Fluorinated cyclic derivatives of sulfonamides and sulfones, compositions thereof, and methods thereof.

Abstract

The present invention provides novel fluorinated cyclic derivatives of sulfonamides and sulfones, compositions thereof, and methods for preparing and using them, which are useful for treating various diseases and disorders related to TRPML activity, such as neurodegenerative diseases, lysosomal storage disorders, muscular dystrophy, common neurodegenerative diseases associated with aging, diseases associated with oxidative stress or reactive oxygen species (ROS), and aging.

Description

[Technical Field]

[0001] Priority claims and related patent applications This application claims priority under U.S. Provisional Patent Application No. 63 / 460,744 filed April 20, 2023, and U.S. Provisional Patent Application No. 63 / 546,566 filed October 31, 2023, the contents of which are incorporated herein by reference by reference to the whole of these respective applications.

[0002] Technical field of inventions The present invention generally relates to novel compounds and their therapeutic uses. More specifically, the present invention provides novel fluorinated cyclic derivatives of sulfonamides and sulfones, their salts, solvates, hydrates, and polymorphs as transient receptor potential cation channel mucolipin subfamily (TRPML) modulators. The present invention also provides pharmaceutical compositions and methods comprising the compounds of the present invention for treating a variety of diseases and disorders associated with or related to TRPML activity, such as neurodegenerative diseases, lysosomal storage disorders, muscular dystrophy, reactive oxygen species (ROS) or oxidative stress-related diseases, metabolic diseases, metastatic cancer, and aging. [Background technology]

[0003] Lysosomes, the cellular recycling centers, can mediate the breakdown of various biomaterials (proteins, lipids, and membranes) into smaller molecules or building blocks, which are then transported from the lysosome for reuse or energy (see, e.g., de Duve 2005 Nat Cell Biol 7(9):847-849, and Parkinson-Lawrence et al. 2010 Physiology (Bethesda) 25(2):102-115). Challenges in either the breakdown process (due to a lack of hydrolytic enzymes) or the transport process can lead to lysosomal accumulation (of accumulated materials) and more than 50 human diseases collectively known as lysosomal storage disorders (LSDs). Lysosomal accumulation can affect lysosomal degradation and membrane transport / tracking, potentially creating positive feedback loops and vicious cycles. Lysosomal accumulation is also observed in common neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, so understanding the underlying mechanisms of the positive feedback loop may lead to therapeutic approaches not only for LSD but also for common sporadic neurodegenerative diseases. Lysosomal localized Ca 2+ The channel TRPML1 has recently been identified as a key regulator of most membrane transport processes in lysosomes. Human mutations in TRPML1 lead to defects in lysosomal transport, lysosomal accumulation, and neurodegenerative and retinal diseases.

[0004] TRP type Ca 2+ TRPML1 (also abbreviated as ML1), a member of the channel superfamily, is a major Ca25 channel in lysosomes. 2+ It is a channel (see, for example, Cheng et al. 2010 FEBS Lett 584(10):2013-21). Loss-of-function mutations in the human TRPML1 gene cause type IV mucolipidosis (ML4), a lysosomal storage neurodegenerative disease. TRPML1 in ML4 patients - / - (ML1 - / -(Omitted) Skin fibroblasts are characterized by the accumulation of enlarged endosomal / lysosomal compartments (vacuoles) in which lipids and other biomaterials accumulate, suggesting transport defects. Analysis of transport dynamics suggests that the main defect lies in the late endocytosis pathway. First, ML1 is likely required for the formation of transport vesicles from late endosomes and lysosomes (LEL) to the trans-Golgi network (TGN) (retrograde transport from LEL to TGN). Second, the fusion of lysosomes with the plasma membrane (called lysosomal exocytosis), a process crucial for the removal of cellular waste, membrane repair, and phagocytosis, is deficient in ML4 cells. Defects in any of these transport processes can lead to lysosome accumulation. Ca from lysosomes 2+ Release (Lysosomal Ca 2+ Since release is essential for both transport processes, ML1 actually regulates lysosome transport. 2- It is assumed to be an emission channel.

[0005] PI(3,5)P2, a low-abundance phosphoinositide, is a major activator of ML1 and a positive regulator of lysosomal transport. Cells lacking TRPML1 and cells deficient in PI(3,5)P2 both exhibit defects in retrograde transport from LEL to Golgi and fusion of autophagosomes and lysosomes, suggesting that the TRPML1-PI(3,5)P2 system represents a common signaling pathway essential for late endocytotic transport.

[0006] Due to the function of lysosomes in lysosome transport, lysosomes are required for quality control regulation of mitochondria, the "power house" of cells, and the major source of endogenous ROS (reactive oxygen species). Mitochondrial damage causes oxidative stress, which is a common feature in most LSDs, neurodegenerative diseases, and aging (Xu et al., 2015 Anna Rev Physiol 77, 57-80). Recent studies have suggested that mitochondria are physically localized in close proximity to lysosomes (Elbaz-Alon et al., 2014 Dev Cell 30, 95-102; Li et al., 2015 Cell Mol Neurobiol 35, 615-621). Therefore, the lysosomal membrane may be an accessible and direct target for ROS signaling. Considering reports that ROS regulate ion channels (Bogeski et al., 2014 Antioxid Redox Signal 21, 859-862), lysosomal conductance via channels such as TRPML1 may mediate ROS regulation of lysosome function. Indeed, electrophysiological studies have revealed that total endolysosomal TRPML1 currents are directly activated by ROS. 21 Lysosomal conductance via channels such as TRPML1 may mediate ROS regulation of lysosome function. Indeed, electrophysiological studies have revealed that total endolysosomal TRPML1 currents are directly activated by ROS.

[0007] Dysregulation may increase ROS levels and oxidative stress, which are thought to underlie various metabolic and neurodegenerative diseases, as well as aging (Barnham et al., 2004 Nat Rev Drug Discov 3, 205-214; Scherz-Shouval et al., 2011 Trends Biochem Sci 36, 30-38). Considering the role of TRPML1 in mediating ROS-induced autophagy, TRPML1 agonists may be able to remove excessive ROS and thereby improve ROS-related diseases and aging, particularly photoaging of the skin.

[0008] The transcription factor EB (TFEB) regulates autophagy and lysosomal biosynthesis. Overexpression of TFEB has been reported to induce cellular clearance in many lysosomal storage disorders, including Pombe disease, cystinosis, and multiple sulfatase deficiency, as well as in neurodegenerative diseases, including Parkinson's disease and Huntington's disease (Settembre et al., 2013 Nat Rev Mol Cell Biol 14(5), pp. 283-296). Therefore, activation of TRPML1 by a TRPML1 agonist may also lead to cellular clearance in all of the aforementioned diseases, potentially providing a therapeutic target for these devastating conditions.

[0009] Previously, potent synthetic agonists against TRPML1 have been reported (Shen et al., 2012 Nat Commun 3, p. 731). These SF-51-related compounds (mucolipin synthetic agonist 1 or ML-SA1) significantly increase [Ca2+] in HEK293 cells that stably or transiently express ML1-4A. cyt We were able to induce an increase. In electrophysiological assays, ML-SA1 was found to be present in whole cells. MLI-4Δ and whole endolysosomal I ML1 It strongly activated ML-SA1. TRPML2 and I TRPML3 It activated one channel, but the remaining six related channels were not activated. Total endolysosomal I ML1 Activation of ML-SA1 (10 μM) was comparable to the effect of the endogenous TRPML agonist PI(3,5)P2 (1 μM), and these agonists were synergistic with each other. ML-SA1 activated endogenous whole endolysosomal TRPML-like currents (I) in all mammalian cell types investigated, including Chinese hamster ovary (CHO), Cos-1, HEK293, skeletal muscle, pancreatic β-cells, and macrophage cells. ML-L ) was activated. ML-SA1 is wild type (WT, ML1 - / + In human fibroblasts, all endolysosomal I ML-L We activated ML4(ML1 - / -Since ML-SA1 was not activated in human fibroblasts, it targets all three TRPMLs, but the expression levels of TRPML2 and TRPML3 are very low, suggesting that TRPML1 is a prominent lysosomal TRPML channel in this cell type. These results suggest that ML-SA1 is a reasonably specific and potent agonist that may be useful in regulating TRPML function.

[0010] [ka]

[0011] High concentrations of ML-SA1 (approximately 10 μM) are required to effectively activate TRPML. Since this concentration is usually difficult to achieve in vivo, ML-SA1 cannot be used to treat the TRPML-related diseases described above. In recent years, several more potent TRPML1 agonists have been developed (see, e.g., International Publication WO2022076383). However, most of these potent agonists are highly hydrophobic molecules that are metabolically unstable and / or have very limited brain permeability, which reduces oral bioavailability and limits exposure to affected organs, particularly the brain.

[0012] There is an urgent need for orally bioavailable, highly permeable, and potent TRPML activators, specifically compounds useful for treating TRPML activity-related disorders such as neurodegenerative diseases, lysosomal storage disorders, muscular dystrophy, ROS or oxidative stress-related diseases, metabolic diseases, metastatic cancer, and aging. [Overview of the Initiative]

[0013] This invention is in part based on novel fluorinated cyclic derivatives of sulfonamides and sulfones, their pharmaceutical compositions, methods for preparing them, and their use in the treatment or reduction of various diseases or disorders. In particular, the compounds, compositions, and methods of this invention are useful for treating diseases or disorders mediated by or associated with TRPML.

[0014] In one embodiment, the present invention generally relates to formula (I):

[0015] [ka] With respect to a compound having the structure of, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, in the formula, Ring A is a 4- to 9-membered carbon ring or heteroring substituted with 1 to 8 F atoms. Ring B is either a substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, pyridadinyl, pyrimidinyl, pyrrolyl, or thiophene, or a substituted or unsubstituted bicyclic or polycyclic carbocyclic or heterocyclic ring system. P is CH, N, or CR 2 And, Q is CH, N, or CR 2 And, U is either C or N, V is either C or N, W is CH, N, C(=O), C(=S), or CR W1 R W2 And R W1 and R W2 Each of these is independently H or C 1-6 It is alkyl, X is either C or N, Y is C, CR Y , or N, R Y is H, F, or C 1-6 It is alkyl, R 1It is selected from the group consisting of F, CHF2, -CF3, -CH2CF3, CF2CH3, CF2CH2F, CF2CHF2, -CF(CH3)2, -OCF3, and -OCH(CH3)2. R 2 These are, independently, halogen, unsubstituted, or substituted C 1-6 Alkyl and C 1-6 Selected from the group consisting of alkoxy, OH, CN, NRR', N(R)C(=O)RR', C(=O)R, and C(=O)NRR', R 3 These are, independently, halogen, CN, CF3, and C. 1-5 Alkyl, C 3-7 Selected from the group consisting of cycloalkyl and heterocycles, R and R' can independently be H or C 1-6 They are alkyl or cycloalkyl groups, and optionally R and R' form a 3-6 membered ring together with the nitrogen or carbon atom to which they are bonded, and optionally, independently, C 1-3 alkyl, halogen, OH, OC 1-3 Substituted with 0 to 3 substituents selected from the group consisting of alkyl and CN, m is 0, 1, 2, 3, or 4. n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. i is 0, 1, or 2.

[0016] In another aspect, the present invention generally relates to pharmaceutical compositions comprising the compounds disclosed herein.

[0017] In another aspect, the present invention generally relates to a unit dose form comprising a pharmaceutical composition containing the compounds disclosed herein.

[0018] In another aspect, the present invention relates generally to a method for treating or reducing a disease or disorder, comprising the step of administering a therapeutically effective dose of one of the compounds disclosed herein to a subject in need of treatment or reduction of the disease or disorder.

[0019] In another aspect, the present invention generally relates to a method for treating or reducing the effects of aging, comprising the step of administering a therapeutically effective dose of one of the compounds disclosed herein to a subject in need of treatment or reduction of the effects of aging.

[0020] In another aspect, the present invention generally relates to a method for treating or reducing oxidative stress or ROS-related diseases or disorders, comprising the step of administering a therapeutically effective dose of a TRPML1 agonist or a composition comprising a TRPML1 agonist as disclosed herein to a subject in need of treatment or reduction of the disease or disorder.

[0021] In another aspect, the present invention generally relates to a method for treating or reducing oxidative stress or ROS-related diseases or disorders, comprising the step of administering a therapeutically effective dose of one of the compounds disclosed herein to a subject in need of treatment or reduction of the disease or disorder.

[0022] In another aspect, the present invention generally relates to the use of the compounds disclosed herein with pharmaceutically acceptable excipients, carriers, or diluents in the preparation of pharmaceuticals for treating diseases or disorders.

[0023] definition Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention pertains. General principles of organic chemistry, as well as specific functional parts and reactivity, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 2006.

[0024] The following terms are intended to have the meanings set forth below, unless otherwise indicated, depending on the context in which they appear.

[0025] The ranges provided herein are understood to be abbreviations for all values ​​within that range. For example, the range 1–16 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0026] All compositions or methods disclosed herein may be combined with any one or more of the other compositions and methods provided herein.

[0027] Any enumeration of chemical groups in any definition of a variable herein includes the definition of that variable as any one of the enumerated groups or a combination of the enumerated groups. Any enumeration of embodiments relating to a variable or aspect herein includes that embodiment as any one of the embodiments or in combination with any other embodiment or part thereof.

[0028] The definitions of specific functional groups and chemical terms are described in detail below. When a range of values ​​is listed, it is intended to include both the values ​​within that range and each of the subranges. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl substituents are intended to be included. Substituents are identified by their conventional chemical formula, and when written from left to right, they equally include chemically identical substituents that would result from writing the structure from right to left; for example, -C(=O)-O- is equivalent to -OC(=O)-.

[0029] The structure of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art. Therefore, where a group can be substituted by one or more of a number of substituents, such substitutions are selected to conform to the principles of chemical bonding and to give a compound that is not inherently unstable and / or is likely to be unstable under ambient conditions (e.g., aqueous, neutral, and some known physiological conditions), as is known to those skilled in the art.

[0030] As used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural form unless explicitly specified in the context.

[0031] As used herein, "at least" a particular value is understood to be that value, as well as all values ​​greater than that value.

[0032] As used herein, the terms “comprises,” “comprising,” or “having,” when used to define compositions and methods, are intended to mean that the compositions and methods include the enumerated elements but do not exclude other elements. The term “consisting essentially of,” when used to define compositions and methods, shall mean that the compositions and methods include the enumerated elements but exclude other elements that are of any essential importance to the compositions and methods. For example, “consisting essentially of” refers to the administration of pharmacologically active agents that are explicitly enumerated but excludes pharmacologically active agents that are not explicitly enumerated. The term “consisting essentially of” does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term “consisting of,” when used to define compositions and methods, shall mean the exclusion of trace elements of other components and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0033] As used herein, the terms “disease” and “disorder” are interchangeable and refer to any condition that impairs or interferes with the normal functioning of a cell, tissue, or organ.

[0034] As used herein, the term "hydrate" means a compound further containing stoichiometric or nonstoichiometric amounts of water bound by non-covalent intermolecular forces.

[0035] As used herein, the term “pharmaceutically acceptable salt” means suitable for use in contact with human and other mammalian tissues without unsuitable toxicity, irritation, or allergic reactions, and that balances with a reasonable benefit-risk ratio. “pharmaceutically acceptable forms” of the compounds disclosed herein include, but are not limited to, their pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, prodrugs, and isotopically labeled derivatives. In one embodiment, “pharmaceutically acceptable forms” include, but are not limited to, their pharmaceutically acceptable salts, esters, prodrugs, and isotopically labeled derivatives. In some embodiments, “pharmaceutically acceptable forms” include, but are not limited to, their pharmaceutically acceptable isomers and stereoisomers, as well as isotopically labeled derivatives.

[0036] In certain embodiments, a pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with the target tissue without inappropriate toxicity, irritation, allergic reactions, etc., and that balances with a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: pp. 1-19. pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable and non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, besilate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyl Examples include c-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, examples of organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0037] Salts can be prepared in situ or separately during the isolation and purification of the compounds of this disclosure by reacting, for example, the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmacochemically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Furthermore, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts may be selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0038] In certain embodiments, the pharmaceutically acceptable form is a “solvate” (e.g., a hydrate). As used herein, the term “solvate” refers to a compound further containing a stoichiometric or non-stoichiometric amount of solvent, bound by non-covalent intermolecular forces. The solvate may be of the compound of this disclosure or a pharmaceutically acceptable salt thereof. If the solvent is water, the solvate is a “hydrate.” Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. As used herein, the term “compound” is understood to encompass the compound and its solvates, as well as mixtures thereof.

[0039] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” refers to a compound that, upon transformation in vivo, results in a compound of the Disclosure or a pharmaceutically acceptable form of such compound. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound by, for example, hydrolysis (e.g., hydrolysis in the blood). In certain cases, the prodrug has improved physical and / or delivery properties compared to the parent compound. When administered to a subject, the prodrug can increase the bioavailability of the compound (e.g., by enabling improved absorption into the blood after oral administration) or improve delivery to a biological compartment of interest (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the compounds of the Disclosure with improved water solubility or active transport across the enteric membrane compared to the parent compound.

[0040] Prodrug compounds often offer advantages to mammals such as solubility, histocompatibility, or delayed release (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are presented in Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” ACSSymposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. Illustrative advantages of prodrugs include, but are not limited to, their physical properties, such as improved water solubility in parenteral administration at physiological pH compared to the parent compound, improved absorption from the gastrointestinal tract, or improved drug stability for long-term storage.

[0041] Prodrugs commonly known in the art include well-known acid derivatives, such as esters prepared by the reaction of a parent acid with a suitable alcohol, amides prepared by the reaction of a parent acid compound with an amine, and basic groups that form acylated base derivatives by reaction. Naturally, other prodrug derivatives may be combined with other features disclosed herein to improve bioavailability. Thus, those skilled in the art will understand that certain compounds of the disclosure having a free amino group, alnide group, hydroxyl group, or carboxylic acid group can be converted into prodrugs. Prodrugs include compounds having amino acid residues, or polypeptide chains of two or more (e.g., two, three, or four) amino acid residues covalently bonded via peptide bonds to a free amino group, hydroxyl group, or carboxylic acid group of a compound of the disclosure. The amino acid residues include 20 naturally occurring amino acids, generally designated by three-letter symbols, and further include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine, and methionine sulfone. The prodrugs also include compounds having a carbonate moiety, carbamate moiety, amide moiety, or alkyl ester moiety covalently bonded to any of the substituents disclosed herein.

[0042] Particularly preferred prodrugs and prodrug salts are those that increase the bioavailability of the compound when administered to a mammal (for example, by making the orally administered compound more readily absorbed into the bloodstream), or that improve the delivery of the parent compound to a biological compartment (e.g., the brain or central nervous system) compared to the parent species. Examples of prodrugs include derivatives in which a group that enhances water solubility or active transport across the intestinal membrane is added to the structure of the formula described herein (e.g., Alexander et al., 1988 J Med Chem 31, pp. 318-322; Bundgaard et al., 1985 Elsevier:Amsterdam pp. 1-92; Bundgaard et al., 1987 J Med Chem 30, pp. 451-454; Bundgaard, H., A Textbook of Drug Design and Development; Harwood Academic Publ.:Switzerland, 1991, pp. 113-191; Digenis et al., Handbook of Experimental Pharmacology 1975, pp. 28, 86-112; Friis et al., Textbook of Drug Design and Development; 2nd edition; Overseas Publ.:Amsterdam, 1996, pp. 351-385; Pitman, 1981 Medicinal Research Reviews) (See pages 1,189-1,1214).

[0043] As used herein, the term “pharmaceutically acceptable” excipient, carrier, or diluent means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in the transport or delivery of the drug of interest from one organ or body part to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; water free of pyrogens; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic, suitable substances used in pharmaceutical formulations. In addition to wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer, the composition may also contain colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants.

[0044] As used herein, the term “polymorph” means a solid crystalline form of a compound or its complex that can be characterized by physical means such as X-ray powder diffraction patterns or infrared spectroscopy. Different polymorphs of the same compound may exhibit different physical, chemical, and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., to heat, light, or moisture), compressibility and density (important for formulation and product manufacturing), hygroscopicity, solubility, and dissolution rate (which may affect bioavailability). Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, where a dosage form composed of one polymorph undergoes more rapid discoloration than one composed of another), mechanical properties (e.g., a tablet disintegrates during storage, so that a kinetically preferred polymorph is converted to a thermodynamically more stable polymorph), or both (e.g., a tablet of one polymorph is more susceptible to destruction in high humidity). Different physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form a solvate than another polymorph, or it may be more difficult to remove impurities by filtration or washing, due to, for example, the shape or particle size distribution of its particles. As used herein, the term “solvate” means a compound further containing stoichiometric or non-stoichiometric amounts of a solvent, such as water, acetone, ethanol, methanol, dichloromethane, or 2-propanol, which are bound together by non-covalent intermolecular forces. As used herein, the term “stable compound” means a compound that is stable enough to enable manufacturing and maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in the production of therapeutic compounds, or isolated or storable intermediate compounds for treating diseases or disorders that respond to therapeutic agents).

[0045] As used herein, the term “stereoisomer” refers to both enantiomers and diastereomers. As used herein, the term “substantially free of other stereoisomers” means that there are less than 25% other stereoisomers, preferably less than 10%, more preferably less than 5%, most preferably less than 2%, or less than “X”% other stereoisomers (where X is a number between 0 and 100). Methods for obtaining or synthesizing diastereomers are well known in the art and may be applied as practically applicable to the final compound or starting materials or intermediates. Other embodiments are embodiments in which the compound is an isolated compound. As used herein, the term “enantiomerically rich in at least X%” means that at least X% of the compound is in a single enantiomer form, where X is a number between 0 and 100.

[0046] As used herein, the terms “treatment” or “treating” of a disease or disorder refer to a method of reducing, slowing, or alleviating such a condition before or after its occurrence. Treatment may target one or more actions or symptoms of the disease and / or underlying pathology. Treatment may be any reduction, or it may be the complete elimination of the disease or its symptoms. For this reason, “treating or treatment” refers to signs of successful treatment or alleviation of the injury, disease, pathology, or condition, including any objective or subjective parameters such as reduction; remission; a decrease in symptoms, or improved tolerance of the injury, condition, or state to the patient; a slower rate of degeneration or decline; further weakening of the final degenerative point; and improvement or stabilization of the patient’s physical or mental health. Treatment or alleviation of symptoms may be based on objective or subjective parameters such as the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. Compared to an equivalent untreated control, the degree of such reduction or improvement may be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% when measured by any standard technique.

[0047] As used herein, the term "alk" or "alkyl" refers to a linear, branched, or cyclic hydrocarbon group having 1 to 12 unsaturated carbon atoms. Wherever it appears herein, numerical ranges such as "1 to 10" refer to each integer within a given range. For example, "1 to 10 carbon atoms" means that an alkyl group can consist of up to 10 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., but this definition also covers occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, "alkyl" means C 1-6 It may be an alkyl group. In some embodiments, "alkyl" is C 1-3 It can be an alkyl group.

[0048] As used herein, the term "alkenyl" refers to a linear or branched hydrocarbon group of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. When an alkenyl group is bonded to a nitrogen atom, it is preferable that such a group is not directly bonded by a carbon atom having a double bond.

[0049] As used herein, the term "alkoxy" refers to an -O-alkyl radical.

[0050] As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon group of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond. When an alkynyl group is bonded to a nitrogen atom, it is preferable that such a group is not directly bonded by carbon atoms having triple bonds.

[0051] As used herein, the term "alkylene" refers to a divalent linear bridge of 1 to 5 carbon atoms connected by a single bond (e.g., -(CH2) x - refers to (where x is 1-5), which can be substituted with 1-3 lower alkyl groups.

[0052] As used herein, the term "alkenylene" refers to a linear crosslink of 2 to 5 carbon atoms that is linked by single bonds and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkenylene groups are -CH=CH-CH=CH-, -CH2-CH=CH-, -CH2-CH=CH-CH2-, -C(CH3)2CH=CH-, and -CH(C2H5)-CH=CH-.

[0053] As used herein, the term "alkynylene" refers to a linear bridge of 2 to 5 carbon atoms having a triple bond, connected by single bonds, and substituted with 1 to 3 lower alkyl groups. Exemplary alkynylene groups are -C≡C-, -CH2-C≡C-, -CH(CH3)C≡C-, and -C≡C-CH(C2H5)CH2-.

[0054] As used herein, the term "arylalkyl" refers to the part of an alkyl group in which a hydrogen atom is replaced by an aryl group.

[0055] As used herein, the terms “cycloalkyl” and “cycloalkenyl” refer to saturated and partially unsaturated cyclic hydrocarbon groups, respectively, having 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms.

[0056] As used herein, the terms “aromatic,” “ar,” or “aryl” refer to 6 to 14 ring atoms (e.g., C) having at least one ring having a conjugated π-electron system that is a carbocyclic structure (e.g., phenyl, fluorenyl, naphthyl, and anthracene). 6-14 Aromatic or C 6-14 This refers to radicals containing an aryl group. The aryl group can be, for example, a 6-membered monocyclic system, a 10-membered bicyclic system, or a 14-membered tricyclic system, each having 6 to 14 carbon atoms.

[0057] As used herein, the term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine, or iodine.

[0058] As used herein, the terms “carbocyclic,” “carbocyclic,” and “carbocykyl” refer to monocyclic or polycyclic radicals that contain only carbon as ring atoms and may be saturated or partially unsaturated, respectively. Fully saturated carbocyclics are called cycloalkyls. Partially unsaturated cycloalkyl groups may be called “cycloalkenyls” if the carbocyclic contains at least one double bond, or “cycloalkynyls” if the carbocyclic contains at least one triple bond. Unless otherwise specified herein, this term is intended to include both substituted and unsubstituted carbocyclic groups. The term “carbocyclic” also includes cyclic structures of bridges and spirocondensations that do not contain heterocyclic atoms. This term also includes monocyclic or fused-polycyclic (i.e., rings that share pairs of adjacent ring atoms) groups. Polycyclic groups include bicycles, tricycles, tetracycles, and so on. Unless otherwise specified herein, carbocyclic groups may be optionally substituted with one or more substituents.

[0059] As used herein, the terms “heteroaryl” or alternatively “heteroaromatic” refer to a 5- to 18-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., those in which 6, 10, or 14 π electrons are shared in a cyclic arrangement) having a ring carbon atom and 1 to 6 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur (“5- to 18-membered heteroaryl”). A polycyclic ring system of heteroaryls may contain one or more heteroatoms in one or both rings. Wherever it appears herein, numerical ranges such as “5-18” refer to each integer within a given range. For example, “5-18 ring atoms” means that a heteroaryl group can consist of up to 18 ring atoms, such as 5 ring atoms, 6 ring atoms, etc. In some examples, heteroaryls may have 5 to 14 ring atoms. In some embodiments, heteroaryl groups have a divalent radical derived from, for example, a monovalent heteroaryl radical, whose name ends in "-yl" by removing one hydrogen atom from the atom with free valence, and adding "-ene" to the name of the corresponding monovalent radical, for example, a pyridyl group with two bonds is pyridylene. The term "heteroaryl" may also refer to a monocyclic or fused ring (i.e., a ring sharing pairs of adjacent atoms) group of 5 to 12 ring atoms containing, for example, 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S (the remaining ring atoms are C), and further having a fully conjugated π-electron system, where 0, 1, 2, 3, or 4 atoms in each ring may be substituted with substituents. Non-limiting examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, quinazoline, isoquinoline, purine, and carbazole.

[0060] As used herein, the terms “heterocyclic,” “heterocyclic,” or “heterocyclyl” refer to fully saturated or partially unsaturated cyclic groups, such as monocyclic, bicyclic, or tricyclic groups of 3 to 7 members, having at least one heteroatom on at least one ring, where 0, 1, 2, or 3 atoms on each ring may be substituted with substituents. Each ring of a heterocyclic group containing heteroatoms may also have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heterocyclic group may be bonded to any heteroatom or carbon atom in the ring or ring system.

[0061] As used herein, the term "oxo" refers to an oxygen atom that, when bonded to carbon, forms a carbonyl group; when bonded to nitrogen, forms an N-oxide group; and when bonded to sulfur, forms a sulfoxide group or sulfone group.

[0062] As used herein, the term “substituent” means a group “substituted” on any of the functional groups described herein, for example, an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heterocyclyl group, or heteroaryl group at any atom of that group. Preferred substituents include halogens, CN, NO2, OR 15 , SR 15 S(O)2OR 15 , NR 15 R 16 , C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR 15 , C(O)NR 15 R 16 , OC(O)NR 15 R 16 , NR 15 C(O)NR 15 R 16 , C(NR 16 )NR 15 R 16 , NR 15C(NR 16 )NR 15 R 16 、S(O)2NR 15 R 16 、R 17 、C(O)R 17 、NR 15 C(O)R 17 、S(O)R 17 、S(O)2R 17 、R 16 、oxo, C(O)R 16 、C(O)(CH2) m OH, (CH2) n OR 15 、(CH2) m C(O)NR 15 R 16 、NR 15 S(O)2R 17 are included, but not limited thereto, and m is independently 0 - 6. R 15 is independently hydrogen, C1 - C4 alkyl, or C3 - C6 cycloalkyl. R 16 is independently hydrogen, alkenyl, alkynyl, C3 - C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1 - C4 alkyl, or C1 - C4 alkyl substituted with C3 - C6 cycloalkyl, aryl, heterocyclyl, or heteroaryl. R 17 is independently C3 - C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1 - C4 alkyl, or C1 - C4 alkyl substituted with C3 - C6 cycloalkyl, aryl, heterocyclyl, or heteroaryl. R 15 、R 16 、and R 17 in each of C3 - C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, and C1 - C4 alkyl may each be optionally substituted with halogen, CN, C1 - C4 alkyl, OH, C1 - C4 alkoxy, NH2, C1 - C4 alkylamino, C1 - C4 dialkylamino, C1 - C2 perfluoroalkyl, C1 - C2 perfluoroalkoxy, or 1,2 - methylenedioxy.

[0063] Any enumeration of chemical groups in any definition of a variable herein includes the definition of that variable as any one of the enumerated groups or a combination of the enumerated groups. Any enumeration of embodiments relating to a variable herein includes that embodiment as any one of the embodiments or in combination with any other embodiment or part thereof.

[0064] Because the compounds of the present invention may contain one or more chiral centers, they may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers, and diastereomer mixtures. All such isomeric forms of these compounds are clearly included in the present invention. The compounds of the present invention may also be represented in multiple tautomers, in which case the present invention clearly includes all tautomers of the compounds described herein. All such isomeric forms of such compounds are clearly included in the present invention. All crystalline forms of the compounds described herein are clearly included in the present invention. [Modes for carrying out the invention]

[0065] The present invention provides novel fluorinated cyclic derivatives of sulfonamides and sulfones as TRPML modulators, including their salts, solvates, hydrates, and polymorphs. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention, as well as the use of such compositions in the treatment of a variety of diseases and illnesses associated with or related to TRPML, such as neurodegenerative diseases, lysosomal storage disorders, muscular dystrophy, ROS or oxidative stress-related diseases, and skin or photoaging-related damage.

[0066] In one embodiment, the present invention generally relates to formula (I):

[0067] [ka] With respect to a compound having the structure of, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, in the formula, Ring A is a 4- to 9-membered (e.g., 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered) carbon ring or heteroring substituted with 1 to 8 F atoms. Ring B is either a substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, pyridadinyl, pyrimidinyl, pyrrolyl, or thiophene, or a substituted or unsubstituted bicyclic or polycyclic carbocyclic or heterocyclic ring system. P is CH, N, or CR 2 And, Q is CH, N, or CR 2 And, U is either C or N, V is either C or N, W is CH, N, C(=O), C(=S), or CR W1 R W2 And R W1 and R W2 Each of these is independently H or C 1-6 It is alkyl, X is either C or N, Y is C, CR Y , or N, R Y is H, F, or C 1-6 It is alkyl, R 1 It is selected from the group consisting of F, CHF2, -CF3, -CH2CF3, CF2CH3, CF2CH2F, CF2CHF2, -CF(CH3)2, -OCF3, and -OCH(CH3)2. R 2 These are, independently, halogen, unsubstituted, or substituted C 1-6 Alkyl and C 1-6 Selected from the group consisting of alkoxy, OH, CN, NRR', N(R)C(=O)RR', C(=O)R, and C(=O)NRR', R 3 These are, independently, halogen, CN, CF3, and C. 1-5 Alkyl, C 3-7 Selected from the group consisting of cycloalkyl and heterocycles, R and R' can independently be H or C 1-6They are alkyl or cycloalkyl groups, and optionally R and R' form a 3-6 membered ring together with the nitrogen or carbon atom to which they are bonded, and optionally, independently, C 1-3 alkyl, halogen, OH, OC 1-3 Substituted with 0 to 3 substituents selected from the group consisting of alkyl and CN, m is 0, 1, 2, 3, or 4. n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. i is 0, 1, or 2.

[0068] In certain embodiments, ring B is either an unsubstituted or substituted phenyl compound.

[0069] In a particular embodiment, i is 0, and ring B is a substituted phenyl

[0070] [ka] That is the case.

[0071] In a particular embodiment, i is 0, and ring B is a substituted phenyl

[0072] [ka] And in the formula, R 3 is a halogen atom (for example, F).

[0073] In certain embodiments, ring B is an unsubstituted pyridinyl

[0074] [ka] That is the case.

[0075] In certain embodiments, ring B is a substituted or unsubstituted thiophene.

[0076] In certain embodiments, i is 0, and ring B is a substituted or unsubstituted thiophene. In certain embodiments, ring B is an unsubstituted thiophene.

[0077] [ka] That is the case.

[0078] In certain embodiments, ring B is substituted or unsubstituted pyrrole. In certain embodiments, ring B is unsubstituted pyrrole

[0079] [ka] That is the case.

[0080] In a particular embodiment, ring B is bicyclo[1.1.1]pentane

[0081] [ka] That is the case.

[0082] In a particular embodiment, ring B is 2-oxabicyclo[2.2.2]octane.

[0083] [ka] That is the case.

[0084] In a particular embodiment, ring B is

[0085] [ka] That is the case.

[0086] In a particular embodiment of (I), X is N.

[0087] In a particular embodiment of (I), X is N, P is CH, Q is CH, U is C, and V is C.

[0088] [ka]

[0089] (I a In a particular embodiment of ), W is N.

[0090] [ka]

[0091] (I a In a particular embodiment of ), W is CH.

[0092] [ka]

[0093] In a particular embodiment of (I), X is C.

[0094] In a particular embodiment of (I), X is C, P is CH, Q is CH, U is N, V ​​is C, and W is N.

[0095] [ka]

[0096] (I)~(I d In a particular embodiment of ), Y is N.

[0097] (I)~(I d In a particular embodiment of ), Y is C.

[0098] (I)~(I d In a particular embodiment of ), Y is CH.

[0099] (I)~(I d In certain embodiments of the invention, ring A is a four-membered carbon ring or heteroring substituted with one or more F atoms.

[0100] (I)~(I d In certain embodiments of the invention, ring A is a five-membered carbon ring or heteroring substituted with one or more F atoms.

[0101] (I)~(I d In certain embodiments of the invention, ring A is a six-membered monocyclic or bicyclic carbon ring or heterocycle substituted with one or more F atoms.

[0102] (I)~(I d In certain embodiments of the invention, ring A is a seven-membered monocyclic or bicyclic carbon ring or heterocycle substituted with one or more F atoms.

[0103] (I)~(I d In certain embodiments of the invention, ring A is an 8-membered bicyclic or heterocyclic carbon ring substituted with one or more F atoms.

[0104] (I)~(I d In certain embodiments of the invention, ring A is a nine-membered bicyclic or heterocyclic carbocyclic ring substituted with one or more F atoms.

[0105] (I)~(I d In certain embodiments of the model, ring A is a heterobicycle substituted with one or more F atoms.

[0106] (I)~(I d In a particular embodiment of the above, ring A is replaced by two or more Fs (e.g., 2, 3, 4, 5, 6, 7, or 8 Fs).

[0107] (I)~(I d In a particular embodiment of ), ring A is

[0108] [ka] It has a structural formula selected from the following.

[0109] (I)~(I d In a particular embodiment of ), ring A is

[0110] [ka]

[0111] [ka]

[0112] [ka] It has a structural formula selected from the following.

[0113] (I)~(I d In a particular embodiment of ), ring A is

[0114] [ka] It has a structural formula selected from the following.

[0115] (I)~(I d In a particular embodiment of ), ring A is

[0116] [ka] And in the formula, R 4 Each of these is independently substituted with D, OH, CN, or 0 to 3 F atoms (e.g., 0, 1, 2, or 3 F atoms) in an arbitrarily selected manner. 1-2 Alkyl or two R 4 These atoms, together with the carbon atoms to which they are bonded, form a 3-4 membered carbocyclic or heterocyclic ring, or two R atoms. 4These, together with the carbon atoms to which they bond, form a 3- to 7-membered (e.g., 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered) carbocyclic or heterocyclic ring. n is 1, 2, 3, 4, 5, or 6. j is 0, 1, 2, 3, or 4.

[0117] In a particular embodiment, j is 0. In a particular embodiment, j is 1. In a particular embodiment, j is 2. In a particular embodiment, j is 3. In a particular embodiment, j is 4.

[0118] (I)~(I d In a particular embodiment of ), R 1 It is CHF2.

[0119] (I)~(I d In a particular embodiment of ), R 1 It is CF2CH3.

[0120] (I)~(I d In a particular embodiment of ), R 1 It is CF2CHF.

[0121] (I)~(I d In a particular embodiment of ), R 1 It is CF2CH2F2.

[0122] (I)~(I d In a particular embodiment of ), R 1 It is F.

[0123] [ka] As a non-restrictive example,

[0124] [ka] These are some examples.

[0125] In certain embodiments, the compound has a structural formula

[0126] [ka] It has.

[0127] In certain embodiments, the compound has a structural formula

[0128] [ka] It has.

[0129] In certain embodiments, the compound has a structural formula

[0130] [ka] It has.

[0131] In certain embodiments, the compound has a structural formula

[0132] [ka] It has.

[0133] In certain embodiments, the compound has a structural formula

[0134] [ka] It has.

[0135] In certain embodiments, the compound has a structural formula

[0136] [ka] It has.

[0137] In certain embodiments, the compound has a structural formula

[0138] [ka] It has.

[0139] In certain embodiments, the compound has a structural formula

[0140] [ka] It has.

[0141] In certain embodiments, the compound has a structural formula

[0142] [ka] It has, in the formula, R 4 Each of these is independently replaced by C, which is arbitrarily substituted with 0 to 3 (e.g., 0, 1, 2, or 3) Fs. 1-2 Alkyl or two R 4 These atoms, together with the carbon atoms to which they are bonded, form a 3-4 membered carbocyclic or heterocyclic ring, or two R atoms. 4 These, together with the carbon atoms to which they bond, form a 3- to 6-membered (e.g., 3-membered, 4-membered, 5-membered, or 6-membered) carbocyclic or heterocyclic ring. n is 1, 2, 3, 4, 5, or 6. j is 0, 1, 2, 3, or 4.

[0143] In certain embodiments, the compound has a structural formula

[0144] [ka] It has, in the formula, R 4 Each of these is independently replaced by C, which is arbitrarily substituted with 0 to 3 (e.g., 0, 1, 2, or 3) Fs. 1-2 Alkyl or two R 4These atoms, together with the carbon atoms to which they are bonded, form a 3-4 membered carbocyclic or heterocyclic ring, or two R atoms. 4 These, together with the carbon atoms to which they bond, form a 3- to 6-membered (e.g., 3-membered, 4-membered, 5-membered, or 6-membered) carbocyclic or heterocyclic ring. n is 1, 2, 3, 4, 5, or 6. j is 0, 1, 2, 3, or 4.

[0145] (I m )~(I n In a particular embodiment of ), R 4 Each of these is independently a C molecule that is optionally substituted with D, OH, CN, or 0 to 3 F atoms. 1-2 It is alkyl.

[0146] (I m )~(I n In a particular embodiment of ), two R 4 These, along with the carbon atoms to which they bond, form a three-membered carbocyclic ring.

[0147] (I m )~(I n In a particular embodiment of ), two R 4 These, along with the carbon atoms to which they bond, form a four-membered carbocyclic or heterocyclic ring.

[0148] (I m )~(I n In a particular embodiment of ), two R 4 These atoms, along with the carbon atoms to which they are bonded, form a 3- to 7-membered carbocyclic or heterocyclic ring.

[0149] (I e )~(I n In a particular embodiment of ), j is 0.

[0150] (I e )~(I n In a particular embodiment of ), j is 1 or 2.

[0151] (I e )~(I n In a particular embodiment of ), j is 3 or 4.

[0152] (I e )~(I n In a particular embodiment of ), j is 1, and R 4 It bonds to a carbon atom adjacent to the N atom. In a particular embodiment, R 4 This is CF3.

[0153] (I e )~(I n In a particular embodiment of ), j is 2 and there are 2 R 4 It is bonded to a carbon atom adjacent to the N atom of ring A. In a particular embodiment, two R 4 One or both of these are C, which is optionally replaced by 1 to 5 Fs. 1-3 It is alkyl.

[0154] (I e )~(I n In a particular embodiment of ), j is 2 and there are 2 R 4 These, along with the carbon atoms to which they are bonded, form a cyclopropyl group.

[0155] (I e )~(I n In a particular embodiment of ), j is 2 and there are 2 R 4 These atoms, along with the carbon atoms to which they are bonded, form a 5- to 7-membered carbocyclic or heterocyclic ring.

[0156] (I)~(I n In a particular embodiment of ), n is an integer selected from 1, 2, 3, 4, 5, or 6.

[0157] In a particular embodiment, n is 1. In a particular embodiment, n is 2. In a particular embodiment, n is 3. In a particular embodiment, n is 4. In a particular embodiment, n is 5. In a particular embodiment, n is 6.

[0158] (I e )~(I n In a particular embodiment of ), R 1 It is CF2CH3.

[0159] (I e )~(I n In a particular embodiment of ), R 1 It is CF2CH2F.

[0160] (I e )~(I n In a particular embodiment of ), R 1 It is CF2CHF2.

[0161] (I e )~(I n In a particular embodiment of ), R 1 It is CHF2.

[0162] (I e )~(I n In a particular embodiment of ), R 1 It is F.

[0163] (I)~(I n In a particular embodiment of ), m is 0.

[0164] (I)~(I n In a particular embodiment of ), m is 1.

[0165] (I)~(I n In a particular embodiment of ), m is 2.

[0166] (I)~(I n In a particular embodiment of ), m is 1 and R 2 teeth,

[0167] [ka] It has an arrangement represented by [this].

[0168] In a particular embodiment, R 2 teeth,

[0169] [ka] It has the following arrangement.

[0170] In a particular embodiment, R 2 It is a halogen.

[0171] In a particular embodiment, R 2 It is Cl.

[0172] In a particular embodiment, R 2 This is a C1 alkyl or alkoxy molecule optionally substituted with an amino, an OH group, and 0 to 3 (e.g., 0, 1, 2, or 3) fluorine atoms.

[0173] Exemplary compounds of the present invention include those listed in Table 1 below.

[0174] [Table 1-1]

[0175] [Table 1-2]

[0176] [Table 1-3]

[0177] [Table 1-4]

[0178] [Table 1-5]

[0179] [Table 1-6]

[0180] [Table 1-7]

[0181] [Table 1-8]

[0182] [Table 1-9]

[0183] [Table 1-10]

[0184] [Table 1-11]

[0185] [Table 1-12]

[0186] In certain embodiments, the compounds disclosed herein have one or more deuterium atoms instead of one or more hydrogen atoms.

[0187] In certain embodiments, the compounds disclosed herein have one deuterium atom instead of one hydrogen atom.

[0188] In another aspect, the present invention generally relates to pharmaceutical compositions comprising the compounds disclosed herein.

[0189] In another aspect, the present invention generally relates to a unit dose form comprising a pharmaceutical composition containing the compounds disclosed herein.

[0190] In a particular embodiment, the unit dosage is a tablet.

[0191] In certain embodiments, the unit dosage is a capsule.

[0192] In another aspect, the present invention relates generally to a method for treating or reducing a disease or disorder, comprising the step of administering a therapeutically effective dose of one of the compounds disclosed herein to a subject in need of treatment or reduction of the disease or disorder.

[0193] In certain embodiments, the methods disclosed herein are suitable for treating diseases or disorders mediated by TRPML. In certain embodiments, the methods disclosed herein are suitable for treating diseases or disorders mediated by loss of function of TRPML1, such as type IV mucolipidosis (ML4) and Niemann-Pick type C (NPC).

[0194] In certain embodiments, the disease or disorder is a lysosomal storage disorder or a related disease or disorder.

[0195] In certain embodiments, the disease or disorder is selected from the group consisting of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, frontotemporal dementia, or related diseases or disorders.

[0196] In certain embodiments, the disease or disorder is neuronal ceroid lipofuscinosis (NCL) or Batten disease, or a related disease or disorder.

[0197] In a particular embodiment, the disease or disorder is an NPC, or a related disease or disorder.

[0198] In certain embodiments, the disease or disorder is Charcot-Marie-Tooth disease (CMT), or a related disease or disorder.

[0199] In certain embodiments, the disease or disorder is age-related macular degeneration (AMD) or a related disease or disorder.

[0200] In certain embodiments, the disease or disorder is cystic fibrosis (CF) or a related disease or disorder.

[0201] In certain embodiments, the disease or disorder is autosomal dominant polycystic kidney disease (ADPKD), or a related disease or disorder.

[0202] In certain embodiments, the disease or disorder is selected from cancers in which TRPML1 is overexpressed in cancer cells.

[0203] In a particular embodiment, the disease or disorder is Batten disease.

[0204] In certain embodiments, the disease or disorder is muscular dystrophy or a related disease or disorder.

[0205] In certain embodiments, the disease or disorder is oxidative stress or ROS, or a related disease or disorder.

[0206] In another aspect, the present invention generally relates to a method for treating or reducing the effects of aging, comprising the step of administering a therapeutically effective dose of one of the compounds disclosed herein to a subject in need of treatment or reduction of the effects of aging.

[0207] In certain embodiments, the effects of aging include skin aging.

[0208] In certain embodiments, the effects of aging include photoaging.

[0209] In another aspect, the present invention generally relates to a method for treating or reducing oxidative stress or ROS-related diseases or disorders, comprising the step of administering a therapeutically effective dose of a TRPML1 agonist or a composition comprising a TRPML1 agonist as disclosed herein to a subject in need of treatment or reduction of the disease or disorder.

[0210] In another aspect, the present invention generally relates to a method for treating or reducing oxidative stress or ROS-related diseases or disorders, comprising the step of administering a therapeutically effective dose of one of the compounds disclosed herein to a subject in need of treatment or reduction of the disease or disorder.

[0211] In one embodiment of the method of the present invention, administration to the subject is performed by oral administration.

[0212] In one embodiment of the method of the present invention, administration to the subject is performed by local administration.

[0213] In another aspect, the present invention generally relates to the use of the compounds disclosed herein with pharmaceutically acceptable excipients, carriers, or diluents in the preparation of pharmaceuticals for treating diseases or disorders.

[0214] In certain embodiments of the use of the present invention, the disease or disorder is a neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, frontotemporal dementia, or a related disease or disorder.

[0215] In certain embodiments, the disease or disorder is selected from cancers in which TRPML1 is overexpressed in cancer cells.

[0216] In a particular embodiment, the disease or disorder is Batten disease.

[0217] In certain embodiments, the disease or disorder is muscular dystrophy or a related disease or disorder.

[0218] In certain embodiments, the disease or disorder is oxidative stress or ROS, or a related disease or disorder.

[0219] In a particular embodiment, the disease or disorder is skin aging.

[0220] In certain embodiments, the disease or disorder is photoaging.

[0221] The specific approaches and compounds disclosed herein are not intended to be limiting. Chemical structures in schemes herein are the same as the names of the same variables (e.g., R 1 , R 2Regardless of whether they are specified by (R, R', X, etc.), the variables defined herein correspond to the definitions (partial, atomic, etc.) of the chemical groups at the corresponding positions in the formulas of the compounds herein. The suitability of chemical groups in compound structures for use in the synthesis of other compound structures is within the realm of what a person skilled in the art can conceive. Further methods for synthesizing the compounds of the formulas herein and their synthetic precursors, including those in routes not explicitly shown in the schemes herein, are within the capabilities of a chemist of the ordinary art. Methods for optimizing reaction conditions and, if necessary, minimizing competing by-products are known in the art. The methods described herein may also further include steps of adding or removing suitable protecting groups before or after the steps specifically described herein in order to ultimately enable the synthesis of the compounds herein. Furthermore, various synthetic steps may be carried out in alternative sequences or orders to obtain the desired compound. Methodologies for synthetic chemical transformations and protecting groups (protection and deprotection) useful for the synthesis of applicable compounds are publicly known in the art, for example, as described in Comprehensive Organic Transformations by R. Larock, VCH Publishers (1989); Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons by TW Greene and PGMWuts (1999); Fieser and Fieser's Reagents for Organic Synthesis by L. Fieser and M. Fieser, John Wiley and Sons (1994); and Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions edited by L. Paquette.

[0222] The methods described herein are intended to convert a compound of one formula into a compound of another formula. The conversion process refers to one or more chemical conversions that can be carried out in situ or by isolation of an intermediate compound. The conversion may involve reacting a starting compound or intermediate with additional reagents using techniques and protocols known in the art, including those in the references cited herein. The intermediate may be used with or without purification (e.g., filtration, distillation, sublimation, crystallization, tritulation, solid-phase extraction, and chromatography).

[0223] The combinations of substituents and variables envisioned in this invention are only those that result in the formation of stable compounds.

[0224] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention intends to encompass all such compounds within its scope, including cis and trans isomers, atrop isomers, R and S enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0225] Isomer mixtures containing any of the various isomer ratios may be used in accordance with the present invention. For example, when combining only two isomers, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are intended by the present invention. Those skilled in the art will readily understand that similar ratios are intended for more complex isomer mixtures.

[0226] For example, if a specific enantiomer of the compound of the present invention is desired, it may be prepared by asymmetric synthesis or by induction with a chiral auxiliary agent, and the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomer salt is formed with a suitable optically active acid or base, and then the diastereomer thus formed is separated by fractional crystallization or chromatography, which is well known in the art, to recover the pure enantiomer.

[0227] Solvates and polymorphs of the compounds of the present invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0228] The present invention also provides compositions comprising an effective amount of any of the formulas herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or prodrug of said compound, and an acceptable carrier. Preferably, the compositions of the present invention are formulated for pharmaceutical use ("pharmaceutical composition"), and the carrier is a pharmaceutically acceptable carrier. The carrier must be "acceptable" in the sense that it is compatible with the other components of the formulation, and in the case of a pharmaceutically acceptable carrier, it must not be harmful to its recipient at amounts typically used in pharmaceuticals.

[0229] Examples of pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0230] The pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including oral and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. In certain embodiments, compounds of the formulas herein are administered transdermally (e.g., using transdermal patches). Other formulations may be conveniently presented in unit dosage forms, e.g., tablets and sustained-release capsules, as well as in liposomes, and may be prepared by any method known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th edition, 1985).

[0231] Such preparation methods involve a step of associating the administered molecule with components such as carriers that constitute one or more minor components. Generally, compositions are prepared by homogeneously and closely associating the active ingredient with a liquid carrier, liposomes, or micronized solid carrier, or both, and shaping the product as needed.

[0232] In certain preferred embodiments, the compounds are administered orally. Compositions of the present invention suitable for oral administration may be provided as individual units such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient, as powders or granules, as solutions or suspensions in aqueous or non-aqueous solutions, or as oil-in-water or water-in-oil liquid emulsions, or filled in liposomes, or as boluses. Soft gelatin capsules may be useful for containing such suspensions and may beneficially increase the absorption rate of the compounds.

[0233] Tablets may be prepared by compression or molding, with one or more auxiliary components of their choice. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, using a suitable machine. Molded tablets may be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent, using a suitable machine. Tablets may be optionally coated or notched, and may be formulated to provide sustained or controlled release of the active ingredient contained therein. Methods for formulating such sustained-release or controlled-release compositions of pharmaceutically active ingredients, including those herein and other compounds known in the art, are known in the art and are described in several published U.S. patents, including, but are not limited to, U.S. Patent Nos. 4,369,172 and 4,842,866, and the references cited herein. The coating can be used to deliver the compound to the intestines (see, for example, U.S. Patent Nos. 6,638,534, 5,217,720, and U.S. Patents Nos. 6,569,457, 6,461,631, 6,528,080, and 6,800,663, and the references cited herein). A useful formulation of the compound of the present invention is in the form of enteric-coated pellets in which the enteric layer contains hydroxypropyl methylcellulose acetate succinate.

[0234] For tablets intended for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, lactose and dried corn starch are useful diluents. When an aqueous suspension is administered orally, the active ingredient is combined with emulsifiers and suspending agents. Specific sweeteners and / or flavorings and / or colorings may be added, if desired.

[0235] Compositions suitable for topical administration include flavored bases, lozenges typically containing ingredients in sucrose and acacia or tragacanth, and lozenges containing active ingredients in an inert base such as gelatin and glycerin, or sucrose and acacia.

[0236] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that are isotonic with the blood of the recipient to whom the formulation is intended, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. The formulations may be supplied in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as sterile water for injection, immediately before use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0237] Such injectable solutions may be, for example, in the form of aqueous or oily suspensions for sterile injection. These suspensions can be formulated according to techniques known in the art, using suitable dispersing and wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic saline. Furthermore, sterile fixative oils are commonly used as solvents or suspension media. For this purpose, any compound fixative oil, including synthetic mono- or diglycerides, may be utilized. Fatty acids, such as oleic acid and its glyceride derivatives, as well as naturally pharmaceutically acceptable oils such as olive oil and castor oil, particularly their polyoxyethylated forms, are useful in injectable preparations. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersions.

[0238] The pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients that are solid at room temperature and liquid at rectal temperature, thereby dissolving in the rectum and releasing the active ingredients. Examples of such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0239] The pharmaceutical compositions of the present invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the field of pharmaceutical formulations and may be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0240] Topical administration of the pharmaceutical compositions of the present invention is particularly useful when the desired treatment involves an area or organ that is easily accessible by topical application. For topical application to the skin, the pharmaceutical compositions should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical compositions may be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention may also be applied topically to the lower intestinal tract by rectal suppository formulations or in suitable enema formulations. Topical transdermal patch and iontophoresis administration are also included in the present invention.

[0241] Particularly preferred derivatives and prodrugs increase the bioavailability of the compound when the compound of the present invention is administered to a mammal (for example, by enabling the orally administered compound to be readily absorbed by the blood) or improve the delivery of the parent compound to a biological compartment (e.g., the brain or central nervous system) compared to the parent species. Preferred prodrugs include derivatives in which a group that enhances water solubility or active transport across the intestinal membrane is added to the structure of the formula described herein (e.g., Alexander et al. 1988 J Med Chem 31, pp. 318-322; Bundgaard 1985 Elsevier:Amsterdam pp. 1-92; Bundgaard et al. 1987 J Med Chem 30, pp. 451-454; Bundgaard, HA Textbook of Drug Design and Development, Harwood Academic Publ.:Switzerland, 1991, pp. 113-191; Digenis et al. Handbook of Experimental Pharmacology 1975 pp. 28, 86-112; Friis et al. A Textbook of Drug Design and Development 2nd edition, Overseas Publ.:Amsterdam, 1996, pp. 351-385; Pitman 1981 Med Res Rev (See pages 1,189-1,1214).

[0242] The application of the therapeutic agent may be local, so as to be administered to the site of interest. Various techniques can be used to deliver the composition of interest to the site of interest, such as injection, catheter, trocar, projectiles, Pluronic® gel, stent, sustained-release polymer, or other devices that provide internal access.

[0243] In another embodiment, the present invention provides a method for impregnating an implantable drug release device, comprising the step of bringing the drug release device into contact with a compound or composition of the present invention. The implantable drug release device includes, but is not limited to, a biodegradable polymer capsule or bullet, a non-degradable, diffusible polymer capsule, and a biodegradable polymer wafer.

[0244] According to another embodiment, the present invention provides an implantable medical device coated with the compound of the present invention or a composition containing the compound, such that the compound is therapeutically active.

[0245] In another embodiment, the composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent is a compound or therapeutic agent that is known to have advantageous properties or demonstrates advantageous activity when administered alone or in combination with any of the compounds of the formulas herein. Drugs that can be usefully combined with these compounds include other kinase inhibitors, as well as / or other chemotherapeutic agents for the treatment of the diseases and disorders discussed above.

[0246] Such agents have been described in detail in the art. Preferably, the second therapeutic agent is an agent useful for treating or preventing cancer.

[0247] More preferably, a second therapeutic agent formulated together with the compound of the present invention is a drug useful for treating TRPML-mediated diseases / disorders.

[0248] In another embodiment, the present invention provides separate dosage forms of the compounds of the present invention and a second therapeutic agent that are associated with each other. As used herein, the term “associated with each other” means that the separate dosage forms are packaged together or otherwise combined with each other so that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within 24 hours, consecutively, or simultaneously).

[0249] In the pharmaceutical composition of the present invention, the compound of the present invention is present in an effective amount. As used herein, the term “effective amount” means an amount sufficient, when administered in an appropriate dosing regimen, to reduce or alleviate the severity, duration, or development of the disorder being treated, to prevent the progression of the disorder being treated, to cause regression of the disorder being treated, or to enhance or improve the preventive or therapeutic effect of another therapeutic agent.

[0250] The interrelationship of dosages in animals and humans (based on milligrams per square meter of body surface area) is described by Freireich et al. in 1966 Cancer Chemother Rep 50: p. 219. Body surface area can be roughly determined from the patient's height and weight (see, for example, Scientific Tables, Geigy Pharmaceuticals, Ardley, NY, 1970, p. 537). The effective dose of the compound of the present invention can range from about 0.001 mg / kg to about 500 mg / kg, more preferably from 0.01 mg / kg to about 50 mg / kg, and more preferably from 0.1 mg / kg to about 2.5 mg / kg. The effective dose also varies, as those skilled in the art will understand, depending on the disease being treated, the severity of the disease, the route of administration, the patient's sex, age, and overall health, the use of excipients, the possibility of concomitant use with other treatments such as the use of other drugs, and the judgment of the physician administering the treatment.

[0251] In the case of a pharmaceutical composition containing a second therapeutic agent, the effective dose of the second therapeutic agent is between approximately 20% and 100% of the dose typically used in a monotherapy regimen using only that agent. Preferably, the effective dose is between approximately 70% and 100% of the usual monotherapy dose. The usual monotherapy doses of these second therapeutic agents are well known in the art (see, for example, Wells et al., 2000 Pharmacotherapy Handbook, 2nd edition, Appleton and Lange, Stamford, Conn., PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. 2000, which are incorporated herein by reference in their entirety).

[0252] Some of the second therapeutic agents mentioned above are expected to act synergistically with the compounds of the present invention. When this occurs, it becomes possible to reduce the effective dose of the second therapeutic agent and / or the compounds of the present invention from the dose required for monotherapy. This has the advantages of minimizing toxic side effects of any of the compounds of the present invention in the second therapeutic agent, synergistically improving efficacy, improving ease of administration or use, and / or reducing the overall cost of preparing or formulating the compounds.

[0253] As used herein, the term “co-administered” means that a second therapeutic agent may be administered together with the compound of the present invention as part of a single-dose form (for example, a composition of the present invention comprising the compound of the present invention and the second therapeutic agent described above) or as a separate multi-dose form. Alternatively, the additional agent may be administered before, consecutively with, or after the administration of the compound of the present invention. In such a combination therapy treatment, the compound of the present invention and the second therapeutic agent are administered together by conventional methods. Co-administration to a subject of a composition of the present invention comprising both the compound of the present invention and the second therapeutic agent does not preclude the administration of the same therapeutic agent, any other second therapeutic agent, or any compound of the present invention separately to the subject at another point in time during treatment.

[0254] The effective doses of these second therapeutic agents are well known to those skilled in the art, and guidelines for administration can be found in the patents and published patent applications referenced herein, as well as in the Pharmacotherapy Handbook, 2nd edition, edited by Wells et al., Appleton and Lange, Stamford, Conn. (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, determining the optimal effective dose range of the second therapeutic agent is within the realm of those skilled in the art.

[0255] In one embodiment of the present invention, in which a second therapeutic agent is administered to the target, the effective dose of the compound of the present invention is less than the effective dose when the second therapeutic agent is not administered. In another embodiment, the effective dose of the second therapeutic agent is less than the effective dose when the compound of the present invention is not administered. In this way, undesirable side effects associated with high doses of either drug can be minimized. Other possible benefits (including, but not limited to, improvements in the administration regimen and / or reductions in drug costs) will be obvious to those skilled in the art.

[0256] In another aspect, the present invention provides the use of any compound of the formulas herein, alone or in combination with one or more of the second therapeutic agents described above, in the manufacture of a pharmaceutical product as a single composition or a separate dosage form, for the treatment or prevention of a subject having the diseases, disorders, or symptoms described herein. Another aspect of the present invention is a compound of the formulas herein for use in the treatment or prevention of a subject having the diseases, disorders, or symptoms described herein. In another aspect, the method herein further includes a step of monitoring the subject's response to the administration of the treatment. Such monitoring may include periodic sampling of the subject's tissue, fluid, specimen, cell, protein, chemical marker, genetic material, etc., as markers or indicators of the treatment regimen. In another method, the subject is pre-screened or identified as needing such treatment by evaluating relevant markers or indicators of suitability for such treatment.

[0257] In one embodiment, the present invention provides a method for monitoring the progress of a treatment. The method includes determining the level of a diagnostic marker (marker) (e.g., any target or cell type as described herein, modulated by the compounds herein) or a diagnostic measurement (e.g., screening, assay) in a subject suffering from or susceptible to the disorder or symptoms described herein, wherein the subject is administered a therapeutic dose of the compounds herein sufficient to treat the disease or symptoms. The level of the marker determined by the method can be compared with the marker level observed in either a healthy normal control or another affected patient to establish the disease state of the subject. In a preferred embodiment, a second level of the marker in the subject is determined at a later point in time than the determination of the first level, and the course of the disease or the effectiveness of the treatment can be monitored by comparing these two levels. In a particular preferred embodiment, the pre-treatment level of the marker in the subject is determined before initiating treatment according to the present invention, and the effectiveness of the treatment can be determined by comparing this pre-treatment level of the marker with the level of the marker in the subject after initiation of treatment.

[0258] In certain embodiments of the method, the level of a marker or marker activity in the subject is determined at least once. Comparing the marker level to another measurement of the marker level obtained previously or later from, for example, the same patient, another patient, or a normal subject may be useful in determining whether the treatment according to the present invention produces the desired effect, thereby allowing for appropriate adjustment of the dosage level. The determination of the marker level may be performed using any suitable sampling / expression assay method known in the art or described herein. Preferably, tissue or body fluid samples are first removed from the subject. Examples of suitable samples include blood, urine, tissue, oral or buccal cells, and hair samples including hair follicles. Other suitable samples will be known to those skilled in the art. The determination of protein levels and / or mRNA levels (e.g., marker levels) in the sample can be performed using any suitable technique known in the art, including but not limited to enzyme immunoassay, ELISA, radiolabeling / assay techniques, blotting / chemiluminescence, and real-time PCR.

[0259] The present invention also provides kits used to treat diseases, disorders, or symptoms thereof, including those described herein. These kits include a) a pharmaceutical composition comprising any compound or salt thereof of any of the formulas described herein, or a prodrug or salt thereof, or a hydrate, solvate, or polymorph thereof (the pharmaceutical composition is contained in the container), and b) instructions describing how to use the pharmaceutical composition to treat diseases, disorders, or symptoms thereof, including those described herein.

[0260] The container may be any container or other sealed or sealable device capable of holding the pharmaceutical composition. Examples include bottles, dividers or multi-chamber holders or bottles (each divider or chamber containing a single dose of the composition), divider foil packets (each divider containing a single dose of the composition), or dispensers for dispensing single doses of the composition. The container may be any conventional shape or form known in the art, made from pharmaceutically acceptable materials, e.g., paper or corrugated boxes, glass or plastic bottles or jars, resealable bags (e.g., those that hold "refills" of tablets for placement in different containers), or blister packs having individual doses for dispensing from the pack according to a treatment schedule. The container used may depend on the exact dosage form it contains; for example, conventional corrugated boxes are not typically used to hold liquid suspensions. It is feasible to commercialize a single dosage form by using more than one container together in a single package. For example, tablets may be contained in a bottle and then in a box. Preferably, the container is a blister pack.

[0261] The kit may further include information and / or instructions from a physician, pharmacist, or subject. Examples of such memory aids include numbers printed on each chamber or compartment containing the dosage corresponding to the day of the regimen in which the so-called tablets or capsules will be taken, or the date of the week printed on each chamber or compartment, or cards with the same kind of information.

[0262] The following examples illustrate, but are not intended to limit, the practical application of the present invention. [Examples]

[0263] [Table 2]

[0264] Compounds and synthesis methods The compounds of the present invention, including those specifically disclosed above and below in this specification, can be prepared as described in the following scheme.

[0265] [Table 3-1]

[0266] [Table 3-2]

[0267] [Table 3-3]

[0268] [Table 3-4]

[0269] [Table 3-5]

[0270] [Table 3-6]

[0271] Synthesis method Intermediate -L1: (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride

[0272] [ka]

[0273] Step 1: To a solution of 2,6-dichlorobenzoyl chloride (5 g, 23.9 mmol, 3.42 mL, 1 equivalent) in toluene (100 mL), 4-methylbenzenesulfonohydrazide (4.22 g, 22.7 mmol, 0.95 equivalents) and diisopropylethylamine (3.70 g, 28.7 mmol, 4.99 mL, 1.2 equivalents) were added. The mixture was stirred at 75°C for 3 hours. LC-MS confirmed that the 2,6-dichlorobenzoyl chloride was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was filtered, and the filter cake was dried under vacuum to obtain the desired 2,6-dichloro-N'-(p-tolylsulfonyl)benzohydrazide (5.5 g, crude) as a yellow solid. MS(ESI): mass calcd. For C 14 H 12 Cl2N2O3S 357.99,m / z found 359.1[M+H] + .

[0274] Step 2: A solution of 2,6-dichloro-N'-(p-tolylsulfonyl)benzohydrazide (1.6 g, 4.45 mmol, 1 equivalent) in thionyl chloride (6.09 g, 51.2 mmol, 3.72 mL, 11.5 equivalents) was stirred at 75°C for 1.5 hours. The reaction mixture was cooled to 60°C, the additional portion of 2,6-dichloro-N'-(p-tolylsulfonyl)benzohydrazide (1.60 g, 4.45 mmol, 1 equivalent) was added, and the reaction mixture was heated over 1 hour to return to 75°C. LC-MS (sample quenched with piperidine) confirmed that the 2,6-dichloro-N'-(p-tolylsulfonyl)benzohydrazide was completely consumed and the desired mass was detected. By concentrating the reaction mixture, the desired (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (1.7 g, crude) was obtained as a yellow gum. MS(ESI): mass calcd. For C 14 H 11 Cl3N2O2S 375.96,m / z found 426.1[M+H+49] + .

[0275] Intermediate -L2:(E)-2,6-difluoro-N'-tosylbenzohydrazonoyl chloride

[0276] [ka]

[0277] Step 1: To a solution of 2,6-difluorobenzoyl chloride (5 g, 28.3 mmol, 3.57 mL, 1 equivalent) in DCM (50 mL), TEA (7.16 g, 70.8 mmol, 9.85 mL, 2.5 equivalents) and 4-methylbenzenesulfonohydrazide (5.80 g, 31.2 mmol, 1.1 equivalents) were added. The mixture was stirred at 15°C for 12 hours. LC-MS confirmed that the 2,6-difluorobenzoyl chloride was completely consumed and one main peak with the desired mass was detected. HCl (1 M, 100 mL) was added to the crude product, and the reaction mixture was concentrated under reduced pressure to obtain the desired N'-(2,6-difluorobenzoyl)-4-methylbenzenesulfonohydrazide (5.0 g, crude) as a white solid. MS(ESI): mass calcd. For C 14 H 12 F2N2O3S 326.05,m / z found 327.2[M+H] + .

[0278] Step 2: A solution of 2,6-difluoro-N'-(p-tolylsulfonyl)benzohydrazide (700 mg, 2.15 mmol, 1 equivalent) in SOCl2 (10 mL) was stirred at 75°C for 0.5 hours. TLC confirmed that the 2,6-difluoro-N'-(p-tolylsulfonyl)benzohydrazide was completely consumed, and a new spot was observed. The reaction mixture was concentrated under reduced pressure to obtain the desired (E)-2,6-difluoro-N'-tosylbenzohydrazonoyl chloride (700 mg, crude) as a pale yellow solid.

[0279] Intermediate -L3:4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1H-indazole

[0280] [ka]

[0281] Step 1: To a solution of 3,3-difluoro-2-methylazetidine (150 mg, 1.04 mmol, 1 equivalent, HCl) in THF (2 mL), TEA (106 mg, 1.04 mmol, 145 μL, 1 equivalent) was added dropwise at 25°C. After addition, the mixture was stirred at this temperature for 10 minutes, and a solution of (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (434 mg, 1.15 mmol, 1.1 equivalents) in THF (2 mL) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 25°C for 20 minutes. LC-MS confirmed that 3,3-difluoro-2-methylazetidine was completely consumed, and a single main peak with the desired mass was detected. This was then separated into 20 mL of water and 40 mL of ethyl acetate. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoro-2-methylazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (500 mg, crude) as a yellow solid. MS(ESI): mass calcd. For C 18 H 17 Cl2F2N3O2S 447.04,m / z found 448.2[M+H] + .

[0282] Step 2: To a solution of N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoro-2-methylazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (500 mg, 1.12 mmol, 1 equivalent) in DMF (10 mL), K2CO3 (771 mg, 5.58 mmol, 5 equivalents) was added. The mixture was stirred at 120 °C for 2 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoro-2-methylazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed and the desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with SiO3 (3 times with 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1-(p-tolylsulfonyl)indazole (450 mg, crude) as a yellow oil. MS(ESI): mass calcd. For C 18 H 16 ClF2N3O2S 411.06,m / z found 412.1[M+H] + .

[0283] Step 3: To a solution of 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1-(p-tolylsulfonyl)indazole (450 mg, 1.09 mmol, 1 equivalent) in MeOH (5 mL), K2CO3 (3.02 g, 21.9 mmol, 20 equivalents) was added. The mixture was stirred at 70°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1-(p-tolylsulfonyl)indazole was completely consumed, and one main peak with the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with Âr (3 times with 10 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1H-indazole (110 mg, crude) as a white solid. MS(ESI): mass calcd.For C 11 H 10 ClF2N3257.05,m / z found 258.0[M+H] + .

[0284] Intermediate-L4:Tert-butyl-4-chloro-3-iodo-1H-indazole-1-carboxylate

[0285] [ka]

[0286] Step 1: To a solution of 4-chloro-1H-indazole (5 g, 32.8 mmol, 1 equivalent) in DMF (20 mL), NIS (8.11 g, 36.1 mmol, 1.1 equivalents) was added. The mixture was stirred at 70°C for 3 hours. LC-MS confirmed that the 4-chloro-1H-indazole was completely consumed and the desired mass was detected. The crude product was added to H2O (50 mL) and extracted with MTBE (50 mL three times). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-iodo-1H-indazole (8 g, crude) as a yellow solid. MS (ESI): mass calcd. For C7H4ClIN2 277.91 m / z found 278.8 [M+H] + .

[0287] Step 2: To a solution of 4-chloro-3-iodo-1H-indazole (8 g, 28.7 mmol, 1 equivalent) in ACN (80 mL), tert-butoxycarbonyl tert-butyl carbonate (9.40 g, 43.1 mmol, 9.90 mL, 1.5 equivalents), TEA (5.81 g, 57.5 mmol, 8.00 mL, 2 equivalents), and DMAP (3.51 g, 28.7 mmol, 1 equivalent) were added. The mixture was stirred at 25°C for 2 hours. LC-MS confirmed that 4-chloro-3-iodo-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was concentrated to obtain the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, eluent with a 0-20% siRNA / petroleum ether gradient at 80 mL / min) to obtain the desired tert-butyl 4-chloro-3-iodoindazole-1-carboxylate (9.5 g, 25.1 mmol, 87.4% yield) as a yellow solid. MS(ESI): mass calcd. For C 12 H 12 ClIN2O2377.96 m / z found 322.8[M+H-56] + .

[0288] Intermediate-L5:4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole

[0289] [ka]

[0290] Step 1: A mixture of tert-butyl 4-chloro-3-iodoindazole-1-carboxylate (300 mg, 792 μmol, 1 equivalent), 3,3,4,4-tetrafluoropyrrolidine (142 mg, 792 μmol, 1 equivalent, HCl), Pd2(dba)3 (72.6 mg, 79.2 μmol, 0.1 equivalent), Cs2CO3 (775 mg, 2.38 mmol, 3 equivalents), and BINAP (49.3 mg, 79.2 μmol, 0.1 equivalent) in toluene (2 mL) was degassed and purged three times with N2. The mixture was stirred at 100°C for 3 hours under an N2 atmosphere. LC-MS confirmed that tert-butyl 4-chloro-3-iodoindazole-1-carboxylate was completely consumed and the desired mass was detected. H2O (20 mL) was added to the crude product, and the resulting solution was extracted with ELISA (15 mL three times). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired tert-butyl 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-carboxylate (200 mg, 508 μmol, 64.1% yield) as a yellow oil. MS(ESI): mass calcd. For C 16 H 16 ClF4N3O2393.09 m / z found 338.1[M+H-56] + .

[0291] Step 2: To a solution of tert-butyl 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-carboxylate (200 mg, 508 μmol, 1 equivalent) in DCM (2 mL), TFA (1.45 g, 12.7 mmol, 943 μL, 25 equivalents) was added. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that tert-butyl 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-carboxylate was completely consumed and the desired mass was detected. The reaction mixture was concentrated under vacuum to obtain the desired 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (200 mg, crude, TFA) as a brown oily substance. MS(ESI): mass calcd.For C 11 H8ClF4N3293.03 m / z found 294.0[M+H] + .

[0292] Intermediate-L6:Tert-butyl 4-fluoro-3-iodoindazole-1-carboxylate

[0293] [ka]

[0294] Step 1: To a solution of I2 (3.73 g, 14.7 mmol, 2.96 mL, 1 equivalent) in DMF (15 mL), 4-fluoro-1H-indazole (2 g, 14.7 mmol, 1 equivalent) and KOH (824 mg, 14.7 mmol, 1 equivalent) were added. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-fluoro-1H-indazole remained and the desired compound was detected. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution (30 mL) at 15°C, then diluted with HCl (50 mL), and extracted with H2O (30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-fluoro-3-iodo-1H-indazole (5.16 g, crude) as a red solid. MS(ESI):mass calcd.For C7H4FIN2261.94,m / z found 262.9[M+H] + .

[0295] Step 2: To a solution of 4-fluoro-3-iodo-1H-indazole (500 mg, 1.91 mmol, 1 equivalent) and tert-butoxycarbonyl tert-butyl carbonate (541 mg, 2.48 mmol, 570 μL, 1.3 equivalents) in DCM (5 mL), TEA (1.93 g, 19.1 mmol, 2.66 mL, 10 equivalents) and DMAP (23.3 mg, 191 μmol, 0.1 equivalent) were added. The mixture was stirred at 15°C for 2 hours. LC-MS confirmed that the 4-fluoro-3-iodo-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 30 mL of RINKAN. The organic phase was separated, washed with 10 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 4 / 1) to obtain the desired tert-butyl 4-fluoro-3-iodoindazole-1-carboxylate (300 mg, 828 μmol, 43.4% yield) as an orange solid. MS(ESI): mass calcd.For C 12 H 12FIN2O2361.99,m / z found 306.9[M+H-56] + .

[0296] Intermediate -L7:(2S)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-carbaldehyde

[0297] [ka]

[0298] Step 1: To a solution of [(2S)-4,4-difluoropyrrolidine-2-yl]methanol (0.7 g, 4.03 mmol, 1 equivalent, HCl) in THF (10 mL), TEA (1.22 g, 12.1 mmol, 1.68 mL, 3 equivalents) was added, and then a solution of (E)-2,6-dichloro-N-tosylbenzohydrazonoyl chloride (1.68 g, 4.44 mmol, 1.1 equivalents) in THF (10 mL) was added dropwise at 0°C. The mixture was stirred at 20°C for 2 hours. LC-MS confirmed that [(2S)-4,4-difluoropyrrolidine-2-yl]methanol was completely consumed and one main peak with the desired mass was detected. H2O (100 mL) was added to the reaction mixture and extracted with ELISA (3 times with 50 mL). The combined organic phases were washed with brine (twice with 30 mL), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the desired N-[(E)-[(2,6-dichlorophenyl)-[(2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-yl]methylene]amino]-4-methylbenzenesulfonamide (2 g, crude) as an orange solid. MS(ESI): mass calcd.For C 19 H 19 Cl2F2N3O3S 477.05,m / z found 478.1[M+H] + .

[0299] Step 2: To a solution of N-[(E)-[(2,6-dichlorophenyl)-[(2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-yl]methylene]amino]-4-methylbenzenesulfonamide (2 g, 4.18 mmol, 1 equivalent) in DMF (20 mL), K2CO3 (1.73 g, 12.5 mmol, 3 equivalents) was added. The mixture was stirred at 100 °C for 4 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-[(2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-yl]methylene]amino]-4-methylbenzenesulfonamide remained, indicating the detection of the desired compound. H2O (200 mL) was added to the reaction mixture and extracted with SiO (3 times with 100 mL). The combined organic phases were washed with brine (twice with 100 mL), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the desired [(2S)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-yl]methanol (1.5 g, crude) as a yellow solid. MS(ESI): mass calcd. For C 19 H 18 ClF2N3O3S 441.07,m / z found 460.2[M+H+18] + .

[0300] Step 3: To a solution of pyridine;sulfur trioxide (630 mg, 3.96 mmol, 3.5 equivalents) in DCM (10 mL) and DMSO (2 mL), TEA (687 mg, 6.79 mmol, 945 μL, 6 equivalents) was added. The mixture was stirred at 0°C for 1 hour. Then, [(2S)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-yl]methanol (500 mg, 1.13 mmol, 1 equivalent) was added to the reaction mixture. The reaction mixture was stirred at 20°C for 11 hours. LC-MS confirmed that [(2S)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-yl]methanol was completely consumed and one main peak with the desired mass was detected. H2O (100 mL) was added to the reaction mixture and extracted with MTBE (50 mL three times). The combined organic phase was washed with brine (50 mL twice), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the desired (2S)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-carbaldehyde (500 mg, crude) as a purple solid. MS(ESI): mass calcd.For C 19 H 16 ClF2N3O3S 439.06,m / z found 440.1[M+H] + .

[0301] Intermediate-L8:1-((S)-1-(4-chloro-1-tosyl-1H-indazole-3-yl)-4,4-difluoropyrrolidine-2-yl)ethane-1-ol

[0302] [ka]

[0303] Step 1: To a solution of (2S)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-carbaldehyde (500 mg, 1.14 mmol, 1 equivalent) in THF (10 mL), MeMgBr (3 M, 757 μL, 2 equivalents) was added under an N2 atmosphere. The mixture was stirred at 0°C for 2 hours. LC-MS confirmed that (S)-1-(4-chloro-1-tosyl-1H-indazole-3-yl)-4,4-difluoropyrrolidine-2-carbaldehyde was completely consumed, and one main peak with the desired mass was detected. The reaction mixture was quenched with HCl (1 M, 20 mL), then H2O (20 mL) was added, and the mixture was extracted with ELISA (3 times with 10 mL). The combined organic phases were washed with brine (twice with 10 mL), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 45%~75%B over 8.0 mins) to obtain the desired 1-((S)-1-(4-chloro-1-tosyl-1H-indazole-3-yl)-4,4-difluoropyrrolidine-2-yl)ethane-1-ol (80 mg, 157.9 μmol, 13.9% yield, 90% purity) as a white solid. MS(ESI): mass calcd.For C 20 H 20 ClF2N3O3S 455.09,m / z found 456.2[M+H] + .

[0304] Intermediate-L9:[(2R)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-yl]methanol

[0305] [ka]

[0306] Step 1: To a solution of [(2R)-4,4-difluoropyrrolidine-2-yl]methanol (500 mg, 2.88 mmol, 1 equivalent, HCl) in THF (10 mL), TEA (1.17 g, 11.5 mmol, 1.60 mL, 4 equivalents) and (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (1.20 g, 3.17 mmol, 1.1 equivalents) were added at 0°C. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that [(2R)-4,4-difluoropyrrolidine-2-yl]methanol had been completely consumed and the desired mass was detected. The reaction mixture was divided into 30 mL of H2O and 50 mL of ethyl acetate. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired N-[(E)-[(2,6-dichlorophenyl)-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-yl]methylene]amino]-4-methylbenzenesulfonamide (1.38 g, crude) as a yellow solid. MS(ESI): mass calcd. For C 19 H 19 Cl2F2N3O3S 477.0,m / z found 478.0[M+H] + .

[0307] Step 2: To a solution of N-[(E)-[(2,6-dichlorophenyl)-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-yl]methylene]amino]-4-methylbenzenesulfonamide (400 mg, 836 μmol, 1 equivalent) in DCM (5 mL), imidazole (114 mg, 1.67 mmol, 2 equivalents) and tert-butyl-chlorodimethyl-silane (151 mg, 1.00 mmol, 124 μL, 1.2 equivalents) were added under N2 at 0°C. The mixture was stirred at 15°C for 0.5 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-yl]methylene]amino]-4-methylbenzenesulfonamide was completely consumed and the desired mass was detected. The reaction mixture was separated into 20 mL of H2O and 30 mL of DCM. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, eluent with a 0-5% ethyl acetate / petroleum ether gradient at 60 mL / min) to obtain the desired (R,E)-N'-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4,4-difluoropyrrolidine-1-yl)(2,6-dichlorophenyl)methylene)-4-methylbenzene sulfonohydrazide (320 mg, 540 μmol, 64.6% yield) as a yellow solid. MS(ESI): mass calcd. For C 25 H 33 Cl2F2N3O3SSi 591.1,m / z found 592.1[M+H] + .

[0308] Step 3: To a solution of (R,E)-N'-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4,4-difluoropyrrolidine-1-yl)(2,6-dichlorophenyl)methylene)-4-methylbenzenesulfonohydrazide (320 mg, 540 μmol, 1 equivalent) in DMF (6 mL), K2CO3 (746 mg, 5.40 mmol, 10 equivalents) was added. The mixture was stirred at 100 °C for 2 hours. LC-MS confirmed that the (R,E)-N'-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4,4-difluoropyrrolidine-1-yl)(2,6-dichlorophenyl)methylene)-4-methylbenzenesulfonohydrazide had been completely consumed and the desired mass was detected. The reaction mixture was separated into 40 mL of H2O and 50 mL of ELISA. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired tert-butyl-dimethyl-[[(2R)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-yl]methoxy]silane (210 mg, crude) as a yellow solid. MS(ESI): mass calcd. For C 25 H 32 ClF2N3O3SSi 555.2,m / z found 556.1[M+H] + .

[0309] Step 4: To a solution of tert-butyl-dimethyl-[[(2R)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-yl]methoxy]silane (200 mg, 360 μmol, 1 equivalent) in DCM (4 mL), TFA (3.07 g, 26.9 mmol, 2 mL, 74.9 equivalents) was added. The mixture was stirred at 15°C for 0.5 hours. LC-MS confirmed that tert-butyl-dimethyl-[[(2R)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-yl]methoxy]silane had been completely consumed and the desired mass was detected. The reaction mixture was divided into 30 mL of H2O and 40 mL of DCM. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 1 / 1) to obtain the desired [(2R)-1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-2-yl]methanol (70 mg, 158 μmol, 44.1% yield) as a white solid. MS(ESI): mass calcd. For C 19 H 18 ClF2N3O3S 444.1,m / z found 445.0[M+H] + .

[0310] Intermediate-L10:3-bromo-4-chloro-1-tetrahydropyran-3-yl-indazole

[0311] [ka]

[0312] Step 1: To a solution of 4-chloro-1H-indazole (5 g, 32.8 mmol, 1 equivalent) in DMF (50 mL), NBS (6.42 g, 36.1 mmol, 1.1 equivalents) was added at 25°C. The mixture was stirred at 70°C for 3 hours. LC-MS confirmed that the 4-chloro-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was poured into H2O (150 mL) at 25°C, and the mixture was stirred at 25°C for 0.5 hours. The mixture was filtered, and the filter cake was washed with H2O (100 mL twice). The solid was collected and dried under reduced pressure to obtain the desired 3-bromo-4-chloro-1H-indazole (7.5 g, 32.40 mmol, 98.9% yield) as a yellow solid. MS(ESI):mass calcd.For C7H4BrClN2229.92,m / z found 230.9[M+H] + .

[0313] Step 2: To a solution of 3-bromo-4-chloro-1H-indazole (6.5 g, 28.1 mmol, 1 equivalent) in  (60 mL), TsOH.H2O (534 mg, 2.81 mmol, 0.1 equivalent) and DHP (3.54 g, 42.1 mmol, 3.85 mL, 1.5 equivalent) were added at 15°C. The mixture was stirred at 80°C for 0.5 hours. LC-MS revealed the presence of a small amount of residual 3-bromo-4-chloro-1H-indazole. Several new peaks were observed on LC-MS, indicating the detection of the desired compound. The reaction mixture was added to water (200 mL) and extracted with  (3 times with 100 mL). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, eluent with a 0-100% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain the desired 3-bromo-4-chloro-1-tetrahydropyran-3-yl-indazole (6.1 g, 19.3 mmol, 68.8% yield) as a white solid. MS (ESI): mass calcd. For C 12 H 12BrClN2O 313.98,m / z found 315.0[M+H] + .

[0314] Intermediate -L11:4-chloro-3-(6,6-difluoro-4-azaspiro[2,4]heptan-4-yl)-1H-indazole

[0315] [ka]

[0316] Step 1: To a solution of 1-benzylpyrrolidine-2,5-dione (3 g, 15.9 mmol, 1 equivalent) in THF (30 mL), Ti(i-PrO)4 (22.5 g, 79.3 mmol, 23.4 mL, 5 equivalents) and EtMgBr (3 M, 18.5 mL, 3.5 equivalents) were added at 0°C. The mixture was stirred at 20°C for 12 hours. LC-MS confirmed that 1-benzylpyrrolidine-2,5-dione was completely consumed. BF3.Et2O (11.3 g, 79.3 mmol, 9.75 mL, 5 equivalents) was added to the mixture. The mixture was stirred at 20°C for 4 hours. LC-MS confirmed that 1-benzylpyrrolidine-2,5-dione was completely consumed and one main peak with the desired mass was detected. The reaction mixture was quenched with 3N hydrochloric acid (30 mL) and extracted with ethyl acetate (60 mL three times). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (0.1% TFA conditions) to obtain the desired 4-benzyl-4-azaspiro[2.4]heptan-5-one (2 g, crude) as a yellow oil. MS(ESI): mass calcd. For C 13 H 15 NO 201.0,m / z found 202.2[M+H] + .

[0317] Step 2: To a solution of 4-benzyl-4-azaspiro[2.4]heptan-5-one (450 mg, 2.24 mmol, 1 equivalent) in THF (20 mL), LiHMDS (1 M, 8.94 mL, 4 equivalents) was added under N2 at -78°C. The mixture was stirred at -78°C for 1 hour. NFSI (2.82 g, 8.94 mmol, 4 equivalents) in THF (10 mL) was added to the mixture at -78°C. The mixture was stirred at 25°C for 12 hours. LC-MS confirmed the presence of residual 4-benzyl-4-azaspiro[2.4]heptan-5-one. Several new peaks were observed on LC-MS, indicating the detection of the desired compound. The reaction mixture was quenched at 0°C by adding saturated NH4Cl aqueous solution (200 mL) and extracted with ELISA (300 mL three times). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 30%~55% B over 8.0 mins) to obtain the desired 4-benzyl-6,6-difluoro-4-azaspiro[2.4]heptan-5-one (100 mg, crude) as a yellow oil. MS(ESI): mass calcd.For C 13 H 13 F2NO 237.10,m / z found 238.2[M+H] + .

[0318] Step 3: To a solution of 4-benzyl-6,6-difluoro-4-azaspiro[2.4]heptan-5-one (110 mg, 464 μmol, 1 equivalent) in THF (3 mL), BH3-Me2S (10 M, 92.7 μL, 2 equivalents) was added. The mixture was stirred at 40 °C for 12 hours. LC-MS confirmed that 4-benzyl-6,6-difluoro-4-azaspiro[2.4]heptan-5-one was completely consumed and the desired compound was detected. MeOH (1 mL) was added to the mixture at 0 °C, and the mixture was stirred at 80 °C for 0.5 hours. The reaction mixture was quenched by adding HCl (1 M, 1 mL) and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 20%~45%B over 8.0 minutes) to obtain the desired 4-benzyl-6,6-difluoro-4-azaspiro[2.4]heptane (85 mg, crude) as a yellow oily substance. MS(ESI): mass calcd.For C 13 H 15 F2N 223.12,m / z found 224.2[M+H] + .

[0319] Step 4: Two reactions were carried out in parallel. 4-benzyl-6,6-difluoro-4-azaspiro[2.4]heptane (30 mg, 134 μmol, 1 equivalent) and Pd(OH)2 / C (40 mg, 28.5 μmol, 10% purity, 2.12 e) in MeOH (5 mL). -1 The mixture (equivalent to) was degassed, purged three times with H2 (15 psi), and then stirred under an H2 atmosphere at 25°C for 5 minutes. LC-MS confirmed that 4-benzyl-6,6-difluoro-4-azaspiro[2.4]heptane was completely consumed and the desired mass was detected. The two reactions were combined for workup. The reaction mixture was filtered and concentrated under reduced pressure to obtain the desired 6,6-difluoro-4-azaspiro[2.4]heptane (40 mg, crude) as a yellow oil. MS(ESI): mass calcd. For C6H9F2N 133.07, m / z found 134.2[M+H]+ .

[0320] Step 5: To a solution of 6,6-difluoro-4-azaspiro[2.4]heptane (35 mg, 263 μmol, 1 equivalent) in THF (1 mL), TEA (266 mg, 2.63 mmol, 366 μL, 10 equivalents) was added dropwise at 25°C. After addition, the mixture was stirred at this temperature for 10 minutes, and then (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (99.3 mg, 263 μmol, 1 equivalent) in THF (1 mL) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 20 minutes. LC-MS confirmed that 6,6-difluoro-4-azaspiro[2.4]heptane was completely consumed and a single main peak with the desired mass was detected. This was then separated into 20 mL of water and 40 mL of ethyl acetate. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired N-[(E)-[(2,6-dichlorophenyl)-(6,6-difluoro-4-azaspiro[2,4]heptan-4-yl)methylene]amino]-4-methylbenzenesulfonamide (140 mg, crude) as a yellow solid. MS(ESI): mass calcd. For C 20 H 19 Cl2F2N3O2S 473.05,m / z found 474.0[M+H] + .

[0321] Step 6: Two reactions were carried out in parallel. To a solution of N-[(E)-[(2,6-dichlorophenyl)-(6,6-difluoro-4-azaspiro[2.4]heptan-4-yl)methylene]amino]-4-methylbenzenesulfonamide (70 mg, 148 μmol, 1 equivalent) in DMF (3 mL), K2CO3 (102 mg, 738 μmol, 5 equivalents) was added. The mixture was stirred at 100 °C for 2 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(6,6-difluoro-4-azaspiro[2.4]heptan-4-yl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed and the desired mass was detected. The two reactions were combined for workup. The reaction mixture was added to water (5 mL) and extracted with SiO3 (3 mL three times). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(6,6-difluoro-4-azaspiro[2.4]heptan-4-yl)-1-(p-tolylsulfonyl)indazole (120 mg, crude) as a yellow oil. MS(ESI): mass calcd.For C 20 H 18 ClF2N3O2S 437.08,m / z found 438.1[M+H] + .

[0322] Step 7: To a solution of 4-chloro-3-(6,6-difluoro-4-azaspiro[2.4]heptan-4-yl)-1-(p-tolylsulfonyl)indazole (120 mg, 274 μmol, 1 equivalent) in MeOH (3 mL), K2CO3 (189 mg, 1.37 mmol, 5 equivalents) was added. The mixture was stirred at 60°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(6,6-difluoro-4-azaspiro[2.4]heptan-4-yl)-1-(p-tolylsulfonyl)indazole had been completely consumed and the desired mass was detected. The reaction mixture was added to water (5 mL) and extracted with ₹ (3 mL three times). The combined organic layer was washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(6,6-difluoro-4-azaspiro[2.4]heptan-4-yl)-1H-indazole (25 mg, crude) as a yellow oily substance. MS(ESI): mass calcd.For C 13 H 12 ClF2N3283.07,m / z found 284.0[M+H] + .

[0323] Intermediate - R1: 4-(1,1-difluoroethyl)benzenesulfonyl chloride

[0324] [ka]

[0325] Step 1: KOH (3.25 g, 57.9 mmol, 1 equivalent) was added to a solution of phenylmethanethiol (7.91 g, 63.7 mmol, 7.46 mL, 1.1 equivalents) in EtOH (100 mL). The mixture was heated under reflux until the KOH was completely dissolved, and then cooled to 25°C. A solution of 1-(4-fluorophenyl)ethanone (8 g, 57.9 mmol, 7.02 mL, 1 equivalent) in EtOH (20 mL) was added dropwise to the mixture, and the mixture was heated to 100°C over 7 hours. TLC (petroleum ether / ethyl acetate = 5 / 1) confirmed that the 1-(4-fluorophenyl)ethanone was completely consumed and a new spot had formed. H2O (100 mL) was added to the crude product and extracted with SiO (3 times with 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 5 / 1) to obtain the desired 1-(4-benzylsulfanylphenyl)ethanone (14 g, crude) as a brown oily substance.

[0326] Step 2: A solution of 1-(4-benzylsulfanylphenyl)ethanone (12 g, 49.5 mmol, 1 equivalent) in DAST (120 mL) was stirred at 70°C for 1 hour. TLC (petroleum ether / ethyl acetate = 5 / 1) confirmed that the 1-(4-benzylsulfanylphenyl)ethanone was completely consumed and two new spots had formed. The reaction mixture was separated into water (200 mL) and ethyl acetate (150 mL three times). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 SepaFlash® Silica Flash Column, eluent with a 0-5% siRNA / petroleum ether gradient at 80 mL / min) to obtain the desired 1-benzylsulfanyl-4-(1,1-difluoroethyl)benzene (2.5 g, 9.46 mmol, 19.1% yield) as a white solid.

[0327] Step 3: To a solution of 1-benzylsulfanyl-4-(1,1-difluoroethyl)benzene (2.5 g, 9.46 mmol, 1 equivalent) in AcOH (20 mL) and H2O (5 mL), NCS (5.05 g, 37.8 mmol, 4 equivalents) was added at 0°C. The mixture was stirred at 20°C for 1 hour. LC-MS confirmed that 1-benzylsulfanyl-4-(1,1-difluoroethyl)benzene was completely consumed and the desired mass was detected (sample quenched with piperidine). The reaction mixture was filtered, and the residue was obtained by concentrating the filtrate under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, 60 mL / min with a 0-5% Â1 / 5% Ether / Petroleum Ether gradient) to obtain the desired 4-(1,1-difluoroethyl)benzenesulfonyl chloride (1.33 g, 5.53 mmol, 58.4% yield) as a yellow oil. MS (ESI): mass calcd. For C8H7F2SO2Cl 239.98, mass found 290.1[M+H+49] + .

[0328] Intermediate -R2:3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-sulfonylfluoride

[0329] [ka]

[0330] Step 1: A mixture of 3-methoxycarbonylbicyclo[1.1.1]pentane-1-carboxylic acid (2 g, 11.8 mmol, 1 equivalent), N-methoxymethaneamine (1.15 g, 11.8 mmol, 1 equivalent, HCl), and DIPEA (9.11 g, 70.5 mmol, 12.3 mL, 6 equivalents) in DCM (50 mL) was mixed with T3P (12.7 g, 20.0 mmol, 11.9 mL, 50% purity, 1.70 equivalents) under a nitrogen atmosphere at 0°C. The mixture was stirred at 20°C for 12 hours. TLC confirmed that 3-methoxycarbonylbicyclo[1.1.1]pentane-1-carboxylic acid was completely consumed and new spots had formed. DCM (50 mL) was added to the reaction product. The mixture was washed with water (50 mL) and HCl (50 mL, 1 M). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 60 mL / min) to obtain the desired methyl 3-[methoxy(methyl)carbamoyl]bicycle[1.1.1]pentane-1-carboxylate (2.3 g, 10.8 mmol, 91.8% yield) as a white solid. 1 ¹H NMR (chloroform-d) δ 3.69(s,3H), 3.67(s,3H), 3.18(s,3H), 2.38(s,6H).

[0331] Step 2: To a solution of methyl 3-[methoxy(methyl)carbamoyl]bicycle[1.1.1]pentane-1-carboxylate (1.8 g, 8.44 mmol, 1 equivalent) in THF (18 mL), MeMgBr (3 M, 2.81 mL, 1 equivalent) was added under a nitrogen atmosphere at -20°C. The mixture was stirred at 15°C for 1 hour. TLC showed that the methyl 3-[methoxy(methyl)carbamoyl]bicycle[1.1.1]pentane-1-carboxylate had been completely consumed, and a new spot had formed. The reaction mixture was gradually quenched under N2 at 0°C by adding saturated NH4Cl aqueous solution (50 mL) and stirred at 25°C for 15 minutes. The THF was removed under vacuum. The resulting solution was diluted with water (30 mL) and extracted with ELISA (3 times with 30 mL). The combined organic phases were washed with brine (twice with 30 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain the desired methyl 3-acetylbicyclo[1.1.1]pentane-1-carboxylate (700 mg, 4.16 mmol, 49.3% yield) as a pale yellow solid.

[0332] Step 3: To a solution of methyl 3-acetylbicyclo[1.1.1]pentane-1-carboxylate (700 mg, 4.16 mmol, 1 equivalent) in DCM (10 mL), DAST (6.71 g, 41.6 mmol, 5.50 mL, 10 equivalents) was added at -78°C. The mixture was stirred at 15°C for 12 hours. TLC confirmed that the methyl 3-acetylbicyclo[1.1.1]pentane-1-carboxylate had been completely consumed, and a new spot had formed. The reaction product was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with dimethyl phosphate (3 times with 50 mL). The organic phase was separated, washed with brine (2 times with 30 mL), dried over Na2SO4, filtered, filtered again, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain the desired methyl 3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carboxylate (450 mg, 2.37 mmol, 56.9% yield) as a pale yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 3.71-3.68 (m, 3H), 2.14-2.09 (m, 6H), 1.63-1.47 (m, 3H).

[0333] Step 4: To a solution of methyl 3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carboxylate (450 mg, 2.37 mmol, 1 equivalent) in H2O (1 mL), MeOH (1 mL), and THF (3 mL), LiOH (113 mg, 4.73 mmol, 2 equivalents) was added. The mixture was stirred at 15°C for 3 hours. TLC confirmed that the methyl 3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carboxylate had been completely consumed, and a new spot had formed. After adjusting the pH of the reaction mixture to 3-4 with 1N HCl, the reaction mixture was divided into H2O (30 mL) and HCl (20 mL three times). The organic phase was separated, washed twice with brine (15 mL each time), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carboxylic acid (300 mg, crude) as a white solid.

[0334] Step 5: To a mixture of 3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carboxylic acid (280 mg, 1.59 mmol, 1 equivalent) and DMF (11.6 mg, 159 μmol, 12.2 μL, 0.1 equivalent) in DCM (3 mL), (COCl)2 (242 mg, 1.91 mmol, 167 μL, 1.2 equivalents) was added at 15°C, and the mixture was stirred at 15°C for 1 hour. TLC confirmed that 3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carboxylic acid had been completely consumed and new spots were detected. The reaction product was concentrated under reduced pressure to obtain the desired 3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carbonyl chloride (300 mg, crude) as a yellow oil.

[0335] Step 6: Sodium 1-oxide pyridine-1-ium-2-thiolate (252 mg, 1.70 mmol, 207 μL, 1.1 equivalents) was added at -5°C to a mixture of 3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carbonyl chloride (300 mg, 1.54 mmol, 1 equivalent) in DCM (2 mL), and the mixture was stirred at -5°C for 2 hours. TLC confirmed that the 3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carbonyl chloride had been completely consumed and new spots were detected. The reaction product was concentrated under reduced pressure to obtain the desired (2-thioxo-1-pyridyl)3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carboxylate (430 mg, crude) as a yellow solid.

[0336] Step 7: A mixture of (2-thioxo-1-pyridyl)3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carboxylate (430 mg, 1.51 mmol, 1 equivalent) and 2-(2-pyridyldisulfanyl)pyridine (996 mg, 4.52 mmol, 3 equivalents) in toluene (20 mL) was degassed three times with Ar and irradiated with a 2000 W halogen lamp at 20°C for 2 hours under an argon atmosphere. LC-MS confirmed that (2-thioxo-1-pyridyl)3-(1,1-difluoroethyl)bicycle[1.1.1]pentane-1-carboxylate was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction product under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain the desired 2-[[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfanil]pyridine (162 mg, crude) as a colorless oil. MS(ESI): mass calcd.For C 12 H 13 F2SN 241.07 m / z found 242.0[M+H] + .

[0337] Step 8: To a mixture of 2-[[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfanyl]pyridine (160 mg, 663 μmol, 1 equivalent) in DCM (10 mL), m-CPBA (404 mg, 1.99 mmol, 85% purity, 3 equivalents) was added at 20°C, and the mixture was stirred at 20°C for 1 hour. LC-MS confirmed that 2-[[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfanyl]pyridine was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction product under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain the desired 2-[[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfanil]pyridine (162 mg, crude) as a colorless oil. MS(ESI): mass calcd.For C 12 H 13 F2SNO2273.06 m / z found 274.0[M+H] + .

[0338] Step 9: EtSH (0.3 g, 4.83 mmol, 357 μL, 13.2 equivalents) was added at 0°C to a mixture of NaH (22.0 mg, 549 μmol, 60% purity, 1.5 equivalents) in THF (2 mL), and the mixture was stirred at 0°C for 1 hour. 2-[[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]pyridine (100 mg, 366 μmol, 1 equivalent) was added to the mixture, and the mixture was stirred at 20°C for 11 hours. TLC confirmed that 2-[[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]pyridine had been completely consumed, and new spots were detected. The mixture was diluted with MTBE (10 mL), the precipitate was filtered, washed with MTBE (10 mL), and dried in a vacuum to obtain the desired [3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfinyloxysodium (40 mg, crude) as a white solid, which was then used directly.

[0339] Step 10: NFSI (86.7 mg, 275 μmol, 1.5 equivalents) was added at 2°C to a mixture of [3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfinyloxysodium (40 mg, 183 μmol, 1 equivalent) in ACN (2 mL), and the mixture was stirred at 20°C for 4 hours. TLC confirmed that the [3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfinyloxysodium had been completely consumed and new spots were detected. The residue was obtained by concentrating the reaction under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 40 mL / min) to obtain the desired 3-(1,1-difluoroethyl)bicycle[1.1.1]pentan-1-sulfonyl fluoride (27.9 mg, 130 μmol, 71.1% yield) as a white solid. 1 ¹H NMR (chloroform-d) δ: 2.47 (s, 6H), 1.62 (m, 3H).

[0340] Intermediate -R3:3-(trifluoromethyl)bicycle[1.1.1]pentane-1-sulfonylfluoride

[0341] [ka]

[0342] Step 1: A solution of 3-(trifluoromethyl)bicycle[1.1.1]pentane-1-carboxylic acid (2 g, 11.1 mmol, 1 equivalent) in DCM (30 mL) was degassed by adding DMF (81.2 mg, 1.11 mmol, 85.4 μL, 0.1 equivalent) and purged three times with N2. (COCl)2 (1.83 g, 14.4 mmol, 1.26 mL, 1.3 equivalents) was added to the mixture at 0°C. The mixture was stirred at 25°C for 1 hour under an N2 atmosphere. TLC (petroleum ether / ethyl acetate = 3 / 1) showed that 3-(trifluoromethyl)bicycle[1.1.1]pentane-1-carboxylic acid was completely consumed, and one new spot was observed (quenched with 0.5 mL of MeOH). By concentrating the reaction mixture, the desired 3-(trifluoromethyl)bicycle[1.1.1]pentane-1-carbonyl chloride (2 g, crude) was obtained as a yellow oil.

[0343] Step 2: A mixture of sodium in toluene (5 mL) and 1-oxidepyridine-1-ium-2-thiolate (2.55 g, 17.1 mmol, 2.09 mL, 1.7 equivalents) was degassed and purged three times with Ar. 3-(trifluoromethyl)bicycle[1.1.1]pentane-1-carbonyl chloride (2 g, 10.1 mmol, 1 equivalent) was added to the mixture at -10°C. The mixture was stirred at 0°C for 1 hour in the dark under an Ar atmosphere. LCMS confirmed that the 3-(trifluoromethyl)bicycle[1.1.1]pentane-1-carbonyl chloride was completely consumed and the desired mass was detected. The reaction mixture was concentrated to obtain the desired (2-thioxo-1-pyridyl)3-(trifluoromethyl)bicycle[1.1.1]pentane-1-carboxylate (2 g, crude) as a yellow oil. MS(ESI):mass calcd.For C12 H 10 F3NO2S 289.04 m / z found 290.2[M+H] + .

[0344] Step 3: (2-thioxo-1-pyridyl)3-(trifluoromethyl)bicycle[1.1.1]pentane-1-carboxylate (2 g, 6.91 mmol, 1 equivalent) was degassed from toluene (50 mL) and purged three times with Ar. 2-(2-pyridyldisulfanyl)pyridine (3.81 g, 17.3 mmol, 2.5 equivalents) was added to the mixture at 0°C. The mixture was stirred under an argon atmosphere and a 1000 W lamp at 25°C for 2 hours. LCMS confirmed that (2-thioxo-1-pyridyl)3-(trifluoromethyl)bicycle[1.1.1]pentane-1-carboxylate was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction product under reduced pressure. Water (30 mL) was added to the residue and extracted with ELISA (three times with 50 mL). The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 97 / 3~90 / 10) to obtain the desired 2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfanyl]pyridine (1.4 g, 5.71 mmol, 82.6% yield) as a yellow solid. MS(ESI): mass calcd.For C 11 H 10 F3NS 245.05 m / z found 246.2[M+H] + .

[0345] Step 4: To a mixture of 2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfanyl]pyridine (1.3 g, 5.30 mmol, 1 equivalent) in DCM (50 mL), m-CPBA (3.23 g, 15.9 mmol, 85% purity, 3 equivalents) was added at 0°C. The mixture was stirred at 25°C for 2 hours. LC-MS confirmed that 2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfanyl]pyridine was completely consumed and the desired mass was detected. The reaction mixture was quenched at 0°C by adding saturated Na2SO3 aqueous solution (30 mL), extracted with ELISA (3 times with 50 mL), and the combined organic layer was washed with saturated Na2CO3 aqueous solution (20 mL). The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1). By concentrating the reaction mixture, the desired 2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]pyridine (1.1 g, 3.97 mmol, 74.9% yield) was obtained as a white solid. MS(ESI): mass calcd. For C 11 H 10 F3NO2S 277.04 m / z found 278.2[M+H] + .

[0346] Step 5: The mixture of NaH (238 mg, 5.95 mmol, 60% purity, 1.5 equivalents) in THF (15 mL) was degassed and purged three times with Ar. EtSH (986 mg, 15.9 mmol, 1.17 mL, 4 equivalents) was added dropwise to the mixture. The mixture was stirred at 0°C for 1 hour. 2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]pyridine (1.1 g, 3.97 mmol, 1 equivalent) was added to the mixture at 0°C. The mixture was stirred under an argon atmosphere at 25°C for 11 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) confirmed that 2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]pyridine had been completely consumed and a new spot had formed. The residue was obtained by concentrating the reaction mixture under reduced pressure. The reaction mixture was washed with MTBE (10 mL), and the filter cake was concentrated under reduced pressure to obtain the residue. By concentrating the reaction mixture, the desired [3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfinyloxysodium (500 mg, 2.25 mmol, 56.7% yield) was obtained as a white solid and used in the next step.

[0347] Step 6: To a solution of [3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfinyloxysodium (500 mg, 2.25 mmol, 1 equivalent) in ACN (20 mL), N-(benzenesulfonyl)-N-fluorobenzenesulfonamide (1.06 g, 3.38 mmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 2 hours. By TLC (petroleum ether / ethyl acetate = 1 / 1), it was observed that the [3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfinyloxysodium had been completely consumed and a new spot had formed. Water (30 mL) was added to the residue and extracted with ethyl acetate (3 times with 50 mL). The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1~10:1) to obtain the desired 3-(trifluoromethyl)bicycle[1.1.1]pentan-1-sulfonyl fluoride (130 mg, 596 μmol, 26.5% yield) as a white solid, which was used in the next step.

[0348] Intermediate -R4:3-Fluorobicyclo[1.1.1]pentane-1-sulfonylfluoride

[0349] [ka]

[0350] Step 1: To a solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (3.6 g, 27.7 mmol, 1 equivalent) in DCM (100 mL), DMF (202 mg, 2.77 mmol, 213 μL, 0.1 equivalent) and (COCl)2 (5.27 g, 41.5 mmol, 3.63 mL, 1.5 equivalent) were added at 0°C. The mixture was stirred at 25°C for 1 hour under an N2 atmosphere. TLC (petroleum ether / ethyl acetate = 3 / 1) showed that the 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid was completely consumed and a new spot was observed (quenched with 0.5 mL of MeOH). By concentrating the reaction mixture, the desired 3-fluorobicyclo[1.1.1]pentane-1-carbonyl chloride (3.6 g, crude) was obtained as a yellow oil.

[0351] Step 2: A mixture of sodium;1-oxidepyridine-1-ium-2-thiolate (4.34 g, 29.1 mmol, 3.55 mL, 1.2 equivalents) in toluene (50 mL) was degassed and purged three times with Ar. 3-Fluorobicyclo[1.1.1]pentane-1-carbonyl chloride (3.6 g, 24.2 mmol, 1 equivalent) was added to the mixture at -10°C. The mixture was stirred at 0°C for 1 hour in the dark under an Ar atmosphere. LC-MS confirmed that the sodium;1-oxidepyridine-1-ium-2-thiolate was completely consumed and the desired mass was detected. By concentrating the reaction mixture, the desired (2-thioxo-1-pyridyl)3-fluorobicyclo[1.1.1]pentane-1-carboxylate (3.6 g, crude) was obtained as a yellow oil. MS(ESI): mass calcd.For C 11 H 10FNO2S 239.04 m / z found 240.2[M+H] + .

[0352] Step 3: A mixture of (2-thioxo-1-pyridyl)3-fluorobicyclo[1.1.1]pentane-1-carboxylate (3.6 g, 15.1 mmol, 1 equivalent) in toluene (100 mL) was degassed and purged three times with Ar. 2-(2-pyridyldisulfanyl)pyridine (8.29 g, 37.6 mmol, 2.5 equivalents) was added to the mixture at 0°C. The mixture was stirred under an argon atmosphere and a 1000 W lamp at 25°C for 2 hours. LCMS confirmed that (2-thioxo-1-pyridyl)3-fluorobicyclo[1.1.1]pentane-1-carboxylate was completely consumed and the desired mass was detected. Toluene was removed by concentrating the reaction mixture under reduced pressure. Water (30 mL) was added to the residue and extracted with ELISA (three times with 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 93 / 7~90 / 10) to obtain the desired 2-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfanyl]pyridine (600 mg, 3.07 mmol, 20.4% yield) as a yellow solid. MS(ESI): mass calcd.For C 10 H 10 FNS 195.05 m / z found 196.2[M+H] + .

[0353] Step 4: To a solution of 2-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfanyl]pyridine (600 mg, 3.07 mmol, 1 equivalent) in DCM (20 mL), m-CPBA (1.87 g, 9.22 mmol, 85% purity, 3 equivalents) was added at 0°C. The mixture was stirred at 25°C for 2 hours. LC-MS confirmed that 2-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfonyl]pyridine was completely consumed and the desired mass was detected. The reaction mixture was quenched at 0°C by adding saturated Na2SO3 aqueous solution (30 mL) and extracted with DCM (3 times with 50 mL). The combined organic layer was washed with saturated Na2CO3 aqueous solution (20 mL). The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain the desired 2-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfonyl]pyridine (500 mg, 2.20 mmol, 71.6% yield) as a white solid. MS(ESI): mass calcd.For C 10 H 10 FNO2S 227.04 m / z found 228.2[M+H] + .

[0354] Step 5: The mixture of NaH (132 mg, 3.30 mmol, 60% purity, 1.5 equivalents) in THF (20 mL) was degassed and purged three times with Ar. EtSH (2.05 g, 33.0 mmol, 2.44 mL, 15 equivalents) was added dropwise to the mixture at 0°C. The mixture was stirred at 0°C for 1 hour. 2-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfonyl]pyridine (500 mg, 2.20 mmol, 1 equivalent) was added to the mixture at 0°C. The mixture was stirred under an Ar atmosphere at 25°C for 11 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) confirmed that 2-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfonyl]pyridine had been completely consumed and a new spot had formed. The residue was obtained by concentrating the reaction mixture under reduced pressure. The reaction mixture was washed with MTBE (10 mL), and the filter cake was concentrated under reduced pressure to obtain the desired (3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfinyloxysodium (340 mg, 1.97 mmol, 89.8% yield) as a white solid, which was used in the next step.

[0355] Step 6: To a solution of (3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfinyloxysodium (340 mg, 1.97 mmol, 1 equivalent) in ACN (15 mL), N-(benzenesulfonyl)-N-fluorobenzenesulfonamide (934 mg, 2.96 mmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 2 hours. TLC (petroleum ether / ethyl acetate = 1 / 1) confirmed that the (3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfinyloxysodium had been completely consumed, and a new spot had formed. Water (30 mL) was added to the residue and extracted with ethyl acetate (3 times with 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain the desired 3-fluorobicyclo[1.1.1]pentane-1-sulfonyl fluoride (100 mg, 595 μmol, 30.1% yield) as a white solid, which was used in the next step.

[0356] Intermediate-R5: [4-(1,1-difluoroethyl)phenyl]sulfinyloxysodium

[0357] [ka]

[0358] Step 1: To a solution of 4-(1,1-difluoroethyl)benzenesulfonyl chloride (1 g, 4.16 mmol, 1 equivalent) in H2O (10 mL), NaHCO3 (698 mg, 8.31 mmol, 323 μL, 2 equivalents) and Na2SO3 (1.05 g, 8.31 mmol, 2 equivalents) were added. The mixture was stirred at 80°C for 2 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) confirmed that the 4-(1,1-difluoroethyl)benzenesulfonyl chloride had been completely consumed and a new spot had formed. The reaction mixture was concentrated under reduced pressure to obtain the residue. MeOH (20 mL) was added to the residue. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the desired [4-(1,1-difluoroethyl)phenyl]sulfinyloxysodium (1 g, crude) as a white solid.

[0359] Compound 1: 4-Chloro-3-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole

[0360] [ka]

[0361] Step 1: To a solution of 7,7-difluoro-3-azabicyclo[4.1.0]heptane (100 mg, 590 μmol, 1 equivalent, HCl) and TEA (597 mg, 5.90 mmol, 821 μL, 10 equivalents) in THF (1 mL), (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (334 mg, 884 μmol, 1.5 equivalents) was added at 0°C, and the solution was stirred at 20°C for 0.5 hours. LC-MS confirmed that the (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride was completely consumed and the desired mass was detected. By concentrating the reaction product, the desired N-[(E)-[(2,6-dichlorophenyl)-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)methylene]amino]-4-methylbenzenesulfonamide (260 mg, crude) was obtained as a yellow oil. MS(ESI): mass calcd.For C 20 H 19 Cl2F2N3O2S 473.05,m / z found 474.1[M+H] + .

[0362] Step 2: To a solution of N-[(E)-[(2,6-dichlorophenyl)-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)methylene]amino]-4-methylbenzenesulfonamide (260 mg, 548 μmol, 1 equivalent) in DMF (5 mL), K2CO3 (1.52 g, 11.0 mmol, 20 equivalents) was added. The mixture was stirred at 100 °C for 2 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)methylene]amino]-4-methylbenzenesulfonamide remained and the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with SiO3 (3 times with 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-1-(p-tolylsulfonyl)indazole (240 mg, crude) as an orange oil. MS(ESI): mass calcd.For C 20 H 18 ClF2N3O2S 437.08,m / z found 438.0[M+H] + .

[0363] Step 3: To a solution of 4-chloro-3-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-1-(p-tolylsulfonyl)indazole (240 mg, 548 μmol, 1 equivalent) in MeOH (5 mL), K2CO3 (1.52 g, 11.0 mmol, 20 equivalents) was added. The mixture was stirred at 70°C for 1 hour. LC-MS confirmed that 4-chloro-3-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-1-(p-tolylsulfonyl)indazole was completely consumed and the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with HCl (3 times with 10 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-1H-indazole (110 mg, crude) as an orange oily substance. MS(ESI): mass calcd.For C 13 H 12 ClF2N3283.07,m / z found 284.0[M+H] + .

[0364] Step 4: To a solution of 4-(1,1-difluoroethyl)benzenesulfonyl chloride (67.9 mg, 282 μmol, 2 equivalents) and 4-chloro-3-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-1H-indazole (40 mg, 141 μmol, 1 equivalent) in DCM (2 mL), TEA (71.3 mg, 705 μmol, 98.1 μL, 5 equivalents) and DMAP (1.72 mg, 14.1 μmol, 0.1 equivalent) were added dropwise. The mixture was stirred at 20°C for 1 hour. LC-MS confirmed that 4-chloro-3-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was concentrated to obtain the crude product. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (TFA)-ACN]; B%: 45%~75%, 8 min) to obtain the desired 4-chloro-3-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole (13.9 mg, 28.5 μmol, 20.2% yield, 100.00% purity) as a white solid. 1 H NMR(DMSO-d6)δ 8.07(d,1H),7.96(d,2H),7.77(d,2H),7.63(m,1H),7.47(d,1H),3.65(brM,1H),3. 28(brM, 1H), 3.04-3.14(m, 1H), 2.86-2.97(m, 1H), 2.00-2.12(m, 2H), 1.92(m, 5H). HPLC: 100.00% (220nm), 92.48% (210nm), 100.00% (254nm). MS(ESI):mass calcd.For C 21 H 18 ClF4N3O2S 487.07,m / z found 488.1[M+H] + .

[0365] Compound 2: 4-Chloro-3-(3,3-difluoroazetidine-1-yl)-1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-1H-indazole

[0366] [ka]

[0367] Step 1: To a solution of 3,3-difluoroazetidine (137 mg, 1.06 mmol, 1 equivalent, HCl) in DCM (5 mL), TEA (1.07 g, 10.6 mmol, 1.47 mL, 10 equivalents) and (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (0.4 g, 1.06 mmol, 1 equivalent) were added at -78°C. The mixture was stirred at 0°C for 0.5 hours. LC-MS confirmed the completion of (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride and the detection of the desired MS. H2O (5 mL) was added to the reaction mixture at 0°C and extracted with ethyl acetate (3 times with 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoroazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (0.45 g, crude) as a yellow oil. MS(ESI): mass calcd.For C 17 H 15 Cl2F2N3O2S 433.02 m / z found 434.0[M+H] + .

[0368] Step 2: To a solution of N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoroazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (0.4 g, 921 μmol, 1 equivalent) in DMF (5 mL), K2CO3 (382 mg, 2.76 mmol, 3 equivalents) was added. The mixture was stirred at 100 °C for 12 hours. LC-MS confirmed the completion of N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoroazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide and the detection of the desired mass. H2O (5 mL) was added to the reaction mixture at 0 °C and extracted with SiO (3 times with 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(3,3-difluoroazetidine-1-yl)-1-(p-tolylsulfonyl)indazole (0.4 g, crude) as a yellow oil. MS(ESI): mass calcd.For C 17 H 14 ClF2N3O2S 397.05 m / z found 398.0[M+H] + .

[0369] Step 3: To a solution of 4-chloro-3-(3,3-difluoroazetidine-1-yl)-1-(p-tolylsulfonyl)indazole (0.3 g, 754 μmol, 1 equivalent) in MeOH (4 mL), K2CO3 (208 mg, 1.51 mmol, 2 equivalents) was added. The mixture was stirred at 50°C for 2 hours. LC-MS confirmed the completion of 4-chloro-3-(3,3-difluoroazetidine-1-yl)-1-(p-tolylsulfonyl)indazole and the detection of the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 4-chloro-3-(3,3-difluoroazetidine-1-yl)-1H-indazole (0.1 g, 410 μmol, 54.4% yield) as a yellow solid. MS(ESI):mass calcd.For C 10 H8ClF2N3243.04 m / z found 244.0[M+H]+ .

[0370] Step 4: To a solution of 4-chloro-3-(3,3-difluoroazetidine-1-yl)-1H-indazole (80 mg, 328 μmol, 1 equivalent) and TEA (332 mg, 3.28 mmol, 457 μL, 10 equivalents) in DCM (1 mL), 4-(1,1-difluoroethyl)benzenesulfonyl chloride (237 mg, 985 μmol, 3 equivalents) and DMAP (4.01 mg, 32.8 μmol, 0.1 equivalent) were added at 0°C. The mixture was stirred at 25°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3,3-difluoroazetidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was quenched with saturated NH4Cl (5 mL) at 0°C and extracted with RINKAN (3 times with 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 50%~80%B over 8.0 minutes) to obtain the desired 4-chloro-3-(3,3-difluoroazetidine-1-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole (56.6 mg, 126 μmol, 38.3% yield, 99.87% purity) as a white solid. 1 H NMR(DMSO-d6)δ 8.08(d,J=8.5Hz,1H),7.99(br d,J=8.1Hz,2H),7.78(br d,J=8.4Hz,2H),7.66(t,J=8.1Hz,1H),7.47(d,J=7.8Hz,1H),4.64(br t,J=12.9Hz,4H),1.94(br t,J=19.1Hz,3H). HPLC: 99.87% (220nm), 99.68% (215nm), 100.00% (254nm). MS(ESI):mass calcd.For C 18 H 14 ClF4N3O2S 447.04 m / z found 448.0[M+H] + .

[0371] Compound 3: 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)indazole

[0372] [ka]

[0373] Step 1: To a solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (5 g, 38.4 mmol, 1 equivalent) in DMF (50 mL), DIPEA (19.9 g, 154 mmol, 26.8 mL, 4 equivalents) and HATU (21.9 g, 57.6 mmol, 1.5 equivalents) were added under an N2 atmosphere at 20°C. The mixture was stirred at 20°C for 1 hour. N-methoxymethaneamine hydrochloride (5.62 g, 57.6 mmol, 1.5 equivalents) was added to the solution at 20°C, and the mixture was stirred at 20°C for 11 hours. TLC revealed that 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid was completely consumed, and a new spot had formed. The residue was diluted with H2O (50 mL) and extracted with ELISA (100 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent with a 0-10% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain the desired 3-fluoro-N-methoxy-N-methyl-bicyclo[1.1.1]pentane-1-carboxamide (5 g, 28.9 mmol, 75.1% yield) as a yellow oil.

[0374] Step 2: To a solution of 1-chloro-3-fluorobenzene (603 mg, 4.62 mmol, 495 μL, 1.6 equivalents) in THF (6 mL), n-BuLi (2.5 M, 1.85 mL, 1.6 equivalents) was added at -78°C, and the solution was stirred at -78°C for 0.5 hours under a nitrogen atmosphere. 3-fluoro-N-methoxy-N-methyl-bicyclo[1.1.1]pentane-1-carboxamide (500 mg, 2.89 mmol, 1 equivalent) was added to the solution at -78°C, and the solution was stirred at -78°C for 1 hour. TLC confirmed the detection of 3-fluoro-N-methoxy-N-methyl-bicyclo[1.1.1]pentane-1-carboxamide and new spots. NH4Cl solution (0.5 mL) was added to the solution, and extraction was performed with  (5 mL twice). The combined organic matter was concentrated to obtain a residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired (2-chloro-6-fluorophenyl)-(3-fluoro-1-bicyclo[1.1.1]pentanyl)methanone (450 mg, crude) as a yellow oily substance.

[0375] Step 3: A mixture of (2-chloro-6-fluorophenyl)-(3-fluoro-1-bicyclo[1.1.1]pentanyl)methanone (300 mg, 1.24 mmol, 1 equivalent) in NH2NH2.H2O (6 mL) was stirred at 100°C for 3 hours. LC-MS confirmed that the (2-chloro-6-fluorophenyl)-(3-fluoro-1-bicyclo[1.1.1]pentanyl)methanone was completely consumed, and one main peak with the desired mass was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (5 times with 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-1H-indazole (40 mg, crude) as a yellow solid. MS(ESI): mass calcd.For C 12 H 10 ClFN2236.05,m / z found 237.0[M+H]+ .

[0376] Step 4: To a solution of 4-chloro-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-1H-indazole (30 mg, 127 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (45.8 mg, 190 μmol, 1.5 equivalents) in DCM (2 mL), TEA (38.5 mg, 380 μmol, 52.9 μL, 3 equivalents) and DMAP (1.55 mg, 12.7 μmol, 0.1 equivalent) were added. The mixture was stirred at 20°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-1H-indazole was completely consumed and one main peak with the desired mass was detected. The reaction mixture was concentrated to obtain the crude product. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 55%~90%B over 8.0 minutes) to obtain the desired 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)indazole (11.3 mg, 25.6 μmol, 20.2% yield, 99.11% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.15(d,J=8.4Hz,1H),8.10(br d,J=8.3Hz,2H),7.83(br d,J=8.3Hz,2H),7.69(t,J=8.1Hz,1H),7.55(d,J=7.7Hz,1H),2.63(d,J=2.1Hz,6H),1.95(t,J=19.1Hz,3H). HPLC: 99.11% (220nm), 99.21% (210nm), 99.09% (254nm). MS(ESI):mass calcd.For C 20 H 16 ClF3N2O2S 440.06,m / z found 441.1[M+H] + .

[0377] Compound 4: 4-Chloro-3-(3,3-difluorocyclobutyl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole

[0378] [ka]

[0379] Step 1: To a solution of 3,3-difluorocyclobutanecarboxylic acid (300 mg, 2.20 mmol, 1 equivalent) in DCM (5 mL), N-methoxymethaneamine hydrochloride (886 mg, 6.61 mmol, 3 equivalents, HCl), HATU (2.51 g, 6.61 mmol, 3 equivalents), and DIEA (2.28 g, 17.6 mmol, 3.07 mL, 8 equivalents) were added. The mixture was stirred at 20°C for 12 hours. LC-MS confirmed that the 3,3-difluorocyclobutanecarboxylic acid was completely consumed and the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with siRNA (10 mL three times). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain the desired 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (300 mg, crude) as a yellow solid. MS(ESI): mass calcd. For C7H 11 F2NO2179.08,m / z found 180.0[M+H] + .

[0380] Step 2: To a solution of 1-chloro-3-fluorobenzene (175 mg, 1.34 mmol, 143 μL, 1.2 equivalents) in THF (6 mL), n-BuLi (2.5 M, 536 μL, 1.2 equivalents) was added at -78°C, and the solution was stirred at -78°C for 0.5 hours under a nitrogen atmosphere. 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (200 mg, 1.12 mmol, 1 equivalent) was added to the solution at -78°C, and the solution was stirred at -78°C for 1 hour. TLC (petroleum ether / ethyl acetate = 3 / 1) confirmed that 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide remained and new spots were detected. NH4Cl solution (0.5 mL) was added to the solution, and extraction was performed with ELISA (5 mL twice). The residue was obtained by concentrating the combined organic matter. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired (2-chloro-6-fluorophenyl)-(3,3-difluorocyclobutyl)methanone (100 mg, crude) as a yellow oily substance.

[0381] Step 3: A mixture of (2-chloro-6-fluorophenyl)-(3,3-difluorocyclobutyl)methanone (100 mg, 402 μmol, 1 equivalent) in NH2NH2.H2O (2 mL) was stirred at 100°C for 3 hours. TLC confirmed that the (2-chloro-6-fluorophenyl)-(3,3-difluorocyclobutyl)methanone had been completely consumed, and a new spot had formed. The reaction mixture was washed by TLC. The reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (5 times with 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(3,3-difluorocyclobutyl)-1H-indazole (40 mg, crude) as a white solid.

[0382] Step 4: To a solution of 4-chloro-3-(3,3-difluorocyclobutyl)-1H-indazole (35 mg, 144 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (52.1 mg, 216 μmol, 1.5 equivalents) in DCM (1 mL), TEA (43.8 mg, 433 μmol, 60.2 μL, 3 equivalents) and DMAP (1.76 mg, 14.4 μmol, 0.1 equivalent) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(3,3-difluorocyclobutyl)-1H-indazole was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was concentrated to obtain the crude product. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 55%~80%B over 8.0 minutes) to obtain the desired 4-chloro-3-(3,3-difluorocyclobutyl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole (4.3 mg, 9.41 μmol, 6.52% yield, 97.76% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.12(dd,J=8.4,17.1Hz,3H),7.82(d,J=8.4Hz,2H),7.70(t,J=8.1Hz,1H),7.54(d,J=7.6Hz,1H),4.03(br dd,J=7.5,9.0Hz,1H),3.21-3.07(m,2H),3.07-2.94(m,2H),1.96(t,J=19.1Hz,3H). HPLC: 97.76% (220nm), 98.82% (210nm), 98.60% (254nm). MS(ESI):mass calcd.For C 19 H 15 ClF4N2O2S 446.05,m / z found 447.0[M+H] + .

[0383] Compound 5: 4-Chloro-1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-3-(3,3-difluoropyrrolidine-1-yl)-1H-indazole

[0384] [ka]

[0385] Step 1: A mixture of tert-butyl 4-chloro-3-iodoindazole-1-carboxylate (300 mg, 792 μmol, 1 equivalent), 3,3-difluoropyrrolidine (137 mg, 951 μmol, 1.2 equivalents, HCl), Pd2(dba)3 (72.6 mg, 79.2 μmol, 0.1 equivalent), Cs2CO3 (775 mg, 2.38 mmol, 3 equivalents), and BINAP (49.3 mg, 79.2 μmol, 0.1 equivalent) in toluene (5 mL) was degassed, purged three times with N2, and then stirred at 100°C for 3 hours under an N2 atmosphere. LC-MS confirmed that tert-butyl 4-chloro-3-iodoindazole-1-carboxylate was completely consumed and the desired mass was detected. The crude product was mixed with H2O (20 mL) and extracted with  (15 mL three times). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired tert-butyl 4-chloro-3-(3,3-difluoropyrrolidine-1-yl)indazole-1-carboxylate (200 mg, 559 μmol, 70.5% yield) as a yellow oil. MS(ESI): mass calcd. For C 16 H 18 ClF2N3O2357.11 m / z found 358.1[M+H] + .

[0386] Step 2: To a solution of tert-butyl 4-chloro-3-(3,3-difluoropyrrolidine-1-yl)indazole-1-carboxylate (200 mg, 559 μmol, 1 equivalent) in DCM (2 mL), TFA (1.59 g, 14.0 mmol, 1.04 mL, 25 equivalents) was added. The mixture was stirred at 15°C for 0.5 hours. LC-MS confirmed that tert-butyl 4-chloro-3-(3,3-difluoropyrrolidine-1-yl)indazole-1-carboxylate was completely consumed and the desired mass was detected. The reaction mixture was concentrated under vacuum to obtain the desired 4-chloro-3-(3,3-difluoropyrrolidine-1-yl)-1H-indazole (200 mg, crude, TFA) as a brown oily substance. MS(ESI): mass calcd.For C 11 H 10 ClF2N3257.05 m / z found 258.1[M+H] + .

[0387] Step 3: To a solution of 4-chloro-3-(3,3-difluoropyrrolidine-1-yl)-1H-indazole (100 mg, 269 μmol, 1 equivalent, TFA) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (97.1 mg, 404 μmol, 1.5 equivalents) in DCM (2 mL), TEA (81.7 mg, 807 μmol, 112 μL, 3 equivalents) and DMAP (3.29 mg, 26.9 μmol, 0.1 equivalent) were added. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3,3-difluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. H2O (20 mL) was added to the crude product and extracted with DCM (3 times with 15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 55%~85% B over 8.0 mins) to obtain the desired 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3-difluoropyrrolidine-1-yl)indazole (13.2 mg, 28.6 μmol, 10.6% yield, 100.00% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.09(d,J=8.5Hz,1H),7.96(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,2H),7.65(t,J=8.1Hz,1H),7.48(d,J= 7.6Hz,1H), 3.88(t,J=13.1Hz,2H),3.70(t,J=7.2Hz,2H),2.50-2.41(m,2H),1.92(t,J=19.1Hz,3H). HPLC: 100.00%(220nm), 100.00%(215nm), 100.00(254nm). MS(ESI):mass calcd.For C 19 H 16 ClF4N3O2S 461.06 m / z found 462.1[M+H] + .

[0388] Compound 6: 4-Chloro-1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole

[0389] [ka]

[0390] Step 1: To a solution of 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (100 mg, 245 μmol, 1 equivalent, TFA) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (88.6 mg, 368 μmol, 1.5 equivalents) in DCM (2 mL), TEA (74.5 mg, 736 μmol, 102 μL, 3 equivalents) and DMAP (3.00 mg, 24.5 μmol, 0.1 equivalent) were added. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. H2O (20 mL) was added to the crude product and extracted with DCM (3 times with 15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 55%~85% B over 8.0 mins) to obtain the desired 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (14.6 mg, 29.1 μmol, 11.9% yield, 99.25% purity) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.15(d,J=8.5Hz,1H),8.06(d,J=8.5Hz,2H),7.82(d,J=8.5Hz,2H),7.73(t,J =8.1Hz,1H),7.57(d,J=7.6Hz,1H),4.35-4.22(m,4H),1.98(t,J=19.1Hz,3H). HPLC: 99.25% (220nm), 98.53% (215nm), 100.00 (254nm). MS(ESI):mass calcd.For C 19 H 14 ClF6N3O2S 497.04 m / z found 498.1[M+H] + .

[0391] Compound 7: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(2R)-3,3-difluoro-2-methylazetidine-1-yl]indazole Compound 8: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(2S)-3,3-difluoro-2-methylazetidine-1-yl]indazole

[0392] [ka]

[0393] Step 1: To a solution of 4-chloro-3-(3,3-difluoro-2-methylcyclobutyl)-1H-indazole (110 mg, 429 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (155 mg, 643 μmol, 1.5 equivalents) in DCM (1 mL), TEA (130 mg, 1.29 mmol, 179 μL, 3 equivalents) and DMAP (5.24 mg, 42.9 μmol, 0.1 equivalent) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(3,3-difluoro-2-methylcyclobutyl)-1H-indazole was completely consumed and one main peak with the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with DCM (3 times with 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-1H-indazole (110 mg) as a white solid. Further separation by SFC (conditions: column: ChiralPak IH, 250*30 mm, 10 μm; mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 15%, isocratic elution mode) yielded two isomers. The structures were arbitrarily assigned. 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(2R)-3,3-difluoro-2-methylazetidine-1-yl]indazole (21.0 mg, 44.5 μmol, 10.4% yield, 97.91% purity, Rt=0.806 min; EE(%)=99.98% by chiral HPLC) was isolated as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.13(d,J=8.5Hz,1H),8.01(d,J=8.3Hz,2H),7.83(d,J=8.4Hz,2H),7.72(t,J=8.1Hz,1H),7.54(d,J=7.8Hz,1H ),5.04-4.91(m,1H),4.77(q,J=11.5Hz,1H),4.57-4.41(m,1H),1.98(t,J=19.1Hz,3H),1.29(d,J=6.5Hz,3H). HPLC: 97.91% (220nm), 97.64% (210nm), 96.97% (254nm). MS(ESI):mass calcd.For C 19 H 16 ClF4N3O2S 461.06,m / z found 462.0[M+H] + . 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(2S)-3,3-difluoro-2-methylazetidine-1-yl]indazole (21.1 mg, 45.0 μmol, 10.5% yield, 98.52% purity, Rt=0.908 min; EE(%)=94.60% by chiral HPLC) was isolated as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.13(d,J=8.4Hz,1H),8.01(d,J=8.4Hz,2H),7.83(d,J=8.4Hz,2H),7.72(t,J=8.1Hz,1H),7.54(d,J=7.6Hz,1H ),5.06-4.91(m,1H),4.77(q,J=11.3Hz,1H),4.57-4.42(m,1H),1.98(t,J=19.1Hz,3H),1.29(d,J=6.5Hz,3H). HPLC: 98.52% (220nm), 98.41% (210nm), 97.10% (254nm). MS(ESI):mass calcd.For C 19 H 16 ClF4N3O2S 461.06,m / z found 462.0[M+H] + .

[0394] Compound 9: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3-fluoroazetidine-1-yl)indazole

[0395] [ka]

[0396] Step 1: To a solution of (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (800 mg, 2.12 mmol, 1 equivalent) in DCM (10 mL), TEA (2.14 g, 21.2 mmol, 2.95 mL, 10 equivalents) and 3-fluoroazetidine hydrochloride (284 mg, 2.54 mmol, 1.2 equivalents) were added at -78°C. The mixture was stirred for 0.5 hours, and then stirred at 0°C for 0.5 hours. LCMS confirmed that the (1E)-2,6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride was completely consumed and the desired mass was detected. By concentrating the reaction mixture, the desired N-[(E)-[(2,6-dichlorophenyl)-(3-fluoroazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (880 mg, crude) was obtained as a yellow oil. MS(ESI): mass calcd.For C 17 H 16 C l2 FN3O2S 415.03 m / z found 415.9[M+H] + .

[0397] Step 2: To a solution of N-[(E)-[(2,6-dichlorophenyl)-(3-fluoroazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (880 mg, 2.11 mmol, 1 equivalent) in DMF (10 mL), K2CO3 (876 mg, 6.34 mmol, 3 equivalents) was added. The mixture was stirred at 100 °C for 12 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(3-fluoroazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide was completely consumed and the desired mass was detected. Water (10 mL) was added to the residue and extracted with SiO3 (3 times with 10 mL). The residue was obtained by concentrating the combined organic matter. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1~1 / 1) to obtain the desired 4-chloro-3-(3-fluoroazetidine-1-yl)-1-(p-tolylsulfonyl)indazole (280 mg, 737 μmol, 34.9% yield) as a yellow oil. MS(ESI): mass calcd.For C 17 H 15 ClFN3O2S 379.06 m / z found 379.9[M+H] + .

[0398] Step 3: To a solution of 4-chloro-3-(3-fluoroazetidine-1-yl)-1-(p-tolylsulfonyl)indazole (280 mg, 737 μmol, 1 equivalent) in MeOH (3 mL), K2CO3 (204 mg, 1.47 mmol, 2 equivalents) was added. The mixture was stirred at 50°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3-fluoroazetidine-1-yl)-1-(p-tolylsulfonyl)indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction product. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1~3 / 1) to obtain the desired 4-chloro-3-(3-fluoroazetidine-1-yl)-1H-indazole (90 mg, 399 μmol, 54.1% yield) as a white solid. MS(ESI):mass calcd.For C 10H9ClFN3225.05 m / z found 225.9[M+H] - .

[0399] Step 4: To a solution of 4-chloro-3-(3-fluoroazetidine-1-yl)-1H-indazole (80 mg, 355 μmol, 1 equivalent) in DCM (1 mL), TEA (179 mg, 1.77 mmol, 247 μL, 5 equivalents), DMAP (4 mg, 35.5 μmol, 0.1 equivalent), and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (171 mg, 709 μmol, 2 equivalents) were added. The mixture was stirred at 25°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3-fluoroazetidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction product. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 40%~70%B over 8.0 minutes) to obtain the desired 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3-fluoroazetidine-1-yl)indazole (16 mg, 36.9 μmol, 10.4% yield, 99.23% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.07(d,J=8.4Hz,1H),7.97(br d,J=8.1Hz,2H),7.78(br d,J=8.2Hz,2H),7.65(br t,J=8.1Hz,1H),7.46(br d,J=7.7Hz,1H),5.59-5.35(m,1H),4.60-4.43(m,2H),4.34-4.17(m,2H),1.95(br t,J=19.1Hz,3H). MS(ESI):mass calcd.For C 18 H 15 ClF3N3O2S 429.05 m / z found 430.0[M+H] + .

[0400] Compound 10: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3-fluoro-3-methylazetidine-1-yl)indazole

[0401] [ka]

[0402] Step 1: TEA (1.07 g, 10.6 mmol, 1.47 mL, 5 equivalents) was added to a mixture of 3-fluoro-3-methylazetidine (319 mg, 2.54 mmol, 1.2 equivalents, HCl) in DCM (8 mL), and (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (800 mg, 2.12 mmol, 1 equivalent) was added to the mixture at -78°C. The mixture was stirred at 0°C for 0.5 hours. LCMS confirmed that the (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride was completely consumed and the desired mass was detected. The reaction mixture was quenched at 0°C by adding saturated NH4Cl aqueous solution (30 mL), extracted with DCM (3 times with 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. By concentrating the reaction mixture, the desired N-[(E)-[(2,6-dichlorophenyl)-(3-fluoro-3-methylazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (800 mg, crude) was obtained as a yellow solid. MS(ESI): mass calcd. For C 18 H 18 Cl2FN3O2S 429.05 m / z found 430.1[M+H] + .

[0403] Step 2: K2CO3 (771 mg, 5.58 mmol, 3 equivalents) was added to a mixture of N-[(E)-[(2,6-dichlorophenyl)-(3-fluoro-3-methylazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (800 mg, 1.86 mmol, 1 equivalent) in DMF (6 mL). The mixture was stirred at 100 °C for 12 hours. LCMS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(3-fluoro-3-methylazetidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide was completely consumed and the desired mass was detected. By concentrating the reaction mixture, the desired 4-chloro-3-(3-fluoro-3-methylazetidine-1-yl)-1-(p-tolylsulfonyl)indazole (700 mg, crude) was obtained as a yellow solid. MS(ESI): mass calcd.For C 18 H 17 ClFN3O2S 393.07 m / z found 394.1[M+H] + .

[0404] Step 3: K2CO3 (561 mg, 4.06 mmol, 2 equivalents) was added to a mixture of 4-chloro-3-(3-fluoro-3-methylazetidine-1-yl)-1-(p-tolylsulfonyl)indazole (800 mg, 2.03 mmol, 1 equivalent) in MeOH (10 mL). The mixture was stirred at 50°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3-fluoro-3-methylazetidine-1-yl)-1-(p-tolylsulfonyl)indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction product. Water (30 mL) was added to the residue and extracted with Âr (3 times with 50 mL). The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1). By concentrating the reaction mixture, the desired 4-chloro-3-(3-fluoro-3-methylazetidine-1-yl)-1H-indazole (200 mg, 834 μmol, 47.0% yield) was obtained as a yellow oil. MS(ESI): mass calcd.For C 11 H 11ClFN3239.06 m / z found 240.2[M+H] + .

[0405] Step 4: To a mixture of 4-chloro-3-(3-fluoro-3-methylazetidine-1-yl)-1H-indazole (200 mg, 834 μmol, 1 equivalent) in DCM (10 mL), TEA (253 mg, 2.50 mmol, 348 μL, 3 equivalents) and DMAP (10.2 mg, 83.5 μmol, 0.1 equivalent) were added at 0°C. The mixture was stirred at 25°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3-fluoro-3-methylazetidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction product. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 60%~90%B over 8.0 minutes) to obtain the desired 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3-fluoro-3-methylazetidine-1-yl)indazole (82.2 mg, 171 μmol, 20.5% yield, 92.23% purity) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.07(d,J=8.4Hz,1H),7.95(d,J=8.6Hz,2H),7.77(d,J=8.6Hz,2H),7.65(t,J=8.1Hz,1H),7.46(d,J=7.6Hz,1H),4 .38-4.14(m,4H),1.94(t,J=19.1Hz,3H),1.68-1.49(m,3H)HPLC:96.32%(220nm),96.20%(215nm),92.23%(254nm). MS(ESI):mass calcd.For C 19 H 17 ClF3N3O2S 443.07 m / z found 444.3[M+H] + .

[0406] Compound 11: 4-Chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-[4-(trifluoromethyl)phenyl]sulfonyl-indazole

[0407] [ka]

[0408] Step 1: To a solution of 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (50 mg, 170 μmol, 1 equivalent) and 4-(trifluoromethyl)benzenesulfonyl chloride (62.5 mg, 255 μmol, 1.5 equivalents) in DCM (1 mL), TEA (86.2 mg, 851 μmol, 119 μL, 5 equivalents) and DMAP (2.08 mg, 17.0 μmol, 0.1 equivalent) were added. The mixture was stirred at 15°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 10 mL of RINKAN. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-[4-(trifluoromethyl)phenyl]sulfonyl-indazole (15.5 mg, 29.2 μmol, 17.2% yield, 94.67% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.10(d,J=8.4Hz,3H),7.95(d,J=8.4Hz,2H),7.69(t,J=8.1Hz,1H),7.53(d,J=7.8Hz,1H),4.23(br t,J=12.1Hz,4H). HPLC: 94.67% (220nm), 100.0% (215nm), 94.83% (254nm). MS(ESI):mass calcd.For C 18 H 11ClF7N3O2S 501.0,m / z found 502.0[M+H] + .

[0409] Compound 12: 4-Chloro-1-[4-(difluoromethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole

[0410] [ka]

[0411] Step 1: To a solution of 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (100 mg, 341 μmol, 1 equivalent) and 4-formylbenzenesulfonyl chloride (105 mg, 511 μmol, 1.5 equivalents) in DCM (1 mL), TEA (103 mg, 1.02 mmol, 142 μL, 3 equivalents) and DMAP (4.16 mg, 34.1 μmol, 0.1 equivalent) were added. The mixture was stirred at 15°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 10 mL of DCM. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 1 / 1) to obtain the desired 4-[4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-yl]sulfonylbenzaldehyde (27 mg, 58.5 μmol, 17.2% yield) as a white solid. MS(ESI): mass calcd. For C 18 H 12 ClF4N3O3S 461.1,m / z found 462.1[M+H] + .

[0412] Step 2: Solution of 4-[4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-yl]sulfonylbenzaldehyde (24 mg, 52.0 μmol, 1 equivalent) in DAST (0.3 mL). The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-[4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-yl]sulfonylbenzaldehyde was completely consumed and the desired mass was detected. The reaction mixture was quenched with sodium bicarbonate in H2O (10 mL), and the mixture was extracted with RINKAN (20 mL). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-1-[4-(difluoromethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (12.3 mg, 24.4 μmol, 46.9% yield, 95.84% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.09(d,J=8.6Hz,1H),8.03(d,J=8.3Hz,2H),7.76(d,J=8.1Hz,2H),7.67(t,J=8.1Hz,1H),7.51(d,J=7.7Hz,1H),7.25-6.93(m,1H),4.23(br t,J=12.2Hz,4H). HPLC: 95.84% (220nm), 94.80% (215nm), 96.15% (254nm). MS(ESI):mass calcd.For C 18 H 12 ClF6N3O2S 483.0,m / z found 484.0[M+H] + .

[0413] Compound 13: 1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-4-fluoro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole

[0414] [ka]

[0415] Step 1: A mixture of tert-butyl 4-fluoro-3-iodoindazole-1-carboxylate (100 mg, 278 μmol, 1 equivalent), 3,3,4,4-tetrafluoropyrrolidine (50 mg, 278 μmol, 1 equivalent, HCl), Pd2(dba)3 (25.5 mg, 27.9 μmol, 0.1 equivalent), Cs2CO3 (272 mg, 835 μmol, 3 equivalents), and BINAP (17.3 mg, 27.9 μmol, 0.1 equivalent) in toluene (2 mL) was degassed, purged three times with N2, and then stirred at 100°C for 3 hours under an N2 atmosphere. LC-MS confirmed that tert-butyl 4-fluoro-3-iodoindazole-1-carboxylate was completely consumed and the desired mass was detected. The crude product was mixed with H2O (20 mL) and extracted with ethyl acetate (15 mL three times). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired tert-butyl 4-fluoro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-carboxylate (100 mg, 265 μmol, 95.17% yield) as a yellow oil. MS(ESI): mass calcd. For C 16 H 16 F5N3O2377.12 m / z found 378.1[M+H] + .

[0416] Step 2: To a solution of tert-butyl 4-fluoro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-carboxylate (100 mg, 265 μmol, 1 equivalent) in DCM (1 mL), TFA (453 mg, 3.98 mmol, 295 μL, 15 equivalents) was added at 0°C. The mixture was stirred at 15°C for 0.5 hours. LC-MS confirmed that tert-butyl 4-fluoro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-carboxylate was completely consumed and the desired mass was detected. The reaction mixture was concentrated under vacuum to obtain the desired 4-fluoro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (100 mg, crude, TFA) as a brown oily substance. MS(ESI): mass calcd.For C 11 H8F5N3277.06 m / z found 278.0[M+H] + .

[0417] Step 3: To a solution of 4-fluoro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (80 mg, 289 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (69.5 mg, 289 μmol, 1 equivalent) in DCM (0.5 mL), TEA (58.4 mg, 577 μmol, 80.3 μL, 2 equivalents) and DMAP (3.53 mg, 28.9 μmol, 0.1 equivalent) were added. The mixture was stirred at 15°C for 0.5 hours. LC-MS confirmed that 4-fluoro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. H2O (20 mL) was added to the crude product and extracted with DCM (3 times with 15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-4-fluoro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (3.2 mg, 6.65 μmol, 2.30% yield, 100% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.06(d,J=8.5Hz,2H),8.00(d,J=8.5Hz,1H),7.82(d,J=8.5Hz,2H),7.79-7.73( m,1H),7.31(dd,J=8.1,11.3Hz,1H),4.39-4.26(m,4H),1.99(t,J=19.1Hz,3H). HPLC: 100.00%(220nm), 100.00%(215nm), 100.00(254nm). MS(ESI):mass calcd.For C 19 H 14 F7N3O2S 481.07 m / z found 482.1[M+H] + .

[0418] Compound 14: 4-Chloro-1-[[3-(1,1-difluoroethyl)-1-bicycle[1.1.1]pentanyl]sulfonyl]-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole

[0419] [ka]

[0420] Step 1: To a solution of 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (50 mg, 170 μmol, 1 equivalent) and 3-(1,1-difluoroethyl)bicycle[1.1.1]pentan-1-sulfonyl fluoride (36.5 mg, 170 μmol, 1 equivalent) in ACN (3 mL), bis[bis(trifluoromethylsulfonyl)amino]calcium (307 mg, 511 μmol, 3 equivalents), TEA (86.2 mg, 851 μmol, 119 μL, 5 equivalents), and Cs2CO3 (277 mg, 851 μmol, 5 equivalents) were added. The mixture was stirred at 90°C for 12 hours. LC-MS confirmed that 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 65%~95%B over 8.0 mins) to obtain the desired 4-chloro-1-[[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (6.7 mg, 13.7 μmol, 8.07% yield, 100.00% purity) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 7.91(d,J=8.50Hz,1 H)7.62-7.70(m,1 H)7.55(d,J=7.63Hz,1 H)4.27(br t,J=12.95Hz,4 H)2.12(s,6 H)1.51(t,J=18.89Hz,3 H). HPLC: 100.00% (220nm), 100.00% (215nm), 100.00% (254nm). MS(ESI):mass calcd.For C 18 H 16 ClF6N3O2S 487.06 m / z found 488.1[M+H] + .

[0421] Compound 15: 4-Chloro-1-[[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]-3-(3,3-difluoro-2-methylazetidine-1-yl)indazole

[0422] [ka]

[0423] Step 1: To a solution of 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1H-indazole (70 mg, 272 μmol, 1 equivalent) and 3-(1,1-difluoroethyl)bicyclo[1.1.1]pentan-1-sulfonyl fluoride (58.2 mg, 272 μmol, 1 equivalent) in ACN (3 mL), bis[bis(trifluoromethylsulfonyl)amino]calcium (163 mg, 272 μmol, 1 equivalent), TEA (137 mg, 1.36 mmol, 189 μL, 5 equivalents), and Cs2CO3 (443 mg, 1.36 mmol, 5 equivalents) were added. The mixture was stirred at 90°C for 12 hours. LC-MS confirmed that 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions; following LCMS; method: column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 65%~95%B over 8.0 min) to obtain the desired 4-chloro-1-[[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]-3-(3,3-difluoro-2-methylazetidine-1-yl)indazole (1.6 mg, 3.54 μmol, 1.33% yield, 100.0% purity) as a white solid. 1 H NMR(DMSO-d6)δ 7.86(br d,J=8.4Hz,1H),7.62(br t,J=8.0Hz,1H),7.53-7.46(m,1H),5.01-4.86(m,1H),4.77(q,J=11.6Hz,1H),4.62-4.48(m,1H),2.09(s,6H),1.51(br t,J=18.9Hz,3H),1.35(br d,J=6.4Hz,3H). HPLC: 100.0% (220nm), 99.72% (215nm), 100.0% (254nm). MS(ESI):mass calcd.For C 18 H 18 ClF4N3O2S 451.1 m / z found 452.1[M+H] + .

[0424] Compound 16: 4-Chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]indazole

[0425] [ka]

[0426] Step 1: To a solution of 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (10 mg, 34.1 μmol, 1 equivalent) and 3-(trifluoromethyl)bicycle[1.1.1]pentan-1-sulfonyl fluoride (8.92 mg, 40.9 μmol, 1.2 equivalents) in ACN (1.5 mL), bis[bis(trifluoromethylsulfonyl)amino]calcium (24.5 mg, 40.9 μmol, 1.2 equivalents), Cs2CO3 (55.5 mg, 170 μmol, 5 equivalents), and TEA (17.2 mg, 170 μmol, 23.7 μL, 5 equivalents) were added. The mixture was stirred at 80°C for 12 hours. LC-MS confirmed that 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction mixture under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 45%~75%B over 8.0 mins) to obtain the desired 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]indazole (5.9 mg, 12.0 μmol, 35.2% yield, 100.00% purity) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 7.84(d,J=8.3Hz,1H),7.60(t,J=8.1Hz,1H),7.50(d,J=7.6Hz,1H),4.22(br t,J=12.2Hz,4H),2.29(s,6H). HPLC: 99.75% (220nm), 99.49% (215nm), 100.00% (254nm). MS(ESI):mass calcd.For C 17 H 13 ClF7N3O2S 491.03 m / z found 492.00[M+H] + .

[0427] Compound 17: 4-Chloro-1-[(3-Fluoro-1-bicyclo[1.1.1]pentanyl)sulfonyl]-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole

[0428] [ka]

[0429] Step 1: To a solution of 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (10 mg, 34.1 μmol, 1 equivalent) and 3-fluorobicyclo[1.1.1]pentan-1-sulfonyl fluoride (6.9 mg, 40.9 μmol, 1.2 equivalents) in ACN (1.5 mL), bis[bis(trifluoromethylsulfonyl)amino]calcium (24.5 mg, 40.9 μmol, 1.2 equivalents), Cs2CO3 (55.5 mg, 170 μmol, 5 equivalents), and TEA (17.2 mg, 170 μmol, 23.7 μL, 5 equivalents) were added. The mixture was stirred at 80°C for 12 hours. LC-MS confirmed that 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction mixture under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 40%~70%B over 8.0 mins) to obtain the desired 4-chloro-1-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfonyl]-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (4.9 mg, 11.1 μmol, 32.57% yield, 97.44% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.90(d,J=8.5Hz,1H),7.67(t,J=8.1Hz,1H),7.57(d,J=7.5Hz,1H),4.34-4.20(m,4H),2.45(d,J=2.3Hz,6H). HPLC: 97.44% (220nm), 96.90% (215nm), 99.84% (254nm). MS(ESI):mass calcd.For C 16 H 13 ClF5N3O2S 441.03 m / z found 442.00[M+H] + .

[0430] Compound 18: 4-Chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1-((3-(trifluoromethyl)bicycle[1.1.1]pentan-1-yl)sulfonyl)-1H-indazole

[0431] [ka]

[0432] Step 1: To a solution of 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1H-indazole (20 mg, 77.6 μmol, 1 equivalent) and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-sulfonyl fluoride (25.4 mg, 116 μmol, 1.5 equivalents) in ACN (2 mL), bis[bis(trifluoromethylsulfonyl)amino]calcium (55.9 mg, 93.1 μmol, 1.2 equivalents), TEA (39.3 mg, 388 μmol, 54.0 μL, 5 equivalents), and Cs2CO3 (126 mg, 388 μmol, 5 equivalents) were added. The mixture was stirred at 80°C for 12 hours. LC-MS confirmed that 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. H2O (20 mL) was added to the crude product and extracted with siRNA (15 mL three times). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 50%~80%B over 8.0 minutes) to obtain the desired 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1-((3-(trifluoromethyl)bicycle[1.1.1]pentan-1-yl)sulfonyl)-1H-indazole (10.5 mg, 23.0 μmol, 29.7% yield, 100.00% purity) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 7.86(d,J=8.0Hz,1H),7.63(t,J=8.1Hz,1H),7.51(d,J=7.1Hz,1H),5.01-4.88(m,1H) ,4.83-4.73(m,1H),4.57(dt,J=10.7,13.4Hz,1H),2.33(s,6H),1.36(d,J=6.5Hz,3H). HPLC: 100.00%(220nm), 100.00%(215nm), 100.00(254nm). MS(ESI):mass calcd.For C 17 H 15 ClF5N3O2S 455.05 m / z found 456.1[M+H] + .

[0433] Compound 19: 4-Chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1-((3-fluorobicyclo[1.1.1]pentan-1-yl)sulfonyl)-1H-indazole

[0434] [ka]

[0435] Step 1: To a solution of 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1H-indazole (10 mg, 38.8 μmol, 1 equivalent) and 3-fluorobicyclo[1.1.1]pentan-1-sulfonyl fluoride (9.79 mg, 58.2 μmol, 1.5 equivalents) in ACN (2 mL), bis[bis(trifluoromethylsulfonyl)amino]calcium (28.0 mg, 46.6 μmol, 1.2 equivalents), TEA (19.6 mg, 194 μmol, 27.0 μL, 5 equivalents), and Cs2CO3 (63.2 mg, 194 μmol, 5 equivalents) were added. The mixture was stirred at 80°C for 12 hours. LC-MS confirmed that 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. H2O (20 mL) was added to the crude product and extracted with siRNA (15 mL three times). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 45%~75%B over 8.0 minutes) to obtain the desired 4-chloro-3-(3,3-difluoro-2-methylazetidine-1-yl)-1-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)sulfonyl]indazole (6.5 mg, 16.0 μmol, 41.3% yield, 100.00% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.91(d,J=8.3Hz,1H),7.69(t,J=8.1Hz,1H),7.57(d,J=7.5Hz,1H),5.06-4.92(m,1H),4.8 9-4.78(m,1H),4.63(dt,J=10.8,13.4Hz,1H),2.49(d,J=2.3Hz,6H),1.42(d,J=6.5Hz,3H). HPLC: 100.00%(220nm), 100.00%(215nm), 100.00(254nm). MS(ESI):mass calcd.For C 16 H 15ClF3N3O2S 405.05 m / z found 406.1[M+H] + .

[0436] Compound 20: 4-Chloro-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole

[0437] [ka]

[0438] Step 1: To a solution of 6,6-difluoro-3-azabicyclo[3.1.0]hexane (150 mg, 964 μmol, 1 equivalent, HCl) in THF (2 mL), TEA (976 mg, 9.64 mmol, 1.34 mL, 10 equivalents) was added dropwise at 25°C. After addition, the mixture was stirred at this temperature for 10 minutes. (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (401 mg, 1.06 mmol, 1.1 equivalents) in THF (2 mL) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 25°C for 20 minutes. LC-MS confirmed that the 6,6-difluoro-3-azabicyclo[3.1.0]hexane was completely consumed and one main peak with the desired mass was detected. The reaction mixture was separated into 20 mL of water and 40 mL of ethyl acetate. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired N-[(Z)-[(2,6-dichlorophenyl)-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)methylene]amino]-4-methylbenzenesulfonamide (440 mg, crude) as a yellow solid. MS(ESI): mass calcd. For C 19 H 17 Cl2F2N3O2S 459.04 m / z found 460.2[M+H] + .

[0439] Step 2: To a solution of N-[(Z)-[(2,6-dichlorophenyl)-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)methylene]amino]-4-methylbenzenesulfonamide (440 mg, 956 μmol, 1 equivalent) in DMF (10 mL), K2CO3 (661 mg, 4.78 mmol, 5 equivalents) was added. The mixture was stirred at 100 °C for 12 hours. LC-MS confirmed that N-[(Z)-[(2,6-dichlorophenyl)-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed and the desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with ELISA (3 times with 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)-1-(p-tolylsulfonyl)indazole (400 mg, crude) as a yellow oil. MS(ESI): mass calcd.For C 19 H 16 ClF2N3O2S 423.06 m / z found 424.1[M+H] + .

[0440] Step 3: To a solution of 4-chloro-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)-1-(p-tolylsulfonyl)indazole (400 mg, 944 μmol, 1 equivalent) in MeOH (10 mL), K2CO3 (652 mg, 4.72 mmol, 5 equivalents) was added. The mixture was stirred at 60°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)-1-(p-tolylsulfonyl)indazole was completely consumed and the desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with  (30 mL three times). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)-1H-indazole (80 mg, crude) as a yellow oily substance. MS(ESI): mass calcd.For C 12 H 10 ClF2N3269.05 m / z found 270.2[M+H] + .

[0441] Step 4: To a solution of 4-chloro-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)-1H-indazole (30 mg, 111 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (40.2 mg, 167 μmol, 1.5 equivalents) in DCM (1 mL), TEA (33.8 mg, 334 μmol, 46.5 μL, 3 equivalents) and DMAP (1.36 mg, 11.1 μmol, 0.1 equivalent) were added. The mixture was stirred at 20 °C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)-1H-indazole was completely consumed and one main peak with the desired mass was detected. The residue was obtained by concentrating the reaction under reduced pressure. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 80*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 50%~80%B over 8.0 minutes) to obtain the desired 4-chloro-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole (6.0 mg, 12.1 μmol, 10.9% yield, 95.51% purity) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.10(d,J=8.4Hz,1H),7.95(d,J=8.4Hz,2H),7.76(d,J=8.6Hz,2H),7.64(t,J=8.1 Hz,1H),7.49(d,J=7.7Hz,1H),4.01(d,J=11.0Hz,2H),3.84-3.75(m,2H),2.62(br d,J=11.7Hz,2H),1.94(t,J=19.1Hz,3H). HPLC: 95.51%(220nm), 95.21%(215nm), 96.48(254nm). MS(ESI):mass calcd.For C 20 H 16 ClF4N3O2S 473.06 m / z found 474.0[M+H] + .

[0442] Compound 21: 4-Chloro-3-(2,2-difluoro-5-azaspiro[2,3]hexane-5-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole

[0443] [ka]

[0444] Step 1: To a solution of (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (364 mg, 964 μmol, 1 equivalent) and TEA (976 mg, 9.64 mmol, 1.34 mL, 10 equivalents) in THF (10 mL), 2,2-difluoro-5-azaspiro[2.3]hexane (150 mg, 964 μmol, 1 equivalent, HCl) was added at -15°C, and the mixture was stirred at 20°C for 12 hours. LCMS confirmed that the (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride was completely consumed and the desired mass was detected. By concentrating the reaction mixture under reduced pressure, the desired N-[(E)-[(2,6-dichlorophenyl)-(2,2-difluoro-5-azaspiro[2,3]hexane-5-yl)methylene]amino]-4-methylbenzenesulfonamide (443 mg, crude) was obtained as a yellow oil. MS(ESI): mass calcd.For C 19 H 17 N3SO2Cl2F2459.04 m / z found 460.1[M+H] + .

[0445] Step 2: A mixture of N-[(E)-[(2,6-dichlorophenyl)-(2,2-difluoro-5-azaspiro[2.3]hexane-5-yl)methylene]amino]-4-methylbenzenesulfonamide (443 mg, 962 μmol, 1 equivalent) and K2CO3 (1.33 g, 9.62 mmol, 10 equivalents) in DMF (4 mL) was stirred at 100 °C for 3 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(2,2-difluoro-5-azaspiro[2.3]hexane-5-yl)methylene]amino]-4-methylbenzenesulfonamide remained and the desired mass was detected. The reaction mixture was poured into ice water (50 mL) and extracted with MTBE (3 times with 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(2,2-difluoro-5-azaspiro[2.3]hexane-5-yl)-1-(p-tolylsulfonyl)indazole (400 mg, crude) as a yellow solid. MS(ESI): mass calcd. For C 19 H 16 N3SO2ClF2423.06 m / z found 424.2[M+H] + .

[0446] Step 3: A mixture of 4-chloro-3-(2,2-difluoro-5-azaspiro[2.3]hexane-5-yl)-1-(p-tolylsulfonyl)indazole (400 mg, 944 μmol, 1 equivalent) and K2CO3 (261 mg, 1.89 mmol, 2 equivalents) in MeOH (4 mL) was stirred at 40°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(2,2-difluoro-5-azaspiro[2.3]hexane-5-yl)-1-(p-tolylsulfonyl)indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction under reduced pressure. Water (50 mL) was added to the residue and extracted with MTBE (3 times with 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(2,2-difluoro-5-azaspiro[2,3]hexane-5-yl)-1H-indazole (130 mg, crude) as a yellow solid. MS(ESI): mass calcd.For C 12 H 10 N3ClF2269.05 m / z found 270.1[M+H] + .

[0447] Step 4: To a solution of 4-(1,1-difluoroethyl)benzenesulfonyl chloride (66.9 mg, 278 μmol, 1.5 equivalents) in DCM (2 mL) and 4-chloro-3-(2,2-difluoro-5-azaspiro[2.3]hexane-5-yl)-1H-indazole (50 mg, 185 μmol, 1 equivalent) in DCM (2 mL), TEA (56.3 mg, 556 μmol, 3 equivalents) and DMAP (2.27 mg, 18.5 μmol, 0.1 equivalents) were added. The mixture was stirred at 20°C for 12 hours. LCMS confirmed that 4-chloro-3-(2,2-difluoro-5-azaspiro[2.3]hexane-5-yl)-1H-indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 4-chloro-3-(2,2-difluoro-5-azaspiro[2,3]hexane-5-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole (20 mg, 41.3 μmol, 22.3% yield, 97.86% purity) as a white solid. 1 H NMR(DMSO-d6)δ 8.06(d,1H),7.95(d,2H),7.76(d,2H),7.64(m,1H),7.45(d,1H),4.27-4.37(m,4H),1.93(m,3H),1.75(brM,2H). HPLC: 97.86% (220nm), 97.09% (215nm), 95.74% (254nm). MS(ESI):mass calcd.For C 20 H 16 ClN3SO2F4473.06 m / z found 474.1[M+H] + .

[0448] Compound 22: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,4-difluoropyrrolidine-1-yl)indazole

[0449] [ka]

[0450] Step 1: A mixture of (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (921 mg, 2.44 mmol, 1 equivalent) and TEA (2.47 g, 24.4 mmol, 3.39 mL, 10 equivalents) in THF (10 mL) was mixed with 3,4-difluoropyrrolidine (350 mg, 2.44 mmol, 1 equivalent, HCl) at -15°C. The mixture was stirred at 20°C for 12 hours. LC-MS confirmed that the (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride was completely consumed and the desired mass was detected. By concentrating the reaction mixture under reduced pressure, the desired N-[(E)-[(2,6-dichlorophenyl)-(3,4-difluoropyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (1.09 g, crude) was obtained as a yellow oil. MS(ESI): mass calcd.For C 18 H 17 N3SO2Cl2F2447.04 m / z found 448.1[M+H] + .

[0451] Step 2: A mixture of N-[(E)-[(2,6-dichlorophenyl)-(3,4-difluoropyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (1.09 g, 2.43 mmol, 1 equivalent) and K2CO3 (3.36 g, 24.3 mmol, 10 equivalents) in DMF (10 mL) was stirred at 100°C for 3 hours. LCMS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(3,4-difluoropyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide remained and the desired mass was detected. The reaction mixture was poured into ice water (50 mL) and extracted with MTBE (3 times with 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(3,4-difluoropyrrolidine-1-yl)-1-(p-tolylsulfonyl)indazole (1 g, crude) as a yellow solid. MS(ESI): mass calcd. For C 18 H 16N3SO2ClF2411.06 m / z found 412.1[M+H] + .

[0452] Step 3: A mixture of 4-chloro-3-(3,4-difluoropyrrolidine-1-yl)-1-(p-tolylsulfonyl)indazole (1 g, 2.43 mmol, 1 equivalent) and K2CO3 (671 mg, 4.86 mmol, 2 equivalents) in MeOH (10 mL) was stirred at 40°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(3,4-difluoropyrrolidine-1-yl)-1-(p-tolylsulfonyl)indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction under reduced pressure. Water (50 mL) was added to the residue and extracted with MTBE (3 times with 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(3,4-difluoropyrrolidine-1-yl)-1H-indazole (250 mg, crude) as a yellow solid. MS(ESI): mass calcd.For C 11 H 10 ClN3F2257.05 m / z found 258.1[M+H] + .

[0453] Step 4: To a solution of 4-(1,1-difluoroethyl)benzenesulfonyl chloride (140 mg, 582 μmol, 1.5 equivalents) and 4-chloro-3-(3,4-difluoropyrrolidine-1-yl)-1H-indazole (100 mg, 388 μmol, 1 equivalent) in DCM (2 mL), TEA (118 mg, 1.16 mmol, 3 equivalents) and DMAP (4.74 mg, 38.8 μmol, 0.1 equivalents) were added. The mixture was stirred at 20°C for 12 hours. LC-MS confirmed that 4-chloro-3-(3,4-difluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,4-difluoropyrrolidine-1-yl)indazole (24.0 mg, 51.4 μmol, 13.2% yield, 98.87% purity) as a white solid. 1 H NMR(DMSO-d6)δ 8.08(d,1H),7.94(d,2H),7.75(d,2H),7.64(m,1H),7.48(d,1H),5.41-5.50(m,1H),5.27-5.37(m,1H),3 .87-4.02(m,2H),3.70-3.85(m,2H),1.92(m,3H)HPLC:98.87%(220nm),98.43%(215nm),99.38%(254nm). MS(ESI):mass calcd.For C 19 H 16 ClF4N3O2S 461.06 m / z found 462.1[M+H] + .

[0454] Compound 23: Mesoform of 4-chloro-1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-3-((3R,4R)-3,4-difluoropyrrolidine-1-yl)-1H-indazole

[0455] [ka]

[0456] Step 1: A mixture of tert-butyl 4-chloro-3-iodoindazole-1-carboxylate (527 mg, 1.39 mmol, 1 equivalent), mesoform 3,4-difluoropyrrolidine (200 mg, 1.39 mmol, 1 equivalent, HCl), Pd2(dba)3 (128 mg, 139 μmol, 0.1 equivalent), Cs2CO3 (1.36 g, 4.18 mmol, 3 equivalents), and BINAP (86.8 mg, 139 μmol, 0.1 equivalent) in toluene (10 mL) was degassed and purged three times with N2. The mixture was stirred at 100°C for 3 hours under an N2 atmosphere. LC-MS confirmed that tert-butyl 4-chloro-3-iodoindazole-1-carboxylate was completely consumed and the desired mass was detected. The crude product was mixed with H2O (20 mL) and extracted with siRNA (3 times with 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired mesoform of tert-butyl 4-chloro-3-(3,4-difluoropyrrolidine-1-yl)indazole-1-carboxylate (150 mg, 419 μmol, 30.1% yield) as a yellow oil. MS(ESI): mass calcd. For C 16 H 18 ClF2N3O2357.11 m / z found 358.1[M+H] + .

[0457] Step 2: To a meso-form solution of tert-butyl 4-chloro-3-((3R,4R)-3,4-difluoropyrrolidine-1-yl)indazole-1-carboxylate (250 mg, 699 μmol, 1 equivalent) in DCM (3 mL), TFA (1 mL) was added. The mixture was stirred at 15°C for 0.5 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) confirmed that the meso-form of tert-butyl 4-chloro-3-((3R,4R)-3,4-difluoropyrrolidine-1-yl)indazole-1-carboxylate had been completely consumed, and a new spot had formed. The residue was obtained by concentrating the reaction mixture under vacuum. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired mesoform of 4-chloro-3-(3,4-difluoropyrrolidine-1-yl)-1H-indazole (250 mg, crude, TFA) as a brown solid.

[0458] Step 3: To a solution of the mesoform of 4-chloro-3-((3R,4R)-3,4-difluoropyrrolidine-1-yl)-1H-indazole (20.0 mg, 53.8 μmol, 1 equivalent, TFA) in DCM (1 mL) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (13.0 mg, 53.8 μmol, 1 equivalent), TEA (27.2 mg, 269 μmol, 37.5 μL, 5 equivalents) and DMAP (657 μg, 5.38 μmol, 0.1 equivalents) were added. The mixture was stirred at 15°C for 0.5 hours. LC-MS confirmed that the mesoform of 4-chloro-3-((3R,4R)-3,4-difluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The crude product was mixed with H2O (20 mL) and extracted by DCM (3 times with 15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired mesoform of 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-((3R,4R)-3,4-difluoropyrrolidine-1-yl)indazole (2 mg, 4.14 μmol, 7.69% yield, 95.53% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.14(d,J=8.0Hz,1H),8.00(d,J=8.5Hz,2H),7.80(d,J=8.5Hz,2H),7.70(t,J=8.1Hz,1H),7.54( d,J=7.4Hz,1H),5.62-5.39(m,2H),4.25-4.03(m,2H),3.82-3.66(m,2H),1.97(t,J=19.1Hz,3H). HPLC: 95.93% (220nm), 95.88% (215nm), 100.00 (254nm). MS(ESI):mass calcd.For C 19 H 16 ClF4N3O2S 461.06 m / z found 462.1[M+H] + .

[0459] Compound 24: 4-Chloro-3-(7,7-difluoro-2-azaspiro[3,3]heptan-2-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole

[0460] [ka]

[0461] Step 1: To a solution of tert-butyl 7-oxo-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.37 mmol, 1 equivalent) in DCM (6 mL), DAST (1.91 g, 11.8 mmol, 1.56 mL, 5 equivalents) was added at 0°C. The mixture was stirred at 15°C for 1 hour. TLC confirmed that the tert-butyl 7-oxo-2-azaspiro[3.3]heptane-2-carboxylate had been completely consumed, resulting in the formation of a new spot. The reaction mixture was separated into 10 mL of H2O and 10 mL of DCM. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired tert-butyl 7,7-difluoro-2-azaspiro[3.3]heptane-2-carboxylate (160 mg, 686 μmol, 28.9% yield) as a white oily substance. 1 H NMR(400MHz,DMSO-d6)δ 4.22(d,J=9.3Hz,2H),3.76(d,J=9.3Hz,2H),2.44(tt,J=8.6,12.3Hz,2H),2.05-1.94(m,2H),1.43(s,9H).

[0462] Step 2: To a solution of tert-butyl 7,7-difluoro-2-azaspiro[3.3]heptane-2-carboxylate (160 mg, 686 μmol, 1 equivalent) in DCM (3 mL), TFA (1.96 g, 17.2 mmol, 1.27 mL, 25 equivalents) was added. The mixture was stirred at 15°C for 1 hour. TLC confirmed that the tert-butyl 7,7-difluoro-2-azaspiro[3.3]heptane-2-carboxylate had been completely consumed, and a new spot had formed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the desired 7,7-difluoro-2-azaspiro[3.3]heptane (300 mg, crude, TFA) as a black oily substance.

[0463] Step 3: TEA (614 mg, 6.07 mmol, 845 μL, 5 equivalents) was added at 0°C to a solution of (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (550 mg, 1.46 mmol, 1.2 equivalents) and 7,7-difluoro-2-azaspiro[3.3]heptane (300 mg, 1.21 mmol, 1 equivalent, TFA) in THF (8 mL). The mixture was stirred at 15°C for 2 hours. LC-MS confirmed that 7,7-difluoro-2-azaspiro[3.3]heptane was completely consumed and the desired mass was detected. The reaction mixture was separated into 30 mL of H2O and 50 mL of RINKAN. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired N-[(E)-[(2,6-dichlorophenyl)-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)]amino]-4-methylbenzenesulfonamide (490 mg, crude) as a yellow solid. MS(ESI): mass calcd. For C 20 H 19 Cl2F2N3O2S 473.1,m / z found 474.1[M+H] + .

[0464] Step 4: To a solution of N-[(E)-[(2,6-dichlorophenyl)-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)methylene]amino]-4-methylbenzenesulfonamide (470 mg, 991 μmol, 1 equivalent) in DMF (5 mL), K2CO3 (685 mg, 4.95 mmol, 5 equivalents) was added. The mixture was stirred at 100 °C for 2 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed and the desired mass was detected. The reaction mixture was divided into 20 mL of H2O and 30 mL of siRNA. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)-1-(p-tolylsulfonyl)indazole (280 mg, crude) as a yellow oil. MS(ESI): mass calcd.For C 20 H 18 ClF2N3O2S 437.1,m / z found 438.1[M+H] + .

[0465] Step 5: To a solution of 4-chloro-3-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)-1-(p-tolylsulfonyl)indazole (280 mg, 639 μmol, 1 equivalent) in MeOH (3 mL), K2CO3 (442 mg, 3.20 mmol, 5 equivalents) was added. The mixture was stirred at 40°C for 1 hour. LC-MS confirmed that 4-chloro-3-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)-1-(p-tolylsulfonyl)indazole had been completely consumed and the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was separated into 10 mL of H2O and 10 mL of RINKAN. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Purification of the crude product by preparative TLC (silica gel, petroleum ether / ethyl acetate = 1 / 1) yielded the desired 4-chloro-3-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)-1H-indazole (70 mg, 247 μmol, 38.6% yield) as a yellow oily substance. MS(ESI): mass calcd.For C 13 H 12 ClF2N3283.1 m / z found 284.1[M+H] + .

[0466] Step 6: TEA (21.4 mg, 212 μmol, 29.4 μL, 2 equivalents) and DMAP (1.29 mg, 10.6 μmol, 0.1 equivalent) were added to a solution of 4-chloro-3-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)-1H-indazole (30 mg, 106 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (38.2 mg, 159 μmol, 1.5 equivalents) in DCM (1 mL). The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-chloro-3-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was diluted with water (10 mL) and extracted with siRNA (3 times with 10 mL). The combined organic phase was washed with brine (3 times with 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(7,7-difluoro-2-azaspiro[3,3]heptan-2-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole (4.1 mg, 8.37 μmol, 13.6% yield, 99.62% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.05(d,J=8.4Hz,1H),7.92(d,J=8.3Hz,2H),7.74(d,J=8.4Hz,2H),7.63(t,J=8.1Hz,1H),7. 45(d,J=7.7Hz,1H),4.34(d,J=9.3Hz,2H),4.13(d,J=9.3Hz,2H),2.49-2.41(m,2H),2.04(br t,J=8.3Hz,2H),1.91(t,J=19.1Hz,3H). HPLC: 99.62% (220nm), 99.38% (215nm), 100.00% (254nm). MS(ESI):mass calcd.For C 21 H 18 ClF4N3O2S 487.1 m / z found 488.1[M+H] + .

[0467] Compound 25: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(7-fluoro-5-azaspiro[2,4]heptan-5-yl)indazole

[0468] [ka]

[0469] Step 1: To a solution of 7-fluoro-5-azaspiro[2.4]heptane hydrochloride (100 mg, 660 μmol, 1 equivalent) in THF (10 mL), TEA (133 mg, 1.32 mmol, 184 μL, 2 equivalents) and (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (299 mg, 792 μmol, 1.2 equivalents) were added at 0°C. The mixture was stirred at 15°C for 2 hours. LC-MS confirmed that the (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride was completely consumed and the desired mass was detected. By concentrating the reaction mixture, the desired N-[(Z)-[(2,6-dichlorophenyl)-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)methylene]amino]-4-methylbenzenesulfonamide (1 g, crude) was obtained as a yellow solid. MS(ESI): mass calcd. For C 20 H 20 Cl2FN3O2S 455.06,m / z found 456.3[M+H] + .

[0470] Step 2: To a solution of N-[(Z)-[(2,6-dichlorophenyl)-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)methylene]amino]-4-methylbenzenesulfonamide (1.0 g, 2.19 mmol, 1 equivalent) in DMF (10 mL), K2CO3 (3.03 g, 21.9 mmol, 10 equivalents) was added. The mixture was stirred at 100 °C for 2 hours. LC-MS confirmed that N-[(Z)-[(2,6-dichlorophenyl)-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed and the desired mass was detected. The reaction mixture was diluted with H2O (20 mL) and extracted with MTBE (3 times with 20 mL). The combined organic phases were washed with brine (3 times with 20 mL), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the desired 4-chloro-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)-1-(p-tolylsulfonyl)indazole (380 mg, crude) as a yellow solid. MS(ESI): mass calcd.For C 20 H 19 ClFN3O2S 419.09,m / z found 420.3[M+H] + .

[0471] Step 3: To a solution of 4-chloro-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)-1-(p-tolylsulfonyl)indazole (380 mg, 905 μmol, 1 equivalent) in MeOH (5 mL), K2CO3 (1.25 g, 9.05 mmol, 10 equivalents) was added. The mixture was stirred at 45°C for 1 hour. LC-MS confirmed that 4-chloro-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)-1-(p-tolylsulfonyl)indazole was completely consumed and the desired mass was detected. The reaction mixture was diluted with H2O (10 mL) and extracted with  (3 times with 10 mL). The combined organic phase was washed with brine (3 times with 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 4-chloro-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)-1H-indazole (90 mg, 338 μmol, 37.4% yield) as a white solid. MS(ESI): mass calcd.For C 13 H 13 ClFN3265.08,m / z found 266.2[M+H] + .

[0472] Step 4: To a solution of 4-chloro-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)-1H-indazole (90 mg, 338 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (122 mg, 508 μmol, 1.5 equivalents) in DCM (2 mL), TEA (68 mg, 677 μmol, 94 μL, 2 equivalents) and DMAP (4.14 mg, 33 μmol, 0.1 equivalent) were added. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-chloro-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was added to H2O (30 mL) and extracted with HCl (3 times with 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 50%~80% B over 8.0 mins) to obtain the desired 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)indazole (6 mg, 12.3 μmol, 3.63% yield, 96.26% purity) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ 8.13-8.03(m,1H),7.92(d,J=8.3Hz,2H),7.80-7.69(m,2H),7.68-7.57(m,1H),7.50-7.41(m,1H),4.85-4.62(m,1H) ),4.25-4.03(m,2H),3.77-3.61(m,1H),3.17-3.08(m,1H),2.00-1.83(m,3H),1.07-0.73(m,3H),0.70-0.58(m,1H). HPLC: 96.81% (220nm), 82.12% (215nm), 96.26% (254nm). MS(ESI):mass calcd.For C 21 H 19 ClF3N3O2S 469.08 m / z found 470.0[M+H] + .

[0473] Compound 26: 4-Chloro-1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-3-((3R,4R)-3,4-difluoropyrrolidine-1-yl)-1H-indazole Compound 27: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(3S,4S)-3,4-difluoropyrrolidine-1-yl]indazole

[0474] [ka]

[0475] Step 1: Two isomers were obtained by separating the mesoform (60 mg, 130 μmol, 1 equivalent) of 4-chloro-1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-3-((3S,4S)-3,4-difluoropyrrolidine-1-yl)-1H-indazole by chiral SFC (column: Daicel ChiralPak IG (250*30 mm, 10 μm); mobile phase: [heptane-EtOH]; gradient: 5%~70%B over 12.0 minutes). The structures were arbitrarily assigned. 4-Chloro-1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-3-((3R,4R)-3,4-difluoropyrrolidine-1-yl)-1H-indazole (11.3 mg, 24.0 μmol, 18.5% yield, 98.24% purity, Rt=3.968 min; EE(%)=100.00%) by chiral HPLC was isolated as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.14(d,J=8.5Hz,1H),8.00(d,J=8.5Hz,2H),7.80(d,J=8.5Hz,2H),7.70(t,J=8.1Hz,1H),7.54( d,J=7.6Hz,1H),5.62-5.38(m,2H),4.25-4.04(m,2H),3.82-3.66(m,2H),1.97(t,J=19.1Hz,3H). HPLC: 98.24% (220nm), 97.92% (215nm), 98.66% (254nm). MS(ESI):mass calcd.For C 19 H 16 ClF4N3O2S 461.06 m / z found 462.1[M+H] + . 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(3S,4S)-3,4-difluoropyrrolidine-1-yl]indazole (9.7 mg, 20.8 μmol, 16.0% yield, 99.21% purity, Rt=4.222 min; EE(%)=95.68% by chiral HPLC) was isolated as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.14(br d,J=8.5Hz,1H),8.00(br d,J=8.0Hz,2H),7.80(br d,J=7.9Hz,2H),7.74-7.67(m,1H),7.54(br d,J=7.7Hz,1H),5.60-5.41(m,2H),4.24-4.06(m,2H),3.82-3.67(m,2H),2.05-1.91(m,3H). HPLC: 99.21% (220nm), 99.12% (215nm), 97.45% (254nm). MS(ESI):mass calcd.For C 19 H 16 ClF4N3O2S 461.06 m / z found 462.1[M+H] - .

[0476] Compound 28: 4-Chloro-3-(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole

[0477] [ka]

[0478] Step 1: To a solution of tert-butyl 7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (1.61 g, 7.62 mmol, 1 equivalent) in DCM (17 mL), DAST (18.4 g, 114 mmol, 15.1 mL, 15 equivalents) was added at 0°C. The mixture was stirred at 35°C for 12 hours. TLC confirmed the presence of residual tert-butyl 7-oxo-5-azaspiro[2.4]heptane-5-carboxylate and the detection of one major new spot of low polarity. The reaction product was quenched with saturated NaHCO3 aqueous solution (20 mL), and the mixture was extracted with DCM (40 mL). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 2g SepaFlash® Silica Flash Column, 60 mL / min with a 0-15% ethyl acetate / petroleum ether gradient) to obtain the desired tert-butyl 7,7-difluoro-5-azaspiro[2.4]heptane-5-carboxylate (680 mg, 2.92 mmol, 38.3% yield) as a white solid.

[0479] Step 2: To a mixture of tert-butyl 7,7-difluoro-5-azaspiro[2.4]heptane-5-carboxylate (580 mg, 2.49 mmol, 1 equivalent) in DCM (9 mL), TFA (4.61 g, 40.4 mmol, 3 mL, 16.2 equivalents) was added. The mixture was stirred at 20°C for 1 hour. TLC confirmed that tert-butyl 7,7-difluoro-5-azaspiro[2.4]heptane-5-carboxylate had been completely consumed and new spots had formed. The reaction product was concentrated under reduced pressure to obtain the desired 7,7-difluoro-5-azaspiro[2.4]heptane (610 mg, crude, TFA) as a light brown oily substance.

[0480] Step 3: To a mixture of 7,7-difluoro-5-azaspiro[2.4]heptane (300 mg, 1.21 mmol, 1 equivalent, TFA) and TEA (2.18 g, 21.5 mmol, 3 mL, 17.8 equivalents) in THF (5 mL), (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (458 mg, 1.21 mmol, 1 equivalent) was added at -15°C. The mixture was stirred at 20°C for 12 hours. LC-MS confirmed that the (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride was completely consumed and the desired mass was detected. By concentrating the reaction under reduced pressure, the desired N-[(E)-[(2,6-dichlorophenyl)-(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)methylene]amino]-4-methylbenzenesulfonamide (575 mg, crude) was obtained as a yellow oil. MS(ESI): mass calcd.For C 20 H 19 Cl2F2N3O2S 473.05,m / z found 474.1[M+H] + .

[0481] Step 4: A mixture of N-[(E)-[(2,6-dichlorophenyl)-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)methylene]amino]-4-methylbenzenesulfonamide (575 mg, 1.21 mmol, 1 equivalent) and K2CO3 (3.35 g, 24.2 mmol, 20 equivalents) in DMF (10 mL) was stirred at 100 °C for 3 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed and the desired mass was detected. The reaction mixture was poured into ice water (50 mL) and extracted with MTBE (3 times with 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-1-(p-tolylsulfonyl)indazole (530 mg, 1.21 mmol, 99.9% yield) as a yellow oil. MS(ESI): mass calcd. For C 20 H 18 ClF2N3O2S 437.08 m / z found 438.1[M+H] + .

[0482] Step 5: A mixture of 4-chloro-3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-1-(p-tolylsulfonyl)indazole (530 mg, 1.21 mmol, 1 equivalent) and K2CO3 (334 mg, 2.42 mmol, 2 equivalents) in MeOH (5 mL) was stirred at 40°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-1-(p-tolylsulfonyl)indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction mixture. The reaction mixture was poured into ice water (10 mL) and extracted with MTBE (3 times with 10 mL). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 4-chloro-3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-1H-indazole (90 mg, 317 μmol, 26.2% yield) as a yellow solid. MS(ESI): mass calcd. For C 13 H 12 ClF2N3283.07 m / z found 284.1[M+H] + .

[0483] Step 6: To a solution of 4-chloro-3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-1H-indazole (50 mg, 176 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (63.6 mg, 264 μmol, 1.5 equivalents) in DCM (2 mL), TEA (35.7 mg, 352 μmol, 49 μL, 2 equivalents) and DMAP (2.15 mg, 17.6 μmol, 0.1 equivalent) were added at 0°C. The mixture was stirred at 15°C for 2 hours. LC-MS confirmed that 4-chloro-3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was added to H2O (30 mL) and extracted with siRNA (30 mL three times). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 4-chloro-3-(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole (35 mg, 71.5 μmol, 40.6% yield, 99.64% purity) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ 8.14-8.05(m,1H),8.00-7.92(m,2H),7.81-7.72(m,2H),7.69-7.61(m,1H),7.53-7.44(m,1H), 4.12-4.00(m,2H),3.74-3.66(m,2H),1.99-1.85(m,3H),1.02-0.95(m,2H),0.91-0.82(m,2H). HPLC: 97.73% (220nm), 97.61% (215nm), 99.64% (254nm). MS(ESI):mass calcd.For C 21 H 18 ClF4N3O2S 487.07 m / z found 488.0[M+H] + .

[0484] Compound 29: 3-(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-4-fluoroindazole

[0485] [ka]

[0486] Step 1: To a mixture of 7,7-difluoro-5-azaspiro[2.4]heptane (300 mg, 1.21 mmol, 1 equivalent, TFA) and TEA (2.18 g, 21.5 mmol, 3 mL, 17.8 equivalents) in THF (5 mL), (1E)-2,6-difluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (418 mg, 1.21 mmol, 1 equivalent) was added at -15°C, and the mixture was stirred at 20°C for 1 hour. LC-MS confirmed that 7,7-difluoro-5-azaspiro[2.4]heptane was completely consumed and the desired mass was detected. By concentrating the reaction under reduced pressure, the desired N-[(E)-[(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)-(2,6-difluorophenyl)methylene]amino]-4-methylbenzenesulfonamide (535 mg, crude) was obtained as a yellow oil. MS(ESI): mass calcd.For C 20 H 19 F4N3O2S 441.11,m / z found 442.1[M+H] + .

[0487] Step 2: A mixture of N-[(E)-[(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-(2,6-difluorophenyl)methylene]amino]-4-methylbenzenesulfonamide (535 mg, 1.21 mmol, 1 equivalent) and K2CO3 (3.35 g, 24.2 mmol, 20 equivalents) in DMF (10 mL) was stirred at 100 °C for 3 hours. LC-MS confirmed that N-[(E)-[(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-(2,6-difluorophenyl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed and the desired mass was detected. The reaction mixture was poured into ice water (50 mL) and extracted with MTBE (3 times with 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-4-fluoro-1-(p-tolylsulfonyl)indazole (510 mg, crude) as a yellow oil. MS(ESI): mass calcd.For C 20 H 18 F3N3O2S 421.11,m / z found 422.1[M+H] + .

[0488] Step 3: A mixture of 3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-4-fluoro-1-(p-tolylsulfonyl)indazole (510 mg, 1.21 mmol, 1 equivalent) and K2CO3 (335 mg, 2.42 mmol, 2 equivalents) in MeOH (5 mL) was stirred at 40°C for 0.5 hours. LC-MS confirmed that 3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-4-fluoro-1-(p-tolylsulfonyl)indazole was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-4-fluoro-1H-indazole (130 mg, 486 μmol, 40.2% yield) as a yellow solid. MS(ESI): mass calcd.For C 13 H 12 F3N3267.1,m / z found 268.1[M+H] + .

[0489] Step 4: To a solution of 3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-4-fluoro-1H-indazole (50 mg, 187 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (67.5 mg, 281 μmol, 1.5 equivalents) in DCM (2 mL), TEA (37.9 mg, 374 μmol, 52.1 μL, 2 equivalents) and DMAP (2.29 mg, 18.7 μmol, 0.1 equivalent) were added at 0°C. The mixture was stirred at 15°C for 2 hours. LC-MS confirmed that 3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-4-fluoro-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was added to H2O (30 mL) and extracted with ELISA (30 mL three times). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 3-(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-4-fluoroindazole (44 mg, 93.0 μmol, 49.71% yield, 99.64% purity) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ 8.00-7.89(m,3H),7.79-7.63(m,3H),7.26-7.16(m,1H),4.15-4.04(m,2H),3.79-3.64(m,2H),2.01-1.85(m,3H),1.04-0.89(m,4H). HPLC: 98.76% (220nm), 98.93% (215nm), 99.64% (254nm). MS(ESI):mass calcd.For C 21 H 18 F5N3O2S 471.1 m / z found 472.0[M+H] + .

[0490] Compound 30: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3-fluoro-4-methylpyrrolidine-1-yl)indazole

[0491] [ka]

[0492] Step 1: To a solution of tert-butyl 3-methyl-4-oxo-pyrrolidine-1-carboxylate (1 g, 5.02 mmol, 1 equivalent) in EtOH (10 mL), NaBH4 (380 mg, 10.0 mmol, 2 equivalents) was added at 0°C. The mixture was stirred at 20°C for 1 hour. TLC confirmed that the tert-butyl 3-methyl-4-oxo-pyrrolidine-1-carboxylate was completely consumed, resulting in the formation of a new spot. The residue was diluted with HCl (1 N, 5 mL), and the resulting mixture was allowed to return to room temperature. The EtOH was evaporated under vacuum. The reaction mixture was added to water (20 mL) and extracted with DCM (3 times with 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the desired tert-butyl 3-hydroxy-4-methyl-pyrrolidine-1-carboxylate (1 g, crude) as a colorless oil.

[0493] Step 2: To a solution of tert-butyl 3-hydroxy-4-methyl-pyrrolidine-1-carboxylate (1 g, 4.97 mmol, 1 equivalent) in DCM (20 mL), DAST (2.40 g, 14.9 mmol, 1.97 mL, 3 equivalents) was added at 0°C. The mixture was stirred at 20°C for 1 hour. TLC showed that the tert-butyl 3-hydroxy-4-methyl-pyrrolidine-1-carboxylate was completely consumed, and two new spots were observed. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution (40 mL) and extracted with DCM (10 mL four times). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the desired tert-butyl 3-fluoro-4-methyl-pyrrolidine-1-carboxylate (190 mg, crude) as a colorless oil.

[0494] Step 3: To a solution of tert-butyl 3-fluoro-4-methyl-pyrrolidine-1-carboxylate (190 mg, 935 μmol, 1 equivalent) in DCM (3 mL), TFA (1 mL) was added. The mixture was stirred at 20°C for 1 hour. TLC confirmed that the tert-butyl 3-fluoro-4-methyl-pyrrolidine-1-carboxylate had been completely consumed, and a new spot had formed. By concentrating the reaction mixture, the desired 3-fluoro-4-methyl-pyrrolidine (200 mg, crude, TFA) was obtained as a yellow oil.

[0495] Step 4: To a solution of 3-fluoro-4-methylpyrrolidine (200 mg, 921 μmol, 1 equivalent, TFA) in THF (3 mL), TEA (932 mg, 9.21 mmol, 1.28 mL, 10 equivalents) was added dropwise at 25°C. After addition, the mixture was stirred at this temperature for 10 minutes. (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (522 mg, 1.38 mmol, 1.5 equivalents) in THF (5 mL) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 25°C for 20 minutes. LC-MS confirmed that 3-fluoro-4-methylpyrrolidine was completely consumed and one main peak with the desired mass was detected. The mixture was divided into 20 mL of water and 40 mL of ethyl acetate. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired N-[(E)-[(2,6-dichlorophenyl)-(3-fluoro-4-methylpyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (400 mg, crude) as a yellow solid. MS(ESI): mass calcd. For C 19 H 20 Cl2FN3O2S 443.06 m / z found 444.0[M+H] + .

[0496] Step 5: To a solution of N-[(E)-[(2,6-dichlorophenyl)-(3-fluoro-4-methyl-pyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (400 mg, 900 μmol, 1 equivalent) in DMF (10 mL), K2CO3 (622 mg, 4.50 mmol, 5 equivalents) was added. The mixture was stirred at 100 °C for 12 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(3-fluoro-4-methyl-pyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed and the desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with ethyl acetate (3 times with 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(3-fluoro-4-methyl-pyrrolidine-1-yl)-1-(p-tolylsulfonyl)indazole (360 mg, crude) as a yellow oil. MS(ESI): mass calcd.For C 19 H 19 ClFN3O2S 407.09 m / z found 408.1[M+H] + .

[0497] Step 6: To a solution of 4-chloro-3-(3-fluoro-4-methylpyrrolidine-1-yl)-1-(p-tolylsulfonyl)indazole (460 mg, 1.13 mmol, 1 equivalent) in MeOH (10 mL), K2CO3 (779 mg, 5.64 mmol, 5 equivalents) was added. The mixture was stirred at 70°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3-fluoro-4-methylpyrrolidine-1-yl)-1-(p-tolylsulfonyl)indazole had been completely consumed and the desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with Âr (3 times with 30 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(3-fluoro-4-methyl-pyrrolidine-1-yl)-1H-indazole (190 mg, 749 μmol, 66.4% yield) as a yellow oil. MS(ESI): mass calcd.For C 12 H 13 ClFN3253.08 m / z found 254.1[M+H] + .

[0498] Step 7: To a solution of 4-chloro-3-(3-fluoro-4-methylpyrrolidine-1-yl)-1H-indazole (190 mg, 749 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (270 mg, 1.12 mmol, 1.5 equivalents) in DCM (1 mL), TEA (227 mg, 2.25 mmol, 313 μL, 3 equivalents) and DMAP (9.15 mg, 74.9 μmol, 0.1 equivalent) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(3-fluoro-4-methylpyrrolidine-1-yl)-1H-indazole was completely consumed and a single main peak with the desired mass was detected. The residue was obtained by concentrating the reaction under reduced pressure. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 50%~80%B over 8.0 minutes) to obtain the desired 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3-fluoro-4-methylpyrrolidine-1-yl)indazole (28 mg, 60.4 μmol, 8.06% yield, 98.70% purity) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.07(d,J=8.4Hz,1H),7.92(br d,J=8.2Hz,2H),7.73(br d,J=8.2Hz,2H),7.61(br t,J=8.1Hz,1H),7.45(br d,J=7.6Hz,1H),5.28-4.94(m,1H),4.18-3.68(m,2H),3.62-3.53(m,1H),3.52-3 .43(m,1H),2.41-2.03(m,1H),1.91(t,J=19.1Hz,3H),1.60-1.45(m,1H),1.10(br d,J=6.7Hz,2H). HPLC: 98.70% (220nm), 99.85% (215nm), 98.73% (254nm). MS(ESI):mass calcd.For C 20 H 19 ClF3N3O2S 457.08 m / z found 458.0[M+H] + .

[0499] Compound 31: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3-difluoro-4-methylpyrrolidine-1-yl)indazole

[0500] [ka]

[0501] Step 1: To a solution of tert-butyl 3-methyl-4-oxo-pyrrolidine-1-carboxylate (500 mg, 2.51 mmol, 1 equivalent) in DCM (5 mL), DAST (2.02 g, 12.6 mmol, 1.66 mL, 5 equivalents) was added at 0°C. The mixture was stirred at 15°C for 1 hour. TLC confirmed that the tert-butyl 3-methyl-4-oxo-pyrrolidine-1-carboxylate had been completely consumed, resulting in the formation of a new spot. The reaction product was quenched with saturated NaHCO3 aqueous solution (20 mL) and extracted with DCM (30 mL). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 1g SepaFlash® Silica Flash Column, 40 mL / min with a 0-15% siRNA / petroleum ether gradient) to obtain the desired tert-butyl 3,3-difluoro-4-methyl-pyrrolidine-1-carboxylate (400 mg, 1.81 mmol, 72.1% yield) as a yellow oily substance. 1 ¹H NMR (400MHz, chloroform-d) δ 3.95 (br d, J=4.5Hz, 1H), 3.80-3.59 (m, 3H), 3.15-3.01 (m, 1H), 1.46 (s, 9H), 1.11 (br d, J=6.8Hz, 3H).

[0502] Step 2: To a solution of tert-butyl 3,3-difluoro-4-methyl-pyrrolidine-1-carboxylate (350 mg, 1.58 mmol, 1 equivalent) in DCM (5 mL), TFA (3.61 g, 31.6 mmol, 2.35 mL, 20 equivalents) was added. The mixture was stirred at 20°C for 1 hour. TLC confirmed that the tert-butyl 3,3-difluoro-4-methyl-pyrrolidine-1-carboxylate had been completely consumed, and a new spot had formed. The reaction mixture was separated into 10 mL of H2O and 10 mL of DCM. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 3,3-difluoro-4-methyl-pyrrolidine (372 mg, crude, TFA) as a white solid.

[0503] Step 3: To a solution of 3,3-difluoro-4-methylpyrrolidine (390 mg, 1.66 mmol, 1 equivalent, TFA) in THF (10 mL), TEA (168 mg, 1.66 mmol, 231 μL, 1 equivalent) and (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (689 mg, 1.82 mmol, 1.1 equivalents) were added at 0°C. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 3,3-difluoro-4-methylpyrrolidine was completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 10 mL of ELISA. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoro-4-methylpyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (766 mg, crude) as a black solid. MS(ESI): mass calcd. For C 19 H 19 Cl2F2N3O2S 461.1,m / z found 462.0[M+H] + .

[0504] Step 4: To a solution of N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoro-4-methylpyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (766 mg, 1.66 mmol, 1 equivalent) in DMF (8 mL), K2CO3 (1.14 g, 8.28 mmol, 5 equivalents) was added. The mixture was stirred at 100 °C for 12 hours. LC-MS confirmed that N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoro-4-methylpyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 10 mL of ELISA. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-3-(3,3-difluoro-4-methyl-pyrrolidine-1-yl)-1-(p-tolylsulfonyl)indazole (700 mg, crude) as a yellow solid. MS(ESI): mass calcd. For C 19 H 18 ClF2N3O2S 425.1,m / z found 426.1[M+H] + .

[0505] Step 5: To a solution of 4-chloro-3-(3,3-difluoro-4-methylpyrrolidine-1-yl)-1-(p-tolylsulfonyl)indazole (700 mg, 1.64 mmol, 1 equivalent) in MeOH (8 mL), K2CO3 (1.14 g, 8.22 mmol, 5 equivalents) was added. The mixture was stirred at 40°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3,3-difluoro-4-methylpyrrolidine-1-yl)-1-(p-tolylsulfonyl)indazole had been completely consumed and the desired mass was detected. The reaction mixture was filtered, and the residue was obtained by concentrating the filtrate under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain the desired 4-chloro-3-(3,3-difluoro-4-methylpyrrolidine-1-yl)-1H-indazole (120 mg, 442 μmol, 26.9% yield) as a white solid. MS(ESI): mass calcd. For C12 H 12 ClF2N3271.1 m / z found 272.1[M+H] + .

[0506] Step 6: To a solution of 4-chloro-3-(3,3-difluoro-4-methylpyrrolidine-1-yl)-1H-indazole (120 mg, 442 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (106 mg, 442 μmol, 1 equivalent) in DCM (2 mL), TEA (89.4 mg, 883 μmol, 123 μL, 2 equivalents) and DMAP (5.40 mg, 44.2 μmol, 0.1 equivalent) were added. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3,3-difluoro-4-methylpyrrolidine-1-yl)-1H-indazole had been completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 10 mL of ELISA. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 70%~95% B over 8.0 mins) to obtain the desired 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3-difluoro-4-methylpyrrolidine-1-yl)indazole (30 mg, 62.3 μmol, 14.1% yield, 98.80% purity) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.08(d,J=8.3Hz,1H),7.95(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,2H),7.65(t,J=8.1Hz,1H),7.49(d,J=7.5Hz,1H),4.09(br d,J=18.0Hz,1H),3.90-3.76(m,2H),3.38(s,2H),1.92(t,J=19.2Hz,3H),1.08(d,J=6.8Hz,3H). HPLC: 98.80% (220nm), 98.82% (215nm), 98.44% (254nm). MS(ESI):mass calcd.For C 20 H 18 ClF4N3O2S 475.1 m / z found 476.1[M+H] + .

[0507] Compound 32: 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-4-amine

[0508] [ka]

[0509] Step 1: To a solution of 4-nitro-2H-indazole (100 mg, 613 μmol, 1 equivalent) in DMF (5 mL), NIS (152 mg, 674 μmol, 1.1 equivalents) was added. The mixture was stirred at 75°C for 2 hours. TLC showed that the 4-nitro-2H-indazole was completely consumed and a new spot had formed. The reaction mixture was diluted with H2O (30 mL) and extracted with MTBE (3 times with 20 mL). The combined organic phase was washed with brine (3 times with 20 mL), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the desired 3-iodo-4-nitro-2H-indazole (200 mg, crude) as a yellow solid.

[0510] Step 2: To a solution of 3-iodo-4-nitro-1H-indazole (200 mg, 692 μmol, 1 equivalent) and tert-butoxycarbonyl tert-butyl carbonate (151 mg, 692 μmol, 159 μL, 1 equivalent) in DCM (10 mL), TEA (140 mg, 1.38 mmol, 192 μL, 2 equivalents) and DMAP (8.45 mg, 69.2 μmol, 0.1 equivalent) were added. The mixture was stirred at 15°C for 2 hours. TLC showed that the 3-iodo-4-nitro-1H-indazole was completely consumed and a new spot had formed. The residue was obtained by concentrating the reaction mixture. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain the desired tert-butyl 3-iodo-4-nitro-indazole-1-carboxylate (140 mg, 360 μmol, 52.0% yield) as a yellow solid.

[0511] Step 3: A mixture of tert-butyl 3-iodo-4-nitro-indazole-1-carboxylate (100 mg, 257 μmol, 1 equivalent), 3,3,4,4-tetrafluoropyrrolidine hydrochloride (46.1 mg, 257 μmol, 1 equivalent), Pd2(dba)3 (23.5 mg, 25.7 μmol, 0.1 equivalent), Cs2CO3 (251 mg, 771 μmol, 3 equivalents), and BINAP (16 mg, 25.7 μmol, 0.1 equivalent) in toluene (2 mL) was degassed, purged three times with N2, and then stirred at 100°C for 12 hours under an N2 atmosphere. TLC showed that the 3-iodo-4-nitro-indazole-1-carboxylate was completely consumed and a new spot had formed. The reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (30 mL three times). The combined organic phase was washed with brine (20 mL three times), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the desired tert-butyl 4-nitro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-carboxylate (320 mg, crude) as a yellow solid.

[0512] Step 4: To a solution of tert-butyl 4-nitro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-carboxylate (270 mg, 668 μmol, 1 equivalent) in DCM (3 mL), TFA (1 mL) was added. The mixture was stirred at 15°C for 0.5 hours. By TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1), it was observed that the tert-butyl 4-nitro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-1-carboxylate had been completely consumed, and a new spot had formed. The reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (3 times with 30 mL). The combined organic phase was washed with brine (2 times with 20 mL), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain the desired 4-nitro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (30 mg, 98.6 μmol, 14.8% yield) as a yellow solid.

[0513] Step 5: To a solution of 4-nitro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (25 mg, 82.2 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (29.7 mg, 123 μmol, 1.5 equivalents) in DCM (3 mL), TEA (25 mg, 246 μmol, 34.3 μL, 3 equivalents) and DMAP (1.00 mg, 8.22 μmol, 0.1 equivalent) were added at 0°C. The mixture was stirred at 15°C for 0.5 hours. LC-MS confirmed that 4-nitro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (3 times with 30 mL). The combined organic phases were washed with brine (twice with 20 mL), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the desired 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-4-nitro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (90 mg, crude) as a brown solid. MS(ESI): mass calcd.For C 19 H 14 F6N4O4S 508.06 m / z found 509.2[M+H] + .

[0514] Step 6: To a solution of 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-4-nitro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (90 mg, 177 μmol, 1 equivalent) in EtOH (2 mL) and H2O (0.4 mL), Fe (9.89 mg, 177 μmol, 1 equivalent) and NH4Cl (9.47 mg, 177 μmol, 1 equivalent) were added. The mixture was stirred at 80°C for 0.5 hours. LC-MS confirmed that 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-4-nitro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole had been completely consumed and the desired mass was detected. The reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (3 times with 10 mL). The combined organic phases were washed with brine (twice with 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-CAN]; gradient: 50%~75%B over 8.0 mins) to obtain the desired 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-4-amine (3 mg, 6.17 μmol, 3.49% yield, 98.45% purity) as a pale yellow solid. 1 HNMR(400MHz,DMSO-d6)δ 7.93-7.89(m,2H),7.75-7.70(m,2H),7.35-7.28(m,1H),7.24-7.20(m,1H), 6.61-6.56(m,1H),5.62-5.57(m,2H),4.20-4.01(m,4H),1.98-1.87(m,3H). HPLC: 96.93% (220nm), 96.30% (215nm), 98.45% (254nm). MS(ESI):mass calcd.For C 19 H 16 F6N4O2S 478.09 m / z found 479.2[M+H] + .

[0515] Compound 33: 1-[4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole-3-yl]-4,4-difluoropyrrolidine-3-ol

[0516] [ka]

[0517] Step 1: To a solution of 5,5-difluoropyrrolidine-3-ol (250 mg, 1.57 mmol, 1 equivalent, HCl) in THF (5 mL), TEA (1.59 g, 15.7 mmol, 2.18 mL, 10 equivalents) was added dropwise at 25°C. After addition, the mixture was stirred at this temperature for 10 minutes. A solution of (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (888 mg, 2.35 mmol, 1.5 equivalents) in THF (2 mL) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 25°C for 20 minutes. TLC showed that the 5,5-difluoropyrrolidine-3-ol was completely consumed and a new spot had formed. This was then separated into 20 mL of water and 40 mL of ethyl acetate. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired N-[(E)-[(2,6-dichlorophenyl)-(2,2-difluoro-4-hydroxy-pyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (720 mg, crude) as a yellow solid.

[0518] Step 2: To a solution of N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoro-4-hydroxy-pyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (720 mg, 1.55 mmol, 1 equivalent) in DMF (10 mL), K2CO3 (1.07 g, 7.75 mmol, 5 equivalents) was added. The mixture was stirred at 100 °C for 2 hours. TLC confirmed that N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoro-4-hydroxy-pyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed, and a new spot had formed. The reaction mixture was added to water (30 mL) and extracted with ethyl acetate (3 times with 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the desired 1-(4-chloro-1H-indazole-3-yl)-4,4-difluoropyrrolidine-3-ol (400 mg, crude) as a yellow oil.

[0519] Step 3: To a solution of 1-(4-chloro-1H-indazole-3-yl)-4,4-difluoropyrrolidine-3-ol (200 mg, 731 μmol, 1 equivalent) in DCM (2 mL), imidazole (99.5 mg, 1.46 mmol, 2 equivalents) and TBSCl (132 mg, 877 μmol, 108 μL, 1.2 equivalents) were added under N2 at 0°C. The mixture was stirred at 20°C for 0.5 hours. LC-MS confirmed that 1-(4-chloro-1H-indazole-3-yl)-4,4-difluoropyrrolidine-3-ol was completely consumed, and one main peak with the desired mass was detected. The reaction mixture was added to saturated NaHCO3 aqueous solution (30 mL) and extracted with DCM (3 times with 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired tert-butyl-[1-(4-chloro-1H-indazole-3-yl)-4,4-difluoropyrrolidine-3-yl]oxydimethylsilane (180 mg, crude) as a yellow oil. MS(ESI): mass calcd.For C 17 H 24 ClF2N3OSi 387.13 m / z found 388.1[M+H] + .

[0520] Step 4: To a solution of tert-butyl-[1-(4-chloro-1H-indazole-3-yl)-4,4-difluoropyrrolidine-3-yl]oxydimethylsilane (100 mg, 258 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (93.1 mg, 387 μmol, 1.5 equivalents) in DCM (1 mL), TEA (78.3 mg, 773 μmol, 108 μL, 3 equivalents) and DMAP (3.15 mg, 25.8 μmol, 0.1 equivalent) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS confirmed that tert-butyl-[1-(4-chloro-1H-indazole-3-yl)-4,4-difluoropyrrolidine-3-yl]oxydimethylsilane was completely consumed, and one main peak with the desired mass was detected. By concentrating the reaction mixture, the desired tert-butyl-[1-[4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole-3-yl]-4,4-difluoropyrrolidine-3-yl]oxydimethylsilane (150 mg, crude) was obtained as a white solid. MS(ESI): mass calcd.For C 25 H 30 ClF4N3O3SSi 591.14 m / z found 592.2[M+H] + .

[0521] Step 5: To a solution of tert-butyl-[1-[4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole-3-yl]-4,4-difluoropyrrolidine-3-yl]oxydimethylsilane (80 mg, 135 μmol, 1 equivalent) in THF (1 mL), TBAF (70.7 mg, 270 μmol, 2 equivalents) was added. The mixture was stirred at 20°C for 0.5 hours. LC-MS confirmed that tert-butyl-[1-[4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole-3-yl]-4,4-difluoropyrrolidine-3-yl]oxydimethylsilane was completely consumed, and one main peak with the desired mass was detected. The residue was obtained by concentrating the reaction under reduced pressure. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 55%~80%B over 8.0 minutes) to obtain the desired 1-[4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole-3-yl]-4,4-difluoropyrrolidine-3-ol (1.1 mg, 2.28 μmol, 1.69% yield, 98.90% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.12(d,J=8.3Hz,1H),7.98(d,J=8.3Hz,2H),7.78(d,J=8.3Hz,2H),7.71-7.64(m,1H),7.52(d, J=7.7Hz,1H),6.33-6.04(m,1H),4.40-4.29(m,1H),4.14-3.74(m,4H),1.95(t,J=19.1Hz,3H). HPLC: 98.90% (220nm), 98.83% (215nm), 100.00% (254nm). MS(ESI):mass calcd.For C 19 H 16 ClF4N3O3S 477.05 m / z found 478.0[M+H] + .

[0522] Compound 34: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(4R)-3,3-difluoro-4-methylpyrrolidine-1-yl]indazole Compound 35: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(4S)-3,3-difluoro-4-methylpyrrolidine-1-yl]indazole

[0523] [ka]

[0524] Step 1: Two isomers were obtained by separating 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3-difluoro-4-methylpyrrolidine-1-yl)indazole (20 mg, 62.3 μmol, 1 equivalent) by chiral SFC (column: Phenomenex Luna CN 100*30 mm*5 μm; mobile phase: [heptane-EtOH]; gradient: 20%~50% B over 10.0 mins). The structures were arbitrarily assigned. 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(4R)-3,3-difluoro-4-methylpyrrolidine-1-yl]indazole (7 mg, 14.7 μmol, 34.9% yield, 98.98% purity, Rt=4.948 min; EE(%)=100.0%) by chiral HPLC was isolated as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.08(d,J=8.4Hz,1H),7.95(d,J=8.4Hz,2H),7.75(d,J=8.5Hz,2H),7.64(t,J=8.1Hz,1H),7.48(d,J=7.6Hz,1H),4.09(br d,J=17.9Hz,1H),3.89-3.77(m,2H),3.38(s,1H),2.78-2.61(m,1H),1.92(t,J=19.1Hz,3H),1.08(d,J=6.9Hz,3H). HPLC: 98.98% (220nm), 99.47% (215nm), 99.10% (254nm). MS(ESI):mass calcd.For C20 H 18 ClF4N3O2S 475.1 m / z found 476.1[M+H] + .

[0525] 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(4S)-3,3-difluoro-4-methylpyrrolidine-1-yl]indazole (8 mg, 16.61 μmol, 39.5% yield, 98.79% purity, Rt=5.261 min; EE(%)=97.88% by chiral HPLC) was isolated as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.08(d,J=8.4Hz,1H),7.95(d,J=8.3Hz,2H),7.75(d,J=8.4Hz,2H),7.64(t,J=8.1Hz,1H),7.48(d,J=7.8Hz,1H),4.09(td,J =11.6,17.9Hz,1H),3.90-3.77(m,2H),3.41-3.36(m,1H),2.75-2.65(m,1H),1.92(t,J=19.1Hz,3H),1.08(d,J=6.8Hz,3H). HPLC: 98.79% (220nm), 98.92% (215nm), 99.06% (254nm). MS(ESI):mass calcd.For C 20 H 18 ClF4N3O2S 475.1 m / z found 476.1[M+H] + .

[0526] Compound 36: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(3R,4R)-3-fluoro-4-methyl-pyrrolidine-1-yl]indazole Compound 37: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(3S,4S)-3-fluoro-4-methylpyrrolidine-1-yl]indazole Compound 38: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(3R,4S)-3-fluoro-4-methyl-pyrrolidine-1-yl]indazole Compound 39: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(3S,4R)-3-fluoro-4-methyl-pyrrolidine-1-yl]indazole

[0527] [ka]

[0528] Step 1: Four isomers were obtained by separating 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3-fluoro-4-methylpyrrolidine-1-yl)indazole (20 mg, 43.68 μmol, 1 equivalent) by chiral SFC (column: Daicel ChiralPak IG (250*30 mm, 10 μm); mobile phase: [heptane-IPA]; B%: 20%, isocratic elution mode). The structures were assigned arbitrarily. 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(3R,4R)-3-fluoro-4-methylpyrrolidine-1-yl]indazole (2.2 mg, 4.55 μmol, 10.4% yield, 94.67% purity, Rt=3.919 min; EE(%)=100.00%) by chiral HPLC was isolated as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 8.12(s,1H),7.95(d,J=8.4Hz,2H),7.77(d,J=8.6Hz,2H),7.66(t,J=8.1Hz,1H),7.50(d,J=7.6Hz,1H),4. 31-4.22(m,1H),3.93-3.76(m,1H),3.65-3.43(m,3H),2.25-2.16(m,1H),1.95(t,J=19.1Hz,3H),1.32(br d,J=6.8Hz,3H). HPLC: 94.67% (220nm), 95.53% (215nm), 86.92% (254nm). MS(ESI):mass calcd.For C 20 H 19 ClF3N3O2S 457.08 m / z found 458.0[M+H] + .

[0529] 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(3S,4S)-3-fluoro-4-methyl-pyrrolidine-1-yl]indazole (1.0 mg, 2.13 μmol, 4.87% yield, 97.38% purity, Rt=4.352 min; EE(%)=93.52% by chiral HPLC) was isolated as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 8.10(d,J=8.8Hz,1H),7.94(d,J=8.3Hz,2H),7.76(d,J=8.4Hz,2H),7.67-7.60(m,1H),7.51-7.45(m,1H),5.25-5.0 7(m,1H),3.94(d,J=5.6Hz,1H),3.64-3.46(m,3H),2.41-2.29(m,1H),1.94(t,J=19.2Hz,3H),1.13(d,J=6.7Hz,3H). HPLC: 97.38% (220nm), 92.54% (215nm), 97.31% (254nm). MS(ESI):mass calcd.For C 20 H 19 ClF3N3O2S 457.08 m / z found 458.0[M+H] + .

[0530] 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(3R,4S)-3-fluoro-4-methylpyrrolidine-1-yl]indazole (1.0 mg, 2.10 μmol, 4.82% yield, 96.33% purity, Rt=4.561 min; EE(%)=44.52% by chiral HPLC) was isolated as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ 8.12(s,1H),7.95(br d,J=7.8Hz,2H),7.80-7.73(m,2H),7.70-7.61(m,1H),7.50(dd,J=3.9,7.7Hz,1H),5.19-4.92( m,1H),4.26(dd,J=2.2,5.3Hz,1H),3.95(d,J=5.5Hz,4H),1.94(dt,J=2.3,19.2Hz,3H),1.33(br d,J=7.0Hz,3H). HPLC: 96.33% (220nm), 97.27% (215nm), 73.24% (254nm). MS(ESI):mass calcd.For C 20 H 19 ClF3N3O2S 457.08 m / z found 458.0[M+H] + .

[0531] 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(3S,4R)-3-fluoro-4-methyl-pyrrolidine-1-yl]indazole (1.2 mg, 2.54 μmol, 5.83% yield, 97.10% purity, Rt=6.393 min; EE(%)=100.0%) by chiral HPLC was isolated as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 8.12(s,1H),7.95(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.65(s,1H),7.50(s,1H),5.28-5.08(m,1H) ),4.21-4.02(m,1H),3.64-3.49(m,3H),2.39-2.34(m,1H),2.01-1.89(m,3H),1.13(d,J=6.7Hz,3H). HPLC: 97.10% (220nm), 98.03% (215nm), 81.97% (254nm). MS(ESI):mass calcd.For C 20 H 19 ClF3N3O2S 457.08 m / z found 458.0[M+H] + .

[0532] Compound 40: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4-trifluoropyrrolidine-1-yl)indazole

[0533] [ka]

[0534] Step 1: To a solution of 5,5-difluoropyrrolidine-3-ol (250 mg, 1.57 mmol, 1 equivalent, HCl) in THF (5 mL), TEA (1.59 g, 15.7 mmol, 2.18 mL, 10 equivalents) was added dropwise at 25°C. After addition, the mixture was stirred at this temperature for 10 minutes. (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (888 mg, 2.35 mmol, 1.5 equivalents) in THF (2 mL) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 25°C for 20 minutes. TLC showed that the 5,5-difluoropyrrolidine-3-ol was completely consumed and a new spot had formed. This was then separated into 20 mL of water and 40 mL of ethyl acetate. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired N-[(E)-[(2,6-dichlorophenyl)-(2,2-difluoro-4-hydroxy-pyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (720 mg, crude) as a yellow solid.

[0535] Step 2: To a solution of N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoro-4-hydroxy-pyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide (720 mg, 1.55 mmol, 1 equivalent) in DMF (10 mL), K2CO3 (1.07 g, 7.75 mmol, 5 equivalents) was added. The mixture was stirred at 100 °C for 2 hours. TLC confirmed that N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoro-4-hydroxy-pyrrolidine-1-yl)methylene]amino]-4-methylbenzenesulfonamide had been completely consumed, and a new spot had formed. The reaction mixture was added to water (30 mL) and extracted with ethyl acetate (3 times with 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 35%~60% B over 8.0 minutes) to obtain the desired 1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-3-ol (60 mg, crude) as a yellow oil.

[0536] Step 3: Two reactions were carried out in parallel. DAST (22.6 mg, 140 μmol, 18.5 μL, 2 equivalents) was added at 0°C to a solution of 1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-3-ol (30 mg, 70.1 μmol, 1 equivalent) in toluene (1 mL). The mixture was stirred at 50°C for 12 hours. Two reactions were carried out in parallel. LC-MS confirmed the presence of residual 1-[4-chloro-1-(p-tolylsulfonyl)indazole-3-yl]-4,4-difluoropyrrolidine-3-ol. Several new peaks were observed on LC-MS, and the desired compound was detected. The two reactions were combined for workup. The reaction mixture was added to water (30 mL) and extracted with Âr (3 times with 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 4-chloro-1-(p-tolylsulfonyl)-3-(3,3,4-trifluoropyrrolidine-1-yl)indazole (60 mg, crude) as a yellow oil. MS(ESI): mass calcd.For C 18 H 15 ClF3N3O2S 429.05 m / z found 430.2[M+H] + .

[0537] Step 4: To a solution of 4-chloro-1-(p-tolylsulfonyl)-3-(3,3,4-trifluoropyrrolidine-1-yl)indazole (60 mg, 140 μmol, 1 equivalent) in MeOH (1 mL), K2CO3 (57.9 mg, 419 μmol, 3 equivalents) was added. The mixture was stirred at 70°C for 1 hour. LC-MS confirmed the presence of residual 4-chloro-1-(p-tolylsulfonyl)-3-(3,3,4-trifluoropyrrolidine-1-yl)indazole. Several new peaks were observed on LC-MS, indicating the detection of the desired compound. The reaction mixture was added to water (30 mL) and extracted with  (30 mL three times). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 1 / 1) to obtain the desired 4-chloro-3-(3,3,4-trifluoropyrrolidine-1-yl)-1H-indazole (20 mg, crude) as a yellow oily substance. MS(ESI): mass calcd.For C 11 H9ClF3N3275.04 m / z found 276.0[M+H] + .

[0538] Step 5: To a solution of 4-chloro-3-(3,3,4-trifluoropyrrolidine-1-yl)-1H-indazole (20 mg, 72.6 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (26.2 mg, 109 μmol, 1.5 equivalents) in DCM (1 mL), TEA (22.0 mg, 218 μmol, 30.3 μL, 3 equivalents) and DMAP (886 μg, 7.26 μmol, 0.1 equivalents) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS confirmed that 4-chloro-3-(3,3,4-trifluoropyrrolidine-1-yl)-1H-indazole was completely consumed and a single main peak with the desired mass was detected. The residue was obtained by concentrating the reaction under reduced pressure. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 50%~75%B over 8.0 minutes) to obtain the desired 4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4-trifluoropyrrolidine-1-yl)indazole (1 mg, 2.04 μmol, 2.81% yield, 97.79% purity) as a pink solid. 1 H NMR(400MHz,DMSO-d6)δ 8.10(d,J=8.5Hz,1H),7.98(br d,J=8.3Hz,2H),7.76(br d,J=8.3Hz,2H),7.67(t,J=8.1Hz,1H),7.51(d,J=7.8Hz,1H),5.59-5.32(m,1H),4.28-3.94(m,3H),3.91-3.78(m,1H),1.93(t,J=19.1Hz,3H). HPLC: 97.79% (220nm), 96.44% (215nm), 96.90% (254nm). MS(ESI):mass calcd.For C 19 H 15 ClF5N3O2S 479.05 m / z found 480.0[M+H] + .

[0539] Compound 41: (3S)-1-[4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole-3-yl]-4,4-difluoro-pyrrolidine-3-ol Compound 42: (3R)-1-[4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole-3-yl]-4,4-difluoropyrrolidine-3-ol

[0540] [ka]

[0541] Step 1: Two isomers were obtained by separating 1-[4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole-3-yl]-4,4-difluoropyrrolidine-3-ol (60 mg, 126 μmol, 1 equivalent) by chiral SFC (column: DAIEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [heptane-IPA]; B%: 20%, isocratic elution mode). The structures were arbitrarily assigned. (3S)-1-[4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole-3-yl]-4,4-difluoro-pyrrolidine-3-ol (5.8 mg, 11.94 μmol, 9.51% yield, 98.41% purity, Rt=4.278 min; EE(%)=100.0%) by chiral HPLC was isolated as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.14(d,J=8.5Hz,1H),8.01(d,J=8.4Hz,2H),7.81(d,J=8.4Hz,2H),7.70(t,J=8.1Hz,1H),7.54(d,J=7.8Hz, 1H),6.17(d,J=5.1Hz,1H),4.42-4.32(m,1H),4.14-3.91(m,3H),3.51-3.45(m,1H),1.98(t,J=19.1Hz,3H). HPLC: 98.41% (220nm), 98.26% (215nm), 98.10% (254nm). MS(ESI):mass calcd.For C 19 H16 ClF4N3O3S 477.05 m / z found 478.0[M+H] + .

[0542] (3R)-1-[4-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-indazole-3-yl]-4,4-difluoro-pyrrolidine-3-ol (4.5 mg, 9.24 μmol, 7.36% yield, 98.09% purity, Rt=4.825 min; EE(%)=91.20% by chiral HPLC) was isolated as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.09(d,J=8.4Hz,1H),7.96(d,J=8.4Hz,2H),7.76(d,J=8.5Hz,2H),7.65(t,J=8.1Hz,1H),7.49(d,J=7.8Hz,1H),6.1 2(d,J=5.1Hz,1H),4.37-4.27(m,1H),4.06-3.86(m,3H),3.43(ddd,J=2.1,4.2,11.3Hz,1H),1.93(t,J=19.1Hz,3H). HPLC: 98.09% (220nm), 98.26% (215nm), 97.30% (254nm). MS(ESI):mass calcd.For C 19 H 16 ClF4N3O3S 477.05 m / z found 478.0[M+H] + .

[0543] Compound 43: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(4R)-3,3,4-trifluoropyrrolidine-1-yl]indazole Compound 44: 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(4S)-3,3,4-trifluoropyrrolidine-1-yl]indazole

[0544] [ka]

[0545] Step 1: Two isomers were obtained by separating 4-chloro-1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-3-(3,3,4-trifluoropyrrolidine-1-yl)-1H-indazole (20 mg) by SFC (column: Daicel ChiralPak IG (250*30 mm, 10 μm); mobile phase: [heptane-EtOH]; B%: 20%, isocratic elution mode). The structures were assigned arbitrarily. 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(4R)-3,3,4-trifluoropyrrolidine-1-yl]indazole (1.0 mg, 1.89 μmol, 4.52% yield, 90.85% purity, Rt=2.851 min; EE(%)=100.00%) by chiral HPLC was isolated as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.10(d,J=8.4Hz,1H),7.98(d,J=8.4Hz,2H),7.76(d,J=8.5Hz,2H),7.67(t,J=8.1Hz,1H),7.51( d,J=7.6Hz,1H),5.59-5.37(m,1H),4.25-3.99(m,3H),3.92-3.76(m,1H),1.93(t,J=19.1Hz,3H). HPLC: 90.85% (220nm), 91.20% (210nm), 88.67% (254nm). MS(ESI):mass calcd.For C 19 H 15 ClF5N3O2S 479.05,m / z found 480.0[M+H] + .

[0546] 4-Chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-[(4S)-3,3,4-trifluoropyrrolidine-1-yl]indazole (1.2 mg, 2.41 μmol, 5.76% yield, 96.33% purity, Rt=3.172 min; EE(%)=100.00%) by chiral HPLC was isolated as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.10(d,J=8.5Hz,1H),7.98(d,J=8.4Hz,2H),7.76(d,J=8.5Hz,2H),7.67(t,J=8.1Hz,1H),7.51( d,J=7.6Hz,1H),5.63-5.37(m,1H),4.25-4.00(m,3H),3.91-3.79(m,1H),1.93(t,J=19.1Hz,3H). HPLC: 96.33% (220nm), 96.57% (210nm), 94.05% (254nm). MS(ESI):mass calcd.For C 19 H 15 ClF5N3O2S 479.05,m / z found 480.0[M+H] + .

[0547] Compound 45: 4-Chloro-1-[[6-(1,1-difluoroethyl)-3-pyridyl]sulfonyl]-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole

[0548] [ka]

[0549] Step 1: DAST (4.03 g, 25.0 mmol, 3.30 mL, 5 equivalents) was added at 0°C to a solution of 1-(5-bromo-2-pyridyl)ethanone (1 g, 5.00 mmol, 1 equivalent) in toluene (10 mL). The mixture was stirred at 80°C for 1 hour. TLC showed that 1-(5-bromo-2-pyridyl)ethanone was completely consumed and a new spot had formed. The reaction mixture was quenched with ice water (10 g) and extracted with ethyl acetate (twice with 10 mL). The residue was obtained by concentrating the combined organic matter. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 5 / 1) to obtain the desired 5-bromo-2-(1,1-difluoroethyl)pyridine (330 mg, 1.49 mmol, 29.7% yield) as a yellow oil. MS(ESI):mass calcd.For C7H6BrF2N 221.0,m / z found 222.0[M+H] + .

[0550] Step 2: A mixture of 5-bromo-2-(1,1-difluoroethyl)pyridine (330 mg, 1.49 mmol, 1 equivalent), phenylmethanethiol (277 mg, 2.23 mmol, 262 μL, 1.5 equivalents), DIEA (384 mg, 2.97 mmol, 518 μL, 2 equivalents), Xantphos (86.0 mg, 149 μmol, 0.1 equivalent), and Pd2(dba)3 (136 mg, 149 μmol, 0.1 equivalent) in dioxane (5 mL) was degassed and purged three times with N2. The mixture was stirred at 100°C for 12 hours under an N2 atmosphere. LC-MS confirmed that 5-bromo-2-(1,1-difluoroethyl)pyridine was completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 10 mL of Âx. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 5 / 1) to obtain the desired 5-benzylsulfanyl-2-(1,1-difluoroethyl)pyridine (230 mg, 867 μmol, 58.3% yield) as a yellow oil. MS(ESI): mass calcd. For C 14 H 13 F2NS 265.1,m / z found 266.1[M+H] + .

[0551] Step 3: To a solution of 5-benzylsulfanyl-2-(1,1-difluoroethyl)pyridine (230 mg, 867 μmol, 1 equivalent) in AcOH (0.8 mL) and H2O (0.2 mL), NCS (463 mg, 3.47 mmol, 4 equivalents) was added. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 5-benzylsulfanyl-2-(1,1-difluoroethyl)pyridine had been completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 10 mL of ethyl phosphate. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 5 / 1) to obtain the desired 6-(1,1-difluoroethyl)pyridine-3-sulfonyl chloride (80 mg, 331 μmol, 38.2% yield) as a white solid. MS(ESI): mass calcd. For C7H6ClF2NO2S 241.0, m / z found 242.0[M+H] + .

[0552] Step 4: DMAP (83 μg, 6.81 μmol, 0.1 equivalent) was added to a solution of 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (20 mg, 68.1 μmol, 1 equivalent) and 6-(1,1-difluoroethyl)pyridine-3-sulfonyl chloride (32.9 mg, 136 μmol, 2 equivalents) in pyridine (1 mL). The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was filtered, and the residue was obtained by concentrating the filtrate under reduced pressure. The residue was purified by preparative HPLC (TFA conditions; method: column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 50%~80%B over 8.0 minutes) to obtain the desired 4-chloro-1-[[6-(1,1-difluoroethyl)-3-pyridyl]sulfonyl]-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (4.3 mg, 8.48 μmol, 12.5% ​​yield, 98.38% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.15(d,J=1.3Hz,1H),8.48(dd,J=2.1,8.4Hz,1H),8.12(d,J=8.4Hz,1H),7 .89(d,J=8.4Hz,1H),7.70(t,J=8.1Hz,1H),7.54(d,J=7.8Hz,1H),4.24(br t,J=12.3Hz,4H),1.95(t,J=19.3Hz,3H). HPLC: 98.38% (220nm), 98.29% (215nm), 98.79% (254nm). MS(ESI):mass calcd.For C 18 H 13 ClF6N4O2S 498.0 m / z found 499.0[M+H] + .

[0553] Compound 46: 5-Chloro-1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)imidazo[1,5-a]pyridine

[0554] [ka]

[0555] Step 1: To a solution of 4-(1,1-difluoroethyl)benzenesulfonyl chloride (1 g, 4.16 mmol, 1 equivalent) in H2O (10 mL), NaHCO3 (698 mg, 8.31 mmol, 2 equivalents) and Na2SO3 (1.05 g, 8.31 mmol, 2 equivalents) were added. The mixture was stirred at 80°C for 2 hours. TLC confirmed that the 4-(1,1-difluoroethyl)benzenesulfonyl chloride was completely consumed and a new spot had formed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was added to MeOH (20 mL). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the desired [4-(1,1-difluoroethyl)phenyl]sulfinyloxysodium (1 g, crude) as a white solid.

[0556] Step 2: To a solution of 3,3,4,4-tetrafluoropyrrolidine (3 g, 16.7 mmol, 1 equivalent, HCl) in DCM (30 mL), NaHCO3 (7.02 g, 83.6 mmol, 5 equivalents) and bis(trichloromethyl) carbonate (2.38 g, 8.02 mmol, 0.48 equivalents) were added at 0°C. The mixture was stirred at 15°C for 1 hour. The reaction product was filtered, and the filtrate was concentrated to obtain the desired 3,3,4,4-tetrafluoropyrrolidine-1-carbonyl chloride (3.3 g, crude) as a white oily substance.

[0557] Step 3: To a solution of (6-chloro-2-pyridyl)methanamine (1.83 g, 12.8 mmol, 0.8 equivalents) in DCM (35 mL), DIEA (10.4 g, 80.3 mmol, 14.0 mL, 5 equivalents) and 3,3,4,4-tetrafluoropyrrolidine-1-carbonyl chloride (3.3 g, 16.1 mmol, 1 equivalent) were added at 0°C. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that the (6-chloro-2-pyridyl)methanamine was completely consumed and the desired mass was detected. The reaction mixture was separated into 30 mL of H2O and 60 mL of DCM. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 60 mL / min) to obtain the desired N-[(6-chloro-2-pyridyl)methyl]-3,3,4,4-tetrafluoropyrrolidine-1-carboxamide (2.74 g, 8.79 mmol, 54.8% yield) as a yellow solid. MS(ESI): mass calcd.For C 11 H 10 ClN3F4O 311.04 m / z found 312.0[M+H] + .

[0558] Step 4: To a solution of N-[(6-chloro-2-pyridyl)methyl]-3,3,4,4-tetrafluoropyrrolidine-1-carboxamide (2.74 g, 8.79 mmol, 1 equivalent) in DCM (30 mL), trifluoromethylsulfonyltrifluoromethanesulfonate (2.98 g, 10.6 mmol, 1.74 mL, 1.2 equivalents) and 2-methoxypyridine (1.06 g, 9.67 mmol, 1.01 mL, 1.1 equivalents) were added at 0°C. The mixture was stirred at 35°C for 1 hour. LC-MS confirmed that N-[(6-chloro-2-pyridyl)methyl]-3,3,4,4-tetrafluoropyrrolidine-1-carboxamide was completely consumed and the desired mass was detected. The reaction mixture was divided into 20 mL of H2O and 30 mL of DCM. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent with a 0-15% ethyl acetate / petroleum ether gradient at 60 mL / min) to obtain the desired 5-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)imidazo[1,5-a]pyridine (2.55 g, 8.68 mmol, 98.8% yield) as a yellow solid. MS(ESI): mass calcd. For C 11 H8N3ClF4293.03 m / z found 294.0[M+H] + .

[0559] Step 5: To a mixture of NIS (613 mg, 2.72 mmol, 1.0 equivalent) in THF (10 mL), 5-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)imidazo[1,5-a]pyridine (800 mg, 2.72 mmol, 1 equivalent) was added at -78°C. The mixture was stirred at 20°C for 0.5 hours. TLC confirmed that 5-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)imidazo[1,5-a]pyridine had been completely consumed and new, less polar spots were detected. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with MTBE (twice with 20 mL). The combined organic matter was dried over Na2SO4 and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 25g SepaFlash® Silica Flash Column, eluent with a 0-10% ethyl acetate / petroleum ether gradient at 50 mL / min) to obtain the desired 5-chloro-1-iodo-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)imidazo[1,5-a]pyridine (230 mg, 548 μmol, 20.1% yield) as a yellow solid.

[0560] Step 6: A mixture of 5-chloro-1-iodo-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)imidazo[1,5-a]pyridine (50 mg, 119 μmol, 1 equivalent), [4-(1,1-difluoroethyl)phenyl]sulfinyloxysodium (81.6 mg, 358 μmol, 3 equivalents), and CuI (90.8 mg, 477 μmol, 4 equivalents) in DMSO (3 mL) under an N2 atmosphere. The mixture was stirred at 110 °C for 12 hours. LC-MS confirmed that 5-chloro-1-iodo-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)imidazo[1,5-a]pyridine was completely consumed and the desired mass was detected. The reaction mixture was poured into water (15 mL) and extracted with MTBE (twice with 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 40%~60% B over 8.0 mins) to obtain the desired 5-chloro-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)imidazo[1,5-a]pyridine (13.4 mg, 26.9 μmol, 22.5% yield, 99.75% purity) as a white solid. 1 H NMR(DMSO-d6)δ 8.00-8.15(m,3H),7.78(d,2H),7.25(m,1H),7.15(m,1H),3.98-4.11(m,4H),1.96(m,3H). HPLC: 99.75% (220nm), 99.72% (215nm), 99.67% (254nm). MS(ESI):mass calcd.For C 19 H 14 SN3ClF6O2497.04 m / z found 498.0[M+H] + .

[0561] Compound 47: 1-((4-(1,1-difluoroethyl)phenyl)sulfonyl)-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole-4-ol

[0562] [ka]

[0563] Step 1: To a solution of 1H-indazole-4-ol (1 g, 7.46 mmol, 1 equivalent) in DMF (10 mL), imidazole (761 mg, 11.2 mmol, 1.5 equivalents) and TBSCl (1.69 g, 11.2 mmol, 1.38 mL, 1.5 equivalents) were added at 0°C, and the reaction mixture was stirred at 20°C for 2 hours. TLC (silica gel, petroleum ether / SiO=1 / 1) confirmed that the 1H-indazole-4-ol was completely consumed and new spots had formed. The reaction mixture was poured into water (120 mL) and stirred at 20°C for 0.5 hours. The mixture was filtered, and the cake was dried under reduced pressure to obtain the desired tert-butyl-(1H-indazole-4-yloxy)-dimethyl-silane (1.85 g, crude) as a black oily substance.

[0564] Step 2: To a solution of tert-butyl-(1H-indazole-4-yloxy)-dimethyl-silane (1.85 g, 7.45 mmol, 1 equivalent) in DCM (20 mL), NIS (1.84 g, 8.19 mmol, 1.1 equivalent) was added at 0°C, and the solution was stirred at 20°C for 2 hours. LC-MS confirmed that tert-butyl-(1H-indazole-4-yloxy)-dimethyl-silane was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain the desired tert-butyl-[(3-iodo-1H-indazole-4-yl)oxy]-dimethyl-silane (2.79 g, crude) as a black oily substance. MS(ESI): mass calcd. For C 13 H 19 IN2OSi 374.03 m / z found 375.0[M+H] + .

[0565] Step 3: To a solution of tert-butyl-[(3-iodo-1H-indazole-4-yl)oxy]dimethyl-silane (2.75 g, 7.35 mmol, 1 equivalent) and TsOH.H2O (140 mg, 735 μmol, 0.1 equivalent) in DCM (30 mL), 3,4-dihydro-2H-pyran (927 mg, 11.0 mmol, 1.01 mL, 1.5 equivalents) was added at 0°C. The solution was stirred at 20°C for 1 hour. LC-MS confirmed that tert-butyl-[(3-iodo-1H-indazole-4-yl)oxy]dimethyl-silane was completely consumed and the desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with MTBE (twice with 30 mL). The combined organic matter was dried over anhydrous sodium sulfate and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain the desired tert-butyl-(3-iodo-1-tetrahydropyran-2-ylindazole-4-yl)oxydimethylsilane (980 mg, 2.14 mmol, 29.1% yield) as a colorless oil. MS(ESI): mass calcd. For C 18 H 27 IN2O2Si 458.09 m / z found 459.0[M+H] + .

[0566] Step 4: To a solution of tert-butyl-(3-iodo-1-tetrahydropyran-2-ylindazole-4-yl)oxydimethylsilane (780 mg, 1.70 mmol, 1 equivalent) in THF (8 mL), TBAF (1 M, 2.04 mL, 1.2 equivalents) was added at 20°C. The mixture was stirred at 20°C for 12 hours. TLC (silica gel, petroleum ether / siRNA = 3 / 1) confirmed that tert-butyl-(3-iodo-1-tetrahydropyran-2-ylindazole-4-yl)oxydimethylsilane had been completely consumed and new spots had formed. The residue was obtained by concentrating the reaction product. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain the desired 3-iodo-1-tetrahydropyran-2-ylindazole-4-ol (0.8 g, crude) as a black oily substance.

[0567] Step 5: Benzyl bromide (477 mg, 2.79 mmol, 331 μL, 1.2 equivalents) was added at 0°C to a mixture of 3-iodo-1-tetrahydropyran-2-ylindazole-4-ol (0.8 g, 2.32 mmol, 1 equivalent) and K2CO3 (964 mg, 6.97 mmol, 3 equivalents) in ACN (10 mL), and the solution was stirred at 20°C for 12 hours. LC-MS confirmed that 3-iodo-1-tetrahydropyran-2-ylindazole-4-ol was completely consumed and the desired mass was detected. The residue was obtained by concentrating the reaction product. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, eluent with a 0-10% ethyl acetate / petroleum ether gradient at 50 mL / min) to obtain the desired 4-benzyloxy-3-iodo-1-tetrahydropyran-2-yl-indazole (600 mg, crude) as a colorless oil. MS(ESI): mass calcd.For C 19 H 19IN2O2434.05 m / z found 435.0[M+H] + .

[0568] Step 6: A mixture of 4-benzyloxy-3-iodo-1-tetrahydropyran-2-yl-indazole (450 mg, 1.04 mmol, 1 equivalent), 3,3,4,4-tetrafluoropyrrolidine (186 mg, 1.04 mmol, 1 equivalent, HCl), Cs2CO3 (675 mg, 2.07 mmol, 2 equivalents), and SPhos Pd G3 (80.9 mg, 104 μmol, 0.1 equivalent) in dioxane (5 mL) was degassed, purged three times with N2, and then stirred at 100°C for 12 hours under an N2 atmosphere. LC-MS confirmed that 4-benzyloxy-3-iodo-1-tetrahydropyran-2-yl-indazole was completely consumed and the desired mass was detected. The crude product was added to H2O (20 mL) and extracted with siRNA (three times with 15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / Â1=3 / 1) to obtain the desired 4-benzyloxy-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-tetrahydropyran-2-yl-indazole (0.4 g, 890 μmol, 85.9% yield) as a brown oily substance. MS(ESI): mass calcd. For C 23 H 23 F4N3O2449.17 m / z found 450.3[M+H] + .

[0569] Step 7: To a solution of 4-benzyloxy-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-tetrahydropyran-2-yl-indazole (0.4 g, 890 μmol, 1 equivalent) in DCM (1 mL), TFA (0.5 mL) was added. The mixture was stirred at 20°C for 0.5 hours. LC-MS confirmed that 4-benzyloxy-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-tetrahydropyran-2-yl-indazole was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / Â1 = 2 / 1) to obtain the desired 4-benzyloxy-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (0.2 g, crude, TFA) as a brown solid. MS(ESI):mass calcd.For C 18 H 15 F4N3O 365.12 m / z found 366.2[M+H] + .

[0570] Step 8: To a solution of 4-benzyloxy-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (0.2 g, 417 μmol, 1 equivalent, TFA) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (100 mg, 417 μmol, 1 equivalent) in DCM (1 mL), TEA (127 mg, 1.25 mmol, 174 μL, 3 equivalents) and DMAP (5.10 mg, 41.7 μmol, 0.1 equivalents) were added. The mixture was stirred at 20°C for 1 hour. TLC (silica gel, petroleum ether / HCl = 3 / 1) confirmed that the 4-benzyloxy-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and new spots had formed. The crude product was added to H2O (20 mL) and extracted with HCl (15 mL three times). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / HCl = 3 / 1) to obtain the desired 4-benzyloxy-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (0.2 g, 351 μmol, 84.2% yield) as a brown oily substance.

[0571] Step 9: To a solution of 4-benzyloxy-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (0.2 g, 351 μmol, 1 equivalent) in MeOH (5 mL) and HCl (0.1 mL), Pd / C (37.4 mg, 35.1 μmol, 10% purity, 0.1 equivalent) was added. The suspension was degassed and purged three times with H2. The mixture was stirred under H2 (15 Psi) at 15°C for 0.5 hours. LC-MS confirmed that 4-benzyloxy-1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole was completely consumed and the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl phosphate = 2 / 1) to obtain the desired 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-4-ol (5.2 mg, 10.7 μmol, 3.06% yield, 98.97% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.25(s,1H),7.99(d,J=8.4Hz,2H),7.79(d,J=8.5Hz,2H),7.58-7.47(m,2 H),6.80(dd,J=0.8,7.6Hz,1H),4.40-4.25(m,4H),1.98(t,J=19.1Hz,3H). HPLC: 94.85% (220nm), 93.11% (215nm), 98.97% (254nm). MS(ESI):mass calcd.For C 19 H 15 F6N3O3S 479.07 m / z found 480.1[M+H] + .

[0572] Compound 48: 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-4-methoxy-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole

[0573] [ka]

[0574] Step 1: To a solution of 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-4-ol (10 mg, 20.9 μmol, 1 equivalent) in ACN (0.5 mL), K2CO3 (14.4 mg, 104 μmol, 5 equivalents) and MeI (14.8 mg, 104 μmol, 6.49 μL, 5 equivalents) were added. The mixture was stirred at 20°C for 1 hour. LC-MS confirmed that 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole-4-ol was completely consumed, and one main peak with the desired mass was detected. The reaction mixture was added to HCl (1 mL, 1 M) and extracted with HCl (3 mL three times). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 55%~90% B over 8.0 mins) to obtain the desired 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-4-methoxy-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (5 mg, 10.0 μmol, 48.0% yield, 98.85% purity) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 7.94(br d,J=8.1Hz,2H),7.73(br d,J=8.3Hz,2H),7.66-7.56(m,2H),6.93(br d,J=7.4Hz,1H),4.20(br t,J=12.2Hz,4H),3.91(s,3H),1.92(br t,J=19.1Hz,3H). HPLC: 98.85% (220nm), 99.10% (215nm), 99.33% (254nm). MS(ESI):mass calcd.For C 20 H 17 F6N3O3S 493.09 m / z found 494.1[M+H] + .

[0575] Compound 49: 4-Chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-[4-(1,1,2-trifluoroethyl)phenyl]sulfonyl-indazole

[0576] [ka]

[0577] Step 1: 3HF.TEA (19.8g, 128mmol, 20mL, 11.4 equivalents) was added to a mixture of 2-bromo-1-(4-bromophenyl)ethanone (3g, 10.8mmol, 1 equivalent). The mixture was stirred at 120°C for 2 hours. TLC confirmed that the 2-bromo-1-(4-bromophenyl)ethanone was completely consumed and a new spot had formed. The reaction mixture was added to ice water (20mL) and extracted with ethyl acetate (10mL three times). The combined organic layer was washed with brine (20mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0~5 / 1) to obtain the desired 1-(4-bromophenyl)-2-fluoro-ethanone (1.8g, crude) as a white solid.

[0578] Step 2: A mixture of phenylmethanethiol (504 mg, 4.05 mmol, 475 μL, 1.1 equivalents), 1-(4-bromophenyl)-2-fluoro-ethanone (800 mg, 3.69 mmol, 1 equivalent), DIEA (953 mg, 7.37 mmol, 1.28 mL, 2 equivalents), Xantphos (213 mg, 369 μmol, 0.1 equivalents), and Pd2(dba)3 (84.4 mg, 92.2 μmol, 0.025 equivalents) in dioxane (10 mL) was degassed and purged three times with N2. The mixture was stirred at 100°C for 3 hours under an N2 atmosphere. TLC showed that the phenylmethanethiol was completely consumed and a new spot had formed. The reaction mixture was added to water (20 mL) and extracted with RINKAN (3 times with 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / Â1 = 1 / 0 to 1 / 1) to obtain the desired 1-(4-benzylsulfanylphenyl)-2-fluoro-ethanone (840 mg, crude) as a yellow solid. MS(ESI): mass calcd. For C 15 H 13 FOS 260.1,m / z found 261.1[M+H] + .

[0579] Step 3: To a solution of 1-(4-benzylsulfanylphenyl)-2-fluoro-ethanone (300 mg, 1.15 mmol, 1 equivalent) in DCM (3 mL), DAST (929 mg, 5.76 mmol, 761 μL, 5 equivalents) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. TLC (silica gel, petroleum ether / Â=5 / 1) confirmed that 1-(4-benzylsulfanylphenyl)-2-fluoro-ethanone was completely consumed and a new spot had formed. The reaction mixture was added to water (20 mL) and extracted with  (10 mL three times). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl phosphate = 1 / 0 to 1 / 1) to obtain the desired 1-benzylsulfanyl-4-(1,1,2-trifluoroethyl)benzene (160 mg, crude) as a colorless oil. MS(ESI): mass calcd.For C 15 H 13 F3S 282.1,m / z found 283.1[M+H] + .

[0580] Step 4: To a solution of 1-benzylsulfanyl-4-(1,1,2-trifluoroethyl)benzene (50 mg, 177 μmol, 1 equivalent) in AcOH (2 mL) and H2O (0.4 mL), NCS (71.0 mg, 531 μmol, 3 equivalents) was added. The mixture was stirred at 20°C for 1 hour. LC-MS (sample quenched with piperidine) confirmed that 1-benzylsulfanyl-4-(1,1,2-trifluoroethyl)benzene was completely consumed and the desired compound was detected. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 times with 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel, petroleum ether / Â1 = 5 / 1) to obtain the desired 4-(1,1,2-trifluoroethyl)benzenesulfonyl chloride (30 mg, crude) as a colorless oil. MS (ESI): mass calcd. For C8H6ClF3O2S 258.0, m / z found 308.0 [M+H+49] + .

[0581] Step 5: TEA (2.76 mg, 27.2 μmol, 3.79 μL, 1 equivalent) and DMAP (3.33 mg, 27.2 μmol, 1 equivalent) were added to a solution of 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (8 mg, 27.2 μmol, 1 equivalent) and 4-(1,1,2-trifluoroethyl)benzenesulfonyl chloride (7.05 mg, 27.2 μmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was divided into 5 mL of H2O and 10 mL of RINKAN. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 55%~75% B over 8.0 mins) to obtain the desired 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-[4-(1,1,2-trifluoroethyl)phenyl]sulfonyl-indazole (2 mg, 3.62 μmol, 13.3% yield, 93.36% purity) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.12-8.02(m,3H),7.80(d,J=8.5Hz,2H),7.68(t,J=8.1Hz,1H),7.52(d,J=7.6Hz,1H),5.06-4.83(m,2H),4.23(br t,J=12.2Hz,4H). HPLC: 93.36% (220nm), 92.65% (215nm), 92.83% (254nm). MS(ESI):mass calcd.For C 19 H 13 ClF7N3O2S 515.0,m / z found 516.0[M+H] + .

[0582] Compound 50: 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-4-methyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole

[0583] [ka]

[0584] Step 1: To a solution of 4-methyl-1H-indazole (3 g, 22.7 mmol, 1 equivalent) in DCM (30 mL), NIS (5.62 g, 25.0 mmol, 1.1 equivalents) was added at 0°C. The mixture was stirred at 20°C for 12 hours. LC-MS confirmed that 4-methyl-1H-indazole remained and the desired mass was detected. By concentrating the reaction mixture, the desired 3-iodo-4-methyl-1H-indazole (5.8 g, crude) was obtained as a yellow solid. MS (ESI): mass calcd. For C8H7IN2 258.0, m / z found 259.0 [M+H] + .

[0585] Step 2: To a solution of 3-iodo-4-methyl-1H-indazole (5.8 g, 22.5 mmol, 1 equivalent) in DCM (60 mL), TsOH.H2O (428 mg, 2.25 mmol, 0.1 equivalent) and 3,4-dihydro-2H-pyran (2.84 g, 33.7 mmol, 3.08 mL, 1.5 equivalent) were added at 0°C. The mixture was stirred at 20°C for 1 hour. LC-MS confirmed that 3-iodo-4-methyl-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with siRNA (3 times with 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired 3-iodo-4-methyl-1-tetrahydropyran-3-yl-indazole (7.6 g, crude) as a yellow solid. MS(ESI): mass calcd. For C 14 H 13 F2NS 265.1,m / z found 266.1[M+H] + .

[0586] Step 3: A mixture of 3-iodo-4-methyl-1-tetrahydropyran-3-yl-indazole (300 mg, 876 μmol, 1 equivalent), 3,3,4,4-tetrafluoropyrrolidine (157 mg, 877 μmol, 1 equivalent, HCl), Cs2CO3 (571 mg, 1.75 mmol, 2 equivalents), BINAP (54.6 mg, 87.7 μmol, 0.1 equivalent), and Pd2(dba)3 (80.3 mg, 87.7 μmol, 0.1 equivalent) in toluene (2 mL) was degassed, purged three times with N2, and then stirred at 100°C for 12 hours under an N2 atmosphere. LC-MS confirmed that 3-iodo-4-methyl-1-tetrahydropyran-3-yl-indazole was completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 10 mL of siRNA. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (silica gel, petroleum ether / siRNA = 4 / 1) to obtain the desired 4-methyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-tetrahydropyran-3-yl-indazole (150 mg, 420 μmol, 47.9% yield) as a yellow solid. MS(ESI): mass calcd. For C 17 H 19 F4N3O 357.1,m / z found 358.1[M+H] + .

[0587] Step 4: To a solution of 4-methyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-tetrahydropyran-3-ylindazole (150 mg, 420 μmol, 1 equivalent) in DCM (2 mL), TFA (239 mg, 2.10 mmol, 156 μL, 5 equivalents) was added. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-methyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1-tetrahydropyran-3-ylindazole had been completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 10 mL of RINKAN. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (silica gel, petroleum ether / Â1 = 2 / 1) to obtain the desired 4-methyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (80 mg, 293 μmol, 69.8% yield) as a white solid. MS(ESI): mass calcd. For C 12 H 11 F4N3273.1,m / z found 274.1[M+H] + .

[0588] Step 5: To a solution of 4-methyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole (38 mg, 139 μmol, 1 equivalent) and 4-(1,1-difluoroethyl)benzenesulfonyl chloride (50.2 mg, 209 μmol, 1.5 equivalents) in DCM (1 mL), TEA (28.2 mg, 278 μmol, 38.7 μL, 2 equivalents) and DMAP (1.70 mg, 13.9 μmol, 0.1 equivalent) were added. The mixture was stirred at 15°C for 1 hour. LC-MS confirmed that 4-methyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-1H-indazole was completely consumed and the desired mass was detected. The reaction mixture was separated into 10 mL of H2O and 10 mL of DCM. The organic phase was separated, washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 50%~80% B over 8.0 mins) to obtain the desired 1-[4-(1,1-difluoroethyl)phenyl]sulfonyl-4-methyl-3-(3,3,4,4-tetrafluoropyrrolidine-1-yl)indazole (12.9 mg, 24.9 μm...

Claims

1. Equation (I): 【Chemistry 1】 A compound having the structure, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, During the ceremony, Ring A is a 4- to 9-membered carbon ring or heteroring substituted with 1 to 8 F atoms. Ring B is either a substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, pyridadinyl, pyrimidinyl, pyrrolyl, or thiophene, or a substituted or unsubstituted bicyclic or polycyclic carbocyclic or heterocyclic ring system. P is CH, N, or CR ２ And, Q is CH, N, or CR ２ And, U is either C or N, V is either C or N, W is CH, N, C(=O), C(=S), or CR Ｗ１ R Ｗ２ And R Ｗ１ and R Ｗ２ Each of these is independently H or C １－６ It is alkyl, X is either C or N, Y is C, CR Ｙ , or N, and R Ｙ is H, F, or C １－６ is alkyl R １ F, CHF ２ , -CF ３ ien-CH ２ CF ３ CF ２ CH ３ CF ２ CH ２ F, CF ２ CHF ２ , -CF(CH ３ ) ２ , -OCF ３ , and -OCH(CH ３ ) ２ Selected from the group consisting of, R ２ These are, independently, halogen, unsubstituted, or substituted C １－６ Alkyl and C １－６ Selected from the group consisting of alkoxy, OH, CN, NRR', N(R)C(=O)RR', C(=O)R, and C(=O)NRR', R ３ These are, independently, halogen, CN, and CF ３ , C １－５ Alkyl, C ３－７ Selected from the group consisting of cycloalkyl and heterocycles, R and R' are independently H or C １－６ They are alkyl or cycloalkyl groups, and optionally R and R' form a 3-6 membered ring together with the nitrogen or carbon atom to which they are bonded, and optionally, independently, C １－３ Alkyl, halogen, OH, OC １－３ Substituted with 0 to 3 substituents selected from the group consisting of alkyl and CN, m is 0, 1, 2, 3, or 4. n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. i is 0, 1, or 2. A compound, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein ring B is a substituted or unsubstituted phenyl compound.

3. i is 0, and ring B is an unsubstituted phenyl 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof.

4. i is 0, and ring B is a substituted phenyl 【Transformation 3】 And in the formula, R ３ The compound according to claim 1, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein is a halogen.

5. R ３ The compound according to claim 4, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein F is present.

6. Ring B is an unsubstituted pyridinyl 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof.

7. The compound according to claim 1, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein ring B is a substituted or unsubstituted thiophene.

8. i is 0, and ring B is an unsubstituted thiophene. 【Transformation 5】 The compound according to claim 7, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof.

9. The compound according to claim 1, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein ring B is a substituted or unsubstituted pyrrole.

10. i is 0 and ring B is unsubstituted pyrrole 【Transformation 6】 The compound according to claim 9, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof.

11. Ring B is bicyclo[1.1.1]pentane 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof.

12. Ring B is 【Transformation 8】 A compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative, selected from the above.

13. A compound according to any one of claims 1 to 12, wherein X is N, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

14. The compound according to claim 13, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein P is CH, Q is CH, U is C, and V is C. 【Chemistry 9】

15. The compound according to claim 14, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein W is N. 【Chemistry 10】

16. The compound according to claim 14, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein W is CH. 【Chemistry 11】

17. A compound according to any one of claims 1 to 12, wherein X is C, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

18. The compound according to claim 17, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein P is CH, Q is CH, U is N, V ​​is C, and W is N. 【Chemistry 12】

19. A compound according to any one of claims 1 to 18, wherein Y is N, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

20. A compound according to any one of claims 1 to 18, wherein Y is C, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

21. A compound according to any one of claims 1 to 18, wherein Y is CH, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein ring A is a four-membered carbocyclic or heterocyclic ring substituted with one or more F atoms.

23. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein ring A is a five-membered carbocyclic or heterocyclic ring substituted with one or more F atoms.

24. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein ring A is a six-membered carbocyclic or heterocyclic ring substituted with one or more F atoms.

25. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein ring A is a heterodicyclic ring substituted with one or more F atoms.

26. A compound according to any one of claims 22 to 25, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein ring A is substituted with two or more F atoms.

27. Ring A is 【Chemistry 13】 A compound according to any one of claims 1 to 21, having a structural formula selected from the above, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

28. Ring A is 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 A compound according to any one of claims 1 to 21, having a structural formula selected from the above, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

29. Ring A is 【Chemistry 17】 A compound according to any one of claims 1 to 21, having a structural formula selected from the above, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

30. Ring A is [Chemistry 18] And in the formula, R ４ Each of these is independently substituted with D, OH, CN, or 0 to 3 F atoms, with C being optionally replaced. １－２ Alkyl or two R ４ These, together with the carbon atoms to which they are bonded, form a 3-4 membered carbocyclic or heterocyclic ring, or two R ４ These, together with the carbon atoms to which they are bonded, form a 3- to 7-membered carbocyclic or heterocyclic ring. n is 1, 2, 3, 4, 5, or 6. j is 0, 1, 2, 3, or 4. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

31. The compound according to claim 30, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein j is 0.

32. The compound according to claim 30, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein j is 1 or 2.

33. R １ CHF ２ The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

34. R １ ga CF ２ CH ３ The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

35. R １ ga CF ２ CH ２ F is the compound according to any one of claims 1 to 32, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

36. R １ ga CF ２ CHF ２ The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

37. R １ A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein F is present.

38. Structural formula 【Chemistry 19】 A compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, having the above.

39. Structural formula 【Chemistry 20】 A compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, having the above.

40. Structural formula 【Chemistry 21】 A compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, having the above.

41. Structural formula 【Chemistry 22】 A compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, having the above.

42. Structural formula 【Chemistry 23】 It has, in the formula, R ４ Each of these is independently replaced by C with 0 to 3 Fs of any choice. １－２ Alkyl or two R ４ These atoms, together with the carbon atoms to which they are bonded, form a 3-4 membered carbon ring or heterocycle, or two R atoms. ４ These, together with the carbon atoms to which they are bonded, form a 3- to 7-membered carbocyclic or heterocyclic ring. n is 1, 2, 3, 4, 5, or 6. j is 0, 1, 2, 3, or 4. The compound according to claim 1 or 30, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

43. Structural formula 【Chemistry 24】 It has, in the formula, R ４ Each of these is independently replaced by C with 0 to 3 Fs of any choice. １－２ Alkyl or two R ４ These atoms, together with the carbon atoms to which they are bonded, form a 3-4 membered carbon ring or heterocycle, or two R atoms. ４ These, together with the carbon atoms to which they are bonded, form a 3- to 7-membered carbocyclic or heterocyclic ring. n is 1, 2, 3, 4, 5, or 6. j is 0, 1, 2, 3, or 4. The compound according to claim 1 or 30, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

44. R ４ However, each can be independently substituted with D, OH, CN, or C, which can be optionally replaced with 0 to 3 F atoms. １－２ The compound according to claim 42 or 43, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein the compound is alkyl.

45. Two R ４ The compound according to claim 42 or 43, or a pharmaceutically acceptable form thereof or isotope derivative thereof, wherein they form a three-membered or four-membered carbocyclic or heterocyclic ring together with the carbon atoms to which they are bonded.

46. Two R ４ The compound according to claim 42 or 43, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein they form a 3- to 7-membered carbocyclic or heterocyclic ring with carbon atoms bonded to the atom.

47. The compound according to claim 46, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein j is 0.

48. The compound according to claim 46, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein j is 1 or 2.

49. j is 1, R ４ The compound according to claim 44, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, wherein a carbon atom adjacent to the N atom is bonded to a carbon atom.

50. R ４ ga CF ３ The compound according to claim 49, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof.

51. j is 2, and both R ４ The compound according to claim 44, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, wherein a carbon atom adjacent to the N atom of ring A is bonded to a carbon atom.

52. Two R ４ One or both of these are C, which is arbitrarily replaced by 1 to 5 Fs. １－３ The compound according to claim 51, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, which is alkyl.

53. j is 2, and there are two R ４ The compound according to claim 45, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein they form a cyclopropyl group together with the carbon atoms to which they are bonded.

54. j is 2, and there are two R ４ The compound according to claim 46, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein they form a 5-7 membered carbocyclic or heterocyclic ring with carbon atoms bonded to the atom.

55. A compound according to any one of claims 38 to 54, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein n is an integer selected from 1 to 4.

56. The compound according to claim 55, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein n is 1.

57. The compound according to claim 55, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein n is 2.

58. The compound according to claim 55, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein n is 3 or 4.

59. R １ ga CF ２ CH ３ The compound according to any one of claims 38 to 58, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

60. R １ ga CF ２ CH ２ F is the compound according to any one of claims 38 to 58, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

61. R １ ga CF ２ CHF ２ The compound according to any one of claims 38 to 58, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

62. R １ CHF ２ The compound according to any one of claims 38 to 58, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

63. R １ A compound according to any one of claims 38 to 58, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein F is present.

64. A compound according to any one of claims 1 to 63, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein m is 1.

65. R ２ but, 【Chemistry 25】 The compound according to claim 64, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, having a configuration selected from the above.

66. R ２ but, 【Chemistry 26】 The compound according to claim 64, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, having the configuration of the compound according to claim 64.

67. R ２ A compound according to any one of claims 64 to 66, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein is a halogen.

68. R ２ The compound according to claim 67, or a pharmaceutically acceptable form or isotope derivative thereof, wherein R is Cl.

69. R ２ However, C is optionally substituted with amino, OH, or 0-3 F atoms. １ A compound according to any one of claims 64 to 66, which is alkyl or alkoxy, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

70. A compound selected from Table 1.

71. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, having one or more deuterium atoms instead of one or more hydrogen atoms.

72. The compound according to claim 71, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, having one deuterium atom instead of one hydrogen atom.

73. A pharmaceutical composition comprising the compound described in any one of claims 1 to 72.

74. A unit dosage form comprising the pharmaceutical composition according to claim 73.

75. The unit dosage form according to claim 74, which is a tablet.

76. The unit dosage form according to claim 74, which is a capsule.

77. A method for treating or reducing a disease or disorder, comprising the step of administering a therapeutically effective amount of a compound according to any one of claims 1 to 72 to a subject who is in need of treatment or reduction of the disease or disorder.

78. The method according to claim 77, wherein the disease or disorder is mediated by a loss of function of TRPML1.

79. The method according to claim 78, wherein the disease or disorder is mucolipidosis type IV (ML4).

80. The method according to claim 77, wherein the disease or disorder is a lysosomal storage disorder or a related disease or disorder.

81. The method according to claim 77, wherein the disease or disorder is a neurodegenerative disease or a related disease or disorder.

82. The method according to claim 81, wherein the disease or disorder is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), or frontotemporal dementia, or a related disease or disorder.

83. The method according to claim 77, wherein the disease or disorder is neuronal ceroid lipofuscinosis (NCL) or Batten disease, or a related disease or disorder.

84. The method according to claim 77, wherein the disease or disorder is Niemann-Pick disease type C (NPC), or a related disease or disorder.

85. The method according to claim 77, wherein the disease or disorder is Charcot-Marie-Tooth disease (CMT) or a related disease or disorder.

86. The method according to claim 77, wherein the disease or disorder is age-related macular degeneration (AMD) or a related disease or disorder.

87. The method according to claim 77, wherein the disease or disorder is cystic fibrosis (CF) or a related disease or disorder.

88. The method according to claim 77, wherein the disease or disorder is autosomal dominant polycystic kidney disease (ADPKD) or a related disease or disorder.

89. The method according to claim 77, wherein the disease or disorder is selected from cancers in which TRPML1 is overexpressed in cancer cells.

90. The method according to claim 77, wherein the disease or disorder is muscular dystrophy or a related disease or disorder.

91. The method according to claim 77, wherein the disease or disorder is oxidative stress or reactive oxygen species (ROS), or a related disease or disorder.

92. A method for treating or reducing the effects of aging, comprising the step of administering a therapeutically effective amount of a compound according to any one of claims 1 to 72 to a subject who is in need of treatment or reduction of the effects of aging.

93. The method according to claim 77, wherein the aging effect includes skin aging.

94. The method according to claim 77, wherein the aging effect includes photoaging.

95. A method for treating or reducing a disease or disorder related to oxidative stress or reactive oxygen species (ROS), comprising the step of administering a therapeutically effective amount of a compound according to any one of claims 1 to 72 to a subject requiring treatment or reduction of the disease or disorder.

96. A method for treating or reducing a disease or disorder related to oxidative stress or reactive oxygen species (ROS), comprising the step of administering a therapeutically effective amount of a compound according to any one of claims 1 to 72 to a subject requiring treatment or reduction of the disease or disorder.

97. The method according to any one of claims 77 to 96, wherein the administration is performed by oral administration.

98. The method according to any one of claims 77 to 96, wherein the administration is performed by local administration.

99. Use of a compound according to any one of claims 1 to 72 in the preparation of a pharmaceutical product for treating a disease or disorder, with a pharmaceutically acceptable excipient, carrier, or diluent.

100. The use according to claim 99, wherein the disease or disorder is mediated by a loss of function of TRPML1.

101. The use according to claim 99, wherein the disease or disorder is mucolipidosis type IV (ML4).

102. The use according to claim 99, wherein the disease or disorder is a lysosomal storage disorder or a related disease or disorder.

103. The use according to claim 99, wherein the disease or disorder is selected from the group consisting of age-related neurodegenerative diseases or related diseases or disorders.

104. The use according to claim 103, wherein the disease or disorder is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), or frontotemporal dementia, or a related disease or disorder.

105. The use according to claim 99, wherein the disease or disorder is neuronal ceroid lipofuscinosis (NCL) or Batten disease, or a related disease or disorder.

106. The use according to claim 99, wherein the disease or disorder is Niemann-Pick disease type C (NPC), or a related disease or disorder.

107. The use according to claim 99, wherein the disease or disorder is Charcot-Marie-Tooth disease (CMT) or a related disease or disorder.

108. The use according to claim 99, wherein the disease or disorder is age-related macular degeneration (AMD) or a related disease or disorder.

109. The use according to claim 99, wherein the disease or disorder is cystic fibrosis (CF) or a related disease or disorder.

110. The use according to claim 99, wherein the disease or disorder is autosomal dominant polycystic kidney disease (ADPKD) or a related disease or disorder.

111. The use according to claim 99, wherein the disease or disorder is selected from cancers in which TRPML1 is overexpressed in cancer cells.

112. The use according to claim 99, wherein the disease or disorder is muscular dystrophy or a related disease or disorder.

113. The use according to claim 99, wherein the disease or disorder is oxidative stress or reactive oxygen species (ROS), or a related disease or disorder.

114. The use according to claim 99, wherein the disease or disorder is skin aging.

115. The use according to claim 99, wherein the disease or disorder is photoaging.

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