Epigenetic modulators alter the epigenetic mechanisms that control gene expression and may be, for example, inhibitors or activators of epigenetic enzymes. Non-limiting examples of epigenetic modulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HDAC) inhibitors. In one or more embodiments, a HIF-2α inhibitor according to the present disclosure is combined with a DNA methyltransferase (DNMT) inhibitor or hypomethylating agent. Exemplary DNMT inhibitors include decitabine, zebularine, and azacitadine. In one or more embodiments, a combination of a HIF-2α inhibitor according to the present disclosure with a histone deacetylase (HDAC) inhibitor is also contemplated. Exemplary HDAC inhibitors include vorinostat, divinostat, abexinostat, panobinostat, belinostat, and trichostatin A.

[0132] In some embodiments, the one or more additional therapeutic agents are ATP-adenosine axis targeting agents. ATP-adenosine axis targeting agents alter signal transduction mediated by adenine nucleosides and nucleotides (e.g., adenosine, AMP, ADP, ATP), for example, by modulating adenosine levels or targeting adenosine receptors. Adenosine and ATP act on different classes of receptors and often have opposing effects on inflammation, cell proliferation, and cell death. For example, ATP and other adenine nucleotides exert antitumor effects through activation of the PS2Y1 receptor subtype, while the accumulation of adenosine in the tumor microenvironment has been shown to inhibit the antitumor function of various immune cells and enhance the immunosuppressive activity of myeloid and regulatory T cells by binding to cell surface adenosine receptors. In certain embodiments, the ATP-adenosine axis targeting agent is an inhibitor of ectonucleotidase, which is involved in the conversion of ATP to adenosine, or an adenosine receptor antagonist. Ectonucleotidases involved in the conversion of ATP to adenosine include ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​also known as CD39 or cluster of differentiation 39) and ecto-5'-nucleotidase (NT5E or 5NT, also known as CD73 or cluster of differentiation 73). Exemplary small molecule CD73 inhibitors include CB-708, ORIC-533, LY3475070, and AB680. Examples of anti-CD39 and anti-CD73 antibodies include ES002, TTX-030, IPH-5201, SRF-617, CPI-006, oleculab (MEDI9447), NZV930, IPH5301, GS-1423, uriledolimab (TJD5, TJ004309), AB598, and BMS-986179. In one embodiment, the present disclosure contemplates the combination of a HIF-2α inhibitor described herein with a CD73 inhibitor, such as those described in WO2017 / 120508, WO2018 / 067424, WO2018 / 094148, and WO2020 / 046813. In a further embodiment, the CD73 inhibitor is quemliclustat (AB680).Adenosine binds to four different G protein-coupled receptors: A1R, A2R, A3R, A4R, A5R, A6R, A7R, A8R, A9R, A10R, A11R, A12R, A13R, A14R, A15R, A16R, A17R, A18R, A19R, A20R, A21R, A22R, A23R, A24R 2A R.A. 2B A2R antagonists bind to and activate A2R, A3R, and A3R. A2R antagonists include etormadenant, inupadenant, taminadenant, caffeine citrate, NUV-1182, TT-702, DZD-2269, INCB-106385, EVOEXS-21546, AZD-4635, imaradenant, RVU-330, ciforadenant, PBF-509, PBF-999, PBF-1129, and CS-3005. In some embodiments, the present disclosure provides a combination of a HIF-2α inhibitor as described herein with an A2R antagonist. A R antagonist, A2 B R antagonist, or A2 A R and A2 B In some embodiments, the present disclosure contemplates a combination of a HIF-2α inhibitor described herein with an adenosine receptor antagonist described in WO2018 / 136700, WO2018 / 204661, WO2018 / 213377, or WO2020 / 023846, WO2020 / 102646. In one embodiment, the adenosine receptor antagonist is etremadenant.

[0133] In some embodiments, the one or more additional therapeutic agents are targeted therapeutic agents. In one aspect, the targeted therapeutic agent may comprise a chemotherapeutic agent, a radionuclide, a hormonal therapeutic agent, or another small molecule drug conjugated to the targeting agent. The targeting agent may be a small molecule, a sugar (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a sugar (including oligosaccharides and polysaccharides), a lipid, a protein, or a peptide, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimally or not expressed in normal tissues), or a neoantigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimally or not expressed in normal tissues), or a neoantigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). In other embodiments, targeted therapeutic agents may inhibit or interfere with specific proteins that aid in tumor growth and / or spread. Non-limiting examples of such targeted therapeutic agents include signal transduction inhibitors, RAS signal transduction inhibitors, inhibitors of oncogenic transcription factors, activators of oncogenic transcription factor repressors, angiogenesis inhibitors, immunotherapeutic agents, ATP-adenosine axis targeting agents, AXL inhibitors, CDK-4 / 6 inhibitors, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists, and PD-1 antagonists. ATP-adenosine axis targeting agents are described above, while other agents are described in more detail below.

[0134] In some embodiments, the one or more additional therapeutic agents are signal transduction inhibitors. Signal transduction inhibitors are agents that selectively inhibit one or more steps in a signal transduction pathway. Signal transduction inhibitors (STIs) contemplated by the present disclosure include, but are not limited to: (i) BCR-ABL kinase inhibitors (e.g., imatinib); (ii) epidermal growth factor receptor tyrosine kinase inhibitors (EGFRTKIs) and anti-EGFR antibodies, including small molecule inhibitors (e.g., gefitinib, erlotinib, afatinib, icotinib, and osimertinib); (iii) inhibitors of the human epidermal growth factor (HER) family of transmembrane tyrosine kinases, such as HER-2 / neu (iv) vascular endothelial growth factor receptor (VEGFR) inhibitors, including small molecule inhibitors (e.g., axitinib, sunitinib, and sorafenib), VEGF kinase inhibitors (e.g., lenvatinib, cabozantinib, XL092, etc.), and anti-VEGF antibodies (e.g., bevacizumab); (v) inhibitors of the AKT family kinase or AKT pathway (e.g., rapamycin); (vi) serine / threonine protein kinase B-Raf (BRAF) (vii) rearrangement in transfection (RET) inhibitors, including, for example, selpercatinib and pralsetinib; (viii) tyrosine protein kinase Met (MET) inhibitors (e.g., tepotinib, tivantinib, cabozantinib, XL092, and crizotinib); (ix) anaplastic lymphoma kinase (ALK) inhibitors (e.g., ensartinib, ceritinib, lorlatinib, crizotinib, and brigatinib). (x) inhibitors of the RAS signaling pathway described elsewhere herein (e.g., inhibitors of KRAS, HRAS, RAF, MEK, ERK); (xi) FLT-3 inhibitors (e.g., gilteritinib); (xii) inhibitors of Trop-2, such as the antibody-drug conjugate sacituzumab govitecan-hziy; (xiii) inhibitors of the JAK / STAT pathway, such as JAK inhibitors including tofacitinib and ruxolitinib, or STAT inhibitors such as napabucasin; (xiv) inhibitors of NF-κB;(xv) cell cycle kinase inhibitors (e.g., flavopiridol); (xvi) phosphatidylinositol kinase (PI3K) inhibitors; (xix) protein kinase B (AKT) inhibitors (e.g., capivasertib, milansertib), and (xx) inhibitors of CDK-4 and / or CDK-6 (e.g., abemaciclib, palbociclib, ribociclib, trilaciclib, etc.). In one or more embodiments, the additional therapeutic agent comprises an inhibitor of CDK-4, CDK-6, EGFR, VEGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-kB, PI3K, AKT, or any combination thereof;

[0135] In some embodiments, the one or more additional therapeutic agents are RAS signaling inhibitors. Oncogenic mutations in RAS family genes, such as HRAS, KRAS, and NRAS, are associated with various cancers. For example, among KRAS family genes, G12C, G12D, G12V, G12A, G13D, Q61H, G13C, and G12S mutations have been observed in multiple tumor types. Direct and indirect inhibitory strategies have been investigated to inhibit mutant RAS signaling. Indirect inhibitors target effectors other than RAS in the RAS signaling pathway, including, but not limited to, inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g., SOS1), mTORC1, SHP2 (PTPN11), and AKT. Non-limiting examples of indirect inhibitors under development include RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, and BI1701963. Direct inhibitors of RAS mutants are also being investigated, generally targeting the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors under development include, but are not limited to, sotorasib (AMG510), MRTX849, mRNA-5671, and ARS1620. In some embodiments, the one or more RAS signaling inhibitors are selected from the group consisting of a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an SOS1 inhibitor, an mTORC1 inhibitor, an SHP2 inhibitor, and an AKT inhibitor. In other embodiments, the one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0136] In some embodiments, one or more of the additional therapeutic agents are inhibitors of phosphatidylinositol 3-kinase (PI3K), particularly inhibitors of the PI3Kγ isoform. PI3Kγ inhibitors can stimulate anti-cancer immune responses through modulation of myeloid cells, for example by inhibiting suppressive myeloid cells, by attenuating immunosuppressive tumor-infiltrating macrophages, or by stimulating macrophages and dendritic cells to produce cytokines that contribute to effective T cells, thereby reducing the development and spread of cancer. Examples of PI3Kγ inhibitors include copanlisib, duvelisib, AT-104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458, and pictilisib. In some embodiments, a HIF-2α inhibitor according to the present disclosure is combined with one or more PI3Kγ inhibitors described in WO2020 / 0247496A1.

[0137] In some embodiments, the one or more additional therapeutic agents are arginase inhibitors. Arginase has been shown to cause or contribute to inflammation-induced immune dysfunction, tumor immune evasion, immunosuppression and immunopathology of infectious diseases. Exemplary arginase compounds include CB-1158 and OAT-1746. In some embodiments, a HIF-2α inhibitor according to the present disclosure is combined with one or more arginase inhibitors described in WO / 2019 / 173188 and WO2020 / 102646.

[0138] In some embodiments, the one or more additional therapeutic agents are inhibitors of oncogenic transcription factors or activators of oncogenic transcription factor repressors. Suitable agents may act at the expression level (e.g., RNAi, siRNA, etc.), through physical degradation, at the protein / protein level, at the protein / DNA level, or by binding in the activation / inhibition pocket. Non-limiting examples include inhibitors of one or more subunits of the MLL complex (e.g., HDAC, DOT1L, BRD4, menin, LEDGF, WDR5, KDM4C (JMJD2C), and PRMT1), inhibitors of hypoxia-inducible factor (HIF) transcription factors, etc.

[0139] In some embodiments, one or more therapeutic agents are inhibitors of anexelekto (AXL). The AXL signaling pathway is associated with tumor growth and metastasis and is thought to mediate resistance to various cancer treatments. Various AXL inhibitors are under development that also inhibit other kinases in the TAM family (i.e., TYRO3, MERTK), as well as other receptor tyrosine kinases, including MET, FLT3, RON, and AURORA, among others. Examples of multikinase inhibitors include sitravatinib, rebastinib, glesatinib, gilteritinib, merestinib, cabozantinib, foretinib, XL092, BMS777607, LY2801653, S49076, GSK1363089, and RXDX-106. AXL-specific inhibitors, such as small molecule inhibitors including DS-1205, SGI-7079, SLC-391, TP-0903 (i.e., duvelmatinib), BGB324 (i.e., bemcentinib), and DP3975; anti-AXL antibodies such as ADCT-601; and antibody-drug conjugates (ADCs) such as BA3011, have also been developed. Another strategy for inhibiting AXL signaling involves targeting GAS6, the ligand for AXL. For example, AVB-500 is under development, as is an Fc-fusion protein that binds to the GAS6 ligand and inhibits AXL signaling.

[0140] In some embodiments, the one or more additional therapeutic agents are inhibitors of p21-activated kinase 4 (PAK4). Overexpression of PAK4 has been demonstrated across a variety of cancer types, including cancers that are particularly resistant to PD-1 therapy. While no PAK4 inhibitors have yet been approved, they are in development, and some, such as ATG-019 and KPT-9274, demonstrate dual PAK4 / NAMPT inhibitor activity. In some embodiments, a compound according to the present disclosure is combined with a PAK4-selective inhibitor. In some embodiments, a compound according to the present disclosure is combined with a PAK4 / NAMPT dual inhibitor, e.g., ATG-019 or KPT-9274.

[0141] In some embodiments, one or more of the additional therapeutic agents is a cyclin-dependent kinase (CDK) inhibitor. In certain embodiments, the inhibitor is a CDK4 and / or CDK6 inhibitor. Exemplary CDK4 and / or CDK6 inhibitors may include abemaciclib, palbociclib, ribociclib, and trilaciclib.

[0142] In some embodiments, one or more of the additional therapeutic agents are (i) drugs that inhibit the enzyme poly(ADP-ribose) polymerase (e.g., olaparib, niraparib, and rucaparib, etc.); (ii) inhibitors of the Bcl-2 protein family (e.g., venetoclax, navitoclax, etc.); (iii) inhibitors of MCL-1; (iv) inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies, magrolimab, etc.); (v) isocitrate dehydrogenase (IDH) inhibitors, e.g., IDH-1 inhibitors or IDH-2 inhibitors (e.g., ivosidenib, enasidenib, etc.).

[0143] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent. Immunotherapeutic agents treat diseases by stimulating or suppressing the immune system. Immunotherapeutic agents useful in treating cancer typically induce or amplify an immune response against cancer cells. Non-limiting examples of suitable immunotherapeutic agents include immunomodulators; cellular immunotherapeutics; vaccines; gene therapy agents; ATP-adenosine axis targeting agents; and immune checkpoint modulators. ATP-adenosine axis targeting agents are described above. Immunomodulators, cellular immunotherapeutics, vaccines, gene therapy agents, and immune checkpoint modulators are further described below.

[0144] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically, a cytokine or chemokine, such as IL1, IL2, IL12, IL18, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharide (LPS); organic or inorganic adjuvants that activate antigen-presenting cells and promote presentation of antigen epitopes on major histocompatibility complex molecules, agonists including, but not limited to, Toll-like receptor (TLR) agonists, mevalonate pathway antagonists, and STING agonists; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, and immunostimulatory oligonucleotides, as well as other T cell adjuvants.

[0145] In some embodiments, the one or more additional therapeutic agents are immunotherapeutics, more specifically cellular therapeutic agents. Cellular therapy is a form of treatment in which viable cells are administered to a subject. In certain embodiments, the one or more additional therapeutic agents are cellular immunotherapeutics that activate or suppress the immune system. Cellular immunotherapeutics useful for treating cancer typically induce or amplify an immune response. The cells can be autologous or allogeneic immune cells (e.g., monocytes, macrophages, dendritic cells, NK cells, T cells, etc.) collected from one or more subjects. Alternatively, the cells can be "(re)programmed" allogeneic immune cells generated from immune progenitor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell progenitor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells may be expanded subsets of cells with distinct effector functions and / or maturation markers (e.g., adaptive memory NK cells, tumor-infiltrating lymphocytes, immature dendritic cells, monocyte-derived dendritic cells, plasmacytoid dendritic cells, conventional dendritic cells (sometimes referred to as classical dendritic cells), M1 macrophages, M2 macrophages, etc.), may be genetically modified to target the cells to specific antigens and / or to enhance the anti-tumor effect of the cells (e.g., engineered T cell receptor (TCR) cell therapies, chimeric antigen receptor (CAR) cell therapies, lymph node homing of antigen-loaded dendritic cells, etc.), may be engineered to express or increase the expression of tumor-associated antigens, or any combination thereof. Non-limiting types of cellular therapy include CAR-T cell therapies, CAR-NK cell therapies, TCR therapies, and dendritic cell vaccines. Exemplary cellular immunotherapeutics include sipuleucel-T, tisagenlecleucel, lysocabtagene maraleucel, idecbutagen biclucel, brexcabtagene autoleucel, and axicabtagene ciloleucel, as well as CTX110, JCAR015, JCAR017, MB-CART19.1, MB-CART20.1, MB-CART2019.1, UniCAR02-T-CD123, BMCA-CAR-T, JNJ-68284528, BNT211, and NK-92 / 5.28.z.

[0146] In some embodiments, one or more additional therapeutic agents are immunotherapeutic agents, more particularly gene therapy agents. Gene therapy agents include recombinant nucleic acids that are administered ex vivo to a subject or a subject's cells to cause heterologous expression of proteins (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, microRNA (miRNA) agents, viral or bacterial gene delivery, etc.) to modify the expression of endogenous genes, as well as gene editing therapeutic agents that may or may not include nucleic acid components (e.g., meganucleases, zinc finger nucleases, TAL nucleases, CRISPR / Cas nucleases, etc.), oncolytic viruses, etc. Non-limiting examples of gene therapy agents that may be useful in cancer treatment include Gendicine® (rAd-p53), Oncorine® (rAD5-H101), talimogene laherparepvec, Mx-dnG1, ARO-HIF2 (Arrowhead), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics), and CTX130 (CRISPR Therapeutics).

[0147] In some embodiments, the one or more additional therapeutic agents are immunotherapeutic agents, more specifically, agents that modulate immune checkpoints. Immune checkpoints are a series of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells). Immune checkpoints function when proteins on the surface of immune cells recognize and bind to their cognate ligands. The present invention contemplates the use of HIF-2α inhibitors described herein in combination with agonists of stimulatory or costimulatory pathways and / or antagonists of inhibitory pathways. Agonists of stimulatory or costimulatory pathways and antagonists of inhibitory pathways, or combinations thereof, may be useful as agents to overcome different immunosuppressive pathways within the tumor microenvironment, inhibit regulatory T cells, reverse / prevent T cell anergy or exhaustion, and induce innate immune activation and / or inflammation at the tumor site.

[0148] In some embodiments, the one or more additional therapeutic agents is an immune checkpoint inhibitor. As used herein, the term "immune checkpoint inhibitor" refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. Immune checkpoint inhibitors can antagonize inhibitory or co-inhibitory immune checkpoints by preventing receptor-ligand binding and / or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which can be selectively upregulated and antagonized in various types of cancer cells, include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T lymphocyte-associated antigen 4); TIM-3 (T cell membrane protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); CD276 (B7-H3); PD-L2 (programmed cell death 1 ligand 2); galectin-9; CEACAM-1 (carcinoembryonic antigen-related cell adhesion molecule 1); CD69 (cluster of differentiation 69); galectin-1; CD113 (poly These include: virus receptor-related 3; nectin-3; GPR56 (G protein-coupled receptor 56); VISTA (V-domain Ig suppressor of T cell activation); natural killer cell receptor 2B4 (cluster of differentiation 244); CD48 (cluster of differentiation 48); GARP (glycoprotein-A repeat dominant protein); PD1H (programmed death-1 homolog); LAIR1 (leukocyte-associated immunoglobulin-like receptor 1); TIM-1 (T cell membrane protein 1); TIM-4 (T cell membrane protein 3); and killer inhibitory receptors, which can be divided into two classes based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs), and ii) C-type lectin receptors (members of the type II transmembrane receptor family).Other less well-defined immune checkpoints described in the literature are also contemplated, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)) [see Pardoll, (April 2012) Nature Rev. Cancer 12:252-64].

[0149] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 antagonist. In further embodiments, the CTLA-4 antagonist can be an antagonistic CTLA-4 antibody. Suitable antagonistic CTLA-4 antibodies include monospecific antibodies, such as ipilimumab or tremelimumab, and bispecific antibodies such as MEDI5752 and KN046.

[0150] In some embodiments, the immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonistic PD-1 antibody. Suitable antagonistic PD-1 antibodies include monospecific antibodies, such as budigalimab, camrelizumab, cosibelimab, dostallimab, emiplimab, ezabenlimab (BI-754091), MEDI-0680 (AMP-514; WO2012 / 145493), nivolumab, pembrolizumab, pidilizumab (CT-011), pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimberelimab; and bispecific antibodies, such as LY3434172. In yet a further embodiment, the PD-1 antagonist can be a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1 (AMP-224). In certain embodiments, the immune checkpoint inhibitor is zimberelimab.

[0151] In some embodiments, the immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist may be an antagonistic PD-L1 antibody. Suitable antagonistic PD-L1 antibodies include monospecific antibodies, such as avelumab, atezolizumab, durvalumab, BMS-936559, and embafolimab, and bispecific antibodies such as LY3434172 and KN046.

[0152] In some embodiments, the immune checkpoint inhibitor is a TIGIT antagonist. In further embodiments, the TIGIT antagonist may be an antagonistic TIGIT antibody. Suitable antagonistic anti-TIGIT antibodies include monospecific antibodies, such as AGEN1327, the antibodies disclosed in WO2021 / 247591, BMS 986207, COM902, AB308, domvanalimab, EOS-448, etigilimab, IBI-929, JS006, M6223, osipelimab, SEA-TGT, tiragolumab, and vibostolimab; and bispecific antibodies such as AGEN1777 and AZD2936. In certain embodiments, the immune checkpoint inhibitor is domvanalimab or an antibody disclosed in WO2021 / 247591.

[0153] In some embodiments, the immune checkpoint inhibitor is a LAG-3 antagonist. In further embodiments, the LAG-3 antagonist may be an antagonistic LAG-3 antibody. Suitable antagonistic LAG-3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273). In certain embodiments, the immune checkpoint inhibitor is a B7-H3 antagonist. In further embodiments, the B7-H3 antagonist is an antagonistic B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, MGA271 (WO11 / 109400), omburtamab, enoblitutuzumab, DS-7300a, ABBV-155, and SHR-A1811.

[0154] In some embodiments, the one or more additional therapeutic agents activate a stimulatory or costimulatory immune checkpoint. Examples of stimulatory or costimulatory immune checkpoints (ligands and receptors) include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2.

[0155] In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist can be an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is an OX40 agonist. In further embodiments, the OX40 agonist can be an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383, MEDI-6469, MEDI-0562, PF-04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonistic CD40 antibody. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD27 agonist. In further embodiments, the CD27 agonist can be an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0156] In some embodiments, one or more of the additional therapeutic agents are agents that inhibit or deplete immunosuppressive immune cells. For example, to inhibit or deplete immunosuppressive macrophages or monocytes, the agent can be a CSF-1R antagonist, for example, a CSF-1R antagonist antibody, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13 / 169264).

[0157] In some embodiments, each additional therapeutic agent can independently be a chemotherapeutic agent, a radiopharmaceutical, a hormonal therapy agent, an epigenetic modulator, a targeting agent, an immunotherapeutic agent, a cellular therapy agent, or a gene therapy agent. For example, in one embodiment, the present disclosure contemplates the use of a HIF-2α inhibitor described herein in combination with one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormonal therapy agent, a targeting agent, an immunotherapeutic agent, a cellular therapy agent, or a gene therapy agent. In another embodiment, the present disclosure contemplates the use of a HIF-2α inhibitor described herein in combination with one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeting agent, an immunotherapeutic agent, or a cellular therapy agent. In another embodiment, the present disclosure contemplates the use of a HIF-2α inhibitor of the present disclosure in combination with one or more chemotherapeutic agents and one or more inhibitors independently selected from: (i) a BCR-ABL kinase inhibitor; (ii) an EGFR inhibitor (e.g., an EGFR TKI or an anti-EGFR antibody); (iii) a HER-2 / neu receptor inhibitor; (iv) an anti-angiogenic agent (e.g., an anti-VEGF antibody, a VEGFR TKI, a VEGF kinase inhibitor, etc.); (v) an AKT inhibitor; (vi) a BRAF inhibitor; (vii) a RET inhibitor; (viii) a MET inhibitor; and (ix) an ALK inhibitor; and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeted agent, an immunotherapeutic agent, or a cellular therapy agent. In another embodiment, the present disclosure contemplates the use of a HIF-2α inhibitor described herein in combination with one or more immunotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormonal therapy, a targeted agent, a chemotherapeutic agent, a cellular therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of a HIF-2α inhibitor described herein in combination with one or more immunotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, or a cellular therapy.In another embodiment, the present disclosure contemplates the use of a HIF-2α inhibitor as described herein in combination with one or more immune checkpoint inhibitors and / or one or more ATP-adenosine axis targeting agents, and / or one or more tyrosine kinase inhibitors and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, an immunotherapeutic agent, or a cellular therapeutic agent. In another embodiment, the present disclosure contemplates the use of a HIF-2α inhibitor of the present disclosure in combination with one or more immune checkpoint inhibitors and / or one or more ATP-adenosine axis targeting agents, and one or more inhibitors independently selected from: (i) a BCR-ABL kinase inhibitor; (ii) an EGFR inhibitor (e.g., an EGFR TKI or an anti-EGFR antibody); (iii) a HER-2 / neu receptor inhibitor; (iv) an anti-angiogenic agent (e.g., an anti-VEGF antibody, a VEGFR TKI, a VEGF kinase inhibitor, etc.); (v) an AKT inhibitor; (vi) a BRAF inhibitor; (vii) a RET inhibitor; (viii) a MET inhibitor; (ix) an ALK inhibitor; (x) an AXL inhibitor, and (xi) an inhibitor of CDK-4 and / or CDK-6. In further embodiments of the above, (a) the targeting agent may be a PI3K inhibitor, an arginase inhibitor, an AXL inhibitor, or a PAK4 inhibitor, a VEGFR inhibitor; an inhibitor of CDK-4 and / or CDK-6, or an anti-angiogenic agent; (b) the immunotherapeutic agent is an ATP-adenosine axis targeting agent or an immune checkpoint inhibitor; and (c) the ATP-adenosine axis targeting agent is A2. A R and / or A2 B(d) the ATP-adenosine axis targeting agent is etormadenant, chemricrustat, or AB598; (e) the immunotherapeutic agent is an anti-PD-1 antagonist antibody or an anti-TIGIT antagonist antibody; (f) the immunotherapeutic agent is zimberelimab, domvanalimab, or AB308; or (g) any combination thereof. In yet further embodiments of the above, the present disclosure contemplates the use of a HIF-2α inhibitor described herein in combination with domvanalimab, etormadenant, chemricrustat, zimberelimab, AB308, or any combination thereof.

[0158] The choice of additional therapeutic agent(s) may be informed by the current standard of care for the particular cancer and / or the mutational status and / or stage of the cancer of interest. Detailed standard of care guidelines have been published, for example, by the National Comprehensive Cancer Network (NCCN). See, for example, NCCN CRC v3.2021, NCCN Hepatobiliary v4.2021, NCCN Kidney Cancer v2.2022, NCCN NSCLC v5.2021, and NCCN PDAC v2.2021.

[0159] Other therapeutic agents In another aspect, the present disclosure contemplates the use of a HIF-2α inhibitor of the present disclosure in combination with one or more additional therapeutically active agents useful in the treatment of immune-related and / or inflammatory-related diseases, disorders or conditions.

[0160] In some embodiments, the one or more additional therapeutically active agents is a nonsteroidal anti-inflammatory drug (NSAID), a cyclooxygenase-2 (COX-2) inhibitor, or a steroid.

[0161] In some embodiments, the one or more additional therapeutically active agents is a JAK inhibitor.

[0162] In some embodiments, the one or more additional therapeutically active agents is an immune checkpoint inhibitor. Suitable immune checkpoint inhibitors are described above.

[0163] In some embodiments, the one or more additional therapeutically active agents are cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies against other human cytokines or growth factors, or antagonists thereof, such as TNF, LT, IL-10, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, or PDGF.

[0164] Specific combinations of active agents can disrupt different points in the autoimmune and subsequent inflammatory cascade, including TNF antagonists, such as chimeric, humanized, or human TNF antibodies, infliximab, adalimumab, anti-TNF antibody fragments (e.g., CDP870), soluble p55 or p75 TNF receptors, their derivatives, p75TNFRIgG (etanercept) or p55TNFR1gG (lenercept), soluble IL-13 receptors (sIL-13), and TNFα-converting enzyme (TACE) inhibitors; IL-1 inhibitors (e.g., interleukin-1 converting enzyme inhibitors) can also be effective. Other combinations include interleukin-11, anti-P7, and p-selectin glycoprotein ligand (PSGL). Other examples of agents useful in combination with the HIF-2α inhibitors described herein include interferon beta-1a; interferon beta-1a; interferon-beta-1b, glatiramer acetate; hyperbaric oxygen; intravenous immunoglobulin; clavulivin; and antibodies to or antagonists of other human cytokines or growth factors (e.g., antibodies to CD40 ligand and CD80).

[0165] The present disclosure also contemplates the use of HIF-2α inhibitors described herein in combination with one or more additional therapeutically active agents useful in the treatment of cardiovascular and / or metabolic-related diseases, disorders and conditions.

[0166] dosage The HIF-2α inhibitors of the present disclosure can be administered to a subject in an amount that depends, for example, on the goal of administration (e.g., the desired degree of relief), the age, weight, sex, health status, and physical condition of the subject to whom the HIF-2α inhibitor is administered; the route of administration; and the nature of the disease, disorder, condition, or symptoms thereof. The dosing regimen may also take into account the existence, nature, and extent of adverse effects associated with the administered agent. Effective dosages and administration regimens can be determined, for example, from safety studies and dose escalation studies, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0167] In general, dosing parameters dictate that the dosage is below the amount that may be irreversibly toxic to the subject (maximum tolerated dose (MTD)) and at least the amount necessary to produce a measurable effect in the subject, as determined, for example, by pharmacokinetic and pharmacodynamic parameters related to absorption, distribution, metabolism, and excretion (ADME), taking into account the route of administration and other factors.

[0168] In certain embodiments, HIF-2α inhibitors contemplated by the present disclosure can be administered (e.g., orally, parenterally, etc.) at dosage levels of about 0.01 mg / kg to about 50 mg / kg of subject body weight per day, or about 1 mg / kg to about 25 mg / kg, one or more times daily, weekly, or monthly to achieve the desired therapeutic effect. In some embodiments, dosages can be delivered at these dosage levels (e.g., a fixed dose of about 0.01 mg / kg to about 50 mg / kg) regardless of subject body weight.

[0169] In certain embodiments, the HIF-2α inhibitors of the present disclosure are administered (e.g., orally, parenterally, etc.) at fixed dosage levels, particularly between about 1 mg and about 1000 mg, and particularly between 1, 3, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg. In some embodiments, the HIF-2α inhibitor is administered at a dose between about 100 mg and about 1000 mg. In some embodiments, the HIF-2α inhibitor is administered at a dose between about 100 mg and about 500 mg. In some embodiments, the HIF-2α inhibitor is administered at a dose between about 500 mg and about 1000 mg. In some embodiments, the HIF-2α inhibitor is administered at a dose of between about 100 mg and about 350 mg. In some embodiments, the HIF-2α inhibitor is administered at a dose of between about 350 mg and about 500 mg. In some embodiments, the HIF-2α inhibitor is administered at a dose of between about 500 mg and about 750 mg. In some embodiments, the HIF-2α inhibitor is administered at a dose of between about 750 mg and about 1000 mg.

[0170] In some embodiments, the HIF-2α inhibitor according to the present disclosure is administered one or more times daily, weekly, or monthly to achieve the desired effect. In some embodiments, the HIF-2α inhibitor is administered once or twice daily. In one embodiment, the HIF-2α inhibitor is administered twice daily. In another embodiment, the HIF-2α inhibitor is administered once daily.

[0171] In certain embodiments, the dosage of the HIF-2α inhibitor is contained in a "unit dosage form." The term "unit dosage form" refers to a physically separate unit, each unit containing a predetermined amount of the HIF-2α inhibitor, alone or in combination with one or more additional agents, sufficient to produce a desired effect. It will be understood that the parameters of the unit dosage form depend on the specific agent and the effect to be achieved. [Example]

[0172] experiment The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their invention. Additional compounds within the scope of the present disclosure can be made using methods based on the methods shown in these examples or other methods known in the art. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0173] All reactions were carried out at the indicated temperatures using Teflon-coated magnetic stir bars and, where noted, under an inert atmosphere. All chemicals were used as received. Reactions were monitored by TLC (silica gel 60 with fluorescent F254, visualized with a short-wave / long-wave UV lamp) and / or LCMS (Agilent 1100 or 1200 series LCMS with UV detection at 254 or 280 nm using one of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm id × 100 mm], Waters XSelect HSS C18 [3.5 μm, 2.1 mm id] × 75 mm], using a binary solvent system [0.1% formic acid in MeCN / 0.1% formic acid in HO]. Flash chromatography was performed on silica gel using an automated system (Teledyne ISCO CombiFlash RF+) optionally equipped with an evaporative light scattering detector, with detection wavelengths of 254 and 280 nm. Reverse-phase preparative HPLC was performed on an Agilent 1260 or 1290 Infinity series HPLC. Samples were eluted with gradient elution on a Gemini C18 110Å column (21.2 mm id x 250 mm) using a binary solvent system (MeCN / HO with acid modifier as needed - e.g., 0.1% TFA or 0.1% formic acid) and detected at variable wavelength. Final compounds obtained by preparative HPLC were concentrated by lyophilization. All reported yields are isolated yields. All assayed compounds were analyzed by 1Purification to ≥95% purity as determined by H NMR or LCMS (Agilent 1100 or 1200 series LCMS with UV detection at 254 or 280 nm using one of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm id × 100 mm], Waters XSelect HSS C18 [3.5 μm, 2.1 mm id] × 75 mm], using a binary solvent system [0.1% formic acid in MeCN / 0.1% formic acid in HO]. H NMR spectra were recorded on a Varian 400 MHz NMR spectrometer equipped with an Oxford AS400 magnet or a Bruker AVANCE NEO 400 MHz NMR spectrometer. Chemical shifts (δ) are reported as parts per million (ppm) relative to residual non-deuterated solvent as an internal standard. The abbreviations s, brs, d, t, q, dd, dt, ddd, dddd, dddt, and m stand for singlet, broad singlet, doublet, triplet, quartet, double doublet, double double doublet, double double double triplet, double double double doublet, and multiplet, respectively.

[0174] Unless otherwise specified, temperatures are in degrees Celsius (°C) and pressure is atmospheric or near atmospheric. Standard abbreviations are used, including: rt or rt = room temperature; min = minute; h or hr = hour(s); ng = nanogram; μg = microgram; mg = milligram; g = gram; kg = kilogram; μl or μL = microliter; ml or mL = milliliter; l or L = liter; μM = micromolar; mM = millimolar; M = concentration; mol = mole; mmol = millimole; aq. = aqueous; calcd = calculated; sat. or satd. = saturated; equiv. = equivalent ( (multiple units); psi = pounds per square inch; mbar = millibar; DCM and CH2Cl2 = dichloromethane; CDCl3 = chloroform-d; CCl4 = carbon tetrachloride; MTBE = methyl tert-butyl ether; THF = tetrahydrofuran; THP = tetrahydropyran; Et2O = diethyl ether; EtOAc = ethyl acetate; DCE = 1,2-dichloroethane; DME = dimethoxyethane; ACN and CH3CN = acetonitrile; NMP = N-methyl-2-pyrrolidone; DMF = N,N-dimethyl Ammoniumformamide; DMSO = dimethyl sulfoxide; EtOH = ethanol; MeOH = methanol; H2 = hydrogen gas; N2 = nitrogen gas; PPh3 = triphenylphosphine; AIBN = azobisisobutyronitrile; CAN = ceric ammonium nitrate; DIBAL-H = diisobutylammonium hydride; DAST = diethylaminosulfur trifluoride; DIAD = diisopropyl azodicarboxylate; BzCl = benzoyl chloride; AgOTf = silver trifluoromethanesulfonate; AgClO4 = silver perchlorate; TB SOTf = tert-butyldimethylsilyl trifluoromethanesulfonate; TFAA = trifluoroacetic anhydride; DHP = 3,4-dihydropyran; TMSCHN2 = trimethylsilyldiazomethane; TMSCF3 = trifluoromethyltrimethylsilane; TMSCF2H = difluoromethyltrimethylsilane; TMSCF2Br = (bromodifluoromethyl)trimethylsilane; TBDPSCl = tert-butyl(chloro)diphenylsilane; TBAF = tetra-n-butylammonium fluoride; 3HF.TEA = triethylamine trihydrofluoride; mCPBA = metachloroperoxybenzoic acid; NBS = N-bromosuccinimide; Na2SO4 = sodium sulfate; MgSO4 = magnesium sulfate; CsF = cesium fluoride; Cs2CO3 = cesium carbonate; NaHCO3 = sodium bicarbonate; NH4OH = ammonium hydroxide; NH3 = ammonia; Et3N = triethylamine; KOH = potassium hydroxide; NaOH = sodium hydroxide; Na2S2O3 = sodium thiosulfate; NaBH4 = borohydride Sodium; LiOH·H2O = lithium hydroxide monohydrate; KOAc = potassium acetate; TsOH·H2O = p-toluenesulfonic acid monohydrate; TsNHNH2 = p-toluenesulfonhydrazide; pTsOH.H2O = p-toluenesulfonic acid monohydrate; HBF4 = tetrafluoroboric acid; OsO4 = osmium tetroxide; TFA = trifluoroacetic acid; HCO2H = formic acid; SiO2 = silicon dioxide; DMAP = 4-dimethylaminopyridine; DMP = Dess-Martin periodinane; NFSI = N-fluoro Benzenesulfonimide; H2SO4 = sulfuric acid; CuCl = copper(I) chloride; CuSCN = copper(I) thiocyanate; (CyCAAC)Rh(COD)Cl = [2-[2,6-bis(1-methylethyl)phenyl]-3,3-dimethyl-2-azaspiro[4.5]dec-1-ylidene]chloro[(1,2,5,6-η)-1,5-cyclooctadiene]rhodium; [RuCl((R)-BINAP)(p-cymene)]Cl = chloro[(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene] [N-(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium; PMB = p-methoxybenzyl; MHz = megahertz; Hz = hertz; ppm = parts per million; ESIMS = electrospray ionization mass spectrometry; NMR = nuclear magnetic resonance; TLC = thin layer chromatography; LCMS = liquid chromatography-mass spectrometry.

[0175] Example 1: 4-[(4S)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-1-yl]-2,2-dimethylbutanenitrile. [ka] Step a: Cyclohexane-1,3-dione (5 g, 44.6 mmol, 1.0 equiv.), TsNHNH2 (8.3 g, 44.6 mmol, 1.0 equiv.), and pTsOH.HO (85 mg, 0.45 mmol, 0.01 equiv.) were dissolved in toluene (297 mL, 0.15 M) and the mixture was stirred for 110 minutes. o The mixture was stirred at C for 30 minutes. After cooling to room temperature, the reaction mixture was filtered and the solid was washed with MTBE to give 4-methyl-N-[(E)-(3-oxocyclohexylidene)amino]benzenesulfonamide (11.63 g, 93%).

[0176] Step b: The product of step a (11.4 g, 40.7 mmol, 1.0 equiv.) was suspended in THF (204 mL, 0.2 M) and EtN (14 mL, 102 mmol, 2.5 equiv.), followed by the addition of TFAA (5.7 mL, 40.7 mmol, 1.0 equiv.) and the mixture was heated to 50°C. o The mixture was stirred at RT for 3 h. After cooling to room temperature, 40 mL of 1 M aqueous NaOH and 40 mL of MeOH were added, and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl, the organic phase was separated, and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 20–60%) to give 3-(trifluoromethyl)-1,5,6,7-tetrahydroindazol-4-one (5.19 g, 62% yield).

[0177] Step c: To the product of step b (5.05 g, 24.7 mmol, 1.0 equiv) in MeOH (124 mL, 0.2 M) was added Selectfluor (9.63 g, 27.2 mmol, 1.1 equiv) and concentrated H2SO4 (0.1 mL). The resulting mixture was heated to reflux for 3 h. After cooling to room temperature, 0.3 M aqueous H2SO4 (10 mL) was added to the reaction mixture. The resulting mixture was heated to reflux for 1 h. After cooling to room temperature, the reaction was quenched with saturated NaHCO3, the organic phase was separated, and the aqueous layer was extracted with DCM. The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 30–60%) to give 5-fluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydroindazol-4-one (2.94 g, 54% yield).

[0178] Step d: To 5-fluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydroindazol-4-one (2.90 g, 13.1 mmol, 1.0 equiv.) in THF (131 mL, 0.1 M) was added DHP (1.8 mL, 19.6 mmol, 1.5 equiv.) and pTsOH.HO (248 mg, 1.31 mmol, 0.1 equiv.), and the mixture was refluxed overnight. The reaction was quenched with saturated NaHCO3, the organic phase was separated, and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 20–60%) to give 5-fluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-6,7-dihydro-5H-indazol-4-one (3.49 g, 87% yield).

[0179] Step e: To a solution of the product from step d (3.40 g, 11.1 mmol, 1.0 equiv) and EtN (9.1 mL, 66.6 mmol, 6.0 equiv) in DCM (28 mL, 0.4 M) was added TBSOTf (5.1 mL, 22.2 mmol, 2.0 equiv) dropwise at 0 °C. The resulting solution was stirred at 0 °C for 1.5 h and then quenched with saturated aqueous NaHCO. The organic phase was separated, and the aqueous phase was extracted with DCM. The combined organic phases were then washed with brine, dried over NaSO, and concentrated to give the silyl enol ether. The crude material was then dissolved in MeCN (55 mL, 0.2 M), and Selectfluor (5.90 g, 16.7 mmol, 1.5 equiv) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 30 min, and then water and DCM were added, and the aqueous phase was extracted with DCM. The combined organic phases were dried over NaSO and concentrated, and the crude residue was purified by column chromatography (SiO, EtOAc in hexanes, 30–60%) to give 5,5-difluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-6,7-dihydroindazol-4-one (2.63 g, 73% yield).

[0180] Step f: To a solution of the product from step e (1.70 g, 5.24 mmol, 1.0 equiv) in DCM (26 mL, 0.2 M) was added HCOH (0.59 mL, 15.7 mmol, 3.0 equiv), and EtN (1.4 mL, 10.5 mmol, 2.0 equiv). o After cooling to 30°C, RuCl(p-cymene) [(R,R)-TsDPEN] (100 mg, 0.16 mmol, 0.03 equiv.) was added, and the resulting mixture was stored in a refrigerator overnight. The reaction was quenched with saturated aqueous NaHCO3, the organic phase was separated, and the aqueous layer was extracted with DCM. The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 10–40%) to give (4S)-5,5-difluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol (1.58 g, 93% yield).

[0181] Step g: The product from step f (1.53 g, 4.69 mmol, 1.0 equiv) was dissolved in DCM (31 mL, 0.15 M), and EtN (1.3 mL, 9.38 mmol, 2 equiv), BzCl (0.82 mL, 7.04 mmol, 1.5 equiv), and DMAP (57 mg, 0.47 mmol, 0.1 equiv) were added. The reaction mixture was refluxed overnight and quenched with saturated aqueous NH4Cl. The organic phase was separated, the aqueous layer was extracted with DCM, the combined organic phases were dried over NaSO, concentrated, and the crude residue was purified by column chromatography (SiO, EtOAc in hexanes, 0–40%) to give [(4S)-5,5-difluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-yl]benzoate (1.90 g, 94% yield).

[0182] Step h: The product from step g (1.85 g, 4.30 mmol, 1.0 equiv) was dissolved in DCM:TFA (5:1, 21.5 mL, 0.2 M) and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated NaHCO, the organic phase was separated, the aqueous layer was extracted with DCM, the combined organic phase was dried over NaSO, concentrated, and the crude residue was purified by column chromatography (SiO, EtOAc in hexanes, 20–50%) to give [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate (1.26 mg, 85% yield).

[0183] Step i: The product from step h (85 mg, 0.245 mmol, 1.0 equiv) was dissolved in DMF (1.2 mL). To this solution was added 4-bromo-2,2-dimethylbutanenitrile (52 mg, 0.294 mmol, 1.2 equiv) and Cs2CO3 (160 mg, 0.490 mmol, 2.0 equiv). The reaction was stirred at ambient room temperature for 48 hours or until LCMS indicated complete consumption of the starting material. The reaction was diluted with H2O and extracted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with water, brine, and dried over MgSO4. Concentration under reduced pressure and purification by flash chromatography (SiO, hexane to 30% EtOAc) gave [(4S)-1-(3-cyano-3-methylbutyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-yl]benzoate (63 mg, 58% yield).

[0184] Step j: The product from step i (60 mg, 0.136 mmol, 1.0 equiv) was dissolved in MeOH (1.4 mL). To this mixture was added 1 M aqueous NaOH (0.68 mL, 0.68 mmol, 5.0 equiv), and the reaction was stirred for 1 h or until the starting material was consumed by LCMS. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with water, brine, and dried over MgSO4. Concentration under reduced pressure and purification by flash chromatography (SiO2, hexanes to 40% EtOAc) afforded the title compound as a pale yellow oil (10.7 mg, 23% yield). 1 H NMR(400 MHz,CDCl3) δ 4.88 (q, J =5.7 Hz,1H), 4.26- 4.19(m, 2H),2.99 - 2.80 (m, 2H),2.65 - 2.45 (m, 2H),2.37 - 2.22 (m, 1H),2.19 - 2.08 (m, 2H),1.40 (d,J = 5.9 Hz, 6H). C 14 H 16 ESI MS [M+H] for F5N3O +, calculated value 338.1, measured value 338.0.

[0185] Example 2: (4S)-1-[(3,3-difluorocyclobutyl)methyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] Step a: To a solution of [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate (200 mg, 0.578 mmol, 1.0 equiv.) in THF (5.8 mL) was added PPh3 (273 mg, 1.04 mmol, 1.8 equiv.), followed by (3,3-difluorocyclobutyl)methanol (141 mg, 1.15 mmol, 2.0 equiv.). DIAD (0.23 mL, 1.15 mmol, 2.0 equiv.) was then added dropwise, and the mixture was stirred at 23 °C for 2 h. After concentration, the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 0-35%) to give the desired compound (92 mg, 35% yield).

[0186] Step b: The deprotection step was carried out as described in Example 1 to give the title compound. 1 H NMR(400 MHz,CDCl3) δ 4.85 (q, J =5.7 Hz,1H), 4.14- 4.04(m, 2H),2.89 - 2.74 (m, 2H),2.74 - 2.62 (m, 4H),2.61 - 2.41 (m, 1H),2.41- 2.20(m, 3H). C 13 H 14 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.0.

[0187] Example 3: 4-[(4S)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-1-yl]-2-methylbutanenitrile. [ka] Step a: [(4S)-5,5-Difluoro-1-(4-methoxy-3-methyl-4-oxobutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-yl]benzoate (1.0 g, 2.17 mmol, 77% yield) was prepared according to the general protocol described in Example 1, step i, using [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate (1.0 g, 2.9 mmol) and methyl 4-bromo-2-methylbutanoate (0.7 g, 3.6 mmol) as alkylating reagents.

[0188] Step b: The methyl ester from step a (200.0 mg, 0.43 mmol) was dissolved in THF (2.0 mL) and a solution of LiOH·HO (91.0 mg, 2.2 mmol) in water (1 mL) was added at ambient temperature. The resulting mixture was vigorously stirred and monitored by TLC analysis. Upon complete consumption of the starting material, the reaction was adjusted to pH ∼3 with 1 M aq. hydrochloric acid, and the product was extracted with EtOAc (3 × 7 mL). The combined organic extracts were washed with brine, dried over NaSO, and concentrated to dryness to yield the desired carboxylic acid (194.0 mg, 0.43 mmol, 100% yield) as a colorless oil.

[0189] Step c: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (108.0 mg, 0.57 mmol) and 1-hydroxybenzotriazole hydrate (95.0 mg, 0.57 mmol, containing 20% ​​water by weight) were added to a solution of the carboxylic acid from step b (194.0 mg, 0.43 mmol) in CH3CN (2.2 mL). After stirring the resulting solution for 1 h, aqueous NH4OH (1.0 mL, 28.0-30.0% based on NH3) was added in one portion. The reaction mixture was stirred at ambient temperature overnight and then partitioned between EtOAc (10.0 mL) and water (10.0 mL). The aqueous phase was separated and further extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated to dryness under reduced pressure. The resulting crude primary amide was used in the next step without further purification.

[0190] Step d: The amide from step c was dissolved in dichloromethane, triethylamine (300 μL, 2.15 mmol) was added, and the reaction mixture was cooled to 0 °C. Trifluoroacetic anhydride (180 μL, 1.3 mmol) was added dropwise, and the resulting colorless solution was stirred at 0 °C for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with dichloromethane (20.0 mL) and washed with 1 M aq. hydrochloric acid (15.0 mL), saturated aqueous NaHCO (15.0 mL), and brine (15.0 mL). The organic extract was dried over NaSO and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO, hexane / EtOAc gradient) to afford the desired nitrile as a colorless oil (155.0 mg, 0.37 mmol, 87% yield).

[0191] Step e: To a solution of the nitrile from step d (155.0 mg, 0.37 mmol) in MeOH (7.5 mL) was added 1 M aqueous NaOH (1.9 mL, 1.9 mmol) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (35.0 mL) and 1 M aqueous NaOH (40.0 mL). The organic phase was separated and washed again with 1 M aqueous NaOH (2 × 20.0 mL) and brine (30.0 mL) to remove residual benzoic acid. The combined organic phases were dried over NaSO and concentrated to dryness, and the crude residue was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the title compound (64.0 mg, 55% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 4.85 (br. s, 1H), 4.29 - 4.08 (m, 2H),3.08 - 2.76 (m, 2H),2.76 - 2.67 (m, 1H),2.67 - 2.42 (m, 2H),2.38 - 2.19 (m, 2H),2.16 - 1.99 (m, 1H),1.36 (d,J = 7.1 Hz, 3H). C 13 H 14 ESI MS [M+H] for F5N3O + , calculated value 324.1, measured value 324.2.

[0192] Example 4: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-[[3-(trifluoromethyl)-1,2-oxazol-5-yl]methyl]-6,7-dihydro-4H-indazol-4-ol. [ka] Step a: Tosyl chloride (290.0 mg, 1.5 mmol), [3-(trifluoromethyl)-1,2-oxazol-5-yl]methanol (0.25 g, 1.5 mmol), and iPrNEt (0.5 mL, 3 mmol) were dissolved in dichloromethane (7.5 mL) at room temperature. The resulting mixture was stirred for 3 h. The reaction was then diluted with dichloromethane (20.0 mL) and washed with 1 M aq. hydrochloric acid (30.0 mL) and brine (30.0 mL). The organic extract was dried over NaSO and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO, hexane / EtOAc gradient) to afford [3-(trifluoromethyl)-1,2-oxazol-5-yl]methyl 4-methylbenzenesulfonate (250.0 mg, 0.78 mmol, 92% yield) as a colorless oil.

[0193] Step b: The tosylate from step a (250.0 mg, 0.78 mmol) was added to a mixture of [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate (225.0 mg, 0.65 mmol) and CsCO (420.0 mg, 1.3 mmol) in DMF (3.3 mL) at ambient temperature. The resulting mixture was vigorously stirred for 1 h. When TLC analysis indicated complete consumption of the alkylating reagent, the reaction was diluted with EtOAc (30.0 mL) and washed with saturated aqueous NHCl (20.0 mL), water (2 × 20.0 mL), and brine (20.0 mL). The organic extract was dried over NaSO and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to afford the corresponding alkylated product (210.0 mg, 0.42 mmol, 65% yield) as a colorless oil.

[0194] Step c: To a solution of the product of step b (210.0 mg, 0.42 mmol) in MeOH (8.4 mL) was added 1 M aqueous NaOH (2.1 mL, 2.1 mmol) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (40.0 mL) and 1 M aqueous NaOH (40.0 mL). The organic phase was separated and washed again with 1 M aqueous NaOH (2 × 30.0 mL) and brine (30.0 mL) to remove residual benzoic acid. The combined organic phases were dried over NaSO and concentrated to dryness, and the crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the title compound (160.0 mg, 96% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 6.54 (s, 1H),5.42 (s,2H), 5.02- 4.70(m, 1H),3.12 - 2.73 (m, 3H),2.73 - 2.42 (m, 1H), 2.41- 2.22(m, 1H). C 13 ESI MS [M+H] for H9F8N3O2 + , calculated value 392.1, measured value 392.1.

[0195] Example 5: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-[2-[1-(trifluoromethyl)cyclopropyl]ethyl]-6,7-dihydro-4H-indazol-4-ol. [ka] Step a: 2-[1-(trifluoromethyl)cyclopropyl]ethanol (44 mg, 0.29 mmol, 1.0 equiv) was dissolved in DCM (1.5 mL, 0.2 M). Triethylamine (80 μL, 0.57 mmol, 2.0 equiv) was added, followed by methanesulfonyl chloride (34 μL, 0.44 mmol, 1.5 equiv). The reaction was stirred at room temperature for 1 h, at which point it was complete by TLC. The reaction was quenched with 1.0 M HCl (10 mL) and extracted with DCM (2 × 10 mL). The combined organics were dried over NaSO, filtered, and concentrated in vacuo. The residue was used directly in the subsequent alkylation without further purification.

[0196] Step b: Using the mesylate prepared in step a, alkylation was carried out as described for Example 1. Benzoyl deprotection was also carried out as described in Example 1. 1 H NMR (400 MHz, chloroform-d) δ 4.87 (s, 1H), 4.18 (t, J = 7.8 Hz, 2H), 2.99 - 2.74 (m, 2H), 2.60 - 2.44 (m, 1H), 2.40 - 2.23 (m, 1H), 2.22 - 2.05 (m, 2H), 1.06 - 0.94 (m, 2H), 0.64 - 0.48 (m, 2H). 14 H 14 ESI MS [M+H] for F8N2O + , calculated value 379.1, measured value 379.1.

[0197] Example 6: (4S)-5,5-Difluoro-1-(4-methoxy-3-methylbutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The starting material was prepared according to the protocol described in the synthesis of Example 3.

[0198] Step a: The methyl ester (0.8 g, 1.74 mmol) was dissolved in THF (17.4 mL), and the resulting solution was cooled to −78° C. under a nitrogen atmosphere. A solution of 1 M DIBAL-H in THF (7.7 mL, 7.7 mmol) was added dropwise over 10 min. The resulting mixture was stirred at −78° C. for 2 h, then warmed to 0° C. and stirred for an additional 2 h. The reaction was quenched by the addition of MeOH (1.0 mL) at 0° C. The resulting solution was diluted with EtOAc (40.0 mL) and saturated aqueous Rochelle's salt (20.0 mL) and then vigorously stirred for 2 h. The organic phase was separated, and the aqueous phase was further extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to dryness. The crude residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to afford the desired alcohol (460.0 mg, 1.1 mmol, 63% yield) as a colorless oil.

[0199] Step b: The alcohol from step a (100.0 mg, 0.24 mmol) was dissolved in dichloromethane (2.4 mL) and 48% aqueous HBF (31.0 μL, 0.24 mmol). After cooling the mixture to 0 °C, a 2 M solution of TMSCHN in EtO (1.0 mL, 1.92 mmol) was added to the reaction mixture. The cooling bath was removed, and the reaction was stirred at ambient temperature overnight. The resulting solution was diluted with dichloromethane (15.0 mL), washed with saturated aqueous NaHCO (20.0 mL), dried over NaSO, and concentrated to dryness. The dry residue was fractionated by column chromatography (SiO, hexane / EtOAc gradient) to afford the corresponding methyl ether (55.0 mg, 0.12 mmol, 51% yield) as a colorless oil.

[0200] Step c: To a solution of the product of step b (55.0 mg, 0.12 mmol) in MeOH (2.5 mL) was added 1 M aqueous NaOH (0.6 mL, 0.6 mmol) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (15.0 mL) and 1 M aqueous NaOH (15.0 mL). The organic phase was separated and washed again with 1 M aqueous NaOH (2 × 10.0 mL) and brine (15.0 mL) to remove residual benzoic acid. The combined organic phases were dried over NaSO and concentrated to dryness, and the crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the title compound (43.0 mg, 100% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 4.84 (s, 1H),4.07 (t,J = 7.7 Hz, 2H),3.29 (s,3H), 3.28- 3.12(m, 2H),2.95 - 2.70 (m, 3H),2.62 - 2.40 (m, 1H),2.33 - 2.16 (m, 1H),1.98 - 1.85 (m, 1H),1.83 - 1.62 (m, 2H),0.93 (dd,J = 6.6, 1.8 Hz,3H). C 14 H 19 ESI MS [M+H] for F5N2O2 + , calculated value 343.1, measured value 343.3.

[0201] Example 7: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-[2-(trifluoromethylsulfanyl)ethyl]-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared from 2-(trifluoromethylsulfanyl)ethanol in a manner similar to that described for Example 5. 1H NMR(400 MHz,CDCl3) δ 4.93 - 4.79(m, 1H),4.29 (t,J = 6.8 Hz, 2H),3.36 (t,J = 6.8 Hz, 2H),2.97 - 2.77 (m, 2H),2.68 (s,1H), 2.65- 2.42 (m, 1H),2.39 - 2.21 (m, 1H). C 11 H 10 ESI MS [M+H] for F8N2O + , calculated value 370.0, measured value 370.1.

[0202] Example 8: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-[2-(trifluoromethylsulfonyl)ethyl]-6,7-dihydro-4H-indazol-4-ol. [ka] Step a: Ruthenium trichloride (4 mg, 0.016 mmol) and sodium periodate (0.15 g, 0.68 mmol) were added to a solution of (4S)-5,5-difluoro-3-(trifluoromethyl)-1-[2-(trifluoromethylsulfanyl)ethyl]-6,7-dihydro-4H-indazol-4-ol (61 mg, 0.14 mmol) in a mixture of MeCN (0.6 mL), CCl (0.6 mL), and water (1.3 mL). The reaction was stirred at room temperature for 1 h, and then it was diluted with dichloromethane (5.0 mL) and saturated aqueous NaSO (5.0 mL). The organic phase was separated, and the aqueous solution was further extracted with dichloromethane (2 × 5 mL). The combined organic solution was washed with brine (5 mL), dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by column chromatography (EtOAc in hexanes, 0-70%) to afford the corresponding trifluoromethyl sulfone (63 mg, 0.16 mmol, 95% yield) as a colorless oil.

[0203] Step b: The product from step a (63 mg, 0.16 mmol) was dissolved in CHCl (0.8 mL) and the solution was cooled to 0 °C. Formic acid (18 μL, 0.47 mmol) and triethylamine (44 μL, 0.31 mmol) were added sequentially, and the solution was purged with nitrogen for 10 min. RuCl(p-cymene)[(R,R)-Ts-DPEN] (3 mg, 0.0047 mmol) was added, and the resulting mixture was stirred at 4 °C for 16 h. Upon completion (TLC monitoring), the reaction mixture was diluted with dichloromethane (5.0 mL), washed with saturated aqueous NaHCO (5 mL) and brine (5.0 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc in hexanes, 0–50%) to afford the final product (52 mg, 0.13 mmol, 82% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 4.87 (q, J =5.7 Hz,1H), 4.55(t, J =6.5 Hz,2H), 4.01- 3.78(m, 2H),3.05 - 2.79 (m, 2H),2.67 - 2.43 (m, 2H),2.40 - 2.22 (m, 1H). C 11 H 10 ESI MS [M+H] for F8N2O3S + , calculated value 402.0, measured value 402.0.

[0204] Example 9: (4S)-5,5-Difluoro-1-(3-methoxypropyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a similar manner to Example 1 from 1-bromo-3-methoxypropane. 1H NMR(400 MHz,CDCl3) δ 4.87 - 4.76(m, 1H),4.09 (t,J = 6.8 Hz, 2H),3.31 - 3.19 (m, 4H),3.16 - 3.06 (m, 1H),2.86 (ddd,J = 16.6, 6.9, 2.5Hz, 1H),2.75 (ddd,J = 16.7, 10.7, 6.3Hz, 1H),2.59 - 2.36 (m, 1H),2.29 - 2.16 (m, 1H),2.07 (tddd,J = 6.9, 6.1, 5.3,0.8 Hz,2H). C 12 H 15 ESIMS [M+H] for F5N2O2 + , calculated value 314.1, measured value 314.1.

[0205] Example 10: (4S)-1-(cyclopropylmethyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared from bromomethylcyclopropane in a manner similar to Example 1. 1 H NMR(400 MHz,CDCl3) δ 4.88 (t, J =6.3 Hz,1H), 3.99- 3.84(m, 2H),2.99 - 2.70 (m, 3H),2.67 - 2.41 (m, 1H),2.37 - 2.19 (m, 1H),1.33 - 1.14 (m, 1H),0.72 - 0.54 (m, 2H),0.46 - 0.28 (m, 2H). C 12 H 13 ESI MS [M+H] for F5N2O + , calculated value 296.1, measured value 296.0.

[0206] Example 11: (4S)-5,5-Difluoro-1-[(3S)-4,4,4-trifluoro-3-methoxybutyl]-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] Step a: TMSCF3 (13.5 mL, 91.35 mmol) and TBAF (1 M in THF, 60.9 mL, 60.9 mmol) were added sequentially to a solution of 3-phenylmethoxypropanal (10.0 g, 60.9 mmol) in THF (300.0 mL) at 0 °C. The resulting mixture was stirred at 0 °C and monitored by TLC analysis. Upon complete consumption of the starting material, the reaction was diluted with EtOAc (300.0 mL) and washed with water (3 × 200.0 mL), followed by brine (200.0 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO2, EtOAc in hexanes, 0–50%) to afford the desired alcohol (13.1 g, 51.8 mmol, 85% yield) as a colorless oil.

[0207] Step b: Dess-Martin periodinane (20.1 g, 47.4 mmol) was added slowly in two portions to a solution of the alcohol from step a (10.1 g, 43.1 mmol) and NaHCO (7.9 g, 94.8 mmol) in CHCl (216.0 mL) at 0 °C. Upon completion of the addition, the reaction was warmed to 23 °C and stirred for 1 h. The reaction was then quenched by the addition of saturated aqueous NaHCO (100.0 mL) and saturated aqueous NaSO (100.0 mL). The resulting biphasic mixture was stirred vigorously for 20 min. The organic layer was separated, and the aqueous layer was further extracted with CHCl (2 × 100.0 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO2, EtOAc in hexane, 0-60%) to give the corresponding trifluoromethyl ketone (9.0 g, 38.8 mmol, 90% yield) as a colorless oil.

[0208] Step c: The trifluoromethyl ketone from step b (5.40 g, 23.3 mmol) was dissolved in DMF (116.0 mL) and cooled to 0 °C. Next, triethylamine (12.9 mL, 93.0 mmol) and formic acid (5.30 mL, 0.14 mmol) were added sequentially. The solution was degassed by sparging with nitrogen gas for 10 min, followed by the addition of RuCl(p-cymene)[(S,S)-Ts-DPEN] (0.59 g, 0.93 mmol). The resulting solution was stirred at 4 °C for 16 h. When TLC analysis showed complete conversion of the starting material, the mixture was diluted with EtOAc (150.0 mL) and washed with water (3 × 100.0 mL), saturated aqueous NaHCO (100.0 mL), and brine (100.0 mL). The organic phase was dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO2, EtOAc in hexane, 0-60%) to give the corresponding chiral alcohol (4.76 g, 20.3 mmol, 87% yield) as a colorless oil.

[0209] Step d: To a suspension of the alcohol from step c (4.50 g, 19.2 mmol) and AgO (13.4 g, 57.6 mmol) in 1,2-dichloroethane (19.0 mL), ℃ Methyl iodide (12.0 mL, 0.19 mmol) was added at 60 °C. The resulting suspension was stirred at 60 °C for 48 h. The reaction mixture was cooled to ambient temperature and filtered through a Celite pad. The Celite pad was further washed with EtOAc (20.0 mL), and the combined filtrates were concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO, EtOAc in hexanes, 0–35%) to afford the desired methyl ether (1.50 g, 6.04 mmol, 31% yield) as a colorless oil.

[0210] Step e: The benzyl ether from step d (1.50 g, 6.0 mmol) was dissolved in MeOH (60.0 mL), and the resulting solution was placed under a nitrogen atmosphere. Palladium on carbon (0.15 g, 10 wt%, 10% Pd) was added to the reaction vial, and the nitrogen atmosphere was replaced with hydrogen using a rubber balloon (1 atm). The mixture was vigorously stirred under a hydrogen atmosphere for 16 h. The resulting suspension was filtered through a Celite pad, washed with EtOAc, and concentrated to dryness under reduced pressure. The resulting crude primary alcohol (0.94 g) was used in the next step without further purification.

[0211] Step f: Tosyl chloride (1.10 g, 5.65 mmol) was added to a solution of the product of step e (0.94 g) and triethylamine (1.10 mL, 5.94 mmol) in CH2Cl2 (29.0 mL) at 0 °C. The reaction was cooled to 23 ℃ The mixture was warmed to rt and stirred for 16 h. 50 μL of morpholine was then added to quench residual tosyl chloride. The solution was washed with 1 M HCl (5.0 mL). The organic phase was separated, and the aqueous phase was further extracted with CHCl (2 × 10.0 mL). The combined organic phases were dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO, EtOAc in hexanes, 0–50%) to afford the corresponding tosylate (0.62 g, 2.0 mmol, 33% yield over two steps) as a white solid.

[0212] Step g: The methyl ether (0.26 g, 0.534 mmol, 67% yield) was prepared in a similar manner as described for Example 1 using the product of step f ([(3S)-4,4,4-trifluoro-3-methoxybutyl]4-methylbenzenesulfonate) as the alkylating reagent.

[0213] Step h: To a solution of the methyl ether from step g (0.26 g, 0.534 mmol) in MeOH (11.0 mL) was added 1 M aqueous NaOH (2.70 mL, 2.70 mmol) at ambient temperature. The resulting mixture was stirred for 3 h. When TLC analysis indicated complete consumption of the starting material, the reaction was quenched with saturated NH4Cl. The organic phase was separated, and the aqueous layer was extracted with EtOAc (2 × 5.0 mL). The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 0–50%) to afford the title compound (0.19 g, 0.497 mmol, 93% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 4.89 (q, J =5.6 Hz,1H), 4.24(ddd, J =14.9, 8.7,6.5 Hz,1H), 4.13(ddt, J =14.5, 7.4,4.2 Hz,1H), 3.62- 3.44(m, 4H),2.97 - 2.78 (m, 2H),2.69 - 2.45 (m, 2H),2.28 (dddd,J = 18.0, 10.6, 8.6,4.6 Hz,2H), 2.15- 1.99(m, 1H). C 13 H 14 ESI MS [M+H] for F8N2O2 + , calculated value 382.1, measured value 382.2.

[0214] Example 12: (4S)-5,5-Difluoro-1-[(3R)-4,4,4-trifluoro-3-methoxybutyl]-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared according to the protocol described in Example 11, using RuCl(p-cymene) [(R,R)-Ts-DPEN] in step c. 1H NMR(400 MHz,CDCl3) δ 4.89 (q, J =5.9 Hz,1H), 4.25(ddd, J =15.0, 8.6,6.6 Hz,1H), 4.14(ddd, J =13.2, 7.1,4.5 Hz,1H), 3.64- 3.43(m, 4H),2.97 - 2.74 (m, 2H),2.65 - 2.43 (m, 2H),2.39 - 2.16 (m, 1H),2.15 - 2.02 (m, 1H). C 13 H 14 ESI MS [M+H] for F8N2O2 + , calculated value 382.1, measured value 382.1.

[0215] Example 13: (4S)-5,5-Difluoro-1-(3-methoxybutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] Step a: The olefin was prepared in a similar manner as described for Example 1 using 4-bromobut-1-ene as the alkylating reagent.

[0216] Step b: A 30 mL screw-cap vial was charged with PdCl (47.0 mg, 0.265 mmol) and CuCl (0.26 g, 2.65 mmol) under a nitrogen atmosphere. A mixture of DMF / HO (3.5 mL / 0.5 mL) was added, and the suspension was stirred vigorously for 1 h while oxygen gas was bubbled through the suspension. The olefin from step a (1.06 g, 2.65 mmol) was added to the reaction, and oxygen was bubbled through the reaction mixture for an additional 0.5 h. The bubbling needle was then removed, and the solution was stirred in a sealed vial for 3 h. The mixture was diluted with EtOAc (10.0 mL) and washed with saturated aqueous NH Cl (2 × 10.0 mL) and brine (10.0 mL). The organic extract was dried over Na SO , filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO2, EtOAc in hexanes, 0-80%) to give the desired ketone (0.63 g, 1.51 mmol, 57% yield) as a colorless oil.

[0217] Step c: Sodium borohydride (46.0 mg, 1.2 mmol) was added to a solution of the ketone from step b (0.50 g, 1.20 mmol) in MeOH (6.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 15 min. Then, it was diluted with water (1.0 mL), and MeOH was evaporated under reduced pressure. The residue was mixed with EtOAc (10.0 mL) and washed with water (5.0 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO2, EtOAc in hexanes, 0–100%) to afford the desired alcohol (0.45 g, 1.08 mmol, 90% yield) as a colorless oil.

[0218] Step d: Aqueous trifluoroboric acid (48 wt% in water, 44.0 μL, 0.239 mmol) and TMSCHN (1.40 mL, 2.87 mmol, 2 M in hexanes) were added to a solution of the alcohol from step c (0.1 g, 0.239 mmol) in CHCl (2.4 mL) at 0 °C. The reaction was allowed to warm to room temperature, and TLC analysis indicated the reaction was complete. The mixture was quenched with saturated aqueous NaHCO (2.0 mL) and extracted with CHCl (2 × 5.0 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated to dryness. The dry residue was fractionated by column chromatography (SiO, EtOAc in hexanes, 0–60%) to afford the desired methyl ether (91 mg, 0.21 mmol, 88% yield) as a colorless oil.

[0219] Step e: To a solution of the methyl ether from step d (91.0 mg, 0.21 mmol) in MeOH (4.2 mL) was added 1 M aqueous NaOH (1.1 mL, 1.10 mmol) at ambient temperature. The resulting mixture was stirred for 3 h. When TLC analysis indicated complete consumption of the starting material, the reaction was quenched with saturated NH4Cl. The organic phase was separated, and the aqueous layer was extracted with EtOAc (2 × 5.0 mL). The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 0–70%) to afford the title compound (55 mg, 0.167 mmol, 80% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 4.89 (d, J =6.4 Hz,1H), 4.12(h, J =5.7, 5.0Hz, 2H),3.27 (dd,J = 5.5, 1.9 Hz,3H), 3.19(dtt, J =15.0, 5.7,2.9 Hz,1H), 2.98- 2.73(m, 2H),2.68 - 2.42 (m, 2H),2.27 (q,J = 7.8, 6.7 Hz,1H), 2.17- 2.00(m, 1H),1.87 (dddd,J = 16.0, 8.8, 4.3,2.0 Hz,1H), 1.14(dd, J =6.2, 1.8Hz, 3H). C 13 H17 ESI MS [M+H] for F5N2O2 + , calculated value 328.1, measured value 328.0.

[0220] Example 14: (4S)-5,5-Difluoro-1-[3-(trifluoromethoxy)butyl]-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The alcohol starting material was prepared according to the protocol described for the synthesis of Example 13.

[0221] Step a: 2-Fluoropyridine (74 μL, 0.86 mmol) and TMSCF (0.13 mL, 0.86 mmol) were added sequentially to a suspension of the alcohol starting material (0.12 g, 0.29 mmol), AgOTf (0.22 g, 0.86 mmol), Selectfluor (0.15 g, 0.43 mmol), and KF (67 mg, 1.15 mmol) in EtOAc (1.5 mL). The reaction was stirred at 23 °C for 16 h and then concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO, EtOAc in hexanes, 0–50%) to afford the desired ether (20 mg, 0.041 mmol, 14% yield) as a colorless oil.

[0222] Step b: To a solution of the trifluoromethyl ether from step a (20.0 mg, 0.041 mmol) in MeOH (0.8 mL) was added 1 M aqueous NaOH (0.21 mL, 0.21 mmol) at ambient temperature. The resulting mixture was stirred for 3 h. When TLC analysis indicated complete consumption of the starting material, the reaction was quenched with saturated NH4Cl. The organic phase was separated, and the aqueous layer was extracted with EtOAc (2 × 3.0 mL). The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (EtOAc in hexanes, 0–40%) to afford the title compound (11.0 mg, 0.0029 mmol, 70% yield) as a colorless oil. 1H NMR(400 MHz,CDCl3) δ 4.87 (q, J =5.7 Hz,1H), 4.37(dq, J =9.6, 4.7,3.5 Hz,1H), 4.11(t, J =7.3 Hz,2H), 3.04- 2.73(m, 2H),2.65 - 2.43 (m, 2H),2.28 (dtd,J = 15.6, 7.9, 3.1Hz, 2H),2.12 (h,J = 6.7, 5.3 Hz,1H), 1.39 (dd,J =6.5, 2.6Hz, 3H). C 13 H 14 ESI MS [M+H] for F8N2O2 + , calculated value 328.1, measured value 328.0.

[0223] Example 15: (4S)-1-[3-(difluoromethoxy)butyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. The alcohol starting material was prepared according to the protocol described for the synthesis of Example 13. [ka]

[0224] Step a: TMSCFBr (0.18 mL, 1.15 mmol) and KOAc (0.22 g, 2.3 mmol) were added to a solution of the alcohol (0.12 g, 0.29 mmol) in CHCl (0.14 mL) and water (0.14 mL). The reaction was stirred at 23 °C for 2 h. It was then diluted with CHCl (2.0 mL) and washed with water (2 × 4 mL). The combined organic phases were dried over NaSO and concentrated, and the crude residue was purified by column chromatography (SiO, EtOAc in hexanes, 0–40%) to give the final product (0.13 g, 0.278 mmol, 97% yield) as a colorless oil.

[0225] Step b: 1 M aqueous NaOH (1.40 mL, 1.40 mmol) was added to a solution of the difluoromethyl ether from step a (0.13 mg, 0.278 mmol) in MeOH (5.60 mL) at room temperature. The resulting mixture was stirred for 3 h. When TLC analysis indicated complete consumption of the starting material, the reaction was quenched with saturated NH4Cl. The organic phase was separated, and the aqueous layer was extracted with EtOAc (2 × 5.0 mL). The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 0–50%) to afford the title compound (90 mg, 0.247 mmol, 89% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 6.23 (t, J =75.2 Hz,1H), 4.87(q, J =5.4 Hz,1H), 4.24(dq, J =12.1, 4.5,3.0 Hz,1H), 4.11(t, J =7.4 Hz,2H), 3.01- 2.70(m, 2H),2.65 - 2.42 (m, 2H),2.37 - 2.14 (m, 2H),2.04 (q,J = 7.7, 5.9 Hz,1H), 1.32(dd, J =6.3, 2.2Hz, 3H). C 13 H 15 ESI MS [M+H] for F7N2O2 + , calculated value 364.1, measured value 364.1.

[0226] Example 16: (4S)-5,5-Difluoro-1-(4,4,4-trifluoro-3-hydroxybutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The olefin starting material was prepared in a manner similar to that described for Example 1 using 4-bromobut-1-ene as the alkylating reagent.

[0227] Step a: Potassium osmate(VI) dihydrate (67 mg, 0.18 mmol), NaIO4 (1.5 g, 7.2 mmol), and 2,6-lutidine (0.42 mL, 3.6 mmol) were added to a solution of the olefin (0.70 g, 1.8 mmol) in THF (9.0 mL) and water (9.0 mL). The solution was stirred at 23 °C for 1 h. Upon completion (TLC analysis), the reaction was diluted with CHCl2 (20.0 mL) and washed with saturated aqueous NaHCO3 (5.0 mL) and brine (10.0 mL). The combined organic phase was dried over NaSO4, filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO2, EtOAc in hexanes, 0–70%) to afford the corresponding aldehyde (0.41 g, 1.02 mmol, 56% yield) as a colorless oil.

[0228] Step b: TMSCF3 (0.20 mL, 1.34 mmol) and TBAF (1 M in THF, 0.89 mL, 0.89 mmol) were added sequentially to a solution of the product from step a (0.36 g, 0.89 mmol) in THF (5.0 mL) at 0 °C. The resulting mixture was stirred at 0 °C and monitored by TLC analysis. After 30 min, the reaction was diluted with EtOAc (15.0 mL) and washed with water (3 × 5.0 mL) and brine (5.0 mL). The organic extract was dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO2, EtOAc in hexanes, 0–60%) to afford the desired alcohol (0.26 g, 0.55 mmol, 62% yield) as a colorless oil.

[0229] Step c: To a solution of the product from step b (50.0 mg, 0.106 mmol) in MeOH (2.1 mL) was added 1 M aqueous NaOH (0.53 mL, 0.53 mmol) at ambient temperature. The resulting mixture was stirred for 3 h. When TLC analysis indicated complete consumption of the starting material, the reaction was quenched with saturated NH4Cl. The organic phase was separated, and the aqueous layer was extracted with EtOAc (2 × 3 mL). The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (EtOAc in hexanes, 0–100%) to afford the title compound (30 mg, 0.082 mmol, 77% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 4.88 (s, 1H),4.29 (dddd,J = 12.1, 9.5, 5.6,2.8 Hz,1H), 4.19(dt, J =14.1, 5.4Hz, 1H),3.94 (d,J = 22.7 Hz, 1H),3.38 (d,J = 5.1 Hz, 1H),2.99 - 2.71 (m, 3H),2.66 - 2.43 (m, 1H),2.31 (ddddd,J = 18.8, 12.7, 9.3,6.2, 3.1Hz, 2H),2.10 (dqd,J = 15.0, 5.2, 3.5Hz, 1H). C 12 H 12 ESI MS [M+H] for F8N2O2 + , calculated value 368.1, measured value 368.2.

[0230] Example 17: (4S)-5,5-Difluoro-1-(4,4,4-trifluoro-3-methoxybutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The alcohol starting material was prepared according to the protocol described in Example 16.

[0231] Step a: Trifluoroboric acid (48 wt% in water, 50 μL, 0.275 mmol) and TMSCHN (1.1 mL, 2.2 mmol, 2 M in hexane) were added to a solution of the alcohol (0.13 g, 0.275 mmol) in CHCl (2.75 mL) at 0 °C. The cooling bath was then removed, and the reaction was left stirring at 23 °C for 20 h. When TLC analysis indicated complete consumption of the starting material, the mixture was quenched with saturated aqueous NaHCO (2.0 mL), and the product was extracted with CHCl (2 × 5.0 mL). The combined organic phases were dried over NaSO, filtered, and concentrated to dryness. The dry residue was fractionated by column chromatography (SiO, EtOAc in hexane, 0–70%) to afford the corresponding ether (22.0 mg, 0.045 mmol, 16% yield) as a colorless oil.

[0232] Step b: To a solution of the methyl ether from step a (22 mg, 0.045 mmol) in MeOH (0.90 mL) was added 1 M aqueous NaOH (0.23 mL, 0.23 mmol) at ambient temperature. The resulting mixture was stirred for 3 h. When TLC analysis indicated complete consumption of the starting material, the reaction was quenched with saturated NH4Cl. The organic phase was separated, and the aqueous layer was extracted with EtOAc (2 × 2.0 mL). The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 0–80%) to afford the title compound (13.3 mg, 0.035 mmol, 77% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 4.89 (q, J =5.9 Hz,1H), 4.25(ddd, J =15.0, 8.6,6.6 Hz,1H), 4.14(ddd, J =13.2, 7.1,4.5 Hz,1H), 3.64- 3.43(m, 4H),2.97 - 2.74 (m, 2H),2.65 - 2.43 (m, 2H),2.39 - 2.16 (m, 1H),2.15 - 2.02 (m, 1H). C 13 H 14 ESI MS [M+H] for F8N2O2 + , calculated value 382.1, measured value 382.0.

[0233] Example 18: (4S)-1-[2-(difluoromethylsulfanyl)ethyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The alkyl bromide starting material was prepared in a manner similar to that described in Example 1 using a large excess of 1,2-dibromoethane (20 equivalents) as the alkylating reagent in NMP.

[0234] Step a: Sodium thiocyanate (0.17 g, 2.14 mmol) was added to a solution of the alkyl bromide starting material (0.65 g, 1.43 mmol) in DMF (3.0 mL). The resulting mixture was stirred at 60 °C for 2 h. Upon cooling to room temperature, CuSCN (0.24 g, 1.90 mmol), CsF (1.20 g, 7.60 mmol), and TMSCFH (0.32 mL, 3.80 mmol) were added, and the reaction was stirred for an additional 24 h. The reaction was diluted with EtOAc (5.0 mL) and washed with water (3 × 5.0 mL) and brine (5.0 mL). The organic phase was dried over NaSO and concentrated, and the crude residue was purified by column chromatography (SiO, EtOAc in hexanes, 0–70%) to afford the sulfide (0.15 g, 0.33 mmol, 34% yield) as a colorless oil.

[0235] Step b: To a solution of the product from step a (0.15 g, 0.33 mmol) in MeOH (8.5 mL) was added 1 M aqueous NaOH (2.2 mL, 2.2 mmol) at ambient temperature. The resulting mixture was stirred for 3 h. When TLC analysis indicated complete consumption of the starting material, the reaction was quenched with saturated aqueous NH4Cl. The organic phase was separated, and the aqueous layer was extracted with EtOAc (2 × 5.0 mL). The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 0–50%) to afford the title compound (87 mg, 0.24 mmol, 72% yield) as a colorless oil. 1H NMR(400 MHz,CDCl3) δ 6.78 (t, J =55.5 Hz,1H), 4.88(q, J =5.7 Hz,1H), 4.29(t, J =6.8 Hz,2H), 3.29(t, J =6.8 Hz,2H), 3.02- 2.78(m, 2H),2.69 - 2.44 (m, 2H),2.39 - 2.20 (m, 1H). C 11 H 11 ESI MS [M+H] for F7N2OS + , calculated value 352.0, measured value 352.1.

[0236] Example 19: (4S)-1-[[3-(difluoromethoxy)-3-methylcyclobutyl]methyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] Step a: TBDPSCl (7.80 mL, 30 mmol) was added to a solution of 3-(hydroxymethyl)cyclobutan-1-one (2.50 g, 25 mmol) and imidazole (3.9 g, 57.4 mmol) in DMF (30 mL) at 0 °C. After 5 min, the reaction was warmed to room temperature and stirred for 1 h. Upon completion, the reaction was diluted with CHCl (30.0 mL) and washed with water (3 × 10.0 mL), saturated aqueous NaHCO (20.0 mL), and brine (20.0 mL). The organic solution was dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO, EtOAc in hexanes, 0–15%) to afford the desired silyl ether (3.0 g, 8.90 mmol, 35% yield) as a colorless oil.

[0237] Step b: Methylmagnesium bromide (3.40 mL, 11.5 mmol, 3.40 M in 2-methyltetrahydrofuran) was added to a solution of cyclobutanone (3.0 g, 8.90 mmol) from step a in diethyl ether (44.0 mL) at 0 °C. The resulting solution was stirred at 0 °C for 1 h. Upon completion by TLC analysis, the reaction was diluted with saturated aqueous NH4Cl (10.0 mL) and EtOAc (100.0 mL). The layers were separated, and the organic phase was washed with brine (70.0 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO2, EtOAc in hexanes, 0–20%) to afford the corresponding tertiary alcohol (1.8 g, 5.08 mmol, 57% yield) as a colorless oil.

[0238] Step c: TMSCFBr (5.6 mL, 36 mmol) and KOAc (3.5 g, 36 mmol) were added to a solution of the tertiary alcohol from step b (1.6 g, 4.5 mmol) in a mixture of dichloromethane (3.0 mL) and water (3.0 mL). The reaction was vigorously stirred at 23 °C for 3 days. It was then diluted with dichloromethane (5.0 mL), and the organic layer was separated. The solution was washed with water (2 × 5.0 mL), dried over NaSO, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO, 0–20% EtOAc in hexanes) to afford the difluoromethyl ether (1.64 g, 4.05 mmol, 90% yield) as a colorless oil.

[0239] Step d: TBAF (6.0 mL, 6.0 mmol, 1 M in THF) was added to a solution of the product from step c (1.76 g, 4.35 mmol) in THF (20.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 30 min. Upon completion, the mixture was partitioned between EtO and water. The organic layer was washed with water (3 × 30.0 mL) and brine (30.0 mL), dried over MgSO, filtered, and concentrated to dryness under reduced pressure. The dry residue was used in the next step without further purification.

[0240] Step e: Tosyl chloride (0.79 g, 4.35 mmol) was added to a solution of the product from step d and triethylamine (0.60 mL, 4.35 mmol) in CHCl (22.0 mL) at 0 °C. The reaction was warmed to 23 °C and stirred overnight. Upon completion, 50 μL of morpholine was added to quench residual tosyl chloride. After 10 min, the reaction mixture was diluted with dichloromethane (20.0 mL) and washed with 1 M aqueous HCl (20.0 mL). The phases were separated, and the aqueous phase was further extracted with CHCl (2 × 10.0 mL). The combined organic phases were dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO, EtOAc in hexanes, 0–30%) to afford an inseparable mixture of tert-butyldiphenylsilanol and the desired tosylate (1.30 g), which was used in the next step without further purification.

[0241] Step f: The difluoromethyl ether (0.17 g, 0.34 mmol, 44% yield) was prepared in a similar manner as described for Example 1 using the product from step e as the alkylating reagent.

[0242] Step g: To a solution of the product from step f (0.17 g, 0.34 mmol) in MeOH (6.9 mL) was added 1 M aqueous NaOH (1.7 mL, 1.7 mmol) at ambient temperature. The resulting mixture was stirred for 3 h. When TLC analysis indicated complete consumption of the starting material, the reaction was quenched with saturated aqueous NH4Cl. The organic phase was separated, and the aqueous phase was further extracted with EtOAc (2 × 10.0 mL). The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 0–50%) to afford the title compound (0.10 g, 0.26 mmol, 74% yield) as a colorless oil. 1H NMR(400 MHz,CDCl3) δ 6.17 (t, J =75.8 Hz,1H), 4.87(q, J =5.7 Hz,1H), 4.08(dd, J =7.1, 1.4Hz, 2H),2.95 - 2.72 (m, 2H),2.65 - 2.43 (m, 3H),2.37 - 2.22 (m, 3H),2.15 (dtd,J = 12.3, 6.8, 2.7Hz, 2H),1.50 (s,3H). C 15 H 17 ESI MS [M+H] for F7N2O2 + , calculated value 390.1, measured value 390.0.

[0243] Example 20: (4S)-1-[2-(2,2-difluorocyclopropyl)ethyl]-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol. [ka] The title compound was prepared from 2-(2-bromoethyl)-1,1-difluorocyclopropane in a manner similar to that described for Example 1. 1 H NMR (400 MHz, chloroform-d) δ 4.86 (q, J = 5.6 Hz, 1H), 4.10 (tt, J = 7.1, 2.4 Hz, 2H), 2.94 - 2.72 (m, 2H), 2.62 (d, J = 3.9 Hz, 1H), 2.59 - 2.39 (m, 1H), 2.35 - 2.20 (m, 1H), 2.17 - 2.04 (m, 1H), 1.96 - 1.83 (m, 1H), 1.49 - 1.35 (m, 2H), 0.90 (td, J = 13.0, 3.6 Hz, 1H). 13 H 13 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.0.

[0244] Example 21: (4S)-5,5-Difluoro-1-[2-(3-fluorooxetan-3-yl)ethyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol. [ka] The title compound was prepared from 2-(3-fluorooxetan-3-yl)ethanol in a manner similar to that described for Example 2. 1 H NMR (400 MHz, chloroform-d) δ 4.85 (q, J = 5.7 Hz, 1H), 4.73-4.54 (m, 2H), 4.38-4.10 (m, 4H), 2.92-2.70 (m, 2H), 2.66-2.62 (m, 1H), 2.63-2.40 (m, 3H), 2.32-2.20 (m, 1H). 13 H 14 ESI MS [M+H] for F6N2O2 + , calculated value 345.1, measured value 345.0.

[0245] Example 22: (4S)-1-(2-cyclopropylethyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol. [ka] The title compound was prepared in a similar manner as described for Example 1 using 2-bromoethylcyclopropane as the alkylating reagent. 1 H NMR(400 MHz,chloroform-d) δ 4.87 (q, J =5.7 Hz,1H), 4.17- 4.00(m, 2H),2.93 - 2.74 (m, 2H),2.61 - 2.42 (m, 2H),2.33 - 2.19 (m, 1H),1.82 - 1.63 (m, 2H),0.64 - 0.51 (m, 1H),0.46 - 0.35 (m, 2H),0.03 - -0.10 (m, 2H). C 13 H 15ESI MS [M+H] for F5N2O + , calculated value 311.1, measured value 311.1.

[0246] Examples 23 and 24: (4S)-1-{[(1R)-2,2-difluorocyclopropyl]methyl}-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol and (4S)-1-{[(1S)-2,2-difluorocyclopropyl]methyl}-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol. [ka] The title compound was prepared in a similar manner as described for Example 1 using 2-(bromomethyl)-1,1-difluorocyclopropane as the alkylating reagent. The diastereomers were separable by flash chromatography (SiO, hexanes to 30% EtOAc).

[0247] First eluting isomer (DIAST-1): 1 H NMR(400 MHz,chloroform-d) δ 4.93 - 4.83(m, 1H),4.18 (dd,J = 15.0, 6.5 Hz,1H), 4.07(dd, J =14.5, 7.7Hz, 1H),2.90 (dd,J = 16.5, 6.8 Hz,1H), 2.77(ddd, J =16.7, 10.8,6.6 Hz,1H), 2.66- 2.42(m, 2H),2.37 - 2.21 (m, 1H),2.13 (tt,J = 13.7, 6.6 Hz,1H), 1.67- 1.51(m, 1H),1.40 - 1.19 (m, 1H). C 12 H 11 ESI MS [M+H] for F7NO + , calculated value 333.1, measured value 333.1.

[0248] Second eluting isomer (DIAST-2): 1H NMR (400 MHz, chloroform-d) δ 4.98 - 4.75 (m, 1H), 4.18 (dd, J = 14.7, 6.7 Hz, 1H), 4.08 (dd, J = 14.9, 7.8 Hz, 1H), 2.88 - 2.74 (m, 2H), 2.61 (s, 1H), 2.59 - 2.40 (m, 1H), 2.36 - 2.21 (m, 1H), 2.12 (td, J = 11.6, 5.6 Hz, 1H), 1.66 - 1.53 (m, 1H), 1.32 - 1.20 (m, 1H). 12 H 11 ESI MS [M+H] for F7NO + , calculated value 333.1, measured value 333.1.

[0249] Example 25: (4S)-1-[2-(2,2-difluorocyclopropoxy)ethyl]-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol. [ka] The title compound was prepared from 2-(2-bromoethoxy)-1,1-difluorocyclopropane in a manner similar to that described for Example 1. 1 H NMR (400 MHz, chloroform-d) δ 4.85 (q, J = 5.7 Hz, 1H), 4.27-4.16 (m, 2H), 4.00-3.85 (m, 2H), 3.54 (tq, J = 7.6, 2.6 Hz, 1H), 3.04-2.71 (m, 2H), 2.58 (s, 1H), 2.55-2.37 (m, 1H), 2.31-2.16 (m, 1H), 1.45 (ddd, J = 16.9, 8.7, 6.5 Hz, 1H), 1.22-1.09 (m, 1H). 13 H 13 ESI MS [M+H] for F7N2O2 + , calculated value 363.1, measured value 363.0.

[0250] Examples 26 and 27: (4S)-1-[(2S)-2-Cyclopropyl-2-fluoroethyl]-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol and (4S)-1-[(2R)-2-Cyclopropyl-2-fluoroethyl]-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol [ka] Step a: To a solution of 2-bromo-1-cyclopropylethanone (142 mg, 0.87 mmol, 1.5 equiv.) and [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate (200 mg, 0.58 mmol, 1.0 equiv.) in DMF (4.0 mL) was added CsCO (378 mg, 1.16 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 1 h and then diluted with EtOAc and HO. The organic phase was separated and washed sequentially with HO twice and brine. The organic solution was then dried over NaSO, filtered, and concentrated. Purification by flash chromatography (SiO, 0–50% EtOAc / hexanes) afforded the ketone product as a colorless oil (157 mg, 0.37 mmol, 63% yield).

[0251] Step b: To a solution of the product from step a (78.3 mg, 0.183 mmol, 1.0 equiv) in methanol (1.8 mL) was added NaBH (27.6 mg, 0.731 mmol, 4.0 equiv) at 0 °C. The resulting solution was stirred at room temperature for 2 h, then quenched with HO and extracted twice with EtOAc. The organic solution was washed with brine, dried over NaSO, filtered, and concentrated. Purification by flash chromatography (SiO, 0–40% EtOAc / hexanes) afforded the alcohol product as a colorless oil (dr 1:1, 61.4 mg, 0.142 mmol, 79% yield).

[0252] Step c: To a solution of the product from step b (61.4 mg, 0.143 mmol, 1.0 equiv) in DCM (1.4 mL) was added DAST (27.1 mg, 22 μL, 0.168 mmol, 1.2 equiv) at 0 °C. The resulting solution was then stirred at room temperature for 2 h and then quenched with saturated aqueous NaHCO3. The mixture was then extracted twice with DCM. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was then redissolved in methanol (2 mL) and treated with NaOH (1 M aqueous solution, 1 mL). The resulting mixture was stirred at room temperature for 1 h, then extracted with EtOAc and concentrated. The crude product was then purified by flash chromatography (SiO, 0–40% EtOAc / hexanes) to afford the two separated diastereomers: (4S)-1-[(2S)-2-cyclopropyl-2-fluoroethyl]-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol (17.0 mg, 51.8 μmol, 36% yield over two steps) and (4S)-1-[(2R)-2-cyclopropyl-2-fluoroethyl]-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol (16.7 mg, 50.9 μmol, 36% yield over two steps). [ka]

[0253] First eluting isomer (DIAST-1): 1H NMR (400 MHz, chloroform-d) δ 4.88 (q, J = 5.8 Hz, 1H), 4.45-4.06 (m, 3H), 3.00 (ddd, J = 16.5, 6.8, 2.4Hz, 1H), 2.81 (ddd, J = 16.7, 10.9, 6.4Hz, 1H), 2.65-2.42 (m, 2H), 2.34-2.19 (m, 1H), 1.02 (ddt, J = 14.3, 10.9, 5.4Hz, 1H), 0.76-0.61 (m, 2H), 0.58-0.49 (m, 1H), 0.42-0.31 (m, 1H). 13 H 14 ESI MS [M+H] for F6N2O + , calculated value 329.1, measured value 329.1.

[0254] Second eluting isomer (DIAST-2): 1 H NMR (400 MHz, chloroform-d) δ 4.89 (q, J = 5.8 Hz, 1H), 4.48-4.06 (m, 3H), 2.97-2.85 (m, 2H), 2.63-2.41 (m, 2H), 2.27 (dtt, J = 18.0, 8.7, 4.0Hz, 1H), 1.04 (ddt, J = 11.8, 8.2, 4.1Hz, 1H), 0.75-0.61 (m, 2H), 0.59-0.49 (m, 1H), 0.45-0.36 (m, 1H). 13 H 14 ESI MS [M+H] for F6N2O + , calculated value 329.1, measured value 329.1.

[0255] Example 28: (4S)-1-(2-cyclopropyl-2,2-difluoroethyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol. [ka] Step a: To a solution of the ketone product (43.0 mg, 0.10 mmol) prepared during the preparation of Example 26 in toluene (0.20 mL) was added deoxofluor (2.7 M in toluene, 0.19 mL, 0.50 mmol, 5.0 equiv.). The resulting solution was then heated at 110 °C overnight, then cooled to room temperature, and quenched with saturated aqueous NaHCO . The mixture was then extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na SO , filtered, and concentrated. The crude material was purified by flash chromatography (SiO , 0–30% EtOAc / Hex) to afford the difluorinated intermediate (14.9 mg). The intermediate was then dissolved in methanol (2 mL) and treated with NaOH (1 M aqueous, 1 mL). The resulting mixture was stirred at room temperature for 2 h, then extracted with EtOAc and concentrated. The crude material was then purified by flash chromatography (SiO 2 , 0-30% EtOAc / hexanes) to afford the title compound (8.7 mg, 25 μmol, 25% yield over two steps). 1 H NMR(400 MHz,chloroform-d) δ 4.89(q, J =5.8 Hz,1H), 4.48(td, J =11.9, 3.9Hz, 2H),3.00 - 2.77 (m, 2H),2.64 - 2.41 (m, 2H),2.28 (dt,J = 14.3, 7.6 Hz, 1H), 1.34- 1.17(m, 1H), 0.70 - 0.46 (m, 4H). C 13 H 13 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.1.

[0256] Example 29: (4S)-1-(2,2-difluorobutyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] Step a: The mesylate intermediate was prepared in a similar manner as described for Example 5.

[0257] Step b: The ketone intermediate was prepared in a similar manner as described for Example 1.

[0258] Step c: To 100 mg of [(4S)-5,5-difluoro-1-(2-oxobutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-yl]benzoate was added 1 mL of DeoxoFluor (50 wt % in toluene), and the reaction mixture was stirred at 70 °C for 16 h. After cooling to room temperature, the reaction was carefully quenched by adding saturated aqueous NaHCO3, and the mixture was diluted with EtOAc. After separating the layers, the aqueous layer was extracted twice more with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude material was purified by column chromatography using a gradient of 0 to 50% EtOAc in hexane to give 48 mg of [(4S)-1-(2,2-difluorobutyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-yl]benzoate.

[0259] Step d: The deprotection step was carried out in a similar manner as described for Example 1. 1 H NMR (400 MHz, chloroform-d) δ 4.88 (app q, J = 5.5 Hz, 1H), 4.38 (t, J = 12.0 Hz, 2H), 3.04 - 2.77 (m, 2H), 2.67 - 2.36 (m, 2H), 2.37 - 2.19 (m, 1H), 2.01 - 1.79 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H). 12 H 14 ESI MS [M+H] for F7NO + , calculated value 335.1, measured value 335.1.

[0260] Example 30: (4S)-5,5-Difluoro-1-[3-(trifluoromethoxy)propyl]-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared from 3-(trifluoromethoxy)propan-1-ol in a manner similar to that described for Example 5. 1 H NMR (400 MHz, chloroform-d) δ 4.92 - 4.85 (m, 1H), 3.95 (td, J = 5.7, 1.7 Hz, 2H), 2.98 - 2.73 (m, 2H), 2.65 - 2.46 (m, 2H), 2.30 (m, 3H). 12 H 13 ESI MS [M+H] for F8N2O2 + , calculated value 369.1, measured value 369.1.

[0261] Example 31: (4S)-1-(4,4-difluorobutyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared from 4,4-difluorobutan-1-ol in a manner similar to that described for Example 2. 1 H NMR(400 MHz,chloroform-d) δ 5.85 (tdd, J =56.4, 5.9,3.0 Hz,1H), 4.88(q, J =5.5 Hz,1H), 4.27- 3.96(m, 2H),2.94 - 2.74 (m, 2H),2.68 - 2.43 (m, 1H),2.28 (dq,J = 14.4, 7.8 Hz,1H), 2.12- 1.99(m, 3H),1.88 (ttd,J = 18.0, 10.4, 9.6,5.3 Hz,2H). C 12 H 14 ESI MS [M+H] for F7NO + , calculated value 335.1, measured value 335.1.

[0262] Example 32: (4S)-1-(3,3-difluorobutyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a similar manner to Example 5 from 3,3-difluorobutan-1-ol. 1 HNMR (400MHz, chloroform-d) δ 4.88 (q, J = 5.7 Hz, 1H), 4.24 (t, J = 7.4 Hz, 2H), 2.98-2.75 (m, 2H), 2.66-2.19 (m, 4H), 1.62 (t, J = 18.6 Hz, 3H). 12 H 14 ESI MS [M+H] for F7NO + , calculated value 335.1, measured value 335.1.

[0263] Example 33: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-(3,3,3-trifluoropropyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared from 3,3,3-trifluoropropan-1-ol in a manner similar to that described for Example 2. 1 H NMR (400 MHz, chloroform-d) δ 4.88 (q, J = 5.7 Hz, 1H), 4.26 (t, J = 7.2 Hz, 2H), 2.95-2.67 (m, 3H), 2.66-2.44 (m, 2H), 2.38-2.22 (m, 1H). 11 H 11 ESI MS [M+H] for F8N2O + , calculated value 339.1, measured value 339.1.

[0264] Example 34: (4S)-5,5-Difluoro-1-[2-(oxolan-2-yl)ethyl]-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a similar manner to Example 2 from 2-(oxolan-2-yl)ethanol. 1 H NMR (400 MHz, chloroform-d) δ 4.87 - 4.79 (m, 1H), 4.16 - 4.08 (m, 2H), 3.91 - 3.78 (m, 1H), 3.72 - 3.58 (m, 2H), 2.88 - 2.81 (m, 2H), 2.59 - 2.40 (m, 1H), 2.29 - 2.19 (m, 1H), 2.19 - 2.09 (m, 1H), 2.01 - 1.91 (m, 1H), 1.91 - 1.79 (m, 3H), 1.53 - 1.40 (m, 1H). 14 H 17 ESI MS [M+H] for F5N2O2 + , calculated value 341.1, measured value 341.1.

[0265] Example 35: (4S)-1-Cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared from cyclohexanol in a manner similar to Example 2. 1 H NMR (400 MHz, chloroform-d) δ 4.86 (t, J = 6.3 Hz, 1H), 3.96-3.83 (m, 1H), 2.93-2.73 (m, 2H), 2.61-2.41 (m, 2H), 2.31-2.18 (m, 1H), 1.90 (qd, J = 10.4, 9.2, 3.6 Hz, 6H), 1.42-1.22 (m, 4H). 14 H 17 ESI MS [M+H] for F5N2O + , calculated value 325.1, measured value 325.1.

[0266] Example 36: (4S)-1-(4,4-difluorocyclohexyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol [ka] The title compound was prepared in a similar manner to Example 2 from 4,4-difluorocyclohexan-1-ol. 1 H NMR (400 MHz, chloroform-d) δ 4.87 (s, 1H), 4.12 - 4.03 (m, 1H), 2.92 - 2.73 (m, 2H), 2.60 (s, 1H), 2.59 - 2.42 (m, 1H), 2.37 - 2.20 (m, 5H), 2.02 - 1.76 (m, 4H). 14 H 15 ESI MS [M+H] for F7NO + , calculated value 361.1, measured value 361.0.

[0267] Example 37: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-[4-(trifluoromethyl)cyclohexyl]-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a similar manner to Example 2 from (cis)-4-(trifluoromethyl)cyclohexan-1-ol. 1 H NMR (400 MHz, chloroform-d) δ 4.87 (s, 1H), 3.92 (ddd, J = 15.8, 9.4, 7.3 Hz, 1H), 2.92 - 2.73 (m, 2H), 2.63 - 2.43 (m, 2H), 2.32 - 2.21 (m, 1H), 2.21 - 2.09 (m, 3H), 2.07 - 1.97 (d, J = 3.4 Hz, 3H), 1.54 - 1.41 (m, 2H). 15 H 16 ESI MS [M+H] for F8N2O + , calculated value 393.1, measured value 393.0.

[0268] Example 38: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-(4,4,4-trifluoro-3-methylbutyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a similar manner to Example 5 from 4,4,4-trifluoro-3-methylbutan-1-ol. 1 H NMR (400 MHz, chloroform-d) δ 4.86 (s, 1H), 4.09 (t, J = 7.7 Hz, 2H), 2.90 - 2.73 (m, 2H), 2.63 - 2.44 (m, 2H), 2.33 - 2.10 (m, 3H), 1.99 - 1.87 (m, 1H), 1.16 (dd, J = 6.9, 1.4 Hz, 3H). 13 H 14 ESI MS [M+H] for F8N2O + , calculated value 367.1, measured value 367.0.

[0269] Example 39: (4S)-1-Butyl-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared from 1-bromobutane in a manner similar to Example 1. 1 H NMR(400 MHz,chloroform-d) δ 4.88 (t, J =6.4 Hz,1H), 4.01(t, J =7.4 Hz,2H), 2.94- 2.72(m, 2H),2.67 - 2.43 (m, 2H),2.34 - 2.19 (m, 1H),1.89 - 1.74 (m, 2H),1.41 - 1.26 (m, 2H),0.94 (t,J = 7.3 Hz, 3H). C 12 H 15 ESI MS [M+H] for F5N2O + , calculated value 299.1, measured value 299.2.

[0270] Example 40: (4S)-5,5-Difluoro-1-(3-methylbutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a similar manner to Example 1 from 1-bromo-3-methylbutane. 1 H NMR (400 MHz, chloroform-d) δ 4.88 (t, J = 6.4 Hz, 1H), 4.02 (t, J = 7.8 Hz, 2H), 2.92-2.74 (m, 2H), 2.69-2.44 (m, 1H), 2.36-2.18 (m, 1H), 1.71 (q, J = 7.2 Hz, 2H), 1.67-1.54 (m, 1H), 0.95 (d, J = 6.4 Hz, 6H). 13 H 17 ESI MS [M+H] for F5N2O + , calculated value 313.1, measured value 313.2.

[0271] Example 41: (4S)-5,5-Difluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a similar manner to Example 1 from (1,1,1-trifluoro-4-iodobutane). 1 H NMR (400 MHz, chloroform-d) δ 4.88 (t, J = 6.3 Hz, 1H), 4.09 (t, J = 6.5 Hz, 2H), 2.91-2.74 (m, 2H), 2.65-2.42 (m, 1H), 2.35-2.22 (m, 1H), 2.22-2.07 (m, 4H). 12 H 12 ESI MS [M+H] for F8N2O + , calculated value 353.1, measured value 353.2.

[0272] Example 42: (4S)-5,5-Difluoro-1-(2-methylsulfonylethyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared from 1-bromo-2-methylsulfonylethan in a manner similar to that described for Example 1. 1 H NMR(400 MHz,CD3OD) δ 4.68 (t, J =6.5 Hz,1H), 4.53(t, J =6.4 Hz,2H), 3.72(ddd, J =6.9, 6.0,0.7 Hz,2H), 3.06(ddd, J =16.8, 6.7,2.4 Hz,1H), 2.89(ddd, J =17.0, 10.7,6.6 Hz,1H), 2.79(s, 3H),2.58 - 2.34 (m, 1H),2.33 - 2.15 (m, 1H). C 11 H 13 ESI MS [M+H] for F5N2O3S + , calculated value 349.1, measured value 349.1.

[0273] Example 43: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-[3-(trifluoromethyl)pentyl]-6,7-dihydro-4H-indazol-4-ol. [ka] Step a: (Carbethoxymethylene)triphenylphosphorane (25 g, 71.8 mmol, 1.02 equiv) was dissolved in EtO (140 mL) and the solution was cooled to 0 °C. 1,1,1-trifluorobutan-2-one (8.9 g, 70.4 mmol, 1.0 equiv) was added dropwise and the reaction was stirred at room temperature for 72 h. The reaction mixture was filtered and directly concentrated in vacuo (700 mbar, 40 °C). The crude residue was purified by vacuum distillation to give the product (4.86 g, 35% yield).

[0274] Step b: Ethyl (E,Z)-3-(trifluoromethyl)pent-2-enoate (4.86 g, 24.8 mmol, 1.0 equiv) was dissolved in EtOH (100 mL, 0.25 M). Pd / C (500 mg, 10 wt%) was added, and the reaction was shaken under 50 psi of H for 16 h. The reaction mixture was sparged with N, filtered through Celite, and concentrated in vacuo (200 mbar, 40 °C). The crude residue was used in the next step without further purification.

[0275] Step c: Ethyl 3-(trifluoromethyl)pentanoate (1.36 g, 6.87 mmol, 1.0 equiv) was dissolved in THF (34 mL, 0.2 M) and the solution was cooled to 0 °C. LiAlH (2.0 M in THF, 6.9 mL, 13.7 mmol, 2.0 equiv) was added dropwise, and the reaction was stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C and quenched with water (1.5 mL). 1.0 M NaOH (5 mL) was added, and the reaction mixture was stirred at room temperature for 15 min. MgSO was added, and the reaction mixture was stirred at room temperature for an additional 15 min. The reaction mixture was then filtered through Celite, and the crude solution of the product alcohol in THF was used directly in the subsequent mesylation without further purification.

[0276] The title compound was prepared in three additional steps in a manner similar to that described for Example 5. 1 H NMR (400 MHz, chloroform-d) δ 4.93 - 4.84 (m, 1H), 4.10 (t, J = 6.5 Hz, 2H), 2.92 - 2.73 (m, 2H), 2.67 - 2.42 (m, 2H), 2.36 - 2.22 (m, 1H), 2.20 - 1.91 (m, 3H), 1.86 - 1.64 (m, 1H), 1.55 - 1.41 (m, 1H), 0.99 (t, J = 6.4 Hz, 3H). 14 H 16 ESI MS [M+H] for F8N2O + , calculated value 381.1, measured value 381.1.

[0277] Example 44: (4S)-1-[2-(3,3-difluorocyclobutyl)ethyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a similar manner to Example 5 from 2-(3,3-difluorocyclobutyl)ethanol. 1 H NMR(400 MHz,CDCl3) δ 4.93 - 4.81(m, 1H),4.05 - 3.94 (m, 2H),2.88 - 2.72 (m, 2H),2.72 - 2.44 (m, 4H),2.34 - 2.20 (m, 1H),2.17 - 2.00 (m, 5H). C 14 H 16 ESI MS [M+H] for F7NO + , calculated value 361.1, measured value 361.0.

[0278] Example 45: (4S)-5,5-Difluoro-1-[(3-fluorocyclobutyl)methyl]-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a similar manner to Example 5 from (3-fluorocyclobutyl)methanol. 1 H NMR(400 MHz,CDCl3) δ 5.21 - 5.00(m, 1H),4.87 (q,J = 5.7 Hz, 1H),4.04 (d,J = 7.8 Hz, 2H),2.91 - 2.81 (m, 2H),2.81 - 2.76 (m, 1H),2.62 - 2.46 (m, 2H),2.45 - 2.30 (m, 2H),2.29 - 2.21 (m, 3H). C 13 H 15 ESI MS [M+H] for F6N2O + , calculated value 329.1, measured value 329.0.

[0279] Example 46: (4S)-1-[(1,1-dioxothietan-3-yl)methyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a similar manner to Example 5 from (1,1-dioxothiethan-3-yl)methanol. 1 H NMR(400 MHz,CDCl3) δ 4.87 (q, J =5.6 Hz,1H), 4.32- 4.24(m, 4H),3.87 - 3.76 (m, 2H),3.30 - 3.18 (m, 1H),2.94 - 2.76 (m, 2H),2.64 - 2.43 (m, 2H),2.36 - 2.23 (m, 1H). C 12 H 14 ESI MS [M+H] for F5N2O3S + , calculated value 361.1, measured value 361.0.

[0280] Example 47: (4S)-5,5-Difluoro-4-methoxy-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazole. [ka] Step a: (4S)-5,5-Difluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol (17 mg, 0.05 mmol, 1.0 equiv) was dissolved in THF (0.5 mL, 0.1 M) and the solution was cooled to 0 °C. NaH (5 mg, 0.21 mmol, 4.2 equiv) was added and the reaction mixture was stirred at 0 °C for 10 min. Next, MeI (17 μL, 0.25 mmol, 5.0 equiv) was added and the reaction was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NH Cl (15 mL) and extracted with EtOAc (2 × 10 mL). The combined organics were dried over Na SO , filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 25% EtOAc in hexanes) to give the title compound (15 mg, 82% yield). 1 H NMR(400 MHz,CDCl3) δ 4.39 (t, J =5.5 Hz,1H), 4.07(t, J =7.0 Hz,2H), 3.63(s, 3H),2.89 - 2.71 (m, 2H),2.64 - 2.44 (m, 1H),2.34 - 2.21 (m, 1H),2.21 - 2.07 (m, 4H). C 13 H 14 ESI MS [M+H] for F8N2O + , calculated value 367.1, measured value 367.2.

[0281] Example 48: (4S)-4,5,5-trifluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazole. [ka] Step a: (4S)-5,5-Difluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol (50 mg, 0.14 mmol, 1.0 equiv) was dissolved in DCM (0.7 mL, 0.2 M) and NaHCO (46 mg, 0.56 mmol, 4.0 equiv) was added, followed by DMP (180 mg, 0.42 mmol, 3.0 equiv). The reaction was stirred at room temperature for 4 h. The reaction was quenched with saturated aqueous NaSO (10 mL) and saturated aqueous NaHCO (10 mL) and extracted with DCM (2 × 10 mL). The combined organics were dried over NaSO, filtered, and concentrated in vacuo. The residue was carried on directly to Step b without further purification.

[0282] Step b: The crude residue from step a (assumed to be 0.14 mmol) was dissolved in DCM (1.4 mL, 0.1 M) and the solution was cooled to 0 °C. HCOH (16 μL, 0.42 mmol, 3.0 equiv), EtN (39 μL, 0.28 mmol, 2.0 equiv), and RuCl(p-cymene)[(S,S)-Ts-DPEN] (5 mg, 0.007 mmol, 0.05 equiv) were added sequentially, and the reaction was stirred under N at 4 °C for 16 h. The reaction was quenched with saturated aqueous NaHCO (15 mL) and extracted with DCM (2 × 10 mL). The combined organics were dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 0 → 50% EtOAc in hexanes) to give the product (35 mg, 71% over two steps).

[0283] Step c: (4R)-5,5-Difluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol (19 mg, 0.05 mmol, 1.0 equiv) was dissolved in DCM (0.5 mL, 0.1 M) and the solution was cooled to 0 °C. DAST (33 μL, 0.25 mmol, 5.0 equiv) was added and the reaction was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NaHCO (15 mL) and extracted with DCM (2 × 10 mL). The combined organics were dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (25% EtOAc in hexanes) to give the product (10 mg, 56% yield). 1 H NMR (400 MHz, chloroform-d) δ 5.47 (dt, J = 52.9, 5.2 Hz, 1H), 4.17 - 4.08 (m, 2H), 3.00 - 2.70 (m, 2H), 2.63 - 2.34 (m, 2H), 2.25 - 2.10 (m, 4H). 12 H 11 ESI MS [M+H] for F9N2 + , calculated value 355.1, measured value 355.1.

[0284] Example 49: (4S)-5,5-Difluoro-4-hydroxy-1-(4,4,4-trifluoro-3-methylbutyl)-6,7-dihydro-4H-indazole-3-carbonitrile. [ka] Step a: To a solution of 1,5,6,7-tetrahydroindazol-4-one (1.16 g, 8.5 mmol) in MeOH (43.0 mL) was added Selectfluor (3.32 g, 9.4 mmol) and concentrated H2SO4 (50.0 μL). The resulting mixture was heated to reflux for 3 h. After cooling to room temperature, 0.3 M aqueous H2SO4 (10 mL) was added to the reaction mixture. The resulting solution was heated to reflux for 1 h. After cooling to room temperature, the reaction was carefully quenched with aqueous NaHCO3 (100.0 mL) and diluted with dichloromethane (100.0 mL). The organic phase was separated, and the aqueous layer was further extracted with dichloromethane (2 × 50.0 mL). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure to give the corresponding α-fluorinated ketone compound. The crude product was used in the next step without further purification.

[0285] Step b: To a solution of the crude α-fluorinated ketone from step a in THF (85.0 mL) was added DHP (1.2 mL, 12.8 mmol) and TsOH·HO (162 mg, 0.85 mmol), and the reaction mixture was refluxed overnight. The resulting solution was diluted with EtOAc (150.0 mL) and washed with saturated aqueous NaHCO (100.0 mL). The organic phase was separated, and the aqueous layer was further extracted with EtOAc (2 × 70.0 mL). The combined organic extracts were dried over NaSO and concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the title compound (690.0 mg, 2.9 mmol, 34% yield over two steps) as a colorless oil.

[0286] Step c: To a solution of the product from step b (630.0 mg, 2.6 mmol) and EtN (2.2 mL, 15.8 mmol) in dichloromethane (13.0 mL) was added TBSOTf (1.2 mL, 5.3 mmol) dropwise at 0 °C. The resulting solution was stirred at 0 °C for 1.5 h, then diluted with dichloromethane (30.0 mL), and then quenched with saturated aqueous NaHCO. The organic phase was separated, and the aqueous phase was further extracted with dichloromethane (2 × 10.0 mL). The combined organic phases were washed with brine (50.0 mL), dried over NaSO, and concentrated to dryness under reduced pressure to provide the crude silyl enol ether. This material was dissolved in acetonitrile (13.0 mL), and Selectfluor (1.4 g, 4.0 mmol) was added portionwise over 5 min at room temperature. The resulting mixture was stirred at room temperature for 0.5 h, then water (20.0 mL) and dichloromethane (40.0 mL) were added. The organic phase was separated, and the aqueous phase was further extracted with dichloromethane (2 × 15.0 mL). The combined organic solution was dried over NaSO and concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to give the corresponding α,α-difluoroketone compound (660.0 mg, 2.57 mmol, 97% yield) as a colorless oil.

[0287] Step d: To a solution of the α,α-difluoroketone from step c (520.0 mg, 2.6 mmol) in dichloromethane (10.0 mL) was added formic acid (230.0 μL, 6.1 mmol) and triethylamine (560.0 μL, 4.1 mmol). The resulting solution was diluted with 0 o The mixture was cooled to +4 °C, and RuCl(p-cymene) [(R,R)-TsDPEN] (39.0 mg, 0.06 mmol) was added in one portion, and the resulting mixture was kept at +4 °C overnight. When TLC analysis showed complete disappearance of the starting material, the mixture was diluted with dichloromethane (30.0 mL), washed with saturated aqueous NaHCO (25.0 mL), dried over NaSO, and concentrated to dryness under reduced pressure to give crude α,α-difluorohydrin. The crude product was used in the next step without purification.

[0288] Step e: The alcohol from step d was dissolved in dichloromethane (20.0 mL), followed by the sequential addition of EtN (560.0 μL, 4.1 mmol), DMAP (24 mg, 0.2 mmol), and benzoyl chloride (350.0 μL, 3.1 mmol). The reaction mixture was refluxed overnight. After TLC confirmed the reaction was complete, the mixture was diluted with dichloromethane (30.0 mL) and quenched with saturated aqueous NHCl (20.0 mL). The organic phase was separated, dried over NaSO, and concentrated to dryness under reduced pressure. The crude residue was purified by column chromatography (SiO, hexane / EtOAc gradient) to give the corresponding benzoylated alcohol (0.77 g, 2.1 mmol, 95% yield over two steps).

[0289] Step f: The product of step e (0.75 g, 2.1 mmol) was dissolved in a trifluoroacetic acid / dichloromethane mixture (1:5, 10 mL), and the solution was stirred at ambient temperature for 4 h. Upon complete removal of the THP group (TLC control), the reaction was diluted with dichloromethane (30 mL) and washed with water (50 mL) and saturated aqueous NaHCO (30 mL). The organic extract was dried over NaSO and concentrated to dryness under reduced pressure. The crude residue was purified by column chromatography (SiO, hexane / EtOAc gradient) to give the corresponding benzoylated alcohol (0.43 g, 1.55 mmol, 74% yield).

[0290] Step g: The tetrahydroindazole from step f (0.40 g, 1.4 mmol) and N-iodosuccinimide (0.42 g, 1.9 mmol) were dissolved in acetonitrile (7.2 mL), and the reaction mixture was refluxed overnight. The mixture was then cooled to ambient temperature, diluted with EtOAc (25.0 mL), and washed with saturated aqueous NaSO (15.0 mL). The organic phase was separated, dried over NaSO, and concentrated to dryness under reduced pressure. The crude residue was purified by column chromatography (SiO, hexane / EtOAc gradient) to give the corresponding iodotetrahydroindazole (0.49 g, 1.21 mmol, 84% yield).

[0291] Step h: A mixture of iodotetrahydroindazole (160.0 mg, 0.40 mmol) and copper(I) cyanide (71.0 mg, 0.80 mmol) in N-methylpyrrolidone (1.0 mL) was placed in a 1-dram vial equipped with a magnetic stir bar and a septum. The mixture was degassed under vacuum and refilled with nitrogen twice and heated at 120 °C for 14 h. Upon completion (TLC monitoring), the reaction was cooled to room temperature, diluted with EtOAc (20.0 mL), and washed with saturated aqueous NH4Cl (15.0 mL), water (15.0 mL), and brine (15.0 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude residue was purified by column chromatography (SiO2, hexane / EtOAc gradient) to give the corresponding cyanotetrahydroindazole (69.0 mg, 0.23 mmol, 58% yield).

[0292] Step i: The alkylating reagent (4,4,4-trifluoro-3-methylbutyl) methanesulfonate (prepared from 4,4,4-trifluoro-3-methylbutan-1-ol in a manner similar to that described in Example 5) (60.0 mg, 0.27 mmol) was added to a mixture of cyanotetrahydroindazole from step h (69.0 mg, 0.23 mmol) and CsCO (150.0 mg, 0.45 mmol) in DMF (1.0 mL) at ambient temperature. The resulting mixture was vigorously stirred for 1 h. When TLC analysis indicated complete consumption of the alkylating reagent, the reaction was diluted with EtOAc (20.0 mL) and washed with saturated aqueous NHCl (20.0 mL), water (2 × 15.0 mL), and brine (15.0 mL). The organic extract was dried over NaSO and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to give the corresponding alkylated product (48.0 mg, 0.11 mmol, 49% yield) as a white solid.

[0293] Step j: To a solution of the alkylated product of step i (48.0 mg, 0.11 mmol) in MeOH (2.2 mL) and THF (1.0 mL) was added 1 M aqueous NaOH (0.6 mL, 0.56 mmol) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (15.0 mL) and 1 M aqueous NaOH (15.0 mL). The organic phase was separated and washed again with 1 M aqueous NaOH (2 × 10.0 mL) and brine (15.0 mL) to remove residual benzoic acid. The combined organic phases were dried over NaSO and concentrated to dryness, and the crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the title compound (2.1 mg, 0.006 mmol, 6% yield) as a colorless oil. Additionally, the corresponding ester product derived from nitrile hydrolysis was isolated (25.0 mg, 0.07 mmol). 1 H NMR(400 MHz,CDCl3) δ 4.88 (t, J =6.7 Hz,1H), 4.11(td, J =7.5, 2.4Hz, 2H),2.93 - 2.70 (m, 3H),2.63 - 2.38 (m, 1H),2.37 - 2.09 (m, 3H),2.01 - 1.88 (m, 1H),1.17 (dd,J = 6.8, 1.0 Hz,3H). C 13 H 14 ESI MS [M+H] for F5N3O + , calculated value 324.1, measured value 324.2.

[0294] Example 50: (4S)-5,5-Difluoro-3-methylsulfonyl-1-(4,4,4-trifluoro-3-methylbutyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The starting material was prepared according to the protocol described in the synthesis of Example 49.

[0295] Step a: The iodopyrazole starting material (100.0 mg, 0.25 mmol), sodium methanesulfinate (76.0 mg, 0.74 mmol), and copper(I) iodide (140.0 mg, 0.74 mmol) were mixed in dimethyl sulfoxide (1.0 mL) and placed in a 1-dram vial. The vessel was evacuated under vacuum and refilled with nitrogen twice. The reaction mixture was heated at 100° C. for 2.5 h. When TLC analysis of an aliquot indicated complete consumption of the starting material, the reaction was cooled to ambient temperature. The resulting solution was diluted with EtOAc (20.0 mL) and washed with saturated aqueous NH4Cl (10.0 mL), water (15.0 mL), and brine (15.0 mL). The organic phase was separated, dried over Na2SO4, and concentrated to dryness under reduced pressure. The crude residue was fractionated by column chromatography (SiO 2 , CH 2 Cl 2 / EtOAc gradient) to afford the desired sulfone (34.0 mg, 0.1 mmol, 39% yield) as a white solid.

[0296] Step b: The alkylating reagent (4,4,4-trifluoro-3-methylbutyl) methanesulfonate (prepared from 4,4,4-trifluoro-3-methylbutan-1-ol in a manner similar to that described in Example 5) (25.0 mg, 0.11 mmol) was added to a mixture of the sulfone from step a (34.0 mg, 0.11 mmol) and CsCO (62.0 mg, 0.19 mmol) in DMF (0.5 mL) at ambient temperature. The resulting mixture was vigorously stirred for 1 h. When TLC analysis indicated complete consumption of the alkylating reagent, the reaction was diluted with EtOAc (15.0 mL) and washed with saturated aqueous NHCl (15.0 mL), water (2 × 10.0 mL), and brine (10.0 mL). The organic extract was dried over NaSO and concentrated to dryness under reduced pressure. The dry residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to afford the corresponding alkylated product (35.0 mg, 0.07 mmol, 76% yield) as a colorless oil.

[0297] Step c: To a solution of the alkylated product from step b (35.0 mg, 0.07 mmol) in MeOH (1.5 mL) and THF (1.0 mL) was added 1 M aqueous NaOH (0.4 mL, 0.36 mmol) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (15.0 mL) and 1 M aqueous NaOH (15.0 mL). The organic phase was separated and washed again with 1 M aqueous NaOH (2 × 10.0 mL) and brine (15.0 mL) to remove residual benzoic acid. The combined organic phases were dried over NaSO and concentrated to dryness, and the crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the title compound (25.0 mg, 91% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 5.09 (ddd, J =7.5, 5.8,1.4 Hz,1H), 4.24- 4.05(m, 2H),3.20 (s,3H), 3.00- 2.72(m, 2H),2.60 - 2.38 (m, 1H),2.37 - 2.10 (m, 2H),2.11 - 1.85 (m, 1H),1.17 (dd,J = 6.9, 2.0 Hz,3H). C 13 H 17 ESI MS [M+H] for F5N2O3S + , calculated value 377.1, measured value 377.1.

[0298] Example 51: (4S,5R)-5-fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-4-ol [ka] Step a: To a solution of 3-(trifluoromethyl)-1,5,6,7-tetrahydroindazol-4-one (2.04 g, 10.0 mmol, 1.0 equiv.) in DMF (0.5 M, 20 mL) at room temperature, Cs2CO3 (4.89 g, 15.0 mmol, 1.5 equiv.) was added, followed by 1,1,1-trifluoro-4-iodobutane (1.47 mL, 12.0 mmol, 1.2 equiv.), and the mixture was stirred at room temperature for 2 h. Upon completion, the reaction was quenched with saturated NH4Cl and diluted with ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (2x), then dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (ISCO, Redisep 40 g column, 0-100% EA / Hex gradient) to give 1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-6,7-dihydro-5H-indazol-4-one as a red oil (2.25 g, 72%).

[0299] Step b: To a solution of the product from step a (2.00 g, 6.37 mmol, 1.0 equiv) in MeOH (0.4 M, 16 mL) at room temperature, Selectfluor (2.48 g, 7.01 mmol, 1.1 equiv) was added, followed by concentrated H2SO4 (34 μL, 0.64 mmol, 0.1 equiv), and the mixture was heated at reflux overnight. Upon completion, the reaction was cooled to room temperature, quenched with saturated NaHCO3, and diluted with ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (2x), then dried over Na2SO4, filtered, and concentrated to give 5-fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-6,7-dihydro-5H-indazol-4-one as a red oil (1.72 g, 82%).

[0300] Step c: To the product of step b (332 mg, 1.00 mmol, 1.0 equiv) in DCM (0.1 M, 10 mL) at room temperature, EtN (277 μL, 2.00 mmol, 2.0 equiv) was added, followed by formic acid (113 μL, 3.00 mmol, 3.0 equiv). The mixture was degassed for approximately 10 min, cooled to 0 °C, and RuCl(p-cymene)[(R,R)-Ts-DPEN] (32 mg, 0.050 mmol, 0.05 equiv) was added. The mixture was stirred at 0 °C overnight. Upon completion, the reaction was concentrated and purified by flash column chromatography (ISCO, Redisep 12 g column, 0-60% EA / Hex gradient) to afford (4S,5R)-5-fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-4-ol and (4S,5S)-5-fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-4-ol (247 mg, 74%) as an inseparable mixture of diastereomers (approximately 2:1 cis:trans).

[0301] Step d: To the product of step c (100 mg, 0.30 mmol, 1.0 eq) and DMAP (9.0 mg, 0.075 mmol, 0.25 eq) in DCM (0.1 M, 3.0 mL) at room temperature, EtN (83 μL, 0.60 mmol, 2.0 eq) was added, followed by benzoyl chloride (42 μL, 0.36 mmol, 1.2 eq), and the mixture was heated to reflux for 5 h. Upon completion, the reaction was cooled to room temperature and quenched with 1 M HCl. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated. The crude residue was purified by flash column chromatography (ISCO, Redisep 12 g column, 0-60% EA / Hex gradient) to give [(4S,5R)-5-fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-4-yl]benzoate as a clear oil (61 mg, 47%) and [(4S,5S)-5-fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-4-yl]benzoate as a clear oil (35 mg, 27%).

[0302] Step e: To a solution of [(4S,5R)-5-fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-4-yl]benzoate (61 mg, 0.14 mmol, 1.0 equiv.) in MeOH (2.25 mL, approximately 0.05 M total) at room temperature, 1 M NaOH (0.75 mL, 0.75 mmol, 5.4 equiv.) was added and the mixture was stirred at room temperature overnight. Upon completion, the reaction was quenched with saturated NH4Cl and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (ISCO (ELS), Redisep 4 g column, 0-60% EA / Hex gradient) to give (4S,5R)-5-fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-4-ol (41 mg, 88%). [ka] 1 HNMR (400 MHz, chloroform-d) δ 5.01 (d, J = 10.2 Hz, 1H), 4.86 (ddt, J = 47.2, 10.3, 3.2 Hz, 1H), 4.08 (t, J = 6.7 Hz, 2H), 2.84 (dddd, J = 16.4, 6.0, 4.3, 1.6 Hz, 1H), 2.64 (ddd, J = 16.2, 9.2, 6.3 Hz, 1H), 2.56–2.37 (m, 2H), 2.23–1.98 (m, 5H). 19 FNMR (376MHz, CDCl3)δ -61.41,-66.01, -195.35. C 12 H 14 ESIMS [M+H] for F7NO + , calculated value 335.1, measured value 335.1.

[0303] Example 52: (4S,5S)-5-Fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-4-ol. Step f: To a solution of [(4S,5S)-5-fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-4-yl]benzoate (35 mg, 0.080 mmol, 1.0 equiv.) in MeOH (2.25 mL, approximately 0.025 M total) at room temperature, 1 M NaOH (0.75 mL, 0.75 mmol, 9.4 equiv.) was added and the mixture was stirred at room temperature overnight. Upon completion, the reaction was quenched with saturated NH4Cl and diluted with ethyl acetate. The combined layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (ISCO (ELS), Redisep 4 g column, 0-60% EA / Hex gradient) to give (4S,5S)-5-fluoro-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-4-ol as a clear oil (6 mg, 22%). [ka] 1 H NMR (400 MHz, chloroform-d) δ 5.05–4.84 (m, 2H), 4.11 (t, J = 6.6 Hz, 2H), 2.80–2.62 (m, 2H), 2.37–2.07 (m, 7H). 19 FNMR (376MHz, CDCl3)δ -61.19, -65.99, -192.87. C 12 H 14 ESIMS [M+H] for F7NO + , calculated value 335.1, measured value 335.1.

[0304] Example 53: (4S)-1-(4,4-difluorocyclohexyl)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] Step a. To a 3-liter, three-necked round-bottom flask was added dichloromethane (1.02 L), followed by cyclopentanedione (40.0 g, 408 mmol). 1-(trifluoroacetyl)imidazole (27.8 g, 408 mmol) was added dropwise via an addition funnel while maintaining the internal temperature below 25 °C. After stirring for an additional 4 h, the reaction was quenched with 1.0 M HCl (800 mL). The precipitate that formed was filtered and washed with water. The cake was sucked dry and then further dried under high vacuum to give the product as an off-white solid (66.46 g, 77%).

[0305] Step b. A suspension of the product from step a (66.46 g, 313 mmol) in n-butanol (782 mL, 0.4 M) was heated to 110 °C for 2 h. After cooling to room temperature, the reaction was concentrated to dryness. Purification by column chromatography (SiO, 0–20% EtOAc / CHCl) afforded the desired product (23 g, 39%) as a yellow solid.

[0306] Step c: To a solution of the product from step b (24.0 g, 126.2 mmol, 1.0 equiv) in MeOH (500 mL, 0.25 M) was added Selectfluor (67.1 g, 189.3 mmol, 1.5 equiv) and concentrated H2SO4 (0.3 mL). The resulting mixture was heated to reflux for 15 h. After cooling to room temperature, 0.3 M H2SO4 (50 mL) was added to the reaction mixture. The resulting mixture was heated to reflux for 1 h. After cooling to room temperature, the reaction was quenched with saturated NaHCO3, the organic phase was separated, and the aqueous layer was extracted with DCM. The combined organic phases were dried over Na2SO4 and concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in DCM, 0–30%) to give the 2-F indanone product (11.28 g, 43% yield).

[0307] Step d: To a solution of the product from step c (11.0 g, 52.9 mmol, 1.0 equiv) in THF (350 mL, 0.15 M), DHP (7.2 mL, 79.3 mmol, 1.5 equiv) and pTsOH.HO (1.0 g, 5.29 mmol, 0.1 equiv) were added, and the mixture was refluxed overnight. The reaction was quenched with saturated NaHCO, the organic phase was separated, and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over NaSO and concentrated, and the crude residue was purified by column chromatography (SiO, EtOAc in hexanes, 20–60%) to give the THP-protected pyrazole (14.7 g, 95% yield).

[0308] Step e: To a solution of the product from step d (13.5 g, 46.2 mmol, 1.0 equiv) and EtN (25.0 mL, 185.0 mmol, 4.0 equiv) in DCM (153 mL, 0.3 M) was added TBSOTf (21.0 mL, 92.4 mmol, 2.0 equiv) dropwise at 0 °C. The resulting solution was stirred at 0 °C for 1.5 h and then quenched with saturated NaHCO (aq). The organic phase was separated, and the aqueous phase was extracted with DCM. The combined organic phase was then washed with brine, dried over NaSO, and concentrated to give the silyl enol ether. The crude material was then dissolved in MeCN (231 mL, 0.2 M), and Selectfluor (24.6 g, 69.3 mmol, 1.5 equiv) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 30 min, then water and DCM were added, and the aqueous phase was extracted with DCM. The combined organic phases were dried over NaSO and concentrated, and the crude residue was purified by column chromatography (SiO, EtOAc in hexanes, 10–40%) to give the difluoro-indanone product (13.6 g, 94% yield).

[0309] Step f: To a solution of difluoro-indanone (13.2 g, 42.5 mmol, 1.0 equiv) in DCM (212 mL, 0.2 M) was added HCOH (4.8 mL, 127.5 mmol, 3.0 equiv) and EtN (11.6 mL, 85.0 mmol, 2.0 equiv). oAfter cooling to 4 °C, RuCl(p-cymene) [(R,R)-TsDPEN] (811 mg, 1.28 mmol, 0.03 equiv.) was added, and the resulting mixture was stored in a refrigerator overnight (4 °C). The reaction was quenched with saturated NaHCO, the organic phase was separated, and the aqueous layer was extracted with DCM. The combined organic phases were dried over NaSO and concentrated, and the crude residue was used without purification.

[0310] Step g: The crude residue from step f was dissolved in DCM (212 mL, 0.2 M) and EtN (11.6 mL, 85.0 mmol, 2 equiv.), BzCl (7.4 mL, 63.8 mmol, 1.5 equiv.), and DMAP (519 mg, 4.25 mmol, 0.1 equiv.) were added. The reaction mixture was refluxed overnight and quenched with saturated NH4Cl. The organic phase was separated, the aqueous layer was extracted with DCM, the combined organic phases were dried over Na2SO4, concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in hexanes, 0–30%) to give the benzoyl-protected indanol product (15.6 g, 88% yield over two steps).

[0311] Step h: The product from step g (15.5 g, 37.2 mmol, 1.0 equiv) was dissolved in DCM:TFA (9:1, 180 mL, 0.2 M) and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated NaHCO3, the organic phase was separated, the aqueous layer was extracted with DCM, the combined organic phase was dried over Na2SO4, concentrated, and the crude residue was purified by column chromatography (EtOAc in hexanes, 20–50%) to give [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate (8.24 g, 66% yield) and 4.74 g of recovered starting material.

[0312] Step i: To a solution of [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate (70 mg, 0.211 mmol, 1.0 equiv.) in THF (1.5 mL) was added PPh3 (100 mg, 0.381 mmol, 1.8 equiv.) and DIAD (75 μL, 0.38 mmol, 1.8 equiv.). The resulting mixture was stirred at room temperature for 30 min. The reaction was concentrated onto Celite and directly purified by flash chromatography (SiO2, hexanes to 40% EtOAc) to give the alkylated product (34.9 mg, 37%).

[0313] Step j: The product of step i (34.9 mg, 0.077 mmol, 1.0 equiv) was dissolved in THF (0.5 mL) and MeOH (0.5 mL). 1 M aqueous NaOH (0.40 mL, 0.40 mmol, 5.0 equiv) was added, and the reaction was stirred for 30 min until LCMS indicated complete consumption of the starting material. The reaction was diluted with EtOAc and quenched with saturated aqueous NH4Cl. The aqueous layer was separated and extracted with additional EtOAc. The combined organic layers were dried over MgSO4. Concentration under reduced pressure and purification by flash chromatography (SiO2, hexanes to 40% EtOAc) afforded the title compound as a colorless oil (19.5 mg, 73%). 1 H NMR(400 MHz,CDCl3) δ 5.06 (dd, J =12.1, 5.5Hz, 1H),4.25 (tt,J = 10.1, 5.4 Hz,1H), 3.58- 3.24(m, 2H),2.41 - 2.22 (m, 2H),2.21 - 2.03 (m, 4H),2.02 - 1.81 (m, 2H). C 13 H 13 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.1.

[0314] Example 54: (4S)-1-(3,3-difluorocyclopentyl)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared via the reaction of [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate with the mesylate derived from 3,3-difluorocyclopentan-1-ol in a manner similar to that described for Example 5. The compound was isolated as a 1:1 mixture of diastereomers in the α-branched cyclopentylmethine. 1 H NMR(400 MHz,CDCl3) δ 5.06 (dd, J =12.0, 5.5Hz, 1H),4.76 - 4.64 (m, 1H),3.49 - 3.24 (m, 2H),2.77 - 2.61 (m, 2H),2.57 - 2.07 (m, 4H). C 12 H 11 ESI MS [M+H] for F7NO + , calculated value 333.1, measured value 333.1.

[0315] Example 55: 4-[(4S)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-1-yl]-2-methylbutanenitrile. [ka] The title compound was prepared in a manner similar to that in Example 3 from [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate. 1H NMR(400 MHz,CDCl3) δ 5.05 (ddd, J =11.9, 5.9,2.1 Hz,1H), 4.51- 4.11(m, 2H),3.65 - 3.22 (m, 2H),2.87 (ddd,J = 11.1, 6.0, 1.8Hz, 1H),2.64 - 2.52 (m, 1H),2.45 - 2.21 (m, 1H),2.21 - 1.98 (m, 1H),1.37 (dd,J = 7.1, 1.1 Hz,3H). C 12 H 12 ESI MS [M+H] for F5N3O + , calculated value 310.1, measured value 310.3.

[0316] Example 56: (4S)-5,5-Difluoro-1-(2-methylsulfonylethyl)-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared in a similar manner as in Example 1 from 1-bromo-2-methylsulfonylethane and [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate. 1 HNMR (400MHz, CDCl3)δ 5.04(dd, J =12.1, 5.7Hz, 1H),4.55 (t,J = 5.9 Hz, 2H),3.64 (t,J = 6.1 Hz, 2H),3.56 - 3.33 (m, 2H),2.97 (d,J = 5.8 Hz, 1H),2.68 (s,3H). C 10 H 11 ESIMS [M+H] for F5N2O3S + , calculated value 335.1, measured value 335.0.

[0317] Example 57: (4S)-1-[(1,1-dioxothietan-3-yl)methyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared in a manner similar to that described for Example 5 using the mesylate derived from (1,1-dioxothietan-3-yl)methanol and [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate. 1 H NMR(400 MHz,CDCl3) δ 5.09 (dd, J =11.8, 5.4Hz, 1H),4.36 (dd,J = 7.7, 1.3 Hz,2H), 4.35- 4.26(m, 2H),3.90 - 3.81 (m, 2H),3.49 - 3.27 (m, 2H),3.27 - 3.15 (m, 1H),2.48 (dd,J = 5.4, 2.0 Hz,1H). C 11 H 11 ESI MS [M+H] for F5N2O3SNa + , calculated value 369.0, measured value 369.0.

[0318] Example 58: (4S)-1-[2-(2,2-difluorocyclopropyl)ethyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared from 2-(2-bromoethyl)-1,1-difluorocyclopropane and [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate in a manner similar to that described for Example 1. 1H NMR (400 MHz, chloroform-d) δ 5.07 (dd, J = 12.0, 5.6 Hz, 1H), 4.29 - 4.01 (m, 2H), 3.59 - 3.08 (m, 2H), 2.48 - 2.23 (m, 1H), 2.24 - 2.04 (m, 1H), 2.03 - 1.80 (m, 1H), 1.42 (d, J = 12.6 Hz, 2H), 1.00 - 0.76 (m, 1H). 12 H 11 ESI MS [M+H] for F7NO + , calculated value 333.1, measured value 333.1.

[0319] Example 59: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-[[2-(trifluoromethyl)cyclopropyl]methyl]-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared from [2-(trifluoromethyl)cyclopropyl]methanol and [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate in a manner similar to that described for Example 2. 1 H NMR (400 MHz, chloroform-d) δ 4.89 (s, 1H), 4.18 - 3.83 (m, 3H), 2.86 (s, 2H), 2.54 (s, 2H), 2.30 (s, 1H), 1.81 - 1.43 (m, 2H), 1.11 (s, 1H), 0.88 (d, J = 14.3 Hz, 1H). 13 H 12 ESI MS [M+H] for F8N2O + , calculated value 365.1, measured value 365.1.

[0320] Example 60: (4S)-5,5-Difluoro-1-[2-(trifluoromethoxy)ethyl]-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a manner similar to that described for Example 2 from 2-(trifluoromethoxy)ethanol and [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate. 1 H NMR (400 MHz, chloroform-d) δ 4.99 - 4.76 (m, 1H), 4.41 - 4.23 (m, 4H), 3.04 - 2.70 (m, 2H), 2.66 - 2.39 (m, 2H), 2.41 - 2.13 (m, 1H). 11 H 10 ESI MS [M+H] for F8N2O2 + , calculated value 355.1, measured value 355.0.

[0321] Example 61: (4S)-5,5-difluoro-1-[(3R)-4,4,4-trifluoro-3-methoxybutyl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared in a manner similar to that in Example 12 from [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate. 1 H NMR(400 MHz,CDCl3) δ 5.16 - 5.01(m, 1H),4.34 - 4.16 (m, 2H),3.59 - 3.47 (m, 4H),3.47 - 3.20 (m, 2H),2.53 (dd,J = 5.8, 2.0 Hz,1H), 2.28 (dddd, J =15.2, 8.6,6.9, 3.4Hz, 1H),2.10 (dddd,J = 14.7, 9.6, 6.4,5.1 Hz,1H). C 12 H 15 ESI MS [M+H] for F8N2O2 + , calculated value 368.1, measured value 368.0.

[0322] Example 62: (4S,5R)-5-Fluoro-1-[3-(trifluoromethoxy)propyl]-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-ol. [ka] Step a: To a solution of 5-fluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-4-one (1.80 g, 6.16 mmol, 1.0 equiv.) in DCM (30 mL, 0.2 M) was added HCOH (0.70 mL, 18.5 mmol, 3.0 equiv.) and EtN (1.7 mL, 12.3 mmol, 2.0 equiv.). At room temperature, RuCl(p-cymene) [(R,R)-TsDPEN] (196 mg, 0.31 mmol, 0.05 equiv.) was added, and the resulting mixture was stirred at room temperature for 3 days. The reaction was quenched with saturated aqueous NaHCO, the organic phase was separated, and the aqueous layer was extracted with DCM. The combined organic phases were dried over Na2SO4, concentrated, and the crude residue was purified by column chromatography (SiO2, EtOAc in DCM, 0-10%) to give the indanol product (1.61 g, 89% yield, 2:1 d.r.).

[0323] Step b: The product from step a (1.50 g, 5.1 mmol, 1.0 equiv) was dissolved in DCM (25 mL, 0.2 M), and EtN (1.4 mL, 10.2 mmol, 2 equiv), BzCl (0.89 mL, 7.65 mmol, 1.5 equiv), and DMAP (62 mg, 0.51 mmol, 0.1 equiv) were added. The reaction mixture was refluxed overnight and quenched with saturated aqueous NH4Cl. The organic phase was separated, the aqueous layer was extracted with DCM, the combined organic phases were dried over NaSO, concentrated, and the crude residue was purified by column chromatography (SiO, EtOAc in hexanes, 0–20%) to give [(4S,5R)-5-fluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-yl]benzoate (1.11 g, 55%) and [(4S,5S)-5-fluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-yl]benzoate (456 mg, 22%).

[0324] Step c: [(4S,5R)-5-fluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-yl]benzoate (1.05 g, 2.64 mmol, 1.0 equiv) was dissolved in DCM:TFA (9:1, 13 mL, 0.2 M) and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated NaHCO, the organic phase was separated, the aqueous layer was extracted with DCM, the combined organic phase was dried over NaSO, concentrated, and the crude residue was purified by column chromatography (SiO, 20:50% EtOAc in hexanes) to give [(4S,5R)-5-fluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl]benzoate (411 mg, 50% yield) and 367 mg of recovered starting material.

[0325] Step d: [(4S,5S)-5-Fluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-yl]benzoate (440 mg, 1.10 mmol, 1.0 equiv) was dissolved in DCM:TFA (9:1, 5.5 mL, 0.2 M) and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated NaHCO, the organic phase was separated, the aqueous layer was extracted with DCM, the combined organic phase was dried over NaSO, concentrated, and the crude residue was purified by column chromatography (SiO, EtOAc in hexanes, 20–50%) to give [(4S,5S)-5-fluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl]benzoate (188 mg, 54% yield) and 141 mg of recovered starting material.

[0326] (4S,5R)-5-Fluoro-1-[3-(trifluoromethoxy)propyl]-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-ol was prepared in a manner similar to that described in Example 5 from the mesylate derived from [(4S,5R)-5-fluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl]benzoate and 3-(trifluoromethoxy)propan-1-ol. [ka] 1 H NMR (400 MHz, chloroform-d) δ 5.43 (ddt, J = 50.1, 6.1, 4.7 Hz, 1H), 5.15 (q, J = 5.5 Hz, 1H), 4.16 (t, J = 6.7 Hz, 2H), 3.98-3.86 (m, 2H), 3.18-2.99 (m, 2H), 2.35-2.23 (m, 3H). 11 H 11 ESI MS [M+H] for F7N2O2 + , calculated value 337.1, measured value 337.0.

[0327] Example 63: (4S,5S)-5-Fluoro-1-[3-(trifluoromethoxy)propyl]-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-ol. (4S,5S)-5-Fluoro-1-[3-(trifluoromethoxy)propyl]-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-ol was prepared in a manner similar to that described in Example 5 from the mesylate derived from [(4S,5S)-5-fluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl]benzoate and 3-(trifluoromethoxy)propan-1-ol. [ka] 1 H NMR(400 MHz,chloroform-d) δ 5.55 - 5.38(m, 1H),5.19 (dd,J = 17.4, 4.2 Hz,1H), 4.15(t, J =6.3 Hz,2H), 3.94(dd, J =5.6, 6.0Hz, 2H),3.35 (ddd,J = 20.2, 16.9, 6.0Hz, 1H),2.85 (ddd,J = 24.0, 17.0, 2.3Hz, 1H),2.28 (p,J = 6.0 Hz, 2H),2.11 (d,J = 4.8 Hz, 1H). C 11 H 11 ESI MS [M+H] for F7N2O2 + , calculated value 337.1, measured value 337.0.

[0328] Example 64: (4S)-5,5-difluoro-1-[(3r,5r)-1,1-difluorospiro[2.3]hexan-5-yl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared from (3s,5s)-2,2-difluorospiro[2.3]hexan-5-ol and [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate in a manner similar to that described for Example 53. 1 HNMR (400MHz, CDCl3)δ 5.07(dd, J= 12.0,5.6 Hz,1H), 4.96(tt, J= 8.6,7.1 Hz,1H), 3.53- 3.26(m, 2H),3.04 -2.92 (m,2H), 2.64- 2.53(m, 2H),2.37 (dd,J =5.6, 2.0Hz, 1H),1.40 (t,J =8.3 Hz,2H). C 13 H 12 ESIMS [M+H] for F7NO + , calculated value 345.1, measured value 345.1.

[0329] Example 65: (4S)-5,5-difluoro-1-[(3s,5s)-1,1-difluorospiro[2.3]hexan-5-yl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared from (3r,5r)-2,2-difluorospiro[2.3]hexan-5-ol and [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate in a manner similar to that described for Example 53. 1 H NMR (400MHz, CDCl3)δ 5.07(dd, J =11.9, 5.6Hz, 1H),4.75 (p,J = 8.0 Hz, 1H),3.49 - 3.24 (m, 2H),2.99 - 2.87 (m, 2H),2.78 - 2.66 (m, 2H),2.37 (dd,J = 5.6, 2.1 Hz,1H), 1.36(t, J =8.3 Hz,2H). C 13 H 12ESI MS [M+H] for F7NO + , calculated value 345.1, measured value 345.1.

[0330] Example 66: (4S)-1-{6,6-difluorospiro[3.3]heptan-2-yl}-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared from 2,2-difluorospiro[3.3]heptan-6-ol and [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate in a manner similar to that described for Example 53. 1 H NMR(400 MHz,CDCl3) δ 5.05 (dd, J =11.9, 5.6Hz, 1H),4.58 (p,J = 8.2 Hz, 1H),3.45 - 3.20 (m, 2H),2.86 - 2.75 (m, 2H),2.75 - 2.58 (m, 6H),2.32 (dd,J = 5.6, 2.1 Hz,1H). C 14 H 14 ESI MS [M+H] for F7NO + , calculated value 359.1, measured value 359.1.

[0331] Example 67: (4S,5R)-1-{6,6-difluorospiro[3.3]heptan-2-yl}-5-fluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared from 2,2-difluorospiro[3.3]heptan-6-ol and [(4S,5R)-5-fluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl]benzoate in a manner similar to that described for Example 53. 1H NMR(400 MHz,CDCl3) δ 5.42 (ddt, J =50.7, 6.3,4.8 Hz,1H), 5.14(q, J =5.5 Hz,1H), 4.58(p, J =8.2 Hz,1H), 3.19- 3.03(m, 2H),2.84 - 2.76 (m, 2H),2.74 - 2.54 (m, 6H),2.28 (dd,J = 6.2, 3.8 Hz,1H). C 14 H 15 ESI MS [M+H] for F6N2O + , calculated value 341.1, measured value 341.1.

[0332] Example 68: (4S)-5,5-difluoro-3-(trifluoromethyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol [ka] Step a: To a solution of [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate (107 mg, 0.32 mmol, 1.0 equiv.) in DMF (2.1 mL, 0.15 M) was added [6-(trifluoromethyl)pyridin-3-yl]boronic acid (122 mg, 0.64 mmol, 2 equiv.), Cu(OAc) (87 mg, 0.48 mmol, 1.5 equiv.), and pyridine (51 μL, 0.64 mmol, 2.0 equiv.). The reaction mixture was stirred under air at room temperature for 16 h, at which point it was diluted with DCM, filtered through Celite, and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography (0–80% EtOAc / hexanes) to give the product (70 mg, 46% yield).

[0333] Step b: To a solution of [(4S)-5,5-difluoro-3-(trifluoromethyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-4,6-dihydrocyclopenta[c]pyrazol-4-yl]benzoate (70 mg, 0.15 mmol, 1.0 equiv) in MeOH (3 mL, 0.05 M) was added 1.0 M NaOH (0.75 mL, 0.75 mmol, 5.0 equiv). The reaction was stirred at room temperature for 2 h, at which point it was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography (0–80% EtOAc / hexanes) to give the product (19 mg, 34% yield). 1 H NMR(400 MHz,chloroform-d) δ 8.95 (d, J =2.5 Hz,1H), 8.24(dd, J =8.6, 2.6Hz, 1H),7.87 (d,J = 8.5 Hz, 1H),5.17 (dd,J = 11.9, 3.9 Hz,1H), 3.85- 3.52(m, 2H),2.66 (d,J = 3.7 Hz, 1H). C 13 ESI MS [M+H] for H7F8N3O + , calculated value 374.1, measured value 374.1.

[0334] Examples 69a and 69b: (4S)-5,5-difluoro-1-[(1R,2S)-2-methoxycyclohexyl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-5,5-difluoro-1-[(1S,2R)-2-methoxycyclohexyl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol [ka] The title compound was prepared from trans-2-methoxycyclohexan-1-ol as an inseparable mixture of diastereomers in a manner similar to that described for Example 53. 1H NMR(400 MHz,chloroform-d) δ 5.03 (d, J =12.1 Hz,2H), 4.43- 4.35(m, 2H),3.71 - 3.65 (m, 2H),3.64 - 3.54 (m, 2H),3.49 - 3.27 (m, 2H),3.18 (s,3H), 3.14(s, 3H),2.16 - 2.06 (m, 4H),1.94 - 1.88 (m, 1H),1.87 - 1.76 (m, 1H),1.68 - 1.29 (m, 10H). C 14 H 17 ESI MS [M+H] for F5N2O2 + , calculated value 341.1, measured value 341.2.

[0335] Example 70: (4S)-5,5-difluoro-1-[(3R,5S)-3,4,5-trifluorocyclohexyl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol [ka] Step a: To a solution of 3,4,5-trifluorophenol (5.5 g, 37.1 mmol, 1.0 equiv) in DCM (75 mL, 0.5 M) was added imidazole (5.1 g, 74.3 mmol, 2.0 equiv), followed by TBS-Cl (6.7 g, 44.6 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 2 h, at which point it was quenched with water (150 mL) and extracted with DCM (100 mL). The combined organics were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography (0–10% EtOAc / hexanes) to give the product (8.6 g, 88% yield).

[0336] Step b: tert-Butyl-dimethyl-(3,4,5-trifluorophenoxy)silane (3.4 g, 13.0 mmol, 1.0 equiv) was dissolved in n-hexane (26 mL, 0.5 M) in a steel Parr bomb lined with a Teflon insert and equipped with a mechanical stirrer. SiO (5.8 g, 0.45 g / mmol) was added, followed by (CyCAAC)Rh(COD)Cl (150 mg, 0.25 mmol, 0.02 equiv). The Parr bomb was pressurized with 500 psi H, evacuated three times, and then pressurized to 1100 psi H. The reaction mixture was stirred under 1100 psi H at approximately 300 rpm for 72 h, at which point the pressure was released and the reaction mixture was filtered through Celite. The filtrate was directly concentrated in vacuo and the crude residue was purified by silica gel flash chromatography (0-80% DCM / hexanes) to afford the product (891 mg, 26% yield).

[0337] Step c: A solution of tert-butyl-dimethyl-[cis-3,4,5-trifluorocyclohexyl]oxysilane (890 mg, 3.32 mmol, 1.0 equiv) in THF (17 mL, 0.2 M) was cooled to 0 °C, and TBAF (1.0 M in THF, 5 mL, 5 mmol, 1.5 equiv) was added dropwise. The reaction mixture was stirred for 3 h until the ice bath had subsided. The reaction was then quenched with saturated aqueous NH4Cl (50 mL), diluted with EtOAc (100 mL), and fractionated. The organics were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography (0–100% EtOAc / hexanes) to give the product (380 mg, 74% yield).

[0338] Step d: To a solution of [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate (78 mg, 0.23 mmol, 1.0 equiv.) in THF (2.3 mL, 0.1 M), cis-3,4,5-trifluorocyclohexan-1-ol (71 mg, 0.46 mmol, 2.0 equiv.), PPh3 (110 mg, 0.42 mmol, 1.8 equiv.), and diisopropyl azodicarboxylate (91 μL, 0.46 mmol, 2.0 equiv.) were added. The reaction was stirred at room temperature for 16 h, at which point it was directly concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography (0–50% EtOAc / hexanes) to afford the product (49 mg, 46% yield).

[0339] Step e: To a solution of [(4S)-5,5-difluoro-1-[(3R,5S)-3,4,5-trifluorocyclohexyl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-yl]benzoate (49 mg, 0.10 mmol, 1.0 equiv.) in MeOH (2 mL, 0.05 M) was added 1.0 M NaOH (0.5 mL, 0.5 mmol, 5.0 equiv.). The reaction was stirred at room temperature for 3 h, at which point it was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography (0–80% EtOAc / hexanes) to afford the product (26 mg, 71% yield). 1 H NMR (400 MHz, chloroform-d) δ 5.35–5.11 (m, 2H), 5.07 (d, J = 12.0 Hz, 1H), 5.01–4.72 (m, 1H), 4.67 (tt, J = 8.7, 4.7 Hz, 1H), 3.53–3.24 (m, 2H), 2.66–2.23 (m, 4H). 13 H 12 ESI MS [M+H] for F8N2O + , calculated value 365.1, measured value 365.1.

[0340] Example 71: (4S)-1-[(3R,5S)-3,5-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol [ka] The title compound was prepared from cis-3,5-difluorocyclohexan-1-ol in a manner similar to that described for Example 70. 1 H NMR (400 MHz, chloroform-d) δ 5.23 - 5.02 (m, 3H), 4.69 (tt, J = 12.0, 3.9 Hz, 1H), 3.54 - 3.23 (m, 2H), 2.67 - 2.38 (m, 4H), 2.38 - 2.15 (m, 2H), 1.96 - 1.61 (m, 1H). 13 H 13 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.1.

[0341] Examples 72 and 73: (4S)-1-[(1R,3S,4R)-3,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-1-[(1S,3R,4S)-3,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol [ka] Step a: To a solution of [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate (475 mg, 1.43 mmol, 1.0 equiv.) in THF (14.3 mL, 0.1 M) were added cis-3,4-difluorocyclohexane-1-ol (390 mg, 2.86 mmol, 2.0 equiv., prepared in a manner similar to that described for Example 70), triphenylphosphine (676 mg, 2.58 mmol, 1.8 equiv.), and diisopropyl azodicarboxylate (0.56 mL, 2.86 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 16 hours, at which point it was directly concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography (0-50% EtOAc / hexanes) to afford a mixture of the desired product and the corresponding N2-alkylated regioisomer in a ca. 2:1 ratio. The N1 / N2 regioisomers were separated by reverse-phase preparative HPLC (Phenomenex C18 column, 20-100% MeCN / HO) to afford a pure sample of the desired N1 regioisomer as a 1:1 mixture of diastereomers (155 mg, 24% yield). This mixture of diastereomers was used for subsequent benzoate deprotection without further purification.

[0342] Step b: To a solution of [(4S)-1-[(1R,3S,4R)-3,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-yl]benzoate and [(4S)-1-[(1S,3R,4S)-3,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-yl]benzoate (155 mg, 0.34 mmol, 1.0 equiv) in about 13.5:1 MeOH / THF (about 7.5 mL, about 0.05 M) was added 1.0 M NaOH (1.7 mL, 1.7 mmol, 5.0 equiv). The reaction was stirred at room temperature for 1.5 hours, at which point it was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 25 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography (0-60% EtOAc / hexanes) to afford the product as a 1:1 mixture of diastereomers (100 mg, 85% yield). The diastereomers were separated by normal-phase preparative HPLC (Waters SunFire Silica column, 5% IPA / hexane) to give pure samples of (4S)-1-[(1R,3S,4R)-3,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-1-[(1S,3R,4S)-3,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol.

[0343] First eluting diastereomer (DIAST-1, 30 mg, 25% yield): 1H NMR (400 MHz, chloroform-d) δ 5.23-5.03 (m, 1H), 5.07 (dd, J = 12.1, 5.4 Hz, 1H), 4.83-4.55 (m, 1H), 4.38 (tt, J = 10.6, 4.2 Hz, 1H), 3.51-3.20 (m, 2H), 2.53-2.41 (m, 1H), 2.39 (dd, J = 5.5, 2.0 Hz, 1H), 2.37-1.98 (m, 5H). 13 H 13 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.1.

[0344] Second eluting diastereomer (DIAST-2, 30 mg, 25% yield): 1 H NMR (400 MHz, chloroform-d) δ 5.24 - 5.03 (m, 1H), 5.07 (d, J = 11.9 Hz, 1H), 4.82 - 4.55 (m, 1H), 4.38 (tt, J = 10.7, 4.1 Hz, 1H), 3.51 - 3.23 (m, 2H), 2.54 - 2.40 (m, 1H), 2.40 - 2.17 (m, 1H), 2.17 - 1.94 (m, 4H). 13 H 13 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.1.

[0345] Example 74: (4S)-5,5-Difluoro-2-(2-phenylethyl)-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol [ka] The title compound was prepared in a manner similar to that described for Example 1 from (4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-ol and 2-phenylethyl bromide. 1HNMR(400 MHz,CDCl3) δ 7.33-7.22 (m, 3H),7.18-7.15 (m,2H), 5.08(dd, J= 5.6, 5.6 Hz,1H), 4.40-4.36(m, 2H),3.95 (td,J = 16.8, 10.8 Hz,1H), 3.27(td, J =16.5, 5.7Hz, 1H),3.16 (m,2H), 2.40(dd, J =5.6, 2.4Hz, 1H). C 15 H 13 ESI MS [M+H] for F5N2O + , Calculated value = 333.1, Measured value 333.1

[0346] Example 75: (4S)-5,5-difluoro-1-[2-(1,2-oxazol-4-yl)ethyl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol [ka] The title compound was prepared from (4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-ol and 4-(2-bromoethyl)thiophene in a manner similar to that described for Example 1. 1 HNMR (400MHz, CDCl3)δ 8.13(s, 1H),7.97 (s,1H), 5.06-5.01(m, 1H),4.23-4.18 (m,2H), 3.21-2.96(m, 4H),2.41-2.38 (m,1H). C 12 H 10 ESIMS [M+H] for F5N3O2 + , Calculated value = 324.1, Measured value 324.1

[0347] Example 76: (4S)-5,5-difluoro-1-(2-thiophen-3-ylethyl)-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol [ka] The title compound was prepared from (4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-ol and 3-(2-bromoethyl)thiophene in a manner similar to that described for Example 1. 1 HNMR (400MHz, CDCl3)δ 7.26(dd, J =4.8, 2.9Hz, 1H),6.79-6.78 (m,1H), 6.70(d, J =5.0 Hz,1H), 4.97(dd, J =11.9, 5.9Hz, 1H),4.23 (t,J = 6.5 Hz, 2H),3.15 (t,J = 6.5 Hz, 2H),2.74 (td,J = 16.7, 15.1, 10.4Hz, 1H),2.60 (td,J = 16.4, 15.5, 4.9Hz, 1H),2.30 (ddd,J = 5.9, 2.1, 0.7Hz, 1H). C 13 H 11 ESI MS [M+H] for F5N2OS + , Calculated value = 339.1, Measured value 339.1

[0348] Example 77: (4S)-5,5-Difluoro-1-[2-(furan-2-yl)ethyl]-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared in a similar manner as described for Example 53 via the reaction of [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate with 2-furanethanol. 1H NMR(400 MHz,CDCl3) δ 7.35 (d, J =1.8 Hz,1H), 6.29(dd, J =3.2, 1.9Hz, 1H),5.92 (d,J = 3.1 Hz, 1H),5.00 (dd,J = 12.0, 5.5 Hz,1H), 4.33(t, J =6.4 Hz,2H), 3.16(t, J =6.4 Hz,2H), 2.95(ddd, J =16.5, 15.0,10.4 Hz,1H), 2.80(td, J =16.0, 5.0Hz, 1H),2.32 (dd,J = 6.0, 2.0 Hz,1H). C 13 H 11 ESI MS [M+H] for F5N2O2 + , calculated value 323.2, measured value 323.1.

[0349] Example 78: (4S)-5,5-Difluoro-1-[2-(furan-3-yl)ethyl]-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared from [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate with 3-furanethanol in a manner similar to that of Example 53. 1 H NMR(400 MHz,CDCl3) δ 7.36 (d, J =1.7 Hz,1H), 7.11(s, 1H),6.12 - 5.87 (m, 1H),5.02 (dd,J = 11.9, 5.6 Hz,1H), 4.21(t, J =6.7 Hz,2H), 3.11- 3.02(m, 1H),2.99 (t,J = 6.7 Hz, 2H),2.91 (td,J = 16.0, 4.8 Hz,1H), 2.38(dd, J =5.8, 2.0Hz, 1H). C 13 H 11 ESI MS [M+H] for F5N2O2 + , calculated value 323.2, measured value 323.1.

[0350] Example 79: (4S)-5,5-Difluoro-1-[2-(3-fluorophenyl)ethyl]-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared in a similar manner as in Example 1 from [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate and 3-fluorophenethyl bromide. 1 H NMR(400 MHz,CDCl3) δ 7.23 (dd, J =7.9, 5.9Hz, 1H),6.97 (td,J = 8.5, 2.6 Hz,1H), 6.72(d, J =7.6 Hz,1H), 6.67(dt, J =9.5, 2.1Hz, 1H),4.98 (dd,J = 11.9, 5.8 Hz,1H), 4.27(td, J =6.6, 2.7Hz, 2H),3.14 (t,J = 6.6 Hz, 2H),2.73 (ddd,J = 16.4, 15.1, 10.3Hz, 1H),2.56 (td,J = 16.0, 4.8 Hz, 1H), 2.27(dd, J =5.9, 2.1Hz, 1H). C 15 H 12 ESI MS [M+H] for F6N2O + , calculated value 351.3, measured value 351.1.

[0351] Example 80: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-[(1R)-3-(trifluoromethyl)cyclohexyl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol. [ka] The title compounds, rel-(1R,3S)-3-(trifluoromethyl)cyclohexanol and [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate, were prepared in a manner similar to that described for Example 53. 1 H NMR(400 MHz,CDCl3) δ 5.07 (dd, J =12.1, 4.8Hz, 1H),4.41 (td,J = 6.3, 3.2 Hz,1H), 3.56- 3.18(m, 2H),2.80 (ddq,J = 13.4, 9.2, 4.6Hz, 1H),2.44 - 2.25 (m, 2H),2.01 (ddd,J = 13.8, 8.7, 4.3Hz, 2H),1.89 (ddq,J = 13.1, 8.8, 4.6Hz, 2H),1.77 (ddd,J = 16.3, 8.8, 4.5Hz, 1H),1.66 (dtd,J = 12.6, 8.5, 3.7Hz, 1H). C 14 H 14 ESI MS [M+H] for F8N2O + , calculated value 379.3, measured value 379.1

[0352] Example 81: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-[(1S,3S)-3-(trifluoromethyl)cyclohexyl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared from rel-(1R,3S)-3-(trifluoromethyl)cyclohexanol and [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate in a manner similar to that described for Example 53. 1H NMR(400 MHz,chloroform-d) δ 5.07 (d, J =12.1 Hz,1H), 4.41(p, J =5.7 Hz,1H), 3.43(ddd, J =16.6, 15.1,10.2 Hz,1H), 3.30(ddd, J =16.5, 15.6,4.6 Hz,1H), 2.75(ddp, J =13.8, 9.5,4.7 Hz,1H), 2.31(dt, J =14.3, 5.8Hz, 1H),2.04 (dddd,J = 18.7, 13.9, 9.5,5.5 Hz,2H), 1.89(ddt, J =13.4, 8.1,4.3Hz,2H), 1.73(dddd, J =41.8, 17.0,8.8, 4.4Hz, 2H). C 14 H 14 ESI MS [M+H] for F8N2O + , calculated value 379.3, measured value 379.1

[0353] Example 82: (4S)-5,5-Difluoro-3-(trifluoromethyl)-1-[(1R,3S)-3-(trifluoromethyl)cyclohexyl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared from 3-(trifluoromethyl)cyclohexanol and [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate in a manner similar to that described for Example 53. 1H NMR(400 MHz,chloroform-d) δ 5.06 (dd, J =12.0, 5.6Hz, 1H),4.13 (tt,J = 12.3, 3.8 Hz,1H), 3.45(ddd, J =16.6, 15.1,10.2 Hz,1H), 3.32(ddd, J =16.5, 15.5,4.7 Hz,1H), 2.34(dd, J =5.6, 2.1Hz, 1H),2.23 (dtt,J = 11.6, 7.3, 3.7Hz, 1H),2.17 - 1.97 (m, 3H),1.97 - 1.72 (m, 2H),1.46 (dt,J = 13.0, 3.2 Hz,1H), 1.38(td, J =12.7, 12.0,2.9 Hz,1H). C 14 H 14 ESI MS [M+H] for F8N2O + , calculated value 379.3, measured value 379.1

[0354] Example 83: (2S)-4-[(4S,5R)-5-fluoro-4-hydroxy-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-1-yl]-2-methylbutanenitrile. [ka] The title compound was prepared from [(4S,5R)-5-fluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-yl]benzoate in a manner similar to that described for Example 3. 1H NMR(400 MHz,chloroform-d) δ 5.46 (ddt, J =50.7, 6.3,4.6 Hz,1H), 5.27- 5.06(m, 1H),4.37 - 4.09 (m, 2H),3.36 - 3.00 (m, 2H),2.57 (dddd,J = 14.2, 12.1, 6.1,3.6 Hz,1H), 2.40(td, J =6.3, 3.9Hz, 1H),2.31 (dtdd,J = 14.7, 9.5, 6.7,5.2 Hz,1H), 2.19- 1.99(m, 1H),1.37 (d,J = 7.1Hz, 3H). C 12 H 13 ESI MS [M+H] for F4N3O + , calculated value 292.3, measured value 292.1.

[0355] Example 84: 3-{[(4S,5R)-5-fluoro-4-hydroxy-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-1-yl]methyl}-1λ 6 -Thietane-1,1-dione. [ka] The title compound was prepared in a similar manner as in Example 62 from [(4S,5R)-5-fluoro-1-(oxan-2-yl)-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-yl]benzoate. 1 H NMR(400 MHz,CDCl3) δ 5.47 (dq, J =50.6, 5.1Hz, 1H),5.18 (q,J = 5.9 Hz, 1H),4.36 - 4.20 (m, 4H),3.92 - 3.81 (m, 2H),3.26 - 3.04 (m, 3H),2.35 (dd,J = 6.5, 4.0 Hz,1H). C 11 H 12 ESIMS [M+H] for F4N2O3S + , calculated value 329.3, measured value 329.1.

[0356] Example 85: (4S)-1-(5,5-difluorooxan-3-yl)-5,5-difluoro-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol. [ka] Step a: To a solution of [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate (250 mg, 0.75 mmol) in CHCN (2.5 mL) was added 2H-pyran-3(6H)-one (110 mg, 1.12 mmol) and T3P (propanephosphonic anhydride, 360 mg, 1.12 mmol). The resulting mixture was stirred for 30 minutes. o The mixture was heated to RT for 12 h. After cooling to room temperature, the reaction was carefully quenched with aqueous NaHCO (10.0 mL) and diluted with dichloromethane (10.0 mL). The organic phase was separated, and the aqueous layer was further extracted with dichloromethane (2 × 5.0 mL). The combined organic phases were dried over NaSO and concentrated to dryness under reduced pressure to give the corresponding ketone compound. The crude residue was purified by flash column chromatography (silica gel, hexane / EtOAc gradient) to give the product (199 mg, 61%).

[0357] Step b: To a solution of the ketone from step a (128 mg, 0.30 mmol) in dichloromethane (2.0 mL), XtalFluor-E (N,N-diethyl-(S,S)-difluorosulfiliminium tetrafluoroborate, 133 mg, 0.60 mmol) and 3HF.TEA (98 mg, 0.60 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with EtOAc (10.0 mL) and washed with saturated aqueous NaHCO (10.0 mL). The organic phase was separated, and the aqueous layer was further extracted with EtOAc (2 × 5.0 mL). The combined organic extracts were dried over NaSO and concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (silica gel, hexane / EtOAc gradient) to afford the title compound (46 mg, 2.9 mmol, 34%) as a colorless oil.

[0358] Step c: To a solution of the alkylated product of step b (25.0 mg, 0.055 mmol) in MeOH (2.0 mL) and THF (1.0 mL) was added 1 M aqueous NaOH (0.6 mL, 0.55 mmol) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (10.0 mL). The combined organic phases were dried over Na2SO4 and concentrated to dryness, and the crude product was purified by column chromatography (silica gel, hexane / EtOAc gradient) to afford the title compound (8.1 mg, 0.023 mmol, 42% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 5.07 (dd, J =11.9, 5.5Hz, 1H),4.47 (td,J = 10.1, 4.9 Hz,1H), 4.07(d, J =11.8 Hz,1H), 3.98(ddt, J =12.8, 9.7,3.3 Hz,1H), 3.79(q, J =10.2 Hz,1H), 3.70- 3.56(m, 1H),3.53 - 3.25 (m, 2H),2.89 - 2.54 (m, 2H),2.53 - 2.24 (m, 1H). C 11 H 12 ESI MS [M+H] for F4N2O3S + , calculated value 349.3, measured value 349.1.

[0359] Example 86: 3-[(4S)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-1-yl]-1λ 6 -thiane-1,1-dione. [ka] Step a: To a solution of [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate (160 mg, 0.48 mmol) and 2H-thiopyran-3-ol, tetrahydro-1,1-dioxide (145 mg, 0.96 mmol) in 1,4-dioxane (1.0 mL), cyanomethylenetrimethylphosphorane (CMMP) (1.9 mL, 1 mol / L) was added. The resulting mixture was stirred for 50 minutes. o The mixture was heated to RT for 12 h. After cooling to room temperature, the reaction was carefully quenched with aqueous NaHCO (10.0 mL) and diluted with dichloromethane (10.0 mL). The organic phase was separated, and the aqueous layer was further extracted with dichloromethane (2 × 5.0 mL). The combined organic phases were dried over NaSO and concentrated to dryness under reduced pressure to give the corresponding ketone compound. The crude residue was purified by flash column chromatography (silica gel, DCM / MeOH gradient) to give the product (42 mg, 19%).

[0360] Step b: To a solution of the alkylated product of step b (42.0 mg, 0.09 mmol) in MeOH (2.0 mL) and THF (1.0 mL) was added 1 M aqueous NaOH (0.5 mL, 0.45 mmol) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (15.0 mL). The combined organic phases were dried over Na2SO4 and concentrated to dryness, and the crude product was purified by column chromatography (silica gel, DCM / MeOH gradient) to afford the title compound (12.6 mg, 0.035 mmol, 38% yield) as a colorless oil. 1H NMR(400 MHz,chloroform-d) δ 5.07 (dt, J =11.9, 4.7Hz, 1H),4.58 (ddt,J = 11.9, 8.2, 3.2Hz, 1H),3.63 (ddd,J = 13.7, 12.0, 6.9Hz, 1H),3.49 - 3.23 (m, 3H),3.21 - 3.05 (m, 1H),3.00 (ddd,J = 14.8, 12.3, 4.2Hz, 1H),2.63 (d,J = 5.4 Hz, 1H),2.31 - 2.07 (m, 4H). C 12 H 13 ESI MS [M+H] for F5N2O3S + , calculated value 361.3, measured value 361.1.

[0361] Example 87: (4S)-1-[(3S)-5,5-difluorooxan-3-yl]-5,5-difluoro-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol. [ka] The starting material was prepared according to the protocol described in the synthesis of Example 85.

[0362] Step a: To a solution of the ketone (133 mg, 0.31 mmol) in dichloromethane (2.0 mL) was added Deoxo-Fluor (342 mg, 1.54 mmol), and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with dichloromethane (10.0 mL) and washed with saturated aqueous NaHCO3 (10.0 mL). The organic phase was separated, and the aqueous layer was further extracted with dichloromethane (2 × 5.0 mL). The combined organic extracts were dried over Na2SO4 and concentrated to dryness under reduced pressure. To a solution of the crude product, mCPBA (54 mg, 0.31 mmol) was added. The resulting solution was diluted with dichloromethane (10.0 mL) and washed with saturated aqueous NaHCO3 (10.0 mL). The organic phase was separated, and the aqueous layer was further extracted with dichloromethane (2 × 5.0 mL). The combined organic extracts were dried over Na2SO4 and concentrated to dryness under reduced pressure. The crude product was used in the next step without purification.

[0363] Step b: To a solution of the alkylated product of step b in MeOH (4.0 mL) and THF (2.0 mL) was added 1 M aqueous NaOH (1.5 mL, 1.5 mmol) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (15.0 mL). The combined organic phases were dried over Na2SO4 and concentrated to dryness, and the crude product was purified by column chromatography (silica gel, hexane / EtOAc gradient) to afford the title compound (2.1 mg, 0.006 mmol, 11% yield) as a colorless oil. 1HNMR (400MHz, CDCl3)δ 5.07(d, J =12.0 Hz,1H), 4.47(tt, J =10.0, 4.7Hz, 1H),4.07 (d,J = 12.3 Hz, 1H),3.98 (ddt,J = 12.8, 10.0, 3.1Hz, 1H),3.87 - 3.72 (m, 1H),3.63 (ddd,J = 27.0, 12.3, 2.2Hz, 1H),3.45 (td,J = 16.0, 9.9 Hz,1H), 3.34(td, J =16.1, 4.4Hz, 1H),2.86 - 2.67 (m, 1H),2.67 - 2.56 (m, 1H),2.42 (dd,J = 14.4, 4.6 Hz,2H). C 11 H 12 ESI MS [M+H] for F4N2O3S + , calculated value 349.3, measured value 349.1.

[0364] Example 88: (4S)-5,5-difluoro-1-[(3R,5S)-3,4,5-trifluorocyclohexyl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The (4S)-5,5-difluoro-3-(trifluoromethyl)-1-(3,4,5-trifluorophenyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol starting material was prepared similarly to Example 114. This substrate (0.23 g, 0.64 mmol, 1 equiv.) was dissolved in dichloromethane (1.5 mL, 0.4 M) in a stainless steel Parr autoclave lined with a Teflon insert and equipped with a mechanical stirrer. Silica gel (0.29 g, oven-dried at 180 °C) was added, followed by (CyCAAC)Rh(COD)Cl (7 mg, 0.013 mmol, 0.02 equiv.). The autoclave was pressurized with 500 psi H2, evacuated three times, and then pressurized to 1100 psi H2. The reaction mixture was stirred under 1100 psi of H at approximately 300 rpm for 18 h, at which point the pressure was reduced and the reaction mixture was filtered through Celite. The filtrate was concentrated directly in vacuo, and the crude residue was purified by column chromatography (SiO, hexane / EtOAc gradient) to give the product (4 mg, 2% yield, dr = 2:1 in favor of the desired product) in a mixture containing an unknown diastereomer in the cyclohexane moiety. 1 H NMR(400 MHz,CDCl3) δ 5.34 - 5.12(m, 1H),5.10 - 5.01 (m, 1H),4.78 - 4.41 (m, 2H),4.30 - 4.18 (m, 1H),3.56 - 3.40 (m, 1H),3.36 (ddd,J = 16.5, 15.4, 4.4Hz, 1H),2.56 - 2.20 (m, 4H),2.10 - 1.94 (m, 1H). 19 FNMR (376MHz, CDCl3, major epimer) δ -61.86, -95.32 (d,J = 235.1 Hz), -101.78(d, J =234.0 Hz), -193.04 (d,J = 14.7 Hz), -218.28(d, J =14.7 Hz). C 13 H 12 ESI MS [M+H] for F8N2O + , calculated value 365.1, measured value 365.1.

[0365] Example 89: (4S)-1-[(3R,5S)-3,5-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol [ka] The title compound was prepared from the corresponding aromatic compound in a manner similar to that described for Example 88. 1 H NMR(400 MHz,CDCl3) δ 5.07 (dd, J =12.0, 5.3Hz, 1H),4.76 - 4.45 (m, 2H),4.18 - 4.04 (m, 1H),3.45 (ddd,J = 16.5, 15.2, 10.1Hz, 1H),3.32 (ddd,J = 16.5, 15.5, 4.5Hz, 1H),2.85 - 2.68 (m, 1H),2.61 - 2.49 (m, 2H),2.45 (dd,J = 5.6, 2.0 Hz,1H), 2.20- 1.98(m, 2H),1.91 - 1.73 (m, 1H). 19 FNMR (376MHz, CDCl3)δ -61.8,-95.27 (d,J = 235.1 Hz), -101.73(d, J =235.1 Hz),-179.19. C 13 H 13 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.2.

[0366] Examples 90a and 90b, and Examples 91a and 91b: (4S)-1-[(rel-1S,3S,4R)-3,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-5,5-difluoro-1-[(rel-1S,3R)-3-fluorocyclohexyl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The (4S)-1-(3,4-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol starting material was prepared similarly to Example 114. This substrate (125 mg, 0.37 mmol, 1 equiv.) was dissolved in dichloromethane (1.5 mL, 0.25 M) in a stainless steel Parr autoclave lined with a Teflon insert and equipped with a mechanical stirrer. Silica gel (165 mg, oven-dried at 180 °C) was added, followed by (CyCAAC)Rh(COD)Cl (4.2 mg, 0.0073 mmol, 0.02 equiv.). The autoclave was pressurized with 500 psi H2, evacuated three times, and then pressurized to 1100 psi H2. The reaction mixture was stirred under 1100 psi of H at approximately 300 rpm for 18 h, at which point the pressure was reduced and the reaction mixture was filtered through Celite. The filtrate was concentrated directly in vacuo, and the crude residue was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford both products separately as diastereomeric mixtures.

[0367] First eluting isomer (2) (Example 90a / b, DIAST-1): (4S)-5,5-difluoro-1-[(rel-1S,3R)-3-fluorocyclohexyl]-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol (4 mg, 0.012 mmol, 3% yield, colorless oil): 1 H NMR(400 MHz,CDCl3) δ 5.06 (dd, J =12.1, 5.6Hz, 1H),4.79 - 4.38 (m, 1H),4.32 - 3.97 (m, 1H),3.45 (dddd,J = 17.2, 15.3, 10.2,2.1 Hz,1H), 3.32(td, J =16.0, 4.7Hz, 1H),2.65 - 2.47 (m, 1H),2.39 (dd,J = 5.6, 2.0 Hz,1H), 2.27- 2.16(m, 1H),2.12 - 1.88 (m, 3H),1.79 - 1.63 (m, 1H),1.55 - 1.29 (m, 2H). 19FNMR (376MHz, CDCl3)δ -61.68,-95.29 (d,J = 234 Hz), -101.86(d, J =234 Hz),-171.00 (d,J = 10.5 Hz). C 13 H 14 ESI MS [M+H] for F6N2O + , calculated value 329.1, measured value 329.0.

[0368] Second eluting isomer (2) (Example 91a / b, DIAST-2): (4S)-1-[(rel-1S,3S,4R)-3,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol (4 mg, 0.012 mmol, 3% yield, colorless oil). 1 H NMR(400 MHz,CDCl3) δ 5.12 - 4.90(m, 2H),4.79 - 4.41 (m, 1H),4.28 (br.s, 1H),3.56 - 3.28 (m, 2H),2.47 - 2.25 (m, 3H),2.21 - 1.90 (m, 2H),1.75 - 1.47 (m, 1H). 19 FNMR (376MHz, CDCl3)δ -61.75,-95.35 (dd,J = 235.1, 20.3 Hz),-101.89 (dd,J = 235.1, 13.0 Hz),-178.12 - -189.21 (m), -199.90- ​​-207.17(m). C 13 H 13 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.1.

[0369] Examples 92 and 93: (4S)-5,5-difluoro-3-(trifluoromethyl)-1-[(2R,4R)-2-(trifluoromethyl)oxan-4-yl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-5,5-difluoro-3-(trifluoromethyl)-1-[(2S,4S)-2-(trifluoromethyl)oxan-4-yl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] Step a: A solution of 2-(trifluoromethyl)oxan-4-one (1.0 g, 5.9 mmol, 1 equiv.) in dry methanol (15 mL, 0.4 M) was placed in a 50 mL round-bottom flask equipped with a magnetic stir bar. The reaction mixture was cooled to 0 °C, and NaBH (0.27 g, 7.1 mmol, 1.2 equiv.) was added in one portion. The reaction was stirred at 0 °C for 1 h. When TLC analysis indicated complete disappearance of the initial ketone, the reaction was diluted with EtOAc (50 mL) and carefully quenched with 1 M aqueous hydrochloric acid (20 mL). The organic phase was separated, and the aqueous layer was further extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over NaSO, and the solvent was evaporated under reduced pressure. The dry residue was fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to give 2-(trifluoromethyl)oxan-4-ol as a single syn-diastereomer (0.73 g, 4.3 mmol, 72% yield).

[0370] Step b: A mixture of [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate (104.0 mg, 0.31 mmol, 1 equiv.), racemic syn-2-(trifluoromethyl)oxan-4-ol (64.0 mg, 0.38 mmol, 1.2 equiv.), and PPh3 (100.0 mg, 0.38 mmol, 1.2 equiv.) in THF (1.5 mL, 0.2 M) was placed in a 2-dram vial equipped with a magnetic stir bar. The mixture was cooled to 0 °C under a N2 atmosphere, and DIAD (75 μL, 0.38 mmol, 1.2 equiv.) was added. The resulting solution was warmed to ambient temperature and stirred overnight. The solution was concentrated to dryness under reduced pressure and directly fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to afford the desired coupling product (111.0 mg, 0.23 mmol, 74% yield) as a mixture of two diastereomers.

[0371] Step c: To a solution of the epimeric mixture from step b (111.0 mg, 0.23 mmol, 1 equiv) in MeOH (4.6 mL, 0.05 M) was added 1 M aqueous NaOH (1.2 mL, 1.2 mmol, 5 equiv) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (25.0 mL) and 1 M aqueous NaOH (25.0 mL). The organic phase was separated and washed again with 1 M aqueous NaOH (2 × 15.0 mL) and brine (15.0 mL) to remove residual benzoic acid. The combined organic phases were dried over NaSO, concentrated to dryness, and the crude products were purified by column chromatography (SiO, hexane / EtOAc gradient) to afford (4S)-5,5-difluoro-3-(trifluoromethyl)-1-[(2R,4R)-2-(trifluoromethyl)oxan-4-yl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-5,5-difluoro-3-(trifluoromethyl)-1-[2-(trifluoromethyl)oxan-4-yl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol separately.

[0372] First elution isomer (DIAST-1, 35 mg, 0.092 mmol, yield 40%): 1 H NMR (400 MHz, CDCl3) δ 5.07 (dd, J = 12.0, 5.5 Hz, 1H), 4.65 - 4.55 (m, 1H), 4.58 - 4.43 (m, 1H), 4.19 - 4.05 (m, 1H), 4.05 - 3.87 (m, 1H), 3.43 (ddd, J = 16.5, 15.3, 10.1 Hz, 1H), 3.29 (td, J = 16.0, 4.4 Hz, 1H), 2.54 (dd, J = 5.6, 2.0 Hz, 1H), 2.33 - 2.13 (m, 4H), 2.10 - 1.96 (m, 1H). 19 FNMR (376 MHz, CDCl3) δ -61.75, -77.47, -95.34 (d, J = 234.5 Hz), -101.73 (d, J = 235.1 Hz). C 13 H 12 ESIMS [M+H] for F8N2O2 + , calculated value 381.1, measured value 381.1.

[0373] Second elution isomer (DIAST-2, 32 mg, 0.084 mmol, yield 37%): 1 H NMR (400 MHz, CDCl3) δ 5.08 (dd, J = 12.0, 5.4 Hz, 1H), 4.77 - 4.45 (m, 2H), 4.19 - 3.86 (m, 2H), 3.54 - 3.21 (m, 2H), 2.49 (dd, J = 5.5, 2.0 Hz, 1H), 2.38 - 2.26 (m, 1H), 2.27 - 2.12 (m, 2H), 2.06 - 1.94 (m, 1H). 19 FNMR (376 MHz, CDCl3) δ -61.74, -77.52, -95.39 (d, J = 235.0 Hz), -101.66 (d, J = 234.6 Hz). C 13 H 12 ESIMS [M+H] for F8N2O2 + , calculated value 381.1, measured value 381.2.

[0374] Examples 94 and 95: (4S)-5,5-difluoro-3-(trifluoromethyl)-1-[(2R,4S)-2-(trifluoromethyl)oxan-4-yl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-5,5-difluoro-3-(trifluoromethyl)-1-[(2S,4R)-2-(trifluoromethyl)oxan-4-yl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] Step a: Carried out according to the protocol of Example 92.

[0375] Step b: A mixture of racemic syn-2-(trifluoromethyl)oxan-4-ol (0.67 mg, 3.94 mmol, 1.0 equiv.), benzoic acid (0.58 g, 4.73 mmol, 1.2 equiv.), and PPh3 (1.24 g, 4.73 mmol, 1.2 equiv.) in THF (20.0 mL, 0.2 M) was placed in a 100 mL round-bottom flask equipped with a magnetic stir bar. The mixture was cooled to 0 °C under a N2 atmosphere, and DIAD (0.93 mL, 4.73 mmol, 1.2 equiv.) was added dropwise over 10 min to maintain the reaction temperature below +10 °C. The resulting solution was warmed to ambient temperature and stirred for 2 h. The solution was concentrated to dryness under reduced pressure and directly fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to afford the desired coupling product (1.02 g, 0.23 mmol, 3.72 mmol, 94% yield) as a yellowish oil.

[0376] Step c: To a solution of the benzoate from step b (1.02 g, 3.72 mmol, 1 equiv) in MeOH (25.0 mL, 0.15 M) was added 1 M aqueous NaOH (18.0 mL, 18.0 mmol, 5 equiv) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction mixture was concentrated to 20 mL under reduced pressure and diluted with EtOAc (50 mL). The organic phase was separated and washed again with 1 M aqueous NaOH (2 × 20.0 mL) and brine (20.0 mL) to remove residual benzoic acid. The combined organic phases were dried over NaSO and concentrated to dryness, and the crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the desired alcohol (0.5 g, 2.94 mmol, 79% yield) as a colorless liquid.

[0377] Step d: A mixture of [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate (200.0 mg, 0.6 mmol, 1 equiv.), racemic anti-2-(trifluoromethyl)oxan-4-ol (100.0 mg, 0.72 mmol, 1.2 equiv.), and PPh3 (190.0 mg, 0.72 mmol, 1.2 equiv.) in THF (3.0 mL, 0.2 M) was placed in a 2-dram vial equipped with a magnetic stir bar. The mixture was cooled to 0 °C under a N2 atmosphere, and DIAD (140 μL, 0.72 mmol, 1.2 equiv.) was added. The resulting solution was warmed to ambient temperature and stirred for 4 h. The solution was concentrated to dryness under reduced pressure and directly fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to afford the desired alkylated product as a mixture of two diastereomers (80 mg, 0.17 mmol, 27% yield) as a white solid.

[0378] Step e: To a solution of the epimeric mixture from step d (80.0 mg, 0.17 mmol, 1 equiv) in MeOH (3.3 mL, 0.05 M) was added 1 M aqueous NaOH (0.8 mL, 1.2 mmol, 5 equiv) at ambient temperature. The resulting mixture was stirred for 1 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (20.0 mL) and 1 M aqueous NaOH (20.0 mL). The organic phase was separated and washed again with 1 M aqueous NaOH (2 × 10.0 mL) and brine (10.0 mL) to remove residual benzoic acid. The combined organic phases were dried over NaSO, concentrated to dryness, and the crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford (4S)-5,5-difluoro-3-(trifluoromethyl)-1-[(2R,4S)-2-(trifluoromethyl)oxan-4-yl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-5,5-difluoro-3-(trifluoromethyl)-1-[(2S,4R)-2-(trifluoromethyl)oxan-4-yl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol separately.

[0379] First eluting isomer (DIAST-1, 23 mg, 0.060 mmol, 36% yield): 1 H NMR(400 MHz,CDCl3) δ 5.06 (dd, J =12.0, 5.5Hz, 1H),4.50 - 4.34 (m, 1H),4.31 (ddd,J = 12.1, 4.9, 1.6Hz, 1H),3.96 - 3.81 (m, 1H),3.63 (td,J = 12.2, 2.4 Hz,1H), 3.47(ddd, J =16.6, 15.3,10.0 Hz,1H), 3.42- 3.27(m, 1H),2.59 - 2.46 (m, 1H),2.37 - 2.25 (m, 1H),2.27 - 2.11 (m, 1H),2.12 - 2.01 (m, 2H). 19 FNMR (376MHz, CDCl3)δ -61.79,-78.85, -95.34(d, J =235.3 Hz),-101.79 (d,J = 235.0 Hz). C13 H 12 ESIMS [M+H] for F8N2O2 + , calculated value 381.1, measured value 381.3.

[0380] Second eluting isomer (DIAST-2, 25 mg, 0.066 mmol, 40% yield): 1 H NMR(400 MHz,CDCl3) δ 5.06 (dd, J =12.1, 5.5Hz, 1H),4.50 - 4.33 (m, 1H),4.30 (ddd,J = 12.1, 4.9, 1.5Hz, 1H),3.87 (ddt,J = 11.8, 8.1, 4.1Hz, 1H),3.63 (td,J = 12.2, 2.3 Hz,1H), 3.47(td, J =15.9, 10.0Hz, 1H),3.34 (td,J = 16.0, 4.3 Hz,1H), 2.60(dd, J =5.5, 2.0Hz, 1H),2.38 - 2.25 (m, 1H),2.24 - 1.97 (m, 2H). C 13 H 12 ESI MS [M+H] for F8N2O2 + , calculated value 381.1, measured value 381.1.

[0381] Example 96: (4S)-5,5-Difluoro-1-(4-fluorocyclohexyl)-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared from cis-4-fluorocyclohexan-1-ol in a manner similar to that described for Example 1. 1H NMR(400 MHz,CDCl3) δ 5.05 (dd, J =12.1, 5.5Hz, 1H),4.87 - 4.37 (m, 1H),4.36 - 3.64 (m, 1H),3.43 (td,J = 16.0, 10.2 Hz,1H), 3.30(td, J =16.1, 4.5Hz, 1H),2.54 (dd,J = 5.7, 1.9 Hz,1H), 2.37- 2.20(m, 1H),2.20 - 2.08 (m, 1H),2.00 - 1.80 (m, 2H),1.76 - 1.57 (m, 2H). 19 FNMR (376MHz, CDCl3)δ -61.64,-95.36 (d,J = 234.8 Hz), -101.82(d, J =235.0 Hz),-174.69. C 13 H 14 ESI MS [M+H] for F6N2O + , calculated value 329.1, measured value 329.1.

[0382] Examples 97 and 98: (4S)-1-[(1R,2R,4R)-2,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-1-[(1S,2S,4S)-2,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared from cis-4-fluorocyclohexan-1-ol in a manner similar to that described for Example 1. The crude product was purified by column chromatography (SiO, hexane / EtOAc gradient, 0-30% over 30 min) to afford (4S)-1-[(1R,2R,4R)-2,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-1-[(1S,2S,4S)-2,4-difluorocyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol, separately.

[0383] First eluting isomer (DIAST-1): 1 H NMR(400 MHz,CDCl3) δ 5.05 (dd, J =12.2, 5.9Hz, 1H),4.88 - 4.46 (m, 2H),4.06 - 3.84 (m, 1H),3.45 (td,J = 16.2, 10.2 Hz,1H), 3.27(ddd, J =16.7, 15.7,4.3 Hz,1H), 2.91- 2.65(m, 1H),2.46 (dd,J = 6.1, 1.9 Hz,1H), 2.39- 2.26(m, 1H),2.23 - 2.11 (m, 2H),1.96 - 1.78 (m, 1H),1.78 - 1.56 (m, 1H). 19 FNMR (376MHz, CDCl3)δ -61.74,-95.22 (d,J = 234.7 Hz), -101.77(d, J =234.9 Hz),-176.39, -179.25. C 13 H 13 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.1.

[0384] Second eluting isomer (DIAST-2): 1H NMR(400 MHz,CDCl3) δ 5.09 (ddd, J =11.9, 5.7,1.4 Hz,1H), 4.87- 4.48(m, 2H),4.06 - 3.92 (m, 1H),3.56 - 3.24 (m, 2H),2.90 - 2.67 (m, 1H),2.51 (d,J = 6.2 Hz, 1H),2.39 - 2.25 (m, 1H),2.27 - 2.10 (m, 2H),1.97 - 1.79 (m, 1H),1.77 - 1.62 (m, 1H). 19FNMR (376MHz, CDCl3)δ -61.76,-95.17 (d,J = 234.1 Hz), -101.92(d, J =233.5 Hz),-176.41 (d,J = 4.1 Hz), -179.68(d, J =4.0 Hz). C 13 H 13 ESI MS [M+H] for F7NO + , calculated value 347.1, measured value 347.1.

[0385] Example 99: (2R)-4-[(4S)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-1-yl]-2-methylbutanenitrile. [ka] Step a: A mixture of α-methylene-γ-butyrolactone (10.0 g, 0.1 mol, 1 equiv.) and [RuCl((S)-BINAP)(p-cymene)]Cl (0.95 g, 1.0 mmol, 0.01 equiv.) in dichloromethane (20 mL, 5 M) was placed in a 100 mL round-bottom flask equipped with a stir bar, a nitrogen inlet needle immersed in the solution, and a nitrogen outlet needle above the solution. Nitrogen gas was bubbled through the solution for 20 min. The resulting homogeneous mixture was then transferred to a stainless steel autoclave and stirred under a hydrogen atmosphere (1500 psi) at ambient temperature for 48 h. Once the hydrogen gas was released from the autoclave, the material was directly fractionated by column chromatography (SiO2, CHCl2 / MTBE gradient) to afford the desired product (10.0 g, 0.1 mol, 100% yield). The enantioselectivity of the reduction (80% ee) was consistent with the diastereomeric mixture obtained during the coupling of the alcohol with the pyrazole moiety in step f. 1 Determined by 1 H NMR analysis.

[0386] Step b: The lactone from step a (10.0 g, 0.1 mol) was mixed with 7M NH3 in MeOH (100 mL) and stirred at ambient temperature for 48 h. 1 When H NMR analysis showed complete consumption of the starting material, the reaction was concentrated under reduced pressure, residual solvent and ammonia were removed by coevaporation with dichloromethane (2 × 100 mL), and the residue was dried in vacuo to give the desired primary amide (11.8 g, 0.1 mol, 97% yield) as a colorless waxy oil.

[0387] Step c: A solution of the primary amide from step b (1.0 g, 8.5 mmol, 1 equiv.) and imidazole (17.9 mmol) in dichloromethane (43.0 mL, 0.2 M) was cooled to 0 °C. TBSCl (1.35 g, 9.0 mmol, 1.05 equiv.) was then added, and the reaction was stirred at ambient temperature for 2 h. The resulting solution was diluted with dichloromethane (50 mL) and washed with water (2 × 100 mL). The organic extract was dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was used directly in the next step without purification.

[0388] Step d. The product of step c was dissolved in dichloromethane (43 mL, 0.2 M), triethylamine (5.9 mL, 42.5 mmol, 5 equiv.) was added, and the resulting solution was cooled to 0 °C. Trifluoroacetic anhydride (3.5 mL, 25.5 mmol, 3 equiv.) was added dropwise over 20 min, and the reaction mixture was stirred at 0 °C for an additional 20 min. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with dichloromethane (40 mL) and washed with 1 M aqueous HCl (2 × 70 mL), water (70 mL), and saturated aqueous NaHCO (2 × 70 mL). The organic extract was dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the desired nitrile (1.1 g, 5.2 mmol, 62% yield over two steps) as a colorless liquid.

[0389] Step e. To a solution of AcOH (8.7 mL, 0.152 mol, 2.05 equiv.) in THF (200 mL) cooled to 0 °C was added a solution of TBAF in THF (147 mL, 0.147 mol, 2.0 equiv., 1 M solution). The mixture was stirred at 0 °C for 5 min, and then the solution of TBS-ether (15.7 g, 7.4 mmol, 1 equiv.) from step d was added dropwise over 20 min. The resulting solution was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with water (2 × 200 mL), saturated aqueous NaHCO3 (2 × 150 mL), and brine (200 mL). The organic extract was dried over sodium sulfate and concentrated to dryness under reduced pressure. The liquid residue was fractionated by column chromatography (SiO2, hexane / EtOAc gradient) to give the desired alcohol (4.4 g, 0.044 mol, 60% yield) as a colorless liquid.

[0390] Step f. A mixture of [(4S)-5,5-difluoro-3-(trifluoromethyl)-1,4,6,7-tetrahydroindazol-4-yl]benzoate (300.0 mg, 0.87 mmol, 1 equiv.), the alcohol from step e (95.0 mg, 0.95 mmol, 1.1 equiv.), and PPh3 (250.0 mg, 0.95 mmol, 1.1 equiv.) in THF (4.5 mL, 0.2 M) was placed in a 2-dram vial equipped with a magnetic stir bar. The mixture was cooled to 0 °C under a N2 atmosphere, and DIAD (190 μL, 0.95 mmol, 1.1 equiv.) was added. The resulting solution was warmed to ambient temperature and stirred for 16 h. The solution was concentrated to dryness under reduced pressure and directly fractionated by column chromatography (SiO 2 , hexane / EtOAc gradient) to give the desired alkylated product (151 mg, 0.35 mmol, 41% yield) as a colorless oil.

[0391] Step g: To a solution of the product from step f (150.0 mg, 0.35 mmol, 1 equiv.) in THF (2.2 mL) and water (1.2 mL) at ambient temperature was added lithium hydroxide monohydrate (74 mg, 1.8 mmol, 5 equiv.). The resulting mixture was stirred for 2 h. When TLC analysis indicated complete consumption of the starting material, the reaction was diluted with EtOAc (20.0 mL) and 1 M aqueous NaOH (20.0 mL). The organic phase was separated and washed again with 1 M aqueous NaOH (2 × 10.0 mL) and brine (10.0 mL) to remove residual benzoic acid. The combined organic phases were dried over NaSO and concentrated to dryness, and the crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford the title compound (94 mg, 0.29 mmol, 83% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3) δ 5.01 - 4.68(m, 1H),4.45 - 4.05 (m, 2H),2.98 (ddd,J = 16.5, 6.8, 2.3Hz, 1H),2.93 - 2.72 (m, 2H),2.72 - 2.42 (m, 2H),2.38 - 2.21 (m, 2H),2.16 - 2.02 (m, 1H),1.37 (d,J = 7.1 Hz, 3H). C 13 H14 ESI MS [M+H] for F5N3O + , calculated value 324.1, measured value 324.3.

[0392] Example 100: (2S)-4-[(4S)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-1-yl]-2-methylbutanenitrile. [ka] The title compound was prepared in a similar manner as described for Example 99 using [RuCl((R)-BINAP)(p-cymene)]Cl for the reduction of α-methylene-γ-butyrolactone. 1 H NMR(400 MHz,CDCl3) δ 4.94 - 4.79(m, 1H),4.27 - 4.09 (m, 2H),2.97 - 2.80 (m, 3H),2.69 - 2.41 (m, 2H),2.36 - 2.21 (m, 2H),2.15 - 2.00 (m, 1H),1.37 (d,J = 7.1 Hz, 3H). C 13 H 14 ESI MS [M+H] for F5N3O + , calculated value 324.1, measured value 324.1.

[0393] Example 101: (4S)-1-[(3R)-3-ethoxy-4,4,4-trifluorobutyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared following the protocol described for Example 61, using iodoethane in step d. 1H NMR(400 MHz,CDCl3) δ 5.08 (dd, J =11.9, 5.7Hz, 1H),4.33 - 4.15 (m, 2H),3.92 - 3.77 (m, 1H),3.67 (dtd,J = 12.8, 6.2, 3.1Hz, 1H),3.57 (dq,J = 9.1, 7.0 Hz,1H), 3.48- 3.22(m, 2H),2.47 - 2.37 (m, 1H),2.27 (dtd,J = 15.2, 7.6, 3.4Hz, 1H),2.19 - 2.07 (m, 1H),1.22 (t,J = 7.0 Hz, 3H). C 13 H 14 ESI MS [M+H] for F8N2O2 + , calculated value 383.1, measured value 383.1.

[0394] Example 102: (4S)-1-[3-(difluoromethoxymethyl)cyclobutyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] Step a: TBDPSCl (12.0 mL, 46.1 mmol) was added to a solution of cis-methyl-3-hydroxycyclobutane-1-carboxylate (5.0 g, 38.4 mmol) and imidazole (6.0 g, 88.4 mmol) in DMF (38 mL) at 0 °C. After 5 min, the reaction was warmed to room temperature and stirred for 1 h. Upon completion, the reaction was diluted with CHCl (40.0 mL) and washed with water (3 × 15.0 mL), saturated aqueous NaHCO (30.0 mL), and brine (30.0 mL). The organic solution was dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The crude residue was used in the next step without further purification.

[0395] Step b: The product from step a (17.0 g) was dissolved in THF (168 mL) and the solution was cooled to 0 °C. LiAlH (2.0 M in THF, 18.4 mL, 36.9 mmol) was added dropwise and the reaction was stirred at room temperature for 15 minutes. The reaction mixture was cooled to 0 °C and quenched with water (10 mL). 1 M NaOH (35 mL) was added and the reaction mixture was stirred at room temperature for 15 minutes. MgSO was added and the reaction mixture was stirred at room temperature for an additional 15 minutes. The reaction mixture was then filtered through Celite and concentrated to dryness under reduced pressure. The crude residue was used in the next step without further purification.

[0396] Step c: TMSCFBr (3.40 mL, 22.0 mmol) and KOAc (2.16 g, 22.0 mmol) were added to a solution of the alcohol from step b (1.50 g) in CHCl (2.20 mL) and water (2.20 mL). The reaction was stirred at 23 °C for 16 h. It was then diluted with CHCl (5.0 mL) and washed with water (2 × 8 mL). The combined organic phases were dried over NaSO and concentrated, and the crude residue was used in the next step without further purification.

[0397] Step d: TBAF (6.20 mL, 6.20 mmol, 1 M in THF) was added to a solution of the product from step c in THF (22.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 30 min. Upon completion, the mixture was partitioned between EtO and water. The organic layer was washed with water (3 × 30.0 mL) and brine (30.0 mL), dried over MgSO, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO, EtOAc in hexanes, 0–60%) to afford the alcohol (0.45 g, 2.96 mmol, 67% yield over two steps) as a colorless oil.

[0398] The title compound was prepared in a similar manner as described for Example 53 in two additional steps. 1H NMR(400 MHz,CDCl3) δ 6.24 (t, J =74.6 Hz,1H), 5.04(dd, J =12.1, 5.7Hz, 1H),4.78 - 4.46 (m, 1H),3.91 (d,J = 4.7 Hz, 2H),3.53 - 3.22 (m, 2H),2.71 - 2.55 (m, 2H),2.55 - 2.30 (m, 4H). C 13 H 13 ESI MS [M+H] for F7N2O2 + , calculated value 363.1, measured value 363.1.

[0399] Example 103: (4S)-1-[3-(difluoromethoxymethyl)cyclobutyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] The title compound was prepared in a manner similar to Example 102 using trans-methyl 3-hydroxycyclobutanecarboxylate. 1 H NMR(400 MHz,CDCl3) δ 6.24 (t, J =74.6 Hz,1H), 5.04(dd, J =12.1, 5.7Hz, 1H),4.71 - 4.48 (m, 1H),3.91 (d,J = 4.7 Hz, 2H),3.61 - 3.18 (m, 2H),2.75 - 2.53 (m, 2H),2.53 - 2.28 (m, 4H). C 13 H 13 ESI MS [M+H] for F7N2O2 + , calculated value 363.1, measured value 363.1.

[0400] Example 104: (4S)-1-[3-(difluoromethoxymethyl)cyclobutyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a manner similar to Example 102 using [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate. 1 H NMR(400 MHz,CDCl3) δ 6.28 (t, J =74.6 Hz,1H), 4.88(q, J =5.7 Hz,1H), 4.70(p, J =7.7 Hz,1H), 3.97(d, J =5.5 Hz,2H), 3.01- 2.66(m, 5H),2.63 - 2.44 (m, 2H),2.43 - 2.31 (m, 2H),2.31 - 2.17 (m, 1H). C 14 H 15 ESI MS [M+H] for F7N2O2 + , calculated value 377.1, measured value 377.1.

[0401] Example 105: (4S)-1-[3-(difluoromethoxymethyl)cyclobutyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indazol-4-ol. [ka] The title compound was prepared in a manner similar to Example 102 using trans-methyl 3-hydroxycyclobutanecarboxylate and [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate. 1 H NMR(400 MHz,CDCl3) δ 6.24 (t, J =74.5 Hz,1H), 5.05(dd, J =12.0, 5.6Hz, 1H),4.68 - 4.52 (m, 1H),3.91 (d,J = 4.7 Hz, 2H),3.61 - 3.18 (m, 2H),2.60 (dddd,J = 11.3, 8.0, 5.3,2.9 Hz,2H), 2.44(dddd, J =15.5, 13.6,11.9, 7.5Hz, 4H). C 14 H 15 ESI MS [M+H] for F7N2O2+ , calculated value 377.1, measured value 377.1.

[0402] Example 106: (4S)-1-[3-[(1S)-1-(difluoromethoxy)ethyl]cyclobutyl]-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] Step a: Using steps a and b from the synthesis of Example 102, [3-[tert-butyl(diphenyl)silyl]oxycyclobutyl]methanol was prepared. [3-[tert-butyl(diphenyl)silyl]oxycyclobutyl]methanol (2.0 g, 5.87 mmol) was dissolved in CHCl (30.0 mL) and NaHCO (0.54 g, 6.46 mmol) was added, followed by DMP (2.80 g, 6.46 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaSO (20 mL) and saturated aqueous NaHCO (20 mL) and extracted with CHCl (2 × 20 mL). The combined organics were dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, EtOAc in hexane, 0-25%) to give the alcohol (1.10 g, 3.25 mmol, 55% yield) as a colorless oil.

[0403] Step b: Methylmagnesium bromide (0.70 mL, 2.11 mmol, 3.0 M in diethyl ether) was added to a solution of the aldehyde from step a (0.55 g, 1.62 mmol) in diethyl ether (8.10 mL) at 0 °C. The resulting solution was stirred at 0 °C for 10 min. Upon completion by TLC analysis, the reaction was quenched with saturated aqueous NH4Cl (4.0 mL) and diluted with EtOAc (10.0 mL). The layers were separated, and the organic phase was washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The crude residue was used in the next step without further purification.

[0404] Step c: TMSCFBr (1.30 mL, 8.10 mmol) and KOAc (0.80 g, 8.10 mmol) were added to a solution of the alcohol from step b (0.59 g) in CHCl (0.80 mL) and water (0.80 mL). The reaction was stirred at 23 °C for 16 h. It was then diluted with CHCl (5 mL) and washed with water (2 × 3 mL). The combined organic phases were dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO, EtOAc in hexane, 0–30%) to afford the ether (0.48 g, 1.19 mmol, 74% yield over two steps) as a colorless oil.

[0405] Step d: TBAF (1.70 mL, 1.67 mmol, 1 M in THF) was added to a solution of the product from step c (0.48 g, 1.19 mmol) in THF (6.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 30 min. Upon completion, the mixture was partitioned between EtO and water. The organic layer was washed with water (3 × 10.0 mL) and brine (10.0 mL), dried over MgSO, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO, 0–60% EtOAc in hexanes) to afford the alcohol (0.16 g, 0.96 mmol, 81% yield) as a colorless oil.

[0406] The title compound was prepared in a similar manner as described for Example 53 in two additional steps. 1 H NMR(400 MHz,CDCl3) δ 6.31 (t, J =75.0 Hz,1H), 5.06(dd, J =12.0, 5.7Hz, 1H),4.68 (tt,J = 8.3, 7.0 Hz,1H), 4.46- 4.27(m, 1H),3.53 - 3.13 (m, 2H),2.86 - 2.64 (m, 2H),2.64 - 2.49 (m, 2H),2.48 - 2.32 (m, 2H),1.27 (d,J = 6.3 Hz, 3H). C 14 H 15 ESI MS [M+H] for F7N2O2 +, calculated value 377.1, measured value 377.1.

[0407] Examples 107a and 107b: (4S)-5,5-difluoro-3-methylsulfonyl-1-[(3R)-4,4,4-trifluoro-3-methoxybutyl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol and (4S)-5,5-difluoro-3-methylsulfonyl-1-[(3S)-4,4,4-trifluoro-3-methoxybutyl]-4,6-dihydrocyclopenta[c]pyrazol-4-ol. [ka] Step a: To a solution of 5-fluoro-1-[(4-methoxyphenyl)methyl]-5,6-dihydrocyclopenta[c]pyrazol-4-one (6.07 g, 23.3 mmol) and EtN (19.4 mL, 0.14 mol) in dichloromethane (117.0 mL), TBSOTf (21.5 mL, 93.3 mmol) was added dropwise at 0 °C. The resulting solution was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure to give the crude silyl enol ether. This material was dissolved in acetonitrile (117.0 mL), and Selectfluor (16.5 g, 46.6 mmol) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was diluted with EtOAc (150.0 mL) and washed with water (2 × 100 mL) followed by brine (100 mL). The organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (SiO2, EtOAc in hexane, 0–60%) to give the corresponding α,α-difluoroketone compound (4.31 g, 15.5 mmol, 66% yield).

[0408] Step b: To a solution of the α,α-difluoroketone from step a (4.86 g, 17.5 mmol) in dichloromethane (88.0 mL) was added formic acid (4.0 mL, 0.105 mol) and triethylamine (9.70 mL, 69.9 mmol). oThe mixture was cooled to +4 °C, and RuCl(p-cymene) [(R,R)-TsDPEN] (0.45 g, 0.67 mmol) was added in one portion. The resulting mixture was maintained at +4 °C overnight. When TLC analysis showed complete disappearance of the starting material, the mixture was diluted with dichloromethane (30.0 mL), washed with saturated aqueous NaHCO (40.0 mL), dried over NaSO, and concentrated to dryness under reduced pressure to give the crude α,α-difluorohydrin. The crude product was purified by column chromatography (SiO, EtOAc in hexane, 0–70%) to give the corresponding α,α-difluoroketone compound (2.73 g, 9.74 mmol, 55% yield).

[0409] Step c: The alcohol from step b (1.53 g, 5.46 mmol) was dissolved in dichloromethane (55.0 mL), followed by the sequential addition of pyridine (1.10 mL, 13.7 mmol) and benzoyl chloride (1.30 mL, 10.9 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 6 h. After TLC confirmed the reaction was complete, the mixture was diluted with dichloromethane (20.0 mL) and washed with water (20 mL), then 1 M HCl (20 mL), and finally brine (20 mL). The organic phase was separated, dried over Na2SO4, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO2, 0–40% EtOAc in hexane) to give the corresponding benzoylated alcohol (1.64 g, 4.27 mmol, 78% yield).

[0410] Step d: The product of step c (0.60 g, 1.56 mmol) was dissolved in a mixture of MeCN (6.40 mL) and water (1.6 mL), and CHCl (3.42 g, 6.24 mmol) was added. The reaction was stirred at room temperature for 30 min. Upon complete removal of the PMB group (TLC control), the reaction was diluted with EtOAc (10 mL) and washed with water (2 × 10 mL), saturated aqueous NaHCO (10 mL), and brine (10 mL). The organic phase was separated, dried over NaSO, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO, 0–70% EtOAc in hexane) to give the corresponding tetrahydroindazole (0.30 g, 1.13 mmol, 73% yield).

[0411] Step e: The tetrahydroindazole from step d (0.90 g, 3.41 mmol) and N-iodosuccinimide (2.30 g, 10.2 mmol) were dissolved in DMF (17 mL), and the reaction mixture was heated at 70 °C for 16 h. The mixture was then cooled to ambient temperature, diluted with EtOAc (15.0 mL), and washed with saturated aqueous NaSO (10.0 mL), then with water (2 × 10 mL), and finally with brine (10 mL). The organic phase was separated, dried over NaSO, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO, 0–80% EtOAc in hexanes) to give the corresponding iodotetrahydroindazole (1.10 g, 2.82 mmol, 83% yield).

[0412] Step f: Iodotetrahydroindazole (0.50 g, 1.28 mmol) from step e was dissolved in DMSO (5.10 mL) and sodium methanesulfinate (0.39 g, 3.84 mmol) and CuI (0.73 g, 3.84 mmol) were added. The reaction was heated to 110 °C for 2.5 h, at which point LCMS indicated complete consumption of the starting material. The reaction was cooled, diluted with EtOAc (10 mL), and saturated aqueous NH4Cl (5 mL) was added. It was stirred at room temperature for 2 h. The organic layer was separated, dried over Na2SO4, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO2, 0–90% EtOAc in hexanes) to give the corresponding methyl sulfone (0.25 g, 0.73 mmol, 57% yield).

[0413] The title compound was prepared in two additional steps using the methyl sulfone from step f in a manner similar to that described for Example 50. The title compound was isolated as a mixture of diastereomers (dr=1:1). 1 H NMR (400 MHz, CDCl3) δ 5.22 (overlapping ddt, J = 12.2, 3.3, 1.6 Hz, 2H), 4.63 (overlapping td, J = 6.6, 6.1, 4.6 Hz, 4H), 3.65 (overlapping dddp, J = 12.9, 9.6, 6.4, 3.2 Hz, 2H), 3.57 (overlaps, 6H), 3.48 - 3.29 (m, 4H), 3.27 (overlaps, 6H), 2.88 (overlapddd, J = 4.5, 3.0, 1.5 Hz, 2H), 2.30 (overlapdddd, J = 20.5, 10.4, 7.4, 3.8 Hz, 2H), 2.23 - 2.09 (overlap m, 2H). C 12 H 15 ESI MS [M+H] for F5N2O4S + , calculated value 379.1, measured value 379.1.

[0414] Examples 108a and 108b: (4S)-1-[(1S,3S)-3-(difluoromethoxy)cyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol and (4S)-1-[(1R,3R)-3-(difluoromethoxy)cyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol. [ka] Step a: To a suspension of cis-1,3-cyclohexanediol (359 mg, 3.0 mmol, 1.0 equiv.), CuI (114 mg, 0.60 mmol, 0.20 equiv.) in MeCN (3 mL) was added a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.641 g, 0.38 mL, 3.6 mmol, 1.2 equiv.) in MeCN (2 mL) at 50 °C over 10 min. The resulting mixture was heated at 50 °C for an additional 50 min, then cooled to room temperature and stirred for an additional 1 h. The reaction mixture was then carefully quenched by slowly adding saturated aqueous NaHCO3, and the mixture was diluted with EtOAc. After separation of the layers, the aqueous layer was extracted twice more with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude material was purified by column chromatography using a gradient of 0-60% EtOAc in hexanes to give cis-3-(difluoromethoxy)cyclohexanol (120 mg, 1.0 mmol, 34% yield).

[0415] Steps b and c: The title compound was prepared from cis-3-(difluoromethoxy)cyclohexanol from step a and [(4S)-5,5-difluoro-3-(trifluoromethyl)-4,6-dihydro-1H-cyclopenta[c]pyrazol-4-yl]benzoate in a manner similar to that of Example 53. The compound was isolated as a mixture of diastereomers. 1H NMR (400 MHz, chloroform-d) δ 6.27 (t, J = 74.8 Hz, 1H), 5.13-5.03 (m, 1H), 4.77-4.67 (m, 1H), 4.61 (tt, J = 9.9, 5.0 Hz, 0.3H), 4.49-4.32 (m, 0.7H), 3.56-3.13 (m, 2H), 2.50-2.35 (m, 1H), 2.31-2.07 (m, 3H), 2.00-1.73 (m, 4H). 14 H 15 ESI MS [M+H] for F7N2O2 + , calculated value 377.1, measured value 377.1.

[0416] Examples 109a and 109b: (4S)-1-[(1S,3S)-4,4-difluoro-3-methoxycyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol and (4S)-1-[(1R,3R)-4,4-difluoro-3-methoxycyclohexyl]-5,5-difluoro-3-(trifluoromethyl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-ol. [ka] Step a: To a solution of 4-hydroxycyclohexanone (5.00 g, 43.8 mmol, 1.0 equiv.) and triethylamine (6.65 g, 9.2 mL, 65.7 mmol, 1.5 equiv.) in DCM (150 mL) was added benzoyl chloride (6.78 g, 5.6 mL, 48.2 mmol, 1.1 equiv.) at room temperature. The resulting solution was stirred at room temperature overnight. The reaction mixture was then quenched by slowly adding saturated aqueous NaHCO3, and the mixture was diluted with DCM. After separating the layers, the aqueous layer was extracted twice more with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The crude material was purified by column chromatography using a gradient of 0–20% EtOAc in hexanes to give the benzoate product (5.23 g, 24.0 mmol, 55% yield).

[0417] Step b: To a solution of the benzoate product from step a (4.00 g, 18.3 mmol, 1.0 equiv) and triethylamine (5.46 g, 7.5 mL, 54.0 mmol, 3.0 equiv) in DCM (90 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (5.81 g, 5.1 mL, 22.0 mmol, 1.2 equiv) at 0 °C. The resulting mixture was continued to stir at this temperature for 30 min before being quenched with saturated aqueous NaHCO. The mixture was diluted with DCM. After separating the layers, the aqueous layer was extracted once more with DCM. The combined organic layers were dried over NaSO and concentrated. The crude material was purified by column chromatography using a gradient of 0–10% EtOAc in hexanes to give the silyl enol ether product (6.01 g, 18.0 mmol, 99% yield).

[0418] Step c: To a solution of the silyl enol ether product from step b (6.01 g, 18.0 mmol, 1.0 equiv.) and N-methylmorpholine N-oxide (3.48 g, 29.7 mmol, 1.65 equiv.) in THF (300 mL) was added OsO solution (approximately 0.08 M in HO, 3.3 mL, 0.27 mmol, 1.5 mol%) at room temperature. The resulting mixture was stirred overnight at room temperature and then quenched with saturated aqueous NaSO. The mixture was diluted with EtOAc. After separation of the layers, the aqueous layer was extracted twice more with EtOAc. The combined organic layers were dried over NaSO and concentrated. The crude material was purified by column chromatography using a gradient of 0–50% EtOAc in hexanes to give the hydroxyketone product (2.85 g, 12.2 mmol, 68% yield) as a mixture of cis and trans isomers in a 1:1 ratio.

[0419] Step d: To a solution of the hydroxyketone product from step c (1.70 g, 7.3 mmol, 1.0 equiv.) and the "proton sponge" 1,8-bis(dimethylamino)naphthalene (2.81 g, 13.1 mmol, 1.8 equiv.) in DCM (37 mL) was added trimethyloxonium tetrafluoroborate (1.73 g, 11.7 mmol, 1.6 equiv.) at room temperature. The resulting mixture was stirred overnight at room temperature. The greenish-gray suspension was then quenched with HO and diluted with DCM. After separation of the layers, the aqueous layer was extracted once more with DCM. The combined organic layers were dried over NaSO and concentrated. The crude material was purified by column chromatography using a gradient of 0 to 20% EtOAc in hexanes to give the trans isomer of the methylated product (1.12 g, 4.5 mmol, 62% yield) and the cis isomer of the methylated product (330 mg, 1.3 mmol, 18% yield).

[0420] Step e: To a solution of the transmethylated product from step d (45.2 mg, 0.182 mmol, 1.0 equiv) in toluene (0.34 mL) was added deoxofluor (2.7 M in toluene, 0.34 mL, 0.91 mmol, 5.0 equiv) at room temperature. The resulting solution was heated at 50 °C for 2 h, then cooled and quenched with saturated aqueous NaHCO3. The mixture was diluted with EtOAc. After separation of the layers, the aqueous layer was extracted twice more with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude material was purified by column chromatography using a gradient of 0 to 15% EtOAc in hexanes to give the difluorocyclohexane product (35.8 mg, 0.132 mmol, 73% yield).

[0421] Step f: To a solution of the difluorocyclohexane product from step e (35.8 mg, 0.132 mmol) in methanol (0.5 mL) was added 1 M aqueous NaOH (1.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then diluted with EtOAc and H2O. After separating the layers, the aqueous layer was extracted twice more with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude trans-4,4-difluoro-3-methoxycyclohexanol (23.0 mg) was directly applied to the next step without further purification.

[0422] Steps g and h: The title compound was isolated as a mixture and p...

Claims

1. Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof. (In the formula, n is 1 or 2; m is 2, 3, 4, 5, 6, 7, or 8, provided that when n is 1, then m is 2, 3, 4, 5, or 6; Each R １ is halo, —OH, and —O—(C １ -C ３ alkyl); R ２ is -C １ -C ６ Alkyl, —CN, and —S(O) ２ -(C １ -C ３ alkyl), wherein said —C １ -C ６ Alkyl and —S(O) ２ -(C １ -C ３ alkyl) is substituted with 0-3 halo; R ３ is 1 to 3 R ４ -C substituted with １ -C ２ Alkyl, -C ３ -C ６ Alkyl, -C ３ -C ８ Cycloalkyl, N, O, S, S(=O), and S(=O) ２ -3 to 7-membered heterocycloalkyl having 1 to 3 heteroatoms or heteroatom groups selected from -Y-(C ３ -C ６ cycloalkyl), —Y—O—(C ３ -C ６ cycloalkyl), N, O, S, S(═O), and S(═O) ２ and -Y-(5-6 membered heteroaryl) having 1 to 3 heteroatoms or heteroatom groups selected from N, O and S, wherein said -C ３ -C ６ Alkyl, -C ３ -C ６ cycloalkyl, -3 to 7 membered heterocycloalkyl, -Y-(C ３ -C ６ cycloalkyl), —Y—O—(C ３ -C ６ -cycloalkyl), -Y-(3- to 6-membered heterocycloalkyl), -X-(phenyl), and -Y-(5- to 6-membered heteroaryl) are each independently selected from 0 to 3 R ４ is substituted with; Each R ４ is halo, -C １ -C ６ Alkyl, -CN, -C １ -C ６ Haloalkyl, —OH, —O—(C １ -C ６ alkyl), -Y-O-(C １ -C ６ alkyl), -S-(C １ -C ６ alkyl), -S(O)-(C １ -C ６ alkyl), and —S(O) ２ -(C １ -C ６ alkyl), wherein said —O—(C １ -C ６ alkyl), -Y-O-(C １ -C ６ alkyl), -S-(C １ -C ６ alkyl), -S(O)-(C １ -C ６ alkyl), and —S(O) ２ -(C １ -C ６ alkyl) is substituted with 0-3 halo; X is -C ２ -C ３ alkylene-; Y is -C １ -C ３ alkylene-).

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. (In the formula, n is 1 or 2; m is 2, 3, 4, 5, 6, 7, or 8, provided that when n is 1, then m is 2, 3, 4, 5, or 6; Each R １ is halo, —OH, and —O—(C １ -C ３ alkyl); R ２ is -C １ -C ６ Alkyl, —CN, and —S(O) ２ -(C １ -C ３ alkyl), wherein said —C １ -C ６ Alkyl and —S(O) ２ -(C １ -C ３ alkyl) is substituted with 0-3 halo; R ３ is 1 to 3 R ４ -C substituted with １ -C ２ Alkyl, -C ３ -C ６ Alkyl, -C ３ -C ６ cycloalkyl, -Y-(C ３ -C ６ cycloalkyl), —Y—O—(C ３ -C ６ cycloalkyl), N, O, S, S(=O), S(=O) ２ and -Y-(5-6 membered heteroaryl) having 1 to 3 heteroatoms selected from N, O and S, wherein said -C ３ -C ６ Alkyl, -C ３ -C ６ cycloalkyl, -Y-(C ３ -C ６ cycloalkyl), —Y—O—(C ３ -C ６ -Y-(3- to 6-membered heterocycloalkyl), -Y-(3- to 6-membered heterocycloalkyl), and -Y-(5- to 6-membered heteroaryl) are each independently selected from 0 to 3 R ４ is substituted with; Each R ４ is halo, -C １ -C ６ Alkyl, -CN, -C １ -C ６ Haloalkyl, —OH, —O—(C １ -C ６ alkyl), -S-(C １ -C ６ alkyl), and —S(O) ２ -(C １ -C ６ alkyl), wherein said —O—(C １ -C ６ alkyl), -S-(C １ -C ６ alkyl), and —S(O) ２ -(C １ -C ６ alkyl) is substituted with 0-3 halo; Y is -C １ -C ３ alkylene-).

3. The compound of formula I has the structure of formula II: 【Chemistry 2】 and optionally the compound of formula II has the structure of formula IIa: 【Transformation 3】 (wherein p is 0 or 1) 2. The compound of claim 1, having the formula:

4. The compound of formula I has the structure of formula III: 【Chemistry 4】 and optionally the compound of formula III has (i) Structure of Formula IIIa: 【Transformation 5】 (wherein p is 0 or 1); (ii) Structure of Formula IIIc: 【Transformation 6】 (wherein p is 0 or 1); (iii) Structure of Formula IIIe: 【Transformation 7】 (wherein p is 0 or 1) 2. The compound of claim 1, having the formula:

5. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof. (In the formula: Each R １ is independently halo or —OH; R ２ is —C substituted with 0 to 3 halo １ -C ６ is alkyl; R ３ is -C １ -C ６ Alkyl, -C ３ -C ８ cycloalkyl, tetrahydropyranyl, or —Y—(C ３ -C ６ cycloalkyl), each of which is 1 to 3 R ４ is substituted with; Each R ４ are independently halo, -C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), -Y-O-(C １ -C ６ alkyl), -S-(C １ -C ６ alkyl), or —S(O) ２ -(C １ -C ６ alkyl), wherein said —O—(C １ -C ６ alkyl), -Y-O-(C １ -C ６ alkyl), -S-(C １ -C ６ alkyl), and —S(O) ２ -(C １ -C ６ alkyl) is substituted with 0-3 halo; Y is -C １ -C ３ alkylene-).

6. Each R ４ Halo, -CN, -O-(C １ -C ３ alkyl), -S-(C １ -C ３ alkyl), and —S(O) ２ -(C １ -C ３ alkyl), wherein said —O—(C １ -C ３ alkyl), -S-(C １ -C ３ alkyl), and —S(O) ２ -(C １ -C ３ 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected from -F, -CN, -OCH 3 , -OCF 2 H, -OCF 3 , -SCF 3 , and -S(O) 2 CF 3 .

7. Each R ４ But, halo, -C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), or —Y—O—(C １ -C ６ alkyl), wherein said —O—(C １ -C ６ alkyl) or -Y-O-(C １ -C ６ 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently -F, -CF 3 , -OCH 3 , -OCF 3 , or -CH(CH 3 )-O-CF 3 .

8. The compound of claim 4, or a pharmaceutically acceptable salt thereof. (In the formula: Each R １ are independently halo or —OH; R ２ is —C substituted with 0 to 3 halo １ -C ６ Alkyl, or —S(O) ２ -(C １ -C ３ alkyl); R ３ is 1 to 3 R ４ -C substituted with １ -C ６ Alkyl, -C ３ -C ６ Cycloalkyl, O and S(=O) ２ -6- to 7-membered heterocycloalkyl having one heteroatom or heteroatom group selected from １ -C ２ Alkylene-(C ３ -C ４ cycloalkyl), O and S(=O) ２ -C having one heteroatom or heteroatom group selected from １ -C ２ alkylene-(4- to 5-membered heterocycloalkyl), —C ２ -C ３ alkylene-(phenyl), and —C having 1 to 2 heteroatoms selected from N, O, and S １ -C ２ alkylene-(5-membered heteroaryl), wherein the —C ３ -C ６ cycloalkyl, -6- to 7-membered heterocycloalkyl, -C １ -C ２ Alkylene-(C ３ -C ４ cycloalkyl), -C １ -C ２ alkylene-(4- to 5-membered heterocycloalkyl), —C ２ -C ３ Alkylene-(phenyl), and -C １ -C ２ Alkylene-(5-membered heteroaryl) is a 5-membered heteroaryl having 0 to 3 R ４ is substituted with; Each R ４ is halo, -CN, -C １ -C ６ Haloalkyl, —OH, —O—(C １ -C ６ alkyl), -(C １ -C ２ alkylene)-O-(C １ -C ６ alkyl), -S(O)-(C １ -C ６ alkyl), and —S(O) ２ -(C １ -C ６ alkyl); wherein said —O—(C １ -C ６ alkyl), -(C １ -C ２ alkylene)-O-(C １ -C ６ alkyl), -S(O)-(C １ -C ６ alkyl), and —S(O) ２ -(C １ -C ６ alkyl) is substituted with 0 to 3 halo).

9. (i)R ２ Ga-CF ３ and (ii) at least one R 1 is —F, and / or (iii) at least one R 1 is —OH; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

10. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 3 【Request Item 11】 【Chemistry 8】 2. The compound of claim 1, wherein: 【Request Item 12】 【Chemistry 9】 2. The compound of claim 1, wherein:

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use as a medicine or in therapy.

15. 13. A pharmaceutical composition comprising a compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for use in treating a disease, disorder, or condition mediated at least in part by HIF-2α, wherein the disease, disorder, or condition is von Hippel-Lindau (VHL) disease, cancer, or an immune-related disease, disorder, or condition. (i) the disease, disorder, or condition is von Hippel-Lindau (VHL) disease, and the von Hippel-Lindau (VHL) disease is associated with renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastoma, or pancreatic neuroendocrine tumor (pNET); or (ii) the disease, disorder, or condition is cancer, and the cancer is selected from the group consisting of cancer of the prostate, cancer of the colon, cancer of the rectum, cancer of the pancreas, cancer of the cervix, cancer of the stomach, cancer of the endometrium, cancer of the uterus, cancer of the brain, cancer of the liver, cancer of the bladder, cancer of the ovaries, cancer of the testes, cancer of the head and neck, cancer of the skin (including melanoma and basal cell carcinoma), cancer of the mesothelium lining, cancer of white blood cells (including lymphoma and leukemia), cancer of the esophagus, cancer of the breast, cancer of the muscle, cancer of connective tissue (including or glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma (including Kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the skin, or testicular seminoma, optionally wherein the cancer is selected from the group consisting of melanoma, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, Kaposi's sarcoma, renal cell carcinoma, head and neck cancer, esophageal cancer, and urothelial carcinoma; (iii) The pharmaceutical composition of claim 15, wherein the disease, disorder, or condition is an immune-mediated disease, disorder, or condition selected from the group consisting of rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergy, fibrosis, anemia fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, Crohn's disease, ulcerative colitis, allergic contact dermatitis and other eczemas, systemic sclerosis, and multiple sclerosis.

17. 16. The pharmaceutical composition of claim 15, for use in conjunction with the administration of one or more additional therapeutic agents.

18. the one or more additional therapeutic agents comprise one or more agents selected from the group consisting of tyrosine kinase inhibitors, cytokine therapy, anti-angiogenic agents, mTOR inhibitors, immune checkpoint inhibitors, inhibitors of CDK-4 and / or CDK-6, agents that target the extracellular production of adenosine, radiation therapy, and chemotherapeutic agents; and optionally (i) the immune checkpoint inhibitor comprises an immune checkpoint inhibitor that blocks the activity of at least one of PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT, or CTLA-4; and / or (ii) the tyrosine kinase inhibitor is cabozantinib, foretinib, gilteritinib, glesatinib, merestinib, rebastinib, or sitravatinib, and / or (iii) The pharmaceutical composition of claim 17, wherein the anti-angiogenic agent is axitinib, bevacizumab, cabozantinib, lenvatinib, pazopanib, sorafenib, sunitinib, or tivozanib.

19. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of any one of claims 1 to 12, in combination with one or more additional therapeutic agents.

20. the one or more additional therapeutic agents comprise one or more agents selected from the group consisting of tyrosine kinase inhibitors, cytokine therapy, anti-angiogenic agents, mTOR inhibitors, inhibitors of CDK-4 and / or CDK-6, immune checkpoint inhibitors, agents targeting the extracellular production of adenosine, radiation therapy, and chemotherapeutic agents; and optionally (i) the immune checkpoint inhibitor comprises an immune checkpoint inhibitor that blocks the activity of at least one of PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT, or CTLA-4; and / or (ii) the tyrosine kinase inhibitor is cabozantinib, foretinib, gilteritinib, glesatinib, merestinib, rebastinib, or sitravatinib, and / or (iii) the anti-angiogenic agent is axitinib, bevacizumab, cabozantinib, lenvatinib, pazopanib, sorafenib, sunitinib, or tivozanib; 20. The pharmaceutical composition of claim 19.

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